Drug and Alcohol Dependence, 30 (1992) 241-246 Elsevier
Scientific
Publishers
Ireland
241
Ltd.
The use of plasma levels to optimize methadone maintenance treatment Norbert Psychiatrische
Loimer and Rainer Schmid
Universitiits Klinik, Wiihringer Giirtel, A-1090 Vienna (Austria)
(Accepted
February
10, 1992)
The question of the optimal methadone dose during maintenance therapy is controversial. For both philosophical and practical reasons, therapeutic drug monitoring has not been generally used. Some therapists prescribe low doses of methadone more for psychological than pharmacological reasons. This study examines, in 104 methadone patients, the relation between selfrating, observer-rating, urine tests, HIV-l serostatus, daily methadone doses and plasma levels of methadone. No differences were found between HIV-1 infected and seronegative patients in these respects. The optimal methadone plasma level as judged by self- and observer-rating was more than 150 ng/ml. For oral methadone, the best results are obtained in patients receiving more than 90 mg daily. We found a significant relationship between methadone dose and plasma levels, also in patients who also used illicit drugs. We conclude that therapeutic drug monitoring should become routine in methadone treatment to achieve optimum results, especially in patients who complain of withdrawal symptoms and continue high-risk behaviour.
Key words: methadone
maintenance
treatment;
drug
monitoring;
Therapeutic drug monitoring is commonly used to monitor patient compliance and to adjust drug dosages to achieve a desired or target plasma drug level. Different methadone plasma concentrations (100 - 400 ng/ml) have been found essential for adequate maintenance (Kreek, 1973, Tennant, 1987, Bell et al., 1988). Recently Dole (1991) recommended that an adequate blocking dose of methadone should reach a blood level of above 200 ng/ml at all times during maintenance therapy to suppress narcotic craving. However, individual variation in pharmacokinetics may influence the metabolism of methadone. There are some individuals in whom even high doses of methadone fail to hold the therapeutic range for the full 24 h (Tennant, 1987). A common strategy to stabilise maintenance patients is dose adjustment. Whereas the dose is increased in some cases, it is decreased in other cases, often for psychological or moral reasons rather than pharmacological ones. Withdrawal reactions play a very important role in
Introduction The pharmacological conditions of opiate addicts may be stabilized by methadone maintenance therapy (Dole and Nyswanger 1965, 1967; Dole, 1989). Clinical success in maintenance treatment might be expected to require stability of the methadone blood level in a pharmacologically effective range, yet there has been surprisingly little interest in integrating plasma methadone monitoring with methadone maintenance treatment. Representatives of non-scientific and anti-medical principles opposing the implementation of methadone, now argue that methadone plasma monitoring diverts attention from the tasks of rehabilitating the addict. On the other hand, with more than 200 000 methadone patients worldwide, monitoring could add significantly to the costs of treatment (Henderson and Harkey, 1990). Correspondence to: N. Loimer, Allgemeines Krankenhaus der Stadt Wien, Psychiatrische Universitatsklinik, Wahringer Gtirtel 18-20, A-1090 Vienna, Austria.
0376-8716/92/.$05.00 0 1992 Elsevier Printed and Published in Ireland
Scientific
Publishers
withdrawal
Ireland
Ltd.
242
behavioural theories of addiction. Most addicts are extremely frightened of withdrawal, but objective rating of withdrawal distress has rarely been used to adjust the methadone dose. Low dose treatments have been reported to have success rates comparable with other studies using higher doses (Craig, 1980). Furthermore it has been shown that high-dose methadone patients perform cognitive and psychomotor tasks as well as selected comparison groups (Appel, 1982). In an earlier study we could not differentiate the psychophysiological responses in patients showing low (~400 nglml) and high (>400 nglml) methadone plasma levels using static and dynamic pupillometry (Loimer et al., 1991a) and skin conductance response. On the other hand patients kept on low dose methadone maintenance have a much higher risk of relapse (Cooper, 1989). Given the spread of HIV by intravenous drug users - now the highest risk group in developed countries - no opportunity for relapse prevention should be ignored. This practical effect of methadone maintenance in reducing i.v. drug use and needle sharing among heroin addicts, now especially important as a means of limiting the spread of AIDS, has been documented (Ball et al., 1988). However, Bell et al. (1990) report that the claim that adequate doses of methadone will suppress illicit drug use oversimplifies the nature of drug dependence. The importance of the measurement of withdrawal symptoms is suggested by the role of withdrawal reactions in the course of maintenance treatment. In the present study the subjectively evaluated and clinically observed symptoms were related to methadone plasma levels during methadone maintenance therapy in order to answer the crucial question: what therapeutic dose in methadone maintenance treatment is necessary to achieve optimal results? Patients
study was performed according to the principles of the declaration of Helsinki. Patients taking part were regularly maintained on methadone. Urine specimens were tested for opiates and other drugs of abuse by EMIT@ tests monthly. Blood samples and measurements were obtained between 12:00 h and 15:OO h. Daily oral methadone ingestion took place between 08:OOh and 1O:OOh. Sample
One hundred and four opiate addicts (35 females, 69 males (age 30.8 years S.D. f 5.2) conforming to DSM-III-R diagnostic criteria (APA, 1987) for opiate dependence with a mean of 13.4, SD. f 5.7, years opiate addiction history were investigated at the Psychiatrische Universitats Klinik, Vienna. Daily oral d,2-methadone dosage averaged 83.3, S.D. f 32.4, mg; stable methadone doses were dispensed to patients for a period of 2 - 45 months (mean 13.3 months). Assessment
scales
The 20-item self-rating scale consisted of pairs of pleasant and unpleasant feelings and covered the following signs and symptoms: concentration, appetite, craving, pessimism, activity, anxiety, sleep, restlessness, mood, irritability, pain, sexual appetite, sweating, diarrhoea, insomnia, tremor, weakness, flashing, aching bones and muscles. To evaluate the degree of these complaints patients had to rate themselves on a visual lOO-mm analogue scale. The total score was calculated by adding up all the 20 items. A global score of withdrawal distress was calculated. The observer-rating scale consists of 11 signs related to withdrawal. These signs were given different weights and rated as absent or present. Possible scores ranged from 0 to a maximum of 29 (Loimer et al., 1991b; Wang et al., 1974).
and Methods Quantitative
Study design
All patients gave informed consent to the study which had been approved by the Ethical Committee of the University of Vienna. The
determination
of methadone
Plasma levels of methadone were determined by means of a newly developed HPLC method. Prior to analysis all plasma samples were preventatively HIV-deactivated by incubation at
243
56°C for 60 min. HPLC separation was done using a mobile phase of 75 mM ammonium acetate (pH G.O)/methanol (1:9) at a flow rate of 1.5 ml/min over a 100 x 4.6 mm column filled with 5 pm bare silica (Partisphere, Whatman). Absorbance detection at 254 nm (SPD-GA, Shimadzu) after on-line photochemical reaction (Beam Boost, ICT) and integration by a data system (CI-10, LDC) was used to quantify the signal. Sample preparation of the blood plasma was done by on-line extraction of 400 ~1 plasma over a 20 x 2 mm pre-column filled with cyclobond I, 40 pm (Astec). included KolomogorovStatistic analyses Smirnov test, t-test and regression analyses. Results In the 104 patients the mean oral dose of d,l-methadone was 83.3 f 32.4 mg plasma methadone levels ranged from 20 to 1308 ng/ml; mean 451.4 f 306.6 ng/ml. Of the patients 51.9% were HIV-1 negative, 39.4% HIV-l positive and in 8.7% the HIV-l status was not obtained. The differences between HIV-l infected and HIV-l negative patients (Table I) did not reach a level of significance (Kolmogorov Smirnov test; t-test). In patients using only methadone as proved by urine analysis, a significant relationship between plasma methadone level and methadone dose was observed by means of regression analyses (r2 = 0.62602, P = 0.000).In patients using additional drugs (opiate, benzodiazepine, barbiturate, methaqualone, amphet-
Table I.
The impact
of HIV-l
infection
on methadone HIV-1
Daily methadone dosage (mg) Methadone plasma levels ng/ml Continuous MMT (months) Body wt. (kg) Body height (cm) Age (years) Opiate addiction (years)
82.3 442.5 11.9 69.6 174.2 30.9 13.4
maintenance.
Negative S.D. S.D. S.D. S.D. S.D. S.D. S.D.
amine, cocaine) this correlation was also observed (r2 = 0.47761, P = 0.0037). Between selfrating (r2 = 0.10312, P = 0.2976) and observer rating (r2 = 0.10312, P = 0.0732) no statistically significant difference could be calculated. Correlations between self assessment and observer assessment were significant (r2 = 0.45303, P = 0.000)as shown by regression analyses. The differences in methadone plasma levels in patients showing no withdrawal signs in self rating (439.2 ng/ml, S.D. + 269.0) and those showing withdrawal signs (477.5 ng/ml, S.D. f 378.3) did not reach statistical significance (F = 1.98, t = 0.59, P = 0.604). The difference in methadone plasma levels between patients showing withdrawal signs in observer rating (426.8 nglml, S.D. f 325.3) and those showing no withdrawal signs (478.9 ng/ml, S.D. f 284.8) did not reach statistical significance (F = 1.30, t = -0.86, P = 0.386). Regarding the oral methadone dosage no significant differences were obtained between patients showing withdrawal signs in self rating 83.9 mg, S.D. f 32.6 and patients feeling comfortable 81.9 mg, S.D. f 32.4 (F = 1.01, t = -0.29, P = 0.774). Also in the assessors’ ratings there were no statistical differences in the daily methadone dose between patients who had no withdrawal signs 85.5 mg, S.D. f 30.8 and patients showing withdrawal symptoms 81.2 mg, S.D. * 33.9 (F = 1.12, t = -0.69, P = 0.492). Following Dole’s (1991) suggestion the measured methadone plasma levels were divided into three groups. In the first group A levels
f 31.2 f 296.6 + 13.3 zt 12.4 z+z 7.8 f 5.8 f 6.1
HIV-l 87.0 469.7 16.4 67.8 175.8 31.0 14.1
Positive S.D. S.D. S.D. S.D. S.D. S.D. S.D.
=t 33.9 + 323.2 f 13.6 zt 12.4 zt 8.2 zt 4.3 zt 4.2
244 Table II.
Correlations between plasma levels and rating scales.
nglml
Self rating (SR)
Observer rating (OR)
A 600 (n = 29)
44.8 S.D. zt 16.3 38.3 S.D. + 15.8 47.5 S.D. zt 17.2
7.4 S.D. * 5.7 2.3 S.D. zt 3.6 3.7 S.D. * 3.8
Statistics: SR, B:C P < 0.05 (df = 52.22, t = -2.42); OR, A:B P < 0.001 (df = 21.53, t = 3.58); OR, A:C P < 0.05 (df = 26.77, t = 2.41); all other correlations did not reach level of statistical significance.
were less than 150 ng/ml (n = 18), in the second group B levels ranged from 150 nglml to 600 nglml (n = 57). The third group C had levels above 600 ng/ml (n = 29). Table II shows the correlation between these groups and self and observer rating. The daily methadone dosages were also divided into three groups: A: dosages below 60 mg (n = 21); B: 60- 90 mg (n = 51) and C: more than 90 mg methadone per day. Table III shows the correlation between these groups and self and observer rating. Discussion The current resurgence of interest in methadone programmes is prompted by the spread of the HIV-l infection among intravenous drug addicts. The historical basis for this medical treatment was the departure from the traditional concept of addiction as misbehavior (Dole, 1989). The essential feature in the treatment is the stability of receptor occupation, which permits interacting systems to function normally. All investigators have found that even with a constant dose of methadone there are large differences in plasma methadone
Table III.
levels among patients. Therefore, it is not surprising that there are good data showing patients responding poorly to methadone treatment. The present results seem to state that there are no associations between the presence or absence of withdrawal symptoms on the one hand and between methadone dosage and levels of plasma methadone on the other. One interesting observation concerns patients with plasma levels greater than 600 ng/ml. These subjects reported withdrawal symptoms. With the advent of AIDS among intravenous drug users all possibilities to reduce the further spread of this infection should be considered. Methadone maintenance is very effective in reducing the dissemination of HIV-l among intravenous drug users and is worldwide used in currently more than 200 000 patients (Henderson and Harkey, 1990). Because of AIDS, methadone is used more and more in chronic maintenance treatment of addiction all over the world (Cooper, 1989). However, there has been little interest in the introduction of therapeutic drug monitoring in methadone maintenance programmes over the years and there has been surprisingly little study of the severity of withdrawal during methadone maintenance
Correlations between methadone dosage and rating scales.
mg
Self-rating (SR)
Observer-rating
A 90 (n = 30)
47.7 S.D. zt 18.9 40.7 S.D. zt 15.4 39.7 S.D. l 16.7
5.9 S.D. * 6.0 3.3 S.D. + 4.3 2.6 S.D. f 2.9
St&istics:
(OR)
OR, A:C P < 0.05 (df = 26.78, t = 2.28); all other correlations
did not reach level of statistical significance.
245
therapy using both self-rating and clinical assessment. Treatment outcome was mostly related to polydrug use, relapse and abstinence. Reconsidering methadone therapy as a medical treatment in cases of opiate addiction, the correlation of withdrawal distress and methadone plasma levels is a possible way to optimize this treatment. The dramatic increase in methadone maintenance programmes in the late 1960s was accompanied by a lowering of the dosage and the introduction of limits on the duration of treatment itself. These historical faults should not be repeated. The subjective and objective well being of the patient can be measured by rating scales and related to plasma levels to prevent premature discontinuation of treatment. Methadone is difficult to use due to the slow response to changes in dose regimen and the wide inter-patient variation in methadone clearance (Gourlay et al., 1986) Steady state plasma levels in chronically treated individuals are essential for the normalization of physiological functions in addicts. According to earlier findings (Kreek et al., 1976, Liu and Wang, 1984), the dosage of methadone does not seem to correspond directly with resulting plasma methadone concentrations, which are a measure for the pharmacological action, but as the results of this study show there was a statistical relation between these parameters. Also in earlier studies methadone plasma concentrations and complaints of withdrawal symptoms in methadone patients have been found to be unrelated to the oral methadone dose (Goldstein, 1971). Higher methadone doses are not harmful for patients during their enrolment in maintenance treatment and do not reduce behavioural arousal (Loimer et al., 1991b). The present findings should be a challenge to achieve adequate individual methadone plasma levels in maintenance programmes. There is no rationale for maintaining patients on low plasma levels of methadone. The AIDS epidemic makes it particularly necessary to stabilize drug abusing patients, as was recommended when methadone treatment was first introduced (Dole and Nyswander, 1965, 1967). Terminating treatment has been the final form of so-called ‘limit-
setting’ that was applied in methadone programmes for intravenous drug users. Adequate plasma levels should lead to better stabilization of those drug addicts who need long-term maintenance. Therapeutic drug monitoring in addition to urine testing is necessary to prevent the drug user from relapse and intravenous drug use. To discover why some individuals perform so poorly during substitution therapy has a new relevance, since methadone is the therapy of choice to keep drug users away from high risk practices (Cooper, 1989). Acknowledgement This work was supported by grant #P 76741Med from the Fond zur Fijrderung der wissenschaftlichen Forschung, Austria. The authors want to express their gratitude to Dr. C. Brewer, London for help in preparing this paper. References American Psychiatric Association (1987) Diagnostic criteria from DSM-III-R. Appel, P.W. (1982) Sustained attention in methadone patients. Int. J. Addict. 17, 1313-1327. Ball, J.C., Myers, C.P. and Friedman, S. (1988) Reducing the risk of AIDS through methadone maintenance treatment. J. Hlth. Sot. Behav. 29, 214- 226. Bell, J., Seres, B., Bowron, P., Lewis, J. and Batey, R. (1988) The use of serum methadone levels in patients receiving methadone maintenance. Clin. Pharmacol. Ther. 43, 623-629. Bell, J., Seres, B., Bowron, P., Lewis, J. and Batey, R. (1990) Serum levels of methadone in maintenance clients who persist in illicit drug use. Br. J. Addict. 85, 1599- 1602. Cooper, J.R. (1989) Methadone treatment and acquired immunodeficiency syndrome. J. Am. Med. Assoc. 262; 12, 1664 - 1668. Craig, R.J. (1980) Effectiveness of low-dose methadone maintenance for the treatment of inner city heroin addicts. Int. J. Addict. 15, 701-710. Dole, V.P. and Nyswander, M. (1965) A medical treatment for diacetylmorphine (heroin) addiction. J. Am. Med. Assoc. 195, 80 - 84. Dole, V.P. and Nyswander, M. (1967) Heroin addiction - a metabolic disease. Arch. Intern. Med. 120, 19-24. Dole, V.P. (1989) Methadone treatment and the acquired immunodefiency syndrome epidemic. J. Am. Med. Assoc. 262; 2, 1681- 1682.
246 Dole, V.P. (1991) Foreword. In: The Effectiveness of Methadone Maintenance Treatment (Ball, J.C. and Ross, A., eds.), pp. VII-VIII. Springer, New York. Goldstein, A. (1971) Blind dosage comparison and other studies in a large methadone program. J. Psychodel. Drugs 4, 177- 181. Gourlay, G.K., Cherry, D.A. and Cousins, M.J. (1986) A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in treatment of severe pain in patients with cancer. Pain 25, 297 - 312. Henderson, G.S. and Harkey, M.R. (1990) The use of therapeutic drug monitoring to improve the effectiveness of methadone treatment, pp. 1 - 32. Department of Alcohol and Drug Programs, State of California. Kreek, M.J., Gutjahr, C.L., Garfield, J.W., Bowen, D.V. and Field, F.H. (1976) Drug interactions with methadone. Ann. N. Y. Acad. Sci. 281, 350-370. Kreek, M.J. (1973) Plasma and urine levels of methadone. N.Y. State J. Med. 73, 2773-2777.
Liu, S.J. and Wang, R.I.H. (1984) Case report of barbiturate-induced enhancement of methadone metabolism and withdrawal syndrome. Am. J. Psychiat. 141, 1287 - 1288. Loimer, N., Schmid, R., Griinberger, J., Jagsch, R., Linzmayer, L. and Presslich, 0. (1991a) Psychophysiological reactions in methadone maintenance patients do not correlate with methadone plasma levels. Psychopharmacology 103, 538 - 540. Loimer, N., Linzmayer, L. and Griinberger, J. (1991b) Comparison between observer assessment and self rating of withdrawal distress during opiate detoxification. Drug Alcohol Depend. 28, 265 - 268. Tennant, F.S. (1987) Inadequate plasma concentrations in some high dose methadone maintenance patients. Am. J. Psychiat. 144, 1349- 1350. Wang, R.I.H., Wiesen, R.L., Lamid, S. and Roh, B.L. (1974) Rating the presence and severity of opiate dependence. Clin. Pharmacol. Ther. 16, 653-658.
Scientific
Publishers
Ireland
241
Ltd.
The use of plasma levels to optimize methadone maintenance treatment Norbert Psychiatrische
Loimer and Rainer Schmid
Universitiits Klinik, Wiihringer Giirtel, A-1090 Vienna (Austria)
(Accepted
February
10, 1992)
The question of the optimal methadone dose during maintenance therapy is controversial. For both philosophical and practical reasons, therapeutic drug monitoring has not been generally used. Some therapists prescribe low doses of methadone more for psychological than pharmacological reasons. This study examines, in 104 methadone patients, the relation between selfrating, observer-rating, urine tests, HIV-l serostatus, daily methadone doses and plasma levels of methadone. No differences were found between HIV-1 infected and seronegative patients in these respects. The optimal methadone plasma level as judged by self- and observer-rating was more than 150 ng/ml. For oral methadone, the best results are obtained in patients receiving more than 90 mg daily. We found a significant relationship between methadone dose and plasma levels, also in patients who also used illicit drugs. We conclude that therapeutic drug monitoring should become routine in methadone treatment to achieve optimum results, especially in patients who complain of withdrawal symptoms and continue high-risk behaviour.
Key words: methadone
maintenance
treatment;
drug
monitoring;
Therapeutic drug monitoring is commonly used to monitor patient compliance and to adjust drug dosages to achieve a desired or target plasma drug level. Different methadone plasma concentrations (100 - 400 ng/ml) have been found essential for adequate maintenance (Kreek, 1973, Tennant, 1987, Bell et al., 1988). Recently Dole (1991) recommended that an adequate blocking dose of methadone should reach a blood level of above 200 ng/ml at all times during maintenance therapy to suppress narcotic craving. However, individual variation in pharmacokinetics may influence the metabolism of methadone. There are some individuals in whom even high doses of methadone fail to hold the therapeutic range for the full 24 h (Tennant, 1987). A common strategy to stabilise maintenance patients is dose adjustment. Whereas the dose is increased in some cases, it is decreased in other cases, often for psychological or moral reasons rather than pharmacological ones. Withdrawal reactions play a very important role in
Introduction The pharmacological conditions of opiate addicts may be stabilized by methadone maintenance therapy (Dole and Nyswanger 1965, 1967; Dole, 1989). Clinical success in maintenance treatment might be expected to require stability of the methadone blood level in a pharmacologically effective range, yet there has been surprisingly little interest in integrating plasma methadone monitoring with methadone maintenance treatment. Representatives of non-scientific and anti-medical principles opposing the implementation of methadone, now argue that methadone plasma monitoring diverts attention from the tasks of rehabilitating the addict. On the other hand, with more than 200 000 methadone patients worldwide, monitoring could add significantly to the costs of treatment (Henderson and Harkey, 1990). Correspondence to: N. Loimer, Allgemeines Krankenhaus der Stadt Wien, Psychiatrische Universitatsklinik, Wahringer Gtirtel 18-20, A-1090 Vienna, Austria.
0376-8716/92/.$05.00 0 1992 Elsevier Printed and Published in Ireland
Scientific
Publishers
withdrawal
Ireland
Ltd.
242
behavioural theories of addiction. Most addicts are extremely frightened of withdrawal, but objective rating of withdrawal distress has rarely been used to adjust the methadone dose. Low dose treatments have been reported to have success rates comparable with other studies using higher doses (Craig, 1980). Furthermore it has been shown that high-dose methadone patients perform cognitive and psychomotor tasks as well as selected comparison groups (Appel, 1982). In an earlier study we could not differentiate the psychophysiological responses in patients showing low (~400 nglml) and high (>400 nglml) methadone plasma levels using static and dynamic pupillometry (Loimer et al., 1991a) and skin conductance response. On the other hand patients kept on low dose methadone maintenance have a much higher risk of relapse (Cooper, 1989). Given the spread of HIV by intravenous drug users - now the highest risk group in developed countries - no opportunity for relapse prevention should be ignored. This practical effect of methadone maintenance in reducing i.v. drug use and needle sharing among heroin addicts, now especially important as a means of limiting the spread of AIDS, has been documented (Ball et al., 1988). However, Bell et al. (1990) report that the claim that adequate doses of methadone will suppress illicit drug use oversimplifies the nature of drug dependence. The importance of the measurement of withdrawal symptoms is suggested by the role of withdrawal reactions in the course of maintenance treatment. In the present study the subjectively evaluated and clinically observed symptoms were related to methadone plasma levels during methadone maintenance therapy in order to answer the crucial question: what therapeutic dose in methadone maintenance treatment is necessary to achieve optimal results? Patients
study was performed according to the principles of the declaration of Helsinki. Patients taking part were regularly maintained on methadone. Urine specimens were tested for opiates and other drugs of abuse by EMIT@ tests monthly. Blood samples and measurements were obtained between 12:00 h and 15:OO h. Daily oral methadone ingestion took place between 08:OOh and 1O:OOh. Sample
One hundred and four opiate addicts (35 females, 69 males (age 30.8 years S.D. f 5.2) conforming to DSM-III-R diagnostic criteria (APA, 1987) for opiate dependence with a mean of 13.4, SD. f 5.7, years opiate addiction history were investigated at the Psychiatrische Universitats Klinik, Vienna. Daily oral d,2-methadone dosage averaged 83.3, S.D. f 32.4, mg; stable methadone doses were dispensed to patients for a period of 2 - 45 months (mean 13.3 months). Assessment
scales
The 20-item self-rating scale consisted of pairs of pleasant and unpleasant feelings and covered the following signs and symptoms: concentration, appetite, craving, pessimism, activity, anxiety, sleep, restlessness, mood, irritability, pain, sexual appetite, sweating, diarrhoea, insomnia, tremor, weakness, flashing, aching bones and muscles. To evaluate the degree of these complaints patients had to rate themselves on a visual lOO-mm analogue scale. The total score was calculated by adding up all the 20 items. A global score of withdrawal distress was calculated. The observer-rating scale consists of 11 signs related to withdrawal. These signs were given different weights and rated as absent or present. Possible scores ranged from 0 to a maximum of 29 (Loimer et al., 1991b; Wang et al., 1974).
and Methods Quantitative
Study design
All patients gave informed consent to the study which had been approved by the Ethical Committee of the University of Vienna. The
determination
of methadone
Plasma levels of methadone were determined by means of a newly developed HPLC method. Prior to analysis all plasma samples were preventatively HIV-deactivated by incubation at
243
56°C for 60 min. HPLC separation was done using a mobile phase of 75 mM ammonium acetate (pH G.O)/methanol (1:9) at a flow rate of 1.5 ml/min over a 100 x 4.6 mm column filled with 5 pm bare silica (Partisphere, Whatman). Absorbance detection at 254 nm (SPD-GA, Shimadzu) after on-line photochemical reaction (Beam Boost, ICT) and integration by a data system (CI-10, LDC) was used to quantify the signal. Sample preparation of the blood plasma was done by on-line extraction of 400 ~1 plasma over a 20 x 2 mm pre-column filled with cyclobond I, 40 pm (Astec). included KolomogorovStatistic analyses Smirnov test, t-test and regression analyses. Results In the 104 patients the mean oral dose of d,l-methadone was 83.3 f 32.4 mg plasma methadone levels ranged from 20 to 1308 ng/ml; mean 451.4 f 306.6 ng/ml. Of the patients 51.9% were HIV-1 negative, 39.4% HIV-l positive and in 8.7% the HIV-l status was not obtained. The differences between HIV-l infected and HIV-l negative patients (Table I) did not reach a level of significance (Kolmogorov Smirnov test; t-test). In patients using only methadone as proved by urine analysis, a significant relationship between plasma methadone level and methadone dose was observed by means of regression analyses (r2 = 0.62602, P = 0.000).In patients using additional drugs (opiate, benzodiazepine, barbiturate, methaqualone, amphet-
Table I.
The impact
of HIV-l
infection
on methadone HIV-1
Daily methadone dosage (mg) Methadone plasma levels ng/ml Continuous MMT (months) Body wt. (kg) Body height (cm) Age (years) Opiate addiction (years)
82.3 442.5 11.9 69.6 174.2 30.9 13.4
maintenance.
Negative S.D. S.D. S.D. S.D. S.D. S.D. S.D.
amine, cocaine) this correlation was also observed (r2 = 0.47761, P = 0.0037). Between selfrating (r2 = 0.10312, P = 0.2976) and observer rating (r2 = 0.10312, P = 0.0732) no statistically significant difference could be calculated. Correlations between self assessment and observer assessment were significant (r2 = 0.45303, P = 0.000)as shown by regression analyses. The differences in methadone plasma levels in patients showing no withdrawal signs in self rating (439.2 ng/ml, S.D. + 269.0) and those showing withdrawal signs (477.5 ng/ml, S.D. f 378.3) did not reach statistical significance (F = 1.98, t = 0.59, P = 0.604). The difference in methadone plasma levels between patients showing withdrawal signs in observer rating (426.8 nglml, S.D. f 325.3) and those showing no withdrawal signs (478.9 ng/ml, S.D. f 284.8) did not reach statistical significance (F = 1.30, t = -0.86, P = 0.386). Regarding the oral methadone dosage no significant differences were obtained between patients showing withdrawal signs in self rating 83.9 mg, S.D. f 32.6 and patients feeling comfortable 81.9 mg, S.D. f 32.4 (F = 1.01, t = -0.29, P = 0.774). Also in the assessors’ ratings there were no statistical differences in the daily methadone dose between patients who had no withdrawal signs 85.5 mg, S.D. f 30.8 and patients showing withdrawal symptoms 81.2 mg, S.D. * 33.9 (F = 1.12, t = -0.69, P = 0.492). Following Dole’s (1991) suggestion the measured methadone plasma levels were divided into three groups. In the first group A levels
f 31.2 f 296.6 + 13.3 zt 12.4 z+z 7.8 f 5.8 f 6.1
HIV-l 87.0 469.7 16.4 67.8 175.8 31.0 14.1
Positive S.D. S.D. S.D. S.D. S.D. S.D. S.D.
=t 33.9 + 323.2 f 13.6 zt 12.4 zt 8.2 zt 4.3 zt 4.2
244 Table II.
Correlations between plasma levels and rating scales.
nglml
Self rating (SR)
Observer rating (OR)
A 600 (n = 29)
44.8 S.D. zt 16.3 38.3 S.D. + 15.8 47.5 S.D. zt 17.2
7.4 S.D. * 5.7 2.3 S.D. zt 3.6 3.7 S.D. * 3.8
Statistics: SR, B:C P < 0.05 (df = 52.22, t = -2.42); OR, A:B P < 0.001 (df = 21.53, t = 3.58); OR, A:C P < 0.05 (df = 26.77, t = 2.41); all other correlations did not reach level of statistical significance.
were less than 150 ng/ml (n = 18), in the second group B levels ranged from 150 nglml to 600 nglml (n = 57). The third group C had levels above 600 ng/ml (n = 29). Table II shows the correlation between these groups and self and observer rating. The daily methadone dosages were also divided into three groups: A: dosages below 60 mg (n = 21); B: 60- 90 mg (n = 51) and C: more than 90 mg methadone per day. Table III shows the correlation between these groups and self and observer rating. Discussion The current resurgence of interest in methadone programmes is prompted by the spread of the HIV-l infection among intravenous drug addicts. The historical basis for this medical treatment was the departure from the traditional concept of addiction as misbehavior (Dole, 1989). The essential feature in the treatment is the stability of receptor occupation, which permits interacting systems to function normally. All investigators have found that even with a constant dose of methadone there are large differences in plasma methadone
Table III.
levels among patients. Therefore, it is not surprising that there are good data showing patients responding poorly to methadone treatment. The present results seem to state that there are no associations between the presence or absence of withdrawal symptoms on the one hand and between methadone dosage and levels of plasma methadone on the other. One interesting observation concerns patients with plasma levels greater than 600 ng/ml. These subjects reported withdrawal symptoms. With the advent of AIDS among intravenous drug users all possibilities to reduce the further spread of this infection should be considered. Methadone maintenance is very effective in reducing the dissemination of HIV-l among intravenous drug users and is worldwide used in currently more than 200 000 patients (Henderson and Harkey, 1990). Because of AIDS, methadone is used more and more in chronic maintenance treatment of addiction all over the world (Cooper, 1989). However, there has been little interest in the introduction of therapeutic drug monitoring in methadone maintenance programmes over the years and there has been surprisingly little study of the severity of withdrawal during methadone maintenance
Correlations between methadone dosage and rating scales.
mg
Self-rating (SR)
Observer-rating
A 90 (n = 30)
47.7 S.D. zt 18.9 40.7 S.D. zt 15.4 39.7 S.D. l 16.7
5.9 S.D. * 6.0 3.3 S.D. + 4.3 2.6 S.D. f 2.9
St&istics:
(OR)
OR, A:C P < 0.05 (df = 26.78, t = 2.28); all other correlations
did not reach level of statistical significance.
245
therapy using both self-rating and clinical assessment. Treatment outcome was mostly related to polydrug use, relapse and abstinence. Reconsidering methadone therapy as a medical treatment in cases of opiate addiction, the correlation of withdrawal distress and methadone plasma levels is a possible way to optimize this treatment. The dramatic increase in methadone maintenance programmes in the late 1960s was accompanied by a lowering of the dosage and the introduction of limits on the duration of treatment itself. These historical faults should not be repeated. The subjective and objective well being of the patient can be measured by rating scales and related to plasma levels to prevent premature discontinuation of treatment. Methadone is difficult to use due to the slow response to changes in dose regimen and the wide inter-patient variation in methadone clearance (Gourlay et al., 1986) Steady state plasma levels in chronically treated individuals are essential for the normalization of physiological functions in addicts. According to earlier findings (Kreek et al., 1976, Liu and Wang, 1984), the dosage of methadone does not seem to correspond directly with resulting plasma methadone concentrations, which are a measure for the pharmacological action, but as the results of this study show there was a statistical relation between these parameters. Also in earlier studies methadone plasma concentrations and complaints of withdrawal symptoms in methadone patients have been found to be unrelated to the oral methadone dose (Goldstein, 1971). Higher methadone doses are not harmful for patients during their enrolment in maintenance treatment and do not reduce behavioural arousal (Loimer et al., 1991b). The present findings should be a challenge to achieve adequate individual methadone plasma levels in maintenance programmes. There is no rationale for maintaining patients on low plasma levels of methadone. The AIDS epidemic makes it particularly necessary to stabilize drug abusing patients, as was recommended when methadone treatment was first introduced (Dole and Nyswander, 1965, 1967). Terminating treatment has been the final form of so-called ‘limit-
setting’ that was applied in methadone programmes for intravenous drug users. Adequate plasma levels should lead to better stabilization of those drug addicts who need long-term maintenance. Therapeutic drug monitoring in addition to urine testing is necessary to prevent the drug user from relapse and intravenous drug use. To discover why some individuals perform so poorly during substitution therapy has a new relevance, since methadone is the therapy of choice to keep drug users away from high risk practices (Cooper, 1989). Acknowledgement This work was supported by grant #P 76741Med from the Fond zur Fijrderung der wissenschaftlichen Forschung, Austria. The authors want to express their gratitude to Dr. C. Brewer, London for help in preparing this paper. References American Psychiatric Association (1987) Diagnostic criteria from DSM-III-R. Appel, P.W. (1982) Sustained attention in methadone patients. Int. J. Addict. 17, 1313-1327. Ball, J.C., Myers, C.P. and Friedman, S. (1988) Reducing the risk of AIDS through methadone maintenance treatment. J. Hlth. Sot. Behav. 29, 214- 226. Bell, J., Seres, B., Bowron, P., Lewis, J. and Batey, R. (1988) The use of serum methadone levels in patients receiving methadone maintenance. Clin. Pharmacol. Ther. 43, 623-629. Bell, J., Seres, B., Bowron, P., Lewis, J. and Batey, R. (1990) Serum levels of methadone in maintenance clients who persist in illicit drug use. Br. J. Addict. 85, 1599- 1602. Cooper, J.R. (1989) Methadone treatment and acquired immunodeficiency syndrome. J. Am. Med. Assoc. 262; 12, 1664 - 1668. Craig, R.J. (1980) Effectiveness of low-dose methadone maintenance for the treatment of inner city heroin addicts. Int. J. Addict. 15, 701-710. Dole, V.P. and Nyswander, M. (1965) A medical treatment for diacetylmorphine (heroin) addiction. J. Am. Med. Assoc. 195, 80 - 84. Dole, V.P. and Nyswander, M. (1967) Heroin addiction - a metabolic disease. Arch. Intern. Med. 120, 19-24. Dole, V.P. (1989) Methadone treatment and the acquired immunodefiency syndrome epidemic. J. Am. Med. Assoc. 262; 2, 1681- 1682.
246 Dole, V.P. (1991) Foreword. In: The Effectiveness of Methadone Maintenance Treatment (Ball, J.C. and Ross, A., eds.), pp. VII-VIII. Springer, New York. Goldstein, A. (1971) Blind dosage comparison and other studies in a large methadone program. J. Psychodel. Drugs 4, 177- 181. Gourlay, G.K., Cherry, D.A. and Cousins, M.J. (1986) A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in treatment of severe pain in patients with cancer. Pain 25, 297 - 312. Henderson, G.S. and Harkey, M.R. (1990) The use of therapeutic drug monitoring to improve the effectiveness of methadone treatment, pp. 1 - 32. Department of Alcohol and Drug Programs, State of California. Kreek, M.J., Gutjahr, C.L., Garfield, J.W., Bowen, D.V. and Field, F.H. (1976) Drug interactions with methadone. Ann. N. Y. Acad. Sci. 281, 350-370. Kreek, M.J. (1973) Plasma and urine levels of methadone. N.Y. State J. Med. 73, 2773-2777.
Liu, S.J. and Wang, R.I.H. (1984) Case report of barbiturate-induced enhancement of methadone metabolism and withdrawal syndrome. Am. J. Psychiat. 141, 1287 - 1288. Loimer, N., Schmid, R., Griinberger, J., Jagsch, R., Linzmayer, L. and Presslich, 0. (1991a) Psychophysiological reactions in methadone maintenance patients do not correlate with methadone plasma levels. Psychopharmacology 103, 538 - 540. Loimer, N., Linzmayer, L. and Griinberger, J. (1991b) Comparison between observer assessment and self rating of withdrawal distress during opiate detoxification. Drug Alcohol Depend. 28, 265 - 268. Tennant, F.S. (1987) Inadequate plasma concentrations in some high dose methadone maintenance patients. Am. J. Psychiat. 144, 1349- 1350. Wang, R.I.H., Wiesen, R.L., Lamid, S. and Roh, B.L. (1974) Rating the presence and severity of opiate dependence. Clin. Pharmacol. Ther. 16, 653-658.
