Opioid withdrawal

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

Overview

Opioid withdrawal occurs due to the cessation of opioids or the administration of an opioid antagonist following a heavy or prolonged use of opioids. Symptoms of withdrawal from opiates include, but are not limited to, depression, aggression and irritability, leg cramps, abdominal cramps, vomiting, diarrhea, insomnia, and cravings for the drug itself. Depending on the quantity, type, frequency, and duration of opioid use, the physical withdrawal symptoms last for as little as 5 days and as much as 14 days.

Historical Perspective

  • 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

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

Half-lives of Opioids Onset of Withdrawal Symtoms Duration of the syndrome
Short half-lives Within 12 h of last use eg, heroin withdrawal lasts 4–5 days
Long half-lives 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: (((21 va asl.)))

Locus coeruleus (LC)

Locus coeruleus (LC): (((((21))))

Acute opioid effects:

    • 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: 9,22  

  • 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 may be caused by discontinuation of repeated use of an opioid.[6]

Differentiating opioid withdrawal from other diseases and conditions

Opioid withdrawal must be differentiated from:[6]

Disease Prominent clinical features Investigations
Hyperthyroidism The main symptoms include:
Essential hypertension Most patients with hypertension are asymptomatic at the time of diagnosis. Common symptoms are listed below: JNC 7 recommends the following routine laboratory tests before initiation of therapy for hypertension:
Generalized anxiety disorder According to DSM V, the following criteria should be present to fit the diagnosis of generalized anxiety disorder:
  1. The presence of sense of apprehension or fear toward certain activities for most of the days for at least 6 months
  2. Difficulty to control the apprehension
  3. Associated restless, fatigue, irritability, difficult concentration, muscle tension or sleep disturbance (only one of these manifestations)
  4. The anxiety or the physical manifestations must affect the social and the daily life of the patient
  5. Exclusion of another medical condition or the effect of another administered substance
  6. 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.
  • 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:
  1. 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.
  2. 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.
  3. The signs or symptoms mentioned above must cause impairment of the daily functioning of the patient.
  4. 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:

Epidemiology and Demographics

Prevalence

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.[6]

Risk Factors

Opioid withdrawal may be caused by discontinuation of repeated use of an opioid in any setting such as:[6]

Screening

Natural History, Complications and Prognosis

Depending on the quantity, type, frequency, and duration of opioid use, the physical withdrawal symptoms last for as little as 5 days and as much as 14 days. The user, upon returning to the environment where they usually used opiates, can experience environmentally implied physical withdrawal symptoms well-after regaining physical homeostasis - or the termination of the physical withdrawal phase by synthesis of endogenous opioids (endorphins) and upregulation of opioid receptors to the effects of normal levels of endogenous opioids. These implied symptoms are often just as distressing and painful as the initial withdrawal phase.

Detoxification is best conducted in an in patient facility that provides a controlled environment. Patients who are isolated and exposed solely to care givers and other patients in this environment have a better rate of staying clean then those who detox out-patient.

Diagnosis

Diagnostic Criteria

DSM-V Diagnostic Criteria for Opioid Withdrawal[6]

  • 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:

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 :[7][8]

Physical Examination

Common physical examination findings of opioid withdrawal include:[7][8][1]

Laboratory Findings

Patients with opioid use disorder (particularly intravenous heroin dependence) may be tested for complications:[9]

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

here are no other diagnostic studies associated with opioid withdrawal.

Treatment

Medical Therapy

Medications used in opioid withdrawal include:[9]

Surgery

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

Primary Prevention

Primary Prevention

References

  1. 1.0 1.1 1.2 1.3 1.4 Kosten TR, Baxter LE (2019). "Review article: Effective management of opioid withdrawal symptoms: A gateway to opioid dependence treatment". Am J Addict. 28 (2): 55–62. doi:10.1111/ajad.12862. PMC 6590307 Check |pmc= value (help). PMID 30701615.
  2. Srivastava AB, Mariani JJ, Levin FR (2020). "New directions in the treatment of opioid withdrawal". Lancet. 395 (10241): 1938–1948. doi:10.1016/S0140-6736(20)30852-7. PMC 7385662 Check |pmc= value (help). PMID 32563380 Check |pmid= value (help).
  3. Kosten TR, O'Connor PG (2003). "Management of drug and alcohol withdrawal". N Engl J Med. 348 (18): 1786–95. doi:10.1056/NEJMra020617. PMID 12724485.
  4. Kleber HD (2007). "Pharmacologic treatments for opioid dependence: detoxification and maintenance options". Dialogues Clin Neurosci. 9 (4): 455–70. PMC 3202507. PMID 18286804.
  5. Kreek MJ, Borg L, Ducat E, Ray B (2010). "Pharmacotherapy in the treatment of addiction: methadone". J Addict Dis. 29 (2): 200–16. doi:10.1080/10550881003684798. PMC 2885886. PMID 20407977.
  6. 6.0 6.1 6.2 6.3 6.4 Diagnostic and statistical manual of mental disorders : DSM-5. Washington, D.C: American Psychiatric Association. 2013. ISBN 0890425558.
  7. 7.0 7.1 Wesson DR, Ling W (2003). "The Clinical Opiate Withdrawal Scale (COWS)". J Psychoactive Drugs. 35 (2): 253–9. doi:10.1080/02791072.2003.10400007. PMID 12924748.
  8. 8.0 8.1 Vernon MK, Reinders S, Mannix S, Gullo K, Gorodetzky CW, Clinch T (2016). "Psychometric evaluation of the 10-item Short Opiate Withdrawal Scale-Gossop (SOWS-Gossop) in patients undergoing opioid detoxification". Addict Behav. 60: 109–16. doi:10.1016/j.addbeh.2016.03.028. PMID 27124502.
  9. 9.0 9.1 Center for Substance Abuse Treatment (2006). "Detoxification and Substance Abuse Treatment". SAMHSA/CSAT Treatment Improvement Protocols. PMID 22514851.

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