Dear Ms. L -

The study to which you refer was ultimately published under the title "A Pilot Open-Label Study of the Efficacy of Subanesthetic Isomeric S(+)- Ketamine in Refractory CRPS Patients," Kiefer RT, Rohr P, Ploppa A, et al, Pain Med. 2008; 9(1): 44-54, a copy of which is attached. As set forth in the lengthy Discussion section at the end of the article, the authors struggle to explain why low dose (as opposed to the high-dose coma treatments in Germany) have no effect on patients with chronic CRPS, while at the same time there are some very good studies which strongly suggest that low dose ketamine is effective in treating acute cases of CRPS, e.g., patients who begin treatment within 3 - 6 months of the onset of symptoms. Accordingly, my read is that the stidy is by no means a rejection of the treatment for those still in the acute phase:

Several trials and case studies have suggested the efficacy of ketamine in CRPS. Takahashi et al. demonstrated complete remission of CRPS after epidural ketamine administration [9]. Effective relief of severe pain and motor dysfunction has been reported for epidural ketamine in combination with morphine and bupivacaine [10]. The topical administration of ketamine ointment is effective in relieving pain and swelling in CRPS type I and CRPS type II patients [11]. Correll and colleagues reported significant pain relief in CRPS patients after prolonged infusions of subanesthetic racemic ketamine [12]. All of these reports suggest that ketamine may be more effective in earlier and more localized CRPS.

* * *

Several possibilities exist to explain the failure of subanesthetic S(+)-ketamine for severe refractory CRPS. In these patients, additional mechanisms, other than those that are NMDAR [N-methyl-D-aspartate receptor]-mediated, may be crucial for maintenance of the disease. Second, the length of time a patient has suffered the disease prior to NMDAR-antagonist intervention may be important for successful NMDAR-antagonist therapy. The dosage of ketamine utilized in this study may have been insufficient to block NMDAR-mediated hyperexcitability of central pain projecting neurons.

The first hypothesis that other mechanisms than those effected through the NMDAR may be important on CRPS is supported by failure of a complete translation of the animal data, which supports a crucial role of the NMDAR, in initiation of some neuropathic pain states with clinical experience [6–8]. Low-affinity, noncompetitive NMDAR-antagonists have failed in clinical randomized controlled trials, to produce significant therapeutic benefit in chronic phantom limb pain, as well as posttraumatic neuropathic pain [20–23]. Dextromethorphan and memantine have failed in clinical randomized controlled trials to benefit diabetic peripheral nerve and post-herpetic neuralgia [23]. Therapeutic efficacy with dextromethorphan has been demonstrated in clinical randomized controlled trials for facial neuralgia, diabetic polyneuropathy, and post-herpetic neuralgia [24–26]. Ketamine has been shown to be effective for ischemic pain, cancer pain, and CRPS [27–29].

The importance of the time of administration of ketamine and its effect on pain is suggested by the success of memantine and ketamine in reducing phantom pain if given perioperatively but its failure to modify established pain [30–32]. The effectiveness of ketamine in early vs established long-standing CRPS pain has not been studied by randomized controlled trials. [pp. 51 - 52; emphasis added.]

Notes

6 Woolf CJ, Salter MW. Neuronal plasticity: Increasing the gain in pain. Science 2000;288:1765–8.
7 Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-D-aspartate (NMDA) receptors in pain: A review. Anesth Analg 2003;97:1108–16.
8 Hocking G, Cousins MJ. Ketamine in chronic pain management: An evidence based review. Anesth Analg 2003;97:1730–9.
9 Takahashi H, Miyazaki M, Nanbu T, Yanagida H, Morita S. The NMDA-receptor antagonist ketamine abolishes neuropathic pain after epidural administration in a case. Pain 1998;75:391–4.
10 Lin TC, Wong CS, Chen FC, Lin SY, Ho ST. Long term epidural ketamine, morphine and bupivacaine attenuate reflex sympathetic dystrophy neuralgia. Can J Anaesth 1998;45:175–7.
11 Ushida T, Tani T, Kanbara T, et al. Analgesic effects of ketamine ointment in patients with complex regional pain syndrome type 1. Reg Anesth Pain Med 2002;27:524–8.
12 Correll GE, Maleki J, Gracely EJ, Muir JJ, Harbut RE. Subanesthetic ketamine infusion therapy: A retrospective analysis of a novel approach to complex regional pain syndrome. Pain Med 2004;5:263–75.
20 Maier C, Dertwinkel R, Mansurian N, et al. Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain— Results of a randomized double-blinded, placebo controlled trial. Pain 2003;103:277–83.
21 Wiech K, Kiefer RT, Töpfner S, et al. A placebo controlled randomized cross-over trial of the NMDA receptor antagonist memantine in patients with chronic phantom limb pain. Anesth Analg 2004;98:408–13.
22 Nikolajsen L, Gottrup H, Kristensen AG, Jensen TS. Memantine (a N-methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery: A randomized, doubleblinded, cross-over study. Anesth Analg 2000;91:960–6.
23 Sang CN, Booher S, Gilron I, Parada S, Max MB. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: Efficacy and dose–response trials. Anesthesiology 2002;96:1053–61.
24 Gilron I, Booher SL, Rowan MS, Smoller MS, Max MB. A randomized, controlled trial of high-dose dextromethorphan in facial neuralgias. Neurology 2000;55(7):964–71.
25 Carlsson KC, Hoem NO, Moberg ER, Mathisen LC. Analgesic effect of dextromethorphan in neuropathic pain. Acta Anaesthesiol Scand 2004;48:328–36.
26 Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology 1997;48(5):1212–8.
27 Persson J, Hasselstrom J, Wiklund B, et al. The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans. Acta Anaesthesiol Scand 1998;42:750–8.
28 Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: A randomized, controlled,double-blind, crossover, double-dose study. J Pain Symptom Manage 2000;20:246–52.
29 Leung A, Wallace MS, Ridgeway B, Yaksh T. Concentration-effect relationship of intravenous alfentanil and ketamine on peripheral neurosensory thresholds, allodynia and hyperalgesia of neuropathic pain. Pain 2001;91(1–2):177–87.
30 Kiefer RT, Wiech K, Topfner S, Unertl K, Birbaumer N. Continuous brachial plexus analgesia and NMDA-receptor blockade in early phantom limb pain: A report of two cases. Pain Med 2002;3:156–60.
31 Kiefer RT, Wiech K, Dieterich HJ, Birbaumer N, Unertl K. The NMDA-receptor antagonist memantine for prevention and therapy of phantom limb pain. Anesthesiology 2003;A:1009.
32 Dertwinkel R, Heinrichs C, Senne I, et al. Prevention of severe phantom limb pain by perioperative administration of ketamine—Results of a pilot study. Acute Pain 2002;4:12–6.

As has been suggested before, the problem, at least in North America, is that too few people are (1) diagnosed with CRPS and (2) in the hands of a competant pain specialist, while their CRPS is still in the acute stage, i.e., when low dose ketamine infusions can actually be effective.

For those in the chronic stage, I completely agree with you, save and except that it's been anecdotally reported here - and I've heard from others - that people who get close to anesthetic doses (500 mg. over 5 hours) may get relief lasting several weeks, but still less than has been observed in some patients with the "highest dose" ketamine coma therapy: complete remission for six months in 6 of 16 patients. Efficacy of Ketamine in Anesthetic Dosage for the Treatment of Refractory Complex Regional Pain Syndrome: An Open-Label Phase II Study, Kiefer RT, Rohr P, Ploppa A, et al, Pain Med. 2008 Feb 5. E-pub ahead of print, free full text at http://www.rsds.org/2/library/articl...a_Dietrich.pdf.

(Does anyone know what the current stats are for remission in terms of years following the coma treatment?)

Finally, let me turn from this aside to the subject of the thread:

Where Schinkel C, Scherens A, Köller M, Roellecke G, Muhr G, and Maier C [above] found no evidence of any statistically significant elevation of Tumor-Necrosis-Factor alpha (TNF-a) in the blood serum of chronic CRPS patients, has anyone here with chronic CRPS taken Remicade (Infliximab) - potential side effects and all - and if so, what has been your experience?

Mike

Attached Files

A Pilot Open-Label Study of the Efficacy of Subanesthetic Isomeric S(+)- Ketamine in Refractor.pdf (188.6 KB, 166 views)

This is very informative;further, I am enjoying the discourse applied within this post/subject matter