Methadone, buprenorphine, and naltrexone to treat illicit drug addiction

Introduction

Addiction to illicit drugs, alcohol, or other substances is a major problem that affects many millions of individuals in the US alone. Drug users are more likely to get, and transmit sexually transmitted infections, and blood borne infections. For instance, 61% of youth between the ages of 15 and 24 have reported using a drug at some point during their life; cannabis was found to be the most commonly used drug (>80%) (1). Drugs can fall into four distinct categories: stimulants, depressants, hallucinogenics, and opioids. The following are the most frequently used illicit drugs: benzodiazepine, opioid, amphetamine, cocaine, ecstasy, and misused volatile substances (4). Drug abuse is typically accompanied by abuse of other drugs, mental illnesses, and anxiety disorders (19). Drugs typically affect the brain most of which lead to the activation of the dopamine system. When a neurotoxin that can deplete dopamine called 6-hydroxydopamine was administered to rats, the rats did not self-administer amphetamine or cocaine (2). Cocaine, amphetamine, and methylphenidate are dopamine reuptake blockers (2). For instance, cocaine has been known to increase release of dopamine, norepinephrine, and serotonin; excessive dopamine results in anger, aggressiveness, hallucinations, and delusions, amongst other symptoms of psychosis (3). Cocaine intake, for instance, results in paranoia in 68% to 84% of individuals, as well as suspiciousness; in particular, 29% to 53% of cocaine users develop hallucinations, and delusions (3). Misuse of illicit drugs can result in acute intoxication, harmful use (ex: hepatitis or depression), dependence syndrome, withdrawal, and psychotic disorders (4). The most serious of these is drug induced psychosis. Drug induced psychosis is psychosis induced by psychotomimetic drugs such as cocaine, LSD, marijuana, methamphetamine, or PCP. Psychosis is a state of mind wherein the individual in question incorrectly perceives reality (5). Typically, auditory hallucinations, delusions, withdrawal, and mental confusion are present. A psychotic episode implies the presence of psychotic symptoms which can subsist for years. Legally, individuals diagnosed with psychosis are not “insane” (5). Alternatively, illicit drugs can result in death. In 2010, approximately 40 393 individuals died from drug-related issues; every 13 minutes, an individual dies in the US due to illicit drugs (6). The goal of this paper is to review the treatment options for illicit drug addiction.

Methadone

Methadone, a full µ-opiate-receptor agonist, acts as an antagonist of receptors that are typically bound by opioids, and is utilized for opioid dependence and the treatment of chronic pain (10, Figure 1). Methadone is not recommended for patients whose drug habits are not severe (< 0.25g heroin/day) (4), and adverse side effects such as respiratory depression with other drugs have been noted (8). Methadone is also accompanied by the following side effects: sweats, constipation, and sexual dysfunction. The average dose of methadone is between 21 and 68 mg (7), and its half-life is approximately one day (but can be as high as 120 hours) (10). In one particular study, patients were administered either 0mg (beginning at 25mg of methadone, and dropping incrementally to 0mg by week 6), 20 mg (beginning at 25 mg and dropping to 20mg at week 5), or 50 mg (beginning at 25mg, and increasing incrementally until at week 6 the dose is 50mg) of methadone. It was shown that patients on the 50 mg treatment had fewer opioid-positive urine by week 4; methadone was not found to affect cocaine positive patients on the three treatments (7). The number of positive urine samples on methadone doses greater than 50 mg is between 21% and 62%; retention on methadone doses greater than 50 mg is between 31% and 90% (25). The authors imply that larger methadone doses should be administered when one wishes to abstain from drug use, and lower doses to control withdrawal (7). In yet another study conducted in 1979, heroin addicts who were administered 60mg of methadone per day showed a drop in use after a 4 month period; further, criminal conviction rates were double in the no-methadone control versus the methadone treatment group (9). However, it should be noted that methadone can result in mortality in some patients. In Australia, mortality due to methadone – approximately 238 individuals from 1990-1995 - was attributed to the fact that proper clinical assessments and review of patients was ignored; mortality in these cases were due to drug-related (44%), medical illness (24%; of which 53% was due to HIV/AIDS), trauma (17%; of which 28% were vehicular accidents, 15% stab wounds, and 13% beatings), suicide (8.8%), drug and medical (2.1%), drug and trauma (1.7%), and unavailable (2.5%) (11). In 93% of the cases, psychoactive drugs - such as benzodiazepine (55%), morphine (34%), other opioids (20%), alcohol (16%), cannabis (16%), and antidepressants (13%) - were detected during autopsy (11). In another study over a 12 year period, approximately 8% of the patients died, however the mean dose was less than the suggested 60-120 mg; in this case, it was reported that approximately 36% died due to drug dependence/related, 7% due to endocarditis/cardiovascular, 8% due to HIV related, 12% due to cancer, 3% due to pneumonia and related, 8% due to accidents, traumas, and self-harm, 5% due to liver disease/hepatitis C, and 20% due to other causes (12). It has been noted that those with psychiatric illness face a higher chance of mortality (12). Yet in another 7 year study, approximately 1.85% (515/28554) of patients on methadone died (13); Buster et al. (14) showed that out of 5200, 42 died on methadone during treatment, and 26 died after treatment. It is suggested that all patients on methadone be tested 3 to 5 days following initial dose to ensure that clinical signs of respiratory depression or arrhythmia are not present (10). An ECG prior to use of methadone is recommended; initial doses should be low, and titration of dose should be slow (10). In particular, for opioid addiction, initial doses should be between 30 – 40 mg/day; increases should be by no more than 10mg/day (10). Further methadone should not be administered if sedation is observed; administration of other drugs can augment symptoms.

Buprenorphine

Buprenorphine, a partial µ-opiate-receptor agonist and κ-receptor antagonist (17), is typically utilized to treat opioid addiction/dependence, and chronic pain (21, Figure 1). In conjunction with naloxone, it is a full µ-opiate-receptor antagonist (17); buprenorphine binds tightly to receptors and as such has a slow dissociation rate (21, 25, 26). Relatively speaking, buprenorphine is used by 65 000 individuals while methadone is used by 6000 to 7000 individuals in France (26). Further, buprenorphine is preferentially administered to individuals with favorable prognoses (26). Buprenorphine is typically available in 2 or 8 mg dose buprenorphine hydrochloride or as a combination of buprenorphine (2 or 8 mg) and naloxone (0.5 or 2 mg); usually, the ratio of buprenorphine to naloxone is 4:1 (21). The initial dose is between 2 to 4 mg administered 12 hours post-abstinence from short-acting opioids; titration is by 2 to 4 mg every 2 hours up to 8-16 mg (days 1, and 2), 12-24 mg (day 3) (21, 26). Doses should not exceed 24 mg per day (26). It is recommended that patients refrain from short-acting opioids for a period of 12 hours, and show signs of opioid withdrawal prior to administration of buprenorphine (21). Relative to a placebo treatment, it has been shown that buprenorphine has been shown to be effective in treating drug use. In a study comparing buprenorphine (max dose of 22.1 mg) to methadone (max dose of 93.1 mg), it was found that fewer individuals on buprenorphine (46.1% with an average of 103.8 days in treatment) completed the treatment as opposed to methadone (74.1% with an average of 141.3 days) after a 24 week period (22). Further, a 60mg dose or above of methadone resulted in 80% retention, and doses of 120 mg or higher resulted in a 91% of the patients completing the treatment; retention on buprenorphine improved with dosage and with a dose of 30-32 mg buprenorphine, the completion rate was about 60% (22). The number of positive urine samples (for illicit drugs after administration) on 8 mg buprenorphine is between 32% and 90%, on 12 mg is 58%, and on 8-16 mg of buprenorphine is 62%; retention on buprenorphine doses greater than 8 mg is between 20% and 68% (25). Given the poor gastrointestinal absorption rates of buprenorphine, it is typically used in conjunction with naloxone, and is significantly less dangerous in the case of an overdose; sublingual bioavailability can result in higher absorption. Short term side effects include headaches, drowsiness, nausea, constipation, sleep problems, depression, anxiety, weight gain, sweating, rash, itching, abdominal pain, lassitude, menstrual effects, and decreased libido (21, 27). Not much is known about the long-term side effects of buprenorphine. When combined with alcohol, opioids, or CNS depressants, respiratory depression might ensue; in combination with intravenous benzodiazepines, death might ensue (21, 23). In one study, 182 individuals out of a total of 391 individuals (47%) died when on buprenorphine (average buprenorphine in blood = 1.4 ug/l); of these, benzodiazepine - Diazepam-group drugs (63%), alprazolam (28%), temazepam (23%), and oxazepam (14%) - was found in approximately 82% of these cases (23). Most individuals who died of buprenorphine poisoning had a buprenorphine concentration between 0 and 2 ul/l (23). However, side effects such as respiratory depression are difficult to remedy; intravenous buprenorphine has resulted in fatal buprenorphine-induced respiratory depression (19). It is recommended that liver function be audited during treatment, and intravenous use is not recommended. Buprenorphine, with a half-life of 37.5 hours, is deemed safer than other antidotes (ex: methadone), does not require constant monitoring, and is very effective (20); there has been concern about non-compliance (18). Buprenorphine, unlike methadone, is available everywhere, however it does not carry the name or fame of methadone, and can be abused/misused. Further, due to stigmatization, and mortality associated with methadone, a patient must utilize methadone for 2 years before being allowed to use of a one month supply at home; buprenorphine does not have such strict regulation (19). However, buprenorphine is deemed expensive ($250-$450 per month) (19, 20). Buprenorphine is not as effective as methadone for severe addicts; addicts on high doses of methadone have a longer abstinence period, higher number of drug-free urine samples, and tend to adhere to treatment regimens longer than do patients on buprenorphine (19). Methadone has also been shown to be preferable to buprenorphine in dual addiction – the treatment of opioid and cocaine dependence for example – in particular when combined with dopaminergic drugs (19). Retention is also lower on buprenorphine. One study compared retention rates of patients on 20 mg and 65 mg methadone and 4 mg and 12 mg buprenorphine. On all four treatments, the rate of opioid use was found to decrease; abstinence from drug use was higher on high-dose (65mg methadone or 12mg buprenorphine) treatments (24). After 24 weeks in the treatment program, individuals on the 65 mg methadone had the highest retention rates (approximately 64.3%), and those on the 4 mg buprenorphine had the lowest retention rates (approximately 34.5%) (24). Further, at least 3 consecutive weeks of abstinence was documented as follows: 65 mg methadone (50%), 20 mg methadone (40%), 12 mg buprenorphine (34.5%), and 4 mg buprenorphine (20.7%) (24). It can be said that higher doses are more effective than smaller doses. However, buprenorphine has a ceiling effect – the latter means that above a given dosage, there is no treatment effect (which is the reason why individuals on the treatment have a lower risk of respiratory depression) (27).

Naltrexone

Naltrexone, a µ and κ opioid receptor antagonist (competitive antagonism) (35), is typically utilized for opioid and alcohol addiction (28, Figure 1). Naltrexone (half-life of 4 hours) is efficiently absorbed by the gastrointestinal tract, and exclusively metabolized in the liver to 6-β-naltrexol (with a half-life of 13 hours) (30). The main problem in using anti-addiction drugs such as methadone or buprenorphine is that it replaces addiction drugs (such as heroin); in other words, an addict might then seek out the anti-addiction drug to abuse (37). Unlike other anti-addiction drugs, naltrexone does not cause dependence on itself (anti-addiction drug) (35). Naltrexone inhibits the euphoric and analgesic effects of drugs such as heroin – as well as that of alcohol, and amphetamine (36) - such that if and when addicts discontinue naltrexone, and subsequently use heroin, the effects of said heroin are intensified which also increases the risk of an overdose (29). However, naltrexone is clinically less effective than methadone. Moreover, methadone must be discontinued approximately 10 to 14 days prior to administration of naltrexone (31). Naltrexone is capable of addressing cravings accompanied by drug use with notable effects 3 to 5 weeks after induction (35). The effects of naltrexone can last between 48 and 72 hours, and does not lead to physical dependence (31). Naltrexone can cause hepatotoxicity in large doses; it is contraindicated for individuals with hepatitis or liver failure (30). Side effects of naltrexone include the following: headaches, sleep disturbance, anxiety, dizziness, nausea, diarrhea, and rashes (28). Administration of 50 mg, 100 mg and 150 mg of naltrexone can suppress 25 mg of heroin for a period of 24, 48 and 72 hours respectively (31, 35). However, naltrexone is also not accompanied by reinforcing effects and as such retention is low (32, 33). In one study on naltrexone, the number of individuals who remained in the treatment for 14-52 weeks was 10/73; in the naltrexone treatment group, it was noted that 1% of the patients were likely to abide by the treatment (34). Naltrexone is best suited for self-motivated individuals; further, it is quite facile to begin and end treatment with naltrexone (35). The problem with naltrexone is as such compliance. As such, sustained release formulations (SRX) – injectable intramuscular suspension and surgically implantable pellets - were developed (36). Polylactide suspensions (380 mg polylactide + naltrexone) are injections administered approximately every 4 weeks or every month (40); surgically implanted capsules are implanted subcutaneously (30 pellets results can last 7 months) with accompanying minor side effects such as pain, itching and redness due to implantation procedure (36). Retention on surgical implants (prodetoxon) was found to be 52% in the treatment group (naltrexone) at week 10 and 28% in the placebo group; treatment effect-wise, the naltrexone group showed a 56% significant improvement with no side effects while the placebo group showed a 14% significant improvement (37). In other words, surgical implants increases retention on naltrexone, and decreases use of illicit drugs. In another experiment with 380 mg of injectable naltrexone XR-NTX, 45% of patients were completely abstinent on XR-NTX while 28% were completely abstinent in the placebo group; the experiment lasted for approximately 24 weeks, and individuals in the XR-NTX group were abstinent 90% of the time while those in the placebo group were abstinent 35% of the time (38). Further, in the XR-NTX group, 50% of individuals has at least one adverse event (32% in the placebo group), and 26% had at least one drug-related adverse event (10% in the placebo group) (38). Naltrexone, in particular, significantly decreases craving (38). Another study compared NR-NTX administered to patients in non-injectable, and injectable modes, and found that the length of stay was much higher in the injected group (23.6 days) compared to the not-injected group (16.4) (39). Naltrexone can also be used in conjunction with other anti-addiction drugs such as buprenorphine (40).

Conclusion

Addiction to illicit drugs is a serious problem that affects both the health and life of the addict. Thus far, only a handful of drugs that can control addiction have been brought to the market, and amongst these are methadone, buprenorphine, and naltrexone. Methadone is very effective, but also not easily acquired; buprenorphine is fairly effective, but quite easily procured, and can be used “at home”. However, both methadone, and buprenorphine are rather addictive (the patient can become addicted to the anti-addiction drug), in such cases, naltrexone may be utilized as it does not cause dependence (though also less effective). Further, a combination of drugs can also be used to treat addiction.

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