Dextromethorphan, an NMDA-receptor antagonist, enhances the analgesic properties of morphine

Abstract

Preclinical studies demonstrated that dextromethorphan hydrobromide (DM) blocks tolerance to the analgesic effects of morphine sulfate (MS) and enhances its analgesic effect. The analgesic enhancing properties of DM in combination with MS have been confirmed in a clinical development program in over 2200 patients. MorphiDex® (MS:DM) is a 1:1 (mg to mg) ratio of morphine sulfate and dextromethorphan hydrobromide. Double-blind, single-dose analgesic efficacy studies in over 800 patients with post-surgical pain demonstrate significantly superior analgesic activity for MS:DM (60:60 mg) over both individual components MS 60 mg and DM 60 mg. MS:DM had a rapid onset of pain relief and at least an 8-hour duration of analgesic effect. ___TAGSTART___BR___TAGEND___Double-blind, multiple-dose studies in 321 patients with cancer and other chronic pain demonstrate MS:DM provides satisfactory pain control, but at a significantly lower mean MS daily dose. In a crossover study (2 weeks per treatment, 89 patients), 80.3 mg/day of MS in MorphiDex® capsules provided equal pain control to 161.5 mg/day of MS alone (P < 0.001). Also, the combination had a significantly longer interval between doses (P = 0.05) and a significantly longer interval between last dose of day and first dose next day (P = 0.01). In a 4-week parallel group study in 232 patients, MS:DM demonstrated pain control at least equivalent to MS alone at a significantly lower MS daily dose (P = 0.04). The data show significant dose escalation for MS alone, but not for MS:DM, to maintain satisfactory pain relief over 4 weeks (P = 0.025). Also, significantly more patients preferred double-blind MS:DM to run-in MS than preferred double-blind MS to run-in MS (P = 0.026). In these double-blind studies, the adverse event profile for MS:DM was similar to that for MS. ___TAGSTART___BR___TAGEND___A 2-week open-label study in 457 patients with chronic pain was conducted to provide guidelines in converting patients from other opioid medication to MS:DM. Patients took only 79% of their prestudy MS equivalent dose as MS from MS:DM (P < 0.0001) and a significantly higher percentage of patients rated MS:DM very good or excellent compared to their prestudy opioid (P < 0.0001). Most patients took 3 to 4 doses per day and used no other opioid for breakthrough pain. MorphiDex® provides a new potent analgesic with a novel mechanism of action and a favorable side effect profile for the treatment of moderate to severe cancer pain.