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Center for Substance Abuse Treatment. A Guide to Substance Abuse Services for Primary Care Clinicians. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 1997. (Treatment Improvement Protocol (TIP) Series, No. 24.)

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A Guide to Substance Abuse Services for Primary Care Clinicians.

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Appendix A—Pharmacotherapy

Donald R. Wesson, M.D. 1

In the context of substance abuse, pharmacotherapy is the treatment of drug or alcohol dependence with medication to achieve one of three ends: detoxification, relapse prevention, or opioid maintenance (see Figure A-1).

Figure A-1: Ways in Which Psychopharmacology is Used to Treat Alcohol or Other Drug Dependencies.

Table

Figure A-1: Ways in Which Psychopharmacology is Used to Treat Alcohol or Other Drug Dependencies.

As part of drug abuse treatment, the term detoxification refers to the process of reversing a patient's physical dependence. (Note: This is not the usual medical meaning of the term detoxification, which implies the removal of a toxin, such as lead, from the body.) If a patient enters treatment inebriated, detoxification includes the period of "sobering up" while the alcohol is being metabolized.

During detoxification, medications are prescribed to reduce the intensity of withdrawal signs and symptoms. Increasingly, patients are being detoxified on an outpatient basis, which is associated with more risks than inpatient detoxification. The section below on outpatient detoxification will help primary care practitioners identify and minimize these risks.

Although detoxification is rarely adequate treatment for drug dependence, it is often an entry point into more definitive treatment. Even in the best of circumstances, however, substance abuse treatment cannot eliminate the chance that a relapse to alcohol or other drug use may occur. To reduce the probability of a relapse, the use of medications is becoming a widespread clinical practice. Drugs prescribed for this purpose directly target substance abuse or treat underlying depression or other psychopathology that can be a comorbid condition for drug dependence. Many alcohol- and drug-abusing patients have comorbid psychiatric disorders, which, if untreated, may predispose many of them to relapse.

Finally, opioid maintenance involves the substitution of heroin with medications such as methadone or levo-alpha-acetyl-methadol (LAAM) that are medically safe, long-acting, and can be taken orally. Opioid maintenance is generally considered a treatment of last resort for opiate abusers who have not had success in abstinence-oriented treatment. Since opioid maintenance treatment remains tightly regulated by the Food and Drug Administration (FDA) and the Drug Enforcement Administration, efforts to incorporate it into general medical practice is still investigational. With the exception of patients hospitalized for treatment of a serious medical or psychiatric disorder, opioid maintenance can only legally be provided in specially licensed clinics.

Pharmacotherapy is an extremely important adjunct in the treatment of drug dependence and will likely become more widespread as substance abuse treatment becomes more integrated with mainstream medical care. While pharmacotherapy skillfully applied is a powerful tool in facilitating recovery, pharmacotherapy alone will not result in the lifestyle changes necessary for long-term recovery.

The Role of Primary Care Providers

Addiction treatment services are increasingly being provided by primary care physicians, nurse practitioners, and physician assistants in the context of patients' general medical care. With continued rationing of health care in the United States, primary care clinicians are providing much of the addiction treatment previously provided by addiction specialists or in drug abuse treatment clinics. Primary care practitioners in managed care plans are the gatekeepers for patients' access to treatment by medical specialists, and those with special expertise in treatment of addictions are sometimes the medical directors of inpatient or outpatient drug dependency treatment programs.

Whatever the setting, primary care clinicians should be able to diagnose drug dependency and either initiate appropriate medical treatment or make a referral to an addiction medicine specialist or drug abuse treatment clinic.

Patients who are referred elsewhere for drug abuse treatment generally return to their primary care physician for followup care, for continued care of previously diagnosed or emergent medical or psychological conditions, and possibly for pharmacotherapy to prevent relapse. Continued case management and treatment of emergent medical conditions may require that patients be treated with medications that have abuse potential, such as opiates for pain relief or sedative-hypnotics for insomnia or anxiety. The prescription of drugs with abuse potential to recovering addicts can be problematic in primary care settings unless the primary care physician understands the recovering addict's unusual relationship with mood-altering drugs.

Pharmacotherapy of Alcohol Dependence

Detoxification

Although some patients can be safely withdrawn from alcohol without medication, guidelines for identifying those patients have not been validated in controlled clinical trials. Clinically, it is safer to provide treatment for patients who may not need it than to withhold medication until patients develop severe withdrawal signs and symptoms.

The alcohol withdrawal syndrome

The alcohol withdrawal syndrome develops in individuals who are tolerant to alcohol, as indicated by a reported history of withdrawal symptoms (particularly in the morning) during periods of heavy drinking and a history of regular morning drinking.

Symptoms of alcohol withdrawal typically begin within 6 to 24 hours after reduction or cessation of alcohol use, and signs and symptoms can be severe even in the presence of a positive blood or breath alcohol level. Alcohol withdrawal signs and symptoms peak in intensity between 24 and 48 hours following cessation of alcohol use, and they generally resolve within 4 or 5 days. The most common signs or symptoms of alcohol withdrawal include tremor of the hands and tongue, hypertension, tachycardia, sweating, nausea, more active deep tendon reflexes, diaphoresis, gastrointestinal (GI) distress, irritability, insomnia, and restlessness.

The most severe manifestation of an inadequately treated withdrawal syndrome is agitated delirium (delirium tremens or DTs), which generally appears 3 to 7 days after withdrawal starts. DTs commonly presents in association with other serious medical illnesses. Impaired attention, disorientation, paranoia, hallucinations, and memory disturbances characterize alcohol withdrawal delirium, which can be life-threatening. Grand mal seizures are another severe manifestation of withdrawal; fewer than 5 percent of those in alcohol withdrawal experience seizures or delirium (American Psychiatric Association, 1994).

Monitoring alcohol withdrawal

A standardized worksheet for assessing alcohol withdrawal symptoms has been developed at the Addiction Research Foundation. The worksheet, known as the Clinical Institute Withdrawal Assessment -- Alcohol (CIWA-Ar) (Sullivan et al., 1989), is reproduced in Appendix C. Observed physical phenomena and interview questions are scored, and decisions to medicate made according to the total. The CIWA-Ar, which can be administered by nurses, has been shown to result in more judicious use of medications and appears to produce more cost-effective care. On an inpatient detoxification ward at an urban Veterans Affairs medical center, 3 hours of nurse training in use of the CIWA-Ar led to reduced medication use and more appropriate levels of treatment for a sample of 50 male subjects (Wartenberg et al., 1990).

A key element in training staff in the use of the CIWA-Ar is to rate signs and symptoms that are reasonably attributable to alcohol withdrawal. A common error, particularly in the elderly, is to attribute a tremor or hypertension to alcohol withdrawal, when, in fact, the signs were present before alcohol withdrawal began.

Alcohol withdrawal: Medications

Benzodiazepines are the medication of choice for initiating alcohol detoxification in a new patient where treatment must be initiated before results of liver function studies are available. They decrease the likelihood of withdrawal seizures and episodes of delirium tremens and suppress severe anxiety, insomnia, tremulousness, tachycardia, rising blood pressure, and grand mal seizures. Benzodiazepines rarely produce respiratory depression, liver toxicity, or allergic reactions. They are cross-tolerant with alcohol.

Among those who should receive benzodiazepines are abruptly abstinent patients with a history of seizures (even in the absence of withdrawal symptoms), patients with symptomatic withdrawal and a history of DTs, patients with underlying conditions that cannot tolerate the symptoms of withdrawal, patients with moderate to severe symptoms scoring higher than 14 on the CIWA-Ar, and those with concurrent acute illness (Foy et al., 1988).

The particular benzodiazepine to be prescribed for alcohol withdrawal is determined by patient characteristics and the pharmacology of the benzodiazepine. The long-acting benzodiazepine chlordiazepoxide (Librium) is the most frequent medication prescribed for alcohol withdrawal in the United States (Saitz et al., 1993) and is the medication of first choice unless there is jaundice or other clinical indicators of severely compromised liver function. Oxazepam (Serax) or lorazepam (Ativan) are acceptable alternatives with patients who have severe liver disease because neither is metabolized by the liver. Many physicians prefer chlordiazepoxide over diazepam (Valium) for alcohol detoxification medication because paradoxical rage and behavioral dysinhibition are more common with diazepam than with chlordiazepoxide. Other benzodiazepines suitable for alcohol withdrawal are clonazepam (Klonopin) and chlorazepate (Tranxene).

Although the dangers of overmedicating in a hospital setting during the first 24 hours are less than those of undermedicating, patients should still be monitored for signs and symptoms of overmedication, which for chlordiazepoxide include obtunded consciousness, ataxia, impairment of short-term memory, sustained horizontal nystagmus, slurred speech, unsteady gait, and, rarely, noxious or belligerent behavior.

Initial dosing is chlordiazepoxide 25 to 50 mg every hour until the patient is becoming less tremulous and pulse rate is decreasing. Some patients will have sustained nystagmus even in the presence of increasing signs and symptoms of withdrawal. In such cases, additional chlordiazepoxide to decrease withdrawal symptoms is reasonable during the first 72 hours of alcohol abstinence. Some patients are inebriated on admission and may require initiation of benzodiazepine treatment before blood levels of alcohol are below 0.1 to prevent emergence of alcohol withdrawal. If adequate control of signs and symptoms of alcohol withdrawal are obtained during the first 48 hours of detoxification and alcohol blood levels are zero, additional chlordiazepoxide is not necessary. Chlordiazepoxide is slowly metabolized, so it is, in effect, "self-tapering." For patients with severe liver disease, administer oxazepam 30 mg every hour.

Patients who are vomiting or having severe diarrhea may not reliably absorb oral benzodiazepines. In such cases, the benzodiazepine should be given by intramuscular injection. Lorazepam in 2 mg doses is the medication of choice because it is reliably absorbed from muscle tissue, unlike chlordiazepoxide or diazepam. A lorazepam injection should be given every hour until tachycardia, profuse sweating, and tremulousness begin to subside. As soon as possible, the patient should be switched to oral chlordiazepoxide (or oxazepam). Patients who are clinically dehydrated should be treated with intravenous (IV) fluids until they are able to reliably retain oral fluids.

Patients with a history of seizures not related to acute alcohol or other drug withdrawal or toxicity (e.g., cocaine) should be maintained on their usual anticonvulsant (e.g., phenytoin [Dilantin], phenobarbital) during detoxification.

Carbamazepine and valproate

Both carbamazepine (Tegretol) and valproate (Depakote, Depakene) enhance GABA function, seemingly by a different mechanism than the benzodiazepines. Both are effective in suppressing alcohol (and benzodiazepine) withdrawal symptoms, and neither produces effects that most alcohol abusers find desirable.

Phenobarbital

Phenobarbital can be used for alcohol detoxification with a patient who is also addicted to sedative-hypnotics. Although phenobarbital has an anticonvulsant activity similar to that of diazepam, because it is long-acting with a half-life of over 72 hours, it has a longer duration of anticonvulsant action, and it increases the seizure threshold. The long latency reduces its abuse potential, plus overuse induces dysphoria, so patients are less likely to overmedicate.

Seizures during alcohol withdrawal are primarily generalized, with fewer than three seizures occurring per withdrawal episode. Most patients either have no seizures or one seizure; seizures typically occur between 12 and 36 hours after the last drink. Patients who have a history of alcohol withdrawal seizures or who have epilepsy may need to be hospitalized for detoxification. Noncompliance with prescribed antiepileptic medications is a common source of epileptic (not alcohol withdrawal) seizures among patients with alcoholism, so a provider should check blood levels and, if necessary, reinitiate these medications for patients experiencing withdrawal.

Alcohol withdrawal: Protocols

There are several acceptable medication protocols for treating alcohol withdrawal:

  • Gradual, tapering doses. Oral benzodiazepines are administered on a predetermined dosing schedule for several days and gradually discontinued; specific protocols vary widely among treatment facilities. As an example, patients may receive 50 mg of chlordiazepoxide (or 10 mg of diazepam) every 6 hours during the first day and 25 mg (or 5 mg of diazepam) every 6 hours on the second and third days (Saitz et al., 1994). Doses of withdrawal medication are usually omitted if the patient is sleeping soundly or showing signs of oversedation.
  • Symptom-triggered therapy. Using the CIWA-Ar, nurses are trained to recognize signs and symptoms of alcohol withdrawal and to administer withdrawal medications to their patients only when signs and symptoms of alcohol withdrawal appear. Studies have demonstrated that appropriate training of nurses in the application of the CIWA-Ar dramatically reduces the number of patients who receive medication (from 75 percent to 13 percent) (Wartenberg et al., 1990). Patients with CWIA-Ar scores below 15 are generally not medicated, while patients with scores between 15 and 30 are administered 25 mg chlordiazepoxide (or equivalent of another benzodiazepine) and reassessed every hour until the score is 20 or below. Patients with scores above 30 are administered 50 mg of chlordiazepoxide and reassessed every hour.
  • Loading dose. A slowly metabolized benzodiazepine is administered for the first day of treatment only (Sellers et al., 1983). Patients in moderate-to-severe withdrawal receive 20 mg of diazepam (or 100 mg of chlordiazepoxide) every 1 to 2 hours until they show significant clinical improvement (such as a CIWA-Ar score of 10 or less) or become sedated. A 1985 study indicates that "oral diazepam loading alone may be sufficient to prevent withdrawal seizures in patients who have had them previously and who have no other reason for having seizures" (Devenyi and Harrison, 1985, p. 799).

The clinical merits of one protocol over another have not received adequate study. One randomized, double-blind controlled study conducted in an inpatient Department of Veterans Affairs (VA) hospital compared fixed-dose and symptom-triggered therapy. The researchers found that patients "treated with symptom-triggered therapy completed their treatment courses sooner and required less [medication] than patients treated using the standard fixed-schedule approach" (Saitz et al., 1994, p. 522). Specifically, they received less chlordiazepoxide (median 100 mg versus 425 mg) and received treatment for a shorter period of time (9 hours versus 68 hours). This indicates that symptom-triggered therapy is an approach that could individualize and improve the management of alcohol withdrawal. "Future studies should evaluate the effect of symptom-triggered therapy on the cost and duration of hospitalization for the treatment of alcohol withdrawal and should identify . . . patient populations for whom symptom-triggered therapy may be appropriate" (Saitz et al., 1994, p. 523).

An example of medication orders for uncomplicated, symptom-triggered alcohol withdrawal appears below.

Inpatient vs. outpatient detoxification

Some patients need to be detoxified in a hospital, where the signs and symptoms of their alcohol withdrawal can be frequently monitored. These include patients

  • With a history of alcohol withdrawal hallucinations, withdrawal seizures, or withdrawal delirium
  • With a documented history of very heavy alcohol use and high tolerance, conferring substantial risk of a severe withdrawal syndrome
  • Who are currently abusing or are dependent on other drugs (particularly sedatives or opioids)
  • Who have a severe comorbid general medical or psychiatric disorder
  • Who are pregnant
  • Who live with people who use alcohol and drugs
  • Who do not have a reliable person to monitor their condition
  • Who have substantial risk of committing suicide

A primary concern with outpatient detoxification is that patients will drive an automobile or otherwise endanger themselves or others. During detoxification, patients' judgment, short-term memory, and motor skills may be impaired due to alcohol withdrawal symptoms or to the medications used to ameliorate withdrawal symptoms. Nonetheless, some patients can be safely and successfully detoxified as outpatients. Good candidates include

  • Patients with a good psychosocial support system
  • Patients without a history of severe withdrawal symptoms and who are not currently severely dependent on alcohol or concurrently abusing other drugs
  • Patients who are attending day treatment or intensive outpatient treatment
  • Patients who agree not to drive an automobile or operate hazardous machinery during detoxification

Detoxification of debilitated, acutely ill patients

Patients who have been drinking heavily for long periods may be malnourished. At the time they present for treatment, they may be dehydrated and have disturbances in electrolyte balance, particularly if they are vomiting or having diarrhea. Stat electrolyte determinations should be part of the initial assessment. Fluid, electrolytes, thiamine, and glucose should be given at the beginning of treatment. Patients undergoing withdrawal who are malnourished are at risk for Wernicke-Korsakoff syndrome. Patients being administered IV fluids should be given 100 mg of thiamine to reduce the probably of developing Wernicke-Korsakoff syndrome.

Hypomagnesemia may produce seizures and cardiac arrhythmias. In patients with normal kidney function, magnesium is safe. Patients who are malnourished and sufficiently ill to be receiving intravenous fluids should receive supplemental magnesium.

Because of the risk of drug accumulation and associated toxicity, use of long-acting benzodiazepines is relatively contraindicated in patients older than 60, particularly those who are hypoxic, hypercapnic, or those who have chronic obstructive pulmonary disease (Mayo-Smith and Bernard, 1995; Liskow et al., 1989). Patients with advanced liver disease should get oxazepam and lorazepam, agents that are not oxidatively metabolized by the liver, because they accumulate less and are less likely to produce excessive sedation. Shorter acting medications may be preferable in patients with severe obstructive lung disease or liver disease with synthetic dysfunction.

Adrenergic agents

On the basis of a small number of clinical studies, it appears that adjunctive atenolol (Tenormin) and clonidine may increase the effectiveness of treatment for alcoholic patients in withdrawal who present in a hyperadrenergic state, that is, with a marked elevation in blood pressure or heart rate. These medications should not be used alone for treatment of withdrawal because they do not prevent seizures or DTs.

Studies suggest that atenolol can help supplement treatment. Compared with patients getting a standard treatment of benzodiazepines, fluids, thiamine, and nutrition, a group receiving adjunctive atenolol as needed for 9 days experienced more prompt resolution of the withdrawal syndrom (Kraus et al., 1985). Similar trials of clonidine produced the same results (Baumgartner and Rowan, 1987, 1991). Beta blockers such as propranolol (Inderal) and atenolol may have an adjunctive role in withdrawal of patients with coronary artery disease (CSAT, 1995a).

Relapse Prevention

Medications used for relapse prevention include those that are administered postdetoxification to increase patients' chances of remaining abstinent from alcohol use.

Disulfiram (Antabuse)

Actions and dosing

Disulfiram deters drinking by triggering an unpleasant physical reaction to alcohol. Few studies convincingly indicate a general usefulness of disulfiram, and many patients are noncompliant. However, patients who succeed at abstinence are often users of disulfiram; the lack of proof should not interfere with its availability to patients and therapists.

Disulfiram interferes with the metabolism of acetaldehyde, an intermediary product in the oxidation of alcohol. As a result, acetaldehyde accumulates in the blood. Drinking alcohol within 12 hours after taking disulfiram produces facial flushing within 15 minutes, then intense vasodilation of the face and neck with suffusion of the conjunctivae, throbbing headache, tachycardia, hyperpnea, and sweating. Nausea and vomiting follow after 30 to 60 minutes and may be so intense as to lead to hypotension, dizziness, and sometimes fainting and collapse. The reaction lasts 1 to 3 hours. Discomfort is so intense that few patients will risk taking alcohol as long as they are taking disulfiram.

Disulfiram may be started when the patient has been free of alcohol for 4 or 5 days. The initial dose is 0.5 gram orally once a day for 1 to 3 weeks. The maintenance dose is adjusted individually; 0.25 to 0.5 gram once a day is usually adequate. Both patient and relatives should be advised that the effects of disulfiram may persist for 3 to 7 days following the last dose. The patient must want to be alcohol abstinent, must cooperate, and should be seen periodically by the physician to encourage his continuing to take disulfiram as part of an abstinence program. The patient should avoid medications that contain alcohol (e.g., tinctures, elixirs, and some over-the-counter liquid cough and cold preparations, which contain as much as 40 percent ethanol).

Providing an adequate dosage of disulfiram is essential to prevent chronic relapses. In a meta-analysis of international studies of the use of disulfiram, Brewer noted a wide range of dosages and found that an adequate dosage varies from patient to patient (Brewer, 1992). Brewer recommends an initial dose of 250 to 500 mg for most patients, but starting those for whom relapse would be disastrous on a dose of 500 mg. Lower dosages may be appropriate for individuals with liver impairment or those who may not require high doses (for example, people with a small body size, some women, and elderly persons).

Patients should receive disulfiram as long as it seems beneficial in helping them to remain abstinent. Patients have been treated up to 16 years with disulfiram (Kristenson, 1992). The optimal length of treatment has not received systematic study.

Caveats

Adverse effects of disulfiram include optic neuritis, peripheral neuritis, polyneuritis, and peripheral neuropathy. Patients should be examined at least every 4 months while taking disulfiram.

Cholestatic hepatitis is an uncommon but potentially serious complication of disulfiram therapy. Liver enzymes that are elevated due to alcohol generally decline while patients are taking disulfiram. Fuller and colleagues found no significant hepatoxicity in patients on disulfiram who do not drink (Fuller et al., 1986). Patients who become jaundiced or who develop anorexia or malaise should have liver function checked.

Occasional skin eruptions are, as a rule, readily controlled by concomitant administration of an antihistaminic drug. In a small number of patients, a transient mild drowsiness, fatigability, impotence, headache, acneiform eruptions, allergic dermatitis, or a metallic or garlic-like aftertaste may be experienced during the first two weeks of therapy. These complaints usually disappear spontaneously with the continuation of therapy or with reduced dosage.

Psychotic reactions have been noted, attributable in most cases to high dosage, combined toxicity (with metronidazole or isoniazid), or to the unmasking of underlying psychoses in patients stressed by the withdrawal of alcohol.

Patients unlikely to abstain are not appropriate candidates for disulfiram, nor are patients with

  • Acute hepatitis
  • Significant cardiac disease
  • Pregnancy (as well as women trying to get pregnant)
  • Severe chronic lung disease or asthma
  • Schizophrenia or manic depressive illness (disulfiram may precipitate psychosis)
  • Suicidal ideation or intent
  • Allergy to rubber
  • Jobs that include handling alcohol or solvents (e.g., painters and mechanics)

Episodic use of disulfiram can be clinically effective. Patients can take disulfiram the day before an event that holds high risk for relapse, for example, a trip alone out of town or a wedding where alcohol is sure to be served. Episodic use may have an added benefit of lowering the risk of disulfiram toxicity (Duckert and Johnsen, 1987). Some patients always carry an unfilled prescription for disulfiram or an unopened vial of the medication, which they may never use. Disulfiram is most likely to be effective when used in conjunction with counseling, regular attendance at Alcoholics Anonymous (AA) or other 12-Step recovery meetings, and frequent medical visits.

Naltrexone

Actions and dosing

In 1994, after a decade of use with opiate abusers, the opiate antagonist naltrexone was approved by FDA for prevention of relapse to alcohol use. By competitively binding at opioid receptors, naltrexone appears to block the pleasurable effects of both alcohol and opiates. When it was approved for treatment of alcohol dependence, the trade name was changed from Trexan to ReVia.

For patients who are alcohol dependent and are not abusers or medicinal users of opiates, naltrexone can be started as soon as alcohol withdrawal symptoms have stopped. Initial dosing is 25 mg (@@@frac12@@@ tablet) once a day with a meal. Occasionally, patients will report feeling stimulated with the first few doses, so it is best administered early in the day. If the patient has no side effects, the dose can be increased to 50 mg once daily.

O'Malley and colleagues found that the best candidates for naltrexone had

  • High levels of alcohol dependence
  • Familial alcoholism
  • High levels of craving
  • Less than a high school education (O'Malley et al., 1996)

In a study of 70 male veterans, fewer naltrexone-treated subjects than placebo-treated subjects (23 percent compared with 54.3 percent, respectively) met criteria for relapse (Volpicelli et al., 1992). Similarly, naltrexone has produced higher rates of abstinence among a sample of 97 patients when combined with supportive (as opposed to cognitive) treatment, reduced relapse rates by 50 percent, and reduced craving (O'Malley et al., 1992).

The study indicated that continuing naltrexone for more than 3 months may be desirable, especially among nonabstainers. Naltrexone is generally well tolerated (Bohn et al., 1994).

Caveats

Because naltrexone adheres very tightly to the : opiate receptor, it is extremely difficult to override the effect of naltrexone either to get "high" or to obtain analgesia. Patients must know that after they are on naltrexone, opiates will not provide pain relief, though nerve blocks and nonopiate analgesics are still effective. Patients who have a medical need for opiates should not be administered naltrexone. Patients who are to have surgery or other medical procedures should not be administered naltrexone within 3 days of the procedures. After the procedure, patients should be restarted on naltrexone 3 days after their last use of opiates. Earlier reinduction of naltrexone is likely to precipitate opiate withdrawal signs and symptoms.

Patients whose serum glutamic-oxaloacetic transaminase (SGOT) or serum glutamic-pyruvic transaminase (SGPT) is greater than 5 times the upper normal range should not be started on naltrexone.

The use of naltrexone is contraindicated for some alcoholic patients, including those

  • With acute hepatitis
  • Who are dependent on opioids (naltrexone precipitates opioid withdrawal)
  • Who have stopped opioid use in the past 2 weeks
  • Who may require intermittent opioid treatment for relief of pain (migraine headaches) or who are scheduled for elective surgery
  • Who are pregnant or trying to become pregnant

Patients should be advised about potential side effects. The most common is nausea or abdominal cramping 30 to 90 minutes following a dose. The GI side effects can often be minimized by having the patient take naltrexone with meals. Much less common are anxiety, insomnia, and malaise (Croop et al., 1995). The cost of naltrexone to the health care system or patient is substantial. Costs for naltrexone range from $2.50 per day in the VA system to between $4 and $6 per day in retail pharmacies.

Medications for psychiatric comorbidities

Antidepressants

A substantial proportion of alcoholic patients seeking treatment report symptoms of depression and anxiety; 25 to 45 percent have been diagnosed as having anxiety disorders (Chambless et al., 1987; Cox et al., 1989). Treatment of withdrawal symptoms like nausea, headaches, and insomnia can substantially improve patients' well-being and outcomes. All patients should be carefully evaluated for signs of serious depression in the early weeks of abstinence; depression in these patients confers a risk of suicide, and treatment planning should include measures to maximize patient safety.

For many depressed or anxious alcoholic patients receiving alcohol counseling, symptoms of depression resolve within 30 days of abstinence. If defining symptoms of a mood disorder have not been observed and noted during earlier periods of abstinence, the clinician should wait for at least 30 days to initiate antidepressant treatment.

Selective serotonin reuptake inhibitors (SSRIs) are now the most commonly prescribed antidepressants because they are better tolerated than the tricyclic medications. Nonetheless, the tricyclics are still inexpensive and useful for patients who can tolerate them. Recent studies have reported imipramine (McGrath et al., 1996) and desipramine (Mason et al., 1996) effective in treating depression among alcoholic patients. Trazodone, in doses of 50 to 100 mg, is often helpful at bedtime as an alternative to sedative-hypnotics.

Anxiolytics

The prescription of benzodiazepines to treat anxiety disorders among those recovering from alcohol and other drug dependencies is controversial. Many addiction specialists believe that recovering patients are likely to develop physical dependency on or overuse benzodiazepines. Because of these dangers, benzodiazepines are generally contraindicated and should not be prescribed to alcoholics by primary care physicians.

Buspirone (Buspar) can sometimes be a useful and nonaddictive alternative to addictive benzodiazepines for treatment of anxiety. Kranzler and colleagues recommend a 12-week regimen of buspirone (5 mg three times daily, increasing every 3 or 4 days to a maximum dose of 40 to 60 mg/day) (Kranzler et al., 1994).

Pharmacotherapy for Benzodiazepine Dependence

Long-term, daily benzodiazepine use can result in physical dependence even when the benzodiazepine is used within usual therapeutic doses.

Physical dependence is caused by neuroadaption of the cells of the brain to the presence of a drug or medication. Physical dependence does not necessarily mean that the patient has an addiction disorder. A patient who has been taking benzodiazepines for months to years for medical reasons may be physically dependent and have withdrawal symptoms when the benzodiazepine is stopped.

The risks of withdrawal are particularly high for people over 65, because their bodies metabolize drugs differently. Rapid benzodiazepine withdrawal has been shown to cause catatonia in older patients (Rosebush and Mazurek, 1996). Primary care clinicians should always consult an addiction medicine specialist about older adults' detoxification from sedatives.

Carbamazepam and valproate can aid in withdrawal from benzodiazepines as well as from alcohol. The use of valproate for withdrawal from benzodiazepines is supported by several case studies (Roy-Byrne et al., 1989; Apelt and Emrich, 1990). In clinical experience with treating benzodiazepine withdrawal and in the controlled clinical trials in treatment of epilepsy, valproate appears to be better tolerated than carbamazepam.In general, patients will fall into one of two categories: One is patients who take relatively fixed doses of benzodiazepines, with or without the prescribing physicians' knowledge and consent. These patients are able to ration their use of benzodiazepines (i.e., they may be physically dependent but are not "out of control"). Discontinuation of therapeutic doses of benzodiazepines may produce psychosis, parathesias, increased sensitivity to sound and light, irritability, acute anxiety, and insomnia.

The second group of patients use benzodiazepines frequently, but generally use as much as is available to them; many also abuse other drugs. Abrupt discontinuation of large doses of benzodiazepines can result in signs and symptoms such as seizures, psychosis, severe anxiety, intense nightmares, and insomnia. As outlined below, the treatment strategy for these two groups of patients is different.

Patients Who Control Their Daily Use

If a patient has been maintained on benzodiazepines for medical purposes, the term for cessation is therapeutic discontinuation or taper rather than detoxification. If the therapeutically prescribed benzodiazepine of dependence is long-acting, it should be slowly tapered on an outpatient basis. For patients who are dependent on a short-acting benzodiazepine, a long-acting one such as clonazepam should be substituted and then slowly tapered.

For patients who can adhere to the withdrawal regimen and who do not have a diagnosable substance abuse disorder, the benzodiazepine is first tapered to the lowest dose that the patient can tolerate. Then a regimen of valproate should begin, starting with 125 mg three times a day. Then the daily dose is increased as tolerated or until the patient is taking 750 to 1200 mg/day and symptoms have abated. The benzodiazepine is then abruptly stopped. Valproate is continued for 30 days and gradually discontinued over a 2-week period.

For patients who have significant depressive symptoms, treatment with an antidepressant may be indicated before initiating the final phase of pharmacological withdrawal. Acceptable antidepressants include nefazodone (Serzone) 300 to 600 mg/day (in b.i.d. dosing) or fluoxetine (Prozac) 10 to 20 mg/day. Both may decrease the metabolism rate of benzodiazepines and valproate.

Patients "Out of Control"

Patients who are abusing benzodiazepines require hospitalization for detoxification because they cannot reliably adhere to a detoxification regimen. The patient should be maintained on a long-acting benzodiazepine such as clonazepam at a dosage that does not produce intoxication. Valproate should be started at 125 mg/day and increased to 750 to 1200 mg as rapidly as tolerated. The long-acting benzodiazepine is discontinued on the third day.

Alcohol and Benzodiazepine Dependence

Some alcoholics also chronically abuse benzodiazepines or other sedative-hypnotics and have a physical dependence on both. Patients may deny drug use generally, so it is wise to specifically inquire about Librium, Valium, Xanax, and Ativan. Urine screening and history from family members can help confirm such a dual dependence. Even if the dual dependence is strongly suspected, patients can be treated initially with chlordiazepoxide until results of liver function studies are available. Patients who do not have laboratory or clinical evidence of acute hepatitis should be started on valproate 250 mg three times a day the first day. On the second day, valproate is increased to 250 mg four times a day. Chlordiazepoxide is used in addition to suppress acute withdrawal signs and symptoms for up to 72 hours.

Pharmacotherapy for Dependence on Other Drugs

Other Sedatives

Nonbenzodiazepine sedatives include barbiturates (such as secobarbital, pentobarbital [Nembutal], and amobarbital); carbamates; and chloral hydrate. Withdrawal from these sedatives is associated with orthostatic changes in blood pressure and pulse and can be life-threatening. The duration of the withdrawal syndrome varies depending on the half-life of the drug and the duration and severity of drug dependence.

Another difference suggested by clinical evidence is the higher risk of withdrawal seizures, including repeated/status withdrawal seizures, in sedative withdrawal than in alcohol withdrawal. The time between the last dose of the drug and peak intensity of symptoms is 24 to 72 hours for pentobarbital, secobarbital, oxazepam, and alprazolam (Xanax) compared with 5 to 8 days for long-acting drugs like diazepam and chlordiazepoxide. For patients addicted to faster acting sedative-hypnotics, one option is to substitute phenobarbital or chlordiazepoxide and then taper those doses. Conversion schedules can be found on pages 32 and 33 of TIP 19, Detoxification From Alcohol and Other Drugs (CSAT, 1995a).

Cannabis

Some people use marijuana chronically, but most do not have a medically significant withdrawal syndrome. No specific pharmacotherapy is needed.

Opioids

In classical pharmacology, opiates are derivatives of thebaine. Many synthetic opiates have been synthesized, and the term opioids encompasses morphine, heroin, codeine, methadone, hydrocodone bitartrate (Vicodin), and hydromorphone (Dilaudid).

Opioid Detoxification

Opioid withdrawal syndrome

Opioid withdrawal ranges from mild drug craving and anxiety to three grades of symptom severity. (See Figure A-2.) Symptoms of withdrawal from heroin or morphine begin 8 to 12 hours after a patient's last dose and last for 5 to 7 days. For methadone, withdrawal begins 12 hours after the last dose and can last for 3 weeks or more, generally at a lower intensity than other opioid abstinence syndromes (CSAT, 1995a).

Figure A-2 Symptoms of Opioid Withdrawl.

Figure

Figure A-2 Symptoms of Opioid Withdrawl.

Patients suffering Grade 1 or even Grade 2 symptoms may be able to be treated with clonidine, a hypertension medication that alleviates most of the milder abstinence symptoms. An initial test dose of 0.1 mg should be administered orally (sublingually if symptoms are acute). If after 45 minutes the patient's diastolic blood pressure is normal and no orthostatic hypotension is evident, then doses of 0.1 to 0.2 mg should be administered orally every 4 to 6 hours. Clonidine also comes in patch form, and patch wearers seem to have fewer drug cravings than those who take the drug orally (CSAT, 1995a).

Outpatient detoxification of opioid-addicted persons using narcotics (usually methadone or LAAM) is legal only in licensed clinics, all of which are medically staffed. When a patient is involved in a clinic-based, outpatient methadone detoxification, the primary care provider may need to work with the clinic staff to integrate agents other than methadone (e.g., clonidine or buprenorphine) into the treatment program. Few data are available on primary-care-based opioid detoxification in the United States. Medications to treat nonspecific symptoms, such as antinauseants, antispasmodics, and anti-inflammatory pain relievers, may be effective in patients with moderate addiction. The judicious, time-limited use of anxiolytics such as hydroxyzine (Vistaril, Atarax) and nonbenzodiazepine sedating medications can help patients sleep and reduce their anxiety. These medications include trazodone, diphenhydramine, doxepin (e.g., Benadryl), imipramine, and amitriptyline.

Primary-care-based opiate detoxification can be successful (O'Connor et al., 1995), and

outpatient opioid detoxification may provide an opportunity to engage more opioid-addicted persons in specialized treatment. However, a primary care practitioner treating such patients should consult an addiction specialist. Many opioid-addicted individuals have multiple problems, and their care should be part of integrated clinical and social support programs. A primary care setting that accepts many such patients must be prepared for clinical challenges and strained resources.

Rapid opioid detoxification

Rapid opioid detoxification protocols involve anesthetizing patients and infusing increasing amounts of opiate antagonists (naloxone [Narcan] or nalmephine) over a 12- to 24-hour period. This plays to some opioid addicts' wish for a quick, painless cure. The procedure has been touted in the press, and some opioid-dependent patients request the procedure. At the time of this writing, the procedure is not part of standard addiction medicine practice and should be left to a small group of physicians who are specializing in it.

Relapse Prevention

Relapse prevention in this context refers to preventing relapse to medically unsupervised opiate use. The two main pharmacotherapies are (1) opiate maintenance with methadone or LAAM and (2) opioid blockade with naltrexone.

Methadone maintenance

Although opioid maintenance therapy still has its detractors, many studies document the efficacy of methadone maintenance among opiate abusers in reducing use of heroin, criminal activity, and activities that put them at risk for acquiring or spreading HIV infection. Some addicts cease use of heroin altogether while on maintenance and relapse to heroin use when maintenance is terminated. The issues surrounding methadone are complex and beyond the scope of this appendix.

Although methadone therapy has been successfully provided in a primary care setting to stable methadone-maintained patients (Novick et al., 1988), there is no consensus on clinical procedures (Wesson, 1988), and the use of methadone for detoxification or maintenance must be provided in specially licensed clinics. An exception is methadone-maintained patients who are hospitalized for treatment of a serious medical illness.

Medically ill, methadone-maintained patients

When methadone-maintained patients are admitted to the hospital for treatment of an acute medical illness, they should normally be kept on their maintenance dose of methadone. The maintenance program should be called to verify the maintenance dose, because patients may not be reliable informants. It is sometimes wrongly assumed that patients' methadone dose will provide adequate analgesia if they are having pain. This is not usually the case for severe pain, and patients should be administered standard opiates such as morphine in addition to their methadone. Their opiate tolerance may be very high, and they may need much larger than standard doses. The best approach is to incrementally administer opiates until satisfactory pain relief has been achieved. (See TIP 1 State Methadone Treatment Guidelines and TIP 20 Matching Treatment to Patient Needs in Opioid Substitution Therapy for more on State treatment guidelines and patient-treatment matching for methadone patients [CSAT 1993, 1995b]).

Naltrexone

Naltrexone is a long-acting competitive antagonist at : opioid receptors that blocks the response to opioids. Naltrexone was approved in 1984 by the FDA for preventing relapse to opiate use. Naltrexone's greatest clinical utility is to prevent relapse to opiate use among patients who are highly motivated to abstain. It has proven extremely useful in the treatment of health professionals and some other opiate-dependent patients (Ling and Wesson, 1984).

While the pharmacological efficacy of oral naltrexone in blocking the effects of heroin and other opiates is well established, compliance problems have limited its utility. Unlike methadone, naltrexone does not provide patients with a beneficial mood-altering effect.

The usual maintenance dose of naltrexone is 50 mg per day. If it is self-administered, once-daily dosing is usual. In some instances, monitoring compliance is desirable (e.g., with a health professional who handles opiates at work). To minimize logistical problems, clinicians generally administer naltrexone according to the following schedule: 100 mg Monday, 100 mg Wednesday, and 150 mg Friday. The increased dose on Friday provides adequate opiate blockade throughout the weekend.

For heroin users, allow at least 7 days after the last opioid dose before administering the first dose of naltrexone. This recommendation also applies to opioids (including propoxyphene [Darvon] and methadone) that may have been used during detoxification. For patients who have been abusing or maintained on methadone, allow at least 10 days following the last dose. Induction protocol is the same as for prevention of alcohol relapse.

Medically ill, naltrexone-maintained patients

The analgesic effects of opiates will be blocked 24 to 72 hours following the last naltrexone dose. If a patient needs pain relief from peripheral injuries, the physician should not attempt to override the opiate blockade by administering extra-therapeutic doses of opiates but rather should use a nerve block. Patients maintained on naltrexone who are facing elective surgery should stop naltrexone three days prior to surgery and resume it several days following the last administration of an opiate.

Cocaine and Methamphetamine

No specific pharmacological detoxification regimen is required for cocaine, crack cocaine, or methampethamine. Use is typically a binge pattern alternating with days to weeks of abstinence. Following cessation from daily use, some patients are agitated, appear depressed, and have difficulty sleeping. Symptomatic treatment with chlordiazepoxide 10 to 25 mg for a few days provides some amelioration of agitation and insomnia.

Nicotine

Nicotine is increasingly being viewed as an addictive drug among addiction medicine specialists. Most people who are dependent on alcohol and other drugs smoke cigarettes. A recently published study reported that the cumulative mortality from tobacco-related causes (50.9 percent) among patients previously treated for alcohol and other drug dependencies exceeded that of alcohol (34.1 percent) (Hurt et al., 1996). As a practical matter, patients undergoing treatment for alcohol or other drug dependencies are often resistant to stopping smoking while they are undergoing treatment. A common response is, "Yes, I want to stop, but not now."

Physicians should aggressively encourage patients to begin a smoking cessation program during the early phases of drug dependency treatment. One approach is to help patients quit smoking while being maintained on nicotine via the transdermal patch or nicotine gum.

Conclusions

Although much has been learned during the past 20 years about the neurophysiology of addiction, drug abuse treatment models have not changed as much as patients' access to drug abuse treatment services has. Cutbacks in public funding of drug abuse treatment have severely limited access to treatment in the public sector, and managed care has severely curtailed access in the private sector. Addiction medicine has responded with some innovations, like greater use of day treatment and intensive outpatient services. Managed care has engendered a greater emphasis on outpatient treatment and curtailed patients' access to specialists.

The fractured health care of the 1990s, however, is an interim condition, and health care reform will eventually be realized in a reasonable way. Although the shape of health care in the future is far from defined, some current trends will likely persist. One such trend is the integration of addiction treatment into mainstream medicine.

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Footnotes

1

Medical and Scientific Director, MPI Treatment Services, Summit Medical Center, Oakland, California; Associate Clinical Professor of Psychiatry, University of California at San Francisco.

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