Drugs for the Treatment of Substance Use and Addictive Disorders
GENERAL PRINCIPLES
Substance use disorders are extremely common and frequently comorbid with other mental disorders. Treating mental disorders without treating comorbid substance use disorders frequently leads to poor outcomes.
Alcohol and drug addiction may mimic a wide range of mental disorders and lead to misdiagnosis or misguided treatment. For example, covert cocaine use may lead to symptoms of anxiety or mania in toxicity or depression on withdrawal. Alcoholism frequently complicates unipolar depression, bipolar disorder, and anxiety disorders, creating a picture in which the proximate cause of symptoms is muddied. Because patients are often not forthcoming about substance use, the unsuspecting clinician may target the psychiatric symptoms of these covert disorders and fail to treat a substance use disorder that is adding complexity to the clinical picture. Moreover, a subset of patients have more than one addiction (e.g., those with opiates dependence frequently also use alcohol or cocaine), and treatment must address each substance.
Substance use may produce a variety of mental and behavioral symptoms even in the absence of dependence. For example, the intermittent binge drinker or cocaine user may exhibit a range of problems from mood lability to risk of accidents. With repetitive use of drugs comes physiologic dependence, an adapted state of brain and other organ systems in which withdrawal symptoms complicate attempts to abstain from drug use. The withdrawal syndrome is substance speci fic. Alcohol and opiates produce physical withdrawal symptoms that can be severe (agitation, tachycardia, insomnia, seizures in the case of the former, severe abdominal cramps, flulike symptoms in the case of the latter). The withdrawal syndrome of nicotine and cocaine, highly addictive drugs, is dominated by mood and cognitive effects such as irritability and difficulty concentrating and also include prominent insomnia and increased appetite. Addiction is the end stage of substance abuse, defined as a compulsive behavior, usually drug use, that is continued despite negative consequences. The results for the person, family, and society may be severe. Addiction is a chronic and relapsing disorder for which effective treatments exist. Most patients require multiple treatment trials before they can sustain abstinence. Individuals with addiction are at high risk of relapse even after extended periods of abstinence, indeed long after withdrawal symptoms other than intense craving to use the drug have subsided.
Treatment of substance use disorders too often ends with detoxification and management of withdrawal symptoms. Because we now know that addiction is a chronic, relapsing disorder that results in brain changes, and because powerful craving to use substances can persist or recur at times of stress or exposure to the drug or drug cues, detoxification and resolution of withdrawal symptoms is really the area at which ongoing outpatient treatment should begin rather than end. The aim of successful treatment is to minimize late relapse (such treatments are often aimed at managing craving elicited by drug-related cues and by stress) and to treat co-occurring mental disorders. In general, extensive (the number of reinforcing sessions and duration of the treatment) rather than intensive (e.g., inpatient rehabilitation, etc.) predict better outcomes.
A number of effective pharmacologic treatments are available for the treatment of addictive disorders. All pharmacologic treatments are recommended to be delivered in combination with psychosocial treatments. Recent studies have examined patients with multiple drug addictions. In some combinations of addiction, medication treatment benefits at least a facet of the addiction. Pharmacologic treatments alone have low long-term success rates and may mislead the patients with substance use disorders, especially addiction, into believing that psychosocial treatments and personal struggles will be less important. Pharmacologic detoxification treatments are more successful than treatments to promote long-term abstinence, although the former treatment must be seen as a prelude to the long-term treatment of persons with addictions. This chapter focuses on the major drugs of abuse and details the pharmacologic treatment of substance abuse disorders.
OPIOID DEPENDENCE
Opioid dependence is associated with severe medical and psychosocial consequences, including violent crimes and spread of HIV infection through unprotected sex or sharing needles used for intravenous injections. Because abused opioids are generally expensive and short acting, persons using these drugs frequently suffer withdrawal symptoms and may go to great extremes such as burglary, prostitution, or drug dealing to prevent withdrawal, although a substantial number finance their addiction through conventional employment. Antisocial personality disorder is often seen in men with heroin dependence, and it is not uncommon to see heroin-dependent women present with mood and anxiety disorders. Those with heroin dependence also commonly misuse alcohol and psychostimulants.
OPIOID WITHDRAWAL
Acute cessation of opioids following chronic use leads to nausea and vomiting, sweating, piloerection (“goose flesh”), hypertension, enlarged pupils, tachycardia, muscle and bone pain, anxiety, and insomnia. Hallucinations and confusion are rare; however, they may be precipitated by use of an opioid antagonist such as naltrexone or naloxone. Treatment is supportive. Opioid withdrawal is extremely uncomfortable but generally not dangerous; however, the intense craving that follows acute abstinence often leads to nonadherence with recommended treatments and relapse to drug use.
DRUGS USED IN THE TREATMENT OF OPIOID WITHDRAWAL
Clonidine
Clonidine is an α2-adrenergic receptor agonist used in the treatment of hypertension that also is useful in the treatment of opioid withdrawal. Because the predominant role of central α2 receptors is to act as autoreceptors with a negative feedback function, the major effect of clonidine is to decrease the activity of central noradrenergic neurons. It is particularly effective in suppressing autonomic symptoms, having proved more effective than morphine or placebo. Several controlled trials have demonstrated that clonidine suppresses many of the signs and symptoms commonly seen in patients withdrawing from narcotics and thereby contributes significantly to patient comfort and compliance. Although a very useful compound to manage the autonomic symptoms of withdrawal, its sedative and hypotensive effects limit its outpatient use and it is clearly less effective than morphine in reducing drug-craving symptoms.
Pharmacology
Clonidine is almost completely absorbed after oral administration, achieving peak plasma concentrations in 1 to 3 hours. Approximately half of the drug is
metabolized in the liver, the rest is excreted unchanged by the kidney, and it has no known active metabolites. It has an elimination half-life of 9 hours; thus, it is usually given in two daily doses. Because clonidine is very lipophilic, it easily penetrates the blood-brain barrier, where it has its principal effects as outlined previously.
metabolized in the liver, the rest is excreted unchanged by the kidney, and it has no known active metabolites. It has an elimination half-life of 9 hours; thus, it is usually given in two daily doses. Because clonidine is very lipophilic, it easily penetrates the blood-brain barrier, where it has its principal effects as outlined previously.
Side Effects and Toxicity
Although most of our clinical experience with clonidine comes from its use for hypertension, the side-effects profiles for both medical and psychiatric patients are similar. About 50% of patients report dry mouth and some degree of sedation during the first 2 to 4 weeks of therapy with gradual improvement of these side effects over that period. An estimated 10% of patients discontinue this agent because of persistent side effects, including sedation, postural dizziness, dry mouth and/or dry eyes, nausea, impotence, and fluid retention (which may be managed with diuretics).
The similarity between central nervous system (CNS) side effects of these drugs and the disorder for which the drugs are used is a significant complication of treatment and management of these patients, demanding that the clinician pay careful attention to mental status and neurologic examination findings. Therefore, sedation, drowsiness, vivid dreams or nightmares, insomnia, restlessness, anxiety, depression, visual or auditory hallucinations (rare), or erectile dysfunction need to be assessed as possible side effects versus symptoms of the illness being treated. Rare idiosyncratic side effects include rash, pruritus, alopecia, hyperglycemia, gynecomastia, and increased sensitivity to alcohol.
Drug interactions are uncommon, but concurrent use with a tricyclic antidepressant may reduce the antihypertensive effect of clonidine. Use with other agents that cause orthostasis (e.g., trazodone or risperidone) may lead to hypotension.
Overdoses may result in decreased blood pressure, heart rate, and respiratory rate. Patients who have overdosed on these agents may be stuporous or comatose with small pupils, their condition mimicking an opioid overdose. Treatment consists of ventilatory support, intravenous fluids or pressors for hypotension, and atropine for bradycardia.
Dose Forms Available
Clonidine is available for oral use only under the trade name Catapres. Tablets are available in 0.1-, 0.2-, and 0.3-mg strengths. Clonidine is available as a long-acting skin patch, providing the equivalent of 0.1 mg three times a day (t.i.d.), 0.2 mg t.i.d., and 0.3 mg t.i.d.
Method of Use
If patients are being withdrawn from opioids and not placed on methadone, then clonidine may be administered beginning at low dosages, such as 0.1 mg twice a day (b.i.d.) or t.i.d. and increased as needed and tolerated. Blood pressure and symptoms of orthostasis should be monitored every 4 hours. Dosage can be gradually increased over the first few days, rarely to exceed 0.3 mg t.i.d. Clonidine best treats adrenergic signs and symptoms (e.g., hypertension, piloerection) and is not particularly effective for the treatment of gastrointestinal symptoms and drug craving. Bone and muscle pain responds well to nonsteroidal antiinflammatory agents (e.g., ibuprofen 400 to 600 mg t.i.d.), and gastrointestinal symptoms may be treated symptomatically with one or a combination of the following: sucralfate 1 g four times a day (q.i.d.), loperamide 2 mg t.i.d., or dicyclomine 10 to 20 mg t.i.d. Successful treatment of acute withdrawal as outlined previously rarely exceeds a few days, allowing for a rapid taper of clonidine when deemed appropriate. In the absence of replacement therapy with opioid agonists, however, the drug craving may be so strong that many opioid addicts relapse following clonidine detoxification, and because of opioid craving they may leave the hospital prematurely to continue using it.
PHARMACOLOGIC TREATMENT OF CHRONIC OPIOID DEPENDENCE
Opioid dependence is a chronic and frequently relapsing condition. Although treatment of opioid withdrawal is generally straightforward, combined pharmacologic and behavioral treatment of long-term sobriety are somewhat less successful. Some reasons for relapse to drug use include strong cravings associated with stress or environmental cues, treatment onset late in the course of the addiction, and co-occurring addictive, psychiatric, or medical disorders. The mainstay of outpatient relapse prevention treatment is opioid replacement pharmacotherapy [i.e., methadone, or buprenorphine]. Antagonist treatment (i.e., naltrexone) alone is generally less effective, except in highly motivated patients with excellent social supports. Patients should be involved in some form of psychosocial therapy addressing abstinence to maintain long-term sobriety and addressing any co-occurring illnesses, for example, HIV infection, posttraumatic stress disorder, or alcohol dependence. Contingency management techniques, such as providing vouchers or the ability to take a dose of methadone home in return for urine, saliva, or expired air screens that are negative for substances, are also useful aids to pharmacotherapy. It is the norm for patients to require multiple courses of treatment before sustained abstinence is attained.
Methadone
Methadone is a long-acting synthetic opioid also used in the treatment of chronic pain. It is commonly used to aid long-term abstinence from opiate use as it blocks access of heroin to the µ-opiate receptor, blocking euphoric effects of heroin. Methadone also ameliorates craving, prevents withdrawal symptoms, and has minimal euphoric effects. Thus, someone who has taken an adequate dose of methadone will not gain a desired hedonic effect from heroin. Of course, methadone does not block the target receptors for nonopiate drugs; therefore, other drugs can produce euphoria in the presence of methadone.
The use of methadone has often proved controversial to those who believe that the goals of treatment should be abstinence. A large body of data, however, suggests that termination of methadone often leads to relapse to heroin and that from a medical and harm avoidance point of view (taking into account the risks of shared needles among heroin users, the possibility of rehabilitation, and reduction in crime), long-term methadone maintenance and perhaps other opioid replacement therapies are the most effective existing treatments for heroin addiction. Use of methadone for opioid replacement, formerly overseen by the Drug Enforcement Administration, is currently under the auspices of the Substance Abuse and Mental Health Services Administration, leading to less stringent practice requirements. More take-home doses are allowed, and after a period of stability, take-home doses of up to 1 month are permissible, though not all states allow this. Well rehabilitated patients often do well with this extended regimen.
Pharmacokinetics
Methadone is rapidly absorbed and highly plasma protein bound; oral absorption is approximately 50% of subcutaneous absorption. It has a steady-state elimination half-life of 25 hours, allowing for once-a-day dosing; it is N-demethylated and conjugated by the liver with modest first-pass effects. Significant reduction in plasma concentration of methadone may occur with coadministration of drugs that induce hepatic enzymes such as carbamazepine, phenobarbital, nevirapine, or other protease inhibitors used in the treatment of HIV infection. Conversely, plasma concentration may be increased when methadone is coadministered with ketoconazole or fluvoxamine.
Pharmacologic Effects
Methadone has pharmacologic effects similar to those of morphine. The drug is an agonist at opioid receptors, particularly at µ-receptors. Opioid receptors are found in various organs and tissues throughout the body, including the brain, where they inhibit the release of acetylcholine, norepinephrine, and substance P and alter the release of dopamine. Methadone’s effects are dose dependent, acting primarily as a CNS, respiratory, and gastrointestinal depressant inducing analgesia without loss of consciousness. Systemic effects are dose dependent and apply to various organ systems. With increasing doses, the following effects may be seen:
CNS: euphoria, sedation, confusion, coma
Cardiovascular: bradycardia, hypotension, shock
Gastrointestinal: nausea and vomiting, constipation, bowel obstruction
Pulmonary: decreased ventilation, pulmonary edema, hypoxia, respiratory arrest
Genital/sexual: decreased libido, impotence, delayed orgasm
Endocrine: hyperprolactinemia and gynecomastia may result with chronic use
Methadone should be used with caution in patients with the following problems:
1. Asthma, chronic obstructive pulmonary disease, preexisting respiratory depression, hypoxia, hypercapnia
2. Volume depletion or drugs with significant α-1 blockade
3. Traumatic brain injury
4. Coadministration of other CNS depressants
5. Acute abdominal pain
6. Alcohol intoxication
Dose Forms Available
The trade name for methadone is Dolophine. Methadone is available as a solution, 120 mg/mL. This may also be available in a cherry-flavored elixir. Tablet forms of 5 or 10 mg are also available. (Tables 6.1 and 6.2).
Method of Use for Withdrawal from Opioids
The mainstay of opiate detoxification is the long-acting opiate methadone. In typical detoxification protocols, the requirement for methadone is determined using objective criteria (hypertension or tachycardia above baseline, dilated pupils, sweating, gooseflesh, rhinorrhea, or lacrimation) rather than subjective complaints. Methadone is administered in dosages of 10 mg orally every 4 hours when at least two objective criteria for withdrawal are met. The total dose of methadone given on day 1 is given the next day in two divided doses. Methadone is then withdrawn by 5 mg per day. The use of methadone for the management of withdrawal in neonates with narcotic abstinence syndrome is best accomplished with dosages of 3 to 4 mg per kilogram per day; reports in the literature find this to be a dose range that optimizes efficacy while minimizing toxicity.
Method of Use for Abstinence from Opioids
When the patient is clinically stable, he or she can be started on a relatively low dosage of methadone, 20 to 40 mg per day. The dosage can be gradually titrated by 5 mg every 3 to 5 days as tolerated to higher dosages, usually reaching a final dosage of 60 to 120 mg per day, although some patients may need higher dosages to maintain abstinence from illicit opioids, especially from heroin. Low doses of
methadone (e.g., 30 to 40 mg) are rarely helpful in maintaining abstinence. The methadone dose should be adjusted to control cravings to prevent relapse, but the clinician is cautioned to monitor the patient carefully to avoid excessive sedation or respiratory depression. Objective observations or information from other sources is sometimes better than relying on patients who may underreport the sedating effects of methadone. Methadone is often dispensed from specialized treatment centers in a liquid form, requiring patients to initially attend the treatment center five times per week. After patients proved themselves reliable by negative urine drug screens, they may begin take-home drug doses.
methadone (e.g., 30 to 40 mg) are rarely helpful in maintaining abstinence. The methadone dose should be adjusted to control cravings to prevent relapse, but the clinician is cautioned to monitor the patient carefully to avoid excessive sedation or respiratory depression. Objective observations or information from other sources is sometimes better than relying on patients who may underreport the sedating effects of methadone. Methadone is often dispensed from specialized treatment centers in a liquid form, requiring patients to initially attend the treatment center five times per week. After patients proved themselves reliable by negative urine drug screens, they may begin take-home drug doses.
TABLE 6.1 Drugs Used in the Treatment of Substance Use Disorders | ||||||||||||||||||||||||||||||||
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Levomethadyl Acetate
Levomethadyl acetate, also known as LAAM, is a long-acting congener of methadone. LAAM is a µ-opioid receptor agonist and has pharmacologic properties similar to those of methadone, with a longer half-life. Similarly, LAAM does not have a “rush” or “high” associated with its use. The advantages of LAAM over methadone is that it may be better tolerated, induces less withdrawal, and requires to use only 3 days per week, reducing the need to attend an opioid replacement
clinic daily. Some patients will prefer methadone to LAAM and vice versa, but there are no clear predictors of which patients will do better on which drug.
clinic daily. Some patients will prefer methadone to LAAM and vice versa, but there are no clear predictors of which patients will do better on which drug.
TABLE 6.2 Dose Range for Drugs Used in the Treatment of Substance Use Disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Although LAMM may be better tolerated than methadone, it is similarly effective as methadone at reducing opioid use. Like methadone, LAAM is controlled under the Substance Abuse and Mental Health Administration and Drug Enforcement Agency regulations and requires specialized treatment centers for administration. These special treatment settings, unfortunately, isolate opioid treatment from mainstream medical treatment.
Occasional cases of torsades de pointes, a rare cardiac arrhythmia, are reported with LAAM use, suggesting that electrocardiogram monitoring should be a regular part of LAAM treatment. Because LAAM is proarrhythmic, it is indicated only for those patients for whom other pharmacologic treatments for opioid dependence have failed; it is not available in Europe because of this cardiac complication. Because of its toxicity, it is not a first-line agent for opioid dependence.
Pharmacology
LAAM is nearly completely absorbed from the gastrointestinal tract and reaches peak concentration within 2 to 4 hours. It is metabolized extensively by the liver, via cytochrome P450 CYP3A4 enzymes, and there are several active metabolites, including nor-LAAM, that are more potent at µ-opioid receptors than LAAM. The drug and its metabolites are excreted through the kidney and bile. The drug should be used cautiously in patients with liver disease because of the potential drug accumulation. LAAM and its active metabolites have long-lasting effects, with an elimination half-life more than 48 hours.
Like methadone and other opioids, LAAM may cause respiratory depression, nausea and vomiting, constipation, as well as a range of CNS effects including sedation, confusion, abnormal dreams, amnesia, sexual dysfunction, or ataxia. LAAM appears to increase QTc on echocardiograms and should be used with great caution in any patient with cardiac disease or taking a drug known to
prolong the Q-T interval (e.g., calcium channel blockers, antimalarials, adenosine, Class II antiarrhythmics, tricyclic antidepressants, chlorpromazine, thioridazine, droperidol).
prolong the Q-T interval (e.g., calcium channel blockers, antimalarials, adenosine, Class II antiarrhythmics, tricyclic antidepressants, chlorpromazine, thioridazine, droperidol).
LAAM is contraindicated for use in patients with the following clinical conditions:
QTc prolongation (QTc greater than 450 milliseconds)
Treatment with monoamine oxidase inhibitors (MAOIs)
Bradycardia or significant heart disease
Treatment with Class I and Class III antiarrhythmics
Treatment with CYP3A4 inducers (e.g., rifampin, phenobarbital, phenytoin) or inhibitors (e.g., ketoconazole, erythromycin, HIV protease inhibitors)
Hypokalemia or hypomagnesemia
LAAM, like other opioids, should be used with caution in patients with heart disease, pulmonary disease, increased intracranial pressure, brain injury, hypothyroidism, or prostatic hypertrophy or in patients concomitantly treated with other CNS depressants. The dose should be carefully titrated in patients with renal or hepatic disease.
Dose Forms Available
LAAM is available as an oral solution, 10 mg/mL. The trade name is Orlaam.
Method of Use
Following detoxification and a careful cardiac history and evaluation, patients can be started on doses of 30 to 40 mg. Subsequent doses are given every other day, and dose increases can be made by 5- to 10-mg intervals. Within 2 weeks, doses can be given 3 days per week on Monday, Wednesday, and Friday, although some patients may not tolerate the 72-hour weekend intervals. Some patients may need a higher dose on Fridays to limit opioid craving or use over the weekend. Patients, at least initially, should be regularly involved in psychosocial treatment aimed at reducing drug and alcohol use.
The target dosage for most patients is between 60 and 100 mg three times per week. Caution should be taken with rapid dose increase because the long half-life may lead to accumulation and delayed sedative effects. The maximum recommended dosage is 140 mg three times per week. For patients being converted from methadone to LAAM, the dose should be approximately 1.2 times higher (e.g., 80 mg of methadone is replaced by 100 mg of LAAM). If a patient misses a few doses, renewed treatment should be restarted at a slightly lower dose. If the patient misses more than a week of treatment, dose titration should start from the beginning.
Buprenorphine
Buprenorphine is a novel synthetic opioid with mixed agonist and antagonist effects at opioid receptors. It is used in the treatment of pain and for abstinence from illicit opioids. It is a schedule III narcotic under the Controlled Substance Act. Unlike methadone, it may be prescribed outside of the usual specialized opioid treatment centers. Buprenorphine is thus an advance over previous treatments because it can be prescribed in office-based settings. Buprenorphine, however, is limited for prescribing only by physicians who meet qualifying requirements, and physicians can treat 30 patients for opioid addiction, though they can apply for a waiver to treat up to 100 patients.
Like other opioids, buprenorphine is a useful replacement agent for persons addicted to heroin or other illicit opioids, although it appears to have no advantage over methadone for maintaining long-term sobriety. Buprenorphine, like the other opioid replacement treatments, has modest benefits, leading to long-term
abstinence in perhaps one third of those with opioid addiction. Many patients drop out of clinical trials. As with the other opioid replacement treatments, buprenorphine should be prescribed in conjunction with psychosocial therapies aimed at preventing relapse. The intensity of required psychosocial intervention is unclear. A recent study found that once-weekly brief visits with a nurse combined with once-weekly prescriptions was just as effective than thrice weekly prescriptions with more intense psychological interventions. Because of its long half-life, buprenorphine may be dosed every other day in some patients.
abstinence in perhaps one third of those with opioid addiction. Many patients drop out of clinical trials. As with the other opioid replacement treatments, buprenorphine should be prescribed in conjunction with psychosocial therapies aimed at preventing relapse. The intensity of required psychosocial intervention is unclear. A recent study found that once-weekly brief visits with a nurse combined with once-weekly prescriptions was just as effective than thrice weekly prescriptions with more intense psychological interventions. Because of its long half-life, buprenorphine may be dosed every other day in some patients.
Buprenorphine has also been studied in combination with naloxone for the treatment of opioid dependence. The rationale for this treatment is that patients taking the combined agonist and antagonist treatment will experience reduced pleasure if they inject the combination pill. Taken orally, naloxone is not absorbed, but if the combination pill is injected, the naloxone enters the brain and potentially antagonizes the effects of the buprenorphine. This deterrent strategy, however, has not been carefully studied in humans, though anecdotal reports suggest that many patients report an unpleasant experience injecting the buprenorphine-naloxone combination pill. For other patients, the low dose of naltrexone may be inadequate for blocking euphoric effects. For unclear reasons, buprenorphine has a ceiling effect in producing euphoric or analgesic effects, and may even have opioid antagonist effects at high doses. For these reasons, buprenorphine is less prone than other opioid for abuse or to cause respiratory depression.
Buprenorphine is as effective as moderate doses of methadone, but may be less effective than high-dose methadone (>80 mg per day) for preventing relapse. Opioid addicts with more severe addictions may do better with methadone than buprenorphine. Abstinence rates from illicit drugs generally range between 20% and 40% in short-term buprenorphine trials. Although buprenorphine may be of benefit in the treatment of opioid addiction, it is not a panacea. An advantage of buprenorphine is that it may be initiated early in the course, within 1 year, of opiate dependence, whereas methadone is limited to those with 1 year or more of opiate dependence.
Pharmacology and Mechanism of Action
Buprenorphine is a potent partial opioid agonist with agonist effects at the µ-receptors and antagonist effects at κ-receptors. These properties are different from other opioid agonists and may contribute to buprenorphine’s limited potential for abuse and opioid antagonist effects at high doses. Because it tightly binds opioid receptors, it may precipitate opioid withdrawal in patients taking less tightly binding opioids such as methadone or heroin. It is only available in sublingual and injectable forms. Like other opioids, buprenorphine causes CNS, gastrointestinal, respiratory, and cardiovascular depression.
Buprenorphine is only moderately absorbed (30% bioavailability) when taken sublingually with a time-to-peak concentration at approximately 2 hours. It is highly protein bound and has a terminal half-life of approximately 37 hours. Buprenorphine is metabolized by the liver via the 3A4 cytochrome via N-dealkylation and glucuronide addition. Drugs that inhibit 3A4 enzymes (ketoconazole, fluvoxamine, HIV protease inhibitors) may increase buprenorphine plasma concentration and lead to unexpected sedation.
Buprenorphine may cause significant sedation, ataxia, or respiratory compromise when used in combination with other sedative drugs, especially benzodiazepines or alcohol. Patients with significant hepatic disease may have concentrations of buprenorphine higher than expected. Buprenorphine should be used with extreme caution in patients with the following clinical conditions or disorders: traumatic brain injury with increased intracranial pressure, chronic obstructive pulmonary disease, asthma, symptomatic hypothyroidism, prostatic hypertrophy,
biliary disease, hepatic dysfunction, congestive heart failure, and respiratory depression. Taken in overdose, buprenorphine requires naloxone in a continuous infusion because of its tight binding to opioid receptors.
biliary disease, hepatic dysfunction, congestive heart failure, and respiratory depression. Taken in overdose, buprenorphine requires naloxone in a continuous infusion because of its tight binding to opioid receptors.
Adverse Effects
Common adverse effects include dizziness, sedation, constipation, respiratory depression, vertigo, nausea, and vomiting. Buprenorphine has fewer cognitive or sedating effects compared with methadone and is preferred by many opioid addicts as a replacement treatment.
Method of Use
Once the patient has mild withdrawal symptoms, he or she can be started treatment with sublingual buprenorphine up to 8 mg on the first day (held under the tongue for 5 to 10 minutes) and then increased to 16 mg as tolerated over the next few days. If the patient is taking a full opioid agonist (e.g., methadone or heroin) and not yet in withdrawal, buprenorphine may induce acute opioid withdrawal. The patient should be observed daily for the first few days to assess tolerance and craving and gradually less often until stabilized. A dose of 16 mg once daily is the usual maintenance dose. Alternatively, because of the drug’s long half-life, dosing may be spread out during the week (i.e., 32 mg three times per week). Patients also should be involved in a psychosocial program such as Narcotics Anonymous with regular, random urine drug screens to evaluate use of other illicit drugs such as cocaine. After the patient has been abstinent and engaged in treatment, usually for several months, the physician may prescribe buprenorphine-naloxone combination tablet for up to 30 days.
Switching from Methadone to Buprenorphine
Patients with less severe addictions and taking moderate doses of methadone (40 to 80 mg per day) are good candidates for switching to buprenorphine. Patients taking higher doses have more difficulty because of difficulty withdrawing down to a dose of 30 mg per day or lower. Switching to buprenorphine at higher doses of methadone often leads to problematic withdrawal symptoms. Ideally patients should be in methadone withdrawal before starting buprenorphine. Methadone’s long half-life requires several days’ wait to be sure that the drug is eliminated from the body. On the other hand, drugs with shorter half-lives such as oxycodone or heroin require brief periods of sobriety before withdrawal ensues and buprenorphine starts. An intermediate switch from methadone to morphine may be a reasonable way for transition to buprenorphine.
Dose Forms Available
Buprenorphine is available as 2- and 8-mg sublingual tablets. The trade name is Subutex. Buprenorphine is also available in a combination tablet with naloxone, each sublingual tablet containing 2 mg of buprenorphine and 0.5 mg of naloxone or 8 mg buprenorphine with 2 mg naloxone. The trade name of the combination tablet is Suboxone. Buprenorphine is available in an injectable form, 0.3 mg/mL. Trade name of the injectable form is Buprenex.
Naltrexone for Opioid Dependence
Use of naltrexone for the treatment of opioid dependence is not as well established as it is for alcohol dependence. Most reports are open label, and earlier controlled studies were confounded by the bitter taste of the oral solution. Moreover, compliance with naltrexone is notoriously poor, especially among newly detoxified heroin addicts. The overall evidence is that naltrexone provides some benefit for opioid addiction, although the benefits are modest and compliance is often poor
because craving is not treated by naltrexone. Naltrexone may be beneficial in highly motivated patients with good social supports. Naltrexone may also be useful for patients with long-term sobriety from illicit opioids after they have been weaned from methadone treatment.
because craving is not treated by naltrexone. Naltrexone may be beneficial in highly motivated patients with good social supports. Naltrexone may also be useful for patients with long-term sobriety from illicit opioids after they have been weaned from methadone treatment.
Pharmacology
The pharmacology is detailed in the section on alcohol dependence.
Method of Use
To ensure that the patient is free of opioids and to prevent a severe withdrawal state related to naltrexone use, a naloxone challenge is best performed first. The clinician should give the patient 0.2 mg of naloxone intravenously and observe for signs or symptoms of opioid withdrawal for several minutes. If there is no evidence of withdrawal, another 0.6 mg can be injected and the patient observed for an additional 15 to 20 minutes. If there are no signs of withdrawal, then the patient can be safely started on naltrexone. Alternatively, the patient can be given naloxone, 0.8 mg subcutaneously, and observed for signs and symptoms of withdrawal for 15 to 20 minutes.
Once the patient is suitable for naltrexone treatment, he or she can be started at 25 mg per day for several days to reduce gastrointestinal distress; the dosage can subsequently be increased to 50 mg daily as tolerated by the patient. Dosages may need to be higher than those for the treatment of alcoholism, and many patients will require 100 mg daily to block the euphoric effects of opioids. A common final dosage regimen is 50 to 100 mg per day on weekdays and 150 mg on weekends. Some patients may be given 150 mg three times per week. These dosage patterns, however, are not well established in clinical trials. Liver function tests should be monitored during the course of naltrexone treatment because of its infrequent propensity to elevate transaminase levels. Patients should be monitored with urine drug screens and be involved in a psychosocial treatment aimed at preventing relapse.
DRUGS USED IN THE TREATMENT OF ALCOHOLISM
Alcohol is ubiquitous across the globe. Most individuals use it safely, but due to its broad availability and the apparently high rates of vulnerability to abuse, alcohol dependence and addiction (alcoholism) are enormous health and social problems worldwide. Alcohol abuse leads to a wide range of medical (e.g., gastrointestinal diseases and traumatic brain injury) and psychosocial consequences (e.g., divorce and legal problems), although often these costs are not readily obvious until the person has been drinking regularly for a decade or more. According to epidemiologic studies, 15% of men have a lifetime history of alcohol dependence, and the World Health Organization lists alcohol dependence among the top 10 diseases afflicting all parts of the world.
Acute or chronic use of alcohol often worsens comorbid mental illnesses, especially mood and anxiety disorders. Although drug treatment is useful in limiting the symptoms of alcohol withdrawal, pharmacologic treatments play a limited role in providing abstinence from alcohol; however, a number of agents have shown benefit in clinical trials.
ALCOHOL WITHDRAWAL TREATMENT
Alcohol has a diversity of effects on cells throughout the brain and the rest of the body. This lack of specificity reflects the general membrane effects that alcohol exerts (in addition to any specific effects on receptors or ion channels) at the very high concentrations that people use to achieve psychotropic effects. A major effect of alcohol is to facilitate some actions of γ-aminobutyric acid (GABA), the major
inhibitory neurotransmitter in the brain (acting via the GABAA receptor) and to inhibit the N-methyl-D-aspartate glutamate receptor, an important excitatory neurotransmitter receptor involved with memory (among other things). With chronic alcohol use, the brain adapts homeostatically to these effects by upregulating excitatory neurotransmission and reducing inhibitory transmission, creating an overall bias toward excitation that is balanced by ongoing alcohol use. With cessation of alcohol, the intrinsic overbalancing toward excitation in many brain circuits leads to withdrawal symptoms. Withdrawal seizures reflect this imbalance in the cerebral cortex. Many patients who drink alcohol on a regular basis have very mild symptoms and rarely come for clinical care. Patients who have withdrawal symptoms often do not come to the attention of physicians until withdrawal symptoms are severe. Early on, mild symptoms may include hypertension, anxiety, tremor, sweating, nausea, and vomiting, although over time, as the condition worsens, withdrawal may include seizures, hallucinations, delirium, cardiac arrhythmias, or even death.
inhibitory neurotransmitter in the brain (acting via the GABAA receptor) and to inhibit the N-methyl-D-aspartate glutamate receptor, an important excitatory neurotransmitter receptor involved with memory (among other things). With chronic alcohol use, the brain adapts homeostatically to these effects by upregulating excitatory neurotransmission and reducing inhibitory transmission, creating an overall bias toward excitation that is balanced by ongoing alcohol use. With cessation of alcohol, the intrinsic overbalancing toward excitation in many brain circuits leads to withdrawal symptoms. Withdrawal seizures reflect this imbalance in the cerebral cortex. Many patients who drink alcohol on a regular basis have very mild symptoms and rarely come for clinical care. Patients who have withdrawal symptoms often do not come to the attention of physicians until withdrawal symptoms are severe. Early on, mild symptoms may include hypertension, anxiety, tremor, sweating, nausea, and vomiting, although over time, as the condition worsens, withdrawal may include seizures, hallucinations, delirium, cardiac arrhythmias, or even death.
Time Course of Alcohol Withdrawal
Although alcohol withdrawal signs and symptoms generally begin after complete metabolism of alcohol, in more severe alcoholism, the withdrawal syndrome may begin when the plasma concentration drops below a certain threshold. During the first day of alcohol withdrawal, typical signs include tremor, tachycardia, sweating, hypertension, mild fever, anxiety, and gastrointestinal distress. For patients with mild withdrawal, these symptoms generally resolve within 2 days. Mild withdrawal generally occurs in younger patients and those who are medically stable.
Patients with a longer history of alcoholism or unstable medical conditions are more likely to develop complicated withdrawal as evidenced by profound changes in blood pressure, severe tremulousness, ataxic gait, and seizures that may occur within the first 36 hours of withdrawal. Patients having a seizure after 36 hours should be evaluated for other causes of seizure (i.e., subdural hematoma, meningitis). An agitated delirium may develop 2 to 4 days after the start of the withdrawal syndrome. The delirium often includes profound sleep-wake cycle disruption, visual or auditory hallucinations, and marked cognitive impairment including the inability to make new memories or complete simple tasks such as clock drawing. More severe withdrawal syndromes may take a week or more to improve, and subtle cognitive impairment may persist for some time, although the chronic alcohol effects are difficult to distinguish from withdrawal effects. Infrequently, patients whose delirium was accompanied by thiamine deficiency may go on to have a profound amnestic disorder (Korsakoff’s syndrome).
General Principles
There are several purposes of pharmacologic treatment of alcohol withdrawal: (a) allow relatively comfortable detoxification such that the patient can move forward with controlled drinking or abstinence, (b) reduce severe symptoms such as seizure or cardiac arrest, and (c) potentially prevent the progression of severity of the withdrawal syndrome over time. A number of medications may be used, often in combination, including drugs that are cross-tolerant with alcohol (i.e., benzodiazepines), drugs used to control adrenergic overactivity (i.e., clonidine or atenolol), drugs used to treat delirium (i.e., haloperidol or risperidone), and drugs used to prevent amnestic syndromes (i.e., thiamine).
Benzodiazepines
The benzodiazepines are the mainstay of the treatment of alcohol withdrawal due to their cross-tolerance with alcohol and their shared agonist effects on GABAA receptors. As described previously, during alcohol withdrawal there is an excess of excitatory (e.g., glutamate) versus inhibitory (e.g., GABA) neurotransmission. This leads to
symptoms such as anxiety, tachycardia, and sweating or, in more severe cases, seizures, arrhythmias, hallucinations, and delirium. The pharmacology of benzodiazepines is described in Chapter 5. The best-studied benzodiazepines for the treatment of alcohol withdrawal are chlordiazepoxide, diazepam, and lorazepam.
symptoms such as anxiety, tachycardia, and sweating or, in more severe cases, seizures, arrhythmias, hallucinations, and delirium. The pharmacology of benzodiazepines is described in Chapter 5. The best-studied benzodiazepines for the treatment of alcohol withdrawal are chlordiazepoxide, diazepam, and lorazepam.
Method of Use—Outpatient Detoxification
The first decision is whether the patient will be treated as an outpatient or an inpatient. Persons younger than 45 years or those generally in good health can be managed as outpatients. Older persons with complicated medical conditions, especially symptomatic cardiac disease or pulmonary disease, or those with a history of severe withdrawal in the past are best treated in the hospital. Occasionally, young persons with severe alcoholism may require hospitalization. To reduce the variation in benzodiazepine plasma concentration, a drug with a long elimination half-life, such as chlordiazepoxide or diazepam, is preferred.
For motivated outpatients, lorazepam or diazepam may be used to control withdrawal symptoms. Patients should be evaluated daily for 2 or 3 days and started on a modest dosage of oral lorazepam (1 to 2 mg t.i.d.) or diazepam (5 to 10 mg t.i.d.) and thiamine 100 mg daily. Alternatively, a loading dose of 20 to 30 mg of diazepam may be administered to the patient in the evening on the first day. Patients should also be encouraged to avoid driving and to maintain fluid intake. If signs and symptoms worsen, the patient should be hospitalized. Once withdrawal is completed, the patient should be enrolled in a psychosocial treatment to maintain abstinence.
Method of Use—Inpatient Detoxification
For patients at risk for more severe withdrawal, treatment is more complex and often requires frequent readjustments depending on the clinical progress over several days. Although many patients will have a benign course, the lethality (15% to 30%) of untreated delirium tremens and other complications of acute alcohol intoxication make it imperative that the high-risk patients be monitored closely. Patients most at risk for severe withdrawal and potentially poor outcome include those with past alcohol withdrawal delirium or withdrawal seizure, recent cardiac or hip surgery, unstable cardiac disease, pneumonia, or other unstable systemic illness.
The clinician must decide whether to start medication immediately or to treat following signs of withdrawal. We recommend waiting for withdrawal signs to develop. The principal advantage of waiting for symptom development is that a lower total dose of benzodiazepine is generally needed.
On admission, physical examination, particularly of the heart, lungs, and neurologic systems, must be performed and then reevaluated daily. Patients also should be thoroughly evaluated for alcohol withdrawal progression every few hours by nursing or physician staff, preferably by use of a standard rating instrument such as the Clinical Institute Withdrawal Assessment-Revised. Key clinical items to be evaluated for alcohol withdrawal include the following: vital signs, other manifestations of autonomic excitation (tremor, sweating), cognitive impairment, sleep-wake disruption, gait abnormality, complaints of chest pain, and presence of hallucinations or confusion.
Benzodiazepines are the mainstay of alcohol withdrawal treatment. Treatment sometimes needs to be aggressive at the beginning to control symptoms; however, dosing must be carefully titrated to limit the sedating effects of these compounds. In general, patients with severe alcohol withdrawal will require significant amounts of benzodiazepine (e.g., 100 mg of diazepam or more) to reduce symptoms. Sometimes, however, aggressive treatment may lead to excessive sedation and respiratory compromise, particularly in smokers with chronic obstructive pulmonary disease or aspiration pneumonia in patients who have recently eaten or consumed fluids.
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