Jcp21342 317.322

A Naturalistic Study of Intramuscular Haloperidol Versus Intramuscular Olanzapine for the Management Kai MacDonald, MD,* Michael Wilson, MD, PhD,Þ Arpi Minassian, PhD,* Gary M. Vilke, MD,Þ Olga Becker, MD,* Kimberly Tallian, PharmD,þ Patrice Cobb, BA,* Rachel Perez,* Barbara Galangue, MA, MS,* and David Feifel, MD, PhD* if offered, voluntary or involuntary treatment with an intramus- Objective: Published research on agitation is limited by the difficulty cular (IM) medication, typically an antipsychotic with or without in generalizing findings from trials using moderately agitated, carefully a benzodiazepine, continue as therapeutic mainstays.4 selected patients treated with single agents. More specifically, there are For many years, haloperidol, often administered in combi- few comparative studies examining common intramuscular (IM) regi- nation with a benzodiazepine or anticholinergic to minimize ex- mens (ie, haloperidol with or without benzodiazepines) with IM atypical trapyramidal symptoms (EPS) and maximize efficacy,5 had been antipsychotics. Therefore, we conducted a retrospective chart review to the gold standard in emergency IM agitation treatment. Start- compare IM olanzapine and haloperidol in a ‘‘real-world’’ population with ing in the early 2000s, clinical trials demonstrating equivalent efficacy and improved tolerability of IM second-generation an- Method: We performed a retrospective evaluation of charts from 146 tipsychotics (IM SGAs),6Y9 have led to their increased use, sup- consecutive emergency department patients who received either IM hal- planting haloperidol as the agent of choice in many settings.4 operidol or IM olanzapine for agitation. We used a clinically oriented Although 2 SGAsVaripiprazole and olanzapineVhave demon- proxy marker of efficacyVthe necessity for additional medication in- strated similar or superior efficacy to IM haloperidol in con- tervention for agitation (AMI)Vas our primary outcome measure.
trolled trials,6,7,9 several clinical questions remain regarding Results: Additional medication intervention for agitation was required the treatment of ‘‘real-world’’ agitation in general and the use of by 43% (13/30) patients when haloperidol was given alone and by 18% (13/72) when haloperidol was given with a benzodiazepine. In the case First, although well designed, inclusive studies have dem- of olanzapine, AMI was required by 29% (6/21) of patients receiving onstrated the benefit of ‘‘haloperidol combination’’ regimens (eg, olanzapine alone and by 18% (2/11) of patients given olanzapine plus a haloperidol/lorazepam or haloperidol/promethazine) over halo- benzodiazepine. A significant percentage of patients had clinical char- peridol alone,5,10 these studies exclude certain agitated patient acteristics (nonpsychiatric triage complaint, drug/alcohol use, severe agi- groups (eg, alcohol-intoxicated patients, delirious patients) that tation) that differ from more selective samples.
are common presentations in emergency settings.11,12 Second, Conclusions: Overall, these finding suggest that in a naturalistic emer- although the previously mentioned trials, reviews,13 and expert gency department setting, haloperidol monotherapy is less effectiveV opinion4 support ‘‘haloperidol combination’’ regimens, registry at least in requiring AMIVthan olanzapine with or without a benzodiazepine trials of IM olanzapine and IM aripiprazole compare them with or haloperidol plus a benzodiazepine. Moreover, these later 3 regimens haloperidol alone, leaving the question of the relative advan- seemed comparable. Prospective studies examining the treatment of real- tage of IM SGAs over haloperidol combination regimens un- world agitation, including head-to-head comparisons of the haloperidol- addressed. One notable exception is a naturalistic trial in India benzodiazepine combination with newer IM antipsychotics, are needed.
that compared 10 mg of IM olanzapine with the haloperidol Key Words: agitation, substance use, chart review, haloperidol, (5 mg)Ypromethazine (25Y50 mg) combination. In that study, both treatments demonstrated equivalent efficacy on a primaryend point of ‘‘tranquil or asleep at 15 and 240 minutes,’’ with a (J Clin Psychopharmacol 2012;32: 317Y322) trend favoring the haloperidol-promethazine combination ona secondary measure of ‘‘additional intervention needed in a Agitation is a common and consequential problem in emer- 4-hour window.’’14 Although this study broadens the base of gency medical settings.1,2 Its diverse etiologies include pri- knowledge regarding the relative efficacy of ‘‘haloperidol com- mary psychiatric causes (eg, mania, personality disorders), bination’’ treatments versus an IM SGA, to our knowledge, substance intoxication, substance withdrawal, and medical con- outside of the studies by our group,12 comparison of the com- ditions.3 Sequelae of agitation include physical and psycholog- monly used IM haloperidol-benzodiazepine combination with ical harm to staff and patients, delayed workup of acute medical issues, prolonged emergency department stays, and occasional Furthermore, although adding a benzodiazepine to IM hal- mortality. Although a significant proportion of agitated patients operidol improves overall efficacy,5 and although some practi- will accept and benefit from treatment with an oral antipsychotic tioners may naturally ‘‘substitute’’ an SGA for haloperidol aspart of a IM antipsychotic-benzodiazepine combination, therehas not been a thorough investigation of the benefits and risks From the Departments of *Psychiatry, †Emergency Medicine, and ‡Pharmacy, of adding a benzodiazepine to any of the IM SGAs. One IM University of California, San Diego, CA.
SGA that has raised special concern in this regard is olanzapine.
Received January 24, 2011; accepted after revision November 29, 2011.
Reprints: Kai MacDonald, MD, Department of Psychiatry, University Several sources of data, including a case report,15 examination of of California, San Diego, 9500 Gilman Dr, MC 8620, La Jolla, postmarketing data,16 naturalistic studies of IM olanzapine,12,17Y19 CA 92093-0804 (e-mail: kai@kaimacdonald.com).
and repeat-dose studies of nonagitated patients (Olanzapine Pre- Copyright * 2012 by Lippincott Williams & Wilkins scribing Information, 2009) raise concern regarding the risk of ISSN: 0271-0749DOI: 10.1097/JCP.0b013e318253a2fe adverse events (AEs; ie, significant sedation and hypotension) Journal of Clinical Psychopharmacology & Volume 32, Number 3, June 2012 Copyright 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology & Volume 32, Number 3, June 2012 with the combination, and the package insert for IM olanzapine screen, blood alcohol level, or comments regarding alcohol in notes the combination is not recommended owing to a lack of nursing or physician notes. This study was approved by the Uni- study (Olanzapine Prescribing Information, 2009).
versity of California, San Diego, Investigational Review Board.
To address several of the previously mentioned issues On the basis of published agitation trials, which have re- concerning the use of IM haloperidol and IM olanzapine in the ported outcomes at 2 hours,6,7 3 hours,5 and 4 hours after dose,14 treatment of real-world agitation, we performed a retrospective we chose a 3-hour postinjection period as our efficacy window.
chart review examining these 2 medications, given alone or in We defined a combination as 2 medications administered within combination with a benzodiazepine. Our primary goal was to 15 minutes of each other, and AMI as any oral or IM medication, assess the relative efficacy and safety of these regimens in a including benzodiazepines or antipsychotics, given 15 minutes maximally inclusive patient sample, using an outcome measure or more after the initial treatment of the indication of ongoing with clear clinical relevance. Our secondary goal was to char- agitation. Regarding the patient’s presenting complaint, we catego- acterize salient patient variables (demographics, triage com- rized these as ‘‘psychiatric-related’’ or ‘‘nonYpsychiatric-related’’ plaints, and the presence of drug and alcohol) in this unselected based on a common understanding of emergency department group to compare our group to patients treated in more con- triage. We coded patients as positive for drugs and alcohol (D/A (+)) if they had a urine drug screen (UDS) that contained am-phetamines, cocaine, alcohol, or marijuana or had chart notes indicating the presence of alcohol, a positive result in the breath-alyzer, or blood alcohol level; benzodiazepine or opioids were not coded positive to avoid potential confounding prescription This structured multicenter retrospective study examined medications. Patients with no indication of alcohol and a neg- medical records of all patients treated with IM olanzapine (Eli Lilly, ative UDS were coded as D/A (j), and a third group had in- Indianapolis, Ind) or IM haloperidol for agitation from October 1, sufficient data: (ie, no alcohol and no UDS). We have reported 2003, to December 1, 2006, in 2 emergency departments: one elsewhere on our more detailed analysis of the smaller subset serving primarily an urban region and one in a community setting with a combined census of 65,000 visits per year. Patient To further characterize our main findings, a subset of charts populations served include a heavy indigent lower socioeco- with sufficiently detailed preintervention and postintervention nomic population at one site and a suburban middle-class pop- documentation were abstracted and blinded for demographic ulation at the other. Notably, the emergency departments at both information and medication administered. These charts were sites treat both psychiatric and medical emergencies without a further analyzed and rated (using pretreatment and posttreatment specific emergency psychiatric unit. Inclusion criteria consisted Clinical Global Impression Y Severity [CGI-S] scale for agitation/ of all emergency department patients who received either IM halo- psychosis, CGI-S for AEs, and Global CGI-I, which balances peridol or olanzapineVwith or without concomitant medicationsV clinical efficacy and AEs) by a group of blinded doctoral-level during the study period. Exclusion criteria included treatment clinicians with extensive experience in the assessment and treat- with any parenteral medication other than haloperidol or olan- ment of agitation. As we had captured efficacy via AMI else- where, only patients receiving a single IM dose within a 3-hour To further characterize our main findings, especially ad- period were rated. In the subgroup of RCs, we focused our anal- verse effect data, a subset of charts with sufficiently detailed ysis on our 4 largest treatment groups: haloperidol 5 mg IM with postintervention documentation was further analyzed and rated or without a benzodiazepine and olanzapine 10 mg IM with or for preinjection level of agitation, improvement, and adverse ef- fects by a trained group of blinded doctoral-level clinicians withextensive experience in the assessment and treatment of agita- tion. Definitions were set a priori. Given the heterogeneous, in- The statistics used in this report are primarily descriptive; dividualized nature of emergency department charting, adverse the study was not powered to detect statistically significant dif- effects and clinical significance were ascertained on a case-by- case basis using clinical judgment from the actual recorded nurs-ing and physician observations (ie, ‘‘pt groggy’’ in chart = clinically significant sedation). As we had captured efficacy viaadditional medication intervention (AMI) elsewhere, only pa- Description of Sample: Medication Combinations, tients who had received a single IM dose within a 3-hour period were rated by our blinded panel. In the subgroup of rated charts Table 1 summarizes the demographics, clinical character- (RCs), we focused our analysis on our 4 largest treatment groups: istics, and antipsychotic regimens of our sample, and Table 2 haloperidol 5 mg IM with or without a benzodiazepine and further characterizes the 19 different IM medication regimens in olanzapine 10 mg IM with or without a benzodiazepine.
our sample. Differences included variations based on antipsy-chotic and dose used, as well as the addition of different IM or intravenous (IV) benzodiazepines or anticholinergics. The most Patients receiving either medication were identified by a common regimens in our sample were haloperidol 5 mg IM search of our computerized emergency department pharmacy da- alone and in various combinations; IM olanzapine was used less tabase; questionable cases were examined by the PI, and cross- checked with the provider ordering and charting system. Datawere extracted by a trained research assistant and included pa- tient demographics, triage chief complaint, medication and dos- ages, and AMI given for agitation within 3 hours after initial Across all doses, we found that substantially fewer agitated dosing. In addition, we examined documentation of pretreatment patients given haloperidol in combination with a benzodiaze- agitation, as well as postintervention efficacy and safety, and pine required AMI compared with those treated with haloperidol presence of drugs or alcohol as determined on urine toxicology alone (43% vs 18%). Using the primary outcome measure of Copyright 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology & Volume 32, Number 3, June 2012 IM Treatment for the Management of Acute Agitation TABLE 1. Demographic Characteristics and Treatment Triage complaint: psychiatric related, n (%) Because of rounding, percents may not equal 100% when added.
‘‘requiring additional medication intervention for agitation’’ (AMI), we found that the addition of a benzodiazepine to hal- operidol decreased the proportion of patients who needed AMI for agitation in the subsequent 3-hour period (Table 3). This TABLE 2. Intramuscular Treatment Regimens in the Haloperidol (n = 114) Haloperidol treatment groups Values in boldface emphases indicate the most common treatment Efficacy is based on the need for AMI within 3 hours; see text.
finding held at both the most common haloperidol dose (43% [13/30] given haloperidol 5 mg alone needed AMI, compared with only 22% [10/46] given haloperidol 5 plus lorazepam 2 mg IM/IV and 19% [12/63] given haloperidol 5 mg and any ben- zodiazepine) as well as in the larger sample of all patients re- ceiving IM haloperidol (43% [18/42] of haloperidol-alone patients needed AMI vs only 18% [13/72] of those receiving IM haloperidol plus any benzodiazepine). Overall, the percentage of patients who needed AMI after being treated with IM olan- zapine, whether given alone (29%) or in combination with a benzodiazepine (9%), was substantially lower than haloperidolmonotherapy (43%) and similar to the haloperidol plus benzo- Because of rounding, percents may not equal 100% when added.
diazepine group (18%). Comparing the most commonly pre- Values in boldface emphases indicate the most common treatment scribed doses of haloperidol (5 mg) and olanzapine (10 mg), given with or without additional medications, rates of AMI were Efficacy is based on the need for AMI within 3 hours; see text.
26% (25/95) for haloperidol and 4.5% for olanzapine (1/22).
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Journal of Clinical Psychopharmacology & Volume 32, Number 3, June 2012 Compared with these more commonly prescribed doses, patients able to clearly ascertain the advantage of the higher dose.21 Fi- treated with lower doses (haloperidol 2.5 mg or olanzapine nally, other trials have compared both 7.5 mg of IM haloperidol 5 mg) received AMI more frequently; those treated with higher given alone6,7 and 10 mg of IM haloperidol given in combina- doses (haloperidol 10 mg or olanzapine 20 mg) did not receive tion with promethazine14 to IM olanzapine 10 mg and reporting comparable efficacy of IM olanzapine with these higher halo-peridol doses. As such, although we note that our institutional bias toward the 5-mg dose of haloperidol may bias our efficacy comparison toward olanzapine, the efficacy of 10 mg of olan- Of the 146 total charts in our study, 44 met our abstraction zapine alone was at least as effective as any haloperidol dose criteria for more detailed consensus ratings, and 28 of 44 fell into our 4 most common dosing groups (haloperidol 5 mg alone These findings offer one of the first, albeit indirect looks [n = 5] or with 2 mg of lorazepam [n = 15], olanzapine 10 mg at the gold standard haloperidol-lorazepam combination versus alone [n = 5] or with 2 mg of lorazepam [n = 3]). The mean (SD) IM olanzapine in a consecutive sample of real-world patients.
CGI-S score for all rated patients was 6.6 (0.57)Vnear the Our finding of superior efficacy of the haloperidol/lorazepam highest CGI rating of 7 (‘‘among the most agitated patients’’)V combination over haloperidol alone concur with groups that and was similar between haloperidol-treated patients (6.65 have studied the addition of the antihistamine/anticholinergic [0.55]) and olanzapine-treated patients (6.6 [0.65]). In the group promethazine10 or benzodiazepines5,22,23 to haloperidol and of 28 administered our most common doses, preinjection extend these findings to more inclusive patient group and a agitation ratings (CGI-S) were higher for patients treated with larger range of haloperidol and benzodiazepine doses than used the haloperidol-benzodiazepine combination (6.7 [0.45]) or in naturalistic fixed-dose studies.5 Our finding suggesting su- olanzapine (6.8 [0.44]) than those treated with haloperidol alone perior efficacy of olanzapine monotherapy over haloperidol (6.2 [0.8]). Consistent with our selection criteria (only receiving monotherapy (at least in the need for AMI) is consistent with 1 injection), CGI-I scores for our rated sample were nearly head-to-head prospective, double-blind, registry trials that identical. The only charted adverse effect we noted was sedation, compared these agents using agitation ratings and found supe- and predictably, the addition of lorazepam to either haloperidol rior short-term efficacy of IM olanzapine over IM haloperidol6,7 or olanzapine yielded higher adverse effect ratings (CGI-S, AE): as well as naturalistic trials that have demonstrated IM olanza- haloperidol 5/lorazepam 2, 3.3 (1.3); haloperidol 5, 2 (1.3); olan- pine’s efficacy in more severely agitated populations.12,14,24 We zapine 10/lorazepam 2, 3.2 (1.9); olanzapine 10, 2 (1.58).
highlight that, in our subset analysis, we found similar levels ofagitation among patients receiving IM olanzapine and those receiving IM haloperidol plus lorazepam, making it unlikely that We examined all available notes of patients who received our efficacy findings are biased as a result of olanzapine-treated IM olanzapine concomitantly with a parenteral benzodiazepine patients being less agitated. We also note that another natural- (n = 11) and found no evidence of clinically significant AEs in istic study indicated a ‘‘duration of effect’’ advantage for the this group, although we note that staff and clinicians in our haloperidol/promethazine combination over IM olanzapine14 sample did not systematically assess either adverse effects or and that our shorter, 3-hour window may therefore have tended vital signs outside standard emergency department monitoring.
to favor olanzapine. Finally, despite its frequency of use, we arenot aware of any published literature comparing the most com- monly used treatment in our sampleVhaloperidol plus benzo- The primary goal of our study was to investigate the effi- diazepinesVwith any newer IM antipsychotic, an example of cacy of IM haloperidol and IM olanzapineValone and in combi- the gap between the extant literature on treatment of agitation nation with a benzodiazepineVin a naturalistic sample of agitated patients. In this retrospective chart review, our main unique Regarding AEs, in the full sample of RCs (n = 44), the only finding was that patients given IM olanzapine required AMI at AE we found was sedation, and we found similar levels with a similar or lower rate than the gold standard haloperidol- both haloperidol/lorazepam and olanzapine/lorazepam, a level lorazepam combination and that both of these regimens were higher than with either haloperidol or olanzapine given alone.
superior to haloperidol alone. Comparing the most commonly This finding comes with the important rejoinder that it is based used regimens in our sample, the rate of AMI among patients only on standard emergency department charting rather than who received IM olanzapine alone at the 10-mg dose (9%) was prospective, predefined assessments. Thus, only highly clini- less than that observed with the most frequently used combi- cally significant AEs were likely to be consistently captured.
nation regimen of IM haloperidol 5 mg plus lorazepam 2 mg This limitation notwithstanding, we found that adding lor- (22%) or haloperidol 5 mg alone (43%). We did not find that azepam to either haloperidol or olanzapine caused AE ratings adding a benzodiazepine to olanzapine reduced AMI signifi- (sedation) to go from an average of ‘‘mild’’ to ‘‘moderate.’’ In cantly relative to olanzapine alone, in contrast to the clear benefit addition, we note that, although EPSs with haloperidol mono- found adding a benzodiazepine to haloperidol.5 Our findings therapy occur at rates of 5% to 16%,7,9,10,25 we found none here expand on those of our earlier smaller report,12 examining documented in our haloperidol-treated group, consistent with a larger number of patients treated with a broader range of our small sample and the fact that prospective assessments of doses and supporting the efficacy of the doses of haloperidol EPS are much more likely to unveil these effects than sponta- (5 mg) and olanzapine (10 mg) that most patients in our sample In our sample, practitioners often extended the gold stan- This comparison raises the important issue of pharmaco- dard practice of adding a benzodiazepine to haloperidol to in- logical equivalency between IM haloperidol and olanzapine. We clude olanzapine. We therefore note that we did not find note regarding this issue that clinicians use both 5- and 10-mg evidence for clinically significant adverse effects of the IM haloperidol doses4 and that although a dose-response curve fa- olanzapine/benzodiazepine combination over and above the vors the 7.5- to 10-mg dose,20 a recent review of several large haloperidol/lorazepam combination. That said, we also note that agitation trials that used both 5- and 10-mg haloperidol was un- the olanzapine/benzodiazepine combination has received attention Copyright 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology & Volume 32, Number 3, June 2012 IM Treatment for the Management of Acute Agitation as having risks around hypotension and bradycardia4,16 and perhaps itated, often nonconsentable group of patientsVincluding even increased mortality.17 Furthermore, a recent study by our patients with medical illness and substance intoxicationVwhich group reported that this combination may aversely affect oxygen- other studies omit. As such, our findings readily apply to real- ation in the ubiquitous alcohol-intoxicated patient.13 Unfortunately, world populations of agitated patients in settings where the registration trials for IM olanzapine add little safety data: few prevalence of substance abuse is high and where medical and patients in these studies received concomitant oral or IM benzo- psychiatric patients are commingled.
diazepines as a ‘‘rescue.’’6,7,25 As such, despite the theoretical and In summary, in this retrospective chart review of 146 con- reported risks of this combination, there exists little substantive secutive agitated patients who received either IM haloperidol or evidence regarding its relative risk compared with other treatments.
IM olanzapine, we found preliminary evidence suggesting that On the other hand, whereas high-quality evidence supports IM olanzapine 10 mg performed no worse than the most effec- the efficacy advantage of adding lorazepam to IM haloperidol,5 tive and most frequently used haloperidol regimen (haloperidol the question of whether adding a benzodiazepine to IM olan- 5 mg + lorazepam 2 mg), that both of these regimens were more zapine provides any clinical benefit is also lacking. Along these efficacious than haloperidol alone, and that unselected agitated lines, we found no compelling evidence for increased efficacy samples differ considerably from patients in controlled trials in of the IM olanzapine/lorazepam combination over IM olanza- triage complaint, presence of drugs and alcohol, and level of pine alone compared with the gold standard haloperidol 5 + agitation. Although we did not find any severe AEs in the small lorazepam 2. Given the increasing use of IM olanzapine, more number of olanzapine-benzodiazepine patients we examined, definitive studies looking at the relative efficacy and safety of the additional efficacy benefit of adding a benzodiazepine to olanzapine monotherapy versus olanzapine/lorazepam combination olanzapine was less clear than with haloperidol, adding another treatment would be welcome. Clearly, until higher-quality evidence caveat to the use of this combination. These efficacy results, can inform the issue, caution should be exercised with this regimen.
some of the first we are aware of examining an IM atypical A last noteworthy set of observations from our sample antipsychotic with haloperidol plus benzodiazepines, mirror pertains to its clinical characteristics. Although practitioners those of controlled trials comparing these agents,5Y7 add support may look to controlled registry trials of emergent agitation to haloperidol 5 plus lorazepam 2 mg or IM olanzapine 10 mg treatments to inform daily practice, these same trialsVby as optimally effective regimens, and support the clinical gener- necessityVoften select patients who do not resemble those seen alization of findings from controlled trials to more diverse real- in the clinical trenches, both in diagnosis and in the level of world patient samples. More broadly, they underscore the need agitation.12,24 With this in mind, we note that, although the for prospective, inclusive, naturalistic studies of agitation, espe- composition (age, sex) of our sample resembles those of other cially head-to-head comparisons of the haloperidol-benzodiazepine naturalistic studies of agitation,5,14,24 our sample differed in 3 combination with newer IM antipsychotics.
significant ways from patients in controlled agitation trials. First,almost half of these highly agitated patients were initially triagedwith ostensibly ‘‘nonpsychiatric’’ chief complaints, although a post hoc assessment reveals that many ‘‘nonpsychiatric’’ issues A heartfelt acknowledgment goes to the late Grace and may have had substance intoxication/withdrawal or primary Margo Ucar who were invaluable in this project.
psychiatric illness as proximate causes (ie, altered level ofconsciousness, seizure, fall, assault). Second, the level of agi-tation in our rated sampleVnear the top of the CGI scaleVwas similar or higher to that in other naturalistic studies5,12,24 andclearly higher than in studies requiring consent. Finally, more Dr MacDonald acknowledges conflict of interest with than half of our sample was positive for drugs or alcohol, even Janssen, Pfizer, and Lilly. Dr Feifel receives research funding using our conservative criteria, which excluded opiate and and is a consultant or speaker for Argolyn, Bristol-Myers benzodiazepine-positive drug screens.
Squibb, Alexza, Shire, Organon, Danipon Sumitomo, Sanofi-Aventis, University of California, San Diego, Abbott, Addrenex,AstraZeneca, Eli Lilly, Wyeth, Janssen, Johnson and Johnson, and Tenzia. All other authors declare no conflicts of interest.
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