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Controlled Drug Administration Studies of High-Dose Buprenorphine in Humans

Discusses the toxicity (alone or in combinations) and abuse potential of buprenorphine

  1. aemetha
    Study Author(s):
    M. A. Huestis
    Journal Name:
    in Forensic Science and Medicine: Buprenorphine Therapy of Opiate Addiction
    Publication Date:
    Buprenorphine was developed in the early 1970s by Reckitt and Colman Products (Hull, UK) as part of a wide-ranging search for an effective analgesic with lower abuse potential and reduced toxicity compared with morphine (1). Many of buprenorphine’s chemical and pharmacological properties, including ready diffusion of the highly lipophilic drug across the blood-brain barrier and its high binding avidity for opiate receptors, led to the selection of this thebaine derivative as the best analgesic compound for further drug development. Despite its high-affinity binding and high potency (25–40 times more potent than morphine), buprenorphine has a lower efficacy for pain relief and is classified as a partial agonist at µ opiate receptors. Buprenorphine dissociates slowly from receptors, resulting in a long duration of action and, potentially, a reduced potential for abuse. These properties led researchers at the United States Public Health Service’s Addiction Research Center to investigate buprenorphine further as a pharmacotherapy for opioid addiction (2). Several important factors need to be considered when reviewing the buprenorphine literature. Over the last 25 yr, investigators have studied the agonist and antagonist characteristics of buprenorphine alone and its interactions when coadministered with other opioids. Buprenorphine may substitute for another opioid, suppress response to an opioid, or precipitate withdrawal from an opioid, depending on the dose of buprenorphine administered and conditions at the time of administration. Careful consideration must be given 14 Huestis to participant drug use history, frequency, magnitude and length of opioid use, buprenorphine dosing regimen, and the nature of studied effects, for all of these parameters can affect the interpretation of research findings. In addition, evaluation of buprenorphine concentration data requires an understanding of the sensitivity and specificity of the analytical method employed. Much of the early buprenorphine literature utilized a highly sensitive but nonspecific radioimmunoassay (RIA) that crossreacted extensively with buprenorphine metabolites. At the time, chromatographic methods could not meet the sensitivity requirements mandated by the low concentrations of buprenorphine and metabolites found in plasma. This chapter reviews controlled drug administration studies of buprenorphine in humans and focuses primarily on its use as a pharmacotherapeutic agent for opioid dependence, but important findings from analgesic research are included when appropriate. It examines buprenorphine’s bioavailability following alternative routes of drug administration, dose effect profiles, abuse liability, and toxicity. The reader is referred to additional discussions on buprenorphine’s efficacy as a replacement maintenance medication in opioid addiction treatment and buprenorphine poisonings in medical examiner cases included in later chapters of this book.