Side Effects of Ketamine in the Long-Term Treatment of Neuropathic Pain

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1 Blackwell Publishing IncMalden, USAPMEPain Medicine American Academy of Pain Medicine? Original ArticlesSide Effects of Peroral KetamineCvrdek PAIN MEDICINE Volume 9 Number PRELIMINARY RESEARCH Side Effects of Ketamine in the Long-Term Treatment of Neuropathic Pain Petr Cvrček, MD Pain Clinic, Department of Anesthesiology Jihlava Hospital, Vrchlického, Jihlava, Czech Republic ABSTRACT ABSTRACT Objectives. Ketamine, noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, has been used in the treatment of chronic neuropathic pain for almost 15 years. The aim of the study was to describe and evaluate side effects of this drug in the group of 32 patients with diabetic polyneuropathy and with postherpetic neuralgia. Design and Patients. In total, 32 patients with postherpetic neuralgia and diabetic polyneuropathy were enrolled into our prospective study. The side effects were divided in two groups. First, the side effects observed within 30 minutes lasting intravenuous infusion of 10 mg of ketamine in 100 ml of normal saline. Second after 3 months of peroral treatment of 30 mg of ketamine five times daily. Results. Sedation was observed in 15.6% of patients after the initial infusion and in 19% of patients in the course of the subsequent oral therapy. In total, 44% (infusion) and 22% (oral administration) of patients reported dizziness. A total of 25% of patients complained about drowsiness and 19% of patients reported dry mouth during oral therapy. In the observed 3-month treatment period, five patients (15.6%) withdrew from the treatment due to a failure of therapy and four patients (12.5%) due to untolerated side effects (dizziness, sedation, loss of appetite, nausea, and vomiting). Conclusions. Ketamine is evaluated as a nonoptimal, however, available NMDA blocker suitable for clinical use. Studying its effects in clinics can be expected to increase our knowledge necessary for the development of new, effective, and safe antineuralgic drug. Key Words. Ketamine; NMDA Receptor; Neuropathic Pain; Chronic Pain Introduction K etamine is a derivate of phencyclidine which is chemically related to hallucinogens. It has already been used for 40 years in anesthesiology because of its ability to induce so called dissociative anesthesia. It is a special type of a cataleptic state in which a patient appears to be completely disconnected from the outside world without inducing a normal sleep, and it also has an analgesic effect [1]. Its main binding site is a phencycli- Reprint requests to: Petr Cvrček, MD, Department of Anesthesiology Jihlava Hospital, Vrchlického 59, Jihlava, Czech Republic. Tel: ; Fax: ; petr.cvrcek@centrum.cz. dine site of the N-methyl-D-aspartate (NMDA) receptor. The possibilities of using the NMDA receptor antagonists for reducing the neuropathic pain have been widely investigated in the second half of the 1990s of the 20th century, as these receptors appeared to be the key site for the transmission of the information from periphery to the central nervous system [2,3 12]. Ketamine proved to be the most accessible among many other products (memantine, amantadine, dextromethorphane, experimentally used AP-5, and others). However, one important question remains unanswered: whether the product is safe even during the longterm use. American Academy of Pain Medicine /08/$15.00/ doi: /j x

2 254 Cvrček Although a consensus in the strategy of its antineuralgic therapy has not been achieved (application form, minimal and maximal dose, dosage frequency, contraindications), it is clear now that the analgesic doses are significantly lower then the anesthetic doses [13,3 7,10,12,14,15]. However, there have been reported some cases of side effects of high doses of ketamine that was administered for a long time [11,16]. On the other hand, the concerns regarding the undesirable effects which are known from the anesthesiology have been cleared (hallucinations, activation of sympathetic system, salivation) [1,13,17]. These undesirable effects practically do not occur with the analgesic dosage. However, it has to be admitted that even the low doses of ketamine have their specificities which may surprise not only the patient but also the physician. Methods A total of 32 patients (21 females and 11 males) with diabetic polyneuropathy (20 patients) and with postherpetic neuralgia (12 patients) were enrolled into our prospective study during the period from January 1, 2002, to December 31, Inclusion criteria were diabetic polyneuropathy and postherpetic neuralgia treated unsuccessfully by means of nonopioid analgetics, opioids, coanalgetics (antidepressant and antiepileptic drugs), and their combination. Exclusion criteria were: children (15 years old and younger); pregnancy and lactation; known hypersesitivity to ketamine; intracranial arterial aneurysma; glaucoma; drug or alcohol addiction; psychosis; dementia; enrolling into other study. Local ethics committee approval was obtained in September After interview, examination and signature of informed consent was the established analgetic treatment (Table 1) supplemented with the initial 30 minutes intravenous infusion of 10 mg of ketamine in 100 ml of normal saline. The infusion was followed by a three months oral treatment with 30 mg of ketamine in 6 ml of normal saline five times daily. The patients were invited for follow-up visits after 7 days and after 1, 2, and Table 1 Analgetic Therapy 3 months. During the entire study period, we monitored the intensity of neuropathic pain according to a 10-degree visual analog scale (VAS), blood pressure values, and heart rate. At the beginning and at the end of the 3-month period, we obtained samples for basic laboratory tests (blood counts, serum sodium, potassium and chloride levels, liver function tests, serum urea, creatinine and amylase levels, urine chemistry and urine sediment examination) to evaluate the effect of ketamine on the parameters to be monitored. After the 3-month treatment, the patients underwent electroencephalograph (EEG) to evaluate the potential presence of epileptogenic activity, if any. In our investigation, we focused on the occurrence of excessive sympathetic activation, qualitative and quantitative consciousness disorders (primary endpoints). We have also been interested in dizziness, nausea and vomiting, dryness in mouth or excessive salivation (secondary endpoints). We have also actively searched for other unexpected and less usual side effects during each control examination. All these data were collected by means of standardized questionnaire and by interview during every visit. Results Established analgetic therapy before the study Number of Patients Nonopioid drugs 23 (72%) Opioids 6 (19%) Coanalgetics 7 (22%) Other (acupuncture, homeopathy) 2 (6%) Figure 1 shows a comparison of the median of the basal intensity of neuropathic pain which was evaluated on the 10-degree VAS VAS 1, intensity of pain after the initial infusion VAS 2, after 1-week oral treatment VAS 3, and after 3 months of oral treatment VAS 4. The data of decrease in pain intensity after the initial infusion (VAS 1 2) and after 1 week of oral treatment (VAS 1 3) (presented as median) have been analyzed using Wilcoxon pair test. Statistically significance was considered to be at P < 0.05 (Table 2). In the observed 3-month treatment period, five patients (15.6%) withdrew from the treatment due to a failure of therapy and four patients (12.5%) due to nontolerable side effects. These effects

3 Side Effects of Peroral Ketamine VAS 1 VAS 2 VAS 3 VAS 4 inensity of pain Figure 1 Median of intensity of neuropathic pain according to 10-degree visual analog scale (VAS) before and during the treatment with ketamine: before treatment (VAS 1); after initial infusion (VAS 2); after 1 week of oral treatment (VAS 3); after 3 months of oral treatment (VAS 4). Table 2 Statistical significance P (Wilcoxon pair test) of analgesic effect of ketamine according to 10-degree visual analog scale (VAS) after initial infusion (VAS 1 2) and after 1 week of oral treatment (VAS 1 3) Decrease in Pain Intensity Numerical P VAS <0.001 VAS included mainly dizziness, sedation, loss of appetite, nausea, and vomiting. Two patients who had received concomitantly dihydrocodeine reported loss of appetite, nausea, and vomiting. It cannot be excluded that a combination of dihydrocodeine and ketamine (and therefore a relative overdose of dihydrocodeine in this combination) was rather responsible for these difficulties than ketamine alone. However, also less significant side effects occurred which did not resulted in discontinuation of the treatment. These side effects are summarized in Table 3. In rare cases, the bizarre complaints occurred as well which included loss of hair, face burning, and tinnitus (these undesirable effects persisted even after discontinuation of ketamine). The causal relationship to the treatment is considered to be uncertain. The excellent circulatory stability in all treated patients, absence of qualitative or quantitative changes of consciousness as well as the absence of the EEG signs of epileptogenic activity is regarded as valuable. For more details see Table 4. Discussion We focused on the differences between our results and literary data as well as the differences between the literary data alone. Dosing Bell and Schmid [14,18] reported that the doses of ketamine above 20 µg/kg/min administered in a continuous intravenous infusion had the anesthetic effects, the lower doses (15 19 µg/kg/min) had an analgesic or antihyperalgesic effect and the doses between 1 and 14 µg/kg/min had no analgesic effect but reduced the amount of opioids and the occurrence of tolerance to them. However, a statistical significant pain relief was achieved in the group of our patients using the average intravenous dose of ketamin of 4.5 µg/kg/min even without a previous medication with opioids. Ketamine vs Norketamine Ebert, Fitzgibbon, and Grant [3,8,15] consider norketamine, which is an immediate metabolite of ketamine, as the key factor for the analgesic effect after oral application. Due to a high first pass Table 3 Adverse events during the treatment with ketamine Adverse Events After Infusion Peroral Treatment Dizziness 14 (43.75%) 7 (22%) Sedation 5 (15.6%) 6 (18.75%) Drowsiness 3 (9.4%) 8 (25%) Dry mouth 5 (15.6%) 6 (18.75%) Euphoria 3 (9.4%) 2 (6.25%) Nausea and vomiting 1 (3%) 3 (9.4%) Memory deterioration 0 3 (9.4%) Feeling of drunkenness 3 (9.4%) 1 (3%) Hallucinations 0 0 Table 4 Awaiting and real side effects after 3-month treatment with ketamine Awaiting Side Effect Real Side Effects Increase of sympathetic activity Blood pressure and heart rate stability Sedation Sedation, drowsiness, dizziness Changes in EEG 0 Hallucinations 0 Salivation Dry mouth Elevated liver enzymes 0 EEG = electroencephalograph.

4 256 Cvrček effect and metabolism in the liver, the serum levels of norketamine after oral administration of ketamine were two to three times higher than after its parenteral administration. The analgesic effect of oral ketamine corresponds to the serum level of norketamine and not to the level of ketamine alone. This indicates that norketamine significantly contributes to the analgesic effect of oral ketamine [3]. Fitzgibbon [8] describes three interesting casuistics. A control of pain has been achieved in all three cases using ketamine in lower oral doses comparing to the previous parenteral doses (25 50% of the basal parenteral dose). This also indicates that the analgesic effect of ketamine is caused by its metabolite norketamine. According to Grant [15], the bioavailability of oral ketamine is only 16% in comparison with 93% achieved after intramuscular application. However, after administration of the same intramuscular and oral doses of ketamine the plasma level of ketamine after intramuscular application is identical to the plasma level of norketamine after oral application of ketamine. In our patients, we started the treatment with intravenous infusion (not intramuscular application reported by Grant) [15]. The effects of this therapy were significantly better than the analgesic effect of the following oral treatment. The median intensity of pain before the treatment reached up 6.6 on the 10-point visual analogous scale, which then dropped to 2.7 after the initial intravenous infusion, but its value of 3.9 remained stabilized with the subsequent oral medication (after 1-week therapy). Hepatotoxicity The views regarding the hepatotoxic activity of high doses of ketamine are very controversial. The literary data appear to be different as well. For example, Hoffmann [10] reduced the postherpetic neuralgia using oral ketamine in a dose of mg/kg/dose five times a day. Stannard and Porter [12] reduced the phantom limb pain with subcutaneous infusion of ketamine in a dose of mg/kg/h administered for several weeks and they did not prove any hepatic impairment. On the contrary, other authors reported jaundice and elevation of liver enzymes already after several days of oral administration of ketamine and these laboratory abnormalities persisted for several months after discontinuation of treatment and even after the pain for which it had been used disappeared [11]. The same laboratory abnormalities have been described even after administration of ketamine in intravenous infusion [16]. In our group of patients, we reported only one case of slight increase of liver enzymes before the treatment with ketamine (ALT 0.85 µkat l 1 ). The laboratory tests became normal in the course of the treatment. Somatic, Psychic, and Others Side Effects The undesirable activation of sympathetic system occurred in no case and we even recorded a slight reduction of blood pressure. Also the concerns regarding confusion and hallucinations proved to be unfounded. Sedation was observed in 15.6% of patients after the initial infusion and in 19% of patients in the course of the subsequent oral therapy. In total, 44% (infusion) and 22% (oral administration) of patients reported dizziness. A total of 25% of patients complained about drowsiness and 19% of patients reported dry mouth during oral therapy. Conclusions Ketamine, a noncompetitive antagonist of NMDA receptors, has been used in the treatment of chronic neuropathic pain for almost 15 years. It is evaluated as a nonoptimal, however, easy available drug suitable for clinical use and there are a lot of experieces with it in anesthesiology. But its routine use in pain management can be accompanied with some side and adverse effects, mainly sedation, drowsiness, dizziness, and dry mouth. These effects may surprise an unskilled physician. Therefore, this treatment should be indicated and managed only by the physician who has the experience in pain management and anesthesiology too. In addition to its therapeutic use, this product serves for gaining further experience with a possibility to influence the neuropathic pain using the blockade of the NMDA receptors, which may initiate the development of new, safe, and effective drug with similar or better pharmacodynamic profile. References 1 Larsen R. Anestezie, 5th edition. Prague: Grada Publishing; Clubb B. Management of neuropathic pain following treatment for breast cancer in the absence of recurrence: A challenge for the radiation oncologist. Australas Radiol 2004;48:

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