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AT Forum NEWS NOTES & UPDATES #104

March – April 2006

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Contents

Methadone Doses Above 80 mg/d Unrelated to SML

Methadone Tapering Difficult, Even in Supportive Setting

MMT in Prison Beneficial, Cost Effective

Methadone vs Buprenorphine Maintenance Compared in Study

Naltrexone for Opioid Addiction Reviewed

Smoking Cessation Unsuccessful in MMT Patients

Factors Affecting Sleep Disorders in MMT Patients Examined

New Evidence: MMT Benefits HIV/HCV-Infected Patients

MMT Effective in Opioid-Addicted Chronic Pain Patients

Methadone Dose Adjustment Not Required With Nelfinavir

Other Drugs Usually Also Involved in Methadone-Related Deaths

Cognitive Impairment During MMT vs Abstinence Studied

Unsafe Needle Use Among New MMT Patients Found

Complex Interactions Between Counseling & Drug Use During MMT

TIP Series Collateral Products from SAMHSA

Compiled & Edited by Stewart B. Leavitt, PhD

Methadone Doses Above 80 mg/d Unrelated to SML

An ongoing study by researchers in Bratislava, Slovak Republic, sought to further clarify the relationship of methadone dose and trough serum methadone level (SML) during continuous methadone maintenance treatment (MMT). The study sample included 64 patients who were divided into two subgroups on the basis of their daily methadone dose: Group 1 = 29 patients with doses up to 80 mg; Group 2 = 35 patients with doses above 80 mg.

The overall SML-to-dose correlation for both groups was: r = 0.570. A strong correlation was found between dose and SML in Group 1: r = 0.799; however, a non-significant correlation close to zero was found in Group 2 (see Graph). These findings strongly suggest that the linear relationship between methadone dose and its serum concentration in lower doses cannot be extrapolated to higher doses. That is, at doses greater than 80 mg/d there may be no consistent relationship of methadone dose and the respective SML it produces in the patient.

Reference: Okruhlica L, Valentova J, Devinsky F, Formakova S, Klempova D. Methadone serum concentration and its relationship to methadone dose revisited. Heroin Add & Rel Clin Probl. 2005;7(4):49-58.

[It has long been assumed that as methadone dose is increased the serum concentration of the drug increases accordingly to produce greater effects. This may be the case at lower doses; however, newer research has consistently shown that such a direct relationship does not exist at higher doses. Thus, for example, a patient receiving a dose well in excess of 100 mg/d methadone may have no more concentration of the drug in his system than a patient receiving 60 mg/d. This helps explain why in some patients, or during pregnancy, what seem like inordinately high methadone amounts may be required to achieve optimally adequate daily dosing. And, to attain these adequate doses, methadone titration needs to be guided by clinical signs/symptoms rather than SML measurements alone. – SB. Leavitt, PhD.]

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Methadone Tapering Difficult, Even in Supportive Setting

Studies have indicated that most opioid agonist-using patients are not able to successfully complete tapering attempts. Little is known, however, about tapering within a treatment environment that is supportive of indefinite agonist treatment and medication tapering.

In this study, all records of patients beginning a slow methadone taper were reviewed (n = 30). No patient successfully completed methadone tapering. Four patients (13.3%) successfully switched to buprenorphine/naloxone, one of whom tapered off buprenorphine/naloxone. Three patients (10%) were continuing their taper at the study’s end. One patient transferred to another program, one was administratively discharged, and one had his taper stopped for mishandling doses. The remaining patients (n = 20, 66.7%) stopped their tapers for the following reasons: feeling unstable/withdrawal symptoms (n = 4), drug use/positive urinalysis results (n = 12), psychiatric instability (n = 3), and pain management (n = 1). Only one patient prematurely left treatment secondary to a failed taper attempt.

The authors conclude that patients attempting methadone tapers should be informed about the difficulty involved and be monitored closely for signs of instability. For a few patients, a taper to a lower methadone dose and a switch to buprenorphine/naloxone are obtainable.

See: Calsyn DA, Malcy JA, Saxon AJ. Slow tapering from methadone maintenance in a program encouraging indefinite maintenance. J Subst Abuse Treat. 2006;30 (2):159-163.

[Although this study highlights challenges associated with medically supervised methadone withdrawal (tapering), based on the sample of only 30 subjects it would be inappropriate to assume that such tapering is unachievable. – SB. Leavitt, PhD.]

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MMT in Prison Beneficial, Cost Effective

Although methadone maintenance treatment (MMT) in community settings is known to reduce heroin use, HIV infection, and mortality among injecting drug users (IDU), little is known about prison-based methadone programs. This paper estimates the cost-effectiveness of the New South Wales (NSW), Australia, prison methadone program. The total program cost was estimated from the perspective of the treatment provider/funder, and the estimated cost per heroin-free day was compared with no methadone while in prison.

Researchers estimated the annual cost of providing prison methadone in NSW to be US$2.1 million (or US$2,357 per inmate per year). The incremental cost effectiveness ratio was US$28 per additional heroin-free day. They concluded that, from a treatment perspective, prison methadone is no more costly than community methadone, and it provides benefits in terms of reduced heroin use in prisons, along with associated reductions in morbidity and mortality.

Reference: Warren E, Viney R, Shearer J, Shanahan M, Wodak A, Dolan K. Value for money in drug treatment: economic evaluation of prison methadone. Drug Alcohol Depend. 2006[Feb 14; Epub ahead of print].

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Methadone vs Buprenorphine Maintenance Compared in Study

In a well-designed randomized clinical trial, Norwegian researchers compared buprenorphine and methadone maintenance therapies for opioid addiction. The following is excerpted from commentary on an English translation of the study report by Dr. Andrew Byrne MB, BS, Redfern, New South Wales, Australia.

There were 50 long-term (>10 years) opioid dependent subjects randomized to receive either 16 mg fixed-dose buprenorphine or variable-dose methadone (mean daily dose 106 mg, range 80-160 mg) during 6 months of observation. Patient retention rate was 85% in the methadone group and 36% for those prescribed buprenorphine. Illicit opioid-positive urine tests were slightly lower in the methadone group (20% vs. 24%). Importantly, the methadone subjects reported less high risk behavior.

The fixed dose buprenorphine dosing schedule here was probably based on a successful Swedish model, but after 2 months patients were automatically switched to double doses every-other-day. This may have caused some of the excess drop-outs. Also, fixed dose schedules are unlikely to be as effective as flexible ones.

Methadone and buprenorphine should both be prescribed in tailored doses according to clinical need, using appropriate increments (eg, 5 mg/d for methadone, 0.4 mg/d for buprenorphine). It is likely that some buprenorphine patients in this trial dropped out because they received too little or too much of the drug (32 mg is the maximum recommended dose).

There is no longer any doubt that both methadone and buprenorphine are effective for substantial numbers of heroin-addicted subjects treated with adequately supervised (and flexible) doses along with psychosocial supports. However, from a body of research, including numerous clinical trials, we know that, when compared to buprenorphine, methadone:

  1. generally suits a higher proportion of the total,
  2. reduces the use of other opiates to a greater degree, and
  3. while in treatment, such patients are less likely to be involved in high risk behaviors.

Methadone is also considered to be safe in pregnancy and is much cheaper and easier to administer. Thus methadone should probably still be our preferred first option and buprenorphine kept in reserve for particular indications. If there are concerns about patients misusing methadone, take-away doses should be limited until stability has been demonstrated. It may be that long-term methadone patients are less likely to fare well on buprenorphine, as shown in this study.

It is unfortunate that decisions for physicians and especially for patients are frequently dictated not by clinical considerations as much as by regulatory constraints. In some countries (and for no logical reason) these [constraints] are far more onerous and odious for methadone.

Dr. Byrne concludes: My feeling is that buprenorphine should be available as an option to all patients who report problems taking methadone. Such patients, however, should be carefully monitored since a high proportion relapse (in this study, 74% within 6 months) and may need to transfer back to methadone or to consider other alternatives such as detoxification. These authors are not the first to use the term ‘gold standard’ for methadone maintenance treatment.

Study Reference: Kristensen O, Espegren O, Asland R, Jakobsen E, Lie O, Seiler S. A randomised clinical trial of methadone vs. buprenorphine to opioid dependants. Tidsskr Nor Laegeforen. 2005;125(2):148-151.

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Naltrexone for Opioid Addiction Reviewed

A systematic review and statistical analysis was conducted to determine the efficacy of naltrexone in reducing illicit opioid use and the potential moderating role of treatment retention. The authors found 15 randomized trials comparing treatment using naltrexone with control groups, and involving 1,071 patients in total.

Significant inconsistencies were found in the efficacy of naltrexone. Level of retention in treatment was found to be a moderator, explaining most of the differences across studies. Overall, naltrexone was significantly better than control conditions in reducing the number of opioid-positive urine tests; however, this effect was only present in the high retention subgroups. Contingency management (CM) approaches increased retention and naltrexone use, resulting in a reduced number of opioid-positive urinalyses.

As other investigators have concluded, these authors noted that retention is important to the success of naltrexone in treating opioid dependence. Contingency management is a promising method for increasing retention.

Reference: Johansson BA, Berglund M, Lindgren A. Efficacy of maintenance treatment with naltrexone for opioid dependence: a meta-analytical review. Addiction. 2006;101(4):491-503.

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Smoking Cessation Unsuccessful in MMT Patients

This study examined the incremental efficacy of a maximal, tailored behavioral treatment over a minimal treatment approach for smoking cessation among MMT patients. Both treatment approaches were applied in combination with the nicotine patch.

The clinical trial with 6-month followup involved 383 patients at 5 MMT centers in Rhode Island. Participants were assigned randomly to nicotine patch (8-12 weeks) plus either (1) a baseline tailored brief motivational intervention, a quit date behavioral skills counseling session, and a relapse prevention follow-up session (Max), or (2) brief advice using the National Cancer Institute’s 4 ‘A’s model (Min).

Participants were on average 40 years of age, 53% male, 78% Caucasian, smoked 27 cigarettes/day on average, and had a mean methadone dose of 95.5 mg/day. At 6 months, the estimate of smoking cessation in the Max group was 5.2% compared with 4.7% in the Min group. Compared with female subjects, males were significantly more than 4 times as likely to be abstinent at 3 and 6 months.

The authors concluded that the tailored behavioral intervention plus nicotine patch did not increase quit rates over patch and minimal treatment. Overall, smoking cessation rates in methadone-maintained smokers are low, with men having greater success.

Source: Stein MD, Weinstock MC, Herman DS, et al. A smoking cessation intervention for the methadone-maintained. Addiction. 2006;101(4):599-607.

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Factors Affecting Sleep Disorders in MMT Patients Examined

To characterize sleep disorders in methadone maintenance treatment (MMT) patients, a team of researchers evaluated sleep quality of 101 patients from an MMT clinic in Israel between July, 2003 and July, 2004 by using the self-report questionnaire Pittsburgh Sleep Quality Index (PSQI). At the same time, patients’ urine tests were analyzed for methadone metabolite, opiates, benzodiazepine, cocaine, cannabis, and amphetamines.

Of the 101 study patients examined, 78% were male, 53% had psychiatric disorders, 47% reported having chronic pain, and 47% had urine positive for benzodiazepine. The mean daily methadone dose was 157 (approximate range: 50 - 260 mg/d). The mean PSQI score was 9; with three-quarters having scores >5, indicating “poor sleepers.” PSQI scores were higher in patients with urine positive for benzodiazepine, chronic pain, and psychiatric disorders, and they correlated significantly with years of opioid abuse before admission to MMT and with the methadone dose. As might be expected, the latter two – years of opioid addiction and methadone dose – also correlated with each other. The PSQI was not correlated with duration in MMT, gender, and age, or with abuse of opioid, cannabis, or cocaine.

The authors concluded that sleep disorders should be evaluated and treated among MMT patients. Of particular concern are those with psychiatric disorders, benzodiazepine abuse, chronic pain, and higher methadone dose.

Reference: Peles E, Schreiber S, Adelson M. Variables associated with perceived sleep disorders in methadone maintenance treatment (MMT) patients. Drug Alcohol Depend. 2006;82(2):103-110.

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New Evidence: MMT Benefits HIV/HCV-Infected Patients

Investigators in British Columbia, Canada, examined the association of methadone maintenance therapy (MMT) with highly active antiretroviral therapy (HAART) adherence and HIV treatment outcomes among a cohort of HIV/HCV co-infected injection drug users (IDUs). Subjects included 278 MMT patients who accessed HAART from 1996 to 2003.

Among participants who reported at least weekly heroin use, MMT was independently associated with lower odds of subsequent weekly heroin use during the follow-up period. MMT also was positively associated with adherence to medication therapy and CD4-cell count rise. The authors concluded that, among HIV/HCV co-infected IDUs on HAART, enrollment in MMT was associated with reduced heroin use, improved adherence, HIV-1 RNA suppression, and favorable CD4-cell count response. Integrating opioid addiction care and HIV care appears to provide improved health outcomes for this vulnerable population.

Reference: Palepu A, Tyndall MW, Joy R, et al. Antiretroviral adherence and HIV treatment outcomes among HIV/HCV co-infected injection drug users: The role of methadone maintenance therapy. Drug Alcohol Depend. 2006 [Mar 14; Epub ahead of print].

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MMT Effective in Opioid-Addicted Chronic Pain Patients

Opioid addiction among chronic pain patients was the initiative for starting a special methadone maintenance treatment (MMT) program for pain patients at the University Hospital of Uppsala, Sweden. This study examined pain relief and quality of life in pain patients with problematic opioid use and investigated background factors explaining problems with opioid use.

Records of all 60 patients included in the MMT program between 1994 and 2002 were studied. An interview was done after a mean of 34 months of methadone treatment regarding pain relief, quality of life, and side effects on 48 patients. Titration of oral methadone in daily doses ranging from 10 mg to 350 mg (mean 99.5 mg/d) was done on all patients. Background factors included low back and musculoskeletal pain in 40%, psychiatric disorders in 68%, and substance use disorder in 32% of the patients.

Before methadone maintenance all patients were on sick leave. After treatment 5 patients returned to work. Ten patients failed treatment: 4 due to intractable nausea, 4 to drug diversion, 1 because of methadone-related arrhythmia, and 1 because of insufficient analgesia. Pain relief was rated good by 75% and moderate by 25% of the patients. Global quality of life was rated at mean score of 50 (0-100 scale), which favorably compares with Swedish chronic pain patients mean score of 33. The investigators concluded that a structured methadone program can be used for treating chronic pain patients with opioid dependence, improving their pain relief and quality of life.

Source: Rhodin A, Gronbladh L, Nilsson LH, Gordh T. Methadone treatment of chronic non-malignant pain and opioid dependence – a long-term follow-up. Eur J Pain. 2006;10(3):271-278.

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Methadone Dose Adjustment Not Required With Nelfinavir

In this investigation, the methadone dose (20-140 mg/day) in 14 HIV-negative MMT patients was stabilized and fixed for at least 1 month before nelfinavir (1,250 mg twice daily for 8 days) was added to the regimen. Concentrations of methadone enantiomers were measured before and during nelfinavir treatment, and the concentrations of nelfinavir and its active metabolite were measured during nelfinavir treatment.

Results indicated that nelfinavir reduced R-methadone, and S-methadone concentrations by 43% and 51%, respectively. Nelfinavir and its metabolite concentrations remained within the normal range of historical data, and no subject experienced opioid withdrawal symptoms during the study or required methadone dose adjustment during or after the study. The authors concluded that, although nelfinavir reduced the plasma concentrations of both R- and S-methadone, it seems to have no impact on the maintenance dose of methadone. Therefore, a routine reduction of methadone dose is not recommended when coadministered with nelfinavir.

Reference: Hsyu PH, Lillibridge J, Daniels E, Kerr BM. Pharmacokinetic interaction of nelfinavir and methadone in intravenous drug users. Biopharm Drug Dispos. 2006;27(2):61-68.

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Other Drugs Also Involved in Methadone-Related Deaths

Patients coming into emergency departments who use methadone frequently also use tricyclic antidepressants (TCAs) and/or benzodiazepines (BZDs), which is a potentially dangerous drug combination. The authors of this study hypothesized that the presence of methadone and a TCA, a BZD, or both is associated with an “accidental” overdose (AOD) death more often than a death from any other cause.

A retrospective chart review was conducted of New York City Office of Chief Medical Examiner data for 2003. Decedents who tested positive for methadone and also were classified as an AOD death, as determined by the medical examiner, were compared with deaths from all other causes for the presence of a TCA, a BZD, or both.

The investigators found that, in 2003, there were 5,817 medical examiner cases, of which 500 (8.6%) were methadone positive. Of those methadone-positive cases, 493 were available for analysis: 95 (19%) also were TCA positive and 158 (32%) also were BZD positive. Stated another way in the study, those having a methadone-related AOD death were approximately 2 times more likely to also have a TCA involved, 1.7 times more likely to have BZDs present, and greater than 4 times more likely to have both TCA and BZD involved. Other drugs also commonly associated with a methadone-associated AOD death included: cocaine, morphine, or additional opioids.

The authors concluded that testing positive for a TCA, a BZD, or both was frequently associated with a methadone-positive AOD death.

Reference: Chan GM, Stajic M, Marker EK, Hoffman RS, Nelson LS. Testing Positive for Methadone and Either a Tricyclic Antidepressant or a Benzodiazepine Is Associated with an Accidental Overdose Death: Analysis of Medical Examiner Data. Acad Emerg Med. 2006[Mar 28; Epub ahead of print].

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Cognitive Impairment During MMT vs Abstinence Studied

An accumulating body of research suggests that former heroin abusers in methadone maintenance therapy (MMT) exhibit deficits in cognitive function. Whether these deficits persist in former methadone maintained patients following discontinuation of MMT is unknown. This study questioned whether former heroin users who have withdrawn from all opioids, including methadone received during MMT, and are drug-free have less pronounced cognitive impairment than patients continuing in long-term MMT.

A series of neuropsychological tests were administered to three groups of subjects: 29 former heroin addicts receiving MMT, 27 former heroin addicts withdrawn from all opioids, and 29 healthy controls without a history of drug dependence. Testing included the Wechsler Adult Intelligence Scale-Revised Vocabulary Test, the Stroop Color-Word Test, the Controlled Oral Word Association Test, the Benton Visual Retention Test, and a Substance Use Inventory.

Both methadone-maintained and drug-abstinent subject groups performed worse than controls on tasks that measured verbal function, visual-spatial analysis and memory, and resistance to distractibility. Abstinent subjects performed worse than their MMT counterparts on tests measuring visual memory and construct formation. Cognitive impairment did not correlate with any index of drug use.

The authors state that they confirmed previous findings of neuropsychological impairment in long-term MMT recipients. Both patients receiving MMT and former heroin users in prolonged abstinence exhibited a similar degree of cognitive impairment, and cognitive dysfunction in patients receiving methadone maintenance may not resolve following methadone discontinuation.

Source: Prosser J, Cohen LJ, Steinfeld M, et al. Neuropsychological functioning in opiate-dependent subjects receiving and following methadone maintenance treatment. Drug Alcohol Depend. 2006[Mar 16; Epub ahead of print].

[Note: This study should not be interpreted to imply that MMT is itself harmful in terms of cognitive performance and, in fact, those subjects continuing in MMT did better on certain tests. At the same time, it appears from this data that MMT may not cure neuropsychological damage that might have resulted from years of prior opioid abuse. – SB. Leavitt, PhD.]

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Unsafe Needle Use Among New MMT Patients Found

Investigators assessed injection practices, means of acquiring and disposing of syringes, and utilization and knowledge of harm reduction resources among injection drug users (IDUs) entering methadone maintenance treatment (MMT). Interviews were conducted with 100 consecutive patients entering an MMT program in the Bronx, NY, including 35 current IDUs who were the focus of this study.

Utilization of unsafe syringe sources was reported by 69% of the 35 IDUs in the sample. Most these subjects (80%) reused syringes, and syringe sharing also was common. Fewer than half knew that non-prescription pharmacy purchase of syringes was possible. The most common means of disposing of injecting equipment were the trash (63%) and syringe exchange programs (49%, see Graph). The researchers concluded that drug users entering treatment under-utilize sanctioned venues to obtain sterile syringes or safely dispose of used injection equipment. Programs providing services to drug users should adopt a proactive stance to address the safety and health issues faced by injectors.

See: McNeely J, Arnsten JH, Gourevitch MN. Sterile syringe access and disposal among injection drug users newly enrolled in methadone maintenance treatment: a cross-sectional survey. Harm Reduct J. 2006;3:8.

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Complex Interactions Between Counseling & Drug Use During MMT

This study investigated the relationship between the type and severity of drug and alcohol use problems, and the provision of drug- and alcohol-counselling in methadone maintenance treatment (MMT) programs in the UK. Researchers also assessed the relationship between content, frequency, and duration of counselling provided during the first month of treatment, and heroin, cocaine, and alcohol use outcomes at 6 months.

The sample comprised 276 MMT patients who were followed-up 6 months after treatment entry. Drug-focused counselling was associated with less frequent heroin and cocaine use at follow-up, but was not related to patients’ pre-treatment drug use. Alcohol-focused counselling was provided for those determined to have higher levels of drinking at admission, but was not significantly associated with drinking outcome at 6 months. Results indicate that there are complex interactions between presenting substance use problems, provision of counselling, and treatment outcomes. Such interactions differ by type of substance.

Source: Gossop M, Stewart D, Marsden J. Effectiveness of drug and alcohol counselling during methadone treatment: content, frequency, and duration of counselling and association with substance use outcomes. Addiction. 2006; 101(3):404-412.

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TIP Series Collateral Products from SAMHSA

The Substance Abuse and Mental Health Services Administration (SAMHSA) publishes Quick Guides that present the primary information from its Treatment Improvement Protocol (TIP) series in a pocket-sized booklet format. Along with this, KAP Keys include screening or assessment instruments, checklists, and summaries of treatment phases. The Keys allow busy clinicians or program administrators to locate information easily and to use this information to enhance treatment services.

Recently published products from SAMHSA include the following:

A full list of Quick Guides and KAP Keys is available at: http://www.kap.samhsa.gov/products/tools/index.htm.

To order FREE copies of these products, contact SAMHSA’s National Clearinghouse for Alcohol and Drug Information (NCADI). Phone: 800-729-6686 or 301-468-2600;  Web: http://www.ncadi.samhsa.gov.

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Notice:

All facts and opinions are those of the sources cited. News reports may have been edited for length and/or modified for clarity without altering essential data as originally published.

Addiction Treatment Forum and its associates do not endorse any medications, products, or treatments described, mentioned, or discussed in any of the sources referenced. Nor are any representations made concerning efficacy, appropriateness, or suitability of any such products or treatments. This News Update is made possible by an educational grant from Mallinckrodt Inc., distributors of methadone and naltrexone.

In view of the possibility of human error or advances in medical knowledge, Addiction Treatment Forum and its associates do not warrant the information contained in the above news updates is in every respect accurate or complete, and they are not responsible nor liable for any errors or omissions that may be found in such information or for results obtained from use of such information.