Pathophysiological and neurochemical mechanisms of postoperative nausea and vomiting

Abstract

Clinical research shows that postoperative nausea and vomiting (PONV) is caused primarily by the use of inhalational anesthesia and opioid analgesics. PONV is also increased by several risk predictors, including a young age, female sex, lack of smoking, and a history of motion sickness. Genetic studies are beginning to shed light on the variability in patient experiences of PONV by assessing polymorphisms of gene targets known to play roles in emesis (serotonin type 3, 5-HT3; opioid; muscarinic; and dopamine type 2, D2, receptors) and the metabolism of antiemetic drugs (e.g., ondansetron). Significant numbers of clinical trials have produced valuable information on pharmacological targets important for controlling PONV (e.g., 5-HT3 and D2), leading to the current multi-modal approach to inhibit multiple sites in this complex neural system. Despite these significant advances, there is still a lack of fundamental knowledge of the mechanisms that drive the hindbrain central pattern generator (emesis) and forebrain pathways (nausea) that produce PONV, particularly the responses to inhalational anesthesia. This gap in knowledge has limited the development of novel effective therapies of PONV. The current review presents the state of knowledge on the biological mechanisms responsible for PONV, summarizing both preclinical and clinical evidence. Finally, potential ways to advance the research of PONV and more recent developments on the study of postdischarge nausea and vomiting (PDNV) are discussed.

Keywords: Anesthesia; Emesis; Nausea; Opioid; Surgery; Vomiting.

© 2013 Published by Elsevier B.V.

Figures

Fig. 1

Model of the phases and stimuli that contribute to postoperative and postdischarge nausea and vomiting (PONV and PDNV). Both inhalational anesthesia and intravenous opioids (e.g., fentanyl) can contribute to PONV, which is defined by most authors as nausea and vomiting experienced in the post-anesthesia care unit (PACU) or in-patient stay in the hospital. PDNV appears to be the result of opioid analgesic usage. Although not well understood, surgery-related effects on gastrointestinal motility (e.g., postoperative ileus) and GI inflammation might also contribute to nausea and vomiting. Patients can also develop tolerance to opioid-induced nausea and vomiting. This model is dependent on the type of surgery and may be shorter or longer periods of PONV and PDNV.,

Fig. 2

Neural pathways and pharmacology of postoperative nausea and vomiting (PONV). A) Brain pathways stimulated by inhalational anesthesia and opioids. Stimulation of three sensory pathways produce the vomiting reflex, including the vestibular nuclei (Vnu), area postrema (AP), and vagal afferent fibers from the gastrointestinal (GI) tract. These inputs project to the nucleus of the solitary tract (NTS), which potentially has output pathways to local brainstem areas to produce the vomiting reflex and projections to the mid- and forebrain for the perception of nausea. Although opioids act directly on brainstem (Barnes et al., 1991), they could also influence vagal afferent signaling by altering GI motility (Viscusi et al., 2009). Inhalational anesthesic agents could enhance 5-HT3 signals at peripheral and central sites to produces emesis or nausea (Parker et al., 1996) (Machu and Harris, 1994). Brain pathways potentially involved in nausea include the parabrachial nucleus (PB), thalamus (Thal), amygdala (Amy), insular cortex (IC), anterior cingulate cortex (ACC), and somatosensory/viscerosensory cortex (SC) (Miller et al., 1996; Napadow et al., 2012). B) Neuropharmacological targets associated with PONV. Opioids have emetic and antiemetic effects in animals and potentially humans too; at low doses morphine produces emesis, but at high doses it acts as an antiemetic (see review, Johnston, 2010). These actions are potentially the result of stimulation of different sites within the emetic neural circuitry, separated by the blood-brain barrier (Barnes et al., 1991). As concentrations of opioids increase in the systemic circulation or if the specific opioid drug is more lipid soluble (e.g., fentanyl), there is a greater antiemetic effect via μ opioid receptors inside the blood-brain barrier (e.g., NTS), counterbalancing the emetic action of opioids on μ opioid receptors in the AP. Other sites of antiemetic actions include serotonin type 3 (5-HT3) receptors in the AP, NTS, and gut vagal afferent fibers (a potential target for inhalational anesthetic agents); dopamine type 2 (D2) receptors in the AP; tachykinin 1 (NK1) receptors in the NTS and other hindbrain nuclei; and histamine 1(H1) and muscarinic 3 or 5 (M3/5) receptors in the Vnu.