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.

A Sad State of Affairs: Psychostimulant Addiction Treatment Leaves Much to be Desired

The authors of a new paper, published ahead of a special issue of Neuropharmacology, give the reader a good look at the current state of psychostimulant substance use disorder treatment - and the results are disappointing. Starting with behavioral treatments and ending with a review of medications, the clear fact remains that there is no single treatment that outperforms most others.

Meta-analyses of behavioral interventions for the treatment of cocaine use disorder have shown modest benefits; while one review found, "there is currently no evidence for a differential treatment effect of any psychosocial treatment in the management of" cocaine or amphetamine use disorders. CBT and Contingency Management (CM) remain the mainstay of psychostimulant treatment, and the authors cite data suggesting a combination of CM plus Community Reinforcement Approach might produce the best outcomes.

In terms of pharmacological treatments, researched medications include antagonist therapy, agonist therapy, medications to treat withdrawal symptoms and medications to treat co-occurring psychiatric symptoms or disorders; and the authors of the present paper devote the bulk of their attention to weighing the evidence of such options.

Naltrexone, they note, has shown some promise in laboratory studies, as it has been shown to weaken amphetamine- and cocaine-related effects in some subjects in both human and animal trials. Because it also seems to weaken the subjective euphoric effects of methylphenidate (Ritalin), one area of promise could be in the combination of naltrexone and methylphenidate to limit the abuse potential of an agonist-like treatment.

Disulfiram (aka Antabuse) has also shown some promise in the lab, but mainly in the treatment of cocaine-use disorders. It was shown to increase the brain ratio of dopamine to norepinephrine and to prevent stress-induced cocaine reinstatement. In pilot studies, disulfiram was shown to be effective in reducing cocaine use in patients with cocaine use disorders (CUD), and among buprenorphine-maintained polydrug users. However, in a more recent study, disulfiram showed less promise reducing cocaine use among methadone-maintained patients. The authors of the review point to evidence that disulfiram may only be effective among CUD patients with specific genotypes - and may be more effective among men than women.

Agonist-like treatments are also reviewed by the authors, and appear to offer some of the more exciting, and possibly effective, interventions for psychostimulant addiction. D-amphetamine has been shown to improve treatment retention and reduce illicit cocaine use in early trials; while a later study showed a reduction in withdrawal and craving, but a failure to reduce methamphetamine use. Not mentioned in the review, but a small study we wrote about in 2012 appeared to show promising results in the combination of mixed amphetamine salts (Adderall) and topiramate (Topamax)

For its part, sustained-release methamphetamine has been tested as a maintenance agent for CUD, and appeared to significantly reduce cocaine-positive urine samples and cocaine craving. The familiar medication, methylphenidate, has been shown to be non-superior to placebo in some studies for meth/amphetamine use and cocaine use, but appears to warrant further research at improved dosages. The other agonist-like medication discussed, modafanil, seems to be an interesting candidate for maintenance treatment. Known to be a cognitive enhancer, modafanil may be useful in addressing the impairments in a range of cognitive functions that can result from psychostimulant addiction; but studies have thus far produced more "equivocal" results in most trials as treatments for cocaine or for methamphetamine - even when combined with D-amphetamine. Post-hoc analysis of the available data does, however, suggest efficacy in the less severe cases of addiction.

Additionally, researchers in Latin America have argued in favor oral coca for the treatment of cocaine use disorder. Their "Handbook on Oral Cocaine as Agonist Therapy for Cocaine Dependence" is an intriguing read, and the authors of the review posit that political, cultural and commercial barriers - not scientific ones - are likely to blame for the "lack of follow-up on this line of research".

A host of other medications have been tried and tested for psychostimulant use disorders, with little success. Vaccines, on the other hand, are now gaining momentum in the field and are being used in multiple studies at various phases. A vaccine that that produces antibodies to prevent cocaine from crossing the blood-brain barrier has performed well in Phase I and Phase II trials. A methamphetamine vaccine is still in preclinical development, but initial results have shown good levels of antibodies in animal models and a Phase I  trial is scheduled to begin in 2015.

Considering the vast global toll which is the result of psychostimulant addiction, treatment for these disorders is as desperately needed as ever. If there is one thing that this review makes clear, it's the fact that we still have a long way to go before we can say that we have effective treatment options for the consumer. A question for readers of this blog: what are the techniques and interventions that you have found to be helpful stimulant use disorders? Is there a particular line of research that you feel would be important to investigate further? Do you see the utility of agonist-like medications? Your thoughts are always appreciated.

Who Benefits from Additional Drug Counseling among Prescription Opioid Dependent Patients on Suboxone?

In a secondary analysis of the Prescription Opioid Addiction Treatment Study (POATS), the original study's author, Roger Weiss, and colleagues parse the data to determine if there are common characteristics among those who benefited from additional opioid dependence counseling (ODC) - above and beyond the standard medical management (SMM) and buprenorphine-naloxone medication. It is a very good question, considering the host of recent studies which found no additional benefit to counseling in terms of measured outcomes, including the large and highly-regarded POATS.

In searching for an answer, the authors looked at two sources of variability - patient characteristics, and adherence to treatment. Specifically, the authors sought to answer three questions: 1) Did participants with more severe problems have better outcomes with SMM + ODC than with SMM alone (N=360)? 2) Among participants with adequate adherence to treatment, were those assigned to SMM + ODC more likely to have successful outcomes than those receiving SMM alone, regardless of severity (n = 266)? And 3), among participants with adequate adherence to treatment, were those with more severe problems more likely to succeed with additional counseling than with standard medical management only (n = 266)?

In response to question 1, the analysis found that "the association between severity and outcome did not vary by treatment condition for any of the three severity measures." Those without past use of heroin had more favorable outcomes across the entire study. Regarding question 2, "adequate adherence" was defined as attending at least 60% of scheduled scheduled sessions in both treatment conditions, and most participants (73.9%) attended at least 60% of sessions. Subjects in the SMM-only condition were more likely meet this criterion but, once again, outcomes did not differ by treatment condition. Finally, in answering question 3, the authors found that, "Among participants who had ever used heroin, those assigned to SMM + ODC were more likely to succeed than those in SMM only (66.7% vs. 35.0%, n = 70, χ2(1) = 6.88, p=.016)."

 Table 1

Likelihood of successful opioid use outcomes at Phase 2, weeks 9–12. ^a

	OR	95% CI      p Value
(a) All participants ( n= 360)
Main effects
Heroin	2.0	1.3–3.3      .004
Chronic pain	1.3	0.8–2.0      .240
Drug severity	2.9	0.2–58.2    .484
Interaction with Phase 2 treatment
Heroin	1.6	0.6–4.2      .342
Chronic pain	0.6	0.2–1.4      .218
Drug severity	0.2	0.0–76.8    .585	.
(b) Participants with adequate adherence to treatment ( n= 266)
Main effect of Phase 2 treatment	0.7	0.4–1.1     .107
Interaction with Phase 2 treatment
Heroin	3.7	1.1–11.8     .03
Chronic pain	0.5	0.2–1.5      .213
Drug severity	1.5	0.001–4023.5   .915

^a All models were adjusted for Phase 1 treatment condition.

Treatment outcomes did not appear to differ among those who had never used heroin, suggesting that prescription opioid-addicted patients with a history of heroin use may be the participants who are most likely to benefit from additional counseling in suboxone treatment. Importantly, those patients had to also attend enough sessions (and receive an adequate "dose" of counseling) in order to see their outcomes improve to rates similar to those without a history of heroin use.

So, do these results line up with the experience of the readers of this blog? Are there populations with whom you believe counseling is especially important? Or, do the results simply reinforce the lessons of past studies? Let us know

Study: Are Drug Screens Sufficient for Adolescent Treatment?

Could it be that we are missing something when it comes to treating adolescents with a substance use disorder? According to a study in the most recent edition of the Journal of Studies on Alcohol Drugs, if you aren't using drug screens when treating this population, the answer is likely "Yes".
In the article, Schuler, et al. looked at data from SAMHSA's CSAT 2007 adolescent treatment database, which tracks outcomes for CSAT-sponsored providers. The total sample consisted of 5,186 adolescents who received either Motivational Enhancement Therapy/Cognitive Behavioral Therapy5 (MET/CBT5) - with or without biological drug screen (BDS) - or were part of the BDS-only or No-Treatment groups within another study. Below is a breakdown of the subjects:

All participants responded to the GAIN structured clinical interview, so scores on the Substance Use Frequency Scale and Substance Problem Scale were the primary outcomes measured. Propensity score methods were used to adjust for baseline differences among youth in the four groups, given the non-randomized nature of the data. The results are striking:

The BDS-only condition seemed to outperform all groups at baseline, 3-, 6- and 12-months on Substance Problem Scale scores and at 6- and 12-months on Substance Frequency Scale scores.
What could account for the significant differences? The authors point out that many adolescents who are involved in treatment and/or the criminal justice system may earn rewards for negative drug screens - or face significant consequences for positive screens. Therefore, the self-report nature of the data could skew the results. That would not necessarily explain the consistent differences across groups, however.

What do you think about these results? If you work with adolescents, does this surprise you? Could evidence like this impact the interventions you use?

Is Addiction Always Permanent?

Recently, a colleague challenged what he perceived to be my "insistence that addiction is permanent." Here is my reply:

Dear John (not his real name):

As you know, I'm well aware of the studies regarding the life course of people who at some point in their lives meet dxic criteria for a SUD. And also, as you are aware, I've been talking about that, and therefore the need to have a wider continuum of care and to individualize approaches to SUDs for at least 10 years. In my presentation, Alcoholism Isn't What It Used to Be, which you frequently reference, I point out that 20 years after onset of DSM IV Alcohol Dependence, the most common outcome is low-risk drinking (40%), followed by abstinence (roughly 1/3), partial remission (about 20%) and then finally currently dependent (8%). So I'm not sure what the basis is for concluding that I have made blanket statements about ALL addicts in ALL circumstances.

 

What I do believe, and here I think the science and epidemiology are equally persuasive, is that in the case of severe addiction, there are brain neuroadaptations that are irreversible. For example, the likelihood of achieving non-abstinent recovery is inversely related to the severity of alcohol dependence. Conversely, abstinent outcomes become more likely as severity increases. This is as true in rodents as in humans. Since rehab and AA are populated almost exclusively by people at the very severe end of the spectrum, the likelihood of sustained non-abstinent recovery for current treatment seekers or AA members is relatively low. Thus, the AA stance is accurate for most AA members. Severity of dependence is the strongest predictor of AA affiliation, especially long-term affiliation, as opposed to a few weeks or months after a spell in rehab. Established heroin or other opioid addiction is another example; thus buprenorphine and methadone maintenance and the virtually complete failure of abstinence (or moderation) for treatment seekers. Those who could stop on the their own do so and therefore do not present for tx. That, of course, is a function of the awfulness, expense, stigmatization and disruption most current treatment includes.

 

At Alltyr Clinic, for example, I have seen many pts who come with a mild AUD who achieve non-abstinent recovery.

 

Just as abstinence is not a requirement for everyone who develops a SUD, neither is moderation possible for a sizeable proportion of them. The size varies by drug: Probably close to 100% of dependent smokers will require lifelong abstinence, whereas, most cannabis users will not, etc. Heroin, meth and cocaine addiction also probably have high to relatively high proportions where abstinence (which includes people taking opioid agonist therapy) is the only positive outcome option. In alcohol, I think it's probably somewhere in the middle, a large minority achieve non-abstinent recovery.

 

So the newer data simply seem to affirm the NESARC data, that conclusions have been based on clinical samples, and that if you look at community samples, the picture is very different. That's true for almost all common complex diseases, such as asthma or arthritis or even hypertension, the difference being that with SUDs there is a very high full remission rate, something that happens in very few other common complex diseases. Depression is very likely to be a pretty good analogue as well.

 

Finally, noting that many people have milder, self-limiting forms of SUDs doesn't mean they aren't brain disesases. How can you have a behavioral illness that doesn't include failures in brain regulation of behavior? It's just that in too many instances, people misinterpret "brain disease" to mean "permanent". Also, it hasn't helped that NIDA and SAMHSA keep stressing the chronicity of addiction, something I constantly fought against when i was at NIH. It's often not chronic. Neither is asthma, but I suspect you wouldn't have trouble thinking of mild, self-limited childhood asthma as a lung disease, or immune disease.

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

Study: Burden of Disease Associated with Alcohol-use Disorders Higher Than Previously Thought

In a paper published online last week in the journal, Alcoholism: Clinical and Experimental Research, a group of international researchers have brought fresh eyes to a familiar data set: the NIAAA's NESARC. Whereas past studies have estimated the alcohol-attributable global burden of disease, or rates of alcohol-attributable deaths and years of life lost, no study has focused specifically on the burden of disease in the United States associated with alcohol-use disorders (AUD). This is important, the authors note, because alcohol-use disorders (including "abuse" and "dependence" from DSM or "the harmful use of alcohol" from ICD) "were identified as the largest disease category contributing to the alcohol-attributable global burden of disease for the year 2004, making up approximately one-third of this burden." By using US-specific data, including population and death statistics as well as Waves 1 and 2 of the NESARC, the authors were able to estimate the burden of disease from AUD in the US in 2005.


Results

"In the United States in 2005, 65,000 deaths, 1,152,000 years of life lost due to premature mortality (YLL), 2,443,000 years of life lost due to disability (YLD), and 3,595,000 disability-adjusted life years (DALYs) lost were associated with AUD. For individuals 18 years of age and older, AUD were associated with 3% of all deaths (5% for men and 1% for women), and 5% of all YLL (7% for men and 2% for women). The majority of the burden of disease associated with AUD stemmed from YLD, which accounted for 68% of DALYs associated with AUD (66% for men and 74% for women). The youngest age group had the largest proportion of DALYs associated with AUD stemming from YLD."

Some figures from the article:

Prevalence of alcohol use disorders by category, sex, and age in 2005. 

And:

Proportion of all deaths associated with alcohol use disorders in 2005, by sex and age


You can read the abstract of the paper by Rehm, et al. here:

http://onlinelibrary.wiley.com/doi/10.1111/acer.12331/abstract

Would love to hear readers reactions to these numbers. 

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