Potentiation of buprenorphine antinociception with ultra‐low dose naltrexone in healthy subjects

Abstract

Previous reports have demonstrated greater antinociception following administration of a buprenorphine/naloxone combination compared to buprenorphine alone among healthy volunteers. The aim of the current investigation was to determine whether buprenorphine antinociception could be enhanced with the addition of ultra-low dose naltrexone, using a range of dose ratios. A repeated-measures, double-blind, cross-over trial was undertaken with 10 healthy participants. The effects of each buprenorphine:naltrexone ratio (100:1, 133:1, 166:1, and 200:1) on cold pressor tolerance time and respiration were compared to the effects of buprenorphine only. The 166:1 ratio was associated with significantly greater tolerance time to cold pressor pain than buprenorphine alone. Minimal respiratory depression and few adverse events were observed in all conditions. These findings suggest that, as previously described with naloxone, the addition of ultra-low dose naltrexone can enhance the antinociceptive effect of buprenorphine in humans. This potentiation is dose-ratio dependent and occurs without a concomitant increase in adverse effects.

A randomized clinical trial of the effects of ultra‐low‐dose naloxone infusion on postoperative opioid requirements and recovery

“…This effect has been observed both in animal experiments and in clinical trials . Recently, drug combinations of the μ receptor antagonist naltrexone or naloxone with oxycodone or buprenorphine have been used to enhance the antinociceptive effect of the opioids and block the development of physical tolerance …”

Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization

“…Thereafter, postoperative pain appeared significantly later in ULDN groups. An interesting double-blind study assessed analgesic properties of buprenorphine combined with ULDN in various relative ratios (1:100, 1:133, 1:166, 1:200, respectively), by testing ten healthy subjects undergoing cold-pressor test [93]. Buprenorphine was given orally at a dose 0.5 μg/kg.…”

The present and future of opioid analgesics in small animal practice

“…The use of ultra-low-dose naloxone or naltrexone (0.001-0.1 lg/kg) has shown to preserve or even enhance the antinociceptive effects of pure l-opioid receptor agonists in rats and mice (Shen & Crain, 1997;Chou et al, 2013). The mechanism of action is thought to be associated with inhibition of a 'switch' that occurs from the inhibitory Gi/Go coupled to excitatory Gs-coupled at the l-opioid receptor after opioid drug administration (Hay et al, 2011). Other mechanisms may also include inhibition of microglia activation and Toll-like receptor 4 (Watkins et al, 2009).…”