Gail Somer

Characteristics of dependent and nondependent regular users of codeine.

Although codeine is a widely used medication, the problems of codeine abuse and dependence have not been well-studied. This study characterized regular codeine users (using at least 3 days per week for 6 months, excluding those using codeine for the treatment of cancer pain) through a self-completed questionnaire. Recruitment through newspaper advertisements resulted in a total of 339 eligible questionnaires. Thirty-seven percent of subjects met DSM-IV criteria for codeine dependence. Dependent subjects (mean age, 40 +/- 10 years) were using an average of 179 (+/-171) mg of codeine per day. Codeine was predominantly used in the form of combination products with acetaminophen. Dependent subjects identified specific problems causally related to their codeine use such as depression (23%), anxiety (21%), and gastrointestinal disturbances (13%). The dependent subjects reported problems with other drugs more than did nondependent users (alcohol, 57% vs. 26%; cannabis, 23% vs. 5%; sedative/hypnotics, 33% vs. 12%; and heroin, 11% vs. 2%, respectively). Most were taking codeine primarily for a chronic pain problem (81%), although the dependent subjects currently found codeine less effective for treating pain than did the nondependent subjects and were more likely to use codeine for pleasurable effects, to relax, or to prevent withdrawal symptoms. This study showed that dependence is associated with the regular use of codeine. Pain is a key issue with these users; however, they are probably not receiving optimal treatment. There is a need to identify individuals experiencing problems with their codeine use and to develop optimal prevention and treatment strategies.

Long-term codeine use is associated with depressive symptoms.

A community survey was conducted among long-term (>6 months) users of codeine-containing products to characterize chronic use of these extensively consumed medications. Respondents recruited through newspaper advertisements completed a mailed questionnaire. Three hundred thirty-nine completed questionnaires were obtained, yielding a response rate of 70%. Codeine dependence/abuse as defined by DSM-IV criteria was present in 41% of the respondents. Two thirds of the subjects had sought help for mental health problems, most often depression (70%). Scores on the Symptom Checklist-90 subscales were modestly elevated, particularly on the Depression subscale (1.2 +/- 0.9). Long-term codeine use is strongly associated with dependence. Depression and depressive symptoms are common. These data suggest that dysphoric mood states may be significant in maintaining long-term codeine use.

Cytochrome P450 2D6 and treatment of codeine dependence.

Oral opioid analgesics such as codeine are used extensively worldwide and are frequently misused. Codeine is a substrate of CYP2D6, a genetically polymorphic P450 enzyme, and is metabolized to the more potent drug morphine. CYP2D6 activity can be inhibited by fluoxetine, and the inhibition of morphine formation may help individuals reduce their use of codeine. Fourteen long-term users of oral opiates (principally codeine) were assessed for an open-label pilot treatment study of fluoxetine 20 mg/day combined with a brief behavioral intervention and structured tapering of the opiate. Eight subjects entered and completed the 8-week treatment. Opiate use decreased by 30% to 100% of baseline use (p < 0.0001) in parallel with a decrease in CYP2D6 activity. Fluoxetine may have a role in the treatment of opiate dependence by decreasing opiate-reinforcing properties.

A controlled trial of ondansetron, a 5-HT3 antagonist, in benzodiazepine discontinuation.

Serotonin is implicated in the etiology of anxiety disorders and in the anxiolytic actions of benzodiazepines. Preclinical studies with 5-HT3 receptor antagonists, including ondansetron, show they have anxiolytic properties and that ondansetron suppresses withdrawal anxiety after abrupt discontinuation of chronic benzodiazepine treatment. We evaluated the efficacy of ondansetron as an adjunctive medication in the discontinuation of benzodiazepines in long-term users. One hundred eight patients who had used alprazolam or lorazepam regularly for > 3 months entered, and 97 completed a randomized double-blind discontinuation treatment program during which they received either ondansetron 2 mg twice daily or placebo and flexibly tapered their benzodiazepine over a 6-week period. There were no significant differences between the patients who had entered and completed treatment. Three weeks postmedication, 63% of the patients discontinued use of benzodiazepine. The percentage of reduction of benzodiazepine daily dosage at all time points in the treatment trial was similar for the ondansetron and placebo groups. Ondansetron had no significant effects on severity of withdrawal symptoms or levels of anxiety. High placebo response may have prevented detection of an ondansetron effect. At 1 year follow-up, 68% of patients reported that they stopped using benzodiazepine. Patient characteristics were more important than ondansetron in tapered benzodiazepine discontinuation.

Characteristics of Long Term Alprazolam Users in the Community

The widespread use of benzodiazepines remains a source of concern to the medical profession and the general public, especially as newer compounds come on the market. Our goal was to characterize long-term alprazolam users in the community and to determine whether such use represented abuse or behavioural dependence. We conducted three community surveys to learn about the natural history of long-term alprazolam use. Current long-term alprazolam users (those using the drug for 3 months or longer) were recruited on three separate occasions 1 year apart by identical newspaper advertisements in the metropolitan Toronto area. All respondents were mailed a questionnaire with a stamped, addressed return envelope. Our data from 312 respondents show that: (1) the majority of patients have a substantial history of prior medication use for symptom control (65%), (2) dose escalation is not a characteristic of long-term use, (3) patients change their initial pattern of regular use to one of symptom control only when required, (4) most physicians do not discuss discontinuation of the drug with their patients, (5) patients frequently try to stop their drug use (with a median of 2 attempts) and often report symptoms upon discontinuation, and (6) patients perceive a need for medication use and indicate that alprazolam is effective (75%). We conclude that some patients persistently use alprazolam but that this use does not represent abuse or behavioral dependence.

Comparative drug effects and abuse liability of lorazepam, buspirone, and secobarbital in nondependent subjects

The pharmacologic effects of lorazepam (2 mg), buspirone (20 mg, 10 mg), secobarbital (100 mg), and placebo were compared in 15 male, experienced, intermittent nontherapeutic drug users. All drugs produced a “drug effect,” however, buspirone 20 mg was significantly less liked than were lorazepam, secobarbital, or buspirone 10 mg (p < .05) but not placebo. Lorazepam was liked better than were other drugs only at 1 hour and only compared with buspirone 20 and placebo. Compared with other drugs, lorazepam drug effects were greater and resulted in more prolonged impairment of a motor tracking task, standing steadiness, and memory. Buspirone 20 mg significantly impaired memory at 1 hour compared with placebo. Subjects were more likely to identify buspirone as unfamiliar. Because buspirone 20 mg was less liked than were other drugs, dose escalation as part of drug abuse is not likely to occur. Lorazepam also was not particularly liked and was not different from placebo on most subjective abuse-relevant measures.

Defining the true therapeutics and clinical pharmacology curriculum in a canadian medical school: Implications for change

Concern over rational drug therapy has led to the close scrutiny of clinical pharmacology and therapeutics teaching. Course syllabuses and timetables portray the official curriculum but rarely reflect true pharmacology and content. The teaching of clinical pharmacology and therapeutics can be uniquely and comprehensively analyzed with a computer‐based curriculum data base that has the capacity to identify overlap, integration, omissions, and correlations. We have developed such a system and applied it to the analysis of one medical school curriculum. Pharmacology and therapeutics teaching represents 22% of the curriculum; however, the majority occurs outside the pharmacology‐controlled courses. Overlap is extensive and unplanned. Our data indicate that the true curriculum differs greatly from that in curriculum schedules and probably from that in the minds of most curriculum planners and teachers. Collaboration among pharmacologists and clinical pharmacologists and many other curriculum officers and teachers is essential if education in this area is to be improved.