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Ketamine and dextromethorphan are widely abused psychoactive substances. Inhibition of N-methyl-d-aspartate receptors (NMDARs) results in neurobehavioural effects including hallucinations, "out of body" sensations and dissociative effects. However, little is known about a possible extended addictive class effect linked to pharmacologically-related amino-adamantane derivatives (e.g., amantadine and memantine). Using a quasi-Bayesian analytic method, we investigated the potential association between the use of approved NMDAR antagonists (i.e., dextromethorphan, ketamine, amantadine and memantine) and the reporting of drug abuse and dependence in the WHO pharmacovigilance database (VigiBase®), which includes >21 million individual case safety reports collected from >130 countries. This disproportionality analysis identified a significant association for all investigated drugs: dextromethorphan (IC = 3.03 [2.97-3.09]), ketamine (IC = 1.70 [1.57-1.83]), amantadine (IC = 0.21 [0.06-0.35]) and memantine (IC = 0.27 [0.13-0.40]), suggesting a class effect for drug abuse and dependence. This first signal requires further investigations, but health professionals need to be alert to the potential of abuse of NMDAR antagonists, especially in the current "opioid epidemic" context, due to their growing interest as non-opioid antinociceptive drugs., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Dextromethorphan (DM) is a low-affinity, non-competitive NMDA receptor antagonist that has shown promise in preclinical and preliminary clinical studies for the reduction of opioid withdrawal symptoms, but when used at higher doses, it is associated with deleterious side effects attributed to its metabolite, dextrorphan. A clinical trial was therefore conducted to test the withdrawal-suppressant effect of a combination of dextromethorphan with quinidine (DM/Q). Quinidine inhibits the metabolism of dextromethorphan, reducing dextrorphan levels. Opioid-dependent patients were admitted to an inpatient unit, stabilized for three days on morphine (25 mg, sc, every six hours), and randomly assigned on day 2 to DM/Q (30 mg/30 mg, twice a day) (n = 22) or matching placebo (n = 9) prior to the discontinuation of morphine on day 4. Withdrawal symptoms, measured with the Modified Himmelsbach Opioid Withdrawal Scale (MHOWS), increased significantly on days 4 and 5 (Z = 3.70, p = .0002), and by day 6, 90% of the sample (28/31) had dropped out of the study. There were no differences between treatment groups on either outcome measure. The combination of dextromethorphan and quinidine appears ineffective as a primary treatment for opioid withdrawal. Future studies should examine dextromethorphan as an adjunct to other anti-withdrawal medications and focus more on the relationship between dextrorphan levels and withdrawal suppression.

Background: Dextromethorphan, a clinically available N-methyl-D-aspartic acid (NMDA) receptor antagonist, has an analgesic effect in patients with diabetic neuropathy. The aim of this study was to evaluate the analgesic and adverse effects of a single high dose of dextromethorphan on spontaneous pain in patients suffering long-term neuropathic pain of traumatic origin., Methods: Fifteen patients with post-traumatic neuropathic pain participated in this placebo-controlled, double-blind, randomized crossover study. On two separate occasions, the participants received 270 mg of dextromethorphan hydrobromide or placebo. Pain intensity, adverse effects and serum concentrations of dextromethorphan and metabolites were registered., Results: Dextromethorphan had a statistically significant analgesic effect compared with placebo, but the effect varied markedly among the patients. Light-headedness was the most important adverse effect reported. Extensive metabolizers of dextromethorphan had an apparently better analgesic effect than poor metabolizers., Conclusion: This report indicates that a single high dose of dextromethorphan has an analgesic effect in patients with neuropathic pain of traumatic origin. The main metabolite dextrorphan seems to be important for the analgesic effect. At the relatively high dose studied, the clinical usefulness of dextromethorphan is limited to that portion of the patient population experiencing analgesia without an unacceptable level of adverse effects.

Background: N-methyl-D-aspartate-receptor antagonists may be useful in pain management. The aim of this study was to evaluate dextromethorphan (DEX), a commonly used oral antitussive drug with NMDA-receptor antagonistic properties, in respect of its analgesic properties as single drug and co-administered with morphine (MO) on experimental ischemic pain. In addition, the analgesic effects of another clinically available NMDA-receptor antagonist, ketamine (KET) as well as of morphine (MO) were tested as active controls., Methods: Nineteen healthy volunteers were included in the study. Experimental ischemic pain was induced using the forearm tourniquet test. Placebo (PLAC), oral DEX (30 and 90 mg, respectively), KET (9 microg kg(-1) min(-1) i.v.), MO (0.1 mg kg(-1), i.v.) and the DEX+MO and KET+MO combinations were evaluated during eight separate experiments. Development of ischemic pain was rated by visual analog scale (VAS) every minute over 30 min and ratings were summed as sum of pain scores (SPS)., Results: DEX by itself did not influence SPS compared to PLAC. The DEX+MO co-administration did not enhance MO-induced analgesia. MO and KET reduced pain ratings by 27% and 39%, respectively. The KET+MO combination showed no enhancement of the analgesic effect in comparison with the respective drugs in monotherapy., Conclusion: DEX in clinical doses has no effect on the present acute ischemic pain model and does not influence MO-induced analgesia. Further studies on other pain modalities are needed in order to evaluate the potential use of DEX in pain treatment.

Background: Experimental studies have demonstrated that peripheral tissue injury may lead to hyperexcitability of nociceptive neurones in the dorsal horn, in part mediated by N-methyl-D-aspartate (NMDA)-receptor mechanisms. Sensitisation of dorsal horn neurones may be an important contributor to postoperative pain. The aim of the present study was to investigate the effect of the NMDA-receptor antagonist dextromethorphan on pain after minor gynaecological surgery, and to evaluate a potential additive effect with ibuprofen., Methods: In a double-blind, placebo-controlled study, 100 patients scheduled for elective termination of pregnancy were randomised to receive placebo, oral ibuprofen 400 mg, oral dextromethorphan 120 mg, or a combination of ibuprofen 400 mg and dextromethorphan 120 mg, 1 h before surgery. Pain and analgesic requirements were assessed 0.5, 1 and 2 h after operation., Results: We observed no effect of dextromethorphan on visual analogue scale (VAS) pain scores or analgesic consumption, and no additive or synergistic analgesic effects between ibuprofen and dextromethorphan. Ibuprofen reduced pain scores compared with placebo, and analgesic consumption compared with both placebo and dextromethorphan. The combination of ibuprofen and dextromethorphan increased preoperative nausea compared with both placebo and ibuprofen, whereas no statistically significant side effects were observed with dextromethorphan alone., Conclusion: No analgesic effects of oral dextromethorphan 120 mg on pain after surgical termination of labour, and no additive analgesic effects when combined with ibuprofen 400 mg, were observed. Ibuprofen reduced both VAS pain scores and analgesic consumption compared with placebo.

Twenty-four inpatients affected by chronic cough completed a single-dose double-blind cross-over study of placebo, glaucine 30 mg and dextromethorphan 30 mg. The study was carried out using a balanced incomplete block design, each patient receiving two of the three experimental treatments. Objective evaluation of cough was ensured by means of a writing cough recorder. Coughs after dextromethorphan and glaucine were fewer than coughs after placebo: however only glaucine was significantly different from placebo in reducing coughs. Treatments were well tolerated: clinical results included a reduction in pulse rate after both dextromethorphan and glaucine , and a large number of patients reporting side effects after dextromethorphan administration.