Many Patients with Alcohol Use Disorders Not Offered Medications

An exhaustive and brand new meta-analysis and systematic review, published today in the Journal of the American Medical Association, paints a disappointing picture of medication access for those with alcohol use disorders (AUD) in the US. The authors included 123 studies, involving nearly 23,000 participants, and determined that while acamprosate and naltrexone have been shown to be effective treatments, fewer than 10% of those who might benefit are ever prescribed an AUD medication.

Here's the Abstract, via JAMA:

IMPORTANCE Alcohol use disorders cause substantial morbidity and early mortality yet

remain greatly undertreated. Medications are considerably underused.

OBJECTIVE To conduct a systematic review and meta-analysis of the benefits and harms of

medications (US FDA-approved and others) for adults with alcohol use disorders.

DATA SOURCES PubMed, Cochrane Library, PsycINFO, CINAHL, EMBASE, FDA website, and

clinical trials registries (January 1, 1970, to March 1, 2014).

STUDY SELECTION Two reviewers selected randomized clinical trials (RCTs) with at least 12

weeks’ duration that reported eligible outcomes and head-to-head prospective cohort

studies reporting health outcomes or harms.

DATA EXTRACTION AND SYNTHESIS We conducted meta-analyses using random-effects

models and calculated numbers needed to treat for benefit (NNTs) or harm (NNHs).

MAIN OUTCOMES AND MEASURES Alcohol consumption, motor vehicle crashes, injuries,

quality of life, function, mortality, and harms.

RESULTS We included 122 RCTs and 1 cohort study (total 22 803 participants). Most assessed

acamprosate (27 studies, n = 7519), naltrexone (53 studies, n = 9140), or both. The NNT to

prevent return to any drinking for acamprosate was 12 (95% CI, 8 to 26; risk difference [RD],

−0.09; 95% CI, −0.14 to −0.04) and was 20 (95% CI, 11 to 500; RD, −0.05; 95% CI, −0.10 to

−0.002) for oral naltrexone (50 mg/d). The NNT to prevent return to heavy drinking was 12

(95% CI, 8 to 26; RD −0.09; 95% CI, −0.13 to −0.04) for oral naltrexone (50 mg/d).

Meta-analyses of trials comparing acamprosate to naltrexone found no statistically significant

difference between them for return to any drinking (RD, 0.02; 95% CI, −0.03 to 0.08) or

heavy drinking (RD, 0.01; 95% CI, −0.05 to 0.06). For injectable naltrexone, meta-analyses

found no association with return to any drinking (RD, −0.04; 95% CI, −0.10 to 0.03) or heavy

drinking (RD, −0.01; 95% CI, −0.14 to 0.13) but found an association with reduction in heavy

drinking days (weighted mean difference [WMD], −4.6%; 95% CI, −8.5% to −0.56%). Among

medications used off-label, moderate evidence supports an association with improvement in

some consumption outcomes for nalmefene (heavy drinking days per month: WMD, −2.0;

95% CI, −3.0 to −1.0; drinks per drinking day: WMD, −1.02; 95% CI, −1.77 to −0.28) and

topiramate (% heavy drinking days: WMD, −9.0%; 95% CI, −15.3% to −2.7%; drinks per

drinking day: WMD, −1.0; 95% CI, −1.6 to −0.48). For naltrexone and nalmefene, NNHs for

withdrawal from trials due to adverse events were 48 (95% CI, 30 to 112) and 12 (95% CI, 7 to

50), respectively; risk was not significantly increased for acamprosate or topiramate.

CONCLUSIONS AND RELEVANCE Both acamprosate and oral naltrexone were associated with

reduction in return to drinking. When directly compared with one another, no significant

differences were found between acamprosate and naltrexone for controlling alcohol

consumption. Factors such as dosing frequency, potential adverse events, and availability of

treatments may guide medication choice.

Would love to know what readers think about the results of this large study. What are the main drivers of this gap, and why aren't more patients requesting these medications? What needs to be done to improve access?

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

Can THC Protect the Brain against Methamphetamine's Toxicity?

A fascinating new study in the journal Neuropharmacology, suggests the brain's endocannabinoid system can be aided in its neuroprotective efforts against the toxicity of methamphetamine by introducing external cannabinoids to increase the system's "endogenous tone". The cannabinoids in question, THC, URB and JZL, appear to inhibit the breakdown of the brain's own endocannabinoids, improving the ability of the brain to protect itself against the "external insult" of overdoses of methamphetamine.

Here is the abstract, via ScienceDirect:

Abstract

Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ⁹-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB₁ and CB₂cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB₂, but not of CB₁, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of methamphetamine considerably reduces the neurotoxicity of the drug through CB₂ receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain.

And here is a table showing levels of two of the major endocannabinoids, AEA and 2-AG,  following doses of methamphetamine:

And finally striatal levels of the cytokine tumor necrosis factor alpha:

Source:
http://www.sciencedirect.com/science/article/pii/S0028390814001099

Baclofen Shows Promise for Treating Relapse in Cocaine Use Disorders

Via ScienceDaily:

Relapse is the most painful and expensive feature of drug addiction -- even after addicted individuals have been drug-free for months or years, the likelihood of sliding back into the habit remains high. The National Institute on Drug Abuse estimates that 40 to 60 percent of addicted individuals will relapse, and in some studies the rates are as high as 80 percent at six months after treatment. Though some relapse triggers can be consciously avoided, such as people, places and things related to drug use, other subconscious triggers related to the brain's reward system may be impossible to avoid -- they can gain entry to the unconscious brain, setting the stage for relapse.

Researchers at Penn Medicine's Center for Studies of Addiction have now found that the drug baclofen, commonly used to prevent spasms in patients with spinal cord injuries and neurological disorders, can help block the impact of the brain's response to "unconscious" drug triggers well before conscious craving occurs. They suggest that this mechanism has the potential to prevent cocaine relapse. The new findings are reported in the Journal of Neuroscience.

"The study was inspired by patients who had experienced moments of 'volcanic craving', being suddenly overcome by the extreme desire for cocaine, but without a trigger that they could put their finger on," says senior author Anna Rose Childress, PhD,research professor of Psychiatry, director of the Brain-Behavioral Vulnerabilities Division in the Perelman School of Medicine at the University of Pennsylvania. Dr. Childress and colleagues previously found that subliminal drug "reminder cues" (the sights, sounds, smells, and memories of the drug) could activate the brain's reward circuit. "Now, we wanted to understand whether a medication could inhibit these early brain responses," said Childress.

Kimberly Young, PhD, an NIH/NIDA Post-doctoral Fellow at Penn, and first author of the study explained that, "Drug reward and motivation is largely mediated by dopamine transmission in the brain's reward circuit -- even drug "reminder cues" can cause dopamine release. Since baclofen and similar medications reduce these effects in laboratory animals, we wanted to examine whether it could prevent drug-cue induced activation in the human brain."

The study tested baclofen, which was approved by the U.S. Food and Drug Administration in 1977 for spasm, on 23 cocaine-dependent men, ages 18 to 55. Each reported using cocaine on at least eight of 30 days before screening. Inclusion in the study required that they stay for up to 10 days in a supervised inpatient drug treatment facility, be drug-free for the duration, not be on any medication affecting dopamine or neurotransmitter response, and have no history of psychosis, seizures, or brain syndromes unrelated to cocaine use.

Upon admission, patients were randomized to receive baclofen or placebo. Over the first six days, patients in the baclofen group received the medication in increasing dosage to 60 mg. While on the full 60 mg dose of baclofen, patients were placed in an fMRI and shown a series of images, to measure their neural responses to "ultra-brief" pictures of cocaine or other comparison pictures. Each of the ultra-brief 33 msec "target" pictures was immediately followed by longer picture of non-drug objects or scenes. Under these conditions, the participants are aware of the longer pictures, but the ultra-brief target pictures remain completely outside conscious awareness -- they are "backward-masked."

"We wanted to present the key stimulus: images of drug use and preparation, sexual images, and other aversive images in a way such that the brain could not consciously process them, but so that we could measure their earliest, subconscious effect on the brain," said Childress.

What the team found was that the patients who were treated with baclofen showed a significantly lower response in the reward and motivational circuits to subliminal cocaine cues versus neutral cues, as compared to the placebo-treated control group. In addition, no difference was seen in the active versus the control group in their response to sexual and aversive cues, indicating that the effects of baclofen on cue-induced brain activation were specific to drug cues.

"These findings suggest that the brain response to drug cues presented outside of awareness can be pharmacologically inhibited, providing a mechanism for baclofen's potential therapeutic benefit in addiction," says Young. "Further studies will show whether the prevention of these early brain responses is associated with reduced rates of craving and relapse in cocaine-dependent patients," added Childress. 

Source: http://www.sciencedaily.com/releases/2014/04/140401172914.htm

This could be exciting news for one of the most difficult substance use disorders to treat. Does anyone have experience using baclofen with patients with cocaine use disorders?

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?

What Aren't More Docs Prescribing Buprenorphine?

On the heels of recent coverage over the "dangers" of the medication buprenorphine, researchers are seeking to better understand what keeps doctors from using one of the two the most effective tools for opioid use disorders at their disposal. The most recent study, "Barriers to Primary Care Physicians Prescribing Buprenorphine", was published in the Annals of Family Medicine and is available in-full online - for free. The study came out of the Rural Opioid Addiction Management in Washington state, during which 120 physicians were trained in opioid addiction and buprenorphine prescribing. Disappointingly, of the 78 respondents who were analyzed for the study, 50 went on to obtain a DATA waiver, yet a mere 22 doctors ever went on to prescribe the medication to anyone. It begs the question: why aren't more docs prescribing buprenorphine?

Here's the breakdown from the piece of perceived barriers to prescribing:

Among the barriers cited by the doctors in the study, "Lack of psychosocial support" was cited as the number one barrier by both prescribers and non-prescribers, despite the lack of evidence that behavioral adjuncts or additional counseling improve outcomes. (Granted, the authors point out that in order to get reimbursed by a number of payers, additional counseling must be offered to patients.)

A quick scan across the literature leads us to another important and common driver of physician attitudes toward this medication: institutional support. It appears that study after study cite the impact of the hospital/clinic/practice culture on the subsequent interest. training and prescription of buprenorphine by its docs. In the present study, "resistance from practice partners" and "lack of institutional support" were commonly cited as barriers. A recent article from the March issue of the Journal of Substance Abuse Treatment described how important "A strong leader championing the new treatment" was to the implementation of buprenorphine prescribing across a large system. 

What do you think? How can we be more effective at impacting change at the prescriber level? If culture plays an important role, how do we improve the culture around this proven tool?

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.