Lack of effect of chronic dextromethorphan on experimental pain tolerance in methadone-maintained patients

Abstract

Good evidence exists to suggest that individuals on opioid maintenance for the treatment of addiction (i.e. methadone) are less tolerant of experimental pain than are matched controls or ex-opioid addicts, a phenomenon theorized to reflect opioid-induced hyperalgesia (OIH). Agonist activity at the excitatory ionotropic N-methyl-D-aspartate (NMDA) receptor on dorsal horn neurons has been implicated in the development of both OIH and its putative expression at the clinical level-opioid tolerance. The aim of this study was to evaluate the potential utility of the NMDA-receptor antagonist, dextromethorphan (DEX), to reverse or treat OIH in methadone-maintenance (MM) patients. Utilizing a clinical trial design and double-blind conditions, changes in pain threshold and tolerance [cold pressor (CP) and electrical stimulation (ES)] following a 5-week trial of DEX (titrated to 480 mg/day) in comparison with placebo was evaluated in a well-characterized sample of MM patients. The sample (n = 40) was 53% male and ethnically diverse (53% Latino, 28% African American, 10% White, 9% other), with a mean age of 48.0 years (SD = 6.97). Based on t-test analyses, no difference was found between groups on CP pain threshold, CP pain tolerance, ES pain threshold or ES pain tolerance, both pre- and postmedication. Notably, DEX-related changes significantly differed by gender, with women tending to show diminished tolerance for pain with DEX therapy. These results support that chronic high-dose NMDA antagonism does not improve tolerance for pain in MM patients, although a gender effect on DEX response is suggested.

Figures

Figure 1

Change scores for cold-pressor (CP) pain threshold and tolerance at peak and trough methadone plasma levels, dextromethorphan (DEX) versus placebo (a) and for electrical stimulation (ES) pain threshold and tolerance at peak and trough methadone plasma levels, DEX versus placebo (b)

Figure 2

Gender versus treatment on cold-pressor pain tolerance at trough methadone plasma levels (*P = 0.04). DEX = dextromethorphan

Figure 3

Potential mechanisms underlying the development of opioid-induced hyperalgesia (adapted from Angst & Clark 2006). NMDA = N-methyl-D-aspartate