627801

research-article2016

TAJ0010.1177/2040622315627801Therapeutic Advances in Chronic DiseaseA. D. Nelson and M. Camilleri

Therapeutic Advances in Chronic Disease

Review

Opioid-induced constipation: advances and

clinical guidance

Ther Adv Chronic Dis

2016, Vol. 7(2) 121134
DOI: 10.1177/
2040622315627801
The Author(s), 2016.
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Alfred D. Nelson and Michael Camilleri

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 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 etal. 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 etal. 2009].

The prevalence of OIC increases with increased

duration of use of opioid analgesics [Camilleri
etal. 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 etal. 1998]. The
prevalence of chronic widespread pain in the general population was about 1015% [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 etal. 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

Correspondence to:
Michael Camilleri, MD
Clinical Enteric
Neuroscience
Translational and
Epidemiological Research
(CENTER), Division of
Gastroenterology and
Hepatology, Mayo Clinic,
Charlton Building, Room
8-110, 200 First Street SW,
Rochester, MN 55905, USA
camilleri.michael@mayo.
edu
Alfred D. Nelson, MBBS
Clinical Enteric
Neuroscience
Translational and
Epidemiological Research
(CENTER), Division of
Gastroenterology and
Hepatology, Mayo Clinic,
Rochester, MN, USA

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Therapeutic Advances in Chronic Disease 7(2)

overdosing (http://www.cdc.gOY/drugoverdose/
dataloverdose.html). Almost 90% of patients
with moderate to severe pain are treated with
opioids [Benyamin etal. 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 notfor-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 etal. 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
etal. 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:
(1) step 1: nonopioids (aspirin, acetaminophen, diclofenac, ibuprofen); then, as
necessary,
(2) step 2: mild opioids (codeine, tramadol);
(3) 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 -opioid agonists
Organ-level effects of 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 opioids
The actions of opioids are mediated through
G-protein coupled receptors [Pappagallo, 2001].
The , and receptors are three classes of opioid receptors [Williams etal. 2013]. The and
receptors [Camilleri etal. 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 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 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 arrestin-2
which causes receptor internalization in the
endosome, prolonging the desensitization of the
receptor (Figure 1) [Claing etal. 2002; Williams
etal. 2013]. The arrestin-2 is detached once
the receptor is dephosphorylated inside the

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AD Nelson and M Camilleri

Figure 1. Mechanism of differential tolerance of opioid receptors in the gastrointestinal tract. Reproduced
with permission from Williams etal. [2013].

endosome, and this releases the receptor back to

the plasma membrane to allow binding of an
agonist. Thus, arrestin-2 is integral to developing short- (<1 day) and long-term (>1 day)
tolerance (Figure 1) [Williams etal. 2013]. The
downregulation of arrestin-2 results in development of tolerance in the ileum in response to
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 arrestin-2 expression.
The preserved arrestin-2 results in receptor
recycling to the plasma membrane [Galligan
and Akbarali, 2014].
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 etal. 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 etal. 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 etal. 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
etal. 2015].
The following outcome measures or assessment
tools for OIC were identified in the systematic
review [Gaertner etal. 2015].
(1) 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).
(2) Patient-related outcome measures: Bowel
Function Index (BFI), Patient Assessment

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Therapeutic Advances in Chronic Disease 7(2)

Figure 2. Bowel Function Index (BFI) assessment for opioid-induced constipation.

Reproduced with permission from Meissner etal. [2009].

of Constipation Symptoms (PAC-SYM),

and global clinical impression of change.
(3) Patient-reported global burden measures:
constipation
distress
and
Patient
Assessment of Constipation Quality of
Life (PAC-QOL) [Gaertner etal. 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 etal.
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 etal. 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].
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 etal. 2015].
Another instrument that has been proposed for
use in clinical studies for OIC utilizes a three-step
module [Camilleri etal. 2011].
(1) 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

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AD Nelson and M Camilleri

complete after recording each BM and
time of occurrence.
(2) 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.
(3) 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 etal. 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
etal. 2014]. The barriers are as follows.
(1) Lack of awareness among clinicians about
OIC in patients on opioid therapy.
(2) If clinicians are aware, they may not ask
patients questions about constipation.
(3) Patients might feel ashamed to disclose
their symptoms to clinicians.
(4) Absence of universal diagnostic criteria for
OIC.
(5) Efforts to screen patients based on Rome
III criteria may not cover the whole spectrum of OIC that might present with
abdominal pain.
(6) 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 etal. 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 etal. 2006]. ClC2 channels are also located in the basolateral membrane
of the jejunum and colon [Cataln et al. 2012],
and lubiprostone leads to internalization of these
basolateral ClC2 channels, which blocks primary
absorption of chloride from the lumen [Cataln
etal. 2012; Jakab etal. 2012].
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 etal. 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 etal. 2014; Jamal etal. 2015].
Lubiprostone-stimulated secretion of Cl ions via
ClC2 channels was inhibited in vitro in T84 cell
lines by methadone [Cuppoletti etal. 2013]. As a
result of these studies, lubiprostone use is contraindicated with OIC related to methadone use.
Lubiprostone, 4 g, 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 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 opioidinduced constipation symptoms and also reduced
the laxative use with only mild opioid withdrawal
symptoms such as yawning, sweating and shivering [Meissner etal. 2000]. Naloxone PR reduced

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Therapeutic Advances in Chronic Disease 7(2)

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 etal. 2011].
Oxycodone and naloxone (both PR preparations)
in combination is superior to PR oral naloxone
alone to treat OIC [Meissner etal. 2009]. Naloxone
displaces oxycodone from the opioid receptors in
the gastrointestinal tract due to high affinity of
naloxone to the opioid receptors. Due to high first
pass metabolism, naloxones 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
etal. 2009]. The risk of experiencing a pain event
with the combination of oxycodone and naloxone
was 13% lower compared with oxycodone alone
[Vondrackova etal. 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 etal. 2014; Poelaert etal. 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 etal. 2014; Poelaert etal. 2015].
The most common adverse effects of the combination of oxycodone and naloxone are nausea,
vomiting, headache, constipation and diarrhea
[Vondrackova etal. 2008; Sandner-Kiesling etal.
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 etal. 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 etal. 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 etal. 1982;
Amin etal. 1994; Holzer, 2004]. Both subcutaneous and intravenous methylnaltrexone decreased
morphine-induced delay in orocecal transit time
[Yuan etal. 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 etal.
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 PACQOL [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 etal. 2011]. An early
response suggested excellent outcome; thus 81%
had at least three RFBMs/week if there was an
early response to methylnaltrexone [Michna etal.
2011b]. Abdominal pain and nausea were the
most common adverse events reported [Iyer etal.
2011; Michna etal. 2011]. Diarrhea, hyperhidrosis and vomiting were also observed [Michna
etal. 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.

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AD Nelson and M Camilleri

Naloxegol
Naloxegol is a polyethylene glycol derivative
(PEGylated) of naloxone [Neumann etal. 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 etal. 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 etal. 2007].

caution due to increase in Cmax and AUC [Bui

et al. 2014]. Naloxegol concentration is not
affected in patients on haemodialysis.

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 etal. 2014].

Axelopran
Axelopran (TD-1211) is a highly potent peripheral opioid receptor antagonist (PAMORA).
Axelopran inhibited loperamide-induced delay in
gastric emptying in rats [Armstrong etal. 2013].
It also increased the number of SBMs and CSBMs
in a dose-dependent manner in humans [Vickery
etal. 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 etal. 2011; 2013a].

One phase II and two phase III studies showed

that naloxegol improves SBMs during the treatment period starting from week 1 [Webster etal.
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 etal. 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, PACSYM and PAC-QOL [Webster etal. 2013; Chey
etal. 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 etal. 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
etal. 2014]. In patients with moderate and severe
renal impairment, naloxegol should be used with

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

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,

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Therapeutic Advances in Chronic Disease 7(2)

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 opioid receptor antagonist.

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
arrestin-2 activation leads to constipation due to
opioid therapy [Akbarali etal. 2014]. Morphine is
more analgesic and has fewer gastrointestinal
adverse effects in arrestin-2 knockout mice [Bohn
etal. 1999]. TRV-130 is a potent opioid agonist
that stabilizes G-protein receptor conformations,
but prevents activation of 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 etal. 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
etal. 2011], and showed improvements in straining, stool consistency and incomplete evacuation
compared with placebo [Webster etal. 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 generelated peptide from the intrinsic primary afferent
neurons [De Maeyer etal. 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 etal. 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

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AD Nelson and M Camilleri

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

27.1% versus 18.9% with p

value < 0.030

Jamal et al.
[2015]

2. RCT

12

418

1 SBM improvement
over baseline frequency
and 3 SBMs/week for at
least 9 weeks
from baseline in SBM
no. at week 8 and overall

Cryer et al.
[2014]

1. RCT
extended to
open label for
52 weeks

12

278

Change in BFI at week 4

compared with baseline
CSBM

2. RCT

12

35

from baseline in BFI

during treatment

1.RCT

460

Rescue-free BM (RFBM)
within 4 h of first dose
Time to BM within first
24 h
PAC SYM

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
40.9 BFI score at week 4 and
34.01 at week 12 compared
with a baseline of 67.4
51% achieved CSBM in OXY
PR compared with 26% in
oxycodone only group at 4
weeks
BFI score change of 23.3
compared with baseline of
61.3 (p < 0.0002)
34.2% had RFBM with MNTX
compared with 9.9% (pla)
46% had RFBM within 24 h
with MNTX compared with
25.3% (pla)
At 4 weeks, MNTX compared
with placebo
0.56 versus 0.30 (p < 0.05)
0.76 versus 0.43 (p < 0.001)
25 mg naloxegol [3.0 versus
0.8 (pla); p = 0.0022]
50 mg naloxegol [3.5 versus
1.0 (pla); p < 0.0001]
Response rates higher with 25
mg naloxegol
Study 04: 44.4% versus 29.4%
(pla), p = 0.001; study 05:
39.7% versus 29.3% (pla),
p = 0.02
Study 04: 0.73 0.05; study
05: 0.80 0.06

Oxycodone
and naloxone
(OXY PR)

Methylnaltrexone
(MNTX)

Naloxegol

2.RCT

1.RCT

460

207

12

641
696

Rectal symptoms
Stool symptoms
Median from baseline in
SBMs/week after 4 weeks

2. RCT (two
studies: 04 and
05)

3 SBMs/week and
increase of 1 SBM
compared with baseline
for 9 of 12 weeks
Severity of straining
Stool consistency

Study 04: 0.66 0.07; study

05: 0.71 0.07

Lowenstein
et al. [2009]

Koopmans
et al. [2014]
Michna et al.
[2011]

Iyer et al.
[2011]
Webster
et al. [2013]

Chey et al
[2014]

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.

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
etal. 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.
Conclusion
The increasing use of opioids for noncancer pain
has dramatically increased the gastrointestinal
adverse effects related to opioids, particularly

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Therapeutic Advances in Chronic Disease 7(2)

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.
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 opioidinduced constipation. Dr Nelson has no conflicts
of interest.

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SAGE journals

Webster, L., Jansen, J., Peppin, J., Lasko, B., Irving,

G., Morlion, B. etal. (2008) Alvimopan, a peripherally
acting mu-opioid receptor (PAM-OR) antagonist for
the treatment of opioid-induced bowel dysfunction:
results from a randomized, double-blind, placebocontrolled, dose-finding study in subjects taking
opioids for chronic non-cancer pain. Pain 137:
428440.
Williams, J., Ingram, S., Henderson, G., Chavkin,
C., Von Zastrow, M., Schulz, S. etal. (2013)

Regulation of mu-opioid receptors: desensitization,

phosphorylation, internalization, and tolerance.
Pharmacol Rev 65: 223254.
Wong, B., Rao, A., Camilleri, M., Manabe, N.,
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of methylnaltrexone alone and in combination with
acutely administered codeine on gastrointestinal and
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884893.
Yuan, C., Foss, J., OConnor, M., Toledano, A.,
Roizen, M. and Moss, J. (1996) Methylnaltrexone
prevents morphine-induced delay in oral-cecal transit
time without affecting analgesia: a double-blind
randomized placebo-controlled trial. Clin Pharmacol
Ther 59: 469475.
Yuan, C., Wei, G., Foss, J., OConnor, M., Karrison,
T. and Osinski, J. (2002) Effects of subcutaneous
methylnaltrexone on morphine-induced peripherally
mediated side effects: a double-blind randomized
placebo-controlled trial. J Pharmacol Exp Ther 300:
118123.

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