Ketamine Analgesia: A Call for Better Science

Pain Medicine 2012; 13: 145–147 Wiley Periodicals, Inc. EDITORIALS Ketamine Analgesia: A Call for Better Science As it becomes clear that NMDA receptors are participant in central sensitization, at least in the dorsal horn [3], the search for a safe, tolerable, and effective NMDA antagonist has become a holy grail for the pharmaceutical industry. Until that compound is identified and vetted, ketamine is the best NMDA antagonist drug that we have. Unfortunately, there is little compelling evidence that ketamine is safe, tolerated, and/or effective in chronic pain conditions. Nonetheless, increasingly it is used clinically in the absence of such evidence. If ketamine were a new approach in chronic pain, the lack of evidence would be understandable; that is not the case. Ketamine was first developed by Parke-Davis in 1962, was first given to U.S. soldiers in the Vietnam war, and is still used as a battlefield anesthetic [4]. It was used in psychiatric research and “recreationally” by notorious academics such as Lilly, Moore, and Altounian in the 1970s [5]. The first report of using ketamine for pain was in 1989 [6]. There are many case series, retrospective reports and Lazarus-like anecdotes, some of them good in a preliminary way, that suggest that ketamine may prove useful for end-stage or intractable neuropathic conditions (e.g., Patil and Anitescu in this issue [7–11]), particularly complex regional pain syndrome (CRPS) [12–14] and phantom limb pain (e.g., Knox et al. [15]). There are four noteworthy RCTs using ketamine in chronic pain conditions. In a good intranasal administration trial, Carr et al. report on 20 subjects in a randomized, double-blind, placebo-controlled, crossover study, with breakthrough pain superimposed on a variety of chronic conditions (13 low back). Breakthrough episodes were at least 48 hours apart and were treated with either intranasal ketamine or placebo. Patients reported significantly 145..147 lower breakthrough pain intensity following intranasal ketamine than after placebo (P < 0.0001), with pain relief occurring within 10 minutes of dosing and lasting for up to 60 minutes [16]. This type of paradigm may be considered in a variety of acute or episodic pain conditions. Naturally, there are substantial concerns about abuse of this formulation [17]. There is good preliminary evidence of efficacy from three subanesthetic dose trials. Sigtermans et al. report on 60 CRPS-type I subjects in a double-blind, randomized, placebo-controlled parallel-group 4.2-day intravenous infusion trial. The primary outcome was a 0–10 numerical rating pain score over a 12-week study period. “Pain scores over the 12-week study period in patients receiving ketamine were significantly lower than those in patients receiving placebo (P < 0.001). The lowest pain score was at the end of week one . . . in week 12, significance in pain relief between groups was lost (P = 0.07). Treatment did not cause functional improvement” [18]. Schwartzman et al. studied CRPS in a small, doubleblind, placebo-controlled outpatient intravenous ketamine model for the treatment of CRPS. Subjects were infused intravenously with normal saline with or without ketamine for 4 hours daily for 10 days. The study was powered for 20 subjects per arm, but was discontinued early at 10 subjects in the placebo group and nine in the ketamine group. The resulting pilot study showed that intravenous ketamine resulted in marginally statistically significant (P < 0.05) reductions in “many” pain parameters. The authors conclude that, “The results of this study warrant a larger randomized placebo controlled trial using higher doses of ketamine and a longer follow-up period” [19]. Dahan et al. conducted a randomized, placebocontrolled, pharmacokinetic–pharmacodynamic modeling study of the effects of S(+)-ketamine in 60 CRPS type 1 subjects with longitudinal (50 days) assessment. They conclude that “long-term S(+)-ketamine treatment is effective in causing pain relief in CRPS-1 patients with analgesia outlasting the treatment period by 50 days” [20]. In these subanesthetic parenteral paradigms, multiple adverse effects and concerns have been mentioned, including dizziness, sedation, nausea, hallucinations, transient liver toxicity, and neurotoxicity. There are no randomized controlled trials available for the high-dose “Ketamine coma” approach (in fact, there are no trials of any kind published). There has been one report of myelopathy from Germany (partially recovered) and one death in a subject with preexisting cardiac disease from 145 Ketamine (RS-2-[2-Chlorophenyl]-2-[methylamino] cyclohexanone) is a drug primarily used for anesthesia in human and veterinary medicine. It is predominately an N-methyl-d-aspartate (NMDA) receptor antagonist [1], but also at high dose has monoamine, muscarinic, mu 2 opioid, and voltage-gated calcium effects [2]. S-ketamine is the more physiologically active enantiomer. It has been formulated for oral, parenteral (SQ, IM, and IV), topical, intranasal, intrathecal, and IR use. It has a range of reported effects in humans including “dissociative” anesthesia, analgesia, hallucinations, elevated blood pressure (as opposed to most anesthetics), and bronchodilitation. It is commonly used in the initiation and maintenance of general anesthesia, and is now more frequently used in intensive care, emergency medicine, battlefield medicine, migraine, treatment of certain psychiatric conditions, and pediatric procedures. It is a popular drug of abuse. pme_1318 Harden Mexico; these 2 are in the context of the approximately 80 high-dose “ketamine coma” cases conducted (Dr. Schwartzman, pers. comm., November 2011). In (high dose) recreational use, there is known mortality [21]. There is inherent risk in any general anesthetic setting and this risk is greatly increased with prolonged anesthesia. Certainly, we must conclude that extended general anesthesia (several days) has a significant risk of mortality and morbidity. The monetary cost of the intensive care necessary to conduct such trials is very high. Thus, for ketamine, perhaps more so than any other compound currently used in pain medicine, there is an immediate need for “high quality, randomized, controlled trials with larger numbers of patients and standardized, clinically relevant routes of administration” [22]. To continue to administer (and to charge for) anesthetic dose ketamine, outside proper IRB-approved protocols, at this experimental stage in the drug’s development is highly questionable. 3 Woolf CJ. Central sensitization: Implications for the diagnosis and treatment of pain. Pain 2011;152:S2– 15. 4 Bonanno FG. Ketamine in war/tropical surgery (a final tribute to the racemic mixture). Injury 2002;33:323–7. 5 Moore M, Alltounian HS. Journeys into the Bright World. Rockport, MA: Para Research; 1978. 6 Maurset A, Skoglund LA, Hustveit O, Oye I. Comparison of ketamine and pethidine in experimental and postoperative p (...truncated)