Effect of metabolic blockade on the psychoactive effects of dextromethorphan.

OBJECTIVE: Variation in the activity of cytochrome P450 2D6 (CYP2D6) affects the pharmacokinetics and effectiveness of dextromethorphan (DM), because it controls the production of dextrorphan, an active metabolite, with higher affinity for the NMDA receptor than the parent compound. This study examined whether pharmacological inhibition of CYP2D6 activity with quinidine would mimic the genetic mutation and thus also alter the psychoactive effects of DM. METHODS: In a single-blind, within-subjects study, eight healthy volunteers (all homozygous for the wild type allele for CYP2D6) received placebo and varying doses of DM, both with and without quinidine pre-treatment. Pharmacokinetic and pharmacodynamic measures were assessed at baseline and every hour post-drug for 6 h. RESULTS: Compared to the no quinidine condition, quinidine pre-treatment decreased the area under the dose-response curve on subjective measures of positively reinforcing effects (e.g., euphoria, p < 0.04; drug liking, p < 0.05), and was significantly greater for measures of dysphoria (e.g., unpleasantness, p < 0.02). These changes corresponded to increased DM and decreased dextrorphan plasma concentrations. CONCLUSIONS: Compared to DM alone, quinidine pre-treatment inhibited DM metabolism and changed its subjective effects, demonstrating that the psychoactive properties of DM are a function of drug metabolism. These results demonstrate the relationship between CYP2D6 activity, plasma drug levels, and psychoactive drug effects, and have implications for both the abuse liability and therapeutic utility of DM.

The role of cytochrome P450 2C19 activity in flunitrazepam metabolism in vivo.

Flunitrazepam, a hypnotic benzodiazepine, is widely prescribed around the world for the treatment of insomnia and as a preanesthetic. In vitro studies have shown that the metabolism of flunitrazepam to desmethylflunitrazepam and 3-hydroxyflunitrazepam is mediated in part by the polymorphic enzyme CYP2C19. The objective was to examine the role of CYP2C19 activity in determining flunitrazepam kinetics in vivo. Sixteen healthy volunteers (14 genotypic extensive metabolizers and 2 poor metabolizers) were recruited who had a wide range of CYP2C19 activity (0.50-28.8), as determined by the omeprazole/ 5-hydroxyomeprazole ratio (OMR) at 3 hours following administration of omeprazole, 20 mg orally. Each subject received flunitrazepam, 1 mg orally. Blood samples were collected immediately before and up to 48 hours after drug administration and were assayed by HPLC for flunitrazepam and its metabolites, 7-aminoflunitrazepam, desmethylflunitrazepam, and 3-hydroxyflunitrazepam. Spearman correlations were determined for OMR and pharmacokinetic parameters. With increasing OMR (decreasing CYP2C19 activity), the ratio of flunitrazepam to both desmethylflunitrazepam and 3-hydroxyflunitrazepam AUCs increased ( r = 0.55, p = 0.03 and r = 0.65, p = 0.01, respectively). However, variation in CYP2C19 activity did not significantly affect the AUCs of flunitrazepam or its metabolites. The authors conclude that CYP2C19 contributes to the metabolism of flunitrazepam to desmethylflunitrazepam and 3-hydroxyflunitrazepam in vivo, but these data suggest that its role is minor and that differences in CYP2C19 activity do not likely substantially influence its clinical effects.

Use of prescription and nonprescription hypnotics in a Canadian elderly population.

BACKGROUND: Hypnotics are commonly used by older adults, yet little is known about the patterns of their use and effectiveness in this population. METHODS: Three thousand eight hundred sixty anonymous, self-report surveys were distributed to community pharmacies (n=356) across Canada to obtain information on the patterns of use of hypnotics from elderly volunteers. RESULTS: The mean age of respondents was 72+/-7 years (range 60 to 95 years) and 66% were women. In the past year, 53% of respondents used hypnotics. Prescription products accounted for 83% of the past year's use (66% benzodiazepines, 11% zopiclone, 4% antidepressants, 2% opioids), and 17% of the products used were over-the-counter (5% herbal, 5% antihistamines, 3% analgesics). Use was regular (50% daily) and chronic (mean duration six years: range two weeks to 30 years). Hypnotics significantly (P<0.001) improved subjective sleep latency (mean 32 min compared with 93 min), number of nocturnal awakenings (mean two compared with four) and total hours of sleep (mean 7 h compared with 4 h). Effectiveness was highly rated: at the most recent use of the product, mean 7.6 (SD+/-2.2) of 10; initially, 7.9 (SD+/-2.3) with a significance of P=0.02. Most respondents (59%) reported side effects, mainly dry mouth (30%), memory problems (22%) and daytime sleepiness (22%), although 60% rated the side effects as mild. The mean number of other medications used was five (range zero to 17). Of the 54 subjects who used nonprescription sleep products, only half (52%) indicated that their physician was aware of this use. CONCLUSIONS: Prescription drugs were primarily used for sleep and were perceived to be effective even with long term use, despite mild side effects.

The role of the brain reward system in depression.

The goal of this review is to familiarize the reader about the potential involvement of the brain reward system (BRS) in symptoms of Major Depressive Disorder (MDD). The authors introduce a novel approach to study the pathophysiology of MDD that includes pharmacological probing of BRS pathways (e.g. d-amphetamine, hydromorphone) together with an elicited and measurable behavioral component (e.g. pleasant effects, increased energy, altered cognition). To this date, the major focus of MDD pathophysiology studies has been to characterize biological differences between healthy subjects and depressed patients such as alteration in the monoaminergic and endocrine systems. The relative importance of the various biological changes has not been elucidated, that is, linking these with specific behavioral manifestations in MDD have rarely been attempted. One core symptom of MDD is a decreased experience of pleasure or interest in previously enjoyed activities (i.e. anhedonia) such as work or hobbies, and is accompanied by decreased motivation or drive. The BRS consists of the neural pathways involved in eliciting rewarding experiences in animals and humans. The hypothesis is that altered BRS function may be an underlying brain mechanism of the loss of pleasure/interest experienced in MDD, and will be manifested through an altered response to a BRS probe. The authors have examined BRS function in MDD by introducing a pharmacological probe (i.e. d-amphetamine/d-amph). Amphetamine is defined as a probe due to its ability to release dopamine within major components of the BRS (i.e. the mesocorticolimbic dopamine system.) In addition to the objective pharmacological effects (e.g. altered heart rate), BRS probes like d-amph elicit reliable and measurable behavior, that is, the hedonic effects. A review of the neurobiology of MDD, the BRS, the rationale for implicating the BRS in depressive symptoms, and preliminary data, are presented in this article.

Flunitrazepam metabolism by cytochrome P450S 2C19 and 3A4.

We have identified CYP2C19 and CYP3A4 as the principal cytochrome P450s involved in the metabolism of flunitrazepam to its major metabolites desmethylflunitrazepam and 3-hydroxyflunitrazepam. Human CYP2C19 and CYP3A4 mediated the formation of desmethylflunitrazepam with Km values of 11.1 and 108 microM, respectively, and 3-hydroxyflunitrazepam with Km values of 642 and 34.0 microM, respectively. In human liver microsomes (n = 4) formation of both metabolites followed biphasic kinetics. Desmethylflunitrazepam formation was inhibited 31% by S-mephenytoin and 78% by ketoconazole, suggesting involvement of both CYP2C19 and CYP3A4. Formation of 3-hydroxyflunitrazepam was also significantly inhibited by ketoconazole (94%) and S-mephenytoin (18%). In support of these chemical inhibition data, antibodies directed against CYP2C19 and CYP3A4 selectively inhibited formation of desmethylflunitrazepam by 26 and 45%, respectively, while anti-CYP3A4 antibodies reduced 3-hydroxyflunitrazepam formation by 80%. Our data also suggest that CYP1A2, -2B6, -2C8, -2C9, -2D6, and -2E1 are not involved in either of these metabolic pathways. We estimate that the relative contributions of CYP2C19 and CYP3A4 to the formation of desmethylflunitrazepam in vivo are 63 and 37%, respectively, at therapeutic flunitrazepam concentrations (0.03 microM). We conclude that the polymorphic enzyme CYP2C19 importantly mediates flunitrazepam demethylation, which may alter the efficacy and safety of the drug, while CYP3A4 catalyzes the formation of 3-hydroxyflunitrazepam.

Comparative abuse liability of intravenously administered remifentanil and fentanyl.

Remifentanil is a short-acting, esterase-metabolized opioid analgesic. This study compared the abuse liability of remifentanil with that of fentanyl and placebo in a randomized, double-blind, crossover study. Twelve recreational users of opioids received increasing doses of remifentanil (0.6, 1.2, 1.8, 2.4, and 3.0 microg/kg), fentanyl (0.4, 0.8, 1.3, 2.0, 3.0, and 4.5 microg/kg) and placebo via an intravenous infusion pump. Subjective measures (Cole/Addiction Research Center Inventory [ARCI] scales and visual analog scale [VAS] items such as "High" and "Good Effects") and physiologic variables (blood pressure, O2 saturation, pupil diameter) were recorded. For each measure, the differences from baseline were reduced to an area under the response curve (AUC) and a peak, and each subject's response to the maximum tolerable dose for each of the two active drug classes and mean response to several placebo infusions were entered into a 12 x 3 analysis of variance. All differences in drug versus placebo effects were significant. Although a majority of the peak effects that were measurable within 4 minutes after drug infusion reflected greater remifentanil effects, only one, High VAS, was statistically significant. In contrast, observations that could only be made > or = 5 minutes after drug infusion predominantly indicated significantly greater fentanyl peak effects, including High VAS, Liking VAS, Good Effects VAS, and Cole/ARCI Abuse Potential. Fentanyl AUCs were generally significantly larger than the corresponding remifentanil AUCs. A drug abuser seeking longer-lasting drug effects might select fentanyl over remifentanil, but these data do not completely rule out remifentanil abuse by some individuals with access to both the drug and the infusion equipment or by those who prefer briefer, repeated effects.

A comparative pharmacokinetic and dynamic evaluation of alprazolam sustained-release, bromazepam, and lorazepam.

Sustained-release (SR) alprazolam may facilitate compliance with oral benzodiazepine treatment of panic disorders that currently requires doses administered three or four times daily. To compare the pharmacokinetic, psychomotor performance, and subjective effects of alprazolam SR (1.5 mg), bromazepam (3 mg taken three times daily), and lorazepam (1 mg taken three times daily), 13 male volunteers (aged 20-45 years) randomly received on four separate occasions one of these medications or placebo. Once before and 11 times after drug administration, the subjects were tested using psychomotor performance tests (manual tracking and digit-symbol substitution test [DSST]) and computerized questionnaires (such as the Tufts University Benzodiazepine Scale [TUBS], the Addiction Research Center Inventory, and the visual analog scales) to determine the subjective effects of the drugs. Blood samples for the determination of the plasma levels of the drugs were collected before and 17 times after the drug was administered. A peak plateau of plasma alprazolam began approximately 6 hours after the dose, which was later than the initial peaks for lorazepam and bromazepam (1-2 hours after the dose). Once this plateau had begun, alprazolam SR sustained that concentration better than did the other two formulations. Of the 10 measures on which the response averaged for the first 14 hours differed among drugs (p < 0.05), bromazepam differed from placebo on two measures, lorazepam on four (including DSST Performance and TUBS Sedation), and alprazolam SR on nine (including all four affected by lorazepam). Lorazepam and alprazolam, but not bromazepam, produced significantly more sedation than placebo. The doses of the three drugs were not equipotent in sedation and mood effects. None of the drugs tested differed from placebo on measures relevant to abuse liability.

Inhibition of cytochrome P450 2D6 modifies codeine abuse liability.

Oral codeine preparations, widely used for analgesia and cough suppression, are abused by some individuals for their mood-altering properties. The enzymatic O-demethylation of codeine is catalyzed by cytochrome P450 2D6 (CYP2D6), leading to the production of metabolites (morphine, morphine-6-glucuronide) that are pharmacologically more potent than codeine. A placebo-controlled, single-blind study was conducted to characterize the subjective effects of codeine associated with abuse liability and to determine the importance of metabolic O-demethylation to codeine abuse liability. Twelve non-drug-dependent subjects received oral administration of placebo and codeine 60, 120, and 180 mg, and a favorite dose (FD) was determined for each subject. The FD was readministered after pretreatment with placebo, 50 mg of quinidine (a specific, selective CYP2D6 inhibitor) once, or 50 mg of quinidine given four times a day for 4 days. Single-dose quinidine pretreatment significantly decreased the recovery of O-demethylated metabolites in plasma (p < 0.01) and resulted in a decrease in the positive (e.g., "high," p < 0.05) and negative (e.g., nausea, p < 0.05) subjective effects of codeine in both the FD120 and FD180 groups. Short-term quinidine pretreatment inhibited codeine O-demethylation more than did single-dose quinidine pretreatment (p < 0.01), and it decreased positive codeine effects in the FD120 group (N = 7), but unexpectedly not in the FD180 group (N = 5). These results suggest that the O-demethylated metabolites contribute substantially to the subjective effects and abuse liability of codeine.

Long-term benzodiazepine therapy does not result in brain abnormalities.

Studies on the association between long-term benzodiazepine use and brain abnormalities have yielded conflicting results. The computed tomographic (CT) scans of 20 long-term users of benzodiazepine (65% men; mean age +/- SD [range], 42 +/- 12.1 years [23-59]; mean daily benzodiazepine dose [diazepam equivalents], 19.5 +/- 16.2 mg [2.5-70]; mean cumulative benzodiazepine exposure, 55.2 g [1.8-198]) were compared with 36 age- (+/-3 years) and sex-matched controls. Controls were prospectively recruited from 96 patients attending a neurology clinic and were interviewed to screen for alcohol and substance use disorders and other conditions possibly leading to brain atrophy. Three neuroradiologists blindly assessed each CT scan for atrophy and measured ventricles (V1, V2, V3), sulci, fissures, cisterns, and folia. Reliability among observers ranged from 0.92 to <0.1, in which case deleting one observer increased all reliabilities to >0.45. No difference in atrophy was found between benzodiazepine users and controls. V1 measures were significantly higher for benzodiazepine users than for controls (mean +/- SD, 12.1 +/- 1.3 vs. 11.1 +/- 2.0;p = 0.02), but measures of third and fourth largest sulci were significantly higher in controls than in benzodiazepine users. Right third and fourth largest sulci (mean +/- SD), respectively, were the following: controls, 0.72 +/- 0.4 and 0.74 +/- 0.7; benzodiazepine users, 0.51 +/- 0.3 and 0.46 +/- 0.3 (p < 0.02). Left third and fourth largest sulci, respectively, were the following: controls, 0.77 +/- 0.6 and 0.65 +/-0.3; benzodiazepine users, 0.53 +/- 0.3 and 0.5 +/- 0.3 (p < 0.02). Long-term benzodiazepine therapy does not result in brain abnormalities that can be demonstrated on CT scans.

The effectiveness of antidepressants in elderly depressed outpatients: a prospective case series study.

BACKGROUND: This study examined the effectiveness of antidepressants in a group of elderly depressed outpatients by assessing depression prevalence and recording adverse events over time. METHOD: A prospective practice-based observational study (1991-1994) included consecutive outpatients at least 65 years of age with a DSM-III-R diagnosis of major affective disorder and who were prescribed antidepressant medications. Depressive symptoms were examined over time (stage 1 = 0 to 2 months; stage 2 = 2 to 6 months; stage 3 = 6 months to 2 years) with the Montgomery-Asberg Depression Rating Scale (MADRS). The cutoff scores of MADRS <18 and MADRS > or =18 were used in survival statistics. Adverse events were recorded systematically. RESULTS: A total of 213 patients were seen over 2677 visits (mean +/- SD age = 75.5+/-6.1 years). MADRS scores for 85.8% of patients declined to below 18 within the first 2 months of antidepressant treatment. MADRS scores were above 18 for 37.3% of patients after 6 months and for 37.1% after 2 years. The mean time to decline in MADRS scores to below 18 in stage 1 was 36.1 days, and there was a significant difference between the antidepressant classes (log rank = 8.3, df = 3, p = .04), with tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)/reversible inhibitors of monoamine oxidase A (RIMAs) having shorter times to response. The mean time to reach scores above cutoff during stage 2 was 144.3 days (log rank = 5.7, df = 3, p = .13) and during stage 3, 538.6 days (log rank = 9.8, df = 3, p = .02). Patients receiving TCAs and MAOIs/RIMAs had longer durations of MADRS scores below cutoff during stage 3 than those taking atypical antidepressants and selective serotonin reuptake inhibitors. All antidepressant classes reported similar adverse event profiles. CONCLUSION: This study systematically examined antidepressant effectiveness in a prospective design. TCAs and MAOIs/RIMAs were shown to be superior in effectiveness during 2 of the 3 treatment stages.

Identifying appropriate subjects for abuse liability studies using prestudy pharmacological testing.

Drug abuse liability testing usually involves a subject population of individuals who are current or former drug abusers. To determine whether choosing subjects from a wider and more diverse population of nondrug abusers results in subjective response patterns that are pharmacologically associated with drug abuse liability, a series of studies were conducted using the prescription opiate hydromorphone and the barbiturate secobarbital to prescreen subjects before their acceptance into large multidrug, multidose abuse liability studies. The results of these prescreening studies show that there were some subjects who were not able to report consistently and reliably relevant drug effects, even though they received pharmacologically active doses as measured by objective indexes such as pupil diameter for the opiate study and psychomotor impairment for the barbiturate study. To test the consistency of these results, several of the subjects from the hydromorphone screening were retested with hydrocodone. The results demonstrate that subjects who were unable to report positive subjective effects of hydromorphone were also unable to respond appropriately to hydrocodone, and subjects who responded appropriately to hydromorphone in the prescreening study consistently responded to another opiate. Using this prescreening methodology has allowed sensitive and reliable data on the abuse liability of benzodiazepine agonists and partial agonists, barbiturates, carbamate compounds, amphetamines, selective serotonin reuptake inhibitors and prescription opiate compounds to be generated using a nondrug abusing population. In conclusion, due to the relative heterogeneity of a population of nondrug abusers compared with a drug abusing population, it is necessary to prescreen subjects for their ability to detect and report subjective drug effects, and to distinguish the effects of an active drug from those of placebo. Selecting subjects from this population has several advantages over selecting subjects from the drug abusing population that outweigh any inconvenience of this simple prescreening methodology.

The use of non-prescription sleep products in the elderly.

UNLABELLED: While sleep disorders are common in the elderly, the use of non-prescription products for sleep in this population has not been fully evaluated. The objectives of this project were to assess the use, perceived effectiveness and toxicity of non-prescription sleep products in an ambulatory elderly population. METHODS: A self-administered 20-question survey was distributed to seniors, aged 60 years or more, during hospital or pharmacy visits. RESULTS: Of the total respondents (N=176, mean age 74+/-7 years, 59% female), 84 (48%) indicated that they had used one or more therapies for sleep within the past year. These included non-prescription products (50% of therapies), prescription products (17%) and non-drug activities such as walking or drinking milk (34%). For those individuals who had used a non-prescription product in the past year (N=47, 27% of total respondents), the most frequently used products were: dimenhydrinate (21%), acetaminophen (19%), diphenhydramine (15%), alcohol (13%) and herbal products (11%). Most took them at least 1 day per week (79%) and 32% took them daily. These products subjectively improved sleep latency (mean 32 vs 61 minutes, p<0.001), number of nocturnal awakenings (mean 2 vs 3 awakenings, p<0.001) and total hours of sleep (mean 6.6 vs 5.4 hours, p<0.001). Mild side-effects were reported by 35 respondents (75%), the most common being dry mouth (N=22) and daytime drowsiness (N=13). Respondents were taking an average of four (SD+/-3, range 0-10) other medications currently. CONCLUSIONS: Non-prescription products are widely used by this population of ambulatory elderly for sleep disturbances. Most of the products were not marketed for sleep; however, they were perceived to be efficacious with low toxicity. The potential for drug interaction is high. Further research is warranted to evaluate the safety and effectiveness of non-prescription sleep products in the elderly.

Risk of drug dependence and abuse posed by barbiturate-containing analgesics.

Concern has been raised that the barbiturate component of barbiturate-containing analgesics constitutes a public and individual health problem because of information from literature before 1966 concerning preclinical and clinical abuse liability, and the dependence risk of barbiturates. The safety of barbiturates alone and in combination in analgesics was reviewed. In addition, information from manufacturers of combination products were evaluated. A meta-analysis was not possible because of the paucity of formal clinical trials. Even though barbiturates have a narrow margin of safety and substantial abuse potential, there is no evidence that barbiturate-containing analgesics without codeine represent a public health or social problem because of their abuse potential. However, proper studies to confirm this theory have not been performed. In the absence of better data concerning efficacy and lack of dependence potential, barbiturate-containing analgesics are not first-line medications for the initiation of treatment for pain. Codeine-containing combination analgesics have the potential to be a more important public health problem than those with only barbiturate in the combination.

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.

Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism: a pilot study.

Dextromethorphan is a nonopioid antitussive metabolized by cytochrome P450 2D6 (CYP2D6) to an active metabolite, dextrorphan. CYP2D6 is polymorphically expressed in humans, with 5 to 10% of Caucasians being homozygous deficient for the active form of the enzyme. In a pilot study, the authors investigated the pharmacologic effects of dextromethorphan in individuals phenotyped and genotyped as extensive metabolizers (EMs, N = 4) and poor metabolizers (PMs, N = 2) of CYP2D6 substrates. Dextromethorphan doses ranged from 0 to 6 mg/kg based on individual subject tolerance. All EMs tolerated 3 to 6 mg/kg dextromethorphan, whereas PMs barely tolerated 3 mg/kg dextromethorphan and therefore received lower doses. As shown in previous studies, plasma kinetics show profound differences in dextromethorphan metabolism between EMs and PMs. Dextromethorphan produced qualitatively and quantitatively different objective and subjective effects in the two groups. Objectively, PMs had greater psychomotor impairment, as measured by a joystick tracking task, compared with EMs on 3 mg/kg dextromethorphan (mean performance +/- SE, 95+/-0.5% for EMs vs. 86+/-6% for PMs; p < 0.05). At this dose, EMs also reported greater abuse potential compared with PMs (p < 0.05), and PMs reported greater sedation and dysphoria compared with EMs (p < 0.01). These data provide preliminary evidence that dextrorphan contributes to dextromethorphan abuse liability, and therefore PMs may be less likely to abuse dextromethorphan.

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.

Safety of ipsapirone treatment compared with lorazepam: discontinuation effects.

OBJECTIVE: To determine discontinuation effects of ipsapirone, a novel azapirone and partial 5-HTIA agonist that has anxiolytic effects clinically and has not caused dependence or withdrawal symptoms in animals, and to compare these effects with those of the benzodiazepine lorazepam, owing to concern about dependence or withdrawal symptoms following use of these drugs. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Outpatient and inpatient treatment. PARTICIPANTS: Sixty-five healthy male volunteers who had experience with sedative-hypnotics or anxiolytics and did not meet DSM-III-R criteria for abuse or dependence. INTERVENTIONS: Participants were randomized to receive ipsapirone 15 mg per day (n = 17), ipsapirone 22.5 mg per day (n = 16), lorazepam 3 mg per day (n = 16), or placebo (n = 16) as outpatients for 36 days (treatment) followed by single-blind placebo as inpatients for 3 days and as outpatients for 6 days (withdrawal). OUTCOME MEASURES: Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Scale (HAM-D), Spielberger State Anxiety Scale, Sleep Quality Questionnaire, General Symptom Checklist, self-rated intoxication, Clinical Institute Withdrawal Assessment--Benzodiazepines (CIWA-Benzo), psychomotor testing and urine drug screen. RESULTS: Only 45 subjects completed the study; discontinuation rates did not significantly differ among treatment groups. At day 39, fewer and less severe symptoms (e.g., insomnia and fatigue) were found on the CIWA-Benzo scale after treatment with ipsapirone or placebo than after treatment with lorazepam (p < 0.05). Subjects reported longer sleep latency and poorer sleep quality after receiving lorazepam than after receiving ipsapirone or placebo. Scores on the HAM-D, Spielberger State Anxiety and HAM-A scales did not change from baseline. CONCLUSIONS: Withdrawal symptoms were detected after discontinuation of therapeutic doses of lorazepam. Significantly fewer symptoms were observed after withdrawal from anxiolytic doses of ipsapirone.