- Email: [email protected]
Interindividual differences in the analgesic response to ketamine in chronic orofacial pain
European Journal of Pain (2001) 5: 233±240 doi:10.1053/eujp.2001.0232, available online at http://www.idealibrary.com on
1
Interindividual differences in the analgesic response to ketamine in chronic orofacial pain Toril Rabben and Ivar éye Department of Pharmacology, Oslo University School of Medicine, Oslo, Norway
The analgesic effect of the N-methyl-D-aspartate (NMDA) receptor blocker ketamine in 17 patients (13 females and four males, age 32±88 years) who had suffered neuropathic orofacial pain for time periods ranging from 6 months to 28 years was examined. The patients were given an i.m. test-dose of 0.4 mg/kg ketamine combined with 0.05 mg/kg midazolam. Four patients did not experience any analgesic effect of the i.m. test-dose. The remaining 13 patients experienced an analgesic effect which lasted for less than 1 h (transient effect) in seven and for several hours (long-term effect) in six. One week later they were given 4 mg/kg ketamine to be taken orally in combination with a hypnotic drug for 3 consecutive nights. All patients who reported a long-term analgesic effect after i.m. ketamine also reported reduced pain intensity on days after taking ketamine at night. The findings of this open study are in accordance with the results from a previous double-blind randomized investigation. In order to evaluate the role of age and pain duration for the analgesic effect of ketamine, the data from the two studies were pooled and a correlation analysis of 43 patients performed. A positive correlation was found between a long painhistory and lack of analgesic effect and also between a short pain-history and a long-term analgesic effect of lowdose ketamine. The apparent relationship between patient age and ketamine response was, however, not statistically significant. Further, patients with pain following a nerve lesion and patients without a known lesion of peripheral nerves were equally distributed between the three response groups. These results indicate that pain mechanisms are subject to alterations with time and that these alterations involve transition from NMDA to nonNMDA receptor-mediated transmission in central pain pathways. # Copyright 2001 European Federation of Chapters of the International Association for the Study of Pain KEYWORDS: neuropathic pain, orofacial pain, ketamine, intramuscular, oral administration, analgesia, NMDA receptors, correlation analyses.
INTRODUCTION The anaesthetic, analgesic, and psychotomimetic effects of ketamine were first described by Domino et al. (1965). Ketamine is effective and reliable as an analgesic in acute somatic pain, but in contrast to opiates its analgesic effect is not inhibited by naloxone, indicating a non-opioid analgesic mechanism (Maurset et al., 1989). The finding that ketamine selectively reduced excitation of central mammalian neurones by Paper received 23 June 2000 and accepted in revised form 14 February 2001. Correspondence to: Toril Rabben, Dept. of Pharmacology, Box 1057 Blindern, N-0316 Oslo, Norway. Tel: (47) 22 85 60 71; Fax: (47) 22 85 44 40; E-mail: [email protected]
N-methyl-D-aspartate (NMDA; Anis et al., 1983), suggested that its analgesic action might be due to inhibition of NMDA receptors. The clinical relevance of this mechanism was supported by the observation that the analgesic effect of ketamine in humans occured at concentrations within its NMDA receptor occupancy range, and that the relative order of potency of (R)- and (S)ketamine as analgesics correlated positively to their affinities as NMDA receptor antagonists (Klepstad et al., 1990). In animal experiments, activation of NMDA receptors in secondary afferent neurons is essential for the increased sensitivity to pain (wind-up) caused by repeated nociceptive stimulation (Davies and Lodge, 1987; Dickenson and Sullivan, 1987). Wind-up may be regarded as an
1090-3801/01/030233 + 08 $35.00/0 & 2001 European Federation of Chapters of the International Association for the Study of Pain
234
experimental model for central sensitization, which is an important mechanism in chronic (pathological) pain. The possibility that NMDA receptor antagonists may be clinically useful in pathological pain states has therefore attracted much attention in recent years (Dickenson, 1990, 1994; Woolf and Thompson, 1991; Coderre et al., 1993). Analgesic effect of ketamine in chronic pain states have been reported by several investigators (Stannard and Porter, 1993; Backonja et al., 1994; Eide et al., 1994, 1995; Nikolajsen et al., 1996). In most of these trials, however, the clinical use of ketamine was limited by its adverse mental effects. In a previous study of patients suffering neuropathic orofacial pain, it was found that ketamine was without analgesic effect in about 1/3 of the patients, 1/3 experienced a short-lasting reduction of pain closely associated with the adverse mental effects, and 1/3 of the patients reported an analgesic effect which outlasted the mental effects by many hours (Rabben et al., 1999). It was also observed that ketamine administered at night worked during sleep to prevent pain the following day in some of these patients. The oldest patients and those with the longest pain history were often non-responders, and the youngest patients with the shortest pain duration were often long-term responders. However, the number of patients was not enough for reliable statistical correlation analyses. Here, data are presented from a study of the analgesic effect of ketamine in another group of 17 patients who had suffered constant neuropathic orofacial pain for highly different time periods. By pooling the results of the present study with those previously published, the role of age, pain duration and the existence of a known peripheral nerve lesion as predictive factors for the response to ketamine in 43 patients was examined.
METHODS Patients suffering constant neuropathic orofacial pain were recruited from departments of oral surgery or from pain clinics in the Oslo area. Patients with known psychiatric disease and patients who scored less than 25 on the visual analogue scale European Journal of Pain (2001), 5
T. RABBEN
AND
I. éYE
(VAS) described below, were excluded. Seventeen patients (13 females and four males, aged 32±88) who had suffered orofacial pain for various time periods (ranging from 6 months to 28 years) entered the study. All had a diagnosis of neuropathic pain which had started following trauma or surgery in 12 and spontaneously in four. One patient, an 88-year-old woman, suffered postherpetic neuralgia which had been severely exacerbated following glycerol injection into the cistern of the trigeminal ganglion. Unlike patients with trigeminal neuralgia (tic douloureux) who suffer bouts of lancinating pain, these patients suffered constant burning or throbbing pain which was often moderate in the morning and increased during the day. All patients had been through extensive clinical examinations and had been treated with analgesics, anti-epileptics, anti-depressants, nerve blocks and other procedures without or with modest or temporary effects. For ethical reasons, this investigation was carried out as an open, observational study. The mental effects of ketamine were explained to each patient and written informed consent was obtained. The patients were instructed to assess pain using a 100 mm vertical VAS, (no pain 0, intolerable pain 100) and asked to record pain at home in the morning and at night for 3 consecutive days. On the fourth day a dose of 0.4 mg/ kg ketamine with 0.05 mg/kg midazolam was injected intramuscularly while the patients were resting in a comfortable position. They recorded pain before injection and every 5 min during the following hour, at night on the day of the injection as well as in the morning and at night the following 3 days. Adverse effects were registered by use of a standardized questionnaire. The patients were then given 4 mg/kg ketamine to be taken as an oral dose at home for 3 consecutive nights. They were told to take other medications as usual and were instructed to record pain in the morning and at night for 3 days before starting oral ketamine, on each day during the ketamine trial and for 3 days afterwards. The correct amount of racemic ketamine hydrochloride was dispensed as a dry powder to be dissolved in about 50 ml of a sugar-free strongly colaflavoured soft drink. The patients were instructed to ingest the ketamine after going to bed at night.
235
IN OROFACIAL PAIN
Patients who did not use clonazepam or hypnotics regularly were instructed to take a hypnotic drug (flunitrazepam or zopiklone) together with ketamine. The protocol was acknowledged by the Regional Ethical Committee. The ketamine used for i.m. injection was the available commercial preparation (Ketalar, Parke±Davies, Pfizer Ireland Pharmaceutical, Dubin, Ireland), the hydrochloride salt for oral use was obtained through Norsk Medisinaldepot (the Norwegian Medical Depot). Correlation analyses In order to examine putative factors predicting an analgesic response to ketamine, the analgesic effect of the i.m. test dose was analyzed for association with age, duration of pain and whether or not the pain was due to a peripheral nerve lesion. To strengthen the statistical power of the correlation analyses, the data from the present study and those obtained in a similar study performed by double-blind technique (Rabben et al., 1999) were pooled. The two studies were identical with respect to patient inclusion criteria, ketamine dose, administration and pain assessment. Correlation analyses could therefore be performed on a total of 43 patients (35 women and eight men, aged 29±89 years, pain duration 0.5±28 years, 33 patients with a diagnosed nerve lesion and 10 without) with constant neuropathic orofacial pain. In order to correlate patient age and duration of pain to ketamine response, we divided the patients into quartiles (age: < 40, 41± 52, 53±65, > 65 years; pain duration: < 1, 2±5, 6± 9, > 9 years). We used cross-tabs to correlate the predictive factors and ketamine response (no analgesic response, transient analgesia and longterm analgesic response), and a two-sided Fisher exact test in the significance testing. A 5% significance level was applied.
RESULTS Intramuscular administration Patients with chronic neuropathic orofacial pain did not respond to an analgesic dose of
Pain assessment by VAS (mm)
K ETAMINE
100 80 60 40 20 0 0
5
10 20 30 40 50 Time after i.m. ketamine (min)
60
FIG. 1. Lack of analgesic effect after ketamine 0.4 mg/ kg combined with midazolam 0.05 mg/kg in four patients suffering chronic orofacial pain. The i.m. injection was given at time 0. Two of the patients were over 80 years old. One patient had suffered constant pain for 28 years; following endodontical treatments, extractions, apical surgery and soft laser therapy the pain had intensified. One patient suffered constant severe pain after surgical removal of a retromaxillary adenocarcinoma followed by reconstructive surgery and infections. She described her pain as unbearable and had attempted suicide twice during the last year.
ketamine in a uniform way. Four patients did not experience any analgesic effect (Fig. 1). This group of non-responders included the two oldest patients (88 and 82 years), the patient with the longest pain history (pain duration 28 years) and the patient who, according to the judgement of the investigators, suffered the most severe pain. The other 13 patients experienced pain reduction after ketamine. In Figure 2, pain is expressed as the percentage of the pain assessment before ketamine injection (pain score in percent of basal levels which were between 40 and 100 mm on the VAS). Seven patients experienced a transient or partly transient pain reduction after injection of ketamine (Fig. 2A). In these patients, pain score was lowest after about 20 min and then returned towards basic level. Six patients experienced an analgesic effect which persisted throughout the test-period of 60 min (Fig. 2B). These patients reported that the analgesic effect remained for the rest of the day and some reported that pain intensity was less than usual also the following day. The main side effects after i.m. ketamine combined with midazolam were sedation and a European Journal of Pain (2001), 5
236
T. RABBEN
AND
I. éYE
general feeling of insobriety. Most of the patients also noted blurred vision and a dry mouth. Inspite of these side-effects, 16 of the 17 patients rated the test as being pleasant. One patient rated the test as slightly unpleasant due to dizziness. The mental effects were present in all patients regardless of an analgesic response and lasted for less than 60 min. Thus, in some patients apparently analgesia persisted for many hours after the mental side-effects had subsided.
Two of the patients who did not respond to i.m. ketamine were excluded, one because she had recently attempted suicide, and one because of his age (82 years). Another two were excluded because they were worried about side-effects. The remaining 13 patients were given three doses of 4 mg/kg ketamine to be taken at home on 3 consecutive nights as described under methods. The results are summarized in Table 1. The five patients who had reported long-term reduction of pain intensity after i.m. ketamine, reported reduced pain intensity or complete analgesia on days after ingesting 4 mg/kg ketamine at night. Also, three of the patients who had reported partially transient analgesic effect after the i.m. test dose reported some reduction of pain intensity on days after ingesting ketamine. The remaining patients did not record any reduction of pain during the 3 days of treatment with 4 mg/kg ketamine taken orally at night. Mental side effects of ketamine taken orally after going to bed at night were reported by three of 13 patients. The most severe effect was reported by a 34-year-old woman who took the first oral dose without a hypnotic or sedative drug. She had a frightening `near death' experience and was unable to sleep for the rest of the night. In spite of this event, she reported reduced pain intensity the following day. Another patient who took the first oral dose without a hypnotic drug, suffered anxiety and hallucinations, but the pain was absent the following day. The third patient reporting psychic side-effects, used clonazepam 1±2 mg, paroxetin 2 mg and ibuprophen 400±800 mg daily. She experienced an unpleasant dizziness before falling asleep the first night after oral ketamine, but she had no side-effects the subsequent nights. A fourth patient took the first oral dose at 11 a.m. because she had severe pain. This patient, who regularly used oxazepam 37.5 mg/day, felt unpleasantly dizzy after ingesting ketamine, but she had no psychotomimetic effects.
Oral administration
The role of age and pain duration
In the second part of the study the effect of ketamine taken orally at night was examined.
A prolonged analgesic effect of ketamine apparently occurred more often in the youngest than in
100 A
Pain score (%)
80 60 40 20 0 0
5
10 20 30 40 50 Time after i.m. ketamine (min)
60
5
10 20 30 40 50 Time after i.m. ketamine (min)
60
100 B
Pain score (%)
80 60 40 20 0 0
FIG. 2. Effect of ketamine on pain score (pain assessment in percent of initial value) in 13 patients suffering chronic orofacial pain. SEM are shown for each registration. A: Mean of seven patients who experienced a transient or partially transient reduction of pain intensity. B: Mean of six patients who experienced a longterm reduction of pain intensity after ketamine.
European Journal of Pain (2001), 5
K ETAMINE
237
IN OROFACIAL PAIN
TABLE 1. Analgesic effect after i.m. (middle column) ketamine (0.4 mg/kg) and oral (right column) ketamine (4.0 mg/kg) given at night in 13 patients suffering neuropathic orofacial pain. The patients are listed according to age. Effects as evaluated by the investigator, based on pain assessment by visual analogue scale and by interviews. Sex/age/duration of pain (years)
i.m. ketamine: 0.4 mg/kg
F/88/5 M/71/8 F/61/7 F/51/1 F/50/28 F/40/8
no effect transient analgesia transient analgesia long-term analgesia no effect long-term analgesia
F/40/2
long-term analgesia
M/38/9 F/38/8 F/36/2
transient analgesia transient analgesia long-term analgesia
F/34/0.5
transient analgesia
M/33/1 F/32/9
transient analgesia long-term analgesia
the oldest patients, and more often in patients with a short history of chronic pain than in patients with a long pain history. In order to analyze for a possible association between an analgesic response and patient age and pain duration, the data from the present and the previous study were pooled, as described under methods. As shown in Figure 3A, the majority of the patients who experienced a long-term relief of pain after i.m. ketamine, had suffered pain for less than 5 years (11/14 or 78.6%). Among the patients with pain which had lasted more than 5 years, only 15.8% experienced a long-term analgesic response after i.m. ketamine ( p < 0.04). Moreover, 62.5% of the patients with pain lasting more than 9 years, had no analgesic effect ( p < 0.05). Mean duration of pain in the patients without analgesic effect after i.m. ketamine was 8.4 years, as compared to 4.0 years in the patients with long-term analgesic effect after ketamine. Patients with a transient analgesic effect were equally distributed between the quartiles, both with respect to age and pain duration. The apparent relationship between patient age and ketamine response (Fig. 3B) was not statistically significant. However, the majority of patients under 40 years old, experienced an
p.o. ketamine: 4 mg/kg no effect no analgesic effect, improved sleep no analgesic effect improved sleep, less pain in the mornings no effect reduced pain intensity on days after ketamine strongly reduced pain intensity on days after ketamine no analgesic effect reduced pain intensity on days after ketamine strongly reduced pain intensity on days after ketamine anxiety and disturbed sleep, reduced pain intensity the following day reduced pain intensity on days after ketamine reduced pain intensity on days after ketamine
analgesic effect (short- or long-term) after ketamine (11/13 or 84.6%) and more patients above 65 years had no analgesic effect (n 5) than longterm analgesic effect (n 1) after the i.m. ketamine injection. Mean age of the patients without analgesic effect after ketamine was 59.7 years, as compared to 48.2 years in the long-term responders. Patients with pain following a nerve lesion and patients without a known lesion of peripheral nerves were equally distributed between the three response groups (no analgesic response, transient analgesia and long-term analgesic response).
DISCUSSION The present study confirms that a single subanaesthetic dose of ketamine may cause a sustained analgesic effect in some patients suffering from constant neuropathic orofacial pain (Rabben et al., 1999). The time-course of the analgesic effect in these patients differs from the time-course of the analgesic effect of ketamine in acute nociceptive pain. The analgesic effect of a single i.m. dose in patients with acute nociceptive pain lasts for 15±30 min and is closely associated with the adverse mental actions (Maurset et al., European Journal of Pain (2001), 5
238
T. RABBEN
6 A Number of patients
5 4 3 2 1 0
<1
2–5 6–9 Pain duration (years)
>9
< 40
41–52 53–65 Patient age (years)
> 65
6 B Number of patients
5 4 3 2 1 0
FIG. 3. Results from correlation analyses in 43 patients with constant neuropathic orofacial pain. A: Pain duration related to type of response. A statistically significant positive correlation was found between a pain history lasting more than 9 years and lack of analgesic effect, and also between a pain history lasting less than 5 years and a long-term analgesic effect of low-dose ketamine. B: Patient age related to type of response. The apparent relationship between patient age and ketamine response was not statistically significant. Long-term analgesia, &; no analgesic effect, &.
1989; Mathisen et al., 1995), reflecting the rapid brain kinetics of ketamine (Hartvig et al., 1995). In contrast, the sustained or long-term reduction of pain intensity in chronic neuropathic orofacial pain persists for many hours after the acute inebriant effects have subsided and after ketamine is expected to be eliminated from the body. A long-term inhibition of pain intensity by ketamine is not limited to patients with neuropathic orofacial pain. Long-term analgesia after parenteral and peroral ketamine has been observed in patients suffering post-herpetic pain, European Journal of Pain (2001), 5
AND
I. éYE
post-traumatic neuropathic pain and fibromyalgia (Hoffmann et al., 1994; éye et al., 1996; Klepstad and Borchgrevink, 1997; Sùrensen et al., 1997). These observations are in concert with the hypothesis that a wind-up like, NMDA receptormediated sensitization may contribute to pathological pain states in humans and that inhibition of NMDA receptors for a relatively short time period may annul the central sensitization in some patients. In patients with chronic orofacial pain, re-kindling of the pathological pain apparently occurs during the subsequent 12±24 h. It is well-known that most analgesic drugs are less effective in chronic neuropathic pain than in acute nociceptive pain. Apparently this also applies for the NMDA receptor antagonist ketamine. In the present study only one third of the patients experienced long-term analgesia. Another third of the patients experienced a partial reduction of pain intensity coinciding with the adverse mental effects. The remaining third of the patients did not experience any decrease in pain inspite of characteristic mental actions. These findings are similar to those of a previous double-blind study of patients with the same diagnoses (Rabben et al., 1999). In both studies, old patients who had suffered neuropathic pain for many years, were more often resistant to the analgesic effect than young patients with a relatively short pain history. The procedures used in both studies were similar and it was therefore possible to look for predictive factors for ketamine analgesia by pooling the data from the two studies. Relating age and pain duration with the response to lowdose ketamine in the 43 patients who attended the ketamine trials, open or blinded, revealed a statistically significant correlation between a long duration of pain (> 9 years) and lack of ketamine response and between a shorter duration of pain (< 5 years) and a long-term analgesic response. This is consistent with a recent observation by Enarson et al., (1999). The apparent association between patient age and ketamine response was not statistically significant. A correlation between duration of chronic pain and analgesic response after a low dose of ketamine could imply that central pain mechanisms are subject to disease-related alterations with
K ETAMINE
239
IN OROFACIAL PAIN
time, which may involve a transition from NMDA to non-NMDA receptor-mediated transmission or changes in the NMDA receptor subunit composition. It is generally held that glutamate is a major neurotransmitter in central pain pathways. Glutamatergic synapses undergo characteristic changes during early maturation of the CNS as well as during experience-dependent synaptic plasticity later in life (Feldman and Knudsen, 1998). These changes involve both modification of the NMDA receptor complex itself and subsequently a possible increase in the number of AMPA receptors. Thus, the relative contribution of AMPA receptors to sensory responses will increase and the contribution of NMDA receptors might decrease. It is tempting to hypothesize that the interindividual variations of the efficiency of ketamine in chronic pain might depend on paindependent plasticity of glutamatergic synapses. A correlation between the existence of peripheral nerve damage in orofacial neuropathic pain and ketamine response was not found. This finding could indicate that NMDA receptor sensitization may be involved in chronic neuropathic pain irrespective of causative factors. Woolf et al. recently suggested that classification of chronic pain should be based on underlying mechanisms rather than on pain aetiology, and that pathophysiological mechanisms can be revealed by use of pharmacological tools (Woolf et al., 1998). Administration of analgesics by the oral route is of great advantage for patients suffering chronic pain. The present study confirms that ketamine given orally has an analgesic effect (Enarson et al., 1999; Lauretti et al., 1999; Rabben et al., 1999). Further, that a single dose of oral ketamine at night may reduce pain intensity the following day in some patients with chronic orofacial pain (Rabben et al., 1999). All patients who experienced a long-term effect of i.m. ketamine and who subsequently received ketamine orally, reported reduced pain intensity the following day. Also, three of the patients who experienced a short-lasting effect of i.m. ketamine reported some reduction of pain intensity on days after oral administration. Thus, a positive response to an i.m. test dose (transient or prolonged) was a predictor of the effect of oral ketamine.
Most of the ketamine given orally is rapidly metabolized to norketamine. Norketamine is also an NMDA receptor inhibitor, but the IC50 is about 10 times higher than for ketamine (unpublished studies from our laboratory). The bioavailability of ketamine given by the oral route has been reported to be about 15% (Grant et al., 1981). Hoffmann et al. (1994) reported the successful treatment of post-herpetic neuralgia in a 39-year-old man with oral ketamine 240± 1000 mg/day. In the present study, a nightly oral dose of 4 mg/kg (160±400 mg) reduced pain in patients who were long-term responders to i.m. ketamine. Oral ketamine at night was well accepted by most patients and some patients wished to continue treatment with ketamine after the study was completed.
ACKNOWLEDGEMENTS We thank Anders Jahres Fond and Familien Blix' Fond for financial support, and Leiv Sandvik, PhD (Med Stat Research, Lillestrùm, Norway) for performing the statistical analysis.
REFERENCES Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methylaspartate. Br J Pharmacol 1983; 79: 565±575. Backonja M, Arndt G, Gombar KA, Check B, Zimmermann M. Response of chronic neuropathic pain syndromes to ketamine: a preliminary study. Pain 1994; 56: 51±57. Coderre TJ, Katz J, Vaccarino AL, Melzack R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 1993; 52: 259±285. Davies SN, Lodge D. Evidence for involvement of N-methylaspartate receptors in ``wind-up'' of class 2 neurons in the dorsal horn of the rat. Brain Research 1987; 424: 402±406. Dickenson AH. A cure for wind up: NMDA receptor antagonists as potential analgesics. Trends Pharmacol Sci 1990; 11: 307±309. Dickenson AH. NMDA receptor antagonists an analgesics. In: Fields HL, Liebeskind JC, editors. Progress in Pain Research and Management. 1 ed. Seattle: IASP press, 1994: 173±187. Dickenson AH, Sullivan AF. Evidence for a role of the NMDA receptor in the frequency dependent
European Journal of Pain (2001), 5
240 potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacology 1987; 26: 1235±1238. Domino EF, Chodoff P, Crossen G. Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther 1965; 6: 279±291. Eide PK, Jùrum E, Stubhaug A, Bremnes J, Breivik H. Relief of post-herpetic neuralgia with the N-methyl-Daspartic acid receptor antagonist ketamine: a doubleblind, cross-over comparison with morphine and placebo. Pain 1994; 58: 347±354. Eide PK, Stubhaug A, éye I, Breivik H. Continuous subcutaneous administration of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine in the treatment of post-herpetic neuralgia. Pain 1995; 61: 221±228. Enarson MC, Hays H, Woodroffe MA. Clinical experience with oral ketamine. J Pain Symptom Manage 1999; 17: 384±386. Feldman DE, Knudsen EI. Experience-dependent plasticity and the maturation of glutamatergic synapses. Neuron 1998; 20: 1067±1071. Grant I, Nimmo W, Clements J. Pharmacokinetics and analgesic effects of IM and oral ketamine. Br J Anaesth 1981; 53: 805±810. Hartvig P, Valtyrsson J, Linder K-J, Kristensen J, Karlsten R, Gustavsson LL, Persson J, Svensson JO, éye I, Antoni G, Westerberg G, LaÊngstrùm B. Central nervous system effects of sub-dissociative doses of (S)-ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers. Clin Pharmacol Therap 1995; 58: 165±173. Hoffmann V, Coppejans H, Vercauteren M, Adriaensen H. Successful treatment of post-herpetic neuralgia with oral ketamine. The Clin J Pain 1994; 10: 240±242. Klepstad P, Borchgrevink PC. Four years' treatment with ketamine and a trial of dextromethorphan in a patient with severe post-herpetic neuralgia. Acta Anaesthesiol Scand 1997; 41: 422±426. Klepstad P, Maurset A, Moberg ER, éye I. Evidence of a role for NMDA receptors in pain perception. Europ J Pharmacol 1990; 187: 513±518.
European Journal of Pain (2001), 5
T. RABBEN
AND
I. éYE
Lauretti GR, Lima IC, Reis MP, Prado WA, Pereira NL. Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy for cancer pain management. Anesthesiology 1999; 90: 1528±1533. Mathisen LC, Skjelbred P, Skoglund LA, éye I. Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain. Pain 1995; 61: 215±220. Maurset A, Skoglund LA, Hustveit O, éye I. Comparison of ketamine and pethidine in experimental and postoperative pain. Pain 1989; 36: 37±41. Nikolajsen L, Hansen CL, Nielsen J, Keller J, ArendtNielsen L, Jensen TS. The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input. Pain 1996; 67: 69±77. Rabben T, Skjelbred P, éye I. Prolonged analgesic effect of ketamine, an N-methyl-D-aspartate receptor inhibitor, in patients with chronic pain. J Pharmacol Exp Ther 1999; 289: 1060±1066. Sùrensen J, Bengtsson A, Ahlner J, Henriksson KG, Ekselius L, Bengtsson M. Fibromyalgia ± are there different mechanisms in the processing of pain? A double blind crossover comparison of analgesic drugs. J Rheumatol 1997; 24: 1615±1621. Stannard CF, Porter GE. Ketamine hydrochloride in the treatment of phantom limb pain. Pain 1993; 54: 227±230. Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, Lipton R, Loeser JD, Payne R, Torebjùrk E. Towards a mechanism-based classification of pain? Pain 1998; 77: 227±229. Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N-methylD-aspartate receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain 1991; 44: 293±299. éye I, Rabben T, Fagerlund T. Analgesic effect of ketamine, an NMDA receptor antagonist, in a patient with neuropathic pain. J Norw Med Assoc 1996; 116: 3130± 3131.
1
Interindividual differences in the analgesic response to ketamine in chronic orofacial pain Toril Rabben and Ivar éye Department of Pharmacology, Oslo University School of Medicine, Oslo, Norway
The analgesic effect of the N-methyl-D-aspartate (NMDA) receptor blocker ketamine in 17 patients (13 females and four males, age 32±88 years) who had suffered neuropathic orofacial pain for time periods ranging from 6 months to 28 years was examined. The patients were given an i.m. test-dose of 0.4 mg/kg ketamine combined with 0.05 mg/kg midazolam. Four patients did not experience any analgesic effect of the i.m. test-dose. The remaining 13 patients experienced an analgesic effect which lasted for less than 1 h (transient effect) in seven and for several hours (long-term effect) in six. One week later they were given 4 mg/kg ketamine to be taken orally in combination with a hypnotic drug for 3 consecutive nights. All patients who reported a long-term analgesic effect after i.m. ketamine also reported reduced pain intensity on days after taking ketamine at night. The findings of this open study are in accordance with the results from a previous double-blind randomized investigation. In order to evaluate the role of age and pain duration for the analgesic effect of ketamine, the data from the two studies were pooled and a correlation analysis of 43 patients performed. A positive correlation was found between a long painhistory and lack of analgesic effect and also between a short pain-history and a long-term analgesic effect of lowdose ketamine. The apparent relationship between patient age and ketamine response was, however, not statistically significant. Further, patients with pain following a nerve lesion and patients without a known lesion of peripheral nerves were equally distributed between the three response groups. These results indicate that pain mechanisms are subject to alterations with time and that these alterations involve transition from NMDA to nonNMDA receptor-mediated transmission in central pain pathways. # Copyright 2001 European Federation of Chapters of the International Association for the Study of Pain KEYWORDS: neuropathic pain, orofacial pain, ketamine, intramuscular, oral administration, analgesia, NMDA receptors, correlation analyses.
INTRODUCTION The anaesthetic, analgesic, and psychotomimetic effects of ketamine were first described by Domino et al. (1965). Ketamine is effective and reliable as an analgesic in acute somatic pain, but in contrast to opiates its analgesic effect is not inhibited by naloxone, indicating a non-opioid analgesic mechanism (Maurset et al., 1989). The finding that ketamine selectively reduced excitation of central mammalian neurones by Paper received 23 June 2000 and accepted in revised form 14 February 2001. Correspondence to: Toril Rabben, Dept. of Pharmacology, Box 1057 Blindern, N-0316 Oslo, Norway. Tel: (47) 22 85 60 71; Fax: (47) 22 85 44 40; E-mail: [email protected]
N-methyl-D-aspartate (NMDA; Anis et al., 1983), suggested that its analgesic action might be due to inhibition of NMDA receptors. The clinical relevance of this mechanism was supported by the observation that the analgesic effect of ketamine in humans occured at concentrations within its NMDA receptor occupancy range, and that the relative order of potency of (R)- and (S)ketamine as analgesics correlated positively to their affinities as NMDA receptor antagonists (Klepstad et al., 1990). In animal experiments, activation of NMDA receptors in secondary afferent neurons is essential for the increased sensitivity to pain (wind-up) caused by repeated nociceptive stimulation (Davies and Lodge, 1987; Dickenson and Sullivan, 1987). Wind-up may be regarded as an
1090-3801/01/030233 + 08 $35.00/0 & 2001 European Federation of Chapters of the International Association for the Study of Pain
234
experimental model for central sensitization, which is an important mechanism in chronic (pathological) pain. The possibility that NMDA receptor antagonists may be clinically useful in pathological pain states has therefore attracted much attention in recent years (Dickenson, 1990, 1994; Woolf and Thompson, 1991; Coderre et al., 1993). Analgesic effect of ketamine in chronic pain states have been reported by several investigators (Stannard and Porter, 1993; Backonja et al., 1994; Eide et al., 1994, 1995; Nikolajsen et al., 1996). In most of these trials, however, the clinical use of ketamine was limited by its adverse mental effects. In a previous study of patients suffering neuropathic orofacial pain, it was found that ketamine was without analgesic effect in about 1/3 of the patients, 1/3 experienced a short-lasting reduction of pain closely associated with the adverse mental effects, and 1/3 of the patients reported an analgesic effect which outlasted the mental effects by many hours (Rabben et al., 1999). It was also observed that ketamine administered at night worked during sleep to prevent pain the following day in some of these patients. The oldest patients and those with the longest pain history were often non-responders, and the youngest patients with the shortest pain duration were often long-term responders. However, the number of patients was not enough for reliable statistical correlation analyses. Here, data are presented from a study of the analgesic effect of ketamine in another group of 17 patients who had suffered constant neuropathic orofacial pain for highly different time periods. By pooling the results of the present study with those previously published, the role of age, pain duration and the existence of a known peripheral nerve lesion as predictive factors for the response to ketamine in 43 patients was examined.
METHODS Patients suffering constant neuropathic orofacial pain were recruited from departments of oral surgery or from pain clinics in the Oslo area. Patients with known psychiatric disease and patients who scored less than 25 on the visual analogue scale European Journal of Pain (2001), 5
T. RABBEN
AND
I. éYE
(VAS) described below, were excluded. Seventeen patients (13 females and four males, aged 32±88) who had suffered orofacial pain for various time periods (ranging from 6 months to 28 years) entered the study. All had a diagnosis of neuropathic pain which had started following trauma or surgery in 12 and spontaneously in four. One patient, an 88-year-old woman, suffered postherpetic neuralgia which had been severely exacerbated following glycerol injection into the cistern of the trigeminal ganglion. Unlike patients with trigeminal neuralgia (tic douloureux) who suffer bouts of lancinating pain, these patients suffered constant burning or throbbing pain which was often moderate in the morning and increased during the day. All patients had been through extensive clinical examinations and had been treated with analgesics, anti-epileptics, anti-depressants, nerve blocks and other procedures without or with modest or temporary effects. For ethical reasons, this investigation was carried out as an open, observational study. The mental effects of ketamine were explained to each patient and written informed consent was obtained. The patients were instructed to assess pain using a 100 mm vertical VAS, (no pain 0, intolerable pain 100) and asked to record pain at home in the morning and at night for 3 consecutive days. On the fourth day a dose of 0.4 mg/ kg ketamine with 0.05 mg/kg midazolam was injected intramuscularly while the patients were resting in a comfortable position. They recorded pain before injection and every 5 min during the following hour, at night on the day of the injection as well as in the morning and at night the following 3 days. Adverse effects were registered by use of a standardized questionnaire. The patients were then given 4 mg/kg ketamine to be taken as an oral dose at home for 3 consecutive nights. They were told to take other medications as usual and were instructed to record pain in the morning and at night for 3 days before starting oral ketamine, on each day during the ketamine trial and for 3 days afterwards. The correct amount of racemic ketamine hydrochloride was dispensed as a dry powder to be dissolved in about 50 ml of a sugar-free strongly colaflavoured soft drink. The patients were instructed to ingest the ketamine after going to bed at night.
235
IN OROFACIAL PAIN
Patients who did not use clonazepam or hypnotics regularly were instructed to take a hypnotic drug (flunitrazepam or zopiklone) together with ketamine. The protocol was acknowledged by the Regional Ethical Committee. The ketamine used for i.m. injection was the available commercial preparation (Ketalar, Parke±Davies, Pfizer Ireland Pharmaceutical, Dubin, Ireland), the hydrochloride salt for oral use was obtained through Norsk Medisinaldepot (the Norwegian Medical Depot). Correlation analyses In order to examine putative factors predicting an analgesic response to ketamine, the analgesic effect of the i.m. test dose was analyzed for association with age, duration of pain and whether or not the pain was due to a peripheral nerve lesion. To strengthen the statistical power of the correlation analyses, the data from the present study and those obtained in a similar study performed by double-blind technique (Rabben et al., 1999) were pooled. The two studies were identical with respect to patient inclusion criteria, ketamine dose, administration and pain assessment. Correlation analyses could therefore be performed on a total of 43 patients (35 women and eight men, aged 29±89 years, pain duration 0.5±28 years, 33 patients with a diagnosed nerve lesion and 10 without) with constant neuropathic orofacial pain. In order to correlate patient age and duration of pain to ketamine response, we divided the patients into quartiles (age: < 40, 41± 52, 53±65, > 65 years; pain duration: < 1, 2±5, 6± 9, > 9 years). We used cross-tabs to correlate the predictive factors and ketamine response (no analgesic response, transient analgesia and longterm analgesic response), and a two-sided Fisher exact test in the significance testing. A 5% significance level was applied.
RESULTS Intramuscular administration Patients with chronic neuropathic orofacial pain did not respond to an analgesic dose of
Pain assessment by VAS (mm)
K ETAMINE
100 80 60 40 20 0 0
5
10 20 30 40 50 Time after i.m. ketamine (min)
60
FIG. 1. Lack of analgesic effect after ketamine 0.4 mg/ kg combined with midazolam 0.05 mg/kg in four patients suffering chronic orofacial pain. The i.m. injection was given at time 0. Two of the patients were over 80 years old. One patient had suffered constant pain for 28 years; following endodontical treatments, extractions, apical surgery and soft laser therapy the pain had intensified. One patient suffered constant severe pain after surgical removal of a retromaxillary adenocarcinoma followed by reconstructive surgery and infections. She described her pain as unbearable and had attempted suicide twice during the last year.
ketamine in a uniform way. Four patients did not experience any analgesic effect (Fig. 1). This group of non-responders included the two oldest patients (88 and 82 years), the patient with the longest pain history (pain duration 28 years) and the patient who, according to the judgement of the investigators, suffered the most severe pain. The other 13 patients experienced pain reduction after ketamine. In Figure 2, pain is expressed as the percentage of the pain assessment before ketamine injection (pain score in percent of basal levels which were between 40 and 100 mm on the VAS). Seven patients experienced a transient or partly transient pain reduction after injection of ketamine (Fig. 2A). In these patients, pain score was lowest after about 20 min and then returned towards basic level. Six patients experienced an analgesic effect which persisted throughout the test-period of 60 min (Fig. 2B). These patients reported that the analgesic effect remained for the rest of the day and some reported that pain intensity was less than usual also the following day. The main side effects after i.m. ketamine combined with midazolam were sedation and a European Journal of Pain (2001), 5
236
T. RABBEN
AND
I. éYE
general feeling of insobriety. Most of the patients also noted blurred vision and a dry mouth. Inspite of these side-effects, 16 of the 17 patients rated the test as being pleasant. One patient rated the test as slightly unpleasant due to dizziness. The mental effects were present in all patients regardless of an analgesic response and lasted for less than 60 min. Thus, in some patients apparently analgesia persisted for many hours after the mental side-effects had subsided.
Two of the patients who did not respond to i.m. ketamine were excluded, one because she had recently attempted suicide, and one because of his age (82 years). Another two were excluded because they were worried about side-effects. The remaining 13 patients were given three doses of 4 mg/kg ketamine to be taken at home on 3 consecutive nights as described under methods. The results are summarized in Table 1. The five patients who had reported long-term reduction of pain intensity after i.m. ketamine, reported reduced pain intensity or complete analgesia on days after ingesting 4 mg/kg ketamine at night. Also, three of the patients who had reported partially transient analgesic effect after the i.m. test dose reported some reduction of pain intensity on days after ingesting ketamine. The remaining patients did not record any reduction of pain during the 3 days of treatment with 4 mg/kg ketamine taken orally at night. Mental side effects of ketamine taken orally after going to bed at night were reported by three of 13 patients. The most severe effect was reported by a 34-year-old woman who took the first oral dose without a hypnotic or sedative drug. She had a frightening `near death' experience and was unable to sleep for the rest of the night. In spite of this event, she reported reduced pain intensity the following day. Another patient who took the first oral dose without a hypnotic drug, suffered anxiety and hallucinations, but the pain was absent the following day. The third patient reporting psychic side-effects, used clonazepam 1±2 mg, paroxetin 2 mg and ibuprophen 400±800 mg daily. She experienced an unpleasant dizziness before falling asleep the first night after oral ketamine, but she had no side-effects the subsequent nights. A fourth patient took the first oral dose at 11 a.m. because she had severe pain. This patient, who regularly used oxazepam 37.5 mg/day, felt unpleasantly dizzy after ingesting ketamine, but she had no psychotomimetic effects.
Oral administration
The role of age and pain duration
In the second part of the study the effect of ketamine taken orally at night was examined.
A prolonged analgesic effect of ketamine apparently occurred more often in the youngest than in
100 A
Pain score (%)
80 60 40 20 0 0
5
10 20 30 40 50 Time after i.m. ketamine (min)
60
5
10 20 30 40 50 Time after i.m. ketamine (min)
60
100 B
Pain score (%)
80 60 40 20 0 0
FIG. 2. Effect of ketamine on pain score (pain assessment in percent of initial value) in 13 patients suffering chronic orofacial pain. SEM are shown for each registration. A: Mean of seven patients who experienced a transient or partially transient reduction of pain intensity. B: Mean of six patients who experienced a longterm reduction of pain intensity after ketamine.
European Journal of Pain (2001), 5
K ETAMINE
237
IN OROFACIAL PAIN
TABLE 1. Analgesic effect after i.m. (middle column) ketamine (0.4 mg/kg) and oral (right column) ketamine (4.0 mg/kg) given at night in 13 patients suffering neuropathic orofacial pain. The patients are listed according to age. Effects as evaluated by the investigator, based on pain assessment by visual analogue scale and by interviews. Sex/age/duration of pain (years)
i.m. ketamine: 0.4 mg/kg
F/88/5 M/71/8 F/61/7 F/51/1 F/50/28 F/40/8
no effect transient analgesia transient analgesia long-term analgesia no effect long-term analgesia
F/40/2
long-term analgesia
M/38/9 F/38/8 F/36/2
transient analgesia transient analgesia long-term analgesia
F/34/0.5
transient analgesia
M/33/1 F/32/9
transient analgesia long-term analgesia
the oldest patients, and more often in patients with a short history of chronic pain than in patients with a long pain history. In order to analyze for a possible association between an analgesic response and patient age and pain duration, the data from the present and the previous study were pooled, as described under methods. As shown in Figure 3A, the majority of the patients who experienced a long-term relief of pain after i.m. ketamine, had suffered pain for less than 5 years (11/14 or 78.6%). Among the patients with pain which had lasted more than 5 years, only 15.8% experienced a long-term analgesic response after i.m. ketamine ( p < 0.04). Moreover, 62.5% of the patients with pain lasting more than 9 years, had no analgesic effect ( p < 0.05). Mean duration of pain in the patients without analgesic effect after i.m. ketamine was 8.4 years, as compared to 4.0 years in the patients with long-term analgesic effect after ketamine. Patients with a transient analgesic effect were equally distributed between the quartiles, both with respect to age and pain duration. The apparent relationship between patient age and ketamine response (Fig. 3B) was not statistically significant. However, the majority of patients under 40 years old, experienced an
p.o. ketamine: 4 mg/kg no effect no analgesic effect, improved sleep no analgesic effect improved sleep, less pain in the mornings no effect reduced pain intensity on days after ketamine strongly reduced pain intensity on days after ketamine no analgesic effect reduced pain intensity on days after ketamine strongly reduced pain intensity on days after ketamine anxiety and disturbed sleep, reduced pain intensity the following day reduced pain intensity on days after ketamine reduced pain intensity on days after ketamine
analgesic effect (short- or long-term) after ketamine (11/13 or 84.6%) and more patients above 65 years had no analgesic effect (n 5) than longterm analgesic effect (n 1) after the i.m. ketamine injection. Mean age of the patients without analgesic effect after ketamine was 59.7 years, as compared to 48.2 years in the long-term responders. Patients with pain following a nerve lesion and patients without a known lesion of peripheral nerves were equally distributed between the three response groups (no analgesic response, transient analgesia and long-term analgesic response).
DISCUSSION The present study confirms that a single subanaesthetic dose of ketamine may cause a sustained analgesic effect in some patients suffering from constant neuropathic orofacial pain (Rabben et al., 1999). The time-course of the analgesic effect in these patients differs from the time-course of the analgesic effect of ketamine in acute nociceptive pain. The analgesic effect of a single i.m. dose in patients with acute nociceptive pain lasts for 15±30 min and is closely associated with the adverse mental actions (Maurset et al., European Journal of Pain (2001), 5
238
T. RABBEN
6 A Number of patients
5 4 3 2 1 0
<1
2–5 6–9 Pain duration (years)
>9
< 40
41–52 53–65 Patient age (years)
> 65
6 B Number of patients
5 4 3 2 1 0
FIG. 3. Results from correlation analyses in 43 patients with constant neuropathic orofacial pain. A: Pain duration related to type of response. A statistically significant positive correlation was found between a pain history lasting more than 9 years and lack of analgesic effect, and also between a pain history lasting less than 5 years and a long-term analgesic effect of low-dose ketamine. B: Patient age related to type of response. The apparent relationship between patient age and ketamine response was not statistically significant. Long-term analgesia, &; no analgesic effect, &.
1989; Mathisen et al., 1995), reflecting the rapid brain kinetics of ketamine (Hartvig et al., 1995). In contrast, the sustained or long-term reduction of pain intensity in chronic neuropathic orofacial pain persists for many hours after the acute inebriant effects have subsided and after ketamine is expected to be eliminated from the body. A long-term inhibition of pain intensity by ketamine is not limited to patients with neuropathic orofacial pain. Long-term analgesia after parenteral and peroral ketamine has been observed in patients suffering post-herpetic pain, European Journal of Pain (2001), 5
AND
I. éYE
post-traumatic neuropathic pain and fibromyalgia (Hoffmann et al., 1994; éye et al., 1996; Klepstad and Borchgrevink, 1997; Sùrensen et al., 1997). These observations are in concert with the hypothesis that a wind-up like, NMDA receptormediated sensitization may contribute to pathological pain states in humans and that inhibition of NMDA receptors for a relatively short time period may annul the central sensitization in some patients. In patients with chronic orofacial pain, re-kindling of the pathological pain apparently occurs during the subsequent 12±24 h. It is well-known that most analgesic drugs are less effective in chronic neuropathic pain than in acute nociceptive pain. Apparently this also applies for the NMDA receptor antagonist ketamine. In the present study only one third of the patients experienced long-term analgesia. Another third of the patients experienced a partial reduction of pain intensity coinciding with the adverse mental effects. The remaining third of the patients did not experience any decrease in pain inspite of characteristic mental actions. These findings are similar to those of a previous double-blind study of patients with the same diagnoses (Rabben et al., 1999). In both studies, old patients who had suffered neuropathic pain for many years, were more often resistant to the analgesic effect than young patients with a relatively short pain history. The procedures used in both studies were similar and it was therefore possible to look for predictive factors for ketamine analgesia by pooling the data from the two studies. Relating age and pain duration with the response to lowdose ketamine in the 43 patients who attended the ketamine trials, open or blinded, revealed a statistically significant correlation between a long duration of pain (> 9 years) and lack of ketamine response and between a shorter duration of pain (< 5 years) and a long-term analgesic response. This is consistent with a recent observation by Enarson et al., (1999). The apparent association between patient age and ketamine response was not statistically significant. A correlation between duration of chronic pain and analgesic response after a low dose of ketamine could imply that central pain mechanisms are subject to disease-related alterations with
K ETAMINE
239
IN OROFACIAL PAIN
time, which may involve a transition from NMDA to non-NMDA receptor-mediated transmission or changes in the NMDA receptor subunit composition. It is generally held that glutamate is a major neurotransmitter in central pain pathways. Glutamatergic synapses undergo characteristic changes during early maturation of the CNS as well as during experience-dependent synaptic plasticity later in life (Feldman and Knudsen, 1998). These changes involve both modification of the NMDA receptor complex itself and subsequently a possible increase in the number of AMPA receptors. Thus, the relative contribution of AMPA receptors to sensory responses will increase and the contribution of NMDA receptors might decrease. It is tempting to hypothesize that the interindividual variations of the efficiency of ketamine in chronic pain might depend on paindependent plasticity of glutamatergic synapses. A correlation between the existence of peripheral nerve damage in orofacial neuropathic pain and ketamine response was not found. This finding could indicate that NMDA receptor sensitization may be involved in chronic neuropathic pain irrespective of causative factors. Woolf et al. recently suggested that classification of chronic pain should be based on underlying mechanisms rather than on pain aetiology, and that pathophysiological mechanisms can be revealed by use of pharmacological tools (Woolf et al., 1998). Administration of analgesics by the oral route is of great advantage for patients suffering chronic pain. The present study confirms that ketamine given orally has an analgesic effect (Enarson et al., 1999; Lauretti et al., 1999; Rabben et al., 1999). Further, that a single dose of oral ketamine at night may reduce pain intensity the following day in some patients with chronic orofacial pain (Rabben et al., 1999). All patients who experienced a long-term effect of i.m. ketamine and who subsequently received ketamine orally, reported reduced pain intensity the following day. Also, three of the patients who experienced a short-lasting effect of i.m. ketamine reported some reduction of pain intensity on days after oral administration. Thus, a positive response to an i.m. test dose (transient or prolonged) was a predictor of the effect of oral ketamine.
Most of the ketamine given orally is rapidly metabolized to norketamine. Norketamine is also an NMDA receptor inhibitor, but the IC50 is about 10 times higher than for ketamine (unpublished studies from our laboratory). The bioavailability of ketamine given by the oral route has been reported to be about 15% (Grant et al., 1981). Hoffmann et al. (1994) reported the successful treatment of post-herpetic neuralgia in a 39-year-old man with oral ketamine 240± 1000 mg/day. In the present study, a nightly oral dose of 4 mg/kg (160±400 mg) reduced pain in patients who were long-term responders to i.m. ketamine. Oral ketamine at night was well accepted by most patients and some patients wished to continue treatment with ketamine after the study was completed.
ACKNOWLEDGEMENTS We thank Anders Jahres Fond and Familien Blix' Fond for financial support, and Leiv Sandvik, PhD (Med Stat Research, Lillestrùm, Norway) for performing the statistical analysis.
REFERENCES Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methylaspartate. Br J Pharmacol 1983; 79: 565±575. Backonja M, Arndt G, Gombar KA, Check B, Zimmermann M. Response of chronic neuropathic pain syndromes to ketamine: a preliminary study. Pain 1994; 56: 51±57. Coderre TJ, Katz J, Vaccarino AL, Melzack R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 1993; 52: 259±285. Davies SN, Lodge D. Evidence for involvement of N-methylaspartate receptors in ``wind-up'' of class 2 neurons in the dorsal horn of the rat. Brain Research 1987; 424: 402±406. Dickenson AH. A cure for wind up: NMDA receptor antagonists as potential analgesics. Trends Pharmacol Sci 1990; 11: 307±309. Dickenson AH. NMDA receptor antagonists an analgesics. In: Fields HL, Liebeskind JC, editors. Progress in Pain Research and Management. 1 ed. Seattle: IASP press, 1994: 173±187. Dickenson AH, Sullivan AF. Evidence for a role of the NMDA receptor in the frequency dependent
European Journal of Pain (2001), 5
240 potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacology 1987; 26: 1235±1238. Domino EF, Chodoff P, Crossen G. Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther 1965; 6: 279±291. Eide PK, Jùrum E, Stubhaug A, Bremnes J, Breivik H. Relief of post-herpetic neuralgia with the N-methyl-Daspartic acid receptor antagonist ketamine: a doubleblind, cross-over comparison with morphine and placebo. Pain 1994; 58: 347±354. Eide PK, Stubhaug A, éye I, Breivik H. Continuous subcutaneous administration of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine in the treatment of post-herpetic neuralgia. Pain 1995; 61: 221±228. Enarson MC, Hays H, Woodroffe MA. Clinical experience with oral ketamine. J Pain Symptom Manage 1999; 17: 384±386. Feldman DE, Knudsen EI. Experience-dependent plasticity and the maturation of glutamatergic synapses. Neuron 1998; 20: 1067±1071. Grant I, Nimmo W, Clements J. Pharmacokinetics and analgesic effects of IM and oral ketamine. Br J Anaesth 1981; 53: 805±810. Hartvig P, Valtyrsson J, Linder K-J, Kristensen J, Karlsten R, Gustavsson LL, Persson J, Svensson JO, éye I, Antoni G, Westerberg G, LaÊngstrùm B. Central nervous system effects of sub-dissociative doses of (S)-ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers. Clin Pharmacol Therap 1995; 58: 165±173. Hoffmann V, Coppejans H, Vercauteren M, Adriaensen H. Successful treatment of post-herpetic neuralgia with oral ketamine. The Clin J Pain 1994; 10: 240±242. Klepstad P, Borchgrevink PC. Four years' treatment with ketamine and a trial of dextromethorphan in a patient with severe post-herpetic neuralgia. Acta Anaesthesiol Scand 1997; 41: 422±426. Klepstad P, Maurset A, Moberg ER, éye I. Evidence of a role for NMDA receptors in pain perception. Europ J Pharmacol 1990; 187: 513±518.
European Journal of Pain (2001), 5
T. RABBEN
AND
I. éYE
Lauretti GR, Lima IC, Reis MP, Prado WA, Pereira NL. Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy for cancer pain management. Anesthesiology 1999; 90: 1528±1533. Mathisen LC, Skjelbred P, Skoglund LA, éye I. Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain. Pain 1995; 61: 215±220. Maurset A, Skoglund LA, Hustveit O, éye I. Comparison of ketamine and pethidine in experimental and postoperative pain. Pain 1989; 36: 37±41. Nikolajsen L, Hansen CL, Nielsen J, Keller J, ArendtNielsen L, Jensen TS. The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input. Pain 1996; 67: 69±77. Rabben T, Skjelbred P, éye I. Prolonged analgesic effect of ketamine, an N-methyl-D-aspartate receptor inhibitor, in patients with chronic pain. J Pharmacol Exp Ther 1999; 289: 1060±1066. Sùrensen J, Bengtsson A, Ahlner J, Henriksson KG, Ekselius L, Bengtsson M. Fibromyalgia ± are there different mechanisms in the processing of pain? A double blind crossover comparison of analgesic drugs. J Rheumatol 1997; 24: 1615±1621. Stannard CF, Porter GE. Ketamine hydrochloride in the treatment of phantom limb pain. Pain 1993; 54: 227±230. Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, Lipton R, Loeser JD, Payne R, Torebjùrk E. Towards a mechanism-based classification of pain? Pain 1998; 77: 227±229. Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N-methylD-aspartate receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain 1991; 44: 293±299. éye I, Rabben T, Fagerlund T. Analgesic effect of ketamine, an NMDA receptor antagonist, in a patient with neuropathic pain. J Norw Med Assoc 1996; 116: 3130± 3131.