Jan W. de Vos1, Jan G.R. Ufkes1, Giel H.A. van Brussel2, Wim van den Brink3


1 Academic Medical Centre, University of Amsterdam, Department of Pharmacology, 1105 AZ Amsterdam, The Netherlands.

2 GG & GD Amsterdam Section GGZ, Drugsdepartment, Valckenierstraat 2, 1018 XG Amsterdam, The Netherlands.

3 Amsterdam Institute for Addiction Research, Jellinek Clinic, Jacob Obrechtstraat 92, 1017 KR Amsterdam, The Netherlands.



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Drug and Alcohol Dependence (1996) 40: 181-184.

Adjusting an adequate methadone dose in methadone maintenance treatment (MMT) is still a paramount problem. Since MMT was introduced many studies were conducted to establish the relation between the pharmacokinetics of methadone and the therapeutic effect. Unfortunately those studies did not lead to a general consensus with regard to well-defined dosage schedules related to clinical goals, i.e. reduction of craving, reduction of additional use of other drugs and reduction of HIV infections. The need of measuring plasma methadone concentrations has also been propagated to evaluate treatment compliance (Wolff and Hay, 1994).

In the Amsterdam MMT program, individual daily methadone doses generally range between 20 to 100 mg, with an average of 54 mg per day (van Brussel et al., 1994). However, in some individual cases much higher doses are provided. In this report an opiate addict claiming a necessary daily dose of at least 300 mg methadone, was examined pharmacokinetically, clinically and psychologically in order to find a rationale for such a request.





Subject History


A 48 year old man with a long history of opiate addiction, is currently under MMT. He is healthy, apart from an unexplained hypercholesterolaemia (14.7 mmol/l) for which he receives, since 1992, 20 mg simvastatin per day. His addiction started with opium use in 1967. In 1969 he suffered from impotention, due to his opiate use. He tried to stop his opiate use, which was unsuccefull. Therefore he turned to the Jellinek Clinic, the first out-patient clinic for addiction in Amsterdam. He then received oral methadone, at the start a dose of 40 mg, which was soon increased to 120 mg per day. Reason for this increase was due to the MMT treatment guidelines introduced at that time in Amsterdam. From 1971 until 1989 he independently increased his daily dose gradually to 400 mg or more per day which he obtained from one or more general practitioners. Under pressure from the regional health authority, these practitioners reduced the dose to 100 mg. Recently the client made a formal complaint, stating that he now was compelled to obtain illegal methadone. During his - unusual - addiction history he smoked heroin for 3 months at age 24 years, but replaced the heroin for methadone, which he prefers. He does not smoke cigarettes nor drinks alcohol, is 178 cm tall and he weighs 79 kg. Currently he usually takes a daily dose of methadone up to 700 mg in one or two doses.


Procedure and analysis


In order to examine his complaint, he was admitted to the crisis, observation and detoxification department (CODA) of the Jellinek Clinic in Amsterdam, a closed metabolic ward. He was admitted for 24 hours. Under supervision he received 250 mg methadone as a linctus orally. After receiving a dose of 250 mg methadone at 0:04 pm the first day, 8 blood samples were taken by venipuncture during the following 24 hours. Also 24-hour urine was sampled. General blood laboratory was performed. The concentrations of methadone and EDDP in plasma and urine were measured using a newly developed HPLC-technique (de Vos et al., 1995). Pharmacokinetic parameters were calculated using standard techniques (Gibaldi and Perrier, 1982). Self reported craving levels were determined on multiple occasions (n=11) independent of the plasma sampling time, using the Experience Sampling Method (ESM). Six questions assessing the presence of craving were answered during 24 hours, using a 7-point Likert scale indicating the severity. The validation and reproducibility of this multiple self report instrument have been published elsewhere (Kaplan, 1992; de Vos et al., 1995, submitted). The craving scale ranges from a low craving (score = -0.25) up to high craving (score = 20.5). Withdrawal signs and symptoms were objectively observed and assessed as present or absent each waking hour of the 24 hour period. The signs adapted from the objective opiate withdrawal scale (OOWS), described by Wang et al. (1974) and Loimer et al. (1991), to be observed were: uncontrollable yawning, running nose, lacrimation, profuse sweating, shivering, abdominal cramps, piloerection, hand tremors, muscular twitches, restlessness and vomiting. Finally the presence of psychopathology was investigated using the General Health Questionnaire (GHQ-28) (Goldberg, 1972) and the Symptom Check List (SCL-90) (Derogatis, 1977). Both questionnaires were filled out between 1 and 4 pm.





Figure 1 Plasma concentration/craving - time curve for methadone, EDDP and craving levels


The methadone dose (250 mg) was administered at time 0 (0:04 pm), the second dose was administered at 23.77 hours (11:50 am) the next day. Plasma methadone concentration: -n-, plasma EDDP concentration: -u-, craving level --, dots indicating the time of measurement.



The Figure (1) shows the plasma concentration - time curve for methadone and EDDP. As can be seen the methadone concentration in plasma just before the methadone ingestion (at 0:02 pm) is extremely high: 3421 ngml-1. This concentration suggests a much higher daily intake than 250 mg methadone. This was confirmed by the client who admitted to have taken 500 mg and 600 mg methadone respectively the previous days. The elimination half-life and the total body clearance are calculated as 37.2 hours and 0.82 mlmin-1kg-1 respectively. The concentrations of methadone and EDDP in the 24-hour urine were 47.05 μgml-1 (0.152 μmolml-1) and 258.13 μgml-1 (0.932 μmolml-1) respectively. The extremely high values of EDDP also confirms the ingestion of high methadone doses the previous days. Liver functions appear to be normal (ASAT = 26 U/l, ALAT = 38 U/l). The cholesterol level is below 6 mmol-1.

The semi-continous course of the self reported craving level over the 24 hour period is also shown in the Figure. The craving remains at a low level (0.5) during most of the day. High craving is seen from 2 hours before, until 2 hours after the methadone administration. On day 1, the craving level drops in the course of 4 hours after the methadone administration to a low level. Withdrawal-like symptoms (profuse sweating, hand tremors, muscular twitches and restlessness) appear to be present from admittance to the ward (10 am) until 2 pm. From 2 pm until the next morning only sweating (not profuse) was observed. Restlessness, profuse sweating and uncontrollable yawning were observed from 9 to 10 pm, the next morning. The physical examination performed 1 hour before and 1 hour after the methadone administration revealed no differences: BP was 150/90 mmHg, pulse was 70 bpm, and breathing frequency was 20 pm, on the first day. The toxicology report of his urine was negative for drugs except for methadone. No psychopathology symptoms were present. The GHQ was scored 0 on all subscales. The total (psychoneuroticism) score for the SCL was 6, indicating no significant psychopathology.





The pharmacokinetic analysis in our patient showed extremely high methadone and EDDP plasma concentrations. The ratio between the plasma methadone concentration and the plasma EDDP concentration is 3:1. This value is very low compared to the values in other opiate addicts (de Vos et al., 1995). An increased metabolic turnover in this subject, might explain the high plasma EDDP and the extremely high urine EDDP concentration. However the methadone half-life calculated was within the range observed in 20 opiate addicts (de Vos et al., 1995). The pharmacokinetic results presented here also do not give evidence to an enhancing influence of simvastatin on the hepatic metabolism of methadone. No literature exists on enhanced hepatic drug metabolizing enzyme activity due to simvastatin. This points to EDDP cumulation rather than an increased metabolism.

Surprisingly the high oral dose was not able to change BP, pulse or breathing frequency. So it is obvious that this patient showed an extremely high tolerance to methadone without any physical harm observed so far.

In spite of the extremely high methadone plasma concentrations, high increases in self reported craving scores are seen around the methadone administration. The self reported craving appeared with the withdrawal signs simultaneously, around the methadone ingestion time. This unexpected rise in craving level together with the extremely high plasma methadone concentration might be explained as a result of conditioned withdrawal as described by Wikler (1973), or as a drug-opposite conditioned response related to the expectance of drug reception (O'Brien et al., 1992). Although no definitive demonstrations on this subject have occurred, high craving or complaining of withdrawal symptoms during adequate plasma methadone levels has been described by others (Horns et al., 1975; Bell et al., 1990; Loimer and Schmid, 1992). Obviously the peak craving levels reflect a subjective state of mind, which seem to be independent of the methadone level in plasma. This can be seen as an example of a sensitization influence of repeated use of drugs on the neural system, making it excessively responsive to the act of drug taking and to stimuli associated with drug taking (Robinson and Berridge, 1993).

In this case report the presence and increase of both objective and subjective craving symptoms is seen around the moment of daily methadone administration. High levels of craving simultaneous with an extremely high plasma methadone concentration, suggests that other factors than plasma methadone concentration play a major role in the experience of craving in this individual. In this case, adjustment of the daily methadone dose should be accompanied by education regarding the daily anticipatory increase of craving towards the usual methadone administration time. This does not mean that plasma methadone concentration levels have no place in dosage adjustment. Measuring plasma methadone concentrations can be helpfull to establish or to exclude a pharmacokinetic cause of inadequate methadone treatment.