AT Forum NEWS NOTES & UPDATES #111

May-June 2007

 Compiled & Edited by Stewart B. Leavitt, PhD

Prior Edition: March/April 2007

List of all News/Updates

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Contents

MMT Curbs Protracted-Abstinence Syndrome

Correlation of Dose and Serum Methadone Level Confirmed

Breastfeeding by Methadone-Maintained Mothers Recommended

Favorable Outcomes in Preterm Infants of Mothers on MMT

HIV Treatment Does Not Spur Illicit Methadone Use

Continued Substance Abuse Hinders MMT Success

Special Training During MMT Improves Family Relations

Effectiveness of Buprenorphine Maintenance vs MMT Compared

Controlling Opioid Withdrawal Due To Buprenorphine-Naloxone

Smoking Patterns in MMT Patients Examined

Depression Has Little Effect on Smoking Cessation in MMT Patients

Does the Smoking-Cessation Drug CHANTIX™ Interact With Methadone?

Relatively Few Patients Consider MMT Clinic as Primary Care Provider

Investigating Illness Outbreak Among MMT Patients

 

MMT Curbs Protracted-Abstinence Syndrome

Stopping heroin use may be followed by a protracted-abstinence (PA) syndrome consisting of craving, negative mood, and physiological changes. PA symptoms have rarely been compared between drug-free and methadone-maintained former heroin users after similar lengths of heroin abstinence. In this study from China, 70 former heroin users were included in 1 of 4 groups:

1. 15-45 days of methadone maintenance treatment (short-term MMT),
2. 5-6 months of MMT (long-term MMT),
3. opiate-free for 15-45 days after methadone-assisted heroin detoxification (short-term post-methadone),
4. opiate-free for 5-6 months after methadone-assisted heroin detoxification (long-term post-methadone).

PA symptoms (negative mood, sleep disturbance, body aches, and craving), and blood pressure and pulse were assessed before and after viewing of a neutral-content videotape compared with viewing of a heroin-content videotape.

Sleep disturbance and the total PA scores were worst in short-term post-methadone participants, mood was best in long-term MMT participants, and cue-induced craving was least severe in long-term MMT participants. Blood pressure and pulse did not differ across groups.

The authors concluded that, even after acute withdrawal the first months of abstinence after methadone-assisted detoxification from heroin may be more difficult in terms of cue-induced craving and other PA symptoms than the first months of heroin abstinence during MMT. Their findings add to the literature supporting long-term MMT as superior for preventing cue-induced heroin craving, rather than methadone-assisted heroin detoxification.

Source: Shi J, Zhao LY, Epstein DH, Zhang XL, Lu L. Long-term methadone maintenance reduces protracted symptoms of heroin abstinence and cue-induced craving in Chinese heroin abusers. Pharmacol Biochem Behav. 2007;87(1):141-145.

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Correlation of Dose and Serum Methadone Level Confirmed

Investigators in Tel-Aviv, Israel, evaluated the relationship between higher methadone doses and methadone serum levels in MMT patients. Using very precise GCMS assays, serum methadone levels (SMLs) were determined in 151 patients receiving stabilized methadone-doses. Urine samples during the month prior to the study-day were analyzed and defined as positive if any sample was positive for any non-prescribed drug.

Methadone dose was significantly correlated with SMLs; however, in 53 patients with no drug abuse this correlation was much stronger (r = 0.53, p < 0.0005) than in 98 patients with any drug abuse (r = 0.25, p = 0.01). The authors assert that this investigation extended the well-established correlation between methadone doses and SMLs in patients receiving low or moderate (60 to 120 mg/day) to high methadone doses (up to 290 mg/day).

Reference: Adelson M, Peles E, Bodner G, Kreek MJ. Correlation between high methadone doses and methadone serum levels in methadone maintenance treatment (MMT) patients. J Addict Dis. 2007;26(1):15-26.

[Comment: It is of interest in this study that continued substance abuse weakened the positive relationship between methadone dose and SML. However, it is not known from this data if a point is reached where, due to counteracting effects extensive drug abuse, there is no or little dose-to-SML relationship; that is, in some patients abusing drugs during MMT there may be no certainty that a specific methadone dose increase will produce a directly corresponding rise in SML for more effective treatment. – Ed (Stewart B. Leavitt, MA, PhD)]

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Breastfeeding by Methadone-Maintained Mothers Recommended

A study from the Center for Addiction and Pregnancy, Johns Hopkins Bayview Medical Center, Baltimore, MD, evaluated concentrations of methadone in breast milk and plasma among a sample of methadone-maintained women in the immediate perinatal period. Twelve methadone-maintained, lactating women provided blood and breast milk specimens 1, 2, 3, and 4 days after delivery. Specimens were collected at the time of trough (just before methadone dose) and peak (3 hours after dosing) maternal methadone levels. Paired specimens of pre-feeding and post-feeding milk were obtained at each sampling time.

There was a significant increase in methadone concentration in breast milk over time for the peak post-feeding samples. However, methadone concentrations in breast milk were considered to be quite small, ranging from only 21 to 314 ng/mL, and were unrelated to maternal daily methadone dose. The authors suggest that results obtained from this study contribute to the recommendation of breastfeeding for methadone-maintained women regardless of methadone dose.

Source: Jansson LM, Choo RE, Harrow C, Velez M, Schroeder JR, Lowe R, Huestis MA. Concentrations of methadone in breast milk and plasma in the immediate perinatal period. J Hum Lact. 2007;23(2):184-190.

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Favorable Outcomes in Preterm Infants of Mothers on MMT

Investigators determined the effect of preterm delivery on the course of neonatal abstinence syndrome (NAS) in infants born to mothers participating in a methadone maintenance treatment (MMT) program. A retrospective study was conducted in which infant and maternal data were collected from the medical records of 53 preterm and 66 term infants. These were selected from all infants born between 1998 and 2002 whose mothers were enrolled in the MMT program at the Thomas Jefferson University hospital, Philadelphia, PA. All infants were managed by a standard protocol using the Neonatal Abstinence Scoring System (NASS) and neonatal opiate solution (NOS).

Preterm infants had shorter lengths of hospital stay, briefer treatment courses, and required less NOS medication than did term infants during the same time period. According to the authors, their data indicate that following exposure to maternal methadone preterm infants have a different [although seemingly favorable] neonatal course than do infants born at term.

Source: Dysart K, Hsieh HC, Kaltenbach K, Greenspan JS. Sequela of preterm versus term infants born to mothers on a methadone maintenance program: differential course of neonatal abstinence syndrome. J Perinat Med. 2007, May 21 [Epub ahead of print].

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HIV Treatment Does Not Spur Illicit Methadone Use

Diversion of methadone outside of treatment programs occurs, yet reasons for use of “street methadone” are characterized poorly. Self-medication for withdrawal symptoms is one plausible explanation. Among HIV-infected drug users, some antiretroviral medications can reduce potency of methadone, yet any association between such effects and the use of supplemental methadone sources remains undetermined.

To estimate the frequency and risk factors for use of street methadone, injection drug users (IDUs) recruited through extensive community outreach in 1988-89 and 1994 were followed semi-annually with questionnaires about health history, use of licit and illicit drugs including methadone, and HIV-related assays.

Of 2,811 IDUs enrolled and eligible for analysis, 493 persons (17.5%) reported the illicit use of street methadone. Its use was more common among women, whites, those 40-59 years old, those who reported withdrawal symptoms, past methadone program attendance (6-12 months before visit), recent heroin injection with or without cocaine (but not cocaine alone), smoking or sniffing heroin, and reported sex trading. However, street methadone use was not associated with HIV infection or its treatment.

The results suggest that older IDUs still using heroin may be using street methadone to treat signs of withdrawal. The absence of a higher rate of street methadone use in HIV seropositive IDUs reveals that interactions between antiviral medications and methadone are not a primary determinant of using methadone illicitly outside of treatment settings.

Reference: Vlahov D, O'Driscoll P, Mehta SH, et al. Risk factors for methadone outside treatment programs: implications for HIV treatment among injection drug users. Addiction. 2007;102(5):771-777.

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Continued Substance Abuse Hinders MMT Success

This study measured rates of ongoing heroin abuse among patients on methadone maintenance treatment (MMT) and sought to identify patient and treatment characteristics associated with poorer outcome. The study was carried out at an outpatient drug treatment clinic in the UK and included all patients who were on MMT during a 3 month period in 2004. Treatment response was measured from analysis of opioid-positive urine samples. Of the 440 patients assessed, 63% were male and their mean age was 32 years (range 17 to 52 years), and 163 patients (37%) had a comorbid psychiatric illness. The average methadone dose was 74 mg/day.

On average, 71% of urine samples were opioid negative. Shorter time in treatment (less than 24 months), lower doses of methadone, cocaine abuse, and intermittent benzodiazepine abuse were each found to be significantly associated with lower rates of illicit-opioid abstinence. Outcomes were not associated with gender, age, or accessing counselling. Dual-diagnosed patients actually tended to have higher rates of abstinence. The authors conclude that MMT patients who abuse cocaine and benzodiazepines are at increased risk of continuing opioid abuse, and higher doses of methadone might be necessary to prevent illicit opioid abuse.

Reference: Kamal F, Flavin S, Campbell F, Behan C, Fagan J, Smyth R. Factors affecting the outcome of methadone maintenance treatment in opiate dependence. Ir Med J. 2007;100(3):393-397.

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Special Training During MMT Improves Family Relations

High rates of child abuse and neglect occur in many families in which either or both parents abuse illicit drugs. This study by researchers in Australia reports on the results of a randomized controlled trial with 64 families having a parent on methadone maintenance treatment (MMT) and in which an intensive, home-based intervention – the Parents Under Pressure (PUP) program – was compared to standard care. A second control group -- brief intervention – consisted of families receiving a two-session parenting education intervention.

The PUP intervention draws from an ecological model of child development by targeting multiple domains of family functioning, including the psychological functioning of individuals in the family, parent-child relationships, and social-context factors. Mindfulness skills were included to address regulation of parental moods, which is a significant problem for this group of parents.

At 3- and 6-month follow-up, PUP families showed significant reductions in problems across multiple domains of family functioning, including a reduction in child abuse potential, rigid parenting attitudes, and child behavior problems. Families in the brief intervention group showed only a modest reduction in child abuse potential but no other changes in family function. There were no improvements found in the standard care group and some significant worsening was observed.

Reference: Dawe S, Harnett P. Reducing potential for child abuse among methadone-maintained parents: Results from a randomized controlled trial. J Subst Abuse Treat. 2007;32(4):381-390.

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Effectiveness of Buprenorphine Maintenance vs MMT Compared

Both methadone and buprenorphine are effective therapies for heroin dependence. Efficacy is best documented for methadone maintenance treatment (MMT), but safety concerns sometimes limit its use. Buprenorphine is believed to offer lower overdose risk and improved access to treatment, but efficacy may be lower. Therefore, researchers at the Karolinska Institute in Stockholm, Sweden, compared adaptive, buprenorphine-based stepped care to optimal MMT.

A randomized controlled trial was undertaken during 2004-2006. It consisted of a 24-day induction phase followed by flexible dosing based on structured clinical criteria, for a total of 6 months. Ninety-six subjects with heroin dependence were randomly assigned to either methadone or to stepped treatment initiated with the buprenorphine-naloxone combination product and then escalated to methadone maintenance if needed. All subjects received intensive behavioral treatment. The primary outcome measure was retention in treatment, and secondary outcomes included analyses of problem severity (Addiction Severity Index) and proportion of urine samples free of illicit drugs.

Overall, 6-month retention was 78%. Stepped treatment involving buprenorphine-naloxone and methadone maintenance therapy outcomes were virtually identical. Among those who completed stepped therapy, 46% remained on buprenorphine-naloxone. The proportion of urine samples free of illicit opioids increased over time and ultimately reached approximately 80% in both the MMT and buprenorphine groups. Problem severity decreased significantly and uniformly in both groups.

The authors suggest that their stepped-treatment approach for heroin addiction using buprenorphine-naloxone appears equally effective compared with optimally delivered methadone maintenance therapy. Together with prior data on the safety advantages of buprenorphine, this suggests that broad implementation of strategies using buprenorphine as a first-line treatment could be considered.

Souce: Kakko J, Grönbladh L, Svanborg KD, et al. A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial. Am J Psychiatry. 2007;164(5):797-803.

[Comment: It is significant to note that more than half (54%) of patients starting on buprenorphine-naloxone therapy needed MMT. Therefore, although buprenorphine might be a first-choice for some patients, the ability to easily transition to MMT could be important for many of them. – Ed (Stewart B. Leavitt, MA, PhD)]

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Controlling Opioid Withdrawal Due To Buprenorphine-Naloxone

A single dose of buprenorphine can precipitate withdrawal in opioid-dependent persons, and the likelihood of this withdrawal increases as the level of physical dependence increases. Researchers tested the acute effects of sublingual buprenorphine-naloxone combination tablets in volunteers with a higher level of physical opioid dependence. Their goal was to identify a buprenorphine-naloxone dose that would precipitate withdrawal (Phase 1), and then to determine if withdrawal could be attenuated by splitting this dose (Phase 2).

They studied 16 subjects maintained on 100 mg/day of methadone. For Phase 1, subjects were randomized to receive either sublingual buprenorphine-naloxone (4 mg:1 mg, 8:2, 16:4, or 32:8), intramuscular naloxone (0.2 mg), oral methadone (100 mg), or placebo. In Phase 2, experimental treatments were methadone, placebo, naloxone, 100% of the buprenorphine-naloxone dose that precipitated withdrawal in Phase 1 (full dose) or half of this dose administered twice in a session (split dose).

Six subjects did not complete the study. Of the 10 who completed, 3 tolerated up to 32 mg:8 mg of buprenorphine-naloxone without evidence of precipitated withdrawal. For the 7 subjects completing both phases, split doses generally produced less precipitated withdrawal as compared with full doses.

The authors concluded that there are considerable difference between individuals in terms of their sensitivity to buprenorphine's antagonist effects. Low, repeated doses of buprenorphine-naloxone (eg, 2 mg:0.5 mg) may be an effective mechanism for safely dosing this medication in persons with higher levels of physical opioid dependence.

Reference: Rosado J, Walsh SL, Bigelow GE, Strain EC. Sublingual buprenorphine/naloxone precipitated withdrawal in subjects maintained on 100 mg of daily methadone. Drug Alcohol Depend. 2007, May 19 [Epub ahead of print].

[Comment: It could be inappropriate to draw significant conclusions from such a small study, with more than a third of the subjects dropping out. However, It is interesting that 30% of completing subjects experienced no withdrawal when administered the highest dose of buprenorphine-naloxone, but this easily could be an aberration with so few total subjects. Furthermore, in actual opioid-addicted patients, outside of laboratory settings, opioid craving resulting from the antagonist effects of buprenorphine-naloxone might be more detrimental than withdrawal in certain patients when transitioning from higher dose methadone to buprenorphine therapy, but the researchers did not investigate this. – Ed (Stewart B. Leavitt, MA, PhD)]

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Smoking Patterns in MMT Patients Examined

Among methadone maintenance treatment (MMT) patients, cigarette smoking prevalence is very high and cessation rates are low. This may in part be due to interactions between methadone administration and cigarette smoking. Researchers at the University of Kansas Medical Center, Kansas City, KS, explored relationships between methadone dose timing and smoking rates.

Twenty methadone patients, during a period of 19 days, used electronic cigarette packs to record their smoking patterns and called a voice mailbox daily to report their methadone dose and timing. The average proportion of daily cigarettes smoked was calculated for 2-hr time blocks preceding and following methadone dose administration.

It was discovered that, for all participants, peak smoking rates occurred soon after methadone administration. Participants smoked a significantly greater proportion of cigarettes in their first 2-hr block after methadone dosing than during their first 2-hr block of smoking of the day. In the 2-4 hr time block after methadone dosing smoking significantly decreased. Thus, there seems to be a relationship between smoking and methadone ingestion, and the researchers recommended that future investigations should examine whether a causal relationship exists, as well as the impact of other types of opioid-addiction treatment medications on smoking patterns.

Reference: Richter KP, Hamilton AK, Hall S, Catley D, Cox LS, Grobe J. Patterns of smoking and methadone dose in drug treatment patients. Exp Clin Psychopharmacol. 2007;15(2):144-153.

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Depression Has Little Effect on Smoking Cessation in MMT Patients

Reports on the effects of depression on successful smoking cessation efforts are inconsistent. Researchers at Brown University Medical School, Providence, RI, tested the hypothesis that higher levels of depression complicate efforts to quit smoking in a methadone maintenance Treatment (MMT) population offered nicotine replacement and a brief behavioral intervention. They recruited 383 participants during 2002 to 2004, and 340 (89%) were assessed at follow- up. Current depressive symptoms were measured using the Psychiatric Diagnostic Screening Questionnaire (PDSQ). Participants were 53% male and 78% Caucasian, with a mean MMT tenure of nearly 4 months.

Twenty-seven percent of the patients met PDSQ screening criteria for Major Depressive Disorder (MDD). Participants with higher levels of depressive symptoms were significantly less likely to set a quit date; however, depression was not associated significantly with motivation to quit smoking at baseline, time to first cigarette, or any behavioral indicator of smoking during the follow-up period. Therefore, the authors concluded that depressive symptoms have little influence on smoking cessation outcomes in this population.

Source: Stein MD, Weinstock MC, Anderson BJ, Anthony JL. Relationship of depression to smoking outcomes in a methadone-maintained population. J Addict Dis. 2007;26(1):35-40.

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Does the Smoking-Cessation Drug CHANTIX™ Interact With Methadone?

[COMMENTARY: An AT Forum reader submitted an e-mail asking if the new smoking-cessation medication CHANTIX would interact in any way with methadone. We noted that CHANTIX tablets contain the active ingredient, varenicline, which has not been shown to directly interact with any medications. And, it’s metabolism and excretion would not appear to interfere in any way with methadone.

However, this is a new agent and it was not specifically tested in methadone-maintained patients. Varenicline does affect certain centers in the brain (mesolimbic dopamine pathways) that might have an influence on perceived methadone effects – patients might need more or less methadone for stability – however, this is unknown at present. Also, in some patients, the mere act of stopping smoking has been known to affect their self-reported responses to methadone.

Clinic staff are asked to let us know of their patients’ experiences with CHANTIX, so we can pass those observations along to AT Forum readers. Contact us at Feedback@ATForum.com. – Ed (Stewart B. Leavitt, MA, PhD)]

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Relatively Few Patients Consider MMT Clinic as Primary Care Provider

Methadone maintenance treatment (MMT) programs often provide onsite primary care. However, It is unclear whether patients in these settings consider the MMT program as their usual source of care. Researchers at Mount Sinai Hospital, New York, NY, conducted interviews of 62 adults in an inner-city MMT clinic offering onsite primary care to determine their usual source of care.

Tenure in MMT ranged from 1 to 27 years (median, 4) and 63% of subjects attended the clinic 5 days per week or more often; also, 76% of them had 1 or more chronic diseases. Only 53% of patients reported having a usual source of care, and those sources included hospital-based clinics (45%), the MMT clinic (23%), private physicians (19%), or other providers (13%). [From this data it appears that only about 12% of patients interviewed considered the MMT clinic as their primary care provider. – Ed.]

Patients were more likely to identify the MMT clinic as their usual source of care if they had cardiovascular disease or HIV. The investigators concluded that successfully promoting appropriate use of onsite primary care at MMT clinics may require a better understanding of patients' perceptions of primary care.

Source: Federman AD, Arnsten JH. Primary care affiliations of adults in a methadone program with onsite care. J Addict Dis. 2007;26(1):27-34.

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Investigating Illness Outbreak Among MMT Patients

In late 2004, New South Wales Health (Australia) received several reports of a serious flaking rash among patients in methadone maintenance treatment (MMT) programs, and the authors of this report sought to identify the extent and likely cause of the outbreak. They initiated active surveillance for cases throughout Australia, a survey of dosing points in NSW, and a case control study of patients receiving methadone syrup (MS) at two clinics.

Between October 2004 and March 2005, 388 cases were identified, largely in NSW. The dosing point survey found almost all cases were in patients prescribed MS. In a further analysis of data from dosing points that dispensed the MS product, the use of take home doses or location of the dosing point in greater western Sydney were associated with illness. In the case control study, MS injection, use of street MS, high doses of MS, frequent takeaway doses, or use of benzodiazepines were associated with illness. Testing found no abnormality in associated batches of the MS itself; however, batches of MS temporally associated with the outbreak were quarantined from use and the outbreak subsided. While a direct causal link could not be established, available evidence suggests that a contaminant may have caused the outbreak.

Reference: McAnulty JM, Jauncey ME, Monger CK, Hailstone ST, Alam NK, Mannes TF, Capon AG, Irvine K, Armstrong PK, Kaldor JM. An epidemiological investigation into an outbreak of rash illness among methadone maintenance clients in Australia. Drug Alcohol Rev. 2007;26(3):321-331.

[Comment: As these investigators found, epidemiological analyses can be important for assessing concerns about newly developed signs/symptoms in patients that might be related to product safety. Similar, unexplained illness appearing in multiple patients on methadone maintenance may signal a need for further investigation of the methadone product as well as other possible contributing factors. Various causes, in addition to the methadone itself, need to be considered. – Ed (Stewart B. Leavitt, MA, PhD)]

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