Opioid induced nausea and vomiting

European Journal of Pharmacology 722 (2014) 67–78

Contents lists available at ScienceDirect

European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar

Review

Opioid induced nausea and vomiting Howard S. Smith 1, Andras Laufer n Albany Medical College, Department of Anesthesiology, 47 New Scotland Avenue, MC-131, Albany, NY 12208, USA

art ic l e i nf o

a b s t r a c t

Article history: Accepted 30 September 2013 Available online 21 October 2013

Opioids are broad spectrum analgesics that are an integral part of the therapeutic armamentarium to combat pain in the palliative care population. Unfortunately, among the adverse effects of opioids that may be experienced along with analgesia is nausea, vomiting, and/or retching. Although it is conceivable that in the future, using combination agents (opioids combined with agents which may nullify emetic effects), currently nausea/vomiting remains a significant issue for certain patients. However, there exists potential current strategies that may be useful in efforts to diminish the frequency and/or intensity of opioid-induced nausea/vomiting (OINV). Published by Elsevier B.V.

Keywords: Nausea Vomiting Opioids Olanzapine NK-1 Antagonists Moxduo Tapentadol

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology of OINV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurotransmitters in OINV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacogenetic issues in OINV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Modulation of opioid signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Dopamine receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Atypical antipsychotic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. 5-HT3 receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Other potential antiemetics for OINV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Tachykinin NK1 (NK-1) receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Other opioid or opioid-like products that may produce less nausea/vomiting than traditional opioid agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Tapentadol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Opioid/opioid combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Opioid/non-opioid combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. Opioid agonist/opioid antagonist combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5. Novel opioid derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67 68 69 70 71 71 71 71 72 72 72 73 73 74 74 74 74 74 75 75 75 75

1. Introduction n

Corresponding author. Tel.: þ 1 518 262 4300; fax: þ1 518 262 4736. E-mail addresses: [email protected] (H.S. Smith), [email protected] (A. Laufer). 1 Tel.: þ1 518 262 4461; fax: þ1 518 262 4462. 0014-2999/$ - see front matter Published by Elsevier B.V. http://dx.doi.org/10.1016/j.ejphar.2013.09.074

Although it is not uncommon for patients being started on opioids to initially experience nausea and/or vomiting, generally tolerance to these effects tends to occur within days to weeks

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(Coluzzi and Pappagallo, 2005). However, it is also appreciated that OINV is not always a transient or short-term adverse effect. In 2007, Portenoy and colleagues reported the results of a 3-year US registry study evaluated more than 200 patients in chronic treatment with controlled-release (CR) oxycodone (Portenoy et al., 2007). The mean daily dose of CR oxycodone was 52.5 mg, and this was associated with adverse effects; the most common being constipation and nausea (Portenoy et al., 2007). Nausea is highly distressing symptom that may occur with or without vomiting and can affect overall outcome, medication (e.g. opioid therapy), compliance, enteral absorption, and quality of life. Opioids possess well known proemetic effects that appear to be related largely to the total opioid dose administered and the degree to which that dose is “acute” vs. “chronic” for a particular patient. These symptoms occur in about one-third of those started on morphine, and the incidence severity is roughly in the same ballpark for all opioids (Lehmann, 1997). However, patients who have experienced these symptoms from a phenanthrene opioid with a hydroxyl group at position 6 (6-OH) (e.g., morphine), may be able to tolerate a “dehydroxylated” phenanthrene opioid (lacking a 6-OH) (e.g. hydromorphone) with less nausea (Wirz et al., 2008). Approximately 60% of patients with advanced cancer report nausea and 30% report vomiting (Davis, 2005). There may be significant interindividual variation in the incidence, intensity, or the development of tolerance of nausea and/or vomiting among various patients. Adverse effects as well as analgesia may depend on patient-specific factors influencing drug metabolism and drug interactions (Smith, 2008a), as well as differences in the pharmacokinetics and/or pharmacodynamics of different opioids (Smith, 2009). Thus, careful titration of a selective trial and error approach (e.g. trying different opioid analgesics; opioid rotation) may reveal a particular beneficial opioid with maximal analgesia and minimal nausea/vomiting for an individual patient, whereas a different opioid analgesic may be similarly optimal for another patient. Moore and McQuay performed a systematic review of oral opioids for chronic noncancer pain which revealed that 25% of patients developed dry mouth, 21% developed nausea, and 15% developed constipation (Moore and McQuay, 2005). Furthermore, a significant proportion of patients on opioids withdrew due to adverse events (Moore and McQuay, 2005). Kalso and colleagues also performed a systematic review of randomized controlled trials of opioids for chronic noncancer pain that reported that roughly 80% of patients experienced at least one adverse event; 32% of patients developed nausea and 15% developed vomiting (Kalso et al., 2004).

2. Pathophysiology of OINV The experience of nausea/vomiting may involve multiple receptors (Smith, 2005). OINV may be difficult to tease apart from chemotherapy-induced nausea/vomiting (CINV), radiation-induced emesis (RIE), or postoperative nausea/vomiting (PONV); thus “pure” OINV has not been extensively well studied alone. Although the precise mechanisms of opioid-induced nausea and vomiting are not entirely certain, multiple and complex mechanisms are likely involved, OINV may be due to multiple opioid effects, including (a) enhanced vestibular sensitivity (symptoms may include vertigo and worsening with motion), (b) direct effects on the chemoreceptor trigger zone, and (c) delayed gastric emptying (symptoms of early satiety and bloating, worsening postprandially). Nausea and vomiting are well-known opioid-induced effects that may possess peripheral and central components. The mechanisms involved in nausea are extremely complex. Low doses of opioids activate mu opioid receptors in the chemoreceptor trigger

zone (CTZ), thereby stimulating vomiting. Alternatively, higher dose opioid doses may suppress vomiting by acting at receptor sites deeper in the medulla. The CTZ is in the floor of the fourth ventricle, a location which is considered in the periphery due to its incomplete blood brain barrier. Opioids can directly stimulate the vestibular apparatus, although the mechanism of action is still unknown. It has been postulated that morphine and synthetic opioids increase vestibular sensitivity, perhaps by opioids activating mu opioid receptors on the vestibular epithelium (Yates et al., 1998). The rate inner ear possesses delta opioid receptors delta and kappa opioid receptors (Otto et al., 2006), however, the role of these receptors in humans remains uncertain. The vestibular apparatus provides direct input into the vomiting center by way of Histamine H1 and cholinergic (AchM) pathways (Popper et al., 2004). Due to the permeability of the blood–brain barrier at the chemoreceptor trigger zone, it is considered “peripheral” and the neurons in the chemoreceptor trigger zone may be exposed to the effects of various drugs, metabolites, and toxins. Endogenous opioids appear to be involved in the mechanisms of opioid-induced vomiting, likely via stimulating mu opioid receptors and delta opioid receptor in the chemoreceptor trigger zone of the vomiting center (Jongkamonwiwat et al., 2003). In addition to mu opioid receptor agonist effect morphine may causes a subunitdependent inhibition of human 5-HT3 receptors (Baptista-Hon and Deeb, 2012) Opioid-induced emesis appears to occur via pathways from the brainstem chemoreceptor trigger zone, tolerance at the central opioid receptor level may at different rates vs. receptors outside the central nervous system (Coluzzi et al., 2012). If the interaction between opioid agonists and opioid receptors in the chemoreceptor trigger zone for a particular opioid is relatively long compared with its peripheral actions, tolerance to the emetic actions of opioids could occur earlier or may be more intense (Herndon et al., 2002). Chronic opioid use may lead to long-term repeated activation of mu opioid receptors in the myenteric and submucosal plexi with subsequent uncoordinated bowel activity, and resultant opioid-induced bowel dysfunction (Thomas, 2008). Opioids reduce peristalsis via decreasing gastrointestinal secretions and relaxing longitudinal muscle in the colon as well as simultaneously/increasing contractions of the circular muscles (Coluzzi et al., 2012). Stool may dry and harden due to the absence of longitudinal propulsion and increased circular muscle activity enhance the tone of the bowel with resultant impaired gastrointestinal motility, bowel distention and cramping (Iasnetsov et al., 1987) that may be associated with nausea and/or vomiting. It is conceivable that opioid-induced effects on the esophagus and esophageal motility may partly contribute to OINV. Kraichely and colleagues retrospectively reviewed 15 patients with dysphagia referred for esophageal manometry while on chronic opioids (Kraichely et al., 2010). All patients demonstrated motility abnormalities. Incomplete lower esophageal sphincter (LES) relaxation (11.571.6 mmHg) was seen in most cases. Ten patients demonstrated nonperistaltic contractions in 4 or ¼3 of 10 swallows. Additional abnormalities included high amplitude contractions, triple peaked contractions, and increased velocity. The average resting lower esophageal sphincter (LES) met criteria for hypertensive LES in three patients. These features were suggestive of spasm or achalasia. Repeat manometry off opiates was performed in three cases. LOS relaxation was noted to be complete upon repeat manometry in these cases, and demonstrated complete improved peristalsis, and a return to normal velocity (Kraichely et al., 2010). Opioids may also at least in part also contribute to OINV by adversely affecting gastric motility and delaying gastric emptying and may in some cases possibly contribute to frank severe gastroparesis (Jakobovits et al., 2007).

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The data of Janssen et al. suggest that endogenous opioids mediate gastric accommodation (e.g. gastric relaxation during food intake) via peripheral mu-opioid receptors. Therefore, effects were less pronounced after naloxone treatment, which indicates that centrally involved mu opioid receptors mediate an opposing effect (Janssen et al., 2011). Mu opioid receptors have been identified on nerve terminals in the myenteric plexus of the stomach (Bagnol et al., 1997). In rats it has been shown that mu opioid receptors agonists inhibit vagal stimulation-induced acetylcholine release in isolated, vascular perfused stomachs (Yokotani and Osumi, 1998). Although endogenous release of opioids in the enteric nervous system during the gastric accommodation reflex has not been described it is conceivable that opioid receptors on acetylcholine releasing nerves are activated during the gastric accommodation reflex inhibiting acetylcholine release which could result in a diminished gastric tone. It appears that endogenous gastric opioids are released upon vagal nerve stimulation in the rat (Weigert et al., 1995), and enkephalins may be the predominant endogenous opioid normally activating neuronal mu opioid receptors in the gut (Sternini et al., 2004). In the medial subnucleus of the tractus solitarii (mNTS) muopioid receptors are localized (Mansour et al., 1995) whereas the presence of endogenous mu receptor agonists as endomorphin-1 and 2 has been described (Martin-Schild et al., 1999). Herman et al. performed a series of experiments in rats that showed that microinjection of mu opioid receptor agonists in the mNTS reduced the gastric tone whereas injection of mu-opioid receptor antagonists per se had no effect on the gastric tone. However, esophageal distension induced gastric tone decrease was blocked by injection of mu-opioid receptor antagonists in the NTS (Herman et al., 2010). The authors proposed that upon activation of the vago-vagal reflex pathway that leads to gastric tone decrease, vagal afferents release opioids (possibly endomorphine-2) that inhibit GABA interneurons in the mNTS. Once the influence of GABA signaling is depressed, glutamate released from the vagal afferents can excite second-order NTS neurons and the vago-vagal reflex pathway that inhibits the gastric tone is activated (Herman et al., 2010). This hypothesis could well explain our findings: we did not observe an effect of methylnaltrexone on basal gastric tone but the food-induced decrease in gastric tone was blocked by methylnaltrexone. Although the precise mechanisms of opioid-induced nausea are incompletely understood, it is likely that a predominant mechanism involves opioid-induced stimulation of the mu-opioid receptor, since it can be successfully treated by opioid receptor antagonists (e.g. naloxone [Naloxone is an antagonist at mu, kappa, and delta opioid receptors, but it is most active at the mu opioid receptor]) [this, however, does not rule out a role for other opioid receptors such as the kappa or delta opioid receptors in contributing to or modulating OINV]. Opioids may induce emesis through multiple receptor mechanisms. Multiple species difference exists. The emetic opiate receptor for morphine in the dog is thought to be the  r subtype (Blancquaert et al., 1986). Rudd and Naylor (1992) reported that morphine-induced emesis in the ferret appeared to be mediated by κ4μ 4δ opioid receptors (Rudd and Naylor, 1992). In dogs, kappa agonists were reported to have an antiemetic effect against apomorphine induced emesis (Blancquaert et al., 1986) and did not affect morphine-induced emesis (Hersom and MacKenzie, 1987). In the ferret, kappa antagonism prevents morphine-induced emesis (Rudd and Naylor, 1992). Dopamine receptor antagonists also effectively block morphine emesis. Thompson et al. reported that morphine emesis in ferrets was due to the morphine molecule itself and not to the major product of morphine metabolism in the ferret, morphine-3-glucuronide (Thompson et al.,

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1992). Clinically, morphine itself, rather than its major metabolite morphine-6-glucuronide was probably the emetogenic agent since the metabolite failed to produce nausea and vomiting at analgesic doses in man (Osbourne et al., 1989). The significant reduction of morphine vomiting in the ferret by ondansetron, metoclopramide and droperidol was consistent with the reduction of postoperative emesis in man by these compounds when morphine was a component of the anesthetic regimen (Kenny et al., 1992; Lind and Breivik, 1970; Middleton, 1973; Mitchelson, 1992; Pinder et al., 1976). The precise mechanisms of ondansetron, a 5-HT3 receptor antagonist, in abolishing morphine emesis is uncertain (Thompson et al., 1992). The emetic effects of some opioids seem most likely to occur secondary to activation of the delta opioid receptor. In clinical settings, multiple receptors may play a role in contributing to nausea/vomiting. Some of the “emetogenic” receptors that have been proposed are dopamine-2 (D2), histamine-1 (H1), delta opioid receptor, 5-hydroxytryptamine (serotonin) (5-HT3), acetylcholine (ACh), tachykinin NK1 (NK-1), and cannabinoid receptor-1 (CB1). Antimemetics that antagonize these receptors include the following:

      

D2—haloperidol H1—promethazine mu/delta opioid receptors—naloxone 5-HT3—ondansetron, tropisetron, dolasetron, granisetron, palonosetron ACh—scopolamine NK-1—aprepitant CB1—dronabinol

3. Neurotransmitters in OINV The dorsal vagal complex is a cluster of nuclei in the dorsomedial medulla. The area postrema (AP), which makes up the majority of the pharmacologically defined chemoreceptive trigger zone (CTZ), is a circumventricular organ that allows bloodborne chemicals (e.g., SP) absorbed by or secreted from the intestinal mucosa to bypass the blood–brain barrier and stimulate the dorsal vagal complex directly (Saito et al., 1999; Yip and Chahl, 1999). The AP/CTZ is populated by neurons containing a broad spectrum of neurotransmitter receptors, including dopaminergic, serotonergic, cholinergic, and cannabinergic receptors, resulting in sensitivity to a wide range of chemical signals. The AP glutamatergic excitatory neurons innervate the nuclei of the tractus solitarii (NTS) (Aylwin et al., 1998; Miller and Leslie, 1994). Glutamatergic and GABAergic phenotypes of NTS neurons project to neurons in the dorsal motor nucleus of the vagus (DMNX) and one or both types project to the central pattern generator. The emetic effects of opioids are thought to be due to multiple mechanisms involving the classical opioid receptors, principally through stimulation of the CTZ, inhibition of intestinal motility, and stimulation of the vestibular apparatus. At the CTZ, mu- and delta-opioid receptors are activated, and signaling to the vomiting center occurs largely via dopamine D2 receptors and serotonin (5-HT3) receptors (DeLander et al., 1992). Genetic variation has been described in genes coding for these receptors. Thus, it appears that the two most important neurotransmitters contributing to OINV may be serotonin and dopamine; and consequently the receptor that seems to be considered the most important receptor in contributing to OINV appears to be the dopamine D2 receptor. If this is the case, then the most important first-line therapeutic agent (at least theoretically in terms of targeting predominant OINV pathophysiology) may be the D2 receptor

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antagonists. Another neurotransmitter that appears to potentially contribute to OINV is serotonin [5-hydroxytryptamine-5-HT]. Autoradiographic and homogenate radiology and binding studies have revealed a remarkably similar distribution of 5-HT3 receptors, with significant densities across the dorsal vagal complex emetic nuclei of different mammalian species with the following density order: NTS⪢AP4DMNX (Pratt et al., 1990). 5-HT in the mNTS excites DMNX neurons at presynaptic level by dysfacilitation of inhibitory GABAergic neurons via activation of 5-HT1A sites, whereas stimulation of postsynaptic DMNX 5-HT2A receptors excites gastrointestinal tract-projecting efferent neurons to both the stomach and intestine (Browning and Travagli, 1999). Moreover, both 5-HT3 and 5-HT4 receptors are involved in the excitability of DMNX gastrointestinal track-projecting neurons, generating long lasting facilitation of motility or prolonged gastric relaxation (Fukushi et al., 2006). Recent evidence indicates that in the least shrew intraperitoneal injection of the 5-HT3 receptor agonist 2-methyl-5-HT caused emesis as well as increased Fos expression not only in the wellaccepted emetic nuclei of the dorsal vagal complex (AP, DMNXm and NTS) but also in the more recently recognized vomit locus, the central pattern generator, as well as in the dorsal raphe and paraventricular thalamic nuclei (Ray et al., 2009a). Despite the extensive involvement of serotonergic neurotransmission in emesis, very little is known about the role of 5-HT in the central pattern generator area. 5-HT has been immunohistochemically identified in fibers in the central pattern generator area (Holtman, 1988; Ray et al., 2009a), and, although 5-HT3 receptors are found in the central pattern generator area (Yoshioka et al., 1994) and possibly 5-HT1A, 5-HT4, and 5-HT7 receptors as well, (Wang et al., 2007) their function in relation to vomiting is unknown. Stimulation of the serotonergic system contributes at least partially to the analgesic effects of opioids (Arends et al., 1998). Acute morphine administration appears to enhance serotonin turnover as evidenced by an increase in its synthesis, release, and metabolism (Arends et al., 1998), especially in projection areas of the dorsal raphe nucleus and median raphe nucleus (Jolas and Aghajanian, 1997); but chronic morphine administration appears to lead to a decrease in the release of 5-HT from the nerve terminals (Jolas et al., 2000). Thus, it appears at least in some clinical circumstances that OINV occurring after acute administration of opioids, may be partly due to serotonin receptor signaling. Although, precise mechanisms remain uncertain it seems that serotonin binding to and signaling via the 5-HT3 receptors is largely responsible for its proemetic effects. This notion is supported by the antiemetic efficacy of 5-HT3 receptor antagonists for the treatment of serotonin-related nausea/vomiting. Kim and colleagues conducted a randomized trial of one hundred non-smoking female patients. Patients scheduled for gynecological laparoscopic surgery were randomly assigned into the palonosetron group (n ¼50) (Kim et al., 2013). They concluded that the effects of palonosetron and ondansetron in preventing PONV were similar in high-risk patients undergoing gynecological laparoscopic surgery and receiving opioid-based IV-PCA (Kim et al., 2013). Although never robustly demonstrated, it is also conceivable that 5-HT4 agonism may partly contribute to antiemetic effects in certain clinical situations (perhaps including OINV). Prucalopride, a selective high-affinity 5-HT4 receptor agonist, significantly improved nausea in 50% of patients with chronic intestinal pseudo-obstruction completing a randomized, double-blind, placebo-controlled, cross-over, multiple n¼1 clinical trial (Emmanuel et al., 2012). Tachykinin NK1 receptor agonists such as substance P represent another potential neurotransmitter that may be involved in OINV.

The ability of emetogens acting at the AP level (apomorphine, morphine, loperamide), via the vagus and splanchnic nerves (CuSO4), or mixed acting (cisplatin, cyclophosphamide, radiation), were shown to be blocked by NK1 receptor antagonists (Diemunsch and Grélot, 2000; Knox et al., 1993; McLean et al., 1996; Tattersall et al., 1996; Watson et al., 1995). Furthermore, ablation of least shrew central tachykinin NK1 receptors reduces GR73632 (a neurokinin agonist)-induced vomiting (Ray et al., 2009b).

4. Pharmacogenetic issues in OINV A wide variety of genes may play a role in contributing to the risk of developing nausea and/or vomiting as well as modifying the intensity of the nausea and/or vomiting (Hornby, 2001). Inter-individual variations in nausea and vomiting among cancer patients receiving opioids may be related to polymorphisms within the genes encoding proteins involved in multiple processes (Breitfeld et al., 2003) including: transport of opioids across membranes at the blood–brain barrier, opioid receptor binding and downstream signaling of opioid effects, as well as modifying systems of opioid effects (e.g. catechol-O-methytransferase gene [COMT], and cannabinoid receptor 1 gene [CNR1]). Multiple genes are also involved in the neural pathways converging in the vomiting center (vestibular, chemoreceptor trigger zone, peripheral gastrointestinal pathways, as well as the vomiting center itself) (e.g. cholinergic receptor muscarinic 3 gene [CHRM3], cholinergic receptor muscarinic 5 gene [CHRM5], and histamine type 1 receptor gene [HRH1]) (Coluzzi et al., 2012). Panchal and colleagues reported on over 100 patients that received general anesthesia for abdominal surgery and screened for mu opioid receptors polymorphisms A118G (Asn 40 Asp) and COMT G1947A (Val 158 Met) polymorphisms (Panchal et al., 2007). The heterozygous patients with A118G and G1947 mutations consumed significantly less morphine in the first 48 postoperative hours and also experienced a significant lower incidence of nausea (Panchal et al., 2007). Zwisler et al. studied ABCB1 polymorphisms and oxycodone analgesia and adverse reactions in an experimental pain study; the variant alleles 2677A and 3453T were protective against nausea and vomiting (Zwisler et al., 2010). However, in a post-operative pain study, use of anti-emetics for morphine-related nausea and vomiting was decreased in patients who were homozygous for the 2677GG/3435CC diplotype (Coulbault et al., 2006). The largest genetic association study of opioid response to date, European Pharmacogenetic Opioid Study (EPOS), included 112 single nucleotide polymorphisms (SNPs) in 25 genes, including OPRM1, OPRK1, and OPRD1 (Klepstad et al., 2011). This study explored genetic associations with oral equivalent morphine dose requirements in 2294 patients taking a variety of strong opioids for cancer-related pain, but did not identify associations with any of the 112 SNPs in 25 candidate genes tested in both development and validation analyses (Klepstad et al., 2011). Two studies of morphine in the post-operative period and one of tramadol for osteoarthritis have reported an association with the variant G allele of rs1799971 and less nausea/vomiting (Kim et al., 2010; Kolesnikov et al., 2011; Sia et al., 2008). The A118G genotype was not associated with fentanyl-induced post-operative nausea and vomiting in another similar sized study of 165 Chinese women who had undergone gynecological surgery (Zhang et al., 2011). Meta-analysis of genetic association studies in opioid response shows only a weak association with nausea in homozygous carriers of the variant G allele of rs1799971 (Walter and Lotsch, 2009). In subanalyses of EPOS, 1579 patients reporting nausea and vomiting scores, symptoms were correlated with genotype

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(Laugsand et al., 2011). Three COMT SNPs were found to be weakly associated with less nausea/vomiting: rs165722C, rs4633T, and rs4680G, although the significance was lost after correcting for multiple testing (Laugsand et al., 2011). Genotype data were incomplete for some of the SNPs tested, which would have reduced the power. COMT metabolizes catecholamines such as dopamine, an important neurotransmitter in the area postrema and vomiting center. Dopamine D2 receptor antagonists such as domperidone are used as anti-emetics. COMT inhibitors increase dopaminergic activity, and therefore nausea and vomiting are prominent side effects (Truong, 2009). Another study of morphine following abdominal surgery reported that carriers with the variant A allele of rs4680 had significantly lower nausea scores and when in combination with the variant G allele of rs1799971 had reduced requirement for anti-emetic treatment (Kolesnikov et al., 2011). In EPOS, three SNPs in the 5-HT (serotonin) receptor 3B gene (HTR3B) were found to be associated with nausea/vomiting on preliminary analysis. Carriers of the rs1176744G, rs3782025T and rs1672717T were associated with less nausea/vomiting (Laugsand et al., 2011). Notably, the association with the G allele of rs1672717 remained significant when corrected for multiple testing. Activation of 5-HT3 receptors in the gastrointestinal tract or CTZ is pro-emetic.

5. Treatment 5.1. Modulation of opioid signaling The classic “direct” treatment of traditional OINV due to potent mu opioid receptors agonists are opioid antagonists (e.g. continuous naloxone infusion, naltrexone, nalmefene). Peripheral acting mu opioid receptors antagonists reduced nausea and vomiting in a few trials that were not designed to specifically look at this effect. Wolff and colleagues performed a meta-analysis of phase 4 clinical trials evaluating the use of alvimopan in patients with postoperative ileus after bowel resection and found a significant reduction in nausea and vomiting from alvimopan as well (Wolff et al., 2007). Subcutaneous Methylnaltrexone (MNTX) was shown to markedly reduce the nausea associated with parenteral morphine administration. This decrease in vomiting may have occurred from an action of MNTX at the CTZ receptors and/or a modulation of afferent impulses from the enteric nervous system to the brain (Yuan and Foss, 1999). Although, 6β-naltrexol is not yet FDA approved in the US and has not been well studied for the treatment of OINV, it is conceivable that 6β-naltrexol may have some beneficial effects for OINV. 6β-Naltrexol is the main human metabolite of naltrexone, accounting for up to 43% of the dose (King et al., 1997; Meyer et al., 1984; Verebey, 1981). Ranking among a class of analogs shown to be neutral antagonists, 6β-naltrexol inhibits activation of opioid receptors, but unlike inverse agonists such as naloxone and naltrexone, does not suppress basal receptor signaling (Divin et al., 2008; Raehal et al., 2005; Sadée et al., 2005; Sirohi et al., 2009; Wang et al., 2001, 2004) In animal models, 6β -naltrexol precipitates a less severe withdrawal compared with the inverse agonists naloxone and naltrexone (King et al., 1997; Wang et al., 2001). Therefore, neutral opioid antagonists may be optimally effective in treatment of unwanted opioid side effects (e.g., opioid induced bowel dysfunction), while avoiding aversion and severe withdrawal (Yancey-Wrona et al., 2011). Other pharmacologic treatments for OINV are similar to the general use of antiemetics as in postoperative nausea/vomiting (PONV) or chemotherapy-induced nausea/vomiting (CINV); although

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some antiemetic agents may be particularly useful for the treatment of OINV. 5.2. Dopamine receptor antagonists Dopamine (D2) receptor antagonists include: butyrophenones, (e.g. droperidol, haloperidol), phenothiazines (e.g. prochloroperazine, perphenazine, and promethazine) which also possesses potent histamine (H1) receptor antagonist, trimethobenzamide, metoclopamide, as well as atypical antipsychotics such as olanzapine, aripiprazole, and risperidone (Smith et al., 2012b). Metoclopramide is a dopamine antagonist with a short-life and is one of the most frequently used dopamine antagonists. However, due to the extrapyramidal symptoms that emerged during its use at high doses for the prevention of chemotherapy induced nausea and vomiting (e.g., 200 mg every 4–6 h), clinicians wound up shying away from relatively high doses (George et al., 2010). The substituted benzamide metoclopramide (at high doses) blocks both dopamine and 5-HT3 receptors and also increases lower esophageal sphincter tone; it exhibits prokinetic activity (facilitating gastric emptying) but again may lead to extrapyramidal side effects (Mehendale and Yuan, 2006) and can, like other D2 antagonists, have a negative impact on “hedonic tone” (Smith, 2006). A 10 mg dose of metoclopramide has become the most commonly used dose (Gralla et al., 1981; Henzi et al., 1999). A systematic review showed this conservative 10 mg dose to have no clinically relevant antiemetic effect (Henzi et al., 1999) A dose–response study of metoclopramide by Wallenborn et al. (Wallenborn et al., 2006) found that doses of metoclopramide higher than 10 mg (e.g. 25–50 mg) were as effective as other antiemetics. In addition to the extrapyramidal symptoms, metoclopramide has also been associated with adverse events related to the cardiovascular system, including one patient experiencing multiple cardiac arrests after repetitive metoclopramide administrations (Bentsen and Stubhaug, 2002). Guidelines discourage use of 10 mg metoclopramide (as well as standard clinical doses of ginger root or cannabinoids) as being ineffective for postoperative nausea and vomiting (PONV) (Gan et al., 2007); however, a comparative study indicates that higher doses (e.g. 20 mg) may be efficacious (Quaynor and Raeder, 2002). Since metoclopramide functions as a D2 receptor antagonist as well as a 5-HT4 agonist, it may be particularly well suited as an antiemetic for OINV. However, in clinical practice, metoclopramide does not seem to have especially potent antiemetic effects; particularly at doses usually employed (e.g.10 mg) (Smith et al., 2012a). Furthermore, there is little evidence to show that prophylactic metoclopramide following acute intravenous morphine, in efforts to provide antiemetic effects is clinically beneficial (Simpson et al., 2011). 5.3. Atypical antipsychotic agents Olanzapine is an atypical antipsychotic agent of the thienobenzodiazepine class. Olanzapine blocks multiple neurotransmitter receptors, including dopaminergic (D1, D2, D3, and D4 [with a high affinity for the D2 receptor with a Ki of 11 μmol/L]), serotonergic (5-hydroxytryptamine 2A (5-HT2A), 5-HT2C, 5-HT3, and 5-HT6), adrenergic α1, histaminic H1, and muscarinic (M1, M2, M3, and M4) receptors. Olanzapine has a high affinity for the 5HT2A receptor, which is up to 5 times greater than the dopamine receptor, resulting in less propensity to the development of extrapyramidal side effects (Prommer, 2013). Multiple clinical trials have shown that olanzapine appears to be an effective antiemetic for chemotherapy-induced nausea and vomiting (Navari et al., 2005, 2007; Passik et al., 2004). Jackson

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and Tavernier (Jackson and Tavernier, 2003) evaluated palliative care patients who suffered from nausea (including opioid-related nausea), which was resistant to initial treatment with traditional antiemetics such as prochlorperazine, promethazine, haloperidol, and lorazepam. Careful dose titration of olanzapine over a period of 7 to 10 days (in the range of 2.5–7.5 mg) given at bedtime prevented excessive sedation, even in patients that could not tolerate other antiemetics due to sedation and resulted in marked improvement in reported nausea. In an open-label pilot study, 15 patients with advanced cancer requiring opioid analgesics for pain. Fifteen patients received 2 days of a washout and placebo “run-in” followed by two day periods on each of three doses of olanzapine (2.5 mg, 5 mg, and 10 mg) (Passik et al., 2002). Olanzapine, at all dose levels, significantly reduced opioid-induced nausea (compared with baseline) and sedation or other adverse effects were not dose limiting. The 5 mg condition was associated with statistically significant improvement in overall quality of life over baseline (Passik et al., 2002). Ishihara and colleagues conducted a multi-institutional retrospective study, in which 619 eligible hospitalized patients receiving oral opioid analgesics for cancer pain were enrolled from 35 medical institutions (Ishihara et al., 2012). The primary endpoint was the incidence of opioid-induced side effects in patients receiving prophylactic medication. The results of the meta-analysis revealed that prophylactic laxatives significantly reduced the incidence of constipation (overall odds ratio¼0.469, 95% confidence interval ¼0.231–0.955, P ¼0.037), whereas dopamine D2 blockers were not effective in preventing opioid-induced nausea or vomiting (Ishihara et al., 2012). Shiokawa et al. published that the emetic effect of morphine was significantly and similarly suppressed by pretreatment with either the dopamine receptor antagonist haloperidol or aripiprazole (Shiokawa et al., 2007). Opioids induce emesis through many various mechanisms: stimulation of the chemoreceptor trigger zone in the brainstem or through enhanced vestibular sensitivity. Several agents that act on receptors in the chemoreceptor trigger zone can be used to combat opioid-induced nausea and vomiting (Costello and Borison, 1977). Dopamine receptor antagonists are commonly used to protect against opioid-induced emesis. Other agents including 5-HT3 receptor antagonists, muscarinic receptor antagonists, and histamine H1 receptor antagonists (e.g. promethazine, hydroxyzine, scopolamine patch, diphenhydramine), cannabinoid receptor agonists, are also utilized in some cases (Bowdle, 1998; Cole et al., 1994; Gupta et al., 1989). Aripiprazole is a dopamine system-stabilizer with potent partial agonist activity at dopamine D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors (Li et al., 2004). Although the exact mechanism by which aripiprazole suppresses morphine-induced emesis unclear, we propose here that the partial antagonistic effect of dopamine receptors and serotonin receptors induced by aripiprazole may be involved in suppression of the morphine-induced emesis by aripiprazole (Shiokawa et al., 2007). Okamoto and colleagues conducted a retrospective chart review to examine whether another atypical antipsychotic, risperidone, is useful for opioid-induced nausea and vomiting in advanced cancer patients (n ¼20) (Okamoto et al., 2007). Risperidone was given as doses of 1 mg once a day. Complete response was observed in 50% of patients (10/20) for nausea and 64% (7/11) for vomiting (Okamoto et al., 2007). 5.4. 5-HT3 receptor antagonists Palonosetron may possess several unique characteristics, including allosteric binding to 5-HT3 receptors with subsequent receptor internalization, negative cooperativity with tachykinin

NK1 receptors, and a long half-life of 40 h (Rojas et al., 2010a, 2010b). The incidence of PONV in two pivotal studies was 74% in the placebo group and 57% in the 0.075 mg palonosetron group in one trial (Candiotti et al., 2008), and 64% and 44% in the other trial (Kovac et al., 2008). This translates to relative risk reductions of 29% (¼1–0.57/0.74) and 31% (¼1–0.44/0.64), which is very similar to the relative risk reductions of about 30% observed with other 5-HT3 receptor antagonists (Apfel et al., 2004). Park and Cho compared 8 mg ondansetron with 0.075 mg palonosetron for the prevention of PONV reported a 67% incidence of PONV in the ondansetron group and 42% in the palonosetron group (Park and Cho, 2011). It is uncertain whether palonosetron's edge was due to its considerably longer half-life (40 h) compared with ondansetron (3–4 h) or whether palonosetron would still be more effective at equipotent doses. Moon and colleagues (Moon et al., 2012) have compared the incidence of PONV in a group who received an 8 mg i.v. bolus of ondansetron plus 16 mg ondansetron added to a fentanyl patient-controlled analgesia (PCA) mixture with that in a group who received just a single 0.075 mg i.v. bolus of palonosetron without any addition to the PCA pump. The incidence of nausea and vomiting and nausea severity were significantly lower in the palonosetron group than in the ondansetron group during 2–24 h. Apfel and Jukar-Rao (2012) has argued that the Park and Cho study (2011) looked more at opioid-induced nausea and vomiting (OINV) than at PONV, since postoperative opioids are one of the primary drivers of PONV, especially delayed PONV (Apfel et al., 1999, 2002; Roberts et al., 2005). OINV affects about 30% of surgical patients, with no difference between morphine and piritramide (Breitfeld et al., 2003) or between morphine and hydromorphone (Hong et al., 2008). Although PCA is commonly used for controlling postoperative pain, patients have reported a lower postoperative quality of life with PCA than with an epidural, perhaps because of a higher incidence of OINV with PCA (Ali et al., 2010). Tramer and Walder performed a systemic review and meta-analysis suggesting that not only the dopamine antagonist droperidol but also other antiemetics such as 5-HT3 receptor antagonists are effective in preventing OINV (Tramer and Walder, 1999). Chung et al. conducted a relatively large study that demonstrated that both 8 and 16 mg ondansetron were effective for treating established OINV (Chung et al., 1999). The study performed by Moon and colleagues (Moon et al., 2012), it was even more impressive to see that the incidence of PONV (or OINV) was significantly lower with 42% in the palonosetron group compared with 62% in the ondansetron group. Droperidol and ondansetron have now received a US FDA black box warning after reports of prolonged QTc interval and severe cardiac complications have been associated with its use. Although the vast majority of anesthesia providers believe that both drugs are sufficiently safe (Habib and Gan, 2008).

6. Other potential antiemetics for OINV 6.1. Tachykinin NK1 (NK-1) receptor antagonists Although aprepitant has not been studied for alleviating “pure” OINV, it seems, intuitively, that it could be a promising agent for this purpose. The acute administration of morphine may cause an increase in central nervous system (CNS) expression of substance P (Cantarella and Chahl, 1996). Furthermore, morphine upregulates functional expression of the NK-1 receptor in cortical neurons (as evidenced by mRNA levels, as well as immunofluorescence and Western blot assays using specific antibody to NK-1 receptor protein), possibly via mu opioid receptors-induced changes in

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Peripheral/ GI Tract (5-HT3)

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Vestibular (M1, H1) Emetic Complex

HTR3A, HTR3B, HTR3C, DRD2, OPRM1, OPRK1

CHRM3, CHRM5, HRH1, PORM1, OPRK1

CHRM3, CHRM5, HRH1,

5-HT3 Antagonists

Muscarinic Antagonists

(5-HT3, NK-1, M1, H1)

“Setrons”

Prodromal Sign Center

Central Pattern Generator Center

(e.g. Scopolamine Patch)

(e.g. Palonesetron)

CTZ DRD2, DRD3, TACR1, HTR3C, CNR1, OPRM1

μ,δ,κ-opioid receptor, D2, NK-1

Opioid Receptor Antagonists (e.g. Naltrexone)

DRAs (e.g. Olanzapine)

NK-1R Antagonists (e.g. Aprepitant)

Fig. 1. Schematic of potential OINV pathophysiology/genetic involvement and potential antiemetic for OINV.

cyclic adenosine monophosphate, leading to activation of the p38 MAPK signaling pathway (via phosphorylation) and activation of the NK-1 receptor promoter (Wan et al., 2006). Therefore, it does not seem unreasonable to study aprepitant—an NK-1 R antagonist used for the treatment of PONV and CINV—for its efficacy in treating OINV (Fig. 1). It is conceivable that OINV may at least partially involve the vestibular apparatus in certain circumstances and there, treatmemt with a scopolamine patch may be potentially useful. Based largely on data from perioperative studies, transdermal scopolamine appears to help ameliorate OINV (Ferris et al., 1991; Harris et al., 1991; Kotelko et al., 1989; Loper et al., 1989; Tarkkila et al., 1995).

7. Other opioid or opioid-like products that may produce less nausea/vomiting than traditional opioid agents 7.1. Tapentadol Tapentadol is a centrally acting analgesic with two mechanisms of action: mu-opioid receptor agonism and norepinephrine reuptake inhibition in a single molecule (Tzschentke et al., 2006, 2007). The combination of these two mechanisms of action may contribute to both the analgesic effect of tapentadol and the reduction in the occurrence of the side effects associated with mu-opioid agonists (Tzschentke et al., 2006). Tapentadol immediate-release is available as 50, 75, and 100 mg tablets and provides 4–6 h of analgesia (Etropolski et al., 2010). It was also as effective as oxycodone in patients presenting with chronic osteoarthritis pain and chronic low back pain (Hale et al., 2009; Hartrick et al., 2009), however, in a bunionectomy trial (Daniels et al., 2009), the composite incidence of nausea and vomiting in patients treated with tapentadol 50 mg every 6 h was significantly lower than in patients treated with oxycodone 10 mg. Oxycodone IR, 15 mg, provided equivalent analgesia to tapentadol IR, 100 mg, but the latter had a significantly lower incidence

of nausea and/or vomiting (53% vs. 70%, respectively; nominal P¼ 0.007) (Daniels et al., 2009). Vorsanger and colleagues performed a post hoc analyses of data from a 90-day clinical trial evaluating the tolerability and efficacy of tapentadol immediate release and oxycodone immediate release for the relief of moderate to severe pain in elderly and nonelderly patients (Vorsanger et al., 2011). They concluded that tapentadol IR was safe and effective for the relief of lower back pain and osteoarthritis pain in elderly patients, and was associated with a better gastrointestinal tolerability profile than oxycodone IR (Vorsanger et al., 2011). However, if doses of over 75 mg of tapentadol IR t.d.s. are compared to low doses oxycodone IR, 5 mg t.d.s., they both similary significant delayed gastric emptying t1/2, small bowel transit, and increased nausea compared to placebo (Jeong et al., in press). Tapentadol extended release (100–250 mg bid) was associated with better gastrointestinal tolerability than oxycodone controlled release (20–50 mg bid) and provided similar analgesia for the management of moderate to severe chronic pain from osteoarthritis (Afilalo et al., 2010) or low back pain (Buynak et al., 2010) and which appears to be sustainable for at least a year (Wild et al., 2010). The incidences of specific gastrointestinal treatmentemergent adverse events (TEAEs) were statistically significantly lower in the tapentadol extended release group compared with the oxycodone controlled release group, including the incidences of constipation (16.9% [166/981] vs. 33.0% [330/1001]; Po 0.001), nausea (20.7% [203/981] vs. 36.2% [362/1001]; P o0.001), vomiting (8.2% [80/981] vs. 21.0% [210/1001]; P o0.001), and the composite of nausea and vomiting (23.3% [229/981] vs. 42.7% [427/1001]; P o0.001) (Lange et al., 2010). Risk of nausea, vomiting, and constipation significantly increased with exposure to tapentadol, oxycodone, or oxymorphone vs. placebo. However, elevated risk per drug exposure of AEs for tapentadol was  3–4 times lower than that of oxycodone, while elevated AE risk per drug exposure of oxycodone was 60 times lower than that for oxymorphone, consistent with reported in vitro receptor binding affinities for these compounds. Simulations show that AE incidence following administration of tapentadol IR is lower

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than that following oxycodone IR intake within the investigated range of analgesic noninferiority dose ratios. This PK/PD analysis supports the clinical findings of reduced nausea, vomiting and constipation reported by patients treated with tapentadol, compared to patients treated with oxycodone (Xu et al., 2012). 7.2. Opioid/opioid combinations Moxduos (morphine/oxycodone 3/2) is a dual-opioid combination of morphine and oxycodone used to treat acute pain but not yet FDA approved in the US Controlled trials with morphine/ oxycodone 3/2 have enrolled approximately 1500 subjects with moderate to severe post-surgical pain who received multiple doses of morphine/oxycodone 3/2 or single-entity opioids for a maximum of 23 days, revealed analgesic efficacy that is at least comparable to the individual components and a 50–75% reduction in moderate to severe AEs, especially nausea and vomiting (Webster, 2012). 7.3. Opioid/non-opioid combinations Although the use of drug combinations for OINV has not been studied, it is not uncommon for clinicians to empirically combine multiple antiemetic agents in attempts to optimize outcomes. Corticosteroids, despite their uncertain mechanism of action, have been utilized as “antiemetic adjuvants” in combination with other antiemetic agents (Munstedt et al., 1999). It is also conceivable, that in the future, (opioids may be combined with agents, which may nullify their emetic effects while maintain or enhancing their analgesic effects (Smith, 2008b). In 2010, Davis and Hallerberg published that neither ondansetron nor metoclopramide (two commonly employed agents utilized to treat OINV) improved opioid-induced emesis, based on a randomized controlled trial (Davis and Hallerberg, 2010), however, this could be partly due to the doses not being pushed high enough. In the future, it is hoped that further research on OINV is conducted, as there remains a relative dearth of robust evidence surrounding “pure” OINV. 7.4. Opioid agonist/opioid antagonist combinations It is too early to tell if there may be any slight advantage of future opioid agonist/opioid antagonist combination products in terms of reduced nausea/vomiting, but preliminarily it would appear that it is not the case [e.g. oxycodone/naloxone (Comelon et al., 2013), oxycodone/naltrexone (Davis et al., 2013)]. 7.5. Novel opioid derivatives Majumdar and colleagues synthesized iodobenzoylnaltrexamide (IBNtxA), a naltrexone derivative (Majumdar et al., 2011a). In vivo, it is a very potent analgesic (ED50¼ 0.48 70.05 mg/kg s.c.), 10 fold more potent than morphine (4.6 70.97 mg/kg s.c.) (Kolesnikov et al., 1993), with a mechanism of action quite distinct from traditional opiates. Using doses approximately fourfold greater than their respective analgesic ED50 values, Majumdar et al. (2011b) observed the expected decrease in respiratory rate in mice receiving morphine (20 mg/kg s.c.), whereas an equivalent dose of IBNtxA (2.5 mg/kg s.c.) did not change the respiratory rate compared with saline. Inhibition of gastrointestinal transit, manifest clinically as constipation, is another major clinical concern. Morphine dramatically inhibited gastrointestinal transit. An equianalgesic dose of IBNtxA (0.6 mg/kg s.c.) lowered transit a small amount, but this effect plateaued, with far greater doses showing no further

inhibition, which clearly distinguished it from the effects of morphine (Majumdar et al., 2011b). The mechanism(s) of IBNtxA actions are quite unique and distinct from any of the traditional opioid receptor agonists. The persistence of IBNtxA analgesia and normal levels of 125I-BNtxA binding in the triple-KO mice rules out a role for delta and kappa1 receptors or any of the full-length mu1 opioid receptors–splice variants, which all contain exon 1.The loss of both IBNtxA analgesia and receptor binding in the exon 11 KO mice clearly implicates a role for exon 11-associated variants that contain only 6-TM domains (Majumdar et al., 2011b).

8. Discussion Nausea and/or vomiting is a terribly distressing experience for anyone which can be quite severe. OINV is not uncommon especially after the initial administration of acute opioid therapy. The variability of opioid responses clinically is well illustrated in comparisons of different genetically defined strains of mice (Pasternak, 2012). Morphine is a potent analgesic in the CD-1 mouse, but not in the CXBK mouse (Rossi et al., 1996). If the different mu opioids acted through a single mu receptor, the effects of other opioid drugs should also be reduced in the CXBK mouse. When this was examined experimentally, morphine was active in CD-1, but not in CXBK mice, while M6G, heroin, and 6-acetylmorphine showed similar analgesic actions in both strains (Rossi et al., 1996). This dissociation of analgesic sensitivity of the different mu opioids in the CXBK mouse strongly implies the presence of more than one mu opioid mechanism of action (Pasternak, 2012). The mechanism of action and pharmacology of opioids is complex. Opioids considered to be highly mu-selective still bind to a large number of mu receptor subtypes, with the various opioids producing subtly different pharmacological response based on the distinct activation profiles of the mu receptor subtypes. Differences in the individual variation in expression of these subtypes have not yet been explored, but they may also play a role in differences in opioid sensitivity (Pasternak, 2012). While different mu opioids bind to all mu receptors and produce similar pharmacological effects, subtle changes in their relative receptor activation may explain subtle differences in their pharmacology (Pasternak, 2012). The effects of opioid analgesics may be influenced by their route of administration, pharmacokinetics/pharmacodymics, receptor binding, downstream signaling, and non-opioid signal modifying mechanism. Genes encoding proteins involved in cross-membrane transport of opioids; especially across the blood–brain barrier, pglycoprotein gene is adenosine triphosphate-binding cassette subfamily member 1 (ABCB1), receptor binding and downstream signaling [opioid receptor mu 1 (gene is OPRM1), opioid receptor kappa 1 (gene is OPRK1), β arrestin (gene is ARRB2), signal transducer and activator of transcription 6 (gene is STAT6)], or modifying system [catechol-o-methyl-transferase (gene is COMPT), cannabinoid receptor 1 (gene is CNR 1)] may play a role in the presence and intensity of opioid effects including nausea/vomiting (Coulbault et al., 2006; Ross et al., 2005; Skarke et al., 2003; Skorpen et al., 2008). Clincial characteristics and SNPs within the HTR3B, COMPT and CHRM3 genes may be partially associated with the variability in opioid-induced nausea and vomiting among cancer patients (Laugsand et al., 2011). Although OINV has not been studied anywhere near as well as opioid-induced analgesia (OIA), it is likely that OINV, similar to OIA, has a significant variability of opioid responses. There are multiple signaling pathways that are affected by morphine treatment, however, one family of intracellular signaling compounds

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that plays an important role in transcription and posttranslational modification of a number of different proteins is the mitogenactivated protein kinases (MAPK) family that has also been shown to play a role in pain hypersensitivity (Ji et al., 2009). One of the members of this pathway is ERK (extracellular signal-regulated protein kinase) activated through phosphorylation, with repeated morphine is increased in neuronal p-ERK levels (Chen et al., 2008; Ma et al., 2001; Narita et al., 2002; Patel et al., 2006). Increases in pERK have been observed specifically in the DRG and corresponding to increases in pain-related neuropeptides and receptors and can be reversed by specific inhibitors of ERK (Chen et al., 2008; Ma et al., 2001). Opioid signaling leading to nausea/vomiting downstream from the mu opioid receptor remains uncertain as well as potential variations in signaling. Furthermore, it is uncertain if there is emetic synergy for opioids combined with other agents.

9. Conclusions Nausea and vomiting are among the most distressing of all symptoms for many patients. Opioids as well as many other drugs may lead to nausea and/or vomiting. Nausea tends to occur roughly one-fifth to one-third of the time with vomiting occurring about half of that. Although the precise mechanisms of opioidinduced nausea and vomiting are not entirely certain, it appears that opioid stimulation of the vestibular apparatus chemoreceptor trigger zone, and receptors in the gastrointestinal tract are three major areas involved. Targeting specific areas and/or receptors/ receptor-subtypes that opioids may directly or indirectly stimulate may lead to improved patient outcomes for patients with OINV who require opioids for medically necessary treatment.

Disclosure The authors have no disclosures and have not published or submitted this manuscript elsewhere.

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