European Review for Medical and Pharmacological Sciences 2006; 10: 121-126 Midazolam as an anti-emetic F. RODOLÀ Istituto di Anestesiologia e Rianimazione, Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore – Rome (Italy) Abstract. – Benzodiazepines have been Benzodiazepines have been involved dur- involved during the years in the prevention and ing the years in the prevention and/or treat- treatment of Post-Operative Nausea and Vomit- ment of PONV: e.g., lorazepam proved an an- ing (PONV). Midazolam, a short acting benzodiazepine ti-emetic effect in younger patients after stra- 5 widely used as a premedicant before surgery, for bismus surgery , as, more recently, diazepam- induction of anaesthesia, and for conscious se- atropine sulfate premedication6. dation, has been particularly studied, sometimes Midazolam has been studied in the last 15-20 with conflicting results. years both for prevention and, less frequently, This paper will discuss the possible mecha- for treatment of established and persistent nisms of action of midazolam in PONV manage- ment and its fields of application (adults and PONV, sometimes with conflicting results. children undergoing surgery, treatment of per- Aim of this paper is to shortly report the sistent postoperative emesis), as far as poten- last researches on this subject, discussing pos- tialities of other non-traditional anti-emetics, sible mechanisms of the anti-emetic effect of maybe ready to get out the arena of case re- midazolam, its fields of application, and con- ports, and the need of further studies on postop- troversy on its use in preventing and treating erative anti-emetics in their efficacy in treating PONV. established PONV. Key Words: Midazolam Benzodiazepines, Midazolam, Post-Operative Nausea and Vomiting (PONV), Anti-emetics. Midazolam hydrochloride is a short-acting benzodiazepine CNS depressant. It may be administered before surgery as a premedicant to relieve apprehension and impair memory, Introduction for induction of anaesthesia (although in comparison with barbiturates its use is associ- Post-Operative Nausea and Vomiting ated with a slower onset of action and a more (PONV), well defined by Knapp and prolonged recovery time), and for conscious Beecher1 since 1956, is an undesired and un- sedation7. pleasant side effect of anaesthesia, both gen- Midazolam may be administered by mouth, eral and regional. Although it may induce se- parenterally, or via the intranasal or endorectal rious complications2, it is most often a minor route in children; preservative free intrathecal problem after surgery: it does not become midazolam has been used for postoperative chronic, and almost never kills; however, it analgesia in caesarean section delivery8. may be very distressing for patients3. A great It has been postulated that a possible variety of drugs with different mechanisms of mechanism for the anti-emetic effect of ben- action, used alone or in combination, more or zodiazepines could be an action at the less expensive, have been used through the chemoreceptor trigger zone reducing synthe- years with the intent to prevent and treat it. sis, release and postsynaptic effect of Nevertheless, its incidence seems to remain dopamine9. Whether benzodiazepines reduce quite constant: according to Kovac4 up to 20- dopamine release centrally, or by blocking 30% of patients undergoing general anaes- the re-uptake of adenosine, causing an thesia still experience PONV, despite all pro- adenosine-mediated reduction of dopamine phylactic measures. release, has been matter of debate10-14. Corresponding Author: Ferdinando Rodolà, MD; e-mail: [email protected] 121 F. Rodolà Dopaminergic neuronal activity and 5-hy- All but one of these studies21 showed at droxytryptamine release may also be reduced least the same beneficial effect of midazolam by binding of midazolam to the GABA ben- on PONV if compared with other premed- zodiazepine complex9,12,15: thus, anxiolysis as a icants, traditional anti-emetic medications, or secondary effect may also contribute to anti- placebo; the institution of a continuous infu- emesis. However, Wang and Klein16, in a sion of midazolam after cardiac surgery24 has cross-sectional study exploring a possible as- been found to be more effective than the ad- sociation between preoperative anxiety and ministration of ondansetron by I.V. boluses. PONV in a group of children undergoing out- patient surgery did not find any predictive Paediatric Surgery value of children’s anxiety for the occurrence Midazolam has been studied as an anti- of PONV. emetic mostly in small patients undergoing strabismus surgery26 or ear-nose-throat (ENT) operations: actually, it is reported that Midazolam in preventing and up to 80% of children not receiving an anti- treating PONV emetic and undergoing adenotonsillectomy may suffer PONV27,28. Avoiding intra- and Midazolam has been used as an anti-emetic peri-operative emetic agents as nitrous oxide in adults and children, both as a preventive and morphine based opioids29, using non- medicine and a rescue medication. Up to the steroidal anti-inflammatory drugs (NSAIDs) turn of century almost only case reports have or codeine as premedicants30, and administer- been published, but in the last few years the ing systematically anti-emetics31 may reduce first randomised controlled studies started to PONV rate down to less than 20%. appear, although dosage, route and modality Safety and effectiveness of midazolam as of administration are still far to be standard- oral premedication, after assessment of seda- ized, and almost every group of Authors used tion, quality of induction and effects on gas- midazolam in a different way. tric contents (residual volume and pH) have been demonstrated by Riva et al32; neverthe- Adult Surgical Population less, papers investigating its ability in pre- Studies reporting postoperative emetic venting PONV, even when not specifically de- symptoms in adults have been performed in signed, report conflicting results. various surgical settings. Midazolam has been Splinter et al33 found a lower incidence of used for monitored sedation in adult patients PONV than a placebo group: 42% vs 57%, scheduled for central venous access17, for still a quite high rate, but used for anaesthe- breast biopsy18, for plastic surgery under sia nitrous oxide and halothane, both known high-volume tumescent local anaesthesia19 or to be emetic. other kind of local anaesthesia20. All but one Zedie et al34 used the same kind of anaes- of these studies20 were not specifically de- thesia for paediatric outpatient surgery, but re- signed to investigate PONV occurrence, and ported a very low 6% of PONV. The Bergen- reported it at a variable rate, whereas more dahl group35 did not find, in a prospective, ran- specific comparative, prospective and con- domized, controlled clinical trial in children trolled investigations on anti-emetic effect of undergoing ENT surgery any particular ad- midazolam have been recently carried out in vantage in administering midazolam as a pre- patients undergoing general anaesthesia. medication. Results of another recent study36 Midazolam has been used for premedica- showed that steroids significantly reduce the tion in patients undergoing orthopaedic21, incidence of PONV, but usual anti-emetic outpatient22 and abdominal surgery23, and as agents, as well as drugs known to possess a preventive drug instituted as a continuous antiemetic properties such as midazolam lack infusion after tracheal extubation in patients any significant protective effect against emesis. undergoing cardiac surgery involving car- diopulmonary bypass24. Its effectiveness for Persistent Emesis the treatment of established PONV has been Persistent (not only postoperative) emesis studied in gynaecological and abdominal may rise to a priority to deal with both for pa- surgery25. tients and physicians, and lead to unanticipat- 122 Midazolam as an anti-emetic ed admissions of up to 1% ambulatory mercial product labelling adverse effects may surgery patients37. Three cases of persistent include hypotension, tachycardia, antero- PONV treated with low dose midazolam giv- grade amnesia (actually in most perioperative en by I.V. infusion have been reported by Di situations a beneficial effect), psychomotory Florio in 19929; the same Author38 later com- excitation, respiratory depression, and even pared midazolam to placebo in patients resis- nausea and vomiting. tant to standard anti-emetic medications, All but amnesia are rare on the whole and achieving statistically significant good results, midazolam may be considered as a quite safe although with a limited number of patients. drug; nevertheless, literature reports some A case of a female patient presenting, ac- conditions that is worth mentioning. cording to a widely used simplified PONV One minor trouble of intranasal adminis- risk score39, two or maybe more predictive tration of midazolam in paediatric patients is characteristics, has been quite recently re- irritation, and children are likely to cry, more ported40. She received a subarachnoid block than after the administration of other drugs for orthopaedic surgery, and developed in the by the same route34. recovery room a severe emetic status resis- A further problem in children may be repre- tant to all class of available anti-emetics. On- sented by paradoxical reactions following I.V. ly midazolam, actually administered primari- administration of midazolam: they include rest- ly to reduce anxiety and prevent bad memo- lessness,