Opioid withdrawal

Resident Survival Guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shakiba Hassanzadeh, MD[2], Kiran Singh, M.D. [3]

Overview[edit | edit source]

Opioid withdrawal occurs due to the discontinuation or reduction of opioid use in individuals with heavy and prolonged opioid use or may be precipitated by the administration of an opioid antagonist in an individual with prolonged opioid use or by the administration of an opioid partial agonist in an individual that is currently using a full opioid agonist. Symptoms of withdrawal from opiates include, but are not limited to, depression, anxiety, irritability, leg cramps, abdominal cramps, nausea, vomiting, diarrhea, insomnia, pain, tremor, rhinorrhea, sweating, and cravings for the drug itself. Depending on the opioid's half-life, the symptoms of opioid withdrawal usually resolve within 5 to 14 days, however, many patients require appropriate treatment. The DSM-V diagnostic criteria is used for the diagnosis of opioid withdrawal. The medications for treatment include methadone, clonidine, buprenorphine, and adjunctive drugs.

Historical Perspective[edit | edit source]

• Opium and its derivatives have been used as medical therapies since 5,000 years ago.^[1]
• In the United States, in the early 20th century, opiates were over-the-counter drugs and were commonly used in medical therapy of various disorders.^[1]
• In the early 1900s, the federal restrictions on opioid access caused suffering and death since there were no effective treatments for the opioid withdrawal symptoms that happened with sudden discontinuation of opioids.^[1]

Classification[edit | edit source]

The onset and duration of opioid withdrawal depends on the half-life of the consumed opioid:^{[2][1][3][4][5]}

Pathophysiology[edit | edit source]

Chronic opioid use leads to changes in different organs and these may be the underlying pathophysiology of opioid withdrawal symptoms, such as:^[6][1]

• Gastrointestinal (GI) tract:
  • Mu opioid receptors:
    • Diarrhea, nausea and vomiting
• Brain:
  • Mesolimbic reward circuits (the ventral tegmental area and its projections to nucleus accumbens, prefrontal cortex and amygdala):
    • Opioid craving, compulsive use and depression
  • Ascending reticular activating system (in the brainstem, thalamus, and hypothalamus):
    • Insomnia
  • Different brain pathways (the locus coeruleus (LC) in the brainstem and its projections including those to the reticular activating system):
    • Physical dependence symptoms

Locus coeruleus (LC)[edit | edit source]

Locus ceruleus(LC):^[6]

• Has norepinephrine (NE) neurons
• Input to several areas of the brain (prefrontal cortex, hippocampus and amygdala)
• Regulates attention, vigilance and autonomic nervous system

Acute opioid effects:

• Drowsiness, hypotension, reduced respiration and muscle tone
• Binding of an opioid to mu-opioid receptors on the neurons in LC causes:
  • Inhibition of the enzymes in the cAMP pathway
  • Decreased firing rate of LC neurons
  • Decreased NE release

Chronic opioid use:

Opioid tolerance occurs with the adaption of LC neurons to opioid inhibition by increasing enzyme activity which leads to:

• Upregulation of the cAMP pathway and production of normal cAMP levels:
  • Return to normal levels of LC firing rate and NE release

Abrupt discontinuation of opioids after opioid tolerance:

Sudden discontinuation of opioids in chronic opioid users that have opioid tolerance causes the following until re-adaptation to the absence of opioids occurs in LC neurons:^[7][8] 

• Hyperactivation of LC
• Increased production of cAMP
• Excessive release of NE

Noradrenergic hyperactivity is the main cause of acute opioid withdrawal symptoms.

Causes[edit | edit source]

Opioid withdrawal symptoms may occur with:^[9]

• Discontinuation or reduction of opioid use in individuals with heavy and prolonged opioid use.
• Precipitation by administrating of an opioid antagonist (such as naloxone or naltrexone) to an individual with prolonged opioid use.
• Precipitation by administrating of an opioid partial agonist (such as buprenorphine) to an individual that is currently using a full opioid agonist.

Differentiating opioid withdrawal from other diseases and conditions[edit | edit source]

Opioid withdrawal must be differentiated from:^[10]

• Sedative-hypnotic withdrawal
• Hallucinogen intoxication
• Stimulant intoxication
• Opioid-induced depressive disorder

Epidemiology and Demographics[edit | edit source]

• The prevalence of opioid withdrawal is 6,000 per 100,000 (60%) of the population that have used heroin one or more time in the prior 12 months.^[10]
• In the USA, the amount of opioids prescribed has increased from 43.8 million prescriptions in 2000 to 89.2 million in 2010.^[11]
• About 4% of adults in the USA regularly use opioids for pain.^[12]

Risk Factors[edit | edit source]

Opioid withdrawal may be caused by discontinuation of repeated use of an opioid in any setting such as:^[10]

• Medical therapy of pain
• Opioid agonist therapy for opioid use disorder
• Recreational use
• Self-treating the symptoms of mental disorders

Natural History, Complications and Prognosis[edit | edit source]

• Depending on the opioid's half-life, the symptoms of opioid withdrawal usually resolve within 5 to 14 days.
• However, many patients require appropriate treatment since the symptoms and distress is severe in the first days after the cessation of opioid use.^[13][14]
• Potential complications of discontinuing opioid use may include:^[15]
  • Emergence of pain
  • Exacerbation of a preexisting pain
  • Requirement of higher doses of opioid to manage pain

Diagnosis[edit | edit source]

Diagnostic Criteria[edit | edit source]

DSM-V Diagnostic Criteria for Opioid Withdrawal^[10][edit | edit source]

History and Symptoms[edit | edit source]

The most common symptoms of opioid withdrawal include :^[16][17]

• Anxiety
• Restlessness
• Irritability
• Insomnia
• Hot flashes
• Chills
• Sweating
• Pupillary dilatation
• Heart pounding
• Lacrimation
• Rhinorrhea
• Yawning
• Gooseflesh
• Nausea, vomiting
• Abdominal cramps
• Diarrhea
• Aches, pain
• Muscle spasms, twitching
• Tremor

Physical Examination[edit | edit source]

Common physical examination findings of opioid withdrawal include:^[16][17][1]

• Anxiety
• Restlessness
• Irritability
• Hypertension
• Tachycardia
• Mydriasis
• Piloerection (such as goose bumps)
• Lacrimation
• Rhinorrhea
• Yawning
• Nausea, vomiting
• Diarrhea
• Sweating
• Muscle spasms, twitching
• Tremor

Laboratory Findings[edit | edit source]

Patients with opioid use disorder (particularly intravenous heroin dependence) may be tested for complications:^[18]

• Laboratory tests
• Tuberculosis
• HIV/AIDS
• Viral hepatitis (especially B and C)
• Other sexually transmitted diseases
• Opportunistic infections

X-ray[edit | edit source]

There are no x-ray findings associated with opioid withdrawal.

Echocardiography or Ultrasound[edit | edit source]

There are no echocardiography/ultrasound findings associated with opioid withdrawal.

CT Scan[edit | edit source]

There are no CT scan findings associated with opioid withdrawal.

MRI[edit | edit source]

There are no MRI findings associated with opioid withdrawal.

Other Imaging Findings[edit | edit source]

There are no other imaging findings associated with opioid withdrawal.

Other Diagnostic Studies[edit | edit source]

Several scales are used in opioid withdrawal syndrome including:^[19]

• Short Opioid Withdrawal Scale (SOWS)^[20][21]
• Objective Opiate Withdrawal Scale (OOWS)^[21]
• Opiate Craving Scale (OCS)
• Opiate Withdrawal Scale (OWS)

Treatment[edit | edit source]

Medical Therapy[edit | edit source]

Medications used in opioid withdrawal include:^[18]

• Methadone
  • Methadone is a long-acting agonist at the μ-opioid receptor
  • Dose:
    • The initial dose is determined by estimating the amount of opioid use and the patient's response.
    • Methadone may be administered once daily, and tapered over 3 to 5 days (in 5 to 10mg daily reductions)
  • Methadone is the most commonly used medication, but patients require adjunctive drugs for nausea, vomiting, diarrhea, and stomach cramps
• Clonidine
  • Clonidine is an α-adrenergic agonist
  • Administered 0.1mg orally
  • A dose of 0.2mg might be used initially in patients:
    • With severe signs of opioid withdrawal
    • Weighing more than 200 pounds
  • Treatment with clonidine requires adjunctive drugs for insomnia, myalgia, bone pain, and headache.
• Buprenorphine
  • Buprenorphine is a partial μ-opioid agonist

• Lofexidine  
  • Has been approved in the United Kingdom for treatment of opioid withdrawal since 1992^[1] 
  • Lofexidine is an α-adrenergic agonist^[19]

Surgery[edit | edit source]

Surgical intervention is not recommended for the management of opioid withdrawal.

Prevention[edit | edit source]

• Refraining from sudden and abrupt discontinuation of opioid use in individuals with opioid dependence.
• Opioid replacement therapy (replace short-acting opioids with long-acting opioids). 
• Opioid tapering (gradual reduction in opioid dose).^[15]
• Early diagnosis and treatment of opioid use dependence.
• Long-term treatment of opioid use dependence.^[1]

References[edit | edit source]

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