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Synopsis
Terminology
Diagnosis
Treatment
Complications and Prognosis
Screening and Prevention

Mar.20.2023

Opioid Withdrawal

Synopsis

Key Points

Opioid withdrawal is a constellation of physical and psychological symptoms that occurs after abrupt cessation of (or significant dosage reduction of) opioids or after administration of an opioid antagonist
Patients with and without opioid use disorder can experience opioid withdrawal. Evaluate whether the patient has opioid dependence alone (without opioid use disorder) or with opioid use disorder (using DSM-5 criteria)
Treating opioid withdrawal is an opportunity to initiate long-term medications for opioid use disorder (eg, methadone, buprenorphine, naltrexone)
Elicit patient goals and use shared decision-making when counseling patients about medications for opioid use disorder
Treat most patients experiencing opioid withdrawal with opioid agonists (methadone or buprenorphine). Treat patients who wish to start naltrexone (an opioid antagonist) with nonopioid adjunctive medications
Use validated clinical scales (eg, Clinical Opiate Withdrawal Scale) to establish the severity of withdrawal and response to treatment
Any provider licensed to dispense controlled substances can dispense (but not prescribe) methadone and buprenorphine to treat opioid withdrawal and/or opioid use disorder in emergency departments, hospitals, and clinics
Provide harm reduction counseling and services to all patients after treating opioid withdrawal

Pitfalls

Administering nonopioid adjunctive medications alone to treat opioid withdrawal is not the standard of care and is not appropriate treatment of opioid use disorder
Monitor patient withdrawal symptoms closely with a validated scale (such as Clinical Opiate Withdrawal Scale) while titrating methadone or buprenorphine
Explore patient goals and opioid use disorder treatment history when counseling about medications for opioid use disorder
Avoid stigmatizing language and be aware of biases against patients with opioid use disorder (as well as biases against treatments)
If a patient declines long-term medications for opioid use disorder treatment, counsel about the risks of untreated opioid use disorder and provide harm reduction counseling and services

Terminology

Clinical Clarification

Opioid withdrawal is a constellation of symptoms that occurs after abrupt cessation, therapeutic discontinuation, or dosage reduction of opioids (ie, μ-receptor agonists), or after administration of an opioid antagonist (naltrexone or naloxone) or in some cases partial opioid agonist (buprenorphine) to a person who is physically dependent on opioids as a result of persistent, regular use
Acute withdrawal symptoms may develop upon abrupt discontinuation of opioids after as few as 5 days of regular and uninterrupted opioid use ^r1
For short-acting opioids (eg, heroin, fentanyl, morphine immediate-release, oxycodone immediate-release), acute withdrawal symptoms usually begin within 12 hours after the last dose, peak in 24 to 48 hours, and diminish over the next 3 to 5 days ^r2^r3
- Illicitly manufactured fentanyl has contaminated the heroin supply throughout the United States ^r4
- The pharmacokinetics of illicitly manufactured fentanyl have not been formally studied; however, fentanyl is highly lipophilic, and data suggest that regular fentanyl use may lead to protracted clearance and prolonged opioid effects ^r5^r6
For longer-acting opioids (eg, methadone) or opioid formulations (eg, oxycodone extended-release, morphine extended-release), acute symptoms usually occur within 30 to 72 hours after last dose (although anxiety may occur before this) and resolve over the next 10 days ^r2^r3
Among people who are opioid-dependent, antagonist-precipitated withdrawal can begin within 1 minute of an IV-administered dose of naloxone and last 30 to 60 minutes. Buprenorphine-induced withdrawal may occur if typical doses of buprenorphine are taken before the patient experiences mild to moderate opioid withdrawal symptoms. Withdrawal symptoms will occur within 90 minutes of sublingual buprenorphine dosage and may last for several days ^r2
Subacute symptoms of opioid withdrawal (eg, protracted abstinence syndrome, postacute withdrawal syndrome) follow the acute withdrawal period and may persist for weeks

Classification

Spontaneous withdrawal follows abrupt cessation of or dramatic reduction in opioid use
Precipitated withdrawal follows administration of an antagonist (eg, naloxone, naltrexone) or in some cases a partial opioid agonist (eg, buprenorphine) to a patient who is physically dependent; symptoms may be more severe than those experienced during spontaneous withdrawal but are shorter lived
- Symptoms caused by use of an antagonist are likely to be more severe than those induced by a partial opioid agonist

Diagnosis

Clinical Presentation

History

Acute symptoms of opioid withdrawal are highly variable and may include some or all of the following:
- Myalgia and arthralgia ^c1^c2
- Hyperalgesia ^c3
- Gastrointestinal symptoms (eg, stomach cramping, nausea, loose stools) ^c4^c5^c6
- Anxiety ^c7
- Dysphoria ^c8
- Irritability ^c9
- Insomnia ^c10
- Hot or cold flashes ^c11^c12
- Poor concentration ^c13
Subacute symptoms of opioid withdrawal (eg, postacute withdrawal syndrome, protracted abstinence syndrome) include:
- Depression ^c14
- Anhedonia ^c15
- Insomnia ^c16
- Fatigue ^c17
- Anorexia ^c18
- Impaired concentration ^c19
- Sleep disturbances ^c20

Physical examination

Signs of opioid withdrawal include:
- Tachycardia ^c21
- Hypertension ^c22
- Diaphoresis ^c23
- Rhinorrhea ^c24
- Oscitation (ie, yawning) ^c25
- Lacrimation ^c26
- Muscle twitching ^c27
- Restlessness ^c28
- Vomiting ^c29
- Diarrhea ^c30
- Piloerection (ie, gooseflesh) ^c31
- Tremor ^c32
- Mydriasis ^c33

Causes and Risk Factors

Causes

Abrupt cessation of or dramatic reduction in opioid use among people physically dependent on opioids
Administration of an antagonist (eg, naloxone, naltrexone) or in some cases a partial opioid agonist (eg, buprenorphine) to a patient who is physically dependent

Risk factors and/or associations ^r7

Genetics

Some evidence supports a genetic component to severity of withdrawal, particularly involving OPRM1, a gene that encodes the μ-opioid receptor ^r8
- Presence of the allele OPRM1 rs6848893 has been associated with worse withdrawal, especially abstinence-induced withdrawal ^c34
- Presence of the allele OPRM1 rs6473797 has been associated with worse antagonist-induced withdrawal ^c35

Other risk factors/associations

Environmental
- Sudden cessation of opioid use during: hospitalization, incarceration, lack of access to opioids (prescribed or nonprescribed)
Drug-drug interactions
- CYP450 inducers can cause reductions in methadone levels leading to withdrawal symptoms. Commonly prescribed CYP450 inducers include: ^r7
  - Various antimicrobials (eg, rifampin, azole class drugs)
  - Some HIV antiretrovirals (eg, efavirenz)
  - Antidepressants (eg, fluvoxamine)
  - Anticonvulsants (eg, carbamazepine, phenobarbital, phenytoin)
  - Spironolactone
Pregnancy: owing to increased metabolic demands and volume expansion, a patient's usual dose of methadone may be insufficient, leading to opioid withdrawal ^r7^c36
Opioid overdose followed by administration of naloxone (by a layperson, by an emergency medical technician, in an urgent care center, or in the emergency department or hospital)

Diagnostic Procedures

Primary diagnostic tools

Diagnosed through focused history and physical examination findings suggesting physical dependence on opioids, namely, repetitive exposure to opioids and uncomfortable and distressing symptoms upon interruption or reduction of opioid use or upon consumption of an opioid antagonist ^r9^c37
Check the Prescription Drug Monitoring Program in your and surrounding states for controlled substances
Drug screening (eg, urine drug screen) can identify or confirm opioid use; however, screening does not confirm physical dependence or opioid use disorder ^c38
- Use caution when interpreting urine drug screens, as 1 dose could cause a positive test result; patient history, clinician observation of withdrawal signs, or both are required to confirm physical dependence on opioids
- Some commonly used opioids (eg, fentanyl, buprenorphine, methadone, oxycodone, tramadol), may not be detected on typical drug screens and may require specific testing ^r10
Test all patients of childbearing age for pregnancy ^r11^c39
Validated withdrawal scoring systems may be used to help identify and determine the severity of opioid withdrawal: Opiate Withdrawal Scale, Clinical Opioid Withdrawal Scale, Subjective Opiate Withdrawal Scale, and Objective Opiate Withdrawal Scale ^r2
- Monitor opioid withdrawal symptoms frequently (eg, every 2 hours) in patients who are at risk for opioid withdrawal and/or exhibiting opioid withdrawal symptoms

Other diagnostic tools

Clinical Opiate Withdrawal Scale ^r12^c40

Each item is scored for severity, and scores are totaled to reflect overall severity of the withdrawal syndrome:
- Severe: higher than 36
- Moderately severe: 25 to 36
- Moderate: 13 to 24
- Mild: 5 to 12

COWS: Clinical Opiate Withdrawal Scale.
Score	Criteria
Resting pulse rate in beats per minute (after sitting or lying for 1 minute)
0	Pulse rate 80 or below
1	Pulse rate 81-100
2	Pulse rate 101-120
4	Pulse rate greater than 120
Sweating (over previous 30 minutes, not accounted for by room temperature or patient activity)
0	No report of chills or flushing
1	Subjective report of chills or flushing
2	Flushed or observable moistness on face
3	Beads of sweat on brow or face
4	Sweat streaming off face
Restlessness (observation during assessment)
0	Able to sit still
1	Reports difficulty sitting still but is able to do so
3	Frequent shifting or extraneous movements of legs/arms
5	Unable to sit still for more than a few seconds
Pupil size
0	Pin size or normal size for room light
1	Possibly larger than normal for room light
2	Moderately dilated
5	So dilated that only rim of iris is visible
Bone or joint aches (if patients was having pain previously, only the additional component attributed to opiates withdrawal is scored)
0	Not present
1	Mild diffuse discomfort
2	Patient reports severe diffuse aching of joints and muscles
4	Patient is rubbing joints or muscles and is unable to sit still owing to discomfort
Runny nose or tearing (not accounted for by cold symptoms or allergies)
0	Not present
1	Nasal stuffiness or unusually moist eyes
2	Nose running or tearing present
4	Nose constantly running or tears streaming down cheeks
Gastrointestinal upset (over the past 30 minutes)
0	No gastrointestinal symptoms
1	Stomach cramps
2	Nausea or loose stool
3	Vomiting or diarrhea
5	Multiple episodes of diarrhea or vomiting
Tremor (observation of outstretched hands)
0	No tremor
1	Tremor felt by examiner but not observed
2	Slight observable tremor
4	Gross tremor or muscle twitching
Yawning (observation during assessment)
0	No yawning
1	Yawning 1 or 2 times during assessment (approximately 2 minutes)
2	Yawning 3 or more times during assessment
4	Yawning several times per minute
Anxiety or irritability
0	None
1	Reports increasing irritability or anxiousness
2	Obviously irritable or anxious
4	Participation in assessment is difficult due to irritability or anxiety
Gooseflesh skin (piloerection)
0	Skin is smooth
3	Piloerection of skin can be felt or hairs standing up on arms
5	Prominent piloerection

Differential Diagnosis

Most common

Benzodiazepine or alcohol withdrawal ^c41^d1
- Early benzodiazepine or alcohol withdrawal symptoms are similar to opioid withdrawal: agitation, anxiety, increased vital signs, tremors, and gastrointestinal distress
  - As withdrawal develops further, symptoms of untreated or undertreated benzodiazepine or alcohol withdrawal are more severe and may be life-threatening (eg, seizures, cardiovascular instability and collapse, coma) compared with opioid withdrawal
- History of sustained benzodiazepine or alcohol use, urine drug screening that supports benzodiazepine or alcohol use, or both helps to differentiate from opioid withdrawal; additionally, benzodiazepines will suppress benzodiazepine or alcohol withdrawal, whereas opioids will not
  - Do not use a single positive urine drug screen alone to support the diagnosis of benzodiazepine or alcohol (or other drug) withdrawal, because a screen could be positive after single use of a substance
Anxiety disorder ^c42
- Co-occurring opioid use disorder and anxiety are common ^r13
- Features similar to opioid withdrawal are present during a panic attack: physical signs and symptoms of anxiety (eg, sweating, palpitations, dizziness, tachycardia)
- Differentiated from opioid withdrawal by relatively fast resolution of symptoms of panic, reaching a peak within minutes of onset
- In most situations, urine drug screen will not show opioids
Gastroenteritis ^c43^d2
- Has features similar to opioid withdrawal: nausea and vomiting, diarrhea, and abdominal discomfort
- Is differentiated by history of exposure to someone with similar symptoms and difference in clinical course
- Urine drug screen for opioids typically yields a negative result in patients with gastroenteritis
- Stool studies may be diagnostic, particularly if gastroenteritis is due to bacterial infection
Viral illness ^c44
- Symptoms may overlap with those of opioid withdrawal (eg, rhinorrhea, myalgia and arthralgias, gastrointestinal symptoms)
- Distinguishing features include fever and history of sick contacts
- Urine drug screen for opioids typically yields a negative result in patients with influenza
Systemic infection ^c45^d3
- Generalized symptoms and signs are similar to those of opioid withdrawal: anxiety, chills, nausea, vomiting, tachycardia, agitation, and diaphoresis
- Differentiated by findings of end-organ dysfunction (eg, acute renal dysfunction, delirium) and cardiovascular instability (eg, hypotension) with an infection source (eg, pneumonia, urinary tract) in septic patients

Treatment

Goals

Medical stabilization and management of opioid withdrawal
Treat most patients who have opioid use disorder with opioid agonist medications for opioid use disorder (ie, methadone or buprenorphine)
Transition patients with opioid use disorder into long-term medications for opioid use disorder treatment according to patient goals
Provide harm reduction counseling and services to all patients after treating opioid withdrawal

Disposition

Admission criteria

Patients presenting with opioid withdrawal should generally be treated in the setting where they present, depending on their goals
Opioid withdrawal does not necessarily require inpatient or medically supervised management; however, many patients benefit from inpatient or medically supervised residential treatment where methadone or buprenorphine can be quickly initiated and titrated to response; patients can then be linked to long-term medications for opioid use disorder treatment
Inpatient or medically supervised management is also appropriate for patients with medical comorbidities that may require management, and for patients with severe withdrawal symptoms ^r14
In the absence of comparative effectiveness data on withdrawal management in outpatient versus inpatient settings, the factors of patient preference, comorbidities, and social circumstances, along with resource availability, should drive decisions about setting ^r2

Recommendations for specialist referral

Refer to an addiction medicine physician, addiction psychiatrist, or medical toxicologist with addiction experience for evaluation, treatment recommendation, and ongoing management; look for subspecialty board certification in addiction medicine or addiction psychiatry when choosing a referral
- Properly trained clinicians (eg, licensed alcohol/drug counselors, social workers) can assess patient and recommend appropriate level and location of care after withdrawal is completed or after patient has started taking methadone or buprenorphine

Treatment Options

The standard of care for treating opioid withdrawal is initiating medication for opioid use disorder with opioid agonist medications such as buprenorphine. Methadone or buprenorphine can be initiated to treat withdrawal symptoms only (started then tapered) or for ongoing opioid use disorder treatment (started then titrated to treat withdrawal symptoms and cravings)

Long-term medications for opioid use disorder reduces opioid use, risky opioid use (ie, injection), morbidity and mortality, and transmission of infectious diseases (eg, HIV, hepatitis C virus) ^r15^r16^r17^r18^r19
Initiating medications for opioid use disorder in the acute care setting:
- Leads to increased engagement with outpatient medications for opioid use disorder treatment ^r20^r21^r22
- Allows the patient to be comfortable enough to stay in the hospital to receive necessary medical treatment
- Improves overall patient and staff experience ^r23
Managing opioid withdrawal only in the short term and without opioid agonist medications for opioid use disorder is not considered a treatment strategy for the patient with opioid use disorder and is not recommended ^r2

History of present illness, earlier history, and shared decision-making

Take a detailed history of the patient's current opioid use and evaluate for opioid use disorder using DSM-5 criteria (history includes type of opioid and amounts used, frequency and route of administration, treatment history, and problems related to their use)
- Medications for opioid use disorder are approved for patients with moderate-severe opioid use disorder by DSM-5 criteria ^r24
- Iatrogenic physical dependence after prolonged controlled use of opioids in inpatient or outpatient settings can generally be managed by gradual opioid taper
Elicit patient goals regarding opioid use and opioid use disorder treatment (goals for abstinence versus reduction in use, interest in medications for opioid use disorder) and explore prior treatment experiences ^r25
Counsel patients on medication options for treating opioid use disorder. Know which medications for opioid use disorder are available locally
Be aware of stigma and bias
- Preferred language includes: ^r26
  - "person with opioid use disorder" (instead of "addict or abuser")
  - "using opioids or abstaining from opioids" (instead of "dirty or clean")
- Consider your own possible biases. Stigma toward substance use disorders is common among clinicians ^r27
- Stigma toward opioid use disorder and medications for opioid use disorder is common among patients. Explore your patient's attitudes toward medications for opioid use disorder and be prepared to counter myths about opioid use disorder: ^r28^r29^r30
  - "Medications are just replacing one addiction with another"
  - "Methadone eats your bones"
  - "Being on medication isn't really being 'clean'"
- "Meet patients where they're at"
  - Not all patients are ready to stop using opioids or other substances
    - Medication for opioid use disorder is beneficial even when patients don't abstain from all nonprescribed opioids
- Counsel on benefits of medications for opioid use disorder and risks of untreated opioid use disorder, but accept your patient's decision if they decline medications for opioid use disorder

Medications for opioid use disorder: selection and initiation

An overarching approach to withdrawal management with medications for opioid use disorder is presented in the accompanying Figure

Selection considerations and initial dosing for opioid agonist medications for opioid use disorder, methadone and buprenorphine, are laid out in the accompanying Table on opioid agonists. Use shared decision-making with the patient to guide selection

Opioid agonist medications for opioid withdrawal.
Medication	Class	Preferred route	Selection considerations	Dosing
Methadone	Full opioid agonist	Oral	• Outpatient treatment requires daily OTP attendance (opioid treatment program) for first 3 months • Can be dosed 2 or 3 times daily to help with pain management for hospitalized patient and will not block other opioid pain medications • Avoid if history of QTc more than 500 milliseconds or of torsades de pointes	• Initial dose: 20-30 mg (10 mg if low opioid tolerance, risk of sedation) • Add 5-10 mg every 4-6 hours as needed • Recommended maximum day 1 dose: 40 mg • If dispensed for withdrawal management only, avoid exceeding 40 mg, then taper by 5-10 mg every 1-2 days as tolerated by the patient • If continuing treatment, increase by 5-10 mg every 3-5 days. Steady state may take 5 days to reach due to methadone's long half life
Buprenorphine (mono-product, or co-formulated with naloxone, which is not absorbed when taken sublingually)	Partial opioid agonist	Sublingual	• Outpatient treatment typically in office-based setting. Prescriptions are generally for 1 week to 1 month in duration • Not ideal for patients who require full opioid agonists for chronic pain or who will experience severe, acute pain in the acute care setting	• Initial dose: 2-4 mg when patient is experiencing moderate opioid withdrawal • Add 2-4 mg every 1-2 hours as needed • Typical day 1 dose: 8-16 mg • Maximum daily dose: 32 mg • If provided for withdrawal management alone, avoid exceeding 16 mg then taper gradually by 2 mg every 2-3 days as tolerated by the patient • If prescribing, counsel to store safely out of reach of children

Both methadone and buprenorphine are safe and effective treatments for opioid use disorder and opioid withdrawal
Methadone, a full opioid agonist with a long half-life, must be titrated more slowly than buprenorphine to avoid risk for opioid overdose
Buprenorphine is a partial opioid agonist with high affinity for the μ-opioid receptor. Buprenorphine's opioid effect plateaus with increased doses, referred to as the ceiling effect (ie, higher doses having no further effect), with less risk of overdose and lower bioavailability than methadone ^r31
- Buprenorphine can displace full agonist opioids from the opioid receptor, which can lead to precipitated withdrawal. To prevent precipitated withdrawal, patients should be in moderate opioid withdrawal before receiving the first dose of buprenorphine
- Low-dose buprenorphine initiation is an emerging practice that does not require patients to experience moderate withdrawal before receiving the first dose of buprenorphine
  - Small doses of buprenorphine are administered (or prescribed) while patients are still receiving (or using) full opioid agonists ^r25
  - There is currently no strong evidence to support using low-dose buprenorphine initiation over traditional initiation procedures ^r25
- Treat patients who experience precipitated withdrawal during buprenorphine initiation with additional buprenorphine to saturate opioid receptors and minimize severe withdrawal symptoms as quickly as possible. Administer nonopioid adjunctive treatments ^r32
There is growing expert consensus that with the increasing prevalence of highly potent fentanyl in heroin, patients have higher opioid tolerance. Higher tolerance may lead to patients experiencing prolonged withdrawal symptoms when starting methadone or buprenorphine
- While more data are required to establish best practices, patients who regularly use fentanyl may benefit from more rapid titration of methadone and buprenorphine ^r33

Naltrexone: An opioid antagonist administered as a monthly depot injection for moderate to severe opioid use disorder ^r34

Naltrexone does not treat opioid withdrawal
Mechanism of action is by blocking opioid receptors to prevent euphoria with opioid use and by affecting the dopaminergic system to reduce opioid cravings ^r34
Naltrexone does not have as robust an evidence-base as methadone and buprenorphine. Methadone and buprenorphine will be preferable to naltrexone for most patients ^r35^r36^r37^r38
Naltrexone can be initiated 7 to 10 days after last opioid use among patients who are opioid dependent. Initiating before then may cause precipitated withdrawal ^r34
- A low-dose naltrexone or naloxone challenge can be given to ensure no precipitation of withdrawal symptoms, before administration of the intramuscular injection

Manage opioid withdrawal in patients who wish to start naltrexone, to reduce time to starting naltrexone

Use nonopioid adjunctive medications

If patients have severe withdrawal symptoms, consider starting a short-acting opioid agonist taper and initiate naltrexone 7 to 10 days after the taper is complete

Nonopioid medications for opioid withdrawal management.
Symptom(s) targeted	Medication	Class	Preferred route	Dose	Comments
Autonomic hyperactivity	Clonidine	Alpha-2 agonist	Oral	0.1-0.3 mg up to every 4 to 8 hours	• Monitor blood pressure and heart rate after initial dose and before uptitration
Autonomic hyperactivity	Lofexidine*	Alpha-2 agonist	Oral	0.54 mg up to four times daily	• Monitor blood pressure and heart rate after initial dose and before uptitration • Lofexidine is FDA approved for opioid withdrawal management; clonidine is not • Lofexidine is very costly
Diarrhea	Loperamide	Peripheral mu opioid agonist	Oral	4 mg followed by 2 mg as needed for loose stools	• Maximum daily dose is 16 mg • Ensure adequate oral hydration
Insomnia	Trazodone	Sedating antidepressant	Oral	25-100 mg nightly
Insomnia	Doxepin	Sedating antidepressant	Oral	10-50 mg nightly
Muscle aches, joint pain, headache	Ibuprofen	Nonsteroidal antiinflammatory	Oral	400-600 mg up to every 6 hours	• Avoid use in severe kidney disease and decompensated cirrhosis • Use with caution in liver disease
Muscle aches, joint pain, headache	Acetaminophen	Aniline analgesic	Oral	650-1000 mg up to every 6 hours	• Avoid use in severe kidney disease and decompensated cirrhosis • Use with caution in liver disease
Anxiety, restlessness	Diphenhydramine	Antihistamine	Oral	25-50 mg up to every 4 hours	• Can help with nausea • Can be used in pregnancy • Can help with lacrimation and rhinorrhea
Anxiety, restlessness	Hydroxyzine	Antihistamine	Oral	25-100 mg up to every 6 hours	• Can help with nausea • Can be used in pregnancy • Can help with lacrimation and rhinorrhea

Regulations on prescribing and/or dispensing medications for opioid use disorder for opioid withdrawal:

For patients without opioid use disorder, there are no regulations on inpatient methadone or buprenorphine dispensing
For patients with opioid use disorder, methadone or buprenorphine can be prescribed or dispensed in most clinical settings by most providers, according to the following regulations:
- Methadone or buprenorphine
  - For patients in emergency departments, hospitals, or clinics, any provider licensed to dispense controlled substances can dispense (but not prescribe) methadone or buprenorphine for:
    - An unlimited time as an adjunct to the management of conditions other than the opioid dependency (eg, myocardial infarction, surgical management) so that opioid withdrawal does not complicate a primary medical problem. This is most relevant to the acute care setting ^r39
    - A maximum of 72 hours while arranging referral for ongoing treatment, if the patient is only being treated for opioid use disorder and opioid withdrawal (and not a primary medical problem) ^r40
  - If the patient is enrolled in outpatient medication for opioid use disorder treatment, contact the program, refer to the state Prescription Drug Monitoring Program, or both to confirm the patient's dosage
- Methadone
  - Methadone can be provided as long-term opioid use disorder treatment or opioid withdrawal management in federally approved opioid treatment programs. A complete listing of US opioid treatment programs that dispense methadone is available on the website of SAMHSA (Substance Abuse and Mental Health Services Administration)^r41
- Buprenorphine
  - Per SAMHSA, "All practitioners who have a current DEA registration [with Drug Enforcement Administration] that includes Schedule III authority, may now prescribe buprenorphine for Opioid Use Disorder in their practice if permitted by applicable state law, and SAMHSA encourages them to do so"; the former X-waiver requirement was ended by newer legislation ^r9^r42
  - Listing of US buprenorphine providers by state is available on the website of SAMHSA^r43

Nonopioid adjunctive treatments for opioid withdrawal:

Nonopioid adjunctive treatments are useful while initiating methadone or buprenorphine, but they do not replace appropriate and timely initiation and titration of methadone or buprenorphine
α-Adrenergic agents may be used to mitigate autonomic withdrawal symptoms
Adjunctive treatments are also useful in treating precipitated withdrawal

Drug therapy

Full opioid agonist ^r2
- If this medication is provided for outpatient management, patient must ensure that medication is kept in a secure location that children cannot access
- Buprenorphine ^r2^r31^c46
  - Buprenorphine Hydrochloride Sublingual tablet; Adults: 2 to 4 mg SL as needed to achieve clinical effectiveness as rapidly as possible, then titrate dose by 2 to 4 mg to a level that holds the person in treatment and suppresses opioid withdrawal signs and symptoms. Target maintenance dose: 16 mg SL once daily. Usual dose range: 4 to 24 mg/day. Max: 32 mg/day.
  - Outpatient treatment typically in office-based setting with certified provider. Prescriptions are generally for 1 week to 1 month in duration
  - Not ideal for patients who require full opioid agonists for chronic pain or who will experience severe acute pain in the acute care setting
  - Long-acting injectable buprenorphine is an emerging treatment for opioid use disorder. It is not a preferred medication for treating opioid withdrawal at this time ^r44^r45^r46
- Methadone ^r47^c47
  - Short-term detoxification
    - Methadone Hydrochloride Oral tablet; Adults: Up to 40 mg/day in divided doses to achieve an adequate stabilizing level. After 2 to 3 days, decrease dose by 20% every 1 to 2 days in hospitalized persons as tolerated; ambulatory persons may need a slower taper.
  - Routine detoxification
    - Methadone Hydrochloride Oral tablet; Adults: 20 to 30 mg PO once, initially; may administer an additional 5 to 10 mg after 2 to 4 hours if withdrawal symptoms have not been suppressed or if symptoms reappear, up to 40 mg/day on day 1. Use lower initial doses for persons whose tolerance is expected to be low at treatment entry. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at 2 to 4 hours after dosing. Subsequently, titrate dose to a level that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring tolerance to sedative effects. Usual dose range: 80 to 120 mg/day. During medically supervised withdrawal from methadone treatment, decrease dose by 10% every 10 to 14 days.
  - Outpatient treatment requires daily opioid treatment program attendance for first 3 months
    - Dose can be divided into 2 or 3 times daily dosing, to help with pain management for hospitalized patients; this medication will not block other opioid pain medications
    - Avoid if history of QTc more than 500 milliseconds or of torsades de pointes
α₂-Adrenergic agonists ^r2
- Clonidine (off-label) ^c48
  - Clonidine Hydrochloride Oral tablet; Adults: 0.1 to 0.2 mg PO every 4 to 6 hours, initially, as needed or as a standing dose in cases of severe withdrawal. Adjust dose until withdrawal symptoms are reduced. Monitor blood pressure and withhold dose if blood pressure is 90/60 mmHg or lower. Dose range: 0.1 to 0.3 mg PO every 4 to 8 hours. Max: 1.2 mg/day on day 1, then 2 mg/day. To discontinue, taper dose over several days while monitoring for signs of withdrawal.
- Lofexidine ^c49
  - Lofexidine Oral tablet; Adults: 0.54 mg PO 4 times daily for up to 14 days. Lower doses may be appropriate as opioid withdrawal symptoms wane. Max: 0.72 mg/dose and 2.88 mg/day. To discontinue, reduce dose by 0.18 mg/dose every 1 to 2 days over 2 to 4 days.

Nondrug and supportive care

For patients in a closed environment (eg, inpatient or residential care), provide a calm, quiet setting ^r47
- Allow rest or moderate activities as desired ^c50^c51
- Offer opportunities to meditate or perform other calming activities ^c52
- Do not force patients to engage in exercise until withdrawal is complete, because exercise may prolong and worsen withdrawal symptoms
- Patients are often anxious and afraid and may respond well to accurate information regarding drugs and withdrawal ^c53
- Patients may be confused and vulnerable; do not provide counseling or psychotherapy during moderate to severe acute withdrawal
Maintain hydration. Oral intake of sport drinks is usually adequate, and IV hydration is rarely necessary ^r3^c54^c55
Harm reduction
- Counsel patients on overdose prevention:
  - If patients are likely to use opioids, they should use small amounts of opioids and titrate up slowly after periods of abstinence when tolerance is low
  - Avoid using opioids alone
  - Avoid mixing opioids with benzodiazepines, alcohol, and other sedatives
  - Have naloxone available when using opioids
- Provide naloxone (formulated as nasal spray or intramuscular injection)
- Refer to syringe services programs where available (for safer injection supplies and other harm reduction materials and services)
- Prescribe sterile syringes and alcohol swabs, according to state laws

Comorbidities

Significantly prolonged QTc interval (more than 500 milliseconds) or arrhythmia history are relative contraindications to use of methadone ^r48^c56^c57
- Treating with methadone doses of 100 mg or less is not associated with QT prolongation ^r49
- There is insufficient evidence to guide ECG screening among patients receiving methadone treatment
- Risks of arrhythmia must be weighed against the risks of untreated or undertreated OUD, which include ongoing risky opioid use and opioid overdose ^r50
  - Counsel patients on risks and benefits of methadone and use a shared decision-making approach
Severe asthma or chronic hypercapnic respiratory failure may increase the risk of methadone in an unmonitored (eg, outpatient) setting beyond the inpatient unit ^r48^c58^c59

Special populations

Pregnant patients with opioid use disorder who are taking buprenorphine or methadone treatment should continue taking these medications during pregnancy to avoid 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 ^r11^d4
- Buprenorphine (in a sublingual tablet or film with or without naloxone) or methadone are used for treatment of opioid use disorder during pregnancy and while breastfeeding ^r51
- When initiating buprenorphine in pregnant patients, special care must be taken to avoid precipitating withdrawal, which can negatively impact the mother and fetus
- ASAM guidelines (American Society of Addiction Medicine) recommend that hospitalization during initiation of treatment with buprenorphine may be advisable due to the potential for adverse events, especially in the third trimester. The decision of whether to hospitalize a patient for initiation of methadone should consider the experience of the clinician as well as comorbidities and other risk factors for the individual patient ^r2
- Neonates of mothers who use opioids regularly or who are monitored and treated for emergence of neonatal opioid withdrawal syndrome ^r52
  - 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 ^r52
  - Neonates with chronic fetal opioid exposure should be observed to monitor for development of withdrawal; duration of monitoring is at least 72 hours (ie, if exposure to immediate-release opioids) and is 4 to 7 days if exposure to buprenorphine or methadone has occurred ^r52
  - Neonatal withdrawal may require treatment with morphine, methadone, or buprenorphine if it cannot be controlled by nonpharmacologic measures ^r52^r53
  - Breastfeeding is associated with reduced neonatal hospital stay and requirements for pharmacologic treatment ^r54
Opioid withdrawal also may occur in breastfed infants of opioid-using mothers when maternal use of opioids is reduced or abruptly discontinued ^r11
- Opioid-using patients who are breastfeeding but wish to stop are advised to gradually reduce breastfeeding to lessen withdrawal symptoms in their nursing children
Chronic pain
- Patients with chronic pain (called persistent pain by some authorities) are at risk of opioid withdrawal when there is a disruption in their long-term opioid therapy
- Patients with chronic pain receiving long-term opioid therapy may benefit from switching from full agonist opioids to buprenorphine, depending on their goals and preferences and the balance of risks/benefits with their current treatment ^r55^r56^r57
  - FDA-approved buprenorphine formulations for chronic pain include the buccal formulation and transdermal patch
  - Buprenorphine-naloxone can be used for patients with chronic pain and opioid use disorder, or off-label for patients with chronic pain alone who require higher opioid dosage ^r56
- Methadone may be effective for chronic pain among people with opioid use disorder if dosed 2 or 3 times daily ^r58
  - Patients with chronic pain and opioid use disorder must receive methadone treatment in an opioid treatment program
    - Methadone programs can offer twice daily dosing for chronic pain, but this should be established before referring patients
Mental health problems
- Comorbid mental health problems are common with opioid use disorder, including anxiety, depression, and posttraumatic stress disorder; link to mental health treatment as needed ^r13
- Patients with severe, persistent mental illness may benefit from the intensive structure of opioid treatment programs over less-intensive office-based buprenorphine treatment
Adolescents
- Buprenorphine and naltrexone are effective in reducing opioid use among adolescents with opioid use disorder and should be offered to all adolescents in combination with behavioral therapy ^r59^r60^r61
- Federal policies specify that adolescents must have 2 failed attempts at behavioral treatment for opioid use disorder before being eligible for methadone treatment ^r59

Monitoring

Closely monitor patients who potentially may begin experiencing withdrawal (eg, every 4 hours, or 1-2 hours after administering first dose of methadone or buprenorphine); use a validated clinical scale (eg, Clinical Opiate Withdrawal Scale)
If the methadone dose required to suppress withdrawal exceeds 120 mg daily, if the patient has a history of prolonged QT interval or arrhythmias, or if the patient is taking other medications that may prolong the QT interval (as seen with methadone) and increase the risk of arrhythmia, consider using ECG to assess the QT interval ^r41

Complications and Prognosis

Complications

Sustained tachycardia ^r2^c60
Electrolyte imbalance ^r2^c61
Hypovolemia ^r2^c62
Increased risk of overdose if patient resumes opioid use, owing to decreased tolerance ^r2^c63

Prognosis

Severe distress can occur when withdrawal is rapidly precipitated by administering an antagonist ^r62^c64
Opioid withdrawal is highly uncomfortable, but it is not life-threatening for most patients

Screening and Prevention

Screening ^c65

At-risk populations

Patients who abruptly discontinue opioids after as few as 5 days of regular and uninterrupted opioid use
Patients with known opioid use who present to the emergency room or hospital
Patients with interruptions in long-term opioid therapy

Prevention ^c66

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