Medications for Opiate Dependence Agonist maintenance treatment for opiate dependence is a

Medications for Opiate Dependence Agonist maintenance treatment for opiate dependence is a

powerful treatment with a large effect size. When properly prescribed, methadone will rapidly induce a dramatic remis- sion in 50% or more of patients. It prevents or reduces illicit opiate use, craving for illicit opiates, criminal behavior associ- ated 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 mortality rates among opioid dependent patients, in part by protecting against overdose. Methadone

243 is also sometimes misunderstood as ‘substituting one drug for

DRUGS FOR TREATING SUBSTANCE ABUSE DISORDERS

another.’ In fact, methadone works by inducing marked toler- ance 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 intoxi- cating 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 well-suited for use as maintenance treatment. It is effective after oral administration and has a long half-life

36 h and it blocks euphoria induced by other opiates. Chronic administration is associated with minimal side effects, the most frequent of which are constipation, excess sweating, reduced sexual interest, but these rarely result in discontinuation of treatment.

The initial dose of methadone maintenance lies in the range 20–40 mg and this is mainly to relieve symptoms due to abstinence. This is followed by an ’induction period’, in which the dose may be increased in increments of 5–10 mg until a dose is achieved that prevents opiate craving and blocks the euphoric effects of illicit opiates. Measures for patient monitoring include subjective reports, interval history, and regular frequent usine toxicology analysis. Although a dose of 40 mg/day may be sufficient for some patients, there is now evidence from several trials that most require 80 mg/day. According to Federal regulations, doses of methadone greater than 120 mg/day require permission, although individual states can specify lower ceiling doses. As with many psychophar- macologic treatments, the most common reason for treat- ment failure in methadone maintenance is inadequte dose, and continued opiate use should prompt consideration of a dosage increase. Some evidence suggests that optimal treat- ment response requires trough methadone blood levels in the range 200–400 ng/mL, 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.

244 HANDBOOK OF PSYCHIATRIC DRUGS

A pragmatic drawback of methadone maintenance is that regulations stipulate that it can only be administered at specially licensed clinics that require frequent attendance (daily at the outset) and that are not even available in many geographic regions. This can be a practical constraint or a disincentive for many patients. On the other hand, it has been shown that the effectiveness of methadone maintenance depends upon regular counseling in conjunction with the medi- cation, which is a requirement of methadone clinics, and more severely dysfunctional patients probably benefit from the struc- ture imposed by clinic rules. Furthermore, many of the better methadone clinics offer primary medical and psychiatric care, which is important since chronic opiate-dependent patients often have multiple medical problems (e.g., hepatitis B and C, HIV) and psychiatric problems (e.g., depression, PTSD).

A recent development is the approval and marketing of the long-acting opiate partial agonist buprenorphine (see also the section above on opiate withdrawal on page 233), which has been shown in clinical trials to have effectiveness equivalent to that of methadone for maintenance treatment. A major differ- ence is that buprenorphine can be prescribed by any physician who has taken a brief training course and received certification, making it more widely available than methadone maintenance. The main regulatory restriction 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 recep- tors but only partially activates them. This may translate into lower abuse potential 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

245 slowly, accounting in part for its long duration of action. When

DRUGS FOR TREATING SUBSTANCE ABUSE DISORDERS

properly dosed, similarly 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) is preferred for both detoxification and maintenance treat- ment, 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 there- fore begin when there are clear signs of withdrawal (or at least

4 h after last use of a short-acting opioid) (see also the section on buprenorphine for detoxification on page 234). There is less experience of induction with buprenorphine in individ- uals 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 h or more is advisable to allow withdrawal symptoms from methadone to manifest clearly. Induction is completed over 2–4 days, depending on the target dose. The recommended dose on day 1 is 16 mg, increasing to 16 mg on day 2 and there- after, and more gradual induction may be associated with a higher risk of drop-out. The dose should be adjusted in incre- ments of 2–4 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 program. The relative ease of withdrawing from buprenorphine may result in a greater tendency to leave the treatment program compared with methadone.

Owing 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 medi- cation can be held at a clinic or by a significant other and administered under observation on a less than daily basis.

246 HANDBOOK OF PSYCHIATRIC DRUGS

Buprenorphine can produce sedation. However, emergence 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 produces 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 over- doses of buprenorphine in combination with benzodiazepines, where deaths were observed. This has led to an exaggerated concern that buprenorphine 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 of over- dose in combination with a variety of other drugs, including buprenorphine, and alcohol. It is likely that the risk of over- dose in such patients would be the same on either methadone maintenance or buprenorphine maintenance.

Naltrexone is a long-acting (24–48 h duration) opioid antag- onist 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 buprenorphine. Furthermore, 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 detoxified, in order not to precipitate withdrawal. Rapid induction methods using buprenorphine, clonidine, and clonazepam have been described, but gener- ally require 5–7 days to carry out. Anesthesia-assisted rapid detoxification and induction onto naltrexone has been shown to involve the same level of discomfort, with increased risk of serious adverse events, and is not recommended. Once a patient is inducted onto naltrexone, if they stop taking the naltrexone and relapse, naltrexone cannot be resumed without precipitating withdrawal, and repeat detoxification is needed.

247 In summary, although some patients benefit from naltrexone,

DRUGS FOR TREATING SUBSTANCE ABUSE DISORDERS

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.