A Meta-Analysis of the Risk of Acute Extrapyramidal Symptoms With Intramuscular Antipsychotics for the Treatment of Agitation

Objective: We examined the evidence for a decreased risk of extrapyramidal symptoms (EPS) with intramuscular second-generation antipsychotics (SGAs) versus intramuscular haloperidol alone or in combination with an anticholinergic agent.

Data Sources: We searched MEDLINE (1950 to the present), and EMBASE and the Cochrane Database through January 16, 2008, for studies published in English of intramuscular SGAs and intramuscular haloperidol alone or in combination with an anticholinergic agent using the following drug names: ziprasidone, Geodon, olanzapine, Zyprexa, aripiprazole, Abilify, haloperidol, and Haldol. We then searched this pool of studies for trials with the terms intramuscular, IM, or injectable. Initially, we included only randomized controlled trials (RCTs). To obtain more data comparing SGAs to the combination of haloperidol and an anticholinergic, we conducted a second analysis including studies of any methodology.

Study Selection: Seven RCTs that compared intramuscular SGAs to intramuscular haloperidol alone were identified. However, we found only one RCT of haloperidol plus an anticholinergic. In the second analysis, we identified 18 studies, including 4 using haloperidol combined with promethazine (an antihistamine with anticholinergic properties).

Data Extraction: The primary outcome measure was acute dystonia; secondary outcome measures included akathisia, parkinsonism, or the need for additional anticholinergic medication. For RCTs, risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for each outcome. When all studies were included in the second analysis, we calculated the risk of acute dystonia.

Data Synthesis: Among RCTs (N = 2032), SGAs were associated with a significantly lower risk of acute dystonia (RR = 0.19, 95% CI = 0.10 to 0.39), akathisia (RR = 0.25, 95% CI = 0.14 to 0.44), and anticholinergic use (RR = 0.19, 95% CI = 0.09 to 0.43) compared with haloperidol alone. When all trials were considered (N = 3425), rates of acute dystonia were higher for haloperidol alone (4.7%) than for SGAs (0.6%) or for haloperidol plus promethazine (0.0%).

Conclusions: Intramuscular SGAs have a significantly lower risk of acute EPS compared to haloperidol alone. However, intramuscular haloperidol plus promethazine has a risk of acute dystonia comparable to intramuscular SGAs. The decision to use SGAs should consider other factors in addition to the reduction of EPS, which can be prevented by the use of an anticholinergic agent.