Withdrawal Syndromes Treatment & Management
- Author: Nathanael J McKeown, DO; Chief Editor: Asim Tarabar, MD more...
The American Academy of Pediatrics has issued a new guideline on the management of iatrogenically induced opioid dependence and withdrawal in children.[11, 12]
Recommendations include the following:
Children exposed to opioids for longer than 14 days usually need to be weaned with a gradual reduction in dose over time
Pain status should be assessed at the time of weaning
Withdrawal symptoms should be assessed with the Sophia Observation Withdrawal Symptoms Scale, which is validated in children, or another validated scale
Weaning protocols should account for the length of opioid exposure and total daily opioid dose
Biofeedback and other behavioral strategies might help with sleep, anxiety/mood symptoms, and pain-related symptoms
Patients in alcohol withdrawal may have a number of medical problems (eg, cardiac or respiratory arrest, multiple trauma) that may take priority in terms of management. Manage these presentations according to existing prehospital protocols.
Patients withdrawing from alcohol sometimes present to the prehospital system as a result of a withdrawal seizure requiring their transport to the ED. Established prehospital protocols for seizures are generally appropriate for these patients.
Administration of intravenous glucose to patients with seizures is controversial because this is thought to precipitate acute Wernicke encephalopathy in patients with chronic alcoholism unless thiamine is also administered. How soon thiamine must be administered after a glucose load to prevent Wernicke encephalopathy is unknown. The time to transport a patient to the ED seems insufficient to result in this complication. In general, withholding glucose until after thiamine is administered is not necessary and potentially life threatening. Thiamine takes several hours to enter into cells, whereas the effects of glucose are almost immediate.
On occasion, patients in advanced alcohol withdrawal may be too combative to safely transport them or to apply physical restraints. In these cases, administer a sedative, such as lorazepam, before transport is attempted.
Emergency Department Care
As in the prehospital setting, immediately life-threatening conditions must be treated first.
Treatment goals for ethanol or sedative-hypnotic withdrawal are as follows:
Stabilization of the patient's condition and prevention of syndrome progression
Treatment of withdrawal by substituting sedative medications
Determination of underlying medical problems and initiation of appropriate treatments
Appropriate disposition for ongoing care and addiction treatment
If bedside glucose testing reveals hypoglycemia, glucose given as dextrose 50% in water (D50W) 25-50 mL is indicated. Concurrent administration of thiamine 100 mg IV is also indicated.
Alcohol withdrawal seizures are typically brief and followed by a brief postictal period. The occurrence of more than 3 seizures or status epilepticus is rare and mandates further investigation.
Most alcohol withdrawal seizures are self-terminating; however, if prolonged, they are usually quickly terminated with benzodiazepines (eg, diazepam, lorazepam). Lorazepam is preferred because it has a long redistribution time that enables it to have prolonged effectiveness, protecting the patient from recurrent seizures. Lorazepam is less dependent on hepatic metabolism than other benzodiazepines, and hepatic function may be impaired in chronic alcoholics.
Occurrence of seizures should prompt bedside glucose determination.
Patients presenting in mild alcohol withdrawal may be treated on an outpatient basis, provided that no underlying conditions require inpatient treatment.
Various regimens are described for outpatient management of alcohol withdrawal syndrome, but the simplest involve administering benzodiazepines with a short half-life and few metabolites (eg, oxazepam) to prevent the accumulation of sedating compounds. This drug is initially administered frequently and in higher doses, with gradual lengthening of the dosing interval and reduction of the dose over 1 week.
Patients must be reliable enough to adjust their own medications, and they must be able to tolerate oral medications.
Low doses of clonidine (eg, 0.1-0.2 mg PO tid) can help reverse central adrenergic discharge, thus relieving tachycardia, hypertension, tachypnea, tremor, and (possibly) some craving for alcohol.
The use of beta-blockers to diminish tachycardia, hypertension, and perhaps anxiety has been described and are occasionally useful; however, their effects mask the warning signs of autonomic hyperactivity if the patient develops DT.
Patients presenting with moderate or severe alcohol withdrawal and DT require inpatient treatment and consideration of ICU admission. Initial emergency care includes the following steps:
The patient should be placed in a quiet room with low lighting.
Physical restraints may be applied to prevent physical injury pending adequate sedation.
In severe withdrawal, abnormalities of fluid, electrolytes, and nutrition are common. The patient's blood chemistry guides appropriate and adequate fluid replacement.
Compared with mild withdrawal, larger doses of substitute medications, as outlined below, are required to treat withdrawal.
Sedative-hypnotic drugs are the primary agents for treatment of alcohol withdrawal syndrome because they are cross-tolerant drugs that modulate GABA functions. These medications commonly include benzodiazepines, barbiturates, propofol, and (in rare cases) ethanol. Clomethiazole and GHB are used in Europe as substitute medications for alcohol withdrawal syndrome. They are currently not available in the United States for the treatment of alcohol-withdrawal syndrome.
No evidence suggests that one sedative-hypnotic is more effective than another, but benzodiazepines have fewer adverse effects.
Benzodiazepines are the mainstay of therapy in the United States and are the primary agents used as substitutes and cross-tolerant medications for alcohol, sedative-hypnotic, or GHB withdrawal. They substitute for the GABA-modulating effects of alcohol and other drugs and are extremely safe and effective.
Benzodiazepines can be administered by using fixed-schedule or symptom-triggered regimens with or without loading. The efficacy profile is better with symptom-triggered therapy than with fixed-schedule dosing in patients admitted for detoxification  but not necessarily for the treatment of DT.
The use of intravenous drugs allows immediate assessment of treatment adequacy compared with the lag time associated with absorption of oral medications. This is a particularly useful factor when using symptom-triggered therapy.
The Clinical Institute Withdrawal of Alcohol Scale, Revised (CIWA-Ar) has been validated and is used for medication administration in symptom-triggered therapy.
The various benzodiazepines have similar efficacies in treating alcohol withdrawal syndrome, though one may choose one drug over another on the basis of the route of administration, onset of effects on agitation, elimination half-life, active metabolites, and/or duration of effects. Typically, a loading dose is given to achieve light sedation, followed by maintenance medication. The amount of medication required to achieve an adequate loading dose varies with the severity of withdrawal.
Lorazepam can be administered intravenously, intramuscularly, or orally. Lorazepam provides a long duration of seizure control because of its slow redistribution. It may have decreased risk of sedation among those with liver disease because of its short half-life and absence of active metabolites. The dosing is 1-4 mg every 5-15 minutes until adequate control of agitation is achieved. Large and rapid doses of lorazepam may cause cardiovascular toxicity due to propylene glycol, the diluent.
Diazepam can be administered intravenously, orally, or PR. Diazepam rapidly controls agitation because of its rapid distribution secondary to its high lipid solubility. However, it has a long duration of action. Its active metabolites help smooth the course of withdrawal and limit breakthrough symptoms; however, prolonged sedation is a risk. Diazepam is initially given at a dose of 5 mg IV. The drug is repeated at 5-20 mg per dose every 5-15 minutes until adequate control of agitation is achieved. After agitation is controlled, an hourly dose is given as needed to maintain light somnolence.
Total dosing of intravenous diazepam should not routinely exceed 100 mg/h or 250 mg in 8 hours. Total dosing of intravenous lorazepam should not routinely exceed 20 mg/h or 50 mg in 8 hours.
Short-acting agents have a higher incidence of rebound symptoms. Short-acting benzodiazepines, such as oxazepam and midazolam, must be tapered carefully to avoid breakthrough symptoms and seizures.
Intermittent intravenous administration of long-acting benzodiazepines and continuous intravenous infusion of short-acting benzodiazepines is effective and acceptable.
In cases not responding to massive doses of benzodiazepines, intravenous infusion of propofol or intravenous boluses of barbiturates (phenobarbital and pentobarbital) should be added as second-line GABA modulators. This treatment is typically effective as the drugs act on different sets of GABA receptors. Propofol also modulates glutamate (NMDA) receptors. Dexmedetomidine is a newer intravenous α -2 agonist (similar to clonidine but more selective) FDA approved for sedation. A continuous infusion produces sedation, anxiolysis, and sympatholysis with no activity at the GABA or opioid receptors and is without respiratory compromise. Several case series have demonstrated success of using of dexmedetomidine in conjunction with benzodiazepines for reducing total amount of benzidiazepines.[17, 18, 19] Further research is needed before it can be recommended routinely.
Neuroleptics are not used as primary agents because studies have demonstrated the superior efficacy of sedative-hypnotics in reducing duration of alcohol withdrawal syndrome and associated mortality.
In a severely agitated patient, neuroleptics such as haloperidol 5 mg IV or IM may be added to sedative-hypnotic agents as an adjunctive therapy and repeated with caution in 30-60 minutes if needed to control agitation. Caution must be taken because haloperidol has been known to decrease the seizure threshold as well as prolong the QT interval.
Several medications are reported to be helpful adjuncts to benzodiazepines and other GABA modulators (barbiturates and propofol ) in the treatment of refractory alcohol-withdrawal syndrome, but they are not recommended as a monotherapy. These include baclofen, haloperidol, carbamazepine, valproic acid, clonidine, and beta-blockers (atenolol).
Adjunctive ketamine reduced benzodiazepine requirements and was well tolerated at low doses in a retrospective study of 23 adult patients with alcohol withdrawal syndrome. Mean initial infusion dose was 0.21 mg/kg/h; median total infusion rate was 0.20 mg/kg/h. Median change in benzodiazepine requirements at 12 and 24 hours after initiating ketamine were -40.0 and -13.3 mg, respectively.
Research in treatment for alcohol withdrawal using less sedating medications have included gabapentin and pregabalin. However, larger trials are needed before this can be recommended further as monotherapy.
Treatment of other types of withdrawal may include the following:
Sedative-hypnotic withdrawal is treated with substituting drugs that have a long duration of action, either a benzodiazepine or phenobarbital, in a maintenance dose for a few days followed by a gradually decreasing dose over 2-3 weeks.
GHB withdrawal can initially be treated with high doses of benzodiazepines, though anecdotally, refractory cases have responded to other sedative agents, such as pentobarbital, chloral hydrate, and baclofen. 
Opioid withdrawal is treated with a long-acting opioid agonist, such as methadone 20-35 mg/d or buprenorphine 4-16 mg/d, and then tapered over days to weeks. Clonidine 0.1-0.2 mg every 4-8 hours also decreases the severity of symptoms. Long-acting benzodiazepines can be added to control insomnia and muscle cramps.
Stimulant-withdrawal syndrome is treated by observation alone and does not require any specific medications.
Monte R, Rabunal R, Casariego E, Lopez-Agreda H, Mateos A, Pertega S. Analysis of the factors determining survival of alcoholic withdrawal syndrome patients in a general hospital. Alcohol Alcohol. 2010 Mar-Apr. 45(2):151-8. [Medline].
Goodson CM, Clark BJ, Douglas IS. Predictors of severe alcohol withdrawal syndrome: a systematic review and meta-analysis. Alcohol Clin Exp Res. 2014 Oct. 38 (10):2664-77. [Medline].
Tarabar AF, Nelson LS. The gamma-hydroxybutyrate withdrawal syndrome. Toxicol Rev. 2004. 23(1):45-9. [Medline].
Wojtowicz JM, Yarema MC, Wax PM. Withdrawal from gamma-hydroxybutyrate, 1,4-butanediol and gamma-butyrolactone: a case report and systematic review. CJEM. 2008 Jan. 10(1):69-74. [Medline].
Mancino MJ, Gentry BW, Feldman Z, Mendelson J, Oliveto A. Characterizing methamphetamine withdrawal in recently abstinent methamphetamine users: a pilot field study. Am J Drug Alcohol Abuse. 2011 Mar. 37(2):131-6. [Medline]. [Full Text].
Findley JK, Park LT, Siefert CJ, Chiou GJ, Lancaster RT, Demoya M, et al. Two Routine Blood Tests-Mean Corpuscular Volume and Aspartate Aminotransferase-as Predictors of Delirium Tremens in Trauma Patients. J Trauma. 2010 Jan 20. [Medline].
Chenet L, McKee M, Leon D, Shkolnikov V, Vassin S. Alcohol and cardiovascular mortality in Moscow; new evidence of a causal association. J Epidemiol Community Health. 1998 Dec. 52(12):772-4. [Medline].
Alexandre J, Benouda L, Champ-Rigot L, Labombarda F. Takotsubo cardiomyopathy triggered by alcohol withdrawal. Drug Alcohol Rev. 2011 Jul. 30(4):434-7. [Medline].
Otero-Anton E, Gonzalez-Quintela A, Saborido J, Torre JA, Virgos A, Barrio E. Prolongation of the QTc interval during alcohol withdrawal syndrome. Acta Cardiol. 1997. 52(3):285-94. [Medline].
Anderson P. New Guideline on Opioid Withdrawal in Children. Available at http://www.medscape.com/viewarticle/818951. Accessed: September 20, 2015.
Galinkin J, Koh JL. Recognition and management of iatrogenically induced opioid dependence and withdrawal in children. Pediatrics. 2014 Jan. 133(1):152-5. [Medline].
Fisher CM. Prompt responses to the administration of ethanol in the treatment of the alcohol withdrawal syndrome (AWS). Neurologist. 2009 Sep. 15(5):242-4. [Medline].
Cassidy EM, O'Sullivan I, Bradshaw P, Islam T, Onovo C. Symptom-triggered benzodiazepine therapy for alcohol withdrawal syndrome in the emergency department: a comparison with the standard fixed dose benzodiazepine regimen. Emerg Med J. 2011 Oct 19. [Medline].
Hack JB, Hoffmann RS, Nelson LS. Resistant alcohol withdrawal: does an unexpectedly large sedative requirement identify these patients early?. J Med Toxicol. 2006 Jun. 2(2):55-60. [Medline].
Muzyk AJ, Fowler JA, Norwood DK, Chilipko A. Role of a2-agonists in the treatment of acute alcohol withdrawal. Ann Pharmacother. 2011 May. 45(5):649-57. [Medline].
Rayner SG, Weinert CR, Peng H, Jepsen S, Broccard AF,. Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the ICU. Ann Intensive Care. 2012. 2(1):12. [Medline].
Tolonen J, Rossinen J, Alho H, Harjola VP. Dexmedetomidine in addition to benzodiazepine-based sedation in patients with alcohol withdrawal delirium. Eur J Emerg Med. 2013 Dec. 20(6):425-7. [Medline].
Muzyk AJ, Revollo JY, Rivelli SK. The use of dexmedetomidine in alcohol withdrawal. J Neuropsychiatry Clin Neurosci. 2012 Summer. 24(3):E45-6. [Medline].
Hayner CE, Wuestefeld NL, Bolton PJ. Phenobarbital treatment in a patient with resistant alcohol withdrawal syndrome. Pharmacotherapy. 2009 Jul. 29(7):875-8. [Medline].
Subramaniam K, Gowda RM, Jani K, et al. Propofol combined with lorazepam for severe poly substance misuse and withdrawal states in intensive care unit: a case series and review. Emerg Med J. 2004 Sep. 21(5):632-4. [Medline]. [Full Text].
Lyon JE, Khan RA, Gessert CE, Larson PM, Renier CM. Treating alcohol withdrawal with oral baclofen: a randomized, double-blind, placebo-controlled trial. J Hosp Med. 2011 Oct. 6(8):469-74. [Medline].
Eyer F, Schreckenberg M, Hecht D, Adorjan K, Schuster T, Felgenhauer N, et al. Carbamazepine and valproate as adjuncts in the treatment of alcohol withdrawal syndrome: a retrospective cohort study. Alcohol Alcohol. 2011 Mar-Apr. 46(2):177-84. [Medline].
Kahkonen S, Bondarenko B, Lipsanen J, et al. Cardiovascular effects of propranolol in patients with alcohol dependence during withdrawal. Int J Psychophysiol. 2007 Dec. 66(3):225-30. [Medline].
Wong A, Benedict NJ, Armahizer MJ, Kane-Gill SL. Evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome. Ann Pharmacother. 2015 Jan. 49 (1):14-9. [Medline].
Bonnet U, Hamzavi-Abedi R, Specka M, Wiltfang J, Lieb B, Scherbaum N. An open trial of gabapentin in acute alcohol withdrawal using an oral loading protocol. Alcohol Alcohol. 2010 Mar-Apr. 45(2):143-5. [Medline].
Oulis P, Konstantakopoulos G. Pregabalin in the treatment of alcohol and benzodiazepines dependence. CNS Neurosci Ther. 2010 Spring. 16(1):45-50. [Medline].
Weinberg JA, Magnotti LJ, Fischer PE, et al. Comparison of intravenous ethanol versus diazepam for alcohol withdrawal prophylaxis in the trauma ICU: results of a randomized trial. J Trauma. 2008 Jan. 64(1):99-104. [Medline].
Bamgbade OA. Dexmedetomidine for peri-operative sedation and analgesia in alcohol addiction. Anaesthesia. 2006 Mar. 61(3):299-300. [Medline].
Darrouj J, Puri N, Prince E, Lomonaco A, Spevetz A, Gerber DR. Dexmedetomidine infusion as adjunctive therapy to benzodiazepines for acute alcohol withdrawal. Ann Pharmacother. 2008 Nov. 42(11):1703-5. [Medline].
DeBellis R, Smith BS, Choi S, et al. Management of delirium tremens. J Intensive Care Med. 2005 May-Jun. 20(3):164-73. [Medline].
Kosten TR, O'Connor PG. Management of drug and alcohol withdrawal. N Engl J Med. 2003 May 1. 348(18):1786-95. [Medline].
Maccioli GA. Dexmedetomidine to facilitate drug withdrawal. Anesthesiology. 2003 Feb. 98(2):575-7. [Medline].
Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med. 2004 Jul 12. 164(13):1405-12. [Medline].
McCowan C, Marik P. Refractory delirium tremens treated with propofol: a case series. Crit Care Med. 2000 Jun. 28(6):1781-4. [Medline].
Nimmerrichter AA, Walter H, Gutierrez-Lobos KE, Lesch OM. Double-blind controlled trial of gamma-hydroxybutyrate and clomethiazole in the treatment of alcohol withdrawal. Alcohol Alcohol. 2002 Jan-Feb. 37(1):67-73. [Medline]. [Full Text].
Olmedo R, Hoffman RS. Withdrawal syndromes. Emerg Med Clin North Am. 2000 May. 18(2):273-88. [Medline].
Reoux JP, Miller K. Routine hospital alcohol detoxification practice compared to symptom triggered management with an Objective Withdrawal Scale (CIWA-Ar). Am J Addict. 2000 Spring. 9(2):135-44. [Medline].
Rovasalo A, Tohmo H, Aantaa R, Kettunen E, Palojoki R. Dexmedetomidine as an adjuvant in the treatment of alcohol withdrawal delirium: a case report. Gen Hosp Psychiatry. 2006 Jul-Aug. 28(4):362-3. [Medline].
Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict. 1989 Nov. 84(11):1353-7. [Medline].