Summary

Opioid withdrawal syndrome is a clinically diagnosed condition resulting from the cessation or reduction of opioids in a physically dependent individual. It is characterized by severe autonomic hyperactivity (tachycardia, hypertension, mydriasis, diaphoresis), gastrointestinal distress (nausea, vomiting, diarrhea), and central nervous system arousal (anxiety, restlessness, myalgias). While intensely uncomfortable, it is typically not life-threatening in adults. The Clinical Opiate Withdrawal Scale (COWS) is the standard tool to objectively assess severity and guide management. The cornerstone of treatment is not simply detoxification, but the initiation of long-term Medications for Opioid Use Disorder (MOUD), which significantly reduces all-cause mortality. First-line agents for inpatient withdrawal management are the opioid agonists buprenorphine or methadone. Buprenorphine, a partial µ-agonist, has a ceiling effect on respiratory depression but carries a risk of precipitating withdrawal if initiated too early. Methadone, a full µ-agonist, has no risk of precipitated withdrawal but requires careful titration and EKG monitoring due to risks of overdose and QTc prolongation. Adjunctive medications are used for symptomatic control. All patients with Opioid Use Disorder (OUD) should be offered harm reduction resources and a naloxone kit upon discharge.

Etiology

The etiology of opioid use disorder (OUD) is multifactorial, stemming from an interplay of genetic predisposition, psychosocial factors, and environmental exposure. The modern opioid crisis in the United States evolved in waves, beginning with the over-prescribing of prescription opioids in the 1990s. As regulations tightened, many individuals transitioned to more accessible and less expensive illicit opioids, primarily heroin. Since approximately 2013, the crisis has been dominated by the proliferation of potent, illicitly manufactured synthetic opioids, most notably fentanyl and its analogs, which now contaminate the majority of the illicit drug supply.

Major risk factors for developing OUD include:

• Personal or family history of substance use disorders.
• History of preadolescent sexual abuse or other significant trauma.
• Co-occurring psychiatric disorders, such as major depressive disorder, anxiety disorders, and PTSD.
• Younger age at first opioid exposure.
• Social determinants of health, including poverty, housing instability, and incarceration.

Pathophysiology

Opioids exert their effects by binding to opioid receptors (µ, κ, δ), which are G-protein coupled receptors found throughout the central and peripheral nervous system. The euphoric and analgesic effects are mediated primarily through µ-receptor agonism in the brain's reward pathways.

Chronic opioid exposure leads to neuroadaptive changes:

1. Tolerance: Receptors become desensitized, and their numbers are down-regulated. This requires escalating doses to achieve the same effect.
2. Dependence: The intracellular signaling cascade adapts. Opioid receptors inhibit adenylyl cyclase, reducing intracellular cyclic AMP (cAMP). With chronic use, the cell compensates by up-regulating the cAMP pathway to maintain homeostasis.

Opioid withdrawal occurs when opioid stimulation is abruptly removed. The now-upregulated cAMP system becomes unopposed, leading to a massive surge of neurotransmitter release, particularly norepinephrine from the locus coeruleus in the brainstem. This noradrenergic hyperactivity is responsible for the classic signs and symptoms of withdrawal: anxiety, restlessness, tachycardia, hypertension, sweating, and piloerection.

Precipitated withdrawal is a key concept for board exams and clinical practice. It occurs when an opioid antagonist (e.g., naloxone) or partial agonist with high receptor affinity (e.g., buprenorphine) is administered to a physically dependent person. Buprenorphine binds tightly to the µ-receptor, displacing full agonists (like heroin or fentanyl) but providing less intrinsic receptor stimulation. This causes a rapid and severe drop in net opioid agonism, triggering an abrupt and often more intense withdrawal syndrome than spontaneous withdrawal.

Signs and Symptoms

The onset and duration of withdrawal vary by the half-life of the opioid used.

• Short-acting opioids (e.g., heroin, fentanyl): Symptoms begin in 6-12 hours, peak at 24-72 hours, and resolve in 5-10 days.
• Long-acting opioids (e.g., methadone): Symptoms begin in 24-72 hours, peak at 4-6 days, and can last for 14-21 days or longer.

Patient-Reported Symptoms:

• Intense craving for opioids
• Anxiety, irritability, restlessness, insomnia
• Myalgias and arthralgias ("bone pain")
• Abdominal cramping, nausea, vomiting, diarrhea
• Chills and hot flashes
• Yawning

Observed Physical Exam Signs:

• Autonomic Hyperactivity: Tachycardia, hypertension, diaphoresis, tachypnea
• CNS Arousal: Restlessness, psychomotor agitation
• Other Objective Signs: Mydriasis (dilated pupils), piloerection ("gooseflesh"), rhinorrhea, lacrimation, tremor

Diagnostic Workup

The diagnosis of opioid withdrawal is clinical, based on a characteristic constellation of signs and symptoms in the context of a suggestive patient history.

1. History: Elicit a non-judgmental substance use history, including the specific opioid(s) used, amount, frequency, route of administration, and time of last use. Assess for DSM-5 criteria for OUD.
2. Objective Assessment: Use a validated scale to quantify withdrawal severity. The Clinical Opiate Withdrawal Scale (COWS) is the most common tool used in the inpatient and emergency setting. It guides the timing and dosing of medications.
   • COWS 5-12: Mild withdrawal
   • COWS 13-24: Moderate withdrawal
   • COWS 25-36: Moderately severe withdrawal
   • COWS >36: Severe withdrawal
3. Laboratory Studies: While not required for diagnosis, labs can identify complications and comorbidities.
   • Urine Drug Screen (UDS): Can confirm recent use but has limitations. It does not diagnose dependence or OUD. Standard immunoassays may not detect synthetic opioids like fentanyl or methadone unless specifically ordered.
   • Basic Metabolic Panel (BMP): Assess for electrolyte disturbances from vomiting or diarrhea.
   • Infectious Disease Screening: Offer screening for HIV, Hepatitis C, and Hepatitis B in all patients with a history of injection drug use.
   • Pregnancy Test: Essential for all patients of childbearing potential, as management strategies differ.

Treatment

The primary goal of inpatient management is to safely and comfortably treat withdrawal while initiating long-term MOUD. Detoxification alone is not the standard of care and is associated with a significantly increased risk of post-discharge overdose and death.

Initiating Buprenorphine

Buprenorphine is a partial µ-opioid receptor agonist with high receptor affinity. It binds strongly to opioid receptors, displacing full agonists like heroin or methadone, which can lead to precipitated withdrawal if administered too early. To avoid this, initiation requires objective signs of withdrawal, such as a Clinical Opiate Withdrawal Scale (COWS) score greater than 8–12.

An important safety feature of buprenorphine is its ceiling effect on respiratory depression, which reduces the risk of overdose compared to methadone. Additionally, the federal X-waiver is no longer required for prescribing buprenorphine, simplifying access in both inpatient and outpatient settings.

Inpatient Initiation Protocol for Buprenorphine:

• Day 1:
  • Start with 2–4 mg sublingual (SL).
  • Reassess in 1–2 hours.
  • If the patient remains in withdrawal (COWS still elevated), repeat the dose.
  • Titrate up to a total of 8–16 mg on Day 1.
• Maintenance:
  • Typical ongoing dose is 16–24 mg SL once daily.

Initiating Methadone

Methadone is a long-acting full µ-opioid receptor agonist. Unlike buprenorphine, it does not cause precipitated withdrawal, which makes it a useful option in patients currently using full agonists. However, methadone carries a higher risk of overdose and respiratory depression, especially in combination with sedatives such as benzodiazepines. It is also known to prolong the QTc interval, so a baseline EKG is recommended prior to initiation.

Methadone has a long and variable half-life, which can lead to drug accumulation and delayed toxicity—a phenomenon known as “stacking.” This necessitates slow and cautious titration, particularly in outpatient settings.

Inpatient Initiation Protocol for Methadone:

• Day 1:
  • Begin with 20–30 mg PO once.
  • Do not exceed 40 mg total on the first day.
  • If breakthrough withdrawal occurs, an additional 5–10 mg may be given 2–4 hours after the initial dose.
• Titration:
  • Increase slowly by no more than 10 mg every 5–7 days when transitioning to outpatient management.

Special Consideration: Fentanyl Withdrawal

• Due to fentanyl's high lipophilicity and potency, patients often have very high tolerance and a prolonged, severe withdrawal course. They may require longer waiting periods before starting buprenorphine to avoid precipitation.
• Low-dose or "microdosing" induction (Bernese Method) is an emerging strategy where very small doses of buprenorphine are initiated while the patient continues using a full agonist, with the buprenorphine dose slowly uptitrated over several days.

Adjunctive Medications for Symptom Control

• Autonomic Symptoms (Anxiety, Restlessness): Clonidine 0.1-0.2 mg PO every 6-8 hours (hold for hypotension SBP <90).
• Nausea/Vomiting: Ondansetron 4-8 mg PO/IV every 8 hours as needed.
• Diarrhea: Loperamide 4 mg PO initially, then 2 mg after each loose stool (max 16 mg/day).
• Myalgias/Arthralgias: Ibuprofen 600 mg PO every 6 hours or Acetaminophen 650-1000 mg PO every 6 hours.
• Insomnia: Trazodone 50-100 mg PO at bedtime or Hydroxyzine 25-50 mg PO at bedtime.

Discharge Planning is Critical

• Provide a warm handoff to an outpatient MOUD provider.
• Prescribe a "bridge" script of buprenorphine to cover the patient until their first outpatient appointment.
• Prescribe naloxone (intranasal or intramuscular) to ALL patients with OUD and provide education on its use to the patient and family.

Pearls

Epidemiology and General Information

• Over 80,000 people died from opioid-related overdoses in the U.S. in 2022, with illicitly manufactured fentanyl being the primary driver.
• Initiation of MOUD is associated with a >50% reduction in all-cause mortality and opioid-related overdose mortality.
• Using person-first language (e.g., "person with opioid use disorder" instead of "addict") is the standard of care and has been shown to reduce stigma and improve provider attitudes toward treatment.

Pathophysiology

• Opioid withdrawal symptoms are primarily driven by noradrenergic hyperactivity in the locus coeruleus. This is a classic board exam question.
• Buprenorphine has a "ceiling effect" on respiratory depression, meaning that beyond a certain dose, it does not produce additional respiratory suppression, making it safer than full agonists like methadone.
• Precipitated withdrawal is caused by the rapid displacement of a full opioid agonist from the µ-receptor by a partial agonist with higher affinity, like buprenorphine.

Etiology and Risk Factors

• Many patients with OUD have significant histories of trauma and co-occurring psychiatric disorders; addressing these is key to long-term recovery.
• The non-medical use of prescription opioids is a major risk factor for future heroin and fentanyl use.
• The modern illicit opioid supply is highly unpredictable and often contaminated with fentanyl, fentanyl analogs, and xylazine ("tranq"), increasing overdose risk.

Clinical Presentation and Diagnosis

• A COWS score ≥ 8 is a commonly used threshold to begin buprenorphine induction in the hospital setting.
• Mydriasis (dilated pupils) is a classic objective sign of opioid withdrawal, whereas miosis (constricted pupils) is a sign of opioid intoxication.
• The DSM-5 criteria for OUD require a pattern of use leading to distress/impairment. Physical dependence (tolerance and withdrawal) alone in the setting of prescribed pain management does not equal OUD.

Treatment

• As of the Mainstreaming Addiction Treatment (MAT) Act of 2022, the federal "X-waiver" is no longer required for clinicians to prescribe buprenorphine. Any prescriber with a standard DEA license can do so.
• While buprenorphine is dosed once daily for OUD maintenance, splitting the total daily dose (e.g., 8 mg TID instead of 24 mg daily) can provide better analgesia for patients with acute pain.
• For patients on maintenance MOUD (buprenorphine or methadone) with acute pain, the standard of care is to continue their home dose and add short-acting full agonist opioids on top for pain control.

Complications

• The period immediately following discharge after detoxification without initiation of MOUD is one of the highest-risk times for fatal overdose, due to loss of tolerance.
• Injection drug use is a major risk factor for serious infectious complications, including endocarditis (especially right-sided/tricuspid valve), septic arthritis, osteomyelitis, spinal epidural abscess, HIV, and Hepatitis C.
• Xylazine, an alpha-2 adrenergic agonist, is an increasingly common adulterant that can cause severe necrotic skin wounds and a withdrawal syndrome that does not respond to opioids.

Trials and Helpful Literature

• Management of opioid use disorder and associated conditions among hospitalized adults: A Consensus Statement from the Society of Hospital Medicine  (JHM, 2022)
• Opioid Withdrawal (STAT Pearls, 2023)

Other Resources

Podcasts

• 5 Pearls on Stigma in Opioid Use Disorder (Core IM, 2021)‍
• #498 Opioid Withdrawal with Dr. Ashish Thakrar (Curbsiders, 2025)

Blog and Reference Materials

• Opioid Use Disorder (VIM Handbook, 2024)‍
• Opioid Use Disorder (UCSF Hospitalist Handbook)‍
• Opioid Withdrawal (WikEM, 2024)

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