Complex regional pain syndrome - Emerging treatments

Botulinum toxin

Botulinum toxin inhibits noncholinergic neurotransmitter release from sensory nerve terminals (in addition to its effects on blocking acetylcholine exocytosis). Botulinum toxin extended the duration of analgesia in CRPS patients when used in conjunction with sympathetic blockade.[98][99]

Oral N-methyl-D-aspartate receptor (NMDA) antagonists

Oral NMDA antagonists have been studied in neuropathic pain but not in CRPS, and many pharmacologic agents with NMDA antagonist properties (e.g., dextromethorphan, memantine, amantadine) are reported to have significantly lower affinity for the NMDA receptor than ketamine, with unclear clinical significance.[100] Further study is necessary.

Free radical scavengers

On the basis that inflammation plays a role in the development of CRPS and is associated with the production of oxygen free radicals, free radical scavengers (dimethyl sulfoxide 50% and N-acetylcysteine) have been tried with some success.[101][102]

Motor cortex stimulation

Direct cortical stimulation (invasive) may be more effective than transcranial magnetic stimulation (noninvasive) in patients with neuropathic pain.[103][104][105] However, these therapies have not been adequately tested in CRPS patients.

Immunomodulatory agents

Inflammation may play a role in the pathophysiology of CRPS. Immunomodulatory agents that reduce inflammation, such as tumor necrosis factor-alpha antagonists, thalidomide, and immune globulins, may therefore have a role in treating CRPS.[106] However, one large randomized controlled trial found that low-dose intravenous immune globulin (IVIG) treatment for 6 weeks was not effective in relieving pain in patients with moderate to severe CRPS of 1 to 5 years’ duration.[107] There is some anecdotal evidence for the efficacy of high-dose IVIG in CRPS, but this has not been tested in trials.[52]

Naltrexone

Naltrexone is an opioid-antagonist with potential immunomodulatory properties, and has been granted orphan drug status by the FDA for the treatment of CRPS. Prominent CRPS symptoms (dystonic spasms and fixed dystonia) were reported to remit in patients after low-dose naltrexone.[108] A randomized controlled trial is under way.[52][109]

Ziconotide

Intrathecal delivery of ziconotide, a novel nonopioid analgesic derived from the toxin of the cone snail species, has been associated with improvements in pain, edema, skin abnormalities, and/or mobility, and a decrease in opioid intake, in patients with CRPS where conventional and interventional treatments had provided inadequate pain relief.[110][111][112]