A phase I study of d-methadone in patients with chronic pain

Abstract

D-Methadone is the d optical isomer of racemic mixture (DL-methadone) used clinically to treat pain and addiction in the United States. D-Methadone is practically devoid of opioid activity but maintains N-methyl-D-aspartate (NMDA) receptor antagonism. Evidence from extensive preclinical studies suggests that NMDA receptor antagonists attenuate neuronal plasticity, reverse opioid analgesic tolerance, and alleviate chronic pain states. The authors conducted a phase I open label study of D-methadone administered for the first time to patients with chronic pain to determine the safety and tolerability of D-methadone. In addition to their long-term regimen of opioids, the patients received 40 mg of D-methadone twice daily for 12 days. Analgesia and toxicity were recorded by the patients in a daily diary and assessed in clinic on days 1, 8, and 12. Eight patients of the 10 enrolled completed the study. Pain scores on Edmonton Symptom Assessment System (ESAS) did not change between days 1 and 12, but five of eight patients (62.5 percent) characterized D-methadone as moderately or very effective in relieving pain on the Global Assessment for pain. Five of the eight patients (62.5 percent) who completed the study requested to start treatment with commercially available methadone (DL-racemic methadone) after completing the study. D-Methadone at the dose of 40 mg PO Q 12 hours was well tolerated. Perspective: This is the first clinical study of D-methadone in patients suffering from chronic pain. Additional phase I and phase II studies are needed to confirm its safety and analgesic effects. If D-methadone is well tolerated, it is likely to become a useful adjuvant to the treatment of a wide spectrum of pain syndromes.

REL-1017 (esmethadone; d-methadone) does not cause reinforcing effect, physical dependence and withdrawal signs in Sprague Dawley rats

“…In summary, the results of these two studies confirm and extend previous data indicating a lack of reinforcing effect, physical dependence, and withdrawal of REL-1017 in animals 8 – 11 , in humans with addictive disorders 12 – 14 , in healthy human volunteers 4 , and in patients 3 , 66 . In these animal models designed to assess reinforcing and withdrawal potential of molecules with therapeutic potential, REL-1017 engendered neither a response pattern consistent with the known pharmacology and abuse of mu opiate agonists, like oxycodone, nor morphine-like or ketamine-like withdrawal after abrupt discontinuation.…”

The N-methyl-D-aspartate receptor antagonist d-methadone acutely improves depressive-like behavior in the forced swim test performance of rats.

“…Studies to evaluate the d-methadone stereoisomer in patients are very limited and suggest that the drug is well tolerated and may potentially exert antianxiety and antidepressant actions (Moryl et al, 2016). The predominant use of d-methadone is in the racemic form of methadone, which is a 50/50 mix of l-methadone and d-methadone.…”