Context Rapid opioid detoxification with opioid antagonist induction using general
anesthesia has emerged as an expensive, potentially dangerous, unproven approach
to treat opioid dependence.
Objective To determine how anesthesia-assisted detoxification with rapid antagonist
induction for heroin dependence compared with 2 alternative detoxification
and antagonist induction methods.
Design, Setting, and Patients A total of 106 treatment-seeking heroin-dependent patients, aged 21
through 50 years, were randomly assigned to 1 of 3 inpatient withdrawal treatments
over 72 hours followed by 12 weeks of outpatient naltrexone maintenance with
relapse prevention psychotherapy. This randomized trial was conducted between
2000 and 2003 at Columbia University Medical Center’s Clinical Research
Center. Outpatient treatment occurred at the Columbia University research
service for substance use disorders. Patients were included if they had an
American Society of Anesthesiologists physical status of I or II, were without
major comorbid psychiatric illness, and were not dependent on other drugs
or alcohol.
Interventions Anesthesia-assisted rapid opioid detoxification with naltrexone induction,
buprenorphine-assisted rapid opioid detoxification with naltrexone induction,
and clonidine-assisted opioid detoxification with delayed naltrexone induction.
Main Outcome Measures Withdrawal severity scores on objective and subjective scales; proportions
of patients receiving naltrexone, completing inpatient detoxification, and
retained in treatment; proportion of opioid-positive urine specimens.
Results Mean withdrawal severities were comparable across the 3 treatments.
Compared with clonidine-assisted detoxification, the anesthesia- and buprenorphine-assisted
detoxification interventions had significantly greater rates of naltrexone
induction (94% anesthesia, 97% buprenorphine, and 21% clonidine), but the
groups did not differ in rates of completion of inpatient detoxification.
Treatment retention over 12 weeks was not significantly different among groups
with 7 of 35 (20%) retained in the anesthesia-assisted group, 9 of 37 (24%)
in the buprenorphine-assisted group, and 3 of 34 (9%) in the clonidine-assisted
group. Induction with 50 mg of naltrexone significantly reduced the risk of
dropping out (odds ratio, 0.28; 95% confidence interval, 0.15-0.51). There
were no significant group differences in proportions of opioid-positive urine
specimens. The anesthesia procedure was associated with 3 potentially life-threatening
adverse events.
Conclusion These data do not support the use of general anesthesia for heroin detoxification
and rapid opioid antagonist induction.
Heroin dependence remains a significant public health problem in the
United States. Most of the approximately 1 million1 heroin-dependent
individuals in the United States are not in treatment. Their main initial
contact with the treatment system is often detoxification,2 partially
because the prevailing societal view favors drug-free approaches and because
restricted access to and inconvenience (eg, daily clinic visits) of methadone
maintenance programs may outweigh their better outcomes.3-5
Throughout the 20th century, many methods of opioid detoxification,
including insulin-induced seizures,6 artificial
hibernation,7 and electroconvulsive therapy,8 have been proposed. These approaches at times produced
greater morbidity and mortality than untreated withdrawal.9,10 However,
despite improvements in recent decades, medically supervised heroin withdrawal
remains plagued by patient discomfort and high dropout rates.11 Many
patients fear the physical discomfort of withdrawal and either avoid treatment
or leave it prematurely. Even those who complete the detoxification process
have high relapse rates,11 partly due to the
absence of continuing treatment, such as antagonist maintenance. These problems
have given rise, in the past 15 years, to ultra-rapid, or anesthesia-assisted
opioid withdrawal and antagonist induction procedures, which have been publicized
as a fast, painless way to withdraw from opioids. However, these treatments
are expensive (up to $7500 in 1997,12 and as
much as $15 000 in 2005), are not covered by insurance, and lack good
evidence to support efficacy.13 There are also
significant concerns about risk, including marked increases in plasma corticotropin,14 cortisol,14 respiration,15,16 sympathetic activity,16 and
catecholamines17,18; suppression
of thyroid hormones19; pulmonary distress14,20; pulmonary edema19;
acute renal failure19; ventricular bigeminy21; psychosis21,22;
delirium23,24; suicide attempts21,25; and deaths associated with the procedure.26-29 In
addition, several reports describe persistent, marked withdrawal symptoms
following the procedure.14,25,30,31 The
eagerness with which both patients and the public have accepted claims of
success highlights the desperation many patients and families feel about treating
opioid dependence. Their vulnerability to unproven promises of success, combined
with the expanding problem of prescription opioid dependence, increased the
need for well-controlled research to test anesthesia-assisted withdrawal.32 Physicians in general practice need such evidence
to advise patients seeking treatment for opioid dependence.
Virtually all published reports on anesthesia-assisted opioid withdrawal
come from nonrandomized, uncontrolled series or trials.14-19,21,23-25,27,30,33-41 An
early double-blind study42 described methohexitone
anesthesia in 18 individuals randomly assigned to receive naloxone or placebo.
But the study only compared withdrawal induced by naloxone vs placebo and
included only a week of follow-up. A single prior randomized controlled study43 compared outpatient anesthesia with an inpatient
alternative, but only 54% of the anesthesia group received naltrexone induction
under anesthesia, making the procedure unrepresentative, and there were no
systematic withdrawal severity measures, precluding comparison of the course
and severity of withdrawal symptoms. All other reports on anesthesia have
been weakened by selection bias or lack of randomized control groups, increasing
the need for a comprehensive randomized trial of the procedure.12,32,44,45
General anesthesia has been offered as a mechanism for rapid induction
of an opioid antagonist at higher dosages than opioid-dependent patients can
usually tolerate. Opioid antagonists (eg, naltrexone, nalmefene) block opioid
effects without themselves producing tolerance, dependence, or psychic effects.
Although maintenance on opioid antagonists typically yields low treatment
retention in unselected samples,46 it fares
better in selected populations.47 A fair study
of the general anesthesia procedure required that comparison treatments use
naltrexone induction procedures. Given the anticipated advent of depot naltrexone
formulations, which could improve the typically poor compliance with oral
naltrexone, procedures for opioid antagonist induction should take on greater
importance.
We conducted a randomized controlled trial to evaluate the safety, tolerability,
and efficacy of anesthesia-assisted rapid opioid detoxification compared with
2 inpatient withdrawal and naltrexone induction procedures: a positive control
of rapid naltrexone induction, using a bridging dose of the partial μ opioid
agonist, buprenorphine48-50;
and a control treatment using clonidine49,51,52 with
delayed naltrexone induction. The choice of the positive control, buprenorphine-assisted
rapid opioid detoxification, was based on successes with bridging doses of
buprenorphine for naltrexone induction.48-50 Buprenorphine
has a longer duration of action and decreased withdrawal symptoms compared
with heroin. The buprenorphine-assisted rapid opioid detoxification procedure
included a single facilitating dose of buprenorphine to minimize the time
required for naltrexone induction and to make it nearly as rapid as the anesthesia
procedure. The other control procedure, clonidine-assisted opioid detoxification,
used the α2-adrenergic agonist, clonidine, which had previously
shown efficacy in outpatient naltrexone induction49 and
which has been a standard of care in treating opioid withdrawal symptoms.51,52 Clonidine ameliorates symptoms of
opioid withdrawal by acting on the locus coeruleus to decrease norepinephrine
secretion.
Individuals seeking heroin detoxification were enrolled between April
2000 and July 2003. To achieve a power of 0.80, the study aimed to enroll
53 patients in each of the 3 groups to observe a predicted 25% absolute difference
(45% vs 20%) in the 12-week treatment retention between anesthesia-assisted
antagonist induction and clonidine-assisted antagonist induction. The data
and safety monitoring board suggested that enrollment stop in July 2003 with
a total of 106 participants because actual differences in withdrawal severity
scores and treatment retention were smaller than anticipated, leading to an
impractically large recalculated sample size (N>400) needed to show significant
withdrawal severity or treatment retention differences.
The institutional review boards of the Columbia University Medical Center
and the New York State Psychiatric Institute approved this protocol. All participants
provided voluntary oral and written informed consent. They provided baseline
demographic information, including open-ended, self-identified race or ethnicity
to allow comparison with results of prior studies. Participants were reimbursed
$3 at each screening visit to defray travel costs and $15 at subsequent clinic
visits to encourage attendance.
During screening, psychological and psychiatric assessments, a medical
history, physical examination, and anesthesia preprocedure assessment were
performed. Screening tests for all patients included complete blood cell count,
chemistries, liver profile, thyroid functions, urinalysis, urine culture,
coagulation profile, chest x-ray, electrocardiogram, and echocardiogram. Patients
were administered or completed the following baseline assessment instruments:
Structured Clinical Interview for the Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition, Addiction Severity Index,53 Beck Depression Inventory II,54 and
Hamilton Depression Scale.55 In addition, opioid
dependence was confirmed in all patients by use of a naloxone challenge test.56 The inclusion and exclusion criteria are shown in
the Box.
Inclusion Criteria
Diagnostic and Statistical Manual
of Mental Disorders, Fourth Edition (DSM-IV)
criteria for opioid dependence of at least 6 months’ duration and seeking
treatment for opioid dependence*†‡
In general good health§∥¶
21 to 50 years of age∥
Able to give informed consent and comply with study
procedures*
American Society of Anesthesiologists physical classification
status I or II (“otherwise healthy, no other medical problems”
for class I, or “a chronic medical condition that is well-controlled,”
eg, hypertension, diabetes, asthma, for class II)*§¶
Exclusion Criteria
DSM-IV criteria for dependence
on alcohol or drugs other than opiates, nicotine, and/or caffeine*†
Pregnancy or lactation or failure to use adequate
means of birth control§∥
History of significant violent behavior*
Diagnosis of schizophrenia and/or major mood disorder*
Significant suicide risk*
Current use of prescribed psychotropic medication
(except for benzodiazepines, which may be prescribed for sleep; must not be
taking other psychotropic medications for a minimum of 2 weeks)*∥
Use of monoamine oxidase inhibitor medication within
2 weeks of study start*∥
History of food or drug allergy, adverse reaction
or sensitivity to any study medication (including malignant hyperthermia,
history of egg allergy)*
Active medical illness, including coronary artery
disease, acute hepatitis, renal failure, insulin-dependent or unstable diabetes,
AIDS dementia or active human immunodeficiency virus or related infection,
tuberculosis, severe thyroid abnormalities†∥¶
Currently taking protease inhibitors∥
Positive urine toxicology result for cocaine on the
day of admission to the hospital†
Body mass index of 40 or higher¶
Inability to provide urine samples free of methadone
during screening†
Blood glucose concentration greater than 160 mg/dL
(8.8 mmol/L)§
Either multiple prior pneumonias or history of a
complicated pneumonia (eg, pneumonia requiring intubation or pneumonia with
empyema)*∥
*Clinical interview.
†Urine toxicology.
‡Naloxone
challenge test.
§Laboratory tests (urinalysis, thyroid function
tests, coagulation profile, 12-lead electrocardiograph, serum and or urine β-human
chorionic gonadotropin).
∥Self-report.
¶Physical examination.
Figure 1 shows the patient flow
for the 169 individuals assessed for eligibility for the study. One hundred
six participants were randomly assigned. Of those, 2 individuals (1 in the
anesthesia-assisted and 1 in the clonidine-assisted groups) were treated but
developed a mixed manic mood syndrome during detoxification and subsequently
revealed a previously concealed history of bipolar disorder. Those patients
were removed from the study. One patient in the anesthesia-assisted group
refused the procedure immediately after learning of the randomization assignment,
and another patient in the anesthesia-assisted group left the hospital several
hours after admission and after receiving clonidine the night before planned
anesthesia. A patient in the buprenorphine-assisted group left the hospital
approximately 28 hours after admission and before naltrexone induction. Another
patient in the anesthesia-assisted group developed pulmonary edema following
anesthesia and was removed from the study.
Randomization to the 3 inpatient procedure groups was accomplished in
blocks of 12, using random, computer-generated assignments, with stratification
by sex. All staff remained unaware of the randomization sequence throughout
the study. In addition, the Berger-Exner test57 was
used to confirm that no selection bias in enrollment occurred. Patients were
not blinded to treatment. Blinding would have required sham anesthesia and
raised practical concerns about the adequacy of blinding a sham procedure
and safety issues related to potential opioid overdose for individuals who
might challenge expected opioid blockade (initially absent in clonidine arm)
with high doses of heroin. All patients were admitted to a National Institutes
of Health–funded general clinical research center at Columbia University
Medical Center, with single rooms and medical-surgical nursing care, on Monday
(day 0) and discharged on Thursday (day 3), with a few exceptions: some patients
seemed unable to ambulate or care adequately for themselves due to fatigue
or sedation; the team needed to rule out adverse cardiac consequences (none
occurred); the patient asked to stay an extra night in the hospital.
Figure 2 provides a schematic
timeline for the screening, inpatient, and outpatient phases of the study.
During the inpatient phase, withdrawal severity was assessed 4 times daily,
at 8:30 AM and 12:30, 4:30, and 10 PM. Withdrawal
assessment time point 1 occurred on day 0 at 4:30 PM, with
subsequent assessment time points numbered sequentially. The withdrawal measures
used were the Subjective Opiate Withdrawal Scale,58 Objective
Opiate Withdrawal Scale,58 and Clinical Institute
Narcotic Assessment.59
All patients were administered clonidine, as needed, up to 0.2 mg every
4 hours (maximum 1.2 mg/d); clonidine was withheld if heart rate and blood
pressure did not remain in the normal range (heart rate >55/min, systolic
blood pressure >90 mm Hg, diastolic blood pressure >55 mm Hg). Clonazepam
was also administered, up to 2 mg every 8 hours, with additional dosing available
for severe persistent withdrawal. Other adjuvant medications were administered
as needed: ketorolac, 30 mg intramuscularly every 6 hours for myalgias, bone
pain, cramping; ondansetron, 8 mg orally every 8 hours or prochlorperazine,
10 mg orally or intramuscularly every 8 hours for nausea and vomiting; octreotide,
100 μg every 8 hours subcutaneously for diarrhea; and acetaminophen, magnesium
hydroxide, and aluminum hydroxide/magnesium hydroxide/simethicone for dyspepsia.
A board-certified anesthesiologist (R.A.W.), assisted by a certified
registered nurse anesthetist, performed anesthesia. Patients received nothing
orally after midnight before the procedure, which always occurred on Tuesday
(day 1) at approximately 8:30 AM. Medications, interventions,
and monitors used before and during anesthesia are shown in Table 1. Anesthesia was maintained for 4 to 6 hours, followed by
approximately 2 hours in the postanesthesia care unit.
Given reports of sudden death27 following
rapid opioid detoxification, patients were monitored with telemetry and continuous
pulse oximetry throughout the inpatient hospitalization. To rule out occult
myocardial ischemia during anesthesia, troponin and serial cardiograms were
performed. Serum chemistries, including calcium and magnesium, were also checked
on day 2.
Unlike the usual use of buprenorphine for maintenance or detoxification,
this procedure used a single facilitating buprenorphine dose to enable more
rapid and comfortable naltrexone induction. The buprenorphine group received
8 mg of sublingual buprenorphine in the evening of day 0. Naltrexone induction
occurred on day 2, with an initial dose of 12.5 mg. Patients received 25 mg
of naltrexone on day 3, and the dosage was increased to 50 mg/d on subsequent
days. Clonidine, clonazepam, and ancillary medications were administered as
described above.
In this group, patients received no anesthetic agents, no buprenorphine,
and no naltrexone during the inpatient phase. Clonidine, clonazepam, ketorolac,
ondansetron, octreotide, prochloperazine, and over-the-counter medications
were given as needed as described above. Naltrexone induction was scheduled
a week following hospital admission. Patients with opioid-negative urine,
reporting little or no opioid use and demonstrating minimal opioid withdrawal
on a naloxone challenge test,56 received naltrexone
on day 7 with an initial dose of 12.5 mg, followed by 25 mg the next day and
50 mg on subsequent days.
Standardized Outpatient Phase
Following hospital discharge, all patients were treated for 12 weeks
with 50 mg of naltrexone daily and twice weekly manual-guided relapse prevention
psychotherapy61 provided by master’s-
and doctoral-level psychotherapists. Patients met with the study psychiatrist
weekly during the first month and monthly thereafter. In the first 2 weeks
after discharge from the hospital, patients with residual withdrawal symptoms
received up to 0.1 mg of clonidine 3 times a day and 10 mg of zolpidem tartrate
and/or 50 mg of trazodone taken orally every night as needed for sleep. At
all outpatient visits, which were scheduled twice weekly, patients met with
their therapist, nursing staff, and the research assistant, and urine was
collected for toxicology. Naltrexone maintenance was strongly encouraged but
not required. Patients still receiving naltrexone at study end were continued
on it, if desired, and referred for additional aftercare. Individuals who
relapsed during outpatient treatment were referred for alternative treatment.
For the evaluation of treatment retention, dropout was
defined as relapse to opioid dependence requiring referral to alternative
treatment (another detoxification or agonist maintenance therapy) or missing
outpatient visits for 2 consecutive weeks. Patients who dropped out of treatment
were counted as retained in treatment through the end of the week of their
last outpatient visit.
The primary outcome measures for this study were (1) opioid withdrawal
severity (assessed using the Subjective Opiate Withdrawal Scale, Objective
Opiate Withdrawal Scale, and Clinical Institute Narcotic Assessment) during
the 4-day inpatient phase of the trial, (2) the proportion of patients completing
inpatient detoxification, (3) the proportion of patients receiving naltrexone
induction (at any dose and at 50 mg), and (4) the number of weeks completed
in treatment. Drug use over the course of the 12-week outpatient treatment
was assessed by examining the proportions of urine specimens that tested positive
for opiates and any drug, defined as positive if any of marijuana, phencyclidine,
benzodiazepine, methadone, cocaine, barbiturate, or amphetamine were present.
All analyses were carried out on the intent-to-treat population and
all tests were 2-tailed with the α significance level set at .05. Baseline
demographic variables and clinical characteristics were compared across groups
using χ2 tests for categorical variables and a 1-factor (treatment)
analysis of variance for continuous variables. The Berger-Exner test was conducted
on each outcome measure to test for selection bias in enrollment that might
not have been captured by baseline comparisons of the sample.
Retention in treatment was compared using Kaplan-Meier curves and the
log-rank statistic. Cox regression was used to examine the effect of naltrexone
induction on retention. Aggregate measures of drug use during the outpatient
phase (proportions of positive urine specimens) were compared using Kruskal-Wallis
1-way analysis of variance by ranks.
To examine time trends during the inpatient phase, models were fitted
on the (postnaltrexone induction) log-transformed withdrawal scores on days
2 and 3 using general estimating equations as implemented by PROC GENMOD (SAS
Institute Inc; Cary, NC). The outcome was modeled as a function of time, treatment
assignment, and time × treatment interaction. Given significant
baseline differences in current marijuana use, days using marijuana was explored
as a covariate in the model but was found not to be a significant factor (P>.20) and therefore excluded from the model.
Demographic and clinical characteristics of the 106 participants were
comparable (Table 2). The Berger-Exner
test for selection bias was performed on all response measures and was found
to be nonsignificant for all outcomes (P >.10). Fifty-three
percent of the participants were white and 72% were men, with a mean (SD)
age of 36 (8) years (range, 21-50 years) and an average 14 (2) years of education.
With respect to baseline drug use, the groups differed significantly only
in marijuana use, with more use among those in the buprenorphine-assisted
group, which used a mean (SD) of 8 (12) days in the month before screening
vs 4 (7) days among those in the anesthesia-assisted and 2 (6) days among
those in the clonidine-assisted groups (F2,103 = 4.23, P=.02). The groups did not differ on any of the Addiction
Severity Index subscales.
Mean opioid withdrawal scores are presented in Figure 3. Withdrawal severity for the anesthesia group was greatest
on day 1, immediately before receiving the anesthesia treatment, and differed
significantly from withdrawal severity in the buprenorphine-assisted and clonidine-assisted
groups (P<.001; withdrawal assessment time point,
3). This greater severity was attributed to anticipatory anxiety about anesthesia
and perhaps less use of the available clonazepam before receiving anesthesia.
Following anesthesia treatment, withdrawal scores among those in the anesthesia-assisted
group decreased, although not below pretreatment levels. For those receiving
buprenorphine, withdrawal severity decreased on both the Clinical Institute
Narcotic Assessment and the Objective Opiate Withdrawal Scale on the day after
receiving buprenorphine, but severity increased (on all 3 withdrawal assessment
instruments) following naltrexone induction on the morning of day 2. Subjective
Opiate Withdrawal Scale mean scores were lower for all groups on measurements
taken at night (10 PM). This pattern was not replicated on
the Objective Opiate Withdrawal Scale or Clinical Institute Narcotic Assessment.
Longitudinal analyses on log-transformed withdrawal scores on days 2 and 3
(withdrawal assessment time points 7 through 12) did not reveal significant
differences in withdrawal severity.
Other Detoxification Outcomes
Table 3 shows the number of patients
in each group completing various study milestones. During outpatient treatment,
no group differences occurred in the proportions, mean (SDs), of urine samples
positive for opiates (anesthesia, 0.54 [0.39]; buprenorphine, 0.62 [0.39];
clonidine, 0.73 [0.41]; χ22 = 3.18, P = .20) or for “any drug use” (anesthesia,
0.50 [0.41]; buprenorphine, 0.65 [0.35]; clonidine, 0.50 [0.42]; χ22 = 2.36, P = .31).
Five patients (14%) in each of the anesthesia-assisted and buprenorphine-assisted
groups and 2 (5.9%) in the clonidine-assisted group were retained 12 weeks
and provided no more than 2 opiate-positive urine specimens during the outpatient
phase (χ22 = 1.49, P = .48).
As shown in Table 3, rates of
naltrexone induction, defined as taking any dose of naltrexone, differed significantly
across groups, with 33 (94%) of 35 patients in the anesthesia-assisted group
and 36 (97%) of 37 in the buprenorphine-assisted group achieving higher rates
of naltrexone induction than the 7 (21%) of 34 in the clonidine-assisted group(χ22 = 64.52, P<.001).
Thirty-three (94%) of 35 patients in the anesthesia-assisted, 27 (73%) of
37 in the buprenorphine-assisted, and 6 (18%) of 34 in the clonidine-assisted
groups received the full 50-mg maintenance dose of naltrexone (χ22 = 45.89, P<.001).
A significant relationship existed between naltrexone induction at the full
50-mg maintenance dose and attrition, with those achieving full-dose induction
at lower risk of dropping out (odds ratio, 0.28; 95% confidence interval,
0.15- 0.51).
Treatment retention (Figure 4)
over the course of the study did not differ significantly across intervention
groups (mean [SE] weeks in treatment, anesthesia 2.83 [0.47] weeks; buprenorphine,
3 [0.45]; and clonidine, 2.47 [0.58]; log-rank2 = 3.57, P = .17). By week 3, more than 50% of the patients
had dropped out of each treatment arm. Although the differences were not significant
overall, 7 (20%) of 35 in the anesthesia, 9 (24%) of 37 in the buprenorphine,
and 3 (9%) of 34 in the clonidine groups remained in treatment for 12 weeks.
Three patients in the anesthesia group experienced serious adverse events.
One developed severe pulmonary edema and aspiration pneumonia approximately
14 hours after extubation, necessitating reintubation and admission to the
intensive care unit for 5 days. The patient’s condition was complicated
by upper airway edema requiring aggressive glucocorticoid treatment. The patient
was discharged home in good condition a week after anesthesia treatment but
quickly relapsed to heroin dependence. The investigators believed that this
episode of pulmonary edema was postobstructive (negative pressure) pulmonary
edema. The patient had concealed but subsequently admitted a history both
of several prior complicated pneumonias and of possible obstructive sleep
apnea. These conditions were subsequently exclusionary. The second patient,
who had concealed a history of bipolar illness during the screening process,
developed a mixed bipolar state about 5 days after anesthesia, with suicidal
ideation requiring hospitalization. The third patient had reportedly stable
insulin-dependent diabetes mellitus but concealed a prior episode of diabetic
ketoacidosis. The patient’s glucose level was difficult to manage following
anesthesia, and the inpatient phase of the study was prolonged by a day. Two
days after discharge, the patient developed diabetic ketoacidosis, resulting
in a 3-day readmission to the hospital. Rapid relapse to heroin dependence
followed discharge. Subsequently, patients with a glucose level greater than
160 mg/dL (8.8 mmol/L) or with insulin-dependent diabetes were excluded from
the study.
This is the first randomized controlled trial of anesthesia detoxification
with a positive control group (buprenorphine-assisted detoxification) and
systematic documentation of postdetoxification withdrawal symptoms. Anesthesia-assisted
treatment was associated with a high rate of naltrexone induction but also
with significant opioid withdrawal symptoms comparable with the alternative
procedures. The buprenorphine-assisted procedure produced naltrexone induction
and 12-week treatment retention comparable with the anesthesia-assisted intervention.
The clonidine intervention produced a low rate of naltrexone induction (21%
vs >90%, P<.001) and nonsignificantly lower rates
of treatment retention (9% vs 20% for anesthesia-assisted group and 24% for
buprenorphine-assisted group) over 3 months. Furthermore, 3 serious, potentially
life-threatening adverse events occurred with the anesthesia procedure.
In the earlier Australian randomized trial,43 anesthesia
was also compared with inpatient clonidine detoxification. However, naltrexone
induction was sometimes delayed for a few days following anesthesia, so that
40 (83%) of 48 participants actually received naltrexone (only 54% during
anesthesia) compared with 14 (28%) of 50 in the clonidine group. Also, as
a result of variable postprocedure levels of care, no systematic measures
of withdrawal severity were made in the days following anesthesia, leaving
unanswered the question62 of whether the procedure
shortens and diminishes the withdrawal process. No adverse events were reported,
and treatment retention appeared even lower than our own at 3 months, with
15% of the anesthesia group vs 2% of the clonidine group remaining in treatment.
By 6 months, heroin use in each cohort was similar.
Uncontrolled reports on the experience with anesthesia for opioid withdrawal
have shown somewhat mixed results. Many argue for the safety and efficacy
of the procedure21,38,40,41,63,64 and
report high rates of naltrexone induction and sustained opioid abstinence.21,35,38,65 Selection
bias and the lack of controls, however, limit the validity and generalizability
of these reports. Anesthesia advocates41,63,66-68 have
claimed minimal withdrawal symptoms following anesthesia. Such reports lent
weight to claims that the severe discomfort of opioid withdrawal could be
avoided, contributing to the willingness of individuals or families to pay
large sums for this unproven approach. However, other studies14,30,31 have
reported significant, sometimes prolonged, withdrawal symptoms in patients
detoxified under general anesthesia. In an open case series of 7 patients,14 persistent and clinically significant withdrawal
was observed for nearly 3 weeks following the procedure, a result that was
consistent with a laboratory study in which continuous naloxone infusion and
anesthesia in rats lengthened and worsened opioid withdrawal signs.69
Two nonrandomized comparison studies merit mention. The first compared
15 patients detoxified under anesthesia with 15 patients receiving 1 to 2
weeks of inpatient methadone taper, with all offered supervised naltrexone
maintenance.65 Withdrawal symptoms were greater
in the anesthesia group immediately following the procedure. Abstinence rates
at 1 month (100%) and 2 months (93%) were extraordinarily high in the anesthesia
group, compared with 40% and 33%, respectively, for the methadone taper, but
statistical significance for treatment retention was lost after 3 months.
The second study retrospectively compared 139 anesthesia patients with 87
inpatients detoxified with methadone over a month.70 The
methadone taper group reported nearly twice the rate of sustained opioid abstinence
(42% vs 22%) in telephone follow-up after 12 to 18 months.
In our study, we took many precautions to screen individuals for preexisting
conditions that increase anesthesia risk. Because pretreatment chest x-rays
and echocardiograms significantly raise costs, they would potentially be omitted
in clinical practice, further increasing risk. Despite these precautions,
1 individual in our study experienced pulmonary edema and aspiration pneumonia.
Careful inpatient monitoring of pulmonary function, which enabled rapid tracheal
intubation and transfer to intensive care, may have saved this patient’s
life. Indeed, in a study of 20 patients treated with anesthesia,27 an
unmonitored patient died in the hospital of unknown causes between 34 and
41 hours after anesthesia treatment.28
The other 2 serious adverse events, an episode of diabetic ketoacidosis
and a bipolar mixed state requiring hospitalization (the patient in the clonidine-assisted
group who had the mixed bipolar reaction did not require hospitalization),
could have occurred with other opioid detoxification approaches, although
the risk of each may have been greater as a result of increased physiological
stress imposed by rapid antagonist exposure and precipitated withdrawal with
anesthesia.17
Given the large doses of opioid antagonists typically used during anesthesia
detoxification procedures, most practitioners have seen anesthesia as a means
principally to achieve rapid antagonist induction. Some believe that rapid
stripping of agonist from opioid receptors may itself be therapeutic,40,62,64 promoting long-term
abstinence. Although the results from our study do not support this thesis,
receptor agonist stripping can nevertheless occur with naltrexone induction
following a single dose of buprenorphine. Some have pointed out that anesthesia
could be offered electively to patients who desire it, because it will bring
more individuals into treatment, especially those who intensely fear opioid
withdrawal.71 Advocates compare this to offering
anesthesia to individuals with dental phobia or for cosmetic surgery.29 However, this argument relies on the usually false
promise that anesthesia eliminates the severe discomfort of opioid withdrawal.
This expectation probably contributed powerfully to patients’ lying
about their medical or psychiatric histories, as occurred with all 3 patients
who experienced serious adverse events in our study.
Treatment retention and abstinence from illicit opioids are important
goals of treatment, but specific detoxification methods, per se, do not appear
to lead to either. Two previous studies43,65 showed
that intermediate-term treatment outcomes at 3 months65 and
at 6 months43 do not differ as a function of
the detoxification approach used. Our results at 3 months, while demonstrating
low rates of sustained abstinence and treatment retention, corroborate these
earlier findings. Physicians must recognize that the method used to achieve
opioid abstinence does not appear to affect the course of this chronic relapsing
disease.
Although a formal cost-efficacy analysis is beyond the scope of this
report, it appears that the cost per successful patient undergoing the anesthesia
procedure is considerably greater than the cost per successful patient undergoing
the buprenorphine procedure. Anesthesia entails major costs not associated
with buprenorphine: obligatory preprocedure testing, physician anesthesiologist
charges, anesthetic medications, operating rooms and possible intensive care
unit beds, postprocedure monitoring, and the cost of treating adverse events
that appear more likely with anesthesia. Considering the lower cost, greater
safety, and equivalent withdrawal severity profile of the buprenorphine-assisted
approach, a buprenorphine-mediated procedure appears preferable to anesthesia
for initiation of opioid antagonist maintenance.
There are a number of limitations to this study. First, the total sample
size of 106 patients for a 3-treatment trial made it difficult to show statistically
significant differences in some important variables, including overall withdrawal
severity and treatment retention. A larger sample might have shown anesthesia
or buprenorphine superior to the other, but it appears this would have required
a sample with more than 4 times the number of participants in the present
study. Second, the sample size limited the ability to find patient subgroups
that might selectively benefit from anesthesia. Third, follow-up data on the
many individuals who dropped out of the study or were referred for additional
treatment were not available, making it difficult to appreciate potential
distal effects of the withdrawal methods used. Fourth, because prescription
analgesic use was negligible and recent methadone use exclusionary, the inclusion
only of patients dependent on heroin may limit generalizability of our findings
to all opioid-dependent individuals. Earlier studies, however, have suggested
that dependence on methadone made anesthesia-assisted withdrawal more difficult24,35 and produced lower subsequent treatment
retention.24 Methadone use also predicted poor
retention in a series of heroin-dependent patients inducted onto naltrexone
using a buprenorphine-mediated procedure similar to buprenorphine-assisted
rapid opioid detoxification.72 These prior
results suggest that naltrexone induction is complicated by methadone and
that anesthesia would not likely fare comparatively better among methadone-maintained
patients.
In summary, this randomized trial of general anesthesia for opioid withdrawal
and naltrexone induction demonstrates no benefit of anesthesia over a safer,
cheaper, and potentially outpatient alternative using buprenorphine as a bridge
to naltrexone treatment. Taken together with the results of earlier studies,31,43,65,70 our
findings suggest that general anesthesia for rapid antagonist induction does
not currently have a meaningful role to play in the treatment of opioid dependence.
Corresponding Author: Eric D. Collins, MD,
Division on Substance Abuse, College of Physicians and Surgeons of Columbia
University, 1051 Riverside Dr, Unit 120, New York, NY 10032 (edc3@columbia.edu).
Author Contributions: Dr Collins had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Collins, Kleber,
Whittington, Heitler.
Acquisition of data: Collins, Kleber, Whittington,
Heitler.
Analysis and interpretation of data: Collins,
Kleber.
Drafting of the manuscript: Collins, Kleber,
Whittington, Heitler.
Critical revision of the manuscript for important
intellectual content: Collins, Kleber, Whittington.
Obtained funding: Collins, Kleber.
Administrative, technical, or material support:
Collins, Kleber, Whittington, Heitler.
Study supervision: Collins, Kleber, Whittington.
Financial Disclosures: Dr Kleber has served
as consultant for and has received an unrestricted grant from Reckitt Benckiser,
the manufacturer of buprenorphine, for issues unrelated to this article. No
other authors reported disclosures.
Funding/Support: This study was supported by
grants DA-12644, DA-00317, and DA-14284 from the National Institute on Drug
Abuse (NIDA) and grant MOI-RR-00645 from the National Institutes of Health
(NIH). The present study was funded entirely by NIH grants.
Role of the Sponsor: The study was reviewed
by the Investigational Review Group at the National Institute on Drug Abuse
when it recommended funding for this project. Beyond the review process, neither
the NIH nor the NIDA had a role in the design, conduct, analysis, or writing
of this study.
Acknowledgment: We wish to thank the following
individuals for their work in support of this research: Marty L. Hill, CRNA,
and Jody Davis, CRNA, Department of Anesthesiology; Edward Nunes, MD, Division
of Substance Abuse, and Dan Bloomfield, MD, Department of Medicine; and Maria
Sullivan, MD, and Jay Mott, MD, Division of Substance Abuse, Department of
Psychiatry, Columbia University Medical Center; Randi Adelman, RN; Research
Assistants Chaim Kozlovsky and Michael Song; and Fatima Garawi, MA, for statistical
support.
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