Management of Withdrawal in Patients with Drug Dependencies
Three medications are now FDA approved for treatment of alco-hol dependence, disulfiram, naltrexone and acamprosate.
Disulfiram is an irreversible inhibitor of aldehyde dehy-drogenase, the enzyme that catalyzes the conversion of alcohol to acetic acid. Inhibiting aldehyde dehydrogenase alters the body’s response to alcohol, leading to an accumulation of acetaldehyde. The resulting reaction is extremely dysphoric but self-limiting and not life-threatening. However, it is associated with hypoten-sion, palpitations, nausea and vomiting, and diaphoresis, which can produce substantial stress to the cardiovascular system, par-ticularly with high doses both of alcohol and of disulfiram. This is generally not dangerous in young, healthy individuals, but could lead to cardiovascular collapse and death in patients with significant cardiovascular or renal disease. Disulfiram has also been associated with liver toxicity, and education of the patient about signs of liver failure, and periodic monitoring of liver func-tions, are advisable.
Disulfiram was approved by the FDA for treatment of alcoholism in an era that required efficacy studies that would not meet today’s standards. The best work to date suggests that disulfiram may reduce the number of drinking days in those al-coholics who drink while taking it. Placebo-controlled studies suggest that compliance with medication taking, rather than the disulfiram itself, is the critical factor in producing a better out-come in persons with alcoholism.
For patients who are well-motivated, disulfiram provides an important disincentive to drink alcohol. It is particularly ef-fective as part of a contract with a spouse, in which the spouse agrees not to comment on the patient’s drinking and the patient agrees to allow the spouse to witness disulfiram ingestion. If di-sulfiram is taken regularly, it will prevent drinking, since even a small amount of intake will make the patient sick.
The usual dose of disulfiram is 250 mg/day. This mini-mizes side effects such as lethargy while maintaining inhibi-tion of aldehyde dehydrogenase. Some patients will report being able to drink without consequence on 250 mg per day. This may simply mean the patient is not actually taking the medication regularly, and should prompt gentle inquiry into compliance. However, some patients do need higher doses, up to 500 mg per day. Disulfiram inhibits dopamine α-hydroxylase and may rarely cause psychosis. It may affect the blood levels of other drugs (for example, levels of antidepressants and phenytoin are increased). Patients should be made aware that products other than alcholic beverages contain alcohol (e.g. shaving lotions) and that the risk of an acetaldehyde reaction persists for up to 2 weeks after the last dose of disulfiram.
The rationale for prescribing naltrexone to prevent alco-hol relapse is based on the hypothesis that the reinforcing effects of alcohol may be mediated via endogenous opiate mechanisms. Naltrexone combined with structured psychosocial treatment has been associated with improvements in complete abstinence, less craving for alcohol when the patient was abstinent, and less drinking once drinking began. Psychosocial treatments that have proven particularly effective in combination with naltrexone are those, such as cognitive-behavioral relapse prevention, that emphasize coping skills for handling various sources of relapse risk. The recommended dose is 50 mg per day. This agent differs from disulfiram in that there is no added ill effect once drinking begins. It may limit the severity of binges, and diminish preoc-cupation with alcohol in abstinent alcoholics. Nausea has been a common side effect early in naltrexone treatment for alcoholism, but is generally mild and clears with continued use. Naltrexone can produce liver toxicity, which is dose dependent, has mainly been observed at much higher doses (200 or 300 mg per day), and resolves with dose reduction. Elevated liver enzymes which do not resolve with dose reduction or discontinuation likely repre-sent another cause of hepatitis (e.g. viral, alcoholic).
Acamprosate has been approved for a number of years in Europe, and recently received FDA approval. Its mechanism is not well understood, but is thought to involve interference with excitatory amino acid mechanisms that may be involved in relapse. Clinical trials have shown a modest effect in reducing relapse risk, and studies are underway to determine if it may have complementary effects to those of naltrexone and whether the combination of the two may be increase effectiveness. Acampro-sate is supplied in 333 mg tablets, and the recommended dosage is two tablets, three times daily. Blister packs, organized accord-ing to the daily schedule of dosing, can be helpful to patients in maintaining compliance. Acamprosate is a generally safe and well tolerated. Diarrhea is the most common side effect.
In the same way that any given antidepressant medica-tion will be helpful to some depressed patients, but not others, naltrexone and acamprosate may similarly have little effect in some patients, but work well in others. As of yet, there are no reliable predictors of which alcoho-dependent patient will benefit from these medications, but clinicians should be encouraged to attempt adequate trials (effective dose, for at least a month) of these medications for patients with problem drinking, and not be discouraged by the fact that some patients will not benefit.
Given the high relapse rates with psychosocial treatment alone, there has been considerable interest in the development of phar-macotherapies for cocaine dependence. Although case reports and small studies have suggested that a variety of agents may be effective, these findings have not been consistently repeated in double-blind studies and no drug has met the criteria for FDA approval. Nevertheless, survey show that many specialists in the management of addiction prescribe drug treatment for cocaine dependence.
The drugs most frequently prescribed for cocaine depend-ence are antidepressants. This is based on the observation that depression is relatively frequent among cocaine addicts and the hypothesis that antidepressants may correct underlying abnor-malities of neurotransmitter function associated with cocaine use. Although desipramine is the most widely studied, initially encouraging reports of its efficacy in relapse prevention have been followed by studies either challenging its efficacy or suggesting its benefits may not continue beyond 6 to 12 weeks. Typical doses are the same as those used to treat depression. Concurrent use of cocaine and an antidepressant increases the risk of cardiotoxic-ity; patients who relapse during treatment should be investigated for additive cardiac effects.
It has been suggested that dopamine receptor blockade may attenuate the euphoric response to cocaine and that treat-ment with an antipsychotic drug may therefore be an appropriate treatment for cocaine dependence. However, experience treating patients with schizophrenia and cocaine dependence do not sup-port this hypothesis. Further cocaine use may increase the risk of extrapyramidal side effects due to dopamine depletion.
Psychomotor stimulants have been suggested as an agonist maintenance treatment strategy. Although early clinical reports suggested stimulants might exacerbate cocaine dependence, more recent placebo controlled trials suggest oral dexedrine may have promise. Patients with attention deficit disorder, which commonly co-occurs with cocaine dependence, may benefit from stimulants. Lithium has only been effective in reducing cocaine use in patients with bipolar disorder and, despite promising early trials, controlled trials have shown that carbamazepine has dis-appointing efficacy. However, more recently, some of the newer anticonvulsants with GABA-enhancing or excitatory amino acid inhibiting effects (e.g topiramate, gabapentin) have shown prom-ise in small placebo controlled trials.
Interestingly, perhaps the most consistent data so far re-garding disulfiram, which has shown promise in a series of small placebo-controlled trials for cocaine dependence, and the effect does not seem to depend on concurrent alcohol use. Since di-sulfram inhibits dopamine β-hydroxylase, which catalyzes the conversion of dopamine to norepinephrine in the brain, it may promote increased levels of brain dopamine, and combat the dopamine depletion engendered by cocaine.
Another pharmacotherapeutic strategy for cocaine depend-ence is to treat comorbid psychopathology, most commonly uni-polar depression, bipolar disorder, attention deficit hyperactivity disorder and anxiety disorders. Such treatment is most likely to have a direct impact on the psychopathology, followed by indi-rect effects of improved functioning and reduced drug use; the benefits of pharmacotherapy for patients without comorbid psy-chopathology remain unclear. The development of an effective pharmacotherapy for cocaine dependence is a research priority of the highest order.
Agonist maintenance treatment for opiate dependence is a power-ful treatment with a large effect size. When properly prescribed, methadone will rapidly induce a dramatic remission in 50% or more of patients. It prevents or reduces illicit opiate use, craving for illicit opiates, criminal behavior associated with acquisition of illicit opiates, and diseases associated with illicit opiate use (such as illness related to infection with human immunodeficiency virus), and improves employment and other aspects of social functioning. Methadone has also been shown to reduce mortal-ity rates among opioid dependent patients, in part by protecting against overdose. Methadone is also sometimes misunderstood as “substituting one drug for another”. In fact, methadone works by inducing marked tolerance such that effects of other opiates are blocked, and no euphoric effects of the methadone itself are experienced. When prescribed with careful titration, methadone is neither intoxicating nor sedating, and it does not interfere with performance of functions that are important for responsible adult roles (e.g., studies have shown that methadone does not impair driving ability).
Methadone is a good choice for maintenance treatment:
· it is orally active
· its half-life exceeds 24 hours
· it suppresses opiate withdrawal syndrome for up to 36 hours
· it blocks the euphoriant effects of other opiates
· side effects are minimal during chronic use; the commonest are constipation, excess sweating and decreased sexual inter-est but they rarely cause discontinuation
Doses of methadone in the early phase of a maintenance program are in the 20 to 40 mg range, primarily to relieve abstinence symptoms. The dose is increased in increments of 5 to 10 mg during the “induction period” over a period of days to weeks until a dose is achieved that prevents opiate craving and blocks the euphoric effects of illicit opiates. Urine toxicology analysis should be carried out regularly and frequently to support subjective reports and interval history. A dose of 40 mg/day is adequate for some patients but there is evidence that most require a dose of 80 mg/day. Under Federal regulations, doses greater than 120 mg/ day require permission, though lower ceilings can be specified in individual states. As with many psychopharmacologic treatments, the most common reason for treatment failure in methadone maintenance is inadequate dose, and continued opiate use should prompt consideration of a dosage increase. There is evidence that trough methadone blood levels should be in the range 200 to 400 ng/ml for optimal treatment response, and blood level monitoring may be useful in nonresponders. Some patients are rapid metabolizers, which can be assessed by comparing peak and trough blood levels. Rapid metabolizers may benefit from a divided, twice daily dose schedule.
A pragmatic drawback of methadone maintenance is regulations require that it can only be administered at specially licensed clinics which require frequent attendance (daily at the outset), and are not even available in many geographic regions. This can be a practical constraint or a disincentive for many pa-tients. On the other hand, it has been shown that the effectiveness of methadone maintenance depends upon regular counseling in conjunction with the medication, which is a requirement of meth-adone clinics, and more severely dysfunctional patients probably benefit from the structure imposed by clinic rules. Further, many of the better methadone clinics offer primary medical and psy-chiatric care, which is important since chronic opiate dependent patients often have multiple medical (e.g. hepatitis B and C, HIV) and psychiatric (e.g. depression, PTSD) problems.
A recent development is the approval and marketing of the long-acting opiate partial agonist buprenorphine, which has been shown in clinical trials to have effectiveness equivalent to that of methadone for maintenance treatment. A major difference is that buprenorphine can be prescribed by any physician who has taken a brief training course and received certification, making it more widely avail-able than methadone maintenance. The main regulatory restric-tion is that individual physicians practicing in an office-based setting are restricted to treating no more than 30 patients with maintenance buprenorphine at any one time.
Buprenorphine has interesting pharmacologic properties. It is a partial agonist, meaning that it binds opiate receptors but only partially activates them. This may translate into lower abuse po-tential compared with full agonists, although buprenorphine has been abused by intravenous injections in other countries where it was widely available. The sublingual formulations marketed for treatment of opioid dependence do appear to have limited abuse potential by themselves, and the Suboxone formulation, which includes naloxone, discourages attempts to extract and inject the contents, since intravenous naloxone will precipitate withdrawal; the naloxone is poorly absorbed by the sublingual or oral routes. Buprenorphine binds almost irreversibly to opiate receptors, and dissociates very slowly, accounting in part for its long duration of action. When properly dosed, similar to methadone, it induces tolerance, blocks the effects of other opiates, and produces little or no sedating or intoxicating effects.
The buprenorphine/naloxone combination (Suboxone) if preferred for both detoxification and maintenance treatment, although some patients may be more sensitive to the presence of the antagonist (naloxone) and tolerate straight buprenorphine (Subutex) better. Because it is a partial agonist, buprenorphine will precipitate withdrawal in individuals who have recently used any opioid drug; treatment should therefore begin when there are clear signs of withdrawal (or at least 4 hours after last use of a short-acting opioid). There is less experience of induction with buprenorphine in individuals using long-acting agents such as methadone, but the risk of precipitated withdrawal is greater. The daily methadone dose should be below 40 mg per day before buprenorphine induction is attempted, and a delay of around 48 hours or more is advisable to allow withdrawal symptoms from methadone to clearly manifest. Induction is completed over 2 to 4 days, depending on the target dose. The recommended dose on day 1 is 16 mg, increasing to 16 mg on day 2 and thereafter and more gradual induction may be associated with a higher risk of drop-out. The dose should be adjusted in increments of 2 to 4 mg to that which keeps the individual in the treatment program and suppresses withdrawal symptoms; the target maintenance dose is 16 mg/day but may range from 4 to 32 mg/day. Buprenorphine should be administered as part of a psychosocial treatment pro-gram. The relative ease of withdrawing from buprenorphine may result in a greater tendency to leave the treatment program com-pared with methadone.
Due to its long duration of action, buprenorphine can be administered every other day (e.g. 32 mg every other day), or even twice per week; this property can be useful for patients where there are concerns about compliance, since the medication can be held at a clinic or by a significant other and administered under observation on a less than daily basis.
Buprenorphine can produce sedation. However, emer-gence of sedation should also raise suspicion of use of other drugs or alcohol. Unlike full opiate agonists (heroin, methadone, other narcotic analgesics) where respiratory depression is a serious risk, buprenorphine by itself produce less respiratory depression. The rate of deaths from drug overdose dropped substantially in France after buprenorphine was introduced for treatment of drug dependence. The one exception was overdoses of buprenor-phine in combination with benzodiazepines where deaths were observed. This has led to an exaggerated concern that buprenor-phine is contraindicated in patients who use benzodiazepines. For patients using benzodiazepines at regular, modest doses, which is the most common pattern even among opiate addicts, buprenorphine is safe. Patients who take large doses or binges of benzodiazepines are at risk for overdose in combination with a variety of other drugs, including buprenorphine, and alcohol. It is likely that the risk of overdose in such patients would be the same on either methadone maintenance or buprenorphine maintenance.
Naltrexone is a long-acting (24 to 48 hour duration) opioid antagonist available in 50 mg tablets. It is effective in blocking the effects of opioids and can be used as a maintenance treat-ment, but its effectiveness has been limited by poor compli-ance. Compliance can be improved with behavioral therapy, but rates of retention in treatment still remain well below what can be expected from agonist maintenance with methadone or bu-prenorpine. Further, naltrexone does not protect against opiate overdose; patients who stop naltrexone are not tolerant and are therefore vulnerable to overdose. Naltrexone is also complicated to manage. It cannot be started until a patient has been fully de-toxified, in order not to precipitate withdrawal. Rapid induction methods using buprenorphine, clonidine and clonazepam, have been described, but generally require 5 to 7 days to carry out. Anesthesia assisted rapid detoxification and induction onto nal-trexone has been shown to involve the same level of discomfort, with increased risk of serious adverse events, and is not rec-ommended. Once a patient is inducted onto naltrexone, if they stop taking the naltrexone and relapse, naltrexone cannot be resumed without precipitating withdrawal, and repeat detoxifi-cation is needed. In summary, while some patients benefit from naltrexone, it is considered a second-line agent, for patients who have failed or refuse agonist treatment. Patients maintained on naltrexone should be warned about the risk of fatal drug overdose if naltrexone is discontinued.
Methadone-maintained patients on medical-surgical units and pregnant patients merit special comment. After admission to gen-eral hospital, the dose of methadone should be verified with the patinet’s maintenance program. The dose should be maintained during the stress of an illness and its treatment. Maintenance methadone will suppress opiate withdrawal but it will not pro-vide analgesia. Patients taking methadone who have severe pain should therefore be treated with nonopiate analgesics or short-acting opiates as needed, noting that higher doses and shorter dose intervals may be needed. Drugs with mixed antagonist-agonist activity, such as pentazopcine and buprenorphine, may provoke opiate withdrawal and shoud be avoided.
Women who become pregnant should be encouraged to contiue their methadone maintenance programme. The dose may need to be reduced during the third trimester and neonatal symptoms due to abstinence should be planned for. Longitudinal studies show that infants exposed to methadone in utero develop normally and parents should be reassured.
By contrast with methadone, nicotine replacement therapy is not intended as an indefinite maintenance therapy. Instead, the aim is to provide a medically safe source of nicotine while gradually reducing the dose. Nevertheless, it is reasonable to speculate whether, in terms of harm reduction, nicotine re-placement is superior to cigarette smoking. Two forms of nicotine are available without prescription: nicotine polacrilex (gum) and a transdermal patch. Both are effective in promoting abstinence.
The FDA has recently approved a sustained-release for-mulation of bupropion for the treatment of nicotine dependence; efficacy is similar to that of nicotine replacement therapy. The recommended dose is 150 mg twice daily; treatment should begin 2 weeks before the date on which smoking will cease. Combin-ing nicotine replacement and bupropion offers greater efficacy and safety than either agent alone for patients who have not suc-ceeded with monotherapy.
Many patients who succeed in initiating abstinence from cigarettes will relapse within 3 to 6 months. Clinicians and pa-tients should not be discouraged by this. The data suggest that most patients who make repeated quit attempts eventually suc-ceed in achieving sustained abstinence.