CLINICAL STUDY: 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 exopioid 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 methadonemaintenance (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 wellcharacterized 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.

Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations

“…Numerous studies have cited dextromethorphan's ability to reduce intra-and post-operative morphine consumption [198][199][200], while others have not replicated these findings [201,202]. Accordingly, Compton et al [203] sought to determine if dextromethorphan would alleviate OIH in methadone maintenance patients. Following a 5-week trial, this group found no effect of dextromethorphan on OIH, as assessed by the cold pressor test and electrical stimulation pain measures [203] (Table 3).…”

“…Accordingly, Compton et al [203] sought to determine if dextromethorphan would alleviate OIH in methadone maintenance patients. Following a 5-week trial, this group found no effect of dextromethorphan on OIH, as assessed by the cold pressor test and electrical stimulation pain measures [203] (Table 3). To date, no other clinical trials have investigated dextromethorphan in the context of OIH during concurrent opioid use.…”

Adverse effects of chronic opioid therapy for chronic musculoskeletal pain

“…24 in clinical settings, nmDa receptor antagonists such as dextromephorthan have been proposed to reduce tolerance, but results overall have been mixed. 25,26 opioid-induced hyperalgesia studies in animal models have indicated that opioid exposure can induce a paradoxical increase in pain sensiti vity and potentially exacerbate pre-existing pain. 22,23 the phenomenon of opioid-induced hyperalgesia is thought to be predominantly the result of central sensitiza tion of pronociceptive pathways and is associated with reduced nociceptive threshold.…”

Effects of Short-Term Oxycodone Maintenance on Experimental Pain Responses in Physically Dependent Opioid Abusers

“…Using healthy volunteers (instead of persons physically dependent on opioids) for laboratory examinations of opioid analgesia reduces confounds and allows investigators to make inferences more clearly about analgesic effects and pain mechanisms. The few studies reporting pain-related outcomes in persons dependent on opioids (typically methadone or buprenorphine-treated individuals) are important because they have demonstrated significant differences in pain and opioid analgesia between these persons and healthy controls 6, 8, 7 .…”

“…The PPT has been used to assess analgesic efficacy of drugs such as ibuprofen, ketamine, tramadol, and codeine 29 . The CPT has been used frequently for hyperalgesic testing in populations dependent on opioids 8, 7 , and it is sensitive to opioid analgesia with morphine 28 , oxycodone 16 , fentanyl 21 , and tramadol 12, 26 .…”