Enhanced Buprenorphine Analgesia with the Addition of Ultra-low-dose Naloxone in Healthy Subjects

Abstract

Animal studies have demonstrated that co-administration of an ultra-low-dose opioid antagonist with an opioid agonist may result in enhanced analgesia. Investigation of this effect in humans has been limited and produced inconsistent findings, with previous reports suggesting that dose ratio may be critical to analgesic potentiation. The aim of the current investigation was to determine whether buprenorphine analgesia could be enhanced with the addition of ultra-low-dose naloxone among healthy volunteers, using a range of dose ratios. Tolerance to cold pressor pain was significantly greater with the combination of buprenorphine and naloxone compared to buprenorphine alone, and this effect was dose ratio dependent. Importantly, this enhanced analgesia occurred without an increase in adverse effects; indeed at some ratios, respiratory depression was attenuated. These findings demonstrate that the addition of ultra-low-dose naloxone can enhance the analgesic effect of buprenorphine in humans without a concurrent increase in side effects.

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

“…At ratios of 100:1, 133:1, and 200:1, changes in nociception were not statistically significant. These findings suggest that the enhanced antinociception previously described with the combination of buprenorphine and naloxone (La Vincente et al, 2008) may also be observed with naltrexone. Consistent with the naloxone study, this effect was dose-ratio dependent.…”

“…A previous study with naloxone demonstrated that the ratio of agonist to antagonist was crucial to potentiation (La Vincente et al, 2008). Such ratios are likely to be different for the various antagonists given their different affinities for the μ‐opioid receptor.…”

“…The dose of buprenorphine was fixed, but a range of doses of naltrexone was evaluated to determine the occurrence and extent of antinociceptive potentiation. Consistent with the previously described study of naloxone (La Vincente et al, 2008), both drugs were administered intravenously to allow for precise control over dosing and to reduce variability due to differences in bioavailability.…”

“…Procedures were as described previously (La Vincente et al, 2008). Upon arrival at the testing centre, participants provided a urine sample that was tested for drugs of abuse (opioids, cannabinoids, benzodiazepines and sympathomimetic amines) by an independent laboratory and, for female subjects, pregnancy.…”

Acupuncture for analgesia in the emergency department: a multicentre, randomised, equivalence and non‐inferiority trial

“…There was no analgesic benefit of adding naloxone to the PCA morphine solution (Sartain & Barry, 1999 Level II; Level II; Level II); in 'ultra low doses' but not in the higher dose studies, the incidence of nausea and pruritus was decreased Level II). In the experimental pain setting in volunteers, the coadministration of ultra-low doses of naloxone to patients given buprenorphine significantly increased tolerance to cold pressor pain (La Vincente et al, 2008 Level II). There is no information about the effect of naloxone in patients taking opioids in the longer term.…”