Implementation of the Plan

Patients likely to experience withdrawal symptoms require detoxification. Past withdrawal symptoms are the best predictor of those in the future, and future withdrawal syndromes should be anticipated to be more severe than those of the past.

Many patients will seek detoxification simply to gain temporary relief from their withdrawal misery, but not every patient should necessarily be detoxified simply because of an expressed desire to do so. Any patient who has never undergone medical detoxification should be given the opportunity as quickly as possible, as should anyone active in treatment who relapses. Medical detoxification should always be undertaken whenever a patient's alcohol or drug use significantly compromises the treatment of any other disorder (e.g., epilepsy, diabetes, cardiovascular dysfunction, anxiety and depressive disorders). Otherwise, detoxification should be undertaken only when part of a broader, mutually agreed-upon, long-range treatment strategy in order to deter poorly motivated patients from employing "revolving door" detoxification as a stopgap measure (e.g., when their drug supply has been temporarily interrupted). A bit of clinical skepticism should be exercised with kindness.

Key to any detoxification is quarantine: sequestering of patients (hosts) from environments in which psychoactive substances (agents) are available.

There are nearly as many detoxification protocols as there are institutions, and no single one will prove right for most patients. With this caveat, suggested strategies follow.

Alcohol. A history of major withdrawal phenomena (e.g., delirium tremens, acute withdrawal hallucinosis, seizures) calls for inpatient detoxification. Fever or significant medical comorbidity (such as pneumonia or systemic infection, liver or other active gastrointestinal disease, a history of cardiac dysfunction, malnourishment, and recent trauma) is also an indication for inpatient detoxification. Patients with psychiatric disorders (such as major depression, mania, panic disorder, and schizophrenia) or who are using multiple psychoactive drugs are best detoxified on inpatient psychiatric units. Patients with histories of major alcohol withdrawal but who are otherwise healthy can sometimes be safely detoxified in residential treatment facilities that have 24-hour medical supervision. Detoxification in such facilities is indicated for patients who have failed outpatient detoxification, who have poor social supports, or who have a limited grasp of the seriousness of their condition.

Many patients can be successfully detoxified by the primary care physician on an outpatient basis, but only if the patient and physician are prepared to see each other briefly in the office on at least an every-other-day basis and if there is a responsible person who can provide 24-hour supervision (which includes accompanying the patient to appointments). This treatment supervisor should be present when the patient is given initial instructions and should have at least telephone access to the physician or a medical treatment facility (or both) on a 24-hour basis.

Outpatient detoxification should be attempted only once and only after the results of baseline laboratory studies, toxicology screens, and a complete physical examination are in hand. At each office visit, disulfiram should be given under supervision (see under "Preventive Maintenance," below), but only after patients have had a negative test for alcohol in their expired air. Patients should also be encouraged to attend Alcoholics Anonymous or other group treatment meetings on a daily basis.

Intermediate- and long-acting benzodiazepines such as lorazepam, ox-azepam, diazepam, and chlordiazepoxide hydrochloride are the drugs of choice for pharmacologic detoxification because of the wide therapeutic window between doses that yield benefit and those that cause toxicity. The choice of benzodiazepine depends on the patients age and hepatic function and on the environment in which detoxification will take place. Chlor-diazepoxide hydrochloride has an average half-life of 24-48 hours but a much longer one in elderly patients and those with impaired hepatic function. It is the drug of choice for patients who are young and otherwise healthy and who will be relatively sparsely supervised. Diazepam has a halflife of about 24 hours and poses fewer hepatic- or age-related constraints. Oxazepams half-life is 8-12 hours, making it the drug of choice for patients who are elderly or have compromised hepatic function. Lorazepam has a 12-18-hour half-life.

The acute onset of action of 25 mg of chlordiazepoxide hydrochloride is roughly equivalent to that of 5 mg of diazepam, 15 mg of oxazepam, and 1 mg of lorazepam. Due to differences in half-lives, giving a single 10-mg dose of diazepam is roughly equivalent to giving 30 mg of oxazepam, followed by 15 mg eight hours later, followed by 7.5 mg eight hours after that, and to giving 2 mg of lorazepam, followed by 1 mg 12 hours later.

For outpatient detoxification, it is recommended that the physician prescribe an initial supply of 10 or 15 pills of 25-mg chlordiazepoxide hydrochloride, 5-mg diazepam, 15-mg oxazepam, or 1-mg lorazepam. The patient should be instructed to take one tablet every hour until calm. An additional pill (i.e., two) should be taken every hour for the following parameters: pulse greater than 90, nervousness, or tremulousness. If, after 24 hours, the patient has taken more than eight pills, one should conclude that detoxification cannot be safely done in an outpatient setting.

If the patient has taken eight or fewer tablets the first day, the dosage should be subsequently tapered to discontinuation. Benzodiazepines may be tapered according to the following schedules: diazepam: days to taper = age rounded to the nearest decade/10; oxazepam/lorazepam: days to taper = (age rounded to the nearest decade + 20)/10. Thus, a healthy 24-year-old could be detoxified safely with diazepam in two days (20/10 = 2) or with oxazepam or lorazepam in four days ((20 + 20)/10 = 4). The last pill each day should be taken at bedtime. A fixed tapering schedule often proves impractical for chlordiazepoxide hydrochloride because of the long half-life of its metabolites, so after the first day, one pill should be taken on a prn basis every two hours only for the withdrawal parameters in the paragraph above. With a chlordiazepoxide hydrochloride taper, one pill should be taken at bedtime at the end of each day that a prn pill is taken, but none should be given at bedtime if no pill is taken during the day. If, in the course of tapering a benzodiazepine, the patient becomes somnolent or shows signs of intoxication, the dose should be reduced. For this reason, the physician should see the patient, together with the person providing supervision and counting pills, on at least an every-other-day basis.

As physiologic withdrawal is a potent sustaining factor for continued alcohol use, some have thought that relapse could be prevented with low-dose maintenance benzodiazepine therapy. However, many studies have shown that the longer patients are maintained on benzodiazepines, the greater the likelihood of relapse. Thus, maintenance benzodiazepines or those with exceedingly long half-lives (e.g., clonazepam) should not be used. Detoxification should be completed as quickly as possible, making the intermediate-acting benzodiazepines more desirable than the long-acting ones.

Some adjunctive agents should be used empirically at the start of medical detoxification. Three doses of magnesium oxide, 400 mg po q8h, can be given to help prevent seizures and hypomagnesemia. Thiamine hy-drochloride, 100 mg po qd, should also be started and continued indefinitely. However, employment of other adjunctive agents (e.g., propranolol hydrochloride for tremulousness and tachycardia, phenytoin or carba-mazepine to prevent seizures) should be avoided, as they raise the risk of delirium and can otherwise complicate treatment. Anticonvulsants have no role in preventing alcohol withdrawal seizures, except for patients with preexisting seizure disorders.

If anything goes awry with outpatient detoxification, the patient should immediately be admitted to a hospital or residential treatment facility with 24-hour medical supervision.

Cocaine. Cocaine withdrawal is characterized by intense drug cravings and the precipitous onset of depression that is often indistinguishable from major depression. This depressive syndrome usually subsides within days but can persist from weeks to months. It carries a high mortality from suicide rather than from physiologic perturbations. Cocaine users are 40-60 times more likely to attempt suicide than nonusers. Patients with suicidal ideation or a history of suicide attempts should be detoxified on an inpatient psychiatric unit. Otherwise, patients can be treated at home under 24hour supervision by a responsible designee.

Cocaine withdrawal cravings and depression often respond quickly to tricyclic antidepressants. Desipramine hydrochloride is the agent most commonly used because it has relatively few anticholinergic side effects, but any tricyclic antidepressant will do. Desipramine hydrochloride should be started at 50 mg po qhs and increased to 300 mg po qhs, if necessary. Blood levels should be monitored, with 150-300 ng/ml considered the therapeutic range. Bupropion hydrochloride is an effective alternative for patients who cannot tolerate tricyclic antidepressants. The immediate-release form of the drug should be started at 75 mg qd and increased, if necessary, to 100 mg tid. (See Chapter 2 for a more detailed discussion of antidepressant dosing.) Patients undergoing outpatient detoxification should attend Narcotics Anonymous meetings (see below) or other drug treatment group meetings on a daily basis.

Opioids. The withdrawal potential of opioids is extremely high, and patients can experience severe physiologic withdrawal after only weeks of taking such drugs. Repeated use to avoid withdrawal is the most potent reinforcer of opioid dependence. Despite these considerations, outpatient detoxification can be attempted, though with the same caveats as for detoxification from alcohol.

Although withdrawal phenomena appear 8-12 hours after the cessation of opioid use, peak intensity is not reached until 48-72 hours, and acute symptoms can persist for four or five more days. For this reason, most conventional three-day inpatient detoxification protocols are, in and of themselves, unsuccessful in preventing relapse by patients who continue to experience withdrawal symptoms after they leave. Further detoxification on an outpatient basis is therefore required.

Patients who are dependent on heroin can be detoxified with methadone or buprenorphine hydrochloride. Methadone provides ideal substitution therapy for heroin detoxification because of its minimal euphoriant effects and 24-hour half-life. When methadone is used for detoxification, federal law mandates that it can be prescribed for only a single three-day period. As the lives of heroin addicts have become focused on drug-seeking activity that is outside the law, physicians should try to evaluate the patients trustworthiness before giving him or her a methadone prescription. The starting dose of methadone should be 10 mg every hour until withdrawal symptoms have abated or until three doses have been given; the dose should then be tapered by 10 mg a day. In this way, a course of methadone, which should be followed by additional measures described below, can be completed in three days. If the taper is poorly tolerated, the physician should consider switching to buprenorphine hydrochloride (see below). If more than 30 mg of methadone is required for relief of symptoms, the patient should have inpatient or medically supervised residential detoxification.

Buprenorphine hydrochloride, an opioid agonist-antagonist, can be used either at the start of heroin detoxification or after a three-day methadone taper. It has a rapid onset of action and a half-life of 6-12 hours. Although buprenorphine hydrochloride is an effective medication, there are three complications to its use: (1) physicians must have approval from the Drug Enforcement Administration (DEA) to prescribe it for outpatient detoxification, (2) it is given intramuscularly, and (3) it can be administered only by appropriately licensed medical personnel. On weekends, methadone can be substituted for buprenorphine hydrochloride with patients who are compliant.

The initial dose of buprenorphine hydrochloride is 0.15 mg im, and it is repeated every hour until withdrawal symptoms abate or four doses have been given. The total dose used is given the next day on a bid basis (half the dose in each injection) and is subsequently tapered by 12.5-25 percent per day, so the medication is discontinued after 4-7 days. If, on the first day of treatment, four 0.15-mg doses do not significantly alleviate withdrawal symptoms, inpatient or residential detoxification is indicated.

Morphine-dependent patients are best detoxified using sustained-release morphine sulfate preparations. Similarly, patients dependent on oxycodone-containing compounds should be detoxified using sustained-release oxy-codone hydrochloride preparations. To get started, calculate the amount of morphine sulfate or oxycodone hydrochloride the patient is currently taking per day. This amount will equal the total daily dose of sustained-release preparation to be taken, first on a q8h basis for 36-48 hours and then on a q12h basis with tapering to discontinuation over a week or two. For example, a patient taking 10 mg of oxycodone hydrochloride every four hours would have a total daily dose of 60 mg. Sustained-release oxycodone hydrochloride would then be given at 20 mg q8h for three doses, followed by 30 mg q12h for two doses, after which the taper to discontinuation on a q12h schedule should begin. Near the end of the taper, morning doses should be eliminated first.

Conversion of other opioids (e.g., codeine, hydrocodone, meperidine) to sustained-release morphine sulfate or oxycodone hydrochloride preparations can be made using tables in the Physicians' Desk Reference.

No detoxification from opioids can ever be free of discomfort. Moreover, many withdrawal symptoms persist for several weeks after the cessation of opioid use, no matter how prolonged the taper. Various adjunctive agents can be used for added relief of symptoms.

Clonidine reduces sympathetically mediated withdrawal symptoms such as tremulousness, sweating, and rhinorrhea. Clonidine can cause marked postural hypotension, so orthostatic vital signs should be monitored at the outset of treatment. (For this reason, too, clonidine should be given with caution to patients who are on other agents that cause adrenergic blockade.) Start clonidine with two 0.1-mg transdermal patches. If this dose produces hypotension or other unwanted effects (e.g., tiredness, nausea), one patch can be removed. If 0.2 mg proves inadequate, a third 0.1-mg patch can be added. Each patch can be worn for up to a week, and the dosage should be subsequently tapered by 0.1 mg/week to discontinuation.

Dicyclomine hydrochloride, 10 mg po q6h prn, can be given to alleviate abdominal cramping and diarrhea. Kaopectate, 30 cc po after loose bowel movements, is also a useful adjunct.

During opioid detoxification, the physician should obtain urine toxicology screens every other day, if not every day, to determine whether the patient is taking unprescribed opioids or other drugs. If so, outpatient detoxification should be viewed as unsuccessful, and detoxification in a medically supervised residential treatment setting recommended. In my view, patients should be given only one chance at outpatient opioid detoxification.

Benzodiazepines and Barbiturates. Withdrawal can occur even when the patient has taken benzodiazepines, especially short-acting ones such as alprazolam and triazolam, in therapeutic doses for only a few months. A primary concern in treating benzodiazepine and all other sedative dependence is preventing major withdrawal phenomena: delirium, hallucinosis, and seizures.

Because of the low abuse liability of benzodiazepines, most patients dependent on one have been prescribed it for anxiety, insomnia, or epilepsy. Occasionally, patients use illegally obtained benzodiazepines to reduce with drawal from alcohol or opioids and may, in the process, become dependent on them. I recommend that patients be detoxified from benzodiazepines if they have been taking them on a daily basis as their mainstay to control psychiatric symptoms (e.g., anxiety) for longer than six months. If the drug was prescribed by a psychiatrist, the primary care physician should contact the psychiatrist to clarify the ongoing role of the medication in the patient's long-term treatment plan. I also suggest detoxification from benzodiazepines if the daily dosage exceeds that recommended by the Physicians' Desk Reference or if patients experience withdrawal symptoms at any dosage. While many benzodiazepine withdrawal symptoms mimic those of anxiety disorders, some are quite different. Included among this latter group are marked tremulousness, cognitive impairment, illusions, hallucinations, paresthesias of the limbs and face, fasciculations, and significant elevations in blood pressure and pulse.

The general considerations for determining whether benzodiazepine or other sedative withdrawal can be accomplished safely on an outpatient basis are the same as those for alcohol detoxification. To minimize the chance of missing dependence on several substances or mistaking hyperthyroidism for sedative withdrawal, the primary care physician should obtain a urine toxicology screen, blood alcohol level, and thyroid function tests. Any psychiatric or neurologic disorder for which the patient initially began taking benzodiazepines must be closely monitored during detoxification.

The starting dose for any sedative taper is often difficult to determine because patients may not accurately report the amount of medication they have been taking—sometimes they have lost count of the pills; at other times they are embarrassed. A starting dose is best determined by contacting the patient's pharmacy or looking at the patient's prescription bottle, ascertaining how many pills were taken during the most recent weeks of usage, and then estimating an average daily dosage.

In benzodiazepine detoxification, it is wise to use the "offending agent" whenever possible because many benzodiazepines have only partial cross-tolerance (see below). This principle should, however, be balanced against a desire to use a benzodiazepine with a long enough half-life to ensure a smooth taper. For purposes of outpatient detoxification, diazepam can be used with patients dependent on chlordiazepoxide hydrochloride or oxazepam. Clonazepam is often used for detoxification from alprazolam or triazolam, but clonazepam has such a long half-life (48-72 hours) that tapers can take several months. Clonazepam should be prescribed with great caution for elderly patients and for those with impaired hepatic function. The starting total daily dose of clonazepam is the cumulative dose required to ameliorate a pulse greater than 90, nervousness, or tremulousness, giving 1 mg of clonazepam po q2h prn after stopping the benzodiazepine to be withdrawn. If more than 4 mg of clonazepam are required within 24 hours, the physician should conclude that detoxification with clonazepam substitution cannot be safely done in a primary care outpatient setting. In general, I recommend psychiatric referral for patients who cannot be tapered off alpra-zolam or triazolam by the primary care physician.

Barbiturate detoxification usually can be best accomplished by substituting phenobarbital for shorter-acting barbiturates by virtue of its excellent cross-tolerance. The acute pharmacologic effect of 30 mg of phenobarbital is roughly equivalent to that of 50 mg of butabarbital sodium or 100 mg of secobarbital sodium. The duration of action of phenobarbital is approximately 12 hours, compared to 6-8 hours for butabarbital sodium and 3-4 hours for secobarbital sodium.

It is important to remember that the elimination of benzodiazepines and barbiturates from the body is described as an inverse logarithmic function. Thus, the time required to reduce the initial dose by 50 percent is also the time required to reduce the then-halved dose by 50 percent. For example, if it takes two weeks to taper the daily dose of lorazepam from 4 mg to 2 mg, it should also take two weeks to reduce the dose from 2 mg to 1 mg, and so on. No matter how slowly a sedative taper is conducted, the final decrement from some amount of drug to zero may precipitate abstinence symptoms. For purposes of outpatient detoxification, I generally recommend that the starting dose of a benzodiazepine or barbiturate taper be reduced after the first seven days. If the patients condition dictates that detoxification be carried out with dispatch, it should be done on an inpatient basis.

As with detoxification from alcohol, adjunctive agents such as propran-

olol hydrochloride and anticonvulsants should be avoided because they only increase the likelihood of delirium and other complications.

The goal of detoxification from any psychoactive substance is absolute abstinence. Detoxification without structured, long-term follow-up should not be undertaken; otherwise, the dependence syndrome will be promptly reinstated.

Identifying and Neutralizing Sustaining Factors. Patients with medical or psychiatric disorders that are helped by the drug on which they are dependent may well be reluctant to undergo detoxification unless they are convinced that those disorders will be adequately treated in the process. For example, an opioid-dependent patient with chronic low back pain may refuse detoxification unless the physician proposes another approach to pain relief (e.g., nortriptyline, biofeedback, physical therapy). Women who are alcohol-dependent should be presumed to have major depression or an anxiety disorder until proven otherwise. The same is true for most benzodi-azepine-dependent patients, regardless of sex.

Conventional wisdom has been that one cannot distinguish between substance-induced and primary mood disorders until patients have been abstinent for several months. However, if the depressive or anxiety states patients experience are a significant sustaining factor in their dependence, the primary care physician does not have the luxury of waiting that long. Practically speaking, most patients will relapse into alcohol or drug use if they do not receive adequate treatment for their underlying complaints after they are detoxified. With dependent patients with comorbid psychiatric disorders, then, close collaboration between the primary care physician and the psychiatrist is essential.

Extinguishing the Habit. Once detoxification and a plan to treat comorbid conditions are under way, the primary care physician should refer patients to alcohol or drug treatment programs. All such programs contain several common elements: concrete "steps" for the patient to follow; membership in a group for peer support, lessening of social embarrassment, and a large reservoir of positive reinforcement and encouragement; involvement of now-abstinent group members to serve as role models whose steps to re covery can be imitated; regular monitoring of progress; provision of strong countermotivation to relapse; recognition of achievements through milestones, anniversaries, and so forth; and regular follow-up over a period of years. (See below for descriptions of Alcoholics Anonymous and Narcotics Anonymous.)

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