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The substances abused must be determined early in treatment, because there are substantial differences in severe complications and in the management of withdrawal from alcohol and sedatives, opiates, and stimulants. Although the initial symptoms of withdrawal — for example, dysphoria, insomnia, anxiety, irritability, nausea, agitation, tachycardia, and hypertension — are similar for all three classes of drugs, complications and therefore treatment can differ greatly. For example, clonidine given to a patient withdrawing from an opioid can mask early symptoms of alcohol or sedative withdrawal and, without specific medication for sedative withdrawal, can lead to seizures. Detoxification is an important first step in substance-abuse treatment. It has three goals: initiating abstinence, reducing withdrawal symptoms and severe complications, and retaining the patient in treatment. Ongoing treatment is needed thereafter to maintain abstinence.
Pharmacologic treatment of drug withdrawal often involves substituting a long-acting agent for the abused drug and then gradually tapering its dosage. The desirable qualities for outpatient medications include administration by mouth, low potential for abuse and overdose, and low incidence of side effects.4 Adequate dosages of appropriate substitute medications are important. Patients often safely attain abstinence without pharmacologic interventions, however, and the threshold for pharmacotherapy differs among abused drugs. The need for medication is signaled by both symptoms and signs in patients withdrawing from alcohol, by severe objective signs in those withdrawing from stimulants, and by specific signs during withdrawal in those withdrawing from opioids. For patients addicted to heroin, sustained opioid stabilization is often a better treatment option than detoxification and abstinence.
Outpatient management is appropriate for patients with mild-to-moderate withdrawal symptoms who have no important coexisting conditions and have a support person willing to monitor their progress closely. The emergence of serious complications, including delirium tremens among patients dependent on alcohol or depression with suicidal ideation or psychotic symptoms among patients dependent on stimulants or opioids, demands inpatient treatment. In addition, coexisting psychiatric and medical disorders must be managed. Care must be supportive and nonjudgmental, yet assertive.
During detoxification, behavioral interventions for ongoing treatment of these chronic relapsing disorders may be started. Such interventions should be more sophisticated than simple referral to self-help groups. Effective treatments include contingency management, motivational enhancement, and cognitive therapies.5,6
Withdrawal from Sedatives (Alcohol and Benzodiazepines)
Clinical Presentation and General Management
The clinical history often suggests alcohol problems, which are seen in 15 to 20 percent of patients in primary care and hospitalized patients.7 Since alcohol withdrawal can be complicated by seizures and delirium and is more severe in persons with more previous episodes of withdrawal or other illnesses, careful evaluation is essential. Such evaluation should include assessment for anemia, thrombocytopenia, and elevated liver-enzyme levels.7,8 Specific symptoms during sedative or alcohol withdrawal that may dictate pharmacotherapy include auditory and tactile disturbances and seizures.
Significant components of the withdrawal syndrome after chronic alcohol use reflect reduced neurotransmission in type A 
-aminobutyric acid pathways and enhanced neurotransmission in glutamate (N-methyl-D-aspartate) pathways.9 Seizures during withdrawal probably result from this altered neurobiology, but the anticonvulsant medication phenytoin is not an effective treatment for alcohol withdrawal.8,10 Benzodiazepines are effective, probably owing to cross-tolerance with ethanol at the type A -aminobutyric acid receptor, where carbamazepine and divalproate are also believed to have their main actions.11,12 On the basis of this neurobiology, antagonism at the N-methyl-D-aspartate receptor is another potential mechanism for relieving symptoms of alcohol and sedative withdrawal and may be important for reducing the toxic effects from repeated episodes of alcohol withdrawal.13
Withdrawal symptoms can be quantified to allow symptom-triggered therapy, in which the patient receives medication only when symptoms exceed a threshold of severity, rather than on a fixed schedule (Table 1). This approach is as effective as fixed-dose therapy but requires significantly less medication and leads to a more rapid detoxification.14,15 It does, however, require careful and frequent monitoring with a validated withdrawal-symptom scale such as the Clinical Institute Withdrawal Assessment for Alcohol (see the Appendix). The categories on this scale are sweating, anxiety, tremor, auditory or visual disturbances, agitation, nausea and vomiting, tactile disturbances, headache, and orientation. Total symptom scores of more than 15 on this scale or a history of withdrawal seizures indicates that medications should be started at presentation.
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Withdrawal from benzodiazepines and other sedatives produces more psychomotor and autonomic nervous system signs than does withdrawal from alcohol, and these signs start between 2 and 10 days after abrupt discontinuation. If medications are used, treatment with anticonvulsant drugs such as carbamazepine will need to be continued for about two weeks, and the dose of benzodiazepines gradually tapered.
Pharmacologic Treatment
Benzodiazepines and Barbiturates
Two major reviews of pharmacotherapy for alcohol withdrawal concluded that benzodiazepines are the treatment of choice on the basis of several outcomes, including the severity of the alcohol-withdrawal syndrome, occurrence of delirium and seizures, adverse effects of the medication, and completion of withdrawal, as well as subsequent entry into rehabilitation.8,12 A meta-analysis comparing benzodiazepines with placebo or with an active control drug included 11 trials, representing a total of 1286 patients.8 There was more often a clinically significant reduction of symptoms within two days with benzodiazepines than with placebo (common odds ratio, 3.28; 95 percent confidence interval, 1.30 to 8.28).8
In addition, in six prospective trials, benzodiazepines, particularly longer-acting ones, were more effective than placebo in reducing the incidence of seizures (risk reduction, 7.7 seizures per 100 patients treated; P=0.003) and delirium (risk reduction, 4.9 cases of delirium per 100 patients treated; P=0.04).8,10,12,17 However, the potential for abuse is greater with agents that have a rapid onset of action, including diazepam, alprazolam, and lorazepam, than for those with slower onset of action, such as chlordiazepoxide, oxazepam, and halazepam.18 Although phenobarbital has a low potential for abuse as compared with other barbiturates and is used by about 10 percent of substance-abuse programs in the United States, its use is supported by only a few controlled studies. Furthermore, phenobarbital has a poorer safety profile than benzodiazepines: it can cause respiratory depression when used in high doses or when combined with alcohol, as may happen with outpatients.19
Other drugs, particularly carbamazepine, do not differ significantly from the benzodiazepines in terms of adverse events (common odds ratio for adverse events associated with benzodiazepines as compared with carbamazepine, 0.67; 95 percent confidence interval, 0.34 to 1.32). Dropout rates in the first seven days are slightly lower with benzodiazepines (common odds ratio, 0.68; 95 percent confidence interval, 0.47 to 0.97).20 Thus, a critical issue may be the potential effectiveness of anticonvulsant agents for outpatient treatment in more severe as well as mild-to-moderate alcohol withdrawal.
The treatment of benzodiazepine or barbiturate dependence has involved either tapering dosages of the agent of dependence or substituting a longer-acting benzodiazepine or phenobarbital, with a gradual reduction in dose over a period of two weeks. Tables in Smith and Wesson21 provide dosage equivalents for use in substituting longer-acting for shorter-acting agents.
Adjuvant Treatments
Although they may be useful as adjuvant treatments, most other agents are unsuitable for use alone during alcohol withdrawal. The phenothiazines and haloperidol reduce signs and symptoms of withdrawal but are significantly less effective than benzodiazepines in preventing delirium (difference in risk, 6.6 cases per 100 patients) and seizures (difference in risk, 12.4 seizures per 100 patients) (P<0.01 for both comparisons).22 Beta-adrenergic antagonists and clonidine reduce autonomic manifestations of withdrawal but have no known anticonvulsant activity.23,24 Symptoms of early withdrawal or impeding delirium may be masked by propranolol.25 Centrally acting alpha-adrenergic agonists such as clonidine ameliorate symptoms in patients with mild-to-moderate withdrawal but probably do not reduce delirium or seizures.26 They may be used in conjunction with benzodiazepines in patients with coexisting conditions such as coronary artery disease. For benzodiazepine withdrawal, however, they have not found much use even when low therapeutic doses are discontinued.21
Anticonvulsant Agents
Although phenytoin has no primary role in the treatment of alcohol-withdrawal symptoms, other anticonvulsant agents, such as carbamazepine, have been in clinical use for this purpose for three decades.27 Carbamazepine is superior to placebo and equal in efficacy to phenobarbital and oxazepam for patients with mild-to-moderate withdrawal symptoms.28,29 Carbamazepine has no significant toxic effects on the blood or the liver when used in seven-day protocols for alcohol withdrawal29,30; it reduces emotional distress better and permits a faster return to work than does oxazepam.30 Carbamazepine has well-documented anticonvulsant activity and prevents alcohol-withdrawal seizures in studies in animals, but data from trials in humans are limited.31 It does not potentiate the central nervous system and respiratory depression caused by alcohol, does not inhibit memory (which occurs with even small doses of benzodiazepines), and has no potential for abuse.21 However, dizziness, vomiting, and nausea are common side effects, particularly at the initial dose of 800 mg per day. Carbamazepine has not been evaluated for treating delirium tremens.
In a recent study of 136 patients with alcohol-withdrawal symptoms, patients treated with carbamazepine had fewer protracted symptoms than did those receiving lorazepam, five days after the medications were stopped.32 This difference in symptom levels persisted for a week. Furthermore, relapse to alcohol use during a follow-up period of three months was less common in the carbamazepine group. Adverse effects such as dizziness and incoordination were also less common in the carbamazepine group (7 percent vs. 20 percent). Some early studies have suggested that carbamazepine is efficacious in patients undergoing benzodiazepine withdrawal, but the data are less extensive than are those for alcohol.21,33
Valproate may also reduce symptoms of alcohol withdrawal. Data have been reported for a total of approximately 2500 patients. The trials have generally been open-label, and not all have reported seizure rates. Two double-blind, randomized studies have been published, however.32,34 In these trials, patients treated with 1000 to 1200 mg of valproate for four to seven days had fewer seizures, dropped out less frequently, had less severe withdrawal symptoms, and used less oxazepam than did controls treated with placebo or carbamazepine.
No controlled trials have been published on the use of gabapentin for alcohol-withdrawal symptoms.
Withdrawal from Opioids
Clinical Presentation
Opioid-withdrawal syndrome resembles a severe case of influenza. In addition, the symptoms include pupillary dilatation, lacrimation, rhinorrhea, piloerection ("gooseflesh"), yawning, sneezing, anorexia, nausea, vomiting, and diarrhea. Seizures and delirium tremens do not occur. Patients who are dehydrated or debilitated can have life-threatening complications.
The time to onset of peak opioid-withdrawal symptoms and their duration after abrupt discontinuation depend on the half-life of the drug involved (Figure 1). For heroin, symptoms peak within 36 to 72 hours and last for 7 to 10 days, whereas for methadone, symptoms peak at 72 to 96 hours but last for 14 days or more, and for buprenorphine, symptoms are less severe and of shorter duration.35,36
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Since the use of opiates for detoxification is legally restricted to inpatient settings and specially licensed outpatient programs, patients in outpatient settings more typically receive clonidine or another adrenergic agent. Recent federal initiatives may loosen the restrictions on the use of buprenorphine, a partial opioid agonist, for the treatment of opioid withdrawal.3,37,38 A summary of pharmacotherapeutic approaches is given in Table 2.
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Substitution of a long-acting, orally active opioid such as methadone or buprenorphine is the approach preferred by most patients. Sublingual buprenorphine provides an effective and comfortable withdrawal and transition from heroin to antagonist treatment with naltrexone, and it appears to be superior to clonidine in this regard.39,40 Buprenorphine starting at 4 to 16 mg daily is equivalent to methadone starting at 20 to 35 mg daily, and the dose of either medication can be tapered relatively quickly over a period of several days from these initial low doses. If these agents are abruptly discontinued, withdrawal symptoms are more severe and last longer with methadone than with buprenorphine (Figure 1).
Patients whose methadone dose is reduced each week by 3 percent of the initial dose drop out less frequently, have less illicit opioid use, and have less severe withdrawal symptoms than do patients whose dose is reduced by 10 percent per week, but only 40 percent of the patients in either group achieve abstinence.41 Reducing the methadone dose from 35 mg over a period of 21 days (a drop of 5 percent per day) offers no advantage in attaining abstinence or relieving withdrawal symptoms over abruptly stopping methadone and substituting clonidine.42 Even protracted methadone dosage tapering over a period of six months has no greater success than more rapid approaches.43
Nonopioid Medications
Opioid drugs are agonists at the µ-opioid receptor, where they inhibit cyclic AMP systems. When chronic opioid use is discontinued, the cyclic AMP system in noradrenergic neurons becomes overactive and noradrenergic brain activity increases, contributing to withdrawal symptoms.44 These neurons also have adrenergic autoreceptors that, when stimulated by clonidine (or lofexidine), decrease neuronal activity and can reduce opioid-withdrawal symptoms. This discovery is the basis for using clonidine or lofexidine to suppress autonomically mediated signs and symptoms of abstinence.45 For heroin withdrawal, clonidine is initiated at a dose of 0.1 to 0.2 mg every four hours, which is tapered starting after day 3, with treatment lasting a total of about 10 days. In patients with insomnia or muscle cramps, clonidine can be augmented with a slow-onset, longer-acting benzodiazepine such as chlordiazepoxide.46 Lofexidine started at 0.2 mg and titrated up to 1.2 mg twice daily is an alternative to clonidine. Patients taking lofexidine are less likely to have hypotension or to drop out of treatment than are those taking clonidine, and they have a more rapid resolution of withdrawal symptoms than do patients taking clonidine.47 Thus, optimal outpatient treatment might substitute 8 mg of buprenorphine per day for heroin, followed by tapering the dose to 2 to 4 mg of buprenorphine per day and then discontinuing it, and then giving lofexidine or clonidine for about five days.
Rapid and "Ultra-Rapid" Detoxification
The combination of clonidine and the long-acting opioid antagonist naltrexone has been successful with inpatients and outpatients during a five-day protocol.48 Although withdrawal symptoms during day 1 were more severe in patients taking naltrexone (12.5 mg) plus clonidine than in those taking clonidine alone, the combination produced better results than clonidine alone in primary care settings. In a study of 125 primary care patients, 24 of 57 patients taking clonidine alone (42 percent) and 64 of 68 of those taking both clonidine and naltrexone (94 percent) successfully completed detoxification (P<0.001).46 A more recent randomized clinical trial compared clonidine, clonidine plus naltrexone, and a new approach using clonidine and naltrexone in combination with buprenorphine.49 After stabilization for as little as three days, patients taking buprenorphine had less severe withdrawal symptoms than did patients in the other two groups. Rapid detoxification is a very intensive intervention, however, and should only be undertaken by clinicians who have had substantial experience working with simpler approaches to withdrawal, such as using clonidine alone or tapering the dosage of methadone in an inpatient setting. Figure 2 shows the severity and duration of withdrawal with these various approaches. Clearly, withdrawal symptoms are mildest in patients taking clonidine and naltrexone in combination with buprenorphine.
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Withdrawal from Stimulants (Cocaine and Amphetamines)
Clinical Presentation
Withdrawal from a stimulant can produce dysphoria with sleep, appetite, and motor disturbances clinically and neurobiologically similar to those seen in depressive disorders.57,58 Severe depressive symptoms may last only 8 to 48 hours, but milder ones typically persist for approximately two weeks. Although no medications have shown efficacy in reducing the severity of withdrawal symptoms, acute stimulant toxicity characterized by delusions, paranoid thinking, and stereotyped compulsive behavior may require neuroleptic agents or benzodiazepines such as chlordiazepoxide in the first 48 hours after abrupt discontinuation. Because those who are dependent on stimulants are often also dependent on alcohol or heroin, withdrawal symptoms due to the discontinuation of these other substances may require concomitant treatment.
Treatment
The monoamine transporter proteins, which act as a reuptake mechanism for terminating synaptic monoaminergic neurotransmission, are blocked by cocaine and amphetamine, leading to massive elevations of synaptic monoamines.59 Repeated cocaine administration reduces levels of postsynaptic receptors (e.g., dopamine D2 receptors), suggesting a role for dopamine agonists.60 Direct dopamine agonists such as bromocriptine and pergolide have shown no efficacy. In a three-month double-blind clinical trial, 5 to 7.5 mg of bromocriptine daily was poorly tolerated and was associated with high dropout rates; furthermore, it produced no reduction in subsequent cocaine use.61 Pergolide also brought about no difference in cocaine use, although pilot work in 21 patients had suggested good response.62 Indirect dopamine agonists, however, appear to have some efficacy. Methylphenidate, a stimulant and an indirect dopamine agonist, did not decrease cocaine use but was associated with a lower dropout rate than placebo.63 Amantadine, another indirect dopamine agonist, was compared with placebo in a double-blind trial involving 42 patients treated for 10 days. Urine samples obtained at two-week and one-month follow-up visits were cocaine-free more often in patients taking amantadine than in those taking placebo.64 Treating more severe cocaine-withdrawal symptoms with propranolol (100 mg daily) may improve treatment retention and reduce cocaine use.65 The withdrawal symptoms of anxiety and depression have also suggested a role for antidepressants, but these agents have a delayed onset of action and may be useful only after the period of withdrawal is over.57,60 Table 3 provides a brief listing of pharmacotherapy for stimulant withdrawal; no agents, however, have shown reliable efficacy.
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Clinical Features of Patients
Substance-dependent patients often have other medical and behavioral health problems as well, such as depression and nicotine dependence. The evaluation and treatment of depression are complicated by the overlapping of depressive and withdrawal symptoms, as well as by shared neurobiologic features.58 Depressive symptoms that persist for more than a week beyond the period of acute withdrawal suggest that treatment with an antidepressant such as a serotonin-reuptake inhibitor may be appropriate.66 Established antidepressant treatment can be continued during detoxification. For patients who smoke, nicotine-replacement therapy (for example, with a transdermal patch) or bupropion can initiate abstinence and reduce rates of relapse.67 These interventions are often begun after detoxification from the other three classes of drugs, but nicotine-replacement therapy can be started during other detoxifications. Smoking cessation can be a critical first step in addressing the wide variety of health problems in substance-dependent patients, who also need screening for human immunodeficiency virus infection and liver disease, appropriate immunizations, and assessment for high-risk sexual activity or physical abuse. Patients found to require additional treatment should be referred for appropriate services. Referrals are also often indicated to social-work, family-counseling, or other social-service agencies.3
Referral as Compared with Direct Treatment
Direct treatment in an outpatient setting requires daily contact for several days to monitor progress and adjust doses of medication. Such treatment, delivered by generalist physicians, may be appropriate for highly motivated patients with mild withdrawal symptoms, as long as their social support systems are strong and any coexisting medical or psychiatric conditions are stable. Given the new federal regulations on the use of buprenorphine in office-based settings, generalist physicians may soon be able to provide extended detoxification to certain patients with opioid dependence.38 Patients with moderate-to-severe withdrawal symptoms, poor social support, or substantial medical or psychiatric conditions that go beyond the depressive symptoms characteristic of withdrawal should be referred to specialized outpatient or inpatient programs for withdrawal treatment. Options include outpatient detoxification programs such as methadone tapering for heroin dependence and residential programs providing both medication management and supportive housing. Withdrawal management is only the first step in long-term treatment; follow-up care is always necessary to prevent relapse.
Supported by grants (P50-DA12762, K05-DA 0454) from the National Institute on Drug Abuse.
Dr. Kosten reports having been a consultant for Xenova and having received speaker's fees from Abbott and Schering.
Source Information
From the Departments of Psychiatry (T.R.K.) and Medicine (P.G.O.), Yale University School of Medicine, New Haven, Conn.; and Veterans Affairs Connecticut Healthcare System, West Haven, Conn. (T.R.K.).
Address reprint requests to Dr. Kosten at Veterans Affairs Connecticut Healthcare System, Psychiatry 151D, 950 Campbell Ave., Bldg. 35, West Haven, CT 06516, or at thomas.kosten@yale.edu.
References
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