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Background: Health services often manage agitated or violent people, and such behaviour is particularly prevalent in emergency psychiatric services (10%). The drugs used in such situations should ensure that the person becomes calm swiftly and safely., Objectives: To examine whether haloperidol plus promethazine is an effective treatment for psychosis-induced aggression., Search Methods: On 6 May 2015 we searched the Cochrane Schizophrenia Group's Register of Trials, which is compiled by systematic searches of major resources (including MEDLINE, EMBASE, AMED, BIOSIS, CINAHL, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings., Selection Criteria: All randomised clinical trials with useable data focusing on haloperidol plus promethazine for psychosis-induced aggression., Data Collection and Analysis: We independently extracted data. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE., Main Results: We found two new randomised controlled trials (RCTs) from the 2015 update searching. The review now includes six studies, randomising 1367 participants and presenting data relevant to six comparisons.When haloperidol plus promethazine was compared with haloperidol alone for psychosis-induced aggression for the outcome not tranquil or asleep at 30 minutes, the combination treatment was clearly more effective (n=316, 1 RCT, RR 0.65, 95% CI 0.49 to 0.87, high-quality evidence). There were 10 occurrences of acute dystonia in the haloperidol alone arm and none in the combination group. The trial was stopped early as haloperidol alone was considered to be too toxic.When haloperidol plus promethazine was compared with olanzapine, high-quality data showed both approaches to be tranquillising. It was suggested that the combination of haloperidol plus promethazine was more effective, but the difference between the two approaches did not reach conventional levels of statistical significance (n=300, 1 RCT, RR 0.60, 95% CI 0.22 to 1.61, high-quality evidence). Lower-quality data suggested that the risk of unwanted excessive sedation was less with the combination approach (n=116, 2 RCTs, RR 0.67, 95% CI 0.12 to 3.84).When haloperidol plus promethazine was compared with ziprasidone all data were of lesser quality. We identified no binary data for the outcome tranquil or asleep. The average sedation score (Ramsay Sedation Scale) was lower for the combination approach but not to conventional levels of statistical significance (n=60, 1 RCT, MD -0.1, 95% CI - 0.58 to 0.38). These data were of low quality and it is unclear what they mean in clinical terms. The haloperidol plus promethazine combination appeared to cause less excessive sedation but again the difference did not reach conventional levels of statistical significance (n=111, 2 RCTs, RR 0.30, 95% CI 0.06 to 1.43).We found few data for the comparison of haloperidol plus promethazine versus haloperidol plus midazolam. Average Ramsay Sedation Scale scores suggest the combination of haloperidol plus midazolam to be the most sedating (n=60, 1 RCT, MD - 0.6, 95% CI -1.13 to -0.07, low-quality evidence). The risk of excessive sedation was considerably less with haloperidol plus promethazine (n=117, 2 RCTs, RR 0.12, 95% CI 0.03 to 0.49, low-quality evidence). Haloperidol plus promethazine seemed to decrease the risk of needing restraints by around 12 hours (n=60, 1 RCT, RR 0.24, 95% CI 0.10 to 0.55, low-quality evidence). It may be that use of midazolam with haloperidol sedates swiftly, but this effect does not last long.When haloperidol plus promethazine was compared with lorazepam, haloperidol plus promethazine seemed to more effectively cause sedation or tranquillisation by 30 minutes (n=200, 1 RCT, RR 0.26, 95% CI 0.10 to 0.68, high-quality evidence). The secondary outcome of needing restraints or seclusion by 12 hours was not clearly different between groups, with about 10% in each group needing this intrusive intervention (moderate-quality evidence). Sedation data were not reported, however, the combination group did have less 'any serious adverse event' in 24-hour follow-up, but there were not clear differences between the groups and we are unsure exactly what the adverse effect was. There were no deaths.When haloperidol plus promethazine was compared with midazolam, there was clear evidence that midazolam is more swiftly tranquillising of an aggressive situation than haloperidol plus promethazine (n=301, 1 RCT, RR 2.90, 95% CI 1.75 to 4.8, high-quality evidence). On its own, midazolam seems to be swift and effective in tranquillising people who are aggressive due to psychosis. There was no difference in risk of serious adverse event overall (n=301, 1 RCT, RR 1.01, 95% CI 0.06 to 15.95, high-quality evidence). However, 1 in 150 participants allocated haloperidol plus promethazine had a swiftly reversed seizure, and 1 in 151 given midazolam had swiftly reversed respiratory arrest., Authors' Conclusions: Haloperidol plus promethazine is effective and safe, and its use is based on good evidence. Benzodiazepines work, with midazolam being particularly swift, but both midazolam and lorazepam cause respiratory depression. Olanzapine intramuscular and ziprasidone intramuscular do seem to be viable options and their action is swift, but resumption of aggression with subsequent need to re-inject was more likely than with haloperidol plus promethazine. Haloperidol used on its own without something to offset its frequent and serious adverse effects does seem difficult to justify.

Background: Health services often manage agitated or violent people, and for emergency psychiatric services such behaviour is particularly prevalent (10%). The drugs used in this situation should ensure that the person swiftly and safely regains composure., Objectives: To examine whether haloperidol plus promethazine is an effective treatment for psychosis induced agitation/aggression., Search Strategy: We searched the Cochrane Schizophrenia Group's Register (January 2008)., Selection Criteria: We included all randomised clinical trials involving aggressive people with psychosis for which haloperidol plus promethazine was being used., Data Collection and Analysis: We reliably selected, quality assessed and extracted data from all relevant studies. For binary outcomes we calculated standard estimations of risk ratio (RR) and their 95% confidence intervals (CI). Where possible we estimated weighted number needed to treat or harm (NNT/H)., Main Results: We identified four relevant high quality studies. One compared the haloperidol plus promethazine mix with midazolam (n=301), one with lorazepam (n=200), one with haloperidol alone (n=316) and one with olanzapine IM (n=300). In Brazil, haloperidol plus promethazine was an effective means of tranquillisation with over two thirds of people being tranquil or sedated by 30 minutes, but midazolam was more swift (n=301, RR 2.9 CI 1.75 to 4.80, NNH 5 CI 3 to 12). In India, compared with lorazepam, more people were tranquil or sedated by 30 minutes if allocated to the combination treatment (n=200, RR 0.26 CI 0.10 to 0.68, NNT 8 CI 6 to 17). Over the next few hours of treatment reported differences are negligible. One person given midazolam had respiratory depression (0.7%, reversed by flumazenil); one given lorazepam (1%) had respiratory difficulty. About 1% of people given any haloperidol treatment experienced a seizure. By 20 minutes intramuscular haloperidol plus promethazine was more tranquillising than intramuscular haloperidol (1 RCT, n=316, RR 0.65 CI 0.49 to 0.87, NNT 7 CI 5 to 17). Haloperidol given without promethazine in this situation causes frequent serious adverse effects (NNH 15 CI 14 to 40). Olanzapine is as rapidly tranquillising as the haloperidol/promethazine combination (1 RCT, n=300, RR tranquil or asleep at 15 mins 0.74 CI 0.38 to 1.41), but did not have an enduring effect and more people needed additional drugs within four hours (1 RCT, n=300, RR 0.48 CI 0.33 to 0.69, NNT 5 CI 4 to 8) and to be re-assessed by the doctor (1 RCT, n=300, RR 0.47 CI 0.30 to 0.73, NNT 6 CI 5 to 12)., Authors' Conclusions: All treatments evaluated within the included studies are effective. Benzodiazepines, however, have the potential to cause respiratory depression, probably midazolam more so than lorazepam, and use of this group of drugs outside of services fully confident of observing for and managing the consequences of respiratory distress is difficult to justify. Haloperidol used on its own is at such risk of generating preventable adverse effects that unless it is the only choice, this evidence directs that this sole treatment should be avoided. Olanzapine IM is valuable when compared with haloperidol plus promethazine but its duration of action is short and re-injection is frequently needed. Haloperidol plus promethazine used in two diverse situations in Brazil and India has much evidence to support its swift and safe clinically valuable effects.

Background: Health services often manage agitated or violent people and for emergency psychiatric services such behaviour is particularly prevalent (10%). The drugs used in this situation should ensure that the person swiftly and safely becomes calm., Objectives: To examine whether haloperidol plus promethazine is an effective treatment for psychosis induced agitation/aggression., Search Strategy: We searched the Cochrane Schizophrenia Group's Register (July 2004)., Selection Criteria: We included all randomised clinical trials involving aggressive people with psychosis for which haloperidol plus promethazine was being used., Data Collection and Analysis: We reliably selected, quality assessed and extracted data from all relevant studies. For binary outcomes we calculated standard estimations of risk ratio (RR) and their 95% confidence intervals (CI). Where possible we estimated weighted number needed to treat or harm (NNT/H)., Main Results: We identified two relevant high quality studies. One compared the haloperidol plus promethazine mix with midazolam (n=301) and one with lorazepam (n=200). The combined results were largely heterogeneous. In Brazil, haloperidol plus promethazine was an effective means of tranquillisation with over two thirds of people being tranquil or sedated by 30 minutes, but midazolam was more swift (n=301, RR 2.9 CI 1.75 to 4.80, NNH 5 CI 3 to 12). In India, however, 95% of people were tranquil or sedated by 30 minutes if allocated to the combination treatment (vs lorazepam, n=200, RR 0.26 CI 0.10 to 0.68, NNT 8 CI 6 to 17). Over the next few hours of treatment reported differences are negligible. One person given midazolam had respiratory depression (reversed by flumazenil), one given lorazepam had respiratory difficulty. A single person given haloperidol plus promethazine had an epileptic fit. Once the initial tranquillisation was administered, few needed additional medications for continued agitation (n=501, 2 RCTs, RR needing additional tranquillising drugs by four hours 1.67 CI 0.62 to 4.54, 4% vs 2%, I squared 50%) and there were no differences in the low levels of use of restraints. About 28% of people in Brazil in both groups had another episode of aggression in the first day after the initial injection (n=301, RR 0.89 CI 0.62 to 1.29). About half of all people in the Indian study were discharged by four hours (n=200, RR 1.13 CI 0.85 to 1.50) and a similar proportion in Brazil by 15 days (n=301, RR 1.05 CI 0.84 to 1.29). Both studies attained 99% follow up for their primary outcomes. Even by two weeks only 4% of people could not be accounted for (n=501, 2 RCTs, RR 0.91 CI 0.38 to 2.17)., Authors' Conclusions: This review suggests that both benzodiazepines work, but that midazolam has a faster onset and thereby reduces the risk of exposure to violence. Both benzodiazepines have the potential to cause respiratory depression, probably midazolam more so than lorazepam, and we would question the use of this group of drugs outside of those services fully confident of observing for and managing the consequences of respiratory distress. Most evidence, however, exists for the haloperidol plus promethazine mix, with currently more than 400 people randomised to the combination. The onset of action is swift and faster than lorazepam. The combination also seems safe with no clear longer term consequences. We would expect policy makers recommending other drug managements to have equally compelling evidence to support their guidance and hope that this would not be founded in conjecture or consensus, which may be more difficult to defend than evidence from high quality studies.