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

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

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









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