Pain resulting from neuropathy is probably the most challenging and difficult painful state to manage.1 Subanaesthetic doses of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, and methadone, a mu-opioid receptor (MOR) agonist and NMDA receptor antagonist, have been used separately as an alternative to treat neuropathic pain, especially in patients refractory to first-line analgesics.1–3 For the purpose of enhancing the analgesic efficacy and reducing the occurrence of adverse effects, multimodal analgesia, a clinical practice achieved by combining different drugs, has been used to improve the therapeutic efficacy of pain therapy.1 Here, we report the therapeutic response of 18 patients (mean age of 50.6 years, range of 23 to 71 years; five men and 13 women) suffering from neuropathic pain of different causes and refractory to conventional analgesics to a combination of methadone and ketamine, as an oral solution, for 6 months.
Table 1 summarises the main characteristics of the patients. All patients went to the Clinical Care & Pain Management of Santa Maria University Hospital (HUSM) between October 2006 and March 2008. The patients who were considered candidates for the experimental treatment claimed neuropathy-related painful sensations poorly responsive to conventional pharmacotherapies. The visual analogue pain (VAS) pain score was the main treatment effect assessed.3 Moreover, we also measured the presence and the degree of allodynia and burning and/or shooting pain. The patients consented to the proposed therapy. Except for opioid drugs, all prior prescribed treatments continued during the experimental period.
Ethical approval for this study (Ethical Committee No. 0050.0.243.000-07) was provided by the Ethical Committee of Federal University of Santa Maria, Santa Maria, Brazil on 13 August 2007.
Prior to starting the methadone and ketamine treatment, the patients tried several conventional analgesics. Around 62, 38, 33 and 17% of the patients tried tricycle antidepressants (amitriptyline and nortryptyline), anticonvulsivants (gabapentin and carbamazepine), opioids (morphine, codeine or tramadol) and non-steroidal anti-inflammatory drugs (acetaminophen), respectively, to manage their pain (Table 1). As shown in Fig. 1a, all prior prescribed treatments failed, as patients had an elevated VAS score (median of 9, range 7 to 10) at the first clinical evaluation.
The solution of methadone with ketamine was prepared by mixing 10 ml of methadone (10 mg ml−1), 20 ml of S(+)-ketamine [50 mg ml−1 (both from Cristália, São Paulo, Brazil] and 70 ml of physiological saline 0.9% (Baxter, São Paulo, Brazil), obtaining a concentration of 1 mg ml−1 of methadone and 10 mg ml−1 of ketamine. Three milligrams of methadone along with 30 mg of ketamine were given three times a day. We based our methadone dose on the recommendations for medical management of chronic non-malignant pain, by the College of Physicians and Surgeons of Ontário, Canada (November 2000, http://http://www.cpsa.ab.ca/Libraries/Pro_TPP/MedicalManagementPain.sflb.ashx). They state that 2.5 mg q8 h−1 (7.5 mg per day) of methadone is well tolerated by patients with chronic non-malignant pain.
Methadone in combination with ketamine gradually reduced the VAS scores (Fig. 1a). After 15 days of treatment, 83% of the patients described a reduction of at least 50% of the VAS (median of 4, range 2 to 5). In 2 months of treatment, the average of VAS score reduction was 75 ± 4%, reaching 86 ± 3% (median of 2, range 0 to 4) at the end of treatment (Fig. 1a). Nevertheless, in 41% of patients, VAS reached a stable value after 2 months. In these cases, the methadone and ketamine was increased to 12 mg of methadone along with 120 mg ketamine daily. Four patients discontinued the treatment: three of them due to complete pain relief and one due to intolerable adverse effects.4 One patient (#12) was only evaluated up to month 3, due to death from their baseline disease.
Altogether, methadone with ketamine reduced 100% of VAS score in seven out of 18 patients (40%). Complete pain relief was reported by one patient after 2 months, and by four patients after 3 months of the treatment. Of them, only one (#16) was evaluated up to 6 months. In this case, the level of pain remained unchanged up to the last evaluation.
Among the 18 patients, 78% presented some degree of allodynia before starting the methadone and ketamine treatment, which, except for one patient, was accompanied by burning and/or shooting pain. The methadone and ketamine treatment abolished the allodynia in all cases, of which 22% did not re-occur after 15 days of treatment, and after 1 month only 50% of the patients complained of some degree of allodynia. Burning and/or shooting pain, although resolved later than allodynia, were almost completely eliminated in all patients (15 of 17; 88%) at month 2 of the treatment.
The incidence of adverse effects was gradually reduced during the methadone and ketamine treatment (Fig. 1b). Overall, adverse effects were reported by 14 of the 18 patients (78%), mainly at the initial stage of the treatment. Somnolence was the most common adverse effect reported (44%), followed by constipation (22%) and nausea (11%). Only one patient reported dizziness and visual hallucinations and another complained of tachycardia in the first 2 weeks of treatment. Nevertheless, except for two cases of excessive sweating, which showed only a slight reduction throughout the treatment, all reported adverse effects were controlled by dose titration, meal orientation and association with other therapies (senna tea; haloperidol; clonazepan) depending on the individual. After 2 months, there were no more complaints of intolerable adverse effects. Although five patients discontinued the treatment (Fig. 1b), only one case was due to intolerable adverse effects (patient #18).
Although we cannot say for sure, it is likely that the analgesic effect observed was quickly apparent because of the high involvement of NMDA receptors, targeted by both methadone and ketamine, in neuropathic pain. The analgesic effect of NMDA receptor antagonists has been demonstrated in patients with neuropathic pain from different causes.2,5 Our results were not unexpected, as ketamine is very effective in complex regional pain syndrome patients,2,5,6 a common condition among cases related here. Although the combination of methadone and ketamine seems to be redundant at the NMDA receptor level, it is currently known that by associating an opioid agonist with an NMDA receptor antagonist it is possible to improve opioid analgesia and delay the development of opioid tolerance.6 Moreover, methadone often provides better analgesia than other opioids in the setting of neuropathic pain.2 In this way, the dual action of methadone both on NMDA and MOR receptors makes it potentially useful for this purpose. As methadone may prolong QT interval, cardiac monitoring must be carried out in patients, especially with the use of chronic high doses (>100 mg per day) and with heart/liver disease.7
In summary, a 6-month routine of combined methadone and ketamine was efficacious in neuropathic pain unresponsive to other analgesics, independent of its causes and with minimal adverse effects.
These results suggest that methadone and ketamine oral solution is a viable choice for patients with refractory neuropathic pain. Nevertheless, these results must be confirmed through blinded and randomised controlled trials and the measure of other global perceived effects (i.e. impact on the quality of life) must be taken into account.
Assistance with the study: none declared.
Financial support and sponsorship: this work was supported by CNPq and CAPES, Brasília, Brazil.
Conflicts of interest: none declared.
Presentation: none declared.
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