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Abstract

Currently opioids are the most frequently used medications for chronic noncancer pain. Opioid-induced constipation is the most common adverse effect associated with prolonged use of opioids, having a major impact on quality of life. There is an increasing need to treat opioid-induced constipation. With the recent approval of medications for the treatment of opioid-induced constipation, there are several therapeutic approaches. This review addresses the clinical presentation and diagnosis of opioid-induced constipation, barriers to its diagnosis, effects of opioids in the gastrointestinal tract, differential tolerance to opiates in different gastrointestinal organs, medications approved and in development for the treatment of opioid-induced constipation, and a proposed clinical management algorithm for treating opioid-induced constipation in patients with noncancer pain.

Keywords

lubiprostone methylnaltrexone naloxegol noncancer pain peripheral µ opioid receptor antagonist tolerance

Introduction

The use of opioids in the treatment of chronic pain has increased in the past decade (http://www.cdc.gov/primarycare/materials/opoidabuse/docs/pda-phperspective-508.pdf). Chronic pain occurs in association with cancer and noncancer conditions. It has been estimated that 20% of patients presenting to physicians’ offices in the United States with pain symptoms were prescribed opioids (http://www.cdc.gov/homeandrecreationalsafety/pdf/Common_Elements_in_Guidelines_for_Prescribing_Opioids-a.pdf). Opioids are more effective than nonopioid analgesics in controlling moderate to severe pain.

Even though opioids are effective in alleviating severe pain, they also cause adverse effects such as physical dependence, tolerance, sedation, hyperalgesia [Hooten et al. 2015] and respiratory depression [Chou et al. 2009]. Gastrointestinal adverse effects have a major impact on health and quality of life in opioid users. Opioid-induced constipation (OIC) is the most common gastrointestinal adverse effect [Kalso et al. 2004; Tack and Corsettii, 2014] causing a significant reduction in the quality of life [Bell et al. 2009; Kumar et al. 2014]. Other common gastrointestinal effects of opioids are nausea, vomiting, abdominal pain, bloating and cramping [Chou et al. 2009].

The prevalence of OIC increases with increased duration of use of opioid analgesics [Camilleri et al. 2014]. Treatment satisfaction with opioids decreases when OIC develops and many patients tend to discontinue opioid therapy when they develop constipation [Coyne et al. 2014]. This review addresses OIC in association with noncancer pain, with focus on recent developments, clinical guidelines and a proposed algorithm for treatment of these patients.

Opioid use in chronic noncancer pain

Chronic pain is described as persistent pain for more than 3 months [Verhaak et al. 1998]. The prevalence of chronic widespread pain in the general population was about 10–15% [Mansfield et al. 2015]. In patients with chronic noncancer pain, the prevalence of OIC varies from 41% to 81% [Kalso et al. 2004; Bell et al. 2009]. The most common indication for opioid use in noncancer pain is musculoskeletal pain, including back pain, degenerative joint disease, fibromyalgia and headache [Chey et al. 2014]. In the United States, 4% of adults are taking chronic opioid therapy, chiefly for noncancer pain. The Centers for Disease Control and Prevention (CDC) estimates that overprescription of opioids by healthcare providers is the reason for opioid-related overdosing (http://www.cdc.gOY/drugoverdose/dataloverdose.html). Almost 90% of patients with moderate to severe pain are treated with opioids [Benyamin et al. 2008].

Pain as the fifth vital sign and the imperative to manage pain

Due to the increase in opioid analgesic use for chronic pain, the Joint Commission on Accreditation of Healthcare Organizations (a not-for-profit organization, whose mission is to continuously improve healthcare for the public in the United States) and the Veterans Health Administration introduced the concept of pain as the fifth vital sign in order to draw attention to the need to provide adequate pain relief to patients [Walid et al. 2008]. The World Health Organization (WHO) recommended the use of opioids for the management of moderate to severe chronic cancer pain; this strategy has been adopted for patients with chronic noncancer pain in recent years [Fine et al. 2009].

WHO developed a three-step ladder for treatment of cancer pain [Jadad and Browman, 1995]. When a patient presents with pain, there should be prompt oral administration of analgesics in the following order:

step 1: nonopioids (aspirin, acetaminophen, diclofenac, ibuprofen); then, as necessary,

step 2: mild opioids (codeine, tramadol);

step 3: strong opioids such as morphine, buprenorphine, fentanyl, hydromorphone, methadone and oxycodone, administered until the patient is free of pain.

Nonopioids can be added along with the opioids for moderate to severe pain.

Gastrointestinal effects and differential tolerance of gut regions to µ-opioid agonists

Organ-level effects of µ opioids

Opioids have pharmacological effects throughout the gastrointestinal tract. They decrease gastric emptying and stimulate pyloric tone, resulting in anorexia, nausea and vomiting. Inhibition of propulsion and increased fluid absorption in the small and large intestine result in delayed absorption of medications, hard dry stools, constipation, straining, sense of incomplete rectal evacuation, bloating and abdominal distention. Other motor effects are increased anal sphincter tone [Musial et al. 1992] and pyloric tone [Camilleri et al. 1986], impaired reflex relaxation in response to rectal distention, and increased amplitude of nonpropulsive segmental contractions. These effects result in impaired ability to evacuate the bowel, as well as abdominal spasm, cramps and pain [Pappagallo, 2001; Kurz and Sessler, 2003]. Decreased gastric, biliary, pancreatic and intestinal secretions interfere with digestion.

Cellular effects of µ opioids

The actions of opioids are mediated through G-protein coupled receptors [Pappagallo, 2001]. The μ, δ and κ receptors are three classes of opioid receptors [Williams et al. 2013]. The μ and δ receptors [Camilleri et al. 1986] are the principal opioid receptors in the gastrointestinal tract; they are expressed predominantly in the submucosal and myenteric plexuses, respectively [Bagnol et al. 1997]. Both these receptors cause membrane hyperpolarization through activation of potassium channels. Apart from the direct activation of K⁺ channels, the activation of opioid receptors also causes inhibition of Ca⁺⁺ channels and production of adenylate cyclase and, hence, decreased neurotransmitter release [Galligan and Akbarali, 2014].

Differential tolerance of gut regions to µ opioids

The exact mechanism of tolerance in humans is not known. The possible mechanisms of tolerance to opioids are hypothesized based on animal studies. Tolerance to the effects of μ opioids [Pasternak, 2001; Pan, 2005] occurs in all gastrointestinal organs, except in the colon. This is the reason why constipation persists and the other gastrointestinal symptoms get better on long-term treatment with opioids [Ling et al. 1989].

When an agonist binds to the G-protein coupled receptor, a kinase phosphorylates the activated receptor resulting in acute desensitization of the receptor. This is followed by either dephosphorylation which leads to activation of the receptor to bind an agonist, or by binding of β arrestin-2 which causes receptor internalization in the endosome, prolonging the desensitization of the receptor (Figure 1) [Claing et al. 2002; Williams et al. 2013]. The β arrestin-2 is detached once the receptor is dephosphorylated inside the endosome, and this releases the receptor back to the plasma membrane to allow binding of an agonist. Thus, β arrestin-2 is integral to developing short- (<1 day) and long-term (>1 day) tolerance (Figure 1) [Williams et al. 2013]. The downregulation of β arrestin-2 results in development of tolerance in the ileum in response to μ opioid agonist [Claing et al. 2002; Galligan and Akbarali, 2014], causing tolerance to morphine; however, this effect is not observed in the colon, due to preserved β arrestin-2 expression. The preserved β arrestin-2 results in receptor recycling to the plasma membrane [Galligan and Akbarali, 2014].

Figure 1.

Mechanism of differential tolerance of µ opioid receptors in the gastrointestinal tract. Reproduced with permission from Williams et al. [2013].

Clinical presentation of OIC

The clinical presentation of OIC does not differ from that of functional constipation except that the constipation occurs with opioid treatment. Prospective studies [Gaertner et al. 2015] have generally identified OIC on the basis of the Rome III criteria definition of constipation. The most common symptoms used as inclusion criteria in these trials are less than three bowel movements (BMs)/week, straining, hard stools and sensation of incomplete evacuation. OIC can occur even at low dosages of opioids [Shook et al. 1987] and can occur at any time after initiation of opioid therapy [Choi and Billings, 2002]. Nausea, vomiting and gastroesophageal reflux are the other symptoms associated with OIC [Tuteja et al. 2010].

Diagnosis of OIC

There is, as yet, no uniform definition for the diagnosis of OIC. A consensus definition proposed for future randomized controlled trials in OIC was based on Cochrane reviews and clinical trials on OIC [Gaertner et al. 2015]. Thus, OIC is defined as a change from baseline in bowel habits and change in defecation patterns after initiating opioid therapy, which is characterized by any of the following: reduced frequency of spontaneous BMs (SBMs); worsening of straining to pass BMs; sense of incomplete evacuation; and harder stool consistency [Gaertner et al. 2015].

The following outcome measures or assessment tools for OIC were identified in the systematic review [Gaertner et al. 2015].

Objective measures: BM frequency, change in BM frequency, time to laxation, laxation within 4 h, gastrointestinal or colonic transit time, and Bristol Stool Form Scale (BSFS).

Patient-related outcome measures: Bowel Function Index (BFI), Patient Assessment of Constipation Symptoms (PAC-SYM), and global clinical impression of change.

Patient-reported global burden measures: constipation distress and Patient Assessment of Constipation Quality of Life (PAC-QOL) [Gaertner et al. 2015].

Following an appraisal of the pros and cons of each outcome measure, the consensus panel proposed the following outcome measures for OIC: BSFS, BFI and PAC-QOL [Gaertner et al. 2015].

BFI is a clinician assessment tool which includes three variables: ease of defecation, feeling of incomplete bowel evacuation, and personal judgment of constipation (Figure 2). Each variable is rated by the patient from 0 to 100, based on the experience in 7 days [Rentz et al. 2009]. A reference range of BFI scores for patients without constipation is from 0 to 28.8. This provides a simple discrimination between patients with and without constipation on opioid therapy [Ueberall et al. 2011].

Figure 2.

Bowel Function Index (BFI) assessment for opioid-induced constipation.

Another screening tool was developed to recognize OIC in patients with and without laxative use. It includes symptoms of incomplete BMs, BMs too hard to pass, straining and feeling of a false alarm. This screening tool would be useful to facilitate communication and the relationship between physicians and patients on opioid treatment [Coyne et al. 2015].

Another instrument that has been proposed for use in clinical studies for OIC utilizes a three-step module [Camilleri et al. 2011].

Step 1 is a four-item module questionnaire about straining, ability to empty bowels completely, pain around the rectum, and stool shape and consistency that patients complete after recording each BM and time of occurrence.

Step 2 is a five-item module questionnaire addressing inability to have a BM, bloating, abdominal pain, bothered by gas and lack of appetite. Patients are instructed to complete the questionnaire each evening to capture symptoms experienced in the previous 24 h.

Step 3 is a module that documents constipation treatments used in the previous 24 h to relieve constipation.

A prospective study was used to appraise the validity, responsiveness and reliability of these bowel diary items. The validity and responsiveness were significant for all diary items except for rectal pain. In addition, the study showed adequate reliability for all diary items except stool consistency for OIC [Camilleri et al. 2011].

Barriers to diagnosis of OIC

Common barriers for the diagnosis of OIC were identified by experts in the field of OIC and have been described in a consensus statement [Camilleri et al. 2014]. The barriers are as follows.

Lack of awareness among clinicians about OIC in patients on opioid therapy.

If clinicians are aware, they may not ask patients questions about constipation.

Patients might feel ashamed to disclose their symptoms to clinicians.

Absence of universal diagnostic criteria for OIC.

Efforts to screen patients based on Rome III criteria may not cover the whole spectrum of OIC that might present with abdominal pain.

Absence of a standard protocol for the treatment of OIC.

Drugs approved for OIC (Table 1)

Lubiprostone

Lubiprostone is a bicyclic fatty acid derived from prostaglandin E1 (PGE1) metabolite which increases fluid secretion in the gastrointestinal tract [Cuppoletti et al. 2004, 2014] by stimulating the cystic fibrosis transmembrane regulator and type 2 chloride channels (ClC2) in the apical membrane to secrete chloride and water into the lumen [Bijvelds et al. 2009; Schiffhauer et al. 2013]. This results in increased peristalsis, laxation, and acceleration of small intestinal and colonic transit [Camilleri et al. 2006]. ClC2 channels are also located in the basolateral membrane of the jejunum and colon [Catalán et al. 2012], and lubiprostone leads to internalization of these basolateral ClC2 channels, which blocks primary absorption of chloride from the lumen [Catalán et al. 2012; Jakab et al. 2012].

Table 1.

Clinical trials of drugs approved for OIC.

Drug	Study type	Study length (weeks)	Study cohort	Study endpoints	Specific outcomes	Reference
Lubiprostone	1. RCT	12	431	⩾1 SBM improvement over baseline frequency and ⩾3 SBMs/week for at least 9 weeks	27.1% versus 18.9% with p value < 0.030	Jamal et al. [2015]
Lubiprostone	2. RCT	12	418	Δ from baseline in SBM no. at week 8 and overall	At 8 weeks, SBMs/week mean 3.3 versus 2.4 (pla), p = 0.005; overall mean, 2.2 versus 1.6 (pla) SBMs/week, p = 0.004	Cryer et al. [2014]
Oxycodone and naloxone (OXY PR)	1. RCT extended to open label for 52 weeks	12	278	Change in BFI at week 4 compared with baseline	40.9 BFI score at week 4 and 34.01 at week 12 compared with a baseline of 67.451% achieved CSBM in OXY PR compared with 26% in oxycodone only group at 4 weeks	Lowensteinet al. [2009]
	1. RCT extended to open label for 52 weeks	12	278	CSBM		Lowensteinet al. [2009]
	2. RCT	12	35	Δ from baseline in BFI during treatment	BFI score change of 23.3 compared with baseline of 61.3 (p < 0.0002)	Koopmanset al. [2014]
Methyl-naltrexone (MNTX)	1. RCT	4	460	Rescue-free BM (RFBM) within 4 h of first dose	34.2% had RFBM with MNTX compared with 9.9% (pla)	Michna et al. [2011]
				Time to BM within first 24 h	46% had RFBM within 24 h with MNTX compared with 25.3% (pla)At 4 weeks, MNTX compared with placebo
				PAC SYM
	2. RCT	4	460	Rectal symptoms	−0.56 versus −0.30 (p < 0.05)	Iyer et al. [2011]
	2. RCT	4	460	Stool symptoms	−0.76 versus −0.43 (p < 0.001)	Iyer et al. [2011]
Naloxegol	1. RCT	4	207	Median Δ from baseline in SBMs/week after 4 weeks	25 mg naloxegol [3.0 versus 0.8 (pla); p = 0.0022]	Websteret al. [2013]
	1. RCT	4	207	Median Δ from baseline in SBMs/week after 4 weeks	50 mg naloxegol [3.5 versus 1.0 (pla); p < 0.0001]	Websteret al. [2013]
	2. RCT (two studies: 04 and 05)	12	641696	⩾3 SBMs/week and increase of ⩾1 SBM compared with baseline for ⩾9 of 12 weeksΔ Severity of strainingΔ Stool consistency	Response rates higher with 25 mg naloxegol	Chey et al [2014]
					Study 04: 44.4% versus 29.4% (pla), p = 0.001; study 05: 39.7% versus 29.3% (pla),p = 0.02Study 04: −0.73 ± 0.05; study 05: −0.80 ± 0.06
					Study 04: 0.66 ± 0.07; study 05: 0.71 ± 0.07

Updated with recent advances from Nelson and Camilleri (2015).

BFI, bowel function index; CSBM, complete spontaneous bowel movement; PAC-SYM, patient assessment of constipation symptoms; pla, placebo; RCT, randomized controlled trial; SBM, spontaneous bowel movement.

Lubiprostone increased the overall frequency of SBMs/week in patients with OIC, with a mean change from baseline of 3.2 compared with 2.4 SBMs/week on placebo [Jamal et al. 2015]. The median time to first SBM with lubiprostone was reduced by 50% compared with placebo [Cryer et al. 2014]. Lubiprostone treatment was also associated with significant improvement in constipation symptoms, such as abdominal discomfort, degree of straining, stool consistency and constipation severity [Cryer et al. 2014; Jamal et al. 2015]. Nausea, diarrhea and abdominal pain were the most common adverse effects [Cryer et al. 2014; Jamal et al. 2015].

Lubiprostone-stimulated secretion of Cl⁻ ions via ClC2 channels was inhibited in vitro in T84 cell lines by methadone [Cuppoletti et al. 2013]. As a result of these studies, lubiprostone use is contraindicated with OIC related to methadone use. Lubiprostone, 4 μg, twice daily, was approved by the US Food and Drug Administration (FDA) for OIC in patients with noncancer pain (http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021908s011lbl.pdf).

Oxycodone and naloxone

Naloxone is an opioid antagonist used intravenously to treat opioid overdosing. When naloxone is used orally, it acts locally on μ opioid receptors in the gastrointestinal tract [Liu and Wittbrodt, 2002]. Prolonged release (PR) naloxone has extensive first pass metabolism (hepatic glucuronidation) which reduces the bioavailability for systematic action of the PR formulation to less than 2% (http://www.medicines.org.uk/emc/). The bioavailability of naloxone is increased due to hepatic impairment which changes the treatment response. Naloxone improved opioid-induced constipation symptoms and also reduced the laxative use with only mild opioid withdrawal symptoms such as yawning, sweating and shivering [Meissner et al. 2000]. Naloxone PR reduced mean colonic transit time by 2.1 h when used in combination with oxycodone PR (20 mg oxycodone/10 mg naloxone) compared with oxycodone PR alone (20 mg) [Smith et al. 2011].

Oxycodone and naloxone (both PR preparations) in combination is superior to PR oral naloxone alone to treat OIC [Meissner et al. 2009]. Naloxone displaces oxycodone from the μ opioid receptors in the gastrointestinal tract due to high affinity of naloxone to the opioid receptors. Due to high first pass metabolism, naloxone’s action is negligible in the systemic circulation. In contrast, the bioavailability of oxycodone is 80%, enhancing its availability for central analgesic action [Burness and Keating, 2014]. When the combination of oxycodone and naloxone was in the ratio of 2:1, the efficacy to relieve constipation was greater and adverse effects fewer compared with other ratios [Meissner et al. 2009]. The risk of experiencing a pain event with the combination of oxycodone and naloxone was 13% lower compared with oxycodone alone [Vondrackova et al. 2008]. Oxycodone and naloxone combination showed improvement in the BFI and pain intensity compared with oxycodone alone [Vondrackova et al. 2008; Meissner et al. 2009; Koopmans et al. 2014; Poelaert et al. 2015]. Thus, the combination of oxycodone and naloxone decreased BFI scores by 48.5 units and increased the median number of complete SBMs (CSBMs)/week threefold compared with oxycodone alone [Lowenstein et al. 2009; Poelaert et al. 2015]. Constipation-related quality of life improved in patients on a combination of oxycodone and naloxone [Mehta et al. 2014; Poelaert et al. 2015].

The most common adverse effects of the combination of oxycodone and naloxone are nausea, vomiting, headache, constipation and diarrhea [Vondrackova et al. 2008; Sandner-Kiesling et al. 2010]. The fixed dose ratio proved to be safer in the long term, with only mild to moderate adverse events and only 13% incidence of severe adverse events [Sandner-Kiesling et al. 2010]. The combination of oxycodone and naloxone at a 2:1 ratio, with a maximum dose of 40 mg of naloxone, proved to be more efficacious in the treatment of OIC [Meissner et al. 2009]; however, due to induction of opioid withdrawal symptoms, the maximum dosing strengths in 2:1 oral combination therapy approved by the FDA is oxycodone 40 mg and naloxone 20 mg (http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205777lbl.pdf).

Methylnaltrexone

Methylnaltrexone is a quarternary N-methyl derivative of naltrexone [Brown and Goldberg, 1985]. Methylnaltrexone has only peripheral action, since the methyl group decreases the lipid solubility and increases polarity, preventing it from crossing into the brain [Russell et al. 1982; Amin et al. 1994; Holzer, 2004]. Both subcutaneous and intravenous methylnaltrexone decreased morphine-induced delay in orocecal transit time [Yuan et al. 1996, 2002].

Methylnaltrexone alone had no effect on colonic transit or stool frequency; in addition, it had no effect on the acute codeine-induced delay in colonic transit in healthy volunteers [Wong et al. 2010]. Methylnaltrexone, 12 mg, once daily or every other day, compared with placebo for 4 weeks in patients with OIC significantly shortened the time to first rescue-free BMs (RFBMs), increased the number of weekly RFBMs, improved degree of straining, decreased sense of incomplete evacuation, and improved PAC-QOL [Michna et al. 2011a]. PAC-SYM scores, specifically the stool and rectal symptoms, were improved with methylnaltrexone once daily or every other day compared with placebo, with no effect on pain scores [Iyer et al. 2011]. An early response suggested excellent outcome; thus 81% had at least three RFBMs/week if there was an early response to methylnaltrexone [Michna et al. 2011b]. Abdominal pain and nausea were the most common adverse events reported [Iyer et al. 2011; Michna et al. 2011]. Diarrhea, hyperhidrosis and vomiting were also observed [Michna et al. 2011].

The FDA has approved 12 mg subcutaneous injection of methylnaltrexone for the treatment of OIC in patients taking opioids for chronic, noncancer pain (http://www.fda.govlNewsEventslNewsroomlPressAnnouncements/2008/ucmI16885.htm). Methylnaltrexone should be used with caution in patients with gastrointestinal perforation, severe and persistent diarrhea, and disruptions in blood brain barrier (http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021964s010lbl.pdf). In addition, there have been case reports of gastrointestinal perforation in association with methylnaltrexone therapy [Mackey et al. 2010], and it has been suggested that there should be a titration phase before the recommended dose of methylnaltrexone is used.

Naloxegol

Naloxegol is a polyethylene glycol derivative (PEGylated) of naloxone [Neumann et al. 2007]. The PEG moiety reduces passive permeability of naloxegol to cross the blood brain barrier. P glycoprotein transporter transports naloxegol from the central nervous system [Faassen et al. 2003]. This causes naloxegol to reach only negligible amounts inside the central nervous system to antagonize the effects of opioids and, therefore, it does not reduce pain relief. Naloxegol antagonized morphine-induced delay in oral cecal transit time [Neumann et al. 2007].

Naloxegol did not change the morphine-induced miosis in 47 of 48 patients on oral naloxegol, which proved that naloxegol had negligible brain entry [Neumann et al. 2007]. The peripheral action of naloxegol was confirmed by the absence of change in the modified Himmelsbach opioid withdrawal scale, which assesses opioid withdrawal symptoms like yawning, lacrimation, rhinorrhea, tremor, perspiration, piloerection, anorexia, restlessness or emesis [Webster et al. 2013; Chey et al. 2014].

One phase II and two phase III studies showed that naloxegol improves SBMs during the treatment period starting from week 1 [Webster et al. 2013; Chey et al. 2014]. Typically, 67% of patients enrolled in these phase III clinical trials were being treated with at least one laxative for OIC [Chey et al. 2014]. The responder rates with 25 mg naloxegol were high in patients who had inadequate response to laxatives [Chey et al. 2014]. Naloxegol improved stool consistency, CSBMs, percentage of days with straining, PAC-SYM and PAC-QOL [Webster et al. 2013; Chey et al. 2014], and was safe and well tolerated.

When given for 52 weeks in patients with OIC and noncancer pain [Webster et al. 2014], the most common side effects were abdominal pain, diarrhea, nausea, headache and flatulence, in descending order [Webster et al. 2014]. Serious adverse events did not occur in any of the randomized controlled trials [Chey et al. 2014; Webster et al. 2014]. QT/QTc interval prolongation was not observed when 150 mg of naloxegol was given to healthy men [Gottfridsson et al. 2013]. Mild to moderate hepatic impairment had only mild effect on the pharmacokinetics [Bui et al. 2014]. In patients with moderate and severe renal impairment, naloxegol should be used with caution due to increase in Cmax and AUC [Bui et al. 2014]. Naloxegol concentration is not affected in patients on haemodialysis.

The FDA approved naloxegol, 12.5 or 25 mg once daily, orally, for OIC in adults with chronic noncancer pain. The FDA also requires surveillance of cardiovascular events in patients on naloxegol (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm414620.htm).

Drugs in developments for OIC

Axelopran

Axelopran (TD-1211) is a highly potent peripheral µ opioid receptor antagonist (PAMORA). Axelopran inhibited loperamide-induced delay in gastric emptying in rats [Armstrong et al. 2013]. It also increased the number of SBMs and CSBMs in a dose-dependent manner in humans [Vickery et al. 2013a; 2013b], with 70% of patients having at least three SBMs/week and an increase in at least one SBM/week response to 15 mg of axelopran. Diarrhea, nausea and abdominal pain were the most common gastrointestinal adverse events and no serious adverse events were reported with axelopran [Vickery et al. 2011; 2013a].

Naldemedine

Naldemedine (S-279995) is a PAMORA currently in phase III clinical trials for the treatment of OIC. Phase II studies evaluated the efficacy of naldemedine for 4 weeks in patients with noncancer pain. The endpoints assessed were number of SBMs/week, opioid withdrawal symptoms, global satisfaction, and treatment related adverse events [ClinicalTrials.gov identifiers: NCT01443403, NCT01122030]. Two ongoing phase III studies are being conducted to evaluate the long-term safety of naldemedine in patients with noncancer pain [ClinicalTrials.gov identifiers: NCT01993940, NCT01965652].

Linaclotide

Linaclotide is a guanylyl cyclase C receptor agonist which increases secretion of chloride into the lumen by increasing the intracellular cyclic guanosine monophosphate (cGMP) [Hardman and Sutherland, 1969]; this, in turn, activates the cystic fibrosis transmembrane regulator [Bryant et al. 2010]. There is an ongoing phase II randomized, controlled trial of linaclotide, administered to patients with OIC receiving chronic opioid treatment for noncancer pain for 8 weeks [ClinicalTrials.gov identifier: NCT02270983].

TRV-130

β arrestin-2 activation leads to constipation due to opioid therapy [Akbarali et al. 2014]. Morphine is more analgesic and has fewer gastrointestinal adverse effects in β arrestin-2 knockout mice [Bohn et al. 1999]. TRV-130 is a potent µ opioid agonist that stabilizes G-protein receptor conformations, but prevents activation of β arrestin-2. This offers potential to maintain analgesic effect while avoiding gastrointestinal adverse events [Chen et al. 2013]. In human studies, TRV-130 showed a decrease in opiate-induced respiratory depression and nausea [Soergel et al. 2014a], but constipation was not evaluated in that study.

TRV-130 has also shown central opioid action, as demonstrated by marked pupillary constriction [Soergel et al. 2014a]. Currently, TRV-130 is being evaluated in patients undergoing abdominoplasty and bunionectomy [ClinicalTrials.gov identifiers: NCT02100748, NCT02335294].

Alvimopan

Alvimopan is a PAMORA approved in the United States for management of postoperative ileus in patients after bowel resection. Alvimopan significantly increased SBM frequency [Irving et al. 2011], and showed improvements in straining, stool consistency and incomplete evacuation compared with placebo [Webster et al. 2008] in patients with OIC. However, alvimopan was not approved by the FDA for treatment of OIC due to reports of adverse cardiovascular events.

Prucalopride

Prucalopride has high selectivity and affinity to 5-HT₄ receptors, which enhance enterokinetic properties in the gastrointestinal tract without risk of cardiovascular toxicity [Emmanuel et al. 1998]. Prucalopride primarily acts by releasing 5-hydroxytryptamine (5-HT), which secondarily releases Acetylcholine (Ach) and calcitonin gene-related peptide from the intrinsic primary afferent neurons [De Maeyer et al. 2008]. In patients with OIC with noncancer pain, prucalopride significantly increased the number of responders with at least three CSBMs/week and an increase of at least one CSBM/week compared with placebo at the end of week 1 [Sloots et al. 2010]. Prucalopride is not yet approved for the treatment of OIC.

Clinical guidance in care of patients with OIC related to noncancer pain

Through a consensus document [Argoff et al. 2015] from a group of experts, it is possible to propose a clinical guidance algorithm (Figure 3) for selection of OIC treatment. The first step involves the use of prophylactic treatment, with increase in water and fiber intake, and osmotic and stimulant laxatives. Since laxatives were proven to be effective in some patients [Ruston et al. 2013], this should be the first line of treatment in patients with diagnosis of OIC. If there is insufficient clinical benefit with laxatives, as evidenced by a BFI score of more than 30 points, the panel recommended treatment with medications (PAMORA, combination of oxycodone and naloxone, lubiprostone). Reassessment of BFI score is useful to monitor improvement in OIC.

Figure 3.

Clinical guidance for treatment of opioid-induced constipation in patients with noncancer pain. BFI, Bowel Function Index; OXN, oxycodone and naloxone; PAMORA, peripheral µ opioid receptor antagonist.

Conclusion

The increasing use of opioids for noncancer pain has dramatically increased the gastrointestinal adverse effects related to opioids, particularly OIC. Previously OIC was most commonly undiagnosed by physicians due to barriers in diagnosis and treatment in these patients. Assessing OIC in the early stages by using BFI score and prophylactic treatment with laxatives will decrease the burden of constipation in patients on opioid treatment. The current recommendation for treatment is to commence OIC-approved therapy (PAMORA, combination of oxycodone and naloxone, or lubiprostone) if the BFI is at least 30 points on prophylactic treatment. Further development of drugs acting at different receptor sites may enhance the treatment of OIC in the future.

Footnotes

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest statement

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Camilleri has served as a consultant to AstraZeneca and Shionogi regarding naloxegol and naldemedine for the treatment of opioid-induced constipation. Dr Nelson has no conflicts of interest.

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Opioid-induced constipation: advances and clinical guidance

Abstract

Keywords

Introduction

Opioid use in chronic noncancer pain

Pain as the fifth vital sign and the imperative to manage pain

Gastrointestinal effects and differential tolerance of gut regions to µ-opioid agonists

Organ-level effects of µ opioids

Cellular effects of µ opioids

Differential tolerance of gut regions to µ opioids

Clinical presentation of OIC

Diagnosis of OIC

Barriers to diagnosis of OIC

Drugs approved for OIC (Table 1)

Lubiprostone

Oxycodone and naloxone

Methylnaltrexone

Naloxegol

Drugs in developments for OIC

Axelopran

Naldemedine

Linaclotide

TRV-130

Alvimopan

Prucalopride

Clinical guidance in care of patients with OIC related to noncancer pain

Conclusion

Footnotes

Funding

Conflict of interest statement

References