Cochrane review suggests adding promethazine to haloperidol to rapidly tranquillise psychotic patients with fewer side effects

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The hallucinations and delusions associated with psychosis can be frightening and may sometimes result in aggressive or violent behaviour. Of course, this can be incredibly challenging for the patient, but it can also be a real test for mental health staff who have to try and minimise the harm that patients do to themselves and others.

Haloperidol is an antipsychotic drug that is widely used to treat psychosis, but also has the benefit of calming people down and helping them to sleep. Clearly many patients don’t think of this rapid tranquillising effect as a ‘benefit’, but when agitation and aggression occur it can sometimes be useful for everyone involved. One of the key problems with haloperidol is the debilitating side effects it can cause, which have been described by many patients as worse than the psychosis itself.

An updated systematic review from the Cochrane Schizophrenia Group looks at the effectiveness and safety of haloperidol (compared to other drugs) for treating psychosis-induced agitation or aggression.  Led by Clive Adams for nearly 20 years, the Cochrane Schizophrenia Group has built a massive trial register of over 100,000 citations and nearly 8,000 papers. This incredible resource gives a great head start for researchers conducting systematic reviews in schizophrenia, because most of the searching work has already been done for them.

The review included 32 randomised controlled trials (RCT) comparing haloperidol (administered orally, intramuscularly or intravenously) with 18 other treatments. Unfortunately, most of the trials were small, at high risk of bias and unrepresentative of real-world practice.

Here’s what they found:

  • 2 RCTs comparing haloperidol with placebo found that:
    • Patients on haloperidol were more likely to be asleep at 2 hours (n=220, risk ratio (RR) 0.88, 95% confidence interval (CI) 0.82 to 0.95)
    • Dystonia (muscle spasms) was more common (n=207, RR 7.49, CI 0.93 to 60.21)
  • 2 RCTs comparing haloperidol with aripiprazole found that:
    • Patients on haloperidol needed fewer injections (n=473, RR 0.78, CI 0.62 to 0.99)
    • Dystonia was more common (n=477, RR 6.63, CI 1.52 to 28.86)
  • 3 RCTs comparing haloperidol with ziprasidone (total n = 739) were too poor to report any meaningful findings
  • 1 RCT comparing haloperidol with zuclopenthixol acetate found that patients on haloperidol needed more than 3 injections (1 RCT, n = 70, RR 2.54, CI 1.19 to 5.46)
  • 3 RCTs comparing haloperidol with lorazepam found that:
    • There was no difference in terms of patients asleep at 1 hour (1 RCT, n = 60, RR 1.05, CI 0.76 to 1.44)
    • However, by 3 hours, significantly more people were asleep in the lorazepam group compared with the haloperidol group (1 RCT, n = 66, RR 1.93, CI 1.14 to 3.27)
    • Numbers of patients needing >1 injection were the same (1 RCT, n = 66, RR 1.14, CI 0.91 to 1.43)

Patients on haloperidol are sometimes prescribed other drugs (in addition) to help reduce the side effects of the haloperidol. The review found the following impact of these combinations:

  • Adding lorazepam did not help with dystonia (1 RCT, n = 67, RR 8.25, CI 0.46 to 147.45; required antiparkinson medication RR 2.74, CI 0.81 to 9.25)
  • 1 more reliable RCT compared haloperidol alone with promethazine and haloperidol in combination and found:
    • More patients on haloperidol alone were not tranquil or asleep by 20 minutes (RR 1.60, CI 1.18 to 2.16)
    • Significantly more patients on haloperidol alone experienced one or more side effects (RR 11.28, CI 1.47 to 86.35)
    • Acute dystonia for patients just taking haloperidol was so common that the trial was stopped after the interim analysis of findings (RR 19.48, CI 1.14 to 331.92)

The reviewers concluded:

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.

Link

Powney MJ, Adams CE, Jones H. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation). Cochrane Database of Systematic Reviews 2012, Issue 11. Art. No.: CD009377. DOI: 10.1002/14651858.CD009377.pub2.

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