Prevalence of methadone injection in three Swiss cities.

OBJECTIVE: Intravenous methadone is associated with increased risk of morbidity and mortality. A previous report from a methadone center in Fribourg, Switzerland, found a high prevalence (43%) of patients who injected oral methadone. We therefore wished to assess the prevalence of methadone injection among patients in oral methadone programs in 3 other Swiss cities--Lausanne, Geneva, and La Chaux-de-Fonds. METHOD: Subjects were randomly selected and interviewed by assistant psychologists who were not on the staff of the study centers. Participation was voluntary and anonymous. RESULTS: 164 patients participated in the study (n = 58 in Lausanne, 52 in Geneva, and 54 in La Chaux-de-Fonds). The prevalence of methadone injection was low (5%) and did not differ significantly between the cities. DISCUSSION: Less liberal policies cannot explain the lower prevalence of methadone injection in these three centers than in Fribourg. The high prevalence of methadone injection there is probably related to its separate methadone injection program: patients in oral methadone programs may be more likely to injection methadone when other patients authorized to do so. IN CONCLUSION: Although the 5% prevalence of methadone injection found in the 3 cities surveyed is low, it is not negligible. These results suggest that information on the risks associated with injection of methadone syrup should be provided to all methadone maintenance. This information is especially necessary when maintenance therapy is provided in the same center, or city as injectable methadone maintenance.

Oral and intravenous methadone use: some clinical and pharmacokinetic aspects.

A sample of 15 patients participating in an injectable methadone trial and of 15 patients in an oral methadone maintenance treatment, who admitted injecting part or all of their methadone take-home doses, were compared to 20 patients in maintenance treatment who use methadone exclusively by mouth. The present study confirms the poorer general health, the higher levels of emotional, psychological or psychiatric problems, the higher use of illicit drugs, and the higher number of problems related to employment and support associated with the use of the intravenous mode of administration of methadone. As expected, due to the shunt of metabolism in the gut wall and of the liver first-pass effect, higher concentration to dose ratios of (R)-methadone, which is the active enantiomer, were measured in the intravenous group (23% increase). This difference reached an almost statistically significant value (P = 0.054). This raises the question whether the effect of a higher methadone dose could be unconsciously sought by some of the intravenous methadone users.

Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers

Steady-state blood concentrations of (R)- methadone (i.e., the active form), (S)-methadone, and (R,S)-methadone were measured before and after introduction of paroxetine 20 mg/day during a mean period of 12 days in 10 addict patients in methadone maintenance treatment. Eight patients were genotyped as CYP2D6 homozygous extensive metabolizers (EMs) and two patients as poor metabolizers (PMs). Paroxetine significantly increased concentrations of both enantiomers of methadone in the whole group (mean increase for (R)-methadone +/- SD, 26 +/- 32%; range, -14% to +83%, p = 0.032; for (S)-methadone, 49 +/- 51%; range, -29% to +137%, p = 0.028; for (R,S)-methadone, 35 +/- 41%; range, -20% to +112%, p = 0.032) and in the group of eight EMs (mean increase, 32%, p = 0.036; 53%, p = 0.028; and 42%, p = 0.036, for (R)-methadone, (S)-methadone, and (R,S)-methadone, respectively). On the other hand, in the two PMs, (S)-methadone but not (R)-methadone concentrations were increased by paroxetine (mean increases of 36% and 3%, respectively). Paroxetine is a strong CYP2D6 inhibitor, and these results confirm previous studies showing an involvement of CYP2D6 in methadone metabolism with a stereoselectivity toward the (R)-enantiomer. Because paroxetine is a mild inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4, increase of (S)-methadone concentrations in both EMs and PMs could be mediated by inhibition of any of these isozymes.

Contribution of CYP2B6 alleles in explaining extreme (S)-methadone plasma levels: a CYP2B6 gene resequencing study.

BACKGROUND: (S)-Methadone, metabolized mainly by CYP2B6, shows a wide interindividual variability in its pharmacokinetics and pharmacodynamics. METHODS: Resequencing of the CYP2B6 gene was performed in 12 and 35 selected individuals with high (S)-methadone plasma exposure and low (S)-methadone plasma exposure, respectively, from a previously described cohort of 276 patients undergoing methadone maintenance treatment. Selected genetic polymorphisms were then analyzed in the complete cohort. RESULTS: The rs35303484 (*11; c136A>G; M46V) polymorphism was overrepresented in the high (S)-methadone level group, whereas the rs3745274 (*9; c516G>T; Q172H), rs2279344 (c822+183G>A), and rs8192719 (c1294+53C>T) polymorphisms were underrepresented in the low (S)-methadone level group, suggesting an association with decreased CYP2B6 activity. Conversely, the rs3211371 (*5; c1459C>T; R487C) polymorphism was overrepresented in the low-level group, indicating an increased CYP2B6 activity. A higher allele frequency was found in the high-level group compared with the low-level group for rs3745274 (*9; c516G>T; Q172H), rs2279343 (*4; c785A>G; K262R) (together representing CYP2B6*6), rs8192719 (c1294+53C>T), and rs2279344 (c822+183G>A), suggesting their involvement in decreased CYP2B6 activity. These results should be replicated in larger independent cohorts. CONCLUSION: Known genetic polymorphisms in CYP2B6 contribute toward explaining extreme (S)-methadone plasma levels observed in a cohort of patients following methadone maintenance treatment.

ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment.

BACKGROUND AND OBJECTIVE: The in vivo implication of various cytochrome P450 (CYP) isoforms and of P-glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment. METHODS: Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam. RESULTS: The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity. CONCLUSION: In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.

Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment.

BACKGROUND AND OBJECTIVE: Recent in vitro studies have suggested an important role of cytochrome P450 (CYP) 2B6 and CYP2C19 in methadone metabolism. We aimed to determine the influence of CYP2B6, CYP2C9, and CYP2C19 genetic polymorphism on methadone pharmacokinetics and on the response to treatment. METHODS: We included 209 patients in methadone maintenance treatment on the basis of their response to treatment and their daily methadone dose. Patients were genotyped for CYP2B6, CYP2C9, and CYP2C19. Steady-state trough and peak (R)-, (S)-, and (R,S)-plasma levels and peak-to-trough plasma level ratios were measured. RESULTS: CYP2B6 genotype influences (S)-methadone and, to a lesser extent, (R)-methadone plasma levels, with the median trough (S)-methadone plasma levels being 105, 122, and 209 ng . kg/mL . mg for the noncarriers of allele *6, heterozygous carriers, and homozygous carriers (*6/*6), respectively (P = .0004). CYP2C9 and CYP2C19 genotypes do not influence methadone plasma levels. Lower peak and trough plasma levels of methadone and higher peak-to-trough ratios were measured in patients considered as nonresponders [median (R,S)-methadone trough plasma levels of 183 and 249 ng . kg/mL . mg (P = .0004) and median peak-to-trough ratios of 1.82 and 1.58 for high-dose nonresponders and high-dose responders, respectively (P = .0003)]. CONCLUSION: Although CYP2B6 influences (S)-methadone plasma levels, given that only (R)-methadone contributes to the opioid effect of this drug, a major influence of CYP2B6 genotype on response to treatment is unlikely and has not been shown in this study. Lower plasma levels of methadone in nonresponders, suggesting a higher clearance, and higher peak-to-trough ratios, suggesting a shorter elimination half-life, are in agreement with the usual clinical measures taken for such patients, which are to increase methadone dosages and to split the daily dose into several intakes.

Contribution of cytochrome P450 and ABCB1 genetic variability on methadone pharmacokinetics, dose requirements, and response

Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements.

ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment

BACKGROUND AND OBJECTIVE: The in vivo implication of various cytochrome P450 (CYP) isoforms and of P-glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment. METHODS: Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam. RESULTS: The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity. CONCLUSION: In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.

Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers

Steady-state blood concentrations of (R)- methadone (i.e., the active form), (S)-methadone, and (R,S)-methadone were measured before and after introduction of paroxetine 20 mg/day during a mean period of 12 days in 10 addict patients in methadone maintenance treatment. Eight patients were genotyped as CYP2D6 homozygous extensive metabolizers (EMs) and two patients as poor metabolizers (PMs). Paroxetine significantly increased concentrations of both enantiomers of methadone in the whole group (mean increase for (R)-methadone +/- SD, 26 +/- 32%; range, -14% to +83%, p = 0.032; for (S)-methadone, 49 +/- 51%; range, -29% to +137%, p = 0.028; for (R,S)-methadone, 35 +/- 41%; range, -20% to +112%, p = 0.032) and in the group of eight EMs (mean increase, 32%, p = 0.036; 53%, p = 0.028; and 42%, p = 0.036, for (R)-methadone, (S)-methadone, and (R,S)-methadone, respectively). On the other hand, in the two PMs, (S)-methadone but not (R)-methadone concentrations were increased by paroxetine (mean increases of 36% and 3%, respectively). Paroxetine is a strong CYP2D6 inhibitor, and these results confirm previous studies showing an involvement of CYP2D6 in methadone metabolism with a stereoselectivity toward the (R)-enantiomer. Because paroxetine is a mild inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4, increase of (S)-methadone concentrations in both EMs and PMs could be mediated by inhibition of any of these isozymes.

Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence

Opioid substitution treatment (OST) for opioid dependence may be limited by adverse events (AEs). Increasing the range of therapeutic options optimizes outcomes and facilitates patient management. An international, multi-center, two-phase study investigated the efficacy and safety of slow-release oral morphine (SROM) versus methadone in patients receiving methadone therapy for opioid dependence. In phase 1 (two way cross-over, 11 weeks each period) patients were randomized to SROM or methadone oral solution. In phase 2 (25 weeks), patients continued treatment with SROM (group A) or switched from methadone to SROM (group B). In total, 211 out of 276 completed phase 1 and 198 entered phase 2 (n = 95 group A, n = 103 group B). Treatment with both SROM and methadone was well tolerated. However, the mean QTc-interval associated with methadone was significantly longer than that under SROM. Higher treatment satisfaction, fewer cravings for heroin, and lower mental stress were reported with SROM. This study adds a significant further weight of evidence that SROM is an effective and well tolerated long-term maintenance treatment for opioid dependence with a beneficial risk profile compared to methadone regarding cardiac effects and supports its clinical utility.

Association between ethnicity and treatment status in opioid dependence therapy using methadone and suboxone drugs

Opioids are drugs with opium-like qualities that are either derived from opiates (drugs created from opium, such as morphine or codeine) or chemically produced. In the U.S. opiate abuse and related deaths have been increasing and traditional maintenance treatment has been Methadone with variable success. However, since 2003 synthetic Buprenorphine has been used since it is prescribed daily by physicians in pill form and should improve outcomes. Comparative studies are limited and the effect of ethnicity on treatment outcome is unknown. ^ Data collected at one clinic from December 2005 through May 2009 were used to compare the association between ethnicity and other socioeconomic variables with treatment status, and to identify factors associated with the dropout among participants. Descriptive tables and multiple logistic regression models were used to examine the data on 1,295 total participants. Of the total, 875 participants (68%) were from the Methadone subsample and 420 participants (32%) from the Buprenorphine subsample; only about 15% stayed in treatment. ^ This study showed that with either Methadone or Buprenorphine maintenance therapy, only about 15% participants stay active over 3.5 years. Methadone treated patients that stayed active in treatment were associated with Caucasian ethnicity and were more likely to be employed. With Buprenorphine maintenance treatment only age over 40 years was associated with continuing activity in the program. Further studies that examine the reasons for the high dropout status and the implication of the socioeconomic and ethnic associations found in this data may help to improve treatment outcomes.^

The Swiss heroin trials: testing alternative approaches

Over half a million heroin misusers receive oral methadone maintenance treatment world-wide1 but the maintenance prescription of injectable opioid drugs, like heroin, remains controversial. In 1992 Switzerland began a large scale evaluation of heroin and other injectable opiate prescribing that eventually involved 1035 misusers. 2 3 The results of the evaluation have recently been reported.4 These show that it was feasible to provide heroin by intravenous injection at a clinic, up to three times a day, for seven days a week. This was done while maintaining good drug control, good order, client safety, and staff morale. Patients were stabilised on 500 to 600 mg heroin daily without evidence of increasing tolerance. Retention in treatment was 89% at six months and 69% at 18 months.4 The self reported use of non-prescribed heroin fell signifianctly, but other drug use was minimally affected. The death rate was 1% per year, and there were no deaths from overdose among participants . . . [Full text of this article]

Role of maintenance treatment in opioid dependence

Methadone maintenance treatment (MMT) involves the daily administration of the oral opioid agonist methadone as a treatment for opioid dependence-a persistent disorder with a substantial risk of premature death. MMT improves health and reduces illicit heroin use, infectious-disease transmission, and overdose death. However, its effectiveness is compromised if low maintenance doses of methadone (

Heroin-assisted treatment as a response to the public health problem of opiate dependence

Injection drug use (involving the injection of illicit opiates) poses serious public health problems in many countries. Research has indicated that injection drug users are at higher risk for morbidity in the form of HIV/AIDS and Hepatitis B and C, and drug-related mortality, as well as increased criminal activity. Methadone maintenance treatment is the most prominent form of pharmacotherapy treatment for illicit opiate dependence in several countries, and its application varies internationally with respect to treatment regulations and delivery modes. In order to effectively treat those patients who have previously been resistant to methadone maintenance treatment, several countries have been studying and/or considering heroin-assisted treatment as a complementary form of opiate pharmacotherapy treatment. This paper provides an overview of the prevalence of injection drug use and the opiate dependence problem internationally, the current opiate dependence treatment landscape in several countries, and the status of ongoing or planned heroin-assisted treatment trials in Australia, Canada and certain European countries.

Characterization of acid-base status in maintenance hemodialysis: physicochemical approach

Acidosis is a common and deleterious aspect of maintenance dialysis. Traditionally, it is considered to be an elevated anion gap acidosis caused by the inability to excrete nonvolatile anions. Stewart`s approach made it possible to identify real determinants of the acid-base status and allowed quantification of the components of these disturbances, especially the unmeasured anions. We performed a cross-sectional study to identify and quantify each component of acidosis in hemodialysis maintenance patients. Sixty-four maintenance hemodialysis patients and 14 controls were enrolled in this study. Gasometrical and biochemical analysis were performed before the midweek dialysis session. Quantitative physicochemical analysis was carried out using the Stewart methodology. Hemodialysis patients were found to have mild acidemia (mean pH: 7.33 +/- 0.06 versus 7.41 +/- 0.05) secondary to metabolic acidosis (serum bicarbonate: 18.8 +/- 0.26 versus 25.2 +/- 0.48 mEq/l). The metabolic acidosis was due to retention of unmeasured anions (6.5 +/- 0.29 versus 3.1 +/- 0.62 mEq/l), hyperchloremia (105.1 +/- 0.5 versus 101.8 +/- 0.7 mEq/l), and hyperphosphatemia (5.90 +/- 0.19 versus 3.66 +/- 0.14 mg/dl). Compared with control values, the unmeasured anions and hyperchloremia had a similar acidifying effect (3.4 and 3.3 mEq/l), corresponding to almost 90% of the metabolic acidosis. Unmeasured anions and hyperchloremia are important components of acidosis in maintenance hemodialysis, in addition to phosphorus. Future studies to determine the etiology and consequences of hyperchloremic acidosis are warranted.