Opioid withdrawal

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Opioid withdrawal syndrome (OWS) refers to the constellation of symptoms that can develop after a sudden cessation or reduction of opioid use following a period of prolonged chronic use. This condition is characterized by sympathetic hyperactivity, flu-like symptoms, and gastrointestinal symptoms. OWS is a clinical diagnosis that can be supported using the DSM-V criteria; the severity of the condition can be scored using validated tools such as the Clinical Opioid Withdrawal Scale (COWS). Opioid replacement therapy with a long-acting opioid agonist (methadone or buprenorphine) and psychosocial support are the cornerstones of treatment. Management of withdrawal symptoms may help to bridge patients to outpatient medication-assisted treatment programs and provide an opportunity to reinforce harm reduction strategies for overdose and relapse prevention. To prevent the development of withdrawal symptoms upon the discontinution of chronic opioid therapy, tapering chronic opioid therapy is essential.

Withdrawal occurs in patients who have physiologic opioid dependence when stimulation of opioid receptors is diminished or blocked.

• Mechanism of opioid withdrawal: decreased stimulation of opioid receptors → ↓ of inhibition of cAMP in locus coeruleus → increased norepinephrine release → dysphoria, CNS hyperactivity ^[2]
• Precipitated withdrawal: exposure to an opioid antagonist (e.g., naloxone) or partial agonist (e.g., buprenorphine) → displacement of opioid agonists from receptors → abrupt onset of severe OWS

Symptoms are caused by sudden cessation or reduction of opioid intake after prolonged chronic use. The onset, peak, and duration of OWS varies primarily based on the half-life of the opioids used (e.g., heroin , methadone ). ^[2][3]

• CNS arousal and sympathetic hyperactivity
  • Tachycardia, hypertension
  • Anxiety, insomnia, irritability, agitation ^[4][5]
  • Mydriasis, yawning, lacrimation, sneezing
  • Hyperreflexia, muscle cramps
• Flu-like symptoms
  • Rhinorrhea, diaphoresis, piloerection, ; thermoregulation disturbances (e.g., chills)
  • Myalgia, arthralgia
• Gastrointestinal symptoms
  • Nausea, vomiting, diarrhea
  • Abdominal pain

Use of short-acting opioids is associated with a higher risk of severe OWS compared to use of long-acting opioids. ^[4]

OWS can be severely uncomfortable, but it is generally not fatal unless the affected individual experiences severe dehydration and electrolyte disturbances that are left untreated. ^[6]

Approach ^[7]

• Clinical diagnosis
  • Review current and past substance use history.
  • Apply DSM-5 diagnostic criteria for opioid withdrawal.
  • Assess severity of withdrawal, e.g., using the COWS.
• Assessment of major comorbidities
  • Consider other substance use disorders (e.g., alcohol use disorder).
  • Screen for major depressive disorder and suicidal ideation.
• Diagnostic studies: Perform to evaluate for complications and differential diagnoses.

A comprehensive clinical history is important, but completion of assessments should not delay or preclude initiating pharmacological treatment for opioid withdrawal. ^[7]

Diagnostic studies ^[7]

Opioid use and withdrawal are not usually associated with abnormal laboratory studies.

• Initial laboratory studies
  • Routine studies: CBC, CMP
  • Viral panels: HIV, viral hepatitis panel
  • β-hCG ^[7]
• Additional investigations (consider based on suspected comorbidities)
  • Toxicology screening (e.g., blood alcohol concentrations, urine drug screen) ^[7]
  • STI screening
  • Diagnosis of latent TB

In many US states, individuals can be penalized for obtaining addiction treatment during pregnancy because substance use during pregnancy is classified as child abuse. Pregnant patients should give informed consent regarding potential legal consequences before receiving drug testing. ^[7][8]

Diagnostic criteria

Withdrawal severity assessment ^[10]

The Clinical Opioid Withdrawal Scale (COWS) is a validated tool that can be used to assess and classify the severity of opioid withdrawal. ^[11]

The COWS is not designed to diagnose opioid withdrawal as most of the signs and symptoms are nonspecific. ^[7]

Approach ^[5][7]

• Offer pharmacological therapy
  • Acute opioid withdrawal: methadone/buprenorphine alone or in combination with symptom-based therapy
  • Maintenance therapy (for OUD): methadone, buprenorphine, or naltrexone (see “Management of opioid use disorder” for details)
• Start general supportive measures
  • Psychosocial support (e.g., shared decision making)
  • Hydration (e.g., IV fluids), electrolyte replacement, nutritional support
  • Harm reduction strategies (e.g., naloxone for opioid overdose reversal)
• Choose an appropriate withdrawal management (WM) setting (i.e., hospital WM, intensive outpatient WM, outpatient WM)
  • Choice depends on patient characteristics.
  • Forced withdrawal is unethical in any setting.
• Consider special patient groups: Involve specialists for pregnant individuals, incarcerated individuals, and those with comorbid chronic pain.

Hospital admission is indicated for patients with severe opioid withdrawal who are unstable or have significant comorbidities (e.g., sepsis, polysubstance intoxication).

Psychosocial support ^[7][12]

• Apply a trauma-informed approach.
• Engage patients with motivational interviewing and shared decision making.
• Inquire about the following:
  • Prior experiences with opioid withdrawal
  • Concerns about uncontrolled withdrawal and pain symptoms ^[5]

The experience of withdrawal is strongly influenced by psychological distress, e.g., anxiety and concerns about withdrawal symptoms being unaddressed. ^[13]

A patient who declines to engage in shared decision making should not be excluded from prompt initiation of appropriate medication management. ^[7]

Approach ^[7]

• Acute management of OWS
  • Initiation of a long-acting opioid agonist is recommended over abrupt cessation of opioid use.
  • Patients already on maintenance therapy for OUD may restart their previous opioid agonist regimen after the dose is verified.
  • A plan for the patient to engage in outpatient WM is not a prerequisite to initiating hospital WM.
• Maintenance therapy for OUD
  • Encourage continuing medication-assisted therapy (e.g., methadone or buprenorphine).
  • Consider a taper from opioid agonists after one year of therapy.
  • For patients interested in complete opioid abstinence, naltrexone may be used.
  • See “Management of opioid use disorder” for details.

Medication-assisted therapy (e.g., with methadone or buprenorphine) is the cornerstone of treatment for OUD.

During an episode of OWS, it is generally safe to resume outpatient methadone or buprenorphine dosing as long as active enrollment and accurate current outpatient dosing have been confirmed. ^[11]

Methadone induction ^[7]

• Indication: subjective features of OWS
• Contraindications: QTc ≥ 500 ms; sedation (e.g., due to substance use, prescribed medications, severe illness) ^[14]
• First-day dosages
  • Start an initial methadone dose under medical supervision. ^[14]
  • Use lower initial methadone dosages for patients in whom low tolerance is expected. ^[7]
  • If cravings and symptoms persist: Give additional lower dosages after 2–4 hours as needed.
• Subsequent dosages
  • On day 2: Use the total dose given on day 1 as a single morning dose.
  • For patients withdrawing from short-acting opioids: Continue a stabilizing dose for 2–3 days , then consider a taper in 6 to 10 days. ^[7]
  • For all other patients: Titrate dose by no more than 10 mg every ∼5 days until a regular maintenance dose is reached. ^[7]

Methadone can only be prescribed in supervised settings. Unsupervised use of methadone may lead to diversion and is associated with an increased risk of overdose.

Buprenorphine induction ^[2][7]

• Indication: objective features of OWS
• First-day dosages
  • Start an initial dosage under medical supervision.
  • If cravings and symptoms persist: Give additional dosages every 1–2 hours as needed. ^[15]
• Subsequent dosages ^[2]
  • On day 2: Use the total dose given on day 1, administered in 2–3 divided doses (max. dose: 16 mg/24 hours).
  • Titrate dose by 2–4 mg every day until a regular maintenance dose is reached. ^[2][7]

To avoid precipitated withdrawal symptoms, buprenorphine should not be initiated until mild or moderate objective signs of withdrawal are observed. ^[2]

• Indications
  • Symptomatic therapy for patients who decline MOUDs
  • Adjunctive therapy to MOUDs (to reduce residual OWS)
• Monitoring ^[7]
  • Observe for respiratory depression and sedation.
  • Consider drug interactions with MOUDs.

Coadministration of opioids with benzodiazepines (or other sedative hypnotics) increases the risk of respiratory depression. However, the harm caused by untreated opioid withdrawal can outweigh this risk and warrants case-by-case risk-benefit analysis. ^[7]

• Opioid overdose prevention
  • Safe use strategies: e.g., using opioids in the company of others, safe opioid storage
  • Naloxone prescription for opioid overdose reversal
• Safe injection practices: e.g., hand hygiene, use of sterile water, cleaning the injection site with alcohol ^[11]
• Counseling on safe sex practices: e.g., use of condoms, STI screening including HIV testing
• Harm reduction resources ^[12]
  • Needle exchange program, e.g., to prevent blood-borne infectious diseases and bacteremia
  • Safe injection sites

Prescribe naloxone to all patients with OUD at discharge (or outpatient followup) and train patients and family members in the use of naloxone for treating opioid overdose. ^[7]

• To prevent withdrawal symptoms when discontinuing chronic opioid therapy, see “Tapering chronic opioid therapy.”

Neonatal abstinence syndrome ^[21][22][23]

Neonatal abstinence syndrome is caused by maternal drug use during pregnancy (typically opioids) that subsequently leads to a withdrawal reaction in the infant.

Clinical features

• Flu-like symptoms: fever and sweating
• Gastrointestinal symptoms
  • Poor feeding
  • Vomiting, diarrhea
  • Failure to thrive
• Respiratory symptoms
  • Tachypnea, apnea
  • Sneezing, nasal congestion
• Sympathetic hyperactivity: hypertension, tachycardia
• CNS stimulation
  • High pitched crying, irritability
  • Muscle tone and movement disorders (e.g., hyperreflexia, tremor, jerking)
  • Seizures
  • Uncoordinated sucking reflexes
  • Disturbance of sleep-wake rhythm

Treatment ^[23][24]

• Supportive: the preferred method of management because pharmacological treatment is associated with side effects, longer hospitalization, and increased risk of infection
  • Swaddling
  • Fluid resuscitation
  • Reduced sensory stimulation (e.g., quiet room, no sudden movements)
• Pharmacological
  • First-line
    • Buprenorphine
    • Methadone
    • Morphine
  • Second-line
    • Phenobarbital
    • Clonidine

• One-Minute Telegram 84-2023-2/3: Buprenorphine in the fentanyl era
• One-Minute Telegram 76-2023-1/3: Missed opportunities in the treatment of OUD
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