Blackwell Science, LtdOxford, UKADDAddiction0965-2140© 2005 Society for the Study of Addiction

100
Original Article
Opioid detoxification under general anaesthesia
Cor A. J. de Jong
et al.

RESEARCH REPORT

General anaesthesia does not improve outcome in

opioid antagonist detoxification treatment: a
randomized controlled trial

Cor A. J. De Jong1, Robert J. F. Laheij2 & Paul F. M. Krabbe2

Novadic—Kentron—Network for Addiction Treatment Services, Nijmegen Institute for Scientist-Practitioners in Addiction, Radboud University Nijmegen,
Nijmegen, the Netherlands,1 Department of Medical Technology Assessment, University Medical Centre Nijmegen, Nijmegen, the Netherlands2

ABSTRACT
Correspondence to:
Cor A. J. de Jong
Novadic—Kentron—Network for Addiction Aim Opioid detoxification by administering opioid-antagonists under general
Treatment Services anaesthesia has caused considerable controversy. This study is conducted to
Nijmegen Institute for Scientist-Practitioners determine whether rapid detoxification under general anaesthesia results in
in Addiction
higher levels of opioid abstinence than rapid detoxification without anaesthesia.
Radboud University Nijmegen
PO Box 9104 Design Randomized controlled open clinical trial from September 1999 to
6500 HE Nijmegen August 2001.
the Netherlands Setting Four addiction centres in collaboration with three general hospitals in
Tel: +31 24 3611165
the Netherlands.
Fax: +31 24 3615594
E-mail: C.deJong@ACSW.ru.nl Participants A total of 272 opioid-dependent patients whose previous
attempts to abstain were unsuccessful.
Submitted 20 April 2004; Intervention Patients received rapid detoxification with general anaesthesia
initial review completed 7 June 2004;
(RD-GA) or without general anaesthesia (RD).
final version accepted 11 October 2004
Measurements Urine screens and an interview (EuropASI) to assess opioid
abstinence; two questionnaires (SOOS, OOWS) to measure withdrawal
RESEARCH REPORT symptoms and one to measure craving (VAS).
Findings One month after the intervention 62.8% of the patients in the RD-
GA group and 60.0% in the RD group were abstinent for opioids (P = 0.71). No
adverse events or complications occurred during RD; however, in the RD-GA
group, five adverse events necessitated admission to a general hospital. The
average 1-month cost for RD was €2517 versus €4439 for RD-GA.
Conclusions Rapid detoxification under general anaesthesia did not result in
higher levels of opioid abstinence than rapid detoxification without anaesthesia.
The cost of the former intervention was much higher.

KEYWORDS Abstinence, anaesthesia, detoxification, opioid, withdrawal

symptoms.

INTRODUCTION are regarded as problematic and are effective only in a

Dependence on opioid drugs is a major health and social
issue in most western societies. An estimated 25 000
heroin-dependent patients live in the Netherlands
(16 000 000 inhabitants). About three-quarters of them
are served by addiction treatment centres, especially by
means of methadone maintenance treatment. About
4500 of the opioid-dependent patients are involved in
drug-free treatment. Interventions directed at abstinence
minority of motivated patients in stable living conditions
with adequate social support [1]. Managed opioid detox-
ification, in which the methadone dose is gradually
reduced, is recommended to achieve opioid abstinence
but this traditional treatment, i.e. methadone tapering,
frequently fails. The completion rate of methadone taper-
ing varies between 20% and 30% and when alpha-
adrenergic agonists are used, the rate is between 44%
and 87.4% [2]. An important reason for this failure is

© 2005 Society for the Study of Addiction doi:10.1111/j.1360-0443.2004.00959.x Addiction, 100, 206–215

patients’ experience of the withdrawal syndrome [3],
which can lead to illicit opioid use to alleviate this syn-
drome. Therefore, alternative approaches have been
introduced to shorten the detoxification period and to
encourage completion of the detoxification, such as the
use of opioid antagonists to accelerate withdrawal. The
rationale underlying this method is that more rapid tran-
sition from opioid use to abstinence may increase detoxi-
fication rates [4]. We found that in 15 of 15 patients
treated with rapid detoxification the transitions to nal-
trexone treatment were successful after 1 week versus six
of 15 patients under methadone tapering [5]. The first
experiments with opioid antagonists date back to the
1970s [6]. Furthermore, relapse can be decreased by nal-
trexone maintenance therapy [7].
By putting patients under sedation or anaesthesia to
suppress their awareness of withdrawal symptoms, the
use of opioid antagonists in detoxification protocols was
refined further [8–11]. Anaesthesia-assisted detoxifica-
tion has been advocated as a rapid and painless way to
undergo detoxification; it may be complemented by nal-
trexone maintenance treatment. Nevertheless, the
administration of opioid antagonists both with and with-
out general anaesthesia to accelerate opioid withdrawal
has caused considerable controversy [12–15]. Part of this
controversy is due to the fact that its efficacy has not been
proved according to standard scientific conventions, to
potentially life-threatening risks, such as aspiration
pneumonia, that patients do not run under conventional
opioid detoxification and to commercialization of the
technique. In addition, detoxification under general ana-
esthesia is assumed to reduce and shorten withdrawal
but much is still unclear about how patients actually
experience the withdrawal. Success rates and the cost of
this treatment also vary widely [16–21].
The aim of this study was to examine whether rapid
detoxification under general anaesthesia confers addi-
tional clinical benefits over rapid detoxification without
anaesthesia in terms of withdrawal symptoms, craving
and abstinence of opioid use.
METHODS
Study design and setting
A prospective, randomized controlled trial was conducted
with two treatment arms. All the patients were treated for
7 days at one of four addiction treatment centres. One
treatment arm consisted of rapid detoxification (RD) with
an opioid antagonist. It was carried out at an in-patient
detoxification centre fully equipped to deliver medically
managed intensive in-patient treatment. The other
treatment arm comprised rapid detoxification with an
opioid antagonist under general anaesthesia (RD-GA).
© 2005 Society for the Study of Addiction
13600443, 2005, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2004.00959.x by Peking University Health, Wiley Online Library on [09/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Opioid detoxification under general anaesthesia 207
Anaesthesia was induced for 4 hours at the operating
theatre of a general hospital in a day-care setting; the
patients were kept for another 4 hours to recover and
were then transferred back to the treatment centre. The
study was conducted between September 1999 and
August 2001. Opioid abstinence assessment took place 1
month after completion of detoxification treatment.
Participants
Participants were recruited from four addiction treat-
ment centres in the Netherlands: Novadic, Jellinek, Par-
nassia and Kentron. Opioid-dependent patients were
eligible for participation in the study if they met the fol-
lowing criteria: diagnosed as opioid-dependent according
to DSM-IV criteria, underwent previously several unsuc-
cessful attempts to become abstinent, expressed the clear
wish to be become abstinent, were over 18 years of age,
were familiar with the Dutch language and had at least
one non-opioid user in their social network. Exclusion
criteria were: severe somatic diseases or psychiatric dis-
orders, pregnancy, AIDS, doubts about the patient’s will-
ingness to co-operate and contraindications regarding
general anaesthesia. Dependence on other drugs or drug
abuse was not an exclusion factor. However, if a patient
had used cocaine 48 hours before detoxification, treat-
ment was not started because of the unpredictable effects
of cocaine on the cardiovascular system during detoxifi-
cation. The Dutch Ethical Assessment Committee for
Experimental Investigations on People approved the
study.
Outcome measures
The primary end-point was opioid abstinence assessed
clinically by analysing urine samples. Urine analyses
were carried out before randomization (baseline) and 1
month after treatment. Other psychoactive drugs were
also assessed clinically 1 month after the completion of
treatment. Urine specimens were analysed for naltrexone
(opioid abstinence) at the Ziekenhuis Apotheek Laborato-
rium Venray and for psychoactive substances by the Jell-
inek laboratory. For the detection of naltrexone, urine
samples were enriched in a three-step extraction process
and analysed subsequently by high pressure liquid chro-
matography (HPLC) with UV detection. Screening at the
Jellinek laboratory was performed on an Olympus AU
600 analyser after immunoassays. The parameters
screened for, the specific techniques used and the cut-off
values were: opiates: EMIT II, cut-off 300 ng/ml mor-
phine; cocaine: CEDIA, cut-off 300 ng/ml benzoylecgo-
nine; methadone: CEDIA, cut-off 100 ng/ml EDDP;
amphetamines/XTC: CEDIA, cut-off 1000 ng/ml
methamphetamine; benzodiazepines: CEDIA HS
Addiction, 100, 206–215

208 Cor A. J. de Jong et al.
(including on-line deglucuronidation), cut-off 200 ng/ml
nitrazepam; cannabinoids: EMIT II, cut-off 100 ng/ml
THC-COOH; ethanol: ADH method (EMIT II), cut-off
0.1 g/l. Opioid abstinence was also assessed by means of
self-reports by patients on the European version of the
Addiction Severity Index (EuropASI). The EuropASI mea-
sures the severity of dysfunction in the following
domains: physical health; employment, work and
income; alcohol; drugs; legal problems; family/social
relations and psychological/emotional problems [22].
The complete EuropASI was used at baseline; at 1 month
follow-up only self-report on drug use was assessed with
this instrument.
The secondary end-point was the intensity of the
signs and symptoms of the withdrawal syndrome experi-
enced prior to, during and after treatment. Patients com-
pleted the Subjective Opioid Withdrawal Scale (SOWS)
with 16 items to determine how they experienced the
withdrawal symptoms [23]. Symptoms were rated on a
five-point scale (maximum score 64). Trained nurse-
observers rated patients on the Objective Opioid With-
drawal Scale (OOWS). The OOWS comprises 13 items to
measure the absence or presence of opioid withdrawal
symptoms, such as vomiting or shivering (maximum
score 13). Symptoms of the opioid withdrawal syndrome
not induced by opioid antagonists usually start two to
three half-lives after the last opioid dose (i.e. 6–12 hours
for heroin and morphine, 36–48 hours for methadone).
Upon cessation of heroin or morphine, symptoms reach
peak intensity within 2–4 days. In this study all patients
were stabilized on an adequate dose of methadone in the
out-patient period before they entered the detoxification
programme. After 7–14 days most of the obvious physi-
cal withdrawal symptoms were gone [4,16]. Therefore,
we recorded withdrawal symptoms twice at baseline
(12.00 a.m. and 7.00 p.m.), three times on each detoxi-
fication day (8.00 a.m. and 10.00 a.m., 7.00 p.m.),
twice during each recovery day (8.00 a.m. and 7.00
p.m.) and at discharge (2.00 p.m). Using the same sched-
ule as the measurement of withdrawal symptoms, the
craving for opioids was measured with a visual analogue
scale.
In addition, the nature and incidence of any adverse
events, particularly those which could potentially com-
promise patient safety, were recorded by the hospital
anaesthesiologists and the medical doctors at the addic-
tion treatment centres. The cost of the two procedures
was calculated at each specific stage on the basis of
standard cost calculations. Unit cost prices were deter-
mined for resource consumption and production fac-
tors (i.e. personnel, material, capacity). An additional
35% was taken for overheads. The cost related to
adverse events and complications was not included in
the overall figure.
© 2005 Society for the Study of Addiction
13600443, 2005, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2004.00959.x by Peking University Health, Wiley Online Library on [09/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Enrolment
Individuals who met the screening criteria gave written
informed consent and underwent physical examination,
including medical history, 2 weeks before the start of the
treatment (pre-assessment). Participants were exam-
ined by the anaesthesiologist according to the Dutch pre-
operative screening protocol [24] 1 week before anaes-
thesia to exclude serious physical dysfunction (e.g. pul-
monary, cardiac and renal disorders). Pairs of
participants who met the inclusion criteria completed a
baseline assessment on the day before admission to the
treatment centre. On the actual day of admission, pairs
of candidates were assigned at random to either the RD
or RD-GA group. Randomization assignments (block
sizes of two) were generated centrally by the project data
manager after pre-assessment using SAS System for
Windows version 8.0. The non-experimental part of
treatment of all patients was financed by the health
insurance system and the experimental part, i.e. general
anaesthesia, by the Ministry of Health, Welfare and
Sports (VWS).
Treatment protocol
In all the patients, detoxification was induced by admin-
istering an opioid antagonist (naltrexone). Except for
some differences in naltrexone schedule (see below)
and, of course, the general anaesthesia procedure, all
the patients were treated for signs and symptoms of
withdrawal with the same set of medication at a same-
dose schedule. At 8.00 a.m. all the patients were pre-
medicated orally with clonidine (0.3 mg) to prevent
high blood pressure, diclofenac (50 mg) to fight pain,
ondansetron (4 mg) against nausea and vomiting, diaz-
epam (10 mg) to control anxiety and transdermal nico-
tine (30 mg/20 cm2) for nicotine withdrawal in the case
of smokers. At 9.00 a.m., naltrexone was administered.
Afterwards a medication set was given according to a
fixed schedule. It included octreotide (0.3 mg subcuta-
neously at 9.15 a.m.) against nausea, vomiting and
diarrhoea; ondansetron (4 mg sublingually at 8.00 and
11.00 a.m., 3.00, 7.00 and 11.00 p.m.) against nau-
sea and vomiting; butylscopolamine (20 mg intramus-
cularly at 11.00 a.m., 3.00, 7.00 and 11.00 p.m.)
against abdominal cramps; diazepam (10 mg intramus-
cularly at 8.00 and 11.00 a.m. and 11.00 p.m.) against
anxiety, and clonidine (0.15 mg subcutaneously at 8.00
and 11.00 a.m., 3.00, 7.00 and 11.00 p.m.). The cloni-
dine dosage was reduced when blood pressure fell below
90% of the baseline pressure. If necessary, haloperidol
(1–3 mg) was administered against severe anxiety and
midazolam (5–10 mg) against insomnia. During the
last 3 days, a symptom-triggered dosage schedule was
used to treat symptoms and signs of withdrawal.
Addiction, 100, 206–215

Naltrexone (50 mg) was continued daily for a period of
10 months.
After the in-patient programme, all the patients were
discharged and treated for 10 months (not discussed
here) in an out-patient setting according to the principles
of the Community Reinforcement Approach [25].
Rapid detoxification under general anaesthesia protocol
(RD-GA)
The participants were screened by the anaesthesiologist
according to the pre-operative screening procedure
before admission to the general hospital [24]. All the sub-
jects were rechecked for opioids in their urine to ensure
that they were actually taking them. The RD-GA patients
were admitted to a general hospital near the addiction
treatment centre (Ignatius Hospital, Breda; Bernhoven
Hospital, Veghel; Westeinde Hospital, The Hague). Gen-
eral anaesthesia was introduced at the operating theatre
based on a standardized protocol.
During anaesthesia, the following parameters were
monitored: electrocardiograph, non-invasive blood pres-
sure, invasive arterial blood pressure, end-tidal carbon
dioxide, oxygen saturation, Bispectral Index (BIS), diure-
sis and temperature. The BIS is a processed EEG parame-
ter to monitor the level of consciousness during
anaesthesia; it was maintained at between 40 and 50
[26]. NaCl 0.9% and glucose 0.45% were infused intra-
venously (1–1.5 l/ hour).
After obtaining the baseline BIS, patients were given
naltrexone (100 mg orally) and tropisetron (5 mg intra-
venously). The latter is a selective competitive 5-HT3
antagonist used as an anti-emetic agent. After the first
signs of withdrawal, general anaesthesia was induced
with propofol (5000 ng/ml) using the target controlled
infusion method (TCI); general anaesthesia was main-
tained for 4 hours with propofol and a target between 40
and 50. After induction, a urinary catheter and an
orogastric tube were inserted. To prevent vomiting and
diarrhoea, 0.05 mg octreotide was administered subcu-
taneously. Because myoclonic reactions can occur in the
first hour of detoxification, gallamine (10 mg) and succi-
nylcholine (0.8–1.0 mg/kg) were administered; subse-
quently, the patients were intubated and ventilated
mechanically with oxygen and air (ratio 3 : 1). At the
end of anaesthesia, 100 mg naltrexone was adminis-
tered through the orogastric tube. When the patients
were fully awake, extubation took place. Subsequently,
the urinary catheter and orogastric tube were removed.
When the patients were responding adequately, had
spontaneous miction, were not vomiting and had no
orthostatic hypotension, they were discharged back to
the addiction centre for further recovery, treatment and
monitoring.
© 2005 Society for the Study of Addiction
13600443, 2005, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2004.00959.x by Peking University Health, Wiley Online Library on [09/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Opioid detoxification under general anaesthesia 209
Rapid detoxification protocol (RD)
Patients in the RD condition were given their regular
dose of methadone on the morning of the day before
naltrexone was given for the first time. In this group, nal-
trexone was given at a dose of 12.5 mg on day 1, 25 mg
on day 2 and 50 mg on day 3, according to the guidelines
as described by Kleber [27].
Relapse prevention
Relapse prevention consists of an adapted protocol based
on the Community Reinforcement Approach (CRA). CRA
treats substance abuse behaviour by modifying positive
reinforcement in the individual’s community context,
and through behavioural skills training [28]. The CRA
protocol in this study encompassed 23 sessions adminis-
tered by physicians and psychosocial therapists. In 13
sessions, a physician administered and monitored com-
pliance for naltrexone (50 mg daily), addictive behav-
iours, craving and the occurrence of any adverse event.
Subjects had to be accompanied by a partner, spouse or
good friend to assist them as a coach during treatment
(non-drug user). The coach specifically assisted the
patient with taking naltrexone. Concurrently, in 10 psy-
chosocial sessions the life-style of the patient was assessed
and discussed. In these sessions attention was paid to
drug-refusing behaviour, relational issues, social network
support, vocational counselling, leisure time, problem-
solving abilities, training in social skills and craving
management.
Data management and statistical methods
A case record form (CRF) was completed for each patient
by non-blinded nursing staff. These forms were designed
with a special software program (Teleform 6.0) that
enables the user to process the data automatically by
scanner [29]. If any data were unclear, the program
asked for feedback from the data manager. After process-
ing, the data were stored automatically in a relational
database (Microsoft Access). The sample size was based
on a Type 1 error rate of 0.05 and a power of 0.80, with
one-sided testing. Relapse rates of 45% and 60% were
expected in the RD-GA group and RD group, respectively,
based on data from the literature [30] and the results of a
pilot study [21]. Therefore, 137 patients were required for
each treatment group. Analyses were based on the
intention-to-treat principle (except for the eight differ-
ently allocated patients immediately after randomiza-
tion). Missing data analysis for continuous variables was
conducted systematically with imputation techniques
(expectation–maximization algorithm). Differences be-
tween the baseline characteristics of the two groups and
abstinence rates were analysed by the c2 test, Fisher’s
Addiction, 100, 206–215
 13600443, 2005, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2004.00959.x by Peking University Health, Wiley Online Library on [09/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
210 Cor A. J. de Jong et al.

exact test (two-tailed) for dichotomous data and the inde-
pendent t-test for continuous data. All statistical tests
were two-sided, with a P-value of 0.05 or less considered
to indicate statistical significance. Analyses were per-
formed with the use of SPSS, version 11.0.
RESULTS
Patient characteristics
A total of 272 opioid-dependent patients participated in
this study. Eight patients received different treatment
from that allocated (Fig. 1). The reason that at the incep-
tion of the study the seven patients who were allocated to
RD were treated under RD-GA was mainly to utilize
planned hospital facilities. In the analysis these eight
patients are not considered as protocol violators. The RD-
GA group contained 137 patients; 26 of them did not
participate in the follow-up 1 month after treatment. In
the RD group, 28 of the initial 135 patients dropped out.
The two groups were well balanced with respect to the
baseline characteristics, including the seven domains of
the EuropASI. None showed a statistically significant
effect. As expected, the domain ‘Drugs’ showed the
highest average score (Table 1). The domains ‘Work,
education and income’, ‘Police’, ‘Family/Social relations’
and ‘Psychological/Emotional problems’ indicated some
degree of suffering.
Concerning the characteristics in Table 1 there were
some significant differences (P-value < 0.01) between the
four centres. The mean severity scores on the ASI for
work, education and income and for justice and police
were lowest in Jellinek (1.3 and 0.41) and highest in Ken-
tron (3.3 and 2.8), whereas the ASI severity score for
drugs was lowest in Kentron (5.9) and highest in Jellinek
(6.7).
Abstinence rates
Urine analysis 1 month after treatment showed that
37.2% in the RD-GA group and 40.0% in the RD group
(P = 0.71) were using opioids (Table 2). The levels of nal-
trexone should reciprocate the opioid levels: urine analy-
sis showed that 86.1% of the RD-GA group was still using
the naltrexone compared to 84.4% in the RD group
(P = 0.73). Self-reported (EuropASI) rates of heroin use
were comparable: 38.7% in the RD-GA group and 43.7%
in the RD group (P = 0.46). A combination of these two
data sources showed rates of 46.0% in the RD-GA group
versus 46.0% in the RD group (P = 1.00).

Registered or Eligible Patients (n = 296)

Not Randomized (n = 24)

Not Meeting Inclusion Criteria (n = 5)
Refused To Participate (n = 19)

Randomization (n = 272)
Rapid Detoxification
Rapid Detoxification
under General Anaesthesia

Received Intervention Received Standard

as Allocated (n = 130) Intervention as Allocated (n = 134)

Did Not Receive Standard Did Not Receive Experimental

Intervention as Allocated (n = 7) Intervention as Allocated (n = 1)

Followed Up until Discharge (day 8) Followed Up until Discharge (day 8)

Addiction Treatment Centre (n = 115) Addiction Treatment Centre (n = 111)

Lost to follow-up (n = 11) Lost to follow-up (n = 13)

Data missing (n = 11) Data missing (n = 11)

Completed 1 month follow-up (n = 111) Completed 1 month follow-up (n = 107)

Lost to follow-up (n = 15) Lost to follow-up (n = 15)

Figure 1 Participant flow diagram

© 2005 Society for the Study of Addiction Addiction, 100, 206–215

 13600443, 2005, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2004.00959.x by Peking University Health, Wiley Online Library on [09/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Opioid detoxification under general anaesthesia 211

Table 1 Baseline characteristics of patients by treatment condition (intention to treat).

Rapid detoxification
under general Rapid detoxification
anaesthesia (n = 135) (n = 137)

Characteristic n n c2, P-value t-value, P-value

Age, mean (SD), years 35.7 (6.3) 137 36.0 (6.5) 135 0.40, 0.735
Sex, % male 82.5 137 81.5 135 0.46, 0.830
Country of birth, % 119 115 3.01, 0.698
Europe 84.0 81.7
Africa 8.4 6.1
USA 5.0 6.1
Other 2.6 6.1
Relationship, % 132 128 3.23, 0.199
Married 10.6 18.0
Never married 74.2 65.6
Divorced/widow 15.2 16.4
Employed, % 131 128 3.16, 0.206
Full-time 45.0 55.5
Part time 13.0 8.6
Unemployed 42.0 35.9
Education, % 132 128 5.64, 0.06
Lower 64.4 77.3
Secondary 25.8 14.8
Higher 9.8 7.8
Drug use, mean (SD)
Years of heroin use 12.0 (5.7) 128 12.1 (6.1) 125 0.25, 0.805
Years of methadone use 7.4 (5.8) 128 7.4 (5.6) 124 0.029, 0.977
Age at first heroin use 20.9 (5.0) 128 20.8 (5.3) 123 0.231, 0.817
Age at first methadone use 24.4 (6.3) 125 23.8 (8.0) 125 0.643, 0.521
Number of previous drug
detoxification treatments, mean (SD) 7.4 (8.0) 129 8.4 (8.0) 127 1.095, 0.275
Heroin use last 30 days, mean (SD) 18.0 (12.6) 126 18.8 (11.9) 126 -0.494, 0.622
Methadone use last 30 days 22.0 (11.7) 126 23.6 (10.1 126 -1.148, 0.250
EuropASI severity scores*, mean (SD)
Physical health 1.2 (1.6) 124 1.1 (1.4) 115 0.458, 0.647
Work, education and income 2.4 (2.2) 121 2.1 (2.3) 115 0.911, 0.363
Alcohol 0.9 (1.6) 121 0.9 (1.7) 120 0.005, 0.996
Drugs 6.2 (1.1) 119 6.3 (1.0) 109 0.749, 0.454
Justice/police 1.5 (1.8) 119 1.7 (2.0) 116 0.738, 0.461
Family/social relations 2.8 (1.9) 116 2.6 (1.8) 111 0.739, 0.461
Psychological/emotional problems 2.1 (1.9) 116 2.1 (1.9) 109 0.264, 0.792

*Range 0–9.

Self-report on the number of days that psychoactive
substances were used in the last 30 days showed no dif-
ferences between the two groups. Therefore, the data on
this outcome measure were analysed in the group as a
whole. There was a significant reduction in the mean
number of days substances were used for heroine (18.4
versus 3.0 days, t-value 16.3, 95% CI: 13.4; 17.2), meth-
adone (22.9 versus 2.9 days, t-value 22.7, 95% CI: 18.6;
22.2), more than 5 alcohol units a day (3.9 versus
2.6 days, t-value 2.1, 95% CI: 0.08; 2.5), cocaine (3.7
versus 2.4 days, t-value 2.5, 95% CI: 0.3; 2.2), more than
one substance a day (18.0 versus 5.1 days, t-value 13.5,
95% CI: 11.0; 14.7) and an increase of the use of
benzodiazepines (6.3 versus 8.6 days, t-value -2.6, 95%
CI: - 4.0; 2.1).
Withdrawal symptoms and craving for opioids
The patients’ subjective reports and the trained nurse-
observers’ objective judgement about the intensity of
withdrawal signs and symptoms were fairly similar
(Fig. 2). There was a significant difference in subjective

© 2005 Society for the Study of Addiction Addiction, 100, 206–215

 13600443, 2005, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2004.00959.x by Peking University Health, Wiley Online Library on [09/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
212 Cor A. J. de Jong et al.

Table 2 Number (intention to treat) of

Rapid detoxification positive urine screens and self–reported
under general Rapid drug use by treatment group 1 month
anaesthesia detoxification after completion of detoxification (per-
Test n = 137 n = 135 P value centages between parentheses).

Urine screens
Opiates (heroin) 51 (37.2) 54 (40.0) 0.71
Naltrexone 118 (86.1) 114 (84.4) 0.73
Methadone 44 (32.1) 48 (35.5) 0.61
Cocaine 56 (40.1) 60 (44.4) 0.62
Benzodiazepine 75 (54.7) 89 (65.9) 0.06
Amphetamine 32 (16.7) 33 (24.4) 0.89
Cannabis 63 (46.0) 69 (51.1) 0.47
EuropASI (self-report)
Heroin 53 (38.7) 59 (43.7) 0.46
Methadone 38 (27.7) 46 (34.1) 0.29
Cocaine 58 (42.3) 69 (51.1) 0.18
Benzodiazepine 74 (54.0) 86 (63.7) 0.11
Amphetamines 23 (16.8) 28 (20.7) 0.44
Cannabis 74 (54.0) 78 (57.8) 0.54
Alcohol 96 (70.1) 107 (79.3) 0.10

100 report between the RD-GA and the RD group at 7.00

RD-GA
40
RD
p.m. the first day (24.4 versus 20.8, t-value 2.53, 95%
36
32 CI: 0.79; 6.41) and at 8.00 a.m. on the second day
VAS craving

28
24
(21.8 versus 16.2, t-value 4.04, 95% CI: 2.87; 8.32),
20 as is the case for the experienced craving at 08.00 a.m
16
12 on the second day (26.4 versus 18.1, t-value 2.17,
8
4
95% CI: 0.77; 15.96). According to the subjective self-
0 reports given by the patients, withdrawal distress and
64
60 craving dropped almost to baseline level after 1 week.
40 RD-GA
36 RD According to the objective ratings, baseline levels were
32
28
reached within 3 days. All patients left the detoxifica-
SOWS score

24 tion units with an adequate dose of naltrexone

20
16 (50 mg).
12
8
4
0 Adverse events and complications
13
12 No adverse events or complications occurred in the RD
11 RD-GA
10 RD
group, whereas five patients had adverse events in the RD-
9
OOWS score

8 GA group. These five patients were thought to be eligible

7
6 for the study after the preoperative screening by the ana-
5
4 esthesiologist because of the absence of exclusion criteria
3
2 at the time of history-taking and examination. One of
1
0 these was a 28-year-old male who had to be treated for
e

Detoxification Recovery extreme drowsiness resulting from anaesthesia. He was

e

arg
lin

(3 days) (3 days)
ch
se

discharged from the general hospital the following day.

Dis
Ba

Measurement
Figure 2 Mean scores on the VAS craving, the Subjective Opiate
Withdrawal Scale (SOWS) and the Objective Opiate Withdrawal
Scale (OOWS) by treatment group collected during 1 week of in-
patient treatment at an addiction centre
His delayed recovery was due probably to pre-existing
abnormal liver metabolism together with hepatitis C,
without severe disturbances of liver functions at the pre-
assessment laboratory testing. A second patient with an
adverse event was a 35-year-old male with a psychiatric
history, who remained very agitated after the detoxifica-
tion. Sedation with propofol was necessary at the inten-

© 2005 Society for the Study of Addiction Addiction, 100, 206–215


sive care unit of the general hospital. The combination of
detoxification and general anaesthesia was assumed to
have elicited a delirium-like psychotic episode. He was dis-
charged from hospital the following day. The third patient
was a 33-year-old male with a history of pulmonary prob-
lems, including chronic obstructive pulmonary disease
(COPD) and pneumonia. He was admitted to the general
hospital because of persistent hypoxia during the recov-
ery period. Chest X-rays revealed pneumonia, which was
treated with antibiotics, theophylline and corticosteroids.
He was discharged from hospital 5 days later, fully recov-
ered. The fourth patient was admitted to the general hos-
pital because of fever. Although no focus could be
detected, antibiotic therapy was started. His body temper-
ature normalized and he was discharged from hospital 4
days later. The fifth patient, a 33-year-old male who aspi-
rated during general anaesthesia, developed a serious pul-
monary complication. He had to be admitted for 4 days
and his aspiration pneumonia was treated with supple-
mental oxygen and antibiotics. This patient also made a
full recovery without residual symptoms.
Financial cost
The average cost was €2517 for RD and €4439 for RD-
GA. The higher cost for RD-GA was due largely to hospi-
talization and general anaesthesia, which amounted to
€2254. The start of detoxification (day 1) in the RD group
costs €430. The cost for the remaining days at the treat-
ment centre was similar in the two groups, approximately
€206 a day.
DISCUSSION
This randomized controlled trial is the first large-scale
RCT in which opioid detoxification under general anaes-
thesia is compared with a similar treatment without gen-
eral anaesthesia. Randomization resulted in two well-
balanced groups with no significant differences between
potentially interactions on the primary outcome mea-
sure, such as addiction history or preceding heroine or
methadone use. The design of the study meets most of the
comments on earlier studies on the use of opioid antago-
nists for opioid withdrawal [3]. The withdrawal symp-
toms are monitored during the first week by means of
objective and subjective measurements. All patients are
offered a long-term, comprehensive treatment approach
in which rapid detoxification followed by a standardized
relapse prevention programme consisting of CRA and
naltrexone maintenance and are interviewed four times
during the study (1, 5, 10 and 16 months after the start
of detoxification). Results of the 1-month follow-up are
reported here.
© 2005 Society for the Study of Addiction
13600443, 2005, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2004.00959.x by Peking University Health, Wiley Online Library on [09/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Opioid detoxification under general anaesthesia 213
Our findings did not support the common belief
among heroin addicts and professionals in the field of
addiction treatment that rapid detoxification under gen-
eral anaesthesia results in a better prognosis of lasting
abstinence. Detoxification under general anaesthesia led
to the same opioid abstinence rate as the treatment with-
out general anaesthesia. Furthermore, and interestingly,
the severity of the withdrawal symptoms was similar in
the two treatment groups. This study did not find any evi-
dence that withdrawal symptoms were less severe in the
patients treated under general anaesthesia. In the gen-
eral anaesthesia group subjective withdrawal stress was
significantly higher at 07.00 p.m. on the first day and at
08.00 a.m. on the second day, as was the experienced
craving at that last moment. According to patients’ self-
report, withdrawal distress approached baseline level
after 1 week, whereas according to the trained observers
symptoms had returned to baseline level within 3 days.
This finding could not be explained by a difference in the
amount of medication that was used in, for instance, the
RD without GA anaesthesia group because both groups
were treated according to a fixed-dose schedule during
the first 3 days.
The abstinence rates for opioids based on the combi-
nation of urine analysis and self-report were 46% in both
groups. There was a slight but significant increase in the
number of days benzodiazepines were used in the first
month. This should be attributed to the prescription of
short-acting benzodiazepines for the treatment of sleep-
ing disorders in this period.
It should be taken into account that the population in
this study appeared to have low levels of social, psycho-
logical and physical distress as measured with the
EuropASI. Nevertheless, the population consists of a reg-
ular group of patients in a methadone maintenance pro-
gramme (MMT) with a generally low educational level,
mostly single and half the patients employed full-time.
The findings of the study may not be applicable to patients
with more severe levels of dependence and complications,
but are not restricted to highly educated and socially well-
integrated groups. At present, the treatment of opioid
dependence can be differentiated into cure, care and pal-
liation [1]. The abstinence-orientated approach described
in this study is indicated in well-stabilized MMT patients
with minor problems in other substance-related domains
than the use of psychoactive substances.
A physician examined all patients during the pre-
assessment and at admission to the addiction treatment
centre. Patients in the RD-GA condition were also
screened by the anaesthesiologist 1 or 2 days before the
detoxification started. Nevertheless, adverse events only
occurred in the RD-GA condition in the included group
of patients. All patients finished the detoxification period
and left the detoxification units with an adequate dose of
Addiction, 100, 206–215

214 Cor A. J. de Jong et al.
naltrexone, favouring a successful transition to mainte-
nance treatment, in contrast with the disappointing suc-
cess rates of the methadone tapering procedures [2]. At
1-month follow-up patient compliance for naltrexone
was about 85% in both detoxification approaches, which
is high in contrast with other studies on this subject
[31].
The cost of the treatment with general anaesthesia
was much higher than that for rapid detoxification with-
out general anaesthesia. Because both treatments
showed an equivalence efficacy in this study, rapid detox-
ification without general anaesthesia is the most cost-
effective treatment [32].
Theoretically, the anaesthesia-based detoxification
approach offers a rapid and painless way to accomplish
detoxification. Critics of this approach stress the fact that
patients are exposed to potentially life-threatening risks
that do not occur with standard opioid detoxification
treatments. While some studies report minimal with-
drawal symptoms post-anaesthesia, or at least no signif-
icant change in severity compared to pre-anaesthesia
[33], the overall impression gained from other studies
[34,35] is that most patients experienced moderate with-
drawal symptoms that persisted for at least a few days fol-
lowing general anaesthesia.
So far, the lack of controlled studies that compared
anaesthesia-based opioid detoxification to other compet-
itive approaches has prevented scientists from drawing
any conclusions about the effectiveness of anaesthesia-
based detoxification. This study has attempted to gain
more knowledge in this field. Despite considerable effort,
urine screens could not be collected from all the partici-
pants at 1 month follow-up. Nevertheless, even the
most conservative scenario, based on the intention-to-
treat principle where participants who could not be
traced for follow-up at 1 month were regarded as
relapsers, showed similar relapse outcomes for both
treatment groups.
CONCLUSIONS
Rapid detoxification results in high percentages of opioid
abstinence at 1 month follow-up (RD-GA 62.8% versus
RD 60.0%). A combination of urine analysis at 1 month
follow-up and self-report on heroine use in the last
30 days before follow-up shows an equal percentage of
abstinence in both groups of 46%. General anaesthesia
did not lead to higher abstinence rates or fewer signs and
symptoms of withdrawal or craving. The method of gen-
eral anaesthesia was much more expensive and a number
of (severe) adverse events occurred. Therefore, in our
opinion general anaesthesia should no longer be used in
rational detoxification guidelines.
© 2005 Society for the Study of Addiction
13600443, 2005, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2004.00959.x by Peking University Health, Wiley Online Library on [09/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Acknowledgements
The Ministry of Health, Welfare and Sports (VWS) and
the Netherlands Organization for Health Research and
Development (ZonMw) funded this project under grants.
These agencies had no role in the conduct, interpretation
or analysis of the study.
References
1. van den Brink, W. & van Ree, J. M. (2003) Pharmacological
treatments for heroin and cocaine addiction. European Neu-
ropsychopharmacology, 13, 476–487.
2. Gowing, L., Farrell, M., Ali, R. & White, J. (2003) Alpha2
adrenergic agonists for the management of opioid
withdrawal. Cochrane Database Systematic Review, 2,
CD002024.
3. Gowing, L., Ali, R. & White, J. (2002a) Opioid antagonists
under heavy sedation or anaesthesia for opioid withdrawal
[Cochrane Review]. The Cochrane Library, Issue, 4.
4. Fishbain, D. A., Rosomoff, H. L., Cutler, R. & Rosomoff, R. S.
(1993) Opiate detoxification protocols. A clinical manual.
Annals of Clinical Psychiatry, 5, 53–65.
5. Krabbe, P. F., Koning, J. P., Heinen, N. & Laheij, R. J., van
Cauter, R. M. & de Jong, C. A. J. (2003) Rapid detoxifica-
tion from opioid dependence under general anaesthesia
versus standard methadone tapering: abstinence rates and
withdrawal distress experiences. Addiction Biology, 8, 351–
358.
6. Bearn, J., Gossop, M. & Strang, J. (1999) Rapid opiate
detoxification treatments. Drug and Alcohol Review, 18, 75–
81.
7. Kirchmayer, U., Davoli, M. & Verster, A. (2002) Naltrexone
maintenance treatment for opioid dependence. Cochrane
Database Systematic Review, 2, CD001333.
8. Loimer, N., Schmid, R., Presslich, O. & Lenz, K. (1988)
Naloxone treatment for opiate withdrawal syndrome. Brit-
ish Journal of Psychiatry, 153, 851–852.
9. Brewer, C. (1997) Ultra-rapid, antagonist-precipitated opi-
ate detoxification under general anaesthetic or sedation.
Addiction Biology, 2, 291–302.
10. Simon, D. L. (1997) Rapid opioid detoxification using opioid
antagonists: history, theory and the state of the art. Journal
of Addictive Diseases, 16, 103–122.
11. McGregor, C., Ali, R., White, J. M., Thomas, P. & Gowing, L.
(2002) A comparison of antagonist-precipitated with-
drawal under anaesthesia to standard inpatient withdrawal
as a precursor to maintenance naltrexone treatment in her-
oin users: outcomes at 6 and 12 months. Drug and Alcohol
Dependence, 68, 5–14.
12. Dyer, C. (1998) Addict died after rapid opiate detoxification.
BMJ, 316, 170.
13. Mayor, S. (1997) Specialists criticise treatment for heroin
addiction. BMJ, 314, 1385.
14. Strang, J., Bearn, J. & Gossop, M. (1997) Opiate detoxifica-
tion under anaesthesia. BMJ, 315, 1249–1250.
15. Roozen, H. G., de Kan, R., van den Brink, W., Kerkhof, A. J.
F. M. & Geerlings, P. J. (2002) Dangers involved in rapid opi-
oid detoxification while using opioid antagonists: dehydra-
tion and renal failure. Addiction, 97, 1071–1073.
16. Mattick, R. P. & Hall, W. (1996) Are detoxification pro-
grammes effective? Lancet, 347, 97–100.
Addiction, 100, 206–215

17. Stephenson, J. (1997) Experts debate merits of 1-day opiate
detoxification under anaesthesia. JAMA, 277, 363–364.
18. Brewer, D. D., Catalano, R. F., Haggerty, K., Gainey, R. R. &
Fleming, C. B. (1998) A meta-analysis of predictors of con-
tinued drug use during and after treatment for opiate addic-
tion. Addiction, 93, 73–92.
19. Kleber, H. D. (1998) Ultrarapid opiate detoxification [Edito-
rial]. Addiction, 93, 1629–1633.
20. O’Conner, P. G. & Kosten, T. R. (1998) Rapid and
ultrarapid opioid detoxification techniques. JAMA, 279,
229–234.
21. Laheij, R. J. F., Krabbe, P. F. M. & de Jong, C. A. J. (2000)
Rapid heroin detoxification under general anaesthesia.
Journal of the American Medical Association, 283, 1143–
1143.
22. Kokkevi, A. & Hartgers, C. (1995) EuropASI: European
adaptation of a multidimensional assessment instrument
for drug and alcohol dependence. European Addiction
Research, 1, 208–210.
23. Handelsman, L., Cochrane, K. J., Aronson, M. J., Ness, R.,
Rubinstein, K. J. & Kanof, P. D. (1987) Two new rating
scales for opiate withdrawal. American Journal of Drug and
Alcohol Abuse, 13, 293–308.
24. Stuyt, P. M. J. & van der Meer, J. W. M. (1997) Gezond-
heidsraadrapport, ‘Preoperatief onderzoek: een herijking
van uitgangspunten’ [Health Council Report, ‘Preoperative
evaluation: reconsideration of basic assumptions]. Neder-
lands Tijdschrift Voor Geneeskunde, 141, 1325–1326.
25. Higgins, S. T. Budney&, A. J. (1999) A Community Reinforce-
ment Plus Vouchers Approach: Treating Cocaine Addiction.
Therapy Manuals for Drug Addiction, Manual 12. Maryland:
National Institute on Drug Abuse.
26. Kearse, L., Rosow, C., Sebel, P., Bloom, M., Glass, P., Howell,
S. & Greenwald, S. (1995) The bispectral index correlates
© 2005 Society for the Study of Addiction
13600443, 2005, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2004.00959.x by Peking University Health, Wiley Online Library on [09/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Opioid detoxification under general anaesthesia 215
with sedation/hypnosis and recall: comparison using mul-
tiple agents. Anesthesiology, 83, A374.
27. Kleber, H. D. (1999) Opioids: detoxification. In: Galanter,
M. & Kleber, H. D., eds. Textbook of Substance Abuse Treat-
ment, 2nd edn, pp. 251–271. Washington DC: American
Psychiatric Press.
28. Meyers, R. J. & Smith, J. E. (1995) Clinical Guide to Alcohol
Treatment: the Community Reinforcement Approach. New
York: Guilford Press.
29. Cardiff Software, Inc. (2004) http://www.cardiff.com,
September.
30. Rosen, M. (1997) Use of pharmacological agents in opiate
detoxification. In: Stine, S. M. & Kosten T. R., eds. New Treat-
ments for Opiate Dependence, pp. 94–104. New York: Guilford
Press.
31. Gowing, L., Ali, R. & White, J. (2002b) Opioid antagonists
with minimal sedation for opioid withdrawal [Cochrane
Review]. Cochrane Library, Issue 4.
32. Drummond, M. F, O’Brien, B, Stoddart, G. L. & Torrance, G.
W. (1997) Methods for the Economic Evaluation of Health Care
Programmes. Oxford: Oxford University Press.
33. Loimer, N., Schmid, R. W., Presslich, O. & Lenz, K. (1998)
Continuous naloxone administration suppresses opiate
withdrawal symptoms in human opiate addicts during
detoxification treatment. Journal of Psychiatry Research, 23,
81–86.
34. Tretter, F., Burkhardt, D., Bussello-Spieth, B., Reiss, J., Wal-
cher, S. & Büchele, W. (1998) Clinical experience with
antagonist-induced opiate withdrawal under anaesthesia.
Addiction, 9, 269–275.
35. Scherbaum, N., Klein, S., Kaube, H., Kienbaum, P., Peters, J.
& Gastpar, M. (1998) Alternative strategies of opiate detox-
ification: evaluation of the so-called ultra-rapid detoxifica-
tion. Pharmacopsychiatry, 31, 205–209.
Addiction, 100, 206–215