Medication For Opioid Use Disorder

Medication for opioid use disorder - UpToDate 02/02/23, 10:17
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Medication for opioid use disorder

Author: Eric Strain, MD
Section Editor: Andrew J Saxon, MD
Deputy Editor: Michael Friedman, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2023. | This topic last updated: Dec 21, 2022.
INTRODUCTION
Opioids, used medically for pain relief, have analgesic and central nervous system
depressant effects, as well as the potential to cause euphoria. Opioid use disorder (OUD) can
be related to misuse of pharmaceutical opioids, heroin, or other opioids such as fentanyl and
its analogs. OUD is typically a chronic, relapsing illness, associated with significantly
increased rates of morbidity and mortality.
Medication for OUD (MOUD) consists of treatment with an opioid agonist or antagonist and
is first-line treatment for most patients with an OUD. MOUD appears to reinforce abstinence
and improve treatment retention [1-4]. Our approach to treating OUD, including choice of
treatment, is discussed elsewhere. Pharmacotherapy for OUD is reviewed here. The
epidemiology, clinical manifestations, course, screening, assessment, diagnosis, and
psychosocial treatment for OUD are reviewed separately. Other topics including those
addressing medically supervised opioid withdrawal, prescription drug misuse, substance use
disorder in clinicians, management of OUD during pregnancy, and treatment of acute pain in
the patient chronically using opioids are also discussed elsewhere:
● (See "Approach to treating opioid use disorder".)

● (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course,
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screening, assessment, and diagnosis".)

● (See "Psychosocial interventions for opioid use disorder".)
● (See "Medically supervised opioid withdrawal during treatment for addiction".)
● (See "Management of acute pain in the patient chronically using opioids for non-cancer
pain".)
● (See "Prescription drug misuse: Epidemiology, prevention, identification, and
management".)
● (See "Substance use disorders in physicians: Epidemiology, clinical manifestations,
identification, and engagement".)
● (See "Substance use disorders in physicians: Assessment and treatment".)
● (See "Overview of management of opioid use disorder during pregnancy".)
APPROACH TO TREATMENT
Our preference is to treat all individuals with opioid use disorder (OUD) with medication for
OUD (MOUD) and psychotherapy. We consider OUD to be a chronic condition and treat
indefinitely. However, in individuals who are fully free of problematic substance use, are
engaged in productive activities, and have stable psychosocial support for at least 6 to 12
months, we support a slow taper off of MOUD at the patient’s request. The general approach
to selecting treatment for OUD, including selecting among MOUD options, is described
separately ( algorithm 1). (See "Approach to treating opioid use disorder", section on
'Assessment of response' and "Approach to treating opioid use disorder", section on
'Duration of therapy for responders'.)
BUPRENORPHINE: OPIOID AGONIST
In individuals with an opioid use disorder (OUD), buprenorphine suppresses withdrawal

symptoms, craving, and blocks the effect of other opioids thereby reducing use [1,5,6]. As a
partial agonist with high affinity for mu-opioid receptor it displaces other agonists from the
receptor (high affinity) potentially precipitating withdrawal (partial agonist) in individuals on
opioids. Although individuals treated with buprenorphine are physically dependent upon the
medications, they do not typically have the pattern and severity of problematic behaviors
associated with use and misuse of heroin or pharmaceutical opioids including fentanyl [7-9].
Choosing among buprenorphine formulations — For most individuals, our initial choice of

opioid agonist for the treatment of OUD is with transmucosal buprenorphine. However, we
prefer to use longer-acting formulations of buprenorphine in individuals with limited
adherence, misuse, and/or diversion of transmucosal buprenorphine. We consider patient
preference and use shared decision-making in formulating the treatment plan. (See
"Approach to treating opioid use disorder", section on 'Shared decision-making'.)
Buprenorphine is available in daily transmucosal formulations, as an extended-release

subcutaneous injection (XR; 30-day), and as a weekly or monthly injectable formulation (CAM
2038) that can be used without a period of transmucosal stabilization. (CAM 2038 is
unavailable in the United States.)
Transmucosal formulations — Buprenorphine is most commonly administered

transmucosally (film strip or tablet) in a combination preparation with naloxone, an opioid
antagonist. The combination is used to prevent individuals from crushing the tablets and
dissolving them for intravenous injection or dissolving the soluble film for injection [10].
Naloxone has little to no bioavailability or activity when administered sublingually but
discourages intravenous buprenorphine misuse since the naloxone can precipitate
withdrawal when given parenterally to individuals with physiologic dependence on opioids.
The ratio of buprenorphine to naloxone is 4:1, and a variety of dose sizes are available (eg,
2/0.5, 4/1, 8/2, 12/3). Additionally, a sublingual tablet form of buprenorphine/naloxone
provides equivalent amounts of the medication as the traditional tablet doses used, but
contains a lower dose of buprenorphine. (For example, one of the formulations provides 5.7
mg dose that is equal to 8 mg of buprenorphine.)
A transmucosal formulation of buprenorphine that does not contain naloxone is also

available. Although allergy to naloxone is extremely rare, some individuals report an allergy.
Additionally, some individuals report unpleasant side effects from the combination
formulation that they do not get from the buprenorphine only formulation. This may be due
to trace amounts of naloxone that may be absorbed transmucosally [11,12]. In those rare
cases, a shared decision-making discussion is needed to decide on the formulation to use.
We determine whether to use the non-naloxone formulation on a case-by-case basis.
Standard induction — We use a standard induction in most clinical scenarios. However, in

some cases, for example, if the individual presents and is not in early withdrawal or for high
levels of physiologic dependence, we often use another protocol, such as low-dose initiation.
(See 'Alternative induction methods for specific circumstances' below.)
Timing and site of initiation — When initiating buprenorphine, the individual needs to

be abstinent from other opioids long enough to enter a state of mild withdrawal (see
'Assessing for withdrawal' below). Time to reach this state varies as a function of the half-life
of the opioid being used by the patient. As examples, withdrawal from heroin or other short-
acting opioids can appear 6 to 12 hours after the last dose, while withdrawal from
methadone can appear in 24 to 36 hours.
Induction can be done in the office, emergency department, or at home. When done in the
office or emergency department, the buprenorphine is given directly to the patient after
assessment for withdrawal. The patient is then given supply of several days lasting until
scheduled follow-up appointment. When done at home, the patient receives two to seven
days of medication depending upon the patient’s circumstances and scheduling of follow-up
appointments and is instructed on how to assess for withdrawal. (See 'Assessing for
withdrawal' below and "Acute opioid intoxication in adults", section on 'Prevention of
recurrent opioid overdose'.)
Assessing for withdrawal — To determine that the patient has entered a state of mild
to moderate opioid withdrawal, we observe the patient for early signs of opioid withdrawal
such as sweating, tremor, piloerection, irritability, or yawning at the time of initiation. We use
a standard measure, the Clinical Opiate Withdrawal Scale (COWS) ( table 1). We consider a
score of 12 or more on the COWS to be objective evidence of mild to moderate withdrawal.
When signs of early withdrawal appear, we begin the induction with buprenorphine.
Buprenorphine ameliorates the withdrawal by binding to and activating the mu-opioid
receptors [10].
If home induction is planned, we instruct the patient how to determine the presence of
sufficient withdrawal to begin induction. We review the objective signs of withdrawal (tremor,
piloerection, sweating) and how to differentiate them from subjective symptoms (eg,
irritability, restlessness). We often ask the patient to use the Subjective Opiate Withdrawal
Scale as a guide to whether they are in mild to moderate withdrawal and whether to begin
induction. Scores of 17 or greater indicate that there is a mild to moderate level of
withdrawal and that induction can start. Tools and handouts for patients and family
members that can be helpful in home inductions can be found in the Providers Clinical
Support System. (See "Medically supervised opioid withdrawal during treatment for
addiction", section on 'Monitoring'.)
Initiating induction — Induction begins with the individual manifesting symptoms of

withdrawal. (See 'Standard induction' above.)
● Day 1 – We typically start transmucosal buprenorphine at a dose of 4 mg (ie, 4 mg/1 mg

of buprenorphine-naloxone). Relief of symptoms may occur in minutes although one to
two hours of observation is needed for full effect. We observe the patient for a full two
hours. At that time, we reassess for symptoms of withdrawal.
• If withdrawal symptoms persist (eg, COWS ≥6 ( table 1)), an additional dose of up

to 4 mg can be administered.
• If the individual has sufficient relief of symptoms (COWS <6) we allow the individual
to go home. We provide a second dose of buprenorphine for the individual to bring
home and take if withdrawal symptoms or craving become prominent before the
next morning.
Federal guidelines recommend a maximum dose of 8 mg (ie, 8/2 mg) on the first day. In
some cases, for example if the individual has been using fentanyl, higher doses may be
needed [13]. Thus, a dose higher than 8 mg can be considered on the first day,
although this is generally the exception rather than the rule. Further dose increases can
occur on subsequent days, as noted below.
● Day 2 – The patient is given a single dose consisting of the total of the doses received
the first day. We monitor the individual over the next one to two hours.
• If residual symptoms are present (ie, COWS ≥6 ( table 1)), we give another 4 mg
(ie, 4 mg/2 mg). We continue to monitor and give 4 mg every two hours depending
on COWS score (ie, COWS score ≥6). We give a maximum total dose of 16 mg (ie,
16/4 mg buprenorphine-naloxone) on day 2.
• If the individual has sufficient relief of symptoms (COWS <6) we allow the individual
to go home and provide further maintenance doses. We typically give patients a
week supply, but the precise number of days of medication given varies depending
upon the patient and their circumstances (eg, social supports at home).
United States federal and European guidelines recommend a maximum dose on day 2
of 16 mg total (ie, 16/4 mg of buprenorphine-naloxone) [13,14].
● Maintenance – We usually do not increase the dose above 16 mg for several days to
one week to allow pharmacologic steady state to be reached. Most individuals will
stabilize on 8 to 16 mg/day of buprenorphine [15]; however, in some cases, particularly
when fentanyl is the primary opioid being used, the individual may need doses up to 32
mg/day [16,17]. The goal of dose maintenance treatment is to ensure there is no opioid
withdrawal, no opioid craving, and no or markedly reduced illicit opioid use.
Alternative induction methods for specific circumstances — In specific circumstances,

we use a modified induction protocol, such as low-dose initiation or aggressive
buprenorphine induction However, evidence to support their use is limited.
● Low-dose initiation – Low-dose initiation (also called microdosing) is a method of

buprenorphine induction that involves frequent administration of small doses (eg, 0.5
to 1 mg) of buprenorphine, which is initiated while the individual is on full agonist [18].
Advocates note that with this method, the transition to buprenorphine/naloxone can
begin without waiting for signs of withdrawal. Additionally, frequent low dosing avoids
precipitation of withdrawal that would otherwise occur with standard doses of
buprenorphine in individuals on opioid agonists. However, most of the evidence for the
value of this approach is based upon case reports. The use of low-dose initiation can
occur in the following clinical scenarios:
• High levels of physical dependence (eg, fentanyl) – As fentanyl has become more
widely misused, there have been reports of difficulties in achieving successful
buprenorphine induction in these patients [19]. This may be related to protracted
fentanyl clearance in some patients [20], or due to higher levels of physical
dependence. We have used low-dose initiation in these individuals to achieve

induction. Other options include waiting longer after the last fentanyl use, giving
buprenorphine at longer intervals (>2 hours between doses) or using methadone
rather than buprenorphine.
• Switching from methadone – We transition individuals from methadone to

buprenorphine using low-dose initiation. With this method, the individual can avoid
tapering methadone down prior to beginning buprenorphine [21]. In one study,
individuals maintained on methadone 100 mg daily received repeated small doses
of buprenorphine-naloxone and did not experience significant precipitated
withdrawal symptoms [22].
• Individuals who present who are not in withdrawal – In some cases individuals
present for induction but have not yet have reached a state of withdrawal. In these
cases, we attempt induction with a lower dose of buprenorphine (eg, 1 mg or less)
given repeatedly at two-hour intervals while monitoring for withdrawal symptoms.
● Aggressive buprenorphine induction in emergency department settings –

Aggressive buprenorphine induction may mitigate withdrawal more aggressively and
facilitate acceptance of buprenorphine and transition to outpatient treatment.
Sublingual buprenorphine (monoproduct formulation) induction using an aggressive
dosing approach (4 to 8 mg initially; up to ≤32mg) has been safely used in emergency
department settings.
In a retrospective case series of emergency department patients, 391 individuals (579

encounters) with OUD were selected for an aggressive buprenorphine induction (based
on history, physical examination, and use of the COWS) [23]. Patients were treated with
buprenorphine of up to 32 mg at a rate dependent on severity of withdrawal symptoms
and adverse effects. No cases of respiratory depression or sedation or other serious
adverse events were reported. These findings may not be generalizable to sublingual
formulations other than monoproduct sublingual buprenorphine, and the procedure
occurred in a supervised setting (the emergency department).
Benefits of using transmucosal buprenorphine — Transmucosal buprenorphine improves
treatment retention, reduces opioid use, and is associated with decreased mortality in
individuals with OUD [1]. As examples:
● In a meta-analysis of clinical trials, treatment retention was greater at low dose (2 to 6

mg; relative risk 1.5, 95% CI 1.2-1.9), medium doses (7 to 15 mg; relative risk 1.74, 95%
CI 1.1-2.7), and high dose (≥16 mg; relative risk 1.82, 95% CI 1.2-2.9) of sublingual
buprenorphine compared with placebo [1]. However, in the meta-analysis, only high-
dose buprenorphine (≥16 mg) was more effective than placebo in suppressing illicit
opioid use (standard mean difference -1.17, 95% CI -1.85 to -0.49). In another trial,
individuals treated with buprenorphine (16 mg) or buprenorphine-naloxone (16 mg/4
mg) more frequently had negative urine opioid screening tests compared with those
who received placebo (21, 18, and 6 percent respectively) [24].
● A retrospective study of administrative health datasets examined mortality in patients

with OUD during periods when they were on buprenorphine-naloxone (13,190 person
years of follow-up) and periods when they were off buprenorphine-naloxone (23,712
person years of follow-up) [25]. All-cause mortality was lower when patients were on
buprenorphine-naloxone compared with periods when patients were off (standardized
mortality ratio 3 versus 11). Mortality due to problematic drug use or accidental drug
poisoning was also lower when patients were on buprenorphine rather than off. (See
"Approach to treating opioid use disorder", section on 'Pharmacologic management'.)
Injectable buprenorphine — The long-acting injectable (LAI) formulation of buprenorphine

is effective for the treatment of OUD [26-28]. We typically use this formulation to address
limited adherence, misuse, or diversion of transmucosal buprenorphine.
● Buprenorphine XR – This is an LAI form of buprenorphine that is administered

subcutaneously. We typically use it after a stabilization on transmucosal buprenorphine
for a minimum of seven days.
• Initiating buprenorphine XR – Buprenorphine XR is administered no more

frequently than every 26 days and typically monthly [29]. The procedure for dose
stabilization depends upon whether the patient has been on transmucosal
buprenorphine for long-term management or for a few days. In either case,
transition to buprenorphine XR can occur directly.
- For patients on long-term treatment with transmucosal buprenorphine (ie,

months or years), the initial dose of buprenorphine XR for the first month is 300
mg. The dose for the second month dose depends on the total daily dose of
buprenorphine previously used. The second dose is 300 mg in individuals who
were using greater than 20 mg/day transmucosal buprenorphine or in those
with persistent craving or withdrawal symptoms. In individuals who were using
8 to 18 mg transmucosal buprenorphine per day, the second month injection
may be 100 mg. In both cases, this is followed by 100 mg monthly maintenance
doses.
- For patients who have been on transmucosal buprenorphine for a relatively

short period (at least seven days, but typically not for weeks), the first month
and the second month doses are each 300 mg, and then subsequent doses are
100 mg.
While the ultimate recommended maintenance dose is 100 mg, a maintenance dose
of 300 mg monthly may be used if the benefits outweigh the risks. For example, if
the patient has continued opioid use or symptoms of withdrawal on the 100 mg
dose, continuation on the 300 mg monthly dose may be indicated. In addition,
situations (eg, extended travel) may arise during maintenance treatment in which a
300 mg dose may be administered to cover a two-month period. Once the situation
has passed, the maintenance regimen should revert to 100 mg/month. Patients who
are receiving 100 mg/month and then receive a 300 mg injection may experience
sedation or other adverse effects due to the higher peak serum concentration.
• Benefits of buprenorphine XR – Individuals with moderate to severe OUD who are

treated with buprenorphine XR are found to have higher abstinence rates than
treatment with placebo. As examples:
- In a multisite clinical trial of 202 patients with moderate to severe OUD

individuals were randomly assigned to treatment with 300 mg injections
monthly for six months versus 300 mg injection monthly for two months,
followed by 100 mg injection monthly for four more months versus placebo [28].
Individuals treated with injectable buprenorphine XR maintained higher
abstinence rates than those treated with placebo (opioid abstinence rates of
41.3 and 42.7 percent versus 5 percent for 300/300, 300/100, and placebo
groups, respectively). The product was well tolerated and had a side effect
profile similar to transmucosal buprenorphine.
- In a separate follow-up observational study, 425 patients with OUD who had
received up to 12 months of monthly buprenorphine XR injections as part of a
clinical efficacy trial were monitored [30]. Longer durations of treatment were
associated with higher rates of sustained abstinence. Additionally, patients had
sustained improvements in mood, pain, and health-related quality of life, as well
as higher employment rates than at the time of pretrial screening.
• Risk evaluation and mitigation strategy (REMS) program for buprenorphine XR

– In the United States, providing buprenorphine XR can only occur through certified
health care settings and pharmacies, as a part of this medication’s REMS program.
There is a restricted distribution system for buprenorphine XR, and the medication is
never given to patients for self-administration. Further information on the REMS
program, including enrollment in the program, can be found on the website.
● CAM2038 – Injectable preparations of buprenorphine (CAM2038) is available in one-

week and one-month dosing. These preparations can be used without a period of initial
transmucosal stabilization. This product is available in Europe, Australia, and parts of
the Middle East.
A clinical trial found injectable CAM2038 to have similar effect to daily, sublingual
buprenorphine in response rates and having urine test results negative for illicit opioids
[27].
Adverse effects — Buprenorphine-related deaths in patients on maintenance therapy have

occurred primarily when buprenorphine is taken in combination with other substances,
especially benzodiazepines and/or alcohol [31,32] and with intravenous misuse of high doses
of buprenorphine [33]. Death is caused by oversedation leading to respiratory depression
and hypoxia. Buprenorphine has a lower potential for lethal overdose compared with
methadone.
Dental problems including dental caries, abscesses, and damaged teeth, many of which have
required extraction may be associated with the use of buprenorphine formulations dissolved
in the mouth [34-36]. Patients who use oral dissolving buprenorphine should rinse around
the teeth and gums with water once the film has completely dissolved. Individuals taking
buprenorphine formulations should notify their dentist that they are taking the drug and
follow up with routine scheduled dental care. The US Food and Drug Administration has
issued a safety advisory for this issue and will be mandating a related label change for
buprenorphine.
Other adverse effects of buprenorphine include headache, nausea, constipation, pain, and
sweating. While these can be distressing to patients, they are not uncommon symptoms
experienced while using opioids. Adherence is relatively rarely disturbed by these effects.
Tapering buprenorphine — We support the strategy of continuing opioid agonist treatment

indefinitely for individuals who have responded to treatment for OUD. However, when the
decision is made to discontinue medication for OUD in individuals on buprenorphine, we
taper over several months if possible.
● Transmucosal buprenorphine – We typically reduce the dose by 2 mg every one to two

weeks. Based on clinical symptoms, such as the emergence of craving or withdrawal,
we may slow down this process as the taper nears the end. If a more rapid taper is
necessary (eg, prior to incarceration), the dose can be reduced by 2 mg every one to
three days.
The relative efficacy of different buprenorphine tapering schedules has not been well
studied, but available data suggest that slow, gradual tapers (eg, over months) are
more effective and better tolerated than rapid tapers (eg, over days) [37].
We include the individual’s primary clinician, program counselor (when the individual is
in an opioid treatment program), and other supports (eg, family members with
authorization) and employ shared decision-making in planning for taper off of any
treatment for OUD. Clinicians without experience tapering a patient off of a
maintenance medication would benefit from consultation with a clinician who has such
experience.
If the individual becomes unstable with recurrent substance use, craving, withdrawal
symptoms, or life stressors, the taper should be halted, and they should be encouraged
to remain on medication until stability is again achieved.
● Longer-acting formulation – Individuals discontinuing buprenorphine XR after

sustained use (ie, at least four to six months) may have detectable plasma and urine
levels of buprenorphine for 12 months or longer [38]. Tapering off the LAI form could
theoretically occur by simply stopping the administrations and allowing the gradual
decrease in blood levels to occur over the subsequent weeks.
Regulation of buprenorphine in United States — Buprenorphine is classified as a schedule

III controlled substance in the United States; its use to treat OUD is limited to certified
clinicians who have registered with the United States Center for Substance Abuse Treatment
of the Substance Abuse and Mental Health Services Administration (SAMHSA) and with the
Drug Enforcement Administration. Information on the training and registration process is
available at the SAMHSA website.
Other information about United States buprenorphine regulations includes:
● Clinicians can register with SAMHSA to prescribe buprenorphine in an office-based

setting for up to 30 patients at a time, without the need to undergo special training or
the assurance of counseling service availability. However, the clinician must complete a
notice of intent at the SAMHSA website.
● Clinicians providing office-based buprenorphine for more than 30 patients at any one
time must still undergo special training and must indicate that they have the capacity to
provide or to refer patients for counseling. (See "Psychosocial interventions for opioid
use disorder".)
● Induction may be accomplished in the clinician’s office under observation or at the

patient’s home [39]. When on a stable dose, patients may receive a prescription for up
to a one-month supply of medication with refills for up to six months, similar to other
schedule III controlled substances.
● Injectable buprenorphine can only be administered through certified health care

settings and pharmacies. (See 'Injectable buprenorphine' above.)
METHADONE: OPIOID AGONIST
Methadone treatment for opioid use disorder (OUD) is available by prescription and utilizes
pharmacy-based dispensing in many countries including Australia, the United Kingdom, and
Canada. In the United States, methadone is dispensed through a federally regulated clinic
system [40,41]. (See 'Regulation of methadone in United States' below.)
Methadone, a long-acting opioid agonist, binds to and occupies mu-opioid receptors,

preventing withdrawal symptoms for 24 hours or longer. Methadone reduces craving for
opioids, and, by maintaining high levels of opioid tolerance, reduces the euphoric effects of
subsequent illicit opioid use. Although individuals treated with methadone are physically
dependent upon the medications, they do not typically have the pattern and severity of
problematic behaviors associated with use and misuse of heroin or pharmaceutical opioids
including fentanyl and are often able to return to a productive lifestyle [7,8].
Methadone formulations — Methadone is typically given as a liquid, often diluted with juice

or water or artificially colored water. (Each patient receives a full cup of uniformly colored
liquid, regardless of the dose of methadone, to reduce anxiety among patients about
differences in dose. The dilution and coloring are also intended to reduce the likelihood of a
patient injecting “take-home” methadone.) Methadone is available in a tablet form, as well as
a dissolvable diskette, and there has been some increase in the use of these forms by opioid
treatment programs in the United States during the coronavirus disease 2019 (COVID-19)
pandemic.
While different formulations of methadone are available, our preference is to avoid switching
formulations if possible. Based upon reports from clinicians and patients, Health Canada
issued a safety alert that switching from one liquid formulation of methadone to another
liquid formulation at the same dose may elicit withdrawal symptoms, which can lead to
nonadherence and problematic substance use [42].
Prior to starting methadone — Prior to beginning treatment with methadone we assess for

potential drug-drug interactions that may help to inform dosing, and the risk of other
medical comorbidities relevant to methadone’s use:
● Drug-drug interactions may occur with several commonly used medications

(anticonvulsants, antibiotics, antidepressants, antiretrovirals) ( table 2). (See 'Other
adverse effects and considerations' below.)
● Methadone may be associated with QTc prolongation. For the majority of patients, an
electrocardiogram (ECG) prior to beginning methadone is not indicated. For individuals
with a history of syncope, arrhythmia, structural heart disease, prolonged QTc, or family
history of prolonged QTc, an ECG should be obtained. Additionally, we get an ECG prior
to treatment with methadone in individuals already being treated with medications that
can prolong QTc.
• For QTc interval >450 msec but <500 msec – We start methadone and monitor the
ECG 30 days after starting and then annually.
• For QTc interval ≥500 msec – We prefer not to start methadone prior to cardiology
consultation. We closely weigh the benefits of treatment with methadone with the
risks of arrhythmia. If methadone is started, we monitor the ECG 30 days after
starting the medication then annually.
As there is no compelling research evidence to base a decision on whether to obtain an ECG

prior to the start of methadone treatment [43-45], we base our decision on clinical
experience.
Initial dose and titration — The typical initial dose of methadone for OUD is 20 to 30 mg in
a single dose. The maximum initial dose allowed by most federal regulations or national
guidelines is 30 mg [46,47]; however, an additional 10 mg may be administered a few hours
later if the individual has significant withdrawal symptoms. The total dose for the first day
should not exceed 40 mg. Observation at three hours after the first dose is recommended, if
possible, to monitor for signs of toxicity or withdrawal.
The initial dose of methadone maintenance treatment varies based upon the time of the last
opioid use, the amount used, and whether the patient has developed a reduction in
tolerance to opioids (eg, patients who were recently released from incarceration or
hospitalization may have significantly reduced tolerance).
Methadone is titrated in 5 to 10 mg increments no more frequently than every two to three

days over several weeks until an initial dose in the range of 60 to 80 mg total daily dose is
reached. Gradual adjustment allows methadone to reach a pharmacologic steady state to
match the patient’s level of opioid tolerance and avoid intoxication or oversedation.
Additionally it may help to avoid the rare but possible event of iatrogenic overdose. If
excessive opioid agonist effects (eg, sedation) occur, further dose increases are halted. If
needed, we titrate beyond 60 to 80 mg per day slowly (eg, 10 mg per week) provided patients
do not have intolerable side effects. The rate of titration and eventual dose is based upon the
intensity of cravings, the presence of opioid withdrawal symptoms (which are assessed daily)
and the cessation of illicit opioid use (as determined by patient reports and urine testing).
Maintenance — Methadone dosing for maintenance treatment varies [48]. Specifying the

dose can be difficult, in part as the dose does not correlate well with blood levels. A relatively
low dose of methadone (eg, 20 to 30 mg per day) attenuates acute opioid withdrawal but is
usually not as effective as higher doses at suppressing craving and blocking the effects of
other opioids, such as heroin. Higher doses (ie, 80 to 100 mg/day) are not overly sedating
following the development of tolerance. Doses of up to 150 mg per day are not uncommonly
used and higher levels of physical dependence associated with fentanyl use may require
higher doses of methadone.
Several randomized trials have found that patients on higher doses of methadone (80 to 100
mg/day) have higher retention rates and lower illicit use of opioids than lower methadone
doses [6,49,50].
In the United States, patients who have reached a steady maintenance dose, take-home
administration of methadone is a consideration. Eligibility for take-home doses is usually
based on adherence to program requirements for counseling and abstinence from illicit
drugs (based on urine toxicology testing), as well as absence of recent criminal activity and
capacity to store the take-home doses safely in the home environment.
Benefits of methadone treatment — Methadone treatment is associated with decreased

all-cause mortality from OUD, reduced risk of mortality from overdose (primarily heroin
overdose), increased likelihood of remaining in treatment and reduced opioid use compared
with those receiving placebo or nonmedication treatment [4,25,51,52].
As examples:
● In a meta-analysis of 11 studies including 1969 individuals with the American

Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition (DSM-IV) opioid dependence who were treated with methadone maintenance,
individuals treated with methadone were more likely to remain in treatment and to
reduce opioid use (relative risk 0.66, 95% CI 0.56-0.78) compared with individuals on
placebo or nonmedication treatment [4].
● A retrospective study of administrative health datasets examined mortality in patients

with OUD during periods when patients were on methadone (188,113 person years of
follow-up) and periods when patients were off methadone (174,431 person years of
follow-up) [25]. All-cause mortality was lower when patients were on methadone
compared with periods when patients were off (standardized mortality ratio 4.7 versus
9.5). Mortality due to problematic drug use or accidental drug poisoning was also lower
when patients were on treatment rather than off. Another observational study
suggested a 70 percent reduction in the risk of mortality with methadone maintenance,
attributable mainly to prevention of opioid (ie, heroin) overdose [52].
Furthermore, methadone maintenance treatment can have beneficial effects beyond the use
of opioids. Methadone treatment has been associated with reductions in the spread of
human immunodeficiency virus [53-55], and in some studies, with reduced criminal behavior
[4,56].
Tapering off of methadone — We support the strategy of continuing opioid agonist

treatment indefinitely for individuals who have responded to treatment for OUD. However,
when the decision is made to discontinue medication for OUD in individuals on methadone,
we taper slowly (over months) and gradually (eg, dose decreases of up to 5 mg/week with
smaller dose decreases as the taper nears the end). We allow and encourage the patient to
pause the taper if instability such as withdrawal symptoms occurs.
Adverse effects — Adverse effects of methadone therapy include constipation, drowsiness,

diaphoresis, peripheral edema, and rarely cardiac arrhythmia [57,58].
Prolonged QTc and cardiac arrhythmias — We check ECG 30 days after starting
methadone and then annually thereafter in individuals at risk for prolonged QTc. This
includes individuals with a history of syncope, arrhythmia, structural heart disease,
prolonged QTc (>450 msec), family history of prolonged QTc or in individuals on other
medications that can prolong QTc. Our response to the ECG findings are as follows:
● For QTc interval >450 msec but <500 msec – We continue treatment and monitor the
ECG annually.
● For QTc interval ≥500 msec – We prefer to discontinue methadone; however, we closely
weigh the benefits of treatment with methadone with the risks of arrhythmia. We often
lower the dose of methadone (if clinically reasonable) while addressing other causative
factors such as hypokalemia or other medications that may cause prolonged QTc.
However, we typically consult with a cardiologist prior to making medication
adjustments.
Studies have noted a significant but weak relationship between the methadone dose and the
degree of QTc prolongation at doses of up to 300 mg/day [59-62]. Additionally, methadone
use in both therapeutic dose and overdose has been associated with QTc interval
prolongation and torsades de pointes, which in some cases has been fatal [63]. However,
while the risk of QTc prolongation in methadone treated patients is controversial, concern
regarding the proarrhythmic potential of methadone prompted a clinician safety alert from
the US Food and Drug Administration.
Some research suggests that substitution of (R,S)-methadone with (R)-methadone reduces

the methadone-induced prolonged QTc interval among individuals with OUD [64]. Further
work is needed to confirm this finding. The (R)-methadone formulation is available in the
European Union and is widely used in Germany, but is not available for clinical use in the
United States. The use of a pure (R)-formulation of methadone also results in lower effective
doses, but its cost is up to 20 percent higher than the racemic formulation [65].
The associated table lists causes of prolonged QTc ( table 3). Drug-induced QTc
prolongation is discussed in detail separately. (See "Acquired long QT syndrome: Definitions,
pathophysiology, and causes".)
Other adverse effects and considerations — Other adverse effects and drug-drug

interactions include:
● Hyperalgesia – Chronic use of methadone and other opioid agonists may result in an
increased sensitivity to pain, which may develop within a month of initiating chronic
opioid therapy [66-68]. A study of patients in methadone treatment programs found
chronic severe pain was reported by 37 percent of the patients, and 65 percent of those
with pain experienced a significant impact on physical and psychosocial functioning
[68]. Patients in methadone treatment may have a history of physical trauma resulting
in chronic pain, but may also have increased sensitivity to pain related to chronic opioid
use [69].
● Overdose – As a full agonist, methadone has a greater potential for lethal overdose
compared with buprenorphine, a partial mu-opioid agonist. Death during induction into
methadone maintenance treatment has been reported in a series of cases from New
South Wales, Australia [70-72]. The overall mortality rate during methadone
maintenance induction was 7.1 deaths per 10,000 inductions [72]. Concurrent
benzodiazepine use was a significant risk factor contributing to likelihood of death both
in methadone maintenance patients and in patients taking methadone for chronic pain
[73].
● Reduced libido and erectile dysfunction – Reduced libido and erectile dysfunction are
common among heroin users and those in treatment for OUD. Methadone use is
believed to contribute to erectile dysfunction, possibly through reduction in serum
testosterone levels; however, psychological and social factors are also associated with
erectile dysfunction [74,75]. These other factors should be considered before
attributing erectile dysfunction solely to methadone treatment.
● Drug interactions and metabolism – Methadone has a number of drug interactions

based on metabolism by the cytochrome P450 isoenzyme system, specifically CYP 3A4,
2D6, and 2B6 ( table 2) [76,77]. Starting or stopping medications that interact with
these enzymes can affect serum methadone levels. This may result in opioid withdrawal
or intoxication.
Daily methadone dose may need adjustment to prevent complications from these
interactions. For example, individuals who concurrently take benzodiazepines or use
alcohol may be more likely to become sedated from methadone and should be
evaluated for the risk of respiratory depression. In these cases, dose of medications
should be adjusted accordingly.
Regulation of methadone in United States — Methadone is regulated in many countries

including the United States, where it is classified as a schedule II drug. Many of the
regulations on methadone’s use are aimed at preventing diversion of medication and
reducing the risk of overdose. Only licensed opioid treatment programs or licensed inpatient
hospital units in the United States are permitted to order and dispense methadone for
withdrawal or long-term treatment of an OUD [78]. Exceptions to this restriction include:
● Patients already receiving methadone from a licensed program may continue to receive
the medication during inpatient hospitalization to treat OUD or other conditions, such
as pain.
● Any clinician or other licensed prescriber may administer methadone (or any other
opioid) to treat a patient with acute opioid withdrawal for up to three days while
arranging for more definitive treatment, provided they follow federal regulations (21
CFR 1306.07(b)). The intent is to relieve suffering and prevent withdrawal that would
complicate the primary medical or surgical condition. While methadone may be
administered to a patient during the 72-hour period, it may not be dispensed or
prescribed for unsupervised use.
To be eligible for methadone maintenance in the United States under federal guidelines, a
prospective patient must have [78]:
● Documentation of the presence of an OUD for at least one year of continuous use.
Exceptions to this criterion include:
• Patients who have been on methadone maintenance within the past two years do
not need to demonstrate current physical dependence or a current OUD if the
program clinician documents a likelihood of an imminent relapse to opioid use.
• Patients recently released from incarceration or hospitalization do not need to show

current physiologic dependence or OUD but are required to have a history of an
OUD and have a clinician document a likelihood of relapse to opioid use and
physiologic dependence.
• Pregnant women are eligible for methadone maintenance even if an OUD has been
present for less than one year.
● Age 18 years or older – Younger individuals are eligible for treatment with the consent
of a parent, guardian, or designated responsible adult if they have current opioid
physical dependence and have at least two previous attempts at detoxification or
psychosocial substance abuse treatment.
Licensed United States outpatient treatment programs are required to provide counseling
and social services in addition to methadone. Patients are required to attend individual
counseling as clinically indicated. (See "Psychosocial interventions for opioid use disorder".)
In addition to federal regulations, many states in the United States have imposed additional
restrictions on methadone for use in the treatment of an OUD.
Switching between agonist treatments — Individuals with physiologic opioid dependence

who are transitioned directly from methadone maintenance to buprenorphine may
experience acute precipitated opioid withdrawal syndrome [79,80]. In these cases, we often
use low-dose buprenorphine induction. (See 'Alternative induction methods for specific
circumstances' above.)
For individuals with physiologic opioid dependence who have a poor response or
unacceptable side effects to buprenorphine, this medication can be discontinued and
methadone started immediately.
NALTREXONE: OPIOID ANTAGONIST
Naltrexone, an opioid antagonist, blocks the effects of opioids if they are used, thus
preventing the user from experiencing opioid intoxication or physiologic dependence with
subsequent use and thus reinforces abstinence.
Prior to treatment with opioid antagonist — Naltrexone should be used only after

completion of a medically supervised withdrawal from opioids because it can precipitate
immediate withdrawal symptoms. Initiation of naltrexone should be medically supervised.
In some cases, a naloxone challenge test is useful to ensure that the patient has completed
withdrawal from opioids and is no longer physically dependent on this class of drugs. If there
are reasons to suspect that the person has not had a sufficient period of opioid abstinence
(eg, an outpatient who has attempted to abstain from opioids on their own for several days),
then a naloxone challenge test should be undertaken.
However, in our experience most patients are forthright about their use when it is explained
that there is a risk of precipitated withdrawal with naltrexone dosing if they have continued
opioid use. When needed, the naloxone challenge test is done as follows:
● The patient should be totally free of spontaneous opioid withdrawal signs and
symptoms at the start of the naloxone challenge session.
● Baseline vital signs are obtained, and naloxone is then administered parenterally
(subcutaneously, intramuscularly [IM], or intravenously) up to a total dose of 0.8 mg.
● The patient is observed for up to one hour, and a validated measure for assessing
opioid withdrawal, such as the Clinical Opiate Withdrawal Scale can be helpful to use.
If any symptoms or signs of opioid withdrawal emerge, or if pulse rate or blood pressure
increases, administration of naltrexone should be postponed for another 24 hours. Since
naloxone has a short half-life, any withdrawal precipitated by naloxone typically will resolve
within one to two hours of administration or less.
Long-acting injectable naltrexone — Our preference is to treat opioid use disorder (OUD)
with long-acting injectable (LAI; or extended-release) naltrexone rather than oral naltrexone.
LAI naltrexone is given every four weeks by deep IM injection in the gluteal muscle at a set
dose of 380 mg per injection. It should be administered in alternating buttocks each month.
The medication is started 7 to 10 days after last opioid use unless a naloxone challenge test
is conducted and confirms the safety of starting oral naltrexone sooner.
The American Society of Addiction Medicine has suggested that in cases of breakthrough
cravings LAI naltrexone may be given every three weeks. However, there are currently no
studies to support this more frequent dosing, and this is not our routine practice.
● Benefits of LAI naltrexone – In randomized trials, LAI naltrexone is more effective than
placebo for opioid dependence [2,81-83]. However, the transition to LAI naltrexone may
be a challenge for some individuals; additionally, trials of LAI naltrexone have been
limited by high dropout rates [2,81]. For example:
• In a trial, 250 individuals with DSM-IV opioid dependence were randomized to

receive 24 weeks of injectable depot formulation of naltrexone versus placebo [2].
The median proportion of weeks of confirmed abstinence was greater in the actively
treated group compared with the placebo group (90 versus 35 percent). However,
these findings exclude 47 percent of the patients who did not complete the study.
• In a trial, 308 individuals in the criminal justice system were randomly assigned to
LAI naltrexone versus treatment as usual (brief counseling and referral to
community treatment program) for a period of 24 weeks [3]. Individuals in the
treatment group had a longer median time to relapse (10.5 versus 5 weeks), a lower
rate of relapse (43 versus 64 percent), and higher rate of opioid negative urine
samples (74 versus 56 percent) versus control group. However, at 78-week follow-up,
rates of opioid-negative urine samples were equal (46 percent in each group).
● Injection site reaction – Naltrexone via IM injection may cause injection site reaction
consisting of pain, tenderness, and swelling at the injection site. In some cases,
abscess, cellulitis, and necrosis have been reported. While treatment for such reactions
is generally supportive, if symptoms appear to be worsening after seven days, further
evaluation with a surgical specialist is warranted.
Oral naltrexone — We typically begin oral naltrexone at 25 mg per day for the first two to
three days before increasing to 50 mg per day. The medication is started 7 to 10 days after
last opioid use unless a naloxone challenge test is conducted and confirms the safety of
starting oral naltrexone sooner. (See 'Prior to treatment with opioid antagonist' above.)
● Benefits of oral naltrexone – Efficacy of oral naltrexone for sustained abstinence in

treatment of individuals with opioid dependence is limited. A meta-analysis of 1158
participants in 13 randomized trials compared oral naltrexone maintenance treatment
with either placebo or no medication for opioid dependence [84]. Primary outcomes
such as sustained abstinence were similar between active and control groups. The
findings from these trials were limited by poor adherence and high dropout rates.
However, oral naltrexone was more effective than placebo in sustaining abstinence in
three trials where patients were monitored for daily adherence by a close relative [84].
● Adverse effects and subsequent considerations – Oral naltrexone has few side
effects or adverse effects. Occasionally patients will report nausea, headache, dizziness,
or fatigue. More severe adverse effects include liver damage, but this is very rare (seen
with supratherapeutic doses) and has always resolved with discontinuation of
naltrexone.
Patients who discontinue antagonist therapy and resume opioid use should be made
aware of the risks associated with an opioid overdose and especially the increased risk
of death. This is due to the loss of tolerance to opioids and a resulting misjudgment of
dose at the time of relapse [85].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Opioid use disorder
and withdrawal".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, “The Basics” and “Beyond the
Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles on
a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
● Basics topics (see "Patient education: Prescription drug misuse (The Basics)" and
"Patient education: Opioid use disorder (The Basics)")
SUMMARY AND RECOMMENDATIONS
● Our approach – We prefer to treat all individuals with opioid use disorder (OUD) with
medication for OUD (MOUD) and psychotherapy. MOUD reinforces abstinence and
improves treatment retention. Our approach to selecting treatments including
medication and psychotherapy is discussed elsewhere ( algorithm 1). (See "Approach
to treating opioid use disorder".)
● Opioid agonists – Opioid agonists (eg, methadone and buprenorphine) suppress

craving and withdrawal symptoms while blocking the acute effects of other opioids.
Although individuals treated with opioid agonists are physically dependent upon the
medications, they do not typically have the severity of problematic behaviors associated
with illicit use or misuse of opioids. (See 'Buprenorphine: Opioid agonist' above and
'Methadone: Opioid agonist' above.)
● Buprenorphine – Buprenorphine is most often given transmucosally as a combination

preparation with naloxone to prevent diversion of the product. It is also available as a
longer-acting injectable formulation. In most formulations, the dose depends on the
duration and dose of prior transmucosal use. (See 'Transmucosal formulations' above
and 'Injectable buprenorphine' above.)
• For most individuals, we use a standard induction to initiate transmucosal

buprenorphine. We wait until the individual shows signs of early withdrawal and
then start 4 mg of buprenorphine and gradually titrate up until withdrawal
symptoms have resolved. (See 'Standard induction' above.)
• For individuals who present for induction without withdrawal symptoms, who have
high levels of physical dependence, or who are transitioning from methadone, we
suggest a low-dose protocol, in which a lower dose than that used for standard
induction is administered more frequently (Grade 2C). (See 'Alternative induction
methods for specific circumstances' above.)
● Methadone – Methadone, a long-acting opioid agonist, binds to mu-opioid receptors,

preventing withdrawal symptoms for 24 hours or more. (See 'Methadone: Opioid
agonist' above.)
• In the United States, administration of methadone takes places in an opioid

treatment program. Take-home doses of methadone may be available based on
program requirements. (See 'Regulation of methadone in United States' above.)
• Methadone carries a risk for lethal overdose. Other adverse effects include QTc
prolongation, drug-drug interactions, and hyperalgesia. (See 'Adverse effects'
above.)
● Opioid antagonists – Naltrexone, an opioid antagonist, prevents the user from

experiencing opioid intoxication or physiologic dependence, thereby reinforcing
abstinence. Naltrexone can precipitate withdrawal in individuals with physiologic opioid
dependence and should be used only after completion of medically supervised
withdrawal. (See 'Naltrexone: Opioid antagonist' above.)
• Naltrexone is available in oral and long-acting injectable (LAI) formulation. We

typically use the LAI naltrexone formulation when addressing limited adherence.
(See 'Long-acting injectable naltrexone' above.)
• Naltrexone LAI may cause an injection site reaction (ie, pain, swelling, abscess,
cellulitis, necrosis). Treatment for injection site reactions is generally supportive;
however, worsening symptoms after seven days warrants evaluation with a surgical
specialist. (See 'Naltrexone: Opioid antagonist' above.)
ACKNOWLEDGMENTS
The UpToDate editorial staff acknowledges Michael Weaver, MD and John Hopper, MD, who
contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Terms of Use.
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8:153.
58. Kleber HD. Treatment of narcotic addicts. Psychiatr Med 1985; 3:389.
59. Ehret GB, Voide C, Gex-Fabry M, et al. Drug-induced long QT syndrome in injection drug
users receiving methadone: high frequency in hospitalized patients and risk factors.
Arch Intern Med 2006; 166:1280.
60. Martell BA, Arnsten JH, Ray B, Gourevitch MN. The impact of methadone induction on
cardiac conduction in opiate users. Ann Intern Med 2003; 139:154.
61. Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of methadone treatment on
cardiac repolarization and conduction in opioid users. Am J Cardiol 2005; 95:915.
62. Peles E, Bodner G, Kreek MJ, et al. Corrected-QT intervals as related to methadone dose
and serum level in methadone maintenance treatment (MMT) patients: a cross-sectional
study. Addiction 2007; 102:289.
63. Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone
users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf
2005; 14:747.
64. Ansermot N, Albayrak O, Schläpfer J, et al. Substitution of (R,S)-methadone by (R)-

methadone: Impact on QTc interval. Arch Intern Med 2010; 170:529.
65. McCance-Katz EF. (R)-methadone versus racemic methadone: what is best for patient
care? Addiction 2011; 106:687.
66. Pud D, Cohen D, Lawental E, Eisenberg E. Opioids and abnormal pain perception: New
evidence from a study of chronic opioid addicts and healthy subjects. Drug Alcohol
Depend 2006; 82:218.
67. Chu LF, Clark DJ, Angst MS. Opioid tolerance and hyperalgesia in chronic pain patients
after one month of oral morphine therapy: a preliminary prospective study. J Pain 2006;
7:43.
68. Rosenblum A, Joseph H, Fong C, et al. Prevalence and characteristics of chronic pain
among chemically dependent patients in methadone maintenance and residential
treatment facilities. JAMA 2003; 289:2370.
69. Compton P, Charuvastra VC, Ling W. Pain intolerance in opioid-maintained former opiate
addicts: effect of long-acting maintenance agent. Drug Alcohol Depend 2001; 63:139.
70. Caplehorn JR, Drummer OH. Mortality associated with New South Wales methadone
programs in 1994: lives lost and saved. Med J Aust 1999; 170:104.
71. Zador DA, Sunjic SD. Methadone-related deaths and mortality rate during induction into
methadone maintenance, New South Wales, 1996. Drug Alcohol Rev 2002; 21:131.
72. Zador D, Sunjic S. Deaths in methadone maintenance treatment in New South Wales,
Australia 1990-1995. Addiction 2000; 95:77.
73. Caplehorn JR, Drummer OH. Fatal methadone toxicity: signs and circumstances, and the
role of benzodiazepines. Aust N Z J Public Health 2002; 26:358.
74. Brown R, Balousek S, Mundt M, Fleming M. Methadone maintenance and male sexual
dysfunction. J Addict Dis 2005; 24:91.
75. Quaglio G, Lugoboni F, Pattaro C, et al. Erectile dysfunction in male heroin users,
receiving methadone and buprenorphine maintenance treatment. Drug Alcohol Depend
2008; 94:12.
76. Kharasch ED. Current Concepts in Methadone Metabolism and Transport. Clin
Pharmacol Drug Dev 2017; 6:125.
77. Dinis-Oliveira RJ. Metabolomics of methadone: clinical and forensic toxicological
implications and variability of dose response. Drug Metab Rev 2016; 48:568.
78. Substance Abuse and Mental Health Services Administration. Federal Guidelines for Opi
oid Treatment Programs. HHS Publication No. (SMA) XX-XXX, Health and Human Services
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79. Strain EC, Preston KL, Liebson IA, Bigelow GE. Buprenorphine effects in methadone-
maintained volunteers: effects at two hours after methadone. J Pharmacol Exp Ther
1995; 272:628.
80. Walsh SL, Eissenberg T. The clinical pharmacology of buprenorphine: extrapolating from
the laboratory to the clinic. Drug Alcohol Depend 2003; 70:S13.
81. Comer SD, Sullivan MA, Yu E, et al. Injectable, sustained-release naltrexone for the
treatment of opioid dependence: a randomized, placebo-controlled trial. Arch Gen
Psychiatry 2006; 63:210.
82. Tiihonen J, Krupitsky E, Verbitskaya E, et al. Naltrexone implant for the treatment of
polydrug dependence: a randomized controlled trial. Am J Psychiatry 2012; 169:531.
83. Sullivan M, Bisaga A, Pavlicova M, et al. Long-Acting Injectable Naltrexone Induction: A
Randomized Trial of Outpatient Opioid Detoxification With Naltrexone Versus
Buprenorphine. Am J Psychiatry 2017; 174:459.
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dependence. Cochrane Database Syst Rev 2011; :CD001333.
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inpatient opiate detoxification: follow up study. BMJ 2003; 326:959.
Topic 7803 Version 66.0
GRAPHICS
Approach to medication treatment for opioid use disorder* ¶
LAI: long-acting injectable.
* This algorithm assumes the individual is not pregnant or breastfeeding. Refer to other
UpToDate content for information on treatment of opioid use disorder in pregnant or
breastfeeding individuals.
¶ In addition to pharmacotherapy, we treat all patients with opioid use disorder with
psychosocial intervention if the patient agrees to it. Refer to other UpToDate content in
determining psychosocial treatment for opioid use disorder.
Δ Supervised daily oral naltrexone is a reasonable alternative to LAI naltrexone in highly

motivated patients who refuse injection and are adherent to medications.
◊ The preferred goal for individuals with opioid use disorder is abstinence from use of all
opioids. However, other responses may include lower frequency of use, diminished
craving, or harm reduction.
§ We treat opioid use disorder as a chronic disorder in all individuals. We continue to treat
indefinitely.
¥ In some individuals who have high levels of physiologic dependence, we treat with
methadone rather than buprenorphine.
Graphic 134961 Version 3.0
Clinical Opioid Withdrawal Scale (COWS)
Patient's name:_______________ Date and time:___/___/___:______
Reason for this assessment:_________________________
Resting pulse GI upset: Over last half-hour

rate:__________beats/minute
Measured after patient is sitting or lying
for one minute
0 pulse rate 80 or below 0 no GI symptoms
1 pulse rate 81 to 100 1 stomach cramps
2 pulse rate 101 to 120 2 nausea or loose stool
4 pulse rate greater than 120 3 vomiting or diarrhea
5 multiple episodes of diarrhea or

vomiting
Sweating: Over past half-hour not Tremor: Observation of outstretched

accounted for by room temperature or hands
patient activity
0 no report of chills or flushing 0 no tremor
1 subjective report of chills or flushing 1 tremor can be felt, but not observed
2 flushed or observable moistness on 2 slight tremor observable

face
4 gross tremor or muscle twitching
3 beads of sweat on brow or face
4 sweat streaming off face
Restlessness: Observation during Yawning: Observation during

assessment assessment
0 able to sit still 0 no yawning
1 reports difficulty sitting still, but is 1 yawning once or twice during

able to do so assessment
3 frequent shifting or extraneous 2 yawning three or more times during

movements of legs/arms assessment
5 unable to sit stil l for more than a 4 yawning several times/minute

few seconds
Pupil size Anxiety or irritability
0 pupils pinned or normal size for 0 none

room light
1 patient reports increasing irritability
1 pupils possibly larger than normal or anxiousness
for room light
2 patient obviously irritable or anxious
2 pupils moderately dilated
4 patient so irritable or anxious that
5 pupils so dilated that only the rim of participation in the assessment is
the iris is visible difficult
Bone or joint aches: If patient was Gooseflesh skin

having pain previously, only the
additional component attributed to
opiates withdrawal is scored
0 not present 0 skin is smooth
1 mild diffuse discomfort 3 piloerrection of skin can be felt or

hairs standing up on arms
2 patient reports severe diffuse aching
of joints/muscles 5 prominent piloerrection
4 patient is rubbing joints or muscles

and is unable to sit still because of
discomfort
Runny nose or tearing: Not accounted Total score:__________

for by cold symptoms or allergies The total score is the sum of all 11 items
0 not present Initials of person
1 nasal stuffiness or unusually moist completing assessment:__________

eyes
2 nose running or tearing
4 nose constantly running or tears

streaming down cheeks
Score: 5 to 12 = mild; 13 to 24 = moderate; 25 to 36 = moderately severe; more than 36 = severe

withdrawal.
GI: gastrointestinal.
Reproduced from: Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs 2003; 35:253.
Cytochrome P450 3A (including 3A4) inhibitors and inducers
Strong inhibitors Moderate Strong inducers Moderate

inhibitors inducers
Adagrasib Amiodarone* Apalutamide Bexarotene

Atazanavir Aprepitant Carbamazepine Bosentan
Ceritinib Berotralstat Enzalutamide Cenobamate
Clarithromycin Cimetidine* Fosphenytoin Dabrafenib
Cobicistat and Conivaptan Lumacaftor Dexamethasone ¶
cobicistat- Crizotinib Lumacaftor- Dipyrone
containing Cyclosporine* ivacaftor Efavirenz
coformulations Mitotane
Diltiazem Elagolix, estradiol,
Darunavir Phenobarbital and norethindrone
Duvelisib
Idelalisib Phenytoin therapy pack Δ
Dronedarone
Indinavir Primidone Eslicarbazepine
Erythromycin
Itraconazole Rifampin Etravirine
Fedratinib
Ketoconazole (rifampicin) Lorlatinib
Fluconazole
Levoketoconazole Mitapivat
Fosamprenavir
Lonafarnib Modafinil
Fosaprepitant*
Lopinavir Nafcillin
Fosnetupitant-
Mifepristone palonosetron Pexidartinib
Nefazodone Grapefruit juice Rifabutin
Nelfinavir Imatinib Rifapentine
Nirmatrelvir- Isavuconazole Sotorasib
ritonavir (isavuconazonium St. John's wort
Ombitasvir- sulfate)
paritaprevir- Lefamulin
ritonavir
Letermovir
Ombitasvir-
Netupitant
paritaprevir-
Nilotinib
ritonavir plus
Ribociclib
dasabuvir
Posaconazole Schisandra
Verapamil
Ritonavir and
ritonavir-
containing
coformulations
Saquinavir
Telithromycin
Tucatinib
Voriconazole
For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above
can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver
enzymes, including CYP3A4, for elimination or activation.
These classifications are based upon US Food and Drug Administration (FDA) guidance. [1,2]
Other sources may use a different classification system resulting in some agents being
classified differently.
Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose,
method, and timing of administration.
Weak inhibitors and inducers are not listed in this table with exception of a few examples.
Clinically significant interactions can occasionally occur due to weak inhibitors and inducers
(eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic
index). Accordingly, specific interactions should be checked using a drug interaction program
such as the Lexicomp drug interactions program included within UpToDate.
Refer to UpToDate topics on specific agents and indications for further details.
* Classified as a weak inhibitor of CYP3A4 according to FDA system. [1]
¶ Classified as a weak inducer of CYP3A4 according to FDA system. [1]
Δ The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4
induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer.
Norethindrone and estradiol are not CYP3A4 inducers.
Data from: Lexicomp Online (Lexi-Interact). Copyright © 1978-2023 Lexicomp, Inc. All Rights Reserved.
References:
1. Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions
Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-
interactions.
2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and
Inducers. Available at: FDA.gov website.
Some reported causes and potentiators of the long QT syndrome*
Congenital
Jervell and Lange-Nielsen syndrome (including "channelopathies")

Romano-Ward syndrome
Idiopathic
Acquired
Metabolic disorders
Hypokalemia
Hypomagnesemia
Hypocalcemia
Starvation
Anorexia nervosa
Liquid protein diets
Hypothyroidism
Bradyarrhythmias
Sinus node dysfunction
AV block: Second or third degree
Analgesic, anesthetic, and sedative drugs

Anesthetic/sedative:
Moderate risk: Propofol
Low risk: Dexmedetomidine ¶
Opioids:
High risk: Methadone
Low risk: Buprenorphine Δ
Androgen deprivation therapy (GnRH agonist/antagonist therapy or bilateral surgical

orchiectomy)
Antianginal drugs
Low risk: Ranolazine (due to bradycardia)
Antiarrhythmic drugs
High risk: Amiodarone ◊ , disopyramide, dofetilide, dronedarone, ibutilide, procainamide,
quinidine, sotalol, vernakalant §
§
Moderate risk: Flecainide, pilsicainide § , propafenone
Anticholinergic drugs (antimuscarinics)

Low risk: Solifenacin
Antihistamines
High risk: Astemizole ¥ , terfenadine ¥
Lower risk: Bilastine § , hydroxyzine
Antimicrobials
Antimalarial:
High risk: Delamanid § , quinidine, quinine
Moderate risk: Chloroquine, halofantrine, piperaquine
Lower risk: Artemether-lumefantrine, hydroxychloroquine (rare reports, noted in
labeling)
Antiparasitic and antiprotozoal:
Moderate risk: Fexinidazole, meglumine antimoniate
Antituberculous:
High risk: Bedaquiline
Azole antifungals:
Moderate risk: Fluconazole, voriconazole
Low to moderate risk: Itraconazole, ketoconazole (systemic)
Clofazimine (moderate risk)
Fluoroquinolones (systemic):
Moderate risk: Gemifloxacin § , levofloxacin, moxifloxacin, sparfloxacin §
Low to moderate risk: Ciprofloxacin, norfloxacin, ofloxacin
Foscarnet (low to moderate risk)
HIV antiretrovirals:
Moderate risk: Saquinavir
Low to moderate risk: Efavirenz, fostemsavir, lopinavir-ritonavir, rilpivirine
Macrolide antibiotics:
Moderate risk: Azithromycin, clarithromycin, erythromycin
Low to moderate risk: Roxithromycin, telithromycin
Metronidazole (low to moderate risk)
Pentamidine (IV) (moderate risk)
Telavancin (low to moderate risk)
Triclabendazole (low to moderate risk)
Antineoplastic drugs
High risk: Adagrasib, arsenic trioxide, ivosidenib, lenvatinib, mobocertinib, selpercatinib,
vandetanib
Moderate risk: Capecitabine, ceritinib, crizotinib, dabrafenib, dasatinib, encorafenib,
floxuridine, fluorouracil (systemic), gilteritinib, inotuzumab ozogamicin, midostaurin,
nilotinib, osimertinib, pazopanib, ribociclib, sunitinib, toremifene, vemurafenib
Lower risk: Bosutinib, eribulin, glasdegib, lapatinib, oxaliplatin, pacritinib, panobinostat,
romidepsin, sorafenib, tamoxifen, vorinostat
Bronchodilators (beta-2 agonists)

Moderate risk: Terbutaline
Lower risk: Albuterol, arformoterol, formoterol, indacaterol, levalbuterol, olodaterol,
salmeterol, vilanterol
Diuretics
Via electrolyte changes (especially hypokalemia or hypomagnesemia)
Gastrointestinal drugs
Antidiarrheal: Loperamide ‡ in overdose (lower risk)
Antiemetics:
Moderate risk: Droperidol, ondansetron (risk with IV use greater than oral)
Low to moderate risk: Amisulpride (IV antiemetic dose), dolasetron, granisetron,
hydroxyzine, tropisetron §
Promotility:
High risk: Cisapride (restricted availability)
Moderate risk: Domperidone §
Low to moderate risk (rare reports): Metoclopramide
Proton pump inhibitors: ‡ Chronic use leading to hypomagnesemia (rare)
Neurologic drugs
Low to moderate risk: Apomorphine, deutetrabenazine, donepezil, ezogabine, fingolimod,
ozanimod † , pimavanserin, ponesimod, tetrabenazine
Oxytocic drugs
Moderate risk: Carbetocin § , oxytocin
Psychotropic drugs
Antidepressants:
Selective serotonin reuptake inhibitors (SSRIs), serotonin modulators, and atypical
agents:
Moderate risk: Citalopram, escitalopram

Low to moderate risk: Fluoxetine, sertraline, trazodone
Low risk: Mirtazapine
Tricyclic and tetracyclic antidepressants (TCAs):**
Moderate risk: Clomipramine, doxepin, and imipramine
Antipsychotics:
High risk: Chlorpromazine, IV haloperidol, sertindole § , ziprasidone
Moderate risk: Amisulpride (oral) § , clozapine, flupentixol § , haloperidol (oral), olanzapine,
pimozide, quetiapine, risperidone, thioridazine
Low to moderate risk: Asenapine, iloperidone, paliperidone, periciazine § , pimavanserin
Others:
Low to moderate risk: Atomoxetine
Low risk: Dexmedetomidine sublingual film ¶
Vasodilator drugs
High risk: Bepridil ¥
Other drugs
High risk: Levoketoconazole, papaverine (intracoronary)
Moderate risk: Etelcalcetide, gadobenate dimeglumine, lofexidine, probucol ¥
Low to moderate risk: Alfuzosin, anagrelide, cocaine (topical), eliglustat, mifepristone,
pasireotide, voclosporin
Herbs: Cinchona (contains quinine), licorice extract (glycyrrhizin) in overuse leading to electrolyte
abnormalities
Other factors
Myocardial ischemia or infarction, especially with prominent T-wave inversions
Intracranial disease
HIV infection
Hypothermia
Toxic exposure: Organophosphate insecticides
This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include
drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to
be safe in most patients but may need to be avoided in patients with congenital long QT
syndrome depending upon clinical circumstances. A more complete list of such drugs is available
at the CredibleMeds website. For clinical use and precautions related to medications and drug
interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of
medications and the Lexicomp drug interactions tool.
AV: atrioventricular; IV: intravenous.
* Classifications provided by Lexicomp according to US Food & Drug Administration guidance:

Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-
Antiarrhythmic Drugs – Questions and Answers; Guidance for Industry US Food and Drug
Administration, June 2017 (revision 2) available at:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM073161.pdf with additional data from CredibleMeds QT drugs list [1,2] . The use of other
classification criteria may lead to some agents being classified differently by other sources.
¶ The United States FDA labeling for the sublingual preparation of dexmedetomidine warns
against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and
sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not
been implicated in TdP.
Δ Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use
disorder, making buprenorphine a suitable alternative for patients with methadone-associated
QTc prolongation. Refer to UpToDate clinical topic reviews.
◊ In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with
torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long
QT syndrome.
§ Not available in the United States.
¥ Withdrawn from market in most countries due to adverse cardiovascular effects.
‡ Over-the-counter; available without a prescription.
† Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical
topic for potential adverse cardiovascular (CV) effects in patients with CV disease.
** Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic
on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic
antidepressant poisoning.
Data from:
1. Lexicomp Online. Copyright ©1978-2023 Lexicomp, Inc. All Rights Reserved.
2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at
http://crediblemeds.org/.
Contributor Disclosures
Eric Strain, MD Grant/Research/Clinical Trial Support: Masimo/Innovative Health Solutions [Opioid use
disorder]. Consultant/Advisory Boards: Caron [Opioid use disorder]; Cerevel [Opioid use disorder];
Crossroads Medical [Opioid use disorder]; Fast Track Drugs and Biologics [Opioid use disorder]; Otsuka
Pharmaceutical Development and Commercialization, Inc [Opioid use disorder]; Pear Therapeutics [Opioid
use disorder]; Sophrosyne Pharmaceutics [Opioid use disorder]. All of the relevant financial relationships
listed have been mitigated. Andrew J Saxon, MD Consultant/Advisory Boards: Alkermes Inc [Opioid use
disorder];Indivior [Opioid use disorder]. Other Financial Interest: Alkermes Inc [Opioid use disorder]. All of
the relevant financial relationships listed have been mitigated. Michael Friedman, MD No relevant
financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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Medication for opioid use disorder - UpToDate 02/02/23, 10:17

Official reprint from UpToDate®

● (See "Approach to treating opioid use disorder".)

screening, assessment, and diagnosis".)

BUPRENORPHINE: OPIOID AGONIST

In individuals with an opioid use disorder (OUD), buprenorphine suppresses withdrawal

Choosing among buprenorphine formulations — For most individuals, our initial choice of

Buprenorphine is available in daily transmucosal formulations, as an extended-release

Transmucosal formulations — Buprenorphine is most commonly administered

A transmucosal formulation of buprenorphine that does not contain naloxone is also

Standard induction — We use a standard induction in most clinical scenarios. However, in

Timing and site of initiation — When initiating buprenorphine, the individual needs to

Initiating induction — Induction begins with the individual manifesting symptoms of

● Day 1 – We typically start transmucosal buprenorphine at a dose of 4 mg (ie, 4 mg/1 mg

• If withdrawal symptoms persist (eg, COWS ≥6 ( table 1)), an additional dose of up

16/4 mg buprenorphine-naloxone) on day 2.

Alternative induction methods for specific circumstances — In specific circumstances,

● Low-dose initiation – Low-dose initiation (also called microdosing) is a method of

dependence. We have used low-dose initiation in these individuals to achieve

• Switching from methadone – We transition individuals from methadone to

● Aggressive buprenorphine induction in emergency department settings –

In a retrospective case series of emergency department patients, 391 individuals (579

Benefits of using transmucosal buprenorphine — Transmucosal buprenorphine improves

● In a meta-analysis of clinical trials, treatment retention was greater at low dose (2 to 6

● A retrospective study of administrative health datasets examined mortality in patients

Injectable buprenorphine — The long-acting injectable (LAI) formulation of buprenorphine

● Buprenorphine XR – This is an LAI form of buprenorphine that is administered

• Initiating buprenorphine XR – Buprenorphine XR is administered no more

transition to buprenorphine XR can occur directly.

- For patients on long-term treatment with transmucosal buprenorphine (ie,

- For patients who have been on transmucosal buprenorphine for a relatively

• Benefits of buprenorphine XR – Individuals with moderate to severe OUD who are

- In a multisite clinical trial of 202 patients with moderate to severe OUD

• Risk evaluation and mitigation strategy (REMS) program for buprenorphine XR

● CAM2038 – Injectable preparations of buprenorphine (CAM2038) is available in one-

Adverse effects — Buprenorphine-related deaths in patients on maintenance therapy have

Tapering buprenorphine — We support the strategy of continuing opioid agonist treatment

● Transmucosal buprenorphine – We typically reduce the dose by 2 mg every one to two

● Longer-acting formulation – Individuals discontinuing buprenorphine XR after

Regulation of buprenorphine in United States — Buprenorphine is classified as a schedule

Other information about United States buprenorphine regulations includes:

● Clinicians can register with SAMHSA to prescribe buprenorphine in an office-based

● Induction may be accomplished in the clinician’s office under observation or at the

schedule III controlled substances.

● Injectable buprenorphine can only be administered through certified health care

METHADONE: OPIOID AGONIST

Methadone, a long-acting opioid agonist, binds to and occupies mu-opioid receptors,

Methadone formulations — Methadone is typically given as a liquid, often diluted with juice

Prior to starting methadone — Prior to beginning treatment with methadone we assess for

● Drug-drug interactions may occur with several commonly used medications

As there is no compelling research evidence to base a decision on whether to obtain an ECG

Methadone is titrated in 5 to 10 mg increments no more frequently than every two to three

Maintenance — Methadone dosing for maintenance treatment varies [48]. Specifying the

Benefits of methadone treatment — Methadone treatment is associated with decreased

● In a meta-analysis of 11 studies including 1969 individuals with the American

● A retrospective study of administrative health datasets examined mortality in patients

Tapering off of methadone — We support the strategy of continuing opioid agonist

pause the taper if instability such as withdrawal symptoms occurs.

Adverse effects — Adverse effects of methadone therapy include constipation, drowsiness,

Some research suggests that substitution of (R,S)-methadone with (R)-methadone reduces

Other adverse effects and considerations — Other adverse effects and drug-drug

● Drug interactions and metabolism – Methadone has a number of drug interactions

Patient's name:_____________ Date and time:_/_/_:______