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Brief Report   |    
Intramuscular Flunitrazepam Versus Intramuscular Haloperidol in the Emergency Treatment of Aggressive Psychotic Behavior
Abraham Dorevitch, Pharm.D.; Nachum Katz, M.D.; Zvi Zemishlany, M.D.; Dov Aizenberg, M.D.; Abraham Weizman, M.D.
Am J Psychiatry 1999;156:142-144.

Abstract

OBJECTIVE: The authors examined the efficacy of intramuscular flunitrazepam compared with intramuscular haloperidol for the immediate control of agitated or aggressive behavior in acutely psychotic patients. METHOD: Twenty-eight actively psychotic inpatients, aged 20–60 years, who were under treatment with neuroleptic agents were selected for the study. Each was randomly assigned on a double-blind basis to receive either 5 mg i.m. of haloperidol (N=13) or 1 mg i.m. of flunitrazepam (N=15) during an aggressive event. Verbal and physical aggression was measured over time with the Overt Aggression Scale. Patients were also rated with the Brief Psychiatric Rating Scale and the Clinical Global Impression scale. RESULTS: Both flunitrazepam and haloperidol exhibited acute antiaggressive activity. This beneficial effect, as assessed by the Overt Aggression Scale, was obtained within 30 minutes. CONCLUSIONS: Intramuscular flunitrazepam may serve as a convenient, rapid, safe, and effective adjunct to neuroleptics in reducing aggressive behavior in emergency psychiatric settings.

Abstract Teaser
Figures in this Article

Benzodiazepines have recently gained interest as a class of drugs for use as alternatives or adjuncts to ongoing antipsychotic agents in emergency settings R15601CHEDAEGA. Lorazepam and diazepam, administered parenterally, have been shown to be a good alternative to parenteral haloperidol for the immediate control of psychotic aggressive or disruptive behavior R15601CHEBAGCE, R15601CHEBCAGB and as an adjunct to lithium in the clinical management of early manic agitation in bipolar patients R15601CHEDFFEF. Intramuscular lorazepam has emerged as the benzodiazepine of choice for immediate control of psychotic disruptive behavior R15601CHECEIGC. Alprazolam, when combined with haloperidol, is also particularly effective in the initial hours of treatment of acutely psychotic schizophrenic patients R15601CHEDGGGB. Intramuscular clonazepam, however, acts more slowly than intramuscular haloperidol R15601CHEDJAFD. Chlordiazepoxide and diazepam are rarely used because their intramuscular administration is associated with prolonged sedation and erratic absorption and is therefore not superior to oral administration R15601CHEBJFGF. This is not true for flunitrazepam, whose intramuscular absorption corresponds to its absorption through the oral route R15601CHECDHAI. To date, flunitrazepam has been investigated primarily as a hypnotic agent in patients with insomnia and in anesthesiology R15601CHEDJGBH. The purpose of the present study was to prospectively investigate the efficacy of intramuscular flunitrazepam versus intramuscular haloperidol in the acute treatment of aggressive psychotic inpatients.

The study group included 28 patients (13 men and 15 women), of whom 19 had schizophrenia, seven had schizoaffective disorder, and two had bipolar disorder. All diagnoses were established according to DSM-IV criteria after a clinical interview in which the guidelines of the Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition R15601CHEDECJH were used. Inclusion criteria for the study were the presence of active psychosis; disruptive or aggressive behavior, pronounced psychomotor agitation, or violent outbursts; and hospitalization in an acute ward.

Patients were assigned by a table of random numbers, on a double-blind basis, to receive either 5 mg i.m. of haloperidol (N=13, five men and eight women; mean age=36.8 years, SD=15.1) or 1 mg i.m. of flunitrazepam (N=15, eight men and seven women; mean age=34.9 years, SD=8.1) during an acute aggressive outburst. Follow-up evaluation was performed with the Overt Aggression Scale R15601CHEBAFHG, a 16-item index specifically designed to assess verbal and physical aggression toward objects, the self, or others. Measurements were made at baseline and at 15, 30, 45, 60, 90, and 120 minutes. All ratings were completed by the same rater (N.K.), who was blind to the study medications. Overall response to treatment was defined as a reduction of at least 50% in Overt Aggression Scale score at 90 minutes. The Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) scale were also administered at baseline to assess the severity of psychotic symptoms.

The study was approved by the institutional review board of the Geha Psychiatric Hospital, Tel Aviv. The need for informed consent was waived by the board, since both study medications are considered acceptable and consistent in clinical settings where rapid control of aggressive, disruptive behavior is needed.

Repeated measures analysis of variance and Fisher’s exact test were used as appropriate in the statistical analyses.

There were no significant differences between the haloperidol and flunitrazepam groups in diagnostic entities (12 schizophrenic and schizoaffective disorders and one bipolar I disorder versus 14 schizophrenic and schizoaffective disorders and one bipolar I disorder), in BPRS variables (mean score=49.0, SD=6.6, versus mean=45.4, SD=6.7), and in CGI scores (mean=4.5, SD=0.5, versus mean=4.5, SD=0.7). The antipsychotic drug treatment was similar in both groups; in the haloperidol group: perphenazine, 5–20 mg/day (N=5); haloperidol, 5–10 mg/day (N=4); levomepromazine, 50 and 200 mg/day (N=2); and zuclopenthixol, 25 mg/day (N=2); in the flunitrazepam group: perphenazine, 5–20 mg/day (N=4); haloperidol, 5–15 mg/day (N=6); levomepromazine, 75 mg/day (N=1); and zuclopenthixol, 25–50 mg/day (N=4). Four patients (two in each group) were taking additional medications including mood stabilizers (carbamazepine and valproic acid) and lorazepam.

As shown in F1, the acute administration of either flunitrazepam, 1 mg i.m., or haloperidol, 5 mg i.m., resulted in a significant reduction in Overt Aggression Scale score (F=72.42, df=6, 156, p<0.001, time effect). However, the maximal antiaggressive effect of flunitrazepam was already achieved 30 minutes after administration, whereas the activity of haloperidol increased gradually. This difference in antiaggressive effect was significant (F=3.10, df=6, 156, p<0.01, time-by-group interaction). In both groups the reduced aggression level lasted for at least 120 minutes following drug administration. No restraint or seclusion was used in either group.

The rate of response reduction in total Overt Aggression Scale score at 90 minutes was 80% (N=12) of the 15 patients in the flunitrazepam group and 92% (N=12) of the 13 in the haloperidol group (p=0.34, Fisher’s exact test). Flunitrazepam and haloperidol each induced marked sedation in three patients.

The use of benzodiazepines in schizophrenia, either alone or in addition to antipsychotics, has been widely studied, but their efficacy remains unclear. Cohen and Khan R15601CHEBHDJA emphasized that when benzodiazepines are used as adjuncts to neuroleptics in the acute treatment of psychotic patients, the major effect is an overall decrease in total neuroleptic dosage. However, most studies of benzodiazepines as neuroleptic adjuncts in schizophrenia have been based on weekly ratings and are not relevant for acute or emergency treatment R15601CHEDGGGB. To our knowledge, this is the first prospective study to investigate the beneficial effect of intramuscular flunitrazepam as an adjunct to neuroleptics in the short-term treatment of acute psychotic aggressive behavior.

We found that flunitrazepam and haloperidol administered intramuscularly were similarly effective in controlling agitated or aggressive behavior in acute psychotic inpatients. The antiaggressive effect of both was reached within 30 minutes. These results confirm earlier studies showing that an intramuscular benzodiazepine, used as an adjunct to ongoing antipsychotic treatment, is equally efficacious as, or superior to, haloperidol added to ongoing neuroleptic treatment R15601CHEDAEGA, R15601CHEBAGCE. It should be noted that the antiaggressive effect of flunitrazepam had worn off at 60 minutes, whereas the effect of haloperidol persisted over 120 minutes (F1); however, this difference was not clinically relevant.

No acute extrapyramidal events were observed in either group. Although the use of benzodiazepines has been associated with assaultive behavior R15601CHEBEGHF, the incidence of clinically adverse sequelae is thought to be less than 1%. We did not observe any excitation or disinhibition in the patients receiving flunitrazepam. Because sedation and reduced anxiety and agitation are probably the most prominent effects of benzodiazepines, the acute management of aggression in disruptive psychotic patients is the most well-founded indication for their adjunctive use in schizophrenic patients. This is particularly true for flunitrazepam, whose hypnotic action predominates over its sedative, anxiolytic, muscle-relaxing, and anticonvulsant effects. A potential advantage of flunitrazepam over lorazepam is its slightly longer half-life (19–22 hours versus 10–20 hours), allowing for prolonged antiaggressive action R15601CHECCFGC, R15601CHECCEAD. It is the unaltered drug, not its metabolites, that is primarily responsible for the clinical effects R15601CHEDJGBH. Although it is not currently marketed in the United States, flunitrazepam is available in Europe and Latin America. Head-to-head comparison of flunitrazepam with lorazepam is warranted.

Our study was limited by the relatively small number of participants, the diagnostic complexity of the group studied, the variability in the antipsychotic pharmacotherapy, and the lack of a placebo control group. Blood levels of haloperidol and flunitrazepam were not measured. Although further large-scale placebo-controlled studies are needed, it appears that flunitraz­epam, administered intramuscularly, may be a safe, rapid, and effective adjunct to neuroleptics in emergency psychiatric settings.

Received Feb. 13, 1998; revision received June 24, 1998; accepted July 6, 1998. From the Talbieh Mental Health Center, Hebrew University Faculty of Medicine; and Geha Psychiatric Hospital, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Address reprint requests to Dr. Dorevitch, Talbieh Mental Health Center, 18 Disraeli St., P.O. Box 4487, Jerusalem 91000, Israel.

 
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FIGURE 1.

Effects of Flunitrazepam and Haloperidol on Overt Aggression Scale Scores of Acutely Psychotic Aggressive Inpatientsa

aScores are means.

Foster S, Kessel J, Berman ME, Simpson GM: Efficacy of lorazepam and haloperidol for rapid tranquilization in a psychiatric emergency room setting. Int Clin Pyschopharmacol  1997; 12:175–179
[CrossRef]
 
Salzman C, Solomon D, Miyawaki E, Glassman R, Rood L, Flowers C, Thayer S: Parenteral lorazepam versus parenteral haloperidol for the control of psychotic disruptive behavior. J Clin Psychiatry  1991; 52:177–180
[PubMed]
 
Lerner Y, Lwow E, Levitan A, Belmaker RH: Acute high-dose parenteral haloperidol treatment of psychosis. Am J Psychiatry  1979; 136:1061–1064
[PubMed]
 
Lenox RH, Newhouse PA, Creelman WL, Whitaker TM: Adjunctive treatment of manic agitation with lorazepam versus haloperidol: a double-blind study. J Clin Psychiatry  1992; 53:47–52
[PubMed]
 
Bodkin JA: Emerging uses for high-potency benzodiazepines in psychotic disorders. J Clin Psychiatry 1990; 51(suppl 5):41–46
 
Barbee JG, Mancuso DM, Freed CR, Todorov AA: Alprazolam as a neuroleptic adjunct in the emergency treatment of schizophrenia. Am J Psychiatry  1992; 149:506–510; correction, 149:1129
[PubMed]
 
Chouinard G, Annable L, Turnier L, Holobow N, Szkrumelak N: A double-blind randomized trial of rapid tranquilization with IM clonazepam and IM haloperidol in agitated psychotic patients with manic symptoms. Can J Psychiatry 1993; 38(suppl 4):S114–S121
 
Salzman C: Use of benzodiazepines to control disruptive behavior in inpatients. J Clin Psychiatry 1988; 49(suppl 12):13–15
 
Mattila MAK, Larni HM: Flunitrazepam: a review of its pharmacological properties and therapeutic use. Drugs  1980; 20:353–374
[PubMed]
[CrossRef]
 
Wickstrom E, Amrein R, Haefefinger P, Hartman D: Pharmacokinetic and clinical observations on prolonged administration of flunitrazepam. Eur J Clin Pharmacol  1980; 17:189–196
[PubMed]
[CrossRef]
 
First MB, Spitzer RL, Gibbon M, Williams JBW: Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition (SCID-P), version 2. New York, New York State Psychiatric Institute, Biometrics Research, 1995
 
Yudofsky SC, Silver JM, Jackson W, Endicott J, Williams D: The Overt Aggression Scale for the objective rating of verbal and physical aggression. Am J Psychiatry  1986; 143:35–39
[PubMed]
 
Cohen S, Khan A: Adjunctive benzodiazepines in acute schizophrenia. Neuropsychobiology  1987; 18:9–12
[PubMed]
[CrossRef]
 
Dietch JT, Jennings JT: Aggressive dyscontrol in patients treated with benzodiazepines. J Clin Psychiatry  1988; 49:184–188
[PubMed]
 
Davis PJ, Cook DR: Clinical pharmacokinetics of the new intravenous anesthetic agents. Clin Pharmacokinet  1986; 11:18–35
[PubMed]
[CrossRef]
 
Hoey LL, Nahum A, Vance-Bryan K: A retrospective review and assessment of benzodiazepines in the treatment of alcohol withdrawal in hospitalized patients. Pharmacotherapy  1994; 14:572–578
[PubMed]
 

FIGURE 1.

Effects of Flunitrazepam and Haloperidol on Overt Aggression Scale Scores of Acutely Psychotic Aggressive Inpatientsa

aScores are means.

+

References

Foster S, Kessel J, Berman ME, Simpson GM: Efficacy of lorazepam and haloperidol for rapid tranquilization in a psychiatric emergency room setting. Int Clin Pyschopharmacol  1997; 12:175–179
[CrossRef]
 
Salzman C, Solomon D, Miyawaki E, Glassman R, Rood L, Flowers C, Thayer S: Parenteral lorazepam versus parenteral haloperidol for the control of psychotic disruptive behavior. J Clin Psychiatry  1991; 52:177–180
[PubMed]
 
Lerner Y, Lwow E, Levitan A, Belmaker RH: Acute high-dose parenteral haloperidol treatment of psychosis. Am J Psychiatry  1979; 136:1061–1064
[PubMed]
 
Lenox RH, Newhouse PA, Creelman WL, Whitaker TM: Adjunctive treatment of manic agitation with lorazepam versus haloperidol: a double-blind study. J Clin Psychiatry  1992; 53:47–52
[PubMed]
 
Bodkin JA: Emerging uses for high-potency benzodiazepines in psychotic disorders. J Clin Psychiatry 1990; 51(suppl 5):41–46
 
Barbee JG, Mancuso DM, Freed CR, Todorov AA: Alprazolam as a neuroleptic adjunct in the emergency treatment of schizophrenia. Am J Psychiatry  1992; 149:506–510; correction, 149:1129
[PubMed]
 
Chouinard G, Annable L, Turnier L, Holobow N, Szkrumelak N: A double-blind randomized trial of rapid tranquilization with IM clonazepam and IM haloperidol in agitated psychotic patients with manic symptoms. Can J Psychiatry 1993; 38(suppl 4):S114–S121
 
Salzman C: Use of benzodiazepines to control disruptive behavior in inpatients. J Clin Psychiatry 1988; 49(suppl 12):13–15
 
Mattila MAK, Larni HM: Flunitrazepam: a review of its pharmacological properties and therapeutic use. Drugs  1980; 20:353–374
[PubMed]
[CrossRef]
 
Wickstrom E, Amrein R, Haefefinger P, Hartman D: Pharmacokinetic and clinical observations on prolonged administration of flunitrazepam. Eur J Clin Pharmacol  1980; 17:189–196
[PubMed]
[CrossRef]
 
First MB, Spitzer RL, Gibbon M, Williams JBW: Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition (SCID-P), version 2. New York, New York State Psychiatric Institute, Biometrics Research, 1995
 
Yudofsky SC, Silver JM, Jackson W, Endicott J, Williams D: The Overt Aggression Scale for the objective rating of verbal and physical aggression. Am J Psychiatry  1986; 143:35–39
[PubMed]
 
Cohen S, Khan A: Adjunctive benzodiazepines in acute schizophrenia. Neuropsychobiology  1987; 18:9–12
[PubMed]
[CrossRef]
 
Dietch JT, Jennings JT: Aggressive dyscontrol in patients treated with benzodiazepines. J Clin Psychiatry  1988; 49:184–188
[PubMed]
 
Davis PJ, Cook DR: Clinical pharmacokinetics of the new intravenous anesthetic agents. Clin Pharmacokinet  1986; 11:18–35
[PubMed]
[CrossRef]
 
Hoey LL, Nahum A, Vance-Bryan K: A retrospective review and assessment of benzodiazepines in the treatment of alcohol withdrawal in hospitalized patients. Pharmacotherapy  1994; 14:572–578
[PubMed]
 
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+

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