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

Ther Adv Chronic Dis

2016, Vol. 7(2) 121­–134

clinical guidance DOI: 10.1177/

2040622315627801

© The Author(s), 2016.

Reprints and permissions:
Alfred D. Nelson and Michael Camilleri http://www.sagepub.co.uk/
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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 prevalence of OIC increases with increased Correspondence to:

Michael Camilleri, MD
The use of opioids in the treatment of chronic duration of use of opioid analgesics [Camilleri Clinical Enteric
pain has increased in the past decade (http:// et al. 2014]. Treatment satisfaction with opioids Neuroscience
Translational and
www.cdc.gov/primarycare/materials/opoidabuse/ decreases when OIC develops and many patients Epidemiological Research
docs/pda-phperspective-508.pdf). Chronic pain tend to discontinue opioid therapy when they (CENTER), Division of
Gastroenterology and
occurs in association with cancer and noncancer develop constipation [Coyne et  al. 2014]. This Hepatology, Mayo Clinic,
conditions. It has been estimated that 20% of review addresses OIC in association with noncan- Charlton Building, Room
8-110, 200 First Street SW,
patients presenting to physicians’ offices in the cer pain, with focus on recent developments, clin- Rochester, MN 55905, USA
United States with pain symptoms were pre- ical guidelines and a proposed algorithm for camilleri.michael@mayo.
edu
scribed opioids (http://www.cdc.gov/homean- treatment of these patients. Alfred D. Nelson, MBBS
drecreationalsafety/pdf/Common_Elements_in_ Clinical Enteric
Neuroscience
Guidelines_for_Prescribing_Opioids-a.pdf). Translational and
Opioids are more effective than nonopioid anal- Opioid use in chronic noncancer pain Epidemiological Research
(CENTER), Division of
gesics in controlling moderate to severe pain. Chronic pain is described as persistent pain for Gastroenterology and
more than 3 months [Verhaak et al. 1998]. The Hepatology, Mayo Clinic,
Rochester, MN, USA
Even though opioids are effective in alleviating prevalence of chronic widespread pain in the gen-
severe pain, they also cause adverse effects such as eral population was about 10–15% [Mansfield
physical dependence, tolerance, sedation, hyper- et  al. 2015]. In patients with chronic noncancer
algesia [Hooten et  al. 2015] and respiratory pain, the prevalence of OIC varies from 41% to
depression [Chou et  al. 2009]. Gastrointestinal 81% [Kalso et  al. 2004; Bell et  al. 2009]. The
adverse effects have a major impact on health and most common indication for opioid use in non-
quality of life in opioid users. Opioid-induced cancer pain is musculoskeletal pain, including
constipation (OIC) is the most common gastroin- back pain, degenerative joint disease, fibromyal-
testinal adverse effect [Kalso et al. 2004; Tack and gia and headache [Chey et al. 2014]. In the United
Corsettii, 2014] causing a significant reduction in States, 4% of adults are taking chronic opioid
the quality of life [Bell et  al. 2009; Kumar et  al. therapy, chiefly for noncancer pain. The Centers
2014]. Other common gastrointestinal effects of for Disease Control and Prevention (CDC) esti-
opioids are nausea, vomiting, abdominal pain, mates that overprescription of opioids by health-
bloating and cramping [Chou et al. 2009]. care providers is the reason for opioid-related

http://taj.sagepub.com 121
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 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 con-
tinuously 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 treat-
ment 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, acetami-
nophen, 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 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 pro-
pulsion and increased fluid absorption in the
small and large intestine result in delayed absorp-
tion of medications, hard dry stools, constipation,
straining, sense of incomplete rectal evacuation,
122 http://taj.sagepub.com
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 non-
propulsive 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 intesti-
nal 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 opi-
oid 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 mem-
brane hyperpolarization through activation of
potassium channels. Apart from the direct activa-
tion 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 toler-
ance to opioids are hypothesized based on ani-
mal studies. Tolerance to the effects of μ opioids
[Pasternak, 2001; Pan, 2005] occurs in all gas-
trointestinal 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 dephospho-
rylation 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

Figure 1.  Mechanism of differential tolerance of µ opioid receptors in the gastrointestinal tract. Reproduced
with permission from Williams et al. [2013].
endosome, and this releases the receptor back to
the plasma membrane to allow binding of an
agonist. Thus, β arrestin-2 is integral to devel-
oping short- (<1 day) and long-term (>1 day)
tolerance (Figure 1) [Williams et al. 2013]. The
downregulation of β arrestin-2 results in devel-
opment of tolerance in the ileum in response to
μ opioid agonist [Claing et  al. 2002; Galligan
and Akbarali, 2014], causing tolerance to mor-
phine; 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].
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
http://taj.sagepub.com 123
AD Nelson and M Camilleri
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 pro-
posed 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 strain-
ing to pass BMs; sense of incomplete evacua-
tion; 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].
(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
Therapeutic Advances in Chronic Disease 7(2)
Figure 2.  Bowel Function Index (BFI) assessment for opioid-induced constipation.
Reproduced with permission from Meissner et al. [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 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 judg-
ment 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 refer-
ence range of BFI scores for patients without con-
stipation is from 0 to 28.8. This provides a simple
124 http://taj.sagepub.com
discrimination between patients with and without
constipation on opioid therapy [Ueberall et  al.
2011].
Another screening tool was developed to recog-
nize 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 treat-
ment [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].
(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

complete after recording each BM and
time of occurrence.
(2) Step 2 is a five-item module questionnaire
addressing inability to have a BM, bloat-
ing, 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 consti-
pation 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 responsive-
ness were significant for all diary items except for
rectal pain. In addition, the study showed ade-
quate 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.
(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 spec-
trum 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 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
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AD Nelson and M Camilleri
lumen [Bijvelds et  al. 2009; Schiffhauer et  al.
2013]. This results in increased peristalsis, laxa-
tion, and acceleration of small intestinal and
colonic transit [Camilleri et al. 2006]. ClC2 chan-
nels 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].
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 con-
stipation symptoms, such as abdominal discom-
fort, 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 con-
traindicated 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 intrave-
nously 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 glucuro-
nidation) 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 treat-
ment response. Naloxone improved opioid-
induced constipation symptoms and also reduced
the laxative use with only mild opioid withdrawal
symptoms such as yawning, sweating and shiver-
ing [Meissner et al. 2000]. Naloxone PR reduced
Therapeutic Advances in Chronic Disease 7(2)
mean colonic transit time by 2.1 h when used in
combination with oxycodone PR (20 mg oxyco-
done/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 bioavail-
ability of oxycodone is 80%, enhancing its availa-
bility for central analgesic action [Burness and
Keating, 2014]. When the combination of oxyco-
done and naloxone was in the ratio of 2:1, the effi-
cacy 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 nalox-
one 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 combi-
nation 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 com-
bination of oxycodone and naloxone at a 2:1
ratio, with a maximum dose of 40 mg of nalox-
one, proved to be more efficacious in the treat-
ment of OIC [Meissner et al. 2009]; however, due
to induction of opioid withdrawal symptoms, the
maximum dosing strengths in 2:1 oral combina-
tion therapy approved by the FDA is oxycodone
40 mg and naloxone 20 mg (http://www.access-
data.fda.gov/drugsatfda_docs/label/2014/
205777lbl.pdf).
126 http://taj.sagepub.com
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 subcutane-
ous 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 short-
ened 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, hyperhidro-
sis 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.govlNewsEv-
entslNewsroomlPressAnnouncements/2008/
ucmI16885.htm). Methylnaltrexone should be
used with caution in patients with gastrointesti-
nal 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 perfo-
ration 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 methylnaltrex-
one 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 gly-
coprotein 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 antago-
nized morphine-induced delay in oral cecal tran-
sit 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 with-
drawal symptoms like yawning, lacrimation, rhi-
norrhea, 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 treat-
ment 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 rand-
omized controlled trials [Chey et  al. 2014;
Webster et al. 2014]. QT/QTc interval prolonga-
tion 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
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AD Nelson and M Camilleri
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 non-
cancer 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 periph-
eral 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 axelo-
pran. 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 cur-
rently in phase III clinical trials for the treat-
ment 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 identi-
fiers: 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 guano-
sine 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,
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 µ opioid receptor antagonist.
controlled trial of linaclotide, administered to
patients with OIC receiving chronic opioid treat-
ment 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 avoid-
ing 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 abdomi-
noplasty and bunionectomy [ClinicalTrials.gov
identifiers: NCT02100748, NCT02335294].
Alvimopan
Alvimopan is a PAMORA approved in the
United States for management of postoperative
128 http://taj.sagepub.com
ileus in patients after bowel resection. Alvimopan
significantly increased SBM frequency [Irving
et al. 2011], and showed improvements in strain-
ing, 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 signifi-
cantly 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
 AD Nelson and M Camilleri

Table 1.  Clinical trials of drugs approved for OIC.

Drug Study type Study length Study Study endpoints Specific outcomes Reference
(weeks) cohort

Lubiprostone 1. RCT 12 431 ⩾1 SBM improvement 27.1% versus 18.9% with p Jamal et al.
over baseline frequency value < 0.030 [2015]
and ⩾3 SBMs/week for at
least 9 weeks
2. RCT 12 418 Δ from baseline in SBM At 8 weeks, SBMs/week mean Cryer et al.
no. at week 8 and overall 3.3 versus 2.4 (pla), p = 0.005; [2014]
overall mean, 2.2 versus 1.6
(pla) SBMs/week, p = 0.004
Oxycodone 1. RCT 12 278 Change in BFI at week 4 40.9 BFI score at week 4 and Lowenstein
and naloxone extended to compared with baseline 34.01 at week 12 compared et al. [2009]
(OXY PR) open label for CSBM with a baseline of 67.4  
52 weeks 51% achieved CSBM in OXY
  PR compared with 26% in
oxycodone only group at 4
weeks
2. RCT 12 35 Δ from baseline in BFI BFI score change of 23.3 Koopmans
during treatment compared with baseline of et al. [2014]
61.3 (p < 0.0002)
Methyl- 1. RCT 4 460 Rescue-free BM (RFBM) 34.2% had RFBM with MNTX Michna et al.
naltrexone within 4 h of first dose compared with 9.9% (pla) [2011]
(MNTX)   Time to BM within first 46% had RFBM within 24 h  
24 h with MNTX compared with
  PAC SYM 25.3% (pla)  
At 4 weeks, MNTX compared
with placebo
2. RCT 4 460 Rectal symptoms −0.56 versus −0.30 (p < 0.05) Iyer et al.
  Stool symptoms −0.76 versus −0.43 (p < 0.001) [2011] 
Naloxegol 1. RCT 4 207 Median Δ from baseline in 25 mg naloxegol [3.0 versus Webster
SBMs/week after 4 weeks 0.8 (pla); p = 0.0022] et al. [2013]
  50 mg naloxegol [3.5 versus  
1.0 (pla); p < 0.0001]
2.  RCT (two 12 641 ⩾3 SBMs/week and Response rates higher with 25 Chey et al
studies: 04 and 696 increase of ⩾1 SBM mg naloxegol [2014]
05)  compared with baseline Study 04: 44.4% versus 29.4%  
  for ⩾9 of 12 weeks (pla), p = 0.001; study 05:  
Δ Severity of straining 39.7% versus 29.3% (pla),
Δ Stool consistency p = 0.02
Study 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.

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 treat-
ment in patients with diagnosis of OIC. If there is
insufficient clinical benefit with laxatives, as evi-
denced 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

http://taj.sagepub.com 129
Therapeutic Advances in Chronic Disease 7(2)
OIC. Previously OIC was most commonly undi-
agnosed by physicians due to barriers in diagno-
sis 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 recommenda-
tion 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 opioid-
induced constipation. Dr Nelson has no conflicts
of interest.
References
Akbarali, H., Inkisar, A. and Dewey, W. (2014)
Site and mechanism of morphine tolerance in the
gastrointestinal tract. Neurogastroent Motil 26: 1361–
1367.
Amin, H., Sopchak, A., Foss, J., Esposito, B.,
Roizen, M. and Camporesi, E. (1994) Efficacy of
methylnaltrexone versus naloxone for reversal of
morphine-induced depression of hypoxic ventilatory
response. Anesth Analg 78: 701–705.
Argoff, C., Brennan, M., Camilleri, M., Davies,
A., Fudin, J., Galluzzi, K. et al. (2015) Consensus
recommendations on initiating prescription therapies
for opioid-induced constipation. Pain Med. DOI:
10.1111/pme.12937.
Armstrong, S., Campbell, C., Richardson, C.,
Vickery, R., Tsuruda, P., Long, D. et al. (2013)
The in vivo pharmacodynamics of the novel opioid
receptor antagonist, TD-1211, in models of opioid-
induced gastrointestinal and CNS activity. Naunyn
Schmiedebergs Arch Pharmacol 386: 471–478.
Bagnol, D., Mansour, A., Akil, H. and Watson,
S. (1997) Cellular localization and distribution of
130 http://taj.sagepub.com
the cloned mu and kappa opioid receptors in rat
gastrointestinal tract. Neuroscience 81: 579–591.
Bell, T., Panchal, S., Miaskowski, C., Bolge, S.,
Milanova, T. and Williamson, R. (2009) The
prevalence, severity, and impact of opioid-induced
bowel dysfunction: results of a US and European
patient survey (probe 1). Pain Med 10: 35–42.
Benyamin, R., Trescot, A., Datta, S., Buenaventura,
R., Adlaka, R., Sehgal, N. et al. (2008) Opioid
complications and side effects. Pain Physician 11:
S105–S120.
Bijvelds, M., Bot, A., Escher, J. and De
Jonge, H. (2009) Activation of intestinal Cl−
secretion by lubiprostone requires the cystic
fibrosis transmembrane conductance regulator.
Gastroenterology 137: 976–985.
Bohn, L., Lefkowitz, R., Gainetdinov, R., Peppel, K.,
Caron, M. and Lin, F. (1999) Enhanced morphine
analgesia in mice lacking Β-arrestin 2. Science 286:
2495–2498.
Brown, D. and Goldberg, L. (1985) The use of
quaternary narcotic antagonists in opiate research.
Neuropharmacology 24: 181–191.
Bryant, A., Busby, R., Bartolini, W., Cordero, E.,
Hannig, G., Kessler, M. et al. (2010) Linaclotide is
a potent and selective guanylate cyclase C agonist
that elicits pharmacological effects locally in the
gastrointestinal tract. Life Sci 86: 760–765.
Bui, K., She, F. and Sostek, M. (2014) The effects
of renal impairment on the pharmacokinetics, safety,
and tolerability of naloxegol. J Clin Pharmacol 54:
1375–1382.
Burness, C. and Keating, G. (2014) Oxycodone/
naloxone prolonged-release: a review of its use in
the management of chronic pain while counteracting
opioid-induced constipation. Drugs 74: 353–375.
Camilleri, M., Bharucha, A., Ueno, R., Burton,
D., Thomforde, G., Baxter, K. et al. (2006)
Effect of a selective chloride channel activator,
lubiprostone, on gastrointestinal transit, gastric
sensory, and motor functions in healthy volunteers.
Am J Physiol Gastrointest Liver Physiol 290: G942–
G947.
Camilleri, M., Drossman, D., Becker, G.,
Webster, L., Davies, A. and Mawe, G. (2014)
Emerging treatments in neurogastroenterology: a
multidisciplinary working group consensus statement
on opioid-induced constipation. Neurogastroent Motil
26: 1386–1395.
Camilleri, M., Malagelada, J., Stanghellini, V.,
Zinsmeister, A., Kao, P. and Li, C. (1986) Dose-
related effects of synthetic human beta-endorphin and
naloxone on fed gastrointestinal motility. Am J Physiol
251: G147–G154.

Camilleri, M., Rothman, M., Ho, K. and Etropolski,
M. (2011) Validation of a bowel function diary
for assessing opioid-induced constipation. Am J
Gastroenterol 106: 497–506.
Catalán, M., Flores, C., González-Begne, M.,
Zhang, Y., Sepúlveda, F. and Melvin, J. (2012)
Severe defects in absorptive ion transport in
distal colons of mice that lack CLC-2 channels.
Gastroenterology 142: 346–354.
Chen, X., Pitis, P., Liu, G., Yuan, C., Gotchev,
D., Cowan, C. et al. (2013) Structure–activity
relationships and discovery of a G protein biased mu
opioid receptor ligand, [(3-methoxythiophen-2-yl)
methyl]({2-[(9r)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]
decan- 9-yl]ethyl})amine (TRV130), for the
treatment of acute severe pain. J Med Chem 56:
8019–8031.
Chey, W., Webster, L., Sostek, M., Lappalainen, J.,
Barker, P. and Tack, J. (2014) Naloxegol for opioid-
induced constipation in patients with noncancer pain.
N Engl J Med 370: 2387–2396.
Choi, Y. and Billings, J. (2002) Opioid antagonists:
a review of their role in palliative care, focusing on
use in opioid-related constipation. J Pain Symptom
Manage 24: 71–90.
Chou, R., Fanciullo, G., Fine, P., Adler, J.,
Ballantyne, J., Davies, P. et al. (2009) Clinical
guidelines for the use of chronic opioid therapy in
chronic noncancer pain. J Pain 10: 113–130.
Claing, A., Laporte, S., Caron, M. and Lefkowitz, R.
(2002) Endocytosis of G protein-coupled receptors:
roles of G protein-coupled receptor kinases and beta-
arrestin proteins. Prog Neurobiol 66: 61–79.
Coyne, K., Currie, B., Holmes, W. and Crawley,
J. (2015) Assessment of a stool symptom screener
and understanding the opioid-induced constipation
symptom experience. Patient 8: 317–327.
Coyne, K., Locasale, R., Datto, C., Sexton, C.,
Yeomans, K. and Tack, J. (2014) Opioid-induced
constipation in patients with chronic noncancer
pain in the USA, Canada, Germany, and the UK:
descriptive analysis of baseline patient-reported
outcomes and retrospective chart review. Clinicoecon
Outcomes Res 6: 269–281.
Cryer, B., Katz, S., Vallejo, R., Popescu, A. and
Ueno, R. (2014) A randomized study of lubiprostone
for opioid-induced constipation in patients with
chronic noncancer pain. Pain Med 15: 1825–1834.
Cuppoletti, J., Chakrabarti, J., Tewari, K. and
Malinowska, D. (2013) Methadone but not morphine
inhibits lubiprostone-stimulated Cl- currents in T84
intestinal cells and recombinant human ClC-2, but
not CFTR Cl– currents. Cell Biochem Biophys 66:
53–63.
http://taj.sagepub.com 131
AD Nelson and M Camilleri
Cuppoletti, J., Chakrabarti, J., Tewari, K. and
Malinowska, D. (2014) Differentiation between
human ClC-2 and CFTR Cl– channels with
pharmacological agents. Am J Physiol Cell Physiol 307:
C479–C492.
Cuppoletti, J., Malinowska, D., Tewari, K., Li,
Q., Sherry, A., Patchen, M. et al. (2004) SPI-0211
activates T84 cell chloride transport and recombinant
human ClC-2 chloride currents. Am J Physiol Cell
Physiol 287: C1173–C1183.
De Maeyer, J., Lefebvre, R. and Schuurkes, J. (2008)
5-HT4 receptor agonists: similar but not the same.
Neurogastroent Motil 20: 99–112.
Emmanuel, A., Kamm, M., Roy, A. and Antonelli, K.
(1998) Effect of a novel prokinetic drug, R093877, on
gastrointestinal transit in healthy volunteers. Gut 42:
511–516.
Faassen, F., Vogel, G., Spanings, H. and Vromans,
H. (2003) Caco-2 permeability, P-glycoprotein
transport ratios and brain penetration of heterocyclic
drugs. Int J Pharm 263: 113–122.
Fine, P., Mahajan, G. and McPherson, M. (2009)
Long-acting opioids and short-acting opioids:
appropriate use in chronic pain management. Pain
Med 10: S79–S88.
Gaertner, J., Siemens, W., Camilleri, M., Davies, A.,
Drossman, D., Webster, L. et al. (2015) Definitions
and outcome measures of clinical trials regarding
opioid-induced constipation: a systematic review. J
Clin Gastroenterol 49: 9–16.
Galligan, J. and Akbarali, H. (2014) Molecular
physiology of enteric opioid receptors. Am J
Gastroenterol 2: 17–21.
Gottfridsson, C., Carlson, G., Lappalainen, J.
and Sostek, M. (2013) Evaluation of the
effect of naloxegol on cardiac repolarization:
a randomized, placebo- and positive-controlled
crossover thorough QT/QTC study in
healthy volunteers. Clinical Therapeutics 35:
1876–1883.
Hardman, J. and Sutherland, E. (1969)
Guanyl cyclase, an enzyme catalyzing the
formation of guanosine 3’,5’-monophosphate
from guanosine triphosphate. J Biol Chem 244:
6363–6370.
Holzer, P. (2004) Opioids and opioid receptors in
the enteric nervous system: from a problem in opioid
analgesia to a possible new prokinetic therapy in
humans. Neurosci Lett 361: 192–195.
Hooten, W., Lamer, T. and Twyner, C. (2015)
Opioid-induced hyperalgesia in community-
dwelling adults with chronic pain. Pain 156:
1145–1152.
Therapeutic Advances in Chronic Disease 7(2)
Irving, G., Pénzes, J., Ramjattan, B., Cousins,
M., Rauck, R., Spierings, E. et al. (2011) A
randomized, placebo-controlled phase 3 trial (Study
SB-767905/013) of alvimopan for opioid-induced
bowel dysfunction in patients with non-cancer pain.
J Pain 12: 175–184.
Iyer, S., Randazzo, B., Tzanis, E., Schulman,
S., Zhang, H., Wang, W. et al. (2011) Effect of
subcutaneous methylnaltrexone on patient-reported
constipation symptoms. Value Health 14: 177–183.
Jadad, A. and Browman, G. (1995) The who analgesic
ladder for cancer pain management: stepping up the
quality of its evaluation. JAMA 274: 1870–1873.
Jakab, R., Collaco, A. and Ameen, N. (2012)
Lubiprostone targets prostanoid signaling and
promotes ion transporter trafficking, mucus exocytosis,
and contractility. Dig Dis Sci 57: 2826–2845.
Jamal, M., Adams, A., Jansen, J. and Webster, L.
(2015) A randomized, placebo-controlled trial of
lubiprostone for opioid-induced constipation in
chronic noncancer pain. Am J Gastroenterol 110:
725–732.
Kalso, E., Edwards, J., Moore, R. and McQuay, H.
(2004) Opioids in chronic non-cancer pain: systematic
review of efficacy and safety. Pain 112: 372–380.
Koopmans, G., Simpson, K., De Andres, J., Lux,
E., Wagemans, M. and Van Megen, Y. (2014) Fixed
ratio (2:1) prolonged-release oxycodone/naloxone
combination improves bowel function in patients
with moderate-to-severe pain and opioid-induced
constipation refractory to at least two classes of
laxatives. Curr Med Res Opin 30: 2389–2396.
Kumar, L., Barker, C. and Emmanuel, A. (2014)
Opioid-induced constipation: pathophysiology,
clinical consequences, and management. Gastroenterol
Res Pract 2014: 141737.
Kurz, A. and Sessler, D. (2003) Opioid-induced
bowel dysfunction: pathophysiology and potential new
therapies. Drugs 63: 649–671.
Ling, G., Paul, D., Simantov, R. and Pasternak, G.
(1989) Differential development of acute tolerance
to analgesia, respiratory depression, gastrointestinal
transit and hormone release in a morphine infusion
model. Life Sci 45: 1627–1636.
Liu, M. and Wittbrodt, E. (2002) Low-dose oral
naloxone reverses opioid-induced constipation and
analgesia. J Pain Symptom Manage 23: 48–53.
Lowenstein, O., Leyendecker, P., Hopp, M.,
Schutter, U., Rogers, P., Uhl, R. et al. (2009)
Combined prolonged-release oxycodone and naloxone
improves bowel function in patients receiving opioids
for moderate-to-severe non-malignant chronic pain: a
randomised controlled trial. Expert Opin Pharmacother
10: 531–543.
132 http://taj.sagepub.com
Mackey, A., Green, L., Greene, P. and Avigan,
M. (2010) Methylnaltrexone and gastrointestinal
perforation. J Pain Symptom Manage 40: e1–e3.
Mansfield, K., Sim, J., Jordan, J. and Jordan, K.
(2015) A systematic review and meta-analysis
of the prevalence of chronic widespread pain
in the general population. Pain 157:
55–64.
Mehta, V., Alaward, S., Kuravinakop, S. and Nikolic,
S. (2014) Effect of a fixed-dose opioid agonist/
antagonist on constipation in patients on long-term
opioids for non-malignant pain unable to tolerate
laxatives. Pain Physician 17: 415–424.
Meissner, W., Leyendecker, P., Mueller-Lissner, S.,
Nadstawek, J., Hopp, M., Ruckes, C. et al. (2009)
A randomised controlled trial with prolonged-
release oral oxycodone and naloxone to prevent and
reverse opioid-induced constipation. Eur J Pain 13:
56–64.
Meissner, W., Schmidt, U., Hartmann, M., Kath,
R. and Reinhart, K. (2000) Oral naloxone reverses
opioid-associated constipation. Pain 84: 105–109.
Michna, E., Blonsky, E., Schulman, S., Tzanis, E.,
Manley, A., Zhang, H. et al. (2011a) Subcutaneous
methylnaltrexone for treatment of opioid-induced
constipation in patients with chronic, nonmalignant
pain: a randomized controlled study. J Pain 12:
554–562.
Michna, E., Weil, A., Duerden, M., Schulman,
S., Wang, W., Tzanis, E. et al. (2011b) Efficacy of
subcutaneous methylnaltrexone in the treatment of
opioid-induced constipation: a responder post hoc
analysis. Pain Med 12: 1223–1230.
Musial, F., Enck, P., Kalveram, K. and Erckenbrecht,
J. (1992) The effect of loperamide on anorectal
function in normal healthy men. J Clin Gastroenterol
15: 321–324.
Nelson, A. and Camilleri, M. (2015) Chronic opioid-
induced constipation in patients with nonmalignant
pain: Challenges and opportunities. Ther Adv
Gastroenterol 8: 206–220.
Neumann, T., Van Patischen, H., Marcantonio,
A., Song, D., Morrison, P. and Eldon, M. (2007)
Evaluation of single oral doses of NKTR118
(PEG-Naloxol) as a peripheral opioid antagonist
(POA): a double-blind placebo-controlled study
in healthy male subjects. J Clin Pharmacol 47:
1210–1210.
Pan, Y. (2005) Diversity and complexity of the mu
opioid receptor gene: alternative pre-mRNA splicing
and promoters. DNA Cell Biol 24: 736–750.
Pappagallo, M. (2001) Incidence, prevalence, and
management of opioid bowel dysfunction. Am J Surg
182: S11–S18.

Pasternak, G. (2001) Incomplete cross tolerance
and multiple mu opioid peptide receptors. Trends
Pharmacol Sci 22: 67–70.
Poelaert, J., Koopmans-Klein, G., Dioh, A., Louis, F.,
Gorissen, M., Logé, D. et al. (2015) Treatment with
prolonged-release oxycodone/naloxone improves pain
relief and opioid-induced constipation compared with
prolonged-release oxycodone in patients with chronic
severe pain and laxative-refractory constipation. Clin
Ther 37: 784–792.
Rentz, A., Yu, R., Muller-Lissner, S. and
Leyendecker, P. (2009) Validation of the bowel
function index to detect clinically meaningful changes
in opioid-induced constipation. J Med Econ 12:
371–383.
Russell, J., Bass, P., Goldberg, L., Schuster, C.
and Merz, H. (1982) Antagonism of gut, but
not central effects of morphine with quaternary
narcotic antagonists. Eur J Pharmacol 78: 255–
261.
Ruston, T., Hunter, K., Cummings, G. and
Lazarescu, A. (2013) Efficacy and side-effect
profiles of lactulose, docusate sodium, and
sennosides compared to peg in opioid-induced
constipation: a systematic review. Can Oncol Nurs J
23: 236–246.
Sandner-Kiesling, A., Leyendecker, P., Hopp, M.,
Tarau, L., Lejcko, J., Meissner, W. et al. (2010)
Long-term efficacy and safety of combined prolonged-
release oxycodone and naloxone in the management
of non-cancer chronic pain. Int J Clin Pract 64:
763–774.
Schiffhauer, E., Vij, N., Kovbasnjuk, O., Kang, P.,
Walker, D., Lee, S. et al. (2013) Dual activation of
CFTR and CLCN2 by lubiprostone in murine nasal
epithelia. Am J Physiol Lung Cell Mol Physiol 304:
L324–L331.
Shook, J., Pelton, J., Hruby, V. and Burks, T. (1987)
Peptide opioid antagonist separates peripheral and
central opioid antitransit effects. J Pharmacol Exp Ther
243: 492–500.
Sloots, C., Rykx, A., Cools, M., Kerstens, R. and De
Pauw, M. (2010) Efficacy and safety of prucalopride
in patients with chronic noncancer pain suffering
from opioid-induced constipation. Digest Dis Sci 55:
2912–2921.
Smith, K., Hopp, M., Mundin, G., Bond, S., Bailey,
P., Woodward, J. et al. (2011) Naloxone as part of a
prolonged release oxycodone/naloxone combination
reduces oxycodone-induced slowing of gastrointestinal
transit in healthy volunteers. Expert Opin Investig
Drugs 20: 427–439.
Soergel, D., Subach, R., Burnham, N., Lark, M.,
James, I., Sadler, B. et al. (2014a) Biased agonism
http://taj.sagepub.com 133
AD Nelson and M Camilleri
of the µ-opioid receptor by TRV130 increases
analgesia and reduces on-target adverse effects versus
morphine: a randomized, double-blind, placebo-
controlled, crossover study in healthy volunteers. Pain
155: 1829–1835.
Soergel, D., Subach, R., Sadler, B., Connell, J.,
Marion, A., Cowan, C. et al. (2014b) First clinical
experience with TRV130: pharmacokinetics and
pharmacodynamics in healthy volunteers. J Clin
Pharmacol 54: 351–357.
Tack, J. and Corsetti, M. (2014) Naloxegol for the
treatment of opioid-induced constipation. Expert Rev
Gastroenterol Hepatol 8: 855–861.
Tuteja, A., Biskupiak, J., Stoddard, G. and Lipman,
A. (2010) Opioid-induced bowel disorders and
narcotic bowel syndrome in patients with chronic
non-cancer pain. Neurogastroent Motil 22:
424–430, e496.
Ueberall, M., Muller-Lissner, S., Buschmann-
Kramm, C. and Bosse, B. (2011) The bowel function
index for evaluating constipation in pain patients:
definition of a reference range for a non-constipated
population of pain patients. J Int Med Res 39: 41–50.
Verhaak, P., Kerssens, J., Dekker, J., Sorbi, M. and
Bensing, J. (1998) Prevalence of chronic benign pain
disorder among adults: a review of the literature. Pain
77: 231–239.
Vickery, R., Li, Y., Kohler, R., Webster, L., Singla,
N. and Daniels, O. (2011) TD-1211 demonstrates
constipation-relieving effects, including decrease in
rescue laxative use, in patients with opioid-induced
constipation. Am J Gastroenterol 106: S513–S514.
Vickery, R., Li, Y., Schwertschlag, U., Singla, N.,
Webster, L. and Canafax, D. (2013a) TD-1211
demonstrates a durable increase in bowel movement
frequency and return toward normal bowel function
in a 5-week PH2B opioid-induced constipation (OIC)
study. J Pain 14: S78.
Vickery, R., Li, Y., Schwertschlag, U., Singla, N.,
Webster, L. and Canafax, D. (2013b) TD-1211 phase
2b study demonstrates increased bowel movement
frequency and constipation-related symptom
improvement in patients with opioid induced
constipation (OIC). Gastroenterology
144: S159.
Vondrackova, D., Leyendecker, P., Meissner,
W., Hopp, M., Szombati, I., Hermanns, K. et al.
(2008) Analgesic efficacy and safety of oxycodone
in combination with naloxone as prolonged release
tablets in patients with moderate to severe chronic
pain. J Pain 9: 1144–1154.
Walid, M., Donahue, S., Darmohray, D., Hyer, L., Jr
and Robinson, J., Jr (2008) The fifth vital sign - what
does it mean? Pain Pract 8: 417–422.
Therapeutic Advances in Chronic Disease 7(2)
Webster, L., Chey, W., Tack, J., Lappalainen, J.,
Diva, U. and Sostek, M. (2014) Randomised clinical
trial: the long-term safety and tolerability of naloxegol
in patients with pain and opioid-induced constipation.
Aliment Pharmacol Ther 40: 771–779.
Webster, L., Dhar, S., Eldon, M., Masuoka, L.,
Lappalainen, J. and Sostek, M. (2013) A phase
2, double-blind, randomized, placebo-controlled,
dose-escalation study to evaluate the efficacy, safety,
and tolerability of naloxegol in patients with opioid-
induced constipation. Pain 154: 1542–1550.
Webster, L., Jansen, J., Peppin, J., Lasko, B., Irving,
G., Morlion, B. et al. (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, placebo-
controlled, dose-finding study in subjects taking
opioids for chronic non-cancer pain. Pain 137:
428–440.
Visit SAGE journals online
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Williams, J., Ingram, S., Henderson, G., Chavkin,
SAGE journals C., Von Zastrow, M., Schulz, S. et al. (2013)
134 http://taj.sagepub.com
Regulation of mu-opioid receptors: desensitization,
phosphorylation, internalization, and tolerance.
Pharmacol Rev 65: 223–254.
Wong, B., Rao, A., Camilleri, M., Manabe, N.,
McKinzie, S., Busciglio, I. et al. (2010) The effects
of methylnaltrexone alone and in combination with
acutely administered codeine on gastrointestinal and
colonic transit in health. Aliment Pharmacol Ther 32:
884–893.
Yuan, C., Foss, J., O’Connor, 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: 469–475.
Yuan, C., Wei, G., Foss, J., O’Connor, 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:
118–123.