Treatment Options
Managing opioid withdrawal alone (generally referred to as detoxification) without initiating ongoing maintainence pharmacotherapy is not considered a treatment strategy for the patient with opioid use disorder and is not recommended r4
- Medication-assisted therapy (eg, methadone or buprenorphine maintenance) combined with appropriate psychosocial interventions is recommended for most patients owing to superior patient retention, greater periods of abstinence from risky use of opioids, and marked reduction in morbidity and mortality
- If the decision is made to manage opioid withdrawal without ongoing medication-assisted therapy, advise patients about the risk of relapse and increased risk of overdose and overdose death
Possible situations in which managed opioid withdrawal without ongoing medication-assisted therapy may be appropriate include: r1
- Patient prefers to regain a drug-free state and maintain abstinence from opioid use without medication assistance. These are typically highly motivated patients (often due to threatened work restrictions) with solid psychosocial support (eg, health professionals, airline pilots)
- Withdrawal management (ie, detoxification) is the only treatment available in the area
- Mild opioid dependence (eg, regular use of relatively low amounts of an opioid and/or history of mild withdrawal symptoms)
- Iatrogenic physical dependence following prolonged controlled use of opioids in outpatients (often managed by gradual dose taper)
- Iatrogenic physical dependence in inpatients who had extended hospitalization for a critical illness and who required prolonged use of opioids (eg, sustained sedation for ventilator tolerance in an ICU patient)
- Weaning protocols are usually in place at institutions and generally support a 5% to 10% daily reduction in the opioid to avoid significant withdrawal discomfort
Preferably, patients presenting in opioid withdrawal are evaluated by a clinician skilled in the assessment of opioid use disorders who can recommend an appropriate initial treatment based on diagnosis as supported by DSM-5r14
- Information required includes reported type of opioid and amounts used, frequency and route of administration, treatment history, last use of opioids, and problems related to their use
Withdrawal risk is determined by amount of drug used and patient-reported severity of withdrawal symptoms, which occur in all opioid-dependent patients r5
- Mild risk: 1 to 2 bags of heroin daily or less than 50 mg oxycodone or equivalent daily (less than 75 morphine mg equivalents)
- Moderate risk: 3 to 6 bags of heroin daily or 50 to 100 mg oxycodone or equivalent daily (75-150 morphine mg equivalents)
- Severe risk: more than 6 bags of heroin daily or more than 100 mg oxycodone or equivalent daily (more than 150 morphine mg equivalents)
- Opioid equivalency data are available, such as that provided by the CDC r15
When withdrawal from opioids without ongoing medication-assisted therapy is considered appropriate, medical management (ie, detoxification) rather than abrupt discontinuation is recommended; life-threatening complications are not a usual component of opioid withdrawal, but medical management is strongly recommended because: r16
- Patients may exit therapy against medical advice and return to active opioid use because they are experiencing marked discomfort and strong drug cravings
- There is a potential for complication of medical and surgical conditions
- The clinician-patient relationship is strained significantly when withdrawal discomfort is not adequately managed
- A poor clinician-patient relationship affects patient trust and makes it difficult to engage the patient and provide direction into effective therapy beyond withdrawal management
Inpatients who develop withdrawal and those experiencing withdrawal who require admission are moved to a quiet area with subdued lighting, where they can rest or ambulate as needed; restraints are not used.r1 According to WHO, physical exercise is not recommended while withdrawal symptoms are present as this may prolong withdrawal and worsen symptom severityr9
- Reassure patients that symptoms are taken seriously and efforts are being made to reduce their severity
Scales such as the Clinical Opioid Withdrawal Scale, Objective Opioid Withdrawal Scale, or the Clinical Institute Narcotic Assessment scale are useful to determine presence of withdrawal, severity of withdrawal, and patient response to therapies r2r4
Medications for management of opioid withdrawal
- Methadone r1r4
- Outpatient methadone detoxification, using a gradually tapering dose, is appropriate when patients are otherwise medically fit and stable
- Methadone tapering for acute withdrawal management usually lasts from 6 to 10 days, decreasing methadone dose by 10% to 20% per day
- In the United States, outpatient methadone detoxification must be provided through a licensed opioid treatment program
- Although buprenorphine is, for the most part, clinically equal to methadone, methadone may be the better choice for patients with any or all of the following: r17
- Lack stable lifestyle (eg, homeless)
- Lack ability to pay for buprenorphine
- Require a broader range of services as may be provided through a comprehensive methadone program (ie, opioid treatment program)
- A complete listing of US methadone treatment providers (ie, opioid treatment programs) by state is available r18r19
- Inpatient hospital setting: methadone may be prescribed by any clinician (including physician assistant and nurse practitioner in some states) with full prescriptive authority (including Drug Enforcement Administration Schedule II through V drugs) to maintain or detoxify an opioid-dependent patient as an adjunct to the management of conditions other than the dependency (eg, myocardial infarction, surgical management) so that opioid withdrawal does not complicate a primary medical problem r20
- It is recommended that the admitting physician be in contact with the patient's opioid use disorder treatment provider to obtain history, including confirmation of the patient's daily dose requirement, and to maintain treatment continuity
- Also, the law allows prescribing clinicians to administer (but not prescribe for outpatient use) methadone for the treatment of opioid withdrawal alone for a nonrenewable 72-hour period while arranging the patient's referral for treatment (known as the 72-hour rule). This allows flexibility for clinicians when confronted with a patient in opioid withdrawal r20
- No more than 1 day's dose of methadone may be administered or given to the patient at a time
- Buprenorphine r4
- In the United States (as a result of the Drug Addiction Treatment Act), buprenorphine, a partial μ-opioid agonist with a very high affinity for the μ-receptor, may be used for opioid detoxification in an outpatient (ie, office-based) setting, provided the prescribing clinician has received appropriate training in use of buprenorphine and Drug Enforcement Administration certification to prescribe from an office or clinic setting r21
- Listing of US buprenorphine providers by state is available r22
- Appears to be equal to methadone in efficacy, but its legal status, allowing prescription and dispensing in an outpatient setting (ie, x-waiver), increases its availability. It can also be dispensed or prescribed from opioid (ie, methadone) treatment programs r23
- Eliminates need for daily visits to obtain medication
- Safer than full agonists (eg, methadone) owing to its ceiling effect (ie, increase in dose reaches a plateau, with higher doses having no further effect), with less risk of overdose and lower bioavailability r23
- Combination of a sedative-hypnotic (eg, ethanol, benzodiazepines) or another opioid with buprenorphine appears to mitigate the ceiling effect
- Safe for use in primary care setting r23
- As with methadone, buprenorphine may be ordered in the inpatient hospital setting by any clinician with full prescribing authority (Drug Enforcement Administration certification) in order to maintain or detoxify an opioid-dependent patient as an adjunct to the management of conditions other than the dependency r21
- 72-hour rule also applies, which allows buprenorphine to be administered, when it is not required as an adjunct to the management of other conditions, for a nonrenewable 72-hour period while arranging the patient's referral for treatment; limited to 1 day's dose administered or given to the patient at a time r21
- Does not allow prescribing for take-away dosing without a Drug Enforcement Administration waiver (ie, x-waiver)
- Buprenorphine taper may be as brief as 3 to 5 days (rare) or as long as 30 or more days; optimum taper duration is determined by patient response. Comparative efficacy between short and long tapers has not been determined, but longer tapers may be better tolerated r4
- Do not initiate buprenorphine until the patient is in mild to moderate withdrawal (ie, Clinical Opiate Withdrawal Scale score of 13 or greater) to avoid precipitated withdrawal; some clinicians hold initial dose until patient has a Clinical Opiate Withdrawal Scale score of 25 or higher, particularly a patient with more severe dependencer2r24
- Buprenorphine is usually provided as a combination sublingual film or tablet containing both buprenorphine and the antagonist naloxone; naloxone is not effective orally or sublingually, but it is effective if improperly used intravenously, decreasing the opioid effect and lowering potential for abuse
- α₂-Adrenergic agonists (eg, clonidine, lofexidine) r1
- Owing to the noradrenergic basis of withdrawal symptoms, α₂-adrenergic agonists have been employed off-label for many years to treat opioid withdrawal; lofexidine was approved for this indication in 2018 r4r25
- Safe and effective at mitigating autonomic withdrawal symptoms and may be given in combination with other nonnarcotic medication targeting specific withdrawal symptoms or with opioid agonists r4
- Hypotension often limits their use, particularly clonidine r25
- Lofexidine has better risk-benefit profile compared with clonidine and is preferred in the outpatient setting r4r26r27
- Ultrarapid (anesthesia-assisted) detoxification using high doses of naloxone while patient in anesthetized is no longer recommended
- Life-threatening adverse events may occur, including cardiac arrest and sudden death. Ultrarapid detoxification is no more efficacious in reducing withdrawal severity than more standard methods of withdrawal managementr28r4
- Not recommended by American Society of Addiction Medicine,r4 and in 2013, the CDC published a warning of possible death with this method r29
Drug therapy
- Opioid agonist therapy r4
- Methadone c55
- If provided for outpatient management, patient must ensure that medication is kept in a secure location that children cannot access.
- For treatment of opioid agonist withdrawal during detoxification treatment.
- Short-term therapy: stabilize opioid agonist withdrawal with methadone (low- and slow-dose initiation owing to prolonged half-life of methadone and risk of inadvertent iatrogenic overdose).
- Methadone Hydrochloride Oral solution; Adults, including pregnant women: 20 to 30 mg PO initially unless low opioid tolerance is expected; use a lower initial dose for these patients. May give an additional 5 to 10 mg 2 to 4 hours after initial dose if withdrawal symptoms have not been suppressed or if symptoms reappear. Max total dose on day 1: 40 mg. Base subsequent days dosing on withdrawal control at the time of expected peak methadone activity (2 to 4 hours after dosing). May take up to 5 days to achieve steady-state dose. Prior to achieving steady state, adequate total daily doses may not hold patients for a full 24 hours. Continue stabilizing dose for 2 to 3 days.
- NOTE: Prescribing clinicians may use methadone to manage withdrawal in an inpatient setting when the patient is admitted for a primary medical problem other than addiction; clinicians do not require government registration to administer or order methadone in this setting r20
- Patients need to show withdrawal symptoms but no signs of sedation or intoxication. Deaths caused by the cumulative effects of methadone have occurred in early treatment
- Patients with a QTc interval of 451 to 499 milliseconds should receive more frequent monitoring and discuss the potential risks versus benefits of treatment, whereas patients with a QTc interval of 500 milliseconds or greater should receive intervention to lower cardiac risk either by discontinuing or lowering the methadone dose or by eliminating contributing factors r30
- After acute stabilization, discontinue methadone
- Methadone Hydrochloride Oral tablet; Adults: Dose decrements as tolerated by patient on a daily basis or at 2-day intervals. Dose sufficient to keep withdrawal symptoms tolerable. Many hospitalized patients may tolerate daily dosage reductions of 20%. In ambulatory patients, a slower downward schedule may be required.
- Methadone Hydrochloride Oral tablet; Pregnant women: Medical withdrawal of methadone maintenance is generally not recommended during pregnancy. If required, slow decrements of 2 to 2.5 mg q7 to q10 days. OB needs to monitor the effects on the fetus.
- For medical management (ie, maintenance treatment) of opiate agonist dependence in conjunction with appropriate social and medical services
- Long-term therapy: initiate methadone maintenance therapy in an opioid treatment program
- Methadone Hydrochloride Oral tablet; Adults: Following induction therapy and detoxification, titrate patients to a dose that prevents opioid withdrawal symptoms for a full 24 hours, reduces drug craving, and blocks/attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Usual dose: 80 to 120 mg/day PO. Pregnant women may require dose adjustments during pregnancy to provide effective dosing. MAINTENANCE: In the U.S., administer under the Code of Federal Regulations (CFR), Title 42, Section 8.12. Continue as long as patient compliant and continued benefit derived. DISCONTINUATION: Avoid abrupt discontinuation due to risk for opioid withdrawal symptoms and relapse of addiction. Individualize rate of taper; generally reduce dose by less than 10% of the established maintenance dose, with 10 to 14-day intervals between dose reductions.
- After maintenance treatment, discontinue methadone
- Methadone Hydrochloride Oral tablet; Adults: Dose decrements as tolerated by patient on a daily basis or at 2-day intervals. Dose sufficient to keep withdrawal symptoms tolerable. Many hospitalized patients may tolerate daily dosage reductions of 20%. In ambulatory patients, a slower downward schedule may be required.
- Buprenorphine r4c56
- If prescribed or dispensed for outpatient management, patient must ensure that medication is kept in a secure location that children cannot access
- Buprenorphine induction
- NOTE: Physicians must meet and maintain the requirements of the Drug Addiction Treatment Act to provide medication-assisted treatment to opioid-dependent patients on an outpatient basis
- NOTE: Prescribing clinicians may use buprenorphine to manage withdrawal in an inpatient setting when the patient is admitted for a primary medical problem other than addiction; clinicians do not require a Drug Addiction Treatment Act waiver to administer or order in this setting r20
- Buprenorphine Hydrochloride Sublingual tablet; Adults: Administer first dose when early signs of opioid withdrawal appear and at least 4 hours after the last used short-acting opioid or 24 hours after last used long-acting opioid. Rapidly titrate dose, in 2 mg to 4 mg increments, until clinical effect is achieved. Use as part of a complete treatment program. Initiate treatment with supervised administration. Single-agent buprenorphine is preferred over buprenorphine; naloxone for induction.
- Subsequent gradual buprenorphine dose reduction r24
- Reducing buprenorphine to eventually discontinue it can occur over a short (ie, 3-7 days), moderate (ie, 10-14 days or longer, with 2 mg [or 10%-20%] sublingual dose reduction every 2-3 days), or longer period
- Reducing buprenorphine over longer periods is believed to be more effective in reducing recurrent use than discontinuing it over shorter periods r24
- α₂-Adrenergic agonists r4
- Clonidine (off-label) c57
- Clonidine Hydrochloride Oral tablet; Adults: The usual initial dose is 0.1 mg to 0.2 mg PO, with titration to a maximum total dose of 1 mg/day PO, administered in two to four divided doses, according to response and tolerability (e.g., blood pressure). Maximal doses are generally administered for two to four days after cessation of the opiate during the time of maximal withdrawal. Clonidine doses are then tapered, and the drug is discontinued 7 to 10 days after cessation of the opiate. American Psychiatric Association (APA) guidelines state that an initial dose of clonidine 0.1 mg PO three times (total 0.3 mg per 24 hours) is usually sufficient to suppress signs of opiate withdrawal. Use of higher doses may be acceptable during inpatient detoxification - monitor for hypotension and sedation. Adjust subsequent dosing until withdrawal symptoms are reduced. Hold the dose if blood pressure falls below 90/60 mmHg, and resume when BP returns to normal. Elderly patients may be more sensitive to the effects (sedation and hypotension) of the usual dosage and may require lower dosages. Clonidine may be a useful alternative to buprenorphine for targeting noradrenergic-mediated withdrawal symptoms such as nausea, vomiting, diarrhea, cramps, and sweating.
- Lofexidine c58
- Lofexidine Oral tablet; Adults: Initially, 0.54 mg (3 x 0.18 mg tablets) PO 4 times daily (given every 5 to 6 hours) is usual dose during peak withdrawal symptoms (e.g., first 5 to 7 days following the last opioid use) ; base dose upon opiate withdrawal symptoms. May use for up to 14 days. Max: 2.88 mg/day (16 tablets/day). Do not exceed 0.72 mg/dose (4 tablets/dose) PO. GERIATRIC PATIENTS: No studies have been performed to determine safety and effectiveness; consider dosage adjustments similar to those recommended in patients with renal dysfunction. DISCONTINUATION: Gradually taper the dose over 2 to 4 days to reduce drug withdrawal symptoms (e.g., reduce by 1 tablet/dose every 1 to 2 days).
Nondrug and supportive care
For patients in a closed environment (eg, inpatient or residential care), provide a calm, quiet setting r9
- Allow rest or moderate activities as desired c60c61
- Offer opportunities to meditate or perform other calming activities c62
- Do not force patients to engage in exercise until withdrawal is complete as exercise may prolong and worsen withdrawal symptoms
- Patients are often anxious and afraid and may respond well to accurate information regarding drugs and withdrawal c63
- Patients may be confused and vulnerable; do not provide counseling or psychotherapy during moderate to severe acute withdrawal
Management advice for difficult behavior r9
- Anxious, agitated, or panicked
- Approach in a confident and calm manner
- Limit number of people attending to patient
- Explain any interventions carefully
- Confusion or disorientation
- Maintain close supervision
- Provide reality orientation by explaining to patient where he or she is and what is happening
- Angry or aggressive
- Ensure that staff is protected and safe
- Maintain calm, reassuring attitude when interacting with patient
- Listen carefully
- Use patient's name and keep interactions personal
- Use calm, open-ended questions
- Maintain a consistent and even voice tone, even if patient is shouting and hostile
- Acknowledge patient's feelings
- Do not challenge patient
- If possible, remove any source of anger
Maintain hydration. Oral intake of sport drinks is usually adequate, and IV hydration is rarely necessary r5c64c65
- Patients are advised to drink 2 to 3 L of fluid daily; hydration is sometimes provided by electrolyte replacement solutions
Acupuncture has been shown to reduce withdrawal symptoms but has little effect on drug cravings r31c66
Providers who administer antagonists must be prepared for possible violent behavior created by precipitated withdrawal
- In controlled settings, titrating to effect using smaller initial doses may reverse respiratory depression while preventing precipitation of full withdrawal
Comorbidities
- Prolonged QT interval or arrhythmia history may preempt use of methadone because it tends to increase QT prolongation r32c67c68
- Treating with methadone doses of 100 mg or less is not associated with QT prolongation r33
- Prolonging the QT interval to more than 500 milliseconds confers risk of arrhythmia r30
- In the United States, the following has been recommended by an expert Substance Abuse and Mental Health Services Administration panel: r30
- Obtain a baseline ECG at time of admission and again within 30 days of the first test for the following patients, with annual monitoring ECG:
- Patients with significant risk factors for QT prolongation, including symptoms suggestive of arrhythmia (eg, episodes of syncope, dizzy spells, palpitations, seizure), history of cardiac arrhythmia, or prolonged baseline QT interval
- Patients receiving other medication that may prolong QT interval
- Patients with family history of premature death
- Patients who have history suggestive of a possible cardiac arrhythmia
- Obtain an ECG when methadone dose exceeds 120 mg/day and for any patient who experiences unexplained syncope or generalized seizures
- Severe asthma or chronic hypercapnic respiratory failure also may preempt the choice of methadone in an unmonitored (eg, outpatient) setting beyond the inpatient unit r32c69c70
Special populations
- Opioid-dependent pregnant patients typically are not withdrawn from opioid drugs owing to the physiologic stress that withdrawal has on the developing fetus and the additional risk of maternal relapse, which threatens the well-being of both mother and fetus r8d4
- Both buprenorphine (in a single component sublingual tablet or film without naloxone) and methadone are used for treatment of opioid use disorder during pregnancy and while breastfeeding; the relative infant dose of buprenorphiner34 and methadoner35 is less than 1% of the maternal dose, adjusted for weight; therefore, maternal treatment alone is not sufficient to suppress neonatal withdrawal syndrome r23
- Newborns of mothers who use opioids regularly or who are maintained on opioids (eg, methadone maintenance) are monitored and treated for emergence of neonatal opioid withdrawal syndrome r36
- Opioid withdrawal may begin as early as 24 to 72 hours after delivery and subacute symptoms and signs of opioid withdrawal may last up to 6 months r36
- Infants with chronic opioid exposure should be observed for at least 72 hours to monitor for the development of withdrawal if exposed to immediate-release opioids and for 4 to 7 days if exposed to buprenorphine or methadone r36
- May require treatment with morphine, methadone, or buprenorphine if cannot be controlled by nonpharmacologic measures r36r37
- Use caution to avoid precipitated withdrawal when initiating buprenorphine in pregnant patients; that is, confirm mild to moderate withdrawal before initiating buprenorphine
- Opioid withdrawal also may occur in breastfed infants of opioid-using mothers when maternal use of opioids is reduced or abruptly discontinued r8
- Opioid-dependent patients who are breastfeeding but wish to stop are advised to gradually reduce breastfeeding to lessen withdrawal symptoms in their nursing children