Opioid Withdrawal

Primer

Opioid Withdrawal is a withdrawal syndrome that develops after stopping or reducing opioid use that has been heavy and prolonged. Opioid withdrawal can also be triggered by administration of an opioid antagonist (e.g. - naloxone or naltrexone) after a period of opioid use.

Epidemiology
  • In clinical settings for heroin users, opioid withdrawal occurs in approximately 60% of individuals.[1]
Prognosis
  • Although opioid withdrawal can be severely debilitating and very uncomfortable due to the physical symptoms, it is not fatal (unlike alcohol withdrawal).
  • Withdrawal symptoms are however, a major reason for opioid re-use to reduce withdrawal symptoms, diverting the withdrawal symptoms to a later time.
    • This can drive the persistence of an ongoing opioid use disorder, and also increases the risk for accidental overdoses.
Risk Factors
  • Heavy opioid use, increased frequency of use, and short half-life opioids can increase the risk for the severity of withdrawal symptoms.

DSM-5 Diagnostic Criteria

Criterion A

Presence of either of the following:

  1. Cessation of (or reduction in) opioid use that has been heavy and prolonged (i.e. - several weeks or longer).
  2. Administration of an opioid antagonist after a period of opioid use.
Criterion B

At least 3 of the following developing within minutes to several days after Criterion A:

  1. Dysphoric mood
  2. Nausea or vomiting
  3. Muscle aches
  4. Lacrimation or rhinorrhea
  5. Pupillary dilation, piloerection, or sweating
  6. Diarrhea
  7. Yawning
  8. Fever
  9. Insomnia
Criterion C

The signs or symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

Criterion D

The signs or symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal from another substance.

Signs and Symptoms

  • The first signs of withdrawal are usually subjective, and include anxiety, restlessness, and muscle aches in the back and legs.
    • Individuals also have more irritability and increased sensitivity to pain.
    • Males may experience spontaneous ejaculations while awake.[2]
  • Objective signs include sweating, dilated pupils, rhinorrhea, lacrimation, yawning, nausea, stomach cramps, diarrhea (“flu-like” symptoms).
    • Piloerection (“cold turkey”) and fever are only seen in severe withdrawal and thus rarely seen.[3]
  • The speed and severity of withdrawal depends on the half-life of the opioid used.
    • Short-acting opioids:
      • Heroin users can have withdrawal symptoms within 6-12 hours after the last dose.
      • Symptoms usually peak within 1-3 days and gradually subside over a period of 5-7 days
    • Long-acting opioids:
      • Methadone, LAAM (L-alpha-acetylmethadol), and buprenorphine users may take up to 2 to 4 days for withdrawal symptoms to occur.
  • For both long-acting and short-acting opioids, less acute withdrawal symptoms (e.g. - anxiety, dysphoria, anhedonia, and insomnia) can persist for weeks to months.

Screening and Rating Scales

Clinical Opioid Withdrawal Scale (COWS)

  • The Clinical Opioid Withdrawal Scale (COWS) is a clinical tool used to monitor withdrawal symptoms, and also to determine when to start Suboxone induction. It includes clinical measures assessed by the physician and not subject to patient reporting such as: pulse rate, pupil size, tremors, and yawning.

Scales for Opioid Withdrawal

Name Rater Description Download
Clinical Opioid Withdrawal Scale (COWS) Clinician An 11-item scale designed to be administered by a clinician. This can be used in both inpatient/outpatient settings to reproducibly rate and monitor common signs and symptoms of opiate withdrawal. COWS Download

Pathophysiology

  • The locus coeruleus, a part of the brain stem, is hypothesized to play an important role in opioid withdrawal.[4] The noradrenergic neurons in the locus coeruleus are thought to become hyperactive during withdrawal.[5]

Differential Diagnosis

  • Other withdrawal disorders
    • The anxiety and restlessness associated with opioid withdrawal can look like a sedative-hypnotic withdrawal. However, opioid withdrawal is also accompanied by rhinorrhea, lacrimation, and pupillary dilation, which is not present in sedative-type withdrawal. A urine drug screen can also be helpful to differentiate the etiology.
  • Other substance intoxication
    • Dilated pupils can also be present in hallucinogen and stimulant intoxication. However, other signs and symptoms of opioid withdrawal (e.g. - nausea, vomiting, diarrhea, abdominal cramps, rhinorrhea, and lacrimation) are not present.
  • Other opioid-induced disorders
    • Opioid withdrawal is different from the other opioid-induced disorders (e.g. - opioid-induced depressive disorder, with onset during withdrawal) because the symptoms in these opioid-induced disorders are in excess of those usually expected with opioid withdrawal and meet full criteria for the relevant disorder.

Investigations

  • Urine drug screen should be ordered to also rule out withdrawal from other drugs or substances of abuse.[6]

Physical Exam

  • Physical examination for signs of opioid withdrawal can be guided by the Clinical Opioid Withdrawal Scale (COWS) and the diagnostic criteria for opioid withdrawal.
  • In particular, sweating, restlessness, pupillary dilation, rhinorrhea, nausea, vomiting, or diarrhea, tremor, and piloerection are objective signs of opioid withdrawal.

Treatment

Symptom Management

  • Non-specific symptoms of acute opioid withdrawal can be managed with the following medications:
    • Anxiety
      • Clonidine 0.1 to 0.2 mg q4h (max 1.2 mg/24h)PRN[7]
    • Anti-emetics/anti-diarrheals
      • Ondansetron 8-16 mg PO/SL q8h PRN for nausea and vomiting
      • Dimenhydrinate 50-100 mg q4-6h PRN (max 400 mg/24 h) for nausea and vomiting
      • Loperamide 4 mg PO once then 2 mg PO after each loose stool (max 16 mg/day)
    • Muscle cramps or pain
      • Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, ketorolac, naproxen
    • Dyspepsia
      • Rabeprazole 20mg qAM PRN
  • However, these medications are not a long term treatment for opioid use disorder, and initiating an opioid replacement therapy is the most important.

Acute Withdrawal Management

  • In settings where an individual newly presents for assessment (e.g., emergency department), and are not willing or interested in starting opioid replacement therapy, the use of regular opioids (such as hydromorphone, slow-release oral morphine, or morphine) temporarily for stabilization may be considered in some jurisdictions, for example:
    • Hydromorphone 8 mg to 16 mg PO q1h prn for opioid withdrawal and cravings, per patient request (hold if sedated or RR<10, maximum 48mg q24hrs)
    • The onset of hydromorphone is usually 15-30 minutes, with peak effects at 30 to 60 minutes, lasting a total of 3 to 4 hours.
    • Vital signs should be monitored 1 hour post-dose

Methadone

  • Methadone is an opioid traditionally used as maintenance therapy in opioid replacement therapy or to help with tapering in people with opioid dependence.

Suboxone

  • To avoid precipitated withdrawal, you must ensure the patient has not used any opioids for at least 12 hours; and the patient is in moderate to severe withdrawal.
  • Using the Clinical Opioid Withdrawal Scale (COWS) is important in determining withdrawal severity.
  • There is strong evidence that supports initiating suboxone in an emergency department setting.[8][9]

Guidelines

Opioid Use Disorder Guidelines

Guideline Location Year PDF Website
Canadian Medical Association Journal (CMAJ) Canada 2018 - Link
BC Centre on Substance Use (BCCSU) Canada 2023 Link Link
META:PHI Canada 2019 Link Link
Canadian Guidelines on Opioid Use Disorder Among Older Adults Canada 2020 PDF Link
National Institute for Health and Care Excellence (NICE) UK 2007 - Link
American Psychiatric Association USA 2006, 2007 - • Guideline (2006)
• Guideline Watch (2007)
• Quick Reference

Resources

For Patients
For Providers
Articles
Research

References

1) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
2) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
3) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
4) K Rehni, A., S Jaggi, A., & Singh, N. (2013). Opioid withdrawal syndrome: emerging concepts and novel therapeutic targets. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), 12(1), 112-125.
5) Ivanov, A., & Aston-Jones, G. (2001). Local opiate withdrawal in locus coeruleus neurons in vitro. Journal of Neurophysiology, 85(6), 2388-2397.
6) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
7) Kleber, H. D. (2007). Pharmacologic treatments for opioid dependence: detoxification and maintenance options. Dialogues in clinical neuroscience, 9(4), 455.
8) D’Onofrio, G., Chawarski, M. C., O’Connor, P. G., Pantalon, M. V., Busch, S. H., Owens, P. H., ... & Fiellin, D. A. (2017). Emergency department-initiated buprenorphine for opioid dependence with continuation in primary care: outcomes during and after intervention. Journal of general internal medicine, 32(6), 660-666.
9) D’Onofrio, G., O’Connor, P. G., Pantalon, M. V., Chawarski, M. C., Busch, S. H., Owens, P. H., ... & Fiellin, D. A. (2015). Emergency department–initiated buprenorphine/naloxone treatment for opioid dependence: a randomized clinical trial. Jama, 313(16), 1636-1644.