Your activity: 106 p.v.
your limit has been reached. plz Donate us to allow your ip full access, Email:

Medically supervised opioid withdrawal during treatment for addiction

Medically supervised opioid withdrawal during treatment for addiction
Kevin A Sevarino, MD, PhD
Section Editor:
Andrew J Saxon, MD
Deputy Editor:
Michael Friedman, MD
Literature review current through: Dec 2022. | This topic last updated: Apr 12, 2022.

INTRODUCTION — Medically supervised opioid withdrawal, also known as detoxification, involves the administration of medication to reduce the severity of withdrawal symptoms that occur when an opioid-dependent patient stops using opioids [1]. Symptoms of opioid withdrawal include drug craving, anxiety, restlessness, gastrointestinal distress, diaphoresis, and tachycardia. Medications used in the treatment of withdrawal symptoms include opioid agonists such as methadone and buprenorphine (a partial agonist), as well as alpha-2 adrenergic agonists such as clonidine and lofexidine.

The principal purpose of supervised withdrawal is to safely and successfully transition the patient to medication for opioid use disorder. Supervised withdrawal alone does not generally result in sustained abstinence from opioids [2], nor does it address reasons the patient became dependent on opioids or the damage that the addiction has done to relationships, employment, finances, and the mental, physical, and spiritual health of the patient. It is important to note that full detoxification from opioids is only achieved in transitioning a patient to the opioid antagonist intramuscular naltrexone; transitioning to either methadone or buprenorphine will still maintain the patient in a state of physiological dependence on opioid agonism.

This topic describes indications and contraindications, monitoring, treatment options, and selection among them in medically supervised opioid withdrawal. Clinical manifestations, course, assessment, and diagnosis of opioid withdrawal are described separately. The management of unplanned withdrawal in the emergency department is also described separately, as is opioid withdrawal in adolescents. Pharmacotherapy and psychosocial interventions for opioid use disorder are also discussed separately. (See "Opioid withdrawal in adults: Clinical manifestations, course, assessment, and diagnosis" and "Opioid withdrawal in the emergency setting" and "Opioid withdrawal in adolescents" and "Medication for opioid use disorder" and "Psychosocial interventions for opioid use disorder".)

INDICATIONS AND CONTRAINDICATIONS — Using medications to lessen the severity of withdrawal symptoms is indicated when opioid dependent patients abruptly stop taking the opioid. Patients may do so for a number of reasons, such as:

As the first step in treatment for opioid use disorder, involving transition to an opioid or nonopioid treatment for opioid use disorder. (See "Medication for opioid use disorder".)

To establish an abstinent state without withdrawal symptoms, which may be a requirement of the patient’s setting or status (eg, incarceration, probation, or a drug-free residential program). (See "Psychosocial interventions for opioid use disorder".)

The patient ran out of the financial means to obtain opioids illicitly.

The clinician who prescribed the opioid stopped doing so or transferred patient (eg, for breaking a treatment agreement).

A patient dependent on heroin is hospitalized and lacked access to the drug.

An opioid-dependent individual wants “a break” from use of the drug.

A patient on maintenance methadone has been administratively discharged from treatment.

Patients planning to stop an opioid analgesic that they have not misused or diverted are not typically referred for medically supervised withdrawal. These patients are more commonly tapered off the medication by the prescribing clinician over whatever period is needed to allow the patient to succeed with the taper (eg, weeks to months) [3]. Considerations in selecting these patients and approaches to the taper are described separately. (See "Use of opioids in the management of chronic non-cancer pain", section on 'Discontinuing therapy'.)

We agree with the recommendation of the American College of Obstetricians and Gynecologists that individuals who are pregnant with opioid use disorder start or continue treatment with an opioid agonist during pregnancy rather than undergo medically supervised withdrawal and attempt to maintain abstinence [4]. Despite earlier case reports, medically supervised withdrawal may be safely conducted during pregnancy [5]. Supervised withdrawal, however, presents a much higher risk to the mother and fetus due to the high rate of subsequent relapse (41 to 96 percent) [6]. Relapse to use of illicit opioids typically results in recurrent episodes of intoxication and withdrawal, with the potential for fetal growth delay, abruptio placentae, preterm labor, passage of meconium, and fetal death [4]. Lifestyle risks and poor prenatal care associated with ongoing illicit opioid use also contribute to worse maternal and fetal outcomes for women not in medication for opioid use disorder (MOUD) compared with those who remain on MOUD [7].

Females who refuse opioid-agonist treatment or do not have it available to them would need to undergo medically supervised withdrawal. This should be performed under the supervision of physicians experienced in prenatal care with fetal monitoring [8]. Withdrawal is safest in the second trimester and typically uses a slow methadone taper [9]. The use of buprenorphine or methadone during pregnancy is discussed separately. (See "Overview of management of opioid use disorder during pregnancy" and "Methadone and buprenorphine pharmacotherapy of opioid use disorder during pregnancy".)

Contraindications, dosing, and adverse effects of medications are described below and in a table (table 1). (See 'Buprenorphine-naloxone' below and 'Methadone' below and 'Alpha-2 adrenergic agonists' below.)

MONITORING — For the purposes of short-term medically supervised withdrawal, it is best to use clinical observation and a structured instrument with a standardized scoring system to assess the progress and severity of withdrawal and to guide medication administration. The severity of withdrawal and its exact symptoms do not always correlate with the daily morphine equivalent dose of the previous drug or the reported duration of use [10].

We use the Clinical Opioid Withdrawal Scale (COWS) (calculator 1) (table 2) [11] because of its ease of use and sensitivity. The COWS rates the severity of 11 signs/symptoms of opioid withdrawal on a scale from 0 to 5. The COWS has been well validated and shows interrater correlation coefficients as high as 0.975 [12,13]. We administer the COWS multiple times each day during supervised withdrawal. In the sections on Administration of standard medications, below, we describe specific measurement intervals and threshold COWS scores used to guide dosing decisions. (See 'Buprenorphine-naloxone' below and 'Methadone' below and 'Alpha-2 adrenergic agonists' below.)

Other well-described instruments are listed below; it is most important that staff become familiar with one tool and use it consistently to achieve high interrater reliability:

Objective Opioid Withdrawal Scale (OOWS) [14]: 13 signs of opioid withdrawal scored present or absent

Subjective Opioid Withdrawal Scale (SOWS) [14]: 16 subjective symptoms self-rated 0 to 5

Clinical Institute Narcotic Assessment (CINA) [15]: 11 self-report and observer rated items, scored 0 to 4 or 0 to 5

Serial monitoring can also reveal unanticipated trends. As an example, if symptom severity does not decrease over time in response to a standard medication (ie, failure to respond to treatment), review recent use history with the patient and obtain urine toxicology to rule out unreported use of another abused substance during the course of supervised withdrawal.

MEDICATION STRATEGIES — In this section, we describe our approach to medically supervised opioid withdrawal. We then go into greater detail about each medication strategy. Medications are described in four categories:

Standard protocols with primary medications that target a broad range of withdrawal symptoms (see 'Standard treatments' below)

Adjunctive medications used in conjunction with standard treatments targeting specific symptoms (see 'Adjunctive medications' below)

Accelerated withdrawal protocols using primary medication combinations and adjunctive drugs (see 'Naltrexone-accelerated withdrawal' below)

Alternative treatments, mostly medications, for which available research is insufficient to establish their efficacy in supervised withdrawal (see 'Other' below)

Many of these medications, described below, have been tested in randomized trials against placebo. Some have also been subjected to head-to-head trials; however, our ability to draw definitive conclusions from comparative trials has been limited by variability among treatment protocols.

Approach to treatment — For most patients with physiologic dependence on opioids undergoing medically supervised withdrawal, we suggest first-line treatment with buprenorphine rather than methadone or an alpha-2 adrenergic agonist.

Buprenorphine versus methadone — Buprenorphine and methadone have comparable efficacy in supervised withdrawal [16,17]. A meta-analysis of five clinical trials with 457 patients found that a similar proportion treated with buprenorphine completed supervised withdrawal compared with patients treated with methadone (53 versus 55 percent; risk ratio 1.04 [0.91, 1.20 95% CI]) [18]. Considerations favoring buprenorphine as our first-line medication include (see 'Buprenorphine-naloxone' below and 'Methadone' below):

Methadone's risk of lethal overdose practically limits its use to monitored inpatient settings, while buprenorphine provides greater flexibility in treatment setting.

In our clinical experience, when administered for detoxification and not maintenance, buprenorphine is more effective at suppressing and controlling withdrawal symptoms as the taper nears completion compared with methadone, with which symptoms are more likely to persist or increase again following taper.

Opioid agonists versus alpha-2 adrenergic agonists — Buprenorphine and methadone have been found to be superior to clonidine or lofexidine in supervised withdrawal [16,17]:

A meta-analysis of 1264 supervised withdrawal participants found that those treated with buprenorphine were more likely to complete treatment compared with those receiving alpha-2 adrenergic agonists (risk ratio 1.59 [1.23, 2.06 95% CI]) [18]. There was no difference in the incidence of adverse effects between groups. (See 'Buprenorphine-naloxone' below and 'Alpha-2 adrenergic agonists' below.)

As an example, a clinical trial of 344 opioid-dependent patients found that a greater proportion of buprenorphine-treated patients completed supervised withdrawal with a last day urine drug screen free of illicit opioids compared with patients receiving clonidine (46 versus 11 percent) [19].

A meta-analysis of five clinical trials with 340 patients found the alpha-2 agonists to be somewhat less effective than methadone taper in ameliorating withdrawal symptoms, as measured by the likelihood of severe withdrawal (risk ratio 1.18, 95% CI 0.81-1.73). (See 'Methadone' below and 'Alpha-2 adrenergic agonists' below.)

In programs and settings that prohibit use of controlled substances including opioid agonists (eg, drug-free residential programs and prisons), we suggest use of an alpha-2 adrenergic medication for supervised withdrawal. No significant difference in efficacy has been found between clonidine and lofexidine; lofexidine may be better tolerated and has been approved by the US Food and Drug Administration (FDA) for treatment of acute opioid withdrawal [20].

These and other medications for supervised opioid withdrawal are described in greater detail below.

Standard treatments

Buprenorphine-naloxone — Buprenorphine, a partial mu-opioid agonist and kappa opioid antagonist, is an effective treatment for opioid withdrawal symptoms. Advantages to its use in supervised withdrawal include a long duration of action, higher affinity for mu-opioid receptor than all opioids except fentanyl, slow dissociation from the receptor, and greater safety in overdose than full agonists such as methadone [21].

Buprenorphine is administered in a combination preparation with naloxone, an opioid antagonist that has poor sublingual bioavailability [22]. The inclusion of naloxone discourages intravenous buprenorphine abuse since the naloxone can precipitate withdrawal when administered parenterally to patients with physiologic dependence on full agonist opioids. The ratio of buprenorphine to naloxone is 4:1. More detailed information on buprenorphine’s pharmacology and use in maintenance treatment are discussed separately. (See "Medication for opioid use disorder", section on 'Buprenorphine: Opioid agonist'.)

A relative disadvantage of buprenorphine is that it can precipitate or worsen opioid withdrawal symptoms if not administered carefully. To avoid this, the patient must be in a state of mild to moderate withdrawal before taking their first dose of buprenorphine (for example, having a Clinical Opioid Withdrawal Scale [COWS] score greater than 10 to 12). When buprenorphine is administered to a patient in withdrawal, they experience a net gain in opioid agonism and relief from withdrawal symptoms. Buprenorphine can only be prescribed for opioid use disorder by clinicians in the United States who have met regulatory conditions for its use, with exceptions for emergency treatment of withdrawal. (See "Medication for opioid use disorder", section on 'Regulation of buprenorphine in United States'.)

Buprenorphine potentially can cause respiratory depression, but its partial agonist properties limit this effect by preventing complete activation of mu-opioid receptors, making the drug relatively safe in overdose. Buprenorphine has been reported to cause fatal respiratory depression when taken in combination with other substances, especially benzodiazepines and alcohol [23], or when abused intravenously at high doses [24]. (See "Approach to treating opioid use disorder" and "Medication for opioid use disorder", section on 'Adverse effects'.)

Common side effects of buprenorphine, which are discussed in more detail separately, include sedation, headache, nausea, constipation, and insomnia. (See "Medication for opioid use disorder", section on 'Adverse effects'.)

Efficacy — Because methadone was a well-established, effective medication for medically supervised opioid withdrawal when buprenorphine was being tested, there are no placebo-controlled trials of buprenorphine’s efficacy in medically supervised withdrawal. Comparative clinical trials, described above, have found that buprenorphine has efficacy in supervised withdrawal that it as good as or somewhat better than methadone, and superior to clonidine. (See 'Buprenorphine versus methadone' above and 'Opioid agonists versus alpha-2 adrenergic agonists' above.)

Administration — Buprenorphine administration to alleviate opioid withdrawal symptoms and subsequent taper can often be accomplished on an outpatient basis. Level of care considerations for medically supervised withdrawal are discussed in detail separately. (See "Opioid withdrawal in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Level of care determination'.)

Induction with buprenorphine is frequently conducted with direct observation by the prescriber. As familiarity with this agent has been gained, some providers will utilize "home induction," where buprenorphine is prescribed and then taken at home as directed. In observed induction, response to a first dose is assessed before allowing the patient to return home. The patient typically goes home with a second dose to be taken if needed six hours or more later and returns the next day. For home induction, the patient is advised to stop using their misused opioid until mild to moderate opioid withdrawal symptoms occur, after which the patient can take their first dose. Again, a second dose should be available if withdrawal symptoms are not controlled or return.

A typical induction (initiating the medication), stabilization (bringing withdrawal symptoms under control), and taper typically has a duration of 5 to 10 days, though longer tapers (up to 28 days) appear to improve symptom control. The optimal taper has not been established [25]. A four-week taper has not consistently shown improved treatment retention or relapse rates [26,27]. One well-controlled trial with high intensity treatment including induction onto naltrexone and daily visits for 28 days, and then thrice weekly visits for the following eight weeks, did show better abstinence rates for the four-week taper versus one- or two-week tapers at the end of 12 weeks of treatment [28].

Induction (day 1) – The timing of buprenorphine initiation is based in part on the half-life of the prior opioid and the time of last use. A table describes dosing and half-life information for commonly used opioids (table 1). A patient dependent on a short-acting agent such as oxycodone would be advised to take their last dose 6 to 12 hours before coming in for initiation. A patient who has been regularly using methadone, a long-acting drug, would take their last dose 36 hours before treatment. For patients transitioning to supervised withdrawal from methadone maintenance treatment, patient’s daily dose should gradually be tapered to 30 mg/day before buprenorphine initiation [29]. Timing can be informed by patients, who usually know how long after their last use withdrawal symptoms will start.

Once the patient is in withdrawal, as assessed by objective scoring of signs of withdrawal (COWS 12 or greater), they are given the first dose of buprenorphine, 2 to 4 mg sublingually. In most cases, 4 mg is well tolerated and allows for fewer reassessments later. Relief of symptoms can occur in minutes, though often 30 to 60 minutes is needed for the full effect. Many will report reductions in COWS score to 5 or less.

If the patient experiences sufficient relief after the initial 4 mg dose (COWS score less than 6), vital signs are stable, and there are no other adverse effects, the patient can go home with a second 4 mg buprenorphine dose, which they are instructed to take if withdrawal symptoms and/or craving becomes prominent prior to the next morning. For inpatients, a COWS score that initially improves and then increases to 10 or more can trigger the second 4 mg dosing in two hours or more.

If withdrawal symptoms are insufficiently controlled following the first dose, up to 4 mg can be given within an hour, which almost always provides marked relief, after which the patient may go home. Given they will not have another dose of buprenorphine-naloxone to use, the patient might be provided scripts for an alpha-2 adrenergic agonist (eg, clonidine), as well as adjunctive, symptomatic medications, based on the most prominent symptoms of withdrawal they report. Some providers allow a first day dose up to 12 mg of buprenorphine. (See 'Alpha-2 adrenergic agonists' below and 'Adjunctive medications' below.)

If withdrawal symptoms worsen following the first dose, it is best to treat with clonidine plus adjunctive, symptom specific medications, as described below. For patients who stopped a short-to-moderate acting opioid, hold the next buprenorphine dose for six to eight hours. For a patient who stopped a long-acting agent, hold the dose until the following morning.

A first-day total buprenorphine dose greater than 8 mg may be an indicator that the patient would be better served in an inpatient setting. (See "Opioid withdrawal in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Level of care determination'.)

Stabilization – The goal of stabilization is to reduce withdrawal symptoms to a minimal level on a stable daily medication dose. Day 2 dosing is based on the total amount of buprenorphine taken on day 1 and the presence/absence of continued withdrawal symptoms. If the patient takes a total of 8 mg on day 1 (usually the case) and reports minimal-to-no withdrawal symptoms upon returning for day 2, 8 mg can be given as a single dose.

If the subject reports continued withdrawal symptoms and/or craving on day 2, the daily dose can be raised to 12 mg/day. Provided other new issues have not arisen, the patient can return to their outpatient or inpatient setting.

If the patient continues to report ongoing symptoms upon returning for day 3, the dose can be raised to 16 mg/day. In most cases (other than withdrawal from long-acting opioids), poor symptom or marked craving on day 3 bodes badly for a successful withdrawal off opioids. Reassessment should be made as to whether the patient might be better served by transitioning to continuing office-based opioid treatment with buprenorphine or referral to an outpatient treatment program (OTP) for methadone maintenance [19]. (See "Medication for opioid use disorder".)

Taper – Once withdrawal symptoms have been well controlled for 24 hours, a gradual taper of patient’s daily buprenorphine dose is started. Buprenorphine’s relatively long duration of action allows for faster tapering, such as:

From 12 mg – Decreases of 2 mg/day, to 10 to 8 to 6 to 4 to 2 mg/day over the next five days

From 16 mg – Decreases of 4 and then 2 mg/day, to 12 to 8 to 6 to 4 to 2 mg/day over the next five days

Decreases from the higher doses seem to be experienced with fewer symptoms than decreases from 4 mg and below. If the patient experiences continued withdrawal symptoms or symptoms emerge as lower doses are reached, there are several therapeutic options:

Slow the taper and hold at the lowest effective dose

Provide clonidine and adjunctive medications, as described below to allow the taper to proceed (see 'Alpha-2 adrenergic agonists' below and 'Adjunctive medications' below)

Raise the buprenorphine dose and provide as continuing office-based opioid treatment, with taper attempted at a later date (see "Medication for opioid use disorder")

Modify the patient's environment to reduce cue or stress-induced relapse risk (eg, residential treatment)

Methadone — Methadone, a full mu-opioid agonist, is an effective treatment for opioid withdrawal symptoms. In contrast to buprenorphine, methadone does not induce withdrawal symptoms when given to a patient with opioid agonist in their system. Methadone has an additive effect on opioids that are already present.

Disadvantages of methadone include that it is not safe in overdose. United States regulations preclude providing the medication to take home except when used for pain management. For these reasons, its use in supervised withdrawal usually requires residential or inpatient treatment. Supervised withdrawal with methadone in the United States is legally restricted to a federally designated OTP, to a maximum of three days in other outpatient settings as the patient awaits admission to an OTP, or to an inpatient hospital setting. When used in a residential or inpatient setting, the admission must be for a reason other than opioid use disorder alone, in which case the methadone taper must be conducted within an OTP.

Adverse effects of methadone include prolonged QTc and potentially fatal cardiac arrhythmia [30]. Methadone should not be used if the QTc is over 500 msec and used with caution if between 450 to 500 msec. Caution should also be used in patients with an elevated risk of bradycardia, hypokalemia, hypomagnesemia, or hypocalcemia, as these will raise risk of QTc prolongation, and with concurrent use of psychotropics or other medications that prolong QTc interval.

Overdose with methadone can be lethal, due to arrhythmia or respiratory depression. Overdose is treated with 0.4 to 0.8 mg naloxone, with repeated doses as needed and rapid transfer to a medical unit [31]. Risks associated with methadone overdose are described in more detail separately.

Because of methadone’s long half-life, its dose needs to be increased cautiously on day 1 of medically supervised withdrawal. The drug will accumulate faster than it is eliminated over a 24 hour dosing interval and can reach dangerous levels. The first dose should not exceed 30 mg, and no more than 40 mg should be given on the first day.

Acute side effects of methadone include constipation, mild drowsiness, excess sweating, peripheral edema, and erectile dysfunction. Constipation should be aggressively treated with docusate/sennosides. Other side effects should abate with the taper. Significant oversedation should not be expected and would indicate too high a dose has been used. Adverse/side effects, drug interactions, and cardiac contraindications/monitoring are described in more detail separately. (See 'Indications and contraindications' above and "Medication for opioid use disorder", section on 'Methadone: Opioid agonist' and "Prevention of lethal opioid overdose in the community".)

Efficacy — A meta-analysis of two randomized trials found methadone to be superior to placebo in medically supervised opioid withdrawal [32]. The trials with a total of 38 patients found that patients receiving methadone were more likely to complete treatment (94.7 versus 47.3 percent) and experienced less severe withdrawal symptoms.

Administration — Methadone taper is based on the substitution of a long-acting opioid for the shorter-acting opioid (eg, heroin), bringing withdrawal symptoms under control, and then slowly tapering the methadone. There are many different approaches to the dosing of methadone substitution and taper. Here we describe our approach as well as some variations.

The duration of methadone taper ranges from five days for an inpatient to 14 days or longer for an outpatient. OTPs might utilize a treatment plan involving a slower taper of 30 to 180 days (long-term detoxification). A briefer, simple paradigm is a five-day course of 25 to 20 to 15 to 10 to 5 mg over five days. We prefer a symptom-guided approach to dosing, described below:

Induction (day 1) – In the absence of opioid withdrawal symptoms/signs, it is difficult to gauge the efficacy of an initial methadone dose; thus, the first dose of methadone is not started until the patient enters mild to moderate withdrawal (a score of 10 to 12 on the COWS (table 2)).

Dosing of methadone on day 1 should not rely as much on the reported opioid agent and daily dose as it should seek a balance between controlling withdrawal symptoms and avoiding oversedation and motor impairment. Conversion of morphine equivalents to methadone dose is difficult as the values vary based on methadone dose and previous tolerance.

The initial methadone dose on day 1 can vary from 10 to a maximum of 20 mg, and the dose over the first 24 hours must not exceed 40 mg. Considerations in choosing an initial methadone dose include:

A typical initial methadone dose is 20 mg.

One could start with 10 mg in a patient who presents with a history of low daily opioid use, such as one to two bags of heroin per day or 5 to 10 mg oxycodone per day.

A more incremental approach requiring closer monitoring is to start with a 10 mg dose irrespective of opioid use history, and reassess COWS after two hours. If COWS is:

-Less than 6, observe

-6 to 12 give a 5 mg dose

-12 or over, give a 10 mg dose

After a second dose, reassess COWS after another two hours, and repeat.

Stabilization – On the morning of day 2, if COWS is under 6, the total dose used over the first 24 hours should be provided on day 2. A daily dose of 40 mg or less will control symptoms in most patients. If COWS remains between 6 to 12 on day 2, the total day 2 dose might be raised by 20 percent (up to 40 mg). If after two hours this does not bring COWS below 6, additional adjunctive treatment as described below may be needed. (See 'Adjunctive medications' below.)

If COWS on day 2 is over 12, or there are other indications that withdrawal symptoms cannot be controlled, a period of maintenance treatment can be considered.

Taper – Dose taper can typically be started after day 2. Dose reduction can be as rapid as 20 percent per day on an inpatient unit, but tapers of one to two weeks or longer are the norm. As an example, one might begin with 40 mg methadone day 1 and then decrease by 10 mg/day until 10 mg is reached, then by 2 mg per day [33]. Other tapering strategies have been described [33,34]. Once 10 to 15 mg a day is reached, patients typically experience greater withdrawal symptoms, necessitating addition of clonidine and adjunctive medications (table 3) or slowing of the taper [35]. (See 'Alpha-2 adrenergic agonists' below and 'Adjunctive medications' below.)

The specific approach to tapering appears to be less important to a successful supervised withdrawal than the patient’s internal motivation and the adequacy of the overall treatment plan [36].

Supervised withdrawal using methadone is not over with the last daily dose. Due to the drug’s long half-life, increased withdrawal symptoms and/or craving can emerge two or more days after the last dose [37,38]. Clonidine and adjunctive medications (table 3) can provide relief [35]. Patients are highly vulnerable to relapse following completion of withdrawal, underscoring the importance of the transition to maintenance treatment if clinically appropriate. (See 'Alpha-2 adrenergic agonists' below and 'Adjunctive medications' below.)

Alpha-2 adrenergic agonists — Alpha-2 adrenergic agonists, including clonidine and lofexidine, lessen many symptoms of opioid withdrawal [39]; they most effectively relieve the autonomic symptoms of sweating, diarrhea, intestinal cramps, nausea, anxiety, and irritability [35,40]. They are least effective for myalgias, restlessness, insomnia, and craving. Compared with reducing doses of methadone, these agents have been found to be comparably efficacious but more likely to cause side effects [41]. Patients typically prefer opioid agonists over alpha-2 adrenergic agonists.

In many clinical settings, alpha-2 adrenergic agonists are no longer used as a primary medication in supervised opioid withdrawal; instead, they are mostly used as adjuncts to treatment with buprenorphine or methadone [42]. They are used first-line in supervised withdrawal in prisons and other environments that prohibit the use of opioid agonists and other controlled substances. Diversion and abuse of adrenergic agonists has been reported (for their sedating effect and for self-treatment of withdrawal symptoms), but the risks are relatively low [43]. (See 'Adjunctive medications' below.)

Alpha-2 adrenergic agonists act on presynaptic receptors that autoregulate noradrenaline release. Hyperactivity of the noradrenergic cell bodies of the locus coeruleus driven by an up-regulated cyclic adenosine monophosphate system leads to a well-defined opioid withdrawal syndrome in animal models [44]. Alpha-2 adrenergic agonists reduce withdrawal symptoms by decreasing locus coeruleus hyperactivity [39]. Drugs of this class have anxiolytic properties by lowering circulating noradrenaline [45].

Among the centrally acting alpha-2 adrenergic agonists that are available in the United States, clonidine is the most widely used for opioid withdrawal [46], and lofexidine was approved for use in 2018 [47]. Tizanidine has not been widely studied as a primary detoxification agent; rather, it is used to relieve muscle spasms occurring during opioid withdrawal. (See 'Adjunctive medications' below.)

Contraindications to the use of this class of agent include hypotension, moderate or worse renal insufficiency, cardiac instability, pregnancy, and psychosis. Tricyclic antidepressants, which desensitize alpha-2 adrenoreceptors, should be stopped three weeks prior to use of clonidine and, presumably, lofexidine [42]. Side effects, principally hypotension and sedation, limit the use of these drugs, though lofexidine induces less hypotension than clonidine [48,49].

Efficacy — There is strong support from clinical trials for the efficacy of alpha-2 adrenergic agonists in withdrawal symptom control and treatment completion compared with placebo [17,48]. A meta-analysis of three clinical trials [48] with a total of 148 opioid dependent patients found that these medications were superior to placebo for treatment completion (55 versus 29 percent; risk ratio 1.95 [1.34, 2.84 95% CI]). As an example [50], a clinical trial in 68 opioid-dependent inpatients found that patient treated with lofexidine, compared with placebo-treated patients, were more likely to complete treatment (34 versus 15 percent) and less likely to experience severe withdrawal symptoms (14 versus 30 percent). A 2017 FDA registration trial for the United States demonstrated the superiority of lofexidine compared with placebo on protocol completion (53 versus 35 percent) [51]. Tizanidine was examined in one study for use in opioid withdrawal [52].

A meta-analysis of multiple randomized trials found alpha-2 adrenergic agonists to be comparable to reducing doses of methadone in ameliorating opioid withdrawal symptoms in DSM-IV opioid dependent patients [41]. No differences were seen between the treatments in severe withdrawal symptoms (risk ratio 1.18, 95% CI 0.81-1.73), peak withdrawal score, overall withdrawal severity, and rate of treatment completion. The duration of treatment was longer with reducing doses of methadone. Hypotensive and other adverse effects were more likely with alpha-2 adrenergic agonists.

Direct comparison of lofexidine and clonidine has not been definitive, but available research suggests equal efficacy between the two drugs with a trend towards less hypotension with lofexidine [53].

Administration — Clonidine can be taken orally or administered via a clonidine patch, changed weekly, at doses equivalent to oral clonidine 0.1, 0.2, and 0.3 mg twice daily. Many programs do not use clonidine patches for supervised withdrawal because of the potential need to make frequent dose adjustments, while other programs prefer clonidine patches because they minimize interruptions and do not require patient requests for medication, which can be difficult to distinguish from drug seeking. The transdermal patch does not provide adequate blood levels for the first 72 hours after application, so oral dosing is required for the first three days regardless of whether the patch is used.

Relief from withdrawal symptoms typically occurs within 30 minutes after a dose. The dose and frequency of clonidine administration are typically limited by sedation and/or orthostatic hypotension; dry mouth and constipation are also common.

Day 1 – To initiate withdrawal with clonidine, opioids are abruptly stopped. Sitting and standing blood pressure are checked prior to treatment and clonidine is given if the blood pressure is at or above 90/60, heart rate greater than 60, and orthostatic hypotension is not present. A test dose of clonidine 0.1 mg (0.2 mg if patient weighs 90 kg [approximately 200 pounds] or more) is given. After 45 minutes, if the blood pressure and pulse remain within these parameters, and symptoms remain prominent (COWS score greater than 8), additional 0.1 mg doses can be administered and repeated every 45 to 60 minutes up to four doses. Subsequently, up to 0.3 mg of clonidine can be given every six hours, with dosing determined by response:

For a COWS 8 to 12, give 0.1 mg

For a COWS over 12, give 0.2 mg

For a COWS exceeding 24, consider changing strategy to buprenorphine-naloxone or methadone

For patients over 90 kg (approximately 200 pounds), the doses of clonidine can be raised by 0.1 mg. The total daily dose typically does not exceed 0.8 mg/day (or for patients 90 kg [approximately 200 pounds] or more, 1.2 mg/day).

Day 2 and after – The amount of clonidine provided on day 1 is totaled and provided daily in divided doses three or four times per day on day 2 typically through day 4. Tapering is usually started around day 5 based on the patient’s level of comfort (ie, minimal symptoms). Tapering is done gradually, with the dose reduced by 0.1 to 0.2 mg/day, to prevent rebound hypertension.

If supervised withdrawal is conducted on an outpatient basis, the vital signs after the first dose should be assessed as above. If the medication is tolerated, no more than a two-day supply should be given before vitals are again assessed. The taper of clonidine is usually completed in 6 to 12 days, though some patients remain on the agent during maintenance naltrexone treatment.

A typical total daily dose of lofexidine is 3.2 mg/day administered in four divided doses. Lofexidine requires less concern for hypotensive effects.

When clonidine is used to treat residual withdrawal symptoms as an adjunct to supervised withdrawal with buprenorphine or methadone taper, the COWS or other scoring instrument can be used to gauge whether an additional dose of the taper agent is needed or whether dosing of clonidine, as described for day 1 above, might be added.

Adjunctive medications — Patients with physiologic dependence on opioids undergoing supervised withdrawal with an opioid agonist, opioid partial agonist, or alpha-2 adrenergic agonist often experience some withdrawal symptoms during the treatment and taper periods. Symptom-specific, adjunctive medications (also known as symptomatic treatment) are used to provide targeted relief of the symptoms below:

Abdominal cramping




Muscle aches


Adjunctive medications used to treat these symptoms are described in a table (table 3). In addition, alpha-2 adrenergic agonists (described above as a primary medication) can also be used as an adjunct to supervised withdrawal with an opioid agonist. (See 'Alpha-2 adrenergic agonists' above.)

Several medications are available for each category of target symptoms (table 3). Clinical staff typically come to prefer one or two medications in each category with which they have become familiar. We note our first-line preferences at the top of each category, but clinical circumstances can favor other options.

Although adjunctive medications are typically needed more frequently in conjunction with alpha-2 adrenergic agonists, they are useful in conjunction with opioid agonists and partial agonists as well. In a study of 234 patients treated with buprenorphine for opioid withdrawal, even among patients receiving 16 mg/day of buprenorphine, a majority of patients needed at least one adjunctive medicine for relief of anxiety, restlessness, or arthralgias [19].

Benzodiazepines are sometimes used to treat anxiety, restlessness, and muscle spasm during inpatient supervised withdrawal; however, their use is to be avoided if possible. Prescribed benzodiazepines can confound urine drug screen surveillance for illicit benzodiazepine use, they are addictive, and they increase the chance of respiratory suppression when coadministered with methadone and buprenorphine. Their use should be reserved for inpatient settings, where frequent clinical monitoring can be performed.

Comorbid psychiatric disorders and medications may impact the choice of symptomatic treatments during the withdrawal. Anxiety disorders, including panic disorder, must be recognized and adequately addressed to facilitate completion of supervised withdrawal. The risk of suicide is elevated in anxiety and mood disorders and must be constantly assessed during the course of detoxification. Trauma-based conditions, such as posttraumatic stress disorder, may adversely affect the patient's ability to tolerate residential or inpatient environments. Lithium levels can vary markedly with withdrawal-associated dehydration and must be monitored closely. Carbamazepine may increase methadone dosing needs, and psychotropics strongly interacting with the CYP2D6 and 3A4 systems may affect levels of methadone and, to a lesser extent, buprenorphine. (See "Opioid withdrawal in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Co-occurring conditions'.)

Naltrexone-accelerated withdrawal — Protocols to accelerate medically supervised withdrawal aim to reduce the transition time to naltrexone treatment of opioid use disorder, thereby reducing risk of relapse, treatment drop-out, patient inconvenience, length of inpatient or residential stay, and treatment costs [54,55]. Naltrexone-accelerated withdrawal was initially developed with the goal of shortening the withdrawal period and not necessarily with the goal of transitioning a patient onto naltrexone maintenance [56]. These approaches are labor intensive and result in greater discomfort early in the course of withdrawal. As such, they require above average clinical skill in monitoring and management of withdrawal symptoms, and they are not used outside of clinical settings specialized in opioid withdrawal treatment and even then, used infrequently.

A resurgence in interest in development of naltrexone-accelerated withdrawal protocols has arisen with the approval of long-acting injectable naltrexone (LAI-NTX) for the treatment of opioid use disorder. The chief disadvantage of this agent is the recommended opioid-free period of 7 to 10 days between cessation of opioid use and initiation of the opioid antagonist [57,58].

A well-described protocol for naltrexone-accelerated withdrawal follows [59]:

Patients abstain from opioids 12 to 24 hours before arriving day 2 in clinic.

On day 2, as long as COWS >5, buprenorphine-naloxone 2 mg, then every one to two hours, to a maximum of 8 mg buprenorphine-naloxone on day 2.

On days 3 to 8, standing clonidine 0.1 to 0.2 mg every four hours and clonazepam 0.5 mg four times daily are used.

On day 4, 10 mg prochlorperazine is given orally (PO) as a pretreatment, then 1 mg oral naltrexone (only available from a compounding pharmacy, which may be impractical for routine clinical use).

On days 5 to 7, 3, 12, and 25 mg oral naltrexone (only available from a compounding pharmacy) are given, then on day 8 LAI-NTX 380 mg. Allowed was adjunctive treatment with clonazepam 0.5 mg four times daily as needed, 0.1 mg every four hours as needed (max 1.2 mg/day); trazodone 100 mg every night at bedtime, zolpidem 10 mg every night at bedtime, and prochlorperazine 10 mg PO three times daily.

Available evidence suggests that naltrexone-accelerated withdrawal can achieve a higher rate of induction onto LAI-NTX in fewer days compared with other approaches:

A meta-analysis comparing use of alpha-2 agonist treatment alone compared with alpha-2 agonist combined with opioid antagonists indicated naltrexone-accelerated protocols may have some advantages, but overall the data are too limited to recommend one approach over another [55].

An outpatient clinical trial randomly assigned 150 patients with DSM-IV opioid dependence to undergo naltrexone-accelerated withdrawal over seven days or a seven-day taper of buprenorphine followed by a one-week wait [59]; induction onto LAI-NTX was then attempted for both groups. More patients in the naltrexone-accelerated group were successfully inducted onto LAI-NTX compared with the buprenorphine taper group (56 versus 33 percent). No difference in COWS or Hamilton Depression Rating scores were observed.

A randomized clinical trial examined a seven-day outpatient detoxification and transition to LAI-NTX study comparing three groups: oral naltrexone induction from day 1 plus sublingual buprenorphine taper, placebo naltrexone plus sublingual buprenorphine taper, or placebo naltrexone plus placebo sublingual buprenorphine taper. Ancillary medications were used to manage withdrawal symptoms, including clonidine, trazadone, and clonazepam. All three groups showed similar rates of induction onto intramuscular naltrexone (47, 41, 47 percent respectfully); however, this protocol involved initiation of very low doses of naltrexone (as low as 0.25 mg naltrexone) at the start of detoxification [60]. Subjects in the active oral naltrexone group were significantly more likely to remain abstinent during the seven-day detoxification period than those in the other two groups (odds ratio = 1.54; 95% CI 1.31-1.80). On day 9, when transition to LAI-NTX was done, the active oral naltrexone group had significantly lower COWS scores than subjects in the other two groups. The study supports the utility of rapid induction onto naltrexone while conducting the buprenorphine taper.

Ultra-rapid or anesthesia-assisted opioid withdrawal — “Ultra-rapid” opioid withdrawal involves use of heavy sedation and intravenous infusion of high-dose naloxone to shorten physiologic detoxification to as little as eight hours [61,62].

We recommend that this approach not be used, consistent with recommendations of the American Society of Addiction Medicine [25] and the National Institute for Health and Care Excellence consortium in England [53]. A meta-analysis of multiple clinical trials [63] of antagonist-induced withdrawal with heavy sedation/anesthesia did not influence the intensity or duration of the withdrawal but had a greater risk of adverse events compared with light sedation (risk ratio 3.21, 95% CI 1.13-9.12). Serious complications including death have been reported [63-66].

Acupuncture — Acupuncture, when combined with opioid-agonist taper, may have some efficacy in reducing withdrawal symptoms. A meta-analysis of 11 clinical trials with 1105 opioid-dependent patients found some evidence suggesting that the combination of acupuncture and opioid taper reduced withdrawal symptoms in comparison with opioid taper alone [67]. Caution should be used in interpreting these findings due to methodologic limitations and differences across trials (eg, in the kind of acupuncture, opioid tapering strategies, and opioid withdrawal scales).

The National Acupuncture Detoxification Association auricular protocol has shown some efficacy in reducing anxiety associated with supervised withdrawal [68].

Other — In addition to methadone, other long-acting opioid agonists such as tramadol extended-release have shown efficacy in tapering opioids to avoid withdrawal [69-72].

Other medications have been studied in small trials or case reports, either alone or combined with methadone taper, gabapentin [71,73], pregabalin [74], N-methyl-D-aspartate agonists [75-77], methadone taper combined with very low dose naltrexone (eg, 0.125 or 0.25 mg) [78,79], ondansetron, a 5-HT3a agonist [80], venlafaxine [81], buspirone [82], dronabinol [83], and cannabinoid-1 receptor (CB1)-agonists [84]. The evidence for these interventions is currently insufficient for us to conclude that they are efficacious or suggest their use in clinical practice.

Kratom — Kratom (Mitragyna speciosa), an herb with opioid and stimulant-like properties, contains indole alkaloids, principally mitragynine and 7-HO-mitragynine, with mu-opioid receptor agonism [85]. It has been used for self-treatment of opioid withdrawal, with little published evidence of efficacy and increasing numbers of reports of lethal overdose and other adverse effects [85]. Kratom should not be used in patients withdrawing from opioids.

Investigation of kratom’s efficacy and toxicity is limited to case reports/series [85]. In higher doses of 5 to 15 g, frequent and prolonged ingestion of kratom for pain or recreational use has been associated with respiratory depression, anorexia, weight loss, seizures, depression, psychosis, physiologic tolerance, and withdrawal (similar to that seen with opioids) [86]. Opioid withdrawal symptoms emerge 12 to 24 hours after last use and persist for up to seven days. There are no controlled trials supportive of specific pharmacologic treatment of kratom withdrawal, but a 2019 review suggested treatment similar to withdrawal from other opioids, specifically alpha-2-adrenergic agonists and symptomatic treatment [87].

Kratom use is prohibited in some countries and states in the United States. The FDA has issued multiple advisories on kratom: on health risks with its use for opioid withdrawal [88], its association with a multistate Salmonella outbreak in 2018 [89], and on a mandatory recall of kratom-containing products associated with Triangle Pharmanaturals, LLC in 2018 [90].

Fentanyl and derivatives — The rapid rise in synthetic opioid exposure, especially fentanyl, means that in many regions the majority of heroin is laced with fentanyl, and fentanyl has become the deadliest agent implicated in opioid overdose death in the United States [91]. Those misusing opioid pain medications increasingly are exposed to fentanyl in tablets believed to be a lower potency opioid (eg, oxycodone) [92]. Fentanyl and fentanyl derivatives have higher affinities and potencies at the mu opioid receptors than the natural and semi-synthetic opioids [93].

The high lipophilicity of fentanyl results in a slow redistribution from tissues back into the plasma. Thus, not only is respiratory suppression more prolonged after overdose, necessitating rapid and repeated administration of naloxone, but the time course of withdrawal is more difficult to predict. There are no controlled trials examining withdrawal from fentanyl. As one might predict from the affinity differences, some suggestion that standard treatment approaches, such as buprenorphine substitution, might not be as effective in those dependent on fentanyl [94].

Opium — In opium producing countries and their neighbors, especially Afghanistan, Iran, Myanmar, and Laos, opium use can be more common than that for other opioids [95]. Withdrawal symptoms from opium are similar to those with other substances, though often milder, with peak symptoms at days 2 to 4. A 2018 meta-analysis of 13 trials in Iran, India, and Thailand did not include any studies comparing active compound with placebo [96]. Studies were either of low or very low quality, and no specific pharmacologic therapies were supported. Overall, treatment of opium withdrawal is likely to be similar to that for other opioids.

COMPLICATIONS — Withdrawal precipitated by buprenorphine and/or a full antagonist like naltrexone is often quicker in onset and more severe than spontaneous withdrawal. Complications can require hospitalization; even intensive care unit admissions have been described [97]. Cases of organic delusional syndromes [98] and stress cardiomyopathy [99,100] have been reported, resulting from both precipitated and spontaneous withdrawal. Seizures are rare (except in withdrawal from meperidine) and may indicate concurrent withdrawal from alcohol or benzodiazepines, or a preexisting seizure diathesis. Severe nausea and vomiting with dehydration may require aggressive intravenous rehydration and correction of electrolyte abnormalities on a medical unit.

Patients undergoing opioid withdrawal are at risk of suicide, driven by the psychic distress and fear that often accompanies opioid withdrawal and/or feelings of failure among patients unable to complete the process. Patients should be assessed for suicidality throughout supervised withdrawal, with positive findings resulting in clinically appropriate increases in the level of observation and follow-up. (See "Suicidal ideation and behavior in adults".)

Another significant risk associated with medically supervised withdrawal is unintentional overdose, often a result of a sequence of events:

Patient elopement during supervised withdrawal.

Resumption of opioid use in the context of severe craving and desire to ameliorate remaining withdrawal symptoms.

Opioid overdose of patient who resumed use at their prewithdrawal “dose.” They are at increased risk of respiratory depression and death due to the loss of tolerance to opioids over the course of supervised withdrawal.

Patients should be warned multiple times of the risks associated with decreased opioid tolerance; they and family or coresidents should be provided take-home naloxone and education on its use [101]. (See 'Continuing care' below and "Prevention of lethal opioid overdose in the community".)

CONTINUING CARE — Medically supervised withdrawal is a first step in a long process of maintaining abstinence [2,102]. High rates of relapse in the month following supervised withdrawal are the norm if withdrawal is not followed by the patient’s successful transition to maintenance treatment [27]. Collaboration between the patient and their clinicians on a treatment plan to follow withdrawal is key to maximizing chances of longer-term success [103,104]. Clinicians participating in supervised withdrawal should aim to develop a therapeutic alliance with the patient, work to build their motivation, and emphasize the need for long-term treatment [53] that includes:

Pharmacotherapy and psychosocial interventions. (See "Medication for opioid use disorder" and "Psychosocial interventions for opioid use disorder" and "Motivational interviewing for substance use disorders" and "Contingency management for substance use disorders: Theoretical foundation, principles, assessment, and components" and "Contingency management for substance use disorders: Efficacy, implementation, and training".)

An intensity of treatment and monitoring with urine drug testing appropriate to the patient’s clinical status and risk of relapse. (See "Continuing care for addiction: Context, components, and efficacy" and "Continuing care for addiction: Implementation".)

Education about decreased opioid tolerance and overdose risks; take-home naloxone and education about its use for overdose [101]. (See "Prevention of lethal opioid overdose in the community".)

CLINICIAN EDUCATION AND TRAINING — The Substance Abuse and Mental Health Services Administration-funded Providers’ Clinical Support System for Medication Assisted Treatment (PCSS) in the United States provides training and educational materials for clinicians using opioid agonists and antagonists for medically supervised opioid withdrawal and maintenance treatment. PCSS provides clinicians with access to a nationwide network of mentors for prescribing clinicians who are unfamiliar with treatment for patients with opioid use disorders.

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".)


Indications and contraindications – Medically supervised opioid withdrawal, also known as detoxification, involves the administration of medication to reduce the severity of withdrawal symptoms that occur when an opioid-dependent patient stops using opioids. Its principal purpose is to safely and successfully transition the patient to subsequent, continuing treatment to maintain abstinence from illicit opioids. (See 'Introduction' above and 'Indications and contraindications' above.)

We agree with the with the recommendation of the American College of Obstetricians and Gynecologists that individuals who are pregnant opioid use disorder start or continue medication for opioid use disorder with an opioid agonist or partial agonist during pregnancy rather than undergo medically supervised withdrawal and attempt to maintain abstinence. Some women may refuse opioid-agonist maintenance treatment in favor of medically supervised withdrawal. (See 'Indications and contraindications' above and "Overview of management of opioid use disorder during pregnancy" and "Methadone and buprenorphine pharmacotherapy of opioid use disorder during pregnancy".)

Monitoring We use the Clinical Opioid Withdrawal Scale (COWS), a structured instrument with a standardized scoring system in conjunction with clinical observation to assess the progress and severity of withdrawal, and guide medication administration. We prefer the COWS because of its ease of use and sensitivity and it is found on the associated table (table 2). (See 'Monitoring' above.)

Treatment preferences – For most patients with physiologic dependence on opioids undergoing medically supervised withdrawal, we suggest first-line treatment with buprenorphine-naloxone rather than methadone or an alpha-2 adrenergic agonist (Grade 2B). If buprenorphine is unavailable or unfamiliar, methadone is a reasonable alternative, provided that the patient is in a closely monitored inpatient or residential setting that can minimize risk of overdose/diversion and the patient lacks cardiac or other contraindications to its use. (See 'Buprenorphine-naloxone' above and 'Methadone' above.)

For patients in settings that prohibit use of controlled substances including opioid agonists (eg, drug-free residential programs, prisons), we suggest use of an alpha-2 adrenergic medication such as clonidine for supervised withdrawal compared with no pharmacologic treatment (Grade 2B). (See 'Alpha-2 adrenergic agonists' above.)

Adjunctive medication – We use symptom-specific adjunctive medications (also known as symptomatic treatment) to provide targeted relief of withdrawal symptoms (eg, cramping, diarrhea, nausea) that occur despite primary-medication treatment (table 3). There are several options for each symptom type. Our first-line preferences are noted on the table. (See 'Adjunctive medications' above.)

Ultra-rapid or anesthesia-assisted opioid withdrawal – We recommend that “ultra-rapid” or anesthesia-assisted withdrawal not be used in medically supervised opioid withdrawal. (Grade 1B). (See 'Ultra-rapid or anesthesia-assisted opioid withdrawal' above.)

Suicide – We assess for suicidality throughout the course of supervised withdrawal. Patients undergoing opioid withdrawal are at risk of suicide, driven by the psychic distress and fear that often accompanies withdrawal and/or feelings of failure among patients unable to complete the process. (See 'Complications' above.)

Continuing care – Medically supervised withdrawal is a first step in a long process of maintaining abstinence. High rates of relapse in the month following supervised withdrawal are the norm if withdrawal is not followed by the patient’s successful transition to maintenance treatment. (See 'Continuing care' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Michael Weaver, MD, and John Hopper, MD, who contributed to an earlier version of this topic review.

  1. Diaper AM, Law FD, Melichar JK. Pharmacological strategies for detoxification. Br J Clin Pharmacol 2014; 77:302.
  2. Mattick RP, Hall W. Are detoxification programmes effective? Lancet 1996; 347:97.
  3. Berna C, Kulich RJ, Rathmell JP. Tapering Long-term Opioid Therapy in Chronic Noncancer Pain: Evidence and Recommendations for Everyday Practice. Mayo Clin Proc 2015; 90:828.
  4. ACOG Committee on Health Care for Underserved Women, American Society of Addiction Medicine. ACOG Committee Opinion No. 524: Opioid abuse, dependence, and addiction in pregnancy. Obstet Gynecol 2012; 119:1070. Reaffirmed 2014.
  5. Bell J, Towers CV, Hennessy MD, et al. Detoxification from opiate drugs during pregnancy. Am J Obstet Gynecol 2016; 215:374.e1.
  6. Jones HE, O'Grady KE, Malfi D, Tuten M. Methadone maintenance vs. methadone taper during pregnancy: maternal and neonatal outcomes. Am J Addict 2008; 17:372.
  7. Wilder C, Lewis D, Winhusen T. Medication assisted treatment discontinuation in pregnant and postpartum women with opioid use disorder. Drug Alcohol Depend 2015; 149:225.
  8. Center for Substance Abuse Treatment. Substance Abuse Treatment: Addressing Specific Needs of Women. Treatment Improvement Protocol (TIP) Series 51. HHS Publication No. (SMA) 09-4426, Substance Abuse and Mental Health Services Administration; Department of Health and Human Services, Rockville, MD 2009.
  9. Dashe JS, Sheffield JS, Olscher DA, et al. Relationship between maternal methadone dosage and neonatal withdrawal. Obstet Gynecol 2002; 100:1244.
  10. Dijkstra BA, Krabbe PF, De Jong CA, van der Staak CP. Prediction of withdrawal symptoms during opioid detoxification. J Opioid Manag 2008; 4:311.
  11. Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs 2003; 35:253.
  12. Altintoprak AE, Evren EC, Aydemir Ö, et al. Reliability and Validity Study of the Turkish Version of the Clinical Opiate Withdrawal Scale. Noro Psikiyatr Ars 2015; 52:89.
  13. Tompkins DA, Bigelow GE, Harrison JA, et al. Concurrent validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices against the Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument. Drug Alcohol Depend 2009; 105:154.
  14. Handelsman L, Cochrane KJ, Aronson MJ, et al. Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse 1987; 13:293.
  15. Peachey JE, Lei H. Assessment of opioid dependence with naloxone. Br J Addict 1988; 83:193.
  16. Gowing L, Ali R, White JM. Buprenorphine for the management of opioid withdrawal. Cochrane Database Syst Rev 2009; :CD002025.
  17. Meader N. A comparison of methadone, buprenorphine and alpha(2) adrenergic agonists for opioid detoxification: a mixed treatment comparison meta-analysis. Drug Alcohol Depend 2010; 108:110.
  18. Gowing L, Ali R, White JM, Mbewe D. Buprenorphine for managing opioid withdrawal. Cochrane Database Syst Rev 2017; 2:CD002025.
  19. Ling W, Amass L, Shoptaw S, et al. A multi-center randomized trial of buprenorphine-naloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Addiction 2005; 100:1090.
  20. Pergolizzi JV Jr, Annabi H, Gharibo C, LeQuang JA. The Role of Lofexidine in Management of Opioid Withdrawal. Pain Ther 2019; 8:67.
  21. Strain EC, Stitzer ML, Liebson IA, Bigelow GE. Comparison of buprenorphine and methadone in the treatment of opioid dependence. Am J Psychiatry 1994; 151:1025.
  22. Comer SD, Sullivan MA, Vosburg SK, et al. Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers. Addiction 2010; 105:709.
  23. Tracqui A, Kintz P, Ludes B. Buprenorphine-related deaths among drug addicts in France: a report on 20 fatalities. J Anal Toxicol 1998; 22:430.
  24. Byrne A. Reducing deaths among drug misusers. Standard of care in Britain was not addressed. BMJ 2001; 323:513.
  25. ASAM: The ASAM National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use, American Society of Addiction Medicine. (Accessed on November 18, 2015).
  26. Dunn KE, Saulsgiver KA, Miller ME, et al. Characterizing opioid withdrawal during double-blind buprenorphine detoxification. Drug Alcohol Depend 2015; 151:47.
  27. Dunn KE, Sigmon SC, Strain EC, et al. The association between outpatient buprenorphine detoxification duration and clinical treatment outcomes: a review. Drug Alcohol Depend 2011; 119:1.
  28. Sigmon SC, Dunn KE, Saulsgiver K, et al. A randomized, double-blind evaluation of buprenorphine taper duration in primary prescription opioid abusers. JAMA Psychiatry 2013; 70:1347.
  29. Breen CL, Harris SJ, Lintzeris N, et al. Cessation of methadone maintenance treatment using buprenorphine: transfer from methadone to buprenorphine and subsequent buprenorphine reductions. Drug Alcohol Depend 2003; 71:49.
  30. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment. Ann Intern Med 2009; 150:387.
  31. Chhabra S, Bull J. Methadone. Am J Hosp Palliat Care 2008; 25:146.
  32. Amato L, Davoli M, Minozzi S, et al. Methadone at tapered doses for the management of opioid withdrawal. Cochrane Database Syst Rev 2013; :CD003409.
  33. Strang J, Gossop M. Comparison of linear versus inverse exponential methadone reduction curves in the detoxification of opiate addicts. Addict Behav 1990; 15:541.
  34. Weaver MF, Jarvis MA, Schnoll SH. Role of the primary care physician in problems of substance abuse. Arch Intern Med 1999; 159:913.
  35. Charney DS, Sternberg DE, Kleber HD, et al. The clinical use of clonidine in abrupt withdrawal from methadone. Effects on blood pressure and specific signs and symptoms. Arch Gen Psychiatry 1981; 38:1273.
  36. Day E. Commentary on Nosyk et al. (2012): detoxification from methadone maintenance therapy: how important is the exact technique that is used? Addiction 2012; 107:1630.
  37. Kleber HD. Pharmacologic treatments for opioid dependence: detoxification and maintenance options. Dialogues Clin Neurosci 2007; 9:455.
  38. Gossop M, Bradley B, Phillips GT. An investigation of withdrawal symptoms shown by opiate addicts during and subsequent to a 21-day in-patient methadone detoxification procedure. Addict Behav 1987; 12:1.
  39. Gold MS, Redmond DE Jr, Kleber HD. Clonidine blocks acute opiate-withdrawal symptoms. Lancet 1978; 2:599.
  40. Jasinski DR, Johnson RE, Kocher TR. Clonidine in morphine withdrawal. Differential effects on signs and symptoms. Arch Gen Psychiatry 1985; 42:1063.
  41. Gowing L, Farrell M, Ali R, White JM. Alpha₂-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev 2016; :CD002024.
  42. Vaughan BR, Kleber HD. Opioid detoxification, chap. 20. In: American Psychiatric Press Textbook of Substance Abuse Treatment, 5th ed, Galanter M, Kleber HD, Brady KT (Eds), American Psychiatric Publishing, Washington DC 2015.
  43. Beuger M, Tommasello A, Schwartz R, Clinton M. Clonidine use and abuse among methadone program applicants and patients. J Subst Abuse Treat 1998; 15:589.
  44. Nestler EJ, Aghajanian GK. Molecular and cellular basis of addiction. Science 1997; 278:58.
  45. Smith RJ, Aston-Jones G. Noradrenergic transmission in the extended amygdala: role in increased drug-seeking and relapse during protracted drug abstinence. Brain Struct Funct 2008; 213:43.
  46. Gold MS, Pottash AC, Sweeney DR, Kleber HD. Opiate withdrawal using clonidine. A safe, effective, and rapid nonopiate treatment. JAMA 1980; 243:343.
  47. Lofexidine (Lucemyra) for opioid withdrawal. Med Lett Drugs Ther 2018; 60:115.
  48. Gowing L, Farrell MF, Ali R, White JM. Alpha2-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev 2014; :CD002024.
  49. Strang J, Bearn J, Gossop M. Lofexidine for opiate detoxification: review of recent randomised and open controlled trials. Am J Addict 1999; 8:337.
  50. Yu E, Miotto K, Akerele E, et al. A Phase 3 placebo-controlled, double-blind, multi-site trial of the alpha-2-adrenergic agonist, lofexidine, for opioid withdrawal. Drug Alcohol Depend 2008; 97:158.
  51. Gorodetzky CW, Walsh SL, Martin PR, et al. A phase III, randomized, multi-center, double blind, placebo controlled study of safety and efficacy of lofexidine for relief of symptoms in individuals undergoing inpatient opioid withdrawal. Drug Alcohol Depend 2017; 176:79.
  52. Rudolf G, Walsh J, Plawman A, et al. A novel non-opioid protocol for medically supervised opioid withdrawal and transition to antagonist treatment. Am J Drug Alcohol Abuse 2018; 44:302.
  53. NICE: National Institute for Health and Clinical Excellence. Drug misuse: opioid detoxification. London: NICE, 2008. (Accessed on November 18, 2015).
  54. Sigmon SC, Bisaga A, Nunes EV, et al. Opioid detoxification and naltrexone induction strategies: recommendations for clinical practice. Am J Drug Alcohol Abuse 2012; 38:187.
  55. Gowing L, Ali R, White JM. Opioid antagonists with minimal sedation for opioid withdrawal. Cochrane Database Syst Rev 2009; :CD002021.
  56. Charney DS, Riordan CE, Kleber HD, et al. Clonidine and naltrexone. A safe, effective, and rapid treatment of abrupt withdrawal from methadone therapy. Arch Gen Psychiatry 1982; 39:1327.
  57. Bisaga A, Mannelli P, Sullivan MA, et al. Antagonists in the medical management of opioid use disorders: Historical and existing treatment strategies. Am J Addict 2018; 27:177.
  58. Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet 2018; 391:309.
  59. 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.
  60. Bisaga A, Mannelli P, Yu M, et al. Outpatient transition to extended-release injectable naltrexone for patients with opioid use disorder: A phase 3 randomized trial. Drug Alcohol Depend 2018; 187:171.
  61. Plunkett A, Kuehn D, Lenart M, Wilkinson I. Opioid maintenance, weaning and detoxification techniques: where we have been, where we are now and what the future holds. Pain Manag 2013; 3:277.
  62. O'Connor PG, Kosten TR. Rapid and ultrarapid opioid detoxification techniques. JAMA 1998; 279:229.
  63. Gowing L, Ali R, White JM. Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal. Cochrane Database Syst Rev 2010; :CD002022.
  64. Collins ED, Kleber HD, Whittington RA, Heitler NE. Anesthesia-assisted vs buprenorphine- or clonidine-assisted heroin detoxification and naltrexone induction: a randomized trial. JAMA 2005; 294:903.
  65. Centers for Disease Control and Prevention (CDC). Deaths and severe adverse events associated with anesthesia-assisted rapid opioid detoxification--New York City, 2012. MMWR Morb Mortal Wkly Rep 2013; 62:777.
  66. Hamilton RJ, Olmedo RE, Shah S, et al. Complications of ultrarapid opioid detoxification with subcutaneous naltrexone pellets. Acad Emerg Med 2002; 9:63.
  67. Liu TT, Shi J, Epstein DH, et al. A meta-analysis of acupuncture combined with opioid receptor agonists for treatment of opiate-withdrawal symptoms. Cell Mol Neurobiol 2009; 29:449.
  68. Carter KO, Olshan-Perlmutter M, Norton HJ, Smith MO. NADA acupuncture prospective trial in patients with substance use disorders and seven common health symptoms. Med Acupunct 2011; 23:131.
  69. Chawla JM, Pal H, Lal R, et al. Comparison of efficacy between buprenorphine and tramadol in the detoxification of opioid (heroin)-dependent subjects. J Opioid Manag 2013; 9:35.
  70. Zarghami M, Masoum B, Shiran MR. Tramadol versus methadone for treatment of opiate withdrawal: a double-blind, randomized, clinical trial. J Addict Dis 2012; 31:112.
  71. Salehi M, Kheirabadi GR, Maracy MR, Ranjkesh M. Importance of gabapentin dose in treatment of opioid withdrawal. J Clin Psychopharmacol 2011; 31:593.
  72. Dunn KE, Tompkins DA, Bigelow GE, Strain EC. Efficacy of Tramadol Extended-Release for Opioid Withdrawal: A Randomized Clinical Trial. JAMA Psychiatry 2017; 74:885.
  73. Sanders NC, Mancino MJ, Gentry WB, et al. Randomized, placebo-controlled pilot trial of gabapentin during an outpatient, buprenorphine-assisted detoxification procedure. Exp Clin Psychopharmacol 2013; 21:294.
  74. Krupitskii EM, Ilyuk BD, Mikhailov AD, et al. A randomized controlled study of the efficacy of pregabalin in the treatment of opiate withdrawal syndrome. Neurosci Behav Physiol 2017; 47:1094.
  75. Amiri S, Malek A, Tofighnia F, et al. Amantadine as Augmentation in Managing Opioid Withdrawal with Clonidine: a randomized controlled trial. Iran J Psychiatry 2014; 9:142.
  76. Lin SK, Pan CH, Chen CH. A double-blind, placebo-controlled trial of dextromethorphan combined with clonidine in the treatment of heroin withdrawal. J Clin Psychopharmacol 2014; 34:508.
  77. Bisaga A, Comer SD, Ward AS, et al. The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans. Psychopharmacology (Berl) 2001; 157:1.
  78. Mannelli P, Peindl K, Wu LT, et al. The combination very low-dose naltrexone-clonidine in the management of opioid withdrawal. Am J Drug Alcohol Abuse 2012; 38:200.
  79. Mannelli P, Gottheil E, Peoples JF, et al. Chronic very low dose naltrexone administration attenuates opioid withdrawal expression. Biol Psychiatry 2004; 56:261.
  80. Doehring A, Hentig Nv, Graff J, et al. Genetic variants altering dopamine D2 receptor expression or function modulate the risk of opiate addiction and the dosage requirements of methadone substitution. Pharmacogenet Genomics 2009; 19:407.
  81. Lin SK, Chen CH, Pan CH. Venlafaxine for acute heroin detoxification: a double-blind, randomized, control trial. J Clin Psychopharmacol 2008; 28:189.
  82. Buydens-Branchey L, Branchey M, Reel-Brander C. Efficacy of buspirone in the treatment of opioid withdrawal. J Clin Psychopharmacol 2005; 25:230.
  83. Bisaga A, Sullivan MA, Glass A, et al. The effects of dronabinol during detoxification and the initiation of treatment with extended release naltrexone. Drug Alcohol Depend 2015; 154:38.
  84. Scavone JL, Sterling RC, Van Bockstaele EJ. Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal. Neuroscience 2013; 248:637.
  85. Warner ML, Kaufman NC, Grundmann O. The pharmacology and toxicology of kratom: from traditional herb to drug of abuse. Int J Legal Med 2016; 130:127.
  86. Singh D, Müller CP, Vicknasingam BK. Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users. Drug Alcohol Depend 2014; 139:132.
  87. Stanciu CN, Gnanasegaram SA, Ahmed S, Penders T. Kratom Withdrawal: A Systematic Review with Case Series. J Psychoactive Drugs 2019; 51:12.
  88. (Accessed on November 21, 2017).
  89. Centers for Disease Control and Prevention. Multistate Outbreak of Salmonella Infections Linked to Kratom. (Accessed on April 09, 2018).
  90. (Accessed on April 05, 2018).
  91. Hedegaard H, Bastian BA, Trinidad JP, et al. Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2011-2016. Natl Vital Stat Rep 2018; 67:1.
  92. Suzuki J, El-Haddad S. A review: Fentanyl and non-pharmaceutical fentanyls. Drug Alcohol Depend 2017; 171:107.
  93. Armenian P, Vo KT, Barr-Walker J, Lynch KL. Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review. Neuropharmacology 2018; 134:121.
  94. Rosenblum A, Cruciani RA, Strain EC, et al. Sublingual buprenorphine/naloxone for chronic pain in at-risk patients: development and pilot test of a clinical protocol. J Opioid Manag 2012; 8:369.
  95. UNODC, World Drug Report 2011. (Accessed on January 28, 2019).
  96. Rahimi-Movaghar A, Gholami J, Amato L, et al. Pharmacological therapies for management of opium withdrawal. Cochrane Database Syst Rev 2018; 6:CD007522.
  97. Hassanian-Moghaddam H, Afzali S, Pooya A. Withdrawal syndrome caused by naltrexone in opioid abusers. Hum Exp Toxicol 2014; 33:561.
  98. Fishbain DA, Goldberg M, Rosomoff RS, Rosomoff H. Atypical withdrawal syndrome (organic delusional syndrome) secondary to oxycodone detoxification. J Clin Psychopharmacol 1988; 8:441.
  99. Spadotto V, Zorzi A, Elmaghawry M, et al. Heart failure due to 'stress cardiomyopathy': a severe manifestation of the opioid withdrawal syndrome. Eur Heart J Acute Cardiovasc Care 2013; 2:84.
  100. Rivera JM, Locketz AJ, Fritz KD, et al. "Broken heart syndrome" after separation (from OxyContin). Mayo Clin Proc 2006; 81:825.
  101. Wheeler E, Jones TS, Gilbert MK, et al. Opioid Overdose Prevention Programs Providing Naloxone to Laypersons - United States, 2014. MMWR Morb Mortal Wkly Rep 2015; 64:631.
  102. Day E, Strang J. Outpatient versus inpatient opioid detoxification: a randomized controlled trial. J Subst Abuse Treat 2011; 40:56.
  103. Hakansson A, Hallén E. Predictors of dropout from inpatient opioid detoxification with buprenorphine: a chart review. J Addict 2014; 2014:965267.
  104. Specka M, Buchholz A, Kuhlmann T, et al. Prediction of the outcome of inpatient opiate detoxification treatment: results from a multicenter study. Eur Addict Res 2011; 17:178.
Topic 7808 Version 42.0