Opioid withdrawal

| Resident
Survival
Guide

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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

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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

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* 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

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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

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Short half-life

* Heroin at 3–5 h

* Within 12 h of last use

* Heroin withdrawal lasts 4–5 days

Long half-life

* Methadone up to 96 h

* 1–3 days after last use

* Methadone withdrawal lasts 7–14 days
* Some last for several weeks

## Pathophysiology

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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)

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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

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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

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Opioid withdrawal must be differentiated from:[10]

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

Disease | Prominent clinical features | Investigations

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Hyperthyroidism | The main symptoms include:

* Palpitations
* Insomnia
* Anxiety
* Weight loss
* Heat intolerance
* Diarrhea
* Depending on the underlying diagnosis, the patient might have exophthalmos 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:

* A 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:

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.

* Vasomotor instability in the form of hot flashes, 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), arthralgia, 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:

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:

* 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 in MEN patients.

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

| Diagnostic lab findings associated with pheochromocytoma include:

* Elevated plasma and urinary catecholamines and metanephrines
* Elevated urinary vanillyl mandelic acid

## Epidemiology and Demographics

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* 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

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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

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* 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

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### Diagnostic Criteria

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#### DSM-V Diagnostic Criteria for Opioid Withdrawal[10]

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“  |

* 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.

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### History and Symptoms

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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

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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

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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

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

### Echocardiography or Ultrasound

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

### CT Scan

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There are no CT scan findings associated with opioid withdrawal.

### MRI

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There are no MRI findings associated with opioid withdrawal.

### Other Imaging Findings

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There are no other imaging findings associated with opioid withdrawal.

### Other Diagnostic Studies

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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

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### Medical Therapy

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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

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

### Prevention

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* 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

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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).CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)

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