Drug Withdrawal: Pearls and Pitfalls

Authors: Drew A. Long, BS (@drewlong2232, Vanderbilt University School of Medicine, US Army) and Brit Long, MD (@long_brit, EM Attending Physician at SAUSHEC, USAF) // Edited by: Courtney Cassella, MD (@Corablacas, EM Resident Physician, Icahn SoM at Mount Sinai) and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

Case 1: A 45-year-old male presents to the ED with one day of myalgias, sweating, and anxiety. He is tachycardic and appears uncomfortable.  On examination, you notice lacrimation, excessive yawning, and a significant tremor.  He denies any illicit drug use, but he does have a history of chronic back pain for which he uses oxycodone. However, he ran out of oxycodone three days ago.

 Case 2: A 33-year-old female presents to the ED feeling depressed.  She has also been sleeping 16 hours per day and experiencing extreme hunger. She is trying to stop meth, for which her boyfriend was recently incarcerated.  Her examination and vital signs are normal, but she wants to know if she needs to be concerned about her symptoms, and more importantly, what she can do to feel better.


This is the second of a two-part series covering withdrawal states. Our first post evaluated the diagnosis and management of alcohol withdrawal. This second discussion will not be all encompassing, but it will cover the more commonly abused agents.



The incidence of opioid abuse has risen drastically in the United States.  Worldwide, between 26.4 million and 36 million people abuse opioids.1 In 2012, an estimated 2.1 million people in the United States had prescription opioid substance use disorders.2 The number of prescription opioids has escalated from an estimated 76 million people in 1991 to 207 million in 2013.3 Specifically, the number of heroin users has increased from 373,000 in 2007 to 681,000 in 2013.4 Along with this increase in opioid prescriptions and opioid abuse, the number of people dependent on opioids and number of opioid overdoses have also increased.

screen-shot-2016-09-10-at-12-11-58-amOpioids are most commonly used for pain management.  Opioids act on transmembrane neurotransmitter receptors (mu, kappa, delta) coupled to G proteins.  These receptors are located in both the central and peripheral nervous systems.  When these receptors are stimulated by opioids, the signal transduction pathway leads to the effects of analgesia in addition to triggering the reward center.5

Opioid withdrawal occurs when a person who is physiologically dependent on opioids either reduces or abruptly stops using opioids.  The diagnosis of opioid withdrawal is made by the history and physical exam.  The signs and symptoms of opioid withdrawal are often vague and nonspecific.  While opioid withdrawal may be uncomfortable, it is rarely life-threatening.  Broad categories of manifestations include gastrointestinal distress, flu-like symptoms, and sympathetic nervous system arousal, which are categorized in Table 1.6


Other common symptoms of opioid withdrawal include yawning, sneezing, dizziness, myalgias, arthralgias, and leg cramps.  While not always present, yawning and lacrimation are helpful due to high specificity for opioid withdrawal.7

The course of opioid withdrawal greatly depends upon which opioid the patient was using.  An opioid must be consumed daily for 3 weeks or more for the patient to become physiologically dependent.  The withdrawal period typically lasts two to three times the half-life of the opioid.6 Characteristics of commonly abused opioids are shown in Table 2. screen-shot-2016-09-10-at-12-15-48-am

A thorough history and physical is vital when assessing a patient suspected of undergoing opioid withdrawal.  Concomitant substance use disorders, mental disorders, and other disorders are common in patients with opioid use disorder.  Nicotine use has been associated with up to 85% of patients undergoing opioid withdrawal.  Mental disorders may be found in up to 70% of patients undergoing opioid withdrawal.  These include major depression, panic disorder, general anxiety disorder, and post traumatic stress disorder.9-11 A systemic review found a prevalence of co-occurring depressive disorders to be 27% and co-occurring anxiety disorders to be 29%.12 It is important to consider that opioid withdrawal may exacerbate co-occurring mental disorders.  Other disorders to consider include comorbid alcohol and benzodiazepine withdrawal, comorbid cocaine and methamphetamine withdrawal, or personality disorders.

Mimics of opioid withdrawal include other intoxication or withdrawal syndromes.  As opioid users usually have insight into their addiction, the history is often enough to establish a diagnosis.  Several other withdrawal syndromes, specifically ethanol and sedative-hypnotic withdrawal, may appear similar to opioid withdrawal.  However, these are much more likely to cause significant tachycardia and hypertension compared to opioid withdrawal.  Additionally, these syndromes may produce seizures and/or hyperthermia.  Another syndrome that may mimic opioid withdrawal is sympathomimetic intoxication.  However, similar to ethanol and sedative-hypnotic withdrawal, this syndrome produces much more severe findings (mydriasis, agitation, tachycardia, hypertension) than opioid withdrawal.7

Opioid withdrawal is not life-threatening, and the mainstay of treatment is management of symptoms.  Patients suffering from opioid withdrawal can undergo medically supervised opioid withdrawal (detoxification).  Symptoms from withdrawal can be managed with multiple agents, including opioids and non-opioids.  Popular agents utilized for managing opioids withdrawal include methadone and buprenorphine.  Methadone is a long-acting opioid, while buprenorphine is a partial opioid agonist.7  Methadone, which may be used in a psychiatric setting, is not an option for ED providers due to inability for patient follow up in the ED setting and risk of overdose.  Buprenorphine is a partial opioid receptor agonist with high affinity. These properties provide a lower risk of respiratory depression which, along with its long duration of action, make it an effective and safe therapy for opioid withdrawal. However, its use is also controversial. This medication is a synthetic agent with less abuse potential and dependence, acting as a partial agonist. If a patient is opioid dependent and given this medication, withdrawal will occur, as buprenorphine has higher receptor affinity and less activity than other opioids.  It is approved in the U.S. for outpatient treatment of opioid dependence, given once daily. Providers are required to have a special waiver from the DEA to prescribe this medication.



Benzodiazepines (BZDs) are sedative-hypnotic agents used for sedation and treatment of anxiety, seizures, withdrawal states, and insomnia.  BZDs act via modulation of the gamma-aminobutyric acid A (GABA-A) receptor, which is the main inhibitory neurotransmitter of the central nervous system.13


BZD withdrawal occurs when any chronic user abruptly decreases or ceases BZD consumption.  Rapid recognition and management of BZD withdrawal is vital as it can be life-threatening.  The signs and symptoms of BZD withdrawal are similar to those associated with withdrawal from other sedative-hypnotics (barbiturates, alcohol, etc.).  Milder symptoms of BZD withdrawal can include headache, nausea, vomiting, tremors, insomnia, agitation, and anxiety.  More severe symptoms may include hallucinations, psychotic behavior, altered mental status, and seizures.  Seizures, while uncommon, are a feared complication of benzodiazepine withdrawal.13,14

Like opioids, the timing of symptoms varies according to the half-life of the BZD involved.  Table 3 depicts the half-life of commonly abused BZDs.  In patients abusing BZDs with shorter half-lives (such as Xanax, Ativan, and Versed) withdrawal symptoms may occur in 1-2 days, while withdrawal symptoms from BZDs with longer half-lives may occur up to two weeks after cessation.15,16


Management of BZD withdrawal depends first on accurate diagnosis by history and characteristic signs and symptoms described above. After identifying withdrawal, treatment should be initiated with a BZD that has a prolonged clinical effect, such as diazepam.18-20 This BZD should be administered intravenously with a goal of eliminating symptoms of withdrawal without causing excessive sedation.  Patients undergoing withdrawal experiencing milder symptoms may be treated with a long-acting oral BZD.  While other agents have been used to treat BZD withdrawal (such as beta blockers, antipsychotics, SSRIs, and antihistamines), they have all been shown to be inferior with standard treatment.18,20 Valproic acid and carbamazepine have not shown any additional benefit and have not been extensively studied to be included in the standard management of BZD withdrawal.21,22

There are several scales for monitoring BZD withdrawal.  The Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) and Clinical Institute Withdrawal Assessment Scale-Benzodiazepines (CIWA-B) are two of the more commonly utilized scales.  The BWSQ is a 20-item self-report, validated questionnaire, while the CIWA-B uses 22-items to assess and monitor the severity of symptoms from withdrawal.  While these scales are helpful, they should not be solely relied upon to monitor complicated withdrawal.  Monitoring of withdrawal should always include careful observation and evaluation of the patient in addition to the Emergency Physician’s clinical judgment.23



Cocaine is a stimulant associated with many life-threatening complications, including seizure, stroke, and myocardial infarction.  Cocaine exerts its effect by enhancing monoamine neurotransmitters in the brain (dopamine, norepinephrine, and serotonin) via blockade of presynaptic reuptake of these neurotransmitters, both in the central and peripheral nervous systems.24


Withdrawal from cocaine, while uncomfortable, is not life-threatening.  The cocaine withdrawal syndrome is highlighted by prominent psychological features.  These include depression, anxiety, fatigue, difficulty concentrating, anhedonia, increased appetite, increased sleep, increased dreaming, and increased craving for cocaine.25,26  Intense symptoms at the beginning of the withdrawal period (the crash) may occur, which may include psychomotor retardation and severe depression with suicidal ideation.  Signs of cocaine withdrawal are typically minor and include musculoskeletal pain, tremors, chills, and involuntary motor movement.27Another potential complication of withdrawal includes myocardial ischemia, which is most commonly seen in the first week of withdrawal.28

Treatment for cocaine withdrawal is mainly supportive, including encouraging the patient to sleep and eat as necessary (especially if the patient is experiencing hypersomnia and increased appetite).29 No drugs have been shown to be beneficial in treating cocaine withdrawal.  For patients with severe agitation or insomnia, a short acting benzodiazepine may be helpful.  Patients with depression lasting several weeks or suicidal ideation may require admission to a psychiatric unit and treatment with antidepressants.29,30 As the relapse risk is high during the early withdrawal period, patients should be referred to an addiction treatment program for further support in abstaining from cocaine use.  Discharge from the ED is appropriate if the patient is stable with no other psychiatric concerns (severe depression, suicidal thoughts, etc.).



Similar to cocaine, methamphetamine is a stimulant that causes the release of monoamine neurotransmitters, while also blocking reuptake.  Amphetamine-type stimulants are the fastest rising drug of abuse worldwide and the second most widely used class of illicit drugs worldwide.31-33 Individuals with chronic amphetamine use have a high incidence of comorbid psychiatric disorders, including primary psychotic disorder, mood disorder, anxiety disorders, and ADHD.34 Depressive symptoms also commonly occur with methamphetamine use.35


Opposed to the euphoric effect of methamphetamine intoxication, withdrawal is marked by a dysphoric state, which is highlighted by depressive symptoms.  These include anhedonia, depression, anxiety, and social inhibition.26 Watson et al. reported that depression peaked at 2-3 days and persisted for 4 days following amphetamine cessation.36 Based on the initial dysphoric state, methamphetamine withdrawal can mimic major depressive disorder.  Other symptoms include irritability, poor concentration, hyperphagia, insomnia or hypersomnia, and psychomotor agitation or retardation.  These symptoms typically last 5 days to two weeks.37

Similar to the management of cocaine withdrawal, the mainstay of amphetamine withdrawal is supportive therapy.  No available treatment has shown to be effective in treatment of amphetamine withdrawal.  Similar to cocaine withdrawal, the patient must be evaluated for severity of depressive symptoms and suicidal ideation and receive in-patient psychiatric treatment if necessary.  If the patient is not actively suicidal nor is suffering from major depressive symptoms, they can be discharged home with warning to return if depressive symptoms worsen.  Importantly, they should be referred to an addiction support and treatment program to help in cessation of amphetamine abuse.38



Caffeinated beverages are the most consumed stimulants in the world.  About 90% of adults in the world consume caffeine on a daily basis.39 Consumption of up to 400 mg of caffeine on a daily basis is safe for most adults.40 Table 3 lists the caffeine content of various beverages.  The most common caffeinated beverages include coffee, tea, and soft drinks.  Caffeine is an antagonist of central and peripheral nervous system adenosine receptors, stimulating the release of excitatory neurotransmitters.41


Caffeine withdrawal, while uncomfortable, is not associated with any adverse medical consequences.  Withdrawal symptoms include headache, fatigue, decreased energy, decreased attentiveness, sleepiness, decreased sense of wellbeing, depressed mood, difficulty concentrating, and irritability.  Of these, headache is the most common symptom experienced.  It is estimated that only about 50 percent of chronic caffeine users experience withdrawal symptoms.  Symptoms typically begin to occur 12-24 hours after ceasing caffeine intake, peak at one to two days, and resolve within one week.43

Management of caffeine withdrawal is supportive.  Patients should be reassured that caffeine withdrawal is not associated with any adverse events or complications.  If the patient’s headache is severe, an anti-inflammatory agent such as ibuprofen can be utilized.  The patient can also be offered caffeine (any caffeinated beverage or soft drink), as re-administration of caffeine reverses the withdrawal symptoms.

Case Resolution

Case 1:  This 45-year-old male was diagnosed with opioid withdrawal from the history and physical.  On further evaluation, he denied any other substance abuse and had no psychiatric history or comorbidities.  As the patient requested detoxification, he was provided information for detoxification centers.

Case 2:  This 33-year-old female was concerned about cessation of methamphetamine.  On further evaluation, she stated she had been feeling down lately but denied any anhedonia or suicidal ideation.  On further evaluation, she admitted to intermittent alcohol use but denied any other substance abuse.  You reassure her that though these symptoms may last for up to two weeks, they are not life-threatening and will improve.  She expresses interest in cessation of methamphetamine abuse, and you refer her to an amphetamine addiction support group and counseling center.


  • The signs and symptoms of opioid withdrawal are often vague and nonspecific, and include gastrointestinal distress, flu-like symptoms, and sympathetic nervous system arousal. Yawning and lacrimation are specific for opioid withdrawal.
  • Alcohol withdrawal and stimulant intoxication can mimic opioid withdrawal. However, these are much more likely to cause significant tachycardia and hypertension compared to opioid withdrawal.
  • Quick recognition of benzodiazepine withdrawal is essential, as this syndrome can be life-threatening.
  • The onset and duration of symptoms of BZD withdrawal depends on the half-life of the BZD.
  • The mainstay of therapy for BZD withdrawal is a BZD with a prolonged clinical effect, with the goal of alleviating symptoms.
  • Both cocaine and amphetamine withdrawal can manifest with depressive symptoms. Patients should be evaluated for suicidal ideation and hospitalized if necessary.
  • Treatment for both cocaine and amphetamine withdrawal is supportive, in addition to consideration and care for any psychological symptoms.
  • Caffeine withdrawal is not associated with any adverse complications. If patients are requesting treatment for withdrawal symptoms, ibuprofen or a caffeinated beverage can provide timely relief.


References/Further Readin

  1. “World Drug Report 2012.”   United Nations Office on Drugs and Crime. http://www.unodc.org/unodc/en/data-and-analysis/WDR-2012.html
  2. “Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings.” NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013.
  3. “America’s Addiction to Opioids: Heroin and Prescription Drug Abuse.” National Institute on Drug Abuse. https://www.drugabuse.gov/about-nida/legislative-activities/testimony-to-congress/2016/americas-addiction-to-opioids-heroin-prescription-drug-abuse#_ftn5
  4. Jones CM, Logan J, Gladden RM, Bohm MK. Vital Signs: Demographic and Substance Use Trends Among Heroin Users-United States, 2002-2013. MMWR Morb Mortal Wkly Rep. 2015 Jul;64(26):719-25.
  5. Strain E. Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis. UpToDate. May 2016.
  6. Sevarino K. Opioid withdrawal: Clinical manifestations, course, assessment, and diagnosis. UpToDate. May 2016.
  7. Stolbach A, Hoffman RS. Opioid withdrawal in the emergency setting. UpToDate. May 2016.
  8. Choo C. Medications Used in Opioid Maintenance Treatment. US Pharm. 2009;34(11):40-53.
  9. Teoh BGJ, Yee A, Habil MH. Psychiatric comorbidity among patients on methadone maintenance therapy and its influence on quality of life. Am J Addict. 2016 Jan;25(1): 49-55. Epub 2015 Dec 21.
  10. Fareed A, Eilender P, Haber M, Bremner J, Whitfield N, Drexler K. Comorbid posttraumatic stress disorder and opiate addiction: a literature review. J Addict Dis. 2013;32(2):168-79.
  11. Rosen D, Smith ML, Reynolds CF. The prevalence of mental and physical health disorders among older methadone patients. Am J Geriatr Psychiatry. 2008 Jun;16(6):488-97.
  12. Goldner EM, Lusted A, Roerecke M, Rehm J, Fischer B. Prevalence of Axis-1 psychiatric (with focus on depression and anxiety) disorder and symptomatology among non-medical prescription opioid users in substance use treatment: systematic review and meta-analysis. Addict Behav. 2014 Mar;39(3):520-31. Epub 2013 Dec 2.
  13. Greller H, Gupta A. Benzodiazepine poisoning and withdrawal. UpToDate. May 2016.
  14. Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl). 2004;176(1):1.
  15. Hood HM, Metten P, Crabbe JC, Buck KJ. Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11. Genes Brain Behav. 2006;5(1):1.
  16. Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, et al. Benzodiazepine dependence: focus on withdrawal syndrome. Ann Pharm Fr. 2009 Nov;67(6):408-13. Epub 2009 Sep 18.
  17. Gussow L, Carlson A. Rosen’s Emergency Medicine, 8th Ed., Chapter 165, 2076-2083.e1. Philadelphia PA: Saunders, 2014.
  18. Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs. 2009;23(1):19.
  19. Voshaar RC, Couvee JE, van Balkom AJ, Mulder PG, Zitman FG. Strategies for discontinuing long-term benzodiazepine use: meta-analysis. Br J Psychiatry. 2006 Sep;189:213-20.
  20. Parr JM, Kavanagh DJ, Cahill L, Mitchell G, McD Young R. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction. 2009 Jan;104(1):13-24. Epub 2008 Oct 31.
  21. Lum E, Gorman SK, Slavik RS. Valproic acid management of acute alcohol withdrawal. Ann Pharmacother. 2006;40(3):441.
  22. Schweizer E, Rickels K, Case WG, Greenblatt DJ. Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy. Effects on withdrawal severity and outcome. Arch Gen Psychiatry. 1991;48(5):448.
  23. Alvanzo A. Management of Substance Withdrawal in Acutely Ill Medical Patients: Opioids, Alcohol, and Benzodiazepines. Society of General Internal Medicine 36th Annual Meeting. 27 April 2013.
  24. Gorelick DA. Cocaine use disorder in adults: Epidemiology, pharmacology, clinical manifestations, medical consequences, and diagnosis. UpToDate. May 2016.
  25. Coffey SF, Dansky BS, Carrigan MH, Brady KT. Acute and protracted cocaine abstinence in an outpatient population: a prospective study of mood, sleep and withdrawal symptoms. Drug Alcohol Depend. 2000;59(3):277.
  26. Lago JA, Kosten TR. Stimulant withdrawal. Addiction. 1994;89(11):1477.
  27. Khantzian EJ, McKenna GJ. Acute toxic and withdrawal reactions associated with drug use and abuse. Ann Intern Med. 1979;90(3):361.
  28. Nademanee K, Gorelick DA, Josephson MA, Ryan MA, Wilkins JN, Robertson HA, et al. Myocardial ischemia during cocaine withdrawal. Ann Intern Med. 1989;111(11):876.
  29. Schuckit MA. Drug and Alcohol Abuse. A Clinical Guide to Diagnosis and Treatment, 6th ed, Springer, New York 2007.
  30. Weiss RD, Greenfield SF, Mirin SM. Intoxication and withdrawal syndromes. In: Manual of Psychiatric Emergencies, Hyman, SE, (Ed), Little, Brown & Co, Boston, MA 1994. p. 279-93.
  31. Degenhardt L, Mathers B, Guarinieri M, Panda S, Phillips B, Strathdee SA, et al. Meth/amphetamine use and associated HIV: Implications for global policy and public health. Int J Drug Policy. 2010 Sep;21(5):347-58. Epub 2010 Feb 1.
  32. World Drug Report 2010, United Nations Publication, Vienna 2010.
  33. UNODC. World Drug Report 2012, Contract No: E.12.XI.1, United Nations Publication, New York 2012.
  34. Salo R, Flower K, Kielstein A, Leamon MH, Nordahl TE, Galloway GP. Psychiatric comorbidity in methamphetamine dependence. Psychiatry Res. 2011 Apr;186(2-3):356-61. Epub 2010 Nov 4.
  35. Zorick T, Sugar CA, Hellemann G, Shoptaw S, London ED. Poor response to sertraline in methamphetamine dependence is associated with sustained craving for methamphetamine. Drug Alcohol Depend. 2011 Nov;118(2-3):500-3. Epub 2011 May 17.
  36. Watson R, Hartmann E, Schildkraut JJ. Amphetamine withdrawal: affective state, sleep patterns, and MHPG excretion. Am J Psychiatry. 1972 Sep;129(3):263-9.
  37. McGregor C, Srisurapanont M, Jittiwutikarn J, Laobhripatr S, Wongtan T, White JM. The nature, time course and severity of methamphetamine withdrawal. Addiction. 2005 Sep;100(9):1320-9.
  38. Srisurapanont M, Jarusuraisin N, Kittirattanapaiboon P. Treatment for amphetamine withdrawal. Cochrane Library. 23 October 2001.
  39. Medicines in my Home: Caffeine and Your Body. Food and Drug Administration. http://www.fda.gov/downloads/UCM200805.pdf
  40. Heckman MA, Weil J, Gonzalez de Mejia E. Caffeine (1,3,7-trimethylxanthine) in foods: a comprehensive review on consumption, functionality, safety, and regulatory matters. J Food Sci. 2010 Apr;75(3):R77-87.
  41. Freholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev. 1999;51(1):83.
  42. Bordeaux B, Lieberman HR. Benefits and risks of caffeine and caffeinated beverages. UpToDate. May 2016.
  43. Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl). 2004;176(1):1.

Leave a Reply

Your email address will not be published. Required fields are marked *