Headaches: Nonsurgical Management

Number: 0462

Table Of Contents

Policy

Scope of Policy

This Clinical Policy Bulletin addresses nonsurgical management of headaches.

1. Medical Necessity

   Aetna considers the following nonsurgical interventions for headaches medically necessary when criteria are met:

   1. Intravenous (IV) administration of dihydroergotamine (DHE) medically necessary for the following indications:

      1. Treatment of status migrainosus (i.e., a debilitating migraine lasting more than 72 hours) in the emergency room, urgent care or hospital setting; or
      2. Treatment of other intractable severe migraine attacks that are unresponsive to analgesics and triptans (e.g., Almotriptan, Amerge, Axert, Frova, Imitrex, Imitrex nasal spray, Maxalt, Maxalt MLT, Onzetra Xsail, Relpax, Sumavel, Treximet, zolmitriptan, zolmitriptan ODT, Zomig, and Zomig ZMT) in the emergency room, hospital or urgent care setting; or
      3. Treatment of cluster headache attacks that do not respond to oxygen or triptans in the emergency room, hospital, or urgent care setting; or
      4. Treatment of medication overuse headache in the inpatient setting;
   2. Intramuscular (IM) ketorolac tromethamine (Toradol) for the short-term (less than or equal to 5 days) management of acute migraine;
   3. Eptinezumab-jjmr (Vyepti) for the preventive treatment of migraine in an adult member when the criteria are met. See CPB 0970 Eptinezumab-jjmr (Vyepti) for coverage criteria for Vyepti;
   4. Intramuscular (IM) and intravenous (IV) steroids for the treatment of acute migraines;
   5. Caffeine citrate infusion for the treatment of post lumbar puncture headache when the member is unable to take caffeine orally;
   6. Intravenous (IV) magnesium for the treatment of acute migraine.

2. Experimental, Investigational, or Unproven

   Aetna considers the following non-surgical interventions for headaches experimental, investigational, or unproven because the effectiveness of these approaches has not been established:

   1. Cranio-sacral therapy for the treatment of headache disorders;
   2. Intra-oral splints for the treatment of tension-type headaches;
   3. Intravenous (IV) DHE for all other types of headache not included in the Medically Necessity Section;
   4. Intravenous (IV) DHE for members with inadequately controlled intermittent migraine attacks who do not have an active, prolonged, and debilitating (i.e., lasting more than 72 hours) headache at the time of admission;
   5. Measurement of serum and/or cerebrospinal fluid (CSF) levels of tumor necrosis factor-alpha for intractable migraine or cluster headache;
   6. The following interventions for the management of members with migraines (not an all-inclusive list):
      
      
      1. Cefaly migraine headband
      2. Chemodenervation with P2G (phenol-glycerine-glucose) for migraine prophylaxis
      3. Intramuscular bupivacaine
      4. Intramuscular ketamine
      5. Intramuscular magnesium
      6. Intramuscular nalbuphine or other opioid agonist-antagonists
      7. Intranasal ketamine
      8. Intranasal lidocaine
      9. Intraoral splints 
      10. Intrathecal dilaudid or hydromorphone
      11. Intravenous aspirin (lysine acetylsalicylate)
      12. Intravenous ketamine
      13. Intravenous lidocaine
      14. Intravenous nalbuphine or other opioid agonist-antagonists
      15. Intravenous propofol
      16. Intravenous valproic acid (Depacon)
      17. Kinetic oscillation stimulation 
      18. Lidocaine injections into the supraorbital nerve and supratrochlear nerve, supraorbital nerve and supratrochlear nerve blocks
      19. Manual trigger points treatment
      20. Melantonin (for prophylaxis of migraine)
      21. Memantine (for prophylaxis of migraine)
      22. Nerivio (remote electrical neuromodulation [REN])
      23. Occipital nerve stimulation
      24. Orally inhaled DHE
      25. Oral magnesium
      26. Spheno-palatine ganglion stimulation
      27. Supraorbital transcutaneous stimulation (for migraines and other types of headaches)
      28. Transcranial magnetic stimulation (e.g., SpringTMS)
      29. Tx360 nasal applicator (spheno-palatine ganglion blockade);

   7. The following interventions for the treatment of cluster headache (not an all-inclusive list):

      1. Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies eptinezumab, erenumab, and fremanezumab
      2. Blockade / stimulation of the sphenopalatine ganglion and its branches
      3. Greater occipital nerve block
      4. Ketamine infusion combined with magnesium
      5. Ketogenic diet
      6. Manual trigger points treatment
      7. Melatonin
      8. Onabotulinum toxin A
      9. Percutaneous bioelectric current stimulation
      10. Sodium oxybate
      11. Sphenopalatine ganglion stimulation;
          
   8. Photo-biomodulation, and the Reed procedure (combined occipital and supraorbital neurostimulation) for the treatment of chronic headaches (e.g., cluster, migraine, and tension headaches);
   9. Combination benztropine mesylate (Cogentin) / diphenhydramine (Benadryl) / promethazine HCl (Phenergan) cocktail with intravenous haloperidol (Haldol) or droperidol (Inapsine) infusion for the treatment of status migrainosus because the effectiveness of this combination for this indication has not been established;
   10. Epidural steroid injection, and radiofrequency ablation for the treatment of cervicogenic headache and neck pain.

3. Related Policies

   See Commercial Pharmacy CPB on Calcitonin Gene-related Peptide (CGRP) Receptor Antagonists for selection criteria.

   See also:

   • CPB 0002 - Oxygen
   • CPB 0011 - Peripheral Electrical Nerve Stimulation for Pain
   • CPB 0113 - Botulinum Toxin
   • CPB 0132 - Biofeedback
   • CPB 0172 - Hyperbaric Oxygen Therapy (HBOT)
   • CPB 0388 - Complementary and Alternative Medicine
   • CPB 0707 - Headaches: Invasive Procedures - for occipital nerve block for occipital neuralgia and other headaches (including migraine)
   • CPB 0735 - Pulsed Radiofrequency
   • CPB 0863 - Nerve Blocks
   • CPB 0970 - Eptinezumab-jjmr (Vyepti).

Background

Migraine is a paroxysmal disorder with attacks of headache, nausea, vomiting, photo- and phonophobia and malaise.  Cluster headaches occur as a severe, sudden headache typified by constant, unilateral pain around the eye, with onset usually within 2-3 hours of falling asleep.  Pharmacologic symptomatic treatment is aimed at reversing, aborting, or reducing pain and the accompanying symptoms of an attack, and to optimize the patient's ability to function normally.

Subcutaneous, intramuscular, and intravenous dihydroergotamine (DHE) can be safely administered in the office, clinic, or emergency room setting at any time during a migraine attack, including the aura.  Intravenous administration provides rapid peak plasma levels and is the most effective form when a rapid effect is desired or for patients with intractable severe headache (status migrainosus, transformed migraine, rebound headache) and cluster headache.  One of the most appropriate indications for intravenous DHE is status migrainosus.  Another important indication of repetitive intravenous DHE administration is a transformed migraine type of chronic daily headache with or without analgesic overuse.  Intramuscular administration is effective for moderate to severe migraine with or without nausea and vomiting in the outpatient setting.  Patients can even be taught to self-administer DHE intramuscularly, thus avoiding emergency room or doctor visits.

For unresponsive patients with severe or ultra-severe attacks, intravenous (IV) prochlorperazine (5 to 10 mg) may be administered in the emergency room, followed immediately by 0.75 mg DHE IV given over 3 minutes.  If there is no relief in 30 mins, another 0.5 mg of DHE IV may be given.  Overall clinical efficacy of DHE is highly satisfactory with a reported 90% of the attacks aborted when the drug was given intravenously.  Occasionally, intravenous fluids and repeated injections of intravenous DHE for about 24 to 72 hours may be necessary to relieve uncontrollable pain.  Hospitalization may be necessary for such prolonged multi-day administration, but only after maximal treatment in the outpatient setting fails to abort the headache.  Various protocols are available for the use of repetitive injections of DHE.  In all of them, an initial test dose of 0.33 mg of DHE plus 5 mg of metoclopramide or prochlorperazine is given, followed by 0.50 mg of DHE with either of the 2 anti-emetics every 6 hours for 48 to 72 hours.  Such therapy allows a break in the headache cycle sufficiently long enough to facilitate the patient's transition to prophylactic therapy.

According to the Food and Drug Administration (FDA)-approved product labeling, DHE-45 administration is contraindicated in any of the following patients:

1. Nursing mothers; or
2. Persons having conditions predisposing to vasospastic reactions such as known peripheral arterial disease, coronary artery disease (in particular, unstable or Prinzmetal's vasospastic angina), sepsis, vascular surgery, uncontrolled hypertension, and severely impaired hepatic or renal function; or
3. Persons on vasoconstrictors because the combination may result in extreme elevation of blood pressure; or
4. Persons with hemiplegic or basilar migraine; or
5. Persons with previously known hypersensitivity to ergot alkaloids; or
6. Pregnant women, as DHE possesses oxytocic properties.

Shafqat, et al. (2020) notes DHE had been found useful in the treatment of various types of migraines and headaches. The usual injectable dose ranges from 0.5 to 1 mg. Dosing is typically limited to a maximum of 3 mg within a 24‑hour period and no more than 6 mg per week. However, studies have shown that doses of up to 3 mg daily may be safely and effectively administered for as long as 7 days when done in a controlled setting. The "Raskin protocol" is a IV DHE protocol for migraine unresponsive to standard treatment. Originally, the protocol is consisted of IV 0.3 mg to 1 mg every 8 hours with IV metoclopramide 10 mg for 2 to 3 days, when compared with different medication treatments over time, the protocol exercised comparable efficacy but with lower risk of adverse events. Different versions of dosing methods has emerged from an adjusted Raskinn protocol for the outpatient infusion setting. For example, doses of IV DHE up to 2 mg daily, administered in divided doses over few hours, for consecutive days. The authors highlighted a prospective study using IV DHE infusion of a total 7.5 mg over 3 consecutive days in the home setting in 35 patients with intractable headache. The results showed DHE one‑third of the patients became headache‑free, while nearly two‑thirds reported improvement after three days.

Fisher et al (2007) evaluated the effectiveness and tolerability of DHE nasal spray for the treatment of headache that is refractory to triptans.  Patients who failed previous treatments with 1 or more triptan formulations were considered refractory to triptan treatment and were included in the study.  Headache severity was assessed by the patient at the center using a visual analog scale (VAS) of 1 to 10 (10 being most severe) at baseline and 4 weeks after initiating DHE.  The responses to DHE were assessed and categorized as complete response (headache symptoms resolved), partial response (greater than or equal to 50% reduction in VAS), or unresponsive (less than 50% reduction in VAS).  Four weeks after DHE use, any adverse event (AE) that occurred during DHE use was reported by the patient at the center.  The effectiveness of DHE was determined by headache severity reductions.  Tolerability was assessed in terms of AE frequency.  A total of 97 patients met the study criteria: 13 patients were lost to follow-up; 33 patients (34.0%) reported a complete response to DHE treatment, 13 (13.4%) experienced a partial response, and 38 (39.2%) were unresponsive.  Seven of 97 patients (7.2%) reported AEs (e.g., nasal congestion, dysphoria) while using DHE.  The authors noted that this retrospective chart review included patients who failed triptan therapy for treatment of headaches.  They reported that 47% of patients experienced partial to complete response to DHE treatment.  Study limitations included the retrospective design, the small sample size, and the use of patient recollection to evaluate the effectiveness and tolerability of DHE.  They stated that randomized, double-blind, controlled studies are needed to ascertain the clinical value of this approach.  This is in agreement with the findings of a pilot study by Weintraub (2006) who reported that repetitive intra-nasal DHEmay be a safe and effective therapy for refractory headaches.  However, interpretation of these results is limited by the open-label, uncontrolled design and the small number of patients.  The author stated that development of a double-blind, placebo-controlled study to further evaluate this treatment regimen is warranted.

Migraine without aura is a complex genetic disease in which susceptibility and environmental factors contribute towards its development.  Several studies suggested that tumor necrosis factors (TNF) (TNF-alpha and lymphotoxin-alpha or TNF-ss) may be involved in the pathophysiology of migraine.  In a case-control study, Asuni et al (2009) evaluated the possibility of an association between TNF gene polymorphisms and migraine without aura.  These researchers examined 299 patients affected by migraine without aura (I.H.S. criteria 2004) and 278 migraine-free controls.  The polymorphisms G308A of the TNF- alpha gene, and G252A of TNF-beta gene were determined by NcoI restriction fragment length polymorphism analysis.  These investigators found a statistically significant difference in allele (p = 0.018; odds ratio [OR] = 1.46; 95% confidence interval [CI]: 1.066 to 2.023) and genotype (trend chi2 = 5.46, df = 1, p = 0.019) frequencies of TNF-beta gene, between cases and controls.  Allele and genotype frequencies of TNF-alpha polymorphism did not differ significantly between the 2 groups.  These data suggested that subjects with the TNFB2 allele have a low-risk of developing migraine without aura and/or that the polymorphism of the TNF-beta gene is in linkage disequilibrium with other migraine responsible genes in the HLA region.

Measurement of TNF-alpha is an indicator of persistent systemic infection or inflammation.  It has been observed that new daily persistent headache (NDPH) may occur following infection and is one of the most treatment-resistant headache types.  A number of investigators have evaluated TNF-alpha levels in serum and cerebro-spinal fluid (CSF) in patients with NDPH, chronic migraine or post-traumatic headache.  These studies have found elevated CSF TNF-alpha levels in persons with these headaches.  The results from these studies suggested that elevated levels of CSF TNF-alpha may play a role in the pathogenesis of migraine and other chronic headaches.  These studies might also suggest that elevated CSF TNF-alpha may be an indicator of refractory headaches.  The studies suggested that TNF-alpha inhibitors may have a therapeutic role in treating patients with migraine and other types of headache (Perini et al, 2005; Rozen and Swidan, 2007; Bo et al, 2009).  However, there are no prospective clinical studies demonstrating the clinical utility of TNF-alpha measurement in migraine or other headache disorders.  Additional studies are needed to further investigate the relationship of CSF TNF-alpha levels in subjects with various types of chronic headache.

Schurks (2009) assessed the modes of administration, effectiveness and safety profile of DHE in the treatment of migraine.  Evidence-based data are scarce.  Parenteral DHE appears to be as effective as or less effective than triptans with regard to pain control, but more effective than other drugs used in the treatment of attacks.  The nasal spray is more effective than placebo, but less effective than triptans.  Additional reports suggest that DHE is especially beneficial in migraine patients not satisfactorily responding to analgesics, in those with long attacks or headache recurrence, and those at risk of medication-overuse headache.  The author noted that the effectiveness of the oral formulation in migraine prevention is not substantiated by clinical trials.

Management of headaches is not an FDA-approved indication for aspirin (lysine acetylsalicylate).  Weatherall et al (2010) stated that intravenous (IV) aspirin has been shown to be effective in the treatment of acute migraine attacks, but little is known about its effectiveness and safety in patients hospitalized for management of severe headache, typically arising from abrupt withdrawal of other acute attack medications.  These investigators presented an audit of their use of IV aspirin in 168 patients in a tertiary referral setting.  The findings demonstrated subjective approval of this medication by the patients and objective improvements in pain scores, a decrease of greater than or equal to 3 points on a 10-point VAS being seen on greater than 25% occasions on which the medication was administered.  Further, side effect rates were low (5.9%), with no serious adverse events.  The authors concluded that IV aspirin is safe, effective, and useful in the inpatient management of headache.  The drawbacks of this study were its uncontrolled, retrospective nature and the results were confounded by the fact that many subjects received more than 1 medication.  The findings of this small study need to be validated by well-designed studies. 

In a randomized, double-blind, placebo-controlled cross-over study, Alstadhaug et al (2010) examined the effects of melantonin as a prophylaxis.  Men and women, aged 18 to 65 years, with migraine but otherwise healthy, experiencing 2 to 7 attacks per month, were recruited from the general population.  After a 4-week run-in phase, 48 subjects were randomized to receive either placebo or extended-release melatonin (Circadin^®, Neurim Pharmaceuticals Ltd., Tel Aviv, Israel) at a dose of 2-mg 1 hour before bedtime for 8 weeks.  After a 6-week washout treatment was switched.  The primary outcome was migraine attack frequency (AF).  A secondary end point was sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI).  A total of 46 subjects completed the study (96%).  During the run-in phase, the average AF was 4.2 (+/- 1.2) per month and during melatonin treatment the AF was 2.8 (+/- 1.6).  However, the reduction in AF during placebo was almost equal (p = 0.497).  Absolute risk reduction was 3% (95% CI: -15 to 21, number needed to treat = 33).  A highly significant time effect was found.  The mean global PSQI score did not improve during treatment (p = 0.09).  The authors concluded that these findings provided evidence that prolonged-release melatonin (2-mg 1 hour before bedtime) does not provide any significant effect over placebo as migraine prophylaxis; thus, such treatment can not be recommended.

Aurora and associates (2011) evaluated the tolerability and effectiveness of MAP0004 (an orally inhaled formulation of DHE delivered to the systemic circulation) compared with placebo for a single migraine in adult migraineurs.  MAP0004 provided significant early onset of pain relief (10 mins, p < 0.05) and sustained pain relief for up to 48 hours with a favorable adverse event profile.  This study was conducted at 102 sites in 903 adults with a history of episodic migraine.  Patients were randomized (1:1) to receive MAP0004 (0.63-mg emitted dose; 1.0-mg nominal dose) or placebo, administered after onset of a migraine headache with moderate to severe pain.  The co-primary end points were patient-assessed pain relief and absence of photophobia, phonophobia, and nausea at 2 hours after treatment.  A total of 903 patients (450 active, 453 placebo) were randomized, and 792 (395 active, 397 placebo) experienced a qualifying migraine.  MAP0004 was superior to placebo in all 4 co-primary end points: pain relief (58.7% versus 34.5%, p < 0.0001), phonophobia-free (52.9% versus 33.8%, p < 0.0001), photophobia-free (46.6% versus 27.2%, p < 0.0001), and nausea-free (67.1% versus 58.7%, p = 0.0210).  Additionally, significantly more patients were pain-free at 2 hours following treatment with MAP0004 than with placebo (28.4% versus 10.1%, p < 0.0001).  MAP0004 was well-tolerated; no drug-related serious adverse events occurred.  The authors concluded that MAP0004 was effective and well-tolerated for the acute treatment of migraine with or without aura, providing statistically significant pain relief and freedom from photophobia, phonophobia, and nausea in adults with migraine compared with placebo.

Baron and Tepper (2010) noted that triptans are very effective for many migraineurs, and since their widespread use, use of ergots has significantly declined.  Unfortunately, there remain many migraineurs who benefit little from triptans, yet respond very well to ergots.  Ergots interact with a broader spectrum of receptors than triptans.  This lack of receptor specificity explains potential ergot side effects, but may also account for efficacy.  The authors stated that the role of ergots in headache should be revisited, especially in view of newer ergot formulations with improved tolerability and side effect profiles, such as orally inhaled DHE.  They noted that re-defining where in the headache treatment spectrum ergots belong and deciding when they may be the optimal choice of treatment is necessary.  Additionally, in a review new drugs and new approaches for acute migraine therapy, Monteith and Goadsby (2011) stated that current pharmacotherapies of acute migraine consist of non-specific and relatively specific agents.  Migraine-specific drugs comprise 2 classes: the ergot alkaloid derivatives and the triptans, serotonin 5-HT(1B/1D) receptor agonists.  The ergots, consisting of ergotamine and DHE, are the oldest specific anti-migraine drugs available and are considered relatively safe and effective.  Ergotamine has been used less extensively because of its adverse effects; DHE is better tolerated.  The triptan era, beginning in the 1990s, was a period of considerable change, although these medicines retained vasoconstrictor actions.  New methods of delivering older drugs include orally inhaled DHE as well as the trans-dermal formulation of sumatriptan, both currently under study.  Furthermore, orally inhaled formulation DHE for the treatment of migraine has not received FDA approval yet.

In a prospective observational study, Bond et al (2011) examined whether weight loss after bariatric surgery is associated with improvements in migraine headaches.  A total of 24 patients who had migraine according to the ID-Migraine screener were assessed before and 6 months after bariatric surgery.  At both time points, patients had their weight measured and reported on frequency of headache days, average headache pain severity, and headache-related disability over the past 90 days via the Migraine Disability Assessment questionnaire.  Changes in headache measures and the relation of weight loss to these changes were assessed using paired-sample t tests and logistic regression, respectively.  Patients were mostly female (88%), middle-aged (mean age of 39.3 years), and severely obese (mean body mass index of 46.6) at baseline.  Mean (+/- SD) number of headache days was reduced from 11.1 +/- 10.3 pre-operatively to 6.7 +/- 8.2 post-operatively (p < 0.05), after a mean percent excess weight loss (% EWL) of 49.4%.  The odds of experiencing a greater than or equal to 50% reduction in headache days was related to greater% EWL, independent of surgery type (p < 0.05).  Reductions in severity were also observed (p < 0.05) and the number of patients reporting moderate to severe disability decreased from 12 (50.0%) before surgery to 3 (12.5%) after surgery (p < 0.01).  The authors occluded that severely obese migraineurs experience marked alleviation of headaches after significant weight reduction via bariatric surgery.  However, they stated that more studies are needed to examine if more modest, behaviorally produced weight losses can effect similar migraine improvements.  The findings of this small, retrospective, uncontrolled study need to be confirmed by randomized controlled trials.  Furthermore, it would be interesting to ascertain if there is a dose-response relationship (i.e., if greater weight loss would lead to greater improvement of migraine headaches).

Posadzki and Ernst (2011) evaluated the effectiveness of spinal manipulations as a treatment for migraine headaches.  A total of 7 databases were searched from inception to November 2010.  All randomized clinical trials (RCTs) investigating spinal manipulations performed by any type of healthcare professional for treating migraine headaches in human subjects were considered.  The selection of studies, data extraction and validation were performed independently by 2 reviewers.  A total of 3 RCTs met the inclusion criteria.  Their methodological quality was mostly poor and ranged between 1 and 3 on the Jadad scale.  Two RCTs suggested no effect of spinal manipulations in terms of Headache Index or migraine duration and disability compared with drug therapy, spinal manipulation plus drug therapy, or mobilization.  One RCT showed significant improvements in migraine frequency, intensity, duration and disability associated with migraine compared with detuned interferential therapy.  The most rigorous RCT demonstrated no effect of chiropractic spinal manipulation compared with mobilization or spinal manipulation by medical practitioner or physiotherapist on migraine duration or disability.  The authors concluded that current evidence does not support the use of spinal manipulations for the treatment for migraine headaches.

The updated evidence-based guidelines on "Pharmacologic treatments and NSAIDs and other complementary treatments for episodic migraine prevention in adults" of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society (Silberstein et al, 2012) states that "Data from older studies regarding verapamil and nimodipine are insufficient when current AAN classification criteria are applied .... Evidence is conflicting or inadequate to support or refute the use of nicardipine, nimodipine, or verapamil for migraine prevention".

In a single-blinded, randomized trial, Bell et al (1990) evaluated the relative effectiveness of 3 non-narcotic agents, chloropromazine, lidocaine, and dihydroergotamine, in the treatment of migraine headache in an emergency department setting.  All patients had an isolated diagnosis of common or classic migraine.  Patients were pre-treated with 500 ml intravenous (IV) normal saline before randomization.  Study drugs as administered were dihydroergotamine 1 mg IV repeated after 30 minutes if the initial response was inadequate; lidocaine 50 mg IV at 20-minute intervals to a maximum total dose of 150 mg as required; or chloropromazine 12.5 mg IV repeated at 20-minute intervals to a total maximum dose of 37.5 mg as required.  Patients were asked to grade headache severity on a 10-point scale before and 1 hour after the initiation of therapy.  Follow-up by phone was sought the following day.  Of 76 patients completing the trial, 24 were randomized to receive chloropromazine, 26 to receive dihydroergotamine, and 26 to receive lidocaine.  Reduction in mean headache intensity was significantly better among those treated with chloropromazine (p < 0 .005).  Persistent headache relief was experienced by 16 of the chloropromazine-treated patients (88.9%) contacted at 12 to 24 hours follow-up compared with 10 of the dihydroergotamine-treated patients (52.6%) and 5 of the lidocaine-treated group (29.4%).  The authors concluded that the relative effectiveness of these 3 anti-migraine therapies appears to favor chloropromazine in measures of headache relief, incidence of headache rebound, and patient satisfaction with therapy.

Reutens et al (1991) performed a prospective, randomized, double-blind, placebo-controlled trial of IV lidocaine (1 mg/kg) in the treatment of acute migraine.  A total of 13 subjects were randomly allocated to receive IV lidocaine; while 12 control subjects received IV normal saline.   Subjects scored the intensity of headache and nausea on separate VAS before the injection and at 10 and 20 mins after injection.  At 20 mins, the mean pain intensity score was 80% of initial intensity in the lidocaine group and 82% in the placebo group.  The difference was not statistically significant; at 20 mins, the 95% CI for the difference between the 2 groups in mean percentage of initial pain score was 2 +/- 29%.  At the dose studied, IV lidocaine has, at best, only a modest effect in acute migraine.

In a double-blind, randomized, controlled trial, Afridi et al (2013) tested the hypothesis that intranasal ketamine would affect migraine with prolonged aura.  These researchers examined the effect of 25-mg intranasal ketamine on migraine with prolonged aura in 30 migraineurs using 2-mg intranasal midazolam as an active control.  Each subject recorded data from 3 episodes of migraine.  A total of 18 subjects completed the study.  Ketamine reduced the severity (p = 0.032) but not duration of aura in this group, whereas midazolam had no effect.  The authors concluded that these data provided translational evidence for the potential importance of glutamatergic mechanisms in migraine aura and offer a pharmacologic parallel between animal experimental work on cortical spreading depression and the clinical problem.  Drawbacks of this study included small number of patients and the design of the study did not exclude an effect of midazolam.  These findings need to be validate by well-designed studies with more patients, higher doses of ketamine and subjects with more migraine attacks.  The authors stated that their study does not endorse the widespread use of ketamine in migraine aura.

Dimitriou et al (2002) evaluated the effectiveness of the blockade of branches of ophthalmic nerve in the management of the acute attack of migraine headache localized to the ocular region.  The study included 70 female patients aged 23 to 60 years who presented to the pain clinic at our hospital with an acute attack of migraine headache localized to the ocular and retro-ocular region.  A targeted history and a neurologic examination were performed in all patients to confirm the diagnosis and at the same time to rule out life-threatening neurological dysfunction.  The method applied was the blockade of the supra-orbital and supra-trochlear nerves which are branches of the ophthalmic nerve.  By the use of a fine short needle 27G the nerves were sought for until paraesthesia is obtained and then 1 ml of lignocaine 2% with adrenaline 1:200,000 was injected in every 1 of the 3 sites of the nerves.  The migraine acute attack was relieved in 58/70 patients (82%), while in 12/70 patients (18%) the results were poor.  The pain relief started 3 to 4 mins after the injection and was completed in 10 to 15 mins.  The authors concluded that these findings supported that the blockade of the branches of the ophthalmic nerve seems to be a safe and effective technique in the management of the acute attack of migraine localized to the ocular and retro-ocular region.  The main drawback of this study was the lack of a control group. 

The authors noted that despite methodologic precautions including concealed allocation, partial un-blinding may have occurred in this trial.  It was difficult to blind peripheral neurostimulation trials because the effective electrical stimulation produces intense paresthesia.  These investigators doubted, however, that un-blinding markedly influenced their results for the following reasons.  The sham response was within the range of that found in other trials with neurostimulation devices.  Compared to the ONSTIM trial of occipital nerve stimulation, it was even higher for the 50% responder rate: 6% in ONSTIM, 12.8% in PREMICE.  Un-blinding could thus have been twice more pronounced in ONSTIM than in PREMICE, if one assumed that it was inversely proportional to the percentage of responders in a sham group.  The rather small difference (7.3%) in compliance rates between verum and sham groups also did not favor massive un-blinding.  If this were the case, one would expect a much lower compliance in the sham group.  Another possible weakness of this trial appeared when data from the different centers were analyzed: patients in the verum group were on average younger than those in the sham group and the duration of their migraine was somewhat shorter.  On post-hoc statistical analyses these researchers were unable, however, to detect an influence of age or of disease duration on treatment outcome.  In the ONSTIM trial, the difference in mean age between the effectively stimulated patients and the smaller "ancillary" group was 9 years.  Overall, both patient groups in PREMICE were well in the age range of migraine patients included in other trials.  These researchers stated that beyond statistics, the question whether the results of the PREMICE trial were clinically relevant merits consideration.  Besides the therapeutic gain for 50% responders, other outcome measures suggested that STS could be of benefit to migraine patients.  It decreased significantly consumption of acute anti-migraine drugs, which is a pharmaco-economical advantage.  In addition, more than 70% of effectively stimulated patients were satisfied with the treatment.  The patients recruited for PREMICE were not the most disabled migraineurs.  Having 4 migraine attacks or 7 migraine days per month, they were similar, however, to those included in topiramate trials and representative of the majority of migraine patients in the general population who are in need of preventive treatment according to international recommendations.  Whether STS treatment is effective in patients with more frequent attacks or with chronic migraine remains to be determined.

In an editorial that accompanied the aforementioned study, Asano and Goadsby (2013) "new therapies are needed in migraines, and further studies of neurostimulation using innovative study designs are warranted to explore the optimum way to create an acceptable evidence base for widespread use of this potentially valuable treatment modality".

Ashkenazi and Levin (2007) stated that peripheral nerve blocks have long been used in headache treatment.  The most widely used procedure for this purpose has been greater occipital nerve (GON) block.  The rationale for using GON block in headache treatment comes from evidence for convergence of sensory input to trigeminal nucleus caudalis neurons from both cervical and trigeminal fibers.  Although there is no standardized procedure for GON blockade, the nerve is usually infiltrated with a local anesthetic (lidocaine, bupivacaine, or both).  A corticosteroid is sometimes added.  Several studies suggested efficacy of GON block in the treatment of migraine, cluster headache, and chronic daily headache.  However, few were controlled and blinded.  Despite a favorable clinical experience, little evidence exists for the efficacy of GON block in migraine treatment.  Controlled studies are needed to better assess the role of GON block in the treatment of migraine and other headaches.

In a retrospective case series, Rosen et al (2009) examined the use of IV lidocaine for refractory chronic daily headache (CDH) patients in an inpatient setting.  This was an open-label, retrospective, uncontrolled study of IV lidocaine for 68 intractable headache patients in an inpatient setting.  These investigators reviewed the medical records of patients receiving IV lidocaine between February 6, 2003 and June 29, 2005.  Pre-treatment headache scores averaged 7.9 on an 11-point scale and post-treatment scores averaged 3.9 representing an average change of 4.  Average length of treatment was 8.5 days.  Lidocaine infusion was generally well-tolerated with a low incidence of adverse events leading to discontinuation of treatment.  The authors concluded that the results of this study suggested benefit of lidocaine treatment and the need for further prospective analyses.  The mechanism of lidocaine in treating headache is unknown.

Also, the European handbook of neurological management of cluster headache and other trigemino-autonomic cephalgias (Evers et al, 2011) stated that "The following were considered but not recommended for treatment of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome: lamotrigine, gabapentin, topiramate, oxcarbazepine, verapamil, intravenous lidocaine, steroids, intravenous phenytoin, and stimulation of the hypothalamus. Lamotrigine is considered first-line treatment".

The AAN’s updated guidelines on "Pharmacologic treatment for episodic migraine prevention in adults" (Silberstein et al, 2012a) and "NSAIDs and other complementary treatments for episodic migraine prevention in adults" (Holland et al, 2012)  had no recommendation for intravenous methylprednisolone or other steroids, or for nalbuphine (Nubain) or other opioid agonist-antagonists for migraine treatment.  Furthermore, the U.S. Headache Consortium’s guidelines on "Migraine headache in the primary care setting" (Matchar et al, 2014) concluded that the clinical and statistical benefits of IV steroids are unknown (insufficient evidence available).

Colombo et al (2013) stated that patients affected by chronic forms of headache are often very difficult to treat.  Refractory patients are so defined when adequate trials of specific drugs (for acute or prophylactic treatment) failed both to reduce the burden of disease and to improve headache-related quality of life.  An escalating approach is suggested to test different kinds of therapies.  All co-morbid factors should be addressed.  The authors concluded that more invasive modalities (such as neurostimulation) or promising approaches such as repetitive transcranial magnetic stimulation (rTMS) could be a future major step as third line therapies.

On March 11, 2014, the FDA allowed marketing of the first device (the Cefaly Migraine Headband) as a preventative treatment for migraine headaches.  This is also the first transcutaneous electrical nerve stimulation (TENS) device specifically authorized for use prior to the onset of pain.  Cefaly is a small, portable, battery-powered, prescription device that resembles a plastic headband worn across the forehead and atop the ears.  The user positions the device in the center of the forehead, just above the eyes, using a self-adhesive electrode.  The device applies an electric current to the skin and underlying body tissues to stimulate branches of the trigeminal nerve, which has been associated with migraine headaches.  The user may feel a tingling or massaging sensation where the electrode is applied.  Cefaly is indicated for patients 18 years of age and older and should only be used once-daily for 20 minutes.

The FDA reviewed the data for Cefaly through the de-novo pre-market review pathway, a regulatory pathway for generally low- to moderate-risk medical devices that are not substantially equivalent to an already legally marketed device (i.e., it did not even go through the 510(k) process).  The agency evaluated the safety and effectiveness of the device based on data from a clinical study conducted in Belgium involving 67 individuals who experienced more than 2 migraine headache attacks a month and who had not taken any medications to prevent migraines for 3 months prior to using Cefaly, as well as a patient satisfaction study of 2,313 Cefaly users in France and Belgium.  The 67-person study showed that those who used Cefaly experienced significantly fewer days with migraines per month and used less migraine attack medication than those who used a placebo device.  The device did not completely prevent migraines and did not reduce the intensity of migraines that did occur.  The patient satisfaction study showed that a little more than 53% of patients were satisfied with Cefaly treatment and willing to buy the device for continued use.  The most commonly reported complaints were dislike of the feeling and not wanting to continue using the device, sleepiness during the treatment session, and headache after the treatment session.  No serious adverse events occurred during either study.

Tso and Goadsby (2014) noted that the shift in the understanding of migraine as a vascular disorder to a brain disorder has opened new avenues for the development of novel therapeutics with neural targets.  The advent of 5-HT1B/1D receptor agonists, the triptans, in the 1990s was a crucial step in the modern evolution of treatment.  The use of triptans, like their predecessors, is limited by their vasoconstrictor effects, and new development has been slowed by poor academic research funding to identify new targets.  The development of agents without vascular effects, such as calcitonin gene-related peptide receptor antagonists and selective serotonin 5-HT1F receptor agonists, will bring more effective treatments to a population currently without migraine-specific options.  In addition, advances in understanding migraine pathophysiology have identified new potential pharmacologic targets such as acid-sensing ion channels, glutamate and orexin receptors, nitric oxide synthase (NOS), and transient receptor potential (TRP) channels.  Although previous attempts to block subtypes of glutamate receptors, NOS, and TRP channels have had mixed outcomes, new molecules for the same targets are currently under investigation.  Finally, an entirely new approach to migraine treatment with non-invasive neuromodulation via transcutaneous neurostimulation (e.g., TENS) or TMS is just beginning.

Conforto et al (2014) stated that high-frequency rTMS of the left dorsolateral prefrontal cortex (rTMS-DLPFC) is an effective treatment for depression.  Preliminary studies indicated beneficial effects of rTMS-DLPFC on pain relief in patients treated for depression, and in patients with chronic migraine.  In this randomized, double-blind, parallel-group, single-center, proof-of-principle clinical trial, these researchers tested the hypothesis that 23 sessions of active rTMS-DLPFC delivered over 8 weeks would be feasible, safe and superior to sham rTMS to decrease the number of headache days in 18 patients with chronic migraine without severe depression.  Per-protocol analysis was performed.  rTMS-DLPFC applied over 8 weeks was feasible and safe in patients with chronic migraine.  Contrary to the primary hypothesis, the number of headache days decreased significantly more in the sham group than in the group treated with active rTMS-DLPFC at 8 weeks.  Average decrease in headache days was greater than 50% in the sham group, indicating a powerful placebo response.  Pain intensity improved in both groups to a similar extent.  The authors concluded that positive results of M1 stimulation in other studies, and the absence of significant benefits of active high-frequency rTMS of the DLPFC in the present study, point to M1 as a more promising target than the DLPFC, for larger trials of non-invasive brain stimulation in patients with chronic migraine.

On July 11, 2014, the California Technology Assessment Forum (CTAF) held a meeting in Los Angeles on "Controversies in Migraine Management" (Tice et al, 2014).  The CTAF Panel discussed the clinical effectiveness and reviewed economic analyses of 4 migraine treatments; 2 devices were considered.  First, for the treatment of acute migraine headache accompanied by aura, 1 well-designed, moderate size study of a single-pulse transcranial magnetic stimulation device (SpringTMS™ by eNeura) showed superior pain relief compared with a sham device, but no benefit was found in several other common outcome measures.  Economic modeling comparing the device with a commonly-used generic triptan found a high relative cost for its potential benefit.  Second, only 1 small trial has been reported of a TENS device (Cefaly) for the prevention of frequent migraine headaches.  This trial, further limited by concerns about unblinding and incomplete reporting of adverse effects, showed improvement in some commonly measured headache outcomes.  At current pricing and with the best estimate of Cefaly’s clinical effectiveness compared with a commonly used generic, oral medication, modeling suggested lower overall benefit and higher cost.  For both devices, the CTAF panel voted that the evidence is inadequate to demonstrate that they are as effective as other currently available care options.

The Work Loss Data Institute’s clinical practice guideline on "Pain (chronic)" (2013) stated that ketamine subanesthetic infusion is not recommended for complex regional pain syndrome (CRPS) and ketamine, in general, is not recommended.  

Lee and Huh (2013) stated that a headache is a common neurological disorder, and large numbers of patients suffer from intractable headaches including migraine, tension headache and cluster headache, etc., with no clear therapeutic options.  Despite the advances made in the treatment of headaches over the last few decades, subsets of patients either do not achieve adequate pain relief or cannot tolerate the side effects of typical migraine medications.  An electrical stimulation of the peripheral nerves via an implantable pulse generator appears to be good alternative option for patients with treatment-refractory headaches.  A number of clinical trials showed considerable evidence supporting the use of peripheral nerve stimulator (PNS) for headaches not responding to conservative therapies.  However, the mechanism by which PNS improves headaches or predicts who will benefit from PNS remains uncertain.  The decision to use PNS should be individualized based on patient suffering and disability.  The authors concluded that further work is imperative.

Huang et al (2014) described the current data evaluating the safety and effectiveness of memantine for the prevention of primary headache disorders.  They performed a literature search using MEDLINE (1966-July 2014) and EMBASE (1973-July 2014) using the search terms memantine, headache, migraine, glutamate, and NMDA.  References of identified articles were reviewed for additional, relevant citations.  All English-language articles dealing with the use of memantine for prevention of primary headache disorders were included.  Data from several retrospective reports and 2 prospective clinical trials suggested that memantine may be a useful treatment option for the prevention of primary headache disorders.  The majority of available literature focused specifically on chronic migraine prevention in refractory patients who had failed multiple previous prophylactic therapies.  In these patients, 10 to 20 mg of memantine daily reduced the frequency and intensity of migraine headaches and was generally well-tolerated, with few adverse events.  Data regarding the effectiveness of memantine for other primary headache disorders such as chronic tension type and cluster headaches were limited.  The authors concluded that "Although further studies evaluating the efficacy of memantine for prevention of primary headache disorders are warranted, memantine may be a reasonable option, used either as monotherapy or adjunctive therapy, in the refractory chronic migraine prophylaxis setting.

An AHRQ assessment of pharmacologic agents for migraine prevention in adults (Shamliyan, et al., 2013) reported that published randomized controlled trials did not examine antidementia drugs. Retrospective review of case series and case reports demonstrated that with memantine treatment, 60 percent of the patients experienced ≥50 percent reduction in monthly migraine frequency, and 80 percent experienced a significant reduction in frequency of aura.

Jurgens et al (2014) noted that CCH is a debilitating headache disorder with a significant impairment of the patients' lives.  Within the past decade, various invasive neuromodulatory approaches have been proposed for the treatment of CCH refractory to standard preventive drug, but only very few RCTs exist in the field of neuromodulation for the treatment of drug-refractory headaches.  Based on the prominent role of the cranial parasympathetic system in acute CH attacks, high-frequency sphenopalatine ganglion (SPG) stimulation has been shown to abort ongoing attacks in some patients in a first small study.  As preventive effects of SPG-stimulation have been suggested and the rate of long-term side effects was moderate, SPG stimulation appears to be a promising new treatment strategy.  The authors stated that as SPG stimulation is effective in some patients and the first commercially available CE-marked SPG neurostimulator system has been introduced for CH, patient selection and care should be standardized to ensure maximal safety and effectiveness.  They noted that as only limited data have been published on SPG stimulation, standards of care based on expert consensus were proposed to ensure homogeneous patient selection and treatment across international headache centers.  These investigators concluded that given that SPG stimulation is still a novel approach, all expert-based consensuses on patient selection and standards of care should be re-reviewed when more long-term data are available.

Tx360 Nasal Applicator (Spheno-Palatine Ganglion Blockade) for the Treatment of Migraine

Candido et al (2013) stated that the spheno-palatine ganglion (SPG) is located with some degree of variability near the tail or posterior aspect of the middle nasal turbinate.  The SPG has been implicated as a strategic target in the treatment of various headache and facial pain conditions, some of which are featured in this manuscript.  Interventions for blocking the SPG range from minimally to highly invasive procedures often associated with great cost and unfavorable risk profiles.  In a pilot study, these researchers presented a novel, FDA-cleared medication delivery device, the Tx360^® nasal applicator, incorporating a trans-nasal needleless topical approach for SPG blocks.  This case-series study featured the technical aspects of this new device and presented some limited clinical experience observed in a small series of head and face pain cases.  After Institutional Review Board (IRB) approval, the technical aspects of this technique were examined on 3 patients presenting with various head and face pain conditions including trigeminal neuralgia (TN), chronic migraine headache (CM), and post-herpetic neuralgia (PHN).  The subsequent response to treatment and quality of life was quantified using the following tools: the 11-point Numeric Rating Scale (NRS), Modified Brief Pain Inventory - short form (MBPI-sf), Patient Global Impression of Change (PGIC), and patient satisfaction surveys.  The Tx360^® nasal applicator was used to deliver 0.5 ml of ropivacaine 0.5% and 2 mg of dexamethasone for SPG block.  Post-procedural assessments were repeated at 15 and 30 minutes, and on days 1, 7, 14, and 21 with a final assessment at 28 days post-treatment.  All patients were followed for 1 year. Individual patients received up to 10 SPG blocks, as clinically indicated, after the initial 28 days.  Three women, aged 43, 18, and 15, presented with a variety of headache and face pain disorders including TN, CM, and PHN were included in this study.  All patients reported significant pain relief within the first 15 minutes post-treatment.  A high degree of pain relief was sustained throughout the 28 day follow-up period for 2 of the 3 study participants.  All 3 patients reported a high degree of satisfaction with this procedure.  One patient developed minimal bleeding from the nose immediately post-treatment that resolved spontaneously in less than 5 minutes.  Longer term follow-up (up to 1 year) demonstrated that additional SPG blocks over time provided a higher degree and longer lasting pain relief.  The authors concluded that SPG block with the Tx360^® is a rapid, safe, easy, and reliable technique to accurately deliver topical trans-nasal analgesics to the area of mucosa associated with the SPG.  This intervention can be delivered in as little as 10 seconds with the novice provider developing proficiency very quickly.  They stated that further investigation is certainly warranted related to technique efficacy, especially studies comparing efficacy of Tx360 and standard cotton swab techniques.  Well-designed controlled double-blind studies with a higher number of patients are needed to prove the effectiveness of the Tx360 nasal applicator for the treatment of headache.

In a double-blind, parallel-arm, placebo-controlled, randomized pilot study, Cady et al (2015) examined if repetitive SPG blocks with 0.5% bupivacaine delivered through the Tx360 are superior in reducing pain associated with CM compared with saline.  Up to 41 subjects could be enrolled at 2 headache specialty clinics in the US.  Eligible subjects were between 18 and 80 years of age and had a history of CM defined by the second edition of the International Classification of Headache Disorders appendix definition.  They were allowed a stable dose of migraine preventive medications that was maintained throughout the study.  Following a 28-day baseline period, subjects were randomized by computer-generated lists of 2:1 to receive 0.5% bupivacaine or saline, respectively.  The primary end-point was to compare numeric rating scale scores at pre-treatment baseline versus 15 minutes, 30 minutes, and 24 hours post-procedure for all 12 treatments.  Spheno-palatine ganglion blockade was accomplished with the Tx360, which allows a small flexible soft plastic tube that is advanced below the middle turbinate just past the pterygopalatine fossa into the intranasal space.  A 0.3 cc of anesthetic or saline was injected into the mucosa covering the SPG.  The procedure was performed similarly in each nostril.  The active phase of the study consisted of a series of 12 SPG blocks with 0.3 cc of 0.5% bupivacaine or saline provided 2 times per week for 6 weeks.  Subjects were re-evaluated at 1 and 6 months post-final procedure.  The final dataset included 38 subjects, 26 in the bupivacaine group and 12 in the saline group.  A repeated measures analysis of variance showed that subjects receiving treatment with bupivacaine experienced a significant reduction in the numeric rating scale scores compared with those receiving saline at baseline (M = 3.78 versus M = 3.18, p = 0.10), 15 minutes (M = 3.51 versus M = 2.53, p < 0.001), 30 minutes (M = 3.45 versus M = 2.41, p < 0.001), and 24 hours after treatment (M = 4.20 versus M = 2.85, p < 0.001), respectively.  Headache Impact Test-6 scores were statistically significantly decreased in subjects receiving treatments with bupivacaine from before treatment to the final treatment (Mdiff = -4.52, p = 0.005), whereas no significant change was seen in the saline group (Mdiff = -1.50, p = 0.13).  The authors concluded that SPG blockade with bupivacaine delivered repetitively for 6 weeks with the Tx360 device demonstrated promise as an acute treatment of headache in some subjects with CM.  Statistically significant headache relief is noted at 15 and 30 minutes and sustained at 24 hours for SPG blockade with bupivacaine vs saline.  They stated that the Tx360 device was simple to use and not associated with any significant or lasting adverse events; further research on SPG blockade is warranted.

In a randomized placebo-controlled trial, Schaffer et al (2015) examined the effectiveness of non-invasive SPG block for the treatment of acute anterior headache in the emergency department (ED) using a novel non-invasive delivery device.  This study was completed in 2 large academic EDs.  Bupivacaine or normal saline solution was delivered intra-nasally (0.3 ml per side) with the Tx360 device.  Pain and nausea were measured at 0, 5, and 15 minutes by a 100-mm visual analog scale.  The primary end-point was a 50% reduction in pain at 15 minutes.  Telephone follow-up assessed 24-hour pain and nausea through a 0- to 10-point verbal scale and adverse effects.  The median reported baseline pain in the bupivacaine group was 80 mm (interquartile range [IQR] 66 mm to 93 mm) and 78.5 mm (IQR 64 mm to 91.75 mm) in the normal saline solution group.  A 50% reduction in pain was achieved in 48.8% of the bupivacaine group (20/41 patients) versus 41.3% in the normal saline solution group (19/46 patients), for an absolute risk difference of 7.5% (95% confidence interval [CI]: -13% to 27.1%).  As a secondary outcome, at 24 hours, more patients in the bupivacaine group were headache free (24.7% difference; 95% CI: 2.6% to 43.6%) and more were nausea free (16.9% difference; 95% CI: 0.8% to 32.5%).  The authors concluded that for patients with acute anterior headache, SPG block with the Tx360 device with bupivacaine did not result in a significant increase in the proportion of patients achieving a greater than or equal to 50% reduction in headache severity at 15 minutes compared with saline solution applied in the same manner.

Calcitonin Gene-Related Peptide Antagonists

Cui and associates (2015) stated that calcitonin gene-related peptide (CGRP) receptor antagonists, such as telcagepant, have been under investigation as a treatment for acute migraine. In a meta-analysis, these researchers evaluated the effectiveness of telcagepant versus placebo and triptans (zolmitriptan or rizatriptan).  Randomized controlled trials were identified from databases using the following search terms: migraine; calcitonin gene-related peptide; calcitonin gene-related peptide receptor antagonists; efficacy; safety, and telcagepant.  The primary outcome measure was pain freedom 2 hours after first treatment.  The secondary outcome measure was pain relief 2 hours after first treatment.  A total of 8 trials were included in the meta-analysis (telcagepant = 4,011 participants).  The difference in pain freedom at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.70, 95% confidence interval = 2.27-3.21, P < 0.001) and triptans over telcagepant (odds ratio = 0.68, 95% confidence interval = 0.56-0.83, P < 0.001). The difference in pain relief at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.48, 95% confidence interval = 2.18-2.81, P < 0.001). The difference in pain relief at 2 hours did not significantly favor telcagepant over triptans or vice versa (OR = 0.76, 95% CI: 0.57 to 1.01, p = 0.061). The authors concluded that these findings indicated that telcagepant can be effective for treating acute migraine; and CGRP receptor antagonists represent a potentially important alternative means of treating acute migraine.

In a meta-analysis, Hong and Liu (2017) evaluated the effectiveness of CGRP antagonisms in treating acute migraine attack. PubMed, Cochrane Library, Web of Science and OvidSP were systematically searched up to April 9, 2015 for RCTs that dealt with the effectiveness of CGRP antagonisms in treating acute migraine attack.  The bias and quality of RCTs were assessed with Cochrane collaboration's tool for assessing risk of bias.  Reviewer manager 5.2 was utilized for data analysis.  A total of 13 publications matched the inclusion criteria, including 10 independent RCTs and 6,803 patients.  Pooled analysis indicated that CGRP antagonisms had better outcomes in number of patients with pain free at 2 hours, 2 to 24 hours sustained pain free, phonophobia free at 2 hours, patients with photophobia free at 2 hours and nausea free at 2 hours post-dose, as compared with placebo.  However, CGRP antagonisms were no superior than 5-HT agonists in the aforementioned indices.  The authors concluded that CGRP antagonisms may be an effective and promising treatment for acute migraine attack.

Bigal and colleagues (2016) evaluated the onset of effectiveness of TEV-48125, a monoclonal antibody against CGRP, recently shown to be effective for the preventive treatment of CM and high-frequency episodic migraine.  A randomized placebo-controlled study tested once-monthly injections of TEV-48125 675/225 mg or 900 mg versus placebo.  Headache information was captured daily using an electronic headache diary.  The primary end-point was change from baseline in the number of headache hours in month 3.  These researchers evaluated the effectiveness of each dose at earlier time-points.  The sample consisted of 261 patients.  For headache hours, the 675/225-mg dose separated from placebo on day 7 and the 900-mg dose separated from placebo after 3 days of therapy (p = 0.048 and p = 0.033, respectively).  For both the 675/225-mg and 900-mg doses, the improvement was sustained through the second (p = 0.004 and p < 0.001) and third (p = 0.025 and p < 0.001) weeks of therapy and throughout the study (month 3, p = 0.0386 and p = 0.0057).  For change in weekly headache days of at least moderate intensity, both doses were superior to placebo at week 2 (p = 0.031 and p = 0.005).  The authors concluded that TEV-48125 demonstrated a significant improvement within 1 week of therapy initiation in patients with CM.

Intramuscular Bupivacaine

Mellick and colleagues (2006) described the 1-year experience of an academic emergency department (ED) in treating a wide spectrum of headache classifications with intramuscular injections of 0.5% bupivacaine bilateral to the spinous process of the lower cervical vertebrae. These investigators performed a retrospective review of over 2,805 ED patients with the discharge diagnosis of headache and over 771 patients who were coded as having had an anesthetic injection between June 30, 2003 and July 1, 2004.  All adult patients who had undergone para-spinous intramuscular injection with bupivacaine for the treatment of their headache were gleaned from these 2 larger databases and were included in this retrospective chart review.  A systematic review of the medical records was accomplished for these patients.  Lower cervical para-spinous intramuscular injections with bupivacaine were performed in 417 patients.  Complete headache relief occurred in 271 (65.1%) and partial headache relief in 85 patients (20.4%).  No significant relief was reported in 57 patients (13.7%) and headache worsening was described in 4 patients (1%).  Overall a therapeutic response was reported in 356 of 417 patients (85.4%).  Headache relief was typically rapid with many patients reporting complete headache relief in 5 to 10 minutes.  Associated signs and symptoms such as nausea, vomiting, photophobia, phonophobia, and allodynia were also commonly relieved.  The authors concluded that their observations suggested that the intramuscular injection of small amounts of 0.5% bupivacaine bilateral to the sixth or seventh cervical spinous process appeared to be an effective therapeutic intervention for the treatment of headache pain in the outpatient setting.

Mellick and Pleasant (2010) performed a retrospective review of all pediatric patients with headaches who were treated with this technique in an ED setting over a 16-month period. A total of 3 separate databases were reviewed to capture all patients younger than 18 years with a diagnosis of headache who received bilateral cervical injections between June 30, 2003, and December 1, 2004, in the Medical College of Georgia and Children's Medical Center EDs.  Their medical records were retrospectively reviewed to determine their response to this procedure.  The headaches of 13 patients younger than 18 years were treated with this procedure.  The mean headache severity was 9.15, and the mean duration of headache was 3.16 days; 6 (46.2%) of 13 patients had complete relief of their headaches, whereas 5 (38.4%) of 13 patients had partial relief.  No significant relief was documented in 2 (15.4%) of 13 patients.  A therapeutic response was documented in 11 (84.6%) of 13 of the patients.  The authors concluded that these retrospective observations suggested that bilateral lower cervical para-spinous intramuscular injections with small amounts of bupivacaine may have a therapeutic role in the management of headache pain in children, and their rate of therapeutic response may be similar to that recently reported for adult headache patients.

Patniyot and Gelfand (2016) performed a qualitative systematic review to evaluate the safety and effectiveness of available treatments for pediatric patients with migraine or benign primary headache in the ED. Scopus, Medline, and PubMed databases were searched for RCTs, retrospective reviews, review articles, and case studies discussing migraine or benign primary headache management that were conducted in the emergency room or outpatient acute care setting in pediatric patients (less than 18 years old).  Meeting abstracts and cited references within articles were also evaluated.  Multiple variables were recorded, including type of treatment, study design, dosing, primary outcome, and side effects.  Therapeutic gain was calculated in studies with a placebo arm.  Treatments were subjectively assessed based on methodology and number of trials for a particular therapy.  A total of 31 studies were included in the final analysis.  Of these, 17 were RCTs, 9 were retrospective reviews, and 5 were prospective chart review studies.  One pertained to IV fluids, 2 to non-specific analgesic use, 5 to dopamine receptor antagonists, 2 to valproic acid, 1 to propofol, 1 to magnesium, 1 to bupivacaine, 13 to triptan medications, and 3 to DHE.  Treatments considered effective for acute migraine or benign primary headache in the analgesic category include ibuprofen, and to a lesser degree acetaminophen.  Ketorolac was not compared to other NSAIDs, but was found to be less effective than prochlorperazine.  Of the phenothiazines, prochlorperazine was considered most effective.  Of the triptan medications, almotriptan, rizatriptan, zolmitriptan nasal spray, sumatriptan nasal spray, and combination sumatriptan/naproxen are effective agents for acute treatment.  Treatments considered probably effective included IV fluids, chlorpromazine, valproate sodium, injectable sumatriptan, and IV DHE.  Treatments with oral zolmitriptan showed inconsistent results, while treatments considered ineffective included isolated oral sumatriptan and oral DHE.  Moreover, there is insufficient evidence to comment on propofol, magnesium, and bupivacaine efficacy.  The authors concluded that of the available evidence, ibuprofen, prochlorperazine, and certain triptan medications are the most effective and safe agents for acute management of migraine and other benign headache disorders in the pediatric population.  They stated that additional studies in this population are needed, and should take into consideration variables such as dosing, co-administered medications, treatment duration, and length of treatment effect.

Intramuscular Nalbuphine

Tek and Mellon (1987) noted that the present treatment for acute attacks of headache is empiric. Intramuscular nalbuphine (Nubain) and hydroxyzine (Vistaril) were assessed for pain relief in a prospective, double-blind clinical trial.  A total of 94 patients were assigned randomly to treatment groups receiving nalbuphine 10 mg, nalbuphine 10 mg plus hydroxyzine 50 mg, hydroxyzine 50 mg, or placebo.  The treatment groups were found to be adequately homogenous with regard to age, sex, type and duration of headaches, and history of prior narcotic use.  All data were analyzed by 1-way analysis of variance.  Patients who had headaches diagnosed as other than classic migraine had significantly greater pain relief with nalbuphine compared to placebo (p < 0.01).  The combination of nalbuphine and hydroxyzine was not significantly more effective than other treatment groups.  In 20 patients with classic migraine, none of the treatment regimens significantly outperformed placebo.  There were no clinically significant adverse effects attributed to the study drugs.  The authors concluded that these findings were similar to others that showed a lack of effectiveness of kappa receptor agonists in classic migraineurs.  They stated that nalbuphine appeared to be clinically useful in other types of severe headache; the findings of this study did not support the routine addition of hydroxyzine for presumed synergistic effect.

Intravenous Propofol

Mosier et al (2013) stated that migraine headaches requiring an ED visit due to failed outpatient rescue therapy present a significant challenge in terms of length of stay (LOS) and financial costs. These researchers hypothesized that propofol therapy may be effective at pain reduction and reduce that length of stay given its pharmacokinetic properties as a short acting intravenous sedative anesthetic and pharmacodynamics on GABA mediated chloride flux.  These investigators presented findings of case series of 4 patients with migraine headache failing outpatient therapy.  Each patient was given a sedation dose (1 mg/kg) of propofol under standard procedural sedation precautions.  Each of the 4 patients experienced dramatic reductions or complete resolution of headache severity; LOS for 3 of the 4 patients was 50% less than the average LOS for patients with similar chief complaints to the authors’ ED; 1 patient required further treatment with standard therapy but had a significant reduction in pain and a shorter LOS.  There were no episodes of hypotension, hypoxia, or apnea during the sedations.  The authors concluded that the finding of this small case series showed a promising reduction in headache symptoms using sedative dosing of propofol.  Moreover, they stated that future research should more formally evaluate the safety, effectiveness, and cost-effectiveness of sedation dosing of propofol for refractory migraines.

On behalf of the Canadian Headache Society, Orr and colleagues (2015) performed a peer-reviewed search of databases (MEDLINE, Embase, CENTRAL) to identify rRCTs and quasi-RCTs of interventions for acute pain relief in adults presenting with migraine to emergency settings. Where possible, data were pooled into meta-analyses.  Two independent reviewers screened 831 titles and abstracts for eligibility; 3 independent reviewers subsequently evaluated 120 full text articles for inclusion, of which 44 were included.  Individual studies were then assigned a US Preventive Services Task Force quality rating.  The grading of recommendations, assessment, development, and evaluation (GRADE) scheme was used to assign a level of evidence and recommendation strength for each intervention.  The authors strongly recommended the use of prochlorperazine based on a high level of evidence, lysine acetylsalicylic acid, metoclopramide and sumatriptan, based on a moderate level of evidence, and ketorolac, based on a low level of evidence.  They weakly recommended the use of chlorpromazine based on a moderate level of evidence, and ergotamine, dihydroergotamine, lidocaine intranasal and meperidine, based on a low level of evidence.  The authors found evidence to recommend strongly against the use of dexamethasone, based on a moderate level of evidence, and granisetron, haloperidol and trimethobenzamide based on a low level of evidence.  Based on moderate-quality evidence, they recommended weakly against the use of acetaminophen and magnesium sulfate.  Based on low-quality evidence, they recommended weakly against the use of diclofenac, droperidol, lidocaine intravenous, lysine clonixinate, morphine, propofol, sodium valproate and tramadol.

In a qualitative systematic review to evaluate the safety and effectiveness of available treatments for pediatric patients with migraine or benign primary headache, Patniyot and Gelfand (2016) noted that there is insufficient evidence to comment on propofol, magnesium, and bupivacaine efficacy.

Oral Magnesium

Teigen and Boes (2015) performed a review of the literature from 1990 to the present on magnesium and migraine. These investigators identified 16 studies aimed at magnesium status assessment in migraine, and 4 intervention trials evaluating the effectiveness of oral magnesium supplementation, independent of other therapies, in the prevention of migraine.  The authors concluded that the strength of evidence supporting oral magnesium supplementation is limited at this time.  They stated that with such limited evidence, a more advantageous alternative to magnesium supplementation, in patients willing to make lifestyle changes, may be to focus on increasing dietary magnesium intake.

Intranasal Lidocaine

In a randomized, double-blind, placebo-controlled clinical trial, Blanda et al (2001) evaluated the effect of intranasal lidocaine for immediate relief (5 minutes) of migraine headache pain.  Patients 18 to 50 years old with migraine headache as defined by the International Headache Society were enrolled in this study.  Patients who were pregnant, lactating, known to abuse alcohol or drugs, or allergic to one of the study drugs, those who used analgesics within 2 hours, or those with a first headache were excluded.  Statistical significance was assessed by using chi-square or Fisher's exact test for categorical variables and Student's t-test for continuous variables.  Patients rated their pain on a 10-centimeter VAS prior to drug administration and at 5, 10, 15, 20, and 30 minutes after the initial dose.  Medication was either 1 ml of 4% lidocaine or normal saline (placebo) intranasally in split doses 2 minutes apart and intravenous prochlorperazine.  Medications were packaged so physicians and patients were unaware of the contents.  Successful pain relief was achieved if there was a 50% reduction in pain score or a score below 2.5 cm on the VAS.  A total of 27 patients received lidocaine and 22 received placebo.  No significant difference was observed between groups in initial pain scores, 8.4 (95% CI: 7.8 to 9.0) lidocaine and 8.6 (95% CI: 8.0 to 9.2) placebo (p = 0.75).  Two of 27 patients (7.4%, 95% CI: 0.8, 24.3) in the lidocaine group and 3of 22 patients (13.6%, 95% CI: 2.8 to 34.9) in the placebo group had immediate successful pain relief (p = 0.47), with average pain scores of 6.9 (95% CI: 5.9 to 7.8) and 7.0 (95% CI: 5.8 to 8.2), respectively.  No difference in pain relief was detected at subsequent measurements.  The authors concluded that there was no evidence that intranasal lidocaine provided rapid relief for migraine headache pain in the emergency department setting.

In a single-center, double-blind, RCT, Avcu and colleagues (2017) evaluated the safety and effectiveness of intranasal lidocaine administration for migraine treatment.  This study was conducted in a tertiary care ED.  Included patients met the migraine criteria of the International Headache Society.  Patients were randomized to intranasal lidocaine or saline solution; all participants received 10 mg of IV metoclopramide.  Patient pain intensity was assessed with an 11-point numeric rating scale score.  The primary outcome measure was the change in pain scores at 15 minutes; secondary outcomes were changes in pain intensity after pain onset and need for rescue medication.  Patients (n = 162) were randomized into 2 groups with similar baseline migraine characteristics and numeric rating scale scores.  The median reduction in numeric rating scale score at 15 minutes was 3 (IQR 2 to 5) for the lidocaine group and 2 (IQR 1 to 4) for the saline solution group (median difference [MD] = 1.0; 95% CI: 0.1 to 2.1).  The reduction in pain score at 30 minutes was 4 (IQR 3 to 7) for the lidocaine group and 5 (IQR 2 to 7) for the saline solution group (MD = 1.0; 95% CI: 0.1 to 2.1).  Need for rescue medication did not differ between the groups, and local irritation was the most common AE in the lidocaine group.  The authors concluded that although intranasal lidocaine was found no more effective than normal saline solution in this study, future studies should focus on patients who present earlier after headache onset.

In a systematic review, Dagenais and Zed (2018) examined the safety and efficacy of intranasal lidocaine in the acute management of primary headaches.  The Medline (1946 to May 2018), Embase (1974 to May 2018), Cochrane Central Register of Controlled Trials (2008 to May 2018), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to May 2018), and ClincialTrials.gov online databases were searched.  Studies conducted in patients with acute primary headache were included if lidocaine was compared with placebo or alternative treatments, lidocaine dosing was specified, and patients' pain before and after treatment were clearly reported.  A total of 6 studies met the inclusion criteria.  Intranasal lidocaine demonstrated potential benefit over placebo in acute pain reduction and need for rescue medication only in the 4 studies deemed to be of poor quality, not in the 2 fair-quality studies.  No study reported benefit in preventing headache recurrence or repeat visits to the ED.  Lidocaine was associated with significantly higher rates of AEs compared with placebo and may result in lower rates of patient satisfaction.  The authors concluded that there is insufficient evidence to support the use of intranasal lidocaine in acute management of primary headaches.  They stated that further research is needed to better examine if intranasal lidocaine has a role in the management of specific primary headache subtypes and whether there is an optimal regimen.

Occipital Nerve Stimulation

Saper et al (2011) noted that medically intractable CM is a disabling illness characterized by headache greater than or equal to 15 days per month.  A multi-center, randomized, blinded, controlled feasibility study was conducted to obtain preliminary safety and efficacy data on occipital nerve stimulation (ONS) in CM.  Eligible subjects received an occipital nerve block, and responders were randomized to adjustable stimulation (AS), preset stimulation (PS) or medical management (MM) groups.  Seventy-five of 110 subjects were assigned to a treatment group; complete diary data were available for 66.  A responder was defined as a subject who achieved a 50% or greater reduction in number of headache days per month or a 3-point or greater reduction in average overall pain intensity compared with baseline.  Three-month responder rates were 39% for AS, 6% for PS and 0% for MM.  No unanticipated adverse device events occurred.  Lead migration occurred in 12 of 51 (24%) subjects.  The authors concluded that the results of this feasibility study offer promise and should prompt further controlled studies of ONS in CM.

Silberstein et al (2012) stated that CM is a debilitating neurological disorder with few treatment options.  Peripheral nerve stimulation (PNS) of the occipital nerves is a potentially promising therapy for CM patients.  In this randomized, controlled, multi-center study, patients diagnosed with CM were implanted with a neurostimulation device near the occipital nerves and randomized 2:1 to active (n = 105) or sham (n = 52) stimulation.  The primary endpoint was a difference in the percentage of responders (defined as patients that achieved a greater than or equal to 50% reduction in mean daily visual analog scale scores) in each group at 12 weeks.  There was not a significant difference in the percentage of responders in the Active compared with the Control group (95% lower confidence bound (LCB) of -0.06; p = 0.55).  However, there was a significant difference in the percentage of patients that achieved a 30% reduction (p = 0.01).  Importantly, compared with sham-treated patients, there were also significant differences in reduction of number of headache days (Active Group = 6.1, baseline = 22.4; Control Group = 3.0, baseline = 20.1; p = 0.008), migraine-related disability (p = 0.001) and direct reports of pain relief (p = 0.001).  The most common adverse event was persistent implant site pain.  The authors concluded that although this study failed to meet its primary endpoint, this is the first large-scale study of PNS of the occipital nerves in CM patients that showed significant reductions in pain, headache days, and migraine-related disability.  They stated that additional controlled studies using endpoints that have recently been identified and accepted as clinically meaningful are warranted in this highly disabled patient population with a large unmet medical need.

Lambru and Matharu (2012) stated that chronic daily headache is a major worldwide health problem that affects 3 to 5% of the population and results in substantial disability.  Advances in the management of headache disorders have meant that a substantial proportion of patients can be effectively treated with medical treatments.  However, a significant minority of these patients are intractable to conventional medical treatments.  Occipital nerve stimulation is emerging as a promising treatment for patients with medically intractable, highly disabling chronic headache disorders, including migraine, cluster headache and other less common headache syndromes.  Open-label studies have suggested that this treatment modality is effective and recent controlled trial data are also encouraging.  The procedure is performed using several technical variations that have been reviewed along with the complications, which are usually minor and tolerable.  The mechanism of action is poorly understood, though recent data suggest that ONS could restore the balance within the impaired central pain system through slow neuromodulatory processes in the pain neuromatrix.  While the available data are very encouraging, the ultimate confirmation of the utility of a new therapeutic modality should come from controlled trials before widespread use can be advocated; more controlled data are still needed to properly assess the role of ONS in the management of medically intractable headache disorders.  The authors noted that future studies also need to address the variables that are predictors of response, including clinical phenotypes, surgical techniques and stimulation parameters.  Finally, the mode of action of ONS is poorly understood and further studies are required to elucidate the underlying mechanisms by which the anti-nociceptive effect is exerted.

The International Association for the Study of Pain's review on "Neuromodulation in Primary Headaches" (2012) states that "After an initial focus on hypothalamic deep brain stimulation (DBS), the less invasive technique of ONS is now widely considered the neuromodulatory approach of first choice in many primary headache disorders.  Despite their increasing popularity, most approaches lack methodologically sound randomized multicenter studies using an appropriate sham paradigm.  Especially in ONS, blinding remains an unresolved issue because effective stimulation induces paresthesias, unlike in hypothalamic DBS.  SPG stimulation represents an emerging alternative in the acute and possibly prophylactic treatment of chronic cluster headache.  The efficacy of various devices for transcutaneous peripheral nerve stimulation (such as the vagal and supraorbital nerves) and their role relative to implantable devices will have to be evaluated in future studies". 

A clinical trial on "Occipital Nerve Stimulation in Medically Intractable Chronic Cluster Headache" (NCT011516531) is recruiting subjects.

Yang and colleagues (2016) noted that patients who suffer from migraines often report impaired quality of life (QOL); ONS is a novel treatment modality for migraines, although few systematic reviews have evaluated whether this therapy is effective.  These researchers evaluated the safety and effectiveness of ONS for treating migraine through a literature review.  They performed a literature search to identify studies that examined ONS for migraine treatment.  Evidence levels of these studies were assessed by recommendations set by the University of Oxford Centre for Evidence-Based Medicine.  A total of 5 RCTs, 4 retrospective studies, and 1 prospective study met the inclusion criteria.  Results from the retrospective studies and case series indicated that ONS significantly reduced the pain intensity and the number of days with headache in patients with migraine.  However, the evidence of ONS effectiveness established by RCTs was limited.  Improvement in the migraine disability assessment (MIDAS) score was more dramatic than improvement in the SF-36 score at follow-up.  The mean complication incidence of ONS was 66% for the reviewed studies.  The authors concluded that future clinical studies should optimize and standardize the ONS intervention process and identify the relationship among the surgical process, effectiveness, and complications resulting from the procedure.

Clark and co-workers (2016) presented functional outcome studies of combined supra-orbital nerve stimulation (SONS) and ONS for CM using verified metrics.  Consecutive patients with both SONS and ONS assessed with MIDAS and Beck Depression Index (BDI) both pre-operatively and post-operatively were studied.  Selected predictor variables included patients with greater than  50% improvement of pain, disability status, number of years from diagnosis to implantation, and narcotic use.  Functional outcome variables included net improvement of ranked MIDAS and BDI scores.  Multi-variate analysis of variance was performed to assess the correlation between the outcome and predictor variables.  A total of 16 patients (12 females; average age of 52 years) were studied.  Follow-up ranged from 5 to 80 months (average of 44.5; σ = 21.4 months).  At most recent follow-up, 8 patients had a positive response (greater than or equal to 50% improvement in headache), which was the only predictor of functional outcome (total MIDAS, MIDAS-B, and BDI) (p = 0.021).  Of note, improvement in functional outcome was only significant during the peri-operative 3 to 6 months period and not throughout long-term follow-up.  Among the predictor variables, a strong inverse correlation was found between disability status and positive response to stimulation (r = -0.582).  The authors concluded that there is a paucity of studies in QOL, productivity, and psychosocial aspects with peripheral nerve stimulation therapy for headache.  Patients with a positive response to SONS and ONS also reported overall improvement in their functional status as reflected by MIDAS and BDI in the peri-operative period; however, this effect waned over the long-term follow-up.

Miller and associates (2016) stated that CM affects up to 2% of the general population and has a substantial impact on sufferers; ONS has been investigated as a potential treatment for refractory CM.  Results from RCTs and open label studies have been inconclusive with little long-term data available.  In an uncontrolled, open-label, prospective study, these investigators examined the safety, long-term effectiveness, and functional outcome of ONS in 53 patients with intractable CM.  Subjects were implanted in a single center between 2007 and 2013; they had a mean age of 47.75 years (range of 26 to 70), had suffered CM for around 12 years and had failed a mean of 9 (range of 4 to 19) preventative treatments prior to implant; 18 patients had other chronic headache phenotypes in addition to CM.  After a median follow-up of 42 months (range of 6 to 97) monthly moderate-to-severe headache days (i.e., days on which pain was more than 4 on the verbal rating score and lasted at least 4 hours) reduced by 8.51 days (p < 0.001) in the whole cohort, 5.80 days (p < 0.01) in those with CM alone and 12.16 days (p < 0.001) in those with multiple phenotypes including CM.  Response rate of the whole group (defined as a greater than 30% reduction in monthly moderate-to-severe headache days) was observed in 45.3% of the whole cohort, 34.3% of those with CM alone and 66.7% in those with multiple headache types.  Mean subjective patient estimate of improvement was 31.7%.  Significant reductions were also seen in outcome measures such as pain intensity (1.34 points, p < 0.001), all monthly headache days (5.66 days, p < 0.001) and pain duration (4.54 hours, p < 0.001).  Responders showed substantial reductions in headache-related disability, affect scores and QOL measures; AEs rates were favorable with no episodes of lead migration and only 1 minor infection reported.  The authors concluded that ONS may be a safe and effective treatment for highly intractable CM patients even after relatively prolonged follow-up of a median of over 3 years.  Moreover, these researchers stated that there are still concerns over the risk to benefit ratio and cost-effectiveness of ONS despite positive open-label data, and a well-designed, double-blind, controlled trial with long-term follow-up is needed to clarify the position of neuromodulation in CM.

Spheno-Palatine Ganglion Stimulation

Puledda and Goadsby (2016) stated that neuromodulation is a promising, novel approach for the treatment of primary headache disorders.  Neuromodulation offers a new dimension in the treatment that is both easily reversible and tends to be very well-tolerated.  The autonomic nervous system is a logical target given the neurobiology of common primary headache disorders, such as migraine and the trigeminal autonomic cephalalgias (TACs).  These investigators reviewed new encouraging results of studies from the most recent literature on neuromodulation as acute and preventive treatment in primary headache disorders, and discussed some possible underlying mechanisms.  These researchers focused on vagal nerve stimulation (VNS) and spheno-palatine ganglion stimulation (SPGS) since they have targeted autonomic pathways that are cranial and can modulate relevant pathophysiological mechanisms.  The initial data suggested that these approaches will find an important role in headache disorder management going forward.  The authors concluded that the armamentarium for the treatment of migraine and the TACs is rapidly expanding thanks to neuromodulation techniques.  The newer methods appear much better tolerated and offer important therapeutic benefits.  Equally attractive in many ways is that bench-based understanding is being applied to neuromodulation to yield bedside advances in treatment.  They stated that clinicians can look forward to the results of a number of ongoing studies and the real possibility to add these exciting methods to their practice.

Robbins et al (2016) noted that CH is an extremely debilitating primary headache disorder that is often not optimally treated.  New evidence-based treatment guidelines for CH will assist clinicians with identifying and choosing among current treatment options.  In a systematic review, these researchers examined the available evidence for the acute and prophylactic treatment of CH; and provided an update of the 2010 American Academy of Neurology (AAN) endorsed systematic review.  Medline, PubMed, and Embase databases were searched for double-blind, randomized controlled trials (RCTs) that examined treatments of CH in adults.  Exclusion and inclusion criteria were identical to those utilized in the 2010 AAN systematic review.  For acute treatment, sumatriptan subcutaneous, zolmitriptan nasal spray, and high flow oxygen remain the treatments with a Level A recommendation.  Since the 2010 review, a study of sphenopalatine ganglion stimulation was added to the current guideline and has been administered a Level B recommendation for acute treatment.  For prophylactic therapy, previously there were no treatments that were administered a Level A recommendation.  For the current guidelines, suboccipital steroid injections have emerged as the only treatment to receive a Level A recommendation with the addition of a 2nd Class I study.  Other newly evaluated treatments since the 2010 guidelines have been given a Level B recommendation (negative study: deep brain stimulation [DBS]), a Level C recommendation (positive study: warfarin; negative studies: cimetidine/chlorpheniramine, candesartan), or a Level U recommendation (frovatriptan).  The authors concluded that this AHS guideline can be used for understanding which therapies have superiority to placebo or sham treatment in the management of CH.  In clinical practice, these recommendations should be considered in concert with other variables including safety, side effects, patient preferences, clinician experience, cost, and the invasiveness of the intervention.  Given the lack of Class I evidence and Level A recommendations, particularly for a number of commonly used preventive therapies, further studies are warranted to demonstrate safety and efficacy for established and emerging therapies (including neurostimulation).

The authors noted that a study examining the use of a novel nVNS was recently published.  It compared adjunctive stimulation as a prophylactic treatment with medical SoC versus SoC alone in a sample of patients with cCH.  The study was not blinded; thus, was excluded from this systematic review.  However, during the randomized phase of the study there was a significant reduction of weekly attack frequency in those treated with VNS, with no serious adverse events (AEs) attributed to the device.  These investigators stated that future studies that are blinded with a sham control are needed to examine the safety and effectiveness of nVNS for treatment of CH.

In a recent review, Lainez and Guillamon (2017) summarized CH pathophysiology and the effectiveness of various neuromodulating techniques.  In patients with cCH, VNS with a portable device used in conjunction with SoC in CH patients resulted in a reduction in the number of attacks.  The authors concluded that new recent non-invasive approaches such as nVNS have shown effectiveness in a few trials and could be an interesting alternative in the management of CH, but require more testing and positive RCTs.

Miller and colleagues (2017) noted that there is growing interest in neuromodulation for primary headache conditions.  Invasive modalities such as ONS, deep brain stimulation (DBS) and SPGS are reserved for the most severe and intractable patients.  Non-invasive options such as VNS, SONS and TMS have all emerged as potentially useful headache treatments.  These researchers examined the evidence base for non-invasive neuromodulation in TACs and migraine.  Although a number of open-label series of non-invasive neuromodulation devices have been published, there is very little controlled evidence for their use in any headache condition.  Open-label evidence suggested that VNS may have a role in the prophylactic treatment of CH and there is limited evidence to suggest it may be useful in the acute treatment of cluster and potentially migraine attacks.  There is limited controlled evidence to suggest a role for SONS in the prophylactic treatment of episodic migraine, however, there is no evidence to support its use in CH; TMS may be effective in the acute treatment of episodic migraine; but there is no controlled evidence to support its use as a preventative in any headache condition.  The authors concluded that non-invasive neuromodulation techniques are an attractive treatment option with excellent safety profiles, however, their use is not yet supported by high-quality RCTs.

National Institute for Health and Care Excellence (NICE)’s interventional procedures guidance on "Transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine" (2016) stated that "Current evidence on the safety of transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine raises no major concerns.  The evidence on efficacy is limited in quantity and quality.  Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research … Clinicians wishing to do transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine should ensure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information … NICE encourages further research on transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine.  Studies should describe whether the procedure is used for treatment or prevention, and whether it is used for cluster headache or migraine.  Clinicians should clearly document details of patient selection and the treatment regimen.  Outcome measures should include changes in the number and severity of cluster headache or migraine episodes, medication use, quality of life in the short and long term, side effects, acceptability, and device durability".

Silberstein and colleagues (2017) noted that a panel of 9 experts, including neurologists, other headache specialists, and medical and pharmacy directors, from 4 health plans (1 integrated delivery network and 3 plans with commercial, Medicare, and Medicaid lines of business), convened to discuss CH.  Topics covered included the current treatment landscape, treatment challenges, economic impact of disease, and gaps in care for patients with CH.  One major challenge in the management of CH is that it is under-recognized and frequently misdiagnosed, leading to delays in and suboptimal treatment for patients who suffer from this painful and disabling condition.  The management of CH is challenging due to the lack of a robust evidence base for preventive treatment, the AEs associated with conventional preventive treatments, the variability of response to acute treatments, and the challenging reimbursement landscape for well-accepted treatments (e.g., oxygen).  The lack of effective prevention for many patients may lead to the excessive use of acute therapies, often multiple times each day, which drives the cost of illness up significantly.  The goal of the panel discussion was to discuss the role of gammaCore, the recently released first nVNS therapy in the acute treatment of patients with eCH, in the management of CH.  The panel reviewed current practices and formulated recommendations on incorporating a newly released therapy into CH management. The panel explored the role of traditional management strategies as well as that of gammaCore in the acute treatment of patients with eCH.  The panel agreed that the treatment guidelines should be updated to reflect the role of gammaCore as a first-line, acute therapeutic option for patients with eCH and that payers should offer coverage of gammaCore to their members who have a diagnosis of eCH.  Healthcare providers, including headache specialists and neurologists, and payers are encouraged to remain up-to-date regarding the results of ongoing clinical trials evaluating the use of gammaCore for the acute and/or preventive treatment of migraine to ensure that patients are being appropriately treated for these conditions and that they have access to treatment through their insurers.  Moreover, the panel noted that additional studies need to be conducted in the United States to verify the role of gammaCore in the preventive therapy of eCH and cCH.

Ho and co-workers (2017) noted that SPG is the largest collection of neurons in the calvarium outside of the brain.  Over the past century, it has been a target for interventional treatment of head and facial pain due to its ease of access.  Block, radiofrequency ablation (RFA), and neuro-stimulation have all been applied to treat a myriad of painful syndromes.  Despite the routine use of these interventions, the literature supporting their use has not been systematically summarized.  These investigators summarized the level of evidence supporting the use of SPG block, RFA and neuro-stimulation.  Medline, Google Scholar, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were reviewed for studies on SPG block, RFA and neuro-stimulation. Studies included in this review were compiled and analyzed for their treated medical conditions, study design, outcomes and procedural details.  Studies were graded using Oxford Center for Evidence-Based Medicine for level of evidence.  Based on the level of evidence, grades of recommendations are provided for each intervention and its associated medical conditions.  A total of 83 publications were included in this review, of which 60 were studies on SPG block, 15 were on RFA, and 8 were on neuro-stimulation.  Of all the studies, 23 had evidence level above case series.  Of the 23 studies, 19 were on SPG block, 1 study on RFA, and 3 studies on neuro-stimulation.  The rest of the available literature was case reports and case series.  The strongest evidence lied in using SPG block, RFA and neuro-stimulation for CH; SPG block also had evidence in treating trigeminal neuralgia, migraines, reducing the needs of analgesics after endoscopic sinus surgery and reducing pain associated with nasal packing removal after nasal operations.  The authors concluded that SPG is a promising target for treating CH using blocks, RFA and neuro-stimulation; SPG block also had some evidence supporting its use in a few other conditions.  Moreover, they stated that most of the controlled studies were small and without replications; further controlled studies are needed to replicate and expand on these previous findings.

Reuter et al (2019) noted that non-invasive neuromodulation therapies for migraine and CH are safe and practical alternative options to pharmacotherapies.  Comparisons of these therapies are difficult because of the heterogeneity in study designs.  In a systematic review of clinical trials, the scientific rigor and clinical relevance of the available data were examined to inform clinical decisions regarding non-invasive neuromodulation.  PubMed, Cochrane Library and ClinicalTrials.gov databases and the World health Organization (WHO)'s International Clinical Trials Registry Platform were searched for relevant clinical studies of non-invasive neuromodulation devices for migraine and CH January 1, 1990 to January 31, 2018), and 71 articles were identified.  This analysis compared study designs using recommendations of the International Headache Society (IHS) for pharmacological clinical trials, the only available guidelines for migraine and CH.  nVNS (3 studies with 350 subjects for CH – 2 for treatment, and 1 for prevention), single-transcranial magnetic stimulation and external trigeminal nerve stimulation (all with regulatory clearance) were well studied compared with the other devices, for which studies frequently lacked proper blinding, sham controls and sufficient population sizes.  nVNS studies demonstrated the most consistent adherence to available guidelines.  Studies of all neuromodulation devices should strive to achieve the same high level of scientific rigor to allow for proper comparison across devices.  Future trials should be rigorously designed to facilitate comparisons across devices.  Well-designed studies, such as those for nVNS that consistently adhere to stringent IHS recommendations for pharmacological trials, may help in the design of future clinical trials until neuromodulation-specific guidelines are established.  Device-specific guidelines for migraine and CH will be soon available; however, adherence to current guidelines for pharmacological trials will remain a key consideration for investigators and clinicians.

The authors stated that the scope of this systematic review was limited by the heterogeneity among the clinical trials analyzed and the unavailability of many of the study results, which precluded a formal systematic meta-analysis of all identified studies; 37 of the 41 studies that were registered with ClinicalTrials.gov or another registry but not published did not have results available, and some did not comprehensively report all study design components examined.  Studies evaluated in this review were heterogeneous in both study design and statistical power (i.e., patient population sample size), which affected the ability to interpret and compare the true effects.  Uniform use of pre-specified outcome measures and other study design components is essential for conducting meta-analyses and cost-benefit analyses to compare different treatment interventions.  It was not the scope of this review to compare the results of these clinical trials as they were heterogeneous.  The results of this review suggested several considerations for the ongoing development of clinical trial guidelines for non-invasive neuromodulation devices in primary headache.  First, in an acute setting, the IHS emphasis on the 1st attack may not be optimal for non-invasive neuromodulation devices.  These devices require patient training to ensure proper administration, which may not be complete at the 1st attack.  To allow for complete patient training with non-invasive neuromodulation devices, it may be advisable to assess the effectiveness of multiple attacks or after proper administration is demonstrated.  Second, the mechanisms of preventive neuromodulation (e.g., electrical or magnetic) treatments in primary headache are indirect, and effectiveness may be multi-dimensional when considering the different pathophysiologies of migraine and CH.  The full preventive potential of a neuromodulation regimen may be best captured with an observational time period equal to that of the IHS-recommended period for pharmacological therapies (i.e., a minimum of 12 weeks).  Third, reproducibility is needed to support the validity of effectiveness outcomes in all therapeutic trials.  Many neuromodulation devices have not yet been evaluated in multiple RCTs.  The field of neuromodulation would benefit if more devices were evaluated in more than 1 rigorous study to support effectiveness outcomes.  Finally, appropriate blinding is a particular challenge in non-invasive neuromodulation trials.  Ideally, the sham device should mimic the active device as closely as possible while avoiding any inadvertent nerve activity.  Sham devices with an active signal risk producing an active therapeutic effect, which could diminish the ability to achieve significant treatment differences.  The suggested modifications to clinical design elements recommended in this review could support scientific rigor and inform the development of recommendations for non-invasive neuromodulation studies in migraine and CH.

NICE’s guideline on "gammaCore for cluster headache" (2019) provided the following recommendations:

• Evidence supports the case for adopting gammaCore to treat cluster headache in the NHS. gammaCore reduces the frequency and intensity of cluster headache attacks and improves quality of life.
• gammaCore is not effective in everyone with cluster headache. Treatment with gammaCore should only continue for people whose symptoms reduce in the first 3 months.

Sanchez-Gomez and colleagues (2021) evaluated the safety and effectiveness of peripheral neurostimulation of the SPG in the treatment of refractory CCH.  Various medical databases were used to perform a systematic review of the scientific literature.  The search for articles continued until October 31, 2016, and included clinical trials, systematic reviews and/or meta-analyses, health technology assessment reports, and clinical practice guidelines that included measurements of efficiency/effectiveness or adverse effects associated with the treatment.  The review excluded cohort studies, case-control studies, case series, literature reviews, letters to the editor, opinion pieces, editorials, and studies that had been duplicated or outdated by later publications from the same institution.  Regarding effectiveness, these investigators found that SPG stimulation had positive results for pain relief, attack frequency, medication use, and patients' QOL.  In the results regarding safety, these researchers found a significant number of AEs in the first 30 days following the intervention.  Removal of the device was necessary in some patients.  Little follow-up data, and no long-term data, were available.  The authors concluded that these findings are promising, despite the limited evidence available.  They considered it essential for research to continue into the safety and efficacy of SPG stimulation for patients with refractory CCH.  In cases where this intervention may be indicated, treatment should be closely monitored.

Evers and Summ (2021) examined the current literature on neurostimulation methods in the treatment of cCH.  These neurostimulation methods include DBS, VNS, greater occipital nerve stimulation, sphenopalatine ganglion stimulation, transcranial magnetic stimulation, transcranial direct current stimulation, supraorbital nerve stimulation, and cervical spinal cord stimulation.  Altogether, only nVNS and SPG stimulation are supported by at least 1 positive sham-controlled clinical trial for preventive and acute attack (only SPG stimulation) treatment.  Other clinical trials either did not control at all or controlled by differences in the stimulation technique itself but not by a sham-control.  Case series reported higher responder rates.  The evidence for these neurostimulation methods in the treatment of cCH is poor and in part contradictive.  However, except DBS, tolerability and safety of these methods are good so that in refractory situations application might be justified in individual cases.

Coppola et al (2022) examined the literature on the use of central and peripheral neuromodulation techniques for chronic daily headache (CDH) treatment.  Although the more invasive DBS is effective in CCH, it should be reserved for extremely difficult-to-treat patients.  Percutaneous occipital nerve stimulation has shown similar efficacy to DBS and is less risky in both cCH and chronic migraine (CM).  nVNS is a promising add-on treatment for CCH but not for CM.  Transcutaneous external trigeminal nerve stimulation may be effective in treating CM; however, it has not yet been tested for CH.  Transcranial magnetic and electric stimulations have promising preventive effects against CM and cCH.  Although the precise mode of action of non-invasive neuromodulation techniques remains largely unknown and there is a paucity of controlled trials, they should be preferred to more invasive techniques for treating CDH.

Anti-Calcitonin Gene-Related Peptide (CGRP) Monoclonal Antibodies (e.g., Eptinezumab, Erenumab, Fremanezumab, and Galcanezumab)

In a randomized, double-blind, placebo-controlled, phase II clinical trial, Tepper and associates (2017) examined the safety and efficacy of erenumab, a fully human monoclonal antibody against the calcitonin gene-related peptide (CGRP) receptor, in patients with chronic migraine.  This was a multi-center study of erenumab for adults aged 18 to 65 years with chronic migraine, enrolled from 69 headache and clinical research centers in North America and Europe.  Chronic migraine was defined as 15 or more headache days per month, of which 8 or more were migraine days.  Patients were randomly assigned (3:2:2) to subcutaneous placebo, erenumab 70-mg, or erenumab 140-mg, given every 4 weeks for 12 weeks.  Randomization was centrally executed using an interactive voice or web response system.  Patients, study investigators, and study sponsor personnel were masked to treatment assignment.  The primary end-point was the change in monthly migraine days from baseline to the last 4 weeks of double-blind treatment (weeks 9 to 12).  Safety end-points were AEs, clinical laboratory values, vital signs, and anti-erenumab antibodies.  The efficacy analysis set included patients who received at least 1 dose of investigational product and completed at least 1 post-baseline monthly measurement.  The safety analysis set included patients who received at least 1 dose of investigational product.  From April 3, 2014, to December 4, 2015, a total of 667 patients were randomly assigned to receive placebo (n = 286), erenumab 70-mg (n = 191), or erenumab 140 mg (n = 190).  Erenumab 70-mg and 140-mg reduced monthly migraine days versus placebo (both doses -6·6 days versus placebo -4.2 days; difference -2.5, 95% CI: -3.5 to -1.4, p < 0.0001); AEs were reported in 110 (39%) of 282 patients, 83 (44%) of 190 patients, and 88 (47%) of 188 patients in the placebo, 70-mg, and 140-mg groups, respectively.  The most frequent AEs were injection-site pain, upper respiratory tract infection, and nausea.  Serious AEs were reported by 7 (2%), 6 (3%), and 2 (1%) patients, respectively; none were reported in more than 1 patient in any group or led to discontinuation.  A total of 11 patients in the 70-mg group and 3 in the 140-mg group had anti-erenumab binding antibodies; none had anti-erenumab neutralizing antibodies.  No clinically significant abnormalities in vital signs, laboratory results, or electrocardiogram findings were identified.  Of 667 patients randomly assigned to treatment, 637 completed treatment; 4 withdrew because of AEs, 2 each in the placebo and 140-mg groups.  The authors concluded that in patients with chronic migraine, erenumab 70-mg and 140-mg reduced the number of monthly migraine days with a safety profile similar to placebo, providing evidence that erenumab could be a potential therapy for migraine prevention.  Moreover, they stated that further research is needed to understand long-term safety and efficacy of erenumab, and the applicability of this study to real-world settings.

In an open-label study, Ashina and colleagues (2017) evaluated the long-term safety and efficacy of erenumab in patients with episodic migraine (EM).  Patients enrolled in a 12-week, double-blind, placebo-controlled clinical trial who continued in an open-label extension (OLE) study will receive erenumab 70-mg every 4 weeks for up to 5 years.  This pre-planned interim analysis, conducted after all participants had completed the 1-year open-label follow-up, evaluated changes in monthly migraine days (MMD), achievement of greater than or equal to 50%, greater than or equal to 75%, and 100% reductions.  Headache Impact Test-6 score, Migraine-Specific Quality of Life (MSQ), Migraine Disability Assessment (MIDAS), and safety.  Data reported as observed without imputation for missing data.  Of 472 patients enrolled in the parent study, 383 continued in the OLE with a median exposure to erenumab of 575 days (range of 28 to 822 days).  Mean (SD) MMD were 8.8 (2.6) at parent study baseline, 6.3 (4.2) at week 12 (beginning of OLE), and 3.7 (4.0) at week 64 (mean change from baseline [reduction] of 5.0 days).  At week 64, 65%, 42%, and 26% achieved greater than or equal to 50%, greater than or equal to 75%, and 100% reduction in MMD, respectively.  Mean HIT-6 scores were 60.2 (6.3) at baseline and 51.7 (9.2) at week 64.  MSQ and MIDAS improvements from baseline were maintained through week 64.  Safety profiles during the OLE were similar to those in the double-blind phase, which overall were similar to placebo.  The authors stated that a drawback of the study was the lack of a placebo group for efficacy and safety comparisons.  It was therefore difficult to interpret the possible relatedness of an AE without a placebo arm, and it is difficult to distinguish spontaneously occurring AEs from AEs due to erenumab.  However, the OLE study is ongoing and will continue to provide a long-term safety experience for erenumab.  Moreover, they noted that retention rates, efficacy, patient-reported outcomes, and safety results after 1 year for erenumab in patients with EM appeared promising; thus, these data support further investigation of erenumab as a potential preventive treatment option for patients with EM.

Goadsby and co-workers (2017) examined the effectiveness of erenumab for the prevention of EM.  These researchers randomly assigned patients to receive a subcutaneous injection of either erenumab, at a dose of 70-mg or 140-mg, or placebo monthly for 6 months.  The primary end-point was the change from baseline to months 4 through 6 in the mean number of migraine days per month.  Secondary end-points were a 50% or greater reduction in mean migraine days per month, change in the number of days of use of acute migraine-specific medication, and change in scores on the physical-impairment and everyday-activities domains of the Migraine Physical Function Impact Diary (scale transformed to 0 to 100, with higher scores representing greater migraine burden on functioning).  A total of 955 patients underwent randomization: 317 were assigned to the 70-mg erenumab group, 319 to the 140-mg erenumab group, and 319 to the placebo group.  The mean number of migraine days per month at baseline was 8.3 in the overall population; by months 4 through 6, the number of days was reduced by 3.2 in the 70-mg erenumab group and by 3.7 in the 140-mg erenumab group, as compared with 1.8 days in the placebo group (p < 0.001 for each dose versus placebo).  A 50% or greater reduction in the mean number of migraine days per month was achieved for 43.3% of patients in the 70-mg erenumab group and 50.0% of patients in the 140-mg erenumab group, as compared with 26.6% in the placebo group (p < 0.001 for each dose versus placebo), and the number of days of use of acute migraine-specific medication was reduced by 1.1 days in the 70-mg erenumab group and by 1.6 days in the 140-mg erenumab group, as compared with 0.2 days in the placebo group (p < 0.001 for each dose versus placebo).  Physical-impairment scores improved by 4.2 and 4.8 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 2.4 points in the placebo group (p < 0.001 for each dose versus placebo), and every day activities scores improved by 5.5 and 5.9 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 3.3 points in the placebo group (p <0.001 for each dose versus placebo). The rates of AEs were similar between erenumab and placebo.  The authors concluded that erenumab administered subcutaneously at a monthly dose of 70-mg or 140-mg significantly reduced migraine frequency, the effects of migraines on daily activities, and the use of acute migraine-specific medication over a period of 6 months.  Moreover, they stated that the long-term safety and durability of the effect of erenumab require further study.

Khan and colleagues (2019) stated that migraine and CH are challenging to manage, with no tailored preventive medications available.  Targeting the calcitonin gene-related peptide (CGRP) pathway to treat these headaches may be the first focused therapeutic option to-date, with the potential for promising efficacy.  These investigators systematically searched PubMed and clinicaltrials.gov for RCTs examining the preventive potential of monoclonal antibodies against the CGRP pathway in the treatment of migraine and CH.  The literature search returned a total of 136 records, of which 32 were eligible for review.  Clinical data from phase II and III clinical trials of the 4 monoclonal antibodies targeting the CGRP pathway: eptinezumab, erenumab, fremanezumab, and galcanezumab, collectively showed a positive effect in the preventive treatment of episodic and chronic migraine.  Multiple phase II and III clinical trials are under way to further determine the efficacy and safety of this new drug class.  It may be particularly important to evaluate the cardiovascular effects of long-term CGRP blockade.  In addition, phase III clinical trials are also currently in progress for the preventive treatment of CH.  The authors concluded that efficacy of anti-CGRP monoclonal antibodies suggested a promising future for the many patients suffering from migraine, and possibly also for the smaller but severely-affected population with CH.

Intravenous Valproic Acid for the Treatment of Intractable Migraine

Reiter and colleagues (2005) described the tolerability and effectiveness of rapid intravenous (IV) valproic acid (VPA) infusions in children with severe migraine headache.  These investigators conducted a retrospective chart review of all children who received intravenous VPA at The Children's Hospital Headache Clinic during an 18-month study period.  Baseline intensity of headache pain, time at which maximum relief was attained, pain reduction following therapy, dose and duration of VPA infusion(s), patient's pulse, blood pressure, respiratory rate, and pulse oximetry were collected; adverse events (AEs) were also recorded.  A total of 31 children (age = 15 +/- 2 years; 81% female) requiring 58 clinic visits and 71 VPA infusions were included.  Most visits (n = 45; 78%) resulted in only 1 dose of VPA (976 +/- 85 mg infused over 12 +/- 4 minutes) for desired pain relief.  Percent pain reduction in those children was 39.8%, with time to maximum relief of 63 +/- 31 minutes.  Some children required a second dose of 500 mg (n = 13 visits; 22%), that was infused over 14 +/- 6 minutes and produced a 57% reduction in pain intensity from baseline; VPA infusions were well-tolerated; AEs described included cold sensation (n = 1), dizziness (n = 3), nausea (n = 1), possible absence seizure (n = 1), paresthesia (n = 2), and tachycardia (n = 2).  The authors concluded that rapid infusion of IV VPA is generally well-tolerated and may play a role in the management of children with acute migraine headache.  Moreover, they stated that prospective, controlled trials to further investigate this treatment in children are needed.

Frazee and Foraker (2008) reviewed the literature regarding the use of IV valproic acid in aborting an acute migraine attack.  A Medline (1967 to June 2007) and bibliographic search of the English-language literature was conducted using the search terms valproic acid and migraine disorders.  All articles identified through the search were included.  Divalproex sodium is approved by the Food and Drug Administration (FDA) for the prevention of migraine headaches.  The use of IV valproic acid has been studied as a possible treatment for acute migraine.  Available studies are small, mostly open-label and non-placebo-controlled, and used variable doses.  Valproic acid has not been shown to be superior to comparator drugs and was inferior to prochlorperazine in 1 trial.  The authors concluded that IV valproic acid has not been proven effective for acute migraine treatment.  They stated that future trials should be larger, placebo-controlled, and use a standardized dose and outcome measures.

Avraham et al (2010) stated that acute confusional migraine (ACM) is a dramatic, rare manifestation of migraine described mostly for children and adolescents.  There are few data on the treatment of an ACM attack.  Prochlorperazine has been suggested as an effective drug.  The authors of some reports have suggested that valproic acid may play a role in the prevention of ACM and as treatment for acute migraine headache in the adult population.  However, this medication has not been reported as first-line, acute therapy for ACM.  The authors reported on the case of a 12-year old girl who presented with an ACM attack that resolved rapidly after IV administration of valproic acid.  (This was a single-case study on the treatment of acute migraine).

Ketamine Infusion Combined With Magnesium for the Treatment of Cluster Headache

Moisset and colleagues (2017) noted that CH is a rare, highly disabling primary headache condition.  As NMDA receptors are possibly overactive in CH, NMDA receptor antagonists, such as ketamine, could be of interest in patients with intractable CH.  These researchers reported the findings of 2 Caucasian men, aged 28 and 45 years, with chronic intractable CH, received a single ketamine infusion (0.5 mg/kg over 2 hours) combined with magnesium sulfate (3,000 mg over 30 minutes) in an out-patient setting.  This treatment led to a complete relief from symptoms (attack frequency and pain intensity) for 1 patient and partial relief (50%) for the second patient, for 6 weeks in both cases.  The authors concluded that the NMDA receptor is a potential target for the treatment of chronic CH; randomized, placebo-controlled studies are needed to establish both safety and efficacy of this approach.

Ketamine Intra-Nasal Administration / Intravenous Infusion for the Treatment of Migraines

In a systematic review and meta-analysis, Orhurhu et al (2019) synthesized evidence from RCTs to evaluate the effectiveness of IV ketamine infusions for pain relief in chronic conditions and examined if any pain classifications or treatment regimens are associated with greater benefit.  These investigators searched Medline, Embase, and Google Scholar, as well as the clinicaltrials.gov website from inception through December 16, 2017 for RCTs comparing IV ketamine to placebo infusions for chronic pain that reported outcomes for greater than or equal to 48 hours after the intervention.  A total of 3 reviewers independently screened the studies, pooled the data, and appraised risk of bias.  Random-effects model was used to calculate weighted mean differences (WMDs) for pain scores and secondary outcomes.  The primary outcome was the lowest recorded pain score at greater than or equal to 48 hours after cessation of treatment.  Secondary outcomes included responder rate and adverse effects.  Among 696 studies assessed for eligibility, 7 met inclusion criteria.  All studies except 1 were at high risk of bias.  These studies randomly assigned 211 patients with neuropathic (n = 2), mixed (n = 2), and non-neuropathic (nociplastic or nociceptive) (n = 3) pain; 3 studies reported significant analgesic benefit favoring ketamine, with the meta-analysis revealing a small effect up to 2 weeks after the infusion (p < 0.0001).  In the 3 studies that reported responder rates, the proportion with a positive outcome was greater in the ketamine than in the placebo group (p = 0.029; I = 0.0%).  No differences were noted based on pain classification or condition.  Compared to low-dose ketamine studies and investigations that evaluated non-CRPS conditions, a small but non-significant greater reduction in pain scores was found among studies that either employed high-dose ketamine therapy (p = 0.213) or enrolled CRPS patients (p = 0.079).  The authors concluded that evidence suggested that IV ketamine provided significant short-term analgesic benefit in patients with refractory chronic pain, with some evidence of a dose-response relationship.  Moreover, these researchers stated that larger, multi-center studies with longer follow-ups are needed to better select patients and determine the optimal therapeutic protocol.  Based on the quality of the evidence from studies in this review and the strength of effect, it is recommended that IV ketamine be used, on a case-by-case basis, as a primary analgesic in patients with chronic pain refractory to more conventional treatments (GRADE: Weak recommendation; low evidence)

The authors stated that this review had several drawbacks including the small number of patients enrolled in trials (median sample size of 24 subjects), which may be attributed to the lack of industry funding for a generic medication, and the lack of standardization for infusion regimens, patient selection, and follow-up periods.  In general, studies for medications that receive FDA approval go through a well-defined process that includes determining the optimal dose via phase-I and -II clinical trials, followed by large-scale randomized trials with stringent selection criteria that typically evaluate participants for 12 weeks.  In contrast, the studies in this review treated small number of patients with refractory pain using myriad dose regimens, and often failed to include secondary outcomes or evaluate intermediate-term effects.  Clinical heterogeneity in the studies included in this review was a significant challenge they attempted to examine but were unable to identify causes.  Furthermore, the difference in effect size required to detect a statistically significant improvement in pain score may not fully reflect the true clinical effect.  For example, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines note, "… in evaluating a new analgesic, if a 2-point decrease on a 0 to 10 numerical rating scale of pain intensity is considered a clinically important improvement for an individual, it should not be inferred that a 2-point difference in pain reduction between the analgesic and placebo must occur before the treatment benefit can be considered clinically important".  Due to the subjectivity of reported pain scores among patients, wide variations in response, and high placebo response rates, the clinical relevance of the differences in effect size is hard to determine.  Finally, chronic pain management includes not only the reduction of pain but also improved QOL, which should be measured via validated instruments.  Unfortunately, their analysis could not account for these outcomes due to limited availability of outcome data.

Thompson et al (2019) conducted a meta-analysis of controlled trials that used experimental models of acute pain and hyperalgesia to examine the analgesic effects of NMDA receptor (NMDAR) antagonists.  A total of 6 major databases were systematically searched (to March 2018) for studies using human evoked pain models to compare NMDAR antagonists with no-intervention controls.  Pain outcome data were analyzed with random-effects meta-analysis.  Searches identified 70 eligible trials (n = 1,069).  Meta-analysis found that low-dose ketamine (less than 1 mg/kg) produced a decrease in hyperalgesic area (standardized mean difference [SMD] 0.54, 95% CI: 0.34 to 0.74, p < 0.001) and a 1.2-point decrease (95% CI: 0.88 to 1.44, p < 0.001) in pain ratings from 4.6 to 3.4 on a 0-10 scale (a 26% reduction).  Similar analgesia was observed for acute and hyperalgesic models and was constant across the dosing range (0.03 to 1.00 mg/kg).  Moderate-to-high variability in effect size was observed and mild side effects (e.g., sedation, sensory disturbance) were common.  No effects of dextromethorphan were found.  Findings provided robust evidence for analgesic and anti-hyperalgesic effects of ketamine, supporting its use for acute and chronic pain management.  However, pain relief was modest, suggesting ketamine may potentially be most useful when opioids are contraindicated, rapid analgesia is required, or for pain resistant to conventional medication.

Pribish et al (2020) stated that "Ketamine, a non-selective NMDA receptor antagonist, is used widely in medicine as an anesthetic agent.  However, ketamine's mechanisms of action lead to widespread physiological effects, some of which are now coming to the forefront of research for the treatment of diverse medical disorders.  This paper aims at reviewing recent data on key non-anesthetic uses of ketamine in the current literature.  MEDLINE, CINAHL, and Google Scholar databases were queried to find articles related to ketamine in the treatment of depression, pain syndromes including acute pain, chronic pain, and headache, neurologic applications including neuroprotection and seizures, and alcohol and substance use disorders.  It can be concluded that ketamine has a potential role in the treatment of all of these conditions.  However, research in this area is still in its early stages, and larger studies are required to evaluate ketamine's efficacy for non-anesthetic purposes in the general population".

Turner et al (2020) noted that ketamine has recently emerged as a promising therapeutic alternative for abortive migraine therapy, likely secondary to N-methyl-d-aspartate antagonism.  Most reports examined adults and the IV route; few used intra-nasal administration or pediatric populations.  Given the limited evidence for intra-nasal ketamine in pediatric migraine populations, these researchers retrospectively reviewed their experience to further characterize safety and effectiveness of intra-nasal ketamine in this population.  They examined the use of intra-nasal ketamine at 0.1 to 0.2 mg/kg/dose up to 5 doses in pediatric migraineurs.  Pain scores (scale = 0 to 10) were recorded at baseline and after each dose.  Response was characterized as pain score reduction to 0 to -3 and/or reduction of at least 50%.  A total of 25 encounters (25 of 34; 73.5%) were responders (mean pain score reduction of -7.2 from admission to treatment completion).  Overall pain reduction from admission to discharge in the entire study population was 66.1%; side effects were mild and transient.  The authors concluded that their experience with intra-nasal ketamine has promising outcomes in both pain relief and side effect minimization.

The authors stated the retrospective design of this study was its main drawback.  Moreover, these researchers stated that future studies to examine most effective regimen as well as sequence within current guideline recommendations are needed.  Head-to-head comparison with current standards of care, such as triptans and DHE, would further delineate intra-nasal ketamine’s true place within the abortive migraine treatment pathway.  For instance, a randomized, prospective head-to-head comparison of DHE and intra-nasal ketamine in patients presenting to an ED for abortive migraine therapy would be especially useful.  Alternative designs could include patients presenting to an ED for abortive migraine therapy; those with a contraindication to DHE would be assigned to intra-nasal ketamine while the remainder would receive IV DHE as usual.  Efficacy could then be more accurately compared in both designs.  Additional studies of merit include examining long-term effects such as depression scores, psychological side effects, tolerance, instances of rebound migraines, and propensity toward patterns of abuse given ketamine’s social stigma.

Chah et al (2021) stated that migraine headaches are the 2nd leading cause of disability worldwide and are responsible for significant morbidity, reduction in the QOL, and loss of productivity on a global scale.  In a systematic review and meta-analysis, these researchers examined the effectiveness of ketamine on migraines and other primary headache disorders compared to placebo and other active interventions, such as midazolam, metoclopramide/diphenhydramine, and prochlorperazine/diphenhydramine.  They carried out an electronic search of databases published up to February 2021, including Medline via PubMed, Embase, Web of Science, and Cochrane Library, a hand search of the bibliographies of the included studies, as well as literature and systematic reviews found through the search to identify RCTs examining ketamine in the treatment of migraine/headache disorders compared to the placebo.  These investigators evaluated the risk of bias according to the Cochrane Handbook guidelines.  The initial search strategy yielded 398 unduplicated references, which were independently assessed by 3 review authors.  After evaluation, this number was reduced to 5 RCTs (2 unclear risk of bias and 3 high risk of bias).  The total number of patients in all the studies was 193.  Due to the high risk of bias, small sample size, heterogeneity of the outcomes reported, and heterogeneity of the comparison groups, the quality of the evidence was very low.  One RCT reported that intra-nasal ketamine was superior to intra-nasal midazolam in improving the aura attack severity, but not duration, while another reported that intra-nasal ketamine was not superior to metoclopramide and diphenhydramine in reducing the headache severity.  In one trial, subcutaneous ketamine was superior to saline in migraine severity reduction; however, IV ketamine was inferior to IV prochlorperazine and diphenhydramine in another study.  The authors concluded that further double-blind controlled studies are needed to examine the effectiveness of ketamine in treating acute and chronic refractory migraines and other primary headaches using intra-nasal and subcutaneous routes.  These studies should include a long-term follow-up and different ketamine dosages in diagnosed patients following international standards for diagnosing headache/migraine.

These researchers stated that the drawbacks of this study included the small number of included studies.  The method of delivery varied throughout the studies, which made the dose comparison difficult.  Furthermore, in many of the control groups, the route of the delivery (such as with IV saline) and the additional medications could potentially have a confounding effect in the comparison of ketamine with control therapies.

Mojica et al (2021) discussed the available evidence and therapeutic considerations for IV drug therapy for refractory chronic migraine (rCM).  The use of aggressive inpatient infusion therapy consisting of IV lidocaine or ketamine, along with other adjunctive medications, has become increasingly common for these patients when all other treatments have failed.  There is a clear need for prospective studies in this population comprised of patients who have largely been excluded from other studies.  These researchers noted that most, if not all, patients with rCM have experienced failure with the Raskin protocol when used without the co-administration of multiple other infusions.  Therefore, a modified, multi-day, aggressive inpatient infusion approach has become increasingly common for rCM and incorporates a variety of other medications, including co-administration with continuous lidocaine or ketamine infusions in a closely monitored setting to mitigate serious AEs.  These investigators stated that a widely accepted standardized set of criteria for rCM diagnosis is needed to further examine the unique demographics, pathophysiological mechanisms, risk factors, and prognostic factors for rCM.  This will facilitate the future research that is needed to identify more effective, safe, and tailored therapeutic approaches to better complement a holistic, multi-disciplinary plan of care.  In addition, these investigators stated that a variety of concerns regarding potentially harmful effects of ketamine arose from data in patients chronically abusing the drug.  Studies have identified long-term effects, including focal decrease in brain connectivity, focal decrease in cortical volumes, impairment within certain cognitive domains, and white matter changes.  However, there are several confounding variables in these studies, and it is not possible to establish causality or implications of the findings from this relatively weak evidence.  These researchers stated that large, controlled longitudinal studies are needed to further examine the long-term effects of ketamine.

In a prospective, observational pilot study (n = 6 patients), Schwenk et al (2021) compared the effects of lidocaine and (R,S)-ketamine infusions and performed metabolite analyses of (R,S)-ketamine to determine its metabolic profile patients with refractory chronic migraine.  One of (R,S)-ketamine's metabolites, (2R,6R)-hydroxynorketamine, has been shown in animal studies to reduce pain, but human studies in patients undergoing continuous (R,S)-ketamine infusions for migraine are lacking.  All 6 patients tolerated both infusions well with mild adverse effects.  The baseline mean pain rating (0 to 10 NRS) decreased from 7.5 ± 2.2 to 4.7 ± 2.8 by end of lidocaine treatment (p ≤ 0.05); but increased to 7.0 ± 1.4 by the post-discharge visit at 4 weeks (p > 0.05 versus baseline).  The baseline mean pain rating before ketamine treatment was 7.4 ± 1.4, which decreased to 3.7 ± 2.3 by the end of the hospitalization (p ≤ 0.05); but increased to 7.2 ± 1.7 by the post-discharge visit at 6 weeks (p > 0.05 versus baseline).  For the primary outcome the change in pain from baseline to end of treatment was greater for ketamine than lidocaine (-3.7 versus -2.8; p ≤ 0.05); but this has minimal clinical significance.  The authors stated that patients with refractory chronic migraine have continuous pain and substantial disability.  These investigators have shown that both lidocaine and (R,S)-ketamine infusions hold potential to reduce short-term pain and "break the cycle" of constant symptoms, with a more pronounced reduction in pain score with (R,S)-ketamine treatment.  In this pilot study, no statistically significant correlation was found between pain scores and circulating levels of (R,S)-ketamine or its metabolites.  Circulating concentrations of (2R,6R)-HNK, however, were at their highest between days 3 and 5, the period of time when pain was at its lowest, suggesting the possibility that this molecule could hold promise as an analgesic that lacks (R,S)-ketamine’s psychomimetic adverse effects, although this should be interpreted with caution given the small sample size.  These results suggested that future studies should be performed to further investigate this.

The authors stated that this study had several drawbacks.  In addition to the small sample size, retrospectively collected pain ratings from the lidocaine hospitalizations were not always assessed at consistent intervals and could be subject to influence based on the time of day and medications given just before assessment.  Follow-up pain ratings were in some cases obtained via telephone call several months following treatment and could be subject to recall bias.  These findings may not be generalizable to other practices where lower (R,S)-ketamine or lidocaine doses were used, or different adjunctive medications were used.  These findings also may not apply to less refractory patients.  Finally, this was an open-label study, and these researchers were unable to control for the additional medications that patients were given during admission, such as dihydroergotamine and ketorolac.  It was unknown how these or other medications might have influenced pain.  These researchers stated that future studies including pre-treatment and post-treatment metabolic phenotyping for CYP2B6 and CYP2A6 activity and urinary excretion are needed to aid in examining if those enzymes play a role in the pharmacological mechanisms responsible for the observed effects.

Ray et al (2022) noted that the use of lidocaine (lignocaine) and ketamine infusion in the inpatient treatment of patients with headache disorders is supported by small case series.  In a retrospective, cohort study, these researchers examined the effectiveness, duration and safety of lidocaine and ketamine infusions.  Patients admitted between January 1, 2018 and July 31, 2021 were identified by ICD code and electronic prescription.  Effectiveness of infusion was determined by reduction in VAS, and patient demographics were collected from review of the hospital electronic medical record.  Through the study period, a total of 83 infusions (50 lidocaine, 33 ketamine) were initiated for a headache disorder (77 migraine, 3 NDPH, 2 SUNCT, 1 cluster headache).  In migraine, lidocaine infusion achieved a greater than or equal to 50% reduction in pain in 51.1% over a mean of 6.2 days (SD 2.4).  Ketamine infusion was associated with a greater than or equal to 50% reduction in pain in 34.4% over a mean of 5.1 days (SD 1.5).  Side effects were observed in 32% and 42.4%, respectively.  Infusion for MOH resulted in successful withdrawal of analgesia in 61.1% of lidocaine, and 41.7% of ketamine infusions.  The authors concluded that lidocaine and ketamine infusions were an effective inpatient treatment for headache disorders; however, these approaches were associated with prolonged LOS and possible side-effects.  Moreover, these researchers stated that further prospective study is needed to confirm these findings.  These investigators noted that overall adverse effects of both infusions in this cohort was high; and further prospective, controlled studies are needed to guide treatment decisions in the inpatient treatment of migraine and headache disorders.

The main drawback of this study was its retrospective design.  Data such as the presence of complications of migraine such as status migrainosus or MOH relied upon the accuracy of documentation at the time, and as such were most liable to under-reporting in this study.  Data detailing all trialed alternate therapies, timing of treatment failure, and duration of symptoms before commencement of infusion was not available.  Similarly, data following discharge was also unavailable, and as such duration of effect, MOH withdrawal or pain freedom was unknown.  Finally, the choice of IV infusion for individual patient was made by the treating neurologist at the time; thus, was subject to patient factors, as well as individual prescribing habits and biases.

Transcutaneous Supraorbital Neurostimulation for the Treatment of Migraines

Piquet et al (2011) stated that transcutaneous neurostimulation (TNS) at extra-cephalic sites is a well-known treatment of pain.  Thanks to recent technical progress, the Cefaly device now also allows supraorbital TNS.  During observational clinical studies, several patients reported decreased vigilance or even sleepiness during a session of supraorbital TNS.  These researchers examined in more detail the potential sedative effect of supraorbital TNS, using standardized psychophysical tests in healthy volunteers.  They performed a double-blind, cross-over, sham-controlled study on 30 healthy subjects.  Subjects underwent a series of 4 vigilance tests (Psychomotor Vigilance Task, Critical Flicker Fusion Frequency, Fatigue Visual Numeric Scale, d2 test).  Each subject was tested under 4 different experimental conditions: without the neurostimulation device, with sham supraorbital TNS, with low frequency supraorbital TNS and with high frequency supraorbital TNS.  As judged by the results of 3 tests (Psychomotor Vigilance Task, Critical Flicker Fusion Frequency, Fatigue Visual Numeric Scale) there was a statistically significant (p < 0.001) decrease in vigilance and attention during high frequency TNS, while there were no changes during the other experimental conditions.  Similarly, performance on the d2 test was impaired during high frequency TNS, but this change was not statistically significant.  The authors concluded that supraorbital high frequency TNS applied with the Cefaly device decreased vigilance in healthy volunteers.  They stated that additional studies are needed to determine the duration of this effect, the underlying mechanisms and the possible relation with the stimulation parameters.  Meanwhile, this effect opened interesting perspectives for the treatment of hyperarousal states and, possibly, insomnia.  This study did not address the use of Cefaly for the treatment of migraines.

Russo and Tessitore (2015) noted that transcutaneous supraorbital neurostimulation (tSNS) has been recently found superior to sham stimulation for episodic migraine prevention in a randomized trial.  These researchers evaluated both the safety and efficacy of a brief period of tSNS in a group of patients with migraine without aura (MwoA).  They enrolled 24 consecutive patients with MwoA experiencing a low frequency of attacks, which had never taken migraine preventive drugs in the course of their life.  Patients performed a high frequency tSNS and were considered "compliant" if they used the tSNS for greater than or equal to 2/3 of the total time expected.  For this reason, 4 patients were excluded from the final statistical analysis.  Primary outcome measures were the reduction migraine attacks and migraine days per month (p < 0.05).  Furthermore, these investigators evaluated the percentage of patients having at least 50% reduction of monthly migraine attacks and migraine days.  Secondary outcome measures were the reduction of headache severity during migraine attacks and HIT-6 rating as well as in monthly intake of rescue medication (p < 0.05).  Finally, compliance and satisfaction to treatment and potential adverse effects related to tSNS have been evaluated.  Between run-in and second month of tSNS treatment, both primary and secondary end-points were met.  Indeed, these researchers observed a statistically significant decrease in the frequency of migraine attacks (p < 0.001) and migraine days (p < 0.001) per month.  They also demonstrated at least 50% reduction of monthly migraine attacks and migraine days in respectively 81% and 75% of patients.  Furthermore, a statistically significant reduction in average of pain intensity during migraine attacks (p = 0.002) and HIT-6 rating (p < 0.001) and intake of rescue medication (p < 0.001) has been shown.  All patients showed good compliance levels and no relevant AEs.  The authors concluded that in patients experiencing a low frequency of attacks, significant improvements in multiple migraine severity parameters were observed following a brief period of high frequency tSNS.  Thus, tSNS may be considered a valid option for the preventive treatment of migraine attacks in patients who cannot or are not willing to take daily medications, or in whom low migraine frequency and/or intensity would not require pharmacological preventive therapies.

The authors stated that this study had several drawbacks.  First, these researchers did not use a tSNS sham device and, therefore, they could not rule-out the possible role of a placebo-effect on primary and secondary outcomes in this study.  In particular, several factors may contribute to the remedial efficacy of tSNS in these patients such as alternative form of medical therapy, patients naïve to preventive treatment and observation period limited to no more than 2 months.  However, the placebo-effect appeared to have a lower impact in the prophylactic treatment than in the acute treatment of migraine attacks.  This could be due to the inherent variability in response measured over a period of months compared with one measured over a period of hours.  Moreover, the effective tSNS superiority respect to sham stimulation for the prevention of migraine headaches has been extensively demonstrated in a previous RCT in a large cohort of patients with migraine.  Nevertheless, in partial disagreement with these findings, Schoenen and colleagues (2013) did not show statistically significant effect on migraine attacks at 2 months, although ameliorating effect on migraine severity vanished in sham treated patients and amplified in effectively treated patients at this time of the study.  These investigators suggested that a greater migraine severity (i.e., frequency of migraine per month and disease duration) and, probably, previous pharmacological anti-migraine preventive therapies may cause a different impact on pain pathways in the 2 migraine populations and consequent different response to the tSNS treatment.  Second, the lack of blinding may weaken the results of the present study.  However, empirical evidence showed that although double-blind RCTs are the gold standard for proving efficacy of a therapeutic procedure, they often suffer from lack of generalizability.  Therefore, the authors believed that these data, in addition to the previous effectiveness and safety results of double-blind RCTs (Schoenen and colleagues, 2013) could provide additional information which may be useful in everyday clinical practice.  Finally, although these findings were consistent with previous studies, the sample size was relatively small (n = 20 available for final analysis).  Thys, they stated that further studies are needed to corroborate these findings and to explore tSNS efficacy and tolerability in patients with migraine compared with preventive treatments used in clinical practice.

The authors stated that this study had several drawbacks.  Because of the small number of evaluable patients (n = 14), the results must be taken with caution.  As discussed, the study design did not allow assessing a direct causal effect of eTNS on brain metabolism since a sham condition is missing.  These investigators found sham stimulation for 3 months would be unethical knowing that there is evidence for eTNS efficacy from an RCT.  The compliance rate with eTNS therapy was rather low.  For preventive drug treatments, adherence varies from 48% to 94% between studies.  Neurostimulation was more time consuming (20 mins daily in this study), which provoked lower compliance.  In the PREMICE trial, patients had a compliance rate of 62%, while participants renting the eTNS Cefaly device via the internet used it on average 58% of the recommended time.  In this study, the authors considered patients who performed at least 30% of the sessions as "compliant"; this threshold was chosen on an empirical basis and experience from clinical practice showing that patients may benefit from eTNS with non-daily use of the device.  However, the minimal time of use to obtain a clinical improvement in migraine is unknown, and may vary between patients.  Although the headache diaries allowed monitoring global intake of acute medications for each patient, they did not allow these researchers to determine the precise proportion of drugs taken within each of the pharmacological classes, analgesics, NSAIDs, triptans, nor its possible change after eTNS. I t is unlikely, however, that such a change would have influenced brain metabolism.

Russo et al (2017) examined the functional re-organization of the pain processing network during trigeminal heat stimulation (THS) after 60 days of eTNS in migraine without aura (MwoA) patients between attacks.  Using whole-brain BOLD-fMRI, functional response to THS at 2 different intensities (41 and 51°C) was investigated interictally in 16 adults MwoA patients before and after eTNS with the Cefaly device.  These researchers calculated the percentage of patients having at least a 50% reduction of monthly migraine attacks and migraine days between baseline and the last month of eTNS.  Secondary analyses evaluated associations between BOLD signal changes and clinical features of migraine.  Before eTNS treatment, there was no difference in BOLD response between MwoA patients and healthy controls (HC) during low-innocuous THS at 41°C, whereas the perigenual part of the right anterior cingulate cortex (ACC) revealed a greater BOLD response to noxious THS at 51°C in MwoA patients when compared to HC.  The same area demonstrated a significant reduced BOLD response induced by the noxious THS in MwoA patients after eTNS (p = 0.008).  Correlation analyses showed a significant positive correlation between ACC BOLD response to noxious THS before eTNS treatment and the decrease of ACC BOLD response to noxious THS after eTNS.  Moreover, a significant negative correlation in the migraine group after eTNS treatment between ACC functional activity changes and both the perceived pain ratings during noxious THS and pre-treatment migraine attack frequency has been found.  The authors concluded that the findings of this study suggested that eTNS treatment with the Cefaly® device induced a functional anti-nociceptive modulation in the ACC that is involved in the mechanisms underlying its preventive anti-migraine efficacy.  Nevertheless, these researchers stated that further observations to confirm whether the observed fMRI effects of eTNS are both related to clinical improvement and specific to anti-nociceptive modulation in migraine patients are mandatory.

The authors noted that this study had several drawbacks.  First, these investigators did not use an eTNS sham device and, therefore, they could not rule out the possible role of a placebo effect in imaging and clinical data.  However, the superiority of effective eTNS respect to sham stimulation for the prevention of migraine headaches has already been demonstrated in a randomized, sham-controlled trial.  Second, the HC did not undergo eTNS treatment, thus, the authors could not determine if the eTNS-induced changes in ACC activation by THS were specific to migraineurs.  By corollary, these researchers could not exclude that these changes could be due to the clinical improvement of patients after eTNS, rather than to the neurostimulation treatment itself.

Intramuscular Injection of Toradol (Ketorolac Tromethamine) for the Treatment of Migraines

In a prospective, randomized, double-blind trial, Duarte et al (1992) compared the effectiveness of IM ketorolac with that of meperidine and hydroxyzine in the treatment of acute migraine headache.  A total of 47 adult patients with migraines enrolled on 50 visits.  Patients were randomly assigned to receive a single injection of either 60 mg ketorolac (group 1) or 100 mg meperidine and 50 mg hydroxyzine (group 2).  Pain assessment was made using both visual-analog scale (VAS) and verbal descriptor scale.  At 60 mins, 15 patients (60%) from group 1 (n = 25) and 14 patients (56%) from group 2 (n = 25) reported a great deal of complete relief (p = 0.77; 60-min mean pain relief scores (3.35 versus 3.37) were [not] different (p = 0.76); 9 patients (36%) from group 1 and 7 patients (28%) from group 2 required additional analgesia (p = 0.76).  The authors concluded that ketorolac was as effective as meperidine and hydroxyzine for the treatment of acute migraine headache.

Turkewitz et al (1992) noted that 61 separate self-injections of ketorolac tromethamine (Toradol) by 16 patients diagnosed with episodic migraine with or without aura were evaluated over a 90-day period for safety, efficacy of pain reduction, and the ability of this therapy program to prevent the necessitation of ED acute care.  Prior to initiation of treatment, patients were formally instructed on IM injection techniques by a member of the nursing staff.  Patients were instructed to call upon the onset of a severe headache interfering with daily functioning and, then, were permitted to proceed with the injection.  Headache intensity ratings were collected prior to injection and intermittently for the following 24 hours.  The results demonstrated safety and efficacy of this form of therapy.  A significant percent of ketorolac usages (64%) resulted in a good response and significant reduction in head pain; 23% of ketorolac usages resulted in a mild response; and only 13% of usages provided no relief.  Furthermore, 13% of all usages failed to prevent the use for ED treatment.

In a prospective, randomized, double-blind trial, Shrestha et al (1996) compared IM ketorolac troinethamine with intravenous (IV) chlorpromazine hydrochloride in treating acute migraine.  These researchers examined the clinical effectiveness of 60 mg of IM ketorolac tromethamine with 25 mg of IV chlorpromazine hydrochloride in patients with acute migraine headache seen in the ED.  Pain intensity, quantitated using the Wong-Baker Faces Rating Scale, was measured every 30 mins for 2 hours in the ED.  Patients returned pain scores at 6, 12, 24, and 48 hours by mail.  A total of 15 patients were entered into each treatment arm.  No differences were seen between the mean pain scores or the mean change in pain scores.  The ketorolac group mean (+/- SEM) pain score decreased from 4.07 +/- 0.18 to 0.73 +/- 0.3 in 2 hours.  The chlorpromazine group pain score decreased from 4.47 +/- 0.17 to 0.87 +/- 0.4; 2 of the 3 non-responders responded to the alternate group's treatment.  No side effects were seen.  The authors concluded that using 60 mg of IM ketorolac tromethamine was as effective as 25 mg of IV chlorpromazine hydrochloride in the treatment of acute migraine headache.  They noted that patients who did not respond to one of these medications may respond to the other.

A paper entitled "Evidence-Based Guidelines for Migraine Headache in the Primary Care Setting: Pharmacological Management of Acute Attacks" (Matchar et al, 2000) stated that "Ketorolac IM is an option that may be used in a physician-supervised setting, although conclusions regarding clinical efficacy cannot be made at this time (Grade C)".

According to the product labeling, ketorolac tromethamine is indicated for the short-term (≤5 days) management of moderately severe acute pain that requires analgesia at the opioid level, usually in a post-operative setting. Therapy should always be initiated with intravenous or intramuscular dosing of ketorolac tromethamine, and oral ketorolac tromethamine is to be used only as continuation treatment, if necessary. The labeling states that the total combined duration of use of ketorolac tromethamine injection and oral ketorolac tromethamine is not to exceed 5 days of use because of the potential of increasing the frequency and severity of adverse reactions associated with the recommended doses. The labeling states that patients should be switched to alternative analgesics as soon as possible, but ketorolac tromethamine therapy is not to exceed 5 days.

Manual Trigger Point Treatment for Cluster Headache and Migraines

Garcia-Leiva et al (2007) stated that tenderness and referred pain have been described in migraine and involved in its pathogenesis.  These researchers examined the prophylactic effectiveness of ropivacaine injections during a 12-week period.  A total of 52 patients agreed to participate in the study; trigger points (TrPs) were examined by manual palpation and injected weekly with 10-mg ropivacaine.  The frequencies of migraine attacks were recorded from 4 weeks before the beginning of injections until 4 weeks after the last one, and a Clinical Global Impression improvement scale was completed in the final visit.  All of the subjects had 1 or more TrPs, located in temporal and/or suboccipital areas in most of the cases.  In 9 (17.3%) patients the frequency of attacks was reduced greater than or equal to 50%, and in 19 (36.5%) cases the reduction was comprised between 11% and 49%.  A total of 31 (59.6%) patients reported to be much or very much improved after finishing the injection period.  In 11 cases rescue medication intake was reduced greater than or equal to 50% in comparison with baseline period, and the attacks of severe intensity decreased significantly; 8 (26.6%) out of 30 patients suffering chronic migraine reverted to episodic migraine.  Local pain in injection sites was reported by 14 patients, and 13 subjects (25.5%) experienced post-injection soreness.  The authors concluded that TrPs inactivation could be an effective palliative measure in the prophylactic management of severe refractory migraine.  The main drawbacks of this trial were its relatively small sample size (n = 52) and the lack of a control group.

Blumenfeld et al (2010) noted that many clinicians use peripheral nerve blocks (NBs) and TrPs injections (TPIs) for the treatment of headaches.  Little is known, however, regarding the patterns of use of these procedures among practitioners in the U.S.  These researchers obtained information on patterns of office-based use of peripheral NBs and TPIs by headache practitioners in the U.S.  Using an Internet-based questionnaire, the Interventional Procedures Special Interest Section of the American Headache Society (AHS) conducted a survey among practitioners who were members of AHS on patterns of use of NBs and TPIs for headache treatment.  Electronic invitations were sent to 1,230 AHS members and 161 provided usable data (13.1%).  Of the responders, 69% performed NBs and 75% performed TPIs.  The most common indications for the use of NBs were occipital neuralgia and CM, and the most common indications for the use of TPIs were chronic tension-type headache and CM.  The most common symptom prompting the clinician to perform these procedures was local tenderness at the intended injection site.  The most common local anesthetics used for these procedures were lidocaine and bupivacaine.  Dosing regimens, volumes of injection, and injection schedules varied greatly.  There was also a wide variation in the use of corticosteroids when performing the injections.  Both NBs and TPIs were generally well-tolerated.  The authors concluded that NBs and TPIs are commonly used by headache practitioners in the U.S. for the treatment of various headache disorders, although the patterns of their use varied greatly.  The main drawback of this study was the low response rate (13.1%) of the survey.  Moreover, of the responders, 75% performed TPIs; and the most common indications for the use of NBs were occipital neuralgia and CM.  It was unclear if CM was the most common indication for TPIs.

Szperka et al (2016) stated that peripheral NBs are often used to treat headaches in adults and children; however, available evidence and practice data from adult headache specialists have shown wide variability in diagnostic indications, sites injected, and medication(s) used.  These investigators described current practice patterns in the use of NBs and TPIs for pediatric headache disorders.  A survey was created in REDCap; it was emailed to the 82 members of the Pediatric and Adolescent Section of the AHS in June 2015.  The survey queried about current practice and use of NBs, as well as respondents' opinions regarding gaps in the evidence for use of NBs in this patient population.  A total of 41 complete, 5 incomplete, and 3 duplicate responses were submitted (response rate complete 50%).  About 78% of the respondents identified their primary specialty as Child Neurology, and 51% were certified in headache medicine; 26 (63%) respondents performed NBs themselves, and 7 (17%) referred patients to another provider for NBs.  Chronic migraine with status migrainosus was the most common indication for NBs (82%), although occipital neuralgia (79%), status migrainosus (73%), CM without flare (70%), post-traumatic headache (70%), and new daily persistent headache (67%) were also common indications.  The most commonly selected clinically meaningful response for status migrainosus was greater than or equal to 50% reduction in severity, while for CM this was a greater than or equal to 50% decrease in frequency at 4 weeks.  Respondents injected the following locations: 100% injected the greater occipital nerve (GON), 69% lesser occipital nerve, 50% supra-orbital, 46% TPIs, 42% auriculo-temporal, and 34% supra-trochlear.  All respondents used local anesthetic, while 12 (46%) also used corticosteroid (8 bupivacaine only, 4 each lidocaine + bupivacaine, lidocaine + corticosteroid, bupivacaine + corticosteroid, lidocaine + bupivacaine + corticosteroid, and 2 lidocaine only).  The authors concluded that despite limited evidence, NBs were commonly used by pediatric headache specialists.  There was considerable variability among clinicians as to injection site(s) and medication selection, indicating a substantial gap in the literature to guide practice, and supporting the need for additional placebo-controlled studies in this area. 

The authors stated that this study had several drawbacks.  The survey response rate was approximately 50%.  Because these researchers used a distribution list without names, they did not have any information on non-responders to the survey, and they did not know if any respondents were not members of the original distribution list.  Even if all pediatric headache specialists who performed NBs answered the survey, this still represented an estimated 1/3 of known pediatric headache specialists.  The survey was emailed only to the members of the AHS Pediatric and Adolescent Section; therefore, the results described use among headache specialists, but did not account for use among other specialists such as concussion specialists.

Falsiroli Maistrello and colleagues (2018) noted that various interventions has been proposed for symptomatology relief in primary headaches.  Among these, manual trigger points (TrPs) treatment gains popularity, however its effects have not been examined yet.  These researchers examined the effectiveness of manual TrP compared to minimal active or no active interventions in terms of frequency, intensity, and duration of attacks in adult people with primary headaches.  They searched Medline, Cochrane, Web Of Science, and PEDro databases up to November 2017 for RCTs.  Two independent reviewers appraised the risk-of-bias (RoB) and the GRADE to evaluate the overall quality of evidence.  A total of 7 RCTs that compared manual treatment versus minimal active intervention were included: 5 focused on tension-type headache (TTH) and 2 on migraine headache (MH); 3 out of 7 RCTs had high RoB.  Combined TTH and MH results showed statistically significant reduction for all outcomes after treatment compared to controls, but the level of evidence was very low.  Subgroup analysis showed a statistically significant reduction in attack frequency (number of attacks per month) after treatment in TTH (MD -3.50; 95% CI: -4.91 to -2.09; 4 RCTs) and in MH (MD -1.92; 95% CI: -3.03 to -0.80; 2 RCTs).  Pain intensity (0 to 100 scale) was reduced in TTH (MD -12.83; 95% CI: -19.49 to -6.17; 4 RCTs) and in MH (MD -13.60; 95% CI: -19.54 to -7.66; 2RCTs).  Duration of attacks (hours) was reduced in TTH (MD -0.51; 95% CI: -0.97 to -0.04; 2 RCTs) and in MH (MD -10.68; 95% CI: -14.41 to -6.95; 1 RCT).  The authors concluded that manual TrPs treatment of head and neck muscles may reduce frequency, intensity, and duration of attacks in TTH and MH, but the quality of evidence according to GRADE approach was very low for the presence of few studies, high RoB, and imprecision of results.  These researchers also noted that the included studies did not report any additional negative effects, while positive effects regarding reduction of medicine consumption were controversial.

The authors stated that this review had several drawbacks that need to be addressed.  Because these investigators did not attempt to identify unpublished RCTs and their inclusion criteria were limited to only 3 languages, a publication bias could have occurred.  The high variability of the delivered treatments prevented them from identifying the most effective technique among those proposed.  Even if epidemiological studies have determined that women are more likely to suffer from TTH and that female gender constitutes a risk factor for this disease, the higher prevalence of women in the TTH subgroup could make the results less applicable to the general population.

Laube et al (2020) noted that CDH is a group of headache syndromes including most commonly CM and chronic tension-type headache, which often overlap, are complicated by medication overuse and are disabling, costly, and variable responsive to Western pharmacotherapies.  There is growing research and awareness of integrative health approaches and therapies to address patients with chronic headache, yet limited examples of how to deliver this approach.  These investigators reviewed a commonly observed challenging case of a patient with overlapping CM and chronic tension-type headache complicated by medication overuse managed with an integrative East-West medicine intervention.  This included person-centered biopsychosocial history taking, traditional Chinese medicine informed acupuncture, TPIs, and contributing factors modifications.  The authors also presented a narrative review of the literature to demonstrate an evidence-informed rationale for incorporating non-pharmacologic approaches to effectively help reduce the symptom burden of this patient population.  Moreover, these investigators advocated for further research into the use of integrative, comprehensive, multi-disciplinary approaches in the routine, and compassionate care of CDH patients.

Melatonin for the Treatment of Cluster Headache and Migraines

In a systematic review, Leite Pacheco and colleagues (2018) evaluated the safety and effectiveness of melatonin for primary headache.  This systematic review followed the Cochrane Handbook for Systematic Reviews of Interventions recommendations and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement.  A total of 4 RCTs were included (351 subjects).  According to the GRADE approach the quality of evidence was very low.  The use of melatonin for migraine showed reduced the number of days with pain and the analgesic consumption when compared with placebo; no benefits on headache intensity, number of headache days and analgesics consumption when compared with amitriptyline; reduced the number of analgesic consumption, the attack frequency and the headache intensity when associated with propranolol plus nortriptyline versus placebo plus propranolol plus nortriptyline; and no difference for any of the interest outcomes when associated with propranolol plus nortriptyline vs sodium valproate plus propranolol plus nortriptyline.  The use of melatonin for cluster headache when compared with placebo showed a reduction in the daily number of analgesic consumption and no difference in the number of daily attacks; AEs were poorly reported by all of the studies.  The authors concluded that the findings of this review showed that so far there are few clinical trials, with poor methodological quality about melatonin for primary headaches.  The available evidence is insufficient to support the use of melatonin in clinical practice for this population.  These researchers stated that further research is needed to evaluate its effects (benefits and harms) for primary headaches patients.

Trigeminal Nerve Stimulation for Migraine

Magis et al (2017) noted that a recent sham-controlled trial showed that external trigeminal nerve stimulation (eTNS) is effective in episodic migraine (MO) prevention.  However, its mechanism of action remains unknown.  These researchers performed 18-fluorodeoxyglucose positron emission tomography (FDG-PET) to evaluate brain metabolic changes before and after eTNS in episodic migraineurs.  A total of 28 individuals were recruited: 14 with MO and 20 healthy volunteers (HVs).  HVs underwent a single FDG-PET, whereas patients were scanned at baseline, directly after a first prolonged session of eTNS (Cefaly) and after 3 months of treatment (uncontrolled study).  The frequency of migraine attacks significantly decreased in compliant patients (n = 10).  Baseline FDG-PET revealed a significant hypo-metabolism in fronto-temporal areas, especially in the orbito-frontal (OFC) and rostral anterior cingulate cortices (rACC) in MO patients.  This hypo-metabolism was reduced after 3 months of eTNS treatment.  The authors concluded that the findings of this study suggested that OFC and rACC are hypo-metabolic in MO patients at rest.  After a 3-month treatment with eTNS, this hypo-metabolism was reduced and the changes were associated with a significant decrease of migraine attack frequency.  It is known that neurostimulation can modulate OFC and rACC activity.  Like cluster and medication overuse headache, MO appeared to be associated with dysfunction of medial frontal cortex areas involved in affective and cognitive dimensions of pain control.  Because this study was under-powered and had no sham arm, these researchers were unable to formally attribute the metabolic changes to the non-invasive neurostimulation treatment.  Nonetheless, the observed effect was likely similar to that found with invasive neurostimulation of peri-cranial nerves, such as pONS.  These researchers stated that further trials are needed to confirm these findings.

An assessment by the Ludwig Boltzmann Institute for Health Technology Assessment on "External stimulation of the trigeminal nerve for the prevention and acute treatment of episodic and chronic migraine" (2018) concluded that "Given the small size of the highly selective sample of patients included in the evidence base (as compared to the large burden of disease that migraine creates), the conclusions about effectiveness and the positive safety profile appear to be inflated.  The target population of e-TNS are not only patients refractory to medication, but mainly drug responsive patients, which makes replacing the use of medication a main objective of e-TNS.  That is why larger controlled trials with best practice interventions (for prevention as well as acute treatment use of e-TNS) as comparators are necessary for potentially considering e-TNS to be part of the standard practice".

Blockade / Stimulation of the Sphenopalatine Ganglion and Its Branches for the Treatment of Cluster and Migraine Headaches

Rosso and colleagues (2019) stated that among cephalgias, CH is the rarest and the most disabling, explaining the appellation of "suicide headache".  Up to 20% of chronic CH are resistant to pharmacotherapies, in which case interventional procedures should be considered.  Many reports evaluated invasive approaches and a wide strand of research is dedicated to the SPG.  These investigators provided an overview on modern applications on the SPG, their outcomes, and their feasibility in terms of risks and benefits.  They reviewed the international literature systematically for procedures targeting the SPG and its branches for episodic CH (ECH) and CCH, including block, stimulation, radiofrequency, stereotactic radiosurgery, and vidian neurectomy.  A total of 17 articles met inclusion criteria.  Comparing the outcomes that have been analyzed, it was possible to notice how the most successful procedure for the treatment of refractory CCH and ECH was the SPG block, which reached 76. 5% and 87% of efficacy, respectively.  Radiofrequency had a wide range of outcomes, from 33% to 70.3% in CCH.  Stimulation of SPG only achieved up to 55% of outcomes in significant reduction in attack frequency in CCH and 71% in ECH.  Radiosurgery and vidian neurectomy on SPG have also been analyzed.  Generally, ECH patients showed better response to standard medical therapies; nevertheless, even this more manageable condition may sometimes benefit from interventional therapies mostly reserved for CCH.  First results appeared promising and considering the low frequency of side effects or complications, one should think of expanding the indications of the procedures also to those conditions.  The authors concluded that outcomes certainly suggested that further studies are needed to understand which method is the most effective and with less side effects.  These researchers stated that placebo-controlled studies would be pivotal, and tight collaboration between neurologists and otorhinolaryngologists should also be central in order to give correct indications, which allow clinicians to expect procedures on the SPG to be an effective and mostly safe method to control either refractory ECH or CCH.

Burkett and colleagues (2020) noted that the SPG is a known current and historical target for therapeutic intervention in headache disorders because of its role in cranial autonomics and vasodilation.  There remains an overall lack of well-established SPG treatment protocols, especially with the advent of newer commercial devices.  A 22 multiple-choice question survey was created to evaluate clinical practice patterns with SPG block and sent to members of the American Headache Society (AHS).  Questions focused on determining indications, preferred applicators, medications applied, perceived efficacy, tolerability, and reimbursement.  A total of 172 of 1,346 (12.8%) AHS members participated; 93 respondents (56.3%) had performed SPG blocks on 50 or fewer patients.  The SphenoCath (42.4%) and the Tx360 (41.8%) were the most common methods of application.  Ease of use was the top reason for provider preference in applicator type.  SPG blocks were mostly used as an as-needed 1-time procedure.  When a scheduled protocol was used, twice-weekly for 6 weeks was most common.  Chronic migraine was the most commonly treated headache disorder and rated the most likely to respond to SPG block.  Experienced clinicians found SPG more helpful as a stand-alone treatment and tended to report that acute relief was not predictive of enduring response.  The authors concluded that the variety of responses strongly suggested that clinicians would benefit from formalized protocols for SPG blocks.  More experienced clinicians may have developed individualized protocols that they felt were more effective.  The authors concluded that the lack of evidence-based protocols contribute to clinicians not performing SPG blocks more frequently.  Moreover, these researchers stated that it is important to determine where SPG block fits into the toolbox of the headache practitioner.  The findings of this survey suggested that according to headache specialists already performing SPG blocks, there is no clear consensus in the therapeutic strategy using SPG blocks as acute versus preventive therapy.  It is notable that the Tx360 applicator has had 4 studies examining its efficacy in chronic migraine and its efficacy in the emergency department setting for treatment of anterior or global headaches.  These studies may offer some possible protocols for treatment, dosing, and scheduling of blocks.  The Allevio and SphenoCath catheters have, thus far, not had any randomized trials examining their use as treatment delivery devices.  Because trials have only been performed on 1 of the 3 commercially available devices, it is also unclear what the basis for the initial protocol development for the Tx360 was and whether it truly represents the best possible protocol.  These investigators stated that prospective, comparative studies as well as systematic assessments of delivery devices, medications used, frequency of use, and efficacy may better refine the indications of SPG blockade as a therapy for headache disorders.

The authors stated that this study had several drawbacks.  First, the way the survey was written allowed those who were infrequent users of SPG blocks to continue answering questions despite limited use.  After the survey was closed, 32 participants were removed from the analyses because of concerns that they represented non-users.  Second, because this was a voluntary survey of clinical practice, these investigators were limited by both the recall bias of the respondents and selection bias as the clinicians who filled out the survey may not represent the larger population using the SPG blocks; i.e., clinicians with either high satisfaction or high dissatisfaction with the procedure may have been more motivated to participate in this survey.  However, these researchers’ stratification by frequency of use may help to alleviate this limitation some because they were able to analyze the opinions of the more experienced (and possibly more satisfied) users separately.  Survey items were also created by the authors and were not previously validated in previous research; thus, it could be possible that responders did not fully understand an item or the item did not accurately examine what it was intended to.  Conflicts of interest of responders were not ascertained, which could include free samples of blocking devices provided to practitioners.  Finally, these investigators wished that they could have taken the opportunity to ask the providers with limited experience (fewer than 25 patients) why they were not using SPG blocks more frequently.  These researchers could only speculate whether their infrequent use was driven by the lack of familiarity with the procedure, an impression of low clinical response, issues of cost/reimbursement, or other reasons.  It must also be considered that more experienced clinicians had the higher number of patients seen because they believed that the procedure is effective; therefore, used it more frequently, regardless of whether this is true or not.

Manual Therapy for the Treatment of Migraines

Falsiroli Maistrello and colleagues (2019) noted that individuals with headache usually experienced significantly lower HR-QOL than the healthy subjects.  In a systematic review, these researchers examined the effectiveness of manual therapy on HR-QOL in patients with TTH, MH or cervicogenic headache (CGH).  They searched RCTs on Medline, Cochrane and PEDro databases.  Treatment was manual therapy compared to usual care or placebo.  The outcome was the HR-QOL that could be measured by HIT-6, Headache Disability Inventory (HDI), MIDAS and Short Form Health Survey 12/36 (SF-12/36).  For the RCT internal validity, these investigators used the Cochrane risk of bias (RoB) tool.  For the level of evidence, they used the GRADE.  These researchers identified a total of 10 RCTs, 7 of which were included into the meta-analysis.  For HIT-6 scale, meta-analysis showed statistically significant differences in favor of manual therapy both after treatment (MD - 3.67; 95% CI: - 5.71 to - 1.63) and at follow-up (MD - 2.47; 95% CI: - 3.27 to - 1.68).  For HDI scale, meta-analysis showed statistically significant differences in favor of manual therapy both after treatment (MD - 4.01; 95% CI: - 5.82 to - 2.20) and at follow-up (MD - 5.62; 95% CI: - 10.69 to - 0.54).  Other scales provided inconclusive results.  The authors concluded that manual therapy should be considered as an effective approach in improving the QOL in patients with TTH and MH, while in patients with CGH, the results were inconsistent.  Moreover, these researchers stated that those positive results should be considered with caution due to the very low level of evidence.  They stated that researchers should in future design primary studies using valid and reliable disease-specific outcome measures.

Greater Occipital Nerve Block for the Treatment of Cervicogenic and Cluster Headaches

Ornello and colleagues (2020) noted that the treatment of CH is challenging in view of the few evidence-based treatments.  In a systematic review and meta-analysis, these researchers examined the safety and efficacy of greater occipital nerve blocks (GONBs) in CH.  They included studies indexed in PubMed and Web of Science from the beginning of indexing to May 5, 2020; they included both observational and randomized studies referring to patients with episodic and/or chronic CH.  These researchers identified 12 studies on 365 patients; 5 studies (2 RCTs) could be included in the meta-analyses.  The pooled proportion of pain-free subjects at 1 month was 50% (95% CI: 24% to 76%) with considerable heterogeneity (I2 = 88%; p < 0.01).  The pooled relative risk ratio of pain freedom at 1 month in active versus control groups in the 2 included RCTs was 4.86 (95% CI: 1.35 to 17.55) without statistical heterogeneity (I2 = 0%; p = 0.39); 3 studies showed decreased attack intensity, frequency, and duration after GONBs.  The studies reported mild and transient AEs.  The authors concluded that despite several drawbacks and considerable heterogeneity, the available data supported the safety and efficacy GONBs for the treatment of CH.  Moreover, these researchers stated that further large randomized trials are needed to establish protocols and indications for GONBs in patients with episodic or chronic CH.

Caponnetto and associates (2021) stated that cervicogenic headache (CGH) is a secondary headache disorder caused by cervical spine or neck soft tissue lesions.  Despite few available evidence-based pharmacological treatments are available, GONBs are considered as therapeutic option.  In June 2020, these investigators carried out a systematic review on PubMed and Scopus, to examine the safety and effectiveness of GONBs in treating CGH.  They included 5 observational studies and 3 non-randomized trials reporting clinical outcomes of 140 CGH patients following GONBs.  Authors performed unilateral GONBs during inter-ictal phase (5 studies) or during pain, injecting local anesthetic (4 studies) or both local anesthetic and steroid (3 studies) at variable time-points.  In 5 studies mean pain reduction ranged from -8.2 (at 2 weeks after the 1st block) to -0.1 (at 1 month after the 3rd block); 1 study documented 66.6% reduction of pain intensity and another study documented a significant median reduction of pain intensity at 3 months (decreased from 5.5 to 2.3), but not at 9 months; and 3 studies reported minor AEs.  The authors concluded that few available studies suggested that GONBs are safe and effective in the treatment of CGH; GONB is a highly tolerable, low cost and repeatable procedure.  Moreover, these researchers stated that larger, randomized studies are needed to confirm the efficacy of the procedure, refine patient selection and injection protocols.

Nerivio - Remote Electrical Neuromodulation (REN) for the Treatment of Migraines

In a prospective, randomized, double-blinded, cross-over, sham-controlled study, Yarnitsky et al (2017) examined the effectiveness of remote non-painful electrical upper arm skin stimulation in reducing migraine attack pain.  Migraineurs applied skin electrodes to the upper arm soon after attack onset for 20 mins, at various pulse widths, and refrained from medications for 2 hours.  Patients were asked to use the device for up to 20 attacks.  In 71 patients (299 treatments) with evaluable data, 50% pain reduction was obtained for 64% of participants based on best of 200-μs, 150-μs, and 100-μs pulse width stimuli per individual versus 26% for sham stimuli.  Greater pain reduction was found for active stimulation versus placebo; for those starting at severe or moderate pain, reduction (i) to mild or no pain occurred in 58% (25/43) of participants (66/134 treatments) for the 200-μs stimulation protocol, and 24% (4/17; 8/29 treatments) for placebo (p = 0.02), and (ii) to no pain occurred in 30% (13/43) of participants (37/134 treatments), and 6% (1/17; 5/29 treatments), respectively (p = 0.004).  Earlier application of the treatment, within 20 mins of attack onset, yielded better results: 46.7% pain reduction as opposed to 24.9% reduction when started later (p = 0.02).  The authors concluded that non-painful remote skin stimulation could significantly reduce migraine pain, especially when applied early in an attack.  This was presumably by activating descending inhibition pathways via the conditioned pain modulation effect.  This treatment may be proposed as an attractive non-pharmacologic, easy to use, adverse event (AE)-free, and inexpensive tool to reduce migraine pain. The authors stated that this study had several drawbacks.  First, the lower rates of completion of the 20 mins of stimulus in the placebo stimuli might indicate that some participants might have identified those stimuli as non-active, and stopped them prematurely, since they realized no pain relief was to be expected.  Maintaining blinding in studies involving neurostimulation treatments is a known challenge.  Although this observation suggested that blinding was incomplete, it was likely that this fact did not result in falsely improved results; on the contrary, had those incomplete stimuli periods been completed, it was most likely that sham effectiveness results would have been lower than currently reported, making the results even more distinct.  Second, no information on major demographic features, beyond age and sex, was collected.  Third, this clinical application was developed based on the conditioned pain modulation concept in pain alleviation.  These researchers did not provide imaging- or neurophysiologic-based proof that this was the underlying mechanism.  It should be noted that this study was sponsored by Theranica Ltd.  D. Yarnitsky serves on the Medical Advisory Board of Theranica Ltd.  L. Volokh is an employee of Theranica Ltd.  A. Ironi is an employee of Theranica Ltd. 

Rapoport and Lin (2019) stated that non-invasive neuromodulation devices represent an emerging field in the acute treatment of migraine.  High efficacy, favorable safety profile, good tolerability and low cost are important factors for the desired shift to non-pharmacological treatments.  This will have the potential to improve the quality of life (QOL) of individuals with migraine; and reduce the risk for adverse events (AEs) and medication overuse headache (MOH).  Nerivio (Theranica Bio-Electronics, Israel) is a novel FDA-cleared (via 510(k)) remote electrical neuromodulation (REN) device for acute treatment of migraine.  These investigators highlighted the mechanism of action of REN and summarized the clinical data.  Nerivio has been studied in 2 randomized trials that provided support for the safety and efficacy of the device.  Post-hoc analyses suggested that the efficacy of REN is non-inferior to usual care in general and to acute pharmacological treatments specifically.  The authors concluded that Nerivio integrates clinically meaningful efficacy with a high safety profile, satisfying a great unmet need in migraine acute care.  The unique mechanism of action, in which the electrical stimulation is applied to peripheral nerves in the upper arm, allows the introduction of an innovative device with high efficacy and superior and improved usability aspects compared with acute pharmacological treatments and other approved devices. 

In a randomized, double-blind, placebo-controlled, multi-center trial, Yarnitsky et al (2019) examined the safety and efficacy of a REN device for the acute treatment of migraine.  This trial was carried out at 7 sites in the U.S. and 5 sites in Israel.  A total of 252 adults meeting the International Classification of Headache Disorders criteria for migraine with 2 to 8 migraine headaches per month were randomized in a 1:1 ratio to active or sham stimulation.  A smartphone-controlled wireless device was applied for 30 to 45 mins on the upper arm within 1 hour of attack onset; electrical stimulation was at a perceptible but non-painful intensity level.  Migraine pain levels were recorded at baseline, 2 hours, and 48 hours post-treatment.  Most bothersome symptoms (MBS) were also recorded.  The primary efficacy endpoint was the proportion of participants achieving pain relief at 2 hours post-treatment (improvement from severe or moderate pain to mild or none, or from mild pain to none).  Relief of MBS and pain-free at 2 hours were key secondary endpoints.  Active stimulation was more effective than sham stimulation in achieving pain relief (66.7% [66/99] versus 38.8% [40/103]; therapeutic gain of 27.9% [95% CI: 15.6 to 40.2]; p < 0.0001), pain-free (37.4% versus 18.4%, p = 0.003), and MBS relief (46.3% versus 22.2%, p = 0.0008) at 2 hours post-treatment.  The pain relief and pain-free superiority of the active treatment was sustained 48 hours post-treatment.  The incidence of device-related AEs was low and similar between treatment groups (4.8% [6/126] versus 2.4% [3/126], p = 0.499).  The authors concluded that the findings of this study suggested that REN is an effective acute migraine treatment with a favorable safety and tolerability profile; REN may be an alternative acute migraine treatment with comparable or superior efficacy to commercially available neuromodulation devices.  These researchers stated that REN has the potential to increase patient adherence, improve migraine management, and improve the health and QOL of individuals with migraine. The authors stated that this study had several drawbacks.  First, there was a low rate of severe baseline pain intensity and high rate of mild pain intensity, presumably due to the early treatment.  Yet, the rates of pain relief were as high for attacks treated at a moderate pain level, as for those treated at a mild pain level.  Second, these investigators did not study the efficacy of the device at intervention periods over 1 hour of symptoms onset.  Finally, selecting an appropriate sham device for successful blinding in neuromodulation studies in migraine is a great challenge.  However, in the current study the sham device produced a solid perceivable stimulus.  As in other neuromodulation studies in migraine, the placebo effect was higher than drug trials.  Yet, the therapeutic gain in the current study was impressive and was not significantly affected by the participants' treatment‐assigned response, providing acceptable evidence that REN treatment is safe and effective as an acute treatment for migraine.

Nierenburg et al (2020) stated that REN is a novel acute treatment of migraine.  Upper arm peripheral nerves are stimulated to induce conditioned pain modulation (CPM) -- an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions.  The REN (Nerivio) is a device cleared by the FDA for acute treatment of migraine in adults who do not have chronic migraine.  In an open-label, single-arm, dual-center, pilot study, these researchers examined the consistency of response over multiple migraine attacks in individuals with chronic migraine who are typically characterized with severe pain intensity, high disability, and less robust response to triptans.  This trial was carried out on adults with chronic migraine.  Participants underwent a 4-week treatment phase in which they treated their migraine headaches with the device for 45 mins within 1 hour of attack onset.  Pain levels were recorded at baseline, 2 hours, and 24 hours post-treatment.  Efficacy outcomes (pain relief and pain-free responses at 2 hours, sustained pain relief and sustained pain-free responses at 24 hours) focused on intra-individual consistency of response across multiple attacks, which was defined as response in at least 50% of the treatments.  A total of 42 participants were enrolled, and 38 participants were evaluable for analyses; 73.7% (28/38) achieved pain relief at 2 hours, 26.3% (10/38) were pain-free at 2 hours, 84.4% (27/32) had sustained pain relief response at 24 hours and 45.0% (9/20) had sustained pain relief response at 24 hours in at least 50% of their treated attacks.  The effects of REN on associated symptoms and improvement in function were also consistent.  The incidence of device-related adverse events (AEs) was low (1.8%).  The authors concluded that REN used for a series of migraine attacks was effective and well-tolerated across attacks.  These researchers stated that REN may offer a safe and effective non-pharmacological alternative for acute treatment in patients with chronic migraine.  These researchers stated that further studies in a larger sample size are needed.

Marmura et al (2020) noted that a recent randomized controlled study showed that 66.7% (66/99) and 37.4% (37/99) of people undergoing remote electrical neuromodulation (REN), a novel non-pharmacological migraine treatment, achieved pain relief and pain freedom, respectively, at 2 hour post-treatment.  Subjects who completed the 6-weeks double-blind phase of this study were offered to participate in an open-label extension (OLE) with an active REN device.  These investigators examined the clinical use of REN, focusing on its potential in reducing the use of acute migraine medications.  The parent study for this OLE was a randomized, double-blind, sham-controlled study of acute treatment conducted on 296 participants enrolled at 12 sites in the U.S. and Israel.  This study included a run-in phase, in which migraine attacks were treated with usual care, and an 8-weeks double-blind treatment phase.  A total of 160 participants continued in an 8-weeks OLE phase in which they could incorporate a REN device into their usual care.  Medication use rate (percentage of participants who treated their attacks only with REN and avoided medications in all their attacks) and pain outcomes at 2 hours post-treatment were compared between the OLE and the run-in phase in a within-subject design.  The analyses were performed on 117 participants with episodic migraine.  During the OLE, 89.7% of the participants treated their attacks only with REN and avoided medications in all their attacks compared with 15.4% in the run-in phase (p < 0.0001).  The rates of pain relief and pain-free in at least 50% of the treatments at 2 hours post-treatment were comparable (pain relief: 58.1% in the run-in phase, and 57.3% in the OLE, p = 0.999; pain-free: 23.1% in the run-in versus 30.8% in the OLE, p = 0.175).  The authors concluded that REN may reduce the use of acute migraine medications; therefore, incorporating REN into usual care may reduce the risk for medication overuse headache (MOH).  Moreover, these researchers stated that future studies should examine if REN will reduce the use of acute migraine medications in a population at risk for MOH. The authors stated that this study had several limitations.  First, this study reported on an 8-weeks OLE phase and did not include a direct observation on the development of MOH.  Second, the study was conducted on people with episodic migraine and did not specifically focus on a population at risk for MOH or chronic migraine.  However, most patients with MOH have an episodic headache history, suggesting that the results could be generalized.  Furthermore, the rate of triptan use in this trial was higher than that of the general population, presumably due to recruitment at specialty centers.  Yet these rates of triptan use reflected the rates observed in the population of adults with migraine with acute medication over-use, which has been associated with an increased risk of MOH.  Third, there was a low rate of severe baseline pain intensity, presumably due to the early treatment.  Finally, the data-set of usual care of multiple attacks included different pharmacotherapies (or no treatment) for a single person, which decreased its scientific purity; however, this intra-individual variability encompassed real-life migraine management, varying across attacks within the same patient; thus, empowering these findings. The lead author and some coauthors reported compensation or research support from Theranica, the manufacturer of the Nerivio device. Three coauthors were employees of Theranica.

Tepper et al (2020) stated that REN is a non-pharmacological acute migraine treatment that stimulates upper-arm peripheral nerves.  These investigators examined the safety and effectiveness of REN for acute treatment of migraine in a real-world setting.  Real-world data were collected from patients who were using REN (Nerivio) between October 1, 2019, and March 31, 2020.  Patients recorded their symptoms at baseline, 2 hours, and 24 hours post-treatment.  Patients were stratified based on the type of visit and provider; in-person visits with headache specialists (HS group) or virtual visits with non-headache specialists (NHS group).  Effectiveness outcome focused on intra-individual consistency of response across multiple attacks.  These researchers found that 58.9% (662/1,123) of the patients in the HS group and 74.2% (23/31) of the patients in the NHS group experienced pain relief at 2 hours in at least 50% of their treated attacks and 20.0% (268/1,339) of the patients in the HS group and 35.6% (16/45) of the patients in the NHS group experienced pain freedom at 2 hours in at least 50% of their treated attacks.  The effects of REN on associated symptoms and improvement in function were also consistent in both groups.  The incidence of device-related AEs was very low (0.5%).  The authors concluded that real-world data confirmed that REN resulted in meaningful clinical benefits with minimal side effects.  These researchers stated that REN may provide an effective drug-free therapeutic option for achieving consistent relief from migraine symptoms and may reduce the use of acute medications. The authors stated that this study had several drawbacks.  First, the effectiveness results were not placebo-controlled; however, even if accounting for the placebo response rate of 45% observed for 2-hour pain relief consistency in previous studies of REN or 32% of other devices for acute treatment, the therapeutic gain in this study (approximately 27% in the HS group, approximately 42% in the NHS group, and approximately 27% in the entire study population) remained clinically meaningful.  Another drawback to interpreting the data was the lack of an International Classification of Headache Disorders, 3rd Edition, diagnosis on these patients.  However, most of the patients in this analysis were prescribed by U.S. headache specialists working in headache clinics; therefore, the presumption was that these patients had a mix of migraine with and without aura, chronic and non-chronic, with and without medication overuse headache.  It would have been useful to match ICHD-3 migraine diagnostic subtype and response rate in addition to the stratification based on the prescribing physician and type of visit.  Yet, the mix at U.S. headache centers tended to tilt toward more chronic migraine and more severely disabled patients, which was supported by the baseline characteristics of the patients in this trial.  The overall positive response rate even in this subgroup of the U.S. migraine patient population was therefore very encouraging.

Grazzi et al (2021) noted that significant side effects or drug interactions can make pharmacotherapy for headache disorders very difficult.  Non-conventional and non-pharmacological treatments are becoming increasingly used to overcome these issues.  In particular, non-invasive neuromodulation (including remote electrical skin stimulation), nutraceuticals, and behavioral approaches are well-tolerated and indicated for specific patient categories such as adolescents and pregnant women.  These investigators presented the main approaches reported in the literature in the management of headache disorders.  They reviewed the available literature published between 2010 and 2020 and carried out a narrative presentation for each of the 3 categories (non-invasive neuromodulation, nutraceuticals, and behavioral therapies).  Regarding non-invasive neuromodulation, these researchers selected transcranial magnetic stimulation, supraorbital nerve stimulation, transcranial direct current stimulation, non-invasive vagal nerve stimulation, and caloric vestibular stimulation.  For nutraceuticals, they selected feverfew, butterbur, riboflavin, magnesium, and coenzyme Q10.  Finally, for behavioral approaches, these investigators selected biofeedback, cognitive behavioral therapy (CBT), relaxation techniques, mindfulness-based therapy, and acceptance and commitment therapy.  These approaches are increasingly seen as a valid therapeutic option in headache management, especially for patients with medication overuse or contra-indications to drug treatment; however, further investigations are needed to consider the effectiveness of these approaches also with respect to the long-term effects.

Hershey et al (2021) stated that migraine is a common disabling neurological disorder.  Current acute treatments for migraine in adolescents are mostly pharmacological and may have limited effectiveness, can cause side effects, and may lead to medication over-use.  There is an unmet need for effective and well-tolerated treatments.  REN is a novel acute treatment of migraine that stimulates upper arm peripheral nerves to induce conditioned pain modulation (CPM)-an endogenous analgesic mechanism.  The REN device (Nerivio ) is a FDA-cleared device for acute treatment of migraine in adults.  In an open-label, single-arm, multi-center study, these researchers examined the safety and effectiveness  of REN in adolescents with migraine.  This trial included adolescents (age of 12 to 17 years) with migraine.  Participants underwent a 4-week run-in phase.  Eligible participants continued to an 8-week treatment phase with the device.  Pain severity, associated symptoms, and functional disability were recorded at treatment initiation, and 2 and 24 hours post-treatment.  The primary endpoints of this study were related to the safety and tolerability of REN.  The secondary endpoints were related to device effectiveness and included the proportion of participants who achieved pain relief at 2 hours post-treatment, and the proportion of participants who were pain-free at 2 hours.  The presented results reflected an interim analysis with subsequent stopping of the rest of the study.  A total of 60 participants were enrolled for the study; of these, 14 failed to meet the run-in criteria, and 1 was lost to follow-up.  A total of 45 participants performed at least 1 treatment, of which 39 participants completed a test treatment with REN.  One device-related AE (2%) was reported in which a temporary feeling of pain in the arm was felt.  Pain relief and pain-free at 2 hours were achieved by 71% (28/39) and 35% (14/39) participants, respectively.  At 2 hours, 69% (23/33) participants experienced improvement in functional ability.  The authors concluded that REN may offer a safe and effective non-pharmacological alternative for acute treatment in adolescents.  Moreover, these researchers stated that further studies in a larger sample size are needed. The authors stated that this study had 2 main limitations.  First, the effectiveness results were not placebo-controlled, which is specifically important in pediatric  studies that typically show a higher rate of placebo response in  adolescents than adults.  However, even if accounting for the high placebo response rate of 55% observed for 2-hour pain relief in previous studies, the therapeutic gain in this study remained clinically  meaningful.  Second, this study was carried out on a small sample  size (n = 45). The lead author received funding to his institution from Theranica, the manufacturer of the Nerivio device, and four coauthors are employees of Theranica.

Grosberg et al (2021) noted that a recent pilot study provided initial support that REN is effective in patients with chronic migraine.  In an open-label, single-arm study, these investigators examined the safety and effectiveness of REN in a large sample of patients impacted by chronic migraine.  Participants entailed patients with chronic migraine who treated their headaches with the REN device (Nerivio) for 4 weeks.  They used an electronic diary to record their symptoms at treatment initiation, 2 hours after treatment, and 24 hours after treatment.  The primary endpoint was the percentage of subjects who achieved pain relief at 2 hours post-treatment.  Secondary endpoints included pain freedom and improvement of associated symptoms and functional disability.  A total of 126 subjects were enrolled into the study, of which 91 subjects had an evaluable treatment with REN.  Pain relief and pain disappearance at 2 hours were achieved by 59.3% (54/91), and 20.9% (19/91) of modified intention-to-treat (mITT) subjects, respectively (with worst-case sensitivity analysis indicating 54.5% and 19.2%, respectively).  Sustained pain relief at 24 hours was observed in 64.4% (29/45) of those who achieved pain relief at 2 hours (with worst-case sensitivity analysis indicating 45.6%).  The findings of the study showed that REN had a favorable effect on nausea, photophobia, and phonophobia and improved functional ability.  One device-related AE was reported.  The authors concluded that the findings of this study showed that REN may provide an alternative non-pharmacological acute therapeutic option in patients with chronic migraine, holding the potential to diminish medication use in a population prone to develop medication overuse headache (MOH). The authors stated that the results of the REN treatment were not compared with those of sham stimulation, which may be considerable.  Yet, comparing the mITT results to an estimated 2-hour pain relief sham response of 38.8% observed in previous studies of REN23 showed a statistically significant and clinically meaningful therapeutic gain (20.5%; p = 0.004), and thus placebo and nocebo effects, while no doubt exist, were unlikely to explain the current results.  An additional limitation was the small number of subjects included in some of the evaluated parameters which stemmed from the analysis approaches in which only patients with a specific symptom reported as present at baseline were included and due to missing data.  Therefore, additional studies in a larger number of subjects are needed.  Finally, data from 91 participants were included in the analysis data-set, whereas 126 participants were recruited to the study.  Data from 35 participants were not included (as detailed in the disposition figure) primarily because of non-adherence with the study's protocol.  More importantly, 27 of the 35 participants were excluded in the run-in phase, in which the REN device was not yet given to the participants and was not used or tested.  This phase was designed particularly for this purpose, i.e., to assess eligibility based on the number of reported attacks and compliance to report pain levels at baseline and at 2 hours post-treatment, regardless of the REN intervention.  A total of 99 participants entered the treatment phase (and received a REN device), of which 8 did not complete their participation in this phase (as detailed in the disposition chart).  Those 8 were within the anticipated 10% of drop-out or data loss.  Regarding the rate of pain freedom (20.9%), although the rate of pain freedom was slightly lower than that of some medications, REN offers a superior safety profile, with nearly no side effects (1.0% AEs in the current trial), i.e., in comparison to the risk of MOH, as well as gastro-intestinal (GI) symptoms and other severe side effects associated with standard care medications for migraine.  Furthermore, the pain relief rates were comparable with those of triptans, and may be superior to nVNS.  It should be noted that this work was supported by Theranica Bio-Electronics LtdTD.

Ailani et al (2021) noted that the American Headache Society previously published a Consensus Statement on the use of newly introduced treatments for adults with migraine.  These investigators provided an update, which was based on the expanded evidence base and emerging expert consensus concerning post-approval usage, provides practical recommendations in the absence of a formal guideline.  They incorporated recent research findings, expert consensus, and patient perspectives into updated guidance on the use of new acute and preventive treatments for migraine in adults.  This update involved 4 steps.  First, review of data regarding the safety, effectiveness, and clinical use of migraine treatments introduced since the previous Statement was published.  Second, incorporation of these data into a proposed update.  Third, review and commentary by the Board of Directors of the American Headache Society and patients and advocates associated with the American Migraine Foundation.  Fourth, consideration of these collective insights and integration into an updated Consensus Statement.  Since the last Consensus Statement, no evidence has emerged to alter the established principles of either acute or preventive treatment.  Newly introduced acute treatments include 2 small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (ubrogepant, rimegepant); a serotonin (5-HT1F ) agonist (lasmiditan); a non-steroidal anti-inflammatory drug (celecoxib oral solution); and a neuro-modulatory device (remote electrical neuromodulation [REN]).  New preventive treatments include an intravenous anti-CGRP ligand monoclonal antibody (eptinezumab).  Several modalities, including neuromodulation (electrical trigeminal nerve stimulation, non-invasive vagus nerve stimulation [VNS], single-pulse transcranial magnetic stimulation [TMS]) and biobehavioral therapy (cognitive behavioral therapy [CBT], biofeedback, relaxation therapies, mindfulness-based therapies, acceptance and commitment therapy) may be appropriate for either acute and/or preventive treatment; a neuromodulation device may be appropriate for acute migraine treatment only (remote electrical neuromodulation [REN]).  The authors concluded that the integration of new treatments into clinical practice should be informed by the potential for benefit relative to established therapies, as well as by the characteristics and preferences of individual patients.

In a retrospective, observational study, Nierenburg et al (2021) examined the self-reported effectiveness and tolerability of REN for the acute treatment of menstrual migraine, via a structured survey that was sent to adult female REN users.  Women aged 18 to 55 years who experienced menstrually-related or pure menstrual migraine and have completed at least 4 REN treatment sessions, participated in this survey study.  Participants completed a short online survey examining effectiveness, satisfaction, and safety outcomes.  A total of 91 participants qualified for the analysis, out of which 74.7% (68/91) reported that the treatment was at least moderately effective (moderately effective 37.4%, very effective 26.4%, extremely effective 11.0%).  Furthermore, 45.1% (41/91) reported satisfaction from REN (slightly satisfied 33%, extremely satisfied 12.1%), while 34.1% were neutral and 20.9% (19/91) were not satisfied.  In addition, 100% of the participants reported that the treatment was at least moderately tolerable (moderately tolerable 8.8%, very tolerable 20.9%, extremely tolerable 70.3%), and 13.2% (12/91) of respondents reported mild short-term side effects.  The authors stated that nearly 75% reported that the treatment was at least moderately effective, 45% reported satisfaction, and 100% of the participants reported that the treatment was at least moderately tolerable; 13% reported mild short-term side effects.  These investigators concluded that this survey study indicated that REN may provide a safe, non-pharmacological therapeutic option for women with menstrual migraine.  They noted that while RCTs are needed to further establish the therapeutic benefits of REN in menstrual migraine, this study indicated that patients found REN effective and very well-tolerated. The authors stated that this study had several drawbacks.  First, the retrospective self-report nature of the study may limit the conclusions of this survey by recall bias.  While this is true, this study provided a naturalistic perspective on the effects of the treatment, and reflected the real-life perceptions that patients have on the intervention, in their own natural environment.  The study was not intended to replace a randomized clinical trial, but rather to present the participants’ reports on their regular migraine care.  Second, the diagnosis of menstrual migraine relied on self-report rather than a physician diagnosis; however, the report questions were identical to the ICHD-3 diagnosis criteria, and were answered as a yes/no response similar to the way a physician would diagnose.  Third, only individuals who completed at least 4 REN treatment sessions were sent a survey (possibly creating a selection bias); therefore, the sample represented REN users and was not meant to reflect the general population.

VanderPluym et al. (2021) conducted a systematic review and meta-analysis to evaluate the benefits and harms of acute treatments for episodic migraine in adults, with the goal of comparing both pharmacologic and nonpharmacologic therapies across multiple clinically relevant outcomes. The review searched multiple databases from inception through February 24, 2021, and included randomized clinical trials and systematic reviews evaluating acute migraine therapies. Evidence for triptans and nonsteroidal anti-inflammatory drugs was synthesized from 15 existing systematic reviews, while 115 randomized clinical trials involving 28,803 patients were reviewed for other interventions. Primary outcomes included pain freedom, pain relief, sustained pain freedom, sustained pain relief, and adverse events. Strength of evidence was graded using Agency for Healthcare Research and Quality methodology. With respect to remote electrical neuromodulation (REN), the review identified evidence from randomized, sham-controlled trials demonstrating that REN was associated with statistically significant improvements in multiple migraine outcomes. Compared with sham stimulation, REN improved pain freedom at 2 hours (relative risk [RR], 1.95; 95% confidence interval [CI], 1.19-3.19; risk difference [RD], 0.14), pain relief at 2 hours (RR, 1.65; 95% CI, 1.22-2.24; RD, 0.21), sustained pain freedom (RR, 2.57; 95% CI, 1.11-5.94; RD, 0.09), and sustained pain relief (RR, 2.27; 95% CI, 1.30-3.95; RD, 0.15). The strength of evidence supporting these findings was graded as moderate. Importantly, no significant differences in adverse events were observed between REN and sham treatment. The authors therefore concluded that REN is one of several nonpharmacologic therapies supported by meaningful evidence for acute migraine treatment and that it can improve both pain outcomes and function without increasing adverse effects. The review also highlighted other neuromodulation approaches, including transcranial magnetic stimulation, external trigeminal nerve stimulation, and noninvasive vagus nerve stimulation, but the strength of evidence supporting REN was among the most robust within the nonpharmacologic treatment category. The authors noted several important limitations. Many included studies compared active treatments with placebo or sham rather than with other active therapies, limiting the ability to draw comparative effectiveness conclusions. Important migraine symptoms beyond pain, such as nausea, photophobia, and phonophobia, were not consistently evaluated. Many clinical trials excluded patients with significant comorbidities, older adults, and individuals with more complex migraine syndromes, limiting generalizability. The included studies were conducted across heterogeneous clinical settings, including outpatient clinics, emergency departments, urgent care centers, and inpatient settings, potentially introducing differences in disease severity and treatment response. In addition, although statistical heterogeneity was generally low, important subgroup analyses based on migraine characteristics and comorbid conditions could not be performed because of insufficient data. These limitations apply to the REN evidence as well as to the broader body of acute migraine treatment literature reviewed in the study.

Hershey et al. (2022) reported a post hoc, within-participant analysis comparing remote electrical neuromodulation (REN) to standard-care medications for acute migraine treatment in adolescents. Data were drawn from a prior open-label, single-arm clinical trial of the REN device (Nerivio) in 35 adolescents. The study used a within-participant comparison: during a run-in phase, participants treated migraine attacks with their usual standard-care medications (triptans or over-the-counter analgesics), and during the intervention phase, they treated attacks with REN. Efficacy was assessed at 2 hours post-treatment using McNemar's test across four endpoints: single-treatment pain freedom, single-treatment pain relief, consistency of pain freedom (response in ≥50% of the first four treatments), and consistency of pain relief. Key results included: -ain freedom at 2 hours: 37.1% with REN vs. 8.6% with medications (P = 0.004); pain relief at 2 hours: 71.4% with REN vs. 57.1% with medications (P = 0.225, not statistically significant); consistent pain freedom: 40.0% with REN vs. 8.6% with medications (P < 0.001); consistent pain relief: 80.0% with REN vs. 57.2% with medications (P = 0.033). The authors concluded that REN may offer higher efficacy than certain standard-care medications for acute migraine in adolescents. However, several important limitations should be noted: this was a post hoc analysis of a small sample (n = 35), the study was open-label and unblinded (no sham control), and the comparison was non-randomized (sequential phases rather than concurrent randomization). The authors acknowledged that a larger-scale, blinded comparative-effectiveness study is needed to confirm these findings. 

Grosberg et al (2022) compared the effectiveness of REN to that of standard-care medications for acute treatments of migraine, using a within-subjects design.  Post-hoc within-subject analysis was performed on data from 78 adult chronic migraine patients who participated in a clinical trial with REN, on 4 endpoints: single-treatment pain relief, single-treatment pain freedom, consistency of pain relief, and consistency of pain freedom.  No statistical differences were found between REN and the tested medications, in any of the effectiveness outcomes: single-treatment pain relief, p = 0.056; single-treatment pain freedom, p = 0.532; consistency of pain relief, p = 0.369; and consistency of pain freedom, p = 1.00.  The authors concluded that these findings suggested that REN may provide an effective non-pharmacological alternative for standard care abortive medications in individuals impacted by chronic migraine. The authors stated that this study had several drawbacks.  First, for each subject, these investigators included all available treatments in each phase.  While this was chosen to allow the largest and least filtered possible dataset, it also introduced variability in the number of treatments per person.  Second, the average number of treatments per person was higher in the REN phase compared with the medications phase and the pain level before treatments was lower in the REN phase compared with the medication phase.  This might be because subjects were part of a clinical trial giving them free access to REN and chose to treat as many attacks as possible with REN in order to test its effect on themselves, as well as more minded to report migraine severity during this phase.  However, both these differences pertained only to the consistency analysis and the single-treatment analysis characteristics were not statistically different.  Relatedly, the number of reported migraines in the REN phase was lower than in the medications phase.  This may suggest a potential preventative effect of using REN, which is now being tested in a dedicated prospective clinical trial.  Lastly, the single-attack analysis was carried out on the first evaluable treatment in the REN phase following a training treatment.  This was performed to allow training, given that REN has a unique mode of operation, but could introduce bias toward response (i.e., if non responders chose not to use REN a second time).  However, only 1 subject (out of 79) withdrew from the trial between the 1st and 2nd treatment; therefore, the potential impact was limited.  Furthermore, all evaluable treatments, including the first treatment, were included in the consistency analysis.

Nierenburg and Stark-Inbar (2022) stated that Nerivio is a wireless, wearable, non-invasive, battery-operated, REN device controlled by a smartphone application.  It is FDA-cleared for the acute treatment of migraine with or without aura in people 12 years and older in the US, and European Conformity (CE) marked for the same indication in the EU.  The American Headache Society Consensus Statement recommends Nerivio as a tier 2 treatment for migraines.  These investigators summarized a series of 5 independent clinical trials and 2 real-world evidence studies that established safety, tolerability and effectiveness of Nerivio in treating migraine attacks.  It further provided up-to-date practical information on device usability.  The authors concluded that based on findings of this review, Nerivio offers a safe and effective non-pharmacological alternative for acute treatment in patients with chronic (and acute) migraine. 

Ailani et al (2022) noted that migraine is a chronic neurological disease that is the primary cause of years lived with disability in individuals under the age of 50 years.  REN is a novel, drug-free, acute treatment of migraine, that is FDA-cleared for episodic and chronic migraine.  As a prescribed digital therapeutic, REN enables large-scale post-marketing research; thereby, providing real-world information on the use of the intervention in a wide range of populations, environments, and situations.  The REN device (Nerivio) includes a secured, personal migraine diary, which patients can use to record their symptoms before treatment and 2 hour post-treatment.  Real-world data on REN treatments were collected via the app from patients across the U.S. who used Nerivio between October 1, 2019, and May 24, 2021.  Data analysis focused on 4 metrics: (i) Per-treatment patterns of REN use as a stand-alone treatment versus in combination with medications; (ii) Per-user intra-individual effectiveness across multiple treatments; (iii) Distribution of treatment intensity among users (the electroceutical equivalent to treatment dose); and (iv) Prevalence and severity of AEs.  Results were as followed: (i) Out of 23,151 treatments, in 66.5% of treatments REN was used as a stand-alone treatment, in 12.9% it was followed by over-the-counter medications, and in 20.6% followed by prescription medications.  (ii) Out of 2,514 patients, response in at least 50% of treatments was achieved in 66.5% of cases for pain relief, and in 22.6% for pain freedom.  (iii) Out of 117,583 treatments, in 80% of cases intensity levels were between 18% and 55% of the stimulator's range.  The mean intensity was 34.3% of the stimulator's output (± 16.6%).  (iv) Out of 12,368 users (121,947 treatments), there were 59 users (0.48%) who reported device-related AEs, 56 (0.45%) of which were mild, 3 (0.03%) were moderate, and none were severe.  The authors concluded that this analysis of real-world clinical data indicated that REN provided a safe, stable, and effective therapeutic option for acute treatment of migraine in real-world settings, both as a stand-alone replacement of pharmaceuticals, as well as an adjunct to medications. The authors stated that this trial had several drawbacks.  First, data were collected only from those patients who chose to use this intervention, which in some cases may imply that they were not satisfied with their previous therapies.  Second, data were collected only from those patients who chose to use the app to report their symptoms. Nevertheless, real-world studies are essential for true evaluation of the effects of an intervention, as they test larger and more diverse populations over longer periods of time and are conducted in various real-world environments and situations.  The use of a single parameter for intra-individual effectiveness across multiple treatments removes the potential bias that could have been implied from users who were treated many times (presumably because they experienced effectiveness) over users who were treated only very few times (perhaps because of lack of effectiveness), since in this kind of analysis frequent users have the same weight as infrequent users.  Lastly, as in all interventions, a certain degree of placebo-effect is to be expected.  A previous double-blind randomized clinical trial of REN indicated a placebo response at a rate of 38.8% for 2-hour pain relief (versus 66.7% change in the active treatment group).  This information could serve as a point of reference, indicating that while a placebo effect no doubt exist, it is not likely to explain the current results.  It should be noted that this study received funding from Theranica Bio-Electronics Ltd.  The funder had the following involvement in the study: the funder designed and performed the analysis together with the other authors, and took part in the writing of the manuscript.  AI, LR, and ST are employees of Theranica Bio-Electronics Ltd and hold stocks.

Buse et al (2022) noted that evidence indicates that combining behavioral treatments with pharmacotherapies for migraine prevention improves effectiveness; however, little is known regarding the outcomes of combining neuromodulation and behavioral interventions for acute treatment of migraine.  REN is a FDA-cleared non-pharmacological migraine treatment.  In a 2-arm observational study, these researchers examined the clinical benefits of augmenting REN treatment with a specially tailored behavioral therapy consisting of Guided Intervention of Education and Relaxation (GIER) for the acute treatment of migraine.  Real-world data were collected from patients across the U.S who were using the REN device.  A total of 85 migraine patients 18 years of age or older who treated their attacks with REN in parallel with the GIER intervention were individually matched on age and sex with 85 patients who used REN alone.  The groups were compared on the proportion of migraine attacks in which they achieved pain relief, pain freedom, improvement of function, and return to normal function, all at 2 hours after treatment.  Data from 170 users were analyzed (85 per group).  Compared with the REN-only group, the REN+GIER group displayed a statistically significant higher proportion of patients achieving consistent pain relief (p = 0.008), consistent improvement in function (p = 0.014), and consistent return to normal function (p = 0.005), all at 2 hours after treatment.  The authors concluded that the findings of this study suggested that combining the GIER behavioral intervention with REN treatment could improve the effectiveness beyond that of REN alone, in terms of both pain level and improvement of disability. The authors stated that this study’s main limitation was its observational nature.  These researchers stated that future prospective random-allocation studies are needed to further establish the present results and to examine longer-term use.  However, the observational real-world design has the advantage of providing valuable information on the real-life effectiveness of the studied interventions.  It should be noted that this study was funded by Theranica Bio-Electronics Ltd. Three of the coauthors are employees of Theranica and hold stock options in the company. Another coauthor received consulting fees from Theranica.

Monteith et al (2023) stated that migraine is a chronic neurological disease manifesting as attacks of disabling head pain and associated symptoms. Remote electrical neuromodulation (REN) is a non-pharmacological, prescribed, wearable device (Nerivio).  This device has been certified by the FDA for the acute and/or preventive treatment of migraine with or without aura in patients 12 years of age or older.  The device is affixed to the user's arm during 45-min treatment sessions and is operated using a smartphone app.  These investigators examined if frequent use of REN for the acute treatment of migraine in adolescents resulted in a reduction in monthly migraine treatment days (MMTD), as previously demonstrated in adults through a dedicated prevention clinical trial.  The study included real-world prospective data from adolescent patients who used REN on at least 10 days every 28-day month, following the REN migraine prevention guideline of an every-other-day pattern.  Additional requirements were at least 3 REN treatment days in each of the 2 subsequent months.  The number of MMTD was used as a proxy measure for the number of monthly migraine days (MMD).  The change in MMTD from the 1st month, taken as a "baseline", to each of the following months was used to evaluate the presence and size of potential migraine preventive benefits of REN in adolescents.  A total of 83 adolescents were eligible for analysis. The users were 15.9 ± 1.3 years of age (mean ± SD), and 89% of them were female.  The results demonstrated a substantial month-to-month reduction in the mean (± SD) number of REN treatment days from 12.6 (± 3.2) MMTD in the 1st month to 9.0 (± 4.8) MMTD in the 2nd month (p < 0.001), and a further decrease to 7.4 (± 4.2) MMTD in the 3rd month (p < 0.001).  This indicated an accumulative reduction of 5.2 (± 4.8) mean REN MMTD from the 1st month to the 3rd month of consecutive REN treatment.  The users also reported consistent 2-hour acute pain responses in at least 50% of their treated attacks, with 61.9% of the users reported experiencing pain relief, 24.5% reported pain freedom, 67.4% indicated relief in functional disability, and 41.3% reported complete freedom from functional disability.  The authors concluded that the frequent use of REN among adolescents as an acute treatment for migraine attacks resulted in a decrease in the mean number of monthly treatment days in the subsequent months, suggesting that REN may have potential preventive benefits for migraine in this subpopulation.  Moreover, these researchers stated that further studies are needed to assess the long-term impact on migraine-related disability and quality of life (QOL) of adolescents using REN for migraine prevention. The authors stated that this study had several drawbacks.  First, the number of MMD was not measured directly but derived from the number of abortive MMTD, and preventive effects were extrapolated from using the device for acute treatment and not directly for migraine prevention.  However, given that the exact same stimulation was used for both abortive and preventive treatment and that the frequency of treatments met the usage pattern in the prevention pivotal trial in adults, deriving MMD from MMTD is clinically meaningful.  Second, as a post-marketing surveillance study, the cohort was selected from the users treated with the REN device, presumably reflecting that those who found it useful were likely to use it more.  To directly assess preventive benefits from treating with the REN wearable device in adolescents, further research is needed with a pre-planned clinical trial including those who require migraine prevention treatment and will report their migraine attacks in a daily migraine diary (migraine days), which is available in the Nerivio® app.  A dedicated study will further allow the collection of patient-centered outcomes, such as treatment satisfaction and quality of life.  Third, frequency swings in the number of monthly migraine attacks are quite common, especially in patients with chronic migraine; therefore, using a single month for migraine baseline assessment may be short.  However, 1 month is the most common baseline period used in migraine studies, including previous REN studies.  Moreover, the reduction in number of MMTD between the 1st and 3rd months was larger than the overall standard deviation of MMTD over all users during the 3 study months, indicating a larger effect of MMTD reduction over that of frequency swings; therefore, suggesting that the reduction of MMTD due to an efficacious REN treatment overcame the natural fluctuations in migraine frequency.  An extended study, tracking adolescents for more treatment months, will shed further light on the long-term effectiveness of REN for migraine prevention in adolescents.  Finally, the patients in this trial had a high attack frequency, which is a known risk factor for migraine chronification, and is associated with the sensitization of migraine-related structures.  As afore-mentioned, the wearable REN device activates an endogenous pain mechanism, the CPM, to abort attacks and preventive migraine days.  However, there is a need for investigations designed to elucidate the underlying central mechanisms that drive the observed therapeutic clinical effects of migraine prevention with REN, and specifically the potential of brain re-organization and neuroplasticity.  It should be noted that this study was supported by Theranica Bio-Electronics Ltd.  S-I, SS, DH, SG, and AI are employees of Theranica Bio-Electronics.

In a prospective, randomized, double-blind, placebo-controlled, multi-center trial, Tepper et al (2023) examined the effectiveness of REN, used every other day, for the prevention of migraine.  The study consisted of a 4-week baseline observation phase, and an 8-week double-blind intervention phase in which participants used either REN or a placebo stimulation every other day.  Throughout the study, participants reported their symptoms daily, via an electronic diary.  A total of 248 participants were randomized (128 active, 120 placebo), of which 179 qualified for the modified intention-to-treat (mITT) analysis (95 active; 84 placebo).  REN was superior to placebo in the primary endpoint, change in mean number of migraine days per month from baseline, with mean reduction of 4.0 ± SD of 4.0 days (1.3 ± 4.0 in placebo, therapeutic gain = 2.7 [CI: -3.9 to -1.5], p < 0.001).  The significance was maintained when analyzing the episodic (-3.2 ± 3.4 versus -1.0 ± 3.6, p = 0.003) and chronic (-4.7 ± 4.4 versus -1.6 ± 4.4, p = 0.001) migraine subgroups separately.  REN was also superior to placebo in reduction of moderate/severe headache days (3.8 ± 3.9 versus 2.2 ± 3.6, p = 0.005), reduction of headache days of all severities (4.5 ± 4.1 versus 1.8 ± 4.6, p < 0.001), percentage of patients achieving 50% reduction in moderate/severe headache days (51.6% [49/95] versus 35.7% [30/84], p = 0.033), and reduction in days of acute medication intake (3.5 ± 4.1 versus 1.4 ± 4.3, p = 0.001).  Similar results were obtained in the ITT analysis.  No serious device-related AEs were reported in any group.  The authors concluded that applied every other day, REN was safe and effective for the prevention of migraine. The authors noted that with respect to limitations of the study, the sub-analyses differentiating between participants who took additional preventive medications and those who did not were based on a partial, smaller sample size of those who took preventive medications.  Moreover, medical history regarding failure on previous preventive medications was not collected during the study, yet 50% of the participants who took an additional preventive medication took 2nd-line preventives, suggesting that 1st-line preventives had failed in the past.  Therefore, for a more profound assessment of the different responses among users of different preventive drugs, as well as history of preventive failures, a designated study may be required.  Another limitation was that the definition of a migraine day included a possible combination of headache and aura, which is not in accordance with IHS guidelines; however, no such instances were recorded; therefore, this had no bearing on the study's results.  Finally, the study's inclusion criteria allowed for a single preventive agent, potentially limiting generalizability of the results in those taking 2 or more preventives.  Relatedly, onabotulinumtoxinA injections as well CGRP mAb injections were allowed (provided that treatment has been stable for at least 2 months), and the specific time-point in the cycle, and administration schedule (every 1/3 months) was not monitored, with some patients potentially experiencing a wearing off effect or a boost effect associated with the injection.

Cowan et al (2023) noted that REN, a prescribed, wearable, FDA-cleared neuromodulation-device for acute and/or preventive treatment of migraine, recently showed effectiveness for migraine prevention when used every-other-day.  In a prospective, randomized, double-blind, placebo-controlled, multi-center study, these investigators examined the clinical benefits and associated direct and indirect cost-savings from REN for migraine prevention.  Following baseline (4 weeks), subjects underwent treatment with REN or placebo (8 weeks), and electronically reported migraine symptoms and acute treatments daily.  Therapeutic-gain was the between-groups difference (REN minus placebo) in change from baseline to the 2nd month of intervention.  Health-economics impact was derived as cost-savings associated with REN's clinical benefits.  Out of 248 subjects randomized (128 active, 120 placebo), 179 (95:84) qualified for mITT analysis.  Significant therapeutic gains favoring REN versus placebo were found (Tepper et al, 2023), including mean (± SD) reduction in number of acute medication days (3.5 ± 0.4 versus 1.2 ± 0.5; gain = 2.2; p = 0.001) and presenteeism days (2.7 ± 0.3 versus 1.1 ± 0.4; gain = 1.6, p = 0.001).  Mean changes of provider visits (reduction of 0.09 ± 0.1 versus increase of 0.08 ± 0.2; p = 0.297), and reduction of absenteeism days (0.07 ± 0.1 versus 0.07 ± 0.2; p = 0.997) were not significant.  Mean annual cost-saving for 1 patient using REN for migraine prevention estimated $10,000 (± $1,777) from reductions in these 4 clinical outcomes relative to baseline without REN treatment.  Extrapolated to a hypothetical U.S. commercial health-plan of 1-million covered lives, assuming the national prevalence of migraine patients on preventive treatment, annual mean (± SE) cost-saving from using REN migraine prevention estimated $560.0 million (± $99.5 million) from reduction in direct (approximately $330 million) and indirect costs (approximately $230 million) measured.  The authors concluded that coverage of the REN-device for migraine prevention may significantly reduce disease-burden and save a 1-million-member payer plan at least $560 million per year. The authors stated that while this was the 1st study to assess and demonstrate cost-saving from REN treatment, a number of study limitations should be acknowledged.  First, several of the endpoints had only scarce occurrences (absenteeism days, provider appointment, and ER visits) or were not at all reported (brain scans and inpatient admissions), limiting the chances of identifying between-groups differences.  Not surprisingly, provider visits are more common than ER visits and brain scans in people with migraine.  A longer study is expected to have higher occurrences of such events, allowing better assessment of the clinical and financial impact of these parameters.  Second, the number of provider appointments and absenteeism days following 2 months of intervention did not significantly differ between REN and placebo.  Yet, the lack of between-groups significance did not negate the contribution and importance of cost-savings from changes in these endpoints in the REN group.  In real-world, there is no "placebo" treatment, and cost-savings results from covering a specific treatment relative to not covering that treatment.  Therefore, even though the difference between the groups in these 2 metrics (which had only scarce occurrences during the study) was not statistically significant, they provided economically meaningful cost-savings from utilizing REN for migraine prevention.  Third, while only a handful of U.S. employers employ more than a million people, there are many commercial health plans that provide health insurance to multiple employers and thus overall cover millions of employees, making the extrapolation presented here relevant for them.  Specific employers can assess the number of their employees that live with migraine and easily scale the cost-savings to their individual plan.  Fourth, the cost-savings presented here might be conservative, under-estimating the full cost-savings from REN preventive treatment.  The current study only assessed cost-savings from endpoints measured during the clinical trial itself and did not include direct cost-savings from the different prices of REN versus other non-generic preventive treatments available in the U.S. which are more expensive.  The study also did not evaluate the indirect costs from the psychological burden of migraine (including anxiety, depression, stress, catastrophizing).  These investigators stated that further research may provide the full cost-effectiveness/cost-utilization analysis aspects associated with using REN to prevent migraine, including acquisition-costs and other burdens.  It should be noted that the study was funded by Theranica Bio-Electronics, LTD.

Esparham et al (2023) stated that nearly 10% of children and adolescents in the U.S. experience migraine.  Pharmacotherapy of migraine in adolescents is limited due to only few FDA-approved medications, limited effectiveness, or lack of tolerability.  REN is a non-pharmacologic abortive treatment for migraine, cleared by the FDA for patients aged 12 years and above.  These researchers examined real-world effectiveness of REN in adolescents aged 12 to 17 years.  Real-world data were collected from patients aged 12 to 17 years treated with the REN device (Nerivio) from January 1, 2021, to May 31, 2022.  Study's endpoints included consistent effectiveness 2 hours after treatment, use of REN as a stand-alone versus as an adjunct therapy, treatment intensity, and safety.  Of 1,629 adolescents included in the study, consistent response in at least 50% of treatments at 2 hours post-treatment was achieved by 60.3% of patients for pain relief, 26.3% for pain freedom, 66.3% for functional disability relief, and 41.2% for functional disability freedom.  Of 2,365 treatments in which medication usage was reported, REN was used as stand-alone therapy in 64.4% of the treatments, REN was combined with over-the-counter medications in 18.6%, and it was combined with prescription medications in 17%.  Mean treatment intensity from 13,716 treatments was 28.5% (± 13.6%) of the max stimulator output.  Only 3 minor device-related AEs were reported.  The authors concluded that this real-world analysis showed the persistent effectiveness of REN for abortive treatment of migraine in adolescents, extending findings of prior clinical trials in adolescents and real-world studies in adults.  Moreover, these researchers stated that future research should measure the percentage of patients who re-fill their prescription and continue using this treatment, albeit this is also influenced by economical/access considerations. The authors stated that this study had several drawbacks.  First, this was not a controlled study -- it had a single-arm of Nerivio users.  Nevertheless, although this implied a difficulty in assessing the results, it was easily compensated using results from numerous clinical trials and RWE studies.  Such a comparison showed that results produced in this study were in line with results previously collected with Nerivio.  Second, effectiveness and medication data were voluntarily provided by patients via the app, which contributed to the fact that not all adolescent users provided the required information at the beginning of the treatment and the following 2 hours.  Nevertheless, complete prospective post-2-hour data resulted in large data-sets (at least 255 participants for each outcome measure), which made this study considerably large. The lead author received honoraria from Theranica, the manufacturer of the Nerivio device. Five of the coauthors are employees of Theranica, and four reported holding stock options in Theranica. One of the coauthors reported participation in Theranica's advisory board.

In a retrospective study, Peretz et al (2023) examined the safety of REN for migraine treatment during pregnancy through 3 months post-partum, relative to other options (medications or no treatment).  It compared women with migraine who treated their migraine with at least 3 REN treatments during pregnancy (REN group) to women with migraine who did not use REN during pregnancy (control group) on critical pregnancy outcomes, with the hypothesis that the groups would not differ on these outcomes.  Eligibility included migraine diagnosis with a frequency of 4 or more migraine days per month for at least 6 months before their pregnancy, last menstrual period between November 1, 2019 and August 1, 2021, age of 18 to 45 years, and 4 or more migraine attacks during the study pregnancy.  An online survey was sent to all women in the specified age range and within the REN device users’ database and to patients in participating headache clinics.  The primary endpoint was gestational age at delivery.  Secondary endpoints were baby's birth weight, miscarriage rate, preterm birth rate, birth defect rate, still-birth rate, rate of babies meeting developmental milestones 3 months post-natal, and emergency room (ER) visits.  Participants provided online informed consent.  Independent t-tests and Fisher exact tests were used to compare continuous endpoints and rates between groups, respectively.  Tests were 2-tailed, with p < 0.05 considered statistically significant.  A total of 171 women completed the study, of which 140 (REN = 59; control = 81) met inclusion criteria for analysis.  No statistical difference was found between groups with regard to demographics.  There was no statistical difference in the primary endpoint of gestational age between the REN (mean ± standard deviation [SD]: 38 weeks and 5 days ± 1 week and 6 days) and control groups (39 weeks and 0 days ± 1 week and 2 days; mean difference [MD] of 3 days; confidence interval: −7 days to 1 day; p = 0.160).  All 7 secondary endpoints did not differ between REN and control groups: newborn weight (mean ± SD: 7.2 ± 1.2 versus 7.2 ± 1.0 pound; MD of 0 pound; CI: -0.4 to 0.4; p > 0.999), miscarriage rate (3.4% versus 3.7%, p = 0.918), preterm birth rate (14.0% versus 6.4%; p = 0.138), birth defect rate (14.0% versus 14.1%, p = 0.991), still-births rate (0% versus 0%; p > 0.999), rate of newborns meeting developmental milestones at 3 months post-natal (96.5% versus 94.9%; p = 0.652), and rate of participants who visited ER during their pregnancy (15.3% versus 17.3%; p = 0.749).  The authors concluded that the findings of this study indicated that the REN device was a safe treatment of migraine during pregnancy, not increasing the risk for adverse pregnancy outcomes; thus, offering a much-needed non-pharmacological alternative for women with migraine during pregnancy.  It should be noted that this study was funded by Theranica Bio-Electronics LTD.

Blumenfeld et al (2023) examined the onset, magnitude, and persistence of effectiveness of REN compared with placebo for the preventive treatment of migraine.  Analysis was carried out on data from a prospective, double-blind, placebo-controlled clinical trial, which assessed the effectiveness of REN for the prevention of migraine.  The number of monthly migraine days (MMD) per group was calculated in 2-week intervals and compared between the groups.  Differences between the active (n= 95) and placebo (n = 84) groups reached significance at 2 weeks: therapeutic gain 0.84 MMD; p = 0.036. 4 weeks gain 1.59 MMD; p = 0.025, 6 weeks gain 2.27 MMD; p < 0.001, 8 weeks gain 2.68 MMD; p < 0.001.  The authors concluded that REN provided rapid and consistent effectiveness in preventive treatment of migraine. These investigators stated that the study's main limitation was its duration.  Given that the double-blind period of the RCT was limited to 8 weeks, longitudinal data regarding the temporal dynamics of distinctions between the active treatment and placebo was not available.  Such a study is currently being conducted.  Furthermore, the analyzed data were taken from a clinical RCT setting.  While RCTs are considered to provide the highest standard of clinical data (in terms of AEs monitoring, effectiveness and more), they may also induce some degree of bias (e.g., via specification of admission criteria).  A real-world analysis of the temporal patterns would complement the presented results, and is currently being conducted.  It should be noted that this study was funded by Theranica Bio Electronics LTD.

Babaei and Rapoport (2023) discussed Nerivio’s structure, mechanism of action, indications for use, application instructions, effectiveness, AEs, tolerability, safety, patient satisfaction, associated application and the research highlights.  The authors stated that the device works well for most individuals living with migraine, often without concomitant medication, is tolerable, safe and causes minimal and mild adverse effects.  It expands migraine therapeutic options and improves patient adherence to treatment.  These investigators noted that Nerivio is easy-to-use and can be worn at any time of the day; it provides a non-pharmacologic option for the optimization of migraine treatment without significant AEs.

Synowiec et al (2024) noted that migraine is a chronic neurological disorder causing severe pain and disability in more than a billion people worldwide.  Ideal treatment should provide long-term effectiveness with minimal side effects.  Previous studies showed that REN is a safe and effective therapeutic option for the acute treatment of migraine in clinical practice.  These investigators examined long-term safety, utilization, and effectiveness of REN during 12 consecutive usage months.  Data from patients with migraine across the U.S. using REN to treat their migraine attacks were electronically collected from the Nerivio device.  All patients who used REN during 12 consecutive months were included, and data were compared across months.  Safety was assessed by the number and type of AEs.  Utilization was measured by the number of monthly treatments.  Effectiveness was evaluated as consistent change in headache pain intensity, functional disability, and disappearance of associated symptoms from baseline to 2 hours post-treatment.  Data were analyzed from 409 people living with migraine who treated with REN for 12 consecutive months, performing a total of 39,531 treatments.  The incidence of device-related AEs (dAEs) was 1.96% (8/409), including 2 negligible (0.49%), 5 mild (1.22%), 1 moderate (0.24% ), and no severe events.  All patients continued treatment with REN despite dAEs.  One-year average monthly utilization was 8.05 treatments (SD 1.15).  Month-to-month utilization did not change during 12 months of consecutive use [F(4.895, 1997.204) = 2.014, p = 0.075, repeated-measures ANOVA].  One-year average effectiveness showed 74.1% of users reported consistent 2-hour pain relief, and 26.0% reported consistent pain freedom.  Month-to-month pain relief and pain freedom did not change during 12 months of consecutive use [F(11, 1069) = 0.55, p = 0.873 and F(11, 1295) = 0.69, p = 0.750 respectively; generalized linear mixed model analysis].  The authors concluded that REN was a safe and well-tolerated acute migraine treatment, with stable effectiveness and utilization over 1 year, making it an advantageous non-drug option for the long-term management of this chronic disease. These investigators stated that while this was the 1st study to assess long-term treatments with REN, there are some study limitations that should be acknowledged.  First, the users included in this analysis constituted a subset of all REN device users.  As in any sub-analysis, there is a concern for selection bias.  In this case, users who did not treat consecutively for 1 year were not included in the study.  These researchers therefore excluded users who did treat for at least 1 year; however, they did not treat in each and every calendar month of the year.  Such a scenario could result from either infrequent attacks or from using a combination of treatments (having a "migraine toolbox") and deciding which treatment(s) to use for each attack.  Some users excluded from this analysis were also those who discontinued treating with REN, and thus did not meet the 12 consecutive treatment months criterion.  Discontinuation of REN could result from lack of effectiveness for some patients.  Pain relief from various acute migraine treatments is around 60%, and despite REN being on the higher end with 66.7% of the patients reporting pain relief in the pivotal REN randomized controlled study of acute treatment of migraine, by Yarnitsky et al (2019), there is no one treatment that works for all patients with migraine.  However, the authors’ only selection criterion was at least 1 treatment per month, for 12 consecutive months, without any additional constraint on the number of monthly treatments, safety, or effectiveness.  Second, this trial did not incorporate additional outcomes such as standardized migraine questionnaires to measure the effects of REN on patients’ QOL, which could show a wider effect than focusing mainly on measures of effectivity.  However, since this was a real-world evidence study and not a clinical trial, there was a limit to the number of questions patients can be asked and expected to answer on a regular basis via a commercial app (i.e., every treatment).  Standardized migraine questionnaires can be embedded in the app and users may be prompted to answer them periodically to examine associations of REN long-term use with QOL and with psychiatric comorbidities in future studies.  Third, although 1-year consecutive use is considered a long period to track patients, studies looking at longer durations could benefit the medical and patient communities.  This is true for all types and families of migraine treatments, pharmacological and devices alike.  However, REN has the benefit that usability information regarding each and every treatment performed is automatically registered into the Nerivio app and database, even without the need for patients to actively record this data, making it more accurate than information from patient or pharmacy-reported drug usage.  Having validated data provides a strong benefit, and future studies can be conducted to track patients over even longer time periods.  It should be noted that Theranica Bio-Electronics Ltd. funded this study, as well as the journal’s Rapid Service fee.  Alit Stark-Inbar and Alon Ironi are employees of and hold stock options in Theranica Bio-Electronics Ltd.; Maya Weinstein and Andrea Synowiec have consulted for Theranica Bio-Electronics Ltd.; Alexander Mauskop has nothing to disclose.

Hershey et al (2024) noted that migraine affects 10% of adolescents and children.  Typical school protocols in the U.S. require pharmacotherapies to be administered by school nurses, often resulting in treatment delays or omissions when migraine attacks occur during school hours.  The REN wearable is an FDA-cleared smartphone-controlled device delivering acute and preventive treatment of migraine attacks in patients aged 8 and above, allowing safe, effective, discreet, and independent usage.  In a retrospective study, these researchers examined treatment patterns, barriers, as well as preferences among school-age students.  REN users (18 years old or younger) were invited to complete an online survey.  Participants signed an assent form, and their parents/legal guardians signed an informed consent form.  A total of 332 patients aged 7 to 17 years (15.5 ± 2.1) participated (80.4% female).  After being prescribed the REN wearable, the percentage of students who treated their headaches at school increased from 78.3% to 89.8%.  Most participants (65.4%) treated with either REN standalone (38.0%) or in combination with medications (27.4%).  Common barriers to treatment included the need to leave class for the nurse's office (64.2%), concerns regarding standing out (42.2%), and 1 barrier unique to REN -- permission needed to use a smartphone in class (22.9%).  The most common reasons given for preferring REN treatment at school were the ability to avoid going to the nurse's office (42.5%) and to treat discreetly (39.2%).  The authors concluded that this trial supported the hypothesis that students often refrain from treating their migraine headaches at school due to the need to leave class and the social discomfort in asking for medications.  The REN wearable offers a drug-free, discrete, and effective treatment that can be self-administered without the need to leave class or face stigma.  These investigators stated that by addressing the key barriers associated with migraine and the treatment of migraine at school, REN has the potential to transform migraine management in school-aged children and adolescents; thus, REN should be examined as a 1st-line therapeutic option covered by insurance for school-aged students living with migraine. The authors stated that the principal drawback of this trial was that all subjects were recruited from the REN data-base; thus, creating a potential bias favoring REN over other treatments.  That said, in almost every study of treatment interventions, whether a controlled trial or a real-world study, participants are typically those who are not fully satisfied with their existing therapies and try more novel treatments.  Moreover, in this trial, there was no recruitment bias favoring frequent REN users or those who were treated with REN within school settings, as any student treated with REN at least once in any location (home, school, elsewhere) was eligible to participate in the study.  These investigators stated that future research and advocacy should focus on increasing awareness to the benefits of REN among school administrators, school nurses, as well as healthcare providers.  Integrating REN into standard school health practices, where traditional pharmacotherapies pose significant challenges, could improve migraine management in students, offering a user-friendly, effective alternative to traditional medications.

Synowiec et al (2025) noted that migraine affects millions of individuals in the U.S., resulting in high healthcare costs and productivity loss.  Traditional pharmacotherapies are often limited in effectiveness and tolerability, creating a need for accessible non-pharmacologic options.  In a coverage with evidence development (CED)  study, these researchers examined the necessity of the REN wearable device for migraine  treatment as a standard payer-covered treatment.  This trial was a real-world post-marketing CED study in 2 clinics for 14 months.  Members (aged 12 to 75 years) of a major U.S. health insurer (Highmark Inc) diagnosed with migraine were prescribed REN as part of their clinical care.  Effectiveness was assessed by change in MIDAS score from baseline to 3 months of treatment and by prospective pain and disability reports 2 hours post-treatment.  Utilization was measured via prescription fulfilment as well as safety via AE reports.  A total of 381 patients (mean [SD] age, 40.5 [13.2] years; 91.1% women) participated.  Change in MIDAS score was calculated from all participants who answered the questionnaire twice (n = 116), showing a significant and clinically meaningful mean (SD) improvement of -12.1 (51.8) points (p = 0.014), from 58.3 (59.0) to 46.2 (44.1).  Of the participants, 77.8% reported pain relief and 33.3% reported pain freedom; 70.6% and 50.0% reported relief and freedom from functional disability, respectively.  Patients used a mean (SD) of 4.0 (3.1) devices annually (extrapolated); 3 minor AEs were reported.  These positive outcomes resulted in the inclusion of REN as a standard treatment for migraine under Highmark policy.  The authors conclude that REN showed significant clinical and functional benefits in patients with migraine.  Additional health insurers are encouraged to consider REN as a standard covered treatment. The authors stated that this study had several drawbacks.  First, the study initially focused solely on acute migraine treatment.  A few months into the program, the indication was expanded to include prevention use as well; however, study end-points were already set and could not evaluate prevention effectiveness directly, leaving room for future research to examine the long-term effectiveness and potential cost-savings associated with REN dual use.  Second, questionnaire completion (MIDAS, TSTQ) was not mandatory, although the response rate of 1/3 was high for real-world health surveys, and missing data analyses showed no differences in prospective efficacy between 3-month MIDAS responders and non-responders.  Furthermore, the fact that more female subjects answered the MIDAS questionnaire aligned with global patterns of surveys.  Third, a full health economics analysis was not included in the current analyses, although ample data supported a positive coverage decision.

Ailani, et al. (2025) conducted a large prospective real-world evidence study to evaluate whether the timing of remote electrical neuromodulation (REN; Nerivio) treatment influences acute migraine outcomes, comparing treatment initiated within one hour of migraine onset ("early") with treatment started more than one hour after onset ("late"). The investigators analyzed data collected through the Nerivio smartphone application from 55,261 U.S. patients who completed 586,981 REN treatments between 2019 and 2024. Patients voluntarily reported treatment timing, headache severity, functional disability, migraine-associated symptoms, and two-hour post-treatment outcomes. Effectiveness analyses were restricted to evaluable treatments in which both baseline and two-hour outcome data were available and REN was used without concomitant acute medication. Across all measured outcomes, early treatment was associated with significantly better results than late treatment (all p<0.001 after Bonferroni correction). At the treatment level, early treatment produced higher rates of pain relief (65.1% vs 46.6%), pain freedom (28.8% vs 14.5%), functional disability relief (58.1% vs 49.3%), functional disability freedom (35.4% vs 20.9%), and freedom from photophobia, phonophobia, and nausea/vomiting. Similar findings were observed at the patient level, where individuals who consistently treated early achieved superior outcomes across all efficacy measures. A youth subgroup analysis also demonstrated significantly improved outcomes with early treatment initiation. The authors concluded that initiating REN within one hour of migraine onset can improve acute treatment efficacy by up to approximately 20 percentage points and may double the likelihood of achieving symptom relief or freedom compared with later treatment. Key study limitations included reliance on self-reported data for migraine symptoms and treatment timing, potential reporting bias, and the fact that two-hour follow-up data were available for only a minority of treatments, which limited efficacy analyses to roughly 10% of reported treatments and patients despite the large overall dataset.

Cocores et al (2025) reviewed neuromodulation techniques currently available for headache management, with a focus on recent advances in non-invasive devices for migraine and trigeminal autonomic cephalalgias.  These investigators stated that c currently available FDA-cleared non-invasive devices for migraine include transcutaneous supra-orbital and supra-trochlear nerve stimulation, single-pulse transcranial magnetic stimulation (sTMS), external concurrent occipital and trigeminal neurostimulation (eCOT-NS), REN, as well as non-invasive VNS (nVNS) with indications for migraine and trigeminal autonomic cephalalgias.  Emerging non-invasive techniques being examined for use in migraine include transcranial direct current stimulation (tDCS), kinetic oscillation stimulation (KOS), as well as auricular transcutaneous VNS (at-VNS).  In addition to primary headache, non-invasive neuromodulation is being examined for co-morbid conditions such as depression.  The authors concluded that there have been rapid developments in the use of non-invasive neuromodulation for primary headache disorders.  Peripheral neurostimulation is a safe and effective way to modulate the central nervous system (CNS) in headache practice.  Moreover, these investigators noted that although there has been wide variability in study design and in each device’s ability to achieve key end-points, these neuromodulation devices have wide applicability.  They stated that despite their safety and effectiveness, limitations of use remain.  With only a few very recent exceptions, devices are generally considered experimental or investigational, and are not covered by conventional insurance plans.  These researchers stated that further investigations are needed to examine cost-effectiveness, which may improve providers’ willingness to recommend neuromodulation and improve overall patient access.  Going forward, research on neuromodulation for the potential treatment of other primary headaches, in addition to secondary headaches such as medication overuse headache and post-traumatic headache is needed. Finally, better methods are needed to optimize clinical trials efforts and to translate evidence into clinical practice.

In a review on "Neuromodulation in chronic migraine: Evidence and recommendations from the GRADE framework", Tana et al (2025) stated that chronic migraine afflicts about 2% of the general population.  It is often refractory to pharmacotherapies and is associated with a significant burden in functions of daily life during ictal phases, productivity loss, as well as direct costs.  Modulation of pain is considered crucial to reduce its impact and to improve the QOL among patients with chronic migraine.  In recent years, neuromodulation in chronic migraine has received growing attention; however, there remains no consensus regarding the effectiveness and safety of these procedures.  Previous invasive methods such as occipital nerve neurolysis and interruption of the trigeminal dorsal root are not indicated due to high rates of relapsing pain and frequent procedural complications.  Although emerging neuromodulation methods, both non-invasive, such as VNS, TMS, REM, as well as invasive, such as DBS, ONS, and high-frequency 10-Hz spinal cord stimulation (HF-10 SNS) have shown promising outcomes in early clinical trials, their use has yet to be integrated into routine clinical practice.  In this review, study evidence and strength of recommendations were assessed by the GRADE system.  The authors concluded that available evidence on the use of neuromodulation for the treatment of chronic migraine, as assessed using the GRADE classification, remains limited, necessitating a cautious approach to their clinical application.  These investigators noted that while integrating neuromodulation with pharmacotherapies and lifestyle modifications could theoretically enhance therapeutic success, especially in treatment-resistant migraine, further investigations are needed to better define its role and clinical impact. 

Werner et al (2024) noted that migraine is a prevalent neurological disorder severely impacting children and adolescents, yet only 1 pharmacotherapy is approved for ages 6 to 12 years.  Remote electrical neuromodulation (REN) is a non-pharmacological, prescribed, wearable device cleared by the FDA for acute and/or preventive treatment of migraine with or without aura in patients 12 years and older.  In a prospective study, these researchers examined the safety and effectiveness of REN in children aged 6 to 11 years.  Acute treatment of migraine data were collected via the REN device (Nerivio) smart-phone app.  Endpoints were device safety (primary); consistent treatment effectiveness (headache pain, functional disability, associated migraine symptoms), and REN‐medication combinations 2 hours post‐treatment.  Children (n = 293), median age of 11 years (IQR = 9 to 11), 73.7 % girls, conducted 5,493 REN treatments; no AEs were reported.  Effectiveness in at least 50 % of REN treatments was calculated from all patients who voluntarily reported pain levels, symptoms, and/or disability at treatment onset and at 2 hours post‐treatment, with 72.2 % (13/18) of patients reporting pain relief, 36.0 % (9/25) pain freedom, 83.3 % (15/18) functional disability relief, and 38.9 % (7/18) functional disability freedom.  Migraine‐associated symptoms disappeared in at least 50 % of REN treatments in 70.0 % (7/10) of patients for nausea/vomiting, 50.0 % (4/8) phonophobia, and 22.2 % (2/9) photophobia; 63.6 % (7/11) reported freedom from at least 1 associated symptom.  REN was used as a stand-alone treatment, with over‐the‐counter medications, and with prescribed headache medications in 45.4 %, 34.4 %, and 20.9 % of treatments, respectively.  The authors concluded that REN may serve as a safe and effective acute treatment of migraine for children. The authors stated that this study had several drawbacks.  First, it was not a controlled trial, and it entailed a cohort of patients using the Nerivio device; thus, it might be more difficult to interpret the placebo contribution.  Nevertheless, the observed findings aligned with findings in previous REN controlled clinical trials as well as in other REN real‐world evidence studies.  Second, while effectiveness rates were high, not all children provided data for effectiveness calculations.  REN effectiveness was calculated from voluntarily in‐app reports of symptoms and use/avoidance of rescue medications at both treatment onset and at 2 hours post‐treatment.  Therefore, because baseline and post‐treatment reports were voluntary, the fact that the data were collected from real‐world treatments (as opposed to a structured clinical trial), and that many children at this young age of 6 to 11 years did not have their own smart-phones and used their parents' smart-phones to administer the REN treatment; therefore, it was not surprising that the children went about their day once they achieved pain freedom or relief from their migraine attacks and did not bother to provide reports.  Moreover, the fact that most patients (76.1 %) continued treating 4 or more treatments even without providing symptom reports by itself represented satisfaction.  This further highlighted the importance of guiding patients to use the REN device -- the same as with other acute treatments of migraine -- a few times before their parents or care-givers decide whether their child should continue using it.  Third, this cohort included all children under the age of 12 years who were treated with REN until the time of data analysis.  The age among the cohort of children was not uniformly distributed, with more children in the older subgroup than the very younger subgroup of 6 to 7 years of age.  This was not surprising, given that the incidence of migraine increases with age.  These researchers stated that more data are continuously collected from all children treating with REN; thus, larger cohorts of young children are expected to be available for future studies.  These researchers stated that a future study examining REN for migraine prevention in this age group is recommended.

Blumovich et al. (2025) evaluated the real-world experience of pediatric patients using the Nerivio remote electrical neuromodulation (REN) device for migraine treatment, with the objective of assessing patient perceptions of headache control, functional outcomes, medication use, satisfaction, and treatment preference in a pediatric neurology clinic population. The investigators conducted a preliminary observational study at a pediatric neurology clinic in Kansas City, Missouri, enrolling patients aged 10 to 18 years who had experience using both acute migraine medications and the REN device. Participants completed two structured retrospective questionnaires, one focused on experiences with acute medications and the other on experiences with REN. The questionnaires assessed headache characteristics, school attendance, daily functioning, treatment effectiveness, medication use, satisfaction, and preference. Functional measures were adapted from the Pediatric Migraine Disability Assessment (PedMIDAS), and analyses were primarily descriptive because of the study’s exploratory design and small sample size. The study included 24 patients, 91.7% of whom were female and most of whom were between 13 and 18 years of age. Regarding the primary outcomes, 33.3% of participants reported that REN completely stopped their headaches, 50.0% reported that it shortened headache duration, and 41.7% reported a reduced need for acute medications after initiating REN. Functional outcomes suggested potential improvement in headache-related disability. Missed full school days remained unchanged at an average of 3.8 days, but missed partial school days decreased slightly from 3.1 to 3.0 days. Days with limited activity decreased from 3.5 to 2.7 days, representing a 23% reduction, and days with less than 50% functioning decreased from 4.1 to 3.2 days, representing a 22% reduction. Treatment preferences varied, with 37.5% preferring Nerivio, 20.8% preferring medications, and 41.7% reporting equal preference for both approaches. Satisfaction was high, as 83.3% of patients stated they wished to continue using the device. Only 12.5% reported mild transient discomfort such as tingling or tightness at the stimulation site, and all continued treatment despite these effects. The study has several important limitations. The sample size was very small and derived from a single tertiary care center, limiting the generalizability of the findings. Outcomes relied entirely on retrospective patient self-report, which introduces recall and reporting bias. Because both medication and REN questionnaires were completed during the same visit, the study reflects patient perceptions rather than prospective longitudinal outcomes, and causal or preventive effects cannot be inferred. The investigators did not systematically collect detailed data regarding headache frequency, the number of REN treatment sessions, or acute medication use before and after device initiation, limiting the ability to quantify treatment effects. In addition, some patients continued to use acute medications alongside REN, which may have confounded treatment attribution. Finally, the analyses were descriptive only and no formal statistical testing was performed, making the findings exploratory and hypothesis-generating rather than definitive.

Orr et al. (2025) conducted a pilot randomized controlled trial to evaluate the feasibility and acceptability of comparing remote electrical neuromodulation (REN) with standard intravenous emergency department (ED) treatment for migraine in children and adolescents, and to determine whether a parallel-group or crossover study design would be more practical for future definitive trials. The investigators used a double-dummy, double-blind design in which participants aged 8 to younger than 18 years who presented to a Canadian tertiary pediatric ED with migraine were randomized to receive either active REN plus intravenous placebo or sham REN plus standard intravenous metoclopramide and ketorolac. The study was conducted in two phases, initially using a parallel-group design and later incorporating a crossover component. The primary outcomes focused on recruitment, retention, protocol feasibility, and participant and staff acceptability, while preliminary efficacy and safety outcomes were also collected. Among 147 screened participants, 65 were eligible and 22 consented to participate, resulting in an enrollment rate of 34% of eligible patients; 19 participants ultimately received treatment and completed all study assessments. Recruitment was more successful during the parallel-group phase than during the crossover phase, with enrollment rates of 1.1 versus 0.6 participants per month, respectively. Participants and ED staff generally reported favorable views of both the study protocol and the use of REN in the ED setting. Youth expressed greater interest in using REN rather than intravenous therapy for future ED visits. Preliminary efficacy data showed reductions in pain severity in both treatment groups. Mean pain reduction from baseline to two hours was 2.4 points in the REN group and 4.0 points in the standard care group. Although the study was not powered to compare efficacy, the differences between groups were relatively small and the investigators noted that REN could potentially be noninferior to standard intravenous therapy. Safety findings were favorable, with no adverse events reported in the REN group and one case of akathisia reported in the standard care group. The study has several important limitations. Its primary purpose was to assess feasibility rather than efficacy, and the small sample size limited the ability to draw definitive conclusions regarding comparative effectiveness or safety. Recruitment occurred during the COVID-19 pandemic, a concurrent respiratory virus surge, and a regional Escherichia coli outbreak, all of which likely negatively affected enrollment. The crossover phase was shorter than the parallel-group phase because of regulatory delays, which may have influenced comparisons between study designs. In addition, approximately 90% of participants were White, limiting the generalizability of the findings to more diverse populations. The authors also noted that nearly one-third of screened patients were excluded solely because they did not meet the strict migraine diagnostic criteria used in the study, suggesting that broader eligibility criteria might improve recruitment in future trials. Despite these limitations, the study demonstrated that a double-dummy trial comparing REN with standard intravenous migraine therapy in pediatric ED patients is feasible and acceptable and provided justification for a larger, adequately powered noninferiority trial.

Charugulla et al. (2025) evaluated the real-world effectiveness and safety of the remote electrical neuromodulation (REN; Nerivio) wearable device for the treatment of episodic and chronic migraine in India, where evidence regarding neuromodulation therapies has been limited. The investigators conducted a retrospective, observational real-world evidence study using deidentified data from the Portea Medical patient support program and the Nerivio smartphone application. The analysis included 1,033 patients aged 12 years or older who had been prescribed the device by neurologists and used it at least once between August 2023 and July 2024. Most participants were female (74.8%), had chronic migraine (84.6%), and had experienced migraine for an average of 10.6 years. Primary outcomes assessed pain relief, pain freedom, functional disability relief, functional disability freedom, and safety, while secondary outcomes included changes in monthly headache days and medication use. The study found that REN provided clinically meaningful benefits for many patients. Two hours after treatment with REN as a standalone therapy, 57.3% of patients reported pain relief, 29.4% achieved pain freedom, 47.1% experienced functional disability relief, and 26.1% reported complete freedom from functional disability. At the three-month follow-up, 70.3% of the overall cohort reported improvement, with 44.3% describing moderate relief and 26.0% reporting significant relief. Mean pain severity measured on the visual analog scale decreased significantly from 8.4 to 6.1, representing a mean reduction of 2.3 points (p < 0.001). REN use was also associated with reductions in migraine burden. Among patients with chronic migraine who initially experienced more than 14 headache days per month, over half reported fewer headache days after treatment. Medication use also decreased significantly, with many patients reducing the frequency or dosage of oral migraine medications. Safety outcomes were favorable. No severe adverse events were reported. Among the 43.9% of patients who provided safety feedback, 38.7% reported no adverse events and only 1.74% reported device-related adverse events, which were generally mild and included arm or hand pain, worsening headache, nausea, and vomiting. Several limitations should be considered when interpreting the findings. The retrospective observational design limits the ability to establish causality, and the absence of a control group prevents direct comparison with alternative migraine treatments. The study relied heavily on patient-reported data collected through a smartphone application and follow-up telephone interviews, creating the potential for recall bias and reporting variability. Missing or incomplete data resulted in varying sample sizes across different analyses. Furthermore, because the study population consisted of patients who received prescription digital therapeutics through a patient support program, the findings may not be fully representative of all individuals with migraine in India. Finally, the study was funded by Dr. Reddy’s Laboratories, the distributor of the device in India, and one author was employed by Theranica, the manufacturer of Nerivio, which introduces the potential for sponsor-related bias.

Alnajjar et al. (2025) conducted a comprehensive systematic review and meta-analysis to evaluate the efficacy and safety of remote electrical neuromodulation (REN) for the acute treatment and prevention of migraine. The investigators sought to address gaps in the existing evidence by synthesizing data from clinical trials and observational studies examining REN, a noninvasive wearable therapy that stimulates peripheral nerves in the upper arm to activate conditioned pain modulation pathways. The review followed PRISMA and Cochrane methodology and was registered in PROSPERO (CRD42024596712). Searches of PubMed, Scopus, Web of Science, and the Cochrane Library through October 2024 identified eligible randomized controlled trials, crossover studies, observational studies, and single-arm trials evaluating REN in children and adults with migraine. Twelve studies involving 9,912 patients were included. Risk of bias was assessed using ROB2, the Newcastle-Ottawa Scale, and NIH quality assessment tools according to study design, and meta-analyses were performed using both single-arm and double-arm approaches. The review found substantial evidence supporting the efficacy of REN for migraine treatment. In the single-arm analyses, 64% of patients experienced pain reduction within 2 hours of treatment, while 22% achieved complete pain freedom at 2 hours. Sustained benefits were also observed, with 59% of patients reporting sustained pain relief at 24 hours and 54% reporting sustained pain-free status at 24 hours. Functional outcomes improved considerably, with 59% of patients experiencing meaningful functional improvement within 2 hours. In addition, 54.6% reported resolution of their most bothersome migraine symptom, and improvements were also observed for nausea or vomiting, photophobia, and phonophobia. In the comparative analyses, REN significantly outperformed sham stimulation for achieving pain-free status at 2 hours (odds ratio 2.77; 95% CI, 1.63-4.71), with sensitivity analyses demonstrating even stronger efficacy estimates after accounting for heterogeneity among studies. These findings led the authors to conclude that REN is an effective nonpharmacologic treatment that can improve pain outcomes, functional ability, and migraine-associated symptoms. Safety findings were favorable. Device-related adverse events occurred in only 0.4% of REN users across more than 19,000 reported treatment exposures. The double-arm meta-analysis showed no statistically significant difference in device-related adverse events between REN and sham treatment (odds ratio 1.45; 95% CI, 0.42-4.94). Reported adverse events were generally mild to moderate, including tingling sensations, skin redness, rash, arm discomfort, or transient visual symptoms, and typically resolved within 24 to 48 hours. No serious or systemic device-related adverse events were reported. The authors therefore concluded that REN demonstrates a favorable safety profile compared with many pharmacologic migraine therapies. Several limitations should be considered when interpreting the findings. The review combined different study designs, including randomized controlled trials, observational studies, and single-arm studies, which may have increased heterogeneity and introduced methodological variability. Much of the pooled evidence came from single-arm studies without control groups, making it difficult to fully exclude placebo effects, patient expectations, or regression to the mean as contributors to the observed outcomes. Follow-up periods were generally short, limiting assessment of long-term efficacy, tolerability, durability of benefit, and cost-effectiveness. The investigators did not perform subgroup analyses according to migraine type, such as episodic versus chronic migraine, which may have obscured differences in treatment response among patient populations. Finally, the included studies varied in methodological quality, and the cumulative long-term adverse effects of neuromodulation remain incompletely understood. Despite these limitations, the authors concluded that REN appears to be an effective and safe treatment option for migraine, while emphasizing the need for larger and longer-term randomized trials.

Birlea et al. (2025) reviewed the proposed mechanism of action of remote electrical neuromodulation (REN) and its application in the treatment and prevention of migraine, with the broader objective of explaining how REN may also be relevant to other idiopathic pain disorders characterized by impaired endogenous pain inhibition. The review focused on the physiological and anatomical basis of conditioned pain modulation (CPM), a descending pain inhibitory mechanism often summarized as "pain inhibits pain." Rather than reporting new clinical data, the authors conducted a narrative review of preclinical, mechanistic, and clinical literature examining CPM, migraine pathophysiology, neurotransmitter systems involved in pain inhibition, and studies evaluating the REN device (Nerivio). The review synthesized evidence from animal studies, human experimental studies, randomized controlled trials, clinical studies, and real-world observational research. The review describes CPM as an endogenous analgesic mechanism mediated through brainstem structures including the periaqueductal gray and rostral ventromedial medulla, which modulate nociceptive signaling through descending inhibitory pathways. The authors summarize evidence that activation of A-delta and C nociceptive fibers can trigger CPM and that neurotransmitters such as serotonin and norepinephrine play central roles in this process. They further review evidence suggesting that individuals with migraine frequently exhibit deficient CPM responses, which may contribute to heightened pain sensitivity, central sensitization, and susceptibility to migraine attacks. Similar CPM deficiencies have also been reported in other idiopathic pain disorders, including fibromyalgia and irritable bowel syndrome. The authors propose that REN works by applying electrical stimulation to the upper arm using a waveform designed to activate A-delta and C fibers, thereby engaging CPM and promoting release of serotonin and norepinephrine that inhibit nociceptive transmission within trigeminal pain pathways. The review also summarizes clinical evidence indicating that REN has demonstrated efficacy for both acute and preventive migraine treatment in randomized controlled trials, clinical studies, and real-world investigations, with efficacy reported to be comparable to several established pharmacologic migraine treatments. The review additionally discusses evidence suggesting reductions in migraine days, headache days, medication use, and procedural pain associated with onabotulinumtoxinA injections in patients treated with REN. The authors conclude that REN represents an innovative, noninvasive, nonpharmacologic treatment that leverages endogenous pain inhibition mechanisms to relieve migraine symptoms. They state that substantial mechanistic, preclinical, and clinical evidence supports CPM as the biological basis for REN's therapeutic effects and that the technology may have future applications in other idiopathic pain disorders characterized by impaired pain modulation. However, the authors acknowledge that some aspects of REN's mechanism remain incompletely understood, particularly how it improves nonpain migraine symptoms such as photophobia, phonophobia, and nausea. The review is also limited by its narrative design, which does not employ systematic review methods, formal literature selection criteria, or quantitative meta-analytic techniques. Because much of the clinical evidence summarized originated from studies sponsored by or involving the manufacturer of the device, the potential for sponsorship bias should also be considered when interpreting the conclusions. In addition, many mechanistic inferences are derived from preclinical and experimental pain studies rather than direct demonstration of biological effects in migraine patients treated with REN.

In International Headache Society's evidence-based guidelines on the use of non-invasive neuromodulation devices for the acute and preventive treatment of migraine (Yuan, et al., 2025), the panel conditionally recommends the use of Nerivio for the treatment of acute migraine attacks in adult subjects with episodic migraine (EM), based on 2 very low quality RCT (weak strength of recommendation, very low quality). For preventative treatment of chronic migraine or EM in adults, the panel recommends the use of Nerivio based on low and very low quality studies (weak strength of recommendation, very low quality). Furthermore, the panel’s recommendation on Nerivio for pediatric patients is limited to expert consensus suggestions only (from published studies not eligible for GRADE evidence), stating Nerivio can be an option for treatment of acute migraine attacks in pediatric patients 8 years old and older and for preventative migraine treatment in adolescents.

An American Headache Society consensus statement states REN can be used as monotherapy or in combination with other treatments in acute and preventive treatment in patients who prefer non-pharmacotherapy approach and those with inadequate response, intolerance, or contraindication to pharmacotherapy. However, the consensus recommendations are not developed through GRADE approach but based on expert opinion only (Ailani, et al., 2021).

Asmar et al. (2026) conducted a prospective, single arm compatibility study to determine whether simultaneous use of the Nerivio remote electrical neuromodulation (REN) wearable and continuous glucose monitoring (CGM) systems interferes with glucose monitoring performance in adults with diabetes. The rationale was that many patients with comorbid diabetes and migraine may use both technologies concurrently, but the effects of REN-generated electrical stimulation and Bluetooth communication on CGM accuracy had not previously been evaluated. The investigators enrolled 21 adults with diabetes who were using either Dexcom G6/G7 or FreeStyle Libre 2/3 CGM systems. Participants completed a single 45 minute in-person study session during which both the CGM and REN devices were operated simultaneously on the same smartphone. CGM measurements were collected during periods when the REN device was active and during brief pauses in stimulation. The primary outcome was the mean absolute relative difference (MARDREN ON/OFF) between glucose readings obtained during REN activation and REN deactivation, with a prespecified compatibility threshold of less than 5%. The study found that concurrent use of REN and CGM devices produced minimal differences in glucose readings. The median MARDREN ON/OFF across all participants was 1.61% (interquartile range, 0.84% to 2.44%), which was significantly below the predefined 5% threshold (p < 0.001). All 21 participants achieved MARD values below 5%, indicating consistent agreement between CGM readings obtained during active and inactive REN use. Results were similar across device manufacturers, with median MARD values of 1.70% for Dexcom devices and 1.05% for Abbott FreeStyle Libre devices. No Bluetooth connectivity problems, sensor malfunctions, missed data transmissions, false alarms, app failures, adverse events, or device-related safety concerns were observed during the study. The authors concluded that simultaneous use of the Nerivio REN wearable and commonly used CGM systems is safe, technically compatible, and does not adversely affect glucose monitoring performance. Several limitations should be considered when interpreting the findings. The study was designed to evaluate technical compatibility rather than clinical efficacy and included only 21 participants, limiting statistical power and generalizability. The single arm, single session design evaluated device performance over a brief period under relatively stable conditions without meals, exercise, sweating, physiologic stress, or hypoglycemic episodes, so compatibility during more dynamic glycemic states remains uncertain. Participants were not required to have migraine, and device compatibility was not assessed during active migraine attacks. In addition, subgroup analyses for Abbott devices included only six participants, including a single FreeStyle Libre 2 user, which limits confidence in device-specific conclusions. Finally, the study was funded by Theranica, the manufacturer of Nerivio, and several authors were company employees, creating the potential for sponsor-related bias despite the objective technical endpoints used.

Nahas et al. (2026) evaluated the long term effectiveness, utilization, safety, and potential development of tachyphylaxis with remote electrical neuromodulation (REN) for acute migraine treatment over a three year period. The investigators conducted a prospective real world evidence cohort study using data collected through the Nerivio mobile application from 224 patients with migraine in the United States who used REN at least once monthly for at least 9 months per year across three consecutive years. The primary endpoint was the absence of tachyphylaxis, defined as no clinically meaningful increase in treatment intensity greater than 2.5 units on a 100 point stimulation scale between consecutive years. Secondary endpoints assessed the consistency of treatment effectiveness, including pain relief, pain freedom, functional disability relief, functional disability freedom, and freedom from associated symptoms, as well as long term adherence and safety. The cohort performed 64,717 treatments during the study period, and outcomes were analyzed using repeated measures statistical models. The study found no evidence of tachyphylaxis over three years of treatment. Average treatment intensity increased only modestly from 35.0 units in year 1 to 38.2 units in year 3, with mean changes of 1.8 units between years 1 and 2 and 1.4 units between years 2 and 3, both below the prespecified threshold for clinically meaningful dose escalation. Consistent effectiveness was maintained throughout the study period. Pain relief was achieved by approximately 72.1% to 76.8% of users, pain freedom by 26.8% to 28.7%, functional disability relief by 65.3% to 70.8%, and functional disability freedom by 31.4% to 38.9%, with no significant differences across years. Similarly, freedom from photophobia, phonophobia, and nausea or vomiting remained stable over time. Monthly utilization remained consistent at approximately 8.0 to 8.8 treatments per month, suggesting sustained adherence. Safety outcomes were favorable, with only two reported device related adverse events (0.9%), consisting of mild or moderate localized skin reactions, neither of which resulted in treatment discontinuation. The study has several important limitations. The analysis included only patients who continued using REN consistently for three years, creating the potential for substantial selection bias because individuals who discontinued treatment due to lack of efficacy, tolerability issues, or adherence challenges were excluded. Of nearly 18,000 patients who initiated REN during the study period, only 224 met the inclusion criteria for long term consistent use. Effectiveness outcomes were based on voluntarily reported patient data, introducing the possibility of reporting bias and limiting the representativeness of the findings. In addition, the study focused exclusively on acute migraine treatment and did not evaluate the long term effectiveness of REN when used for migraine prevention. Finally, the study was funded by Theranica, and several authors were employees or had financial relationships with the company, which should be considered when interpreting the results.

Rastogi et al. (2026) evaluated the safety and tolerability of high frequency use of remote electrical neuromodulation (REN; Nerivio) for migraine treatment in real world clinical practice. The objective was to determine whether using REN more frequently than its labeled indication, including multiple treatments within a single day or near daily use, was associated with an increased risk of device related adverse events. This prospective real world evidence study analyzed data collected from January 2020 through August 2025 from REN users across the United States. Investigators identified 1,863 patients who met predefined criteria for frequent use, including 1,654 patients who completed four or more 45 minute treatments in a single day at least once and 310 patients who used the device on at least 25 of 28 days in a month; 101 patients met both definitions. The study population was predominantly female (82.1%) with a mean age of 38.8 years, and participants completed 79,362 treatments meeting the frequent use criteria. Safety data were collected through the device application and customer support reports, and adverse events were classified according to standard regulatory criteria, with particular attention to device related adverse events (dAEs), seriousness, severity, and event type. The study found that high frequency REN use was associated with a favorable safety profile. Across all 1,863 patients, only 17 individuals (0.91%) reported a device related adverse event, corresponding to just 0.02% of treatments. In the multiple treatments per day group, 16 patients (0.97%) reported dAEs, while 6 patients (1.94%) in the daily treatment group reported dAEs. No serious device related adverse events occurred. Reported events were generally negligible to moderate in severity and consisted primarily of localized skin irritation, arm soreness, tingling, burning sensations, or muscle spasms. Most events resolved without medical intervention, and nearly all affected patients continued using the device after the event occurred. The authors noted that dAE rates observed during frequent use were similar to or lower than those reported in prior randomized controlled trials and large real world studies of REN, suggesting that more intensive treatment patterns did not appear to increase safety risks. Several limitations should be considered. Because the study relied on voluntary real world adverse event reporting through the application and customer support system, underreporting and reporting bias are possible. Patients who experienced adverse effects may have stopped using the device without reporting their experience, potentially leading to underestimation of adverse event rates. The treatment level analyses did not account for repeated measures or clustering of multiple treatments within the same patient. The subgroup of participants younger than 18 years was relatively small, limiting conclusions regarding safety in pediatric populations. In addition, the study focused exclusively on safety and was unable to evaluate treatment effectiveness under these high frequency use patterns because the design of the application questionnaires did not allow reliable attribution of outcomes to individual treatment sessions when multiple treatments occurred in a short period. Finally, the study was funded by Theranica, the manufacturer of the REN device, and several authors reported employment or advisory relationships with the company.

Cheng et al. (2026) evaluated whether remote electrical neuromodulation (REN) could reduce the acute procedural pain and postprocedural headache associated with onabotulinumtoxinA (BoNT-A) injections for chronic migraine. Patients receiving BoNT-A often undergo 31 to 40 injections per treatment session, which can be painful and may contribute to treatment avoidance or discontinuation. The investigators conducted a single-center, randomized, single-blind, sham-controlled crossover study at Mayo Clinic Arizona involving adults with chronic migraine who were receiving routine BoNT-A treatment. Participants first underwent a baseline injection session without a device and then completed subsequent treatment sessions using active REN and sham stimulation in randomized order. REN was applied to the upper arm beginning 10 minutes before injections and continued through the procedure. Pain intensity was measured using a 0 to 100 visual analog scale before, during, and after the injection session. The primary outcome was procedural pain intensity, while secondary outcomes included postprocedural headache incidence and adverse events. The study enrolled 80 participants but was stopped early after a prespecified interim analysis demonstrated a strong efficacy signal favoring REN. Final analysis included 60 participants with a mean age of 48 years, of whom 82% were female. Baseline preprocedural pain levels did not differ between active REN, sham, and no-device conditions. During BoNT-A administration, however, active REN significantly reduced pain compared with baseline, producing a mean reduction of 15 points on the visual analog scale (p < 0.001). After the procedure, active REN reduced pain by 19.1 points compared with baseline (p < 0.001), whereas sham treatment produced no significant pain reduction. REN also substantially reduced the incidence of postprocedural headache. Only 15% of REN-treated participants reported headache after the procedure compared with 39% during baseline visits and 55% during sham treatment sessions. The odds of postprocedural headache were significantly lower with REN (odds ratio 0.28; 95% confidence interval 0.10 to 0.69; p = 0.008). No additional adverse events were reported in either the active or sham treatment groups. These findings suggest that REN may be an effective nonpharmacologic strategy for improving patient comfort during BoNT-A administration and reducing treatment-related headaches. The study has several limitations. The single-center design may limit the generalizability of the findings to broader patient populations. Injections were performed by three different clinicians, introducing potential variability in technique and pain perception. The investigators did not record the exact number of injections administered, the timing of acute migraine medications before the procedure, or whether tolerance from previous BoNT-A treatments influenced outcomes. Although the trial was randomized and sham controlled, randomization did not fully balance baseline characteristics such as age and treatment history, and the effectiveness of blinding was not formally assessed. The study was also stopped early because of efficacy, resulting in a smaller sample size than originally planned and potentially reducing precision of effect estimates. Finally, pain outcomes were based on subjective patient reporting, and the study did not evaluate patient satisfaction, procedural anxiety, or the impact of REN on the long-term effectiveness of BoNT-A therapy.

Canales-Rodríguez et al. (2026) conducted a systematic review of noninvasive neuromodulation trials for migraine and cluster headache, with a specific focus on adherence to International Headache Society (IHS) methodological guidelines, efficacy outcomes, and the quality of supporting evidence. The review included remote electrical neuromodulation (REN) as one of the principal noninvasive migraine treatments evaluated across the literature. The authors performed a systematic search of MEDLINE, Embase, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform for clinical trials published between January 1990 and October 2024. Seventy eligible trials were identified. For REN specifically, the review included four acute migraine studies involving 524 participants and one preventive migraine study involving 248 participants. The investigators evaluated study design characteristics, use of sham controls and blinding, adherence to IHS-recommended endpoints, risk of bias using the Cochrane RoB 2 tool, and certainty of evidence using the GRADE framework. Regarding REN, the review found that acute-treatment studies generally demonstrated strong methodological quality. Four acute migraine trials evaluated REN, including two randomized, double-blind, sham-controlled studies. Both sham-controlled trials assessed the IHS-recommended endpoint of 2-hour pain freedom. The review identified a pivotal randomized trial in which active REN achieved a significantly higher 2-hour pain-free rate than sham treatment, with 37.4% of participants becoming pain free compared with 18.4% receiving sham stimulation. This represented an absolute benefit of 19.0%, with a 95% confidence interval of 5.5% to 34.7%. Based on GRADE assessment, the certainty of evidence for acute REN treatment was rated as moderate. For migraine prevention, one double-blind, randomized, sham-controlled trial evaluated REN in 248 patients, 86% of whom were female. This study adhered to both IHS-recommended primary and secondary efficacy endpoints. REN produced a statistically significant reduction in monthly migraine days, with an average reduction of 2.7 days relative to sham treatment (95% confidence interval, −3.9 to −1.5 days; p < 0.001). The certainty of evidence for preventive REN was also rated as moderate. The review further noted that REN was among the few neuromodulation modalities supported by randomized controlled trials that closely adhered to IHS methodological recommendations for both acute and preventive migraine treatment. The authors identified several limitations affecting the REN evidence base and the broader neuromodulation literature. Although REN demonstrated statistically significant efficacy in both acute and preventive migraine treatment, the certainty of evidence was downgraded because of imprecision related to sample size. The review also emphasized substantial heterogeneity across neuromodulation studies regarding treatment protocols, endpoint definitions, timing of intervention, and adherence to guideline-recommended methodology. In addition, many neuromodulation studies evaluated recommended outcomes as secondary rather than primary endpoints, complicating comparisons across trials and assessments of guideline adherence. Finally, because many included studies were completed before publication of the most recent IHS neuromodulation guidelines, methodological consistency across studies was variable. Despite these limitations, the authors concluded that REN has some of the strongest evidence among available noninvasive neuromodulation modalities for migraine and should be considered a promising treatment option supported by moderate-quality evidence.

Caffeine Citrate Infusion for the Treatment of Post Lumbar Puncture Headache

Zeger and colleagues (2012) noted that cosyntropin has been reported to be effective in the treatment of post-dural puncture headaches (PDPHs); however, there is a lack of data regarding its effectiveness.  In a prospective, randomized, double-blind trial, these researchers compared the effectiveness of cosyntropin with that of caffeine in the treatment of PDPH.  They carried out an interim analysis of a study of adult patients presenting to the emergency department with a PDPH.  Patients were randomized to receive either IV caffeine or IV cosyntropin.  Values on a 100-mm VAS were recorded at 0, 60, and 120 mins to evaluate pain.  Rescue therapy was documented on the study data forms.  Its effectiveness was determined by the need for this therapy.  A total of 37 patients were included and 4 patients were excluded from the analysis because of protocol violations or incomplete data; analysis was based on ITT.  Caffeine was 80% (95% CI: 60% to 100%) effective and cosyntropin was 56% (95% CI: 33% to 79%) effective in treating PDPHs.  The group's VAS scores at 0, 60, and 120 mins were 80 mm, 41 mm, 31 mm for caffeine; and 80 mm, 40 mm, 33 mm for cosyntropin, respectively (p = 0.66).  The authors concluded that caffeine was not more effective than cosyntropin in treating patients with PDPHs, and there was no difference in the degree of pain relief on VAS assessment.

The authors stated that this study had several drawbacks.  Needle size and type were reported to be factors in preventing PDPHs.  The typical kits used by these researchers had 20-G cutting needles, but some of the lumbar punctures in this study were carried out with 22-G cutting needles.  These investigators were unable to control this potential confounder.  Furthermore, since increasing volume of CSF is thought to be one of the mechanisms, through which cosyntropin works, these researchers did not study potential delayed effects and/or may not have allotted enough time to maximize its effectiveness.

In a Cochrane review, Ona and associates (2015) examined the safety and effectiveness of drugs for the treatment of PDPH in adults and children.  This was an updated version of the original Cochrane review published in Issue 8, 2011, on "Drug therapy for treating post-dural puncture headache".  These investigators included 13 small RCTs (479 participants) in this review (at least 274 participants were women, with 118 parturients after a lumbar puncture for regional anesthesia).  In the original version of this Cochrane review, only 7 small RCTs (200 participants) were included.  Pharmacological drugs assessed were oral and IV caffeine, subcutaneous sumatriptan, oral gabapentin, oral pregabalin, oral theophylline, IV hydrocortisone, IV cosyntropin and IM adrenocorticotropic hormone (ACTH). Two RCTs reported data for PDPH persistence of any severity at follow-up (primary outcome).  Caffeine reduced the number of participants with PDPH at 1 to 2 hours when compared to placebo.  Treatment with caffeine also decreased the need for a conservative supplementary therapeutic option.  Treatment with gabapentin resulted in better VAS scores after 1, 2, 3, and 4 days when compared with placebo and also when compared with ergotamine plus caffeine at 2, 3, and 4 days.  Treatment with hydrocortisone plus conventional treatment showed better VAS scores at 6, 24 and 48 hours when compared with conventional treatment alone and also when compared with placebo.  Treatment with theophylline showed better VAS scores compared with acetaminophen at 2, 6 and 12 hours and also compared with conservative treatment at 8, 16 and 24 hours.  Theophylline also showed a lower mean "sum of pain" when compared with placebo.  Sumatriptan and ACTH did not show any relevant effect for this outcome.  Theophylline resulted in a higher proportion of participants reporting an improvement in pain scores when compared with conservative treatment.  There were no clinically significant drug AEs.  The rest of the outcomes were not reported by the included RCTs or did not show any relevant effect.  Moreover, these researchers stated that these findings should be interpreted with caution due to the quality of the evidence found: the limited number of studies, the diversity of drugs assessed, and outcomes measured, the small sample sizes (13 studies involving a total of 479 participants) and the bias presented as well as their limited generalizability, as nearly 50% of the participants were post-partum women in their 30s.

A statement on post-dural lumbar puncture headache from the American Society of Anesthesiologists (2021) states that "Oral caffeine in the dose of 300-500 mg is recommended once or twice a day. Intravenous caffeine can be given if the parturient is unable to drink."

Intravenous Magnesium for the Treatment of Migraine

Miller et al (2019) stated that non-traumatic headaches comprise up to 4% of all emergency department (ED) visits.  Current practice is moving toward multi-modal analgesia regimens that limit narcotic use.  In a systematic review, these investigators examined the following research question: In patients with non-traumatic headaches (Population), does administration of intravenous (IV) magnesium sulfate (Intervention) compared to placebo, corticosteroids, dopamine antagonists, ergot alkaloids, non-steroidal anti-inflammatory drugs (NSAIDs), triptans, or usual care result in better pain control, lower rate of recurrence at 24 hours, lower requirements for rescue analgesia, and less adverse medication effects (Outcomes)?  Scholarly databases and relevant bibliographies were searched, as were clinical trial registries and relevant conference proceedings to limit publication bias.  Studies were not limited by date, language, or publication status.  Inclusion criteria were: (i) RCT, (ii) patients age 18 years or older, (iii) non-traumatic headache, (iv) patients treated in ED or an outpatient acute care treatment center, and (v) magnesium sulfate administered intravenously.  Eligible comparison groups included: placebo, conventional therapy, dopamine antagonist, NSAID, corticosteroid, ergot alkaloid, or triptans.  Out of 4,018 identified references, 7 RCTs (545 participants) that treated migraine headaches (n = 6) and benign non-traumatic headaches (n = 1) met inclusion criteria.  Pain intensity was improved with magnesium sulfate versus comparators at 60 to 120 mins, but not at earlier time-points.  Result for the endpoint of pain reduction by 50% were conflicting as 3 studies reported that headache was improved, unchanged, and less with magnesium sulfate.  Complete pain relief was improved with magnesium sulfate in 1 study, and in the migraine with aura (MA) subgroup in another.  The need for rescue analgesia at any point was improved with magnesium sulfate in 1 study, and in the MA subgroup in another; and 24-hour headache recurrence was improved with magnesium sulfate in 1 study, but unchanged in a second.  The intended meta-analysis was not performed due to the clinical heterogeneity among studies.  The authors concluded that while they could not draw a firm conclusion on the effectiveness or benefit of IV magnesium sulfate in the treatment of acute non-traumatic headaches, the existing evidence indicated potential benefits in pain control beyond 1 hour, aura duration, and need for rescue analgesia.

Kandil et al (2021) noted that due to the healthcare burden associated with migraines, prompt and effective treatment is vital to improve patient outcomes and ED workflow.  A prospective, randomized, double-blind trial enrolled adults who presented to the ED with a diagnosis of migraine from August of 2019 to March of 2020.  Pregnant patients, or those with renal impairment were excluded.  Patients were randomized to receive IV magnesium, prochlorperazine, or metoclopramide.  The primary outcome was change in pain from baseline on a numeric rating scale (NRS) evaluated at 30 mins after initiation of infusion of study drug.  Secondary outcomes included NRS at 60 and 120 mins, ED length of stay (LOS), necessity for rescue analgesia, and adverse effects.  A total of 157 patients were analyzed in this study: 61 patients received magnesium, 52 received prochlorperazine, and 44 received metoclopramide.  Most patients were white females, and the median age was 36 years.  Hypertension and migraines were the most common co-morbidities, with a third of the patients reporting an aura.  There was a median decrease in NRS at 30 mins of 3 points across all 3 treatment arms.  The median decrease in NRS (inter-quartile range [IQR]) at 60 mins was -4 (2 to 6) in the magnesium group, -3 (2 to 5) in the metoclopramide group, and -4.5 (2 to7) in the prochlorperazine group (p = 0.27).  There were no statistically significant differences in ED LOS, rescue analgesia, or adverse effects.  The authors concluded that IV magnesium was not inferior to prochlorperazine or metoclopramide at 30 mins when treating headaches and migraines in the ED despite patients requiring greater rescue analgesia.  Although prochlorperazine may be more effective at controlling pain at 1 hour, it may also result in greater adverse effects.  These researchers stated that IV magnesium may be used as an adjunctive agent for the treatment of migraines; or may serve as a safe alternative when agents such as prochlorperazine or metoclopramide are not appropriate.

The authors stated that drawbacks of the study included the unexpected premature termination of recruitment, which ultimately lead to unequal treatment arms and the study being underpowered.  This made it difficult to draw conclusions regarding if one agent fared better for migraine abortion.  In addition, there was no uniform protocol for time to initiation of medications in the ED before study drug administration or for rescue therapy.  This ultimately could have confounded the results of this study since it is unknown if pain relief was related to the administration of the study drug versus adjunctive therapies.  Furthermore, the choice of adjunctive therapies was at the physician's discretion.  Approximately 1/3 of patients received additional therapies before 120 mins, which may have also confounded migraine relief.  Finally, although there was no difference in ED LOS between groups, the LOS may have varied due to the timing of presentation to the ED, and prioritization for high acuity patients.

In a meta-analysis of 21 studies investigating the role of intravenous magnesium for the treatment of acute migraine attacks and oral magnesium for migraine prevention, Chiu, et al. (2019) reviewed 11 studies (n = 948) on the effects of intravenous magnesium for treatment of acute migraine and 10 studies (n = 789) on the effects of oral magnesium on prevention of migraine. Intravenous magnesium significantly alleviated acute migraine within 15 - 45 minutes, 120 minutes, and 24 hours after the initial infusion (Odd ratios [ORs] = 0.23, 0.20, and 0.25, respectively). Oral magnesium significantly reduced the frequency and severity of migraine (ORs = 0.20 and 0.27). Although the meta-analysis had large sample size and high internal validity with including only randomized controlled trials, the heterogenicity of study designs and some with inadequate randomization may introduce potential selection bias in study participants.

In the practice advisory for intravenous management of headache disorders in hospitalized patients, the American Society of Regional Anesthesia and Pain Medicine steering committee recommends intravenous magnesium sulfate given as 1g to 2g infused over 15 minutes in admitted patients with migraine (with or without aura), in those who do not have elevated serum magnesium level, history of hypersensitivity to magnesium, neuromuscular disease, or heart block. The recommendations are mostly based on studies including emergency department subjects. The findings of various studies showed intravenous magnesium sulfate infusion is superior to placebo/controls and dexamethasone/metoclopramide while demonstrating non-inferior efficacy to sumatriptan, metoclopramide, and prochlorperazine (Hoydonckx, et al., 2026)

Preventive Treatment of Refractory Chronic Cluster Headache

Membrilla et al (2023) stated that preventive treatment for refractory chronic cluster headache (rCCH) is challenging and many therapies have been tried.  In a systematic review and meta-analysis, these investigators examined what could be considered the therapy of choice in rCCH.  This review was carried out following the PRISMA guidelines.  They conducted a systematic search in Medline, Embase, Cochrane, clinicaltrials.gov, and the WHO's-International-Clinical-Trials-Registry-Platform.  Studies on the preventive treatment for rCCH as defined by the European Headache Federation consensus statement were included.  A meta-analysis of the pooled response rate was conducted for the different therapies.  Of 336 results, 45 were eligible for inclusion.  Most studies examined the effect of neuromodulation as a preventive treatment for rCCH.  The most studied neuromodulation technique was occipital nerve stimulation (ONS), with a pooled response rate in the meta-analysis of 57.3% (95% CI: 0.481 to 0.665).  Deep brain stimulation (DBS) was the 2nd most studied treatment with a pooled response rate of 77.0% (95% CI: 0.594 to 0.957).  DBS results were more heterogeneous than ONS, which could be related to the different stimulation targets in DBS studies; and reported more serious AEs than in ONS studies.  The remaining therapies (anti-CGRP pathway drugs, warfarin, ketamine-magnesium infusions, serial occipital nerve blocks, clomiphene, onabotulinum toxin A, ketogenic diet, sphenopalatine ganglion radiofrequency or stimulation, vagus nerve stimulation, percutaneous bioelectric current stimulation, upper cervical cord stimulation, and vidian neurectomy) presented weaker results or have less quality of evidence.  The authors concluded that the findings of this systematic review and meta-analysis suggested that ONS could be the 1st therapeutic strategy for patients with rCCH based on the current evidence.

Epidural Steroid Injection and Radiofrequency Ablation for the Treatment of Cervicogenic Headache and Neck Pain

Orhurhu et al (2021) noted that headache is a very common condition that affects 5% to 9% of men and 12% to 25% of women in North America and Europe.  Globally, the prevalence of active headaches among adults is 47%.  The most common type of headache is tension headaches (38% of adults), followed by migraines (10%), and chronic headaches (3%).  While the majority of headaches are benign, the disorder can severely influence a patients' QOL, which is directly reflected in societal costs.  In a systematic review, these investigators examined available evidence on the use of radiofrequency ablation (RFA) for the treatment of headache, including pain outcome measures, secondary outcomes, and complications.  This systematic review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.  Two reviewers independently scored the methodological quality of the selected studies.  Due to heterogeneity of studies, a best-evidence synthesis of the available prognostic factors was provided.  In the present investigation, these researchers evaluated 18 studies composed of 6 RCTs, 6 prospective studies, and 6 retrospective studies.  All the studies assessed pain improvement with RFA in patients with headache.  Most studies targeted the occipital nerve for treatment.  Complications were mostly mild and self-limiting, including eyelid swelling, rash, superficial infection of the procedural site, and worsening of headache.  The authors concluded that this review discussed several studies that suggested the effectiveness of RFA in the treatment of headaches.  Outcomes varied based on the difference in approaches regarding continuous RF versus pulsed RF, temperature, and duration of administration.  The majority of the studies discussed in this review indicated a therapeutic benefit of RFA for headaches over a short-term period.  Pain outcomes beyond 1 year were under-studied and further studies are needed to determine the long-term effects of RFA for headaches.

The authors stated that the drawbacks of this review included a large variability in definitions of trigeminal neuralgia, RF technique, and patient selection bias was observed in the selected cohort of studies.  Furthermore, there was a paucity of strong longitudinal RCTs and prospective studies.

Suer et al (2022) stated that chronic neck pain is often multi-factorial and is a leading cause of pain and disability.  Cervical facet joint pain is a common cause of neck pain and, in addition to more conservative modalities, can be treated with RFA of the respective medial branch nerves.  Cervicogenic headaches (CHAs) are a frequent complaint in pain clinics in the U.S. and can be targeted via a similar procedural approach.  In a systematic review, these researchers evaluated RCTs of cervical facet joint pain and CHAs with the objective of establishing a current level of evidence for the treatment of these etiologies of pain with RFA.  Database search, from inception through July 2021, was carried out identifying RCTs for cervical medial branch RFA.  Two reviewers independently evaluated the studies to identify those meeting criteria.  Primary outcome measures included pain relief and duration of pain relief.  Secondary outcome measures included function, sleep, mood, return-to-work, additional treatments, and complications.  A total of 4 RCTs met inclusion criteria and were selected for this review, each showed low risk of bias.  Of these studies, 3 were unique with the 4th being a subgroup analysis.  Primary outcome measures of pain relief and duration of relief were variable with successful relief ranging from 30% to 50% and median duration of pain relief also showing a wide variety.  Function and psychological distress were also variably reported and found variable relief to treatment with no difference between groups in 2 of the studies.  The authors concluded that based on this systematic review, the effectiveness of cervical facet RFA in treatment of chronic neck pain has Level II evidence.  These investigators stated that the primary limitations of the review were the paucity of adequately powered RCTs, variability in patient population, heterogeneous treatment outcomes, and follow-up intervals did not allow for meta-analyses.  These researchers stated that there remain many questions going forward in relation to cervical RFA that highlight the need for further research into this treatment for chronic neck pain.

Ekhator et al (2023) noted that dysfunction of the cervical spine and its anatomical features, mostly innervated by the C1, C2, and C3 spinal nerves, could result in a secondary headache known as CHA, mainly characterized by unilateral pain.  The effectiveness of pharmacotherapies and physical therapy (PT) is currently the subject of scant literature.  Interventional pain management techniques can be applied when conservative treatments fail.  In a systematic review and meta-analysis, these investigators examined the safety and effectiveness of RFA and epidural steroid injection (ESI) in the treatment of patients with CHA and neck pain.  A total of 3 databases -- PubMed, Cochrane CENTRAL Library, and Embase were searched, and 110 studies were identified.  A total of 9 screening processes were included for review and meta-analysis.  Statistical evaluation was performed via STATA version 17 (College Station, TX: StataCorp LLC) and effect measures were reported via random effects model risk ratios.  The main subject of focus included the following 3 outcomes: incidences of pain relief, degree and duration of pain, as well as incidences of AEs.  The findings showed both interventions relieved pain by a factor of greater than 50%, demonstrating a relative effects RR of 1.45 (-0.50 to 3.39) for RFA: pain relief, 84.76 (82.82 to 86.69) RFA: AEs, and 19.46 (18.80 to 20.11) ESI: pain relief at 95% CI; and the effectiveness of RFA and ESI differ.  Both interventions were effective in the reduction of CHA pain intensity; however, their complication rates and pain duration were considerably different.  With ESI, the headaches could still recur weekly, demanding the use of oral analgesics to deal with them.  On the other hand, RFA exhibited a low complication rate.  The authors concluded that improving guidance from imaging technologies, RFA has the potential to be the most effective interventional treatment.

The authors stated that this study could not arrive at conclusive decisions because few studies examined the effectiveness of RFA and ESI in the treatment of CHAs . The included studies generalized pain and injection; thus, lacking the specificity needed to arrive at distinct results.  The difficulty in diagnosing CHAs typically contributed to the study's limitations, as different headaches fundamentally share characteristics and symptoms such as cervical pain.  The difficulty in diagnosis essentially resulted in few subjects in the research for CHA interventions.  Moreover, the study was limited by the subjectivity of pain, which demanded that the research depends on the subjects' feelings.  The difficulty in diagnosis resulted in a small sample size, affecting the accuracy of the studies included in the research.

Photo-Biomodulation for the Treatment of Primary Headache

In a systematic review, Gomez et al (2022)examined  the safety and effectiveness of photo-biomodulation as an adjuvant treatment for primary headache.  These investigators carried out a systematic review of randomized clinical trials.  For such, electronic searches were conducted in the Medline, Embase, Cochrane Library, LILACS, PEDro, PsycInfo, Clinicaltrials.gov., and WHO/ICTRP databases, with no restrictions imposed regarding language or year of publication.  These researchers included studies that examined any photo-biomodulation therapy as an adjuvant treatment for primary headache compared to sham treatment, no treatment, or another intervention.  The methodological assessment was carried out using the Cochrane Risk of Bias tool.  The certainty of the evidence was classified using the GRADE approach.  A total of 4 randomized clinical trials were included; most of the included studies had an overall high risk of bias.  Compared to sham treatment, photo-biomodulation had a clinically important effect on pain in individuals with primary headache.  The authors concluded that despite the benefits reported for other outcomes, the estimates were imprecise, and the certainty of the evidence was graded as low.  These researchers stated that these findings were considered insufficient to support the use of photo-biomodulation in the treatment of primary headache; they stated that randomized clinical trials, with higher methodological quality, are needed to enhance the reliability of the estimated effects.

Combined Emgality (Galcanezumab-gnlm) Injection) and Quilipta (Atogepant) for the Preventive Treatment of Migraines

Tringali and Navarra (2019) noted that CGRP is a peptide neurotransmitter with potent vasodilating properties.  CGRP is believed to play a primary role in the pathogenesis of migraine.  As such, CGRP and its receptors are obvious druggable targets for novel anti-migraine agents.  While the development of small-molecule CGRP receptor antagonists started first, none of these agents is yet available in clinical practice.  Conversely, both anti-CGRP and anti-CGRP receptor monoclonal antibodies (mABs) completed clinical development, and the 1st representatives of these 2 classes are available on the market.  MABs are approved for prevention of migraine attacks in chronic or episodic migraine, involving long-term treatments.  In light of the physiological role exerted by CGRP in the regulation of vascular tone, the potential risks of a long-term inhibition of CGRP functions raised diffuse concerns.  These concerns were correctly addressed by the anti-CGRP receptor mABs erenumab with a 5-year, open-label clinical trial; however, this study is currently ongoing, and results are not yet available, leaving some uncertainty on the profile of erenumab long-term safety.  Similar concerns can be raised with direct anti-CGRP mABs, which entrap the peptide preventing receptor activation.  However, evidence exists that plasma CGRP is detectable in patients chronically treated with anti-CGRP mABs.  Assuming that plasma CGRP is an indirect marker of peptide levels at the vascular receptor sites, such residual CGRP would maintain a physiological level of receptor stimulation, in spite of a well-established anti-migraine activity of the mABs.  This might represent a potential advantage in the safety profile of anti-CGRP mABs, but it needs to be confirmed and expanded with data on free plasma CGRP.

Mullin et al (2020) provided the 1st clinical report that 2 CGRP therapies, a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody, can be used concomitantly to treat refractory migraine.  Case reports were presented of 2 patients participating in a long-term safety study of rimegepant 75 mg oral tablets for acute treatment.  After FDA approval of erenumab, both patients started subcutaneous erenumab monthly as allowed per protocol.  Patients were women 44 and 36 years of age with greater than or equal to 2 decades of self-reported suboptimal response to multiple migraine medications.  Patient 1 used rimegepant for 6 months and then started erenumab 70 mg subcutaneous monthly.  Despite a response to preventive treatment with erenumab, she experienced substantial relief treating 7 of 7 acute attacks with rimegepant and eliminated regular, frequent use of ibuprofen and a caffeinated analgesic.  Patient 2 used rimegepant for 60 days before starting erenumab 140 mg subcutaneously monthly.  While on erenumab, 9 of 9 attacks treated with rimegepant responded.  She stopped near-daily use of injectable ketorolac and diphenhydramine.  While using rimegepant alone or together with erenumab, patients reported no related AEs.  The authors concluded that rimegepant 75 mg may be effective for acute treatment during concomitant erenumab preventive administration.  The mechanism underlying the benefits of concomitant use of a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody is unknown and additional studies are needed to determine whether these or other differences are the primary drivers of the effectiveness of combination therapy with rimegepant and erenumab.  Classification of Evidence: IV.

Berman et al (2020) examined the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a mAb targeting the CGRP ligand or receptor (CGRP mAb) for the preventive treatment of migraine.  This was a sub-study nested within an open-label, multi-center, long-term safety study in adults with 2 to 14 monthly migraine attacks of moderate-to-severe pain intensity.  A subgroup experiencing 2 to 8 monthly attacks and taking a stable dose of a CGRP mAb also took rimegepant 75 mg as needed up to once-daily for acute treatment for 12 weeks.  The 13 patients (11 women [85%]; mean age of 49.9 years) enrolled in the sub-study were being treated with CGRP mAbs (erenumab [n = 7], fremanezumab [n = 4], or galcanezumab [n = 2]).  Mean (SD) time in the rimegepant treatment period was 9.6 (4.6) weeks.  Mean (SD) 4-week rimegepant exposure was 7.8 (5.5) doses; a total of 224 doses were taken.  Five (38%) patients reported 1 or more on-treatment AEs.  Of these, 2 (15%) patients had mild or moderate nasopharyngitis; no other AEs occurred in 2 or more patients; 3 patients had AEs of mild or moderate severity that were considered potentially treatment-related.  No patients had serious AEs, AEs leading to discontinuation, or aminotransferase levels greater than 3× the upper limit of normal.  The authors concluded that rimegepant, when used as an oral acute treatment in patients receiving CGRP mAbs as preventive treatment, was well-tolerated; no safety issues were identified.  Moreover, these researchers stated that studies involving larger patient populations are needed to confirm these findings.  Moreover, these investigators stated that caution is needed during concomitant use of rimegepant and the CGRP mAbs given the limited body of evidence to-date.

In an open‐label, 2‐arm, multicenter, phase-Ib clinical trial, Jakate et al (2021) examined the impact of 2 CGRP‐targeted mAbs, erenumab and galcanezumab, on the pharmacokinetic (PK) profile, safety, and tolerability of ubrogepant.  This study enrolled adults with migraine; subjects were randomized to arm 1 (ubrogepant ± erenumab) or arm 2 (ubrogepant ± galcanezumab).  The PK profile of ubrogepant was characterized for administration before and 4 days after CGRP‐targeted mAb injection.  Participants received single‐dose ubrogepant 100 mg on day 1, subcutaneous erenumab 140 mg (arm 1) or galcanezumab 240 mg (arm 2) on day 8, and ubrogepant 100 mg once-daily on days 12 to 15.  In each study arm, serial blood samples were drawn on days 1 and 12 for measurement of plasma ubrogepant concentrations.  The primary outcomes were area under the plasma ubrogepant concentration-time curve (AUC) from time 0 to t post‐dose (AUC0–t) and from time 0 to infinity (AUC0–inf), and maximum plasma concentration (C max) of ubrogepant when ubrogepant was administered before or after a single dose of erenumab or galcanezumab.  Vital signs and laboratory parameters were monitored.  A total of 40 participants enrolled (20 per arm; mean [standard deviation] ages, 32.2 [8.9] and 38.4 [8.8] years; 50% [10/20] and 60% [12/20] female in arms 1 and 2, respectively).  There were no significant differences in ubrogepant C max after versus before erenumab administration (geometric least‐squares mean [LSM] ratio, 1.04 [90% CI: 0.93 to 1.16]), and no significant differences in AUC0–t (1.06 [0.96 to 1.16]) or AUC0–inf (1.05 [0.96 to 1.15]).  Similarly, ubrogepant C max (1.00 [90% CI: 0.82 to 1.20]), AUC0–t (1.05 [0.90 to 1.23]), and AUC0–inf (1.05 [0.90 to 1.22]) geometric LSM ratios were statistically equivalent after galcanezumab versus ubrogepant alone.  Treatment‐emergent AEs (TEAEs) were similar to those reported with each treatment alone.  No serious TEAEs, TEAEs leading to discontinuation, or clinically relevant changes in laboratory parameters or vital signs were reported.  The authors concluded that the PK profile of ubrogepant did not change; and no safety concerns were identified when ubrogepant was co-administered with erenumab or galcanezumab.  These researchers noted that the lack of PK interactions or new safety concerns provided some reassurance on the safety of concomitant use; however, broader safety conclusions will require longer term evaluation of concomitant use in larger populations.

The authors stated that this study had several drawbacks.  First, the sample size was relatively small, with 40 participants overall and 20 allocated to each treatment arm.  While this population size was considered adequate for identifying potential PK interactions, it was insufficient for detecting potential safety issues.  Second, this study did not examine the effect of ubrogepant on the PK profiles of the mAbs.  Third, the study had a short duration of treatment and ubrogepant was administered at set time-points, and not during a migraine attack, when CGRP levels may be elevated.  Fourth, the effectiveness of concomitant use for migraine relief was not evaluated.  Fifth, as this study did not include a method of allocation concealment, the authors could not rule out the potential impact of selection bias.  These researchers stated that additional real‐world data are needed to fully characterize the safety of ubrogepant with CGRP‐targeted mAbs.

Cranio-Sacral Therapy

In a systematic review and meta-analysis, Carrasco-Uribarren et al (2024) examined the effectiveness of cranio-sacral therapy in improving pain and disability among patients with headache disorders.  PubMed, Physiotherapy Evidence Database, Scopus, Cochrane Library, Web of Science, and Osteopathic Medicine Digital Library databases were searched in March 2023.  Two independent reviewers searched the databases and extracted data from RCTs comparing cranio-sacral therapy with control or sham interventions.  The same reviewers assessed the methodological quality and the risk of bias using the PEDro scale and the Cochrane Collaboration tool, respectively.  GRADE was used to rate the certainty of the evidence.  Meta-analyses were conducted using random effects models using RevMan 5.4 software.  The searches retrieved 735 studies, and 4 studies were finally included.  The cranio-sacral therapy provided statistically significant but clinically unimportant change on pain intensity (MD = -1.10; 95% CI: -1.85 to -0.35; I2 = 44%), and no change on disability or headache effect (SMD = -0.34; 95% CI: -0.70 to 0.01; I2 = 26%).  The certainty of the evidence was down-graded to very-low.  The authors concluded that very-low certainty of evidence suggested that cranio-sacral therapy produced clinically unimportant effects on pain intensity, whereas no significant effects were observed in disability or headache effect.

Intra-Oral Splints for the Treatment of Migraine and Tension-Type Headaches

In a systematic review, Martinez-Alvarez et al (2023) examined the effectiveness of intra-oral splints in the treatment of migraine and tension-type headaches.  These investigators carried out a literature search within 7 electronic databases (Medline, PubMed, Embase, CINAHL PLUS with full text, Cochrane Library Trials, Web of Science, and Scopus) with no date limits or language restrictions up to June 12, 2022.  Strict inclusion and exclusion criteria were set for article selection.  At the same time as data extraction, each study's risk of bias (RoB) was evaluated using the Cochrane tool to assess their RoB.  Subsequently, the Cochrane GRADE was used to evaluate the certainty of the evidence.  A total of 4 controlled clinical trials were included. These trials were heterogeneous in terms of diagnosis, design of the intra-oral splints, and tools for reporting the results, which made it difficult to compile the data as well as evaluate its quality.  Studies reported a reduction in the frequency of headache and pain intensity when using intra-oral splints; however, this therapy was not superior to medications.  The authors concluded that the evidence was very-low for the use of intra-oral splints as a therapeutic alternative to medication in the treatment of migraine and/or tension-type headaches due to the low quality and limited sample size of the studies included in this review; therefore, future well‐conducted RCTs are needed.

The authors stated that the main drawback of this systematic review was the reduced number of RCTs and their high risk of bias.  In addition, the studies included in this review presented great heterogeneity, especially in three factors: diagnosis, the design of the intra-oral appliances, and the outcomes' tool, which made it difficult to assess the quality of evidence of the review and did not allow a meta‐analysis.  Another drawback was the short duration of the studies analyzed, except for 1 study that analyzed the results at 12 months follow‐up.

Kinetic Oscillation Stimulation

Kinetic oscillation stimulation (KOS) has been examined for acute treatment of migraine.  KOS when administered to the nasal cavity, is believed to stimulate the mucosa, and possibly activate the sensory nerve terminals with afferents in the trigeminal nerve.  The device consists of an inflatable tip that provides targeted stimulation via a minimally invasive oscillating balloon catheter.

In a randomized-controlled, double-blinded, single-center, pilot study, Juto and Hallin (2015) examined the relief of migraine pain, especially in the acute phase, by comparing active treatment (i.e., KOS in the nasal cavity) with placebo.  A total of 36 patients were randomized 1:1 using a placebo module to active or placebo treatment.  Treatment was administered with a minimally invasive inflatable tip oscillating catheter.  Symptom scores (0 to 10 VAS) were obtained before treatment, every 5 mins during treatment, at 15 mins, 2, and 24 hours post-treatment, as well as daily (0 to 3 migraine pain scale) from 30 days pre-treatment until Day 60 post-treatment.  A total of 35 patients were evaluated (active, n = 18; placebo, n = 17).  The primary end-point was the change in average pain score from before treatment to 15 mins after treatment.  Subjects who received active treatment reported reduced pain, namely, average VAS pain scores fell from 5.5 before treatment to 1.2 15 mins after treatment, while the corresponding scores for recipients of placebo fell from 4.9 to 3.9.  The changes in pain scores differed between the 2 treatments by 3.3 points (95% CI: 2.3 to 4.4; p < 0.001).  Already 5 mins into the treatment, the difference (1.9 points) was significant (p = 0.007).  The difference was like-wise significant at 2 hours post-treatment (3.7 points, p < 0.001).  One patient experienced an AE (a vasovagal reaction with full spontaneous recovery) during placebo treatment.  The authors concluded that KOS was a safe and effective treatment for acute migraine pain.  Moreover, these researchers stated that further investigations in particular, multi-center studies with long-term follow-up durations are needed.

Cocores et al (2025) examined neuromodulation techniques currently available for headache management with a focus on recent advances in non-invasive devices for migraine and trigeminal autonomic cephalalgias.  These researchers stated that currently available FDA-cleared non-invasive devices for migraine include transcutaneous supra-orbital and supra-trochlear nerve stimulation, single-pulse transcranial magnetic stimulation (sTMS), external concurrent occipital and trigeminal neurostimulation (eCOT-NS), remote electrical neuromodulation (REN), and non-invasive vagal nerve stimulation (nVNS) with indications for migraine and trigeminal autonomic cephalalgias.  Emerging non-invasive techniques being examined for use in migraine include transcranial direct current stimulation (tDCS), KOS, and auricular transcutaneous vagal nerve stimulation (at-VNS).  In addition to primary headache, non-invasive neuromodulation is being investigated for co-morbid conditions such as depression.  The authors stated that ongoing research is needed to determine effectiveness in other headache disorders and co-morbid conditions.

B Vitamins (including B1/Thiamine, B6, B12) for the Management of Migraines

Ghods et al. (2022) stated previous studies have indicated that thiamine supplementation may improve migraine headaches in patients with Wernicke-Korsakoff syndrome. In a double-blind, placebo-controlled, randomized trial, Ghods and colleagues investigated the impact of high-dose oral supplementation of vitamin B1 on episodic migraines in 40 premenopausal women with intermittent migraine attacks. The investigators reported significant reduction in the severity, frequency, duration of migraine attacks, and decreased the Migraine Disability Assessment (MIDAS) score in patients who received daily oral thiamine 990 mg supplementation for 12 weeks. On the contrary, no significant differences were identified in the placebo group except for severity of migraine attacks. Furthermore, in comparison to placebo, thiamine supplementation group demonstrated significant greater reduction in the severity of migraine headaches. The researchers noted the relatively small sample size of the study though clarified the statistical power was sufficiently robust to detect significant differences. Moreover, the authors too emphasized the limitation of focusing solely on females in the study and short-term duration, which limits the generalizability of the results to male patients and thiamine’s comprehensive influence on episodic migraine. Despite this, the authors emphasized the study results indicate that high-dose thiamine supplementation may be a beneficial adjunctive treatment for episodic migraine though further research involving longer intervention durations is essential to confirm these results.

Li et al. (2022) stated past inadequately robust studies indicate nutrients supplementation, such as magnesium, riboflavin, thiamine, niacin, vitamin B6, vitamin B12, and folate may be beneficial in migraine prevention. In a prospective cohort, the researchers evaluated the association of migraine risk and dietary intake of the above mitochondria-related nutrients though migraine patients identified in UK Biobank. Among the 202,656 patients assessed, 0.9% (n=1844) patients experienced migraines, and the researchers reported these patients had significantly lower intake of mitochondrial-related nutrients. Additionally, niacin and vitamin B12 demonstrate risk reduction of migraine of 3% (p=0.01) and 4% (p=0.04) respectively. Though not randomized and without a comparator group, the authors concluded that dietary supplementation of mitochondria-related nutrients may be beneficial in the prevention and treatment of migraine, particularly with niacin and vitamin B12. However, the authors did emphasize that future, well designed interventional studies are needed to determine the clinical benefit in reducing migraine risk through adjusting dietary intake or supplementation of such nutrients.

Similarly, in a double-blind, placebo-controlled, randomized, clinical trial of 120 females with episodic migraine, Nematgorgani et al. (2022) reported significant reduction in migraine attacks and improvement in migraine disability score (both p < 0.001) in each of the 6 vitamin groups (B1, n=20; B12, n=20; B9, n=20; vitamin B complex, n=20), administered oral daily for 12 weeks, compared to placebo. The authors concluded vitamins B1, B6, B12, and B9, and a combination of these vitamins may prove to be an effective adjuvant option in the treatment and prophylaxis of episodic migraine. Further large trials with long-term follow-ups will be required to validate the role of such vitamins supplementation in migraine management.

Furthermore, the 2025 guideline update to acute treatment of migraine for adults in emergency department by the American Headache Society (Robblee, et al., 2025) and International Headache Society's global practice recommendation for the acute pharmacological treatment of migraine (Puledda, et al., 2024) do not mention the use of vitamin B in the management of migraines.

Appendix

The diagnostic criteria for medication overuse headache from the International Classification of Headache Disorders, third edition (ICHD-3) are as follows:

• Headache occurring on 15 or more days per month in a patient with a pre-existing headache disorder; and
• Regular overuse for more than three months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache:
  
  
  • Regular intake, for ≥10 days per month for >3 months, of ergotamines, triptans, opioids, or combination analgesics, or any combination of ergotamines, triptans, simple analgesics, nonsteroidal anti-inflammatory drugs (NSAID) and/or opioids without overuse of any single drug or drug class alone or when the pattern of overuse cannot be reliably established; or
  • Regular intake, for ≥15 days per month for >3 months, of simple analgesics (ie, acetaminophen, aspirin, or NSAID); and
    
    
• Not better accounted for by another ICHD-3 diagnosis.

Patients who meet criteria for both medication overuse headache and chronic migraine are given both diagnoses.

Source: Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, third edition (beta version). Cephalalgia. 2013;33(9):629-808. 

References