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Withdrawal Syndromes Treatment & Management

  • Author: Nathanael J McKeown, DO; Chief Editor: Asim Tarabar, MD  more...
 
Updated: Sep 21, 2015
 

Approach Considerations

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
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Prehospital Care

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.

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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.[13] 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 [14] 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.[15] 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.[16] 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[20] and propofol[21] ) in the treatment of refractory alcohol-withdrawal syndrome, but they are not recommended as a monotherapy. These include baclofen,[22] haloperidol, carbamazepine,[23] valproic acid,[23] clonidine,[16] and beta-blockers (atenolol).[24]

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.[25]

Research in treatment for alcohol withdrawal using less sedating medications have included gabapentin[26] and pregabalin.[27] 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. [28]
  • 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.
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Contributor Information and Disclosures
Author

Nathanael J McKeown, DO Assistant Professor, Department of Emergency Medicine, Oregon Health and Science University School of Medicine; Medical Toxicologist, Oregon Poison Center; Attending Physician, Emergency Medicine, Portland Veteran Affairs Medical Center

Nathanael J McKeown, DO is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Patrick L West, MD Clinical Instructor, Medical Toxicology Fellow, Department of Emergency Medicine, Oregon Health and Sciences University; Staff Physician, Department of Emergency Medicine, Portland Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Specialty Editor Board

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Michael J Burns, MD Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center

Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Theodore J Gaeta, DO, MPH, FACEP Clinical Associate Professor, Department of Emergency Medicine, Weill Cornell Medical College; Vice Chairman and Program Director of Emergency Medicine Residency Program, Department of Emergency Medicine, New York Methodist Hospital; Academic Chair, Adjunct Professor, Department of Emergency Medicine, St George's University School of Medicine

Theodore J Gaeta, DO, MPH, FACEP is a member of the following medical societies: American College of Emergency Physicians, New York Academy of Medicine, Society for Academic Emergency Medicine, Council of Emergency Medicine Residency Directors, Clerkship Directors in Emergency Medicine, Alliance for Clinical Education

Disclosure: Nothing to disclose.

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