Drugs DOI 10.1007/s40265-013-0084-5

REVIEW ARTICLE

Treatment of Opioid-Induced Constipation: Focus on the Peripheral l-Opioid Receptor Antagonist Methylnaltrexone Richard L. Rauck

 Springer International Publishing Switzerland 2013

Abstract Most prescribed opioids exert their analgesic effects via activation of central l-opioid receptors. However, l-opioid receptors are also located in the gastrointestinal (GI) tract, and activation of these receptors by opioids can lead to GI-related adverse effects, in particular opioid-induced constipation (OIC). OIC has been associated with increased use of healthcare resources, increased healthcare costs, and decreased quality of life for patients. Nonpharmacologic (e.g., increased fiber uptake) and pharmacologic agents (e.g., laxatives) may be considered for the treatment and prevention of OIC. However, many interventions, such as laxatives alone, are generally insufficient to reverse OIC because they do not target the underlying cause of OIC, opioid activation of l-opioid receptors in the GI tract. Therefore, there has been keen interest in antagonism of the l-opioid receptor in the periphery to inhibit the effects of opioids in the GI tract. In this review, currently available pharmacologic therapies for the treatment and prevention of OIC are summarized briefly, with a primary focus on the administration of the peripheral l-opioid receptor antagonist methylnaltrexone bromide in patients with OIC and advanced illness who are receiving palliative care. Also, clinical trial data of methylnaltrexone treatment in patients with OIC and other pain conditions (i.e., chronic noncancer pain and pain after orthopedic surgery) are reviewed. Data support that methylnaltrexone is efficacious for the treatment of OIC and has a favorable tolerability profile.

R. L. Rauck (&) Carolinas Pain Institute, PA, The Center for Clinical Research, LLC, 145 Kimel Park Drive, Suite 330, Winston-Salem, NC 27103, USA e-mail: [email protected]

1 Introduction Chronic constipation is a common disorder with a multifactorial pathophysiology [1] that can be classified into one of three different types based on etiology: primary, secondary, or iatrogenically induced [2]. Primary constipation is attributed to extrinsic factors (e.g., inadequate physical activity, insufficient dietary fiber and/or fluid consumption) [2], whereas secondary constipation is a result of disease pathologies (e.g., intestinal obstruction, stroke, hypercalcemia) [2, 3]. Finally, iatrogenically induced constipation occurs as a result of the use of pharmacologic agents, including antacids, iron supplements, and opioids (i.e., opioid-induced constipation [OIC]) [2]. The three types of constipation differ in etiology but are characterized by similar symptoms, which may include bowel movements that occur fewer than 3 times per week, involve straining, contain lumpy or hard stools, or are accompanied by the sensation of incomplete evacuation [4]. Opioids modulate pain relief through the three major classes of G-protein-coupled receptors in the brain and spinal cord, namely the l-, d-, and j-opioid receptors [5]. However, most of the analgesic effects attributed to opioid treatment occur primarily at the l-opioid receptor. The antidiarrheal effects of opioids have long been known, with their use as a treatment for this ailment dating to ancient times [6]. These effects are not surprising, considering the complex opioid system interplay in the gut. Results of studies in humans [7] and rats [8, 9] have shown that opioid actions in the gastrointestinal (GI) tract lead to decreased GI motility, increased fluid absorption from the gut, and decreased intestinal secretion, with subsequent hardening and drying of the stool and extending the duration that the stool remains in the lumen of the GI tract [10]. Also, opioid use may increase sphincter tone and reduce defecation

R. L. Rauck

reflex by decreasing sensitivity to distention and increasing internal anal sphincter tone [10]. These effects of opioids are mediated primarily by l-opioid receptors in the GI tract and, although useful for the management of diarrhea, these l-opioid receptor-mediated actions can also lead to the condition of OIC [10]. Many patients who receive opioid therapy are likely to develop OIC [11]. OIC is often the predominant symptom of a broader condition, known as opioid-induced bowel dysfunction. This condition includes additional gastrointestinal symptoms, such as nausea, vomiting, and gastroesophageal reflux (see review by Brock et al.) [12]. The prevalence of OIC in patients with chronic noncancer pain (CNCP) who are receiving opioids has been reported to be 57 % [13]; and in patients with advanced illness receiving palliative care, the prevalence has been reported to be as high as 94 % [14]. Patients with OIC have a greater burden of disease compared with demographically matched patients receiving opioids who do not have OIC [15, 16]. Patients with OIC use a greater amount of healthcare resources and have increased mean healthcare costs compared with patients receiving opioids who do not have OIC. For example, based on claims data, the percentage of patients with OIC with C1 hospital admission was significantly greater when compared with that of patients without OIC (55.7 vs 34.5 %, respectively; p \ 0.001) [16]. In a study focused on patients with cancer, the number of hospital admissions was significantly greater in patients with versus those without OIC (2.3 vs 1.3, respectively; p \ 0.0001), and the number of inpatient days was significantly greater for patients with versus those without OIC (18.7 vs 10.0; p \ 0.0001) [15]. Compared with patients without OIC, patients with OIC had a significantly increased probability of an inpatient hospital admission (odds ratio [OR], 2.1; p \ 0.001), outpatient visit (OR, 4.7; p = 0.008), or emergency department visit (OR, 2.3; p \ 0.001). Greater healthcare resource use by patients with cancer and OIC, compared with patients without OIC, was associated with significant increases in mean total healthcare costs and costs attributed to specific types of healthcare (i.e., inpatient, outpatient, emergency department, nursing home, home healthcare, laboratory services, pharmacy, and other outpatient or ancillary care; Table 1). Cost attributed to hospice care was the only healthcare parameter examined that did not differ significantly between patients with and without OIC [15]. Increased use of healthcare resources and increased healthcare costs are not the only burdens patients with OIC may face. OIC has been shown to negatively affect patients’ quality of life (QOL), work productivity, and daily activities [17, 18]. Findings from the use of various QOL assessment tools, including the SF-8TM Health Survey (QualityMetric, Lincoln, RI, USA) and EQ-5DTM

(EuroQol Group, Rotterdam, The Netherlands), evaluating mostly patients with noncancer pain, have suggested decreased QOL in patients with OIC versus those without the condition [17, 19]. Compared with patients without OIC, patients with OIC also missed significantly more time from work and experienced significantly more overall work (i.e., work productivity loss) and activity impairment [17]. Results from the Work Productivity and Activity Impairment questionnaire (Reilly Associates, New York, NY, USA) indicated that a greater percentage of patients with OIC experienced absenteeism (i.e., missed time from work), experienced presenteeism (i.e., working while impaired), and had activity impairment compared with patients without OIC (p \ 0.05 for all comparisons) [17]. A variety of nonpharmacologic and pharmacologic agents may be used for the treatment and prevention of OIC. However, many interventions, such as the use of laxatives alone, are ineffective for the treatment and prevention of OIC in many patients [20, 21]. Thus, there remains a need for alternative approaches to laxative use and nonpharmacologic interventions for the treatment of OIC [21]. This article will briefly discuss some of these agents, but will focus on the peripherally acting l-opioid receptor antagonist methylnaltrexone for the pharmacologic management of OIC.

2 Treatment and Prevention of OIC Nonpharmacologic interventions for treating constipation include increasing fluid intake, physical activity, and consumption of dietary fiber [22, 23]. However, because these interventions are generally insufficient for the prevention or treatment of OIC, laxatives are recommended for patients receiving long-term therapy with opioids [23]. 2.1 Laxatives Historically for OIC, guidelines and recommendations for the prevention and management of chronic constipation or constipation in patients receiving palliative care have been followed [1, 11, 24]. However, in 2012, the American Society of Interventional Pain Physicians, as part of guidelines for responsible opioid prescribing, and the European Association for Palliative Care, as part of guidelines for use of opioids in the treatment of cancer pain, separately recommended that laxatives be prescribed as prophylaxis or as treatment for OIC [25, 26]. Although laxatives were recommended, the European Association for Palliative Care indicated that the evidence for laxatives was anecdotal [25], and the American Society of Interventional Pain Physicians stated there was no evidence to recommend one laxative versus another [26]. A meta-analysis,

Methylnaltrexone and OIC

cited in the European Association for Palliative Care guidelines [26], reported a lack of randomized clinical trial data for laxatives in the management of OIC in palliative care [27]. Of the 4 randomized controlled laxative (e.g.,

Table 1 Healthcare costs associated with opioid-induced constipation in patients with cancer Costs, $US

Patients with OICa (n = 821)

Patients without OIC (n = 821)

Percent change in cost due to OIC

P value

61,826

26,657

132

\0.001

Outpatient

5,537

3,403

63

\0.001

Emergency department

1,394

638

119

\0.001

Inpatient

Nursing home

1,708

554

208

0.04

Home healthcare

2,644

1,639

61

0.02

Hospice Laboratory services

558 1,990

297 1,145

88 74

0.62 \0.001

Pharmacy

23,217

14,020

66

\0.001

Other outpatient Total

39,876

20,015

99

\0.001

138,605

66,188

109

\0.001

a

Patients with opioid-induced constipation (OIC) had increased rates of concurrent use of C2 opioids, opioid discontinuation, and opioid switching compared with patients without OIC Adapted with permission from Candrilli et al. [15]

lactulose, senna) studies identified (through December 2010) in the meta-analysis, none were placebo controlled and two had [50 % attrition rates [27]. Laxatives and other pharmacologic interventions that may be used for the treatment of OIC are summarized in Table 2 [23, 28–34]. An initial course of treatment with a stimulant laxative (i.e., sennoside, bisacodyl) is recommended for patients receiving opioids, with an increase in dose as needed [23]. Stimulant laxatives exert their action on the nerve plexus of the intestinal smooth muscle, thereby altering permeability of the intestinal mucosa and promoting peristaltic motility [23, 28]. A second class of laxatives, the detergent laxatives or stool softeners (i.e., docusate), work as surfactants by increasing GI secretion and decreasing surface tension, which permits water to enter the bowel and results in softer, more lubricated bowel movements [23]. The bulk-forming laxatives are derived from natural plant polysaccharides (e.g., psyllium) or synthetic agents (e.g., calcium polycarbophil), both of which are not digested as they move through the GI tract [23]. Consuming sufficient water is essential for patients who take bulk-forming laxatives, as they act by absorbing water and increasing fecal mass and frequency of bowel movements. Bulk-forming laxatives are not recommended for use in patients with advanced illness or with poor functional status who may have insufficient fluid intake, because constipation may increase and fecal impaction is a risk [23].

Table 2 Pharmacologic interventions for the treatment and prevention of opioid-induced constipation [23, 28–34] Treatment

Mechanism of action

Example(s)

Stimulant laxative

Promotion of peristaltic motility

Sennosides, bisacodyl

Detergent laxative

Increase gastrointestinal secretion and decrease surface tension

Docusate

Bulk-forming laxative

Absorption of water, thus increasing fecal mass

Psyllium, calcium polycarbophil

Secretion of fluid into intestinal lumen

Magnesium hydroxide, sodium bisphosphate

Saccharines (sugar alcohols)

Metabolism to short-chain fatty acids by gut bacteria

Lactulose, sorbitol

Macrogol

Decrease gastrointestinal transit time

Polyethylene glycol 3350

Prokinetic agents

Target 5-hydroxytryptamine subtype 4 (5-HT4) receptor to improve gastrointestinal motility

Tegaserod, cisapridea

Chloride channel agonists

Stimulation of intestinal fluid secretion, resulting in softer stool and increased colonic transit and stool frequency

Lubiprostone

Peripheral l-opioid receptor antagonists

Targeting of peripheral l-opioid receptor, without affecting analgesia due to its inability to cross the blood–brain barrier

Methylnaltrexoneb, alvimopanc

Osmotic laxatives Magnesium and sodium salts

a

Tegaserod and cisapride have been withdrawn from the market because of an association with cardiac-related adverse events

b

Methylnaltrexone bromide is currently the only l-opioid receptor antagonist available worldwide for the treatment of opioid-induced constipation. In the United States, it is indicated for the treatment of opioid-induced constipation in patients with advanced illness receiving palliative care when laxative therapy has not been sufficient

c

Alvimopan is approved only in the United States and is indicated to accelerate the time to upper and lower gastrointestinal recovery after partial large or small bowel resection surgery with primary anastomosis

R. L. Rauck

Osmotic laxatives, such as magnesium and sodium salts (i.e., magnesium hydroxide, magnesium citrate, sodium biphosphate), are hyperosmolar solutions that function by establishing a gradient between the intestinal lumen and bowel wall, leading to the secretion of fluid into the intestinal lumen [23, 28]. However, they are not recommended for use in patients with congestive heart failure or renal insufficiency because they can lead to an imbalance in electrolytes and sodium/fluid overload. Saccharines or sugar alcohols (i.e., lactulose, sorbitol), a second subclass of osmotic laxatives, are metabolized by gut bacteria to short-chain fatty acids (e.g., lactate, acetate) [23, 28] and increase transit time through the colon by stimulating smooth muscle peristalsis [23]. Finally, polyethylene glycol (PEG) 3350 is in the macrogol subclass of osmotic laxatives [23, 28]. This electrolyte solution can decrease GI transit time, and it does not increase gas production, a common problem in patients receiving saccharines. In critically ill patients receiving opioid therapy, PEG 3350 had greater efficacy than lactulose in inducing bowel movements [35]. 2.2 Opioid Rotation Reducing the opioid dose or switching opioids, also known as opioid rotation, is another pharmacologic intervention that is used for the prevention or treatment of OIC but has the potential to adversely affect the analgesic benefit of opioid therapy [21]. However, a 2004 meta-analysis that evaluated opioid rotation or switching to improve analgesia and opioid tolerability concluded that for reports of opioid rotation or switching, it was unclear whether improved outcomes were truly a drug effect or merely improved tolerability as a result of dose reduction [36]. A 2011 systemic review conducted to assist in development of the European Palliative Care Research Collaborative cancer pain guidelines concluded that although a number of studies had been conducted since the 2004 meta-analysis was published, the conclusions drawn were still appropriate, and there remains a low level of evidence for opioid rotation or switching [37]. For opioid dose reduction, the results of one study reported that [90 % of patients who decreased their opioid dosage or stopped their opioid usage altogether because of associated constipation had increased pain as a result, negatively affecting QOL [18]. In some cases, patients with OIC increase their use of opioids to treat the pain associated with OIC, further exacerbating their OIC and the pain symptoms resulting from OIC [38]. 2.3 Peripherally Restricted l-Opioid Receptor Antagonists Opioids are among the most commonly prescribed drugs for patients with pain and advanced illness [30]. However,

opioids not only bind l-opioid receptors in the brain and central nervous system, where they exert analgesic effects, but also bind l-opioid receptors in the periphery, including the GI tract [8, 9]. Therefore, binding of opioids to the l-opioid receptors in the GI tract can lead to OIC in patients receiving opioid therapy. The l-opioidreceptor antagonist naloxone can reverse OIC, but in doing so, also can decrease the analgesic effects of opioids because of their ability to cross the blood–brain barrier [30, 39, 40]. Thus, the introduction of peripherally restricted l-opioid-receptor antagonists that cannot cross the blood–brain barrier and are capable of reversing OIC without affecting analgesia are welcome additions to the limited arsenal physicians have to treat and prevent OIC in their patients. Two l-opioid receptor antagonists, oral alvimopan (Entereg; Cubist Pharmaceuticals, Inc., Lexington, MA, USA) and subcutaneous methylnaltrexone bromide (Relistor; Salix Pharmaceuticals, Inc.; Raleigh, NC, USA), are currently available in the United States. Both are considered peripheral l-opioid receptor antagonists with limited ability to cross the blood–brain barrier. In vitro data suggest that alvimopan binds with a higher affinity (Ki = 0.6 nM) compared with methylnaltrexone (Ki = 110 nM) and has a slower dissociation rate from the l-opioid receptor (30 vs 0.46 min, respectively) [41]. Alvimopan is currently only indicated in postoperative patients following partial large or small bowel resection surgery with primary anastomosis to accelerate upper and lower gastrointestinal recovery and is not indicated for the treatment of OIC [33]. Unlike alvimopan, methylnaltrexone is also available outside the United States and is approved in [50 other countries. In addition, several orally administered l-opioid receptor antagonists are in various stages of development, including an oral formulation of methylnaltrexone, bevenopran (formerly CB-5945 and ADL5945; Cubist Pharmaceuticals, Inc., Lexington, MA, USA), naloxegol (formerly NKTR-118; AstraZeneca, Wilmington, DE, USA), TD-1211 (Theravance, Inc., South San Francisco, CA, USA), and S-297995 (Shionogi Inc., Florham Park, NJ, USA) [19, 42, 43]. Alvimopan has been evaluated in clinical trials in patients with OIC and CNCP, but is not indicated for OIC because the clinical development program was discontinued. Promising results were observed with alvimopan in two phase 2 randomized, double-blind, placebo-controlled trials in patients with opioid bowel dysfunction [44, 45]. In one of these studies (for which 88.1 % of subjects had CNCP), 43 and 54 % of patients treated with alvimopan 0.5 or 1.0 mg once daily, respectively, achieved C1 bowel movement within 8 h of administration daily for 21 days, compared with 29 % treated with placebo (p \ 0.001 versus both alvimopan groups). Only the 1.0 mg alvimopan

Methylnaltrexone and OIC

dose had a significantly faster time to first bowel movement after the first dose (3 h) compared with placebo (21 h; p \ 0.001) [44]. During two phase 3 trials of alvimopan 0.5 mg administered twice daily in patients with CNCP, only one trial met the primary endpoint [46, 47]. A significantly greater percentage of patients (72 %) treated with alvimopan 0.5 mg twice daily achieved a response (C3 spontaneous bowel movements per week and a mean increase from baseline of C1 spontaneous bowel movement per week) compared with patients treated with placebo (48 %; p \ 0.001) [46]. In the second phase 3 trial, 63 % of patients treated with alvimopan 0.5 mg twice daily achieved a response compared with 56 % of patients treated with placebo (p = 0.21) [47]. A 6-month interim analysis of data from a 12-month, phase 3, placebo-controlled safety study in patients with OIC taking opioids for CNCP identified an increased risk of myocardial infarction in 538 patients treated with alvimopan 0.5 mg twice daily (1.3 %) compared with that in 267 patients receiving placebo (0 %) [48]. When these data were combined with results from five additional studies in patients with OIC and CNCP, 1.6 and 1.0 % of patients receiving alvimopan (n = 1,728) or placebo (n = 790), respectively, experienced cardiovascularrelated AEs. Also, patients who received alvimopan compared with patients who received placebo had an increased frequency of neoplasms (2.8 vs 0.7 %, respectively) and fractures (3.7 vs 1.1 %, respectively) [48]. As a result of these AE findings during the now discontinued OIC clinical development program, a black box warning was issued for the approved indication of accelerating the time to upper and lower GI recovery after partial large or small bowel resection surgery with primary anastomosis. Alvimopan is currently recommended for short-term inpatient use for postoperative ileus and is available for use only in hospitals that are registered in and have met all the requirements of the Entereg Access Support and Education program [33]. As mentioned previously, increased risk of myocardial infarction was observed with alvimopan versus placebo in patients with OIC taking opioids for CNCP [43]. Patients with these AEs were at high risk for cardiovascular disease, and AEs did not appear to be related to the treatment duration [48]. Similarly, controlled observational studies have identified that patients on chronic opioid therapy are at increased risk for cardiovascular AEs [49, 50]. Differences in patient risk for cardiovascular events dependent on opioid prescribed also have been observed [50]. Overall, a causal relationship between alvimopan, l-opioid-receptor antagonism, and these events has not been established [33].

At present, methylnaltrexone bromide, a quaternary N-methyl ammonium derivative of naltrexone, is the only peripheral l-opioid receptor antagonist approved for the treatment of OIC and is indicated for the treatment of patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient [30, 34]. Currently available as a subcutaneous injection, methylnaltrexone has restricted ability to cross the blood–brain barrier at therapeutic doses, thus sparing patients the reduction in analgesia from opioids [28, 30]. 2.3.1 Methylnaltrexone in Patients with OIC and Advanced Illness The results of a single-dose, phase 3 study of subcutaneous methylnaltrexone 0.15 and 0.30 mg/kg and placebo (N = 154) in patients with OIC and advanced illness showed that there was no dose-response relationship based on these two doses; the higher dose of methylnaltrexone was associated with an increased incidence of abdominal pain [51]. In this study, baseline laxative use for the duration of the study was permitted. Of patients receiving methylnaltrexone 0.15 or 0.30 mg/kg, 96 and 93 %, respectively, maintained baseline laxative use compared with 96 % of patients receiving placebo. A significantly greater proportion of patients receiving methylnaltrexone 0.15 or 0.30 mg/kg in the double-blind phase of the study had a rescue medication-free (rescue-free) bowel movement within 4 h of receiving the study drug compared with patients receiving placebo (61.7 or 58.2 vs 13.5 %, respectively; p \ 0.001 for both methylnaltrexone doses vs placebo). The median time to rescue-free bowel movement after study drug administration was significantly shorter in patients who received methylnaltrexone 0.15 or 0.30 mg/kg than in patients who received placebo (1.1 or 0.8 vs[24 h, respectively; p \ 0.001 for both methylnaltrexone doses vs placebo). Of the patients who responded to methylnaltrexone within 4 h, approximately 50 % had a response within 30 min of receiving the study drug [51]. A multiple-dose, phase 3 study of subcutaneous methylnaltrexone 0.15 mg/kg or placebo every other day for 2 weeks (N = 133) was also conducted in this patient population [52]. Baseline laxative use was permitted during the study, and 98 and 99 % of patients who received methylnaltrexone or placebo, respectively, reported laxative use. Results of this study showed that a significantly greater number of patients treated with methylnaltrexone had a rescue-free bowel movement within 4 h of receiving the initial dose of study drug versus those receiving placebo (48 vs 15 %, respectively; p \ 0.001; Fig. 1). In addition, significantly more patients receiving methylnaltrexone had a rescue-free bowel movement within 4 h of receiving C2 of the first four doses of study drug

R. L. Rauck

(p \ 0.001; Fig. 1). Furthermore, 39 % of patients receiving methylnaltrexone had a rescue-free bowel movement within 4 h of receiving C4 of seven doses of study drug within a 13-day period compared with only 6 % of patients receiving placebo (p \ 0.001). Among patients responding to methylnaltrexone within 4 h of receiving the first dose of study drug, approximately half had a rescue-free bowel movement within 30 min. The median time to rescue-free bowel movement after receiving the first dose of study drug was 6.3 h in patients receiving methylnaltrexone versus [48 h in those receiving placebo (p \ 0.001) [52]. The results of a post-hoc analysis of the double-blind phase of the multiple-dose study showed that patients with response to previous doses of methylnaltrexone were likely to continue to respond to subsequent doses of the drug [53]. In contrast, patients with a lack of response to initial doses of methylnaltrexone (dose 1 or doses 1 and 2) had a reduced likelihood of response to subsequent doses. In the 3-month open-label extension phase of the study, patients who had received placebo during the double-blind phase of the study and then crossed over to receive methylnaltrexone during the open-label phase, had response rates comparable with the response rates of patients receiving methylnaltrexone in both the double-blind and open-label phases of the study [52]. The most common AEs with methylnaltrexone treatment (pooled) during the double-blind phase of the singledose study were abdominal pain, flatulence, and nausea, which appeared to be dose dependent [51]. In the doubleblind phase of the multiple-dose study, the most commonly reported AEs with methylnaltrexone and placebo were abdominal pain (17 and 13 %, respectively), flatulence (13

Fig. 1 Time to rescue-free bowel movement within 4 h of receiving the first dose of study drug or within 4 h of receiving C2 of the first four doses of study drug, respectively, was significantly reduced in patients receiving methylnaltrexone compared with patients receiving placebo. Adapted with permission from Thomas et al. [52]

and 7 %, respectively), and vomiting (13 and 13 %, respectively) [52]. Methylnaltrexone did not affect pain scores or lead to opioid withdrawal symptoms in patients enrolled in either the single-dose or multiple-dose studies [51, 52]. During the 3-month open-label phase of the multiple-dose study, abdominal pain (30 %) was the most frequently reported AE [52]. A post-hoc analysis was conducted to further characterize the AE of abdominal pain reported during the two trials in patients with advanced illness (n = 165, methylnaltrexone; n = 123, placebo) [54]. The incidence of abdominal pain decreased after the first dose of methylnaltrexone (pooled incidence before next dose administered; 23 % [first dose], 13 % [second dose], \10 % [by fifth dose]), and the rate of rescue-free bowel movements remained stable. Interestingly, abdominal pain occurred 4 times more often after the first dose of methylnaltrexone in patients with a rescue-free bowel movement within 4 h than in those who did not achieve a rescue-free bowel movement within 4 h (80.0 vs 20.0 %, respectively). The incidence of abdominal pain may be related to the process of undergoing a bowel movement, because the incidence of abdominal pain also increased in the placebo-treated responders [54]. Rare cases of gastrointestinal perforation have been reported in patients with advanced illness and conditions that may impact the structural integrity of the gastrointestinal tract wall (e.g., colon cancer, peptic ulcer) [55]. 2.3.2 Methylnaltrexone in Patients with OIC and CNCP Methylnaltrexone was also investigated as a potential treatment of OIC in patients with CNCP. In a phase 3, double-blind, randomized, placebo-controlled trial, a significantly greater percentage of patients receiving subcutaneous methylnaltrexone 12 mg once daily (n = 150) or every other day (n = 148) had a rescue-free bowel movement within 4 h of study drug administration compared with patients receiving placebo (n = 162; 33.3 or 35.1 vs 9.9 %, respectively; p \ 0.001 for both groups vs placebo; Fig. 2a) [56]. Also, a significantly greater mean percentage of active injections per patient of methylnaltrexone 12 mg once daily resulted in a rescue-free bowel movement within 4 h of study drug administration compared with placebo once daily (28.9 vs 9.4 %, respectively; p \ 0.001; Fig. 2b). Similarly, a significantly greater mean percentage of active injections per patient of methylnaltrexone 12 mg every other day resulted in a rescue-free bowel movement within 4 h of study drug administration compared with placebo every other day (30.2 vs 9.3 %, respectively; p \ 0.001; Fig. 2b) [56]. Results from a post-hoc analysis showed that response (i.e., the percentage of patients with a rescue-free bowel

Methylnaltrexone and OIC

movement within 4 h of receiving study drug) to C2 of the first four doses of methylnaltrexone was associated with greater probability of response to subsequent doses of study drug [57]. Responders also had an increased number of rescue-free bowel movements and a greater percentage of successive injections likely to result in rescue-free bowel movements. Also, patients receiving methylnaltrexone once daily or every other day for 4 weeks had a significant improvement from baseline in Patient Assessment of Constipation-Quality of Life (PAC-QOL) scores compared with patients receiving placebo (33 or 27 vs 18 %, respectively; p \ 0.001 and p = 0.014 vs placebo, respectively) [56]. Response to methylnaltrexone was consistent during the open-label extension of the study, showing that efficacy and tolerability of methylnaltrexone were maintained for up to an additional 8 weeks [58]. The

long-term efficacy of methylnaltrexone was also supported by results of a 48-week, open-label study of subcutaneous methylnaltrexone administered to patients with OIC and CNCP (N = 1,034) at least once weekly up to once daily [59]. Results of this study showed that 34.1 % of methylnaltrexone injections per patient resulted in a rescue-free bowel movement within 4 h of administration, and a mean increase from baseline of 1.5 rescue-free bowel movements per week was observed during the entire 48-week treatment period [59]. During the randomized, double-blind, placebo-controlled 4-week study, the most commonly reported AE was abdominal pain, reported in 19.3 and 15.5 % of patients treated with methylnaltrexone 12 mg once daily or every other day, respectively, versus 3.7 % of patients treated with placebo [56]. Diarrhea, nausea, and hyperhidrosis were also reported more frequently during treatment with methylnaltrexone than with placebo. Only 1 drug-related serious AE was reported during the study: on Day 1 of treatment with methylnaltrexone, a patient developed extrasystoles that resolved on that same day [56]. During the 48-week open-label study, methylnaltrexone was generally well tolerated, with a safety profile comparable with that in the 4-week study [60]. The most commonly reported AEs were abdominal pain (24.0 %), diarrhea (16.4 %), nausea (15.1 %), hyperhidrosis (8.9 %), and vomiting (7.2 %). 2.3.3 Methylnaltrexone in Patients with OIC After Orthopedic Surgery

Fig. 2 a Methylnaltrexone 12 mg once daily or every other day significantly increased the percentage of patients with a rescue-free bowel movement compared with patients receiving placebo. b A significantly greater mean percentage of active injections per patient of methylnaltrexone 12 mg once daily or every other day resulted in a rescue-free bowel movement within 4 h of receiving study drug compared with the respective placebo injections. *Patients who received methylnaltrexone or placebo on alternating days. Data from Michna et al. [56]

Subcutaneous methylnaltrexone has been assessed for the treatment of acute OIC in a small study of patients undergoing rehabilitation after orthopedic surgery [61]. Patients who were acutely constipated, receiving l-agonist opioid analgesics, and expected to require daily opioid analgesics for at least 7 days postrandomization were enrolled in a randomized, double-blind, placebo-controlled, phase 2 study received subcutaneous methylnaltrexone 12 mg once daily (n = 18) or placebo (n = 15) for up to 4 or 7 days. A significantly greater percentage of patients receiving methylnaltrexone experienced a rescue-free bowel movement within 2 or 4 h of receiving the first dose compared with patients receiving placebo (33.3 or 38.9 vs 0 or 6.7 %, respectively; p = 0.021 and p = 0.046, respectively, vs placebo). Patients receiving methylnaltrexone also had a significantly shorter median time to rescue-free bowel movement than that for patients receiving placebo (15.8 vs 50.9 h, respectively; p = 0.02, log-rank test) [61]. The safety profile (through 14 ± 3 days posttreatment) of methylnaltrexone was similar to that of placebo, with GI-related AEs most commonly reported in the methylnaltrexone group (1 [5.6 %] report each of abdominal

R. L. Rauck

distention, abdominal pain, abdominal tenderness, constipation, diarrhea, and nausea). No serious AEs were reported. Treatment with subcutaneous methylnaltrexone did not affect pain scores or lead to opioid withdrawal symptoms [61]. 2.4 Chloride Channel Agonists Another pharmacologic intervention for the treatment of constipation is the use of chloride channel agonists, which function by activating type 2 chloride channels in the apical membrane of the intestinal epithelium, thereby stimulating intestinal fluid secretion, accelerating colonic transit, and softening stools [28, 31]. Lubiprostone (Amitiza; Takeda Pharmaceuticals America, Inc., Deerfield, IL, USA) 24 lg administered twice daily was approved in 2013 by the US Food and Drug Administration for the treatment of OIC in adults with CNCP [32]. Data from three double-blind, 12-week, placebo-controlled, phase 3 trials and one 9-month, open-label, phase 3 trial have been reported, in US prescribing information and in abstract form, for lubiprostone 24 lg twice daily in patients with OIC and CNCP [32, 62–64]. In one double-blind study, lubiprostone 24 lg twice daily did not achieve a statistically significant improvement from baseline in spontaneous bowel movements at week 8 versus placebo (2.7 vs 2.5, respectively; p = 0.8, the primary endpoint of the study) [32]. However, in patients who did not reduce the dose of lubiprostone, a significant improvement was observed at week 8 versus placebo (p = 0.023) [62]. In a second double-blind study that did not exclude patients receiving diphenylheptane opioids (e.g., methadone), this primary efficacy endpoint was achieved (3.3 [lubiprostone] vs 2.4 [placebo]; p = 0.004) [32]. In a third double-blind study that excluded patients receiving diphenylheptane opioids, a significantly larger percentage of patients treated with lubiprostone achieved a response (defined as having C3 spontaneous bowel movements per week for C9 weeks and an increase from baseline of C1 spontaneous bowel movements per week during 12 weeks of treatment) compared with placebo (29.6 vs 18.9 %, respectively; p = 0.04) [63]. The openlabel trial enrolled patients who had participated in either of the former two double-blind trials [64]. During the openlabel study, significant improvements from baseline in frequency of spontaneous bowel movements were observed for each month of treatment (1.4 [baseline] vs 4.9–5.3 [monthly range] per week; p \ 0.001 vs baseline for all months). 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 AEs were nausea (11 vs 5 %, respectively) and diarrhea (8 vs 2 %, respectively) [32].

2.5 Prokinetic Agents Prokinetic agents are serotonin agonists that improve intestinal motility by targeting primarily the 5-hydroxytryptamine type 4 (5-HT4) receptor and have been considered in conditions of impaired gut motility, such as irritable bowel syndrome with constipation. However, use of the serotonin agonists cisapride (Propulsid; Janssen Pharmaceuticals, Inc, Titusville, NJ, USA) and tegaserod (Zelnorm; Novartis Corporation, East Hanover, NJ, USA) was associated with rare occurrence of cardiovascular AEs, including lengthening of the QT interval, stroke, and ventricular arrhythmia [29]. These deleterious cardiac effects have been attributed to interaction between cisapride and the cardiac hERG (human ether-a`-go-go) potassium channel and an increase in ST-segment depression in patients with cardiovascular risk factors receiving tegaserod [29, 65, 66], which led to the current restricted compassionate use of cisapride and the restricted emergency use of tegaserod in the United States [67, 68]. However, prucalopride (Resolor, Shire Pharmaceuticals Limited, Hampshire, UK), a newer generation 5-HT4 agonist, is approved in Europe for the treatment of chronic constipation in females who are refractory to laxative therapy [69]. It would appear that prucalopride is not currently in continued clinical development for the treatment of OIC. In addition, a phase 2 trial did not meet its primary endpoint—the percentage of patients with OIC and noncancer pain who had a mean increase from baseline of C1 spontaneous complete bowel movement per week during a 4-week period—(prucalopride 4 mg [40.3 %]; prucalopride 2 mg [35.9 %]; placebo [23.4 %]) [69]. This result may have been related to the small sample size. Prucalopride appears to have a more favorable overall cardiac safety profile than cisapride and tegaserod [70].

3 Conclusions OIC is a common problem in patients receiving long- or short-term opioid therapy, and it can adversely affect patient QOL and recovery after surgery [17, 18, 61]. Effective management of OIC may have a positive effect on patient outcomes and may help to reduce healthcare costs associated with the length of hospitalization and use of healthcare resources (i.e., use of nursing care to administer rescue therapy for OIC and visits to the emergency department for rescue therapy) [17, 18, 61]. Because laxatives do not target the underlying pathophysiology of OIC, involving opioid activation of l-opioid receptors in the GI tract, laxative treatment has generally been considered insufficient. Therefore, there has been keen interest in antagonism of peripheral l-opioid receptors to inhibit

Methylnaltrexone and OIC

the GI-related adverse effects of opioids. Methylnaltrexone is indicated for the treatment of OIC in patients with advanced illness receiving palliative care who have had an insufficient response to laxatives [34]. Methylnaltrexone has also been investigated in patients with OIC and CNCP. Methylnaltrexone does not appear to affect pain scores or lead to opioid withdrawal symptoms, and overall data suggest that methylnaltrexone is a well-tolerated and efficacious treatment option in the management of OIC. Acknowledgments Technical editorial and medical writing support was provided by Sophie Bolick, PhD, and Marci Mikesell, PhD, Synchrony Medical Communications, LLC, West Chester, PA, USA, under the direction of the author, Richard Rauck, MD. Funding for this support was provided by Salix Pharmaceuticals, Inc., Raleigh, NC, USA.

References 1. American College of Gastroenterology Chronic Constipation Task Force. An evidence-based approach to the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(Suppl 1):S1–4. 2. McMillan SC. Assessing and managing opiate-induced constipation in adults with cancer. Cancer Control. 2004;11(3 Suppl): 3–9. 3. Hsieh C. Treatment of constipation in older adults. Am Fam Physician. 2005;72(11):2277–84. 4. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology. 2006;130(5):1480–91. 5. Schumacher MA, Basbaum AI, Way WL. Opioid analgesics and antagonists. In: Katzung BG, editor. Basic and Clinical Pharmacology. New York: McGraw-Hill Medical; 2009. p. 531–52. 6. Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept. 2009;155(1–3):11–7. 7. Yuan CS, Foss JF, O’Connor M, et al. Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial. Clin Pharmacol Ther. 1996;59(4):469–75. 8. Manara L, Bianchi G, Ferretti P, et al. Inhibition of gastrointestinal transit by morphine in rats results primarily from direct drug action on gut opioid sites. J Pharmacol Exp Ther. 1986;237(3): 945–9. 9. Tavani A, Bianchi G, Ferretti P, et al. Morphine is most effective on gastrointestinal propulsion in rats by intraperitoneal route: evidence for local action. Life Sci. 1980;27(23):2211–7. 10. Leppert W. The role of opioid receptor antagonists in the treatment of opioid-induced constipation: a review. Adv Ther. 2010;27(10):714–30. 11. Chou R, Fanciullo GJ, Fine PG, American Pain Society; American Academy of Pain Medicine Opioid Guidelines Panel, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113–30. 12. Brock C, Olesen SS, Olesen AE, et al. Opioid-induced bowel dysfunction: pathophysiology and management. Drugs. 2012;72(14): 1847–65. 13. Cook SF, Lanza L, Zhou X, et al. Gastrointestinal side effects in chronic opioid users: results from a population-based survey. Aliment Pharmacol Ther. 2008;27(12):1224–32. 14. Sykes NP. The relationship between opioid use and laxative use in terminally ill cancer patients. Palliat Med. 1998;12(5):375–82.

15. Candrilli SD, Davis KL, Iyer S. Impact of constipation on opioid use patterns, health care resource utilization, and costs in cancer patients on opioid therapy. J Pain Palliat Care Pharmacother. 2009;23(3):231–41. 16. Iyer S, Davis KL, Candrilli S. Opioid use patterns and health care resource utilization in patients prescribed opioid therapy with and without constipation. Manage Care. 2010;19(3):44–51. 17. Bell T, Annunziata K, Leslie JB. Opioid-induced constipation negatively impacts pain management, productivity, and healthrelated quality of life: findings from the National Health and Wellness Survey. J Opioid Manage. 2009;5(3):137–44. 18. Bell TJ, Panchal SJ, Miaskowski C, et al. The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European patient survey (PROBE 1). Pain Med. 2009;10(1):35–42. 19. Penning-van Beest FJ, van den Haak P, Klok RM, et al. Quality of life in relation to constipation among opioid users. J Med Econ. 2010;13(1):129–35. 20. Camilleri M. Opioid-induced constipation: challenges and therapeutic opportunities. Am J Gastroenterol. 2011;106(5):835–42. 21. Panchal SJ, Muller-Schwefe P, Wurzelmann JI. Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden. Int J Clin Pract. 2007;61(7):1181–7. 22. Ternent CA, Bastawrous AL, Morin NA, et al. Practice parameters for the evaluation and management of constipation. Dis Colon Rectum. 2007;50(12):2013–22. 23. Walters JB, Montagnini M. Current concepts in the management of opioid-induced constipation. J Opioid Manage. 2010;6(6): 435–44. 24. Brandt LJ, Prather CM, Quigley EM, et al. Systematic review on the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(Suppl 1):S5–21. 25. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2—guidance. Pain Physician. 2012;15(Suppl 3):S67–116. 26. Caraceni A, Hanks G, Kaasa S, et al. Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol. 2012;13(2):e58–68. 27. Candy B, Jones L, Goodman ML, et al. Laxatives or methylnaltrexone for the management of constipation in palliative care patients. Cochrane Database Syst Rev. 2011;(1):CD003448. 28. Thomas JR, Cooney GA, Slatkin NE. Palliative care and pain: new strategies for managing opioid bowel dysfunction. J Palliat Med. 2008;11(Suppl 1):S1–19. 29. Tack J. Current and future therapies for chronic constipation. Best Pract Res Clin Gastroenterol. 2011;25(1):151–8. 30. Bader S, Jaroslawski K, Blum HE, et al. Opioid-induced constipation in advanced illness: safety and efficacy of methylnaltrexone bromide. Clin Med Insights Oncol. 2011;5:201–11. 31. Emmanuel A. Current management strategies and therapeutic targets in chronic constipation. Ther Adv Gastroenterol. 2011;4(1):37–48. 32. Amitiza (lubiprostone) capsules [package insert]. Deerfield: Takeda Pharmaceuticals America, Inc.; 2013. 33. Entereg (alvimopan) capsules [package insert]. Lexington, MA: Cubist Pharmaceuticals, Inc., 2012. 34. Relistor (methylnaltrexone bromide) subcutaneous injection [package insert]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2012. 35. van der Spoel JI, Oudemans-van Straaten HM, Kuiper MA, et al. Laxation of critically ill patients with lactulose or polyethylene glycol: a two-center randomized, double-blind, placebo-controlled trial. Crit Care Med. 2007;35(12):2726–31. 36. Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database Syst Rev. 2004;(3):CD004847.

R. L. Rauck 37. Dale O, Moksnes K, Kaasa S. European Palliative Care Research Collaborative pain guidelines: opioid switching to improve analgesia or reduce side effects. A systematic review. Palliat Med. 2011;25(5): 494–503. 38. Fallon M, O’Neill B. ABC of palliative care. Constipation and diarrhoea. BMJ. 1997;315(7118):1293–6. 39. Sykes NP. An investigation of the ability of oral naloxone to correct opioid-related constipation in patients with advanced cancer. Palliat Med. 1996;10(2):135–44. 40. Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioidinduced constipation and analgesia. J Pain Symptom Manage. 2002;23(1):48–53. 41. Cassel JA, Daubert JD, DeHaven RN. [3H]alvimopan binding to the l opioid receptor: comparative binding kinetics of opioid antagonists. Eur J Pharmacol. 2005;520:29–36. 42. Diego L, Atayee R, Helmons P, et al. Novel opioid antagonists for opioid-induced bowel dysfunction. Expert Opin Investig Drugs. 2011;20(8):1047–56. 43. A study of S-297995 for the treatment of opioid-induced constipation in subjects with non-malignant chronic pain receiving opioid therapy [ClinicalTrials.gov identifier NCT01443403]. 2012 Nov 27 [online]. Bethesda: US National Institutes of Health, ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01443403. (Accessed 1 Feb 2013). 44. Paulson D, Kennedy DT, Donovick RA, et al. Alvimopan: an oral, peripherally acting, l-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction—a 21-day treatment-randomized clinical trial. J Pain. 2005;6(3):184–92. 45. Webster L, Jansen JP, Peppin J, et al. Alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain. Pain. 2008;137:428–40. 46. Jansen J-P, Lorch D, Langan J, et al. A randomized, placebocontrolled phase 3 trial (Study SB-767905/012) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain. J Pain. 2011;12(2):185–93. 47. Irving G, Pe´nzes J, Ramjattan B, et al. A randomized, placebocontrolled phase 3 trial (Study SB-767905/013) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain. J Pain. 2011;12(2):175–84. 48. Bream-Rouwenhorst HR, Cantrell MA. Alvimopan for postoperative ileus. Am J Health Syst Pharm. 2009;66(14):1267–77. 49. Solomon DH, Rassen JA, Glynn RJ, et al. The comparative safety of analgesics in older adults with arthritis. Arch Intern Med. 2010;170(22):1968–78. 50. Carman WJ, Su S, Coo SF, et al. Coronary heart disease outcomes among chronic opioid and cyclooxygenase-2 users compared with a general population cohort. Pharmacoepidemiol Drug Saf. 2011;20:754–62. 51. Slatkin N, Thomas J, Lipman AG, et al. Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients. J Support Oncol. 2009;7(1):39–46. 52. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med. 2008;358(22):2332–43. 53. Chamberlain BH, Cross K, Winston JL, et al. Methylnaltrexone treatment of opioid-induced constipation in patients with advanced illness. J Pain Symptom Manage. 2009;38(5):683–90. 54. Slatkin NE, Lynn R, Su C, et al. Characterization of abdominal pain during methylnaltrexone treatment of opioid-induced constipation in advanced illness: a post hoc analysis of two clinical trials. J Pain Symptom Manage. 2011;42(5):754–60.

55. Corken Mackey A, Green L, Greene P, et al. Methylnaltrexone and gastrointestinal perforation. J Pain Symptom Manage. 2010;40(1):e1–3. 56. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study. J Pain. 2011;12(5):554–62. 57. Michna E, Weil AJ, Duerden M, et al. Efficacy of subcutaneous methylnaltrexone in the treatment of opioid-induced constipation: a responder post hoc analysis. Pain Med. 2011;12(8):1223–30. 58. Blonsky E, Watier A, Schulman S, et al. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with chronic non-malignant pain: open-label results [abstract no. 149]. Reg Anesth Pain Med. 2009;34(5):98. 59. Webster L, Michna E, Khan A, et al. The long-term efficacy of subcutaneous methylnaltrexone for the treatment of opioidinduced constipation in patients with chronic nonmalignant pain [abstract no. 376]. J Pain. 2011;12(Suppl 4):P70. 60. Webster L, Michna E, Khan A, et al. The long-term safety of subcutaneous methylnaltrexone for the treatment of opioidinduced constipation in patients with chronic nonmalignant pain [abstract no. 378]. J Pain. 2011;12(Suppl 4):P70. 61. Anissian L, Schwartz HW, Vincent K, et al. Subcutaneous methylnaltrexone for treatment of acute opioid-induced constipation: phase 2 study in rehabilitation after orthopedic surgery. J Hosp Med. 2012;7(2):67–72. 62. Cryer BL, Katz S, Vallejo R, et al. A phase 3, randomized, double-blind, placebo- controlled clinical trial of lubiprostone for the treatment of opioid-induced bowel dysfunction in patients with chronic, non-cancer pain [abstract no. 906]. Gastroenterology. 2010;138(5 Suppl 1):S129. 63. Jamal MM, Mareya SM, Woldegeorgis F, et al. Lubiprostone significantly improves treatment response in non-methadone opioid-induced bowel dysfunction patients with chronic, noncancer pain: results from a phase 3, randomized, double-blind, placebo-controlled clinical trial [poster no. 848a]. Digestive Diseases Week 2012, San Diego; May 19–22, 2012. 64. Spierings E, Joswick T, Lindner E, et al. Long-term safety and efficacy of lubiprostone in opioid-induced bowel dysfunction in patients with chronic, non-cancer pain: results of a phase 3, openlabel clinical trial [abstract no. 322]. Am J Gastroenterol. 2012;107(Suppl 1):S138. 65. Mohammad S, Zhou Z, Gong Q, et al. Blockage of the HERG human cardiac K? channel by the gastrointestinal prokinetic agent cisapride. Am J Physiol. 1997;273(5 Pt 2):H2534–8. 66. Pasricha PJ. Desperately seeking serotonin… A commentary on the withdrawal of tegaserod and the state of drug development for functional and motility disorders. Gastroenterology. 2007;132(7): 2287–90. 67. Tack J, Camilleri M, Chang L, et al. Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders. Aliment Pharmacol Ther. 2012;35(7): 745–67. 68. Zelnorm (tegaserod maleate) information. 2012 May 11 [online]. Silver Spring, MD: US Department of Health and Human Services, US Food and Drug Administration. http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand Providers/ucm103223.htm (Accessed 1 Feb 2013). 69. Sloots CEJ, Rykx A, Cools M, et al. Efficacy and safety of prucalopride in patients with chronic noncancer pain suffering from opioid-induced constipation. Dig Dis Sci. 2010;55(10): 2912–21. 70. Quigley EMM. Prucalopride: safety, efficacy and potential applications. Therap Adv Gastroenterol. 2012;5(1):23–30.