Opioid withdrawal

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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.[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-life of Opioids Onset of Withdrawal Symptoms Duration of the syndrome
Short half-life
  • Within 12 h of last use
  • Heroin withdrawal lasts 4–5 days
Long half-life
  • 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:[6][1]

Locus coeruleus (LC)

Locus ceruleus(LC):[6]

Acute opioid effects:

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

Opioid withdrawal symptoms may occur with:[9]

Differentiating opioid withdrawal from other diseases and conditions

Opioid withdrawal must be differentiated from:[10]

Disease Prominent clinical features Investigations
Hyperthyroidism The main symptoms include:
  • 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: 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 a 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 restlessness, 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 pheochromocytoma are those of sympathetic nervous system hyperactivity, symptoms usually subside in less than one hour and they may include:

Please note that not all patients with pheochromocytoma experience all of the classical symptoms.

Diagnostic lab findings associated with pheochromocytoma include:

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.[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

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

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Criteria

DSM-V Diagnostic Criteria for Opioid Withdrawal[10]

  • 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

History and Symptoms

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

Physical Examination

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

Laboratory Findings

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

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:[19]

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

Treatment

Medical Therapy

Medications used in opioid withdrawal include:[18]

Surgery

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

Prevention

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 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 Mazei-Robison MS, Nestler EJ (2012). "Opiate-induced molecular and cellular plasticity of ventral tegmental area and locus coeruleus catecholamine neurons". Cold Spring Harb Perspect Med. 2 (7): a012070. doi:10.1101/cshperspect.a012070. PMC 3385942. PMID 22762025.
  7. Kosten TR, George TP (2002). "The neurobiology of opioid dependence: implications for treatment". Sci Pract Perspect. 1 (1): 13–20. doi:10.1151/spp021113. PMC 2851054. PMID 18567959.
  8. Cao JL, Vialou VF, Lobo MK, Robison AJ, Neve RL, Cooper DC; et al. (2010). "Essential role of the cAMP-cAMP response-element binding protein pathway in opiate-induced homeostatic adaptations of locus coeruleus neurons". Proc Natl Acad Sci U S A. 107 (39): 17011–6. doi:10.1073/pnas.1010077107. PMC 2947876. PMID 20837544.
  9. Diagnostic and statistical manual of mental disorders : DSM-5. Arlington, VA Washington, D.C: American Psychiatric Association,American Psychiatric Association. 2013. ISBN 0-89042-555-8. OCLC 830807378.
  10. 10.0 10.1 10.2 10.3 Diagnostic and statistical manual of mental disorders : DSM-5. Washington, D.C: American Psychiatric Association. 2013. ISBN 0890425558.
  11. Sites BD, Beach ML, Davis MA (2014). "Increases in the use of prescription opioid analgesics and the lack of improvement in disability metrics among users". Reg Anesth Pain Med. 39 (1): 6–12. doi:10.1097/AAP.0000000000000022. PMC 3955827. PMID 24310049.
  12. Volkow ND, McLellan AT (2016). "Opioid Abuse in Chronic Pain--Misconceptions and Mitigation Strategies". N Engl J Med. 374 (13): 1253–63. doi:10.1056/NEJMra1507771. PMID 27028915.
  13. Mattick RP, Breen C, Kimber J, Davoli M (2014). "Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence". Cochrane Database Syst Rev (2): CD002207. doi:10.1002/14651858.CD002207.pub4. PMID 24500948.
  14. Jarvis BP, Holtyn AF, Subramaniam S, Tompkins DA, Oga EA, Bigelow GE; et al. (2018). "Extended-release injectable naltrexone for opioid use disorder: a systematic review". Addiction. 113 (7): 1188–1209. doi:10.1111/add.14180. PMC 5993595. PMID 29396985.
  15. 15.0 15.1 Burma NE, Kwok CH, Trang T (2017). "Therapies and mechanisms of opioid withdrawal". Pain Manag. 7 (6): 455–459. doi:10.2217/pmt-2017-0028. PMID 29125396.
  16. 16.0 16.1 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.
  17. 17.0 17.1 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.
  18. 18.0 18.1 Center for Substance Abuse Treatment (2006). "Detoxification and Substance Abuse Treatment". SAMHSA/CSAT Treatment Improvement Protocols. PMID 22514851.
  19. 19.0 19.1 Doughty B, Morgenson D, Brooks T (2019). "Lofexidine: A Newly FDA-Approved, Nonopioid Treatment for Opioid Withdrawal". Ann Pharmacother. 53 (7): 746–753. doi:10.1177/1060028019828954. PMID 30724094.
  20. Gossop M (1990). "The development of a Short Opiate Withdrawal Scale (SOWS)". Addict Behav. 15 (5): 487–90. doi:10.1016/0306-4603(90)90036-w. PMID 2248123.
  21. 21.0 21.1 Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD (1987). "Two new rating scales for opiate withdrawal". Am J Drug Alcohol Abuse. 13 (3): 293–308. doi:10.3109/00952998709001515. PMID 3687892.

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