Wednesday, April 30, 2014

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
95% CI      p Value
(a) All participants ( n= 360)
Main effects
1.3–3.3      .004

Chronic pain
0.8–2.0      .240

Drug severity
0.2–58.2    .484

Interaction with Phase 2 treatment
0.6–4.2      .342

Chronic pain
0.2–1.4      .218

Drug severity
0.0–76.8    .585
(b) Participants with adequate adherence to treatment ( n= 266)
Main effect of Phase 2 treatment
0.4–1.1     .107

Interaction with Phase 2 treatment
1.1–11.8     .03

Chronic pain
0.2–1.5      .213

Drug severity
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

Thursday, April 17, 2014

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:


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:


Friday, April 4, 2014

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. 

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?