Journal Club

Dear Friends and Colleagues;
Attached a series of articles published in Family Medicine Journals and Magazines regarding substance Abuse and Dependence:
1) Baclofen Cuts Alcohol Use in Cirrhosis Patients
2) Warning Reissued for Fentanyl Deaths, Side Effects
3) FDA Warns About Methadone-Related Deaths, Serious Events
4) Research Sought on Physicians' Addiction Recovery

I look forward to your comments.

Bernd

====================================================================================
Family Practice News
Volume 38, Issue 2, Page 23 (15 January 2008)

Baclofen Cuts Alcohol Use in Cirrhosis Patients

JOHN R. BELL (Associate Editor)
Alcohol-dependent persons with cirrhosis of the liver who were treated with baclofen, a ?-aminobutyric acid-B receptor agonist, were more than six times as likely to cease their alcohol use as were patients who took a placebo, according to a study.

The trial is the first “in which effectiveness and safety of an anticraving drug has been investigated in individuals with advanced liver disease,” wrote Dr. Giovanni Addolorato of the Catholic University of Rome, and colleagues. They reported results for 84 alcohol-dependent patients with a diagnosis of cirrhosis who were randomly assigned in equal number to a 12-week regimen of either baclofen or placebo.

The baclofen dosage was 5 mg three times daily for the first 3 days and 10 mg three times daily thereafter. Mean patient age was 49 years in both groups. Patients were seen weekly for the first month, then every 2 weeks until the end of the study (Lancet 2007;370:1915-22).

At 12 weeks, 30 (71%) of the 42 patients in the baclofen group were abstinent from alcohol, compared with 12 (29%) of the 42 patients in the placebo group (odds ratio 6.3).

In addition, those given baclofen showed improvements in measures of liver function, including ALT, bilirubin, international normalized ratio, ?-glutamyltransferase, and albumin. The drug was also associated with a greater number of nondrinking days than was placebo (63 days vs. 31 days), as well as a lower rate of relapse to heavy drinking at 60 days (19% vs. 45%).

Treatment with baclofen also reduced alcohol cravings, as measured with the obsessive-compulsive drinking scale.

Baclofen was not associated with any hepatotoxicity. There were no incidents of encephalopathy or hyperammonemia and no serious events leading to discontinuation of the drug. Tolerability was reported as fair, with headache, tiredness, vertigo, and sleepiness reported in small numbers of patients in both groups.

These results “suggest that baclofen, because of its anticraving action and safety, could have an important role for treatment of alcohol-dependent patients with advanced liver disease,” the researchers wrote. They cautioned that further studies are needed to establish optimal treatment duration and longer-term tolerance.

In a commentary accompanying the report, Dr. James C. Garbutt of the University of North Carolina at Chapel Hill, and Barbara Flannery, Ph.D., of RTI International, Baltimore, called the findings “surprisingly robust” and of potentially great clinical importance, given the routine exclusion of alcoholic patients with cirrhosis from trials of anticraving drugs because of the concern about hepatotoxicity (Lancet 2007;370:1884-5).

They also noted that the higher dropout rate in the placebo group (31%) versus the baclofen group (14%) is of interest, because it may have skewed the results in favor of baclofen, given that these were assumed to be because of relapse, and thus affected the primary end point.

The study authors declared no financial conflict of interest. The study was supported by the Italian Ministry for University, Scientific, and Technological Research, and by the European Research Advisory Board.
====================================================================================
Family Practice News
Volume 38, Issue 2, Page 23 (15 January 2008)

Warning Reissued for Fentanyl Deaths, Side Effects

Recent reports of death and life-threatening side effects associated with the fentanyl patch prompted the Food and Drug Administration to once again issue a warning about improper prescribing and use of the transdermal administration.

The last warning came in 2005 after similar reports.

The warning applies to the name brand Duragesic patch (manufactured by Johnson & Johnson) as well as other, generic versions of the patch, and to all dosages, Dr. Robert Rappaport said during a teleconference with reporters.

This particular warning does not, however, apply to other fentanyl formulations.

A warning about the buccal formulation of fentanyl was issued in September 2007. Fentanyl was approved in 1990 for opioid-tolerant patients who had chronic, moderate to severe pain.

The patch is given most commonly to patients who have cancer.

“The fentanyl patches are to be prescribed only for patients who are already tolerant of opioid drug products,” according to Dr. Rappaport.

“Unfortunately, what we are still seeing is that, in some cases, prescribers are giving these patches to patients who are not opioid tolerant, [either] for treatment post surgery, for mild pain, even for a headache. And in those patients this can cause serious and life-threatening respiratory depression.”

Signs of fentanyl overdose include trouble breathing or slow or shallow breathing, slow heartbeat, severe sleepiness, cold or clammy skin, trouble walking or talking, or feeling faint, dizzy, or confused, according to the agency.

Dr. Rappaport, who is the FDA's director of the division of anesthesia, analgesia, and rheumatology products, also emphasized the importance of patient education.

“The prescribers must inform and educate their patients about how to use these products and the dangers of using them in certain ways.

“For instance, [the patches] cannot be used in a setting where they would be exposed to heat, such as in a hot tub, [with] a heating pad, or a heated water bed,” he emphsized, because the high temperatures may increase the amount of fentanyl that reaches the blood stream.

For a full guide to the proper handling, disposal, and replacement of the patches, see www.fda.gov/cder/drug/infopage/fentanyl/fentanyl_apply.pdf.

“We are working with the … manufacturers to continue to add more warnings and cautions on the label and more instructions on the proper use of these products. And we're adding a medication guide that patients will receive with their product at the pharmacy as well,” said Dr. Rappaport.

Although the Food and Drug Administration has said that it did not have available the exact numbers of serious adverse events that have been reported since the last warning, Dr. Rappaport confirmed that at least one event had occurred when a physician prescribed the patch for headache relief, “and it's likely to be a considerably higher number than that.”

In July 2005, the agency issued a similar warning that the patch should be used only in strict accordance with the directions on the product label and in the package insert.

Dr. Rappaport defended the usefulness of the patch in opioid-resistant patients who suffer from chronic pain. However, although these products “fill an important need, improper use and misuse can be life-threatening,” he added.

Health care professionals who encounter any adverse or serious events associated with fentanyl are urged to contact the MedWatch program atwww.fda.gov/medwatch/report/hcp.htmor by telephone at 800-FDA-1088.

=====================================================================================
Family Practice News
Volume 36, Issue 24, Page 5 (15 December 2006)

FDA Warns About Methadone-Related Deaths, Serious Events

Reports of deaths, cardiac arrhythmias, respiratory depression, and other serious adverse events in people treated with methadone for pain prompted the Food and Drug Administration to issue a public health advisory and revise its prescribing information for methadone hydrochloride.

The advisory, which appeared Nov. 27 on the FDA's Web site, states that deaths and life-threatening side effects have been reported in patients just starting treatment with methadone and in those who have switched from other narcotic analgesics to methadone.

“These adverse events are the possible result of unintentional methadone overdoses, drug interactions, and methadone's cardiac toxicities (QT prolongation and Torsades de Pointes),” according to the information for health care professionals also posted on the site. The FDA emphasizes that physicians who prescribe methadone should be familiar with the drug's toxicities and distinctive pharmacologic properties, and that patients on methadone should be closely monitored, particularly when treatment is started and when the dose is adjusted.

The FDA has not changed any requirements governing methadone administration or dosage, according to officials who participated in a teleconference about the advisory. The new label represents the first revision in decades, however, and contains detailed prescribing information not previously available. For example, an expanded section on drug-drug interactions includes drugs that did not exist when physicians started prescribing methadone for pain control in the 1940s. The revision also contains a new table on converting oral morphine to oral methadone for chronic administration.

Conversion tables for other opioids and time frames for methadone rotation are not provided—primarily because these are difficult issues. “Where we did not see consensus in the literature we remained silent,” said Dr. Celia Jaffe Winchell, a team leader for addiction-treatment drugs in the FDA's Center for Drug Evaluation and Research.

Although methadone-related deaths have been on the rise for some years, Dr. Winchell said the FDA decided to act now because recent reports of adverse events and deaths “suggest a lack of information about methadone on the part of prescribers and patients may have played a role.”

These recent reports followed growing use of methadone for chronic pain, according to Dr. Winchell. Starting in the 1970s, methadone prescribing had been largely confined to tightly regulated addiction treatment programs. Over the last decade, calls for better treatment of chronic pain led to resurgence of analgesic use with a wide spectrum of practitioners, not just pain and addiction specialists, starting to prescribe methadone.

“One of the things we are trying to achieve with this series of patient and physician alerts is to educate people about just how complicated the use of methadone can be,” said Dr. Robert Rappaport, director of the FDA's Division of Anesthesia, Analgesia, and Rheumatology Products.

The FDA cannot stop methadone prescribing by physicians who are not pain specialists, Dr. Rappaport said. And even if it could, there are not enough pain specialists to meet the need. Therefore, the agency is seeking to increase knowledge about special properties of methadone that can put patients at risk.

“What we are trying to do is to get the word out to everybody,” Dr. Rappaport said.

Methadone's analgesic effects last for 4–8 hours, but its elimination half-life is 8–59 hours. Because of that, methadone's peak respiratory depressant effects “typically occur later and persist longer than its peak analgesic effects,” according to the FDA.

The agency recommends that physicians evaluate drugs that will be administered with methadone for potential interactions, that the risks of methadone should be carefully weighed against its potential benefits—and that the 40-mg dispersible methadone tablets should not be prescribed for pain, since this formulation is approved only for detoxification and maintenance treatment of narcotic addiction.

Because cross-tolerance between methadone and other opioids is incomplete, switching patients from other opioids to methadone is complex, so patients with a tolerance for other opioids can experience a methadone overdose.

The FDA also recommends that health care professionals who prescribe methadone carefully read and follow the prescribing information for Dolophine, the marketed methadone product, which was revised and approved on Nov. 17. Methadone is approved for moderate to severe pain that is not responsive to nonnarcotic analgesics, as well as for detoxification and maintenance treatment of opioid addiction.

The public health advisory on methadone, new prescribing information, and information for patients and physicians can be found atwww.fda.gov/cder/drug/infopage/methadone/default.htm. Serious adverse events associated with methadone can be reported to the FDA's MedWatch program atwww.fda.gov/medwatch/report.htm, by fax at 800-FDA-0178, or by calling 800-FDA-1088.

Senior Writer Elizabeth Mechcatie contributed to this report.
=====================================================================================
Family Practice News
Volume 38, Issue 1, Page 47 (1 January 2008)

Research Sought on Physicians' Addiction Recovery

CORONADO, CALIF. — Of 104 physicians in New York state who were admitted to substance abuse treatment programs between 2003 and 2004 and were monitored for a mean of 41 months by the state's Committee for Physicians' Health, only 9 (9%) were discharged because of noncompliance with program expectations.

That might spell success at first glance, but at the annual meeting of the American Academy of Addiction Psychiatry, Dr. Marc Galanter emphasized the need for more research to optimize treatment outcomes for physicians in recovery.

“There are still a number of issues to be considered,” said Dr. Galanter, professor of psychiatry and director of the division of alcoholism and drug abuse in the department of psychiatry at New York University, New York. “One is the need for prospective study—following the treatment contemporaneously—which we have yet to see,” he said. “Another is to better understand the role of medication.

Buprenorphine inevitably will be used more widely; however, the question of whether physicians should be allowed to practice while taking opioid maintenance therapy is likely to become a political issue at the state level. Dr. Galanter advised that a more active role for cognitive-behavioral therapy “be studied because this is a modality that is currently regarded as essential to effective treatment.”

Dr. Galanter based his remarks on results from a study he led that sought to provide an independent evaluation of the oversight and rehabilitation of 104 substance-abusing physicians who had completed their monitoring period by the New York State Committee for Physicians' Health (CPH). About 30% of physicians who enroll in the CPH program receive at least 28 days of inpatient treatment. Components of ambulatory management include workplace monitoring, 12-step program attendance, and random urine toxicologies.

The researchers, who were not affiliated with CPH, selected the 104 records at random (Am. J. Addict. 2007;16:117–23). The mean age of the study participants was 42 years, most (96) were male, about half (51) were married, and 66 were employed as physicians at the time of admission.

More than half (59) had a history of substance abuse treatment, and 38 had attended 12-step meetings before program admission. In addition, 33 were in psychotherapy of some sort prior to admission, and 27 were taking psychiatric medications, primarily antidepressants.

“This underlines the importance of psychiatric input and oversight in these programs,” said Dr. Galanter, who is also the editor of the journal Substance Abuse.

The most common primary substance of abuse was alcohol (38), followed by prescription opiates (35). The top five medical specialties represented were anesthesia (22 physicians), internal medicine (11), family medicine (10), obstetrics and gynecology (9), and pediatrics (8).

On average, the overall period of treatment and monitoring was 41 months, and 30 participants required inpatient hospitalization at study entry.

Fifteen physicians did not want to attend 12-step meetings but were pressed by counselors to do so. Of those, nine later went. “The outcome of those pressed to go was not significantly different from that of the other patients,” he said. “So apparently the coercive nature of the treatment in that regard was not compromising to the outcome.”

Of the 104 patients, 38 relapsed as confirmed by urine toxicology or by confirmation from an informed source. Even under good circumstances, some relapse is inevitable before the patient is stabilized, Dr. Galanter said.

“The pressure of the needs of public health that they experience puts them in a difficult position,” Dr. Galanter said. “My impression is that it's remarkable how effective they are in balancing the physician needs against the demands of the general public.”

Predictors of relapse included past use of cocaine, unemployment at the time of program admission, a greater mean number of urines tested, and a longer length of program involvement.

Nine patients were discharged for noncompliance with program expectations. “They essentially lost the option of practicing medicine,” he said. “Relatively speaking, this gives you an idea of a very good outcome, considering that full compliance is essential to success in this program.”