A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania

There are no rapid-acting intramuscular formulations of atypical antipsychotics available for quickly calming an agitated patient with bipolar disorder. In this study, 201 agitated patients with bipolar mania were randomly assigned to receive one to three injections of the atypical antipsychotic olanzapine (10 mg, first two injections; 5 mg, third injection), the benzodiazepine lorazepam (2 mg, first two injections; 1 mg, third injection), or placebo (placebo, first two injections; olanzapine, 10 mg, third injection) within a 24-hour period. Agitation was measured at baseline, every 30 minutes for the first 2 hours, and at 24 hours after the first injection using the Positive and Negative Syndrome Scale-Excited Component subscale and two additional agitation scales. At 2 hours after the first injection, patients treated with olanzapine showed a significantly greater reduction in scores on all agitation scales compared with patients treated with either placebo or lorazepam. At 24 hours after the first injection, olanzapine remained statistically superior to placebo in reducing agitation in patients with acute mania, whereas patients treated with lorazepam were not significantly different from those treated with placebo or olanzapine. Furthermore, no significant differences among the three treatment groups were observed in safety measures, including treatment-emergent extrapyramidal symptoms, the incidence of acute dystonia, or QTc interval changes. These findings suggest that intramuscular olanzapine is a safe and effective treatment for reducing acute agitation in patients with bipolar mania.     

A test of the concept of ‘underlying depressive illness’ in the treatment of anxiety states

Summary

In order to test the validity of the concept of anxiety states masking an underlying depressive illness, patients clinically diagnosed as suffering from anxiety or tension states were treated on a random double-blind basis for 4 weeks with either a pure anxiolytic, lorazepam, or an anxiolytic / antidepressant preparation, fluphenazine with nortriptyline. Patients' self ratings were very similar to the physicians' ratings which showed that fluphenazine / nortriptyline was associated with significantly greater overall improvement (p<0.01), as well as significantly greater improvement in the group of symptoms specifically related to depression (p<0.05). These results suggest that a depressive element is present in an appreciable proportion of patients presenting with apparent anxiety states, and antidepressant as well as anxiolytic treatment is required.

Patients selected on the basis that they had improved satisfactorily at the end of the 4-weeks' treatment were followed up for a further 3 months without medication, and the relapse rate was 24%, irrespective of previous treatment. More of the patients treated with lorazepam had to be excluded from the follow-up because of failure to improve, and these probably represented the proportion (19%) of this population with an appreciable depressive element to their illness.     

Gender-related differences in response to placebo in benzodiazepine withdrawal: a single-blind pilot study

RATIONALE: Benzodiazepines have dependency-producing properties, and the majority of patients who are prescribed benzodiazepines and are treated for benzodiazepine dependency are women. Inability to cope with withdrawal symptoms may lead to continued consumption of benzodiazepines, often with the development of tolerance and dose escalation as a consequence. OBJECTIVE: In the present study we analyzed gender-related differences in reactions to placebo injections in a placebo-controlled study of the effects of the benzodiazepine antagonist flumazenil among patients previously treated for benzodiazepine dependency and healthy controls. METHODS: Ten patients and ten controls (five males and five females in each group) received two placebo injections (separated by 15 min) on two separate occasions (1-13 weeks apart). The patients had been benzodiazepine free for 47 (4-266) weeks on the first occasion. Subjective ratings of symptoms, thought to be important during/after withdrawal of benzodiazepines, were made before and after each injection, as well as registrations of blood pressure and heart rate. RESULTS: An overall difference existed between previously benzodiazepine-dependent subjects and healthy controls, with patients scoring higher on negative and somatic aggregates and lower on a positive aggregate. A four-way interaction (group x gender x occasion x time) was found for negative and somatic aggregates, which could mainly be explained by the reactions of female patients. Thus, females had the highest base-line ratings and were the only group that showed a significant reduction in symptom ratings after placebo injections on the first occasion. Gender differences were also found for systolic and diastolic blood pressure. There was no significant response to placebo among male patients or for controls (males or females) for ratings of any variable. CONCLUSIONS: The results suggest that there might be gender-specific differences in reactions to placebo injections, with female patients being more affected. Arguments for and against explanatory factors such as expectation, provider factors, habituation, regression toward the mean, and reduction of anxiety are presented.     

A Double-Blind Study of Lorazepam versus the Combination of Haloperidol and Lorazepam in Managing Agitation

Study Objective . To compare the utility of intramuscular lorazepam (LZ) with the combination of intramuscular haloperidol (HDL) and LZ to control acutely agitated behavior. Design . Randomized double-blind comparison. Setting . Psychiatric emergency service of a large, university-affiliated, municipal hospital. Patients . Twenty subjects treated on the psychiatric emergency service. Interventions . Patients received an injection of either LZ 2 mg (11 patients) or HDL 5 mg plus LZ 2 mg (9 patients). The Overt Aggression Scale (OAS), visual analog scales reflecting agitation and hostility, and the Clinical Global Impressions (CGI) severity scale were administered at baseline and 30, 60, 120, and 180 minutes after the injection. Measurements and Main Results . Planned data comparisons included categoric assignment of patients as improved, as defined by decreases in outcome measures 60 minutes after the injection, as well as continuous variables up to 180 minutes after the injection. A significantly greater percentage of subjects receiving combined treatment improved on the specific measures 60 minutes after dosing (p<0.05). Kaplan-Meier survival analyses showed significant between-group differences in survival curves plotted for the entire study period (p<0.05). Repeated measures analyses of variance studying group differences showed that both groups improved over time, but between-group differences were not significant. The powers of these analyses were low due to the small sample. No serious adverse effects occurred in either treatment group. Conclusion . Our results suggest superior efficacy for HDL-LZ over LZ alone. Categoric tests of improvement at 60 minutes provided the strongest evidence of group differences.     

Management of acute agitation in patients with bipolar disorder: efficacy and safety of intramuscular aripiprazole

To investigate the efficacy and safety of intramuscular (IM) aripiprazole for the treatment of agitation in patients with bipolar I disorder, manic or mixed episodes. In total, 301 patients experiencing acute agitation were randomized to IM aripiprazole 9.75 mg per injection (n = 78), IM aripiprazole 15 mg per injection (n = 78), IM lorazepam 2 mg per injection (n = 70), or IM placebo (n = 75) in this double-blind multicenter study. Patients could receive up to 3 injections over 24 hours. Primary efficacy measure was mean change in Positive and Negative Syndrome Scale Excited Component score from baseline at 2 hours after first injection. Mean improvements in Positive and Negative Syndrome Scale Excited Component score at 2 hours were significantly greater with IM aripiprazole (9.75 mg, -8.7; 15 mg, -8.7) and IM lorazepam (-9.6) versus IM placebo (-5.8; P 相似文献   

劳拉西泮与地西泮注射液治疗焦虑状态的随机双盲平行对照研究

目的：评价劳拉西泮注射液治疗焦虑状态的疗效和安全性。方法：采用多中心随机双盲、阳性药平行对照的方法。以地西泮为对照,受试者分别肌内注射劳拉西泮2～6 mg·d~(-1)与地西泮10～30 mg·d~(-1),疗程7 d。结果：125名受试者参加研究。劳拉西泮组63人,地西泮组62人。治疗结束时,2组HAMA总分与基线相比有非常显著差异(P＜0．01),2组减分绝对值比较无显著差异(P＞0．05)。以HAMA总分减分率(50%)判断有效率,劳拉西泮组为67%,地西泮组为71%,2组间比较无显著差异(P＞0．05)。2药常见的不良反应为胃肠道和中枢神经系统症状,多为轻度、一过性；2组不良反应发生的频率比较无显著差异(P＞0．05)。结论：劳拉西泮注射液与地西泮注射液相似,是安全有效的治疗焦虑状态的药物。     

A double-blind crossover controlled study of lorazepam (Wy 4036) and diazepam

Summary

A double-blind crossover trial was carried out in 21 hospitalised patients suffering from various psychoneurotic conditions to compare the anxiolytic effectiveness of lorazepam and diazepam. Patients were divided into two groups and treated either with 1?mg. or 2.5?mg. lorazepam 2- to 3-times daily, or with 5?mg. or 12.5?mg. diazepam 2- to 3-times daily for a period of 10 days. Dosage levels were determined by the initial severity of symptoms. After a wash-out period of 5 days on placebo, patients were then crossed over on comparable dosage to the alternative drug for a further 10 days. The results, as assessed on the Hamilton Rating Scale for anxiety, showed that although both drugs produced a good or excellent response in all 21 patients, lorazepam gave superior results in nearly all the patients treated, with a prompt and greater percentage remission of symptoms than did diazepam. Mild side-effects were reported in only 3 patients.     

A double-blind trial of ‘Nethaprin Dospan’ in chronic asthmatic children

Summary

In a study on 36 children with chronic asthma using a randomised double-blind crossover technique comparing ‘Nethaprin Dospan’ against placebo there was considerable improvement in average PEFR and FEV, values in those patients on active medication. These findings were statistically significant at the p < 0.01 level. A sustained broncho-dilator effect way noted over the 9-hour period of assessment. Wheezing, both on normal expiration and on squeezed expiration, was significantly reduced in the treated group (p<0.01). Cardiovascular side-effects encountered in the study- were minimal.     

Evaluation of the efficacy and safety of home treatment with the recombinant human C1-inhibitor in hereditary angioedema resulting from C1-inhibitor deficiency

ObjectiveConestat alpha, a C1-inhibitor produced by recombinant technology (rhC1-INH) is an acute treatment for edematous attacks occurring in hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE). Our study evaluated the efficacy and safety of rhC1-INH administered during HAE attacks, and for short-term prophylaxis (STP).Materials & methodOur prospective study analyzed the course of 544 HAE attacks experienced by the 21 C1-INH-HAE patients treated, as well as the outcome of 97 instances of STP implemented with rhC1-INH. Using a purpose-designed questionnaire, the patients recorded relevant, treatment-related information.ResultsTime to the administration of rhC1-INH was 90.0 min (median) after the onset of HAE attacks. The symptoms started to improve as early as 60 min after the injection of rhC1-INH, and the attack resolved 730.0 min after treatment. The interval between the onset of the HAE attack and the administration of rhC1-INH correlated with time until the onset of improvement (R = 0.2053 p < 0.0001), and with time to the complete resolution of symptoms (R = 0.2805, p < 0.0001). Nine patients received STP with rhC1-INH in 97 instances. STP successfully prevented the HAE attack within 72 h of the event on 93/97 occasions. No local and serious systemic adverse events/effects were observed.ConclusionsTreatment with rhC1-INH is effective and safe both for acute management, and for STP. Following the onset of an HAE attack, early administration of rhC1-INH may reduce time to the improvement and to the complete resolution of symptoms. Repeated administration of rhC1-INH does not impair its efficacy.     

A double-blind trial of methocarbamol versus placebo in painful muscle spasm

Summary

A double-blind trial of methocarbamol versus placebo was carried out in 59 matched pairs of patients suffering from painful muscle spasm. Methocarbamol {1500?mg. q.d.s) was found to be effective in approximately 60 % of patients compared with 30 % of patients receiving placebo (p< 0.01). Side-effects were of almost equal incidence in the two groups.     

Anxiety therapy in the neoplastic patient

Summary

A clinical study was carried out in 73 neoplastic patients suffering from anxiety and other emotional upsets to assess the effectiveness and tolerance of lorazepam. Patients were given individualised daily doses ranging from 1.5 mg to 3 mg lorazepam for 15 to 60 days. Results, as assessed by the response of anxiety, tension, erethism and insomnia, showed that only 4 (5%) patients failed to obtain some relief There was complete disappearance of all symptoms in 29 (40%) after 15 days, relief of at least one major symptom and reduction in the others in 27 (37%), and slight reduction in one or more symptoms in 13 (18%) patients. Side-effects were minimal and disappeared within a few days with continued treatment.     

Evaluation of lorazepam as an oral preanaesthetic medication. A comparative double-blind study with diazepam and placebo

Summary

A series of 143 patients scheduled for minor or moderate surgical procedures received, in double-blind fashion, a single preanaesthetic dose of either 4?mg. lorazepam, 20?mg. diazepam, or placebo 1 hour preoperatively. Blood pressure, heart rate, and respiratory rate, as well as the apparent sedative state of the patient, were determined the evening before surgery and again in the operating room an hour after premedication.

After premedication, 18 lorazepam patients (37%), 7 diazepam patients (15%), and 3 placebo patients (6%) were considered well sedated. Results with lorazepam were significantly better than with either diazepam or placebo. Increased sedation after premedication was noted in 55% of lorazepam patients, 39% of diazepam patients, and 23 % of placebo patients.

Changes in blood pressure, heart rate, or respiratory rate with either active drug were not appreciably different from placebo.     

Section B Clinical experience with lorazepam in the treatment of neurotic patients

Summary

A double-blind crossover study was designed to compare the anxiolytic properties of the benzodiazepines, lorazepam and diazepam, and to evaluate the principal side-effects prior to lorazepam's wider use in patients. Thirty patients with psychic or somatic symptoms of anxiety were given one active drug for a month, a placebo for 15 days and the other active drug for one month. Both lorazepam 1.25?mg. t.d.s., and diazepam 5?mg. t.d.s., alleviated anxiety to the same extent and gave a similar incidence of side-effects.

Further use of lorazepam in a large number of patients has shown that most benefit from 1?mg. t.d.s. This dose could be increased progressively to 2.5?mg. t.d.s. It is suggested that lorazepam deserves particular attention since it is the most potent member of the benzodiazepine anxiolytics in clinical use.     

The use of lorazepam TID for chronic insomnia

Patients with primary insomnia typically complain of daytime fatigue and stress and have been shown to have long latencies on the Multiple Sleep Latency Test and increased whole body metabolism. However, typical treatment strategies for patients with insomnia rarely include any component to deal with these daytime symptoms. In the present study it was hypothesized that a 24-h treatment, lorazepam 0.5 mg TID, would be superior to an evening treatment, lorazepam 1.5 mg HS, in patients with primary insomnia. In a repeated measures crossover design, 12 patients with chronic insomnia received placebo or lorazepam 0.5 mg TID in one 4-night lab stay and placebo or lorazepam 1.5 mg HS in another lab stay. Both doses of medication were effective in improving objective and subjective measures of sleep and in reducing nocturnal whole body metabolic rate. Latencies on daytime nap testing were significantly reduced from a 14-min average to an average of 10 and 12 min, respectively, in the lorazepam 0.5 and 1.5 mg conditions. Significant differences were not found on psychomotor performance. Subjective reports of anxiety and confusion were increased in the morning after receiving lorazepam 0.5 mg in the evening but tension was reduced and subjective alertness was improved in the evening after daytime administration of lorazepam 0.5 mg. It was concluded that measurement and treatment of daytime symptoms is appropriate in patients with chronic insomnia but that rebounds in anxiety near the end of metabolic activity of lorazepam may make it a poor treatment choice.     

Section B Review of two years clinical experience with lorazepam

Summary

Lorazepam has been used during the past two years to treat approximately 250 hospital patients suffering from symptoms of anxiety and tension. In-patients and outpatients of all ages have been treated. The average dosage range was 0.5 to 5?mg. lorazepam t.d.s. The highest daily dose was 30?mg.; the longest duration of treatment almost 2 years. Distinct improvement in symptoms such as anxiety, restlessness, agitation, tension, irritability and insomnia has been noted in about 70% of patients with very few side-effects. Typical case histories are discussed. It is concluded that lorazepam is an effective, extremely well-tolerated drug, particularly suitable for out-patients provided the dosage is carefully adjusted.     

Reflux symptom relief with omeprazole in patients without unequivocal oesophagitis

Background : As many as 50% of patients with reflux symptoms have no endoscopic evidence of oesophagitis. This multicentre study was designed to assess symptom relief after omeprazole 20 mg once daily in patients with symptoms typical of gastro-oesophageal reflux disease but without endoscopic evidence of oesophagitis.
Methods : Patients ( n =209) were randomized in a double-blind study to receive either omeprazole 20 mg once daily ( n =98) or placebo ( n =111) for 4 weeks. Symptoms were assessed at clinic visits and using daily diary cards, with patient-completed questionnaires providing additional data on symptoms and on psychological disturbance.
Results : On completion, symptom relief favoured omeprazole: 57% of patients on omeprazole were free of heartburn (vs. 19% on placebo), 75% were free of regurgitation (47%) and 43% were completely asymptomatic (14%), each with P <0.0001. Fewer patients in the omeprazole group required alginate/antacid relief medication ( P <0.05). Symptom relief (time to first heartburn-free day) was more rapid with omeprazole (2 vs. 5 days on placebo; P <0.01). A greater reduction in anxiety occurred in the omeprazole group ( P <0.05).
Conclusion : Omeprazole 20 mg once daily is effective in providing relief of the symptoms typical of gastro-oesophageal reflux disease in patients with essentially normal oesophageal mucosa.     

Effects of benfluorex on patients with endogenous hypertriglyceridaemia

Summary

Twenty-two patients showing persistent endogenous hypertriglyceridaemia after an individually designed diet for 1 month were randomly divided into two groups. Each was treated during two crossover consecutive 40-day periods, either starting with benfluorex (450?mg/day) or with placebo. They were followed as out-patients and were investigated at the start of the study, and at the end of each treatment period. A number of laboratory measurements were undertaken at each visit, including triglycerides, cholesterol, uric acid, fatty acids, and glucose and insulin after an oral glucose tolerance test. The results showed a significant (p<0.01) reduction in triglyceride blood levels of 32.7% after benfluorex treatment compared to 11.7% with placebo, irrespective of the treatment order. Other laboratory measurements were in the normal range, and there were no significant changes, except for uric acid which showed a small decrease but of little clinical significance. Benfluorex would appear to have an important therapeutic effect on endogenous hypertriglyceridaemia.     

Treatment of Acute Anxiety and Agitation by Intravenous Administration of Lorazepam

Summary

Fifty acutely anxious and\or agitated patients requiring immediate sedation were treated with intravenous lorazepam. Most patients responded to a dose of 5 to 10?mg. (average 7.5?mg.), and the sedative-hypnotic effect became apparent within 5 minutes of injection, except in severe cases. In these patients, dosage was increased to 15 to 20?mg., and even to 30 to 40?mg. in those with delirium tremens, who proved difficult to treat with lorazepam alone. Side-effects were minimal and not troublesome, and there was no evidence of respiratory depression or cardiovascular effects, even in the elderly patients treated. Local tolerance of the injection was very good.     

Intramuscular/oral lorazepam in acute alcohol withdrawal and incipient delirium tremens

Summary

An open study was carried out in 21 chronic alcoholics with severe withdrawal symptoms and incipient delirium tremens to evaluate the efficacy of adjuvant treatment with intramuscular lorazepam (5?mg). All symptoms subsided within 2 hours after a single injection and remained under control with oral lorazepam (mean daily dose 7?mg). No adverse reactions attributable to lorazepam were observed.     

Long-term comparison of alprazolam, lorazepam and placebo in patients with an anxiety disorder

In a double-blind, placebo-controlled study of 200 patients with moderate to moderately severe anxiety we compared the anxiolytic efficacy and safety of alprazolam and lorazepam. Dosing was flexible and ranged from 1 to 4.5 mg/day of alprazolam and from 2 to 9 mg/day of lorazepam. The mean daily dose at the end of the 16 week study was alprazolam 3.3 mg and lorazepam 5.1 mg. Both active drugs were significantly more effective than placebo in relieving the symptoms of anxiety on the Hamilton Anxiety Rating Scale, with a trend toward more improvement in the alprazolam group in the later weeks of the study. Target Symptoms, Physician's and Patient's Global Impressions and the Self Rating Symptom Scale indicate that alprazolam and lorazepam were superior to placebo. The major side effects were sedation and drowsiness; the frequency was similar for alprazolam and lorazepam and twice as high for active drug as placebo. An overall rating of side effect severity was not significantly different among the three groups.