Withdrawal Syndromes Treatment & Management

Treatment considerations include the following:

• Symptoms of alcohol withdrawal are often mild or absent in the emergency department (ED) and may manifest only after the patient is admitted to the hospital for other reasons (eg, multiple trauma).

• Patients may require admission for associated conditions (eg, gastrointestinal bleed, pancreatitis). In these cases, use of sedatives may be more complex if the patient is hypotensive from blood or third-space fluid losses.

• In uncomplicated cases of withdrawal, the sedative regimen can be continued until the patient is calm and vital signs are normalized. At that point, the sedative can be tapered by decreasing the dose or lengthening the dosing interval over 3-4 days.

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 emergency department (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 is 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.

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.

Ethanol Withdrawal

Alcohol withdrawal seizures are typically brief and followed by a brief postictal period. The occurrence of more than three 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 provides 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 patients with chronic alcoholism.

Phenobarbital is sometimes used as an adjunctive or alternative treatment for alcohol withdrawal syndrome. The benefit of phenobarbital as a first-line treatment is that its longer half-life could eliminate the need for addition medications at discharge. ^[13]   

In patients receiving symptom-triggered lorazepam for the acute management of alcohol withdrawal syndrome, Ibarra reported that more patients were discharged within 3 days if they received a single parenteral dose of phenobarbital on hospital day one. Of patients receiving lorazepam and phenobarbital, 9 of 40 were discharged within 3 days, compared with only 2 of 38 who received lorazepam only (P < 0.05). ^[14]  

Hawa, et al conducted a retrospective study comparing 543 patients given lorazepam for alcohol withdrawal syndrome to 63 patients who received phenobarbital. In this cohort, the group receiving phenobarbital had significantly shorter hospital stays than the group receiving lorazepam (2.8 versus 3.6 days, P < 0.001). In addition, the phenobarbital group had lower rates of all-cause 30-day readmission (11.11% versus 14.18%, P = 0.020) and 30-day emergency department (ED)_ visits after discharge (11.11% versus 18.6%, P = 0.015). ^[15]

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. See Follow-up/Further Outpatient Care.

Patients presenting with moderate or severe alcohol withdrawal and delirium tremens (DT) require inpatient treatment and consideration of intensive care unit (ICU) admission. Initial emergency care includes the following steps:

• Place the patient 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, severe withdrawal mandates larger doses of substitute medications (see Alcohol Withdrawal Drug Therapy).

Other Withdrawal Syndromes

Sedative-hypnotic withdrawal is treated by 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.

Gamma hydroxybutyrate (GHB) withdrawal can initially be treated with high doses of benzodiazepines, although anecdotally, refractory cases have responded to other sedative agents, such as pentobarbital, chloral hydrate, and baclofen. ^{[16, 17]}

Treatment of opioid withdrawal in the ED is typically limited to supportive measures such as antiemetics (eg, ondansetron), antispasmodics (eg, octreotide, dicyclomine), and non-opioid analgesics (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], acetaminophen); clonidine 0.1-0.2 mg every 4-6 hours or lofexidine 0.54–0.72 mg every 6 hours may be useful in treating autonomic components of opioid withdrawal; clonazepam, 0.5–2.0 mg every 4–8 hours, may reduce anxiety. ^[18] Patients who are able to tolerate oral fluids and who are clinically stable may be discharged with appropriate prescriptions. Patients with intractable vomiting and those with clinically significant metabolic derangements from gastrointestinal fluid/electrolyte loss may require admission.

Emergency providers may administer but not prescribe methadone or buprenorphine to a patient for acute opioid withdrawal symptoms while arranging the patient's referral for treatment. According to US federal law, such treatment is limited to a maximum of 72 hours and only 1 day's medication may administered at one time. Due to logistical considerations in arranging referral to an opioid treatment program, it is uncommon for emergency providers to undertake treatment with methadone or buprenorphine in the ED. 

Stimulant-withdrawal syndrome is treated with observation alone and does not require any specific medications. Patients may be discharged once their mental status has normalized. Patients with persistent depressed mental status may require admission. In such patients, diagnostic testing for other causes of altered mental status should be undertaken. 

Pediatric Opioid Withdrawal

The American Academy of Pediatrics has issued a guideline on the management of iatrogenically induced opioid dependence and withdrawal in children. ^[19] 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, ^[20] 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.

Transfer

Because of the risk of seizures, patients in active withdrawal from alcohol are unstable for transfer until they have received adequate sedation.  Decisions about when to transfer largely depend on underlying associated conditions that may have stabilization requirements of their own (eg, pancreatitis, acute myocardial infarction).  

Patients in opiate withdrawal are generally stable for transfer unless underlying conditions render them unstable.

For patients who are admitted to the hospital for alcohol or sedative-hypnotic withdrawal, see Alcohol Withdrawal Drug Therapy section below.

Patients who are admitted to the hospital for complications of opioid withdrawal (eg, electrolyte disturbances, intractable vomiting, or end-organ damage) may be treated with the supportive medications discussed in the section Emergency Department Care, above. Federal law allows inpatient providers to administer opioid agonist medications such as methadone and buprenorphine to prevent opioid withdrawal that would complicate the patient's hospital course.

Should such therapy be undertaken, patients should be referred to appropriate outpatient treatment programs at the time of discharge to avoid interruption of detoxification or maintenance treatment regimens. 

Methadone may be started at a dose of 10-20 mg and titrated to relief of a patient's withdrawal syndrome. Use of a validated opioid withdrawal metric such as the Clinical Opiate Withdrawal Scale (COWS) may be helpful in quantifying the severity of opioid withdrawal and titrating opioid agonist medication. Due to its long half-life, serum and tissue methadone concentrations rise over the first several days of scheduled daily methdone dosing and patients should be monitored for signs of opioid toxicity. 

Buprenorphine may be started at a dose of 2-4 mg and titrated to relief of the withdrawal syndrome. Buprenorphine is a partial opioid agonist and administration of buprenorphine to patient with opioid tolerance who is not in withdrawal may result in a severe precipitated opioid withdrawal syndrome. Therefore patients must be in moderate-to-severe opioid withdrawal (eg, COWS > 12) before being given buprenorphine.

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, dexmedetomidine, ketamine, propofol, and (in rare cases) ethanol. ^{[21, 22, 23]}

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.

Benzodiazepines are the mainstay of therapy in the United States and are the primary agents used as substitutes and cross-tolerant medications for alcohol withdrawal syndrome. ^[24] They are also effective in sedative-hypnotic and GHB withdrawal. Benzodiazepines substitute for the gamma aminobutyric acid (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 Clinical Institute Withdrawal of Alcohol Scale, Revised (CIWA-Ar) has been validated and is used for medication administration in symptom-triggered therapy. In this approach, medication is given only when the CIWA-Ar score is higher than 8 points. ^[25] The efficacy profile is better with symptom-triggered therapy than with fixed-schedule dosing in patients admitted for detoxification ^[26] but not necessarily for the treatment of DT.

Intravenous administration of 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 various benzodiazepines have similar efficacies in treating alcohol withdrawal syndrome, though one drug may be chosen 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 per rectum. 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. ^{[27, 28]} Combination treatment is typically effective as the drugs act on different sets of GABA receptors. Propofol also modulates glutamate (NMDA) receptors. ^[29] A meta-analysis suggested that barbiturates, alone or in combination with benzodiazepines, are at least as effective as benzodiazepines in the treatment of alcohol withdrawal syndrome, with acceptable tolerability and safety profiles similar to those of benzodiazepines in this setting. ^[24] Other agents used in combination therapy have included the following:

• Baclofen ^[30]
• Haloperidol
• Carbamazepine ^[31]
• Valproic acid ^[31]
• Clonidine ^[32]
• Beta-blockers (atenolol) ^[33]

Dexmedetomidine is an intravenous α-2 agonist (similar to clonidine but more selective) that is approved by the US Food and Drug Administration (FDA) for ICU and procedural sedation. A continuous infusion produces sedation, anxiolysis, and sympatholysis with no activity at the GABA or opioid receptors and is without respiratory compromise. ^[32] Dexmedetomidine has proved useful for reducing hypertension and tachycardia and lowering benzodiazepine requirements. ^{[34, 35]} However, it has not been convincingly shown to improve clinical endpoints such as need for mechanical ventilation or length of stay in the intensive care unit or hospital. ^{[35, 36]}

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. However, in a severely agitated patient, a neuroleptic 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.

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. ^[37]

Less-sedating medications that have been studied for treatment of alcohol withdrawal have included gabapentin ^{[38, 39]} and pregabalin. ^[40] However, evidence to date suggests that these agents are more effective for maintaining abstinence in recovering alcoholics. ^{[41, 42]}

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. These drugs are occasionally useful, but their effects mask the warning signs of autonomic hyperactivity if the patient develops delirium tremens (DT). ^[33]

Addiction treatment programs

Referral of patients with chronic alcoholism or intravenous drug use to ongoing treatment programs is worthwhile, even if only a minority of these patients maintain sobriety for long periods. Numerous agencies offer inpatient and outpatient treatment programs; the most successful groups appear to be Alcoholics Anonymous and Narcotics Anonymous.

The following options are available for people addicted to heroin:

• Methadone is a long-acting opiate that prevents occurrence of somatic withdrawal symptoms but does not produce sedation or euphoria equivalent to heroin.

• Buprenorphine is a μ-opioid agonist/antagonist and is prescribed in a manner that is similar to methadone.

• Both treatment programs require patient compliance and motivation. This appears to be the limiting factor in their success rates.

• Patients withdrawing from chronic stimulant abuse are best cared for under medical supervision; refer these patients to appropriate institutions or agencies.