This article was downloaded by: [Virginia Commonwealth UniversityLibraries]On: 27 September 2013, At: 05:16Publisher: RoutledgeInforma Ltd Registered in England and Wales Registered Number: 1072954Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,UK

Journal of Addictive DiseasesPublication details, including instructions forauthors and subscription information:http://www.tandfonline.com/loi/wjad20

Alterations in MethadoneMetabolism During LatePregnancyMargaret A. E. Jarvis MD a , Susanna Wu-Pong PhD b ,Janet S. Kniseley PhD a & Sidney H. Schnoll MD, PhDa

a Division of Substance Abuse Medicine, Departmentsof Psychiatry and Internal Medicineb Department of Pharmaceutics, Medical Collegeof Virginia Campus of Virginia CommonwealthUniversity, Richmond, VA, 23298, USAPublished online: 12 Oct 2008.

To cite this article: Margaret A. E. Jarvis MD , Susanna Wu-Pong PhD , Janet S.Kniseley PhD & Sidney H. Schnoll MD, PhD (1999) Alterations in Methadone MetabolismDuring Late Pregnancy, Journal of Addictive Diseases, 18:4, 51-61, DOI: 10.1300/J069v18n04_05

To link to this article: http://dx.doi.org/10.1300/J069v18n04_05

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Alterations in Methadone MetabolismDuring Late Pregnancy

Margaret A. E. Jarvis, MDSusanna Wu-Pong, PhDJanet S. Kniseley, PhD

Sidney H. Schnoll, MD, PhD

ABSTRACT. Traditionally, methadone maintenance therapy has beena once-daily dosing schedule. The current study evaluates the effective-ness of this regimen during pregnancy. A total of 23 pregnant and 16non-pregnant opioid-dependent patients were studied in two phases toevaluate pregnancy-dependent changes in methadone pharmacokinet-ics. In the first phase, pregnant patients had a statistically significanthigher elimination rate constant (k) and lower half-life compared tonon-pregnant controls. In the second phase, the apparent clearance(Cl/F) was significantly greater during pregnancy, with preliminarydata suggesting that this observation results from a decrease in thefraction of dose absorbed (F). The implications of these findings ondosing regimens during pregnancy is discussed. [Article copies availablefor a fee from The Haworth Document Delivery Service: 1-800-342-9678. E-mailaddress: getinfo@haworthpressinc.com <Website: http://www.haworthpressinc.com>]

KEYWORDS. Heroin, methadone, pregnancy, metabolism, pharmaco-kinetics, dosing

Margaret A. E. Jarvis, Janet S. Kniseley, and Sidney H. Schnoll are affiliated withthe Division of Substance Abuse Medicine, Departments of Psychiatry and InternalMedicine, and Susanna Wu-Pong is affiliated with the Department of Pharmaceutics,Medical College of Virginia Campus of Virginia Commonwealth University, Rich-mond, VA 23298.

Address correspondence to: Margaret A. E. Jarvis, Fairfield Psychiatric Clinic,300 South Maple, Fairfield, IA 52556.

Special thanks to Ms. Diane Green for her assistance with subject recruitment,data collection, and data entry.

This research was funded by NIDA grants #DA00189 and #DA06094.

Journal of Addictive Diseases, Vol. 18(4) 1999E 1999 by The Haworth Press, Inc. All rights reserved. 51

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INTRODUCTION

In the United States, methadone maintanence has become the stan-dard of care for pregnant opioid-dependent women. While some meth-adone clinics carefully individualize dosing to treat addiction (andmay even use methadone plasma concentrations to do so) many clinicsonly provide the usual standard of a once-daily and/or a strictly lowdose regimen which may not provide the best therapy, especiallyduring pregnancy.

The pharmacokinetic-pharmacodynamic relationship of methadonefor analgesia or sedation has been well studied,1-7 but is poorly under-stood in opioid-addiction, particularly during pregnancy. Pond et al.8report that methadone plasma concentrations are lower during thesecond and third trimester of pregnancy than after delivery. For agiven dose, increased excretion of methadone metabolites in urine andsymptoms of withdrawal were observed in pregnant patients. Othersreport that twice daily dosing, particularly later in pregnancy, in-creases compliance with programmatic requirements and decreasescocaine use.9,10

The relationship between pregnancy, methadone metabolism anddosing was examined in the present study to determine whether once-daily dosing is adequate in pregnant opioid-dependent patients.Twenty-three pregnant and sixteen non-pregnant female patients weredosed with methadone, and plasma concentrations sampled for phar-macokinetic analysis. The study was designed to evaluate metha-done’s apparent clearance, elimination, and absorption in pregnant andnon-pregnant patients, and to determine if opioid-dependent pregnantpatients may benefit from modifications in traditional dosing regimensto improve compliance and thus, safety to the fetus.

METHODS

Heroin- and methadone-dependent female patients were recruitedto participate in a study of the effects of methadone withdrawal andpharmacokinetics during pregnancy. The participants were housed inthe Clinical Research Center at the Medical College of Virginia Cam-pus of Virginia Commonwealth University for the duration of thestudy. All participants gave informed consent for the study and HIV

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testing (approved by the Committee on the Conduct on Human Re-search) prior to enrollment. Upon admission, all patients received ahistory and physical exam, and routine lab tests were taken (includingan HIV test). In general, prior prescribed medications were continuedduring the study, and additional medications prescribed if medicallyindicated. Patients requiring medications which are known to altermetabolic enzyme activity were not included in the study. Non-en-zyme altering drugs prescribed most commonly included multivita-mins, acetaminophen, ibuprofen, trazadone, clonidine and antacids.Although cigarette smoking is known to alter enzyme activity, thedistribution of smokers in the study was fairly uniform betweengroups: 85% of the patients enrolled in the study were smokers, withsmokers accounting for 80-91% of pregnant and non-pregnant groups(Table 1).

A major consideration which significantly influenced study designwas fetal safety. Since either abrupt cessation of methadone in metha-done-maintained patients or delay in initiation of methadone therapyin heroin-dependent patients could jeopardize the safety of the fetusby inducing either rapid withdrawal or poor compliance, initiating astudy in drug-free patients was not feasible with this group of patients.Therefore, both pregnant and non-pregnant patients were uniformlydosed with methadone prior to the study. Heroin-dependent womenwere first stabilized on methadone before beginning the pharmacoki-

TABLE 1. Patient Demographics, by Pregnancy (PG)

All Patients Phase I (taper) Phase IImean SD mean SD mean SD

PG Non-PG PG Non-PG PG Non-PGn = 23 n = 16 n = 11 n = 5 n = 12 n = 11

Age (years) 29 4 38 7 28 5 40 6 29 4 36 7

Weight (kg) 68 13 67 11 66 10 70 20 71 16 65 4

Gestational Age 28 5 30 4 27 6(weeks)

Smoker (%) 87 81 83 82 91 80

Race* (% white) 35 40 36 40 33 40

*All non-white patients were African-American.

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netic study. The dose was established by monitoring withdrawalsymptoms during the first 24 hours following initiation of therapy.11

The patients continued to take the same dose for the next 2 to 5 daysuntil beginning the study. Patients who entered the study alreadymaintained on methadone continued taking their usual dose. The doseand date of the patients’ most recent methadone dose were confirmedby the methadone clinic.

The study was conducted in two phases, each of which was de-signed to measure pharmacokinetic parameters either during steadystate or non-steady state conditions. In the first phase (Phase I), thepatients were dosed with methadone, then blood collected two hoursafter the dose and immediately preceding the next dose on the follow-ing day. Over the subsequent 4 to 12 days, the patients’ methadonedoses were progressively decreased, and ‘‘peaks’’ and troughs mea-sured. In the second phase (Phase II), the patients had blood sampledimmediately prior to dosing (−3 minutes) and 0.25, l, 1.5, 2, 2.5, 4, 6,8, 12, 16, 20, and 24 hours post-dose. All blood samples were centri-fuged and plasma separated and stored at −4_C. Samples were ana-lyzed using published methods12,13 by mixing with 0.1 M phosphatebuffer (pH 6.0) and 100 μg mepivicaine as an internal standard. Sam-ples were then applied to a solid phase extraction column (SPE col-umn Ansys, SPEC.3mL.MP3, Irvine, CA), treated with 0.1 M aceticacid and methanol, and eluted with 0.5 ml methylene chloride:isopro-panol (80:200). Samples were dried and then reconstituted with 50 μlof ethylacetate prior to injection into the GC/MS.

Pharmacokinetic calculations were performed using PKAnalyst(MicroMath, Salt Lake City, UT) using standard non-compartmentalanalysis (for review, see14) which was used to reduce the number ofassumptions regarding methadone disposition. Methadone kineticswere previously described to follow first order input and elimina-tion,1-8 so the present model also assumed first order input and elimi-nation. One-way analysis of variance was used to calculate P values(JMP 3.1, SAS Institute, Cary, NC).

RESULTS

The present study represents a unique opportunity to examine theeffect of pregnancy on methadone pharmacokinetics. However, safetyconcerns also significantly influenced the design of this study. As a

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result, all patients could not be at steady-state or completely free ofmethadone, heroin or other medications prior to or during the studybecause of (1) possible adverse consequences to the fetus resultingfrom drug withdrawal15-19 and (2) a high drop-out rate of patientsenrolled in the study. Demographics of the patients admitted to thestudy are summarized in Table 1.

Despite these limitations, this study presents important evidencethat methadone metabolism and possibly absorption can change sig-nificantly during pregnancy. In Phase I of this study, the eliminationrate constant, k, was measured for each patient during the methadonetaper by measuring ‘‘peak’’ and trough plasma concentrations. Sincemethadone doses were decreasing during the study, none of the pa-tients were at steady state. However, k was higher in pregnant com-pared to non-pregnant patients, and also appeared to decrease duringthe 10-day taper in both groups (from 0.044 hr−1 0.02 to 0.023hr−1 0.002 for pregnant patients and from 0.034 hr−1 0.01 to0.018 hr−1 0.01 for non-pregnant patients; p < 0.04) (Figure 1).

A more detailed pharmacokinetic study was performed in Phase IIpatients where 13 blood samples were collected during the 24 hour

FIGURE 1. Patients in phase I. Patients were started on methadone mainte-nance, then doses tapered over a 4 to 12 day period. ( ) indicates averagek values of pregnant patients, (-----) indicates k values for non-pregnant pa-tients. k is significantly lower as a function of time (P < 0.04) and in non-preg-nant patients (P = 0.00).

80

70

60

50

40

30

20

10

02 3 4 5 6 7 8 9 10 11 121

# Days in Taper

k× 10−3

(hr−1)

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dosing interval. Although variations in patient doses were not statisti-cally significant when compared as a function of pregnancy or steady-state status, the dose was expected to directly influence Cmax but notother pharmacokinetic parameters assuming linear (not saturable) phar-macokinetics. Pregnant patients participating in Phase II had mostlynon-statistically significant differences in the measured pharmacoki-netic parameters with the exception of apparent clearance (Cl/F)(Table 2). A preliminary study using IV methadone designed to mea-sure F (the fraction of drug absorbed) in a separate group of fourpatients, also suggested that F may decrease during pregnancy (F =0.52 0.29, mean SD, n = 4), where

F=AUCpo∕Dpo

AUCiv∕Div

where AUC is the area under the plasma concentration vs. time curvefor a single dosing interval following an IV or oral (po) dose, D, of thedrug.

DISCUSSION

Because of the ethical and safety limitations of testing drugs duringpregnancy, little is known about the effect of pregnancy on drug dis-

TABLE 2. Pharmacokinetics in Phase II Patients*

Pregnant Non-Pregnant P Steady-State Non-Steady Pn = 12 n = 11 n = 14 State

n = 9

k (hrs−1) 0.078 0.069 0.042 0.024 0.12 0.069 0.073 0.048 0.017 0.44ka (hrs−1) 1.32 1 2.6 3.6 0.23 1.32 1.2 1.32 0.12 0.44tmax (hrs) 5.3 7.5 2.8 1.3 0.32 376 541 149 20 0.47Cmax 210 114 301 128 0.09 239 120 123 75 0.24(ng/ml)Dose (mg) 39 20 47 18 0.33 44 21 23 12 0.41V/F (L) 165 36 144 41 0.21 159 33 181 52 0.36Cl/F 148 53 95 56 0.05 136 51 171 70 0.62(mL/min)

*Data expressed as mean SD.

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position or metabolism. As a result, dosing during pregnancy is usual-ly empirically determined from studies in non-pregnant, usually malesubjects or patients. The implications for the mother may be thatsuboptimal dosing is provided during pregnancy. The risk to opioid-dependent patients is particularly concerning, since failure to ade-quately treat the patient’s addiction can result in fetal exposure toillicit substances and infections such as HIV. Methadone has beenused for decades in the treatment of opioid addiction during pregnan-cy, yet optimal methadone dosing during pregnancy has not yet beenclearly established.

The data from Phase I of the present study suggest that methadoneelimination is significantly more rapid for pregnant patients comparedto non-pregnant patients (half-life 19 vs. 30 hours, respectively) andwill likely require higher or more frequent dosing during pregnancy tomaintain therapeutic plasma concentrations. These findings are con-sistent with previous studies which demonstrate that methadone bloodlevels fall more rapidly in both humans and animals in the later stagesof pregnancy, resulting in symptoms of withdrawal.8,20 Pond et al.8indicated that methadone doses should be increased during pregnancyif symptoms recur, or the dose should be split if symptoms are greaterat the end of the dosage interval. These studies are in agreement withWittman and Segal9 who demonstrated that twice-daily dosing re-duces fetal stress and increases maternal comfort.

In addition to pregnancy-dependent changes ink values in Phase Ipatients, k values also decreased during the 10 day taper in bothpregnant and non-pregnant groups (Figure 1). The cause of the ob-served decreasing k values during the 10 day taper is unclear sincechronic dosing of methadone has been previously reported to result inenzyme induction, which would increase k.4,21,22 However, signifi-cant changes in enzyme activity are not likely to occur over the courseof a 10 day taper. Rather, the observed decreases in k more likely arethe result of efflux of drug from a second tissue compartment asoriginally suggested by Anggard et al.21

To more thoroughly investigate these observations, a more detailedpharmacokinetic study was performed in Phase II patients. Whenpharmacokinetic parameters were compared between pregnant andnon-pregnant Phase II patients, only apparent clearance (Cl/F) wasstatistically different at the P < 0.05 level (Table 2), possibly resultingfrom insufficient sample size (Type II error). Pond et al.8 also reported

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pregnancy-dependent differences in clearance; however, both the ap-parent clearance (Cl/F) and volume of distribution (V/F) measured inthis study were approximately 50% lower than the respective Cl/F andV/F values observed by Pond et al.8

The reason for this discrepancy in Cl/F and V/F is unclear, but mayresult from the comparatively low F (fraction of drug absorbed) in thepregnant patients in this study (F = 0.52) compared to F= 0.81-0.95 innon-pregnant patients reported by Nilsson et al.24 Only one femalepatient was included in the Nilsson et al. study, and F was measured tobe very close to 1.0.24 Therefore, pregnancy may also decrease thefraction of methadone absorbed (F) and thus would impact apparentclearance and volume of distribution (Cl/F, V/F). Indeed, drug bio-availability is dependent on many patient variables including somewhich are known to be influenced by gender and hormone levels. Forexample, progesterone, which is elevated during the luteal phase of themenstrual cycle, reportedly produced a slowing of the small intestinetransit time during the luteal phase.25,26 Gill et al.,27 found a signifi-cantly slower emptying of the solid-phase marker during the lutealcompared with the follicular phase. Compared with men, womenempty both solids and liquids more slowly.28 Gastric acid secretion isan additional factor to consider in drug absorption. Grossman et al.29

found a decrease in gastric acid secretion in women that may haveimplications for basic drugs such as methadone. Thus, differences inhormone concentrations during the different phases of pregnancycould significantly alter the absorption of orally administered drugs,such as methadone.

A higher k value was also measured in patients at steady statecompared to nonsteady state pregnant and non-pregnant patients, afinding consistent with the enzyme induction hypothesis,4,21,22 al-though the value did not achieve statistical significance (Table 2).

Although many of the pharmacokinetic parameters were not signifi-cantly different between pregnant and non-pregnant patients (Table 2),a trend regarding drug absorption can be observed. The combinationof (non-statistically significant) increased tmax, reduced Cmax, de-creased F and ka (absorption rate constant) in pregnant patients cumu-latively suggest that slower, less extensive methadone gastrointestinalabsorption may also contribute to lower plasma concentrations duringpregnancy. These findings support the conclusions by Pond et al.8 andWittman and Segal9 that modifications in methadone dosing during

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pregnancy may be required for optimal control of withdrawal in op-ioid-dependent patients.

In conclusion, the data from this study provide preliminary evi-dence that methadone metabolism may be accelerated during pregnan-cy. This finding, combined with possible decreases in bioavailability(F) and absorption rate constant (ka) of methadone during pregnancy,suggest that pregnant patients on traditional methadone maintenancemay be at much higher risk for treatment failure. Appropriate metha-done dosing becomes particularly important in pregnant patients be-cause of the health risks associated with continued heroin use (HIV,hepatitis C, etc.) and the corresponding potential risks to the fetus.Therefore, during pregnancy, serious evaluation of patient complaintsof a dose ‘‘not holding’’ through a 24 hour period are recommended.Individualization of methadone treatment by increasing the dose and/or decreasing the dosing interval may be required during pregnancy tomaximize compliance.

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