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FISET ET AL
mous cell carcinoma has been reported arising in cutaneous lesions of DLE, usually in association with
hypopigmentation, solar damage, and scarring.
References
.I Oral Maxillofac
50:645-649,
Surg
1992
DMD, PHD,$
646
Table 1.
Midazolam
Dosage (mg)
Other Drugs
Patient
Sex/Age (yr)
5
12
Unknown
2
0.5
Morphine (1 mg)
None
Unknown
Promethazine
None
M/3 I
F/49
Unknown
F/57
F/l4
Drug Response
Reversal Drug
Reference
Hostility, assault
Violent movement
Confusion, aggressiveness
Uncooperative, movement
Hostility, confusion,
hallucination
Amobarbital
Flumazenil
Flumazenil
Physostigmine
Haloperidol
Lobo, Miwa
RodrigoS
Ricou et al4
Knaack-Steineggar et al*
Bemakis et al3
Report of Case
Table 2. Treatment Groups for a Multisite Clinical Trial on the Safety and Efficacy
of Intravenous Sedative Agents
Group
First Syringe*
1
2
3
4
5
Saline
Saline
Saline
Fentanyl
Fentanyl
Second Syringe?
Saline
Midazolam
Midazolam
Midazolam
Midazolam
to
to
to
to
end
end
end
end
point
point
point
point
Third Syringe$
Fourth Syringeg
Saline
Saline
Saline
Saline
Methohexital
Saline
Saline
Midazolam
Saline
Methohexitalll
647
FISET ET AL
Discussion
On the surface, this case appears to be a simple toxic
overdose with midazolam as a direct extension of drug
pharmacologic effects. 25 Established treatment guidelines were followed, but during titration the end-point
signs of ptosis and slurred speech were never observed,
although the patients speech pattern did slow. This
was confirmed following analysis of the videotape recording of the procedures. Thus, the desired sedative
effects of the drug never appeared, leaving only undesirable side effects.
The sedative effects of benzodiazepines are primarily
mediated by brainstem GABA-benzodiazepine neurons.26 These neurons inhibit a system of ascending
neurochemical pathways that normally exert a tonic
activating influence on cortical and subcortical stimuli.27 In contrast, effects of ataxia and memory impairment/confusion
are mediated via GABA-benzodiazepine receptors in the cerebeIlar and hippocampal/
forebrain areas.26 Thus, in this patient, brainstem receptors were either not sufficiently activated or the
arousal pathways they normally inhibit were too overactive to be suppressed. In contrast, those benzodiazepine receptors in other neuroanatomic regions were
sufficiently activated.
Because ethanol has potent acute effects on the
GABA-benzodiazepine complex,28 it is possible that
prolonged drinking could cause permanent alterations
in this receptor system and thereby alter a patients
responsivity to benzodiazepines. Evidence from animal
studies does show that the responsivity of ethanol-dependent mice to benzodiazepines may differ markedly
depending on the behavioral effect examined.29 Furthermore, molecular genetic studies showing regional
differences in the type of mRNA-coding for the benzodiazepine recepto? suggest that there may be different types of receptors in different brain regions, providing another possible mechanism for differential
behavioral susceptability.
648
drinking alcoholics advocate use of nitrous oxide/oxygen analgesia as the sole supplement to local anesthesia, citing the dissociative feelings induced by oral
and IV sedation as possible triggers for relapse and/or
untoward clinical behaviors.32 Despite the attractiveness of this recommendation, little clinical research has
been conducted to test its efficacy and provide a rationale for its use.
No conclusions, of course, should be drawn from a
single case report. However, this report, which was
broad in its documentation and included a history of
alcohol dependency, suggests that alcohol usage may
be an important contributing factor in disinhibitory
responses to benzodiazepines. Clinical trials of sedation
strategies with alcohol-dependent populations, though
desirable, may be unfeasible. Therefore, additional case
reports, including documentation of alcohol use histories, should be published to help provide a clearer
rationale for recommending treatment strategies using
sedative agents in such patients.
References
1. LoboBL, Miwa LI: Midazolam disinhibition reaction. Drug Intell
Clin Pharm 22:725, 1988
2. Knaack-Steinegger R, Schou J: Therapy for paradoxical reactions
to midazolam during regional anesthesia. Anaesthetist 36: 143,
1987
3. Bumakis TG, Berman DE: Hostility and hallucinations as a
consequence of midazolam administration. DICP 23:67 1,
1989
4. Ricou B, Forster A, Bruckner A, et al: Clinical evaluation of a
specific benzodiazepine antagonist (RO 15-1788). Br J Anaesth
58: 1005, 1986
5. Rodrigo CR: Flumazenil reverses paradoxical reaction with
midazolam. Anesth Prog 38:65, 1991
6. Litchfield NB: Complications of intravenous diazepam: adverse
psychological reactions (an assessment of 16,000 cases). Anesth
Prog 27:175, 1980
7. Dietch JT, Jennings RK: Aggressive dyscontrol in patients treated
with benzodiazepines. J&t Psychiatry 49: 184, 1988
8. Gardos G: D&inhibition of behavior bv antianxietv_ drugs.
_ Psv_
chosomatics 21:1025, 1980
.
9. Rosenbaum JF, Woods SW, Groves JE, et al: Emergence of hostility during alprazolam treatment. Am J Psychiatr 141:792,
1984
10. Lion A, Azcarate CL, Koepke HH: Paradoxical rage reactions
during nsvchotronic medication. Dis Nerv Svs 36:557, 1975
11. Zisook S, DeVaul l& Adverse behavioral effects of benzodiazepines. J Fam Pratt 5:963, 1977
12. Strahan A, Rosenthal J, Kaswan M, et al: Three case reports of
acute paroxysmal excitement associated with alprazolam
treatment. Am J Psychiatry 142:859, 1985
13. Gardner DL, Cowdry RW: Alprazolam-induced dyscontrol in
borderline personality disorder. Am J Psychiatry 14298, 1985
14. Binder RL: Three case reports of behavioral disinhibition with
clonazepam. Gen Hosp Psychiatry 9: 151, 1987
15. Fava M, Borofsky GF: Sexual disinhibition during treatment
with a benzodiazepine: A case report. Int J Psychiatry Med
21:99, 1991
16. Kales A, Bixler EO, Vela-Bueno A, et al: Comparison of short
and long half-life benzodiazepine hypnotics: Triazolam and
quazepam. Clin Pharmacol Ther 40:378, 1986
17. Edwards R, Mosher VB: Alcohol abuse, anaesthesia, and internal
care. Anaesthesia 35:474, 1980
18. Bruce DL: Alcoholism and anesthesia. Anestb Analg 62:84, 1983
649
OZAKl ET AL
J Oral Maxtllofac
50349~652.
27.
28.
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30.
3 1.
32.
Practice: Risks and Benefits. Washington, DC, American Psychiatric Press, 199 1
Hobson JA, Steriade M: Neuronal basis of behavioral state control, in Bloom FE (ed): Handbook of Physiology Section 1:
The Nervous System, vol 4. Intrinsic Regulatory Systems of
the Brain. Bethesda, MD, American Physiological Society,
1986, pp 710-767
Ticky MK, Burch TP, Davis WC: The interaction of ethanol
and the benzodiazepine-GABA receptor ionophore complex.
Pharmacol Biochem Behav 18:15, 1983
Chan AWK, Lamgun M, Leong FW, et al: Does chronic ethanol
confer full cross-tolerance to chlordiazepoxide? Pharmacol
Biochem Behav 30:385, 1988
Royce JE: Alcohol Problems and Alcoholism: A Comprehensive
Survey. New York, NY, The Free Press, 1989, p 21
Petersen JK, Milgrom P: Pain Relief In the Orofacial Regions.
Copenhagen, Munksgaard, 1989
American Dental Association: Treating the active or recovering
chemically dependent dental patient. Chicago. IL. American
Dental Association, 1989
Surg
1992
DMD