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Ketamine is a dissociative anesthetic and its primary mechanism of action is considered to be through antagonism of the N-methyl-D-aspartate (NMDA) receptor. For many years it has been used in the treatment of chronic pain, but not fully entrenched in pain treatment, perhaps because of its potential addictive and psychomimetic qualities and lack of controlled clinical trials. From a pain perspective the primary role of ketamine in low doses is as “an ‘anti-hyperalgesic’, ‘anti-allodynic’ or ‘tolerance-protective’ agent” (see Visser and Schug 2006). A number of groups have reported prolonged effects on pain following ketamine dosing via oral, intranasal, topical or intravenous routes and single doses vs. multi-day (Goldberg et al. 2005) or continuous administration over days (Kiefer et al. 2008b) in open-label studies.
Our current therapeutic armamentarium is quite limited in terms of analgesic efficacy in controlled trials. Some would argue that the small efficacy (both at a population level and the magnitude of change in VAS score) this is related to the fact that we need to consider mechanistic approaches to chronic pain subgroups. However, patients and clinicians find themselves in a position of “what to do now”. In the paper published in this volume by Sigtermans et al., (Sigtermans et al. 2009) the authors report on the effects of a prolonged infusion (4.2 days) of low dose ketamine group (n=30) vs. placebo group (n=30) and followed their pain scores over 12 weeks. Pain scores were lower initially but still significantly different at 12 weeks post infusion. Significantly there was no functional improvement that accompanied the decrease in their pain. This study provides one of the first placebo-controlled trials in CRPS patients on the use of ketamine for chronic pain.
With the onset of chronic pain (including CRPS) a number of changes in brain function occur in the human brain including but not limited to: (1) central sensitization (Millan 1999); (2) functional plasticity in chronic pain and in CRPS (Flor et al. 2006; Maihofner et al. 2007); (3) gray matter volume loss in CRPS (Geha et al. 2008); (4) chemical alterations (Grachev et al. 2002); (5) altered endogenous function (Seifert et al. 2009). Such changes are through to be in part a result of excitatory amino acid release in chronic pain. Excitatory amino acids are present throughout the brain and are normally involved in neural transmission but may contribute to altered function with excessive release producing increased influx of calcium and potentially neural death. Here lies the conundrum the use of an agent that potentially could do the same, and even more so given that it may be acting on neurons that may already be compromised (see (Winkelheide et al. 2009)) but may also have neuroprotective properties by mechanisms that include reducing phosphorylation of glutamate receptors resulting in decreased glutamatergic synaptic transmission and reduced potential excitotoxicity (see (Snyder et al. 2007)). Alternatively, ketamine may affect glia regulation of glutamate and inhibit glutamate release within glia (Verkhratsky and Kirchhoff 2007). However, by whatever mechanism ketamine acts on CRPS pain, there does seem to be a dose/duration effect in that longer doses at levels tolerated by patients seem to prove more effective in terms of the duration of effects (Figure 1). Intravenous ketamine treatment in anesthetic dose reportedly produced months of pain relief and quality of life and ability to work (Kiefer et al. 2008a).
So what could be happening in the brain and what is required to alter brain systems and reverse the symptomatic state? Ketamine may diminish glutamate transmission and “resets” brain circuits, but it seems that a minimal dose and or duration of treatment is required. Alternatively, ketamine may produce neurotoxicity and damage or produce a chemical lesion of affected neurons. These two issues are important to understand in future trials. Reports from patients who have had anesthetic doses have included prolonged pain relief for many months (Kiefer et al. 2008a). While the authors did not address issues such as the effect of dosing duration or repetitive dosing at say 6 weeks, they do show a level of efficacy based on NNT that equals or betters most drug trials for this condition.
Although the authors did not find an improvement in functional activity, such changes may be more difficult to discern in a short period where maximal pain relief was observed. In other reports following anesthetic doses of ketamine, improvement in pain and other neuropsychologial evaluation at 6 weeks post treatment were reported, albeit these were not controlled trials (Koffler et al. 2007). Nevertheless there may be lessons from other diseases that affect the brain it is noteworthy that acute ketamine doses seems to reverse depression (Machado-Vieira et al. 2009) and ketamine decreased prevalence of post-traumatic stress disorder (PTSD) in soldiers receiving ketamine during their surgery for treatment of their burns (McGhee et al. 2008). In addition ketamine attenuates post-operative cognitive dysfunction following cardiac surgery that has been known to produce significant changes in cognition (Hudetz et al. 2009). The data suggest that the drug can alter or prevent other conditions based on its NMDAR activity where other drugs NMDA receptor antagonists are perhaps not as effective in these or pain conditions. Lastly, NMDA antagonists have been used in degenerative disease (and pain may be considered a degenerative disease as defined by loss of gray matter volume, see above) with mixed effects perhaps relating to how they act on specific NMDA subtypes (Lipton 2004). Taken together, ketamine may act not only on sensory systems affecting pain intensity, but on a constellation of brain regions that are involved in the pain phentype.
As a community we have a major opportunity to define the efficacy and use of a drug that may offer more to CRPS (and perhaps other) patients than is currently available. This is clearly an opportunity that needs urgent attention and a number of questions remain to be answered. For example, Is ketamine more effective in early stage disease? How does ketamine provide long-term effects? Clearly, further controlled trials evaluating dose, duration, anesthetic vs. non-anesthetic dosing are needed. Few of us really understand what it is like to suffer from a chronic pain condition such as CRPS. Ketamine therapy may be a way forward that can be brought into our clinical practice through further controlled studies that will allow for appropriate standards for use in patients.