For More Than Half a Century, Haloperidol Has Been Used As a First

Time to retire haloperidol? For emergency agitation, evidence suggests newer alternatives may be a better choice Joseph M. Pierre, MD or more than half a century, haloperidol has been used as a first- Health Sciences Clinical Professor Department of Psychiatry and line medication for psychiatric agitation constituting a “behav- Biobehavioral Sciences ioral emergency” when a patient cannot or will not take oral David Geffen School of Medicine at UCLA F medication. Today, haloperidol is most commonly administered as Los Angeles, California an IM injection along with an anticholinergic medication to minimize Disclosure The author reports no financial relationships with any extrapyramidal symptoms (EPS) and a benzodiazepine for additional companies whose products are mentioned in this article, sedation. The multiple-medication “cocktail” is often referred to by dou- or with manufacturers of competing products. ble-entendre nicknames, such as “B-52” or “5250” (ie, haloperidol, 5 mg; lorazepam, 2 mg; and diphenhydramine, 50 mg). In this article, I discuss whether haloperidol, a first-generation antipsychotic (FGA) medication developed in 1958, still deserves to be the IM “gold standard” for man- aging emergency psychiatric agitation. Earlier evidence of haloperidol’s efficacy The initial “discovery” of antipsychotic medications was made in 1951 based on the inadvertent observation that chlorpromazine had the potential to calm surgical patients with autonomic activation. This calm- ing effect, described as “désintéressment” (meaning a kind of “indiffer- ence to the world”),1 resulted in a new class of medications replacing barbiturates and bromides as go-to options to achieve “rapid tranquilization” of psychiatric agitation.2 Although the ability of antipsychotic medications to gradually reduce positive symptoms, such as delusions and hallucinations, has been attributed to dopamine (D2) antagonism, their more immediate sedating and anti-agitation effects are the result of broader effects as histamine (H1) and alpha-1 adrenergic antagonists. In the 1970s, haloperidol emerged as a first-line option to manage agitation due to its IM and IV availability, as well as its relative lack Current Psychiatry SARA TYSON Vol. 19, No. 5 19 of sedation and orthostasis compared with most common strategy to achieve rapid low-potency D2 antagonists such as chlor- tranquilization in the psychiatric emergency promazine. However, haloperidol was setting.13 However, while the combination observed to have a significant risk of acute has been justified as a way to reduce the EPS, including dystonic reactions.2 From the antipsychotic medication dose and EPS 1970s to the 1990s, numerous prospective risk,2 few studies have compared combi- clinical trials of haloperidol for the treat- nations containing <5 mg of haloperidol. Time to retire ment of acute psychotic agitation, including As a result, the apparent superiority of haloperidol? several randomized controlled trials (RCTs) combined haloperidol and lorazepam com- comparing haloperidol to lorazepam, were pared with either medication alone may be conducted.3 The design and outcomes of a simple cumulative dose effect rather than the haloperidol vs lorazepam RCTs were true synergism. It is also important to note fairly consistent4-7: that adding lorazepam to haloperidol does • adult participants with acute agitation not mitigate the risk of EPS such as dystonia and a variety of psychiatric diagnoses, for in the absence of anticholinergic medica- whom informed consent often was waived tion.8 To date, however, there have been no Clinical Point due to agitation severity clinical trials investigating the efficacy of IM Adding lorazepam • randomization to either IM haloperi- haloperidol, lorazepam, and benztropine or dol, 5 mg, or IM lorazepam, 2 mg, admin- diphenhydramine given together. to haloperidol does istered every 30 minutes until agitation not mitigate the risk resolved of extrapyramidal • behavioral outcomes measured over Newer RCTs tell a different story symptoms several hours using various rating scales, With the availability of second-generation without consistent assessment of EPS antipsychotics (SGAs) in IM formulations, • equivalent efficacy of haloperidol and clinical trials over the past 2 decades have lorazepam, with symptom resolution usu- focused on comparing SGAs with haloperi- ally achieved after 1 to 2 doses (in 30 to dol alone as the “gold standard” control 60 minutes), but sometimes longer for acute agitation. Compared with pre- • anticholinergic “rescue” allowed for vious trials of haloperidol vs lorazepam, EPS, but not administered prophylactically these clinical trials of SGAs vs haloperidol • EPS, including dystonia and akathisia, included8,14-22: were significantly more frequent with halo- • Study participants who signed informed peridol compared with lorazepam.8 consent (and were likely less agitated) • IM haloperidol doses typically >5 mg In recognition of the greater risk of EPS with (eg, 6.5 to 10 mg). haloperidol compared with lorazepam, and the fact that most study participants were As with studies comparing lorazepam already taking standing doses of antipsy- with haloperidol, the results of these RCTs chotic medications, some researchers have revealed that IM aripiprazole, olanzapine, recommended using benzodiazepines alone and ziprasidone were at least as effective as as the optimal treatment for agitation.4,9 A IM haloperidol, with haloperidol having a 2012 Cochrane review concluded that the significantly increased risk of akathisia, dys- involuntary use of haloperidol alone “could tonia, and other EPS.8,14-22 The greater EPS be considered unethical.”10,11 However, risk of haloperidol is not surprising given other studies that examined the combina- the use of comparison doses up to 10 mg. Discuss this article at tion of haloperidol and lorazepam com- An updated 2017 Cochrane review of www.facebook.com/ pared with either medication alone found haloperidol for psychosis-induced aggres- MDedgePsychiatry that the combination of the 2 medications sion or agitation concluded that9: was associated with a more rapid resolu- • haloperidol is an effective intervention, tion of symptoms, which suggests a supe- although the evidence is “weak” rior synergistic effect.6,7,12 By the late 1990s, • significant treatment effects may take combined haloperidol and lorazepam, often as long as 1 to 2 hours following multiple Current Psychiatry 20 May 2020 mixed within a single injection, became the IM injections • in contrast to SGAs, treatment with emergent akathisia.26,28 No clinical trials of IM haloperidol carries a significant risk of EPS haloperidol combined with benztropine or • adding a benzodiazepine “does not diphenhydramine have been published, but have strong evidence of benefit and carries several studies suggest that combining halo- MDedge.com/psychiatry risk of additional harm.” peridol with promethazine—a phenothiazine with strong antihistaminergic and anticholinergic activity, but only weak antidopaminer- Haloperidol’s well-known toxicity gic activity—can decrease the risk of dystonia Haloperidol has been associated with relative to haloperidol alone.8,22,29,30 However, numerous adverse effects: there have also been reports of promethazine causing dystonia.31,32 In addition, 1 trial Akathisia and other acute EPS. Treatment of IM haloperidol, 2.5 mg, combined with with even a single dose of IM haloperidol promethazine reported that 74% of patients can result in acute EPS, including dystonia still had at least 1 form of EPS.30 Because the and akathisia. At best, such adverse effects clinical trials of haloperidol with prometha- are subjectively troubling and unpleasant; at zine did not specifically assess for akathisia, worst, akathisia can exacerbate and be mis- promethazine’s ability to decrease the risk of Clinical Point taken for agitation, leading to administration akathisia remains unknown. Haloperidol may be of more medication23 and the possible devel- opment of suicidal or violent behavior.24-25 In Cardiotoxicity. Although low-potency anti- an especially poor the studies reviewed above, the overall rate of psychotic medications such as chlorproma- choice for patients EPS was as high as 21% after treatment with zine are more sedating than haloperidol, with agitation haloperidol,16 with parkinsonism occurring the latter is preferred as an IM antipsychotic who are at risk for in up to 17% of patients,19 dystonia in up to medication for agitation because of its lower arrhythmia 11%,7 and akathisia in up to 10%.15 However, risk of hypotension.2 In terms of cardiac because specific EPS were assessed inconsis- effects, all antipsychotic medications carry a tently, and sometimes not at all, the rate of risk of QTc prolongation, with possible pro- akathisia—arguably the most relevant and gression to the potentially lethal arrhythmia counter-therapeutic adverse effect related to torsades de pointes as a result of interference agitation—remains unclear. with cardiac potassium channels.33 In 2007, In another study that specifically assessed the FDA added a “black-box” warning about for akathisia in patients treated with halo- this risk for haloperidol, in the wake of a peridol, up to 40% experienced akathisia 6 disproportionately high number of reported hours after a single oral dose of 5 mg.26 Even cases associated with IV administration, a single dose of IV prochlorperazine, another sometimes even after a single dose.34 dopamine-antagonist routinely used to treat Although

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