Clinical Policy Title: Ketamine (Ketalar ) and intravenous regional sympathetic nerve blockade for treatment of complex regional pain syndrome

Clinical Policy Title: Ketamine (Ketalar®) and intravenous regional sympathetic nerve blockade for treatment of complex regional pain syndrome Clinica...
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Clinical Policy Title: Ketamine (Ketalar®) and intravenous regional sympathetic nerve blockade for treatment of complex regional pain syndrome Clinical Policy Number: 00.02.01 Effective Date: Initial Review Date: Most Recent Review Date: Next Review Date:

June 1, 2013 March 21, 2013 March 18, 2015 March 2016

Policy contains: • CRPS. • Ketamine. • Intravenous regional sympathetic nerve blockade (IVRB).

ABOUT THIS POLICY: AmeriHealth Caritas has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas’

clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of “medically necessary,” and the specific facts of the particular situation are considered by AmeriHealth Caritas when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. AmeriHealth Caritas’ clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. AmeriHealth Caritas’ clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas will update its clinical policies as necessary. AmeriHealth Caritas’ clinical policies are not guarantees of payment.

Coverage policy AmeriHealth Caritas considers the use of ketamine (Ketalar®) for the treatment of complex regional pain syndrome (CRPS) to be investigational and, therefore, not medically necessary. AmeriHealth Caritas considers the use of intravenous regional sympathetic nerve blockade for the treatment of CRPS to be investigational and, therefore, not medically necessary. Limitations: The use of ketamine for CRPS is not medically necessary. The use of intravenous regional sympathetic nerve blockade for CRPS is not medically necessary. Alternative covered services: • Oral pharmacotherapy with analgesics, antidepressants and anticonvulsants, anti-inflammatory medications, corticosteroids, and bone loss medications. • Physical therapy or other covered manipulation therapy. Background 1

Therapeutic pain management is often difficult to accomplish, and certain diseases present more challenges than others to both clinicians and individual patients. CRPS is one of these challenging disease entities. As signified in its title, pain is the preeminent component of CRPS. The syndrome is part of a classification of neuropathic pain disorders, and these are related to pathology in the peripheral and central nervous system. There is no cure for CRPS, and the chronic nature of the disease, combined with the expectancy that the pain will worsen over time, adds to the burden of effective pain management. The International Association for the Study of Pain (IASP) considers CRPS to be a syndrome that usually develops after an initiating noxious event, and is not limited to the distribution of a single peripheral nerve. The pain is regional in location, with neither a specific nerve territory nor dermatome. Usually, it displays a distal predominance of abnormal sensory, motor sudomotor, vasomotor edema or other trophic manifestation. The pain is also characterized by either a continuing evoked or spontaneous occurrence disproportionate to the initiating event. This disproportion may be either in the time or the degree of pain related to the usual course of recuperation after the noxious event. CRPS pain is also associated with the presence of edema, changes in skin circulation, allodynia, hyperalgesia and abnormal sudomotor activity. CRPS symptoms include pain that is usually accompanied by a sensation of burning and worsen in intensity. The pain usually affects the extremities and may spread from the site of the injury to affect the entire limb. CRPS pain may also spread to the corresponding limb on the opposite of the body. Currently, there are two recognized types of CRPS. These are: Type 1: Previously known as reflex sympathetic dystrophy syndrome (RSD), it occurs most often after an illness or injury that did not directly damage the nerves in the affected limb. It may develop after any type of trauma, especially a fracture. The majority of people with CRPS have type 1. Type 2: Once referred to as causalgia, type 2 follows any identified injury to a nerve. Other possible causes of CRPS suggested by professional literature include, but are not limited to, nonsurgical procedures, drug exposure, stroke with hemiplegia and cervical spondylosis. The causative mechanism why an injury may trigger CRPS is not completely understood. CRPS research during the past decade indicates multifactorial causes with both peripheral and central nervous system involvement. These mechanisms may include inflammation, altered sympathetic and catecholaminergic function, altered somatosensory representation in the brain, genetic factors, and psychophysiologic interactions (Bruehl, 2010). CRPS may develop as a result of an inappropriate response or dysfunctional link between transmissions in the peripheral and central nervous system. Research suggests that a reduction in small-diameter nerve fibers is evident in CRPS type 1, and that the spontaneous pain develops when a portion of the nervous system that normally conducts pain signals becomes electrically overactive (Oaklander 2006). The pain may be attributed to the activation of pain receptors (nociceptors) that transduce and encode noxious stimuli (Dworkin 2003). Other research suggests an individual’s pain system develops a capacity for increased sensitivity after injury, a nociceptor sensitization, which may lead to the development of persistent pain (Cheng and Ji 2008). 2

Diagnosis of CRPS: There is no uniformly accepted list of diagnostic criteria or a single test that can definitively diagnose CRPS. This disease occurs in both genders and individuals of all ages, though literature suggests that CRPS may be more common between the ages of 40 and 60. The onset of CRPS symptoms usually occur within one month of the noxious event (Harden 2001). Clinical findings are the gold standard for the diagnosis of CRPS, and these are based on individual physical examination and medical history. The physical and medical history may include the following: • • • •

A damaging, painful event to a limb, or not moving a limb for a long period of time. The presence of pain that is not proportionate to any stimulus, such as pain with light touch. A history of swelling, changes in temperature or skin blood flow in the affected limb. The absence of any other cause for the above-listed symptoms.

Studies have been conducted for the validity of skin surface temperature recordings in the diagnosis of CRPS. These studies were based on calculated methods using thermographic data to diagnose acute CRPS 1 in fracture patients (Niehof 2008). Study data suggested that the most pronounced differences among subgroups involved vasomotor signs in the CRPS 1 group. The result illustrated the limited use of skin surface temperature to discriminate between CRPS 1 patients. The use of the following procedures may provide important information to assist in a diagnosis of CRPS; however, their use may still yield an incomplete clinical picture and borderline diagnosis. Imaging methods are not able to differentiate between CRPS 1 and the results of post-traumatic changes. These procedures have a low sensitivity and a low predictive value, suggesting their worth only as adjunct tools to establish a diagnosis in dubious cases (Schürmann 2007): • • • •

Bone scan. This procedure is designed to detect changes in the bone. A radioactive substance is injected into the veins; the substance permits the viewing of the bones with a special camera. Sympathetic nervous system tests. These tests are used to detect changes in the sympathetic nervous system of the affected limbs; differences in results between limbs may indicate CRPS. X-rays. An x-ray may detect the loss of mineral content from the bone, a symptom seen in the later stages of CRPS. Magnetic resonance imaging (MRI). The images from this test may show changes within the affected tissues.

Treatment for CRPS: Therapeutic approaches to CRPS are not uniform and, in some cases, are controversial. Some of the difficulty lies in the incomplete knowledge surrounding the causative factors for CRPS types 1 & 2. This lack of knowledge has slowed the progress of research for effective CRPS treatments. General consensus in professional literature supports early diagnosis with aggressive treatment for CRPS. Ideally, early treatment will stem the scale and scope of the symptoms, with a possible containment of the progression of the syndrome (Schwartzman 2000). Improvement and even remission of CRPS is possible if treatment begins within a few months of the first symptoms. Individuals presenting with severe pain are less likely to have successful pain amelioration or resolution than those presenting with moderate pain. Rehabilitation may be


extended due to a delay in the initiation of treatment. Permanent tissue damage, impairment, and living with chronic pain may occur without therapeutic intervention (Atkin 2003). Treatment of CRPS should begin immediately after it is diagnosed and directed towards the recovery of function in the affected extremity or body region. Often, a combination of various therapies is necessary. Treatment should be comprehensive, multidisciplinary, emphasize functional restoration and pain management, and be specifically tailored to the individual case. Proposed treatment options may include the following: • •

• • • •

Physical & occupational therapy. Pain relievers: Over-the-counter (OTC) pain relievers, such as aspirin, ibuprofen and naproxen, may ease pain and inflammation. For pain not relieved by OTC products, opioid medications may be an option. Taken in appropriate doses, these may provide acceptable pain control. Antidepressants and anticonvulsants: These medications may be used to treat pain that originates from a damaged nerve (neuropathic pain). Corticosteroids: Steroid medications may reduce inflammation and improve mobility in the affected limb. Bone-loss medications. Sympathetic nerve-blocking medication: Injection of an anesthetic to block pain fibers in the affected nerve(s) may provide pain relief.

Other treatment methods to address CRPS may include the use of sympathetic nerve blocks and surgical procedures. Currently, the role of surgery to treat CRPS is limited. Sympathetic nerve blocks with a variety of medications have been used for CRPS pain. Research within the last decade revealed the scarcity of published evidence to support the use of local anesthetic sympathetic blockade as the 'gold standard' treatment for CRPS, and no conclusions concerning the effectiveness of this procedure could be drawn. Randomized controlled trials are needed to address the value of sympathetic blockade with local anesthetic for the treatment of CRPS (Cepeda 2005). Spinal cord stimulation may also be effective for reducing pain in approximately two thirds of CRPS patients not responding to other treatments, but its efficacy appears to diminish over time (Henson and Bruehl 2010). The use of intrathecal (IT) infusion of analgesic medications to treat patients with chronic refractory pain has increased since its inception in the 1980s. The advent of new algorithmic tracks for neuropathic and nociceptive pain is an important step in improving patient care, and the need for clinical research in IT therapy is ongoing. Specific brands of infusion systems have been FDA-approved for use in IT. However, the use of IT analgesics in not generally recommended (AHRQ 2012). Recent conclusions from an interdisciplinary expert panel encourage continued research and development, including the development of new drugs, devices and safety recommendations to improve the care of patients with chronic pain (Deer 2012). Intravenous regional sympathetic nerve blockade (IVRB) has also been proposed as a treatment for CRPS. These procedures are designed to introduce a concentration of medication into a finite area at the sympathetic nerve endings in a particular region of the body. The intent is to produce a sympathetic denervation without disrupting motor activity. The substances used in IVRB have not been wholly 4

supported for use in CRPS. Professional literature suggests that ethical reasons should allow individuals to undergo a well-defined trial of a finite number of nerve blocks if attempts at functional restoration have been unsuccessful (Harden 2001). The use of ketamine for CRPS: Ketalar is a well-known, rapid acting anesthetic drug granted New Drug Application (NDA) approval more than 40 years ago (February 19, 1970). It has both antinociceptive and antihyperalgesic effects primarily based on the antagonism of the N-methyl-D-aspartate (NMDA) receptor. Central NMDA receptors activated by excitatory amino acid glutamate are involved in pain processing, neuronal plasticity and central sensitization. The rationale to use ketamine for the treatment of CRPS is based on this ability to block NMDA receptors. As an NMDA antagonist, it has been purported to reduce continuous and evoked pain when given in prolonged and low doses to individuals with injuries of both the peripheral and central nervous system. Ketamine has been used off-label, administered topically or intravenously in small, subanesthetic doses, as an analgesic for treating painful conditions (Hocking and Cousins 2003). Extended use of ketamine at anesthetic dosages ("ketamine coma") remains a controversial and unproven treatment for CRPS. Sigtermans (2009) conducted a double-blind, randomized placebo-controlled trial with 60 participants with severe pain. Each participant received either ketamine or saline infused over four days at an inpatient facility. The ketamine was titrated at regular intervals to a maximum dosage of 30mg per hour for a 70 kilogram patient. Infusion rates were increased when pain relief was deemed insufficient. Blood pressures were monitored, and liver function studies were conducted daily. Pain scores over the 12-week monitoring period were significantly lower than those in patients receiving placebo (P < 0.001); however, the significance was not present between the groups at week 12 (P = 0.07). Patients receiving the drug experienced more psychomimetic side effects than controls (93 percent vs. 17 percent, P < 0.001). Ketamine treatment did not cause functional improvement in either group. The authors suggest that a fourday treatment with low-dose ketamine is safe, with psychomimetic side effects acceptable to most patients. Another double-blind, randomized placebo-controlled trial with 21 participants diagnosed with refractory CRPS was conducted by Schwartsman (2009). Nine participants were placed in the ketamine group and 10 in the placebo group. All participants were subjected to daily four-hour infusions with either ketamine or normal saline according to their respective group for 10 days (five days on, two days off, five days on). The maximum ketamine rate was 0.35 mg/kg/hour, not to exceed 25 mg/our over a four-hour period; this was a sub-anesthetic dose of ketamine. All participants were monitored at two weeks, and then monthly for a period of three months. After treatment the ketamine group showed a 21.4 percent reduction in pain to 6.01 ± 0.6 (P< 0.01), with both a sensory and affective component demonstrated of a decrease in pain that lasted for the three-month follow-up period. The placebo group demonstrated a non-significant 3.1 percent reduction to 6.98 ± 0.5 (P > 0.05), with no demonstrable treatment effects. There was no change in participant activity in either the pre- or post-treatment phase. Side effects were described as nausea, headache, tiredness or dysphoria in four out of nine patients in the ketamine group and in two out of ten patients in the placebo group. The authors also note two points in relation to the addition of midazolam and clonidine with the dose of ketamine: the apparent lack of psychomimetic side effects and that, in their experience, only a five-day course of intravenous ketamine at anesthetic doses with midazolam and 5

clonidine would provide complete, lasting remission of CRPS symptoms for over five years. The trial was terminated prematurely as the researchers found that ketamine at doses of 50 mg/hour provided a much larger relief from pain that lasted for a longer period of time with the absence of complications. However, the authors note the necessity for larger, randomized, placebo-controlled trials using higher doses of ketamine, with lengthier follow-up periods. Although the rationale for using ketamine seems appropriate, studies to date have not yet validated its benefit using objective outcome parameters with double-blind, randomized control trial methodology. Questions of safety remain regarding the use of repeat infusion of ketamine for the return of CRPS pain. Additionally, multiple researchers have not been able to determine optimal treatment regimens for the use of ketamine in CRPS (Sunder 2008; Bell and Moore 2010; Azari 2012). A summary of the main issues are as follows: • • • • •

The optimal duration and dosing of ketamine infusions. The effectiveness of the setting for the infusions (inpatient versus outpatient). Using ketamine on its own or as an adjunct to regional anesthetic blocks. Ketamine usage in diagnosed refractory cases of CRPS. The use of ketamine prior to an established diagnosis of CRPS.

Methods Searches: AmeriHealth Caritas searched PubMed and the databases of: • UK National Health Services Centre for Reviews and Dissemination. • Agency for Healthcare Research and Quality’s National Guideline Clearinghouse and other evidencebased practice centers. • The Centers for Medicare & Medicaid Services. Searches were conducted on February 9-February 11, 2014 using the terms "complex regional pain syndromes/drug therapy"[MeSH] OR "complex regional pain syndromes/therapy"[MeSH] OR “reflex sympathetic dystrophy” AND "kIVetamine"[MeSH]. Searches of PubMed were updated on March 11, 2015. Included were: •

• •

Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes — sometimes referred to as efficiency studies — which also rank near the top of evidence hierarchies.

Findings: One additional systematic review (Cossins 2013) and one meta-analysis (O’Connell 2013) were identified for this policy. One was a Cochrane synthesis of available systematic reviews (O’Connell). No economic analyses were identified. 6

For IV ketamine, the available evidence is insufficient to support its effectiveness in patients with either Type 1 or Type 2 CRPS. The available evidence from RCTs is limited by small sample sizes, variable administration and short duration. Reporting of adverse effects was notably lacking given that ketamine is toxic and a drug of abuse. While IV ketamine appears effective for short-term pain relief, both authors cite the need for independent confirmation in larger studies of longer duration that incorporates systematic evaluation of adverse effects. For IVRB, there is strong evidence that guanethidine is not effective in treating CRPS and appears to be associated with the risk of significant adverse events. Results from studies of IVRB using ketanserin, bretylium, atropine or dropiredol are inconclusive. Recent evidence-based guidelines further cite the lack of good-quality supportive outcome studies of IVRB for treatment of CRPS to inform clinical practice (Harden 2013).

Summary of clinical evidence: Citation Cossins (2013)

Content, Methods, Recommendations Key Points: • Systematic review of two RCTs for intravenous (IV) ketamine, two RCTs of IVRB with methylprednisolone, parecoxib or ketorolac. • Quality of evidence: low to moderate for low-dose IV ketamine infusion in long-standing CRPS; low to high for IVRB studies; studies were small and of short duration. • IV infusion of low-dose ketamine (four and a half days of continuous treatment or 10 consecutive working days of outpatient treatment) significantly reduced pain, which reverted back to normal more slowly than the short ketamine half-life would have demanded. • Systematic reporting of adverse effects is lacking; anecdotal evidence of liver failure with prolonged or repeated treatment has been reported. • IVRB with 5 mg of parecoxib, 1 mg/kg lignocaine and 30 mg clonidine in 10 mL normal saline, plus systemic normal saline decreased pain more than either IV parecoxib (20 mg) with IV regional lidocaine and clonidine, or a control group in long-standing CRPS (one high quality RCT). • IVRB of 40 mg methylprednisolone in 10 mL of 2% lidocaine, given as one block per week for three weeks were no more effective than saline blocks in early CRPS (one low quality RCT). • IVRB lignocaine (50 mL 0.5%), either alone or together with ketorolac one week apart in random sequence was not effective in reducing pain when compared with the lignocaine injection (one high-quality RCT). • Overall, limited evidence of effectiveness of IV ketamine or IVRB in persons with CRPS.

O’Connell (2013) Cochrane review

Key Points: • Meta-analysis of two RCTs of IV ketamine. Trials were small, short duration with high risk of bias. • Low-quality evidence that IV ketamine may be effective for pain when compared with placebo; effects not sustained beyond four to 11 weeks 7

• • • • •

post-treatment. Meta-analysis of three systematic reviews of IVRB. Trials were small with high risk of bias. Moderate-quality evidence that IVRB with guanethidine is not effective in CRPS and appears to be associated with the risk of significant adverse events. Very low-quality evidence that IVRB ketanserin and IVRB bretylium may be effective. Very low-quality evidence that IVRB atropine and IVRB dropiredol are not effective. Results are inconclusive.

Glossary Allodynia — The perception of pain due to a stimulus that does not usually cause pain, e.g., clothing. Chronic pain — Pain lasting for longer than three months, or beyond the time of expected healing. Central sensitization — The increased excitability of nociceptive neurons in the spinal cord, triggered from constant or extremely noxious input related to tissue or nerve damage. Hyperalgesia — Increased sensitivity and/or pain from a noxious stimulus that usually causes pain. Medically Necessary- A service or benefit is Medically Necessary if it is compensable under the MA Program and if it meets any one of the following standards: • •

The service or benefit will, or is reasonably expected to, prevent the onset of an illness, condition or disability. The service or benefit will, or is reasonably expected to, reduce or ameliorate the physical, mental or developmental effects of an illness, condition, injury or disability.

The service or benefit will assist the Member to achieve or maintain maximum functional capacity in performing daily activities, taking into account both the functional capacity of the Member and those functional capacities that are appropriate for Members of the same age. Nociceptor — A sensory receptor for pain that is capable of converting and transferring noxious stimuli. Noxious stimulus — Any stimulus that may damage body tissues. Related policies: AmeriHealth Caritas Utilization Management program description. References Professional society guidelines: Agency for Healthcare Quality (AHRQ). United States Department of Health and Human Services. Complex regional pain syndrome/reflex sympathetic dystrophy medical treatment guidelines. Updated December 8

28, 2012. [AHRQ Website]. Available at: Accessed March 11, 2015. Harden RN, Oaklander AL, Burton AW, et al. Complex regional pain syndrome: practical diagnostic and treatment guidelines, 4th edition. Pain Med. 2013 Feb;14(2):180 – 229. Perez RS, Zollinger PE, Dijkstra PU, et al. CRPS I task force. Evidence based guidelines for complex regional pain syndrome type 1. BMC Neurol. March 2010. 31; 10:20. [BMC Website]. Available at: Accessed March 11, 2015. The International Association for the Study of Pain (IASP). Classification of chronic pain. Original 1986. Revised 2011. [IASP Web site.] Available at: Accessed March 11, 2015. Peer-reviewed references: Alexander GM, Peterlin BL, Perreault MJ, Grothusen JR, Schwartzman RJ. Changes in plasma cytokines and their soluble receptors in complex regional pain syndrome. J Pain. 2012 Jan;13(1):10 – 20. Azari P, Lindsay DR, Briones D., et al. Efficacy and safety of ketamine in patients with complex regional pain syndrome: a systematic review. CNS Drugs. 2012 Mar 1;26(3):215 – 28. Backonja M, Arndt G, Gombar KA, Check B, Zimmermann M. Response of chronic neuropathic pain syndromes to ketamine: a preliminary study. Pain. Jan 1994;56(1):51 – 7. Bruehl S. An update on the pathophysiology of complex regional pain syndrome. Anesthesiology. 2010 Sep; 113(3):713 – 25. Available at: Accessed March 11, 2015. Cepeda MS, Carr DB, Lau J. Local anesthetic sympathetic blockade for complex regional pain syndrome. Cochrane Database Syst Rev. 2005;19:CD004598. Cheng J, Ji RR. Intracellular signaling in primary sensory neurons and persistent pain. Neurochem Res. 2008. October, 33(10):1970 – 1978 Cossins L, Okell RW, Cameron H, Simpson B, Poole HM, Goebel A. Treatment of complex regional pain syndrome in adults: a systematic review of randomized controlled trials published from June 2000 to February 2012. Eur J Pain. 2013 Feb; 17(2):158 – 73. Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation. 2012 Sep – Oct;15(5):436 – 64; discussion 464-6. Epub 2012 Jul 2. Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in Neuropathic Pain: Diagnosis, Mechanisms, and Treatment Recommendations. Arch Neurol. 2003;60:1524 – 1534. Goldberg M, Torjman M, Schwartzman R, et al. Pharmacodynamic profiles of ketamine (R-) and (S+) with five day inpatient infusion for the treatment of complex regional pain syndrome. Pain Physician. July 2010; 13(4);379 – 387. 9

Harden R, Bruehl S, Perez R, et al. Validation of proposed diagnostic criteria (the "Budapest Criteria") for Complex Regional Pain Syndrome. Pain. 2010 Aug;150(2):268 – 74. Available at: Harden RN and Bruehl SP. Diagnosis of complex regional pain syndrome: signs, symptoms, and new empirically derived diagnostic criteria. Clinical Journal of Pain. 2006;22:415 – 419 Harden RN. Complex regional pain syndrome. Br J Anaesth. 2001;87:99 – 106. Hayes, Inc. Hayes Medical Technology Report. Intravenous Ketamine for chronic nonmalignant pain. Lansdale, Pa. Hayes, Inc.; March, 2011. Henson P, Bruehl S. Complex regional pain syndrome: state of the art update. Curr Treat Options Cardiovase Med. 2010:12(2):156 – 67. Hocking G, Cousins MJ. Ketamine in chronic pain management: an evidence-based review. Anesth Analg. 2003 Dec;97(6):1730 – 9. Hardena RN, Bruehl S, Perez R, et al. Pain. 2010 August;150(2):268 – 274. Available at: Accessed March 11, 2015. Jadad A, Carroll D, Glynn D, McQuay, H. Centre for Reviews and Dissemination (CRD). Abstract and Commentary for: Intravenous Regional sympathetic blockade for pain relief in reflex sympathetic dystrophy: a systematic review and a randomized, double-blind crossover study. National Health Service, University of York: York, U.K. 3:2003b. Ji RR, Woolf C. Neuronal plasticity and signal transduction in nociceptive neurons: Implications for the initiation and maintenance of pathological pain. Neurobiology of Disease. 2001 Feb;8(1):1 – 10 Kiefer RT, Rohr P, Ploppa A, et al. A pilot open-label study of the efficacy of subanesthetic isomeric S(+)ketamine in refractory CRPS patients. Pain Med. 2008 Jan – Feb;9(1):44 – 54. Kiefer RT, Rohr P, Ploppa A, et al. Efficacy of ketamine in anesthetic dosage for the treatment of refractory complex regional pain syndrome: an open-label phase II study. Pain Med. 2008;9:1173 – 1201. National Institute of Neurological Disorders and Stroke (NINDS). [NINDS website]. Complex Regional Pain Syndrome Fact Sheet. Last updated February 23, 2015. Available at: hy.htm. Accessed March 11, 2015. Niehof SP, Beerthuizen A, Huygen FJ, Zijlstra FJ. Using skin surface temperature to differentiate between complex regional pain syndrome type 1 patients after a fracture and control patients with various complaints after a fracture. Anesth Analg. 2008;106(1):270 – 277. International Anesthesia & Analgesia Society. [Anesthesia & Analgesia Web site.] Available at: Accessed March 11, 2015. Oaklander A, Rissmiller J, Gelman L, et al. Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy). Pain. 2006 Feb;120:235 – 243. 10

O'Connell NE, Wand BM, McAuley J, Marston L, Moseley GL. Interventions for treating pain and disability in adults with complex regional pain syndrome. Cochrane Database Syst Rev. 2013;4:Cd009416. Perez RS, Kwakkel G, Zuurmond WW, de Lange JJ. Treatment of reflex sympathetic dystrophy (CRPS type 1): a research synthesis of 21 randomized clinical trials. J Pain Symptom Manage. Jun 2001;21(6):511 – 26. Perez RS, Zollinger PE, Dijkstra PU, et al. CRPS I task force. Evidence based guidelines for complex regional pain syndrome type 1. BMC Neurol. March 2010. 31; 10:20. Rowbotham MC. Pharmacologic management of complex regional pain syndrome Clin J Pain. 2006 Jun;22(5):425 – 9. Schürmann M, Zaspel J, Löhr P, et al. Imaging in early posttraumatic complex regional pain syndrome: A comparison of diagnostic methods. Clin J Pain. 2007;23(5):449 – 457. Schwartzman R, Alexander G, Grothusen J, et al. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: A double-blind placebo controlled study. Pain. 2009;147:107 – 115. Schwartzman R. New treatments for reflex sympathetic distrophy. New England Journal of Medicine. 2000;343:654 – 656. Schwartzman R, Alexander G, Grothusen J. The use of ketamine in complex regional pain syndrome: possible mechanisms. Expert Rev Neurother. 2011;11(5):719 – 734. Sigtermans M, van Hilten J, Bauer M. Ketamine produces effective and long-term pain relief in patients with complex regional pain syndrome type 1. International Association for the Study of Pain (IASP). Pain. June 18, 2009. Stanton-Hicks M, Baron R, Boas R, et al. Consensus report: complex regional pain syndromes: guidelines for therapy. Clin J Pain. 1998;14:155 – 166. Sunder RA, Toshniwal G, Dureja G. Ketamine as an adjuvant in sympathetic blocks for management of central sensitization following peripheral nerve injury. J Brachial Plex Peripher Nerve Inj. Oct 25 2008;3:22. Clinical trials: Searched on March 11, 2015 using terms ketamine | condition: complex regional pain syndrome | open studies: one study found. Randomized Controlled Trial of Ketamine Infusion With Continuous Epidural Infusion for Treatment of Complex Regional Pain Syndrome. Available at: Centers for Medicare & Medicaid Services (CMS) national coverage determination (NCDs): As of the writing of this policy, there was no CMS coverage determination addressing percutaneous therapy with ketamine or IVRB or systemic IV administration for CRPS. CMS local coverage determinations (LCDs): As of the writing of this policy, there were no LCDs addressing percutaneous therapy with ketamine or IVRB or systemic IV administration for CRPS. 11

Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly.

CPT Code



ICD-9 Code




Reflex sympathetic dystrophy, unspecified


Reflex sympathetic dystrophy of the upper limb


Reflex sympathetic dystrophy of the lower limb


Reflex sympathetic dystrophy of other specified site


Causalgia of upper limb


Causalgia of lower limb



ICD-10 Code G56.40 G56.41 G56.42 G57.70 G57.71 G57.72 G90.5 G90.50 G90.511 G90.512 G90.513 G90.519 G90.521 G90.522 G90.523 G90.529 G90.59



Causalgia of unspecified upper limb Causalgia of right upper limb Causalgia of left upper limb Causalgia of unspecified lower limb Causalgia of the right lower limb Causalgia of the left lower limb Complex regional pain syndrome I, (CRPS I) Complex regional pain syndrome I, unspecified Complex regional pain syndrome I of right upper limb Complex regional pain syndrome I of left upper limb Complex regional pain syndrome I of upper limb bilateral Complex regional pain syndrome I of unspecified limb Complex regional pain syndrome I of right lower limb Complex regional pain syndrome I of left lower limb Complex regional pain syndrome I of lower limb bilateral Complex regional pain syndrome I of unspecified lower limb Complex regional pain syndrome I of other specified site 12

G90.8 M89.00 M89.011 M89.012 M89.019 M89.021 M89.022 M89.029 M89.031 M89.032 M89.039 M89.041 M89.042 M89.049 M89.051 M89.052 M89.059 M89.061 M89.062 M89.069 M89.071

Other disorders of autonomic nervous system Algoneurodystrophy, unspecified site Algoneurodystrophy, right shoulder Algoneurodystrophy, left shoulder Algoneurodystrophy, unspecified shoulder Algoneurodystrophy, right upper arm Algoneurodystrophy, left upper arm Algoneurodystrophy, unspecified upper arm Algoneurodystrophy, right forearm Algoneurodystrophy, left forearm Algoneurodystrophy, unspecified forearm Algoneurodystrophy, right hand Algoneurodystrophy, left hand Algoneurodystrophy, unspecified hand Algoneurodystrophy, right thigh Algoneurodystrophy, left thigh Algoneurodystrophy, unspecified thigh Algoneurodystrophy, right lower leg Algoneurodystrophy, left lower leg Algoneurodystrophy, unspecified lower leg Algoneurodystrophy, right ankle and foot

HCPCS Level II J3490



Ketamine, IV


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