Ketamine for chronic non-cancer pain

PAIN 141 (2009) 210–214

www.elsevier.com/locate/pain

Topical review

Ketamine for chronic non-cancer pain Rae Frances Bell * Multidisciplinary Pain Clinic/Regional Centre of Excellence in Palliative Care, Haukeland University Hospital, 5021 Bergen, Norway

1. Introduction Ketamine was developed in the 1960s as an anaesthetic agent, and is given intravenously or intramuscularly for surgical anaesthesia. It is also used in subanaesthetic doses as an adjuvant to opioids in the treatment of refractory pain in cancer patients, acute post-operative pain, and in the management of refractory chronic non-cancer pain, although not approved by regulatory authorities for these conditions. In this paper, the pharmacology, liabilities, and evidence from double-blind, controlled studies in patients with chronic non-cancer pain will be reviewed. Use of perioperative ketamine to prevent post-operative acute and chronic pain is beyond the scope of this review. A 1:1 racemic mixture of ketamine has long been made available. The S (+) ketamine isomer now available has an analgesic potency approximately twice that of the racemic mixture [2]. There may be fewer adverse effects, although this is poorly documented. The majority of clinical studies have used racemic ketamine. Pharmacokinetically, ketamine has short distribution and elimination half lives; steady state is achieved in 10–15 h. Ketamine undergoes an extensive hepatic metabolism by the cytochrome p450 system, primarily via N-demethylation to norketamine, and has stereoselective pharmacokinetics. Norketamine, also an NMDA receptor antagonist, has a 2–4fold lower affinity for the non-competitive site on the NMDA receptor and is only one-third to one-fifth as potent as ketamine. Ketamine interacts with a number of receptors and channels. The analgesic effect is thought to be due to antagonism of the Nmethyl-D-aspartic acid (NMDA) receptor. Both ketamine enantiomers bind with higher affinity to the PCP binding site on the NMDA receptor than at other receptors [38], and ketamine analgesia is not reversed by naloxone [39,42]. Consistent with actions at the NMDA receptor, ketamine inhibits hyperalgesia and allodynia [15,53]. In a human healthy volunteer study, ketamine had a synergistic analgesic effect with opioids [50]. In animal studies, ketamine and other non-competitive NMDA receptor antagonists attenuate opioid tolerance development and reverse-established tolerance [1,32]. The clinical opioid-sparing effect of ketamine is well documented in acute post-operative pain, but the optimal dose is unresolved [6,18]. Increasing ketamine doses above 30 mg/24 h did not increase the morphine-sparing effect. This suggests that large doses of ketamine are not required for morphine sparing, an obser-

* Tel.: +47 55974012; fax: +47 55974010. E-mail address: [email protected]

vation supported by clinical reports on cancer pain. Short-term infusions of ketamine are also used clinically to enable rapid opioid tapering, or to restrict total opioid dose, as when treating postoperative pain in addicts, but documentation for this practice is lacking. Ketamine is a phencyclidine (‘‘angel dust”) derivate, and is increasingly used as a drug of abuse. Although the mortality rate is low, there are concerns regarding the neurotoxic effects. Recreational users usually administer ketamine intranasally or by injection. Users can experience psychological dependence and craving, but there is little documented evidence of physiological withdrawal symptoms [41]. 2. Ketamine for chronic non-cancer pain: what is the evidence for efficacy? A 2003 review on ketamine for chronic non-cancer pain covering the years 1966 through 2002 found 11 controlled trials and many uncontrolled trials and anecdotal reports [29]. Chronic pain conditions from neuropathic (central pain, phantom limb pain, post-herpetic neuralgia, and CRPS) to ischaemic pain and fibromyalgia were included. Reduction of hyperalgesia and allodynia was common in neuropathic pain patients. Adverse effects (dizziness, sedation, nausea and psychotomimetic adverse effects) were common. The optimal route of administration of ketamine was unclear, and long-term data were lacking. The small number of trials and data heterogeneity precluded formal meta-analysis. Based on the quality of the trials, the authors concluded that ‘‘the evidence for efficacy of ketamine for treatment of chronic pain is moderate to weak”. Placebo-controlled testing to identify responders was advocated, along with nighttime dosing of oral ketamine to minimize adverse effects. A search of PubMed using the terms ‘‘ketamine” AND ‘‘chronic pain” (Limits ‘‘human” and ‘‘clinical trial”), year by year searches (covering 2006–2008) using the terms ketamine AND clinical AND pain, plus cross-referencing increases the total to 29 controlled trials with a total of 579 patients. Table 1 provides basic information on each trial along with the authors’ conclusions regarding outcomes. For this Topical Review, the trials were not analyzed using systematic review methodology. The newer trials predominantly address chronic neuropathic pain (including phantom limb), but also whiplash-associated pain, temporomandibular joint arthralgia, atypical odontalgia, breakthrough pain and migraine prophylaxis. Two controlled trials of topical ketamine for chronic neuropathic pain [36,37], two trials on temporomandibu-

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R.F. Bell / PAIN 141 (2009) 210–214 Table 1 Controlled trials of ketamine in chronological order of publication. Trial

Pain type

Route/duration of treatment

Backonja et al. [5] N = 6

Chronic neuropathic

Single IV bolus

Eide et al. [15] N = 8

Post-herpetic neuralgia

Eide et al. [16] N = 9

Central dysesthesia pain after spinal cord injury Peripheral neuropathic

Felsby et al. [19] N = 10 Max et al. [40] N = 8

Post-traumatic pain with widespread allodynia

Nicolodi et al. [45] N = 17 + 17 Sørensen et al. [52] N = 18

Acute migraine/refractory migraine prophylaxis Fibromyalgia

Nikolajsen et al. [46] N = 11

Stump and phantom limb pain

Eide and Stubhaug [17] N = 1

Glossopharyngeal neuralgia

Persson et al. [48] N = 8

Arteriosclerosis obliterans with rest pain in the lower extremity

Haines et al. [28] N = 21

Chronic neuropathic

Rabben et al. [49] N = 26

Trigeminal pain

Graven-Nielsen et al. [26] 1. N = 29 2. N = 15

Fibromyalgia

Leung et al. [35] N = 12

Post-nerve injury

Furuhashi-Yonaha et al. [23] N = 8 Chronic neuropathic

Mitchell et al. [43] N = 35 Lynch et al. [36] N = 20

Painful limb ischaemia Chronic neuropathic

Kvarnstrøm et al. [30] N = 12

Chronic peripheral neuropathic of traumatic origin

Carr et al. [8] N = 20

Breakthrough pain (16 patients chronic pain, 4 patients cancer pain) Spinal cord injury with pain below the level of injury

Kvarnstrøm et al. [31] N = 10

Lemming et al. [33] N = 33

Whiplash

Lynch et al. [37] N = 92 Vranken et al. [56] N = 33

Neuropathic pain with allodynia, hyperalgesia, or pinprick hypesthesia Central pain

Gottrup et al. [24] N = 20

Nerve injury pain

Lemming et al. [34] N = 20

Chronic whiplash-associated pain

Baad-Hansen et al. [4] N = 20

Atypical odontalgia (AO)

Ayesh et al. [3] N = 18

Temporomandibular joint arthralgia

Castrillon et al. [9] N = 14

Chronic myofascial pain in temporomandibular disorder Eichenberger et al. [14] N = 20 (10 Phantom limb pain treated with ketamine)

Outcomes

Ketamine (KET) versus placebo. KET relieved ongoing pain in all patients with peripheral nervous system (PNS) disease-related pain, and in 2 of 3 patients with central pain and dysesthesia syndromes. KET improved allodynia, hyperalgesia and after sensation Single IV bolus Crossover. Morphine (M) vs KET vs placebo. KET normalised abnormal heat pain sensations in 4 patients. KET but not M produced significant relief of pain. Wind-up-like pain significantly inhibited by KET but aggravated by M Single IV bolus Crossover. KET vs alfentanil (ALF) vs placebo. Continuous and evoked pain markedly reduced by both drugs IV bolus + infusion/1 h Crossover. KET vs. Magnesium (MG) vs placebo. KET but not MG reduced spontaneous pain and the area of allodynia IV/2 h Crossover. KET vs ALF vs placebo. Both drugs relieved allodynia. KET also relieved background pain. Appreciable relief from both drugs accompanied by unpleasant adverse effects Single SC bolus/sc bolus x 3 KET vs placebo. KET gave marked relief of pain both as an acute daily for 3 weeks treatment and as a prophylactic therapy IV/30 min Crossover. KET 0.3 mg/kg vs morphine 0.3mg/kg vs placebo. KET reduced pain intensity during and after the test period, decreased tenderness at tender points and increased endurance IV bolus + infusion/45 min KET vs placebo. KET increased pressure pain thresholds and reduced wind-up like pain. Side effects observed in 9/11 patients Oral/2 days  10 N of 1. KET vs placebo. KET caused marked pain relief, including relief of pain on swallowing IV infusion 5 min KET vs M. Dose-dependent analgesic effect of KET. KET 0.30 and 0.45 mg/kg higher analgesic potency than morphine 10 mg. Dose dependent adverse effects Oral once a day/6 weeks 10/21 withdrew due to KET adverse effects. 9 entered N of 1 KET vs placebo study. KET produced consistent analgesia in 3/9 Oral as single evening KET vs placebo. Five of 26 patients reported pain relief dose/3 days . IV infusion 30 min Crossover. KET vs placebo. 1. IV infusion identified 17 responders . IV infusion 30 min 2. KET reduced pain at rest and pain produced by im infusion of hyper-tonic saline. KET reduced local and referred pain areas and reduced pressure pain threshold IV infusion/20 min Crossover. KET vs ALF vs placebo. Both drugs caused dosedependent increases in cold and cold pain thresholds, reductions in stroking pain scores and reduction in area of stroking hyperalgesia. In addition, KET reduced the von Frey hyperalgesia area Oral/7 days KET vs placebo. KET reduced pain severity and allodynia. KET plasma concentrations were below levels of detection (0.05 lg mL 1) in all patients despite good pain relief IV infusion KET vs placebo. KET improved pain relief Topical/2 days Crossover. KET vs amitriptyline (A) vs (KET +A) vs placebo. No difference from placebo in any group IV infusion 40 min Crossover, KET vs lidocaine 2.5 mg/kg vs placebo. Mean reduction in VAS 55% KET, 34% lidocaine, 22% placebo. 50% reduction in 7/12 KET, 4/12 lidocaine, 2/12 placebo Intranasal. Up to 60 min Crossover. KET reduced breakthrough pain within 10 min of dosing, lasting up to 60 min IV infusion/40 min Crossover. KET vs lidocaine (L) vs placebo. KET gave 50% pain score reduction in 5/10 patients. Adverse effects were frequent in both drug groups IV infusion/30 min Crossover. KET vs L vs M vs placebo. KET gave minimum 50% pain reduction in 14 of 30 patients Topical/3 weeks Parallel group: KET vs A vs (A+KET) vs placebo. No difference between groups Iontophoresis/1 week Parallel group. S-KET vs placebo.75 mg S-ketamine daily improved health status and QOL but not pain scores. 50 mg had no effect IV/30 min Crossover. KET vs L vs placebo.KET significantly reduced both ongoing pain and evoked pain to brush and pinprick IV infusion/65 min Crossover. placebo/placebo (P/P) vs (P/remifentanil (REM)) vs (KET/P) vs (KET/REM). The combination of KET/REM gave more effective pain relief than the single drugs or placebo IV infusion. At least Crossover. S-KET vs fentanyl vs placebo. No effect of S-KET on 120 min spontaneous AO pain or capsaicin-evoked pain Single intra-articular Crossover. KET vs placebo. No effect on pain or somatosensory injection. measures Single injection in Crossover. KET vs placebo. No effect of KET on pain scores, masseter muscle pressure pain threshold or pressure pain tolerance IV infusion 1 h Crossover. KET 0.4 mg/kg vs calcitonin (C) vs (KET + C) vs placebo. KET, but not C, reduced phantom limb pain

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lar joint pain [3,9] and one trial on atypical odontalgia were negative [4]. Overall, 24 of the 29 trials were reported as positive. The trials used different routes of administration of ketamine, with the majority (18 trials) using the intravenous route. The treatment period in 21 trials was under 4 h. There are no studies that would meet the minimum expected of a phase 2 or 3 registration trial in terms of sample size and duration of treatment. Two trials lasted three weeks (one topical and one daily subcutaneous injection) [37,45]. An N of 1 design study started with 21 subjects, but 10 dropped out due to adverse effects, leaving 9 to enter the N of 1 phase lasting for six weeks [28]. In summary, while the current literature provides evidence for acute relief of chronic non-cancer pain, information supporting the efficacy and tolerability of ketamine in the long-term treatment of chronic pain is extremely limited. Whether ketamine is an appropriate treatment for any specific chronic pain condition, including migraine prophylaxis and fibromyalgia, needs further study. 3. Routes of administration/dose Routes of administration of ketamine are numerous: intravenous, subcutaneous, intramuscular, epidural, intrathecal, intraarticular, intranasal, oral, and topical. Given the potential for abuse it would seem prudent to avoid rapid-acting formulations/routes of administration in long-term treatment or frequent intermittent treatment. As yet there is a limited clinical documentation regarding the oral and topical routes. There have been suggestions that oral ketamine is more potent than parenteral ketamine. The initial case report by Fisher and colleagues described a patient with chronic neuropathic pain who was successfully switched, after one day of stable analgesia with a subcutaneous infusion of ketamine 5 mg/h to oral ketamine, titrated to 25 mg  3 [20]. They concluded that when converting from a subcutaneous infusion of ketamine to the oral route, there is a need for a lower dose, and suggested that this may be due to the analgesic effects of the metabolite norketamine. Subsequent case reports described similar findings with suggested sc-oral dose ratios ranging from 3:1 to 1:1 [7,21]. A study in healthy volunteers investigating the pharmacokinetics and analgesic activity of intramuscular and oral ketamine in a dose of 0.5 mgkg 1 reported that pain threshold elevation after intramuscular ketamine occurred at a plasma concentration of 150 ng/ml, and after the oral dose at a plasma concentration of only 40 ng/ml [25]. This was, however, revised in a second paper where they concluded that pain threshold elevation occurred at plasma concentrations over 160 ng/ml and that in view of the extensive first-pass metabolism, oral administration of ketamine in a dose of 0.5 mg/kg is not satisfactory for producing analgesia [11]. No significant correlations between analgesia and plasma norketamine concentrations were found. This is consistent with the results of another experimental study examining the effects of intravenous ketamine and alfentanil on acute sensory thresholds and capsaicin-evoked hyperalgesia [58]. Ketamine at a concentration of 150 ng/ml decreased capsaicin-induced von Frey hair hyperalgesia, significantly elevated von Frey hair induced pain thresholds and decreased capsaicin-induced pain. What then can be the explanation for the ease of switching from parental ketamine to a lower oral dose? In the case reports, ketamine was an adjuvant to opioid, and ketamine doses before switching to oral were relatively high, ranging from 120 mg/24 h to 500 mg/24 h [20,21]. One explanation could be that ketamine doses were in excess of what is required to improve opioid analgesia. Alternatively, the higher parenteral dose may have contributed

to an initial ‘‘wind-down” of hyperalgesia, with opioid analgesia subsequently improved and maintained by the lower oral dose. 4. Adverse effects and toxicology There are good arguments for keeping ketamine doses as low as possible. Clinical use of ketamine is limited due to psychotomimetic and other dose-dependent adverse effects, which include hallucinations, agitation, nightmares, dizziness and nausea. At higher doses (>2 mg/kg IV), ketamine can cause delirium, impaired motor function, amnesia, anxiety, panic attacks, mania, insomnia, and high blood pressure. Long-term subcutaneous administration is associated with painful indurations at the needle site, necessitating frequent change of site and/or site maintenance with hydrocortisone or heparin cream. Hepatic failure has been described as a rare but serious adverse effect after treatment with high doses of oral ketamine. The NMDA receptor is implicated in modulating functions, such as learning and memory processing. Frequent abuse of ketamine has been shown to cause long-lasting memory impairment and altered prefrontal dopaminergic function [13,44]. Recreational users of ketamine report flashbacks that can recur days or weeks after use [22]. Preclinical studies have demonstrated deleterious effects of ketamine on the developing nervous system [47,60]. A recent study in mice found that ketamine affects important proteins involved in normal maturation of the brain and induces functional deficits in the adult individual [55]. There is a controversy in the literature regarding the safety of epidural and spinal ketamine. These routes of administration are generally not recommended due to unclear toxicity issues. Recent data indicate that intrathecal NMDA receptor antagonists including ketamine have a risk of serious spinal toxicity when used chronically [57,59]. Ketamine has the potential to cause addiction. Repeated administration of subanaesthetic doses in rats caused an escalation of stimulant effects (sensitization) [54]. Sensitization may be considered the opposite of tolerance, and is a characteristic of drugs such as cocaine. Trujillo and colleagues found the results sufficiently disturbing to issue a warning regarding the clinical use of intermittent subanaesthetic doses of ketamine: ‘‘Repeated administration of ketamine may lead to increases in psychoactive and behavioral effects and a compulsive pattern of use, even after very low doses” [54]. Recently, cases of ulcerative cystitis have been described in individuals who chronically abused ketamine [12,51]. Secondary renal damage has been reported in severe cases [10]. One case report describes ketamine-associated cystitis in a 16 year being treated with oral ketamine for CRPS [27]. Some pain clinic physicians treat chronic neuropathic pain with intermittent infusions of ketamine. There is currently no documentation for this practice, and we do not know the importance of the duration or frequency of treatments, or the implications of receiving intermittent parenteral treatment over time. 5. Conclusions The current literature suggests that ketamine in subanaesthetic doses can provide short-term relief of refractory neuropathic pain in some patients. The size and scope of controlled clinical trials to date are insufficient to support longer term use in any particular chronic pain disorder. Ketamine is a drug of addiction with neurotoxic effects and unpleasant adverse effects. There are long-term safety issues, indicating a need for caution. Ketamine should only be used after careful assessment of risk/ benefit for the individual patient and should be administered by

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