Cross-tolerance and μ agonist efficacy in pigeons treated with LAAM or buprenorphine

The mechanism responsible for decreased opioid use during opioid substitution therapy is not fully understood. To examine whether l-α-acetylmethadol (LAAM) or buprenorphine attenuate behavioral effects of opioids through cross-tolerance, discriminative stimulus effects of high and low efficacy μ agonists were examined following 3- or 7-day treatment with LAAM or buprenorphine in pigeons discriminating between saline and heroin or between saline and buprenorphine, respectively. Heroin, buprenorphine and nalbuphine occasioned high levels of drug-appropriate responding in both groups; κ opioids and non-opioids occasioned predominantly saline-appropriate responding. Administration of LAAM (3.2 mg/kg) or buprenorphine (3.2 mg/kg) occasioned predominantly heroin- or buprenorphine-appropriate responding, respectively. After discontinuation of LAAM treatment, the potency in occasioning heroin-key responding was markedly decreased for nalbuphine, slightly decreased for buprenorphine, and unchanged for heroin. Following discontinuation of buprenorphine treatment, the potency in occasioning buprenorphine-key responding was decreased for nalbuphine and unchanged for buprenorphine and heroin. Thus, greater cross-tolerance developed from LAAM and buprenorphine to low efficacy μ agonists as compared to a higher efficacy agonist. Failure of LAAM and buprenorphine treatment to modify the effects of heroin, under conditions that attenuate the effects of lower efficacy μ opioids, provides a possible rationale for why heroin abuse persists in some patients receiving large doses of agonists in substitution therapy.