Higher Methadone Research Articles

Methadone as HIV prevention: High Volume Methadone Sites to decrease HIV incidence rates in resource limited settings

The link between injection drug use and HIV has been extensively described. Despite worldwide prevention efforts, injection drug use continues to be a risk factor for HIV transmission and both HIV and injection drug use continues to spread across the globe. Although methadone has demonstrated multiple health benefits including the reduction in injection drug use and HIV acquisition, the utilisation of methadone in many areas of the world remains one of secondary, rather than primary, HIV prevention. As a result, many who finally begin methadone enter treatment having accumulated medical and mental health problems as a result of delayed treatment. Rapid access to treatment and a more aggressive policy that realizes that methadone can help reduce opioid drug use is necessary if methadone is effectively going to act as primary HIV prevention. To delay access to methadone only increases the probability that the individual will acquire an infectious disease that is more costly to the individual in terms of morbidity and mortality and more costly to society as a whole.

15-Year survival and retention of patients in a general hospital-affiliated methadone maintenance treatment (MMT) center in Israel

We have extended our previous 10-year follow-up study of MMT retention for another 5 years and added data on survival of all patients ever admitted to our MMT clinic (6/1993 to 6/2007). Data were calculated from admission to MMT until leaving, death, or study closure (6/2008). Ninety-four of a total of 613 patients (4711.6 person-years [py]) died. Cancer was the primary cause of death for those who remained in treatment, and overdose for those who left MMT. Longer survival ( p = 0.051) with a trend for a lower mortality rate ( p = 0.08) was noted among the 464 patients who stayed in treatment ≥1 year (1.8/100 py), compared with the 149 patients who left MMT <1 year (2.6/100 py). Predictors of survival in multivariate analyses were younger age (<40 years) at admission, living with a spouse/partner, being hepatitis B sera-negative, not abusing benzodiazepines on admission (interaction effect), not being referred directly from hospitalization to MMT, and not leaving the MMT program for hospitalization. The two latter variables also predicted longer retention, as did a high methadone dose (≥100 mg/d), no opiate and, no benzodiazepine abuse after 1 year and either having any DSM-IV-TR Axis I, or no Axis I&II psychiatric diagnoses. Unlike retention, mortality was associated with pre-treatment severity and comorbidities thus only partially reflects MMT outcome (opiate abstinence and treatment success). Benzodiazepine abuse reduced both retention and survival, emphasizing the high priority that should be given to stopping it.

High Dose versus Moderate Dose Methadone Maintenance: Is There a Better Outcome?

ABSTRACT Methadone dosing has been an issue of controversy among clinicians for a long time. Few recent studies reported that doses above 100 mg daily seem promising in better control of illicit opiate use for some patients, but more research is needed to support that notion. A retrospective chart review for patients maintained on methadone at Atlanta Veterans Affairs Medical Center was conducted. Patients were categorized into two groups: patients on a methadone dose of 60 to 100 mg daily (n = 34) and patients on a methadone dose greater than 100 mg daily (n = 25). Those charts were compared for urine drug screens for opiates and cocaine (first four from admission and most recent four screens), retention or drop out from the program, and Addiction Severity Index (ASI) composite score at admission and most recent score. The results of the first and last four urine drug screens for opiates showed that the moderate dose group was positive 23% and 17%, respectively. However, the high dose group was positive 14% and 8%, respectively. These results showed statistical significance (Chi-Square = 8.04, df = 3 and p =.03). ASI scores for drugs did not show statistically significant improvement for the moderate dose group (p =.19) but showed statistically significant improvement for the high dose group (p =.0002) when the result of the first and last ASI scores among each group were compared. The ASI scores for family problems showed statistically significant improvement for the moderate dose group (p =.03). High doses of methadone greater than100 mg daily may provide a better outcome for illicit opiate use among some patients who would not respond to moderate doses.

Electrocardiogram Characteristics of Methadone and Buprenorphine Maintained Subjects

ABSTRACT There has been recent concern about the association between high dose methadone and prolongation of QTc in the electrocardiogram. QTc is the time from the beginning of the QRS complex to the end of the T have as measured on an electrocardiogram and corrected for heart rate. To date, no association has been made between methadone and buprenorphine in commonly used doses and prolonged QTc. Electrocardiograms were performed on groups of methadone (n = 35, mean daily dose ± standard deviation, 69 ± 29 mg) and buprenorphine (n = 19, mean daily dose 11 ± 5 mg) subjects and a group of non-opioid dependent controls (n = 17). Mean QTc did not differ (p = 0.45) between methadone, buprenorphine, or controls. Methadone subjects were significantly (odds ratio of 7.8) more likely to have U waves than buprenorphine and controls combined. Methadone subjects with U waves were maintained on higher (p = 0.004) doses (89 ± 29 mg/day) than methadone subjects without U waves (60 ± 24 mg/day). Methadone subjects taking 60 mg and above had higher (p = 0.02) QTc (405 ± 29 milliseconds) than methadone subjects taking less than 60 mg per day (381 ± 27 milliseconds). Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.

Tricyclic antidepressants and Benzodiazepines abuse, among former heroin addicts currently in Methadone maintenance treatment (MMT)

Background and Aims:The tricyclic antidepressant amitriptyline was suspected to be abused among methadone maintenance treatment (MMT) patients in Israel. Given its potentially dangerous interaction with methadone, and even more so with benzodiazepines (BDZ), which is highly abused among MMT patients, we did a cross sectional studied all 303 patients (February, 2007).Methods:Evidence of tricyclics presence in one of the 2±0.5 random urine samples (range1-4) that are routinely taken for opiates, cocaine BDZ, amphetamines, and cannabis. Modified addiction severity index (ASI) and variables from patients’ records.Results:48(15.8%) were positive for amitriptyline. They were similar to the others in age, gender, presence of DSM-IV psychiatric disorders, and QTc interval on ECG. Logistic regression (multivariate analyses) found that the extent of being amitriptyline positive was higher in BDZ abusers (OR=11.6 95%CI 4.4-30.7), in subjects with positive antibody to hepatitis C (OR=2.2, 95%CI 1.02-4.9) and in patients treated with high dose methadone (>150 mg/day) (OR=2.4, 95%CI 1.2-4.9). Amitriptyline was found in 12 (7.5%) of the “privileged” group members who, by definition, should not be abusing drugs.Conclusion:The high prevalence of amitriptyline abuse, even among “privileged” patients, and in combination with BDZ abuse, emphasizes the importance of routine monitoring in order to decrease the potential risk associated with amitriptyline combined with methadone and BDZ, and to implement appropriate interventions.

619: High dose methadone maintenance (HDMM) and its effect on neonatal abstinence syndrome (NAS)

ABSTINENCE SYNDROME (NAS) MONA PRASAD, SUSIE LIM, DEBRA GARDNER, LEANDRO CORDERO, PHILIP SAMUELS, Ohio State University, Department of Obstetrics and Gynecology, Columbus, Ohio, The Ohio State University, Department of Obstetrics and Gynecology, Columbus, Ohio, Ohio State University, Department of Pharmacy, Columbus, Ohio, Ohio State University, Department of Pediatrics, Columbus, Ohio OBJECTIVE: To evaluate the effects of HDMM on NAS. STUDY DESIGN: The amount of methadone required for maintenance of opiate-addicted patients during pregnancy is increasing. Many patients require maintenance doses of 100 mg per day at term. The neonatal effects HDMM has not not been investigated. We employed a retrospective chart review, 2002-present, of all infants with antenatal methadone exposure to examine the effect of HDMM on NAS. RESULTS: 72 infants were identified to have antepartum methadone exposure. The avg maternal methadone daily dose 101 / 50mg; avg length of stay (LOS) 23.9 / 16 days; avg days requiring meds for NAS 19 / 14 days. 6 babies required medication upon discharge. The most common neonatal complication was jaundice (n 12). When comparing lower dose methadone with higher dose methadone, no statistically significant differences were identified in LOS or days on meds for NAS. We do identify a statistically significant difference in EGA and birthweight. Similar results were identified when comparing the extremes ( 50 mg vs 150 mg) of dosing as well. Breastfed infants have fewer days of medications for NAS versus bottle-fed infants (17 vs 25, p 0.06). CONCLUSION: NAS appears to be dependent on more than degree of dosing alone. Perhaps specific pharmacokinetics/pharmacodynamic parameters warrant investigation to understand NAS fully. Breastfeeding should be considered in women on methadone maintenance, regardless of dose. This study suggests that aggressive treatment of addiction with HDMM may contribute to an environment conducive to prolongation of pregnancy, which may be beneficial to the neonate in terms of avoidance of neonatal comorbidities.

Comparative toxicology of fatal heroin overdose cases and morphine positive homicide victims

To compare the blood toxicology of heroin overdose cases and morphine positive homicide victims. Analysis of coronial cases. Sydney, Australia. Cases A total of 705 cases of death due to opioid toxicity and 28 morphine positive homicide cases (1 January 1998-31 December 2002). There was no significant difference between the median morphine concentrations of the overdose and homicide groups (0.50 versus 0.45 mg/l). The overdose group was more likely to have blood alcohol (OR 3.21) present, but less likely to have methadone (OR 0.26) and cannabis (OR 0.04). There was a significant negative correlation between blood morphine and alcohol concentrations among the overdose group (rho = -0.32), but not among the homicide group (rho = -0.03). Independent predictors of a higher blood morphine concentration were a lower alcohol concentration and a higher methadone concentration. Morphine concentrations per se are not diagnostic of overdose. The study confirms the salience of concomitant alcohol consumption in such events.

The effect of methadone on the QTc interval in advanced cancer patients

9064 Background: Methadone (ME) has been used increasingly for pain control and for maintenance in drug addiction programs. Its use is increasing in cancer patients (pts), mainly as part of opioid rotation. Some recent reports suggest that ME may prolong QTc interval and cause torsade de pointes in pts on high dose ME. The purpose of our study was to determine the effect of initiation of ME on QTc interval in pts with cancer pain. Methods: We enrolled 101 pts in this prospective study. These pts had never been on ME before. Pts were followed clinically and electrocardiographically for QTc changes from baseline. EKG was obtained at baseline (QTc0), 2 (QTc2), 4 (QTc4), and 8 (QTc8) weeks. We recorded other contributing factors for QTc prolongation such as medication interactions with ME and electrolyte disturbances. QTc is prolongation is defined as &gt; 430 ms in males and &gt; 450 ms in females. In our study, significant QTc prolongation was defined as = 10% increase from baseline or QTc = 500 msec. Results: 74 pts (73%) had normal QTc (group A) and 27 pts (27%) had prolonged QTc (group B) at baseline. Significant increase in QTc in group A males occured in 1 of 16 (6%) at week 2, 2 of 10 (20%) at week 4, and 0 of 8 (0%) at week 8. Significant increase in QTc in group A females occured in 3 of 32 (10%) at week 2, 1 of 21 (5%) at week 4, and 0 of 12 (0%) at week 8. These pts had multiple contributing factors for QTc prolongation. QTc &gt; reference for males occured in 6 of 16 (37%) at week 2, 4 of 10 (40%) at week 4, and 1 of 8 (12%) at week 8; in females, 1 of 32 (3%) at week 2, 3 of 21 (14%) at week 4, and 1 of 12 (8%) at week 8 ( Table 1 ). 2 of 27 pts (7%) from group B had a significant prolongation at week 2: one of them had an increase from 498 to 509 ms, then to 512 at week 4 and 486 at week 8. Conclusions: Baseline prolonged QTc is a common finding. QTc prolongation = 500 ms is rare in pts receiving ME for cancer pain. No data exists for other opioids. There was one case of temporary increase in QTc &gt; 500 ms. There was no evidence of severe arrhythmias or torsade de pointes clinically or on EKG. ME dose was = 50 mg/day in the majority of these pts. [Table: see text] No significant financial relationships to disclose.

Buprenorphine Replacement Therapy for Adolescents with Opioid Dependence: Early Experience from a Children’s Hospital-Based Outpatient Treatment Program

Opioid use by adolescents is on the rise and replacement therapy is an effective treatment. Methadone replacement has been used safely and effectively with adults, but methadone programs are often unattractive to teenagers. Buprenorphine is a new replacement therapy that has been shown to be as effective as high dose methadone and may be better suited for the treatment of younger patients. We describe the experiences of several adolescent patients who received treatment from an outpatient adolescent substance abuse program that operates within a children’s hospital, with an emphasis on issues of adolescent development.

Correlation Between High Methadone Doses and Methadone Serum Levels in Methadone Maintenance Treatment (MMT) Patients

Aims: To evaluate the relation between high methadone doses and methadone serum levels in MMT patients. Design:One hundred fifty-one steady methadone-dose patients were evaluated for methadone serum levels using GCMS. Urine samples during the month prior to the study-day were analyzed and defined as positive if any sample was positive for any drug. Findings:Methadone dose correlated with methadone serum levels (Pearson R = 0.36, p < 0.0005). In 53 patients with no drug abuse, correlation was stronger (R = 0.53, p < 0.0005) than in 98 patients with any drug abuse (R = 0.25, p = 0.01). Conclusions:We extended the well-established correlation between methadone doses and serum levels in patients receiving low or moderate (60 to 120 mg/day) to high methadone doses (up to 290 mg/day)

High-Dose Methadone Maintenance in Rats: Effects on Cocaine Self-Administration and Behavioral Side Effects

It has been demonstrated that high-dose methadone maintenance is efficacious in reducing cocaine abuse in opioid-dependent individuals, but it is not clear whether this is caused by an action of methadone on the direct reinforcing properties of cocaine or on cocaine seeking. Also, it is not clear whether high-dose methadone maintenance may induce behavioral side effects, which could limit its clinical use. Here, we report that high-dose methadone maintenance (20-40 mg/kg/day) does not reduce, and even enhances cocaine (10-30 mg/kg, i.p.)-induced elevation in dopamine concentration in the ventral striatum measured by in vivo microdialysis. In parallel, however, rats maintained on high-dose methadone (30 mg/kg/day) seek and consume significantly less cocaine than controls when tested for intravenous cocaine (0.5 mg/kg/infusion) self-administration on a progressive ratio schedule of reinforcement. This reduction in cocaine self-administration does not result from impaired sensory-motor functioning as rats maintained on high-dose methadone show normal locomotor activity. Furthermore, the reduction in responding for cocaine does not seem to result from general behavioral deficits as male rats maintained on high methadone doses respond normally to palatable food and thermal pain, although their sexual responses to receptive females are greatly suppressed. Taken together, these results from studies in rats support the usefulness of larger doses of methadone to reduce severe cocaine abuse in opioid-dependent individuals and possibly in the management of pure-cocaine addiction.

QTc Prolongation and Torsades de Pointes Associated with Methadone Therapy

Oral methadone therapy is an effective and increasingly popular treatment for opioid dependency and chronic pain. Although it is not typically considered pro-dysrhythmic, we present the unique case of a 52-year-old HIV-positive woman without underlying cardiac disease who developed QTc prolongation and pulseless Torsades secondary to high dose methadone therapy.

Corrected‐QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients—a cross‐sectional study

To determine and evaluate QTc intervals in electrocardiograms (ECGs) of former heroin addicts, currently in methadone maintenance treatment (MMT), as previous reports suggest that methadone may prolong QTc intervals, thus possibly increasing the risk for Torsade de pointes (TdP). Cross-sectional study. Between January 2003 and September 2004, patients on a steady dose of methadone for at least 2 weeks were studied. This study is a subset of 153 patients, of whom 151 patients participated in a study of high methadone doses and serum levels. A total of 138 patients in MMT for a minimum of 100 days up to 10.7 years, receiving 40-290 mg/day methadone dose, participated. Patients had an ECG at the time when blood was drawn for determination of serum methadone levels at around 24 hours after the last oral methadone dose. Corrected-QT intervals (QTc) were calculated using the Bazett formula. Of 138 patients studied, 98 (71%) were male. Mean QTc interval was 418.3 +/- 32.8 milliseconds (ms). Mean methadone dose was 170.9 +/- 50.3 mg/day and mean serum methadone level was 708.2 +/- 363.1 ng/ml. Methadone dose and serum levels did not correlate with QTc. Three patients had QTc intervals above 500 ms ('prolonged'). After 2 +/- 0.4 years of follow-up, two patients died; they were two of three patients with very prolonged QTc. Causes of death were not attributed to cardiac origin. An additional 19 patients had QTc intervals of between 450 and 499 ms ('possibly prolonged'). None of these QTc > or = 450 ms patients had any cardiac problems. Methadone doses of all 22 patients were > 120 mg/day. Methadone maintenance is generally safe; however, the possible toxicity of high dose (> 120 mg/day) should be monitored for QTc.

Methadone Death, Dosage and Torsade de Pointes: Risk-Benefit Policy Implications

Methadone maintenance treatment (MMT) for opioid dependency has consistently shown important heath, social and legal benefits. What started as a small experimental program in Lexington, Kentucky has grown and expanded substantially over 35 years. Its practice is now well established both in specialized centers and in the broader community. In society, methadone deaths represent an important issue of public safety: methadone diversion to and ingestion by nontolerant individuals outside of treatment. Within treatment, methadone deaths occur most commonly in the early stabilization period (due to issue of tolerance), in periods of transition, or among certain individuals who abuse other substances (opioids, benzodiazepines, or alcohol). Research suggests moderately high methadone dosages help improve patient retention. Results from pharmacodynamic, kinetic and stereospecific studies continue to support the importance of individualizing dose. For some patients, much larger doses may be necessary to fully achieve all pharmacotherapy goals of treatment. Practitioners must be cautious however as certain patients on higher dosages are predisposed to torsade de pointes and increased mortality. Policymakers have a responsibility in their decision-making to balance the quality of life benefits for patients within MMT with the risks of increased mortality both for individuals within treatment and the general public.

False Reduction in Serum Methadone Concentrations by BD Vacutainer® Serum Separator Tubes (SST™)

Methadone maintenance is the primary treatment modality in the US for opioid dependence, with doses typically titrated to therapeutic response such as improvement of withdrawal symptoms or abstinence from drug use. Serum methadone concentrations are used to guide dosing in patients who do not respond to high methadone doses, may be poorly compliant, have excessive sedation or withdrawal symptoms, are pregnant, or have potential drug interactions. In settings with limited onsite laboratory facilities, such as methadone maintenance clinics, it is common practice to collect blood samples in serum separator tubes (SST). The gel in the SST™ forms a barrier between cells and serum after centrifuging, allowing for easier storage and transport. However, the gel in the SST may bind to and decrease the concentration of certain hydrophobic drugs, leading to erroneously low results (1)(2)(3)(4). Factors such as specimen volume, storage time, storage temperature, and the type of gel used …

Pharmacokinetics and Pharmacodynamics of Methadone Enantiomers in Hospice Patients With Cancer Pain

Racemic methadone is increasingly used to manage cancer pain. The authors studied 13 terminally ill patients with cancer pain, who underwent switching (rotation) from morphine to methadone. The relationship between initial morphine dose and final methadone dose, the pharmacokinetics of R- and S- methadone, and the degree of pain control and side effects were investigated. Preswitching serum morphine concentrations and second daily plasma concentrations of methadone were measured. The brief pain inventory (BPI) was used to assess pain every second day. "Worst pain" as measured by the BPI improved by >/=20% in 6 of the 13 patients. The mean morphine to methadone conversion ratio was 5.2 with wide interpatient variability (range 1.3 to 11). Average steady-state concentrations were 197 (98 to 379) mug/L and 272 (55 to 378) mug/L for R- and S-methadone, respectively. Mean population pharmacokinetic parameters for a 1-compartment model were 455 L and 338 L for apparent volume of distribution and 53.3 hours and 31.5 hours for half-life for R- and S- methadone, respectively. Bayesian estimates of apparent oral clearance for individual patients were 0.082 (0.052 to 0.112) L/kg/h and 0.117 (0.061 to 0.173) L/kg/h for R- and S- methadone, respectively (mean and 95% confidence interval). The low and variable clearance values generally resulted in slow achievement of steady-state concentrations over several days; inappropriately high plasma methadone levels occurred in 1 patient. Whereas optimal pain control was achieved in 46% of patients, there was no relationship with plasma concentrations of methadone. Best practice for methadone use in this patient group should include monitoring of both pain and methadone concentration.

High Methadone Dose Significantly Reduces Cocaine Use in Methadone Maintenance Treatment (MMT) Patients

Aim: To evaluate whether effective methadone treatment affects cocaine use. Methods: Four hundred twenty-one consecutive patients admitted to a methadone maintenance clinic in Israel (1993-2002) were prospectively studied. Patients' urine samples were analyzed for cocaine during months 1 and 13. Results: On admission 55(13.1%) of 421 patients had urine positive for cocaine and 366 had negative. Of the 55 cocaine-positive patients, 45(81.8%) stayed in treatment at least one year, as did 267(73%) cocaine-negative. After one year (n = 312) 31 of 45 cocaine users stopped and 25 of 267 started. Methadone dose was highest in 31 patients who stopped cocaine (176.1 ± 42.1 mg/ day), followed by 14 who did not stop (161.4 ± 37.5 mg/day), and 25 who started during treatment (122.9 ± 48.7 mg/day), or 242 who never used cocaine (119.5 ± 48.4 mg/day) (ANOVA, F = 15.6, p < 0.0005). Conclusions: High methadone dose may reduce cocaine use in patients addicted to both heroin and cocaine.

LES TRAITEMENTS DE SUBSTITUTION A L’HEROÏNE. ANALYSE DES SOLUTIONS ACTUELLES, EVOLUTIONS ET PERSPECTIVES.

Drugs used for treatment of narcotic addicts (buprenorphin at high concentration or methadone) have different advantages and disadvantages. The author has tried to insist on what can be complementary between both treatments. Two new formulations of buprenorphin at high concentration (Suboxone and Subutex NF) are described and proposed to replace Subutex®.

Harm reduction interventions, behaviours and associated health outcomes in France, 1996–2003

To track the effect of the French harm reduction programme targeted at intravenous drug users (IDUs) and associated health outcomes. Since 1996, we have collected monthly sales of sterile syringes and substitution treatments (buprenorphine high dosage and methadone) sold to IDUs in the 23 000 pharmacies in France and collated these figures in a single data base (SIAMOIS). To this data base we have also added the number of syringes distributed through community associations, as well as methadone treatments prescribed in public drug dependence clinics. For the period 1996-2003 we analysed syringe sales and prescribed substitution treatments as indicators of access to harm reduction services. We compared variations of these figures over time with trends in health outcome indicators [annual number of fatal overdoses, hepatitis C virus (HCV) and human immunodeficiency virus (HIV) prevalence among intravenous drug users], risk behaviour indicators (rate of syringe sharing or rate of syringe re-use) and legal indicators (heroin and cocaine use-related arrests). The number of sterile syringes sold or distributed to IDUs increased from 1996 to 1999 (+ 21%) and then decreased dramatically from 1999 to 2003 (-40%). In 2003, we estimated that more than 100,000 drug users used substitution treatments. Between 1996 and 2003, a decrease in syringe sharing and syringe re-use was observed, HIV prevalence among IDUs decreased from 40% to 20% and HCV prevalence remained high (60-70%). From 1996 to 2003, arrests due to heroin use declined (from 17 328 to 4025) and deaths due to overdoses also decreased (from 465 to 89), whereas arrests for cocaine use increased from 1184 to 2511. Our results indicate that, since 1996 in France, IDUs have had greatly improved access to sterile syringes and substitution treatments. The decrease in syringe sharing and re-use practices and of HIV prevalence during the same time period indicates that the harm reduction policy implemented in France has had a positive impact. However, because of the persistent sharing and re-use of syringes and a remaining high HCV prevalence in IDUs, efforts to facilitate access to sterile syringes must continue, and targeting of at-risk groups must be improved. Behavioural surveys associated with HIV and HCV seroprevalence data are needed to further assess prevention of blood-borne infections among IDUs in France.

Structure as a Determinant of Treatment Dose

Abstract This study examined the role of total session exposure on during-treatment outcomes in a sample of 298 methadone maintained clients. The total number of minutes actually spent in counseling sessions during a 6-month period was used to create a measure of client exposure to treatment. Clients were divided into three groups: low (< 270 minutes), medium (270-399 minutes), and high (400+ minutes). Results supported the hypothesis that clients in the low exposure group did not develop as much rapport or “bond” as well with their counselors as clients in the higher treatment exposure groups. Several factors predicted which clients spent more time in counseling sessions, namely: being female, heavy alcohol use, a history of childhood problems, higher metha-done dosage, and structured counseling sessions. Among these, the most significant predictor of clients being in the high treatment exposure group was participation in structured counseling sessions. This finding supports the use of structured treatme...