Curr Gastroenterol Rep (2013) 15:334

DOI 10.1007/s11894-013-0334-4

NEUROMUSCULAR DISORDERS OF THE GASTROINTESTINAL TRACT (S RAO, SECTION EDITOR)

Opioid Induced Bowel Disease: a Twenty-first Century

Physicians’ Dilemma
Considering Pathophysiology and Treatment Strategies

Ankush Sharma & M. Mazen Jamal

Published online: 9 July 2013

# Springer Science+Business Media New York (outside the USA) 2013

Abstract The treatment of cancer-associated pain as well as for use in OIBD. Further investigational research will pro-
chronic non-cancer-related pain (CNCP) is an increasingly mulgate more information and allow for better and more
relevant topic in medicine. However, it has long been rec- efficient treatment options for OIBD.
ognized that opiates can adversely affect many organ sys-
tems, most notably the gastrointestinal system. These are Keywords Opioid induced bowel dysfunction .
referred to as the spectrum of “opioid-induced bowel dys- Constipation . Opioid induced constipation . OIBD . OBD .
function” (OBD) or what we will refer to as “opioid-induced Cancer associated constipation . Non cancer associated
bowel disease” (OIBD) which include constipation, nausea, constipation . Methylnaltrexone . Lubiprostone
vomiting, delayed gastric emptying, and gastro-esophageal
reflux disease (GERD), and a newer entity known as nar-
cotic bowel syndrome (NBS). Opioid analgesics are increas- Introduction
ingly being used for the treatment of cancer pain, non-
cancer-associated pain, and postoperative pain. As we The treatment of cancer-associated pain as well as chronic
achieve our goals towards pain control, we need to be non-cancer-related pain(CNCP) is an increasingly relevant
cognizant of and competent in how to prevent and treat topic in medicine. The literature suggests that pain is often
OIBD. The basis is due in part to µ-receptor activation, under-treated by physicians and thus there has been a push
decreasing the peristaltic contraction and leading to sequelae nationally to be more conscientious about effective pain
of OIBD. Treatment beyond lifestyle interventional strategy control. The annual cost of untreated pain in terms of lost
will employ laxatives and stool softeners. However, studies income, decreased productivity, and direct healthcare costs
performed while patients were already using laxativies and is estimated to be more than $60 billion annually in the
stool softeners have elicited the necessity of peripherally United States [1]. The mainstay for pain control has been
acting agents such as methylnaltrexone (MNTX) and opiates, ranging from oxycodone to methadone to
alvimopan. Patients responded dramatically to both medica- hydromorphone, especially in cancer patients suffering from
tions, but these studies were limited to patients that were moderate to severe pain [2]. It is therefore not surprising that
deemed to have advanced illness. Lubiprostone, while dif- there has been an increase in the therapeutic use of opioids in
ferent in its mechanism of action from MNTX and the past decade or so, as it is imperative to manage pain
alvimopan, has proven effective and should be considered reported by patients [3], which includes both cancer-related
and non-cancer (CNCP)-related pain alike. In fact, those pa-
tients who are in their terminal phases of cancer are on opioid
This article is part of the Topical Collection on Neuromuscular
Disorders of the Gastrointestinal Tract
medications greater than 50 % of the time in an effort to
improve their quality of life [4].
A. Sharma It has long been recognized, however, that opiates can
Department of Internal Medicine, University of California Irvine
Medical Center and Medical School, Orange, CA, USA adversely affect many organ systems, most notably the
e-mail: [email protected] gastrointestinal system. These are referred to as the spec-
trum of “opioid induced bowel dysfunction” (OBD) or what
M. M. Jamal (*) we will refer to as “opioid-induced bowel disease” (OIBD)
Long Beach VA Medical Center, University of California Irvine,
Long Beach, CA, USA which include constipation, nausea, vomiting, delayed gas-
e-mail: [email protected] tric emptying and gastro-esophageal reflux disease (GERD),
334, Page 2 of 7 Curr Gastroenterol Rep (2013) 15:334

Table 1 Manifestations Pathophysiology

of opioid-induced bowel Abdominal distention
dysfunction [30, 31] Abdominal growling
When trying to understand OIBD, it is critical to know that
Abdominal mass
there are three different types of opioid receptors that affect
Abdominal pain
the gastrointestinal (GI) system including mu(μ), kappa(κ),
Blood with stool
and delta(δ) receptors. Studies in animals and humans have
Change in abdominal size
revealed endogenous opioids are present in the GI tract and
Change in flatus
inhibit normal gut motility, thus exerting their suppressing
Change in frequency
effects in times of stress or trauma [9, 10]. When these
Decreased appetite
receptors are stimulated by endogenous or exogenous opi-
Dry, hard stool
ates, they reduce neuronal excitability and acetylcholine
Headache
release with an overall inhibitory effect on the neuron [11].
Inability to pass stool
In the GI tract, μ-receptors are widely distributed in the
Increased abdominal pressure submucosa of the stomach and proximal colon as well as
Indigestion in the ileal mucosa where they influence ion transport ex-
Oozing liquid stool change [3]. Interestingly, μ-receptors in the brain are re-
Rectal fullness sponsible for pain perception and can depress respiratory
Rectal mass function. In the gut, however μ-receptors will decrease
Rectal pain with stool bowel motility which leads to a cascade of events that
Rectal pressure culminate in OIBD [12]. Opioid receptor activation in the
Reprinted from Small volume of stool bowel wall interferes with normal contractility, thus
McMilan, with permis- Straining at stool straining the bowel to work harder to move fecal contents.
sion from Cancer Swollen rectal veins While segmental motor tone and contractility were in-
Control
creased, longitudinal propulsive peristalsis was decreased
[13]. This causes increased churning due to delay in gastric
emptying, and increased fluid absorption which dries and
and a newer studied entity known as narcotic bowel syn- hardens the stool [12]. In addition, opiates stimulate absorp-
drome (NBS). We will use the term opioid-induced bowel tion of fluids by stimulating sensory receptors that activate a
disease to include the same spectrum. The most common reflex arc [9, 14]. This cascade of events described above
and debilitating side effect that patients complain of is eventually leads to all symptoms inclusive in OIBD, of
opiate-induced constipation(OIC). Studies show a preva- which the most common cause is constipation. A variety
lence of OIC ranging from 40 to 63 % in cancer- of traditional and more novel treatments are available for
associated hospice patients, and between 41 and 59 % in patients with constipation, with the latter ones logically
non-malignant pain [5, 6]. This change in bowel dysfunction attacking the peripheral opioid receptors.
negatively affects a patient’s quality of daily living and can
essentially lead to more serious undesirable side effects that
cause further morbidity to patients. The spectrum of OIBD OIBD and its Impact on Patients
is often overlooked and not anticipated, leading to delayed
treatment, inefficiency, and excess costs in the healthcare The Internet-based PROBE study that was performed in
system. In addition, it leads to functional and physical January 2006 was designed to assess the impact of OBD in
deterioration of the patient if not sought after and treated patients who were taking opiates for a prolonged period of
[7]. Table 1 summarizes the undesirable effects of opioids time. A total of 322 patients completed the survey, and a
[8]. For this reason, understanding the pathophysiology, majority of them (89 %) had been suffering from their chronic
epidemiology, and available treatment options for OIBD pain condition for over year, and were on 1 or 2 different
will aid the physician’s dilemma; Physicians should be opioid medications. Results showed that 70 % of patients
comfortable with treating significant pain with opiates, but reported having greater than 3 bowel movements per week
more importantly anticipate and treat opioid-induced bowel prior to taking any treatment for their pain. At the time of the
disease. In this review article, we will discuss the current survey, the proportion reporting fewer than 3 bowel move-
burden of OIBD and how it is impacting patients. An ments per week increased to 45 % [15••]. In addition, patients
effective management strategy for OIBD involves a thor- complained of development of other common side effects, of
ough understanding of the pathophysiology, a detailed his- course constipation (81 %) and straining to pass a bowel
tory and physical examination, and effective treatment plan movement (58 %) being the top two. Figure 1 shows the
with the patient. percentage of each side effect along with its frequency.
Curr Gastroenterol Rep (2013) 15:334 Page 3 of 7, 334

Fig. 1 Frequency of the most

common symptoms of OBD
[15••]. (Reprinted from Bell et
al., with permission from
American Academy of Pain)

The impact of OIBD can be supported by Fig. 2, pain, however, also producing substantial negative GI side
which shows at least a moderate negative impact on effects that affect quality of life. These adverse effects can
patients overall quality of life. The symptoms most often even supersede the pain patients are suffering, and cause
reported as having a moderate to severe impact of daily them to discontinue their therapy [16].
living included passing gas, bloating, upper abdominal As patients’ chronic medical conditions continue to be
discomfort reflux, heartburn, and lower abdominal pain treated by opiates, the potential for OIBD can only contin-
[15••]. It should be noted, however, that this study could ue to grow. While patients will continue to develop opioid
be subject to survey bias in that patients were likely tolerance for pain relief, and require increasing doses of
more to respond in those that had a negative impact on opiates, there is little chance that they will develop tole-
their life. rance to OIBD [17]. Thus, patients will continue to report a
Our dilemma as physicians is further accentuated with myriad of GI symptoms as their pain medications are
the evidence that opioids provide improvement for chronic increased.

Fig. 2 Impact of the most

common symptoms of OBD on
ADL. (Reprinted from Bell et
al., with permission from
American Academy of Pain)
334, Page 4 of 7 Curr Gastroenterol Rep (2013) 15:334

and the physician. For example, several studies and

personal experience will tell you that constipation is
indeed the most recognized side effect of opiates, but
do we always try to elicit this history from our patients?
In a study published by McMillan et al., 80 % of
patients had symptoms of constipation, but chart review
only showed that 14 % were evaluated for constipation
on paper [20]. Perhaps patients do not feel it medically
necessary to share such private information or feel that
it is their problem to deal with on their own and not the
physicians’. Regardless, a good and accurate history is
essential to breakdown this barrier.
A high index of suspicion for any OIBD should
Fig. 3 Vicious cycle of patient–physician interaction in NBS. Patient
presents with a pain, either caused by a structural condition (e.g., IBD), follow administration of opiates. Detailed questions
postsurgery, or functional GI disorder and narcotics are started. The concerning patients’ past medical history and current
patient develops symptoms of NBS. Subsequent evaluation is medications will heighten awareness of impending GI
unrevealing and the narcotics are escalated to treat the abdominal pain side effects [13]. Note any recent changes in the stool
with worsening of NBS. This prompts the patient to increase health
care use or make emergency room visits, which leads to physician pattern such as diarrhea alternating with constipation
frustration, leading to a maladaptive therapeutic interaction with addi- with or without abdominal pain. In the elderly or acute-
tional use of narcotics. The cycle continues until the syndrome is ly ill patient, consider assessing increased agitation or
recognized and treatment is initiated. Reprinted from Grunkemeier et altered mental status as a manifestation of constipation
al.
[13]. A thorough physical exam should precede assessing
patient’s ability to swallow and performing an abdominal
Narcotic Bowel Syndrome (NBS) exam, noting any abnormalities.

Narcotic Bowel Syndrome, or NBS, is a subset of OIBD

characterized by chronic or frequently recurring abdominal Current Medical Treatment
pain that worsens with continued or escalating doses of nar-
cotics [18••]. In essence, when abdominal pain is the predom- Laxatives
inant symptom, the condition has been termed NBS. Often,
ironically opiates are initiated in order to treat functional Current non-complex strategies for both preventing and
abdominal pain where it only further contributes to the prob- treating constipation include a variety of laxatives, stool
lem [19]. Although pain is the main feature, there is certain softeners, or a combination thereof [21••].
concomitant overlap with other features of OIBD ranging from
constipation to nausea. The most perplexing feature of NBS is Osmotic Laxatives
recognizing how narcotic analgesics aggravates the pain that is
being treated. There have been three proposed mechanisms, all This class of laxatives work by exerting their osmotic effects
of which account for opioid tolerance and pain (Fig. 3). pulling water into the gut lumen. Thus, they are not
NBS introduces a new meaning to physicians’ dilemma in absorbed into the gut and can cause the uncomfortable side
that it requires not only a good index of clinical suspicion, but effect of abdominal distention and cramps [13]. Examples
a great relationship with the patient to convince them that include lactulose, sorbitol, and magnesium citrate to name a
opioids are not the answer, but the root of the problem. few, but clinicians should pay particular attention to electro-
Treatment beyond a good patient–physician relationship en- lyte abnormalities that can occur with administration of
tails a disciplined narcotic withdrawal protocol, along with these drugs.
antidepressants (TCA, SSRI), anxiolytics (benzodiazepines),
sympatholytics (clonidine), and psychological adjuncts form Stimulant Laxatives
great concomitant treatment strategies [18••].
These class of drugs actually induce colonic contractions,
possibly counteracting the effects of opiates on decreased
Assessment of Opioid-Induced Bowel Disease peristalsis [17]. Examples include bisacodyl and senna, and
are usually used for short-term therapy, but could be used in
Despite the GI side effects of opioids being well combination with stool softeners (docusate) for more long-
known, there is a disconnect between both the patient term and effective use.
Curr Gastroenterol Rep (2013) 15:334 Page 5 of 7, 334

100 Placebo

Cumulative Percentage of
Bulk-Forming Laxatives

Patients With First SBM

90 Lubiprostone 24 µg BID
P=0.022
80 70.7
Median times
This class includes indigestible fibers which form bulk by 70
Placebo, 38.5 h P=0.016 60.4
60
attracting luminal water and increase stool bulk, allowing 50
Lubiprostone, 24.3 h 49.0
P=0.019
for better passage of the stool. Examples include psyllium, 40 P=0.021
37.8

polyethylene glycol, and cellulose. It should be noted that 30 P=0.002 P=0.017 22.5
20 13.3 16.0 14.1
they are likely not appropriate for patients with opioid- 5.0 8.6
10
induced constipation since opiates inhibit colonic peristalsis 0
4 8 12 24 48
and increasing stool bulk can lead to painful symptoms and
Time After First Dose, h
possibly obstruction [22].
Fig. 4 Response to first SBM with lubiprostone compared to placebo.
Opioid Antagonists This shows significant response at 4, 8, 12, 24, and 48 h [29]. Reprinted
from Jamal et al.
Because of the knowledge of the effect opiates have on
μ-receptors, a newer class of drugs has been studied and A follow-up study examined the dose of 0.15 mg/kg
is available for use against OBD. Drugs of this class are which was administered then every other day and the re-
known as peripherally acting μ-opioid receptor antago- sponse in the MNTX group showed laxation within 4 h as
nists (PAMORAs) which selectively block μ-receptors compared to the placebo group [26]. Overall, more than
outside of the CNS [8]. The initial drug of this class 75 % of the patients responded to one of the first three doses
was naloxone; however, trials involving naloxone proved and the median time to response was 30 min [8].
that this drug acts both centrally and peripherally. Methylnaltrexone is typically given every other day as a
Naloxone not only reversed constipation but also re- subcutaneous injection as needed to induce a bowel move-
versed the analgesic effects of opioids and hastened ment, rarely exceeding once every 24 h. The dose is 8 mg
withdrawal [23, 24]. In the USA, two PAMORAS have for patients weighing 84 to less than 136 lb (38 to less than
been approved by the US Food and Drug Administration 62 kg) and 12 mg for patients weighing 136–251 lb (62–
(FDA) for treatment of opioid-induced bowel disease in 114 kg), otherwise we suggest the standard 0.15 mg/kg for
patients whose response from laxatives are poor, as long less than 84 kg [27]. Certainly, further studies are needed to
as they did not have compromised bowel integrity or identify the optimal dosing of methylnaltrexone and stratify
obstruction. based on advanced illness, cancer, and other non-cancer-
associated pain opioid induced bowel disease.
Methylnaltrexone
Alvimopan
In the past decade, methylnaltrexone (MNTX) has been
extensively studied and results from clinical trials have Alvimopan is also an orally administered peripherally acting
proved this drug to be effective. In a study conducted by opioid antagonist, without reversing analgesia and or
Thomas et al., the proportion of patients who had rescue- prompting opioid withdrawal. It has been used primarily in
free laxation within 4 h after receiving the first dose of the postsurgical patients and not yet approved for OIC; howev-
study drug was 48 % in the methyl naltrexone group, as er, emerging evidence is proving its medical utility. In a
compared with 15 % in the placebo group; similarly, signif- study involving 522 patients on opioids for non-cancer pain,
icantly more patients in the methylnaltrexone group had alvimopan demonstrated a significant dose response to re-
rescue-free laxation (defecation) within 4 h after two or ducing OBD compared to placebo: 54, 43, and 29 % of
more of the first four doses, as compared with the placebo patients demonstrated laxation within 8 h after alvimopan 1,
group (P<0.001 for both comparisons) [21••]. In a double- 0.5 mg, or placebo, respectively (P<0.001) [28].
blind study of patients with advanced illnesses on palliative
care with opioid-induced constipation, MNTX was admin- Lubiprostone
istered. Patients were given 1, 5, and 12.5 mg subcuta-
neously and time to laxation was measured. The median Lubiprostone is an orally active drug that activates ClC-2
time to laxation was >48 h for the 1-mg dose group, com- chloride channels to enhance intestinal fluid secretion and
pared to 1.26 h for all patients receiving ≥5 mg (P=0.0003) motility [29]. This drug was recently tested among patients
[25]. There was no apparent dose response above 5 mg. This with chronic non-cancer pain and with a diagnosis of OIC,
study helps elucidate the effective dose of which MNTX and it carefully excluded patients who were on confounding
should be given, but these studies were performed on pa- medications (anticholinergics, TCA, laxatives, etc.). The
tients with advanced illness. results showed that the median time to first spontaneous
334, Page 6 of 7 Curr Gastroenterol Rep (2013) 15:334

bowel movement (SBM) was significantly shorter with antagonists for example in the treatment of non-opiate in-
lubiprostone versus placebo (24.3 vs. 38.5 h, respectively), duced constipation has not yet been fully assessed [26].
with a significantly higher proportion of patients treated Lubiprostone has shown promise in its safety and efficacy
with lubiprostone reporting bowel movements within less for CNCP-induced OIBD, but perhaps further studies are
than 48 h of the first dose (see Fig. 4) [29]. Lubiprostone 24 needed to evaluate this with OIBD in patients being treated
mcg BID for the treatment of OIBD was well tolerated and for cancer. Further investigational research will promulgate
exhibited a rapid and safe response, making this a feasible more information and allow for better and more efficient
option. Thus, to date, it is the only oral medication for treatment options for OIBD.
treating OIBD and further studies should elucidate its
effectiveness. Compliance with Ethics Guidelines

Conflict of Interest Ankush Sharma declares that he has no conflict

of interest.
Discussion M. Mazen Jamal declares that he has no conflict of interest.

Opioid analgesics are increasingly being used for the treat- Human and Animal Rights and Informed Consent This article
does not contain any studies with human or animal subjects performed
ment of cancer pain, non-cancer-associated pain, and post- by any of the authors.
operative pain. As we achieve our goals towards pain con-
trol, we need to be cognizant and competent on how to
prevent and treat OIBD. The basis is due in part to μ-
receptor activation, decreasing the persistaltic contraction References
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