Lewis Nelson
Withdrawal syndromes, which include discrete physiologic and psychological effects, occur following the discontinuation or dose reduction of certain drugs and medications. Anticipating and recognizing the early signs of withdrawal allow for timely treatment and may help prevent the development of serious withdrawal manifestations.
Ethanol withdrawal is a common, potentially life-threatening syndrome (see Chapter 282), and is similar to that occurring after the cessation or dose reduction of sedative-hypnotics such as benzodiazepines, barbiturates, and chloral hydrate, as well as γ-hydroxybutyrate (GHB) and its congeners (e.g., 1,4-butanediol), and baclofen. All of these drugs enhance the activity of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) at the GABAA/benzodiazepine receptor/chloride–channel complex and induce long-standing adaptations in receptor function.
Withdrawal symptoms associated with opioids are common, although generally not life-threatening, and have grown increasingly important during the decade-long epidemic of prescription opioid misuse. Antidepressants, particularly the selective serotonin reuptake inhibitors (SSRIs), and cocaine are associated with discontinuation syndromes that are likened to withdrawal, but are less severe. Somatic and psychological symptoms predominate.
Physical dependence is a prerequisite for the development of a withdrawal syndrome, and is generally accompanied by tolerance. The dose of the drug, its duration of action, frequency of administration, and duration of abuse all contribute to the development of dependence and are related to the severity of withdrawal. More severe withdrawal phenomena may be associated with a longer period of abuse or a history of previous withdrawal episodes. Sporadic use of a drug does not generally induce the receptor adaptations required for the development of dependence, and therefore withdrawal. For example, use of GHB recreationally (e.g., on weekends) does not result in dependence and withdrawal does not occur, whereas it does follow cessation in frequent, several-times-daily users, such as body-builders. Similarly, the withdrawal associated with heroin use is typically less intense than that associated with methadone since the later is long acting and blood concentrations remain elevated around-the-clock. Complete abstinence and a serum drug level of zero are not required, nor is abuse (i.e., use simply for pleasurable central nervous system [CNS] effects). Physiologic dependence does not require excessive doses, and it may occur after prolonged treatment with therapeutic doses for appropriate indications.
Withdrawal from sedative-hypnotics is characterized by intense sympathetic stimulation. The underlying mechanism is not fully elucidated, but it occurs when compensatory CNS mechanisms that counteract the depressant effects of sedative-hypnotics are activated. Such mechanisms involve changes in GABA and glutamate receptor activity, including down-regulation of the GABA receptor complex and upregulation of the N-methyl-D-aspartate (NMDA) glutamate receptors. Benzodiazepine withdrawal results in excitatory effects because there is less baseline GABA inhibition and enhanced neuronal activity through overactive NMDA receptors.
Withdrawal from opioids may also involve an increase in sympathetic discharge, but by a different mechanism. Decreased opioid receptor stimulation increases catecholamine release in the locus ceruleus of the CNS. The severe catecholamine surges seen with sedative–hypnotic withdrawal are not observed during typical opioid withdrawal.
CLINICAL PRESENTATION
The clinical presentation of drug withdrawal varies significantly among patients. Although this may relate to variations in the degree of drug use and reporting, there are also individual factors that underlie the severity of withdrawal. Some patients develop significant withdrawal following cessation of exposure, while others with similar use patterns develop minimal effects. Some patients may present with complications of drug abuse, such as pneumonia, endocarditis, and skin abscess, or an unrelated problem, such as a myocardial infarction or motor vehicle accident, and develop withdrawal symptoms while in the emergency department (ED) or after admission. Others present to the ED due to unintended abstinence or because they desire detoxification.
Sedative-hypnotic withdrawal may be indistinguishable from ethanol withdrawal except for differences in the time course (Table 351.1). Because many benzodiazepines have a long elimination half-life and active metabolites, withdrawal manifestations may be delayed after cessation of drug use. Lorazepam withdrawal may begin within 2 days of the last dose, whereas diazepam withdrawal may require a week or more before the onset of symptoms.
TABLE 351.1
Withdrawal Syndromes Commonly Seen in the ED
The clinical presentation of sedative-hypnotic withdrawal varies in intensity and duration. Mild withdrawal symptoms include anxiety, apprehension, irritability, dysphoria, and insomnia (1). Other symptoms may include anorexia, nausea, and vomiting. Mild autonomic and CNS hyperactivity is characterized by tachycardia, hypertension, irritability, and hyperreflexia. Unlike patients with severe withdrawal, patients with mild withdrawal have a clear mental status. Most patients with mild withdrawal recover uneventfully after a few days, but some may develop more serious withdrawal manifestations.
Hallucinations, delusions, myoclonus, seizures, and agitation may appear in patients with more severe withdrawal. Tachycardia, hypertension, tachypnea, hyperthermia, diaphoresis, and mydriasis may develop, as may tachyarrhythmias. At times, a new-onset seizure heralds the onset of sedative-hypnotic withdrawal. These patients may or may not have tremulousness and other sympathetic hyperactivity before seizure activity begins. Seizures tend to be generalized and tonic-clonic. Severe withdrawal, including seizures, may occur after the administration of flumazenil to patients chronically taking benzodiazepines. Withdrawal from long-acting benzodiazepines may persist for 3 weeks.
Withdrawal from GHB, or its congeners γ-butyrolactone (GBL) or 1,4-butanediol, may also produce severe withdrawal (2). Withdrawal from these agents is frequently seen in body-builders, who ingest GHB multiple times per day as opposed to sporadic recreational users. Autonomic and CNS abnormalities are the most common effects and may include anxiety and tremor. More severe GHB withdrawal is characterized by severe agitation, tachycardia, hypertension, insomnia, auditory and visual hallucinations, and delirium. The onset of symptoms may appear as early as 1 to 6 hours after the last dose, and the symptoms may persist for as long as 5 to 15 days. Few deaths from GHB withdrawal have been reported (also see Chapter 309).
The withdrawal syndrome from oral or intrathecal baclofen generally starts 12 to 72 hours after discontinuation. Typical findings include sleeplessness, confusion, agitation, hallucinations, delusions, hyperthermia, and hypertonia. Interestingly, seizures may occur in the setting of either baclofen toxicity or withdrawal (3). In some cases, there is profound muscle rigidity resembling neuroleptic malignant syndrome or malignant hyperthermia.
Mild opioid withdrawal includes lacrimation, rhinorrhea, yawning, diaphoresis, anxiety, restlessness, and dysphoria. Piloerection is particularly characteristic. The patient may exhibit mild elevations in pulse, blood pressure, and respiratory rate, but these changes are usually not significant. More severe opioid withdrawal is characterized by vomiting, diarrhea, abdominal pain, and dehydration. Severe agitation, seizures (except in neonatal withdrawal), mental status changes, and dramatic vital sign abnormalities do not typically occur with opioid withdrawal due to abstinence but do occur with opioid withdrawal precipitated by naloxone.
The severity and time course of the opioid withdrawal syndrome depends on the pharmacokinetics of the opioid. Withdrawal from shorter-acting agents (e.g., heroin) usually begins within 4 to 8 hours after the last dose, peaking by 36 to 72 hours while that from longer-acting agents (e.g., methadone) typically occurs 36 to 72 hours after the last dose and may persist for up to 2 weeks. Withdrawal from long-acting opioids tends to be more severe than that from shorter-acting agents.
The sudden onset of opioid withdrawal may occur after an opioid antagonist such as naloxone is given to an opioid-dependent patient (4) and may be severe. As a result of naloxone’s short half-life, withdrawal symptoms do not usually persist beyond 40 to 60 minutes. Treatment with additional opioid to reverse these short-lived effects is not indicated. Opioid withdrawal from the long-acting opioid antagonist naltrexone may result in a markedly prolonged withdrawal period lasting up to 24 hours and treatment is difficult. A cautious attempt to overcome the receptor blockade with an opioid is possible, though many simply provide supportive care including antiemetics and benzodiazepines. Giving opioids without full agonist properties, such as buprenorphine (Suboxone; a partial agonist), to a stable opioid-dependent patient may also precipitate withdrawal symptoms. Interestingly, buprenorphine can be used to quell existing or extant opioid withdrawal due to the same pharmacologic properties.
Antidepressant withdrawal/discontinuation may result in anxiety, insomnia, lethargy, nausea, vomiting, headache, imbalance, sensory abnormalities, and possibly aggressive and impulsive behavior. In most cases, these symptoms are mild and transient. Withdrawal from cocaine may result in lethargy, dysphoria, and depression (5).
DIFFERENTIAL DIAGNOSIS
The differential diagnosis for a patient with a withdrawal syndrome is broad and includes many other serious conditions that may require different therapy (Table 351.2). Because drug-dependent patients are particularly prone to develop many of these conditions, careful exclusion of other etiologies is critically important. Examination may help to distinguish an anticholinergic toxidrome (dry skin, decreased bowel sounds, urinary retention, mydriasis, tachycardia) from a sympathomimetic toxidrome (moist skin, normal bowel sounds, no urinary retention, mydriasis, tachycardia).
TABLE 351.2
Differential Diagnosis of Major Withdrawal Symptoms
Sedative-hypnotic withdrawal may be particularly difficult to distinguish from an underlying anxiety disorder. Differentiating withdrawal seizures from other types of seizures may also be difficult particularly without an accurate history. Other common causes include pre-existing idiopathic epilepsy, posttraumatic epilepsy, and other complications of drug abuse (e.g., hypoglycemia, hypomagnesemia, hyponatremia, head trauma). Poor anticonvulsant compliance with underlying seizure disorders may add to the diagnostic confusion. In the setting of baclofen use, a seizure could result from either overdose or withdrawal.
Opioid withdrawal must be distinguished from ethanol and other sedative-hypnotic withdrawal because of the significant differences in therapy. Clinical findings of significant sedative-hypnotic withdrawal, such as confusion, agitation, and seizures, are not generally seen with opioid withdrawal; opioid withdrawal symptoms such as piloerection, yawning, lacrimation, and rhinorrhea are not seen with ethanol and sedative-hypnotic withdrawal. Some patients, however, may be withdrawing from both substances. Gastrointestinal (GI) manifestations of opioid withdrawal must be differentiated from abdominal pathology and gastroenteritis.
ED EVALUATION
Patients presenting with drug withdrawal require a comprehensive assessment. Patients initially should have cardiac monitoring and a fingerstick glucose and oxygen saturation analysis. The physician should obtain a complete history of substance abuse, previous withdrawal episodes, and all current and former medications. If possible, family, friends, and prehospital personnel can be interviewed to gain additional information.
Physical examination should focus on vital signs, including rectal temperature; cardiovascular, neurologic, and pulmonary systems; the skin; the abdomen; and the eyes. Close attention should be directed to any stigmata of chronic liver disease or evidence of intravenous (IV) drug use. There should be assessment for obvious and occult traumatic injury and complications of drug abuse, such as pneumonia, skin abscesses, bacterial endocarditis, acquired immunodeficiency syndrome, pancreatitis, liver disease, and GI bleeding (see Chapter 308).
Laboratory studies that may prove helpful include a complete blood count; electrolytes, glucose, blood urea nitrogen, and creatinine levels; liver function tests; lipase; coagulation profile; and ethanol level. A urine drug screen may be positive or negative for the offending agent, but can also be misleading. For example, rapid urine drug screens may not detect synthetic or semisynthetic opioids such as methadone or oxycodone, respectively. In patients with significant agitation, a creatine phosphokinase determination may detect rhabdomyolysis.
An elevated temperature may require a sepsis workup, including urine and blood cultures, chest radiograph, and, often, a lumbar puncture. Obtaining a head computed tomography (CT) scan before lumbar puncture is suggested in patients presenting with either focal neurologic deficits or high risk for intracranial hemorrhage. Patients with a first-time seizure in the setting of withdrawal should be evaluated in the same manner as any other patient with a new seizure. Subsequent withdrawal seizures do not necessarily require extensive reevaluation.
KEY TESTING
• Screening laboratory testing is of limited value in diagnosis but important for identifying precipitating causes or comorbid conditions. This includes a complete blood count; electrolytes, glucose, blood urea nitrogen, and creatinine levels; liver function tests; lipase; coagulation profile; and ethanol level.
• Head CT may be useful in differentiating the etiology of other causes of altered mental status or seizure.
• Urine drug testing for abused substances is difficult to interpret given the high prevalence of concomitant use of substances unrelated to the clinical presentation and the limitations of the assay for detecting certain abused drugs.
ED MANAGEMENT
Drug withdrawal syndromes, particularly sedative-hypnotic withdrawal, must be recognized and treated in a timely fashion. A successful treatment strategy must address several basic goals: (1) alleviating symptoms, (2) preventing progression, (3) avoiding complications, and (4) recognizing and treating coexisting medical problems. Planning for long-term rehabilitation and drug independence is usually better done as part of inpatient management.
Initial treatment should be directed at readily correctable causes of altered mental status. Oxygen should be given if the oxygen saturation is low, and an IV line should be established. Glucose and thiamine should be administered if there is evidence of hypoglycemia and malnutrition respectively. Volume resuscitation is often necessary, particularly in patients with severe withdrawal manifestations and dehydration.
Significantly agitated patients may initially need to be physically restrained to prevent injury, establish IV access, and facilitate sedation. Soft restraints should be used but prolonged use of restraints is discouraged, because continued struggling against them may lead to rhabdomyolysis, hyperthermia, and metabolic acidosis. Once IV access is obtained and chemical sedation has achieved behavioral control, physical restraints should be discontinued.
Achieving adequate sedation is the cornerstone of successful treatment of sedative-hypnotic withdrawal. It may prevent progression to agitated delirium with its attendant complications. Reinstitution of therapy with the withdrawn drug or a cross-tolerant one is required for proper sedation. Many agents have been used over the years, but benzodiazepines have proven to be the most effective. Compared with other sedative-hypnotic agents such as barbiturates, benzodiazepines are more easily titrated and produce less respiratory depression and cardiovascular effects (6).
Diazepam (Valium, oral and IV), chlordiazepoxide (Librium, oral only), midazolam (Versed, IV only), and lorazepam (Ativan, oral and IV) are the most commonly used agents for ethanol withdrawal and can also be used for sedative-hypnotic withdrawal. These agents are eliminated over several days and are preferred over benzodiazepines with shorter half-lives. Compared with short-acting agents, long-acting agents may be more effective in preventing withdrawal seizures and contribute to smoother withdrawal with fewer rebound effects. Active metabolites of diazepam and chlordiazepoxide prolong their therapeutic effect. In elderly patients and those with hepatic dysfunction, lorazepam, which has no active metabolites, may be preferred. In other cases, lorazepam does not appear to offer any distinct advantage over diazepam or chlordiazepoxide.
IV dosing is preferred in most cases of sedative-hypnotic withdrawal. Agitation may preclude oral administration, and GI dysfunction may impair drug absorption. IV therapy can be readily titrated. Intramuscular (IM) lorazepam or midazolam may be useful in the agitated patient before IV access is established but IM diazepam absorption is erratic and should be avoided.
The dose of benzodiazepines required to achieve proper sedation must be individualized and varies considerably, depending on the patient’s tolerance to the drug. Symptom-triggered therapy is preferred to fixed-schedule therapy. Frequent IV boluses should be given until the patient has achieved a calm state. Diazepam, 5 to 20 mg IV, can be given every 5 to 15 minutes until the patient is sedate but arousable. For ethanol withdrawal, chloridazepoxide, 50 mg PO titrated hourly, is a typical oral dose. Usually, sedation is obtained before respiratory depression develops, but close airway observation is always required.
Failure to obtain immediate sedation need not prompt switching to an alternative agent. Mixing different drugs or different routes of administration may increase the risk of adverse effects, particularly respiratory depression. However, if a patient does not respond completely to the chosen benzodiazepine, the use of another cross-tolerant agent at low dose may be valuable. Phenobarbital has a relatively slow onset of action, about 10 minutes, and a long duration of effect that allows gradual self-tapering. Phenobarbital is more likely to cause excessive sedation and respiratory depression and monitoring is important. For patients with sedative–hypnotic withdrawal resistant to benzodiazepines and barbiturates, propofol by bolus (20 mg/dose) or titrated infusions will almost always be successful. However, its use requires high-level monitoring and typically mechanical ventilation.
Withdrawal seizures should also be treated with benzodiazepines or barbiturates. Phenytoin is ineffective in treating or preventing withdrawal seizures and should be reserved for patients with an underlying seizure disorder who require maintenance phenytoin therapy.
Neuroleptics such as the phenothiazines and butyrophenones (e.g., haloperidol) should not be used alone for sedative-hypnotic withdrawal. Although useful for severe agitation, these neuroleptics are not cross-tolerant with ethanol or sedative-hypnotics, do not prevent or suppress withdrawal, and may result in hypotension, impaired thermoregulation, a lowered seizure threshold, and dystonic reactions. Uncontrolled clinical experience suggests that neuroleptics may be adjunctive therapy for patients with refractory agitation and hallucinations and in treating concomitant nausea, vomiting, and GI cramps.
Sympatholytic therapy with β-blockers (e.g., propranolol) and central adrenergic agonists (e.g., clonidine, dexmedetomidine) has been used for sedative-hypnotic withdrawal, but have certain disadvantages. Sympatholytics are not cross-tolerant with sedative-hypnotics and do not prevent agitation, confusion, or seizures. Moreover, their ability to normalize vital signs may mask a deteriorating clinical situation.
Once withdrawal is controlled, the dose of sedative-hypnotic should be gradually reduced over a period of 3 weeks to 3 months, depending on the dosage and duration of prior use. To avoid precipitating another episode of withdrawal, the dose should generally be tapered by no more than 10% a day although in outpatient practice it is done considerably more slowly.
The approach to GHB withdrawal is similar to that for other sedative-hypnotic withdrawal. Severe cases are often resistant to benzodiazepine treatment and require barbiturates or propofol. Neuroleptics should be avoided if possible.
Reinstitution of baclofen is the initial step in the management of baclofen withdrawal. For patients exhibiting symptoms and signs of more significant withdrawal, high-dose IV benzodiazepine treatment in addition to resumption of baclofen may be required. For patients with acute opioid withdrawal, administration of an opioid treats both the physiologic effects of withdrawal and the psychological effects, particularly craving. Methadone, 10 mg IM or PO can be administered in the ED, but it should not be prescribed for use after discharge. Parenteral administration guarantees absorption in the vomiting patient. Symptomatic improvement usually occurs within 30 to 60 minutes. Buprenorphine suppresses opioid withdrawal and the associated cravings and some EDs initiate buprenorphine therapy in the ED with prearranged follow-up in a buprenorphine clinic (7). Special credentialing is required to use buprenorphine in the treatment of opioid detoxification.
The decision to administer an opioid is based on clinical and social circumstances, and it is not uniformly done, especially since opioid withdrawal is not medically life-threatening. Clonidine may offer symptomatic relief because it decreases sympathetic activity in the locus ceruleus, although it does not eliminate craving. An initial oral dose of 0.1 to 0.2 mg is recommended. Because hypotension may be particularly problematic after the first dose, the blood pressure should be monitored for 2 hours while the patient remains in the ED. A dose of 0.1 to 0.2 mg every 4 to 6 hours may help prevent recurrence of opioid-withdrawal symptoms.
Detoxification is generally not initiated in the ED and requires referral to an appropriate facility. Federal regulations restrict the use of methadone for detoxification or maintenance to Substance Abuse and Mental Health Services Administration’s (SAMHSA) designated programs. Rapid and ultrarapid opioid detoxifications for inpatients followed by naltrexone maintenance therapy have also been used in recent years. These controversial techniques utilize antagonist-precipitated opioid withdrawal as a quick “cure” for opioid dependence. Complications include persistent withdrawal symptoms, pulmonary edema, and death (8).
Reinstitution of drug therapy and gradual tapering of the dose is recommended for antidepressant discontinuation syndrome. Benzodiazepines can be used for signs and symptoms of adrenergic hyperactivity. The treatment of cocaine withdrawal is supportive.
CRITICAL INTERVENTIONS
• Administer diazepam or other long-acting benzodiazepine to patients with sedative-hypnotic withdrawal, adding barbiturates or propofol for refractory cases.
• Administer opioids, such as methadone or buprenorphine, for the acute manifestations of opioid withdrawal. Clonidine and benzodiazepines are alternatives.
DISPOSITION
Patients with moderate to severe sedative–hypnotic withdrawal should be admitted. Because withdrawal usually persists for several days, admitted patients should be closely monitored for signs of progression and treated as necessary. The level of care depends on clinical severity. Because of potential complications, patients requiring IV sedation are best managed in an intensive or intermediate care unit. Patients with less severe withdrawal may be managed and observed on a medical floor, psychiatric floor, hospital-based detoxification unit, or detoxification unit outside of the hospital. Patients with mild withdrawal may also need to be admitted for the evaluation and treatment of concomitant medical problems that have not been adequately addressed. An inpatient setting, including detoxification, provides a protected environment away from the temptations of illicit drug use.
Outpatient management should be attempted only if the patient can be discharged home with a supportive family member or friend and appropriate outpatient follow-up can be arranged. Supervised withdrawal in the home setting, under the direction of a visiting nurse, may be appropriate in some of these circumstances.
Patients who present to the ED with opioid withdrawal may be discharged home if they do not have other concomitant medical problems that require hospital admission and they can tolerate oral fluids. Offering the patient a limited supply of clonidine (if tolerated in the ED) may help prevent further withdrawal symptoms. Prescriptions for opioids should not be given. A brief intervention and referral to a treatment program is strongly recommended.
Social service, detoxification, or substance-abuse counseling and psychiatric referrals should be offered to all patients with a history of substance abuse.
Common Pitfalls
• Failure to consider the possibility of drug withdrawal in patients with signs and symptoms of adrenergic hyperactivity.
• Failure to appreciate that sedative-hypnotic withdrawal is potentially life-threatening, whereas abstinence-induced opioid withdrawal, although uncomfortable, does not cause significant morbidity.
• Failure to appreciate that neuroleptics do not cross-react with sedative-hypnotics and are not the primary treatment of sedative-hypnotic withdrawal.
• Failure to appreciate that GHB withdrawal may begin within hours of the last dose and be relatively resistant to treatment.
• Failure to appreciate that baclofen withdrawal may occur in the setting of intrathecal baclofen pump dysfunction.
ACKNOWLEDGMENTS
We would like to thank Paul M. Wax and Richard Barrera who were authors of this chapter in previous editions.
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