Curr. Treat. Options in Oncol.

(2019) 20: 91
DOI 10.1007/s11864-019-0686-6

Palliative and Supportive Care (MP Davis, Section Editor)

Opioid-Induced Constipation
in Oncological Patients: New
Strategies of Management
Ricard Mesía, MD1
Juan Antonio Virizuela Echaburu, MD2,*
Jose Gómez, MD3
Tamara Sauri, MD4
Gloria Serrano, MD5
Eduardo Pujol, MD6
Address
1
Servicio de Oncología Médica, Instituto Catalán de Oncología, Badalona, Spain
*,2
Servicio de Oncología Médica, Hospital General Universitario Virgen Macarena,
Seville, Spain
Email: [email protected]
3
Hospital la Fe, Valencia, Spain
4
Hospital Clinic de Barcelona, Barcelona, Spain
5
Hospital Infanta Leonor, Madrid, Spain
6
Hospital Clínico Lozano Blesa, Zaragoza, Spain

Published online: 19 December 2019

* The Author(s) 2019. This article is an open access publication

This article is part of the Topical Collection on Palliative and Supportive Care

Keywords Cancer I Opioid-induced constipation I Opioid analgesics I Pain I Naloxegol I Laxatives

Opinion statement
Cancer-associated pain has traditionally been treated with opioid analgesics, often in
escalating doses. Opioid-induced constipation (OIC) is a common problem associated with
chronic use of opioid analgesics. Typical treatment strategies to alleviate constipation are
based on dietary changes, exercise, and laxatives. However, laxatives have a nonspecific
action and do not target underlying mechanisms of OIC. This article will review prevalent,
clinical presentation and recommendations for the treatment of OIC. An independent
literature search was carried out by the authors. We reviewed the literature for randomized
controlled trials that studied the efficacy of laxatives, naloxone, and naloxegol in treating
OIC. Newer strategies addressing the causal pathophysiology of OIC are needed for a more
effective assessment and management of OIC. Finally, traditional recommended therapies
are appraised and compared with the latest pharmacological developments. Future re-
search should address whether naloxegol is more efficacious by its comparison directly
with first-line treatments, including laxatives.
91 Page 2 of 14 Curr. Treat. Options in Oncol. (2019) 20: 91

Introduction
Pain is one of the most common symptoms related with symptom, it affects 60 to 90% of cancer patients with
cancer and its treatment [1]. Pain prevalence in patients opioids [4], between 10% and 20% of the population
is 33% after curative treatment, 59% during curative experiencing constipation at baseline; however, some of
treatment, and 64% in patients with metastases or in them develop it because of the opioids (OIC), but, in
advanced stage disease. A multicenter study in Spain has others, constipation is an exacerbation of the pre-
demonstrated that approximately 55% of all cancer pa- existing one (opioid-exacerbated constipation, OEC)
tients suffer from pain [2]. Pharmacotherapy, especially [5]. Traditional treatment strategies to alleviate consti-
opioids, is the principal modality for managing chronic pation, such as laxatives, are also used to manage OIC;
pain in cancer patients. This type of therapy could be however, laxatives do not address the underlying opioid
related with different adverse effects in these patients. receptor-mediated cause of OIC and are often ineffec-
Opioid-induced bowel dysfunction (OIBD) is a fre- tive. A novel approach for selectively and locally an-
quent complication of long-term opioid treatment, tagonizing the gastrointestinal effects of opioids in-
which affects 40–80% of patients treated with opioids. volves the coadministration of a peripherally acting
It can cause reduced quality of life (QOL) and insuffi- μ-opioid receptor antagonist (PAMORA) with negligi-
cient treatment of pain [3]. Opioid-induced constipa- ble availability to the central nervous system (CNS),
tion (OIC) is the most frequent and bothersome such as oral naloxegol.

Materials and methods

An independent literature search was carried out by the authors (during No-
vember 2017) with the abovementioned search strategy and the following
details were extracted: trial site, year, trial methods, participants, interventions,
and outcomes.
We conducted the review protocol using the Preferred Reporting Items for
Systematic Reviews and Meta-analyses (PRISMA) guidelines. We used the fol-
lowing search protocol in PubMed: (“Opioid-induced constipation” [All Fields]
OR (“Opioid-induced constipation” [Supplementary concept]) OR (“cancer
and constipation” [Supplementary concept] OR “cancer and constipation”
[All Fields] OR (“Opioid-induced bowel dysfunction” [Supplementary concept]
OR “Opioid-induced bowel dysfunction” [All Fields] OR “laxatives” [All
Fields]) OR (“laxatives” [Supplementary concept] OR “naloxegol” [Supplemen-
tary concept] OR “naloxegol” [All Fields]).
We reviewed the literature for randomized controlled trials that studied the
efficacy of laxatives, naloxone, and naloxegol in treating OIC.
The articles were selected following these preferences: English language,
human and animal studies, and research support. Case reports have been
excluded from this review. The retrieved studies were screened for inclusion
and exclusion criteria.

Results
After applying our research protocol, 83 publications were identified, 20 of
which were clinical trials. Also, taken into account were observational studies
on laxatives, naloxone, and naloxegol in patients with OIC, in different
environments.
Curr. Treat. Options in Oncol. (2019) 20: 91 Page 3 of 14 91

The current review starts by providing a brief overview of the pathophysio-

logical mechanisms whereby opioids modify GI function. After addressing the
use of laxatives and opioid receptor antagonists for treatments of OIC, the
article goes on to discuss emerging strategies to avoid OIBD and the clinical
utility of PAMORAs.

Pain and cancer

Advanced cancer patients frequently suffer from pain at all stages of the disease,
during active treatment, during metastatic stage disease, and after the cancer had
been cured. Pain is undertreated in 31 to 65% of these patients, although
adequate pain relief is considered feasible in 86% of patients with cancer [6].
Although reports vary widely, the range of reported prevalence of pain is highest
for the following tumors: head and neck (67–91%); prostate (56–94%); uterine
(30–90%); genitourinary (58–90%); breast (40–89%); pancreatic (72–85%);
gastrointestinal (44–74%); and lung/bronchus (44–67%) [7].
The cause of pain is a verifiable lesion or disorder that is likely to produce
pain through direct tissue injury or through a related process, such as inflam-
mation [8]. Overall, 3 in 4 patients suffer from cancer-related pain while most
of the remaining pain syndromes are caused by disease-modifying therapy.
Mucosal pain that affects diet occurs during active cancer therapy and is a
common chronic complaint in survivors that affects diet and QoL [9].
Opioid analgesics have a significant role to play in the management of
chronic pain. They are therefore integrated with strategies that include an
interventionist, psychological, physical, or complementary focus to improve
the treatment of pain, enabling rehabilitation [10]. Common adverse effects to
opioid treatment include nausea, headache, confusion, and gastrointestinal
(GI)-related symptoms [11].

Opioid-induced bowel dysfunction and constipation

GI-related symptoms, normally referred as (OIBD), are the most common and
bothersome adverse events of opioid treatment. Up to 80% of patients who
receive opiates experience OIBD symptoms such as dry mouth, nausea, acid
reflux, loss of appetite, abdominal pain, bloating, and symptoms related to
constipation (OIC) [3].
OIBD symptoms are mediated by opioid interaction with peripheral μ-
opioid receptors located at the gastrointestinal tract. Enteric opioid receptors
(predominantly μ and δ) are located in the submucosal and myenteric plexus,
respectively, in addition to immune cells in the lamina propria of the cellular
wall. The activation of these receptors inhibits excitatory and inhibitory neural
pathways within the enteric nervous system that coordinates motility. These
mechanisms reduce peristaltic contractions (due to the inhibition of excitatory
neural pathways), increase GI muscle activity, and elevate resting muscle tone,
spasm and non-propulsive motility patterns (due to the inhibition of the
inhibitory neural pathways). As a result, delayed gastric emptying and intestinal
transit slowing is induced [11]. Activation of opioid receptors by opioid ad-
ministration inhibits secretion of several regulatory neurotransmitters of GI
tract, which leads to the discoordination of GI tract motility [12]. Spastic
achalasia-like esophageal dysmotility, for instance, is the result of non-
peristaltic esophageal contraction with incomplete relaxation of the lower
91 Page 4 of 14 Curr. Treat. Options in Oncol. (2019) 20: 91

esophageal sphincter after opioid administration. In the small and large intes-
tine, these imbalances lead to increased segmental contraction and decreased
propulsive forward peristalsis, which manifest clinically by constipation, gut
spasm, and abdominal cramps [13]. In addition, direct activation of μ-opioid
receptors (MOP) in the enteric nervous system inhibits vasoactive intestinal
peptide (VIP) secretion and subsequently decreases pancreaticobiliary secretion
and gut absorption and hence, harder and drier stool.
OIC prevalence rates ranged from 15 to 90% based on an analysis of 16
clinical trials and observational studies identified in patients with or without
cancer [14] and from 70 to 100% among hospitalized patients. This variation
may be attributable, among others, to patient population assessed, study de-
sign, and the lack of standardized definition of constipation across studies.
Only few studies have described OIC in cancer patients. 62% of the patientes
showed a problematic degree of constipation, according to the Knowles–
Eccersley–Scott symptom (KESS) score, in the DYONISOS study
(DYsfonctiONs Intestinales induiteS par les OpioıdS forts), a cross-sectional
observational study with 520 cancer patients in France [15]. In a study carried
out in Spain with 317 ambulatory patients undergoing treatment with different
opioids for chronic pain, whether caused by cancer or not, 94.6% of patients
reported at least one symptom of OIBD. The most frequent symptom was
constipation (91.6%). Almost half the patients reported three or more symp-
toms with a severity equal to or greater than 4 according to the numeric rating
scale (11-point scale, from 0 to 10) [16].
Relevant impairment of QoL in patients with cancer pain and OIC has been
reported. Cancer patients with OIC have significantly reduced QoL compared
with those cancer patients without OIC, as measured by both the condition-
specific Patient Assessment of Constipation–Quality of Life (PAC-QOL) and the
generic Short Form-12 questionnaires [15]. OIC negatively affect pain manage-
ment, productivity, and patients’ QoL [3] and also increase the use of healthcare
resources and costs. The risk of having an all cause inpatient hospitalization,
emergency department visit, and office or other outpatient visit was nearly twice
higher in patients on chronic opioid treatment with OIC [15].
Recently, OIC definition has been proposed as a change, when initiating
opioid therapy, from baseline bowel habits and defecation patterns that is char-
acterized by any of the following symptoms: reduced bowel frequency; develop-
ment or worsening of straining; a sense of incomplete evacuation; or a patient’s
perception of distress related to bowel habits [17]. Rome Foundation has en-
dorsed such definition and included OIC as a new bowel disorder, the first OIC
diagnostic criteria have been described in the new Rome IV publication. Consen-
sus definition and diagnostic criteria for OIC are now pending adoption to guide
clinical and epidemiological research and to inform treatment recommendations.
Patient reported outcome measures are also important to identify OIC. To
ensure OIC assessment, patient constipation evaluation scales are recommend-
ed. The most commonly used include the Constipation Assessment Scale
(CAS), Patient Assessment of Constipation Symptoms (PAC-SYM), Bowel
Function Diary, and the Bowel Function Index (BFI) [18]. The American
Academy of Pain Medicine along with The American Gastroenterology Asso-
ciation recommend using the BFI to ensure rapid and reliable assessment of
OIC in clinical practice [19]. BFI is a practical and clinically responsive tool
that has been validated in OIC. The BFI is responsive to changes in symptoms
Curr. Treat. Options in Oncol. (2019) 20: 91 Page 5 of 14 91

severity and across a broad range of patients. The BFI score range from 0 to
100 points, with higher scores indicating a more severe condition, and ≥ 30
points indicating constipation. Furthermore, a BFI ≥ 30 is considered a crite-
rion to initiate specific pharmacological treatment such as PAMORA for
patients on laxative treatment. Failure to first-line treatment should be de-
termined rapidly to provide adequate relief to the patients with OIC [20].
A working group of experts identified the most common barriers for the
diagnosis and treatment of OIC [21]. Lack of awareness among doctors about
OIC in patients receiving opioid therapy, patients’ embarrassment at revealing
their symptoms to doctors, doctors’ inability to ask the patient about constipa-
tion, the absence of universal diagnostic criteria, and the need of specific
treatment for OIC that alleviate constipation while maintaining central analge-
sia are some of the main obstacles. These barriers alert us that underdiagnosis
and undertreatment of OIC might be a frequent clinical issue among patients
with OIC. Temporality is important for the differential diagnosis of OIC,
therefore, inquiring patients regarding their bowel habits at the time of initiat-
ing opioid therapy, and during the treatment, would help to provide a more
successful treatment for their patients with OIC symptoms. Introducing Rome
IV diagnostic criteria in clinical practice is also essential.

Treatments of opioid-induced constipation

Although OIC is one of the most common causes of constipation in cancer
patients, there are many other possible factors that can affect bowel movements
and exacerbate constipation: cancer itself, cancer treatment, inactivity, poor
fluid intake and nutrition, etc. Chemotherapy alters the intestinal microbiome
resulting in reduced nucleotide and energy metabolism, cofactors and vitamins,
signal transduction, and xenobiotic degradation as well as increased glycan
metabolism [22]. This dysbiosis may be one of the mechanisms for chemo-
therapy mucositis, weight loss, and constipation. When making treatment
decisions for OIC, all this potential etiologies and combinations of causes
should be taken into consideration.
Anticipating and preventing OIC or treating it when it is mild is always
easier. Once constipation is established, management can be much more
difficult.
First-line treatments for OIC typically involve laxatives, increased dietary
fiber, fluid intake, and exercise; however, these are associated with limited
efficacy and do not address the underlying mechanism of OIC [3]. Therefore,
implementation of new strategies should focus on more specific and targeted
OIC treatment to provide a more satisfactory OIC management in patients with
cancer. Furthermore, concomitant therapeutic strategies using traditional ther-
apies and a more specific OIC treatment might be necessary when functional
constipation and OIC overlapped.

Prevention and treatment of constipation

Dietary fiber and exercise

There is little evidence that healthy lifestyle changes and exercise improve OIC
symptoms; however, data from functional constipation has traditionally been
extrapolated to these patients. In healthy subjects, physical activity reduces colon
91 Page 6 of 14 Curr. Treat. Options in Oncol. (2019) 20: 91

transit time by stimulating colorectal motility. In patients with chronic idiopathic

constipation, moderate physical activity 30–60 min per day improves the con-
sistency of stools [23]. Adequate fluid intake is important to promote normal
bowel function. However, patients with OIC would not benefit from additional
dietary fiber unless their current intake is deficient. If fiber is excessively increased,
it might put these patients at risk for bowel obstruction due to the decreased
peristalsis, delayed gastric emptying, and prolonged intestinal transit time that
occur with OIC [24]. Additionally, side effects of fiber mainly include the
production of gas causing abdominal discomfort and flatulence. Soluble fiber
pectins, guar, and ispaghula produce viscous solutions in the gastrointestinal tract
that slow absorption in the small intestine. This may reduce the absorption of
cholesterol and inhibit the activity of the pancreatic enzyme and the digestion of
protein, leading to an anti-nutritive effect.

Laxatives
The routine prescription of laxatives for prophylaxis and treatment of intestinal
dysfunction induced by opioids in cancer patients is recommended by the
European Society of Medical Oncology (ESMO) [25•] and by the European
Expert Consensus [26], that indicates that prophylactic treatment of OIC with
laxatives can be considered, although more supporting evidence is needed.
Laxatives have shown to be effective to manage functional constipation, but
OIC and functional constipation have different physio-pathological mechanism
[27]. Laxatives may help defecation trough localized effects in the colon, but do
not directly address the spectrum of the underlying mechanisms of OIC. There is
limited evidence of laxative efficacy in the treatment of OIC. No randomized,
controlled, double-blinded trials investigating the efficacy of conventional laxa-
tives in OIC patients have shown superiority of one laxative over the other [28].
A prospective open-label study has suggested that polyethylene glycol and
sodium picosulfate might be better than lactulose for cancer patients with
opioids [29]. Various studies have demonstrated that laxatives do not alleviate
OIC symptoms in some patients and may be associated with adverse events such
as bloating, flatulence, sudden urge to defecate, electrolyte imbalances, dehydra-
tion and bowel obstruction, which can affect daily activities [3, 30].
Table 1 shows the benefits and side effects of the laxatives investigated in
patients with OIC.
A study by Kumar et al. [36] observed that 54% of patients being treated
with opioids and laxatives did not achieve the desired level of symptom
(constipation) improvement more than half the time.
A failure of laxative treatment can be determined by a BFI score 9 30 points,
and OIC treatment with PAMORA can be considered [25•, 26].

Drugs for opioid-induced constipation

Several recent treatment guidelines recommend taking into account therapies
based on peripherally acting opioid antagonists when starting opioid therapy or
in patients with OIC who do not respond to laxatives [25•, 26, 28]. In the
process of drug development, the initial strategy was to investigate the use of the
μ-opioid receptor antagonist naloxone for the treatment of OIC [37].
Table 1. Effect of laxatives in patients treated with opioids

Reference Study design Patient population Dosing regimen Efficacy outcome

Emmanuel A cross-sectional online or Patients who had taken opioid 1. Patients used osmotic laxative Laxative side effects were reported in
et al. telephone survey analgesics (n = 198, 100%). 2. Patients used stimulant laxative 75%, most commonly gas,
2017 Patients with cancer (n = 3, 1.5%) bloating/fullness, and a sudden urge to
[30] defecate. As assessed by the Bowel
Function Index, laxatives did not
improve the symptoms of constipation
Hawley and Nonrandomized, Patients with cancer who had 1. Thirty patients received the In the docusate plus sennosides protocol,
Byeon nonblinded sequential taken opioid analgesics sennosides-only (S) protocol 57% cancer patients were requiring
2008 cohort study (n = 60). (17.2–25.8 mg) additional interventions when
[31] 2. Thirty patients received the sennosides compared with cancer patients
(17.2–25.8 mg) plus docusate (DS) following the sennosides alone
protocol (200 mg) protocol (40%)
Curr. Treat. Options in Oncol. (2019) 20: 91

Agra et al. Randomized, open trial Patients with terminal cancer 1. Treated with senna (min 12 mg, max The number of defecation days was similar
1998 (taking codeine or morphine) 48 mg), (n = 43) in both groups (senna: mean, 8.9 days;
[32] (n = 91) 2. Treated with lactulose: (min 10 g, max lactulose: mean, 10.6 days). Findings
40 g), (n = 48) do not provide evidence of the greater
efficacy of senna over lactulose in
terminal cancer patients treated with
opioids
Christensen Cross-sectional online Participants treated with opioid for Both prescribed and non-prescribed Less than half (48%) of the laxative users
et al. survey a minimum of 4 weeks laxative users were asked to specify were satisfied with the laxative they
2016 and confirmed ever what type of laxatives they bought. All were using to relieve their constipation
[33] experiencing OIC (n = 417) laxative users were categorized
according to number of different
brands of laxatives used (one laxative,
two or more laxatives), frequency of
laxative use (daily 6–3 days/week;
1–2 days/week)
Coyne et al. Cross-sectional patient Participants who had confirmed of Both prescribed and non-prescribed Of patients who took the recommended
2014 survey and chart review daily opioid therapy laxative users (osmotic, stimulants, dose of laxatives, 94% did not get an
[34] data from the baseline ≥ 30 mg for ≥ 4 weeks and stool softeners) adequate response.
assessment of an self-reported opioid-induced
ongoing longitudinal constipation (n = 617)
study
Tarumi Prospective, randomized, Hospice patients and had a 1. The docusate group received two There was no significant benefit of
et al. double-blind, Palliative Performance Scale 100 mg docusate (dioctyl sodium docusate plus sennosides compared
2013 placebo-controlled trial score of 20% or more (n = 74) sulfosuccinate) tablets twice daily plus with placebo plus sennosides in
[35] one to three sennoside tablets managing constipation in hospice
(8.6 mg/ tablet) patients
2. The placebo group received two
cornstarch capsules twice daily, in
addition to one to three sennoside
tablets (8.6 mg/tablet)
Page 7 of 14 91
91 Page 8 of 14 Curr. Treat. Options in Oncol. (2019) 20: 91

Peripherally acting μ-opioid receptor antagonists

The objective of PAMORAs treatment is to reestablish intestinal function.
PAMORAs bind exclusively to the peripheral μ-opioid receptors avoiding opi-
oid union to them. The therapeutic mechanisms of action imply a selective and
competitive binding of the drug to the enteric μ-opioid receptors [38].
PAMORAs are the best option treatment to alleviate OIC symptoms without
affecting central analgesia [38]. Available PAMORAs include naltrexone,
alvimopan, methylnaltrexone, naloxegol, and naldemedine. All PAMORAs
have demonstrated efficacy in the treatment of OIC [36]. Rauck et al. [39], in
a randomized, double-blind trial showed that oral formulation of
methylnaltrexone is efficacious and well-tolerated for OIC. Naldemedine is a
novel PAMORA recently approved for the treatment of OIC [40–45]. Sponta-
neous BM is achieved earlier with naldemedine (16.1 or 18.3 h) than with
placebo (46.7 or 45.9 h, respectively) [41]. Song et al. [43] in a meta-analysis
have suggested that naldemedine can improve the number of patients achieving
spontaneous BM and its frequency. Furthermore, authors reported a higher
incidence of serious adverse events in patients receiving naldemedine than
placebo, mainly in cancer patients.
Merchan et al. [46] in a recent study compared the effectiveness and safety of
oral naloxone versus subcutaneous methylnaltrexone in a medical intensive
care unit. Both agents showed similar results on efficacy and safe. The time to
first BM for oral naloxone and subcutaneous methylnaltrexone were 30 and
24 h.

Naloxegol
Naloxegol is a PEGylated derivative of the opioid antagonist naloxone [4, 38].
Pegylation converts naloxegol to a substrate for the p-glycoprotein transporter
(P-gp); this reduces central passive permeability compared with naloxone. Due
to the reduction in permeability and the increase in the flow of naloxegol
through the hematoencephalic barrier, related to the P-gp transporter, the
penetration of the naloxegol into the central nervous system is negligible. It
was shown that cerebral entry with naloxegol was insignificant as it did not
modify morphine-induced miosis in 47 of 48 patients being treated with oral
naloxegol [47]. Naloxegol antagonizes the μ-receptor in the GI tract, decreasing
the OIC effects without reversing the central analgesic effect [38]. Naloxegol
have shown to mitigate the gastric peristaltic effects of morphine without
significantly affecting analgesia [38]. Naloxegol has shown to be effective not
only against placebo but also by indirect comparisons with other interventions,
and naloxegol has been neither associated with an increased risk of severe
adverse events nor with a reduction in analgesia of background opioid analgesic
drug [38]. Most relevant studies of naloxegol are shown in Table 2.
The Ki values of naloxegol at the cloned human μ-opioid receptor ranged
from 6.5 to 8.5 nM. The pKi values of naloxegol and methylnaltrexone
corresponded to respective geometric mean Ki values of 7.42 nM and
22.1 nM, showing that naloxegol bound human μ-opioid receptors with
three-fold greater affinity than methylnaltrexone [47]. Floettmann et al.
[48••] described the results of several studies that employed standard pharma-
cologic measures of opioid activity and pharmacokinetic measures of CNS and
Curr. Treat. Options in Oncol. (2019) 20: 91 Page 9 of 14 91

Table 2. Summary of the most relevant naloxegol studies. Details of relevant naloxegol studies

Author/year Webster et al. 2013 [49] Chey et al. 2014 [50]

Phase II III
N N = 207; ≥ 18 years old; oral KODIAC-04 N = 652; KODIAC-05 N = 700;
morphine 30–1000 mg 18–84 years old; oral morphine
30–1000 mg 9 4 weeks with good pain
control and no cancer diagnosis, GI
obstruction or increased risk for bowel
perforation who had confirmed, active OIC
Study design Multicenter, randomized, DB, placebo-controlled, Multicenter, randomized, DB, parallel-group,
and dosing dose-escalation; 5 mg, 25 mg, and 50 mg placebo-controlled. Naloxegol 12.5 mg,
orally in sequential cohorts with placebo-control 25 mg, or placebo for 12 weeks
AE Abdominal pain, diarrhea, and nausea with Diarrhea, abdominal pain, nausea, vomiting;
increased frequency and severity in 50 mg no evidence of opioid withdrawal or
group; no evidence of opioid withdrawal worsening pain. More common in
or worsening pain 25 mg group
Variables efficacy Primary endpoint: Primary endpoint:
and outcomes -Change in spontaneous bowel movements (BMs)/ -Twelve-week response rate (≥ 3 spontaneous
week over baseline at the end of week 1 statistically BMs/week and ≥ 1 spontaneous
significantly improved compared with placebo at BMs over baseline for ≥ 9/12 weeks and ≥ 3/4
25 mg and 50 mg doses of the final weeks)
Secondary endpoints: -Higher response for 25 mg group over
-Change over baseline across weeks 2, 3, and 4 placebo for both trials and for 12.5 mg
-Change over baseline at the end of week 4 group over placebo in KODIAC-04 trial
-Time after first dose of naloxegol to first laxation
-Improvement over baseline compared with
placebo maintained in 25 mg and 50 mg
cohort over 4 weeks.

demonstrated that naloxegol relieves OIC-associated symptoms in patients

with chronic noncancer pain.
Naloxegol does not significantly inhibit the activity of CYP1A2,
CYP2C9, CYP2D6, CYP3A4, CYP2C19, P-glycoprotein, breast cancer re-
sistance protein, organic anion-transporter (OAT)1, OAT3, organic cation
transporter-2, organic anion-transporting polypeptide (OATP)1B1, or
OATP1B3, nor does it significantly induce the activity of CYP1A2,
CYP2B6, or CYP3A4 [41].
A pooled analysis [51] of patients being treated with laxatives for 4 days
showed that those with an inadequate response to one or more types of
laxatives had response rates of 42.5% and 47.7% for naloxegol 12.5 and
25 mg/day vs those receiving a placebo (30.1%) (p = 0.005 and p G =0.001,
respectively) and those with an inadequate response to two or more types of
laxatives had response rates of 44.3% and 44.4% versus 30.0%, respectively
(both p = 0.05).
To rule out any adverse cardiac events noted with its predecessor alvimopan,
an additional trial was conducted (NCT01325415). A randomized, placebo-
91 Page 10 of 14 Curr. Treat. Options in Oncol. (2019) 20: 91

controlled crossover thorough the QT/QTC study with therapeutic (25 mg) and
supratherapeutic (150 mg) naloxegol or moxifloxacin 400 mg or placebo in
health volunteers demonstrated no significant cardiovascular changes [52]. In
addition, a new clinical trial (NCT03087708) was started in University of
Minnesota, to determine feasibility and safety of long-term administration of
two doses of naloxegol in patients with advanced NSCLC receiving first-line
pemetrexed-based chemotherapy.
Naloxegol has been approved in the European Union for any patient (cancer
patient and noncancer patient) suffering with OIC and with an inadequate
response to at least one laxative after at least 4 days treatment in the 2 weeks
previous to the diagnosis.
In addition SEOM recommend the use of naloxegol in cancer patients with
OIC and an inadequate response to first-line treatments (e.g., dietary changes
and over-the-counter laxatives) [53••].

Additional agents and mechanisms to OIC control

Linaclotide is a peptide agonist of the guanylate cyclase-C receptor
involved in the intracellular conversion of guanosine 5-triphosphate to
cyclic guanosine monophosphate [54]. Linaclotide has been shown to be
an effective and well-tolerated agent for the treatment of chronic consti-
pation [55–58]. Lubiprostone is a specific activator of the type 2 chlo-
ride channels at the intestinal epithelium whose activity increases the
liquidity of contents [59]. Compared with placebo, lubiprostone has
demonstrated to increase spontaneous BM frequency and response rate,
and to improve OIC-related symptoms [60–64]. Prucalopride is a highly
selective serotonin receptor agonist showing gastrointestinal prokinetic
activity. Prucalopride has demonstrated activity in chronic constipation,
and European guidelines actually recommend its use [56].

Conclusion
Pain is a major problem in all stages of cancer. Analgesic drugs are used to
manage chronic pain and as part of a multifaceted focus that integrates strate-
gies with an interventionist, psychological, physical, or complementary ap-
proach, seeking to improve the treatment of pain and enabling rehabilitation.
A common consequence of opiate use, due to the distribution of μ-receptors, is
OIC.
Although the evidence is limited and may present some contraindications,
the routine prescription of laxatives is recommended for patients who receive
opioid analgesia. In some studies, it can be observed that laxatives do not
address OIC symptoms in some patients and can cause adverse events that affect
daily activities such as bloating, flatulence, and a sudden urge to defecate.
Furthermore, laxatives assist defecation through localized effects in the colon,
while OIC arises following stimulation of the enteric μ-opioid receptors. Al-
though traditional treatment such as laxatives or the increase of dietary fiber is
often insufficient to relieve OIC symptoms, a series of new and more specific
pharmacological approaches have emerged. Several treatment guidelines recom-
mend taking into account strategic therapies based on PAMORAs when starting
opioid therapy or in patients with OIC who do not respond to laxatives.
Curr. Treat. Options in Oncol. (2019) 20: 91 Page 11 of 14 91

Among currently available PAMORAs, daily administration of oral

naloxegol seems to be the most appropriate. Naloxegol is effective for
the treatment of OIC who do not respond to traditional laxatives.
Naloxegol has shown response rates significantly higher versus placebo
in the overall patient population and in patients classified as laxative-
inadequate responder treated with 25 mg for both studies and 12.5 mg
for one study, in two randomized, placebo-controlled, phase 3 trials.
Naloxegol present a well-tolerated safety profile. Adverse events are
more frequently GI and mild to moderate in severity and occurred at the
time of initiation of naloxegol treatment. Severe adverse events are rare,
and no bowel perforation has been reported, differing of what was
noticed in seven patients treated with subcutaneously administered
methylnaltrexone.
Altogether, naloxegol should be considered as an important alternative for
the treatment of OIC in cancer patients. Future research should address whether
naloxegol is more efficacious by its comparison directly with first-line treat-
ments, including laxatives.

Acknowledgment
Authors would express gratitude to Meisys for helping in the elaboration of the manuscript.

Compliance with Ethical Standards

Conflict of interest
Ricard Mesía has received compensation from Merck, Bristol-Myers Squibb, MSD, Kyowa, AstraZeneca, Nanobiotix,
and Roche for Service as a consultant. Juan Antonio Virizuela declares that he has no conflict of interest. Jose Gómez
declares that he has no conflict of interest. Tamara Sauri declares that she has no conflict of interest. Gloria Serrano
declares that she has no conflict of interest. Eduardo Pujol declares that he has no conflict of interest.
This work was supported by Kyowa Kirin Farmaceutica SLU. The authors received research funding from Kyowa
Kirin Farmaceutica SLU for this colaboration.

Human and animal rights and informed consent

All reported studies/experiments with human or animal subjects performed by the authors have been
previously published and complied with all applicable ethical standards (including the Helsinki Declara-
tion and its amendments, institutional/national research committee standards, and international/national/
institutional guidelines).

Open Access
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction
in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made.
91 Page 12 of 14 Curr. Treat. Options in Oncol. (2019) 20: 91

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