Complex Regional Pain Syndrome (CRPS) / Reflex Sympathetic Dystrophy (RSD): Treatments

Number: 0447

(Replaces CPB 550)

Policy

1. Aetna considers continuous epidural analgesia medically necessary for the treatment of members with intractable complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy (RSD), when all of the following selection criteria are met:

   • Members have experienced pain for more than 3 months despite conservative therapy (e.g., exercises, physical modalities and medications); and 
   • Members have failed a trial of physical therapy; and  
   • Members have failed a trial of nerve blocks with local anesthetics and steroids.

   Aetna considers continuous epidural analgesia experimental and investigational for the treatment of CRPS when criteria are not met.

2. Aetna considers sympathetic blocks (e.g., stellate ganglion block [cervical sympathetic block] and lumbar sympathetic block) medically necessary for the treatment of CRPS when conservative treatments, including analgesia and physical therapy, have failed.  Up to 3 sympathetic blocks are considered medically necessary to diagnose a member's pain and achieve a therapeutic effect; if the member experiences no pain relief after 3 injections, additional injections are not considered medically necessary.  Repeat sympathetic blocks for CRPS beyond the first 3 injections are considered medically necessary when provided as part of a comprehensive pain management program, which includes physical therapy, patient education, psychosocial support, and oral medications, where appropriate.  It is not considered medically necessary to repeat sympathetic blocks more frequently than once every 7 days. 

3. Aetna considers dorsal column stimulators medically necessary durable medical equipment for the management of CRPS if the member meets all of the criteria listed in CPB 0194 - Spinal Cord Stimulation. For doral root ganglion stimulation for CRPS, see CPB 0194 - Spinal Cord Stimulation.

4. Aetna considers intravenous administration of guanethidine, ketamine (including "ketamine coma" -- extended use of ketamine at anesthetic dosages), lidocaine or midazolam experimental and investigational for the treatment of CRPS, other types of chronic pain, and depression because their effectiveness for these indications has not been established.

5. Aetna considers intrapleural analgesia experimental and investigational for the treatment of CRPS with chronic pain involving the thoracic dermatomes since there is a lack of scientific evidence to support its effectiveness for this indication.

6. Aetna considers neurolysis of the spinal accessory nerve experimental and investigational in the treatment of CRPS and post traumatic chronic pain syndrome because there is inadequate evidence in the peer-reviewed published clinical literature regarding its effectiveness.

7. Aetna considers the following approaches experimental and investigational for the treatment of CRPS because their effectiveness for this indication has not been established:

Background

Spinal administration of opioids has been demonstrated to be effective in the management of patients with chronic malignant pain.  It has also been used in the treatment of chronic non-malignant pain such as reflex sympathetic dystrophy (RSD), also known as complex regional pain syndrome (CRPS).  In some patients who have failed physical therapy and medical treatment, hospitalization (4 to 6 days) for continuous epidural narcotic analgesia, with or without local anesthetics, may be necessary to break the pain cycle and prevent worsening of RSD symptoms.  This route of administration allows maximum narcotic effect in the dorsal horn with very low blood levels, thus minimizing toxicity.

On the other hand, there is a lack of scientific evidence on the effectiveness of intrapleural analgesia for treatment of CRPS with chronic pain involving the thoracic dermatomes.

Ketamine hydrochloride, an agent used for general anesthesia, has local anesthetic effects as well as N-methyl-D-aspartate (NMDA) receptor antagonist action.  During the last decade it has been shown that low, sub-anesthetic doses of ketamine may produce effective analgesia, especially when combined with opioids (Bell et al, 2002).  Moreover, it has been suggested that ketamine may have potential in treating CRPS as co-analgesics when used in combination with opioids (Hewitt, 2000; Singh and Patel, 2001).  However, there is insufficient evidence to support the use of intravenous ketamine in the treatment of CRPS/RSD.  Hord and Oaklander (2003) noted that some common treatments (e.g., local anesthetic blockade of sympathetic ganglia) are not supported by the aggregate of published studies.

In an evidence-based review on the use of ketamine in the management of chronic pain, Hocking and Cousins (2003) concluded that the evidence for efficacy of ketamine for treatment of chronic pain is moderate to weak and that further controlled studies are needed.  Additionally, Kingery (1997) noted that intravenous ketamine is not a realistic option for treatment of chronic neuropathic pain due to intolerable side-effects associated with long-term infusion.

The effectiveness of systemic lidocaine in the treatment of chronic pain (e.g., intractable neuropathic pain) has not been established.  In a randomized controlled study (n = 22), Taskaynatan and colleagues (2004) examined the effect of intravenous regional anesthesia (Bier block) with methylprednisolone and lidocaine in CRPS type I.  These investigators concluded that Bier block with methylprednisolone and lidocaine in CRPS type I does not provide long-term benefit in CRPS, and its short-term benefit is not superior to placebo.  Furthermore, in a review on chronic neuropathic pain (Harden 2005), intravenous lidocaine is not listed as a treatment option.  In addition, guidelines from the International Research Foundation for RSD/CRPS (2003) do not state that intravenous lidocaine is indicated for CRPS.

In a Cochrane systematic review, Cepeda et al (2005) reviewed the evidence supporting the use of intravenous regional anesthesia (Bier blocks) for CRPS.  The investigators identified 2 small randomized double-blind cross-over studies that evaluated 23 subjects.  The combined effect of the 2 trials produced a relative risk (RR) to achieve at least 50 % of pain relief 30 mins to 2 hrs after the sympathetic blockade of 1.17 (95 % confidence interval [CI]: 0.80 to1.72).  The investigators stated that it was not possible to determine the effect of sympathetic blockade on long-term pain relief because the 2 randomized controlled trials (RCTs) evaluated different outcomes.  Cepeda et al (2005) concluded that this systematic review revealed the scarcity of published evidence to support the use of local anesthetic sympathetic blockade as the "gold standard" treatment for CRPS.  The 2 randomized studies that met inclusion criteria had very small sample sizes; therefore, no conclusion concerning the effectiveness of this procedure could be drawn.  The investigators concluded that there is a need to conduct RCTs to address the value of sympathetic blockade with local anesthetic for the treatment of CRPS.

In a review on the management of patients with RSD/CRPS type I, Berthelot (2006) stated that mirror visual feedback was introduced recently for the rehabilitation of these patients.  This approach entails the use of visual input from a moving, unaffected limb to re-establish the pain-free relationship between sensory feedback and motor execution.  However, the author concluded that the effectiveness of mirror visual feedback in treating RSD/CRPS type I needs to be assessed in RCTs.

Rothgangel and associates (2011) evaluated the clinical aspects of mirror therapy (MT) interventions after stroke, phantom limb pain and CRPS.  A systematic literature search of the Cochrane Database of controlled trials, PubMed/MEDLINE, CINAHL, EMBASE, PsycINFO, PEDro, RehabTrials and Rehadat, was made by 2 investigators independently.  No restrictions were made regarding study design and type or localization of stroke, CRPS and amputation.  Only studies that had MT given as a long-term treatment were included.  Two authors independently assessed studies for eligibility and risk of bias by using the Amsterdam-Maastricht Consensus List.  A total of 10 randomized trials, 7 patient series and 4 single-case studies were included.  The studies were heterogeneous regarding design, size, conditions studied and outcome measures.  Methodological quality varied; only a few studies were of high quality.  Important clinical aspects, such as assessment of possible side effects, were only insufficiently addressed.  For stroke, there is a moderate quality of evidence that MT as an additional intervention improves recovery of arm function, and a low quality of evidence regarding lower limb function and pain after stroke.  The authors stated that the quality of evidence in patients with CRPS and phantom limb pain is also low.  Firm conclusions could not be drawn.  Little is known about which patients are likely to benefit most from MT, and how MT should preferably be applied.  Future studies with clear descriptions of intervention protocols should focus on standardized outcome measures and systematically register adverse effects.

In a pilot study, Kiefer and colleagues (2008a) investigated the effectiveness of subanesthetic isomeric S(+)-ketamine in refractory CRPS patients.  Four refractory CRPS patients received continuous S(+)-ketamine-infusions, gradually titrated (50 mg/day to 500 mg/day) over a 10-day period.  Pain intensities (average, peak, and least pain) and side effects were rated on visual analog scale (VAS), during a 4-day baseline, over 10 treatment days, and 2 days following treatment.  Quantitative sensory testing (QST: thermo-, mechanical detection, and pain thresholds) was analyzed at baseline and following treatment.  Subanesthetic S(+)-ketamine showed no reduction of pain and effected no change in thermo- and mechanical detection or pain thresholds.  This procedure caused no relevant side effects.  The lack of therapeutic response in the first 4 patients led to termination of this pilot study.  The authors concluded that S(+)-ketamine can be gradually titrated to large doses (500 mg/day) without clinically relevant side effects.  There was no pain relief or change in QST measurements in this series of long-standing severe CRPS patients.

In an open label phase II study, Kiefer et al (2008b) examined the effectiveness of ketamine in anesthetic dosage in refractory CRPS patients who had failed available standard therapies.  A total of 20 American Society of Anesthesiologists (ASA) I-III patients suffering from refractory CRPS received ketamine in anesthetic dosage over 5 days.  Outcome criteria were pain relief, effect on the movement disorder, quality of life, and ability to work at baseline and up to 6 months following treatment.  Significant pain relief was observed at 1, 3, and 6 months following treatment (93.5 +/- 11.1 %, 89.4 +/- 17.0 %, 79.3 +/- 25.3 %; p < 0.001).  Complete remission from CRPS was observed at 1 month in all patients, at 3 months in 17, and at 6 months in 16 patients.  If relapse occurred, significant pain relief was still attained at 3 and 6 months (59.0 +/- 14.7 %, p < 0.004; 50.2 +/- 10.6 %, p < 0.002).  Quality of life, the associated movement disorder, and the ability to work significantly improved in the majority of patients at 3 and 6 months. The authors concluded that these findings suggest benefit in pain reduction, associated CRPS symptoms, improved quality of life and ability to work following anesthetic ketamine in previously refractory CRPS patients.  However, they stated that a RCT will be needed to prove its effectiveness.

Goldberg et al (2005) reported on the effectiveness of low-dose outpatient ketamine infusion for the treatment of CRPS diagnosed by International Association for the Study of Pain criteria in patients who have failed conservative treatment.  Patients diagnosed with CRPS by a single neurologist were assigned to receive a 10-day outpatient infusion of ketamine supervised by an anesthesiologist/pain management specialist.  The infusion was administered in a short procedure unit after each patient had been instructed on how to complete a pain questionnaire.  Monitoring consisted of continuous ECG, pulse oximetry, and non-invasive blood pressure every 15 mins.  Patients made journal entries each day prior to the infusion of 40 to 80 mg of ketamine.  Subjects were also asked to rate their pain intensity using a verbal analog scale of 0 to 10 and the affective component using a verbal scale of 0 to 4.  There was a significant reduction in pain intensity from initiation of infusion (day 1) to the 10th day, with a significant reduction in the percentage of patients experiencing pain by day 10 as well as a reduction in the level of their "worst" pain.  The nadirs of pain were lower by day 10 with a significant reduction in the incidence of "punishing pain".  Moreover, there was a significant improvement in the ability to initiate movement by the 10th day.  The authors concluded that a 4-hr ketamine infusion escalated from 40 to 80 mg over a 10-day period can result in a significant reduction of pain with increased mobility and a tendency to decreased autonomic dysregulation.  They also stated that although pain data showed some variability, the results are encouraging and point to the need for additional studies.

Webster and Walker (2006) examined the safety and effectiveness of prolonged low-dose, continuous intravenous (IV) or subcutaneous ketamine infusions in non-cancer outpatients.  A total of 13 outpatients with neuropathic pain were administered low-dose IV or subcutaneous ketamine infusions for up to 8 weeks under close supervision by home health care personnel.  Using the 10-point VAS, 11 of 13 patients (85 %) reported a decrease in pain from the start of infusion treatment to the end.  Side effects were minimal and not severe enough to deter treatment.  Prolonged analgesic doses of ketamine infusions were safe for the small sample studied.  The authors concluded that these findings demonstrate that ketamine may provide a reasonable alternative treatment for non-responsive neuropathic pain in ambulatory outpatients.  Moreover, the authors stated that additional studies should follow to ascertain optimal dose and duration for specific pain disorders and to minimize side effects.  They also noted that questions regarding which patients would be most susceptible to this type of therapy and when treatment should be instituted remain unanswered. 

Kiefer and associates (2007) described the treatment of an intractable CRPS-I patient with anesthetic doses of ketamine supplemented with midazolam.  The patient presented with a rapidly progressing contiguous spread of CRPS from a severe ligamentous wrist injury.  Standard pharmacological and interventional therapy successively failed to halt the spread of CRPS from the wrist to the entire right arm.  Her pain was unmanageable with all standard therapy.  As a last treatment option, the patient was transferred to the intensive care unit and treated on a compassionate care basis with anesthetic doses of ketamine in gradually increasing (3 to 5 mg/kg/h) doses in conjunction with midazolam over a period of 5 days.  On the 2nd day of the ketamine and midazolam infusion, edema, and discoloration began to resolve and increased spontaneous movement was noted.  On day 6, symptoms completely resolved and infusions were tapered.  The patient emerged from anesthesia completely free of pain and associated CRPS signs and symptoms.  The patient has maintained this complete remission from CRPS for 8 years now.  The authors concluded that in a patient with severe spreading and refractory CRPS, a complete and long-term remission from CRPS has been obtained utilizing ketamine and midazolam in anesthetic doses.  This intensive care procedure has very serious risks but no severe complications occurred.  The psychiatric side effects of ketamine were successfully managed with the concomitant use of midazolam and resolved within 1 month of treatment.  The authors stated that large RCTs are needed to confirm the finding of this single case.

In a case report, Shirani et al (2008) described the effect of ketamine infusion in the treatment of severe refractory CRPS I.  The patient was initially diagnosed with CRPS I in her right upper extremity.  Over the next 6 years, CRPS was consecutively diagnosed in her thoracic region, left upper extremity, and both lower extremities.  The severity of her pain, combined with the extensive areas afflicted by CRPS, caused traumatic emotional problems for this patient.  Conventional treatments failed to provide long-term relief from pain.  The patient was then given several infusions of IV ketamine.  After the 3rd infusion, the edema, discoloration, and temperature of the affected areas normalized.  The patient became completely pain-free.  At 1-year follow-up, the patient reported that she has not experienced any pain since the last ketamine infusion.  The authors concluded that treatment with IV ketamine appeared to be effective in completely resolving intractable pain caused by severe refractory CRPS I.  Moreover, they stated that more research on this treatment is needed to better define its effectiveness in CRPS.

Sigtermans et al (2009) evaluated if ketamine improves pain in CRPS-1 patients.  A total of 60 patients (48 females) with severe pain participated in a double-blind randomized placebo-controlled parallel-group trial.  Patients were given a 4.2-day intravenous infusion of low-dose ketamine (n = 30) or placebo (n = 30) using an individualized step-wise tailoring of dosage based on effect (pain relief) and side effects (nausea/vomiting/psychomimetic effects).  The primary outcome of the study was the pain score (numerical rating score: 0 to 10) during the 12-week study period.  The median (range) disease duration of the patients was 7.4 (0.1 to 31.9) years.  At the end of infusion, the ketamine dose was 22.2 +/- 2.0 mg/hr/70 kg body weight.  Pain scores over the 12-week study period in patients receiving ketamine were significantly lower than those in patients receiving placebo (p < 0.001).  The lowest pain score was at the end of week 1: ketamine 2.68 +/- 0.51, placebo 5.45 +/- 0.48. In week 12, significance in pain relief between groups was lost (p = 0.07).  Treatment did not cause functional improvement.  Patients receiving ketamine more often experienced mild-to-moderate psychomimetic side effects during drug infusion (76 % versus 18 %, p < 0.001).  The authors concluded that in a population of mostly chronic CRPS-1 patients with severe pain at baseline, a multiple day ketamine infusion resulted in significant pain relief without functional improvement.  However, it is important to note that the significance in pain relief between groups was lost in week 12.

Henson and Bruehl (2010) stated that although the pathophysiology of CRPS is unclear, it appears to reflect multiple interacting mechanisms.  In addition to altered autonomic function, a role for inflammatory mechanisms and altered somatosensory and motor function in the brain is increasingly suggested.  Several possible risk factors for development of CRPS, including genetic factors, have been identified.  Few treatments have been proven effective for CRPS in well-designed clinical trials.  However, recent work suggests that bisphosphonates may be useful in CRPS management and that the NMDA receptor antagonist ketamine significantly reduces CRPS pain when administered topically or intravenously at subanesthetic dosages.  Extended use of ketamine at anesthetic dosages ("ketamine coma") remains a controversial and unproven treatment for CRPS.  Spinal cord stimulation may be effective for reducing pain in approximately 2/3 of CRPS patients not responding to other treatments, but its efficacy appears to diminish over time.

Collins and colleagues (2010) performed a meta-analysis evaluating the effects of (individual) NMDA receptor antagonists on neuropathic pain, and the response (sensitivity) of individual neuropathic pain disorders to NMDA receptor antagonist therapy.  PubMed (including MEDLINE), EMBASE and CENTRAL were searched up to October 26, 2009 for RCTs on neuropathic pain.  The methodological quality of the included trials was independently assessed by 2 authors using the Delphi list.  Fixed or random effects model were used to calculate the summary effect size using Hedges' "g" (unbiased estimator).  The outcome of measurements was the reduction of spontaneous pain.  A total of 28 studies were included, meeting the inclusion criteria.  Summary effect sizes were calculated for subgroups of studies evaluating ketamine IV in CRPS, oral memantine in post-herpetic neuralgia and, respectively, ketamine IV, and oral memantine in post-amputation pain.  Treatment with ketamine significantly reduced pain in post-amputation pain (pooled summary effect size: -1.18 (95 % CI: -1.98 to 0.37, p = 0.004).  No significant effect on pain reduction could be established for ketamine IV in CRPS (-0.65 [95 % CI: -1.47 to 0.16], p = 0.11) oral memantine in post-herpetic neuralgia (0.03 [95 % CI: -0.51 to 0.56], p = 0.92) and for oral memantine in post-amputation pain (0.38 [95 % CI: -0.21 to 0.98], p = 0.21).  The authors concluded that based on this systematic review, no conclusions can yet be made about the efficacy of NMDA receptor antagonists on neuropathic pain.  They stated that additional RCTs in homogenous groups of pain patients are needed to explore the therapeutic potential of NMDA receptor antagonists in neuropathic pain.

Sabia et al (2011) noted that historically, CRPS was poorly defined, which meant that scientists and clinicians faced much uncertainty in the study, diagnosis, and treatment of the syndrome.  The problem could be attributed to a non-specific diagnostic criteria, unknown pathophysiologic causes, and limited treatment options.  The 2 forms of CRPS still are painful, debilitating disorders whose sufferers carry heavy emotional burdens.  Current research has shown that CRPS-1 and CRPS-2 are distinctive processes, and the presence or absence of a partial nerve lesion distinguishes them apart.  Ketamine has been the focus of various studies involving the treatment of CRPS; however, currently, there is incomplete data from evidence-based studies.  The question as to why ketamine is effective in controlling the symptoms of a subset of patients with CRPS and not others remains to be answered.  A possible explanation to this phenomenon is pharmacogenetic differences that may exist in different patient populations.

Azari and colleagues (2012) reviewed published literature for evidence of the safety and effectiveness of ketamine in the treatment of CRPS.  PubMed and the Cochrane Controlled Trials Register were searched (final search May 26, 2011) using the MeSH terms "ketamine", "complex regional pain syndrome", "analgesia" and "pain" in the English literature.  The manuscript bibliographies were then reviewed to identify additional relevant papers.  Observational trials were evaluated using the Agency for Healthcare Research and Quality criteria; randomized trials were evaluated using the methodological assessment of RCTs.  The search methodology yielded 3 randomized, placebo-controlled trials, 7 observational studies and 9 case studies/reports.  In aggregate, the data available reveal ketamine as a promising treatment for CRPS.  The optimum dose, route and timing of administration remain to be determined.  The authors concluded that RCTs are needed to establish the safety and effectiveness of ketamine and to determine its long-term benefit in CRPS.

MacDaniel (2003) reported 3 cases in which electroconvulsive therapy (ECT) for depression led to the relief of co-morbid CRPS as well as depression.  In one of the cases, concomitant fibromyalgia was not relieved during 2 separate series of ECT.  Wolanin et al (2007) reported a case of CRPS in a patient who also suffered from medically refractory depression.  She was treated with ECT for her depression and subsequently was relieved of all her CRPS symptoms.  The subject, a 42-year old female, underwent a series of 12 standard bi-temporal ECT  for medically refractory depression.  Physical examination and QST were performed before and after the patient's treatment with ECT.  This standard treatment procedure for refractory depression completely resolved the patient's depressive symptoms.  In addition, the patient's CRPS symptoms were also reversed.  Physical examination as well as QST carried out before and after the ECT treatment correlated with her CRPS symptom improvement.  The authors concluded that ECT was effective in the treatment of severe refractory CRPS in this patient.  The findings of these studies need to be validated by well-designed studies.

Kemler and associates (2008) assessed the effectiveness of spinal cord stimulation (SCS) in reducing pain due to CRPS-I at the 5-year follow-up.  The authors performed a randomized trial in a 2:1 ratio in which 36 patients with CRPS-I were allocated to receive SCS and physical therapy (PT) and 18 patients to receive PT alone.  Twenty-four patients who received SCS pluse PT also underwent placement of a permanent spinal cord stimulator after successful test stimulation; the remaining 12 patients did not receive a permanent stimulator.  These researchers evaluated pain intensity, global perceived effect, treatment satisfaction, and health-related quality of life.  Patients were examined before randomization, before implantation, and every year until 5 years thereafter.  A total of 10 patients were excluded from the final analysis.  At 5 years post-treatment, SCS plus PT produced results similar to those following PT for pain relief and all other measured variables.  In a sub-group analysis, the results with regard to global perceived effect (p = 0.02) and pain relief (p = 0.06) in 20 patients with an implant exceeded those in 13 patients who received PT.

In a prospective, RCT, Fischer et al (2008) evaluated the effectiveness of occlusal splint (OS) therapy on self-reported measures of pain in patients with chronic CRPS as compared with a non-treatment group.  A total of 20 patients with CRPS were randomly assigned to either the OS or control group.  Patients in the OS group were asked to use the OS at night-time and for 3 hrs during day-time for a total of 7 weeks; the control group had no stomatognathic intervention.  The primary outcome was self-reported assessment of CRPS-related pain on numerical rating scales.  Secondary outcome measures were the temporomandibular index (TMI), and the Short Form 36 Health Survey (SF-36).  All patients had TMD signs and symptoms, but OS had no effect on CRPS-related pain on the numerical rating scale (p > 0.100).  The changes in the TMI scores over time were 16.6 % +/- 24.6 % (improvement) in the OS group and -21.3 % +/- 25.9 % (impairment) in the control group that was significant (p = 0.004).  There were no differences in the changes of SF-36 scores between groups (p = 0.636).  The authors concluded that the use of OS for 7 weeks has no impact on CRPS-related pain, but improved signs and symptoms of TMD pain.  They stated that future studies should include an active control group and evaluate if long-term changes in measures of oral health impact general health in CRPS-related pain.

van Rijn and colleagues (2009) stated that dystonia in CRPS responds poorly to treatment.  Intrathecal baclofen (ITB) may improve this type of dystonia, but information on its efficacy and safety is limited.  A single-blind, placebo-run-in, dose-escalation study was carried out in 42 CRPS patients to evaluate whether dystonia responds to IT.  Thirty-six of the 38 patients, who met the responder criteria received a pump for continuous ITB administration, and were followed-up for 12 months to assess long-term efficacy and safety (open-label study).  Primary outcome measures were global dystonia severity (both studies) and dystonia-related functional limitations (open-label study).  The dose-escalation study showed a dose-effect of baclofen on dystonia severity in 31 patients in doses up to 450 microg/day.  One patient did not respond to treatment in the dose-escalation study and 3 patients dropped out.  Thirty-six patients entered the open-label study.  Intention-to-treat analysis revealed a substantial improvement in patient and assessor-rated dystonia scores, pain, disability and quality-of-life (Qol) at 12 months.  The response in the dose-escalation study did not predict the response to ITB in the open-label study.  Eighty-nine adverse events occurred in 26 patients and were related to baclofen (n = 19), pump/catheter system defects (n = 52), or could not be specified (n = 18).  The pump was explanted in 6 patients during the follow-up phase.  Dystonia, pain, disability and Qol all improved on ITB and remained efficacious over a period of 1 year.  However, ITB is associated with a high complication rate in this patient group, and methods to improve patient selection and catheter-pump integrity are warranted.

Tran et al (2010) summarized the evidence derived from RCTs pertaining to the treatment of CRPS.  Using the Medline (January 1950 to April 2009) and Embase (January 1980 to April 2009) databases, the following medical subject headings (MeSH) were searched: "complex regional pain syndrome", "reflex sympathetic dystrophy", and "causalgia" as well as the key words "algodystrophy", "Sudeck's atrophy", "shoulder hand syndrome", "neurodystrophy", "neuroalgodystrophy", "reflex neuromuscular dystrophy", and "posttraumatic dystrophy".  Results were limited to RCTs conducted on human subjects, written in English, published in peer-reviewed journals, and pertinent to treatment.  The search criteria yielded 41 RCTs with a mean of 31.7 subjects per study.  Blinded assessment and sample size justification were provided in 70.7 % and 19.5 % of RCTs, respectively.  Only bisphosphonates appear to offer clear benefits for patients with CRPS.  Improvement has been reported with dimethyl sulfoxide, epidural clonidine, ITB, motor imagery programs, spinal cord stimulation, and steroids, but further trials are required.  The available evidence does not support the use of calcitonin, vasodilators, or sympatholytic and neuromodulative intravenous regional blockade.  Clear benefits have not been reported with stellate/lumbar sympathetic blocks, mannitol, gabapentin, and physical/occupational therapy.  The authors concluded that published RCTs can only provide limited evidence to formulate recommendations for treatment of CRPS.  In this review, no study was excluded based on factors such as sample size justification, statistical power, blinding, definition of intervention allocation, or clinical outcomes.  Thus, evidence derived from "weaker" trials may be over-emphasized.  These researchers stated that further well-designed RCTs are warranted.

In a randomized, double-blind, placebo-controlled cross-over study, Goebel et al (2010) assessed the effectiveness of intravenous immunoglobulin (IVIG) in patients with longstanding CRPS.  Persons who had pain intensity greater than 4 on an 11-point (0 to 10) numerical rating scale and had CRPS for 6 to 30 months that was refractory to standard treatment were enrolled in this trial.  Subjects received IVIG, 0.5 g/kg, and normal saline in separate treatments, divided by a washout period of at least 28 days.  The primary outcome was pain intensity 6 to 19 days after the initial treatment and the cross-over treatment.  A total of 13 eligible participants were randomly assigned; 12 completed the trial.  The average pain intensity was 1.55 units lower after IVIG treatment than after saline (95 % CI: 1.29 to 1.82; p < 0.001).  In 3 patients, pain intensity after IVIG was less than after saline by 50 % or more.  No serious adverse reactions were reported.  The authors concluded that low-dose IVIG can reduce pain in refractory CRPS.  The drawbacks of this trial were small sample size, recruitment bias, and chance variation could have influenced results and their interpretation.  The authors stated that more studies are needed to determine the best immunoglobulin dose, the duration of effect, and when repeated treatments are needed.

In an editorial that accompanied the afore-mentioned study, Birklein and Sommer (2010) noted that "a less obvious but critical limitation is the missing placebo response, which raises doubts about the adequacy of blinding.  The observed response to IVIG (20 % to 30 % pain reduction from baseline) is in the range that one would expect for the placebo response.  Another concern relates to the definition of "refractory to standard treatment" as a criterion for patient eligibility.  Study participants had not tried certain treatments that have been shown to have some effectiveness in randomized, controlled trials, such as motor or sensory learning, steroids, bisphosphonates, and sympathetic blocks .... A closer look at the individual treatment responses in Goebel and colleagues' study shows another reason that future trials should use "enriched" designs.  Although 3 of 13 patients had very positive responses, the remaining 10 patients had no or only a transient response.  If one could identify patients likely to respond, the efficacy of treatment and the cost-effectiveness ratio might be greatly improved.  Only then might IVIG offer what we have long looked for: a safe, effective, easy-to-adhere-to, and scientifically validated treatment for CRPS".

In a pilot study, Breuer and colleagues (2008) examined the safety and effectiveness of ibandronate (a highly potent bisphosphonate) for the treatment of CRPS.  A total of 10 patients received 6-mg ibandronate infusions on each of 3 days.  The infusions were preceded by a 2-week baseline period, and followed by a 4-week follow-up period.  One subject dropped out after the first infusion because of a decreased glomerular filtration rate.  Aside from transitory flu-like symptoms characteristic of bisphosphonate treatments, the drug was well-tolerated.  Significant post-intervention improvements were observed in average and worst pain ratings; the neuropathic pain qualities of "unpleasant", "sensitive", "deep", "intense", "surface", "hot","cold", "sharp", and "dull"; and hyperalgesia and allodynia.  Subjects with hand CRPS improved significantly more than those with foot CRPS in average and worst pain, as well as in the following neuropathic pain qualities: "dull", "intense", "deep" and "time".  The authors concluded that these findings justify a randomized, double-blind, placebo-controlled trial of ibandronate that should perhaps be limited to patients with hand CRPS.

Brunner et al (2009) performed a systematic review of all RCTs to evaluate the benefit of biphosphonates in the treatment of CRPS-1 patients with bone loss.  These investigators selected RCTs comparing biphosphonates with placebo, with the goal of improving pain, function and quality of life in patients with CRPS-1.  Two reviewers independently assessed trial eligibility and quality, and extracted data.  Where data were incomplete or unclear, conflicts were resolved with discussion and/or trial authors were contacted for further details.  They calculated the study size weighted pooled mean reduction of pain intensity (measured with a VAS).  Four trials of moderate quality fulfilled the inclusion criteria.  In respect to function and quality of life there was a trend in favor of biphosphonates but differences in outcome assessment impeded pooling of results.  Two trials provided sufficient data to pool pain outcomes.  Biphosphonates reduced pain intensity by 22.4 and 21.6 mm on a VAS after 4 and 12 weeks of follow-up.  Data on adverse effects were scarce.  The authors concluded that the very limited data reviewed showed that bisphosphonates have the potential to reduce pain associated with bone loss in patients with CRPS -1.  However, at present there is insufficient evidence to recommend their use in practice.

In a randomized, double-blind, placebo-controlled, parallel-group trial, Munts et al (2010) examined the safety and effectiveness of a single intrathecal administration of 60 mg methylprednisolone (ITM) in chronic patients with CRPS.  The primary outcome measure was change in pain (pain intensity numeric rating scale; range of 0 to 10) after 6 weeks.  With 21 subjects per group, the study had a 90 % power to detect a clinically relevant difference (greater than or equal to 2 points).  After 21 patients (10 on ITM) were included, the trial was stopped prematurely after the interim analysis had shown that ITM had no effect on pain (difference in mean pain intensity numeric rating scale at 6 weeks 0.3, 95 % CI: -0.7 to 1.3) or any other outcome measure.  These researchers did not find any difference in treatment-emergent adverse events between the ITM and placebo group.  The authors concluded that a single bolus administration of ITM is not effective in chronic CRPS patients, which may indicate that spinal immune activation does not play an important role in this phase of the syndrome.

In a pilot study, Safarpour et al (2010) investigated the effectiveness and tolerability of botulinum toxin A (BoNT-A) in allodynia of patients with CRPS.  A total of 14 patients were studied -- 8 patients were participants of a randomized, prospective, double-blind, placebo-controlled protocol; 6 patients were studied prospectively in an open-label protocol.  Patients were rated at baseline and at 3 weeks and 2 months after BoNT-A administration.  Ratings included brief pain inventory, McGill pain questionnaire, clinical pain impact questionnaire, quantitative skin sensory test, sleep satisfaction scale, and patient global satisfaction scale.  BoNT-A was injected intradermally and subcutaneously, 5 units/site into the allodynic area (total dose 40 to 200 units).  None of the patients with allodynia showed a significant response after treatment.  The treatment was painful and poorly-tolerated.  The authors concluded that intrademal and subcutaneous administration of BoNT-A into the allodynic skin of the patients with CRPS failed to improve pain and was poorly-tolerated.

Basford et al (2003) assessed the physiological effects of linearly polarized red and near-infrared (IR) light and quantitated its benefits in people with upper extremity pain due to CRPS I (RSD).  This was a 2-part study.  In the 1st phase, 6 adults (aged 18 to 60 years) with normal neurological examinations underwent transcutaneous irradiation of their right stellate ganglion with linearly polarized 0.6 to 1.6 microm light (0.92 W, 88.3 J); 2nd phase consisted of a double-blinded evaluation of active and placebo radiation in 12 subjects (aged 18 to 72 years) of which 6 had upper extremity CRPS I and 6 served as "normal" controls.  Skin temperature, heart rate (HR), sudomotor function, and vasomotor tone were monitored before, during, and for 30 mins following irradiation.  Analgesic and sensory effects were assessed over the same period as well as 1 and 2 weeks later.  Three of 6 subjects with CRPS I and no control subjects experienced a sensation of warmth following active irradiation (p = 0.025).  Two of the CRPS I subjects reported a greater than 50 % pain reduction.  However, 4 noted minimal or no change and improvement did not reach statistical significance for the group as a whole.  No statistically significant changes in autonomic function were noted.  There were no adverse consequences.  The authors concluded that irradiation was well-tolerated.  There is a suggestion in this small study that treatment is beneficial and that its benefits are not dependent on changes in sympathetic tone.  They stated that further evaluation is warranted.

In a systematic review, Dirckx and colleagues (2012) described the current empirical evidence for the effectiveness of administering the most commonly used immunomodulating medication (i.e., bisphosphonates, glucocorticoids, immunoglobulins, thalidomide, and tumor necrosis factor-α antagonists) in CRPS patients.  PubMed was searched for original articles that investigated CRPS and the use of one of the afore-mentioned immunomodulating agents.  The search yielded 39 relevant articles: from these, information on study design, sample size, duration of disease, type and route of medication, primary outcome measures, and results was examined.  The authors concluded that theoretically, the use of immunomodulating medication could counteract the ongoing inflammation and might be an important step in improving a disabled hand or foot, leading to further recovery.  However, they stated that more high-quality intervention studies are needed.

Chronic pain generally refers to persistent, non-acute, sometimes disabling pain in the extremities or other areas of the body. The pain can be associated with a known cause such as a major or minor injury, or it can be a symptom of a painful chronic condition or be of unknown etiology. Chronic pain syndrome is a diagnosis of exclusion. It is usually considered ongoing pain lasting longer than 6 months, with some using three months as a minimum criteria. It is associated with diffuse arthralgia and myalgia without signs of joint swelling, muscle weakness, weight loss or fever. Post traumatic pain syndrome is one of the historical terms used to describe excess pain with or without sympathetic dysfunction. 

The spinal accessory nerve is the eleventh cranial nerve. It emerges from the skull and receives an extra root (or accessory) from the upper part of the spinal cord. This nerve supplies the sternocleidomastoid and trapezius muscles. The sternocleidomastoid muscle is in the front of the neck and turns the head while the trapezius muscle moves the scapula, turns the head to the opposite side, and helps pull the head back. Neurolysis is the destruction of nerves to promote analgesia or pain relief.

Diazgranados et al (2010) conducted a randomized, placebo-controlled, double-blind, cross-over, add-on study to determine whether an N-methyl-D-aspartate-receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression.  The main outcome variable was measured using the Montgomery-Asberg Depression Rating Scale primary efficacy measure scores.  The results illustrated that within 40 minutes depressive symptoms significantly improved in subjects receiving ketamine compared with placebo, with a drug difference effect size being largest at day 2; 71 % of subjects responded to ketamine and 6 % responded to placebo.

Aan et al (2012) conducted a systematic review of all available published data on the antidepressant effects of ketamine, including all recently completed, ongoing, and planned studies.  They reported that as of the publication of their report, 163 patients, primarily with treatment-resistant depression, had participated in case studies, open-label investigations, or controlled trials.  All reported trials used a within-subject, cross-over design with inactive placebo controls.  Response rates for the clinical trials and open-label investigations ranged from 25 % to 85 % 24 hours post-treatment.  Seventy-two hours post-treatment response rates in the afore-mentioned studies was 14 % to 70 %.  The authors concluded that further research of ketamine for individuals with severe mood disorders is warranted, but they did not recommend administration outside of the hospital setting due to the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks. 

Martin et al (2013) described, for the first time, the use of multiple peripheral nerve catheters to treat CRPS type I in a 10-year old girl who had failed multi-modal pharmacologic regimens.  At separate times, a peripheral nerve catheter was placed to treat CRPS of the distal left lower extremity as well as the right upper extremity.  The goal of this therapy was to relieve pain and thereby allow the re-initiation of intensive PT.  A continuous infusion of 0.1 % ropivacaine was infused via the catheters for approximately 60 hours.  The patient was subsequently able to participate in PT as well as activities of daily living with improved eating, sleeping, and mood.  The authors concluded that although many therapeutic modalities have been tried in CRPS type I, given the debilitating nature of the disorder and the variable response to therapy, new and alternative therapeutic interventions, such as continuous peripheral nerve catheters, are needed.  The findings of this single case study need to be validated by well-designed studies.

An UpToDate review on “Prevention and management of complex regional pain syndrome in adults” (Abdi, 2014) states that “Experimental approaches -- Several different approaches have been of interest for the treatment of longstanding or refractory CRPS, including intravenous ketamine, intravenous magnesium, tadalafil, mirror therapy, and intravenous immunoglobulin”.

The Colorado Division of Workers' Compensation’s medical treatment guidelines on “Complex regional pain syndrome/reflex sympathetic dystrophy” (2011) noted that “Sympathetic injections are generally accepted, well-established procedures.  They include stellate ganglion blocks and lumbar sympathetic blocks. Unfortunately, there are no high quality randomized controlled trials in this area." 

The Washington State Department of Labor and Industries’ guidelines on “Work-related complex regional pain syndrome (CRPS): Diagnosis and treatment” (2011) stated that “Sympathetic blocks have long been a standard treatment for CRPS and can be useful for a subset of cases.  Stellate ganglion blocks (cervical sympathetic blocks) and lumbar sympathetic blocks are widely used in the management of upper and lower extremity CRPS. There is limited evidence to confirm effectiveness.  An initial trial of up to three sympathetic blocks should be considered when the condition fails to improve with conservative treatment, including analgesia and physical therapy." 

Hey et al (2014) identified through case study the presentation and possible pathophysiological cause of complex regional pain syndrome and its preferential response to stellate ganglion blockade.  Complex regional pain syndrome can occur in an extremity after minor injury, fracture, surgery, peripheral nerve insult or spontaneously and is characterized by spontaneous pain, changes in skin temperature and color, edema, and motor disturbances.  Pathophysiology is likely to involve peripheral and central components and neurological and inflammatory elements.  There is no consistent approach to treatment with a wide variety of specialists involved.  Diagnosis can be difficult, with over-diagnosis resulting from undue emphasis placed upon pain disproportionate to an inciting event despite the absence of other symptoms or under-diagnosed when subtle symptoms are not recognized.  The International Association for the Study of Pain supports the use of sympathetic blocks to reduce sympathetic nervous system over-activity and relieve complex regional pain symptoms.  Educational reviews promote stellate ganglion blockade as beneficial.  Three blocks were given at 8, 10 and 13 months after the initial injury under local anesthesia and sterile conditions.  Physiotherapeutic input was delivered under block conditions to maximize joint and tissue mobility and facilitate restoration of function.  The authors concluded that this case demonstrated the need for practitioners from all disciplines to be able to identify the clinical characteristics of complex regional pain syndrome to instigate immediate treatment and supports the notion that stellate ganglion blockade is preferable to upper limb intravenous regional anesthetic block for refractory index finger pain associated with complex regional pain syndrome. 

An UpToDate review on “Prevention and management of complex regional pain syndrome in adults” (Abdi, 2014) states that “Local sympathetic blocks (e.g., stellate ganglion block) with local anesthetic, while of unproven benefit in terms of the long-term outcome, nevertheless may provide a short-term decrease in pain that can be diagnostically useful and that can help with mobilization of the affected limb.  The author has experience in using clonidine in combination with local anesthetics for stellate ganglion and lumbar sympathetic nerve blocks successfully, but its value needs to be systematically studied.  Stellate ganglion blocks may be performed at one week intervals and may be repeated several times.  This treatment is abandoned if an immediate response (e.g., improved temperature and decreased pain) does not occur following the first or second nerve block”.

Connolly et al (2015) examined the available literature and synthesized published data concerning the treatment of CRPS with ketamine.  The search was conducted utilizing the databases Medline, Embase and the Cochrane Central Registry of Controlled Trials.  All relevant articles were systematically reviewed.  The search yielded 262 articles, 45 of which met the inclusion/exclusion criteria.  Of those included, 6 were reviews, 5 were randomized placebo-controlled trials, 13 were observational studies, and 21 were case reports.  The authors concluded that there is no high quality evidence available evaluating the effectiveness of ketamine for CRPS and all manuscripts examined in this review were of moderate to low quality.  They stated that there is currently only weak evidence supporting the effectiveness of ketamine for CRPS, yet there is clearly a rationale for definitive study.

In a Cochrane review, Straube et al (2013) stated that the concept that many neuropathic pain syndromes (traditionally this definition would include CRPS) are "sympathetically maintained pains" has historically led to treatments that interrupt the sympathetic nervous system.  Chemical sympathectomies use alcohol or phenol injections to destroy ganglia of the sympathetic chain, while surgical ablation is performed by open removal or electrocoagulation of the sympathetic chain or by minimally invasive procedures using thermal or laser interruption.  These investigators reviewed the evidence from randomized, double blind, controlled trials on the safety and effectiveness of chemical and surgical sympathectomy for neuropathic pain, including CRPS.  Sympathectomy may be compared with placebo (sham) or other active treatment, provided both participants and outcome assessors are blind to treatment group allocation.  On July 2, 2013, these investigators searched CENTRAL, MEDLINE, EMBASE, and the Oxford Pain Relief Database.  They reviewed the bibliographies of all randomized trials identified and of review articles and also searched 2 clinical trial databases, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, to identify additional published or unpublished data.  They screened references in the retrieved articles and literature reviews and contacted experts in the field of neuropathic pain.  Randomized, double-blind, placebo or active controlled studies assessing the effects of sympathectomy for neuropathic pain and CRPS were selected for analysis.  Two review authors independently assessed trial quality and validity, and extracted data.  No pooled analysis of data was possible.  Only 1 study satisfied the inclusion criteria, comparing percutaneous radiofrequency thermal lumbar sympathectomy with lumbar sympathetic neurolysis using phenol in 20 participants with CRPS.  There was no comparison of sympathectomy versus sham or placebo.  No dichotomous pain outcomes were reported.  Average baseline scores of 8 to 9/10 on several pain scales fell to about 4/10 initially (1 day) and remained at 3 to 5/10 over 4 months.  There were no significant differences between groups, except for "unpleasant sensation", which was higher with radiofrequency ablation.  One participant in the phenol group experienced post sympathectomy neuralgia, while 2 in the radiofrequency group and 1 in the phenol group complained of paraesthesia during needle positioning.  All participants had soreness at the injection site.  The authors concluded that the practice of surgical and chemical sympathectomy for neuropathic pain and CRPS was based on very little high quality evidence.  Sympathectomy should be used cautiously in clinical practice, in carefully selected patients, and probably only after failure of other treatment options.  In these circumstances, establishing a clinical register of sympathectomy may help to inform treatment options on an individual patient basis.

In a review on “Complex regional pain syndrome”, Birklein et al (2015) states the following:

• Magnetic resonance imaging (MRI) is helpful for eliminating differential diagnoses; but not for diagnosing CRPS.
• Quantitative sensory testing (QST) is not suitable for making a diagnosis.
• Botulinum has very limited effects
• Gabapentin might have a marginal but clinically unimportant effectiveness
• The value of IV immunoglobulins needs to be confirmed

Guidelines from the Royal College of Physicians on complex regional pain syndrome (Goebel et al, 2012) state that amputation should not be used to provide pain relief in CRPS. Amputation may worsen CRPS, with CRPS occuring in the stump.. Amputation may be considered in rare cases of intractable infection of the infected limb.

Ketamine for the Treatment of Complex Regional Pain Syndrome

Oaklander and Horowitz (2015) stated that CRPS is the current consensus-derived name for a syndrome usually triggered by limb trauma. Required elements include prolonged, disproportionate distal-limb pain and microvascular dysregulation (e.g., edema or color changes) or altered sweating.  CRPS-II (formerly "causalgia") describes patients with identified nerve injuries.  CRPS-I (formerly "reflex sympathetic dystrophy") describes most patients who lack evidence of specific nerve injuries.  Diagnosis is clinical and the pathophysiology involves combinations of small-fiber axonopathy, microvasculopathy, inflammation, and brain plasticity/sensitization.  Females have much higher risk and workplace accidents are a well-recognized cause.  Inflammation and dysimmunity, perhaps facilitated by injury to the blood-nerve barrier, may contribute.  Most patients, particularly the young, recover gradually, but treatment can speed healing.  Evidence of effectiveness is strongest for rehabilitation therapies (e.g., graded-motor imagery), neuropathic pain medications, and electric stimulation of the spinal cord, injured nerve, or motor cortex.  Investigational treatments include ketamine, botulinum toxin, immunoglobulins, and transcranial neuromodulation.  Non-recovering patients should be re-evaluated for neuro-surgically treatable causal lesions (nerve entrapment, impingement, infections, or tumors) and treatable potentiating medical conditions, including polyneuropathy and circulatory insufficiency.

Xu and colleagues (2016) noted that CRPS remains a challenging clinical pain condition. Multi-disciplinary approaches have been advocated for managing CRPS.  Compared with spinal cord stimulation and intrathecal targeted therapy, IV treatments are less invasive and less costly.  These investigators reviewed the literature on IV therapies and determine the level of evidence to guide the management of CRPS.  They searched PubMed, Embase, Scopus, and the Cochrane databases for articles published on IV therapies of CRPS up through February 2015.  The search yielded 299 articles, of which 101 were deemed relevant by reading the titles and 63 by reading abstracts.  All these 63 articles were retrieved for analysis and discussion.  These researchers evaluated the relevant studies and provided recommendations according to the level of evidence.  The authors concluded that there is evidence to support the use of IV bisphosphonates, immunoglobulin, ketamine, or lidocaine as valuable interventions in selected patients with CRPS.  However, they stated that high-quality studies are needed to further evaluate the safety, effectiveness, and cost-effectiveness of IV therapies for CRPS.

Kim et al (2016) examined the effects of long-term frequent ketamine treatment on cognitive function in [AQ-A] CRPS patients. A total of 30 CRPS patients were divided into 2 groups based on both the duration and frequency of ketamine treatment; the long-term frequent ketamine treatment (LF) group (n = 14) and the non-LF group (n = 16).  Participants were asked to complete a questionnaire packet including demographic and clinical characteristics and potential variables affecting cognitive function.  Then, they performed the neuropsychological test.  Results indicated that the LF group performed significantly poorer than the non-LF group on the digit span, digit symbol, Controlled Oral Word Association Test, and Trail Making Test, but not the Stroop task.  The authors concluded that patients with CRPS receiving long-term frequent ketamine treatment showed impairment in cognitive function (specifically executive function) compared with those who do not.  These findings may have implications for clinical assessment and rehabilitation of cognitive function in CRPS patients.

Goldberg et al (2005) reported on the effectiveness of low-dose outpatient ketamine infusion for the treatment of CRPS diagnosed by International Association for the Study of Pain criteria in patients who have failed conservative treatment.  Patients diagnosed with CRPS by a single neurologist were assigned to receive a 10-day outpatient infusion of ketamine supervised by an anesthesiologist/pain management specialist.  The infusion was administered in a short procedure unit after each patient had been instructed on how to complete a pain questionnaire.  Monitoring consisted of continuous ECG, pulse oximetry, and non-invasive blood pressure every 15 mins.  Patients made journal entries each day prior to the infusion of 40 to 80 mg of ketamine.  Subjects were also asked to rate their pain intensity using a verbal analog scale of 0 to 10 and the affective component using a verbal scale of 0 to 4.  There was a significant reduction in pain intensity from initiation of infusion (day 1) to the 10th day, with a significant reduction in the percentage of patients experiencing pain by day 10 as well as a reduction in the level of their "worst" pain.  The nadirs of pain were lower by day 10 with a significant reduction in the incidence of "punishing pain".  Moreover, there was a significant improvement in the ability to initiate movement by the 10th day.  The authors concluded that a 4-hr ketamine infusion escalated from 40 to 80 mg over a 10-day period can result in a significant reduction of pain with increased mobility and a tendency to decreased autonomic dysregulation.  They also stated that although pain data showed some variability, the results are encouraging and point to the need for additional studies.

Sigtermans et al (2009) evaluated if ketamine improves pain in CRPS-1 patients.  A total of 60 patients (48 females) with severe pain participated in a double-blind randomized placebo-controlled parallel-group trial.  Patients were given a 4.2-day intravenous infusion of low-dose ketamine (n = 30) or placebo (n = 30) using an individualized step-wise tailoring of dosage based on effect (pain relief) and side effects (nausea/vomiting/psychomimetic effects).  The primary outcome of the study was the pain score (numerical rating score: 0 to 10) during the 12-week study period.  The median (range) disease duration of the patients was 7.4 (0.1 to 31.9) years.  At the end of infusion, the ketamine dose was 22.2 +/- 2.0 mg/hr/70 kg body weight.  Pain scores over the 12-week study period in patients receiving ketamine were significantly lower than those in patients receiving placebo (p < 0.001).  The lowest pain score was at the end of week 1: ketamine 2.68 +/- 0.51, placebo 5.45 +/- 0.48. In week 12, significance in pain relief between groups was lost (p = 0.07).  Treatment did not cause functional improvement.  Patients receiving ketamine more often experienced mild-to-moderate psychomimetic side effects during drug infusion (76 % versus 18 %, p < 0.001).  The authors concluded that in a population of mostly chronic CRPS-1 patients with severe pain at baseline, a multiple day ketamine infusion resulted in significant pain relief without functional improvement.  However, it is important to note that the significance in pain relief between groups was lost in week 12.

Schwartzman et al (2009) stated that CRPS is a severe chronic pain condition that most often develops following trauma.  The pathophysiology of CRPS is not known but both clinical and experimental evidence demonstrate the important of the NMDA receptor and glial activation in its induction and maintenance.  Ketamine is the most potent clinically available safe NMDA antagonist that has a well-established role in the treatment of acute and chronic pain.  This randomized double-blind placebo controlled trial was designed to evaluate the effectiveness of intravenous ketamine in the treatment of CRPS.  Before treatment, after informed consent was obtained, each subject was randomized into a ketamine or a placebo infusion group.  Study subjects were evaluated for at least 2 weeks prior to treatment and for 3 months following treatment.  All subjects were infused intravenously with normal saline with or without ketamine for 4 hours (25 ml/hour) daily for 10 days.  The maximum ketamine infusion rate was 0.35 mg/kg/hour, not to exceed 25 mg/hour over a 4-hour period.  Subjects in both the ketamine and placebo groups were administered clonidine and versed.  This study showed that intravenous ketamine administered in an out-patient setting resulted in statistically significant (p < 0.05) reductions in many pain parameters.  It also showed that subjects in the placebo group demonstrated no treatment effect in any parameter.  The authors concluded that the results of this study warrant a larger randomized placebo controlled trial using higher doses of ketamine and a longer follow-up period.  The main drawbacks of this study were:

1. its small size (n = 26);
2. non-stratification of patients either by length of time with the illness or by the temperature of the affected area; and
3. lack of a cross-over arm.

In a preliminary report, Puchalski and Zyluk (2016) noted that chronic, refractory CRPS remains very difficult to treat.  A sub-anesthetic low-dose ketamine has shown promise in advanced CRPS.  These investigators examined the efficacy of ketamine in anesthetic dosage in chronic, refractory CRPS patients that had failed available standard therapies.  A total of 5 women, mean age of 34 years with long-standing, a mean of 8 years', CRPS received ketamine in anesthetic dosage over 10 days.  The patients received 1 to 5 ketamine courses.  The effect of gradual pain reduction was observed beginning on the 4(th)-5(th) day of treatment, associated with a decrease in the intensity of the allodynia (pain at light touch).  No improvement in function (finger range of motion, grip strength) of the affected hands was noted in any patient.  This beneficial analgesic effect was confined to 1.5 to 2.5 months after treatment and then pain relapsed to the baseline level.  The authors concluded that the results of this study showed a short-term analgesic effect for this therapy, with no effect on movement and function of the affected limbs.  Nevertheless, this method brings hope to the most severely ill patients who cannot be offered any other reasonable therapeutic option.

In a systematic review on “Intravenous therapies for complex regional pain syndrome”, Xu et al (2016) concluded that “high-quality studies are needed to further evaluate the safety, efficacy, and cost-effectiveness of IV therapies (e.g., bisphosphonates, immunoglobulin, ketamine, or lidocaine) for CRPS.

In a meta-analysis, Zhao and colleagues (2018) examined the efficacy of ketamine in the treatment of CRPS.  A search of Embase, PubMed, Web of Knowledge, Cochrane, Clinical Trial.gov , and FDA.gov between January 1, 1950 and August 1, 2017  was conducted to evaluate ketamine infusion therapy in the treatment of CRPS.  These researchers selected RCTs or cohort studies for meta-analyses.  I2 index estimates were calculated to test for variability and heterogeneity across the included studies.  The primary outcome is pain relief.  The effect of ketamine treatment for CRPS was assessed by 0 to 10 scale numerical rating pain score.  The secondary outcome is the pain relief event rate, which is defined as the percentage of participants who achieved 30 % or higher pain relief in each of the qualified studies.  The meta-analysis results showed that the ketamine treatment led to a decreased mean of pain score in comparison to the self-controlled baseline (p < 0.000001).  However, there was a statistical significance of between-study heterogeneity.  The immediate pain relief event rate was 69 % (95 % CI: 53 % to 84 %).  The pain relief event rate at the 1 to 3 months follow-ups was 58 % (95 % CI: 41 % to 75 %).  The current available studies regarding ketamine infusion for CRPS were reviewed, and meta-analyses were conducted to evaluate the efficacy of ketamine infusion in the treatment of CRPS.  The authors concluded these findings suggested that ketamine infusion can provide clinically effective pain relief in short-term for less than 3 months.  However, because of the high heterogeneity of the included studies and publication bias, additional RCTs and standardized multi-center studies are needed to confirm this conclusion.  Furthermore, studies are needed to prove long-term efficacy of ketamine infusion in the treatment of CRPS.

Furthermore, an UpToDate review on “Complex regional pain syndrome in adults: Prevention and management” (Abdi, 2018) stated that “Other pharmacologic treatments for CRPS with limited evidence include alpha adrenergic drugs, ketamine, and intravenous immune globulin”.

Ketamine for the Treatment of Depression

Abdallah et al (2015) stated that ketamine is the prototype for a new generation of glutamate-based antidepressants that rapidly alleviate depression within hours of treatment. Over the past decade, there has been replicated evidence demonstrating the rapid and potent anti-depressant effects of ketamine in treatment-resistant depression.  Moreover, pre-clinical and biomarker studies have begun to elucidate the mechanism underlying the rapid antidepressant effects of ketamine, offering a new window into the biology of depression and identifying a plethora of potential treatment targets.  These investigators discussed the efficacy, safety, and tolerability of ketamine, summarized the neurobiology of depression, reviewed the mechanisms underlying the rapid antidepressant effects of ketamine, and discussed the prospects for next-generation rapid-acting anti-depressants.  The authors concluded that although a single infusion of ketamine appears to be safe, the long-term safety of repeated ketamine dosing is not fully known.  They stated that as a prototype for rapid-acting anti-depressants, ketamine has provided an exciting new direction that may offer hope of rapid therapeutics for patients who are suffering from depression.

Sanacora and Schatzberg (2015) noted that large “real world” studies demonstrating the limited effectiveness and slow onset of clinical response associated with the existing anti-depressant medications has high-lighted the need for the development of new therapeutic strategies for major depression and other mood disorders. Yet, despite intense research efforts, the field has had little success in developing anti-depressant treatments with fundamentally novel mechanisms of action over the past 6 decades, leaving the field wary and skeptical about any new developments.  However, a series of relatively small proof-of-concept studies conducted over the last 15 years has gradually gained great interest by providing strong evidence that a unique, rapid onset of sustained, but still temporally limited, anti-depressant effects can be achieved with a single administration of ketamine.  These researchers stated that “We are now left with several questions regarding the true clinical meaningfulness of the findings and the mechanisms underlying the anti-depressant action”.   These investigators shared their opinions on these issues and discussed paths to move the field forward.  The authors concluded that “we remain in disagreement over what we have learned from our experience with ketamine and another NMDAR drugs to date for the treatment of mood disorders.  We agree that there is clear evidence that ketamine can produce rapid transient antidepressant-like effects, but remain divergent in our opinions on the mechanisms mediating these effects and the potential to act on what we know to initiate novel treatment approaches or suggest novel pathways for drug development. We agree that it is premature to conclude that any single mechanism is solely responsible for the antidepressant response, and that the response is potentially mediated through complex pathways downstream from ketamine’s direct actions at any receptor.  We strongly agree that pre-clinical studies should explore potential alternative MoAs [mechanism of actions] and that more clinical studies are needed to clearly establish the true clinical effectiveness and safety of the treatment before it is made widely available in the clinical setting”.

In a “Letter to the Editor”, da Frota Ribeiro et al (2016) stated that “Mounting evidence from a series of small clinical trials and case series suggests ketamine can have rapid and robust antidepressant and possibly anti-suicidal effects in patients who did not respond to standard treatment options.  However, because of the variable psychotomimetic effects of ketamine in healthy volunteers and exacerbation of previously experienced positive symptoms in schizophrenic volunteers, patients previously experiencing psychotic features have been excluded from the reported studies and trials.  We have used ketamine as an anti-depressant on several occasions in patients with severe treatment-resistant major depressive episodes with good results.  Recently, after seriously considering the risks and benefits of providing off-label ketamine treatment (0.5 mg/kg continuous intravenous infusion over 40 min) based on this knowledge, we treated two patients with psychotic features complicating severe depressive episodes.  To our knowledge, this is the first report describing the use of ketamine as treatment in patients with a history of psychosis …. Further evidence is needed to establish the efficacy of ketamine in the treatment of mood disorders and the safety of providing the treatment to patients with psychotic features before broadening its use in clinical settings, especially when considering repeated administrations.  However, this very small case series suggests that it may be possible to study patients with the diagnosis of major depression with psychotic features in future clinical trials; this is especially important because these patients are often among the most severely depressed and treatment resistant patients seen in the clinical setting”.

Compression Sleeve for the Treatment of Complex Regional Pain Syndrome

An UpToDate review on “Prevention and management of complex regional pain syndrome in adults” (Abdi, 2016) does not mention the use of compression sleeve as a management tool.

Intrathecal Adenosine and Clonidine for the Treatment of Complex Regional Pain Syndrome

Rauck et al (2015) stated that pre-clinical data suggested that intrathecal adenosine and clonidine reduced hypersensitivity, but only clonidine reduced pain. These researchers tested the effects of these interventions in patients with chronic pain.  A total of 22 subjects with pain and hyperalgesia in a lower extremity from CRPS were recruited in a double-blind cross-over study to receive intrathecal adenosine, 2 mg, or clonidine, 100 μg.  Primary outcome measure was proportion with greater than or equal to 30 % reduction in pain 2 hours after injection, and secondary measures were pain report, areas of hypersensitivity, and temporal summation to heat stimuli.  Treatments did not differ in the primary outcome measure (10 met success criterion after clonidine administration and 5 after adenosine administration), although they did differ in pain scores over time, with clonidine having a 3-fold greater effect (p = 0.014).  Both drugs similarly reduced areas of hyperalgesia and allodynia by approximately 30 % and also inhibited temporal summation.  The percentage change in pain report did not correlate with the percentage change in areas of hyperalgesia (p = 0.09, r = 0.08) or allodynia (p = 0.24, r = 0.24) after drug treatment.  Both intrathecal adenosine and clonidine acutely inhibited experimentally-induced and clinical hypersensitivity in patients with CRPS.  The authors concluded that although these drugs did not differ in analgesia by the primary outcome measure, their difference in effect on pain scores over time and lack of correlation between effect on pain and hypersensitivity suggested that analgesia does not parallel anti-hyperalgesia with these treatments.

Furthermore, an UpToDate review on “Prevention and management of complex regional pain syndrome in adults” (Abdi, 2016) does not mention the use of intrathecal adenosine and clonidine as a therapeutic option.

Movement Representation Techniques for the Treatment of Complex Regional Pain Syndrome

Thieme et al (2016) noted that relatively new evidence suggested that movement representation techniques (i.e., therapies that use the observation and/or imagination of normal pain-free movements, such as mirror therapy, motor imagery, or movement and/or action observation) might be effective in reduction of some types of limb pain. These researchers summarized the evidence regarding the effectiveness of those techniques by performing a systematic review with meta-analysis. They searched Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, AMED, PsychINFO, Physiotherapy Evidence Database, and OT-seeker up to August 2014 and hand-searched further relevant resources for RCTs that studied the effectiveness of movement representation techniques in reduction of limb pain. The outcomes of interest were pain, disability, and quality of life. Study selection and data extraction were performed by 2 reviewers independently. They included 15 trials on the effects of mirror therapy, (graded) motor imagery, and action observation in patients with CRPS, phantom limb pain, post-stroke pain, and non-pathological (acute) pain. Overall, movement representation techniques were found to be effective in reduction of pain (standardized mean difference [SMD] = -0.82, 95 % CI: -1.32 to -0.31, p = 0.001) and disability (SMD = 0.72, 95 % CI: 0.22 to 1.22, p = 0.004) and showed a positive but non-significant effect on quality of life (SMD = 2.61, 95 % CI: -3.32 to 8.54, p = 0.39). Especially mirror therapy and graded motor imagery should be considered for the treatment of patients with CRPS. Furthermore, the results indicated that motor imagery could be considered as a potential effective treatment in patients with acute pain after trauma and surgery. To-date, there is no evidence for a pain-reducing effect of movement representation techniques in patients with phantom limb pain and post-stroke pain other than CRPS. The authors concluded that they synthesized the evidence for the effectiveness of movement representation techniques (i.e., motor imagery, mirror therapy, or action observation) for treatment of limb pain. They stated that these findings suggested effective pain reduction in some types of limb pain; further research should address specific questions on the optimal type and dose of therapy.

Graded Motor Imagery and Mirror Therapy

Mendez-Rebolledo et al (2017) stated that graded motor imagery (GMI) and mirror therapy (MT) is thought to improve pain in patients with CRPS types 1 and 2.  However, the evidence is limited and analysis are not independent between types of CRPS.  These investigators analyzed the effects of GMI and MT on pain in independent groups of patients with CRPS types 1 and 2.  Searches for literature published between 1990 and 2016 were conducted in databases; RCTs that compared GMI or MT with other treatments for CRPS types 1 and 2 were included.  A total of 6 articles met the inclusion criteria and were classified from moderate to high quality.  The total sample was composed of 171 participants with CRPS type 1; 3 studies presented GMI with 3 components and 3 studies only used the MT.  The studies were heterogeneous in terms of sample size and the disorders that triggered CRPS type 1.  There were no trials that included participants with CRPS type 2.  The authors concluded that GMI and MT can improve pain in patients with CRPS type 1; however, there is insufficient evidence to recommend these therapies over other treatments given the small size and heterogeneity of the studied population.

Furthermore, a Cochrane review on "Physiotherapy for pain and disability in adults with complex regional pain syndrome (CRPS) types I and II" (Smart et al, 2016) stated that there is very low quality evidence that graded motor imagery (GMI; 2 trials, 49 subjects) may be useful for improving pain and functional disability at long-term (6 months) follow-up in people with CRPS I compared to usual care plus physiotherapy. In a Cochrane review, Smart and colleagues (2016) examined the effectiveness of physiotherapy interventions for treating the pain and disability associated with CRPS types I and II.  These investigators searched the following databases from inception up to February 12, 2015: CENTRAL (the Cochrane Library), Medline, Embase, CINAHL, PsycINFO, LILACS, PEDro, Web of Science, DARE and Health Technology Assessments, without language restrictions, for RCTs of physiotherapy interventions for treating pain and disability in people CRPS.  They also searched additional online sources for unpublished trials and trials in progress.  These researchers included RCTs of physiotherapy interventions (including manual therapy, therapeutic exercise, electrotherapy, physiotherapist-administered education and cortically directed sensory-motor rehabilitation strategies) employed in either a stand-alone fashion or in combination, compared with placebo, no treatment, another intervention or usual care, or of varying physiotherapy interventions compared with each other in adults with CRPS I and II.  The primary outcomes of interest were patient-centered outcomes of pain intensity and functional disability.  Two review authors independently evaluated those studies identified through the electronic searches for eligibility and subsequently extracted all relevant data from the included RCTs.  Two review authors independently performed “risk of bias” assessments and rated the quality of the body of evidence for the main outcomes using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.  The authors included 18 RCTs (739 participants) that tested the effectiveness of a broad range of physiotherapy-based interventions.  Overall, there was a paucity of high quality evidence concerning physiotherapy treatment for pain and disability in people with CRPS I.  Most included trials were at “high” risk of bias (15 trials) and the remainder were at “unclear” risk of bias (3 trials).  The quality of the evidence was very low or low for all comparisons, according to the GRADE approach.  These researchers found very low quality evidence that GMI (2 trials, 49 participants) may be useful for improving pain (0 to 100 VAS) (MD -21.00, 95 % CI: -31.17 to -10.83) and functional disability (11-point numerical rating scale) (MD 2.30, 95 % CI: 1.12 to 3.48), at long-term (6 months) follow-up, in people with CRPS I compared to usual care plus physiotherapy; very low quality evidence that multi-modal physiotherapy (1 trial, 135 participants) may be useful for improving “impairment” at long-term (12 month) follow-up compared to a minimal “social work” intervention; and very low quality evidence that MT (20 trials, 72 participants) provided clinically meaningful improvements in pain (0 to 10 VAS) (MD 3.4, 95 % CI: -4.71 to -2.09) and function (0 to 5 functional ability subscale of the Wolf Motor Function Test) (MD -2.3, 95 % CI: -2.88 to -1.72) at long-term (6 month) follow-up in people with CRPS I post stroke compared to placebo (covered mirror).  There was low to very low quality evidence that tactile discrimination training, stellate ganglion block via ultrasound and pulsed electromagnetic field therapy compared to placebo, and manual lymphatic drainage combined with and compared to either anti-inflammatories and physical therapy or exercise are not effective for treating pain in the short-term in people with CRPS I.  Laser therapy may provide small clinically insignificant, short-term, improvements in pain compared to interferential current therapy in people with CRPS I; adverse events (AEs) were only rarely reported in the included trials.  No trials including participants with CRPS II met the inclusion criteria of this review.  The authors concluded that the best available data showed that GMI and MT may provide clinically meaningful improvements in pain and function in people with CRPS I although the quality of the supporting evidence is very low.  Evidence of the effectiveness of multi-modal physiotherapy, electrotherapy and manual lymphatic drainage for treating people with CRPS types I and II is generally absent or unclear.  They stated that large scale, high quality RCTs are needed to test the effectiveness of physiotherapy-based interventions for treating pain and disability of people with CRPS I and II.

Dorsal Root Ganglion Stimulation

Song and colleagues (20114) reviewed the evidence supporting the use of spinal cord stimulation (SCS) for the approved indications and discussed some emerging neuromodulation technologies that may potentially address pain conditions that traditional SCS has difficulty addressing.  These researchers noted that SCS has been reported to be superior to conservative medical management and re-operation when dealing with pain from failed back surgery syndrome.  It has also demonstrated clinical benefit in CRPS, critical limb ischemia, and refractory angina pectoris.  Furthermore, several cost analysis studies have demonstrated that SCS is cost-effective for these approved conditions.  Despite the lack of a comprehensive mechanism, the technology and the complexity in which SCS is being utilized is growing.  Newer devices are targeting axial low back pain and foot pain, areas that have been reported to be more difficult to treat with traditional SCS.  Percutaneous hybrid paddle leads, peripheral nerve field stimulation, nerve root stimulation, dorsal root ganglion stimulation (DRGS), and high frequency stimulation are actively being refined to address axial low back pain and foot pain.  High frequency stimulation is unique in that it provides paresthesia free analgesia by stimulating beyond the physiologic frequency range.  The preliminary results have been mixed and a large RCT is underway to evaluate the future of this technology.  Other emerging technologies, including DRGS and hybrid leads, also showed some promising preliminary results in non-randomized observational trials.  The authors concluded that SCS has demonstrated clinical efficacy in RCTs for the approved indications.  In addition, several open-label observational studies on peripheral nerve field stimulation, hybrid leads, DRGS, and high frequency stimulation showed some promising results.  However, large RCTs demonstrating clear clinical benefit are needed to gain evidence based support for their use.

Liem and associates (2015) stated that DRGS is a new therapy for treating chronic neuropathic pain.  Previous work has demonstrated the effectiveness of DRGS for pain associated with failed back surgery syndrome, CRPS, chronic post-surgical pain, and other etiologies through 6 months of treatment; this report described the maintenance of pain relief, improvement in mood, and quality of life through 12 months.  Subjects with intractable pain in the back and/or lower limbs were implanted with an active neurostimulator device.  Up to 4 percutaneous leads were placed epidurally near DRGs.  Subjects were tracked prospectively for 12 months.  Overall, pain was reduced by 56 % at 12 months post-implantation, and 60 % of subjects reported greater than 50 % improvement in their pain.  Pain localized to the back, legs, and feet was reduced by 42 %, 62 %, and 80 %, respectively.  Measures of quality of life (QOL) and mood were also improved over the course of the study, and subjects reported high levels of satisfaction.  More importantly, excellent pain-paresthesia overlap was reported, remaining stable through 12 months.  The authors concluded that despite methodological differences in the literature, DRGS appeared to be comparable to traditional SCS in terms of pain relief and associated benefits in mood and QOL.  Its benefits may include the ability to achieve precise pain-paresthesia concordance, including in regions that are typically difficult to target with SCS, and to consistently maintain that coverage over time.  This was an industry-sponsored study; additional independent data from well-designed studies are needed to ascertain the effectiveness of DRGS.

In a prospective case series, Van Buyten and co-workers (2015) examined the effects of DRGS for the management of CRPS.  A total of 11 subjects diagnosed with uni- or bi-lateral lower-extremity CRPS were recruited as part of a larger study involving chronic pain of heterogeneous etiologies.  Quadripolar epidural leads of a newly developed neurostimulation system were placed near lumbar DRGs using conventional percutaneous techniques.  The neurostimulators were trialed; 8 were successful and permanently implanted and programed to achieve optimal pain-paresthesia overlap.  All 8 subjects experienced some degree of pain relief and subjective improvement in function, as measured by multiple metrics.  One month after implantation of the neurostimulator, there was significant reduction in average self-reported pain to 62 % relative to baseline values.  Pain relief persisted through 12 months in most subjects.  In some subjects, edema and trophic skin changes associated with CRPS were also mitigated and function improved; DRGS was able to provide excellent pain-paresthesia concordance in locations that are typically hard to target with traditional SCS, and the stimulation reduced the area of pain distributions.  The authors concluded that  DRGS appeared to be a promising option for relieving chronic pain and other symptoms associated with CRPS.

In a single-case study, van Bussel and associates (2015) reported on the effectiveness of DRG stimulation in a patient with CRPS type I of the knee.  The subject was a 48-year old woman with CRPS type I of the right knee, diagnosed according to the Budapest criteria set, received DRG stimulation for intractable CRPS type I of the knee.  After a successful trial period with 3 DRG stimulation leads on spinal levels L2, L3, and L4 (covering 90 % of the painful area of her knee), a definitive pulse generator was implanted.  Three months after implantation, the entire painful area was covered, and the patient reported a numeric rating scale score of 1 to 2.  The authors concluded that placement of 3 DRG stimulation leads at levels L2, L3, and L4 in a patient with intractable CRPS type I of the knee resulted in major pain relief.  Moreover, they recommended further investigation of the effect of DRG stimulation on pain due to CRPS of the knee.

Garg and Danesh (2015) presented a case where DRGS was performed to treat CRPS in the distal upper extremity.  A 43-year old female underwent a right elbow arthroscopy with open reduction and internal fixation after sustaining a radial head fracture.  Several months after her surgery, she experienced hyperesthesia, skin color changes, decreased range of motion (ROM), weakness distal to the right olecranon, and was diagnosed with CRPS.  Aggressive physical therapy, non-steroidal anti-inflammatory drugs (NSAIDs), and neuropathic agents provided mild relief.  Open capsular release, hardware removal, and chondral debridement of the elbow did not provide alleviation.  A diagnostic stellate ganglion block provided complete relief for 2 weeks.  A therapeutic block allowed 1 day of relief, followed by recurrence of her symptoms.  She underwent an SCS trial for treatment.  Scar tissue in the posterior epidural space prevented catheter advancement, causing it to exit the C6 foramen.  Incidental stimulation of the DRG occurred.  On follow-up, patient reported greater than 70 % relief of her pain.  On the VAS, her maximal pain decreased from 8/10 to 4/10, with resolution of her initial symptoms and ability to perform all of her activities of daily living (ADL).  The authors concluded that this was the only reported case of utilizing DRGS for CRPS of the distal upper extremity; DRGs appeared to be an effective option for targeting painful areas in CRPS.  These preliminary findings need to be validated by well-designed studies.

Deer and colleagues (2017) noted that animal and human studies showed that electrostimulation of DRG neurons may modulate neuropathic pain signals.  ACCURATE, a pivotal, prospective, multi-center, randomized-comparative effectiveness trial, was conducted in 152 subjects diagnosed with CRPS or causalgia in the lower extremities.  Subjects received DRGS or DCS.  The primary end-point was a composite of safety and effectiveness at 3 months and subjects were assessed through 12 months for long-term outcomes and adverse events (AEs).  The pre-defined primary composite end-point of treatment success was met for subjects with a permanent implant who reported 50 % or greater decrease in VAS from pre-implant baseline and who did not report any stimulation-related neurological deficits.  No subjects reported stimulation-related neurological deficits.  The percentage of subjects receiving greater than or equal to 50 % pain relief and treatment success was greater in the DRG arm (81.2 %) versus the DCS arm (55.7 %, p < 0.001) at 3 months.  Device-related and serious AEs were not different between the 2 groups; DRGS also demonstrated greater improvements in QOL and psychological disposition.  Finally, subjects using DRGS reported less postural variation in paresthesia (p < 0.001) and reduced extraneous stimulation in non-painful areas (p = 0.014), indicating DRGS provided more targeted therapy to painful parts of the lower extremities.  The authors concluded that as the largest prospective, randomized comparative effectiveness trial to-date, the results showed DRGS provided a higher rate of treatment success with less postural variation in paresthesia intensity compared to SCS.  These encouraging findings need to be validated by well-designed RCTs.

Furthermore, an UpToDate review on “Complex regional pain syndrome in adults: Prevention and management” (Abdi, 2017) does not mention DRG stimulation as a management tool.

Pulsed Radiofrequency

In a case-series study, Albayrak and colleagues (2016) examined the effects of pulsed radiofrequency (PRF) applied to the DRG for treatment of post-stroke CRPS.  Subjects were a 69-year old woman and a 48-year-old women who suffered post-stroke CRPS type 1.  The patients had complete resolution of their symptoms, which was maintained at 10 and 5 months of follow-up.  The authors concluded that the findings of these cases illustrated that PRF applied to cervical DRG might play a significant role in multi-modal approach of CRPS type 1 management after stroke.  Moreover, they stated that further RCTs are needed to support this argument.

Intravenous Immunoglobulin

In a randomized, multi-center, double-blinded, placebo-controlled trial in 7 UK pain management centers, Goebel and colleagues (2017) examined if low-dose IVIG is effective for reducing pain in long-standing CRPS.  Patients were eligible if they had moderate or severe long-standing CRPS that they had experienced for up to 5 years.  Participants were randomly allocated to receive 0.5 g/kg IVIG, the active intervention, or visually indistinguishable 0.1 % albumin in saline placebo.  Randomization was initiated by study sites via an independent online randomization system and was 1 : 1 with varying block sizes, stratified by study center.  Subjects, investigators and assessors were blinded to group assignment.  The study drug/placebo was infused intravenously at the study centers on day 1 and day 23 after randomization.  The primary outcome was the 24-hour average pain intensity between day 6 and day 42, on an 11-point (0 to 10) numeric rating scale (NRS), compared between the groups.  Outcomes were analyzed using a mixed-effects regression model that used 37 measurements of pain intensity (the primary outcome) per participant.  All patients who received an infusion and provided any outcome were included in the intention-to-treat analysis.  A total of 111 patients were recruited and assigned between August 27, 2013 and October 28, 2015; 3 patients were excluded because they had been inappropriately randomized, 5 patients were withdrawn from the primary analysis because they provided no outcomes and 103 patients were analyzed for the primary outcome.  The average pain score in the IVIG group was 0.27 units (95 % CI: 0.24 to 0.80 units) higher than in the placebo group.  Therefore, there was no significant evidence of a treatment effect at the 5 % level and there was no significant difference between groups; 6 serious AEs but no suspected unexpected serious adverse reactions were reported during the blinded and open-label phase.  The authors concluded that low-dose IVIG was not effective in relieving pain in patients with moderate-to-severe CRPS of 1 to 5 years’ duration.

Free-Flap Surgery and Vein Wrapping

In a single-case study, Seo and colleagues (2017) reported the results of free-flap surgery and vein wrapping of the superficial peroneal nerve surgery for the treatment of CRPS.  A 39-year old man underwent an arthroscopic synovectomy and open repair of the anterior talofibular ligament at the ankle, and pain developed after surgery.  The patient did not show improvement following conservative treatment.  A pain clinician inserted a spinal cord stimulator.  Even though his symptoms improved by 50 %, the focal symptoms around the left ankle remained.  After undergoing adhesiolysis operation, the patient’s symptoms did not improve, and they worsened further under conservative management for an additional 10 months.  These investigators excised the hypersensitive skin and cover the defect with distant healthy tissue to relieve the patient’s symptoms.  At the 3 years follow-up after flap surgery, intractable allodynia at the flap site disappeared.  Severe symptoms developed around the surgical scar; the pain was not diffuse.  The patient was diagnosed with CRPS type II based on these clinical findings.  The authors noted that vein wrapping of the peripheral nerves was first described by Masear et al.  It can protect nerves by inhibiting tissue adhesion, improving the gliding of the nerve, and decreasing scarring within the nerve trunk.  However, hypersensitivity did not disappear on the distant area of the flap site in this case.  Thus, the effect of vein wrapping of the nerve was doubtful in this case.  The authors concluded that careful consideration in replacing the hypersensitive skin with healthy tissue by the free-flap surgery is recommended.  They stated that this can be one of the treatment methods for the CRPS type II.  These preliminary findings need to be validated by well-designed studies.

Transcranial Direct Current Stimulation / Transcranial Magnetic Stimulation

In a randomized, proof of concept study, Lagueux and colleagues (2018) examined the effectiveness of graded motor imagery (GMI) plus active transcranial direct current stimulation (tDCS) compared with the GMI plus sham tDCS in the treatment of CRPS type I.  A total of 22 patients (n = 11 per group) were randomly assigned to the experimental (GMI + tDCS) or placebo (GMI + sham tDCS) group.  GMI treatments lasted 6 weeks; anodal tDCS was applied over the motor cortex for 5 consecutive days during the first 2 weeks and once-weekly thereafter.  Changes in pain perception, QOL, kinesiophobia, pain catastrophizing, anxiety and mood were monitored after 6 weeks of treatment (T1) and 1-month post-treatment (T2).  GMI + tDCS induced no statistically significant reduction in pain compared with GMI + sham tDCS.  Although these researchers observed significant group differences in kinesiophobia (p = 0.012), pain catastrophizing (p = 0.049), and anxiety (p = 0.046) at T1, these improvements were not maintained at T2 and did not reached a clinically significant difference.  The authors found no added value of tDCS combined with GMI treatments for reducing pain in patients with chronic CRPS.  However, given that GMI + sham tDCS induced no significant change, further studies comparing GMI + tDCS and tDCS alone are needed to further document tDCS's effect in CRPS.

Nardone and associates (2018) noted that the sensory and motor cortical representation corresponding to the affected limb is altered in patients with CRPS.  Transcranial magnetic stimulation (TMS) represents a useful non-invasive approach for studying cortical physiology.  If delivered repetitively, TMS can also modulate cortical excitability and induce long-lasting neuroplastic changes.  In this review, these investigators performed a systematic search of all studies using TMS to explore cortical excitability/plasticity and repetitive TMS (rTMS) for the treatment of CRPS.  Literature searches were conducted using PubMed and Embase.  A total of 8 articles matching the inclusion criteria were identified; 114 patients (76 females and 38 males) were included in these studies.  Most of them have applied TMS in order to physiologically characterize CRPS type I.  Changes in motor cortex excitability and brain mapping have been reported in CRPS-I patients.  Sensory and motor hyper-excitability were in the most studies bilateral and likely involve corresponding regions within the central nervous system rather than the entire hemisphere.  Conversely, sensorimotor integration and plasticity were found to be normal in CRPS-I.  TMS examinations also revealed that the nature of motor dysfunction in CRPS-I patients differed from that observed in patients with functional movement disorders, limb immobilization, or idiopathic dystonia.  The authors concluded that TMS studies may thus lead to the implementation of correct rehabilitation strategies in CRPS-I patients.  They stated that 2 studies have begun to therapeutically use rTMS; this non-invasive brain stimulation technique could have therapeutic utility in CRPS.. Moreover, these researchers stated that further well-designed studies are needed to corroborate initial findings.

In a non-randomized, open-label, pilot trial, Gaertner and co-workers (2018) employed a TMS protocol that may lead to significant pain relief for upper and lower extremity CRPS.  This study entailed 21 participants.  These investigators individualized TMS coil positioning over motor cortex of somatic pain location, and administered intermittent theta-burst stimulation followed by 10-Hz high-frequency stimulation using a deeper targeting coil.  They assessed response (greater than or equal to 30 % pain reduction) from a single session (n = 5) and 5 consecutive daily sessions (n = 12) and compared change in pain from baseline, after 1 treatment and 1-week post-treatment between groups using a mixed ANVOA.  Both groups demonstrated significant pain reduction after 1 session and 1-week post-treatment; however, no group differences were present.  From a single session, 60 % of participants responded at Week 1.  From 5 sessions, 58 % and 50 % of participants responded at Weeks 1 and 2, respectively; 2 from each group achieved greater than 50 % pain reduction beyond 6 to 8 weeks.  No serious AEs occurred.  Although headache and nausea were the most common side-effects, these researchers urged careful monitoring to prevent seizures with this protocol.  The authors concluded that they used a TMS protocol that, for the first time, led to significant pain relief in upper and lower extremity CRPS, and will soon examine this protocol in a larger, controlled trial.

Miscellaneous Investigational Interventions

Pickering and Morel (2018) noted that neuropathic pain is difficult to treat and is associated with a decline in QOL.  Etiologies of neuropathic pain are numerous and a number of pathologies display neuropathic characteristics.  Of the various N-methyl-d-aspartate antagonists that are alternatives to be recommended in 1st-line treatment of neuropathic pain, memantine has the safest side-effect profile and has long been approved in Alzheimer's disease.  The review covered memantine studies in post-herpetic neuralgia, diabetic pain, post-operative pain, CRPS, chronic phantom limb pain, opioid-refractory pain and fibromyalgia.  Results were inconclusive because of studies with poor levels of evidence, paucity of trials and small samples.  Two recent randomized trials, however, showed significant efficacy of memantine: one demonstrated prophylactic effects against post-operative neuralgia and pain-associated psychological impairment; in the other, memantine improved pain and cognition in fibromyalgia.  Both studies found no side effects or AEs.  The authors concluded that given the high rate of therapeutic failure in chronic states, often because of AEs, the excellent benefit/risk ratio of memantine in these pilot studies encouraged further exploration of this drug in neuropathic pain prevention and in fibromyalgia in larger-scale studies.

Duong and colleagues (2018) stated that although multiple treatments have been advocated for CRPS, the levels of supportive evidence are variable and sometimes limited.  These investigators provided a critical analysis of the evidence pertaining to the treatment of CRPS derived from recent RCTs.  The Medline, Embase, Psychinfo, and CINAHL databases were searched to identify relevant RCTs conducted on human subjects and published in English between May 1, 2009 and August 24, 2017.  The search yielded 35 RCTs of variable quality pertaining to the treatment of CRPS.  Published trials continue to support the use of bisphosphonates and short courses of oral steroids in the setting of CRPS.  Although emerging evidence suggested a therapeutic role for ketamine, memantine, intravenous immunoglobulin, epidural clonidine, intrathecal clonidine/baclofen/adenosine, aerobic exercise, mirror therapy, virtual body swapping, and dorsal root ganglion stimulation, further confirmatory RCTs are needed.  Similarly, trials also suggested an expanding role for peripheral sympathetic blockade (i.e., lumbar/thoracic sympathetic, stellate ganglion, and brachial plexus blocks).  The authors concluded that since their prior systematic review article (published in 2010), 35 RCTs related to CRPS have been reported.  Nevertheless, the quality of trials remains variable; thus, further research is needed to continue investigating possible treatments for CRPS.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
01996	Daily hospital management of epidural or subarachnoid continuous drug administration
62324 - 62325	Injection(s), including indwelling catheter placement, continuous infusion or intermittent bolus, of diagnostic or therapeutic substance(s) (eg, anesthetic, antispasmodic, opioid, steroid, other solution), not including neurolytic substances, interlaminar epidural or subarachnoid, cervical or thoracic
62326	Injection(s), including indwelling catheter placement, continuous infusion or intermittent bolus, of diagnostic or therapeutic substance(s) (eg, anesthetic, antispasmodic, opioid, steroid, other solution), not including neurolytic substances, interlaminar epidural or subarachnoid, lumbar or sacral (caudal); without imaging guidance
62327	Injection(s), including indwelling catheter placement, continuous infusion or intermittent bolus, of diagnostic or therapeutic substance(s) (eg, anesthetic, antispasmodic, opioid, steroid, other solution), not including neurolytic substances, interlaminar epidural or subarachnoid, lumbar or sacral (caudal); with imaging guidance (ie, fluoroscopy or CT)
63655	Laminectomy for implantation of neurostimulator electrodes, plate/paddle, epidural
63661	Removal of spinal neurostimulator electrode percutaneous array(s), including fluoroscopy, when performed
63662	Removal of spinal neurostimulator electrode plate/paddle(s), placed via laminotomy or laminectomy, including fluoroscopy, when performed
63663	Revision including replacement, when performed, of spinal neurostimulator electrode percutaneous array(s), including fluoroscopy, when performed
63664	Revision including replacement, when performed, of spinal neurostimulator electrode plate/paddle(s), placed via laminotomy or laminectomy, including fluoroscopy, when performed
63685	Insertion or replacement of spinal neurostimulator pulse generator or receiver, direct or inductive coupling
63688	Revision or removal of implanted spinal neurostimulator pulse generator or receiver
64479 - 64484	Injection(s), anesthetic agent and/or steroid, transforaminal epidural, with imaging guidance (fluoroscopy or CT) [not covered for bier block]
64520	Injection, anesthetic agent; lumbar or thoracic (paravertebral sympathetic) [sympathetic nerve blocks] [not covered for bier block]
64530	Injection, anesthetic agent; celiac plexus, with or without radiologic monitoring [sympathetic nerve blocks] [not covered for bier block]
CPT codes not covered for indications listed in the CPB:
Pulsed radiofrequency, free-flap surgery and vein wrapping, oral memantine, vitual body swapping, transcranial direct current stimulation - No specific code:
23900	Interthoracoscapular amputation (forequarter)
23920 - 23921	Disarticulation of shoulder
24900 - 24931	Amputation, arm through humerus; open, circular (guillotine)
25900 - 25909	Amputation, forearm, through radius and ulna
25920 - 25924	Disarticulation through wrist
25927 - 25931	Transmetacarpal amputation
27290	Interpelviabdominal amputation (hindquarter amputation)
27295	Disarticulation of hip
27590 - 27596	Amputation, thigh, through femur, any level
27598	Disarticulation at knee
27880 - 27886	Amputation, leg, through tibia and fibula
27888	Amputation, ankle, through malleoli of tibia and fibula (eg, Syme, Pirogoff type procedures), with plastic closure and resection of nerves
27889	Ankle disarticulation
28800 - 28805	Amputation, foot
28810	Amputation, metatarsal, with toe, single
28820 - 28825	Amputation, toe
32554	Thoracentesis, needle or catheter, aspiration of pleural space; without imaging guidance [intrapleural analgesia]
32555	with imaging guidance [intrapleural analgesia]
64702 - 64727	Neuroplasty (Exploration, Neurolysis or Nerve Decompression)
90281	Immune globulin (Ig), human, for intramuscular use
90283	Immune globulin (IgIV), human, for intravenous use
90284	Immune globulin (SCIg), human, for use in subcutaneous infusions, 100 mg
90867	Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; initial, including cortical mapping, motor threshold determination, delivery and management
90868	Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; subsequent delivery and management, per session
90869	Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; subsequent motor threshold re-determination with delivery and management
90870	Electroconvulsive therapy (includes necessary monitoring)
Other CPT codes related to the CPB:
64400 - 64455, 64490 - 64505, 64510 - 64517	Introduction/injection of anesthetic agent (nerve block), diagnostic or therapeutic [not covered for local anesthetic blockade of sympathetic ganglia] [not covered for bier block]
96360	Intravenous infusion, hydration; initial, 31 minutes to 1 hour
+ 96361	each additional hour (List separately in addition to code for primary procedure)
96365 - 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
96369 - 96371	Subcutaneous infusion for therapy or prophylaxis (specify substance or drug)
97010 - 97168	Physical medicine and rehabilitation evaluations and modalities
HCPCS codes covered if selection criteria are met:
A4290	Sacral nerve stimulation test lead, each
C1816	Receiver and/or transmitter, neurostimulator (implantable)
L8680	Implantable neurostimulator electrode, each
L8681	Patient programmer (external) for use with implantable programmable neurostimulator pulse generator
L8682	Implantable neurostimulator radiofrequency receiver
L8683	Radiofrequency transmitter (external) for use with implantable neurostimulator radiofrequency receiver
L8685	Implantable neurostimulator pulse generator, single array, rechargeable, includes extension
L8686	Implantable neurostimulator pulse generator, single array, non-rechargeable, includes extension
L8687	Implantable neurostimulator pulse generator, dual array, rechargeable, includes extension
L8688	Implantable neurostimulator pulse generator, dual array, non-rechargeable, includes extension
L8689	External recharging system for battery (internal) for use with implantable neurostimulator
HCPCS codes not covered for indications listed in the CPB:
A6549	Gradient compression stocking/sleeve, not otherwise specified
J0135	Injection, adalimumab, 20 mg
J0153	Injection, adenosine, 1 mg (not to be used to report any adenosine phosphate compounds)
J0475	Injection, baclofen, 10 mg
J0476	Injection, baclofen, 50 mcg for intrathecal trial
J0585	OnabotulinumtoxinA, 1 unit
J0586	OnabotulinumtoxinA, 5 units
J0587	RimabotulinumtoxinB, 100 units
J0717	Injection, certolizumab pegol, 1 mg (code may be used for medicare when drug administered under the direct supervision of a physician, not for use when drug is self administered)
J0735	Injection, adenosine, 1 mg (not to be used to report any adenosine phosphate compounds)
J1438	Injection, etanercept, 25 mg
J1459	Injection, immune globulin (Privigen), intravenous, nonlyophilized (e.g., liquid), 500 mg
J1561	Injection, immune globulin, (Gamunex-C/Gammaked), nonlyophilized (e.g. liquid) 500 mg
J1566	Injection, immune globulin, intravenous, lyophilized (e.g., powder), not otherwise specified, 500 mg
J1568	Injection, immune globulin, (Octogam), intravenous, nonlyophilized (e.g., liquid) 500 mg
J1569	Injection, immune globulin, (Gammagard liquid), nonlyophilized, (e.g. liquid), 500 mg
J1572	Injection, immune globulin, (Flebogamma Dif), intravenous, nonlyophilized (e.g., liquid) 500 mg
J1740	Injection, ibandronate sodium, 1 mg
J1745	Injection, infliximab, 10 mg
J2920	Injection, methylpredisone sodium succinate, up to 40 mg
J2930	Injection, methylpredisone sodium succinate, up to 125 mg
J3475	Injection, magnesium sulfate, per 500 mg
J3489	Injection, zoledronic acid, 1 mg
S8420	Gradient pressure aid (sleeve and glove combination), custom made
S8421	Gradient pressure aid (sleeve and glove combination), ready made
S8422	Gradient pressure aid (sleeve), custom made, medium weight
S8423	Gradient pressure aid (sleeve), custom made, heavy weight
S8424	Gradient pressure aid (sleeve), ready made
Other HCPCS codes related to the CPB:
J2760	Injection, phentolamine mesylate, up to 5 mg
ICD-10 codes covered if selection criteria are met:
G90.50 - G90.59	Complex regional pain syndrome (CRPS I)
ICD-10 codes not covered for indications listed in the CPB:
G89.21 - G89.29	Chronic pain, not elsewhere classified
G89.3	Neoplasm related pain (acute) (chronic)
G89.4	Chronic pain syndrome
Gluanethidine, Ketamine, Lidocaine or Midazolam for the treatment of depression:
Gluanethidine, Ketamine:
No specific code
HCPCS codes not covered for indications listed in the CPB:
J2001	Injection, lidocaine HCL for intravenous infusion, 10 mg
J2250	Injection, midazolam HCI, per 1 mg
ICD-10 codes not covered for indications listed in the CPB:
F32.0 - F33.9	Major depressive disorder

The above policy is based on the following references: