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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. Most attacks of mild migraine and cluster headache can be effectively treated by anti-emetics followed by analgesics such as aspirin, acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs). Moderate to severe attacks are successfully treated utilizing combinations of ergotamine tartrate (ET), dihydroergotamine (DHE), and sumatriptan (Imitrex) with anti-emetics, simple analgesics, NSAIDs, and/or opiates. For severe migraine headaches, alternative medications include intravenous administration of neuroleptics such as chlorpromazine (Thorazine) and prochlorperazine (Compazine), occasionally corticosteroids such as prednisone, hydrocortisone, dexamethasone, and methylprednisone, and lastly parenteral narcotic analgesics such as meperidine and the nasal spray butorphanol tartrate (Stadol NS). Moreover, corticosteroid therapy may also be indicated in patients with status migrainosus. Subcutaneous, intramuscular, and intravenous 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: Nursing mothers; or 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 Persons on vasoconstrictors because the combination may result in extreme elevation of blood pressure; or Persons with hemiplegic or basilar migraine; or Persons with previously known hypersensitivity to ergot alkaloids; or Pregnant women, as DHE possesses oxytocic properties.
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; 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. Khatami et al (2011) stated that cluster headache (CH) manifests with periodic attacks of severe unilateral pain and autonomic symptoms. Nocturnal attacks may cause severe sleep disruption. In about 10 % of cases, patients present with a chronic CH (CCH), which is often medically intractable. Few attempts have been made to improve headache via pharmacological modulation of sleep. In an open-label study, 4 patients with CCH and disturbed sleep received increasing dosages of sodium oxybate (SO), a compound known to consolidate sleep and to increase slow-wave sleep. Response to SO was monitored by serial polysomnography, and actimetry, along with pain and sleep diaries. Sodium oxybate was effective in all 4 patients as shown by an immediate reduction in frequency (up to 90 %) and intensity (greater than 50 %) of nocturnal pain attacks and improved sleep quality. These effects were long-lasting in 3 patients (mean 19 months, range of 12 to 29 months) and transient (for 8 months) in 1 patient. Long-lasting improvement of daytime headaches was achieved with a latency of weeks in 2 patients. Sodium oxybate was safe, with mild-to-moderate adverse effects (e.g., amnesia, dizziness, vomiting, and weight loss). The authors concluded that SO may represent a new treatment option to reduce nocturnal and diurnal pain attacks and improve sleep quality in CCH. This study provides Class IV evidence that oral SO at night improves sleep and reduces the intensity and frequency of headaches in patients with CCH. Drawbacks of this study included; (i) open-label study with small number of subjects (n = 4), (ii) study was not placebo-controlled, (iii) SO did not completely eliminate headaches, and effects on daytime headaches were delayed and less sustained, and (iv) some adverse events needed long-term supervision and symptomatic treatments. Well-designed studies are needed to confirm the effectiveness of SO in the treatment of CCH. 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".
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