Methadone maintenance is an effective treatment for chronic opioid abusers and the only pharmacotherapy currently approved to treat pregnant clients. State and local policy has set limits on the highest dose of methadone that can be administered, 30-40 mg/day for nonpregnant clients and even lower limits of 20-30 mg or less for pregnant clients. However, based on NIDA funded research it is well known that methadone doses in the range of 60-100 mg/day are optimal as an effective regimen to retain clients in treatment programs and prevent relapse to illicit drug use including IV heroin. One result of these outmoded low-dose treatment policies is that HIV infection and AIDS are spreading at an alarming rate among clients in methadone maintenance programs; 75% of HIV-infected babies are born to IV drug abusers or their sexual partners. Clearly, a new evaluation of methadone maintenance is needed to assess the neurobehavioral risk in the offspring in light of its proven efficacy for the prevention of exposure to HIV infection. The proposed animal studies will deliver either 10, 15, or 20 mg/kg/day of methadone to pregnant rats on the last two weeks of gestation by the use of the implanted osmotic minipump, a technique shown to be the most pharmacologically relevant model of methadone maintenance yet developed. One control group will be pair-fed and watered to the high dose methadone dams and implanted with minipumps that deliver saline. A second control group will be nontreated. Surrogate fostered offspring will be evaluated from birth to adulthood to determine both short- and long-term neurobehavioral effects. Endpoints will include tailflick analgesia in response to methadone challenge, locomotor ontogeny, measurement of the rest-activity cycle, acoustic startle, and seizure thresholds in response to pentylenetetrazol. A major goal of these studies is to provide sound preclinical scientific data on the developmental effects of methadone that could contribute to a safe but efficacious dosing regimen for pregnant clients so as to reduce risk of relapse to IV drug use and exposure to HIV infection.
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