Download Ketamine for the treatment of Complex Regional Pain Syndrome

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
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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).
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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
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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:
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•
•
•
•
•
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:
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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:
•
•
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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.
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•
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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
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•
•
•
•
•
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: http://guidelines.gov/content.aspx?id=38440. 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: http://www.biomedcentral.com/1471-2377/10/20. 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: http://www.iasppain.org/PublicationsNews/Content.aspx?ItemNumber=1673. 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: http://www.rsds.org/pdfsall/Bruehl_Anesthesiology_2010.pdf. 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.
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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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914601/pdf/nihms222091.pdf. 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: http://www.ninds.nih.gov/disorders/reflex_sympathetic_dystrophy/detail_reflex_sympathetic_dystrop
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: http://www.anesthesiaanalgesia.org/content/106/1/270.full.pdf+html. 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.
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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 clinicaltrials.gov 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: http://ClinicalTrials.gov/show/NCT02094352.
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.
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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
Description
Comment
ICD-9 Code
Description
Comment
337.20
Reflex sympathetic dystrophy, unspecified
337.21
Reflex sympathetic dystrophy of the upper limb
337.22
Reflex sympathetic dystrophy of the lower limb
337.29
Reflex sympathetic dystrophy of other specified site
354.4
Causalgia of upper limb
355.71
Causalgia of lower limb
733.7
Algoneurodystrophy
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
Description
Comment
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
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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
Description
Comment
Ketamine, IV
13