Monday, September 13, 2010

Acamprosate Review Concludes It's Effective

The most recent meta-analysis regard acamprosate concluded that it was safe and effective for treating alcohol dependence, with a number needed to treat (NNT) of 9 (9 patients have to be treated to prevent one relapse.) This NNT is quite acceptable. I remain skeptical, however. I'm going to look the paper over in more detail and weigh in with my own take.


Medscape Medical News

Acamprosate May Be Helpful to Treat Alcohol Dependence

Laurie Barclay, MD

September 13, 2010 — Acamprosate appears to be effective and safe for supporting continuous abstinence after detoxification in alcohol-dependent patients, according to the results of a systematic review reported September 8 in the Cochrane Database of Systematic Reviews.

"Alcohol dependence is among the main leading health risk factors in most developed and developing countries," write Susanne Rösner, from the University of Munich in Munich, Germany, and colleagues. "Therapeutic success of psychosocial programs for relapse prevention is moderate, but could potentially be increased by an adjuvant treatment with the glutamate antagonist acamprosate."

To compare the efficacy and tolerability of acamprosate vs placebo or active control, the reviewers searched the Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, PubMed, EMBASE, and CINAHL in January 2009. They also asked manufacturers and investigators for data from unpublished studies.

Inclusion criteria were double-blind, randomized controlled trials (RCTs) comparing drinking-related outcomes obtained with acamprosate vs those obtained with placebo or with other pharmacotherapy. Two authors independently extracted data; one author evaluated trial quality, and a second author verified this assessment. Primary efficacy outcomes were confirmed with use of meta-analyses of individual patient data.

There were 24 RCTs meeting selection criteria, enrolling a total of 6915 alcohol-dependent participants. Risk of any drinking was significantly lower with acamprosate vs placebo (relative risk [RR], 0.86; 95% confidence interval [CI], 0.81 - 0.91). The number needed to treat [NNT] to benefit was 9.09 (95% CI, 6.66 - 14.28), and cumulative abstinence duration MD was significantly higher (10.94; 95% CI, 5.08 - 16.81). However, gamma-glutamyltransferase (GGT) levels, heavy drinking, and other secondary outcomes did not reach statistical significance.

"Acamprosate is certainly no magic bullet, but it is a safe and effective treatment for patients who are trying to stop drinking," Dr. Rösner said in a news release. "The benefits we have seen in these trials are small. However, we must remember that these are additional benefits on top of those from other non-drug therapies."

The only adverse effect reported more frequently with acamprosate vs placebo was diarrhea (RD, 0.11; 95% CI, 0.09 - 0.13). The NNT to harm was 9.09 (95% CI, 7.69 - 11.11). Compared with nonprofit-funded trials, findings from industry-sponsored trials were not significantly different, and the linear regression test did not demonstrate any significant risk for publication bias (P = .861).

"Acamprosate appears to be an effective and safe treatment strategy for supporting continuous abstinence after detoxification in alcohol dependent patients," the study authors write. "Even though the sizes of treatment effects appear to be rather moderate in their magnitude, they should be valued against the background of the relapsing nature of alcoholism and the limited therapeutic options currently available for its treatment."

Limitations of this study include those inherent in the included trials, such as poor compliance with assigned study drug, as well as some heterogeneity between studies.

Three of the reviewed trials compared acamprosate vs naltrexone. These trials showed comparable effects of the 2 drugs on return to any drinking, return to heavy drinking, and cumulative abstinence duration.

"Patients' doubts and reservations against a strategy that uses one substance to treat dependency on another should be taken seriously, while interventions that have been shown to work should not kept back from patients," Dr. Rösner said.

The Federal Ministry of Education and Research supported this study.

Tuesday, September 7, 2010

The Only Effective Treatment for Opioid Dependence is Maintenance (again)

Here is a report on Medscape about a large study comparing short and long-term tapering strategies using Suboxone to treat prescription opioid dependence. As with virtually every other study comparing taper and discontinuation with maintenance, virtually all participants relapsed following discontinuation. It didn't matter whether they tapered over one month or nine. It didn't matter whether they received only medical management or enhanced addiction counseling. Drug free treatment for established (> 1 years) opioid dependence does not work! (Except in highly unusual situations such as airline pilots or physicians who are required to get a shot of extended release naltrexone once a month.)In spite of this and dozens of other high quality studies, treatment programs continue to promote "drug free" treatment for opioid dependence, thus condemning their unwitting customers to relapse. And why? Because they don't believe in it. How would you feel if your doctor knew of an antibiotic that would treat your chronic infection but who didn't tell you about it because she didn't believe in using drugs to treat infections? Or who knew of a surgery that would cure your disability but didn't offer it and discouraged you from having it because he didn't believe in surgery? How long are we going to let this happen before treatment programs are held accountable to offer scientifically sound treatment and advice?


Authors and Disclosures
Caroline Helwick
From Medscape Medical News
For Prescription Opioid Dependence, Relapses Associated With Shorter Treatment Course
Caroline Helwick
May 24, 2010 (New Orleans, Louisiana) — In persons dependent on prescription opioids, tapering with buprenorphine during a 9-month period, whether initially or after a period of substantial improvement, led to nearly universal relapse in the National Drug Abuse Treatment Clinical Trials Network Prescription Opioid Addiction Treatment Study, presented here at the American Psychiatric Association 2010 Annual Meeting.
"There has been virtually no research on the treatment of persons dependent on prescription opioids, in spite of the major increase in prescription opioid abuse and in the numbers of persons entering treatment for addiction to prescription opioids," said Roger D. Weiss, MD, professor of psychiatry at Harvard Medical School, Boston, and chief of the Division of Alcohol and Drug Abuse, McLean Hospital, Belmont, Massachusetts.
The study, which is the largest treatment study ever conducted for prescription opioid dependence (POD), sought to answer several questions regarding the optimal length of pharmacotherapy, the value of intense counseling, and the role of chronic pain.
Specifically, the study asked whether adding individual drug counseling to buprenorphine-naloxone (a semisynthetic opioid and a partial agonist) plus standard medical management improves outcomes, what duration of buprenorphine is best for these patients, and whether presence or absence of current chronic pain influences outcomes.
"The trial was designed to help the physician manage patients who are dependent on opioids and want off the drugs but refuse treatment in a drug abuse treatment program," Dr. Weiss said.
The study enrolled 653 persons with POD and offered them standard medical management, which included buprenorphine (usually 12 - 16 mg maximum, adjusted for addiction, not pain), an initial 1-hour visit, and weekly 20-minute sessions with a physician who counseled the patients and monitored for drug adverse effects. Half the group remained in this standard medical management (SMM) group and half received enhanced medical management (EMM), which included twice-weekly 60-minute individualized drug counseling focusing on interpersonal issues, coping with triggers and high-risk situations, homework, and so forth.
Under a somewhat complicated schema, patients were evaluated after periods of individualized buprenorphine tapering and maintenance and were assessed for abstinence from opioids at various times.
Study Population
All patients had a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, diagnosis of opioid dependence and had used opioids for at least 20 of the last 30 days. Other substance abuse disorders were allowed, with the exception of active heroin use or history of injecting heroin. All patients expressed an interest in stopping opioids.
The population was made up of 60% men, was 91% white, had a mean age of 33 years, was likely to be cigarette smokers (71%), and had been using opioids for an average of 4.5 years. Most patients had received some college education and were employed full-time. There were no significant differences at baseline between the SMM and EMM groups.
A number of patients reported current chronic pain (42%), and some were taking opioids for this condition. Although current polypharmacy was uncommon, many patients reported a lifetime history of heroin use (23%), alcohol abuse (60%) or dependence (27%), cannabis abuse (47%) or dependence (15%), and cocaine abuse (32%) or dependence (18%). Stimulant and sedative use were less common.
Opioids used within 30 days included sustained-release oxycodone (35%), hydrocodone (32%), immediate-release oxycodone (19%), methadone (6%), and others (8%).
Thirty percent of subjects had received some previous treatment for opioid dependency, primarily "self help" (59%), inpatient/residential treatment (42%), outpatient counseling (40%), and methadone maintenance (31%).
"For most subjects, this was the first treatment for opioid dependence," said Dr. Weiss.
Treatment and Maintenance
Treatment success was defined as 4 or fewer days of opioid use per month, no positive urine screens for opioids for 2 consecutive weeks, no other formal substance abuse treatment, and no injection of opioids.
Phase 1 included 1 month of tapering and 2 months of stabilization. At the end of this time, few patients were successfully treated, and enhanced management did not influence the results, Dr. Weiss reported.
In the SMM group, only 7% met the criteria for success, as did just 6% of the EMM group (P = .45). "Nearly all patients relapsed after a 4-week taper," Dr. Weiss said.
Patients who relapsed were asked to enter phase 2, at which time 360 patients were again randomly assigned to SMM or EMM and received 3 months of buprenorphine stabilization, then had treatment tapered for 1 month, with a 2-month follow-up.
At the end of the stabilization (at week 12), substantial improvement was noted for 52% of the EMM group and 47% of the SMM group, though again there was no additional benefit to enhanced management (P = .3). Substantial improvement was defined as abstinence for 3 or more of the final 4 weeks of buprenorphine stabilization (urine-confirmed self-report).
However, by the end of the stabilization period, many patients had relapsed again, Dr. Weiss reported.
"We went from an average success rate of 49% to 26% at week 16,"he said. At week 24 (8 weeks posttaper), only 9% of patients remained successfully treated.
"At the end of the study, we were back into phase 1 territory," he said. "Seven of 8 patients doing well on buprenorphine maintenance had relapsed."
Predictors of Outcome
The only predictor outcome was ever-use of heroin. At week 12, improvement was noted for 37% of those reporting lifetime heroin use compared with 54% of those without such a history (P = .003); at week 24, this was 5% and 10%, respectively (P = .13). "Having dabbled in heroin was a bad prognostic sign," Dr. Weiss observed.
The presence of chronic pain did not influence outcomes. Patients with chronic pain were equally likely to enter phase 2 (indicating early treatment failure) and were equally likely to be substantially improved at week 12 of phase 2 (53% vs 47% for those without chronic pain).
Chronic pain tended to be lumbar/sacral (65%) and classified as only moderate (median 4.4 on 10-point scale) but was of long duration, as more than half the patients had suffered from it for at least 4 years, he said.
"Interestingly, we found that in many cases the patient's pain got better," he added. More than half the subjects reported at least a moderate reduction of pain from baseline (≥30%), and one third had a substantial improvement (≥50%).
Nevertheless, Dr. Weiss said one cannot assume that buprenorphine itself improved the pain, as there was no control group, "but it is an intriguing possibility," he commented.
Sean Mackey, MD, PhD, associate professor of anesthesia and chief of the Division of Pain Management at Stanford University, Palo Alto, California, who delivered an overview of the treatment of pain in patients with addiction at the session, commented on the current study for Medscape Psychiatry.
He was particularly interested in the finding that persons with a history of heroin use had worse outcomes. "Could it be that prior exposure to heroin fundamentally alters the neurobiology in this group such that they need higher doses of buprenorphine to prevent relapse?" he asked.
Dr. Mackey maintained that the study is important because it asked a clinically relevant question: "Does putting people on a short period of buprenorphine maintenance combined with counseling lead to reductions in relapse? It's a great idea, and a wonderful hypothesis, because if it does work then this would be a huge win. We would not have to use extended maintenance. Unfortunately, it did not work, but the study needed to be done."
He further noted that the standard management group was likely getting better care in this study than is delivered in usual practice, which may have diluted potential differences.
Dr. Weiss has reported receiving research support from Eli Lilly. Dr. Mackey has disclosed no relevant financial relationships.
American Psychiatric Association 2010 Annual Meeting: Symposium 36, presentation 4. Presented May 23, 2010.
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