CLINICAL TRLALS AND THERAPEUTICS Measuring compliance in methadone maintenake paiients: Use of a pharmacologk indicator to "estimate" methadone plasma levels A quantitative indicator of compliance is not available for methadone-the drug of choice for the treatment of opioid addiction. We successfully used low-dose phenobarbital (a valid pharmacologic indicator) to measure compliance by incorporating the drug into the methadone medication of patients attending an addiction unit. Plasma phenobarbital and methadone concentrations were measured in 20 (11 clinicbased and 9 community-based) patients receiving long-term treatment with the phenobarbital level-todose ratio, together with interviews, to validate methadone measurements and to monitor compliance. Patients attending the unit on a daily basis and who consumed their medication in the clinic were substantially more compliant than community-based patients. Laboratory measurements of phenobarbital and methadone helped to identify the use of illicit methadone, as well as incorrect self-administration, THER1991;50:199-207.) such as the consumption of several days' dosage at one time. (CLINPHARMACOL
Kim Wo@ PhD, Alastair Hay, PhD, Duncan Raistrick, MD, MRC, Robert Calvert, PhD, and Morgan Feely, MD, FRCP(Ire1) Leeds, England Methadone, a semisynthetic opioid, is usually the drug of choice for the treatment of opioid addiction. Earlier reports suggested considerable intraindividual and interindividual variation in the kinetics of methadone in adults. This reported variability between individuals has led many physicians to question the value of plasma methadone measurement^.^ As a consequence, very few plasma measurements of methadone are carried out on individuals to relate drug dosage to plasma concentrations, and no attempt has been From the Department of Chemical Pathology and the Leeds Addiction Unit, Old Medical School, University of Leeds, and the Pharmacy and the Clinical Pharmacology Unit, Department of Medicine, Leeds General Infirmary. Funded by the Medical Research Council, London, England. Received for publication Nov. 13, 1990; accepted April 10, 1991. Reprint requests: Kim Wolff, PhD, Department of Chemical Pathology, Old Medical School, University of Leeds, Leeds LS2 9JT, England. 13/1/30167
made to use these measurements to assess patient compliance. In an earlier study at the Leeds Addiction Unit, we reported that there is a good linear relationship between dose (in milligrams per kilogram per day) and plasma methadone concentrations at steady state over the dosage range of 3 to 100 mg methadone per day.4 In the normal course of events no attempt is made to assess whether the addicts receiving methadone at the addiction unit are fully compliant or whether they supplement, or sell, some of their prescriptions. The only routine assessment of the addicts is a commercial urine screen, called Toxilab (Analytical Systems Inc., Laguna Hills, Calif.), which detects drugs of abuse. This urine screening procedure is only qualitative and cannot be used to assess methadone compliance accurately. More than 150 compounds have been considered as potential indicators of ~ o m p l i a n c ebut , ~ so far none of these have proved to be sufficiently good at discrimi-
199
200 Wolf et al. nating between those who take their drugs and those who do not. ~ i b o f l a v i nhas ~ been most frequently used, but as with other markers (e.g., quinine) it is not ideal because of its presence in food and beverages. The use of low-dose phenobarbital as a quantitative indicator of compliance, in which the drug is incorporated into the treatment under scrutiny, has been described recently,7 and it appears to be more accurate than residual tablet counts or prescription monitors for assessing ~ o m ~ l i a n c We e . ~ therefore decided to use low-dose phenobarbital to assess compliance in patients on methadone. Phenobarbital is suitable as an indicator of longterm compliance because it has a long half-life (tk; 96 hours), as well as little interindividual variation and even less intraindividual variation in its pharmacokinetics in adult^.^ Its long ti,, appears to give it considerable advantages over short t,,, indicators (markers) of compliance.9 In the dosages used to assess compliance, phenobarbital has no enzyme-inducing properties,'' no apparent sedative e f f e ~ t , " " ~and a direct linear relationship between dose and steady-state concentration in plasma.7 In addition, after almost 80 years of extensive use, very few factors have been shown to effect the kinetics of phenobarbital and, of the established enzyme inducers, only rifampin13 is able to stimulate the metabolism of this drug. l 4
METHODS Subjects and study protocol. Approval was obtained from the local research ethics committee (Leeds Western Health Authority) before the study began. Thirty patients who were attending the Leeds Addiction Unit for treatment were randomly recruited for the study as nonpaid volunteers. The subjects were representative of two different patient types: Clinicbased patients, aged 23 to 34 years (mean ? SD, 27 ? 3.4 years), attended the clinic on a daily basis to receive their prescriptions, and community-based patients, aged 26 to 60 years (mean & SD, 34.5 ? 9.7 years) collected their prescriptions from a pharmacy and had infrequent contact with the addiction unit. Clinic-based patients had been prescribed methadone for periods ranging from 0.75 to 24 months (mean SD, 7.6 7 months), and community-based patients had been prescribed methadone for 1 to 60 months (mean t SD, 21.6 + 19.5) before the study began. All patients were informed of the purpose of the study and gave their consent to blood and urine sampling. Low doses (non-enzyme-inducing) of phenobarbital (0.125 mgtml) were incorporated into the metha-
*
*
CLlN PH.4RMACOI. THEK AUGUST 1991
done linctus (1 mgtml; methadonelphenobarbital, ratio of 8 : I), and differing daily amounts were prescribed to the patients. Attendance at the clinic for blood sampling was arranged for a preset day and time on a weekly, every-other-week, or monthly basis. Plasma measurements of phenobarbital and methadone, together with interviews, were used to assess compliance. Measurements were made after patients were assumed to have reached steady state for both drugs on /~ for other patients: the basis of average t ~ determined t& for methadone = 24 hours15; t& for phenobarbital = 4 days.7 The community-based patients were generally in the study longer (21.5 It 9 weeks; range, 7 to 35 weeks) than the clinic-based patients (12.5 ? 10.5 weeks; range, 6 to 45 weeks). Blood (10 ml) was drawn by venipuncture into heparinized Monovette blood collection tubes (Sareston Ltd., Leicester, England) before the consumption of the daily dose of the methadone-phenobarbital mixture. After centrifugation at room temperature for 5 minutes (1000g), plasma was transferred to clean plastic tubes (10 ml) and stored at -20" C until analysis.
Analytic methods Details of the procedure for measuring methadone are available e l ~ e w h e r e . ~The . ' ~ following text refers to the analysis of phenobarbital in plasma unless specifically indicated. Drugs and reagents. Phenobarbital and butabarbital (internal standard) were both obtained from Sigma Chemical Co. Ltd. (Poole, England). Methanol, isopropanol acetonitrile, ethylacetate, and hexane (all HPLC grade) were obtained from Rathburn Chemicals Ltd. (Walkerburn, Scotland). Liquid chromatography. The HPLC system consisted of a model 510 solvent-delivery system [Millipore (U.K.) Ltd., Waters Chromatography Division, Harrow, England] and a model 2311401 Gilson autosampler (Anachem U.K. Ltd., Luton, England) with a 100 p1 loop. Separation was performed with a Spherisorb ODs C,, column, 12.5 cm X 0.46 cm internal diameter, with 5 p particles (Technic01 Ltd., Stockport, England). Phenobarbital was detected at 2 14 nm with a model 455 liquid chromatography spectrophotometer coupled to a model 747 data-module integrator, both from Waters Chromatography Division. Sample treatment. Plasma phenobarbital concentrations were measured by a method adapted from Peaker et a1. " Briefly, the phenobarbital method required patient plasma, quality control, and plasma phenobarbital standards (0.2 ml) to be added to acid-washed,
VOLUME 50 NUMBER 2
Measuring compliance with a manie~ 201
conical glass tubes (15 mL) with glass stoppers (Orme scientific, Manchester, England) with 0.05 ml of butabarbital (internal standard, 4 mg/L) in aqueous methanol (50: 50 vollvol). Each conical tube was then thoroughly mixed on a vortex mixer (3 seconds) and allowed to stand for 5 minutes. A mixture of ethylacetate and hexane (3 :2 vol/vol) was prepared and 2.5 ml added to each tube. These tubes were stoppered and vortex mixed (for 15 seconds) before centrifuging (500g, 4" C) for 2 minutes. The supernatant was transferred to glass tubes (5 ml) and dried down in a Univap Model GV2 refrigerated solvent trap and centrifugal evaporator (Uniscience Ltd., London, England) at 40' C for 15 minutes. Extracts were reconstituted with 0.1 ml of the mobile phase, capped, and stored at -20" C or transferred to conical vials (1.1 ml) for immediate analysis. Plasma extract (50 p1) was injected onto the ODs column in a mobile phase consisting of water, methanol, acetonitrile, and isopropanol (126 :46 :24 :4 vollvol). The flow rate was 1.4 mllmin, and the retention times were 4.0 and 5.0 minutes for phenobarbital and butabarbital, respectively. Assay validation. Day-to-day assay reproducibility of phenobarbital was assessed by analysis of a quality control (QC) sample. Two different QC samples were used throughout the 30-month study. The mean ? SD and correlation coefficient of the two QC samples are as follows: QC- 1 was 1.06 0.05 mg/L (coefficient of variation [CV], 4.6%; n = 14) and QC-2 was 0.44 + 0.03 mg/L (CV, 6.8%; n = 16). Within-day assay reproducibility was 4.2% (n = 10). Accuracy was assessed by measuring plasma fortified with phenobarbital over the concentration range of 0.2 to 1.0 mgIL, and the relationship between the quantity of methadone found to that added was linear with a regression line of y = 0.023 1 . 0 2 2 ~r; = 0.99. Mean recovery of phenobarbital was 96.3% 6.1% (range, 93% to 102%). The sensitivity of the HPLC assay for phenobarbital with a signal-to-noise ratio of 3 was 40 ng. In comparison, the sensitivity of the HPLC method for methadone (same signal-to-noise ratio) was 5 ng, which was considerably lower than the concentrations of the drug observed in our patients. In our study, measurements of phenobarbital in plasma ranged from 0.2 to 3.7 mg/L, whereas methadone concentrations in plasma were slightly lower, ranging from 0.03 to 1.1 mg/L. Compliance. In this study the calculation of the phenobarbital level-to-dose ratio, which takes into account a patient's weight, was used to validate methadone measurements and to monitor compliance. The
*
+
*
level-to-dose ratio (LDR) was calculated from the following equation: LDR
=
Phenobarbital concentration (mgiL I ) Prescribed phenobarbital dose (mgikg '124 hr-
I)
A similar equation was used to calculate the equivalent methadone level-to-dose ratio. In our investigation we used expected ranges of level-to-dose ratios from previously studied healthy volunteers: for subjects aged 50 years and younger the phenobarbital level-to-dose ratio was 9.7 to 14.5; for subjects more than 50 years of age the level-to-dose ratio was 11.9 to 17.4.17 Definition of noncompliance. Noncompliance was defined as interview evidence of methadone misuse, such as the sale of part of a prescribed dose, supplementation of a prescription with illicit methadone, or a plasma phenobarbital level-to-dose ratio that fell substantially above or below the age related range in healthy volunteers (see above). As a further guide we also monitored the relationship between the methadone and phenobarbital level-to-dose ratios in all of our patients.
RESULTS Twenty patients (1 1 clinic-based and 9 communitybased) provided a complete set of data, eight patients defaulted, leaving before treatment was completed, and two patients were excluded from the results because one took therapeutic amounts of phenobarbital (patient 5), and the other was given methadone capsules and not the methadone-phenobarbitone linctus (patient 14). Of those who completed the study, seven clinic-based (Table I) and two community-based patients (Table 11) had normal age-related mean phenobarbital level-to-dose ratios. Five clinic-based and six community-based patients had phenobarbital level-to-dose ratios that were below the age-related range for normal individuals. Of those in the clinic-based group who were in this category (mean level-to-dose ratios, 7.08 to 8.30), three had normal (expected) level-to-dose ratios at some point during the study. In the community-based group, five patients had level-to-dose ratios consistently lower than the normal age-related range (mean level-to-dose ratios, 5.19 to 8.01). One patient (No. 17, Table 11) had a mean phenobarbital level-to-dose ratio above the reported normal range. Dosage reduction in this patient took place during the study and samples were collected before the patient had reached a new steady state; this may have contributed to the high level-to-dose ratio. Through
CLIN PHARMACOL THEK AUGUST 1991
202 Wolf e t al. Table I. Clinic-based patients: level-to-dose ratios for phenobarbital and methadone Phenobarbital LDR Patient No.
Age (yr)
Dose (mglday)
Mean
rt
SD
Range
Methadone LDR Mean t SD
Range
1 2 3 3a 4 4a 5 6 7
8 9 10 Mean SD Median LDR, Level-to-dose ratio. *Omitting values for patient 5, who self-prescribed phenobarbital.
Table 11. Community-based patients: level-to-dose ratios for phenobarbital and methadone Phenobarbital LDR Patient No.
Age (yr)
Dose (mglday)
Mean t SD
Range
Methadone LDR Mean t SD
Range
10a 11 12 13 14 15 16 17
18 19
Mean SD Median *Omitting values for patient 14, who removed phenobarb~talfrom her methadone capsules
our urine screening procedure we know that this patient continued to misuse drugs during the study. This misuse may have included phenobarbital (as a drug of abuse) or heroin, which is frequently "cut" with phenobarbital. On questioning, two clinic-based and four community-based patients admitted to poor compliance. Of these six noncompliers, three (patients 7, 11, and 13) supplemented their methadone prescriptions with more of the narcotic (Fig. l), two (patients 10a and 18) took
their prescriptions at variable intervals (incomplete compliance; Fig. 2), and one (patient 8) took a 3-day prescription of methadone at one time (Fig. 3). The literature suggests that compliance is much improved at doses above 60 mg methadone per day.I8 We were unable to substantiate this view because our patients (except patient 3a) were not prescribed doses in excess of 60 mg methadone per day (Table I, 11). To establish whether the variation observed in the clinic- and community-based groups differed signifi-
VOI.UME 50 NUMBER 2
Intraindividual variation LDR (%) Methadone LDRI Phenobarbital Methadone phenobarbital LDR ratio
Intraindividual variation LDR (%) Methadone LDRI Phenobarbital Methadone phenobarbital LDR ratio
cantly, we used a Mann-Whitney U test (nonparametric test for independent data). Intraindividual variation for the phenobarbital level-to-dose ratio in the clinicbased group was a CV of 13% + 7% (mean ? SD; median, 11%) that ranged from 6% to 29%. Variation was much greater in the community-based group ( p < 0.05) with a CV of 21% t 11% (mean +- SD; median, 29) and a range from 4% to 34%. Interindividual variation in the phenobarbital level-to-dose ratio between clinic-based patients was lower (CV, 19.2%)
Measun'n. compliance with a marker 203 than in the community-based group (CV, 45.4%). In both groups the intraindividual variation in the methadone level-to-dose ratio was higher than that observed for phenobarbital, mean CV was 24% ? 18% (median, 16; range, 7% to 64%) for the clinic-based group and mean CV was 31% ? 19% (median, 36; range, 9% to 55%) for the community-based methadone group. To investigate metabolic tolerance we compared methadone concentrations in plasma, as well as the relationship between the methadone and phenobarbital level-to-dose ratios during the first and last months of treatment. To test for significant changes in the data collected during these periods, we performed a Student t test for correlated data. Nme clinic-based patients had lower mean plasma concentrations of methadone at the end of the study ( p < 0.05) and eight of these patients had lower methadonelphenobarbital level-to-dose ratios. Equivalent statistics could not be applied to the community-based group because too few patients were available for comparison. For instance, patient 11 and 13 misused illicit methadone, patients 10a and 18 misused prescribed methadone, and patients 17 and 19 had their doses reduced during treatment.
DISCUSSION Low-dose phenobarbital has been used successfully as a pharmacologic indicator of compliance in various therapeutic dosing regimes,12.'%nd in this study we showed that phenobarbital can also be used as an indicator of compliance with methadone treatment. The long plasma tl/, of phenobarbital enables compliance to be monitored over the preceding weeks; adequate plasma levels of phenobarbital will not be achieved simply by the ingestion of a few doses of phenobarbital (in the methadone-phenobarbital mixture) a few days before sample collection. '' The variation in plasma methadone level-to-dose ratios observed in our patients was much less than we were led to expect from the observations of other^.'^.'^ Dosing irregularities (incomplete compliance) may account for some of the variation in reported plasma concentrations. The shorter tlI2of methadone (t& = 24 hours) makes plasma drug concentrations susceptible to daily alterations in dosing schedules, whereas plasma phenobarbital, with its longer ty2, is much less affected. Failure to monitor compliance may have contributed to the variation in plasma methadone concentrations. Community-based patients had greater variation in their phenobarbital level-to-dose ratios, suggesting
CLIN PHARMrZCOL THER AUGUST 1991
204 Wolf et al. Phenobarbital
Methadone LDR
0.41
(
~ e t h a d o n eLOR
* he no barbital
LDR r18
LDR
I
Sample collection (weeks)
Fig. 1. Shows sample collections from patient 7, who took illicit methadone to supplement his
prescription at the end of the study. LDR, Level-to-dose ratio. that patients were less compliant when they do not attend the addiction unit. In the unit, methadone is taken under observation once every 24 hours. This variation can be seen clearly with one patient who was more compliant when attending the clinic (No. 10) than when he was based in the community (No. 10a). This finding is significant because it is generally believed that patients who receive permission to collect their prescriptions from local pharmacies are usually compliant. Many patients in this study had very low phenobarbital level-to-dose ratios, which could have been caused by methodological error, pharmaceutical error, patient error, sampling and dosing irregularities, incomplete compliance, or noncompliance. Methodological error is unlikely because the HPLC method for analyzing phenobarbital is both robust and efficient, with an intraindividual CV of 3.7% (repeat analysis of old samples). Incorrect preparation of the methadone-phenobarbital mixture remains a possible source of error, and it is difficult to assess this because the mixture was prepared only on demand. To rule out preparation of the mixture as a problem, we traced the batch number of those patients who had particularly low or high phenobarbital level-to-dose ratios. In every case we found that the patients with discrepant values had received their methadone from the same batch as a patient with
a normal level-to-dose ratio. Furthermore, analysis of freshly prepared methadone-phenobarbital mixtures in the laboratory showed the ratio of the mixture to be correct when medication was dispensed from the top or bottom of the bottle. Errors in level-to-dose ratios will also occur if a patient does not consume all of the methadone prescribed. Because most of our patients were prescribed the lowest dose of methadone that would prevent withdrawal symptoms, they probably took all their prescriptions. The majority of the clinic-based patients rinsed out the vessels from which they took their methadone-phenobarbital mixtures with water and swallowed this residue. Consumption of methadone at the unit was monitored by the staff, and it is unlikely that anyone left some of his or her medication. Indeed, patients often complained that their doses were inadequate. Another reason for low phenobarbital level-to-dose ratios could be some error in dispensing. This was investigated. The staff members at the unit were asked to measure out a range of methadone doses. We found no difference in what staff members were asked to measure and what they actually dispensed. The chaotic lifestyle of drug addicts creates difficulties for investigations such as ours, and dosing schedules were sometimes changed during the study to suit patients. Clinic-based patients were occasionally al-
VOLUME 50 NUMBEK 2
Measu~ingcompliance with a ma&er 205 Methadone LDR
Phenobarbital
43Methadone LDR
1
5
9
*
Phenobarbital
LDR
13 17 21 25 Sample collection (weeks)
LDR
X
29
33
Fig. 2. Incomplete compliance (in which patients take their medication but not in the way prescribed) was observed in patient 18, who consumed more than the prescribed daily amount in the first half of the week and had to abstain in the second half. LDR, Level-to-dose ratio.
lowed to take their methadone medication off the premises, and the timing of take-home privileges often coincided with a fluctuation in the methadone level-todose ratio. We also noted that patients in the community-based group often took their prescriptions at times other than those stipulated. Doses would be subdivided and taken at intervals over 24 hours (patients IOa, 15, and 18 in Table 11). The consumption of subdoses in this manner is unlikely to have any clinical significance. Twenty years ago, single and twice-daily methadone dosing schedules were compared in patients and were shown to have no effect on either symptom complaints or on the misuse of h e r ~ i n . ~ Standardizing the timing of the predose measurements was also difficult for our patients. Many clinicbased patients collected their prescriptions twice a week rather than on a daily basis (patients 3, 4a, 6, 8, and 10 in Table I), whereas the community-based patients attended the clinic only once every 2 weeks (patients 10a, 1l , 13, 16, and 19) or monthly for appointments. Some patients (patients 14, 15, 17, 18) were unwilling (or unable because of employment) to attend more frequently. Only one patient (No. 12, Table 11) was seen once a week. Phenobarbital level-to-dose ratios may also be low if the patient is incompletely compliant or is noncom-
pliant. Incomplete compliance-in which patients take their medication but not to the extent or in the way prescribed-was commonly observed in the community-based group and could be a major cause of variation in plasma methadone concentrations in these patients. This was most apparent in two patients (patients 10a and 18), both of whom consumed more than the prescribed daily amount in the first half of a week and therefore had to abstain in the second half. The occurrence of incomplete compliance, rather than noncompliance (failure to consume any medication in a particular dosing interval), is probably attributable to the nature of methadone itself. The purpose of prescribing a semisynthetic opioid such as methadone relates to its ability to block (cross-tolerate) the euphoric effects of heroin and also to prevent the onset of withdrawal symptoms.21 Thus, for many patients, the consumption of some methadone is a necessity, especially when other illicit opioids are unavailable. Measuring the concentration of both methadone and phenobarbital enabled us to differentiate between consistent and irregular dosing patterns. The incorporation of low-dose phenobarbital into the methadone linctus makes the timing of sampling for phenobarbital unimportant, for at steady state the between-dose fluctuation in plasma phenobarbital concentration is sma11.~
CLlN PHARMACOL THER AUGUST 1991
206 Wolfetal. Methadone LDR
Phenobarbital
LDR
* Methadone LDR A- Phenobarbital
1
5
9
13
LDR
17 21 25 29 33 Sample collection (weeks)
37
41
45
Fig. 3. Shows sample collections from patient 8, who took a 3-day prescription at one time. LDR, Level-to-dose ratio.
The measurement of either methadone or phenobarbital alone has limitations because phenobarbital levels would not indicate when the last dose was taken, and patients who take most of their medication, but who take it irregularly and sometimes in large quantities, may not be detected. Methadone measurements on their own would require strictly controlled dosing and sampling times, and this would be impractical for a drug clinic. The misuse of small quantities of methadone obtained illicitly would probably be difficult to detect with lowdose phenobarbital. Nilsson et a1.22 reported that plasma methadone concentrations decrease as a consequence of metabolic tolerance in patients receiving long-term methadone treatment. This may be one reason that some patients do less well in treatment and some are noncompliant. A few of our clinic-based patients did have lower plasma methadone concentrations at the end of treatment, as well as lower methadonelphenobarbital levelto-dose ratios. Additional study is needed to determine whether this phenomenon contributes to the occurrence of incomplete compliance in certain individuals. The use of low-dose phenobarbital as a pharmacologic marker of compliance gave valuable insight into methadone maintenance programs and highlighted two critical issues for clinicians: the use of illicit methadone and the incorrect self-administration of the drug.
Patients who attended the unit on a regular basis and consumed their medication in front of the staff were substantially more compliant than community-based patients. Measurement of compliance in communitybased patients would therefore seem to be particularly important.
References 1. Goldstein A. Blind comparison of once-daily and twicedaily dosage schedules in a methadone program. CLIN PHARMACOL THER1971;12:59-63. 2. lnturrisi CE, Verebely K. Levels of methadone in plasma during methadone maintenance. CLINPHARMACOL THER1972;13:633-47. 3. Horns WH, Radio M, Goldstein A. Plasma levels and symptom complaints in patients maintained on daily dosage of methadone hydrochloride. CLINPHARMACOL THER1975;17:363-49. 4. Wolff K, Sanderson M, Hay AWM, Raistrick D. Methadone concentrations in plasma and their relationship to drug dosage. Clin Chem 1991;37:205-9. 5. Insull W Jr. Evaluation and recommendations for adherence marker development by working groups of the workshop-appendix: list of actual and potential adherence markers and devices. Controlled Clin Trials 1984;5:584-7. 6. Jones IH. Riboflavine as an indicator of drug taking behaviour. Med J Aust 1967;54:202-4.
VOLUME 50 NUMBER 2
7. Feely M, Cooke J, Price D, Singleton S , Mehta A. Low dose phenobarbitone as an indicator of compliance in drug therapy. Br J Clin Pharmacol 1987;24:77-83. 8. Pullar T, Kumar S, Tindall H, Feely M. Time to stop counting the tablets. CLINPHARMACOL THER1989;46: 163-8. 9. Hardy E, Kumar S, Peaker S, Feely M, Pullar T. A comparison of a short half-life marker (low-dose isoniazid), a long half-life pharmacological indicator (lowdose phenobarbitone) and measurements of a controlled release "therapeutic drug" (metoprolol, Metoros) in reflecting incomplete compliance by volunteers. Br J Clin Pharmacol 1990;30:437-41. 10. Price D, Mehta A, Park BK, Hay AWM, Feely M. The effect of low dose phenobarbitone on three indices of hepatic microsomal enzyme induction. Br J Clin Pharmacol 1986;22:744-7. I I. Kumar S, Pullar T , Feely MP. The dose of phenobarbitone used to measure compliance does not seem to impair pyschomotor function. Br J Clin Pharmacol 1989;28:749P-50P. 12. Pullar T, Birtwell AJ, Wiles PG, Hay AW, Feely MP. Use of a pharmacologic indicator to compare compliance with tablets prescribed to be taken once, twice, or N THER1988;44:540-5. three times daily. C L ~PHARMACOL 13. Kumar S, Peaker S, De Souza N, Haigh JRM, Cooke NJ, Feely MP. Assay of a short half-life therapeutic drug vs a long half-life indicator for the assessment of compliance in tuberculosis. Br J Clin Phannacol 1989;28:733P-4P.
Measun'ng cor*zpliancewith a marker 207 14. Kutt H. Phenobarbitone interactions with other drugs. In: Levy R, Mattson R , Meldrum B, Peny JK, Dreifuss FE, eds. Antiepileptic drugs. 3rd ed. New York: Raven Press, 1989:313-27. 15. Dole VP, Kreek MJ. Plasma methadone levels sustained by a reservoir of drug in tissue. Proc Natl Acad Sci USA 1973:70:10. 16. Wolff K, Shanab M, Sanderson M, Hay A. Screening for drugs of abuse: effect of heat-treating urine for safe handling of samples. Clin Chem 1990;36:908-10. 17. Peaker S, Mehta AC, Kumar S, Feely M. Measurement of low (subtherapeutic) phenobarbitone levels in plasma by high performance liquid chromatography: application to patient compliance studies. J Chromatogr 1989;497:308-12. 18. Nathan JA, Karan LD. Substance abuse treatment modalities in the age of HIV spectrum disease. J Psychoactive Drugs 1989;21:423-9. 19. Kreek MJ. Plasma and urine levels of methadone. NY State J Med 1973;73:2773-7. 20. Anggard E, Gunne LM, Holmstrand J, McMahon RE, Sandberg CG, Sullivan HR. Disposition of methadone in methadone maintenance. CLIN PHARMACOL THER 1975;17:258-66. 21. Dole VP, Nyswander ME, Kreek MJ. Narcotic blockade. Arch Intern Med 1966;118:304-9. 22. Nilsson MI, Anggard E, Holmstrand J, Gunne LM. Pharmacokinetics of methadone during maintenance treatment: adaptive changes in the inductive phase. Eur J Clin Pharmacol 1982;22:343-9.
Kim Wo@ PhD, Alastair Hay, PhD, Duncan Raistrick, MD, MRC, Robert Calvert, PhD, and Morgan Feely, MD, FRCP(Ire1) Leeds, England Methadone, a semisynthetic opioid, is usually the drug of choice for the treatment of opioid addiction. Earlier reports suggested considerable intraindividual and interindividual variation in the kinetics of methadone in adults. This reported variability between individuals has led many physicians to question the value of plasma methadone measurement^.^ As a consequence, very few plasma measurements of methadone are carried out on individuals to relate drug dosage to plasma concentrations, and no attempt has been From the Department of Chemical Pathology and the Leeds Addiction Unit, Old Medical School, University of Leeds, and the Pharmacy and the Clinical Pharmacology Unit, Department of Medicine, Leeds General Infirmary. Funded by the Medical Research Council, London, England. Received for publication Nov. 13, 1990; accepted April 10, 1991. Reprint requests: Kim Wolff, PhD, Department of Chemical Pathology, Old Medical School, University of Leeds, Leeds LS2 9JT, England. 13/1/30167
made to use these measurements to assess patient compliance. In an earlier study at the Leeds Addiction Unit, we reported that there is a good linear relationship between dose (in milligrams per kilogram per day) and plasma methadone concentrations at steady state over the dosage range of 3 to 100 mg methadone per day.4 In the normal course of events no attempt is made to assess whether the addicts receiving methadone at the addiction unit are fully compliant or whether they supplement, or sell, some of their prescriptions. The only routine assessment of the addicts is a commercial urine screen, called Toxilab (Analytical Systems Inc., Laguna Hills, Calif.), which detects drugs of abuse. This urine screening procedure is only qualitative and cannot be used to assess methadone compliance accurately. More than 150 compounds have been considered as potential indicators of ~ o m p l i a n c ebut , ~ so far none of these have proved to be sufficiently good at discrimi-
199
200 Wolf et al. nating between those who take their drugs and those who do not. ~ i b o f l a v i nhas ~ been most frequently used, but as with other markers (e.g., quinine) it is not ideal because of its presence in food and beverages. The use of low-dose phenobarbital as a quantitative indicator of compliance, in which the drug is incorporated into the treatment under scrutiny, has been described recently,7 and it appears to be more accurate than residual tablet counts or prescription monitors for assessing ~ o m ~ l i a n c We e . ~ therefore decided to use low-dose phenobarbital to assess compliance in patients on methadone. Phenobarbital is suitable as an indicator of longterm compliance because it has a long half-life (tk; 96 hours), as well as little interindividual variation and even less intraindividual variation in its pharmacokinetics in adult^.^ Its long ti,, appears to give it considerable advantages over short t,,, indicators (markers) of compliance.9 In the dosages used to assess compliance, phenobarbital has no enzyme-inducing properties,'' no apparent sedative e f f e ~ t , " " ~and a direct linear relationship between dose and steady-state concentration in plasma.7 In addition, after almost 80 years of extensive use, very few factors have been shown to effect the kinetics of phenobarbital and, of the established enzyme inducers, only rifampin13 is able to stimulate the metabolism of this drug. l 4
METHODS Subjects and study protocol. Approval was obtained from the local research ethics committee (Leeds Western Health Authority) before the study began. Thirty patients who were attending the Leeds Addiction Unit for treatment were randomly recruited for the study as nonpaid volunteers. The subjects were representative of two different patient types: Clinicbased patients, aged 23 to 34 years (mean ? SD, 27 ? 3.4 years), attended the clinic on a daily basis to receive their prescriptions, and community-based patients, aged 26 to 60 years (mean & SD, 34.5 ? 9.7 years) collected their prescriptions from a pharmacy and had infrequent contact with the addiction unit. Clinic-based patients had been prescribed methadone for periods ranging from 0.75 to 24 months (mean SD, 7.6 7 months), and community-based patients had been prescribed methadone for 1 to 60 months (mean t SD, 21.6 + 19.5) before the study began. All patients were informed of the purpose of the study and gave their consent to blood and urine sampling. Low doses (non-enzyme-inducing) of phenobarbital (0.125 mgtml) were incorporated into the metha-
*
*
CLlN PH.4RMACOI. THEK AUGUST 1991
done linctus (1 mgtml; methadonelphenobarbital, ratio of 8 : I), and differing daily amounts were prescribed to the patients. Attendance at the clinic for blood sampling was arranged for a preset day and time on a weekly, every-other-week, or monthly basis. Plasma measurements of phenobarbital and methadone, together with interviews, were used to assess compliance. Measurements were made after patients were assumed to have reached steady state for both drugs on /~ for other patients: the basis of average t ~ determined t& for methadone = 24 hours15; t& for phenobarbital = 4 days.7 The community-based patients were generally in the study longer (21.5 It 9 weeks; range, 7 to 35 weeks) than the clinic-based patients (12.5 ? 10.5 weeks; range, 6 to 45 weeks). Blood (10 ml) was drawn by venipuncture into heparinized Monovette blood collection tubes (Sareston Ltd., Leicester, England) before the consumption of the daily dose of the methadone-phenobarbital mixture. After centrifugation at room temperature for 5 minutes (1000g), plasma was transferred to clean plastic tubes (10 ml) and stored at -20" C until analysis.
Analytic methods Details of the procedure for measuring methadone are available e l ~ e w h e r e . ~The . ' ~ following text refers to the analysis of phenobarbital in plasma unless specifically indicated. Drugs and reagents. Phenobarbital and butabarbital (internal standard) were both obtained from Sigma Chemical Co. Ltd. (Poole, England). Methanol, isopropanol acetonitrile, ethylacetate, and hexane (all HPLC grade) were obtained from Rathburn Chemicals Ltd. (Walkerburn, Scotland). Liquid chromatography. The HPLC system consisted of a model 510 solvent-delivery system [Millipore (U.K.) Ltd., Waters Chromatography Division, Harrow, England] and a model 2311401 Gilson autosampler (Anachem U.K. Ltd., Luton, England) with a 100 p1 loop. Separation was performed with a Spherisorb ODs C,, column, 12.5 cm X 0.46 cm internal diameter, with 5 p particles (Technic01 Ltd., Stockport, England). Phenobarbital was detected at 2 14 nm with a model 455 liquid chromatography spectrophotometer coupled to a model 747 data-module integrator, both from Waters Chromatography Division. Sample treatment. Plasma phenobarbital concentrations were measured by a method adapted from Peaker et a1. " Briefly, the phenobarbital method required patient plasma, quality control, and plasma phenobarbital standards (0.2 ml) to be added to acid-washed,
VOLUME 50 NUMBER 2
Measuring compliance with a manie~ 201
conical glass tubes (15 mL) with glass stoppers (Orme scientific, Manchester, England) with 0.05 ml of butabarbital (internal standard, 4 mg/L) in aqueous methanol (50: 50 vollvol). Each conical tube was then thoroughly mixed on a vortex mixer (3 seconds) and allowed to stand for 5 minutes. A mixture of ethylacetate and hexane (3 :2 vol/vol) was prepared and 2.5 ml added to each tube. These tubes were stoppered and vortex mixed (for 15 seconds) before centrifuging (500g, 4" C) for 2 minutes. The supernatant was transferred to glass tubes (5 ml) and dried down in a Univap Model GV2 refrigerated solvent trap and centrifugal evaporator (Uniscience Ltd., London, England) at 40' C for 15 minutes. Extracts were reconstituted with 0.1 ml of the mobile phase, capped, and stored at -20" C or transferred to conical vials (1.1 ml) for immediate analysis. Plasma extract (50 p1) was injected onto the ODs column in a mobile phase consisting of water, methanol, acetonitrile, and isopropanol (126 :46 :24 :4 vollvol). The flow rate was 1.4 mllmin, and the retention times were 4.0 and 5.0 minutes for phenobarbital and butabarbital, respectively. Assay validation. Day-to-day assay reproducibility of phenobarbital was assessed by analysis of a quality control (QC) sample. Two different QC samples were used throughout the 30-month study. The mean ? SD and correlation coefficient of the two QC samples are as follows: QC- 1 was 1.06 0.05 mg/L (coefficient of variation [CV], 4.6%; n = 14) and QC-2 was 0.44 + 0.03 mg/L (CV, 6.8%; n = 16). Within-day assay reproducibility was 4.2% (n = 10). Accuracy was assessed by measuring plasma fortified with phenobarbital over the concentration range of 0.2 to 1.0 mgIL, and the relationship between the quantity of methadone found to that added was linear with a regression line of y = 0.023 1 . 0 2 2 ~r; = 0.99. Mean recovery of phenobarbital was 96.3% 6.1% (range, 93% to 102%). The sensitivity of the HPLC assay for phenobarbital with a signal-to-noise ratio of 3 was 40 ng. In comparison, the sensitivity of the HPLC method for methadone (same signal-to-noise ratio) was 5 ng, which was considerably lower than the concentrations of the drug observed in our patients. In our study, measurements of phenobarbital in plasma ranged from 0.2 to 3.7 mg/L, whereas methadone concentrations in plasma were slightly lower, ranging from 0.03 to 1.1 mg/L. Compliance. In this study the calculation of the phenobarbital level-to-dose ratio, which takes into account a patient's weight, was used to validate methadone measurements and to monitor compliance. The
*
+
*
level-to-dose ratio (LDR) was calculated from the following equation: LDR
=
Phenobarbital concentration (mgiL I ) Prescribed phenobarbital dose (mgikg '124 hr-
I)
A similar equation was used to calculate the equivalent methadone level-to-dose ratio. In our investigation we used expected ranges of level-to-dose ratios from previously studied healthy volunteers: for subjects aged 50 years and younger the phenobarbital level-to-dose ratio was 9.7 to 14.5; for subjects more than 50 years of age the level-to-dose ratio was 11.9 to 17.4.17 Definition of noncompliance. Noncompliance was defined as interview evidence of methadone misuse, such as the sale of part of a prescribed dose, supplementation of a prescription with illicit methadone, or a plasma phenobarbital level-to-dose ratio that fell substantially above or below the age related range in healthy volunteers (see above). As a further guide we also monitored the relationship between the methadone and phenobarbital level-to-dose ratios in all of our patients.
RESULTS Twenty patients (1 1 clinic-based and 9 communitybased) provided a complete set of data, eight patients defaulted, leaving before treatment was completed, and two patients were excluded from the results because one took therapeutic amounts of phenobarbital (patient 5), and the other was given methadone capsules and not the methadone-phenobarbitone linctus (patient 14). Of those who completed the study, seven clinic-based (Table I) and two community-based patients (Table 11) had normal age-related mean phenobarbital level-to-dose ratios. Five clinic-based and six community-based patients had phenobarbital level-to-dose ratios that were below the age-related range for normal individuals. Of those in the clinic-based group who were in this category (mean level-to-dose ratios, 7.08 to 8.30), three had normal (expected) level-to-dose ratios at some point during the study. In the community-based group, five patients had level-to-dose ratios consistently lower than the normal age-related range (mean level-to-dose ratios, 5.19 to 8.01). One patient (No. 17, Table 11) had a mean phenobarbital level-to-dose ratio above the reported normal range. Dosage reduction in this patient took place during the study and samples were collected before the patient had reached a new steady state; this may have contributed to the high level-to-dose ratio. Through
CLIN PHARMACOL THEK AUGUST 1991
202 Wolf e t al. Table I. Clinic-based patients: level-to-dose ratios for phenobarbital and methadone Phenobarbital LDR Patient No.
Age (yr)
Dose (mglday)
Mean
rt
SD
Range
Methadone LDR Mean t SD
Range
1 2 3 3a 4 4a 5 6 7
8 9 10 Mean SD Median LDR, Level-to-dose ratio. *Omitting values for patient 5, who self-prescribed phenobarbital.
Table 11. Community-based patients: level-to-dose ratios for phenobarbital and methadone Phenobarbital LDR Patient No.
Age (yr)
Dose (mglday)
Mean t SD
Range
Methadone LDR Mean t SD
Range
10a 11 12 13 14 15 16 17
18 19
Mean SD Median *Omitting values for patient 14, who removed phenobarb~talfrom her methadone capsules
our urine screening procedure we know that this patient continued to misuse drugs during the study. This misuse may have included phenobarbital (as a drug of abuse) or heroin, which is frequently "cut" with phenobarbital. On questioning, two clinic-based and four community-based patients admitted to poor compliance. Of these six noncompliers, three (patients 7, 11, and 13) supplemented their methadone prescriptions with more of the narcotic (Fig. l), two (patients 10a and 18) took
their prescriptions at variable intervals (incomplete compliance; Fig. 2), and one (patient 8) took a 3-day prescription of methadone at one time (Fig. 3). The literature suggests that compliance is much improved at doses above 60 mg methadone per day.I8 We were unable to substantiate this view because our patients (except patient 3a) were not prescribed doses in excess of 60 mg methadone per day (Table I, 11). To establish whether the variation observed in the clinic- and community-based groups differed signifi-
VOI.UME 50 NUMBER 2
Intraindividual variation LDR (%) Methadone LDRI Phenobarbital Methadone phenobarbital LDR ratio
Intraindividual variation LDR (%) Methadone LDRI Phenobarbital Methadone phenobarbital LDR ratio
cantly, we used a Mann-Whitney U test (nonparametric test for independent data). Intraindividual variation for the phenobarbital level-to-dose ratio in the clinicbased group was a CV of 13% + 7% (mean ? SD; median, 11%) that ranged from 6% to 29%. Variation was much greater in the community-based group ( p < 0.05) with a CV of 21% t 11% (mean +- SD; median, 29) and a range from 4% to 34%. Interindividual variation in the phenobarbital level-to-dose ratio between clinic-based patients was lower (CV, 19.2%)
Measun'n. compliance with a marker 203 than in the community-based group (CV, 45.4%). In both groups the intraindividual variation in the methadone level-to-dose ratio was higher than that observed for phenobarbital, mean CV was 24% ? 18% (median, 16; range, 7% to 64%) for the clinic-based group and mean CV was 31% ? 19% (median, 36; range, 9% to 55%) for the community-based methadone group. To investigate metabolic tolerance we compared methadone concentrations in plasma, as well as the relationship between the methadone and phenobarbital level-to-dose ratios during the first and last months of treatment. To test for significant changes in the data collected during these periods, we performed a Student t test for correlated data. Nme clinic-based patients had lower mean plasma concentrations of methadone at the end of the study ( p < 0.05) and eight of these patients had lower methadonelphenobarbital level-to-dose ratios. Equivalent statistics could not be applied to the community-based group because too few patients were available for comparison. For instance, patient 11 and 13 misused illicit methadone, patients 10a and 18 misused prescribed methadone, and patients 17 and 19 had their doses reduced during treatment.
DISCUSSION Low-dose phenobarbital has been used successfully as a pharmacologic indicator of compliance in various therapeutic dosing regimes,12.'%nd in this study we showed that phenobarbital can also be used as an indicator of compliance with methadone treatment. The long plasma tl/, of phenobarbital enables compliance to be monitored over the preceding weeks; adequate plasma levels of phenobarbital will not be achieved simply by the ingestion of a few doses of phenobarbital (in the methadone-phenobarbital mixture) a few days before sample collection. '' The variation in plasma methadone level-to-dose ratios observed in our patients was much less than we were led to expect from the observations of other^.'^.'^ Dosing irregularities (incomplete compliance) may account for some of the variation in reported plasma concentrations. The shorter tlI2of methadone (t& = 24 hours) makes plasma drug concentrations susceptible to daily alterations in dosing schedules, whereas plasma phenobarbital, with its longer ty2, is much less affected. Failure to monitor compliance may have contributed to the variation in plasma methadone concentrations. Community-based patients had greater variation in their phenobarbital level-to-dose ratios, suggesting
CLIN PHARMrZCOL THER AUGUST 1991
204 Wolf et al. Phenobarbital
Methadone LDR
0.41
(
~ e t h a d o n eLOR
* he no barbital
LDR r18
LDR
I
Sample collection (weeks)
Fig. 1. Shows sample collections from patient 7, who took illicit methadone to supplement his
prescription at the end of the study. LDR, Level-to-dose ratio. that patients were less compliant when they do not attend the addiction unit. In the unit, methadone is taken under observation once every 24 hours. This variation can be seen clearly with one patient who was more compliant when attending the clinic (No. 10) than when he was based in the community (No. 10a). This finding is significant because it is generally believed that patients who receive permission to collect their prescriptions from local pharmacies are usually compliant. Many patients in this study had very low phenobarbital level-to-dose ratios, which could have been caused by methodological error, pharmaceutical error, patient error, sampling and dosing irregularities, incomplete compliance, or noncompliance. Methodological error is unlikely because the HPLC method for analyzing phenobarbital is both robust and efficient, with an intraindividual CV of 3.7% (repeat analysis of old samples). Incorrect preparation of the methadone-phenobarbital mixture remains a possible source of error, and it is difficult to assess this because the mixture was prepared only on demand. To rule out preparation of the mixture as a problem, we traced the batch number of those patients who had particularly low or high phenobarbital level-to-dose ratios. In every case we found that the patients with discrepant values had received their methadone from the same batch as a patient with
a normal level-to-dose ratio. Furthermore, analysis of freshly prepared methadone-phenobarbital mixtures in the laboratory showed the ratio of the mixture to be correct when medication was dispensed from the top or bottom of the bottle. Errors in level-to-dose ratios will also occur if a patient does not consume all of the methadone prescribed. Because most of our patients were prescribed the lowest dose of methadone that would prevent withdrawal symptoms, they probably took all their prescriptions. The majority of the clinic-based patients rinsed out the vessels from which they took their methadone-phenobarbital mixtures with water and swallowed this residue. Consumption of methadone at the unit was monitored by the staff, and it is unlikely that anyone left some of his or her medication. Indeed, patients often complained that their doses were inadequate. Another reason for low phenobarbital level-to-dose ratios could be some error in dispensing. This was investigated. The staff members at the unit were asked to measure out a range of methadone doses. We found no difference in what staff members were asked to measure and what they actually dispensed. The chaotic lifestyle of drug addicts creates difficulties for investigations such as ours, and dosing schedules were sometimes changed during the study to suit patients. Clinic-based patients were occasionally al-
VOLUME 50 NUMBEK 2
Measu~ingcompliance with a ma&er 205 Methadone LDR
Phenobarbital
43Methadone LDR
1
5
9
*
Phenobarbital
LDR
13 17 21 25 Sample collection (weeks)
LDR
X
29
33
Fig. 2. Incomplete compliance (in which patients take their medication but not in the way prescribed) was observed in patient 18, who consumed more than the prescribed daily amount in the first half of the week and had to abstain in the second half. LDR, Level-to-dose ratio.
lowed to take their methadone medication off the premises, and the timing of take-home privileges often coincided with a fluctuation in the methadone level-todose ratio. We also noted that patients in the community-based group often took their prescriptions at times other than those stipulated. Doses would be subdivided and taken at intervals over 24 hours (patients IOa, 15, and 18 in Table 11). The consumption of subdoses in this manner is unlikely to have any clinical significance. Twenty years ago, single and twice-daily methadone dosing schedules were compared in patients and were shown to have no effect on either symptom complaints or on the misuse of h e r ~ i n . ~ Standardizing the timing of the predose measurements was also difficult for our patients. Many clinicbased patients collected their prescriptions twice a week rather than on a daily basis (patients 3, 4a, 6, 8, and 10 in Table I), whereas the community-based patients attended the clinic only once every 2 weeks (patients 10a, 1l , 13, 16, and 19) or monthly for appointments. Some patients (patients 14, 15, 17, 18) were unwilling (or unable because of employment) to attend more frequently. Only one patient (No. 12, Table 11) was seen once a week. Phenobarbital level-to-dose ratios may also be low if the patient is incompletely compliant or is noncom-
pliant. Incomplete compliance-in which patients take their medication but not to the extent or in the way prescribed-was commonly observed in the community-based group and could be a major cause of variation in plasma methadone concentrations in these patients. This was most apparent in two patients (patients 10a and 18), both of whom consumed more than the prescribed daily amount in the first half of a week and therefore had to abstain in the second half. The occurrence of incomplete compliance, rather than noncompliance (failure to consume any medication in a particular dosing interval), is probably attributable to the nature of methadone itself. The purpose of prescribing a semisynthetic opioid such as methadone relates to its ability to block (cross-tolerate) the euphoric effects of heroin and also to prevent the onset of withdrawal symptoms.21 Thus, for many patients, the consumption of some methadone is a necessity, especially when other illicit opioids are unavailable. Measuring the concentration of both methadone and phenobarbital enabled us to differentiate between consistent and irregular dosing patterns. The incorporation of low-dose phenobarbital into the methadone linctus makes the timing of sampling for phenobarbital unimportant, for at steady state the between-dose fluctuation in plasma phenobarbital concentration is sma11.~
CLlN PHARMACOL THER AUGUST 1991
206 Wolfetal. Methadone LDR
Phenobarbital
LDR
* Methadone LDR A- Phenobarbital
1
5
9
13
LDR
17 21 25 29 33 Sample collection (weeks)
37
41
45
Fig. 3. Shows sample collections from patient 8, who took a 3-day prescription at one time. LDR, Level-to-dose ratio.
The measurement of either methadone or phenobarbital alone has limitations because phenobarbital levels would not indicate when the last dose was taken, and patients who take most of their medication, but who take it irregularly and sometimes in large quantities, may not be detected. Methadone measurements on their own would require strictly controlled dosing and sampling times, and this would be impractical for a drug clinic. The misuse of small quantities of methadone obtained illicitly would probably be difficult to detect with lowdose phenobarbital. Nilsson et a1.22 reported that plasma methadone concentrations decrease as a consequence of metabolic tolerance in patients receiving long-term methadone treatment. This may be one reason that some patients do less well in treatment and some are noncompliant. A few of our clinic-based patients did have lower plasma methadone concentrations at the end of treatment, as well as lower methadonelphenobarbital levelto-dose ratios. Additional study is needed to determine whether this phenomenon contributes to the occurrence of incomplete compliance in certain individuals. The use of low-dose phenobarbital as a pharmacologic marker of compliance gave valuable insight into methadone maintenance programs and highlighted two critical issues for clinicians: the use of illicit methadone and the incorrect self-administration of the drug.
Patients who attended the unit on a regular basis and consumed their medication in front of the staff were substantially more compliant than community-based patients. Measurement of compliance in communitybased patients would therefore seem to be particularly important.
References 1. Goldstein A. Blind comparison of once-daily and twicedaily dosage schedules in a methadone program. CLIN PHARMACOL THER1971;12:59-63. 2. lnturrisi CE, Verebely K. Levels of methadone in plasma during methadone maintenance. CLINPHARMACOL THER1972;13:633-47. 3. Horns WH, Radio M, Goldstein A. Plasma levels and symptom complaints in patients maintained on daily dosage of methadone hydrochloride. CLINPHARMACOL THER1975;17:363-49. 4. Wolff K, Sanderson M, Hay AWM, Raistrick D. Methadone concentrations in plasma and their relationship to drug dosage. Clin Chem 1991;37:205-9. 5. Insull W Jr. Evaluation and recommendations for adherence marker development by working groups of the workshop-appendix: list of actual and potential adherence markers and devices. Controlled Clin Trials 1984;5:584-7. 6. Jones IH. Riboflavine as an indicator of drug taking behaviour. Med J Aust 1967;54:202-4.
VOLUME 50 NUMBER 2
7. Feely M, Cooke J, Price D, Singleton S , Mehta A. Low dose phenobarbitone as an indicator of compliance in drug therapy. Br J Clin Pharmacol 1987;24:77-83. 8. Pullar T, Kumar S, Tindall H, Feely M. Time to stop counting the tablets. CLINPHARMACOL THER1989;46: 163-8. 9. Hardy E, Kumar S, Peaker S, Feely M, Pullar T. A comparison of a short half-life marker (low-dose isoniazid), a long half-life pharmacological indicator (lowdose phenobarbitone) and measurements of a controlled release "therapeutic drug" (metoprolol, Metoros) in reflecting incomplete compliance by volunteers. Br J Clin Pharmacol 1990;30:437-41. 10. Price D, Mehta A, Park BK, Hay AWM, Feely M. The effect of low dose phenobarbitone on three indices of hepatic microsomal enzyme induction. Br J Clin Pharmacol 1986;22:744-7. I I. Kumar S, Pullar T , Feely MP. The dose of phenobarbitone used to measure compliance does not seem to impair pyschomotor function. Br J Clin Pharmacol 1989;28:749P-50P. 12. Pullar T, Birtwell AJ, Wiles PG, Hay AW, Feely MP. Use of a pharmacologic indicator to compare compliance with tablets prescribed to be taken once, twice, or N THER1988;44:540-5. three times daily. C L ~PHARMACOL 13. Kumar S, Peaker S, De Souza N, Haigh JRM, Cooke NJ, Feely MP. Assay of a short half-life therapeutic drug vs a long half-life indicator for the assessment of compliance in tuberculosis. Br J Clin Phannacol 1989;28:733P-4P.
Measun'ng cor*zpliancewith a marker 207 14. Kutt H. Phenobarbitone interactions with other drugs. In: Levy R, Mattson R , Meldrum B, Peny JK, Dreifuss FE, eds. Antiepileptic drugs. 3rd ed. New York: Raven Press, 1989:313-27. 15. Dole VP, Kreek MJ. Plasma methadone levels sustained by a reservoir of drug in tissue. Proc Natl Acad Sci USA 1973:70:10. 16. Wolff K, Shanab M, Sanderson M, Hay A. Screening for drugs of abuse: effect of heat-treating urine for safe handling of samples. Clin Chem 1990;36:908-10. 17. Peaker S, Mehta AC, Kumar S, Feely M. Measurement of low (subtherapeutic) phenobarbitone levels in plasma by high performance liquid chromatography: application to patient compliance studies. J Chromatogr 1989;497:308-12. 18. Nathan JA, Karan LD. Substance abuse treatment modalities in the age of HIV spectrum disease. J Psychoactive Drugs 1989;21:423-9. 19. Kreek MJ. Plasma and urine levels of methadone. NY State J Med 1973;73:2773-7. 20. Anggard E, Gunne LM, Holmstrand J, McMahon RE, Sandberg CG, Sullivan HR. Disposition of methadone in methadone maintenance. CLIN PHARMACOL THER 1975;17:258-66. 21. Dole VP, Nyswander ME, Kreek MJ. Narcotic blockade. Arch Intern Med 1966;118:304-9. 22. Nilsson MI, Anggard E, Holmstrand J, Gunne LM. Pharmacokinetics of methadone during maintenance treatment: adaptive changes in the inductive phase. Eur J Clin Pharmacol 1982;22:343-9.
