NIH RELAIS Document Delivery NIH-10053718 NIH -- W1 JO905CI PAOLO DEPETRILLO NIAAA, 10 CENTER DR. MSC 1256/NIH BLDG. 10 ROOM 3C103 BETHESDA, MD 20892-1256 ATIN: SUBMITTED: 2001-10-26 15:55:22 PHONE: 301-496-9420 PRINTED: 2001-10-30 09:43:11 FAX 301-402-0445 REQUEST NO: NIH-10053718 E-MAIL: SENT VIA: LoaN Doc 4807883 NIH Fiche to Paper Journal TITLE JOURNAL OF SUBSTANCE ABUSE PUBLISHER/PLACE: Ablex Norwood Nj VOLUME/ISSUE/PAGES: 1989;1(4):453-60 453-60 DATE: 1989 AUTHOR OF ARTICLE Swift RM; Dudley M; DePetrillo P; Camara P; Griffiths Ws TITLE OF ARTICLE: Altered methadone pharmacokinetics in pregnancy: i ISSN: 0899-3289 OTHER NOS/LETTERS: Library does NOT report holding title 9001404 2485290 SOURCE: PubMed CALL NUMBER: wi so90scs REQUESTER INFO: W986 DELIVERY: E-mail: pbdp@helix.nih.gov REPLY: Mail: NOTICE: THIS MATERIAL MAY BE PROTECTED BY COPYRIGHT LaW (TITLE 17. U.S. CODE) ‘Mational-Institutes-of -Health,-Bethesda ,-MD-RN Ke \ Journal of Substance Abuse, 1, 453-460 (1989) aie COMMUNICATIONS} Altered Methadone Pharmacokinetics | in Pregnancy: | Implications For Dosing Robert M. Swift," Michael Dudley,* Paolo DePetrillo,+ Paul Camara,* William Griffiths,» | {Bepume o tay ad amon ni Meine ad »Pathology,(Brown University Program in iigdand “Division ‘of Clinical Pharmacology, Roger Williams General Hospital [Providence, Rhode Island \ay Lower plasma methadone levels have been reported in pregnant women re- ceiving methadone maintenance for heroin addiction. Methacione pharmacok- inetics was examined in a 24-year-old woman 8 months pregnant with twins, Who experienced severe withdrawal symptoms beginning 10-12 hours after her daily 30 mg methadone dose. Methadone plasma concentration-time data were fit to a one-compartment pharmacokinetic model by extended least-squares i regression, Estimated halflife for methadone was 8.1 hours, which is much shorter than the usual methadone half-life (greater than 24 hours). Plasma methadone concentrations were estimated for the cases of a) in- creasing the 30 mg methadone dose by 3056 and administering it once daily and b) continuing the 30 mg methadone dose but administering it at 12-hour intervals ‘Although the model is derived from a single subject, the simulations per- formed clearly suggest a need for altered methadone dosing in pregnancy. More sustained plasma methadone levels are achieved with twice-daily dosing of methadone than are achieved by administering an increased methadone dose ‘once daily. Twice-daily dosing would be expected to produce fewer withdrawal symptoms and, ultimate, improved compliance with treatment. } INTRODUCTION Opiate abuse among pregnant woman is a problem of considerable concern. Pregnant women who are heroin addicts are at risk for a variety of obstectrical complications including anemia, toxemia, and shortened labor, hypertension, cellulitis, and septicemia (Keith, Donald, Rosner, Mitchell, & Bianchi, 1986; This work was supported in part by a grant from the Pharmaceutical Manufacturer's As: sociation Foundation, Correspondence and requests for reprints should be sent to Robert M. Swift, Department ‘of Psychiatry, Roger Willame General Hospital, 825 Chalkstone Avenue, Providence, RI 02908. 45348 RM. Swift, M. Dudley, P. DePetrllo, P. Camara, and W. Grifiths Stone, Salerno, Green, & Zelson, 1971). Adverse effects on the neonate include prenatal malnutrition, intrauterine growth retardation, fetal distress, tind increased mortality. Infants born to opiate dependent mothers experience a neonatal withdrawal syndrome which begins within several days following birth and which may be protracted (Zuspan, Gumple, Mejia-zelaya, Madden, & Davis, 1975). Pregnant addicts and their offspring are at increased risk for contracting infectious diseases such as hepatitis B, tuberculosis, sexually transmitted diseases, and the acquired immunodeficiency syndrome (AIDS). ‘in the case of AIDS, studies indicate that heterosexual intravenous (IV) drug users constitute the second largest group who have acquired human immunodeficiency virus (HIV) infection and AIDS in the U.S. (Centers For Disease Control (CDC), 1986). Over half of the cases of AIDS in children occurred where a parent was an IV drug abuser (Oleske, Minnefor, & Cooper, 1983; Rubinstein, Sidelick, Gupta, & Bernstein, 1983). The increased risk results both through infection from contaminated paraphenalia for IV drug lise and via prostitution activities (Keith, Donald, & Rosner, 1986; Marcus, Hans, Patterson, & Morris, 1984) "An effective means of reducing IV drug use is methadone maintenance. Methadone is acceptable to many IV opioid addicts and is associated with high retention in treatment, reduction in IV drug use, decreased criminality, and. improved psychological status (Craddock, Hubbard, & Bray, 1982 MeLellan, Luborsky, Woody, & O'Brien, 1982; Sells, 1979; Senay, 1985). Methadone maintenance has become a major modality of long-term treatment of opioid abuse and dependence, with over 85,000 individuals currently ‘maintained on methadone in the United States. Several studies report efficacy of methadone maintenance in the treatment of the pregnant addict, as well (Marcus, Hans, Patterson, & Morris, 1984, NIDA, 1979; Ramer & Lodge, 1975; Schnoll, 1986; Stimmel & Adamson, 1976), Pregnant women involved in methadone maintenance programs have significantly improved prenatal care, improved fetal outcomes, and reduced mortality when compared to pregnant women using street drugs (Blinick, Jerez, & Wallach, 1973; Finnegan, 1979; Rementeria & Lotongkhum, 1978) In spite of the reported efficacy of methadone maintenance, itis commonly observed that pregnant opiate addicts who receive methadone maintenance for opioid dependence often experience difficulties with treatment compliance. ‘As a group, these clients have a higher frequency of continued illicit drug ise, ay monitored by urine surveillance (Edelin, Gurganious, Golar, Oellerich, KyciAbaogye, & Hamid, 1988; Mackie-Ramos & Rice, 1988), The reasons fox treatment noncompliance are multifactorial, and include psychological and social factors. Many of these women are unmarried, unemployed, and have chaotic social and family relationships. There are also physiological changes which occur during pregnancy, which may increase the vulnerability for return to drug use. in pregnant women, the pharmacokinetics of methadone appears to be altered, although the reasons for the alterations are not established. Pond, Kreek, Tong, Raghunath, and Benowitz (1985) reported a pregnancy-related