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 programs and provide an opportunity to reinforce for overdose and relapse prevention.
Mechanism of physiologic dependence 
- Acute opioid use: The opioid binds to the μ-opioid receptor in the locus coeruleus, leading to inhibition of cAMP, which results in the following.
- Repeated use: neurons in the locus coeruleus upregulate the cAMP pathway → norepinephrine levels return to normal → opioid tolerance
- Withdrawal: abrupt opioid cessation → end of inhibition of cAMP in locus coeruleus → increased norepinephrine release → dysphoria, CNS hyperactivity
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 ). 
- CNS arousal and sympathetic hyperactivity
- Flu-like symptoms
- Gastrointestinal symptoms
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. 
- Clinical diagnosis
- Assessment of major comorbidities
- 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. 
Diagnostic studies 
- Initial laboratory studies
- Additional investigations (consider based on suspected comorbidities)
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. 
|DSM-5 diagnostic criteria for opioid withdrawal |
|A) Fundamental criteria|
|B) Presence of ≥ 3 symptoms/signs|
|C) Symptom characteristics|| |
|D) Alternative diagnoses|| |
|All criteria must be fulfilled to confirm the diagnosis.|
Withdrawal severity assessment 
Clinical Opioid Withdrawal Scale
|Minimum possible score (no symptoms)||Maximum possible score (severe symptoms)|
≤ 80 BPM (0)
|> 120 (4)|
|Sweating||No chills, flushing, or sweating (0)||Sweat streaming off the face (4)|
|Restlessness||Able to sit still (0)||Unable to sit still for more than a few seconds (5)|
|Pupil size||Pinned or normal for room light (0)||Only the rim of the iris is visible (5)|
|Bone, joint, or muscle aches||None (0)||Rubbing joints or muscles and unable to sit still due to discomfort (4)|
|Rhinorrhea or lacrimation||Constantly running nose or streaming tears (4)|
|GI symptoms||Multiple episodes of diarrhea or vomiting (5)|
|Tremor||Gross tremor or muscle twitching (4)|
|Yawning||Several times per minute (4)|
|Anxiety or irritability||Irritability or anxiousness that makes participation in the assessment difficult (4)|
Interpretation (total combined score)
The COWS is not designed to diagnose opioid withdrawal as most of the signs and symptoms are nonspecific. 
- Offer pharmacological therapy
- Start general supportive measures
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.
Psychosocial support 
- Apply a .
- Engage patients with and .
- Inquire about the following:
A patient who declines to engage in shared decision making should not be excluded from prompt initiation of appropriate medication management. 
Medications for opioid use disorder (MOUDs)
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
|Overview of long-acting medications for opioid use disorder |
|Risk of precipitating withdrawal|| || || |
|Important considerations|| || |
|Withdrawal treatment setting|| |
- Indication: subjective features of OWS
- Contraindications: QTc ≥ 500 ms; sedation (e.g., due to substance use, prescribed medications, severe illness) 
- First-day 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. 
- For all other patients: Titrate dose by no more than 10 mg every ∼5 days until a regular maintenance dose is reached. 
- Indication: objective features of OWS
- Start an initial dosage under medical supervision.
- If cravings and symptoms persist: Give additional dosages every 1–2 hours as needed. 
Subsequent dosages 
- 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. 
- Symptomatic therapy for patients who decline MOUDs
- Adjunctive therapy to MOUDs (to reduce residual OWS)
- Observe for respiratory depression and sedation.
- Consider with MOUDs.
|Medications for symptom-based treatment of opioid withdrawal |
|Symptom type||Treatment regimens|
|Sympathetic hyperactivity||Autonomic symptoms|| |
|Muscle spasms|| |
|Gastrointestinal||Nausea and vomiting|| |
|Abdominal cramps|| |
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. 
Harm reduction strategies
- Opioid overdose prevention
- : e.g., hand hygiene, use of sterile water, cleaning the injection site with alcohol 
- : e.g., use of condoms, including
Harm reduction resources 
- Needle exchange program, e.g., to prevent and
- Safe injection sites
Special patient groups
Neonatal abstinence syndrome 
- Flu-like symptoms: fever and sweating
- Gastrointestinal symptoms
- Respiratory symptoms
- Sympathetic hyperactivity: hypertension, tachycardia
- CNS stimulation
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