Efficacy of lorazepam and haloperidol for rapid tranquilization in a psychiatric emergency room setting. Droperidol vs. haloperidol in the initial management of acutely agitated patients. A comparison of parenteral loxapine and haloperidol in hostile and aggressive acutely schizophrenic patients. A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients. A double-blind comparison between loxapine and haloperidol by parenteral route in acute schizophrenia. Combined therapy with low-potency neuroleptic levomepromazine as an adjunct to haloperidol for agitated patients with acute exacerbation of schizophrenia. Comparative study of the effectiveness of zuclopenthixol acetate and haloperidol in acutely disturbed psychotic patients. Intramuscular flunitrazepam versus intramuscular haloperidol in the emergency treatment of aggressive psychotic behavior. A double-blind comparison of haloperidol with perphenazine in acute psychiatric episodes. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Parenteral lorazepam versus parenteral haloperidol for the control of psychotic disruptive behavior. Rapid tranquilization of acutely psychotic patients with intramuscular haloperidol and chlorpromazine. Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine. Parenteral haloperidol for rapid control of severe, disruptive symptoms of acute schizophrenia. Relative efficacy of parenteral haloperidol and thiothixene for the emergency treatment of acutely excited and agitated patients. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. Intramuscular ziprasidone compared with intramuscular haloperidol in the treatment of acute psychosis. Ziprasidone I.M. Study Group. Loxapine versus haloperidol parenterally in acute psychosis with agitation. A double-blind study. Efficacy of combinations of intramuscular antipsychotics and sedative-hypnotics for control of psychotic agitation. Comparison of injectable haloperidol and chlorpromazine.
The efficacy of a benzodiazepine was compared with that of a neuroleptic for the rapid tranquilization of patients presenting at a psychiatric emergency room service. Thirty-seven highly agitated patients exhibiting psychotic symptoms were randomly assigned to receive either 2 mg lorazepam or 5 mg haloperidol as needed every 30 min for 4 h. Administration route was either intramuscular injection or oral concentrate. Symptom ratings were conducted each hour using double-blind procedures. Both medications reduced symptom ratings on the Brief Psychiatric Rating Scale and Global Clinical Impression of Overall Symptom Severity Scale. Global Clinical Impression scores for the two medication groups did not differ significantly either at baseline or at 4 h after entry into the study. However, Global Clinical Impression scores of patients in the lorazepam group were less severe at intermittent ratings. The groups did not differ on the Brief Psychiatric Rating Scale at any rating time. No differences were found either in the number of doses administered or in the administration route selected. Given the potential for severe extrapyramidal symptoms developing hours or days after a single dose of haloperidol, lorazepam may provide an excellent alternative for the rapid tranquilization of the acutely agitated psychotic patient in the emergency room setting. In a double-blind clinical study, 27 acutely agitated patients were treated with an intramuscular injection of 5 mg of droperidol or 5 mg of haloperidol from identical appearing vials. At 30 minutes following treatment, 81% of the patients treated with haloperidol but only 36% treated with droperidol required a second injection (p less than .05). Thus, droperidol, a safe butyrophenone neuroleptic, appears to be a drug of choice for rapid and reliable control of acute agitation. In a parallel groups, double-blind study, 54 acutely psychotic schizophrenics were given loxapine or haloperidol parenterally for 24 to 72 hours, then orally for a total study period of up to 10 days. Dosage ratios of loxapine to haloperidol ranged from a minimum of 2.7:1 to a maximum of 4.4:1. Both groups showed significant and rapid improvement from baseline. Forty-eight percent of the loxapine patients and 33% of the haloperidol patients achieved and maintained a global severity of illness rating of mild or better. By the end of the study, 84% of the loxapine patients and 63% of the haloperidol patients had achieved an improvement rating of moderate or marked. This difference approached significance (p less than .10). The most frequently reported adverse experiences were dystonic reactions and akathisia. The number and severity of adverse experiences did not differ significantly between drug groups. Intramuscular loxapine was at least as effective as haloperidol in the initial management of hostile and aggressive schizophrenic patients. The maintenance of therapeutic response after conversion to oral concentrate was comparable with the two drugs. To determine if midazolam is superior to lorazepam or haloperidol in the management of violent and severely agitated patients in the emergency department. Superiority would be determined if midazolam resulted in a significantly shorter time to sedation and shorter time to arousal.
                This was a randomized, prospective, double-blind study of a convenience sample of patients from an urban, county teaching emergency department. Participants included 111 violent and severely agitated patients. Patients were randomized to receive intramuscular midazolam (5 mg), lorazepam (2 mg), or haloperidol (5 mg).
                The mean (+/-SD) age was 40.7 (+/-13) years. The mean (+/-SD) time to sedation was 18.3 (+/-14) minutes for patients receiving midazolam, 28.3 (+/-25) minutes for haloperidol, and 32.2 (+/-20) minutes for lorazepam. Midazolam had a significantly shorter time to sedation than lorazepam and haloperidol (p < 0.05). The mean difference between midazolam and lorazepam was 13.0 minutes (95% confidence interval [95% CI] = 5.1 to 22.8 minutes) and that between midazolam and haloperidol was 9.9 minutes (95% CI = 0.5 to 19.3 minutes). Time to arousal was 81.9 minutes for patients receiving midazolam, 126.5 minutes for haloperidol, and 217.2 minutes for lorazepam. Time to arousal for midazolam was significantly shorter than for both haloperidol and lorazepam (p < 0.05). The mean difference in time to awakening between midazolam and lorazepam was 135.3 minutes (95% CI = 89 to 182 minutes) and that between midazolam and haloperidol was 44.6 minutes (95% CI = 9 to 80 minutes). There was no significant difference over time by repeated-measures analysis of variance between groups in regard to changes in systolic and diastolic blood pressure (p = 0.8965, p = 0.9581), heart rate (p = 0.5517), respiratory rate (p = 0.8191), and oxygen saturation (p = 0.8991).
                Midazolam has a significantly shorter time to onset of sedation and a more rapid time to arousal than lorazepam or haloperidol. The efficacies of all three drugs appear to be similar. nan nan To study the effectiveness, frequency of administration and side effects of zuclopenthixol acetate (ZPTA) and haloperidol (HAL) in the treatment of acute psychotic disturbance with aggression.
                Purposive sampling method was employed in a group of psychotic patients with aggression admitted to Songkla Neuropsychiatric Hospital, they were randomly divided into 2 groups: ZPTA group and HAL group. All of the patients were evaluated daily for 7 consecutive days using the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression Scale (CGI). Statistical analysis was performed by using the Student t-test and Linear regression.
                There were 70 patients with diagnosis of schizophrenia, mania and acute psychosis. Thirty-eight patients were randomly assigned to the ZPTA group and were given 50-100 mg of the drug, while 32 patients received HAL 5-10 mg. The result showed a significant reduction in BPRS or CGI scores in both groups. Patients treated with ZPTA required less frequent administration than did those on HAL (p < 0.05). There was no statistically significant difference in the reduction in scores between the two groups. Nor was there a statistical difference in reduction of aggression based on BPRS rating. Each group of patients showed a few side effects of mild degree.
                Both ZPTA and HAL were effective in the treatment of acute psychosis with aggression, but frequency of administration was lower in the ZPTA group The authors examined the efficacy of intramuscular flunitrazepam compared with intramuscular haloperidol for the immediate control of agitated or aggressive behavior in acutely psychotic patients.
                Twenty-eight actively psychotic inpatients, aged 20-60 years, who were under treatment with neuroleptic agents were selected for the study. Each was randomly assigned on a double-blind basis to receive either 5 mg i.m. of haloperidol (N=13) or 1 mg i.m. of flunitrazepam (N=15) during an aggressive event. Verbal and physical aggression was measured over time with the Overt Aggression Scale. Patients were also rated with the Brief Psychiatric Rating Scale and the Clinical Global Impression scale.
                Both flunitrazepam and haloperidol exhibited acute antiaggressive activity. This beneficial effect, as assessed by the Overt Aggression Scale, was obtained within 30 minutes.
                Intramuscular flunitrazepam may serve as a convenient, rapid, safe, and effective adjunct to neuroleptics in reducing aggressive behavior in emergency psychiatric settings. nan Rapid tranquilization is a routinely practiced method of calming agitated psychotic patients by use of neuroleptics, benzodiazepines, or both in combination. Although several studies have examined the efficacy of the three approaches, none have compared these treatments in a prospective, randomized, double-blind, multicenter trial. Ninety-eight psychotic, agitated, and aggressive patients (73 men and 25 women) were prospectively enrolled during an 18-month period in emergency departments in five university or general hospitals. Patients were randomly assigned to receive intramuscular injections of lorazepam (2 mg), haloperidol (5 mg), or both in combination. Patients in each treatment group received 1 to 6 injections of the same study drug within 12 hours, based on clinical need. They were evaluated hourly after the first injection until at least 12 hours after the last. Efficacy was assessed on the Agitated Behavior Scale (ABS), a modified Brief Psychiatric Rating Scale (MBPRS), Clinical Global impressions (CGI) scale, and an Alertness Scale. Effective symptom reduction was achieved in each treatment group with significant (P < .01) mean decreases from baseline at every hourly ABS evaluation. Significant (P < .05) mean differences on the ABS (hour 1) and MBPRS (hours 2 and 3) suggest that tranquilization was most rapid in patients receiving the combination treatment. Study event incidence (side effects) did not differ significantly between treatment groups, although patients receiving haloperidol alone tended to have more extrapyramidal system symptoms. The superior results produced by the combination treatment support the use of lorazepam plus haloperidol as the treatment of choice for acute psychotic agitation. In a double-blind, prospective study, 2 mg of intramuscular lorazepam and 5 mg of intramuscular haloperidol were equally effective in controlling aggression, agitation, and assaultive behavior. Although lorazepam and haloperidol produced an equivalent mean decrease in aggression, significantly more subjects who received lorazepam had a greater decrease in aggression ratings than haloperidol recipients; this effect was independent of sedation. Lorazepam produced significantly fewer extrapyramidal symptoms. These data support the current clinical practice of using lorazepam (alone, or in combination with a neuroleptic) for control of acute aggressive and assaultive behavior. nan To determine whether haloperidol alone results in swifter and safer tranquillisation and sedation than haloperidol plus promethazine.
                Pragmatic randomised open trial (January-July 2004).
                Psychiatric emergency room, Rio de Janeiro, Brazil.
                316 patients who needed urgent intramuscular sedation because of agitation, dangerous behaviour, or both.
                Open treatment with intramuscular haloperidol 5-10 mg or intramuscular haloperidol 5-10 mg plus intramuscular promethazine up to 50 mg; doses were at the discretion of the prescribing clinician.
                The primary outcome was proportion tranquil or asleep by 20 minutes. Secondary outcomes were asleep by 20 minutes; tranquil or asleep by 40, 60, and 120 minutes; physically restrained or given additional drugs within 2 hours; severe adverse events; another episode of agitation or aggression; additional visit from the doctor during the subsequent 24 hours; overall antipsychotic load in the first 24 hours; and still in hospital after 2 weeks.
                Primary outcome data were available for 311 (98.4%) people, 77% of whom were thought to have a psychotic illness. Patients allocated haloperidol plus promethazine were more likely to be tranquil or asleep by 20 minutes than those who received intramuscular haloperidol alone (relative risk 1.30, 95% confidence interval 1.10 to 1.55; number needed to treat 6, 95% confidence interval 4 to 16; P=0.002). No differences were found after 20 minutes. However, 10 cases of acute dystonia occurred, all in the haloperidol alone group.
                Haloperidol plus promethazine is a better option than haloperidol alone in terms of speed of onset of action and safety. Enough data are now available to change guidelines that continue to recommend treatments that leave people exposed to longer periods of aggression than necessary and patients vulnerable to distressing and unsafe adverse effects.
                Current Controlled Trials ISRCTN83261243 [controlled-trials.com]. Intramuscular haloperidol, at three dose levels, (5 mg, 2 mg, and 1 mg) chlorpromazine (25 mg), and placebo were compared for efficacy, rapidity of therapeutic onset, and safety in 50 acute psychotic patients requiring rapid control. The drugs were administered parenterally under double-blind conditions at half-hour intervals until successful control of moderate to very severe symptomatology was achieved or a maximum of four injections had been given. Global evaluation, BPRS, and target symptom ratings were performed. The overall results indicated that the 5 mg and 2 mg haloperidol doses were significantly superior to the 1 mg haloperidol and 25 mg chlorpromazine doses and to placebo. Transfer of patients to oral haloperidol was satisfactorily accomplished. Side effects for all medications were minimal and included slight to moderate EPS and drowsiness. The use of antiparkinson drugs completely controlled the extrapyramidal symptoms. In this double-blind study, haloperidol (n = 15) and thiothixene (n = 15), administered parenterally in emergency rooms and outpatient facilities to 30 acutely excited, agitated psychotic patients in hourly doses of 4 mg. or 8 mg., as needed over a four-hour period (total dosage ranging from 4 to 32 mg.), achieved rapid tranquilization in 30 patients. Significant improvement was shown over a six-hour period on BPRS Total Score, the four factors--Thinking Disorder, Anergic state, Excitement and Disorientation, and Depression and also on hourly ratings of 17 symptoms of a Psychiatric Target Symptom Profile. No significant differences were found between the haloperidol-treated and thiothixene-treated groups. Few adverse reactions were noted, all of them mild, the most frequent being drowsiness in six patients. An intramuscular (IM) formulation of olanzapine has been developed because there are no rapid-acting IM atypical antipsychotic drugs currently available in the United States for treating acute agitation in patients with schizophrenia.
                Recently hospitalized acutely agitated patients with schizophrenia (N = 270) were randomized to receive 1 to 3 IM injections of olanzapine (2.5, 5.0, 7.5, or 10.0 mg), haloperidol (7.5 mg), or placebo within 24 hours. A dose-response relationship for IM olanzapine in the reduction of agitation was assessed by measuring the reduction in Positive and Negative Syndrome Scale Excited Component (PANSS-EC) scores 2 hours after the first injection. Safety was assessed by recording adverse events and with extrapyramidal symptom scales and electrocardiograms at 24 hours after the first injection.
                Olanzapine exhibited a dose-response relationship for reduction in agitation (F(1,179)= 14.4; P<.001). Mean PANSS-EC reductions 2 hours after the first injection of olanzapine (2.5 mg = -5.5; 5.0 mg = -8.1; 7.5 mg = -8.7; 10.0 mg = -9.4) were superior to those with placebo (-2.9; P =.01 vs olanzapine at 2.5 mg; P<.001 for each other olanzapine dose) but not with haloperidol (-7.5). A dose of 5.0, 7.5, or 10.0 mg of olanzapine caused a greater reduction in agitation than placebo 30 minutes after the first injection. There were no differences between treatment groups for hypotension, the most frequently reported adverse event, or for clinically relevant changes in the QTc interval. There was a greater incidence of treatment-emergent parkinsonism during treatment with IM haloperidol (16.7%) than with 2.5 (P =.03), 5.0 (P =.03), or 7.5 mg (P =.01) of IM olanzapine (0%) or with placebo (0%) (P =.01).
                Intramuscular olanzapine at a dose of 2.5 to 10.0 mg per injection exhibits a dose-response relationship in the rapid treatment of acute agitation in patients with schizophrenia and demonstrates a favorable safety profile. Standard treatment for acute psychotic agitation often involves intramuscular administration of the benzodiazepine lorazepam and the antipsychotic haloperidol. This study compared the efficacy and safety of oral treatment with the atypical antipsychotic risperidone plus lorazepam with those of standard intramuscular treatment. We hypothesized that the efficacy and speed of action of both treatments would be similar.
                In a prospective, parallel-group, randomized, rater-blinded noninferiority study conducted at 24 sites in the United States, 162 patients exhibiting agitation associated with active psychosis were randomly assigned to receive either oral treatment with 2 mg of risperidone plus 2 mg of lorazepam (N = 83) or intramuscular treatment with 5 mg of haloperidol plus 2 mg of lorazepam (N = 79). The change scores on a 5-item acute-agitation cluster from the Positive and Negative Syndrome Scale (hallucinatory behavior, excitement, hostility, uncooperativeness, and poor impulse control) were the main outcome measure. The study was conducted from January 8 to August 8, 2001.
                Mean acute-agitation cluster scores were similar in the 2 groups at baseline. Mean score improvements at 30, 60, and 120 minutes after dosing were significant at each timepoint in both groups (p <.0001) and were similar in both groups (p >.05). Both treatments were well tolerated.
                A single oral dose of risperidone plus lorazepam was as effective as parenterally administered haloperidol plus lorazepam for the rapid control of agitation and psychosis. These findings suggest that this oral regimen is an acceptable alternative to the current intramuscular treatment for acute psychotic agitation. This 7-day, randomized, open-label, multicenter, international study compared the efficacy and tolerability of intramuscular (i.m.) ziprasidone with haloperidol i.m. and the transition from i.m. to oral treatment in hospitalized patients with acute psychotic agitation (related to DSM-III-R diagnoses).
                Patients received up to 3 days of flexible-dose ziprasidone i.m. (N = 90) or haloperidol i.m. (N = 42) followed by oral treatment to day 7. After an initial ziprasidone i.m. dose of 10 mg, subsequent i.m. doses of 5 to 20 mg could be given every 4 to 6 hours (maximum daily dose = 80 mg) if needed, followed by oral ziprasidone, 80-200 mg/day. Haloperidol i.m. doses of 2.5 to 10 mg were given on entry, followed by 2.5 to 10 mg i.m. every 4 to 6 hours (maximum daily dose = 40 mg) if needed, then by oral haloperidol, 10-80 mg/day.
                The mean reductions in Brief Psychiatric Rating Scale (BPRS) total, BPRS agitation items, and Clinical Global Impressions-Severity scale scores were statistically significantly greater (p < .05, p < .01, and p < .01, respectively) after ziprasidone i.m. treatment compared with haloperidol i.m. treatment. Further reductions in these scores also occurred in both groups following transition to oral treatment. Ziprasidone was associated with a lower incidence of movement disorders and a reduced requirement for anticholinergic medication during both i.m. and oral treatment compared with haloperidol. Movement disorder scale scores improved with ziprasidone i.m. and oral treatment, but deteriorated with haloperidol. Other adverse events were rare with both treatments.
                Ziprasidone i.m. was significantly more effective in reducing the symptoms of acute psychosis and was better tolerated than haloperidol i.m., particularly in movement disorders. The transition from ziprasidone i.m. to oral ziprasidone was effective and well tolerated. nan The combination of haloperidol, 5 mg, and lorazepam, 4 mg, was both effective and safe for managing agitated behavior in an open trial with acutely psychotic patients. The combination also appeared to be superior to its individual components when studied in a randomized, nonblind trial. The principle of the combined use of antipsychotics and sedative-hypnotics was further tested by comparing two new combinations: thiothixene, 5 mg, and lorazepam, 4 mg, versus haloperidol, 5 mg, and phenobarbital sodium, 130 mg. These combinations had comparable efficacy and safety, and the level of transquilization approached that produced by the haloperidol-lorazepam combination in the preceding studies. nan
If no other alternative exists, sole use of intramuscular haloperidol could be life-saving. Where additional drugs to offset the adverse effects are available, sole use of haloperidol for the extreme emergency, in situations of coercion, could be considered unethical. Addition of the sedating promethazine has support from better-grade evidence from within randomised trials. Use of an alternative antipsychotic drug is only partially supported by fragmented and poor-grade evidence. Evidence for use of newer generation antipsychotic alternatives is no stronger than that for older drugs. Adding a benzodiazepine to haloperidol does not have strong evidence of benefit and carries a risk of additional harm.
After six decades of use for emergency rapid tranquillisation, this is still an area in need of good independent trials relevant to real world practice.