Despite its beneficial use in the treatment of acute or chronic pain, morphine induces various side effects such as nausea, vomiting and more importantly pruritus upon neuraxial injection [
11,
14]. Pruritus - an unpleasant and irritating sensation leading to scratching - is a common adverse effect of neuraxial morphine with the highest prevalence (up to 100%) associated with intrathecal morphine administration [
11]. It is generally mild and localized to the face and trunk, but it can be severe and cause significant maternal discomfort [
15]. Despite its frequent occurrence and practice of utilizing various pharmacological therapies including antihistamines, 5-HT3 receptor antagonists, opiate antagonists, propofol (hypnotic agent), non-steroidal anti-inflammatory drugs (NSAIDS) and anti-dopaminergic drugs, there are no consistently effective therapies established for opioid-induced pruritus [
3,
11,
16].
Pruritus caused by opioids develops shortly after analgesia and the prevalence, onset time, duration and severity depends on the type, route and dosage of opioid used. Lipid soluble opioids, such as fentanyl and sufentanil invoke pruritus of shorter duration. The use of the minimum effective dose of such opioids and the addition of local anaesthetics seems to decrease the prevalence and the severity of pruritus. Pruritus induced by intrathecal administration of morphine is of longer duration and difficult to treat. Intrathecal administration of opioids reaches the peak concentrations in the cerebrospinal fluid (CSF) almost immediately compared to the epidural administration. In epidural administration of opioids, the rise to peak concentration in CSF is relatively delayed (10–20 minutes with fentanyl and 1–4 hours with morphine) [
3]. Furthermore, the epidural space contains an excessive venous plexus which assists in extensive vascular reabsorption of opioids administered epidurally. Therefore, the side effect of opioids such as pruritus is more common and intense in intrathecal morphine administration than in epidural administration [
17].
Though pruritus is considered as the most common side effect of neuraxial administration of opioids, with the reported incidence between 30% and 100%, the exact mechanism behind the neuraxial opioid induced pruritus is yet unclear [
14]. It is probably not related to histamine release since antihistamines are ineffective in the therapy of pruritus caused by neuraxial morphine [
18] and, as well, other opioids such as fentanyl and sufentanil that do not release histamine also cause pruritus when administered into the neuraxis [
19]. Another theory proposes that opioid receptors that are located both supraspinally and at the spinal cord level are activated by morphine. The μ receptor is mainly responsible for pain modulation and some side effects, especially pruritus and nausea or vomiting which explains the antipruritic effects of μ antagonists such as nalbuphine and naloxone [
12,
20]. Thirdly, pruritus from neuraxial opioids may also be related to the excitatory effects of opioids on the nocifensive and non-nocifensive neurons in the anterior and posterior spinal horns [
21]. Propofol, which has an inhibitory effect on the dorsal horn of the spinal cord, may relieve such neuraxial opioid-induced pruritus [
22]. Lastly, the evidences from various studies and clinical practice for the treatment of postoperative nausea, vomiting and pruritus have strongly proposed 5-HT3 receptor interaction by opioids as a probable mechanism [
12,
14]. Fan has reported that morphine can activate 5-HT3 receptors by a mechanism independent of opioid receptors [
23] which implies the direct stimulation of 5-HT3 receptors in the dorsal horn of the spinal cord and in the medulla by intrathecal morphine injection possibly leading to pruritus [
12]. 5-HT3 receptors are abundant in the dorsal horn of the spinal cord and the spinal tract of the trigeminal nerve in the medulla [
14]. 5-HT3 receptor antagonists, such as ondansetron, are effective in the prevention and treatment of PONV [
24,
25]. Studies have also shown that 5-HT3 receptor antagonists significantly reduced the risk of pruritus compared to placebo whereas some studies showed no significant differences, thus creating the conflict regarding the efficacy of prophylactic 5-HT3 receptor antagonists in neuraxial opioid-induced pruritus prevention [
4,
7,
9,
12,
14,
24,
26]. A metaanalysis by George et al. suggests that prophylactic 5-HT3 receptor antagonists were ineffective in reducing the incidence of pruritus but significantly effective in reducing the severity and the need for treatment of pruritus in parturients who received intrathecal morphine for cesarean delivery. They were also effective for the treatment of established pruritus. However, more studies are recommended to settle the conflict regarding the efficacy of prophylactic 5-HT3 receptor antagonists in neuraxial opioid-induced pruritus prevention [
25]. We, thus, intended to assay in our study the efficacy of prophylactic administration of 5-HT3 receptor antagonist ondansetron in the prevention of intrathecal morphine induced pruritus and PONV. We chose the dose of 4 mg of ondansetron as it has been proven successful in the treatment of intrathecal morphine-induced pruritus [
12,
27]. However, the dose of 4–8 mg or 0.1 mg kg
-1 are also in practice [
9,
14]. Additionally, other 5-HT3 antagonists, such as tropisetron, granisetron and dolasetron are also used [
14].
This study showed that the incidence of pruritus after intrathecal morphine injection in patients undergoing cesarean delivery was frequent (88%) which can be prophylactically managed by IV administration of ondansetron, which was similar to the study done by Yeh et al. [
9]. On the other hand, the incidence of PONV can, as well, be effectively managed prophylactically by injection of ondansetron. However, for those patients who developed pruritus, the onset and duration were similar in both groups. Although IV ondansetron significantly reduced the incidence of intrathecal morphine-induced pruritus, this complication still occurred in approximately 16% of the patients, which suggests that these patients might need other treatment regimens such as naloxones (opioid receptor antagonists) or propofol (antagonist to excitatory effect on the dorsal horn of the spinal cord). However, we limited our study to a single type of 5-HT3 antagonist i.e., ondansetron with a fixed dose of 4 mg. Hence, a study examining dose-dependent effects and with 5-HT3 antagonists of different potency would be worthwhile to conduct in the future in this population.