Efficacy of Full µ-Opioid Receptor Agonists is not Impaired by Concomitant Buprenorphine or Mixed Opioid Agonists/Antagonists – Preclinical and Clinical Evidence

Abstract

Buprenorphine and the mixed agonists/antagonists nalbuphine and pentazocine, formerly classified as µ-opioid (MOP) receptor antagonists, have more recently been shown to be partial to full agonists of the human MOP receptor. These receptors do not necessarily have to be maximally activated for a full physiological response. Partial agonists can also sufficiently stimulate signaling processes leading to a full analgesic response, as shown by the effectiveness of buprenorphine, nalbuphine and pentazocine in animal pain models and in clinical settings where these drugs induce analgesia with full efficacy without a ceiling effect. Submaximal doses of MOP receptor analgesics combined with submaximal doses of buprenorphine, pentazocine, or nalbuphine result in additive to over-additive antinociceptive effects in animal experiments. Only when doses are given that exceed the therapeutic dose range may the antinociceptive effect be reduced to the effect of either opioid alone. The analgesic effects of pentazocine and nalbuphine combined with morphine are reported to be additive or over-additive in various clinical pain conditions. Buprenorphine, which clinically behaves as a full MOP receptor agonist for pain relief, can be combined with full opioid agonists without precipitating withdrawal. Thus, the overall evidence on the analgesic effects of buprenorphine, pentazocine or nalbuphine combined with opioid analgesics under various clinical pain conditions contradicts the consensus that these compounds diminish MOP receptor analgesia when co-administered with a full MOP receptor agonist.

Efficacy and Tolerability of Co-Administering Full µ-Opioid Receptor Agonists with Buprenorphine and Mixed Opioid Agonists

“…The authors describe overall evidence on analgesic effects of buprenorphine, pentazocine or nalbuphine in co-administration with opioid analgesics, under various clinical pain conditions. They contradict the consensus that these compounds diminish μ-opioid (MOP) receptor analgesia when co-administered with a full MOP receptor agonist and may potentially provoke opioid withdrawal [1].…”

“…We read with great interest the paper by van Niel, J. Schneider and Tzschentke [1] titled "Efficacy of Full μ-Opioid Receptor Agonists is not Impaired by Concomitant Buprenorphine or Mixed Opioid Agonists/Antagonists -Preclinical and Clinical Evidence". The authors describe overall evidence on analgesic effects of buprenorphine, pentazocine or nalbuphine in co-administration with opioid analgesics, under various clinical pain conditions.…”

Preoperative Management of Opioid and Nonopioid Analgesics: Society for Perioperative Assessment and Quality Improvement (SPAQI) Consensus Statement

“…[50][51][52] There has been no evidence to suggest that butorphanol, nalbuphine, or pentazocine significantly interfere with full mu opioid receptor agonists, but rather, they act synergistically when used at clinically relevant doses. 53,54 It is reasonable to continue these agents preoperatively, as long as one remembers this synergistic response.…”

Prevalence of high-risk drug-drug interactions in paediatric inpatients: a retrospective, single-centre cohort analysis

“…Also, randomised studies have shown that comedication with nalbuphine can reduce the incidence of post-operative, morphine-induced pruritus in opioid-naive patients [42,43], including children [44]. Neither reduced efficacy of opioid agonists nor withdrawal symptoms after combination with nalbuphine could be observed in several studies [41,42,[45][46][47]. An additive analgesic effect was even noted in a randomised cohort trial when the drugs were given simultaneously, probably explained by the agonistic and hence additional analgesic effect of nalbuphine on the kappa receptor [45].…”