Opioid induced constipation in cancer patients: pathophysiology, diagnosis and treatment

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1 Expert Review of Quality of Life in Cancer Care ISSN: (Print) (Online) Journal homepage: Opioid induced constipation in cancer patients: pathophysiology, diagnosis and treatment Amir Rumman, Zane R. Gallinger & Louis W. C. Liu To cite this article: Amir Rumman, Zane R. Gallinger & Louis W. C. Liu (2016) Opioid induced constipation in cancer patients: pathophysiology, diagnosis and treatment, Expert Review of Quality of Life in Cancer Care, 1:1, 25-35, DOI: / To link to this article: Accepted author version posted online: 14 Dec Published online: 20 Jan Submit your article to this journal Article views: 1474 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at Download by: [ ] Date: 27 December 2017, At: 19:53

2 EXPERT REVIEW OF QUALITY OF LIFE IN CANCER CARE, 2016 VOL. 1, NO. 1, REVIEW Opioid induced constipation in cancer patients: pathophysiology, diagnosis and treatment Amir Rumman a, Zane R. Gallinger b and Louis W. C. Liu b a Department of Medicine, University of Toronto, Toronto, Ontario, Canada; b Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada ABSTRACT Opioid-induced constipation (OIC) has emerged as a major contributor to morbidity in cancer patients. OIC is common, difficult to treat and causes significant reductions in the quality-of-life of cancer patients. It results from opioid action on gut mu-receptors, which leads to the disruption of bowel motility, mucosal transport and defecation reflexes. Laxatives are cornerstone in the management of OIC despite their relatively limited effectiveness and lack of strong evidence supporting their use. In the past few years, novel therapeutics have emerged for the management of OIC. These include; prokinetic agents, peripherally-acting mu-opioid receptor antagonists (PAMORAs), secretagogues and opioid receptor agonist/antagonist combination tablets. This article will review the mechanism of OIC in cancer patients and describe the novel therapeutic options for its prevention and management. Introduction Opioids are frequently used for the treatment of pain syndromes in patients with cancer [1]. The World Health Organization analgesic ladder for cancer pain management suggests initiating opioid therapy, along with non-opioid adjuncts, for moderate to severe pain [2,3]. This is due to the favorable safety profile, ease of titration, and efficacy of opioids for several types of cancer pain syndromes, including somatic, visceral, as well as neuropathic pain [4 6]. It is estimated that up to 90% of patients with cancer experience a pain syndrome at some time during the course of their illness and treatment, and most will need opioid analgesics [7]. Despite their effectiveness as analgesics in cancer patients, opioids result in a myriad of gastrointestinal (GI) side effects [8]. The syndrome of opioid-induced GI adverse effects has been termed opioid-induced bowel dysfunction (OIBD) [9]. The most common and problematic component of OIBD is opioid-induced constipation (OIC) [10,11]. The prevalence of OIC in cancer patients ranges from 23% to over 90% [2,12]. The impact of constipation on the quality of life of cancer patients on opioid therapy is significant [13]. In a study assessing symptom distress using a standardized scale, cancer patients were more likely to rate constipation as a cause of severe symptom distress (18%) than pain (6%) [14]. Furthermore, OIC is the most common reasons for cancer patients to avoid or discontinue opioid ARTICLE HISTORY Received 16 November 2015 Accepted 10 December 2015 Published online 20 January 2016 KEYWORDS Opioid-induced constipation; opioid-induced bowel dysfunction; opioid complications; cancer; pain management use, often sacrificing adequate pain control to avoid constipation [15]. As a result, the management of OIC has emerged as a major determinant of successful analgesic therapy in cancer patients. In this article, we will review the mechanism of OIC and its management in cancer patients. We will also outline novel and emerging therapeutics for OIC and OIBD. Pathophysiology of OIC Normal bowel function requires the coordination of motility, mucosal transport, and defecation reflexes [9]. Opioids interfere with these normal processes across the entirety of the GI system. The resulting syndrome, OIBD, has several manifestations, including constipation, abdominal distension, pain, and discomfort, as well as bloating, nausea, and vomiting (Table 1). Less commonly, secondary complications such as intestinal pseudo-obstruction, gastrooesophageal reflux, as well as malabsorption syndromes may result [16]. OIC is the most common and most problematic manifestation of OIBD. It specifically results from the impairment of normal propulsive peristalsis, inhibition of intestinal mucosal secretion, enhancement in intestinal fluid absorption, and disordered anal sphincter function. Opioid-induced gut dysmotility On the receptor level, OIC arises from opioid-mediated actions on receptor populations within the GI tract, and CONTACT Louis W. C. Liu Louis.Liu@uhn.ca Division of Gastroenterology, Department of Medicine, University of Toronto, 399 Bathurst St, 8MP-329, Toronto, Ontario, Canada Taylor & Francis

3 26 A. RUMMAN ET AL. Table 1. Pathophysiology and clinical manifestations of opioid-induced bowel dysfunction. Target organ Motor and physiologic effects Clinical effects Esophagus Dysmotility of LES [17,18] EGJ outflow obstruction [18,19] GERD, and rarely dysphagia Nausea, vomiting Stomach Decreased gastric motility [18] Nausea, vomiting, anorexia, abdominal discomfort Decreased pyloric tone [20] Pancreas and biliary system Decreased pancreatic secretions [21] Decreased biliary secretions [21] Biliary contraction [22] Impaired digestion, abdominal discomfort Maldigestion, malabsorption Right upper quadrant pain Small bowel Reduced propulsive peristalsis [23] Delayed absorption Enhanced fluid absorption [24] Colon Reduced propulsive peristalsis [25,26] Enhanced fluid absorption [24] Nonpropulsive contractions [22,27] Rectum and anus Decreased rectal sensitivity [28] Increased anal sphincter tone [29] LES: Lower esophageal sphincter; EGJ: Esophageo-gastric junction; GERD: Gastroesophageal reflux disease. Hard, dry stools Constipation Hard, dry stools Spasms, abdominal pain Incomplete evacuation, straining to a much lesser extent, within the central nervous system (CNS) [28]. Within the GI tract, delta-, kappa-, and mu-opioid (OP1, OP2, and OP3) receptors contribute to opiate-induced inhibition of muscle activity [30]. Normally, opioid peptides and opioid receptors are expressed by distinct enteric neurons and intestinal muscle cells. When released from these neurons, opioid peptides are suspected to act as transmitters in the enteric regulation of propulsive motility and peristalsis [31]. The inhibitory effect of opioids on the release of these peptides is twofold. First, it results in attenuation of normal propulsive motility and peristalsis. Second, it evokes tonic spasms and nonpropulsive motility patterns in the small intestines and colon [32,33]. This results in delayed gastric emptying, slowed intestinal transit, abdominal cramping, and constipation. In the CNS, opioids act as agonists at four receptor subtypes: delta, kappa, and mu, as well as the opioid receptor like-1 (ORL-1) receptor. Activation of these receptors centrally achieves analgesia [33]. It is also postulated to contribute to reduced GI propulsion, possibly by altering autonomic outflow from the CNS to the enteric nervous system [33]. The majority of human studies assessing the pathophysiology of OIC were conducted in healthy young volunteers. However, the majority of cancer patients are elderly. In the United Kingdom, 74% of cancer cases are diagnosed in individuals at least 60 years old; more than one-third of cases occur in people aged over 75 years [16]. In the United States, in 2007, 11.7 million men and women of all ages suffered from some form of invasive cancer, of those, 70% were at least 60 years of age [16]. The pathophysiology of OIC in these patients is probably further compounded by intrinsic changes to colonic motility secondary to aging. These include reduced number and responsiveness of neurons in the myenteric plexus [34], increased colonic collagen deposition [35], and a reduction in the amplitude of inhibitory nerve input to the circular muscle layer of the colon, resulting in lack of segmental motor coordination [36]. Opioids effect on mucosal secretion Activation of the opioid receptors in the GI tract results in inhibition of submucosal water and electrolyte secretion [27]. It also increased fluid retention and absorption from the luminal space. Furthermore, opioid therapy results in increasing sympathetic tone which serves to further reduce secretions into the lumen [37]. The net result of these effects is increased fluid absorption from the lumen and formation of harder, dryer stools. Opioids effect on defecation reflexes Opioid therapy results in increasing tone to both the ileocecal and the anal sphincters, which contributes to constipation through two mechanisms. Not only is the defecation reflex blunted through reduced rectal and anal sensitivity to fullness in the rectal vault [38] but anal sphincter dysfunction also contributes to the sensation of anal blockage and incomplete defecation commonly encountered in patients with OIC [28]. Defining OIC in cancer patients Defining OIC There is no standard definition of OIC in the medical literature. In a recent systemic review of 47 clinical trials, only 16 studies provided a clear definition of OIC [39]. The definitions provided were highly variable and relied on objective measure only in 17 of the trials. Traditional measures, such as the Bristol Stool Scale or the frequency of bowel movements can provide an objective

4 EXPERT REVIEW OF QUALITY OF LIFE IN CANCER CARE 27 assessment of the clinical status of a patient with constipation and their response to treatment [40]. However, given the complexity of OIC symptoms, these measures may be overly simplistic and may not adequately reflect the impact of constipation experienced by the patient. Furthermore, only a moderate correlation was demonstrated between stool consistency and colonic transit time, a major determinant of OIC [40]. For that reason, the Rome III criteria have been used to define OIC in clinical trials and in clinical practice. Despite being developed for functional constipation, these criteria provide a standardized definition that can be used across trials. The criteria include straining at defecation, passage of lumpy or hard stools, sensation of incomplete evacuation or anorectal obstruction, the need to use manual maneuvers to facilitate defecation, and passing fewer than three stools per week [41]. Several other subjective scales have been developed and validated to aide in the complex assessment of patients with OIC in cancer patients specifically. The Bowel Function Index (BFI) is the most widely used tool due to its simplicity [42]. This clinician-administered tool allows easy measurement of OIC from the patient s perspective. The BFI is a clinician-administered survey composed of three questions that assess the ease of defecation, the feeling of incomplete bowel evacuation, and the personal judgment of the patient regarding constipation. Patients score these questions based on their personal experience in the preceding 7 days. Each question is scored using a numeric scale ranging from 0 (no symptoms) to 100 (severe symptoms), and the final score is calculated as the mean of the three component scores. This score has been shown to be reliable and responsive to change in OIC severity, with a 12-point change in score constituting a clinically relevant change in constipation [42]. Recently published consensus recommendations for the treatment of OIC suggest that treatment should be initiated in patients with BFI score of greater than or equal to 30 points and an inadequate response to first-line interventions [43]. Other measures include the Patient Assessment of Constipation (PAC), which comprises two clinician-administered surveys: the symptom survey (PAC-SYM) and the quality of life survey (PAC-QOL) [44]. The PAC-SYM comprises 12 items divided to three symptom domains: stool symptoms, rectal symptoms, and abdominal symptoms. The PAC-QOL comprises 28 items divided into four domains: dissatisfaction, physical discomfort, psychological discomfort, and worries and concerns. The benefit of the PAC survey includes its comprehensive nature and the focus on the quality-of-life burden of OIC. This is particularly important given the increasing awareness of the significant impact of OIC on the quality of life of cancer patients [45]. The downsides include a longer duration of administration compared to the BFI, and lack of validation in cancer patients with OIC. A recent multidisciplinary consensus panel organized through the American Academy of Pain Medicine Foundation published criteria for the definition of OIC [39]. The panel recommended that OIC-defining criteria should include a set of objective measures (stool frequency and consistency), one or more patient-reported outcomes (straining, BFI score), and patient-reported global burden measures of OIC (PAC-QOL). Although these criteria are likely to be useful in clinical trials, their use in a clinical setting is likely limited due to the time-consuming nature of completing multiple surveys. Therapeutic options for OIC The therapeutic options for the management of OIC can be broadly divided into non-pharmacologic and pharmacologic interventions. Non-pharmacologic interventions include dietary modification and biofeedback training. Pharmacologic interventions can be further divided into indirect-acting treatments, which include laxatives, stool softeners, and prokinetic agents, and direct-acting treatments, which target the underlying mechanism of OIC by antagonizing gut opioid receptors without significantly affecting the central opioid receptors. These include peripherally acting mu-opioid receptor antagonists (PAMORAs) and opioid receptor agonist and antagonist combination agents. Non-pharmacologic options Non-pharmacologic therapeutic options have been studied for chronic idiopathic constipation (CIC) but have not been investigated in cancer patients with OIC. These options include dietary interventions (adequate hydration and increased fiber intake), biofeedback training, and opioid switching. Non-pharmacologic therapies alone are unlikely to be sufficient in the prevention and management of OIC, but may serve as adjuncts to pharmacologic therapy. In a trial of fiber supplements in patients with constipation, less than half of the patients responded to treatment [46]. In this trial, patients were assessed according to the etiology of their constipation: slowed transit, dyssynergic defecation, and idiopathic constipation. Only approximately 20% of slow transit and dyssynergic defecation patients benefitted from fiber, whereas over 80% of patients with idiopathic

5 28 A. RUMMAN ET AL. constipation had a partial or complete improvement of their symptoms. Since the primary pathophysiologic disturbance in OIC is disordered motility, increasing dietary fiber alone is unlikely to be beneficial. Paradoxically, increasing fiber intake may worsen OIC as it adds bulk to an already dry stool [33]. Similarly, there is no evidence that constipation can successfully be treated by increasing fluid intake unless there is evidence of dehydration [47]. Biofeedback training has been used to treat constipation in CIC patients with dyssynergic defecation but has not been studied in patients with OIC [48]. Opioid switching or rotation has been suggested when further dose escalation of opioid therapy to achieve adequate analgesia is limited by GI adverse effects [49]. The most frequent switch is from morphine, hydromorphone, or fentanyl to methadone. Success rates of 40 80% have been reported [49]. There are no randomized trials to support the practice of opioid switching in cancer patients on chronic opioid therapy to alleviate adverse events [50,51]. A systemic review conducted to help develop cancer pain management guidelines for the European Palliative Care Research Collaborative concluded that there is a low level of evidence for opioid rotation or switching [50]. Pharmacologic options Agents not targeted to opioid receptors Pharmacologic options for the treatment of OIC are summarized in Table 2. A wide array of laxatives has been used for OIC. These include stimulants laxatives, stool softeners, and osmotic laxatives. Osmotic and stimulant laxatives are frequently prescribed with opioids to prevent the development of OIC [12]. The European Association for Palliative Care guidelines for opioid therapy in cancer patients endorse a strong recommendation for routine prescription of laxatives with opioids for prevention and management of OIC [49,52]. Despite this recommendation, a significant proportion of patients are prescribed opioids without concomitant laxative prescription. In a recent Norwegian retrospective analysis of 2982 cancer outpatients on opioid therapy, 44.4% did not receive laxatives at all [53]. Only 24.7% of patients received laxatives at the time of opioid prescription and 22.0% received laxative after opioid prescription [53]. Although laxatives are commonly used, the efficacy in treating OIC in cancer patients is limited [12,54]. Furthermore, there is a paucity of evidence to guide the selection of the optimal laxative for OIC [55]. To date, there is no compelling evidence which suggests that one laxative agent should be recommended over others in cancer patients. However, when laxatives are used, a combination of two or more laxatives with different modes of action is likely to be more effective than a single agent, particularly in cases of resistant OIC [49]. A Cochrane review of five studies assessed the effectiveness of various laxatives (lactulose, Senna, co-danthramer, misrakasneham, docusate, and magnesium hydroxide with liquid paraffin) in palliative patients Table 2. Pharmacologic options for the treatment and prevention of opioid-induced constipation and their motor and physiologic effects. Class agents Mechanism of action Motor and physiologic effect Stimulant laxatives Senna Bisacodyl Osmotic laxatives Magnesium hydroxide PEG3350 Lactulose Stool softener Docusate Mineral oil Bulk-forming agents Psyllium fiber Prokinetics Prucalopride Secretagogues Lubiprostone Linaclotide Peripheral mu-opioid receptor antagonists Methylnaltrexone Alvimopan Opioid receptor agonist and antagonist combination tablets Oxycodone naloxone Anti-absorptive, secretory, and prokinetic effects on colon Poorly absorbable substances that serve as osmotic agents to draw water into the intestinal lumen Anionic surfactants with an emulsifying detergent-like property that increase the content of water in stool Fluid retention in stool 5-HT 4 receptor agonist Chloride channel-2 agonist Guanylate cyclase C agonist Antagonize gut mu-opioid receptors. Due to inability to cross blood brain barrier, they do not affect central mu-opioid receptors Antagonize gut mu-opioid receptors. Due to inability to cross blood brain barrier, they do not affect central mu-opioid receptors Improved stool consistency and enhanced colonic motility Improved stool consistency and increased stool water content Increased stool weight and improved stool consistency Increased stool weight and improved stool consistency Enhanced colonic contractility Stimulation of intestinal fluid secretion, lubrication of stool, and enhanced motility Analgesia with minimal disruption of bowel motility, mucosal transport, or defecation reflexes Analgesia with minimal disruption of bowel motility, mucosal transport or defecation reflexes

6 EXPERT REVIEW OF QUALITY OF LIFE IN CANCER CARE 29 [55]. Since all five studies compared different laxatives or combinations of laxatives, it was not possible to ascertain whether individual laxatives were more effective than others or caused fewer adverse effects. A larger Cochrane review in adult patients with chronic constipation found that polyethylene glycol was better than lactulose in outcomes of stool frequency and form, and the need for rescue laxatives [56]. However, the generalizability of these findings to cancer patients with OIC is unclear given the small sample size of the studies. Prokinetics. Conventional prokinetics have been used with minimal success in patients with OIC. Common GI prokinetics, such as metoclopramide and domperidone, are considered to be foregut prokinetics that are not indicated nor studied in patients with chronic constipation or OIC. Furthermore, toxicities from conventional prokinetics limit their widespread use in OIC. For example, metoclopramide can cause extrapyramidal side effects (incidence of 0.2%) and domperidone can increase the chance of cardiac arrhythmias [57]. Two serotonergic prokinetics, cisapride and tegaserod, have been removed from the market due to cardiac toxicity. However, prucalopride, a relatively new medication available in certain countries has shown to be efficacious in CIC with no significant toxicity and is a potential therapeutic agent for OIC. Prucalopride. Prucalopride is a highly selective 5-HT 4 receptor agonist. It has been shown to promote colonic motility. Unlike older prokinetics, there is no clinically significant cardiac toxicity. The additional advantage to prucalopride is that it has a low potential for drug interactions. Drug half-life is 21 h and 60% is excreted unchanged in the urine. The starting dose is 2 mg daily which is reduced to 1 mg for the elderly and those with a glomerular filtration rate of less than 30 ml/min/1.73 m 2. No dose reduction is needed for hepatic failure. Prucalopride has been shown in randomized trials to improve bowel function and constipation symptoms in patients with idiopathic, non-opioid-induced constipation [58]. Prucalopride is licensed in several countries for women with CIC unresponsive to laxatives. It has also been studied in a phase II, double-blind, placebocontrolled randomized trial in noncancer patients with OIC [59]. Patients were randomized to prucalopride 2 mg, 4 mg, and placebo for 4 weeks. The primary outcome was the proportion of patients with an increase from baseline of one spontaneous bowel movement (SBM) per week. The results in prucalopride-treated patients were 35.9% on 2 mg, 40.3% on 4 mg, and 23.4% on placebo. The severity of OIC was significantly improved in patients on 4 mg. Rescue laxative use was reduced. Abdominal pain and nausea were the most commonly reported adverse events. Although this trial did not meet its primary end point, this could be related to small sample size and further studies are needed to study the role of prucalopride in OIC. Secretagogues. Two novel secretagogues, linaclotide and lubiprostone, have been used for CIC and are potential therapeutics for OIC. Linaclotide. Linaclotide is a novel guanylate cyclase C (GC-C) agonist. It acts on the intestinal enterocyte and stimulates the cystic fibrosis transmembrane conductance regulator chloride channels resulting in increased fluid secretion into the gut lumen [60]. Linaclotide has also been shown to improve constipation and blunt visceral hypersensitivity, resulting in improvement of abdominal pain and discomfort [60]. Linaclotide is locally active and not absorbed systemically, hence low drug-to-drug interaction. It is well tolerated with the most commonly reported side effect being diarrhea. Linaclotide has been indicated for the treatment of CIC and irritable bowel syndrome with constipation (IBS-C) but has not been studied in OIC [61]. The unique analgesic properties of linaclotide may complement its anti-constipation properties in OIC. There are no trials reported in cancer patients, but studies are underway (NCT ) to assess its effectiveness in noncancer patients with OIC. Lubiprostone. Lubiprostone acts on CIC-2 and reduces constipation by increasing intestinal secretions and improving intestinal transit. It has also been shown to create an anti-inflammatory luminal milieu by altering gut flora and mucus composition [62]. However, unlike linaclotide, it does not appear to improve abdominal pain. In randomized trials involving patients with IBS-C, 8 μgoflubiprostonedosetwicedailyand24μgdosedtwice daily reduced constipation and improved stool consistency and bloating. The most commonly reported adverse effects were nausea, diarrhea, and abdominal pain [63]. Lubiprostone has been studied in chronic noncancer pain patients with OIC. The results from two double-blind, 12- week, placebo-controlled, phase III trials and one 9-month, open-label, phase III trial have been reported. In a double-blind study that did not exclude patients receiving methadone or similar opioids, primary end point was change from baseline (i.e. last 2 weeks of screening) in the frequency of SBMs at week 8, calculated based on the patient s daily record of SBM and rescue medication use [64]. The primary efficacy end point was achieved (3.3 for lubiprostone vs. 2.4 for

7 30 A. RUMMAN ET AL. placebo; p = 0.004). In a second double-blind study that excluded patients receiving methadone or similar opioids, a significantly larger percentage of patients treated with lubiprostone achieved a response (defined as having three SBMs per week for 9 weeks and an increase from baseline of one SBMs per week during 12 weeks of treatment) compared with placebo (27.1% vs. 18.9%, respectively; p = 0.030) [65]. The open-label trial enrolled patients who had participated in either of the former two double-blind trials [66]. Patients received open-label lubiprostone 24 μg twice daily for an additional 36 weeks. The primary end point was the change from baseline in monthly SBM frequency, calculated based on daily reports in electronic patient diaries. During the open-label study, significant improvements from baseline in frequency of SBMs were observed for each month of treatment (1.4 at baseline vs monthly range with treatment per week; p < 0.001). In an overall pooled analysis of 860 patients treated with lubiprostone for up to 12 months and 632 patients treated with placebo for up to 12 weeks, respectively, the most common adverse events were nausea (11% vs. 5%, respectively) and diarrhea (8% vs. 2%, respectively). Agents targeted to opioid receptors In the past 5 years, novel agents have been developed specifically for the treatment of OIC. These agents antagonize the gut mu-opioid receptors with the intention of blocking downstream effects that cause OIBD and OIC. The use of opioid antagonists, although effective in treating OIBD and OIC, has been initially limited because the agents will cross the blood brain barrier and antagonize the central opioid receptors, thereby diminishing the analgesic effect. Drug development has, therefore, been focused on creating opioid receptors that act peripherally in the gut and have minimal or no central antagonism. To achieve this goal, two distinct therapeutic classes were developed. PAMORAs are agents that are administered either orally or subcutaneous in conjunction with the opioids. Opioid receptor agonist and antagonist combination drugs are administered orally and provided analgesia and concomitant prevention of OIC. The first PAMORA to be developed for clinical use was methylnaltrexone [67]. This is a charged methylated derivative of the commonly used opioid antagonist naltrexone. Due to its charge and methylation, methylnaltrexone does not readily cross the blood brain barrier [67]. It is administered subcutaneously and has been approved for the treatment of OIC in palliative patients who failed maximal laxative therapy. It has been shown to be effective in patients with OIC, including those with cancer, in a phase III randomized clinical trial [68]. It was found to reduce the oral-cecal transit time by over 2 h and is shown to be effective in more than half of individuals treated [69]. The most commonly reported adverse effects were abdominal pain, diarrhea, and nausea. GI perforation has been reported as a rare complication of methylnaltrexone use, particularly in patients with structural GI disease [70]. These reports resulted in the US FDA amendment to the drug s prescribing information to include a warning that methylnaltrexone be used with caution in patients with a known or suspected GI lesion, such as cancer, peptic ulcer, or Ogilvie syndrome. Despite being effective in treating OIC, methylnaltrexone is cumbersome to administer because it requires subcutaneous injection. Several oral alternatives have been developed and studied in patients with OIC. These include naloxegol and alvimopan. The latter is not approved for chronic treatment of OIC but is used for short-term (less than 7 days) management of postoperative ileus [71]. The long-term use of alvimopan is limited due to concerns about increasing risk of ischemic cardiac events [72]. To date, studies of methylnaltrexone and naloxegol have not demonstrated an increase in cardiovascular risk as seen in alvimopan. Naloxegol, on the other hand, has been approved for chronic use in patients with OIC, including use in cancer patients. Naloxegol is a PEGylated derivative of naloxone. This orally administered agent does not readily cross the blood brain barrier [73]. In addition to being orally administered, naloxegol does not require dose adjustment in patients with renal failure and mild-tomoderate hepatic impairment. Additionally, it does not appear to prolong the QT interval [74,75]. The efficacy of naloxegol has been demonstrated in two, large phase II clinical trials, KODIAC-04 and KODIAC-05 [76]. These studies enrolled 652 and 700 noncancer patients with OIC, respectively. Patients were randomized to naloxegol (12.5 and 25 mg) versus placebo for a treatment duration of 12 weeks. The primary end point was the percentage of patients having greater than or equal to three SBMs per week and with at least one SBMs per week increase from baseline, for at least 9 weeks out of the 12-week treatment period and for at least 3 of the last 4 weeks of treatment. The primary end point was met with in the 25 mg groups in both KODIAC-04 and KODIAC-05 and for the 12.5 mg dose in KODIAC-04. Both pain control scores and total daily opioid dose were unaffected by naloxegol treatment and assessment of opioid-mediated central analgesia was unaltered by treatment with naloxegol. The most commonly reported adverse events were GI related and mild in severity.

8 EXPERT REVIEW OF QUALITY OF LIFE IN CANCER CARE 31 Prolonged-release oxycodone-naloxone combination tablet (PR-OXN) has been validated for the treatment of cancer-related pain and prevention of OIC. The combination tablet provides prolonged-release oxycodone and prolonged-release naloxone with a ratio of 2:1. Naloxone antagonizes the opioid receptors in the gut, while its extensive first-pass hepatic metabolism ensures the lack of antagonist influence on the central-mediated analgesic effect of the opioids [77]. In a randomized control trial comparing PR-OXN to prolonged-release plain oxycodone (PR- OX), mean BFI score was significantly lower with PR- OXN after 4 weeks of treatment. Mean total laxative intake was 20% lower with PR-OXN. Analgesic control was not diminished with PR-OXN and significant improvements in constipation-specific quality-of-life assessments were noted with PR-OXN. Overall, rates of adverse drug reactions were similar between PR- OXN and PR-OX[78]. Similar findings were demonstrated in three observational studies of cancer patients with OIC [79 81]. A limitation of PR-OXN was highlighted in a case report of a cancer patient with very high opioid requirements (240 mg of oxycodone daily). When started on equi-analgesic dose of PR-OXN (240 mg/120 mg, which exceeds the recommended maximum daily dose of 160 mg/80 mg), the patient experienced a marked reduction in analgesic benefit despite receiving a similar dose of oxycodone. The pharmacodynamic properties of the combination tablet may limit the analgesic properties of PR-OXN at high opioid requirements [82]. Another limitation of PR-OXN is that it is contraindicated in patients with moderate-to-severe hepatic impairment [83]. Emerging therapies At the time of this review, several novel therapies for constipation are in various stages of development. These include three additional 5-HT 4 agonists: mosapride (NCT , NCT ), naronapride (NCT ), and velusetrag (NCT ). The latter two have been shown to have favorable outcomes in CIC and IBS-C, but are yet to be tested in cancer patients with OIC [84]. Several PAMORAs are also under study in patients with OIC. These include naldemedine (NCT and NCT ), bevenopran (NCT and NCT ) and axelopran. No results have been disseminated to date, but it is hoped that these targeted interventions will result in reductions in the burden of OIC in cancer patients. Bile acid transporter inhibitors are in development as novel therapeutics for constipation. Bile acid synthesis, secretion, and intestinal absorption are important to colonic motility and secretion. Constipation has been associated with reduced bile acid secretion and synthesis leading to reduced bile acid in stool [85]. It is postulated that blocking the bile acid transporter will result in increased GI motility and reduces constipation. Elobixibat is a promising novel therapy for constipation but has not been studied in OIC [86]. Expert commentary OIC is common in cancer patients receiving opioid therapy for analgesia. Despite the lack of well-designed randomized trials, osmotic and stimulant laxatives remain the mainstay of therapy for treating OIC. Due to the limitations of these laxative regimens in cancer patients with OIC, novel agents need to be considered in patients who fail conventional laxative therapy. Options with proven benefit in patients with OIC include 5-HT 4 receptor agonist prucalopride (phase II trial only) and chloride channel agonist lubiprostone. Both have demonstrated efficacy in CIC and lubiprostone in IBS-C; prucalopride has shown benefit in patients suffering from OIC, and lubiprostone has recently been approved in United States for OIC. Linaclotide, a GC-C receptor agonist, has also been shown to be efficacious for CIC and IBS-C, and studies for OIC patients are ongoing. To date, there have been no head-to-head trials comparing these agents. PAMORAs are therapeutic agents that target the pathophysiological mechanism of OIC and are indicated for patients with laxative-resistant OIC. Subcutaneous methylnaltrexone is useful for OIC in palliative patients, including cancer patients. Alvimopan, an oral PAMORA, is effective for shortterm use to prevent post-operative ileus. Due to concerns around cardiovascular risk, it is not approved for long-term use in OIC agents. Naloxegol, an oral PAMORA, is effective for laxativeresistant OIC patients but has not been studied specifically in OIC patients with cancer. It is likely to be efficacious based on studies in patients treated with opioid for nonmalignant pain. Combination oral prolonged-release oxycodone naloxone is an option for patients who are on 80 mg or less of oxycodone a day. It may not be used in patients with hepatic impairment. Several studies are underway to assess the efficacy of novel PAMORAs, prokinetic agents, and secretagogues. Further research is needed to validate benefits of these novel agents in cancer patients with OIC.

9 32 A. RUMMAN ET AL. Five-year view Increasing recognition of the burden and morbidity of OIBD and OIC in cancer patients over the past 5 years has translated into the development of many novel therapeutic options for the treatment of these challenging entities. OIC is slowly but surely transitioning from a poorly characterized and undertreated condition to a well-defined clinical entity. Major contributions have been made to the definition of the clinical syndrome and to elucidating its complex pathophysiology and impact on quality of life. Similarly, great strides have been made in studying and validating novel and existing therapeutics for OIC. As our understanding of OIC matures and novel agents continue to make their way down the drug development pipeline, we anticipate increasing awareness of OIC among clinicians. A paradigm shift from conventional laxatives toward the novel agents that target the underlying pathophysiological mechanism of OIBD is expected to occur as clinical guidelines mature to include specific recommendations for the treatment of OIC in cancer patients. Despite all this progress, several important questions remain unanswered. Novel agents need to be tested Key issues and validated specifically in OIC given the unique pathophysiology of the disease. Head-to-head comparative studies of the new agents are needed to evaluate whether one agent is superior to another. Additionally, the long-term safety of these novel agents needs to be studied carefully. Specific strategies need to be developed to minimize OIC in cancer patients, thus improving their quality of life. The cost benefit profile of these novel therapies needs to be assessed given the high epidemiological burden of OIC. Increasing clinician awareness of the importance of OIC in cancer patients needs to be fostered and the adoption of standardized subjective and objective measures need to be encouraged in routine clinical practice. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Opioid therapy, although effective in the treatment of cancer-related pain syndromes, is associated with significant GI adverse effects. OIBD is a syndrome of diverse GI adverse effects that results from disruption of bowel motility, mucosal transport, and defecation reflexes. OIC is the most common and troublesome component of OIBD, resulting from the action of opioids on gut opioid receptors. OIC is common in cancer patients on opioid therapy. OIC significantly reduces the quality of life of cancer patients and is challenging to treat. The severity and impact of OIC should be defined by objective indexes, patient-reported outcomes, and patient-reported global burden measures. Non-pharmacologic therapies (dietary fiber supplements, increased fluid intake, and opioid switching) are unlikely to be sufficient in the prevention and management of OIC, but may serve as adjuncts to pharmacologic therapy. Laxatives are commonly prescribed for the prevention and treatment of OIC, albeit limited efficacy. There is a paucity of evidence supporting the use of one laxative agent over others in cancer patients. When laxatives are used, a combination of two or more laxatives with different modes of action is likely to be more effective than a single agent. Both prucalopride, a 5-HT 4 receptor agonist, and lubiprostone, a chloride channel-2 agonist, have been shown to be effective in the treatment of OIC compared to placebo in noncancer patients with OIC. PAMORAs (methylnaltrexone and naloxegol) and opioid receptor agonist/antagonist combination tablets (oxycodone naloxone combination) are emerging effective treatments for OIC. By antagonizing mu-opioid receptors in the gut and not the CNS, these agents hampered the pathophysiologic impacts of OIBD without compromising analgesia. Several new 5-HT 4 receptor agonists, secretagogues, and PAMORAs are currently under investigation. Further research is needed to identify effective and efficacious treatments for the management of OIBD and OIC in cancer patients. References Papers of special note have been highlighted as: of interest of considerable interest 1. Bruera E, Paice JA. Cancer pain management: safe and effective use of opioids. 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