We observed significant reduction in incidence of PONV in clonidine group as compared to midazolam and placebo group.
Four major neurotransmitter system appear to play important roles in mediating the emetic response viz. dopaminergic, histaminic (H1), cholinergic/muscarinic and serotonergic (5 HT3
). As there are four different types of receptors, there are at least four sites of actions at more than one receptor, but the commonly used drugs have a more prominent action at one or two receptors.[5
] Midazolam possibly acts as an antiemetic by decreasing dopamine input at the chemoreceptor trigger zone in addition to decreasing anxiety. It may also decrease adenosine reuptake. This leads to an adenosine-mediated reduction in the synthesis, release, and postsynaptic action of dopamine at the chemoreceptor trigger zone.[6
] Moreover it may also decrease dopaminergic neuronal activity and 5-hydroxytryptamine (5-HT) release by binding to the γ-amino butyric benzodiazepine complex.[8
The mechanism of antiemetic effects of clonidine is not known and probably multifactorial. It decreases sympathetic outflow, reduces anxiety, provide sedation and decreases anesthetic and analgesic requirements.[9
] High sympathetic tone and catecholamine release may trigger nausea and vomiting.[10
] The analgesic effect of clonidine, by a reduced need for opioid as known emetogens,[10
] might influence the incidence of PONV.
Clonidine decreases sympathetic tone, attenuates heart rate, arterial blood pressures, and plasma renin activity were lower during and after pneumoperitoneum.[9
] Preoperative clonidine decreases intraoperative stress response and improves hemodynamic stability.[9
] The hemodynamic effects of midazolam are dose related: the higher the plasma level, the greater the decrease in systemic blood pressure.[15
] The mechanism by which midazolam maintain a relatively stable hemodynamic involves the preservation of homeostatic reflex mechanisms.[16
Apnea and respiratory depression occurs with benzodiazepines in a dose-dependent manner[16
] and more likely to occur in the presence of opioids. Clonidine have minimal depressant effects on ventilation and it does not significantly potentiates opioid induced depression of ventilation.[17
Clonidine use resulted in lower VAS, better pain relief and lesser rescue analgesic requirements. This was possibly because of activation of post-synaptic α2 receptor in substantia gelatinosa of spinal cord, as well as the descending noradrenergic pathway.[18
Limitations of this study are that we have used nitrous oxide, isoflurane and fentanyl which are known to potentiate emesis. According to the pharmacokinetics of midazolam and clonidine, a different length of preoperative observation was necessary. Different age groups have different emesis potential. We did not use antianxiety premedication, which is also limitation of our study.
This study supports the study done by Mikawa et al
] in children which found that clonidine to be better than midazolam. The additive effect of oral midazolam and clonidine for PONV prophylaxis in granisetron-premedicated adult patients undergoing laparoscopic cholecystectomy has not been adequately studied and further research in this field is needed.
To conclude, clonidine has higher antiemetic efficacy than midazolam. Clonidine decreases the sympathetic discharge and act as a preemptive analgesic. Oral clonidine is better adjuvant, than midazolam, for PONV prophylaxis, in granisetron-premedicated patients undergoing laparoscopic cholecystectomy.