Summary

Chapter 1

Chapter 1 describes the questions leading to this study, the aims and, the methods used. During the past 25 years experience has been gained with methadone maintenance treatment (MMT) in the Netherlands. Many heroin-dependent individuals continue, despite the maintenance treatment with methadone and the support from the MMT facilities, to use heroin or other illegal drugs. The use of heroin or other illegal drugs, besides the daily methadone maintenance dose, can be caused by an inadequate methadone dose, an inadequate plasma methadone concentration or other factors. This study was performed to illucidate why some MMT patients, despite receiving methadone, continue to display craving for heroin. The methods used in this study include the determination of the pharmacokinetics of methadone, measuring the level of craving and assessing the presence of psychopathology. The use of other illegal drugs is evaluated through urine sampling. The individual dependency history is recorded. The influence of a rapid acting synthetic opiate (dextromoramide), which is administered besides methadone, on the level of craving is measured as well. In this study both l-methadone and d,lmethadone are compared with regard to the level of craving, the individual dose adjustment requirements and illegal drug use. The purpose of this thesis is to describe and to evaluate the diverse factors which may contribute to craving during MMT. *

Chapter 2

In a closed metabolic ward the pharmacokinetics of methadone and its primary metabolite (EDDP) were studied in twenty long-term heroin-dependent patients. After administration of the daily oral dose of methadone-HCI (mean: 60 mg, range: 10 225 mg) blood samples were taken and analysed, using a newly developed highperformance liquid chromatography (HPLC) method. The steady-state plasma concentrations of the 20 subjects varied from 65 to 630 ng ml~' and from 5 to 55 ng ml-', whereas the peak concentrations were 124 to 1255 ng ml~' and 10 to 301 ng ml~: for methadone and EDDP respectively. The calculated ratios between the area under the curve (AUC(024h)) for methadone and the AUC(024h, for EDDP varied from 5.9 to 44.6, indicating interindividual differences in metabolic activity. In 19 out of 20 subjects the pharmacokinetics of oral methadone at steady-state are best described using a two compartment model. The mean body clearance was 1.64 ml min~' kg~', whereas the mean elimination rate constant (|) and plasma half-life (t~S) were 0.026 h-' (range: 0.013 - 0.053 h-') and 31.2 h (range: 13 - 53 h) respectively. Differences of gender were also found. A poor correlation was found between the methadone dose and the steady-state level. A much better correlation was found between the normalized steady-state level and the body clearance.

Chapter 3

TO study the pnarmacokinetics of dextromoramide in long-term heroin-dependent patients on methadone maintenance treatment (MMT) a reverse-phase HPLC technique was developed to monitor dextromoramide and methadone concentrations in plasma simultaneously. After liquid-liquid extraction from plasma, dextromoramide and methadone were determined using a Supelcosil LC-ABZ column and a mobile phase of KH2phosphate buffer (25 mM, pH 2.5) mixed with acetonitrile (80:20, v/v) and UV detection at 206 nm. The method was found to be sufficiently sensitive, specific and reproducible to apply in six subjects on MMT for many years, receiving orally administered dextromoramide as adjuvant. Pharmacokinetic data sets for dextromoramide in each subject were conducted and analysed furtherly, indicating short elimination half-life values (71 min, range: 31-152 min). Contrary to previous studies, in all subjects tested the pharmacokinetics of dextromoramide are best described using an one-compartment model.

Chapter 4

Results are presented and discussed of a clinical study of 20 long-term heroindependent patients currently enrolled in methadone maintenance treatment (MMT) and hospitalized in the Jellinek Clinic in Amsterdam. The purpose of this study was to better understand the craving and pharmacokinetics associated with difficulties in determining an optimal dosage schedule in MMT. Plasma methadone concentrations were determined using a newly developed HPLC (high-performance liquid chromatography) procedure. Drug craving was measured using the Experience Sampling Method (ESM), a new technique for measuring craving in MMT which provides data not previously reported in methadone literature. Within the subjects medicated in the normal therapeutic dosage range of MMT (10 - 90 mg/day), a significant relationship ~vas found.between higher methadone dose and higher craving levels, a finding that counters much of the accepted knowledge on MMT. Supporting this finding, some subjects showed high plasma methadone trough levels and high craving lqvels. At the group level, no significant relationships were found between craving and kinetic parameters, such as plasma methadone trough level and half-life. Three specific craving paKerns were identified that related to daily fluctuations: high peak of the craving score just before the patients receive methadone around 09:00, an elevation in craving at around noon and a clear group difference of those subjects which show an increase in craving level between 14:00 and 22:00 and those which show a decrease. The results suggest that factors other than pharmacokinetics such as anticipatory conditional response and/or circadian influences might also be affecting craving.

Chapter 5

A clinical case study is presented of an opiate-dependent patient, currently under methadone maintenance treatment (MMT), who claims the need of a higher daily methadone dose. He is admitted to a closed metabolic ward, where he receives 250 mg methadone per day. During 24 hours both pharmacokinetic parameters and craving levels are measured simultaneously. Results show extremely high methadone concentrations and its primary metabolite EDDP in plasma and urine. The craving level shows a distinguished peak around the methadone administration on both measured days. Withdrawal symptoms as well as self reported craving did not correspond at all to the extremely high methadone concentration level in plasma. So we suggest that in individual cases if high methadone doses and plasma methadone levels are not able to diminish craving symptoms, dose adjustment should be accompanied by education regarding daily anticipatory increase of opiate craving.

Chapter 6

This study aims at establishing the effect of dextromoramide on opiate craving among long-term heroin-dependent patients in methadone maintenance therapy. Six subjects currently stabilised on methadone (mean dose 72.5 mg per day, range: 60 100 mg), were administered 5 or 10 mg dextromoramide in addition to methadone. During the study the methadone maintenance dose was diminished according to the individual drug dependent's expectation of the effect of dextromoramide. The increase of dextromoramide plasma concentration strongly correlated with the decrease of opiate craving. In addition, a high peak level of craving just before drug administration was seen in three cases. The results suggest beneficial effects of a short-acting opiate on diminishing craving in heroin-dependent patients who are difficult to stabilise with methadone maintenance treatment alone.

Chapter 7

The clinical effectiveness of l-methadone maintenance treatmant (LMMT) carried out using d,l-methadone or l-methadone have been compared in ambulatory heroindependent subjects. A total of 40 heroin-dependent subjects, previously maintained on l-methadone in Frankfurt am Main (Germany), were divided into two groups under randomised double-blind conditions and seceived either an equivalent dose of 1methadone as d,l-methadone or remained on the previous l-methadone treatment. Requests for a change in the dose of d, l-methadone and l-methadone were recorded, urine samples for determination of illicit drug use were collected and the individual level of opiate craving was. determined over a 22-day observation period. There was no significant difference between the two groups in the number of requests for a dose change (dose increase < 10 %). However, there was a significant increase in heroin use in the group which continued to receive 1methadone. Although there was less variability in opiate craving in the group receiving d,l-methadone the mean intensity of opiate craving did not differ between the two groups. The mean l-methadone dose: I-methadone plasma concentration ratio, an index of the bioavailability of l-methadone in individual subjects, showed no significant change when the treatment was changed to d,l-methadone. The mean dmethadone: I-methadone plasma concentration ratio was 1.17. There was no significant difference between these ratios for Day 15 and Day 22. The mean 1methadone: EDDP plasma concentration ratio in the l-methadone group was 22.2 and the d,l-methadone: EDDP plasma concentration ration was 18.4. The plasma EDDP concentration increased 3-fold after starting treatment with d,l-methadone. These findings suggest that d,l-methadone can be used in MMT of heroin-dependent subjects but that further studies are required to evaluate pharmacokinetic interactions between both methadone stereoisomers.

Chapter 8

ln this paper the final results are presented as a part of a larger study, which was designed to explore which parameters are involved in continued opiate craving among patients in methadone maintenance treatment (MMT). Tvmenty long-term heroin-dependent patients currently enrolled in MMT have been assessed for correlations betvçeen opiate craving, methadone pharmacokinetics and the presence of current psychopathology. In this presentation the correlation betvmeen the level of opiate craving and the presence of psychopathology is described. In a previous publication no significant correlations at group level vçere found betvveen opiate craving and methadone pharmacokinetics. Psychopathology has been measured using the General Health Questionnaire, the Symptom Checklist and the Addiction Severity Index. Craving has been measured using the Experience Sampiing Method. In this relatively small random sample, no significant correlation betvveen the level of craving and the presence of current psychopathology could be established. From the findings of the present and tvvo previous studies vçe conclude that both methadone pharmacokinetics and general psychopathology can not explain high craving among heroin-dependent patients in methadone maintenance treatment. Other factors influencing the individual experience of craving such as personality characteristics or cue-exposure should be investigated.