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]

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Overview

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

• Opium and its derivatives have been used as medical therapies since 5,000 years ago.
• 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.
• 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.

Classification

The onset and duration of opioid withdrawal depends on the half-life of the consumed opioid:

Half-lives of Opioids	Onset of Withdrawal Symtoms	Duration of the syndrome
Short half-lives Heroin at 3–5 h	Within 12 h of last use	Heroin withdrawal lasts 4–5 days
Long half-lives Methadone at up to 96 h	1–3 days after last use	Methadone withdrawal lasts 7–14 days Some last for several weeks

Pathophysiology

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

• 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)

Locus ceruleus(LC):

• 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
• Due to binding of an opioid to m-opioid receptors on the neurons in LC which 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: 

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

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

Causes

Opioid withdrawal symptoms may occur with:

• 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

Opioid withdrawal must be differentiated from:

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

Disease	Prominent clinical features	Investigations
Hyperthyroidism	The main symptoms include: Palpitations Insomnia Anxiety Weight loss Heat intolerance Diarrhea Depending on the underlying diagnosis, the patient might have exophthalmus or goiter	The patient usually has elevated T3 and T4 TSH might be increased or decreased depending on the underlying cause Thyroid stimulating antibodies (TSI) might be increased in cases of Graves’ disease
Essential hypertension	Most patients with hypertension are asymptomatic at the time of diagnosis. Common symptoms are listed below: Headache Blurry vision Dyspnea Epistaxis Tinnitus Fatigue Drowsiness	JNC 7 recommends the following routine laboratory tests before initiation of therapy for hypertension: 12-Lead electrocardiogram (ECG) Urinalysis, including urinary albumin excretion or albumin/creatinine ratio Blood glucose Blood hematocrit Serum electrolytes, especially potassium Serum calcium Lipid profile: Total cholesterol, LDL, HDL, triglycerides Creatinine or estimated GFR
Generalized anxiety disorder	According to DSM V, the following criteria should be present to fit the diagnosis of generalized anxiety disorder: The presence of sense of apprehension or fear toward certain activities for most of the days for at least 6 months Difficulty to control the apprehension Associated restless, fatigue, irritability, difficult concentration, muscle tension or sleep disturbance (only one of these manifestations) The anxiety or the physical manifestations must affect the social and the daily life of the patient Exclusion of another medical condition or the effect of another administered substance Exclusion of another mental disorder causing the symptoms	-
Menopause	The perimenopausal symptoms are caused by an overall drop, as well as dramatic but erratic fluctuations, in the levels of estrogens, progestin, and testosterone. Some of these symptoms such as formication etc may be associated with the hormone withdrawal process. Vasomotor instability in the form of hot flushes, including night sweats and sleep disturbances Urogenital atrophy causing itching, dryness, bleeding, watery discharge, urinary frequency, urinary urgency and urinary incontinence Skeletal symptoms in the form of osteoporosis (gradually developing over time), artharlgia, myalgia and back pain Psychological manifestations such as mood disturbance, irritability, fatigue, memory loss and depression Sexual disorders: decreased libido, vaginal dryness, problems reaching orgasm and dyspareunia	B-HCG should always be done first to rule out pregnancy especially in women under the age of 45 years FSH can be measured but it can be falsely normal or low TSH, T3 and T4 to rule out thyroid abnormalities Prolactin can be measured to rule out prolactinoma as a cause of menopause
Opioid withdrawal disorder	According to DSM V, the following criteria should be present to fit the diagnosis of opioid withdrawal: Cessation of (or reduction in) opioid use that has been heavy and prolonged (i.e.,several weeks or longer) or administration of an opioid antagonist after a period of opioid use. Development of three or more of the following criteria minutes to days after cessation of drug use: dysphoric mood, nausea or vomiting, muscle aches, Lacrimation or rhinorrhea, pupillary dilation, piloerection, or sweating, diarrhea, yawning, fever, and insomnia. The signs or symptoms mentioned above must cause impairment of the daily functioning of the patient. The signs or symptoms mentioned above must not be attributed to other medical or mental disorders.	Urine drug screen to rule out any other associated drug abuse Routine blood work such as electrolytes and hemoglobin to rule out any associated disease explaining the symptoms
Pheochromocytoma	The hallmark symptoms of a pheochromocytoma are those of sympathetic nervous system hyperactivity, symptoms usually subside in less than one hour and they may include: Palpitations especially in epinephrine producing tumors. Anxiety often resembling that of a panic attack Sweating Headaches occur in 90 % of patients. Paroxysmal attacks of hypertension but some patients have normal blood pressure. It may be asymptomatic and discovered by incidence screening especially MEN patients. Please note that not all patients with pheochromocytoma experience all classical symptoms.	Diagnostic lab findings associated with pheochromocytoma include: Elevated plasma and urinary catecholamines and metanephrines Elevated urinary vanillyl mandelic acid

Epidemiology and Demographics

• 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.
• In the USA, the amount of opioids prescribed has increased from 43.8 million prescriptions in 2000 to 89.2 million in 2010.
• About 4% of adults in the USA regularly use opioids for pain.

Risk Factors

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

• 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

• 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.
• Potential complications of discontinuing opioid use may include:
  • Emergence of pain
  • Exacerbation of a preexisting pain
  • Requirement of higher doses of opioid to manage pain

Diagnosis

Diagnostic Criteria

DSM-V Diagnostic Criteria for Opioid Withdrawal

“

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. AND B. Three (or more) 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 AND C. The signs or symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. AND 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.

”

History and Symptoms

The most common symptoms of opioid withdrawal include :

• 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

Common physical examination findings of opioid withdrawal include:

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

Laboratory Findings

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

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

X-ray

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

Echocardiography or Ultrasound

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

CT Scan

There are no CT scan findings associated with opioid withdrawal.

MRI

There are no MRI findings associated with opioid withdrawal.

Other Imaging Findings

There are no other imaging findings associated with opioid withdrawal.

Other Diagnostic Studies

Several scales are used in opioid withdrawal syndrome including:

• Short Opioid Withdrawal Scale (SOWS)
• Objective Opiate Withdrawal Scale (OOWS)
• Opiate Craving Scale (OCS)
• Opiate Withdrawal Scale (OWS)

Treatment

Medical Therapy

Medications used in opioid withdrawal include:

• 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 
  • Lofexidine is an α-adrenergic agonist

Surgery

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

Prevention

• 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)
• Early diagnosis and treatment of opioid use dependence.
• Long-term treatment of opioid use dependence.