Researchers: Supervised Methadone and Buprenorphine Dosing Adds Little Therapeutic Benefit

Methadone, the full agonist synthetic opioid, is one of the most tightly regulated medications on the planet - at least, that is, when it's being used to treat opioid addiction.  Here in Minnesota, no fewer than 5 regulatory bodies oversee the clinics that provide methadone maintenance treatment (MMT).  One of the core federal requirements of "opiate treatment programs" is daily supervised dosing, requiring patients to come daily to the clinic to receive their dose, observed by trained nursing staff for at least the first 3 months.  After that, patients earn one additional day of "take-home" doses at a time until they've earned 1 week (after the 8th month of treatment), then 2 weeks (after the first year in treatment), and finally 4 weeks of take-home doses (after 2 years of sustained participation in the program).  The rationale for these highly restrictive federal rules, ostensibly, has been that it will protect patient safety, decrease diversion, and will improve outcomes among MMT patients.

A recent review of the literature throws these assumptions into question.  The review, analyzed and shared by the folks at Drug and Alcohol Findings, found "no evidence that supervising consumption meant patients were better safeguarded or that the treatment more effectively reduced illegal drug use."  Instead, these policies tend to be quite costly to programs and burdensome to patients.  They reinforce negative stereotypes about MMT patients and have prevented people from seeking potentially lifesaving treatment. 

Here at Alltyr Clinic, we routinely hear from patients that the ability to receive a monthly prescription of Suboxone has meant they could keep their job or maintain their role within the family.  With all the national attention being given to the recent spike in overdose statistics, maybe it's time the feds re-visit these burdensome regulations and increase access to the highly effective treatments. 

From the Findings UK article:

Supervised dosing with a long-acting opioid medication in the management of opioid dependence
http://findings.org.uk/PHP/dl.php?file=Saulle_R_1.txt&s=eb&sf=sfnos

Key points
From summary and commentary

Guidelines recommend making opioid-dependent patients take their methadone or other opioid substitutes at the clinic or pharmacy to safeguard the patient and prevent medication being ‘diverted’ to other people.

Randomised trials and studies study which monitored patients in routine treatment afforded no evidence that supervising consumption meant patients were better safeguarded or that the treatment more effectively reduced illegal drug use.

However, introduction of supervision to UK treatment services was associated with fewer methadone-related overdose deaths.

Findings and expert opinion support initial supervised consumption and its relaxation on an individual basis, depending on assessment of the patient.

Maintenance, not abstinence, will save addicts' lives

Read Dr W's Op-Ed in this week's Star Tribune:

http://www.startribune.com/opinion/commentaries/246619891.html

Researchers Take a Novel Approach to Vivitrol Induction

Researchers and clinicians at Duke University performed a small, open label study to test a new induction protocol for opioid detoxification in an outpatient setting. Much has been written about the pros and cons of antagonist medication for opioid dependence, with most evidence supporting agonist medications like buprenorphine or methadone. One of the most difficult aspects of maintenance antagonist treatment is the detoxification and induction phases of treatment, considering the intolerability of the experience to most patients - especially those in outpatient settings. So, the authors of a new study, published recently in Drug and Alcohol Dependence, sought to make this experience a little more tolerable. The administered increasing doses of naltrexone and decreasing doses of buprenorphine to treatment-seeking opioid addicts until their first dose of extended-release injectable naltrexone (Vivitrol). The results were encouraging:

Abstract

BACKGROUND

The approval of extended release injectable naltrexone (XR-NTX; Vivitrol®) has introduced a new option for treating opioid addiction, but studies are needed to identify its place within the spectrum of available therapies. The absence of physiological opioid dependence is a necessary and challenging first step for starting XR-NTX. Outpatient detoxification gives poor results and inpatient detoxification is either unavailable or too brief for the physiological effects of opioids to resolve. Here we present findings from an open label study that tested whether the transition from opioid addiction to XR-NTX can be safely and effectively performed in an outpatient setting using very low dose naltrexone and buprenorphine.

METHODS

Twenty treatment seeking opioid addicted individuals were given increasing doses of naltrexone starting at 0.25 mg with decreasing doses of buprenorphine starting at 4 mg during a 7-day outpatient XR-NTX induction procedure. Withdrawal discomfort, craving, drug use, and adverse events were assessed daily until the XR-NTX injection, then weekly over the next month.

RESULTS

Fourteen of the 20 participants received XR-NTX and 13 completed weekly assessments. Withdrawal, craving, and opioid or other drug use were significantly lower during induction and after XR-NTX administration compared with baseline, and no serious adverse events were recorded.

CONCLUSIONS

Outpatient transition to XR-NTX combining upward titration of very low dose naltrexone with downward titration of low dose buprenorphine was safe, well tolerated, and completed by most participants. Further studies with larger numbers of subjects are needed to see if this approach is useful for naltrexone induction.

Mean opioid withdrawal and craving scores during induction and after naltrexone extended release administration (Days 1-9), using SOWS (Subjective Opioid Withdrawal Scale), COWS (Clinical Opioid Withdrawal Scale) and VAS (Visual Analog Scale) for craving. Time point scores are the results of the mean score of each day of treatment, error bars represent + -1 SEM. Number of participants is reported on the X-axis.

In-treatment proportion of opioid positive urine samples (Day1-9, N = 20).

Source:

http://www.sciencedirect.com/science/article/pii/S0376871614000568

SAMHSA Releases State and National Behavioral Health Barometer

The federal Substance Abuse and Mental Health Services Administration recently released its yearly report on the general state of behavioral health needs and services in the US. Based on population and treatment-facility data sets from state to state, the Behavioral Health Barometer is a sweeping, in-depth look into adolescent and adult drug use, treatment and mental health service utilization.

Among the highlights:
- Nationally, youth and young adult use of nonmedical pain relievers is declining in general.
- Past-month cigarette use among teens nationally and locally is declining, although Minnesota saw a small increase in 2011-2012
-Over 50% of Minnesota adolescents, and over 60% of adolescents nationally, did not receive treatment for their past-year depressive episode.
-In Minnesota, only 6.6% of people with past-year alcohol dependence received treatment. For illicit drugs, the number is 14.6%
-In Minnesota, while the number of people receiving methadone treatment has increased by nearly 1000 people since 2008, the number of people receiving buprenorphine has actually decreased in that time (owing to a sharp drop from 2008-2009.

The national report is here:
http://www.samhsa.gov/data/StatesInBrief/2K14/National_BHBarometer.pdf

Read the MN report here:
http://store.samhsa.gov/shin/content/SMA13-4796/SMA13-4796MN.pdf

And find your state here:
http://store.samhsa.gov/product/Behavioral-Health-Barometer-2013/SMA13-4796

Vermont Governor Devotes Entire State of the State Address to Drug Addiction

From yesterday's NY Times:

In Annual Speech, Vermont Governor Shifts Focus to Drug Abuse

In a sign of how drastic the epidemic of drug addiction here has become, Gov. Peter Shumlin on Wednesday devoted his entire State of the State Message to what he said was “a full-blown heroin crisis” gripping Vermont.

“In every corner of our state, heroin and opiate drug addiction threatens us,” he said. He said he wanted to reframe the public debate to encourage officials to respond to addiction as a chronic disease, with treatment and support, rather than with only punishment and incarceration.

“The time has come for us to stop quietly averting our eyes from the growing heroin addiction in our front yards,” Governor Shumlin said, “while we fear and fight treatment facilities in our backyards.”

...

Read the rest of the story here: 

http://www.nytimes.com/2014/01/09/us/in-annual-speech-vermont-governor-shifts-focus-to-drug-abuse.html

Cochrane Releases New Reviews on MAT

The highly-respected Cochrane Library, known for its meticulous reviews of the current state of medical knowledge, has updated and released two reviews on medication-assisted treatment recently. The first, "Maintenance agonist treatments for opiate-dependent women", aims to " assess the effectiveness of any maintenance treatment alone or in combination with psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions for child health status, neonatal mortality, retaining pregnant women in treatment and reducing the use of substances." The second, "Pharmacological interventions for drug-using offenders" aims to " assess the effectiveness of pharmacological interventions for drug-using offenders in reducing criminal activity and/or drug use." In both cases, the authors note the effectiveness of opioid medications in assisting patients to achieve desired outcomes (although the effect on criminal activity in the second study was significant, but less pronounced). However, they cautioned against generalizing the findings as the body of evidence of both topics is still too small.

Here are the abstracts, via Wiley:

Maintenance agonist treatments for opiate-dependent pregnant women

Abstract

Background

The prevalence of opiate use among pregnant women can range from 1% to 2% to as high as 21%. Heroin crosses the placenta and pregnant, opiate-dependent women experience a six-fold increase in maternal obstetric complications such as low birth weight, toxaemia, third trimester bleeding, malpresentation, puerperal morbidity, fetal distress and meconium aspiration. Neonatal complications include narcotic withdrawal, postnatal growth deficiency, microcephaly, neuro-behavioural problems, increased neonatal mortality and a 74-fold increase in sudden infant death syndrome.

Objectives

To assess the effectiveness of any maintenance treatment alone or in combination with psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions for child health status, neonatal mortality, retaining pregnant women in treatment and reducing the use of substances.

Search methods

We searched the Cochrane Drugs and Alcohol Group Trials Register (September 2013), PubMed (1966 to September 2013), CINAHL (1982 to September 2013), reference lists of relevant papers, sources of ongoing trials, conference proceedings and national focal points for drug research. We contacted authors of included studies and experts in the field.

Selection criteria

Randomised controlled trials assessing the efficacy of any maintenance pharmacological treatment for opiate-dependent pregnant women.

Data collection and analysis

We used the standard methodological procedures expected by The Cochrane Collaboration.

Main results

We found four trials with 271 pregnant women. Three compared methadone with buprenorphine and one methadone with oral slow-release morphine. Three out of four studies had adequate allocation concealment and were double-blind. The major flaw in the included studies was attrition bias: three out of four had a high drop-out rate (30% to 40%) and this was unbalanced between groups.

Methadone versus buprenorphine: the drop-out rate from treatment was lower in the methadone group (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.41 to 1.01, three studies, 223 participants). There was no statistically significant difference in the use of primary substance between methadone and buprenorphine (RR 1.81, 95% CI 0.70 to 4.69, two studies, 151 participants). For both, we judged the quality of evidence as low. Birth weight was higher in the buprenorphine group in the two trials that could be pooled (mean difference (MD) -365.45 g (95% CI -673.84 to -57.07), two studies, 150 participants). The third study reported that there was no statistically significant difference. For APGAR score neither of the studies which compared methadone with buprenorphine found a significant difference. For both, we judged the quality of evidence as low. Many measures were used in the studies to assess neonatal abstinence syndrome. The number of newborns treated for neonatal abstinence syndrome, which is the most critical outcome, did not differ significantly between groups. We judged the quality of evidence as very low.

Methadone versus slow-release morphine: there was no drop-out in either treatment group. Oral slow-release morphine seemed superior to methadone for abstinence from heroin use during pregnancy (RR 2.40, 95% CI 1.00 to 5.77, one study, 48 participants). We judged the quality of evidence as moderate.

Only one study which compared methadone with buprenorphine reported side effects. For the mother there was no statistically significant difference; for the newborns in the buprenorphine group there were significantly fewer serious side effects.

In the comparison between methadone and slow-release morphine no side effects were reported for the mother, whereas one child in the methadone group had central apnoea and one child in the morphine group had obstructive apnoea.

Authors' conclusions

We did not find sufficient significant differences between methadone and buprenorphine or slow-release morphine to allow us to conclude that one treatment is superior to another for all relevant outcomes. While methadone seems superior in terms of retaining patients in treatment, buprenorphine seems to lead to less severe neonatal abstinence syndrome. Additionally, even though a multi-centre, international trial with 175 pregnant women has recently been completed and its results published and included in this review, the body of evidence is still too small to draw firm conclusions about the equivalence of the treatments compared. There is still a need for randomised controlled trials of adequate sample size comparing different maintenance treatments.

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006318.pub3/abstract

 

Pharmacological interventions for drug-using offenders

Abstract

Background

The review represents one in a family of four reviews focusing on a range of different interventions for drug-using offenders. This specific review considers pharmacological interventions aimed at reducing drug use and/or criminal activity for illicit drug-using offenders.

Objectives

To assess the effectiveness of pharmacological interventions for drug-using offenders in reducing criminal activity and/or drug use.

Search methods

Fourteen electronic bibliographic databases (searched between 2004 and 21 March 2013) and five additional Web resources (searched between 2004 and 11 November 2011) were searched. Experts in the field were contacted for further information.

Selection criteria

Randomised controlled trials assessing the efficacy of any pharmacological interventions for reducing, eliminating or preventing relapse in drug-using offenders were included. Data on the cost and cost-effectiveness of interventions were reported.

Data collection and analysis

We used standard methodological procedures as expected by The Cochrane Collaboration.

Main results

A total of 76 trials across the four reviews were identified. After a process of prescreening had been completed, 17 trials were judged to meet the inclusion criteria for this specific review (six of the 17 trials are awaiting classification for the review). The remaining 11 trials contained a total of 2,678 participants. Nine of the eleven studies used samples with a majority of men. The interventions (buprenorphine, methadone and naltrexone) were compared to non pharmacological treatments (e.g., counselling) and other pharmacological drugs. The methodological trial quality was poorly described, and most studies were rated as 'unclear' by the reviewers. The biggest threats to risk of bias were generated through blinding (performance and detection bias) and incomplete outcome data (attrition bias). When combined, the results suggest that pharmacological interventions do significantly reduce subsequent drug use using biological measures, (three studies, 300 participants, RR 0.71 (95% CI 0.52 to 0.97)), self report dichotomous data (three studies, 317 participants, RR 0.42, (95% CI 0.22 to 0.81)) and continuous measures (one study, MD -59.66 (95% CI -120.60 to 1.28)) . In the subgroups analysis for community setting, (two studies, 99 participants: RR 0.62 (95% CI 0.35 to 1.09)) and for secure establishment setting, (one study, 201 participants: RR 0.76 (95% CI 0.52 to 1.10)), the results are no longer statistically significant. Criminal activity was significantly reduced favouring the dichotomous measures of re arrest, (one study, 62 participants, RR 0.60 (95% CI 0.32 to 1.14)), re-incarceration, (three studies, 142 participants, RR 0.33 (95% CI 0.19 to 0.56)) and continuous measures (one study, 51 participants, MD -74.21 (95% CI -133.53 to -14.89)). Findings on the effects of individual pharmacological interventions on drug use and criminal activity show mixed results. Buprenorphine in comparison to a non pharmacological treatment seemed to favour buprenorphine but not significantly with self report drug use, (one study, 36 participants, RR 0.58 (95% CI 0.25 to 1.35)). Methadone and cognitive behavioural skills in comparison to standard psychiatric services, did show a significant reduction for self report dichotomous drug use (one study, 253 participants, RR 0.43 (95% CI 0.33 to 0.56)) but not for self report continuous data (one study 51 participants) MD -0.52 (95% CI -1.09 to 0.05)), or re incarceration RR 1.23 (95% CI 0.53 to 2.87)). Naltrexone was favoured significantly over routine parole and probation for re incarceration (two studies 114 participants, RR 0.36 (95% CI 0.19 to 0.69)) but no data was available on drug use. Finally, we compared each pharmacological treatment to another. In each case we compared methadone to: buprenorphine, diamorphine and naltrexone. No significant differences were displayed for either treatment for self report dichotomous drug use (one study, 193 participants RR 1.23 (95% CI 0.86 to 1.76)), continuous measures of drug use MD 0.70 (95% CI -5.33 to 6.73) or criminal activity RR 1.25 (95% CI 0.83 to 1.88)) between methadone and buprenorphine. Similiar results were found for comparisons with Diamorphine with no significant differences between the drugs for self report dichotomous drug use for arrest (one study, 825 participants RR 1.25 (95% CI 1.03-1.51)) or Naltrexone for dichotomous measures of re incarceration (one study, 44 participants, RR 1.10 (95% CI 0.37 to 3.26)), and continuous outcome measure of crime MD -0.50 (95% CI -8.04 to 7.04)) or self report drug use MD 4.60 (95% CI -3.54 to 12.74)).

Authors' conclusions

Pharmacological interventions for drug-using offenders do appear to reduce overall subsequent drug use and criminal activity (but to a lesser extent). No statistically significant differences were displayed by treatment setting. Individual differences are displayed between the three pharmacological interventions (buprenorphine, methadone and naltrexone) when compared to a non pharmacological intervention, but not when compared to each other. Caution should be taken when interpreting these findings, as the conclusions are based on a small number of trials, and generalisation of these study findings should be limited mainly to male adult offenders. Additionally, many studies were rated at high risk of bias because trial information was inadequately described.

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010862/abstract

MMT and 12-Step Groups: Stigma Persists

In his latest contribution to the academic literature, William L. White and colleagues turn their focus on 12-Step participation among patients in methadone maintenance treatment (MMT). Rates of self-reported Narcotics Anonymous (NA) and Alcoholics Anonymous (AA) attendance were very high; however, participants frequently reported that their MMT status prevented them from taking part in many of the "key ingredients" of the groups that most members take for granted. When asked about the experience, nearly half of all respondents who had attended NA or AA reported that they had "received negative comments about methadone use" and nearly "a quarter (24.4%) reported having had a serious problem within NA or AA related to their status as a methadone patient."

The following table from the report details the "frequency with which respondents faced particular challenges":

Table 4: NA and AA Responses to MMT Patient Status                                NA            AA

Response to MM Patient Status:                                                                         (n=228)     (n=142)

Received negative comments about methadone use                                                43.0%     45.1%

Were pressured to reduce the dose of methadone                                                  21.9%     23.2%

Were pressured to stop taking methadone                                                             32.9%     34.5%

Were denied the right to speak at a meeting because of being
in methadone treatment                                                                                         14.5%      14.1%

Were denied the right to become a sponsor because of being                                  8.8%        9.9%
in methadone treatment


White and colleagues implemented this small study at not-for-profit opioid treatment program (OTP) in the Northeastern US. A total of 322 respondents answered a 53-question survey about their participation in recovery support groups. Of the 322, 259 (80.4%) reported a primary affiliation with a recovery support group. Of these, 88.8% reported it to be in some way a 12-Step group. Importantly, 66% of respondents reported past-year NA/AA participation, with 88-89% reporting the group was "helpful".

Despite these figures, the authors found MMT patients had low rates of participation in the "key ingredients" that seem to be critical influencers of long-term recovery outcomes: having a home group (50%), having a sponsor (26%), sponsoring others (13%), attending 12-Step social events (23%), and active step work (21%).

Anecdotally, we see a lot of patients at Alltyr who have a hard time finding a place in the local 12-Step scene. We even began compiling a list of medication-friendly meetings in the Twin Cities as we learned about them, but the stigma associated with maintenance is still prevalent. Could it be that we are on the verge of another breakthrough in medication acceptance? After all, there was a time when you weren't considered "sober" if you were on antidepressant or antipsychotic medications (but now, as Dr W likes to say, you're more likely to be referred to the psychiatrist by your sponsor than by anyone else). We would be interested to hear reader stories about this experience - or opinions on the topic. Are things changing - or not?

See the full paper by White, et al., here: http://www.williamwhitepapers.com/pr/2013%20Co-participation%20in%2012-Step%20Groups%20and%20Methadone%20Maintenance.pdf

New Findings in Medication-Assisted Treatment

Some interesting new studies are showing promising results for patients all over the world:

Turns out, Quality of Life improvements aren't just for the wealthy:
Quality of Life (QoL) scores significantly improved in ALL four domains (psychological, physical, social and environmental) of the WHO QoL scale in patients in low and middle income countries, according to the authors of a systematic review of 13 studies involving over 1800 participants. The findings, published online last week in the Journal of Drug and Alcohol Dependence, show that despite the apparent lack of resources in these countries, opiate replacement therapy with methadone or buprenorphine can be an effective treatment tool - with scores increasing along with the length of time at followup - and offering outcomes comparable to those seen in high income countries.
You can read the abstract of the study by Feelemeyer, et al., here: http://www.sciencedirect.com/science/article/pii/S0376871613004225

The methadone of methamphetamine?:
In encouraging news for stimulant users, a small study has shown methylphenidate (Ritalin) to both improve symptoms and reduce use episodes, in a cohort of criminal justice-involved stimulant users with co-occurring ADHD. Similar findings have been published supporting mixed-amphetamine salts (Adderall) plus topiramate (Topamax) for the treatment of cocaine dependence, and more recently topiramate by itself. The authors of the small study note the high prevalence of ADHD among stimulant users in the criminal justice population and in their research used dosages that were high enough to be therapeutically effective for patients with a history of substance use disorders (a flaw, they argue, in previous studies of this kind). Could it be that we are getting closer to an accepted agonist maintenance treatment for stimulant use disorders? Read the results of the Swedish study by Konstenius, et al., published online this month in the journal Addiction:
http://onlinelibrary.wiley.com/doi/10.1111/add.12369/abstract

Groups could improve access to AUD medications:
And finally, in a new study in the Journal of Substance Abuse Treatment, researchers have shown that group pharmacotherapy is an effective intervention for patients on medication-assisted treatment of alcohol use disorders. The authors provide a brief description of this novel approach and their experiences implementing the program. They note that, for many clinicians, providing ongoing monitoring of these effective medications can create a barrier to implementation. What the team found however, was that a "medication group" was not only feasible, but it actually increased their patients' access to meds like disulfiram (Antabuse), naltrexone and acamprosate (Campral). Read the abstract from the report by Dr Shannon Robinson and a team at San Diego's VA Health Care System here: http://www.sciencedirect.com/science/article/pii/S0740547213001347