Anxiolytic Efficacy of Alprazolam Compared to Diazepam and Placebo

Transcription

1 J Int Med Res (1980) 8,139 Anxiolytic Efficacy of Alprazolam Compared to Diazepam and Placebo Barry M Maletzky, MD, 1345 SE Harney Street, Portland, Oregon 97202, U.S.A. The anxiolytic effects ofalpraxolam ( mg), diazepam (5-60 mg) and placebo were evaluated in eighty-six out-patients suffering from moderate to severe psychoneurotic anxiety in this 28-day, double-blind study. Efficacy was evaluated using five rating instruments, three rated by the physician (Hamilton Anxiety Rating Scale, Physician's Global Impressions and Target Symptoms) and two by the patients (Self-Rating Symptom Scale and Patient's Global Impressions). Alprazolam was more effective than placebo on all five measures of efficacy and, on several parameters, more effective than diazepam as well. The incidence of side-effects was lowest in the alprazolam group and decreased steadily over the course of the study, whereas the incidence in the diazepam and placebo groups remained relatively unchanged. Introduction Alprazolam (Xanax<li') is a triazolobenzodiazepine, a novel compound incorporating a triazol ring in the basic benzodiazepine structure. The triazolobenzodiazepine class of compounds is different from currently marketed benzodiazepines both chemically and, to a certain extent, pharmacologically. Earlier clinical studies have demonstrated the anxiolytic activity of alprazolam in patients suffering from manifest anxiety (Itil et at 1973, Fabre & Harris 1974) and in chronic alcoholics suffering anxiety associated with alcohol withdrawal (Fabre, Gainey & Kemple 1977). Doses used ranged from 0 5 to 4 5 mg given for 18 to 28 days. Side-effects were generally mild and no laboratory, vital signs, or other physical abnormalities were observed. The efficacy of alprazolam coupled with its apparent low toxicity served to encourage further testing. The present study was done to compare the anxiolytic efficacy of alprazolam, diazepam and placebo in treating anxious psychoneurotic patients as well as to further evaluate the safety of alprazolam. Methods The trial was double-blind with random allocation to alprazolam, diazepam, or placebo arranged so that in each group of six patients there were two patients on each drug treatment. The medications were in identicalappearing capsules and were taken orally either b.i.d, or t.i.d, for 28 days. Dosage was adjustable from two to twelve capsules daily depending upon individual patient response. The study population was composed of outpatients suffering from moderate to severe anxiety. Anxiety symptoms must have been present for a minimum of one- month and /80/ $02 00 Cambridge Medical Publications Limited

2 140 patients must have been between 18 and 70 years of age. Patients who were psychotic or significantly depressed, addicted to alcohol or other drugs, sensitive to benzodiazepines, or suffering from serious physical disease and women of child-bearing potential were excluded. All patients signed an informed consent after having the study fully explained. Patients were removed from all psychotropic medication from 4 to 7 days prior to beginning the study. During this time they were screened for inclusion in the study via physical examination, laboratory evaluation, medical history, and psychiatric background information. At the end of this period, but before beginning study medication, the severity of the patients' anxiety was assessed using five rating scales. Three of these (Hamilton Anxiety Rating Scale (Hamilton 1959), Physician's Global Impressions, and Target Symptoms) were rated by the physician and the remaining two (Self-Rating Symptom Scale and Patient's Global Impressions) by the patient. Baseline data also included symptomatology and vital signs. Follow-up evaluations were done at Weeks 1,2 and 4 and included assessment of anxiety, symptomatology, and vital signs. Side-effects were defined as those symptoms which worsened or were reported for the first time during the course of the study. Efficacy parameters were analyzed using one-way analysis of variance to test for differences with The Journal ofinternational Medical Research respect to change from initial for those measures which had initial evaluations and with respect to actual scores for measures which did not have initial evaluations (Neter & Wasserman 1974). All statistical computations were done using the Statistical Analysis System (Barr et al 1976). Physical examinations and laboratory evaluations were repeated at the end of the study. Results Of the eighty-six patients evaluated, thirty-one were in the alprazolam group, thirty were in the diazepam group, and twenty-five were in the placebo group. Demographic and diagnostic data are presented in Table 1. The drug treatment groups were well matched for gender, age, psychiatric diagnosis and onset of symptoms. The number of patients who discontinued treatment early because of either ineffectiveness of the medication or side-effects is shown in Table 2. No alprazolam patients dropped out for either reason whereas one diazepam patient and three placebo patients dropped out due to ineffective medication and four diazepam patients and one placebo patient due to side-effects. At the end of the study the average daily dose taken by alprazolam patients was 1 8 mg compared to 33 0 mg by diazepam patients and 7 8 capsules by placebo patients. Table 1 Demographic and diagnostic data Parameter N=31 N=30 N=25 Gender: Male Female Age: Mean (range) 37 5 (22-61) 38 5 (20-69) 35 7 (18-56). Psychiatric diagnosis: Anxiety neurosis Mixed anxiety depression Other Onset of symptoms: < 2 Weeks Months > 1 Year

3 Barry M Maletzky 141 Table 2 Completion/drop-out data Number of patients evaluated Number of drop-outs due to ineffective medication Number of drop-outs due to side-effects Number of patients who completed the study Table 3 summarizes the results of four of the five efficacy measures. At Week 1, alprazolam patients were slightly more improved than diazepam patients. Over the 4 week course of the trial, alprazolam patients continued to improve and at the end of the study were significantly less anxious than placebo patients as measured by all five efficacy parameters. In contrast, the diazepam group showed little further improvement after Week 2 and at the end of the trial was only slightly, but not significantly, better than placebo. As a consequence, at the Week 4 evaluation the anxiolytic efficacy of alprazolam was superior to diazepam as demonstrated by mean scores of the Hamilton Anxiety Rating Scale, two of the Physician's Global Impressions (How much has the patient changed from initial? and What was the therapeutic effect of the drug?), both Patient's Global Impressions and Target Symptoms. Target Symptoms consisted of three symptoms listed by each patient for which he most wanted relief. The results of the Target Symptoms scores paralleled the results of the other efficacy parameters with alprazolam, but not diazepam, providing significant relief compared to placebo at the final evaluation. The most frequently reported side-effect was drowsiness which was reported forty times by twenty-one patients in the alprazolam group, forty-eight times by twenty-four patients in the diazepam group and twenty-eight times by fourteen patients in the placebo group. This occurrence of drowsiness was significantly higher in the diazepam group compared to the placebo group while the occurrence in the alprazolam group was not significantly different from placebo. In addition, three diazepam patients reported severe sedation, in two cases of such severity as to cause withdrawal from the study. No other sideeffects were reported significantly more frequently in the drug groups than in the placebo group; however, confusion and syncope were reported more frequently by diazepam patients (sixteen and five reports, respectively) than by alprazolam patients (eight and nil reports, respectively). It is interesting to note that the incidence of sideeffects decreased in the alprazolam group during the 4-week course of the study contrasted with an increased incidence in the diazepam group. Overall, the alprazolam group reported the fewest side-effects even though it was comprised of the largest number of patients. No clinically significant abnormalities in physical examinations, laboratory evaluations, or vital signs were noted, Discussion and Conclusions The patients evaluated in this clinical trial were moderately to severely anxious at the time of enrolment. Patients on alprazolam improved steadily throughout the 4-week course of the study and at termination of treatment were significantly less anxious than patients on placebo as measured by all five efficacy parameters. Diazepam patients, on the other hand, showed lesser improvement than alprazolam patients during the first 2 weeks and did not improve further after Week 2. Therefore, by Week 4 alprazolam patients manifested significantly less anxiety than diazepam patients. Drop-out rate is another indication of efficacy. No patients on alprazolam dropped

4 Table 3 Comparison ofmeans ofefficacy parameters Efficacy parameter Initial Week 1 Week 2 Week 4 Initial Week 1 Week 2 Week 4 Initial Week 1 Week 2 Week 4 Hamilton Anxiety Total Score 28 I ** Physician's Global Impression: How mentally ill is the patient?" * 2 9* How much has the patient changed?" * 2 1** Therapeutic effect of the drug?" ** Self-Rating Symptom Scale Total Score * I I 55 2 Patient's Global Impressions: How felt since last visit?" * 2 7** How felt since start of medication?" * 2 7 * "Seven point scale from I = Normal, to 7 = Most Extremely Ill. "Seven point scale from I = Very Much Better, to 7 = Very Much Worse. "Five point scale from I = Worse, to 5 = Marked. * Alprazolam significantly better than placebo. *. Alprazolam significantly better than diazepam and placebo.....j:>. N '1:> l:: l::ḻ.sa,? l::l. ::: l::ḻ l::l... 2' - 25 :::-

5 Barry M Maletzky out early. However, five diazepam patients discontinued the drug before completing 4 weeks of treatment, four of these because of side-effects. This indicates that patients experience beneficial therapeutic effect with fewer annoying or intolerable side-effects on alprazolam treatment. Four placebo patients discontinued medication early and, as could be expected, three were due to ineffective medication. The number of side-effects reported substantiates the drop-out rate data in that, of the three treatment groups, the fewest sideeffects were reported by the alprazolam group. Of additional interest, the incidence of sideeffects in alprazolam patients decreased steadily during the course of treatment while the incidence in diazepam patients increased. Drowsiness was the most frequently reported side-effect and was. reported less frequently and by fewer patients in the alprazolam group than in the diazepam group. Overall, the results of this trial support the conclusion that alprazolam is an effective anxiolytic. Alprazolam not only reduced the 143 clinical manifestation of anxiety, but was significantly more effective than placebo and, on several parameters, more effective than diazepam as well. These results, coupled with the lower incidence of side-effects, make alprazolam a promising drug for the treatment of anxiety. REFERENCES Barr, A J, Goodnight J H, Sail J P & Helwig J T (1976) A User's Guide to SAS-76. SAS Institute, Raleigh, North Carolina. Fabre L F Jr, Gainey A & Kemple S (1977) Pilot open-label study of alprazolam (U-31,889) in anxious alcoholic out-patients. Journal of International Medical Research 5, 26 Fabre L F Jr & Harris R T (1974) Pilot open-iable study on U-31,889 in anxious inpatients, Current Therapeutic Research 16, 1010 Hamilton M (1959) The assessment of anxiety states by rating. British Journal ofmedical Psychology 32, 50 Itil T M, Polvan N, Egilmez S, Saletu B & Marasa J (1973) Anxiolytic effects of a new triazolobenzodiazepine. Current Therapeutic Research 15,603 Neter J & Wasserman W (1974) Applied Linear Statistical Models, 429, Irwin, Homewood, Illinois.