OROS-Methylphenidate, Placebo Show Equal Efficacy for Adolescents With ADHD and Substance Abuse Disorders

Nancy A. Melville

December 09, 2009

December 9, 2009 (Los Angeles, California) — In failing to meet its primary objective of showing the superior efficacy of osmotic-release methylphenidate (OROS-MPH; Concerta, Ortho-McNeil-Janssen Pharmaceuticals, Inc) compared with placebo in the treatment of adolescents with attention-deficit hyperactivity disorder (ADHD) and substance abuse issues, a new study is nevertheless significant for a secondary, unexpected finding: improvements were equal with placebo and active treatment, investigators announced here at the American Academy of Addiction Psychiatry (AAAP) 20th Annual Meeting & Symposium.

Whereas most ADHD medication trials show a wide separation between the medication and placebo groups, the researchers said they were "stunned" to find that the placebo group, receiving only cognitive behavioral therapy (CBT), showed significant improvement — just as much, in fact, as the medication group, which also received CBT.

A big difference between this study and others is the CBT component, said lead author Paula Riggs, MD, professor of psychiatry at the University of Colorado School of Medicine, Aurora.

"With most psychostimulant studies, it's just the medication alone against the placebo," she said. "What this suggests, however, is that we can do more for these adolescents than simply throw a psychostimulant at them."

Although research on the efficacy of psychostimulants among patients with ADHD is considerable, few studies have looked at the safety and efficacy of the drugs among adolescents with ADHD and substance abuse disorders.

The study, said to be the first of its size to evaluate the issue of adolescents with ADHD and substance abuse disorders, was a 16-week randomized controlled trial involving 303 adolescents, aged 13 to 18 years, at 11 community-based treatment programs affiliated with the National Institute of Drug Abuse clinical trials network.

At baseline, 91% of the subjects had a cannabis use disorder, 56% abused alcohol, 12.9% abused hallucinogens, about 10% abused cocaine, and smaller numbers abused amphetamine and opioids.

Participants were randomly assigned to placebo (n = 152) or OROS-MPH (n=152), titrated to a dose of 72 mg/day. All subjects also received background treatment of individual CBT on a weekly outpatient basis that was targeted to substance abuse and not ADHD.

Although there were no serious adverse events, the adverse events were significantly higher in the OROS-MPH group, with an average of 2.4 events compared with 1.6 events in the placebo group. The adverse events included abdominal discomfort, nervousness, and transient increased heart rate. However, tolerability of the drug was high, with 96% of subjects achieving the 72-mg daily dose and 86% sustaining the level through the study.

Results of the trial were first reported last month in Honolulu, Hawaii, at the American Academy of Child & Adolescent Psychiatry 56th Annual Meeting. Here at the AAAP meeting, investigators were able to reflect on the findings.

The fact that as many as 79% of the participants in the OROS-MPH group and 76% in the placebo group completed the 16-week trial was the first surprise of the study, Dr. Riggs said.

"That really struck us as being weird because these are adolescents with severe psychopathology — including major depression in addition to substance abuse disorders," she told Medscape Psychiatry. As a comparison, she noted that a recent cannabis use intervention trial had only 52% completion. "That study was only 12 weeks, and the subjects had less severe psychopathology and [more] dependence issues," she pointed out.

Even more surprising were the outcomes for ADHD symptoms, with a reduction in symptoms that were both impressive and nearly identical in both groups, Dr. Riggs said, with 46% in the OROS-MPH group and 45% in the placebo group showing improvement.

"The fact that we had a clinically significant reduction in ADHD symptoms among both groups was a shocker," Dr. Riggs said.

Substance abuse, likewise, was clinically and statistically reduced in both groups, with a 43% reduction in the number of days of drug use among the OROS-MPH group and 33% reduction in the placebo group. The difference between the groups was not considered significant, however, because of the trajectory of change from baseline to week 16.

Notably, the study shares a commonality with 3 other controlled trials that showed a similar unusual lack of distinction between improvement in the medication and placebo groups — these studies also all had the unique component of including CBT as an outpatient drug treatment, Dr. Riggs said.

"Those trials also had interestingly significant reductions in ADHD symptoms with no difference between groups in the context of individual CBT offered as treatment," she said.

The findings underscore the need for additional research that focuses on the effects of CBT vs medication, Dr. Riggs added.

"This study wasn't designed to evaluate the separate and combined effects of OROS-MPH and CBT, but there simply is no literature comparing CBT with medication, and we need to address that and look into the specific symptoms that might respond to CBT."

In the meantime, the study also holds merit as being the first to show OROS-MPH to be safe and well-tolerated among ADHD patients with substance abuse disorders.

"The take-home message from this study is that, in the context of individual CBT, you may get clinically significant improvement in ADHD symptoms without medication," Dr. Riggs said.

Frances R. Levin, MD, president-elect of the AAAP and professor of clinical psychiatry at the College of Physicians and Surgeons of Columbia University, New York City, noted that the role of CBT in treating ADHD has traditionally been overlooked, and the new data may help move things in a new direction.

"The problem has been this dogma that medications were the way to go, and they affected the core symptoms of the disorder, and if you even suggested CBT for ADHD, you would get trounced."

As a result, studies often are not designed to evaluate the role of CBT as a primary outcome measure.

"What we struggle with in clinical trials is picking a study design according to whether you think you will get a positive or negative outcome," she said. "But in the substance abuse field, the outcome measure is sort of a constantly moving target, so a negative outcome may not mean there aren't important findings there."

However, she added that there are still plenty of questions about the role of CBT ADHD and substance abuse.

"It's clear that you need other approaches on top of medication to effectively treat ADHD and substance abuse, and perhaps this data indicates that CBT alone can be effective," she said. "But I think it's still preliminary, and I have questions about the methodology, response rates, and design, and I'm not absolutely convinced that we have an answer about CBT yet."

The study was funded by the National Institute on Drug Abuse. Dr. Riggs and Dr. Levin have disclosed no relevant financial relationships.

American Academy of Addiction Psychiatry 20th Annual Meeting & Symposium: Symposium 3. Presented December 5, 2009.

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