Curr Oncol Rep (2015) 17:55 DOI 10.1007/s11912-015-0481-x

PALLIATIVE MEDICINE (A JATOI, SECTION EDITOR)

New Options in Constipation Management Mellar Davis 1,2,3 & Pamela Gamier 1,2,3

# Springer Science+Business Media New York 2015

Abstract Constipation is common in the general population and for those on opioids and/or who are suffering from advanced cancer. Self-management consists of dietary changes, exercise, and laxatives. However, responses to selfmanagement efforts are often inadequate to relieve the subjective and objective experience of constipation. Multiple new anti-constipating medications have recently been tested in randomized trials and the following are available commercially: probiotics, prucalopride, lubiprostone, linaclotide, elobixibat, antidepressants, methylnaltrexone, alvimopan, and naloxegol. This review will discuss the evidence-based benefits of these medications and outline an approach to managing constipation. Keywords Constipation . Probiotics . Prokinetics . Lubiprostone . Linaclotide . Transporter . Mu receptor . Antagonist

Introduction Adults defined as 18 years or older have a 16 % prevalence of constipation increasing to 33 % after age of 60 years. The diagnosis of the irritable bowel syndrome (IBS) is hampered by the overlapping symptoms that occur with organic This article is part of the Topical Collection on Palliative Medicine * Mellar Davis [email protected]; http://www.clevelandclinic.org/palliative 1

Cleveland Clinic Lerner School of Medicine Case, Western Reserve University, 9500 Euclid Avenue, T34, Cleveland, OH 44195, USA

2

Clinical Fellowship Program, Cleveland, OH, USA

3

Palliative Medicine and Supportive Oncology Services, Taussig Cancer Institute, Cleveland, OH, USA

gastrointestinal diseases. As a result, symptom-based diagnostic criteria were developed to be used by physicians to make a diagnosis of IBS after excluding warning signs and symptoms of organic illness. Observation of symptom clusters leads to the development of the Rome I criteria which were further revised into the Rome II and III criteria [1–4]. Constipation defined as one of the functional bowel symptoms from the Rome III criteria (Table 1) will be predictably reported in two thirds of the population over a 3-month period of time [5]. Constipation is more common in women than men particularly the diagnosis of chronic idiopathic constipation (CIC) by the ROME III criteria, in non-whites, and the elderly [6]. A sedentary existence, low income, limited education, past history of sexual abuse, depression, and opioids are risk factors for chronic constipation. Constipation is divided into primary or secondary when related to an underlying organic illness. Certain characteristics in the history identify individuals who are likely to be suffering from secondary constipation such as weight loss, anemia, bloody stools, and family history of colon cancer. Conditions contributing to constipation obtained through a history are poor diet, little physical activity, constipating drugs, metabolic disorders such as diabetes, and neurologic diseases. Previous surgery can result in constipation as sequelae. Constipation is a negative outcome to perineal, pelvic, abdominal, or obstetrical surgery and can also lead to defecation disorders [7]. There are no particular features within the medical history which can separate the different types of constipation (normal transit, slow transit, and defecation disorders). There are no specific symptoms particular to functional constipation which is clearly limited to a particular constipation subtype. The presence of two or more symptoms during at least 25 % of bowel movements within the Rome III criteria distinguishes patients with CIC from constipation found in the normal population. The presence of abdominal pain and constipation

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Table 1 Rome criteria III for chronic idiopathic constipation and irritable bowel syndrome-constipation Individuals must have 2 or more symptoms for at least 3 months in the last 6 months. 1. Straining during >25 % of defecations 2. Lumpy or hard stools >25 % of defecations 3. Sensation of incomplete evacuation >25 % of defecations 4. Sensation of obstruction or blockage >25 % of defecations 5. Manual maneuvers to facilitate defecation >25 % of defecations 6. Fewer than 3 defecations per week (spontaneous without requiring a laxative) (CSBM/W) 7. Loose stools are rarely present without the use of a laxative Irritable bowel syndrome C includes the above plus abdominal pain or discomfort 3 days or more a month within the last 3 months improved with defecation, onset with change in stool frequency, or with stool appearance.

symptoms defined by the Rome III separate Irritable Bowel Syndrome-Constipation (IBS-C) from CIC (Table 1) [8]. Chronic idiopathic constipation is normal transit in 59 % of patients and slow transit in 13 % while 25 % have a defecation disorder. Defecation disorders are managed by biofeedback and neuromuscular conditioning rather than by laxatives and are excluded from constipation interventional trials. Defecation disorders are characterized by an abnormal descent of the perineum during defecation and colonic regional transit profiles which differ from slow transit constipation [9]. Defecation disorders are differentiated from slow and normal transit constipation by anorectal manometry and rectal balloon expulsion tests [10]. Several hundred million dollars of cathartics and laxatives are sold each year in the USA [6]. Attempts at self-management often fail [11]. Chronic constipation increases health care costs, lowers work productivity, and impairs daily activity [12].

Opioid-Induced Constipation Opioid-induced constipation (OIC) results largely from opioid receptor agonist binding to enteric neuron mu receptors widely expressed throughout the gastrointestinal (GI) tract. Receptor activation prevents neurotransmitter release, impairs peristalsis, causes segmentation through circular smooth muscle contraction, impairs intestinal secretion, and increases luminal fluid reabsorption [13]. The end results are nausea, gastroparesis, early satiety, secondary pseudo-obstruction, and constipation [14••]. Opioids will cause increasing abdominal pain (termed the narcotic bowel syndrome). This syndrome is a central hyperalgesia caused by the opioid in 5 % of individuals [15]. Tolerance does not occur with constipation [14••]. There is no consensus definition for OIC. Most trials of anticonstipation agents do not define OIC in the study and most often rely on a history of opioid use, a defecation frequency of

less than three complete spontaneous bowel movements per week (CSBM/W), hard lumpy stools, incomplete evacuation, and infrequent spontaneous bowel movements (bowel movements without the use of a laxative within 24 h of defecation) [14••, 16••, 17]. This is inadequate for the full spectrum of OIC. The change in bowel habit and onset of symptoms at the time of initiating opioid therapy is probably the most important feature. The pathophysiology of OIC is distinctly different from CIC and IBS-C [14••, 16••]. Drugs which work for CIC and IBS-C may in fact be ineffective for OIC.

Treatment of Constipation Probiotics Gut microbiota plays a significant role in GI motility, immunity, and secretion and is altered in a wide variety of disease processes associated with constipation including obesity, IBSC, and cancer [18, 19]. Microbiota is involved in various normal metabolic activities, ferments unused energy substrates, reduces bowel pH, produces vitamins and hormones, enhances gut immunity, and prevents pathologic bacteria overgrowth [20]. Individuals with CIC have reduced Bifidobacterium and Lactobacillus species in their gut microbiome relative to the normal population [21]. Certain Lactobacillus species (acidophilus NCFM) reduce visceral hypersensitivity presumably by upregulating mu and cannabinoid receptors in the gut [22]. Probiotics containing Escherichia coli Nissle 1917 directly stimulate smooth muscle and increase motility [23]. Laxatives work indirectly to improve constipation through normalizing gut flora [21]. Individuals with severe CIC undergoing therapeutic colectomy have reduced Lactobacillus and Bifidobacterium species in stool preoperatively which increase postoperatively [24]. Chemotherapy alters the intestinal microbiome resulting in reduced nucleotide and energy metabolism, cofactors and vitamins, signal transduction, and xenobiotic degradation as well as increased glycan metabolism [25••]. This dysbiosis may be one of the mechanisms for chemotherapy mucositis, weight loss, and constipation [25••]. A systematic review with meta-analysis of randomized trials summarized the evidence for effect of probiotics on intestinal transit. Individuals were either normal volunteers or suffered from CIC. There were eight parallel and three crossover trials. Bifidobacterium and Lactobacillus species were most frequently used in doses between 5 × 108 and 9.7 × 1010 colony-forming units (CFU). Intestinal transit times were shortened overall [standard mean difference, SMD 0.4, 95 % confidence intervals (CI) 0.2 to 0.58; P less than 0.001]. Improvement was greatest in females with constipation. The largest treatment effect was seen with Bifidobacterium species (SMD ranged between 0.54 and 0.72) [26].

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A systematic review evaluated probiotics in CIC. There were 14 randomized trials and 16 separate probiotics with doses between 108 and 3×1010 CFU/day. Duration of study ranged between 2 and 8 weeks. Whole gut transit time was reduced by 12.4 h (95 % CI 2.5–22 h; P=0.01). Rectosigmoid transit time was reduced 4 h (95 % CI 0.4 to 7.6 h). Stool consistency measured by the Bristol Stool Form scale improved (SMD 0.55, 95 % CI 0.27 to 0.82; P=0.00001). Bloating was reduced (SMD −0.77, 95 % CI −0.07 to −1.46; P=0.003). Incomplete evacuation improved (SMD −0.77, 95 % CI −0.39 to −1.14) and stool consistency improved (SMD −0.74, 95 % CI −0.28 to −1.19, P equal 0.001). Stool evacuation improved (SMD 0.81, 95 % CI 0.15–1.48; P=0.02). Adverse effects were similar to placebo [27]. These are robust findings of both objective and multiple subjective improvements in constipation. There are no direct comparisons between probiotics and laxatives or licensed medications such as lubiprostone and linaclotide. The optimal dose and bacterial composition are not established. Recent randomized trials have found that probiotics reduce chemotherapy, radiation-induced mucositis, and diarrhea [28]. Prokinetics The pathophysiology of constipation (normal transit, slow transit, and defecation disorders) is such that prokinetics will not address all contributing mechanisms to constipation. Prokinetics will not correct sphincter malfunction, reduced luminal secretion, visceral hypersensitivity, and visceral motor tone [29]. Intestinal transit can improve under the effects of prokinetics, yet symptoms continue to be present. Older prokinetics such as broad-spectrum cholinergics, anticholinesterases, and cisapride have side effects through binding to offtarget receptors which can result in bladder spasms and cardiac arrhythmias. Anticholinesterases are useful since this drug class reverses Ogilvie syndrome and pseudo-intestinal obstruction [29]. Prokinetic dopamine receptor antagonists (D2 antagonists) are prone to cause extrapyramidal side effects and depend on release of acetylcholine for prokinetic effects [30]. Anticholinergic drugs will block the prokinetic benefits. The European Medicines Agency’s Committee on Medicinal Products for Human Use has recommended limiting the use of metoclopramide-containing medicines, restricting the dose and duration of use to minimize the known risks of serious neurological adverse effects. These metoclopramide and domperidone can cause gynecomastia and galactorrhea. These prokinetics are primarily effective in treating foregut motility disorders rather than constipation [31]. A group of prokinetics patterned after cisapride regulate acetylcholine release via serotonin receptors (5-HT4) on myenteric neurons. Benefits to these 5-HT4 agonists largely center on gastroparesis and dyspepsia and secondarily on constipation [32]. Two serotonergic prokinetics, cisapride and tegaserod,

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have been removed from the market due to cardiovascular adverse events [33]. Prucalopride is a third-generation benzofuran 5-HT4 receptor agonist prokinetic which has high affinity and selectivity for the receptor. It is not arrhythmogenic and promotes colonic motility [34]. Three randomized trials demonstrated that prucalopride improved bowel function and constipation symptoms in individuals with CIC without defecation disorder [35, 36]. Adverse effects were headache (in 25–30 %), nausea (12–25 %), abdominal pain (16–23 %), and diarrhea (12–19 %). The additional advantage to prucalopride is that it has a low potential for drug interactions and is not a P-glycoprotein substrate. Drug half-life is 21 h; 60 % is excreted unchanged in the urine. Doses are 2 mg daily which are reduced to 1 mg for the elderly and those with a GFR of less than 30 mL/m per 1.73 m2. No dose reduction is needed for hepatic failure [34]. Prucalopride is licensed in several countries (not in the USA) for women with CIC unresponsive to laxatives [37]. A recent randomized trial compared prucalopride with Macrogol/PEG 3350 plus electrolytes in patients with CIC. Prucalopride was noninferior for the primary outcome but PEG was superior in improving gastrointestinal transit, stool frequency, and number of spontaneous bowel movements [38]. Prucalopride has also been used to treat OIC, the results of which will be discussed under that section. Three additional 5-HT4 agonists are in development or available in different countries. Mosapride is available in Asian countries. A dose of 15 mg daily improves stool frequency and symptoms associated with constipation [39]. In a small randomized trial involving patients with IBS-C, there were no statistically significant differences between mosapride and placebo in specific symptoms (pain straining and bloating), nor in stool frequency or consistency by Bristol Stool Form scale, or incomplete evacuation [40]. Naronapride has been shown to improve symptoms and CSBM/W in individuals with CIC [41]. Velusetrag in a phase II trial improved CIC in a dose-dependent fashion [42]. A meta-analysis of benefits to 5-HT4 agonist prokinetics used greater than/equal to 3 CSBM/W and greater than 1 spontaneous bowel movement (SBM) per week as primary outcomes. Improvement in quality of life was also included using the Patient Assessment of Constipation, Quality of Life Scale (PAC-Qol) and Patient Assessment of ConstipationSymptom scale (PAC-Sym). Thirteen randomized trials demonstrated that 5-HT4 agonists increase CSBM/W (relative risk, RR 1.85), SBM (RR 1.57), and improved quality of life (RR 1.51) and symptoms (RR 1.47). Adverse effects were also increased over placebo (RR 1.25) and were most commonly headaches, diarrhea, and nausea [41]. Selective 5-HT4 agonists in recent development are promising prokinetics with a greater safety profile than cisapride. However, trials have been done selectively in those with cancer and constipation. There are anecdotal reports that prucalopride improves constipation in other disorders, such

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as spinal cord injury, scleroderma, intestinal pseudo-obstruction, and ileus after partial colectomies [36, 43–45].

Linaclotide Linaclotide is a first-in-class minimally adsorbed 14-aminoacid peptide agonist of guanylate cyclase C drug that acts on the intestinal enterocyte [46]. The result is stimulation of chloride channels (CIC-2) and increase secretion of fluid into the gut lumen (Fig. 1). It is presently licensed for CIC and IBS-C in the USA. Oral bioavailability is 0.1 %, and less than 1 % is excreted in the stool in the first 24 h [47]. Linaclotide undergoes proteolysis within the GI tract. However, it is resistant to pepsin, trypsin, aminopeptidases, and chymotrypsin proteolysis and thus is able to bind to duodenal and jejunal chloride channels. Linaclotide is converted to an active metabolite (MM-419447) which has the same pharmacodynamics and pharmacokinetics as the parent drug [47]. Besides increasing luminal fluid, linaclotide also increases GI transit and reduces visceral hypersensitivity [47].

Fig. 1 Linaclotide and lubiprostone are chloride channel agonists but have a distinctly different mechanism of action. Linaclotide derived from the enterotoxin of E. coli stimulates guanylate cyclase C (GC) which generates cyclic guanosine-3-5 monophosphate (CGMP) which in turn activating the chloride channel through cystic fibrosis transmembrane conductance regulator (CFTR). Lubiprostone can activate chloride channels directly and through CFTR-linked chloride

In randomized trials, linaclotide at 145 μg day was best tolerated with improvement in CSBM/W and symptoms in patients with CIC. Patients with IBS-C best responded to the 290-μg day dose [48, 49]. The number needed to treat to benefit one individual (NNT) ranged between 5 and 8. Linaclotide tends to be very well tolerated and, in most studies, the attrition rate was less than 4 % and largely due to diarrhea [50]. Linaclotide is unique in that it is both anti-constipating and analgesic reducing visceral hypersensitivity. There are no trials reported in cancer patients. Individuals with mechanical bowel obstruction should not be treated with linaclotide. Linaclotide pharmacology is such that few if any drug interactions are anticipated.

Lubiprostone Lubiprostone also acts on CIC-2, resulting in increased intestinal secretions and accelerated intestinal transit (Fig. 1). Lubiprostone activates a prostaglandin receptor (EP4) which in turn activates cystic fibrosis conductance regulators

channels. The latter interaction may be via a prostaglandin receptor (EP4). Once the channel is open on the apical epithelial membrane, chloride enters enterocyte via a NA+-K+-2CL active transporter. There are natural activators of GC, guanylin and uroguanylin, which regulate chloride channels through the same mechanism as linaclotide. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography ©2015. All rights reserved

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(CFTR) [51]. Activation of EP4 receptors stimulates colonic smooth muscle and gastric longitudinal muscle via vagal nerve endings [52]. Lubiprostone also changes mucin, which improves gut microbiome favoring an anti-inflammatory environment [53]. Unlike linaclotide, lubiprostone does not increase pain thresholds [54]. Oral bioavailability is less than 1 %. Renal failure does not impair lubiprostone pharmacokinetics. Mild-to-moderate hepatic impairment (Child-Pugh class A and B) increases the lubiprostone metabolite M3 which results in greater adverse effects at standard doses of lubiprostone. Starting doses need to be reduced with liver disease [55]. Lubiprostone metabolism does not involve cytochromes; catabolism is via carbonyl reductase in the stomach and jejunum [55]. Lubiprostone is unlikely to have major drug interactions. In healthy volunteers, lubiprostone 24 μg twice daily slows gastric emptying, increases gastric fasting volume, reduces maximum tolerated gastric volumes, and accelerates small bowel and colon transit [56]. The effects on gastric motility may be behind the nausea with lubiprostone. In randomized trials involving patients with IBS-C, 8 μg twice daily and 24 μg twice daily reduced abdominal pain and improved CSBM/W, stool consistency, straining, and bloating. The 8-μg dose had the best risk– benefit ratio [57]. Adverse effects were nausea (6.3 %), diarrhea (6.5 %), and abdominal pain (3.7 %) [58]. A unique adverse effect occurs with the initial dose; a minority of patients develop acute transit dyspnea. Ischemic colitis has also been described with lubiprostone [58, 59]. Oral lubiprostone is approved for CIC at doses of 24 μg twice daily and IBS-C at 8 μg twice daily. The approval for CIC is limited to women who have not responded to laxatives since there were few men on studies. Lubiprostone is also licensed for OIC which will be discussed later. There are no studies exclusive to individuals with cancer and constipation. Like linaclotide, lubiprostone is contraindicated in mechanical bowel obstruction.

Bile Acid Transporter Inhibitors Bile acids are synthesized, hydroxylated, and conjugated in the liver. The predominate bile acids are chenodeoxycholic acid and cholic acid. The rate-limiting step to synthesis involves the enzyme cholesterol-7-alpha hydroxylase which is reflected in serum levels of 7-alpha-hydroxy-7-cholesten-3one (C4) [60]. Bile acids undergo enterohepatic recirculation through reuptake in the distal ileum via sodium-dependent transporters [61]. Bile acid synthesis, secretion, and intestinal absorption are important to colonic motility and secretion [62]. Constipation has been associated with reduced bile acid secretion and synthesis leading to reduced bile acid in stool; blocking the transporter increases GI motility and reduces constipation [62]. Oral chenodeoxycholic acid doses of 750–

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1,000 mg/day in IBS-C increase bowel movements, decrease stool consistency, and shorten the time to defecation [63]. Elobixibat (A3309) reduces bile acid enterohepatic recirculation and upregulates bile acid synthesis as measured by serum C4 levels, depletes liver cholesterol, and reduces serum LDL [64]. In a phase I trial, elobixibat accelerated colonic transit in a dose-dependent fashion. In a randomized phase II trial, 15 and 20 mg/day improved stool consistency, increased the number of SBMs, reduced straining, and improved the passage of stool in women with CIC [65]. In a dose-finding randomized trial, elobixibat compared to placebo increased C4, reduced LDL cholesterol and increased colonic transit from 3 to 1.9 days, and increased the number of SBM and CSBM/W in patients with CIC. Adverse effects were the same as placebo [66]. In a large randomized trial involving patients with CIC, the 10 and 15 mg dose increased SBMs and reduced the time to SBM (12 h with the 10-mg dose, 7 h with the 15mg dose versus 24 h with placebo). There was increased spontaneous laxation within 24 h on elobixibat compared with placebo (75 % on 15 mg/day and 45 % on placebo). Complete spontaneous bowel movements per week increased in a dose-dependent fashion. Stool consistency and bloating improved on the 10- and 15-mg dose. Adverse effects were abdominal pain and diarrhea, which were also dose-dependent. This was particularly prominent on the 15-mg dose [67]. Elobixibat is a promising anti-constipating drug. However, there are no trials in cancer nor in OIC. Elobixibat, due to its prokinetic effects, should not be used in those with mechanical bowel obstruction.

Antidepressants Constipation is as much subjective sensation as objective reduction in bowel movements. Symptoms can be quite distressing. Antidepressants have been used to treat symptoms of IBS [68]. Tricyclic antidepressants have been reported to treat diarrheaprone IBS but worsen constipation [69]. Several studies suggest that selective serotonin reuptake inhibitors (SSRIs) improve constipation symptoms. The mechanism would likely involve activation of 5-HT4 receptors. Intravenous citalopram induces small intestinal phase 3 contractions after 35±6.4 min, compared to 120±17 min after placebo, shortens migrating motor complex cycle length, and increases the motility index during phase 2 in the antrum and small intestine [70]. A randomized trial compared fluoxetine 20 mg/day with placebo in a 12th week study involving patients with IBS-C. Compared with placebo, fluoxetine improved CSBM/W and constipation symptoms. Adverse effects were no greater than placebo [71]. A second study titrated citalopram from 20 to 40 mg/day and matching placebo over 6 weeks. Eligible patients had IBS-C. Citalopram improved straining and incomplete evacuation [72]. In a meta-analysis of antidepressant

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trials for IBS-C, both tricyclic and SSRI antidepressants improved global symptoms (RR 1.38, 95 % CI 1.08 to 1.77). Tricyclics were more effective for diarrhea-prone IBS and SSRIs for IBS-C [73]. Though antidepressants are commonly used in patients on opioids and in those with cancer, little are known about their benefits or lack of benefits on constipation symptoms in these populations.

Drug Management of Opioid-Induced Constipation Opioid-induced constipation is one of the most common side effects with chronic opioid therapy; nearly 1/3 of individuals on opioids state that constipation is their most bothersome symptom [74]. Since the pathophysiology of OIC is distinctly different from CIC and IBS-C, anti-constipating drugs for CIC and IBS-C may be ineffective [17]. Response assessment in randomized trials used similar outcomes such as CSBM/W and SBM but also distinctly different outcomes such as laxation within a timeframe of treatment. Symptom questionnaires in OIC studies included the PAC-Qol and PAC-Sym but also other validated tools such as the Bowel Function Index (BFI) [16••]. The European Association of Palliative Care and National Comprehensive Cancer Network recommend prophylactic laxatives at the onset of opioid therapy despite the fact that there are no randomized trials to validate such a practice. More than half of individuals remain constipated despite taking laxatives [75]. Currently, no gastrointestinal society has published guidelines for managing OIC [76]. Opioid rotation has been used as a means to treating OIC. Several studies found that fentanyl is less constipating than morphine [77]. Tapentadol is less constipating than oxycodone [78]. In countries where the combination product of sustained-release oxycodone/sustained-release naloxone is available and oxycodone doses are less than 80 mg/day, rotation to the combination improves constipation [79].

Non-Opioid Receptor Antagonists Lubiprostone Lubiprostone increases intestinal secretions and increases peristalsis, whereas opioids do the opposite [80]. Therefore, lubiprostone is effective in treating OIC. In three randomized trials, lubiprostone 24 μg was used twice daily to treat individuals with chronic non-cancer pain on opioids with less than 3 CSBM/W. Response was defined as greater than or equal to 3 CSBM/W for 9 of 12 weeks of the trial and at least one SBM per week over baseline every week. Responses were seen in 27.1 % of lubiprostone treated patients versus 18.9 % on placebo (NNT 12). The second study had the same design and

with a definition of response the same except the trial was 8 weeks. Responses occurred in 24.3 % on lubiprostone versus 15.3 % on placebo (NNT=11). A third study was negative [81–84]. Individuals on methadone do not respond to lubiprostone. Lubiprostone has been licensed for the use in OIC excluding methadone [85]. Prucalopride A phase II double-blind placebo-controlled trial randomized patients between 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 SBM per week. Secondary outcomes were the proportion of individuals with greater than or 3 CSBM/W, weekly frequency of SBMs, severity of constipation as rated by the patient, and efficacy of treatment as rated by the patient. Responses in prucalopridetreated patients were 35.9 % on 2 mg, 40.3 % on 4 mg, and 23.4 % on placebo (NNT=8 on 2 mg and 6 on 4 mg). Over the 4 weeks, 60.7 % of the 2 mg treated and 69 % of the 4 mg treated patients achieved the primary outcome versus 43.3 % of placebo-treated patients (NNT 5.7 and 4, respectively). Patient rated severity of constipation and effectiveness were significantly improved on the 4-mg dose relative to placebo. Rescue laxative use was reduced with prucalopride. The most common adverse effects were abdominal pain and nausea. The incidence of abdominal pain was significantly higher on the 4-mg dose group relative to placebo [86]. Peripheral Acting Mu Opioid Receptor Antagonists Peripheral acting mu opioid receptor antagonists (PAMORAs) have been extensively developed to treat OIC spurred on by the nonspecific nature of stimulating laxatives and poor responses in general [87]. Methylnaltrexone is a quaternary polar opioid which prevents it from crossing the blood–brain barrier and reversing analgesia. It is indicated for individuals with OIC and constipation unresponsive to laxatives. It is not licensed for maintenance therapy or to prevent constipation and unfortunately requires parenteral administration (though there are trials of oral methylnaltrexone). Methylnaltrexone reduces the oral–cecal transit time by 130 min and is effective in half of individuals with OIC refractory to laxatives [88]. Laxation occurs within 4 h of administration in approximately a third of individuals. Stool form is improved as measured by the Bristol Stool Form scale and a sense of complete evacuation. Adverse effects are abdominal pain (17 %), diarrhea (9 %), and nausea (10 %) [88–90]. In a meta-analysis, the risk of not responding to treatment relative to placebo was 0.66 (95 % CI 0.63 to 0.75) with a NNT of 3 for improvement in constipation. No opioid withdrawal symptoms were noted in trials [91••].

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Alvimopan is a highly polar quaternary mu receptor antagonist which binds to opioid receptors with a greater affinity than methylnaltrexone. It has an equipotent active metabolite produced in the gastrointestinal tract [92]. Three of four randomized trials of alvimopan demonstrated improved OIC over placebo. In the first study, 0.5 mg improved responses determined to by SBM within 8 h of taking alvimopan relative to placebo. The NNT was 4. Adverse effects were greater with alvimopan (43 versus 33 % for placebo) [93]. In the second study, 1 mg of alvimopan improved SBM over 3 weeks and had the best risk–benefit profile compared to 2 mg/day [94]. The next two studies compared alvimopan 0.5 mg daily or twice a day to placebo in over 1,000 patients. Responses were defined as greater than or equal 3 CSBM/W and greater than one SBM per week over baseline. The first study was negative. The second study was positive with a response recorded in 46 % of placebo-treated patients, 61 % of those receiving the 0.5-mg dose, and 72 % of those receiving 0.5 mg twice daily. Adverse effects were abdominal pain (10 %), headache (9 %), and diarrhea (6.5 %) [94–96]. In a meta-analysis, the relative risk of failure compared with placebo was 0.7 (95 % CI 0.65 to 0.78) with a NNT of 5. There was a trend for greater side effects with alvimopan [91••]. Unfortunately, a 12-month safety study of alvimopan 0.5 mg versus placebo demonstrated greater cardiovascular events with alvimopan such that the FDA approval was limited to hospitalized patients and only for reversing postoperative ileus in patients on opioids. Fortunately, long-term studies of methylnaltrexone and naloxegol (to be discussed) have not demonstrated the same cardiovascular risk [97, 98]. Naloxegol Naloxegol is a pegylated naloxone taken by mouth. The pegylated derivative prevents the drug from crossing the blood–brain barrier. In animal models, the dose which reverses gastrointestinal effects (measured by the ED50) and the dose which reversed analgesia separated better than equivalent doses of oral naloxone [99]. Naloxegol is metabolized by the mixed function oxidase CYP-3A4 and is excreted in bile [100]. Only 6 % of the drug is excreted in urine. Mild-to-moderate hepatic impairment (Child-Pugh class A and B) has minimal effect on naloxegol pharmacokinetics. There is no dose reduction needed for renal failure [101]. In humans, naloxegol is rapidly absorbed and has a half-life of 4–8 h. There is no evidence of QTC prolongation with the drug [102]. A phase II study compared naloxegol 5, 25, and 50 mg with placebo in individuals on opioids for chronic nonmalignant pain demonstrated a median change in CSBM/W of 1 for placebo, 2.9 for the 25-mg dose, and 3.3 for the 50-mg dose of naloxegol [103]. In a 12-week randomized trial involving patients with nonmalignant pain on opioids, responses (defined as greater than or equal to 3 CSBM/W, greater than or equal to 1

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SBM over baseline in 9 of 12 weeks, and at least 3 of the last 4 weeks of study) were 29.4 % for placebo, 40.8 % for 12.5 mg of naloxegol, and 44.4 % for 25 mg of naloxegol (NNT of 8.8 and 6.6, respectively) [104]. In a second randomized trial using the same response criteria, placebo responses were 29.3 % and in those receiving 25 mg of naloxegol 39.2 % (NNT of 10) [105]. Naloxegol is licensed in the USA for laxative refractory OIC in patients with chronic nonmalignant pain. PAMORAs in Development TD-1211 is a multivalent orally administered PAMORA. In a 5-week phase II randomized trial comparing 5, 10, and 15 mg to placebo in patients with OIC, SBMs over 4 weeks increased from 0.8 for placebo to 1.5 for 5 mg, 2.7 for 10 mg, and 2.4 for the 15-mg dose of TD-1211 [106]. S-297995 (naldemdine) was evaluated in a trial involving patients with chronic pain requiring 90 mg or more of morphine equivalents daily for a minimum of 3 months and experiencing OIC. Randomization involved one of six cohorts (0.01, 0.03, 0.1, 0.3, 1, or 3 mg). There was a statistically significant dose-dependent increase from the baseline in the number of SBM at 24 h post-dose starting with 0.3 mg. The medication was generally well tolerated, and there was no evidence of opioid withdrawal (Shionogi Annual Report 2011). CBC-5945 (benvenopran) has been tested in a randomized controlled trial involving patients with OIC and nonmalignant pain. Doses of 0.25 mg once daily and twice daily were compared with placebo. There was an increase in the number of CSBM over 4 weeks. Placebo increased CSBM to 1.4 (mean), the 0.25-mg dose increased the number to 2.58, and the twice daily dose increased the number to 3.42. A phase III trial is now open comparing 0.25 mg twice daily with placebo twice daily (NCT01696643). Sustained-release oral naloxone is being tested alone in patients with OIC. In a phase II randomized trial involving patients with chronic nonmalignant pain, doses of sustained-release naloxone of 2.5 mg twice daily, 5 mg twice daily, 10 mg twice daily, and 20 mg twice daily were compared with placebo. The primary outcome was treatment of emergent side effects and secondary outcome was changes in SBM per week. Symptoms, quality of life, and opioid withdrawal were also assessed. There were no serious adverse effects. Spontaneous bowel movements per week increased in a dose-dependent fashion; placebo with 1.19, up to 5.19 with the 20-mg twice daily dose. Differences from placebo were seen beginning with the 5-mg dose. Symptoms of constipation improved as well as quality of life [107]. Multiple PAMORAs are in development. Methylnaltrexone, alvimopan, naloxegol, and the combination of sustainedrelease naloxone/sustained-release oxycodone are commercially available in several countries. Alvimopan use is limited due

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to cardiovascular side effects. And methylnaltrexone and naloxegol are license to treat laxative-resistant OIC. The combination product is limited to patients who are on 80 mg or less of oxycodone a day and is not available in the USA. Individuals with liver disease and shunting may potentially have reversal of analgesia with sustained-release naloxone, whereas naloxegol may not reverse analgesia. Almost all these drugs have not been licensed to be used in cancer patients and so separate trials will need to be done. These agents are likely to be effective in reversing postoperative ileus for those on opioids.

Conclusions Despite the lack of randomized trials, laxatives remain the first choice for treating constipation, in part due to cost of newer agents. Polyethylene glycol has the greatest evidence for benefit and compares favorably to prucalopride and should be used initially. Stimulating laxatives are reasonable to add to polyethylene glycol in those failing to respond. The prokinetic prucalopride and chloride channel agonist lubiprostone are licensed for CIC and IBS-C; prucalopride has evidence for benefits in patient suffering from OIC, and lubiprostone is licensed for OIC. These two medications are reasonable to use in laxative-resistant constipation. Linaclotide is licensed for laxative-resistant CIC and IBS-C. There are no head to head comparisons between lubiprostone and linaclotide which guide choices between agonists. Linaclotide is presently und e rg o i n g t r i a l s c e n t e r e d o n p a t i e n t s w i t h O I C . Methylnaltrexone is licensed for laxative refractory OIC. The drawback to methylnaltrexone is the requirement of parenteral injection. Alvimopan is limited to postoperative ileus managed in the hospital and short-term use. It is not licensed for OIC. Naloxegol is now licensed for laxative refractory OIC in patients with nonmalignant pain. It is orally administered which is an advantage over methylnaltrexone. Naloxegol should not be used to prevent constipation from opioids and should only be used when constipation fails to respond to laxative therapy. Naloxegol has not been studied in patients with cancer on opioids with presumed OIC. Future studies will need to be done to validate benefits in this population.

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