1. health and fitness
2. disease
3. chronic pain

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SEPTEMBER 2013
REPORT
Management of Opioid-Induced
Constipation in Patients
With Advanced Illness
of pain related to tumor enlargeoderate to severe pain is a
ment, metastasis or, as another
common clinical problem
Faculty
example, neuropathic pain in the
among patients with advanced illsetting of diabetes mellitus. Other
ness, particularly in the palliative
Darren Brenner, MD
times, the pain may be iatrogenic
care setting. Although cancer pain
Assistant Professor of Gastroenterology
in etiology, such as complicahas historically received the most
and Hepatology
tions related to radiation therapy
attention, patients with AIDS,
Northwestern University Feinberg
for the treatment of cancers, or
advanced congestive heart failure,
School of Medicine
neuropathy induced by antiretroand advanced lung disease also
Chicago, Illinois
viral or chemotherapeutic agents.
commonly experience pain.1
Unfortunately, the prevalence of
“When we look at patients with
Joseph Pergolizzi, MD
pain is quite high in the palliative
advanced illness, pain is one of
Adjunct Associate Professor of
care setting.”
the most prevalent symptoms
Pharmacology
In fact, a meta-analysis of
that patients report,” said Joseph
Temple University School of Medicine
studies published during the
Pergolizzi, MD, adjunct associate
Philadelphia, Pennsylvania
past 40 years found that 64%
professor of pharmacology, Temof patients with advanced-stage
ple University School of Medicine
cancer reported significant pain
in Philadelphia, Pennsylvania.
in their daily lives.2 Another review, which included patients
“This pain can arise due to the illness itself, such as in cases
M
Indication
®
RELISTOR is indicated for the treatment of opioidinduced constipation in patients with advanced illness
who are receiving palliative care, when response to laxative therapy has not been sufficient. Use of RELISTOR
beyond four months has not been studied.
Contraindications
RELISTOR is contraindicated in patients with known
or suspected mechanical gastrointestinal obstructions.
Please see Important Safety Information throughout
and brief summary of Prescribing Information on
page 12.
Supported by
REPORT
with advanced illnesses such as cancer, AIDS, heart disease,
chronic obstructive pulmonary disease (COPD), and renal disease
reported that the prevalence of pain across 28 studies ranged
between 34% and 96%.3 Moreover, the prevalence of pain
among patients receiving hospice care may be as high as 90%.4
“The severity of pain has an important influence in the choice
of treatment strategy,” Dr. Pergolizzi explained. “When patients
report moderate to severe pain, that’s where we really rely on
the opioids. In fact, escalating doses of opioids are oftentimes
the only effective option for pain control in advanced disease.”
This notion is endorsed by guidelines from several major societies in the United States, such as the American College of Physicians and the National Comprehensive Cancer Network, which
recommend that opioids should be used for the treatment of
moderate to severe pain in patients with advanced illness.5,6
Opioids, however, are associated with numerous adverse
events (AEs), including nausea, sedation, pruritus, and respiratory depression.5,7 Perhaps the most common opioid AEs are
those affecting the gastrointestinal (GI) tract, including opioidinduced constipation (OIC).8-10 The following report provides
an overview of OIC, including a review of its epidemiology,
risk factors, and how its pathophysiology and management
differ from that of primary constipation, as well as a review
of data for recently approved options for the management of
this condition.
Pathophysiology of OIC
Darren Brenner, MD, assistant professor of gastroenterology and hepatology, Northwestern University Feinberg
School of Medicine in Chicago, Illinois, noted that, “in terms
of pathophysiology, OIC is quite distinct from other forms of
constipation.” For example, physiologic constipation results
from extrinsic, non–disease-related factors that affect bowel
function, such as decreased physical activity and inadequate dietary fiber and fluid intake. These factors may cause
decreased bowel motility and increased transit time, which
allows more time for fluid resorption in the intestinal lumen,
leading to hard and dry stools.9 In other cases, constipation
may result from pathologic conditions in the setting of underlying GI, nervous system, or metabolic disorders that interfere
with GI motility or fluid absorption/secretion.9,11
“In contrast, OIC is mediated by the effect of opioids on
opioid receptors that are located throughout the GI tract and
the enteric nervous system,” said Dr. Brenner. The 3 major
opioid receptors in the enteric nervous system are the μ-, γ-,
and κ-subtypes.12 The μ-receptors are widely distributed in
the GI tract submucosa as well as the ileal mucosa, where
they influence ion transport changes.12 The primary mediator involved in the development of OIC is the μ-opioid receptor; inhibition of excitatory and inhibitory neurotransmitters
occurs when opioid agonists bind to this receptor, causing
multiple effects that contribute to OIC.7,13,14 These include
inhibition of gastric emptying, reduction of mucosal secretions, and a decrease in peristalsis throughout the GI tract,
thereby delaying transit.14,15
Furthermore, opioids stimulate non-propulsive motility,
intestinal segmentation and tone, and increased pyloric and
ileocecal sphincter tone. Opioids also result in increased
absorption of fluids, mainly by delayed transit—increasing contact time for absorption—and by stimulating mucosal sensory
receptors that activate a reflex arc that facilitates further fluid
absorption.14 All of these pathophysiologic processes conspire
to result in hard, dense stools and decreased motility, resulting in significant constipation14 that may be refractory to traditional strategies used to alleviate constipation.15
“Patients with advanced illness also may have autonomic
dysfunction leading to GI motility disorders. For example, HIV
affects local humoral immunity and causes motility disturbances
via its influence on autonomic nerves,” said Dr. Pergolizzi.
“Using opioids for any treatment [in patients with advanced
illness] is going to be detrimental to the GI tract given the
plethora of μ-opioid receptors located across the entire intestinal lining,” said Dr. Brenner. “However, treatment guidelines
still rely on opioids for the treatment of moderate to severe
pain, and I don’t see that changing any time soon. So the best
thing we can do is develop strategies to overcome adverse GI
events related to their use.”
Nonselective opioid-receptor antagonists such as naloxone and naltrexone target the μ-, γ-, and κ-opioid receptors,
which led to interest in their use for opioid therapy.15 However,
both agents can cross the blood–brain barrier and antagonize receptors that mediate the analgesic effect of opioids.12,16
Important Safety Information
RELISTOR ® (methylnaltrexone bromide) Subcutaneous
Injection is contraindicated in patients with known or suspected
mechanical gastrointestinal obstruction.
If severe or persistent diarrhea occurs during treatment,
advise patients to discontinue therapy with RELISTOR and
consult their physician.
Rare cases of gastrointestinal (GI) perforation have been
2
reported in advanced illness patients with conditions that may
be associated with localized or diffuse reduction of structural
integrity in the wall of the GI tract (ie, cancer, peptic ulcer,
Ogilvie’s syndrome). Perforations have involved varying regions
of the GI tract (eg, stomach, duodenum, colon). Use RELISTOR
with caution in patients with known or suspected lesions of the
GI tract. Advise patients to discontinue therapy with RELISTOR
REPORT
“The last thing that we want to do in the palliative care setting is to reduce the analgesic effects of our opioids, because
our primary goal is to reduce pain in these patients,” said
Dr. Pergolizzi.
Epidemiology and Consequences of OIC
OIC is an anticipated side effect of opioid therapy. Its overall relevance to the clinical community continues to increase,
mainly because of the rising therapeutic use of opioids.17 For
example, OIC rates in patients receiving cancer treatment
and opioids can range from 69% to 90%,18,19 and studies of
patients with advanced cancer who are receiving hospice care
report rates as high as 87%.20 Additionally, among individuals with advanced illnesses other than cancer who are receiving opioid therapy, the prevalence of opioid-induced GI AEs
approaches 90%.21
“In the palliative care patient with advanced disease, we
are more aggressive in the use of opioids to reduce pain with
the goal of comfort,” said Dr. Pergolizzi. “Although we try to
balance the role of analgesic-related side effects, oftentimes,
relief of pain is more important for these patients. As such,
we typically use higher dose of opioids, which results in more
adverse effects.”
Risk factors for OIC include advanced age, opioid type/
strength, and advanced illness (eg, cancer, AIDS, or cardiovascular disease).18,20,21 Furthermore, the risk for OIC increases
with relative immobility, dehydration, and altered nutritional
intake, all of which are common in patients with advanced illnesses, particularly in the palliative care setting.21 Although
patients may slowly acquire a tolerance to opioid-related
side effects such as nausea or sedation, OIC may continue
unabated throughout treatment.21
Dr. Pergolizzi said that there are several notable consequences of OIC. “First, OIC can result in other GI symptoms,
including nausea and vomiting and a decreased ability to take
in oral medications and nutrients. Second, if patients have no
remedy to relieve the symptoms and complications of OIC as
an outpatient, they really have no other option than to come
to the emergency department to be evaluated. In some cases,
the symptomatology and consequences of OIC are sufficiently severe to warrant hospitalization for more aggressive
interventions,” he said. “When you consider the patient with
advanced illness, especially those in the palliative care setting,
they would really rather not be hospitalized provided they have
some option to adequately relieve OIC at home.”
The consequences of OIC are diverse and significant. Clinical manifestations include abdominal pain, distension, and
nausea and vomiting.9 When left untreated, OIC may lead to
inadequate absorption of oral medications, fecal impaction,
hemorrhoids, bowel obstruction, and intestinal perforation.9
“There is a vicious circle that exists between opioid use for
the relief of pain and the subsequent pain and discomfort that
can result from the development of secondary constipation,”
said Dr. Pergolizzi. “Specifically, patients are given opioids to
relieve the primary pain related to their advanced illness but
end up developing OIC, which can, itself, be a painful condition. [When laxative agents provide insufficient relief,] patients
are then faced with the choice of either refraining from further
opioid therapy to relieve OIC, in which case the pain from their
primary condition is not adequately treated, or taking larger
doses of opioids and potentially worsening the pain associated with OIC.”
Treatment of OIC in Advanced Illness
Physiologic constipation is typically managed through a
combination of behavioral strategies and the use of agents
designed to increase stool bulk, improve intestinal motility, and/
or aid the passage of stools through softening agents.9 Supportive strategies include increased hydration and improved
patient mobilization—which can be difficult for patients with
advanced illness—along with addressing the etiologic triggers
of constipation.9
Laxatives are the first-line therapeutic option for OIC, and the
various classes of laxative agents used to relieve physiologic
mechanisms of constipation are summarized in Table 1.22,23
However, data from clinical trials suggest that conventional
laxatives (eg, over-the-counter laxatives, polyethylene glycol,
lactulose, magnesium citrate) may not offer adequate symptom relief for some patients.15,21
As reviewed in the section on the pathophysiology of different types of constipation, OIC in advanced illness is unique
from other forms of constipation. “When we look at laxatives
Important Safety Information (continued)
and promptly notify their physician if they develop severe,
persistent, and/or worsening abdominal symptoms.
Use of RELISTOR has not been studied in patients with
peritoneal catheters.
Use of RELISTOR beyond four months has not been studied.
Safety and efficacy of RELISTOR have not been established
in pediatric patients.
The most common adverse reactions reported with
RELISTOR compared with placebo in clinical trials were
abdominal pain (28.5%), flatulence (13.3%), nausea (11.5%),
dizziness (7.3%), diarrhea (5.5%), and hyperhidrosis (6.7%).
Please see Important Safety Information throughout and
brief summary of Prescribing Information on page 12.
3
REPORT
Table 1. Conventional Laxative Options for Opioid-Induced Constipation in Advanced Illness
Type
Attributes
Examples
Side Effects/Complications
Bulk laxatives
Dietary fiber; causes water
retention in the colon and
increases stool bulk
Psyllium husk,
methylcellulose
Increased gas; risk for bowel
obstruction in patients with
strictures
Osmotic laxatives
Salt content retains fluid
retention and increased
intestinal secretions
Sorbitol, lactulose,
polyethylene glycol,
magnesium citrate
Electrolyte imbalances;
increased gas, nausea,
and dehydration
Stool softeners
Decrease surface tension
to lubricate and soften
fecal matter
Dioctyl sodium, calcium
sulfosuccinate
Require adequate fluid
intake, useless in patients with
compromised bowel motility
Stimulants
Increase colonic motility
and electrolyte transport;
stimulate fluid secretion
Senna, cascara,
bisacodyl
Electrolyte imbalances;
abdominal pain, nausea,
and colonic dysmotility
From references 22 and 23.
and stool softeners, we see dramatic variability in terms of the
response to such agents across our patient populations. A lot
of that has to do with the specific mechanisms of constipation,
particularly in patients with OIC,” said Dr. Pergolizzi.
Another strategy that has been recommended to relieve AEs
while maintaining analgesia is that of opioid rotation.5,24 This
tactic is predicated on the fact that patients react differently to
various types of opioids, which implies both incomplete crosstolerance and distinct variations in their pharmacodynamics
and opioid-receptor binding affinities.24,25 However, this strategy has shown only moderate benefits in the reduction of OIC
and other related AEs. Narabayashi and colleagues investigated the safety of an opioid rotation in cancer patients and
found that side effects commonly recurred after switching from
one agent to another.26 There also are therapeutic equivalence
concerns when switching from one opioid to another. Current
recommendations are based on studies conducted within different patient populations that analyzed dose equivalency, not
pain management.24,25
The relative ineffectiveness of traditional strategies for OIC
has prompted research and development of targeted therapies, as some patients require additional therapeutic options.
Important Safety Information
RELISTOR ® (methylnaltrexone bromide) Subcutaneous
Injection is contraindicated in patients with known or suspected
mechanical gastrointestinal obstruction.
If severe or persistent diarrhea occurs during treatment,
advise patients to discontinue therapy with RELISTOR and
consult their physician.
Rare cases of gastrointestinal (GI) perforation have been
4
reported in advanced illness patients with conditions that may
be associated with localized or diffuse reduction of structural
integrity in the wall of the GI tract (ie, cancer, peptic ulcer,
Ogilvie’s syndrome). Perforations have involved varying regions
of the GI tract (eg, stomach, duodenum, colon). Use RELISTOR
with caution in patients with known or suspected lesions of the
GI tract. Advise patients to discontinue therapy with RELISTOR
REPORT
Blood-Brain Barrier
Opioid
RELISTOR
Mu-opioid
μ-opioid
receptor
receptor
Figure 1. Relistor inhibits opioids from
m binding with μ-receptors in tissues such as the gastrointes
gastrointestinal tract.
“Until recently, the only agents available were
ere those being
used to treat the more typical types of constipation—bulknstipation—bulking agents, osmotic and stimulant laxatives,” said Dr. Brenner.
“Now we’re moving into an era where we’re developing [second-line] agents that focus on the precise pathophysiologic
mechanisms of OIC to provide specific and effective antidotes.”
Peripheral Opioid-Receptor Antagonists
The limitations of nonselective opioid antagonists have
prompted the development of agents that do not cross
the blood–brain barrier. These agents ideally would avoid the
of opioidanalgesic-dampening and opioid-withdrawal effects
ef
receptor antagonists while maintaining therapeutic
efficacy for
therape
the alleviation of OIC.15
N-methylation of naltrexone results in a charged derivative,
methylnaltrexone (Relistor, Salix Pharmaceuticals), which has
restricted ability to cross the blood–brain barrier in humans
because of its polarity and low lipid solubility.27 Relistor antagonizes μ-opioid receptors, which reverses opioid-induced
delays on GI motility in a dose-dependent manner.27 Figure 1
shows Relistor blocking opioids from binding to μ-receptors
within the GI tract.
Important Safety Information (continued)
and promptly notify their physician if they develop severe,
persistent, and/or worsening abdominal symptoms.
Use of RELISTOR has not been studied in patients with
peritoneal catheters.
Use of RELISTOR beyond four months has not been studied.
Safety and efficacy of RELISTOR have not been established
in pediatric patients.
The most common adverse reactions reported with
RELISTOR compared with placebo in clinical trials were
abdominal pain (28.5%), flatulence (13.3%), nausea (11.5%),
dizziness (7.3%), diarrhea (5.5%), and hyperhidrosis (6.7%).
Please see Important Safety Information throughout and
brief summary of Prescribing Information on page 12.
5
REPORT
Placebo
80
RELISTOR 0.15 mg/kg
70
62%
a
58% a
Patients, %
60
RELISTOR 0.30 mg/kg
48% a
50
40
30
20
16%
14%
10
0
(n=52)
(n=47)
(n=55)
Study 1
(n=71)
(n=62)
Study 2
Figure 2. Laxation response rates within 4 hours of the first dose during clinical trials of Relistor in
patients with advanced illness.
a
P<0.0001 vs placebo
From reference 27.
The efficacy and safety of Relistor for OIC in patients with
advanced illness were investigated in 2 clinical trials (Figure 2).27
Slatkin and colleagues conducted a randomized double-blind,
placebo-controlled trial that compared a single subcutaneous
injection of Relistor (0.15 mg/kg or 0.30 mg/kg) with placebo
for OIC.21 The study included 154 patients with advanced illness such as cancer or other end-stage conditions (eg, cardiovascular disease, HIV/AIDS) who were receiving palliative
care.21 Participants had received opioid therapy for at least
3 days before study randomization and had not experienced a
bowel movement within 48 hours of the first dose.21
Within 4 hours of treatment, laxation response rates for
Relistor doses of 0.15 mg/kg (n=47) and 0.30 mg/kg (n=55)
were 61.7% and 58.2%, respectively, compared with 14%
for placebo (P<0.0001). In fact, roughly half of the Relistor
responders defecated within 30 minutes of receiving the
agent.21 Within 24 hours, laxation rates remained steady for
0.15 mg/kg Relistor (68.1%) and 0.30 mg/kg Relistor (63.6%)
compared with placebo (26.9%).21
The investigators reported comparable efficacy between
both doses of Relistor, but patients in the 0.30 mg/kg treatment
arm had higher rates of abdominal pain (38.2% vs 27.7%).21
Important Safety Information
RELISTOR ® (methylnaltrexone bromide) Subcutaneous
Injection is contraindicated in patients with known or suspected
mechanical gastrointestinal obstruction.
If severe or persistent diarrhea occurs during treatment,
advise patients to discontinue therapy with RELISTOR and
consult their physician.
Rare cases of gastrointestinal (GI) perforation have been
6
reported in advanced illness patients with conditions that may
be associated with localized or diffuse reduction of structural
integrity in the wall of the GI tract (ie, cancer, peptic ulcer,
Ogilvie’s syndrome). Perforations have involved varying regions
of the GI tract (eg, stomach, duodenum, colon). Use RELISTOR
with caution in patients with known or suspected lesions of the
GI tract. Advise patients to discontinue therapy with RELISTOR
REPORT
Table 2. Common Adverse Reactions Associated With Relistor During Clinical Trials in Patients
With Advanced Illness
RELISTOR a
(n=165)
Placebo
(n=123)
Pts (%)
Pts (%)
Abdominal pain
47 (28.5)
12 (9.8)
Flatulence
22 (13.3)
7 (5.7)
Nausea
19 (11.5)
6 (4.9)
Dizziness
12 (7.3)
3 (2.4)
Diarrhea
9 (5.5)
3 (2.4)
Hyperhidrosis
11 (6.7)
8 (6.5)
Adverse Reaction
a
Includes doses of 0.075, 0.15, and 0.30 mg/kg
From reference 27.
Other common AEs related to Relistor during this trial in the
0.15 mg/kg and 0.30 mg/kg treatment arms were flatulence
(12.8% and 14.5%), nausea (4.3% and 14.5%), and dizziness
(4.3% and 9.1%).21
In a similar study by Thomas and colleagues, 133 patients
who had received opioids for at least 2 weeks and developed
OIC that was refractory to the use of laxatives were randomly
assigned to receive subcutaneous Relistor (0.15 mg/kg; n=63) or
placebo (n=71) every other day for 2 weeks.28 Participants were
recruited from palliative care settings and had advanced illness
such as cancer, cardiovascular disease, COPD, emphysema,
Alzheimer’s disease, or dementia.28 The proportion of patients
who experienced laxation within 4 hours was significantly higher
in the Relistor group than in the placebo group (48% vs 15%,
respectively; P<0.0001).28 Additionally, the median time to laxation after the first dose was significantly shorter in the Relistor
group than in the placebo group (6.3 vs 48 hours, respectively;
P<0.002).28 The most common AEs related to Relistor during
this trial were abdominal pain (17%), flatulence (13%), nausea
(11%), increased body temperature (8%), and dizziness (8%).28
The study by Thomas and colleagues also included an
open-label extension in which patients received Relistor as
Important Safety Information (continued)
and promptly notify their physician if they develop severe,
persistent, and/or worsening abdominal symptoms.
Use of RELISTOR has not been studied in patients with
peritoneal catheters.
Use of RELISTOR beyond four months has not been studied.
Safety and efficacy of RELISTOR have not been established
in pediatric patients.
The most common adverse reactions reported with
RELISTOR compared with placebo in clinical trials were
abdominal pain (28.5%), flatulence (13.3%), nausea (11.5%),
dizziness (7.3%), diarrhea (5.5%), and hyperhidrosis (6.7%).
Please see Important Safety Information throughout and
brief summary of Prescribing Information on page 12.
7
REPORT
needed each day for 3 months. A total of 89 patients entered
this phase of the trial (47 from the Relistor group, 42 from
the placebo group).28 By the end of the 3-month extension,
patients from the placebo group improved their rescuefree response rates from 11% to 52%; patients from the initial Relistor group improved their response rates from 45%
to 57%.28 Median time to laxation for all patients was less
than 45 minutes.28 The most common AEs during this phase
were abdominal pain (30%), progression of malignant neoplasm (24%), nausea (21%), and vomiting (20%). Serious AEs
related to Relistor were muscle spasms (1 patient) and exacerbated pain (1 patient); 32 deaths occurred, with all attributed
to underlying disease.28
In both the Slatkin and Thomas studies, participants were
permitted to continue their previously initiated laxative therapy,
just not within 4 hours of study treatments. Figure 2 provides
laxation rates from the 2 clinical trials of Relistor within 4 hours
of the first dose.27
“In the 2 pivotal trials, the clinical benefit associated with
the fact that methylnaltrexone does not cross the blood–brain
barrier was confirmed by observations showing there was no
analgesic-stealing effect,” said Dr. Pergolizzi. Indeed, in both
trials there was no change in pain scores or evidence of central-opioid withdrawal in response to Relistor.21,28
Abdominal pain and flatulence were the most common AEs
attributed to Relistor during the 2 clinical trials (Table 2).27 A
post hoc analysis of abdominal pain rates during these studies found that it consisted primarily of abdominal cramping and
did not affect patients’ overall evaluation of pain.29 These AEs
were mostly mild to moderate in severity and did not affect
patients’ global evaluation of pain. The incidence of abdominal
pain in Relistor-treated patients was highest following the first
dose and it decreased with subsequent doses.29 Of note, rare
postmarketing cases of GI perforation have been reported in
association with Relistor, particularly in patients with abnormal
structural integrity in the walls of the GI tract, such as those
with cancer, peptic ulcer, or Ogilvie’s syndrome. As a result,
the prescribing information includes a warning that Relistor
should be used with caution in patients with a known or suspected GI tract lesions.27
On the basis of these trials, in 2008 the FDA approved
the use of Relistor for the treatment of OIC in patients with
advanced illness who are receiving palliative care, when
response to laxative therapy has not been sufficient. 27
Relistor is administered as a subcutaneous injection, and a
typical schedule is 1 dose every other day as needed, but
not to exceed more than 1 dose in a 24-hour period.27 Use of
Relistor beyond 4 months has not been studied.
The recommended dose of Relistor is 8 mg for patients who
weigh between 38 and 61 kg; 12 mg for patients who weigh
between 62 and 114 kg; and 0.15 mg/kg for patients who fall
outside of these weight ranges.27 Only patients who require an
8- or 12-mg dose should be prescribed prefilled syringes. No
dose adjustment is required in patients with mild or moderate
renal impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min), dose reductions of Relistor by
one half are recommended.27 If severe or persistent diarrhea
occurs during treatment, patients should discontinue therapy
with Relistor and consult their physician. If patients develop
severe, persistent, and/or worsening abdominal symptoms,
they should discontinue therapy with Relistor and promptly
notify their physician. Use of Relistor has not been studied in
patients with peritoneal catheters.
Dr. Pergolizzi views subcutaneous Relistor administration
as one of several unique advantages. “The fact that we can
administer this agent via the subcutaneous route in patients
undergoing palliative care is important, as many of these
patients are unable to take in medications by mouth due to
nausea, dysphagia, or decreased levels of consciousness. OIC
itself can also cause significant nausea and may preclude oral
medication intake for some patients,” he said.
Treatment Algorithm for Opioid-Induced
Constipation in Advanced Illness
With the approval of Relistor for the treatment of OIC in
patients with advanced illness who are receiving palliative care
when laxative therapy has not been sufficient, Drs. Brenner
and Pergolizzi discussed the current landscape and clinical
management of OIC in patients with advanced illness, including a potential treatment algorithm (Figure 3).
“According to the FDA-approved labeling, methylnaltrexone is indicated for the second-line treatment of OIC. Therefore, the first step for patients with OIC will still be a trial of
Important Safety Information
RELISTOR ® (methylnaltrexone bromide) Subcutaneous
Injection is contraindicated in patients with known or suspected
mechanical gastrointestinal obstruction.
If severe or persistent diarrhea occurs during treatment,
advise patients to discontinue therapy with RELISTOR and
consult their physician.
Rare cases of gastrointestinal (GI) perforation have been
8
reported in advanced illness patients with conditions that may
be associated with localized or diffuse reduction of structural
integrity in the wall of the GI tract (ie, cancer, peptic ulcer,
Ogilvie’s syndrome). Perforations have involved varying regions
of the GI tract (eg, stomach, duodenum, colon). Use RELISTOR
with caution in patients with known or suspected lesions of the
GI tract. Advise patients to discontinue therapy with RELISTOR
REPORT
OIC in a patient with advanced
illness undergoing
palliative care
ª
Trial of oral first-line laxative agent
ª
Nonresponse or insufficient response
ª
Relistor Trial
Subcutaneous injection every other day, as needed,
but no more frequently than 1 dose in a 24-h period
Approved doses:
• 8 mg for patients weighing 38-61 kg
• 12 mg for patients weighing 62-114 kg
• 0.15 mg/kg for patients whose weight falls
outside of these ranges
ª
the traditional laxative therapies. For patients who fail to have
a response to the traditional agents, you would proceed to
methylnaltrexone. The mechanism of action for methylnaltrexone is well-suited for the treatment of OIC, so if the patient
describes a clinical history in which they had regular bowel
movements then developed constipation after initiation of opioid therapy, I would use methylnaltrexone,” said Dr. Pergolizzi.
“Methylnaltrexone is indicated to be used when other laxatives have failed. But if a patient has a clear history of OIC
[and hasn’t responded to first-line therapies], I wouldn’t spend
a great deal of time switching from one laxative to another
before prescribing methylnaltrexone,” said Dr. Brenner.
According to Dr. Pergolizzi, determining the success of laxative therapy is, thankfully, not all that difficult. “When prescribing medications for the treatment of OIC, you have an easy,
objective end point to follow: Has the patient had symptomatic relief in terms of a bowel movement or not? Methylnaltrexone offers a predictable and rapid response in the majority of
patients with OIC,” he said.
Conclusion
OIC is a highly prevalent side effect of opioid therapy. The
pathophysiology of OIC is unique from that of physiologic constipation or constipation due to primary GI, neurologic, or metabolic conditions. Conventional therapies may be ineffective in
restoring normal bowel function in patients with OIC. Relistor is
an effective second-line therapy and initial prescription option
for the treatment of OIC in patients with advanced illness who
are receiving palliative care.
Nonresponse or insufficient response
ª
Rescue therapy
(ie, enemas, manual disimpaction)
Figure 3. Faculty-proposed treatment
algorithm for OIC in advanced illness.
OIC, opioid-induced constipation
Important Safety Information about
RELISTOR
RELISTOR ® (methylnaltrexone bromide) Subcutaneous
Injection is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.
If severe or persistent diarrhea occurs during treatment,
advise patients to discontinue therapy with RELISTOR and
consult their physician.
Rare cases of gastrointestinal (GI) perforation have been
reported in advanced illness patients with conditions that may
Important Safety Information (continued)
and promptly notify their physician if they develop severe,
persistent, and/or worsening abdominal symptoms.
Use of RELISTOR has not been studied in patients with
peritoneal catheters.
Use of RELISTOR beyond four months has not been studied.
Safety and efficacy of RELISTOR have not been established
in pediatric patients.
The most common adverse reactions reported with
RELISTOR compared with placebo in clinical trials were
abdominal pain (28.5%), flatulence (13.3%), nausea (11.5%),
dizziness (7.3%), diarrhea (5.5%), and hyperhidrosis (6.7%).
Please see Important Safety Information throughout and
brief summary of Prescribing Information on page 12.
9
REPORT
be associated with localized or diffuse reduction of structural
integrity in the wall of the GI tract (ie, cancer, peptic ulcer, Ogilvie’s syndrome). Perforations have involved varying regions of
the GI tract (eg, stomach, duodenum, colon). Use RELISTOR
with caution in patients with known or suspected lesions of the
GI tract. Advise patients to discontinue therapy with RELISTOR
and promptly notify their physician if they develop severe, persistent, and/or worsening abdominal symptoms.
Use of RELISTOR has not been studied in patients with
peritoneal catheters.
Use of RELISTOR beyond four months has not been studied.
Safety and efficacy of RELISTOR have not been established
in pediatric patients.
The most common adverse reactions reported with
RELISTOR compared with placebo in clinical trials were
abdominal pain (28.5%), flatulence (13.3%), nausea (11.5%),
dizziness (7.3%), diarrhea (5.5%), and hyperhidrosis (6.7%).
References
8.
Glare P, Walsh D, Sheehan D. The adverse effects of
morphine: a prospective survey of common symptoms
during repeated dosing for chronic cancer pain. Am J
Hosp Palliat Med. 2006;23(3):229-235.
9.
Mancini I, Bruera E. Constipation in advanced cancer
patients. Support Care Cancer. 1998;6(4):356-364.
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van den Beuken-van Everdingen MH, de Rijke JM,
Kessels AG, et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol.
2007;18(9):1437-1449.
3.
Solano JP, Gomes B, Higginson IJ. A comparison of
symptom prevalence in far advanced cancer, AIDS, heart
disease, chronic obstructive pulmonary disorder, and renal
disease. J Pain Symptom Manage. 2006;31(1):58-69.
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Fine PG, Portenoy RK. Opioid therapy in advanced medical
illness. In: William Roberts, Colleen Sauber, eds. A Clinical
Guide to Opioid Analgesia. New York, NY: McGraw-Hill;
2004:115-120.
Kutner JS, Kassner CT, Nowels DE. Symptom prevalence
at the end of life: hospice providers’ perceptions. J Pain
Symptom Manage. 2001;21(6):473-480.
Swarm R, Abernethy AP, Anghelescu DL, et al; NCCN
Adult Cancer Pain. Adult cancer pain. J Natl Compr Canc
Netw. 2010;8(9):1046-1086.
Qaseem A, Snow V, Shekelle P, et al; Clinical Assessment
Subcommittee of the American College of Physicians.
Evidence-based interventions to improve the palliative
care of pain, dyspnea, and depression at the end of life:
a clinical practice guidelines from the American College of
Physicians. Ann Intern Med. 2008;148(2):141-146.
Bader S, Jaroslawski K, Blum HE, Becker G. Opioid-induced
constipation in advanced illness: safety and efficacy of
methylnaltrexone bromide. Clin Med Insights Oncol.
2011;5:201-211.
Please see brief summary of Prescribing Information on
page 12.
10. Clemens KE, Klaschik EK. Managing opioid-induced constipation in advanced illness: focus on methylnaltrexone
bromide. Ther Clin Risk Manage. 2010;6:77-82.
11. Wingate D, Hongo M, Kellow J, et al. Disorders of gastrointestinal motility: towards a new classification. J Gastroenterol
Hepatol. 2002;(17 suppl):S1-S14.
12. Camilleri M. Opioid-induced constipation: challenges and
therapeutic opportunities. Am J Gastroenterol. 2011;106(5):
835-842.
13. Kurz A, Sessler DI. Opioid-induced bowel dysfunction:
pathophysiology and potential new therapies. Drugs.
2003;63(7):649-671.
14. De Schepper HU, Cremonini F, Park MI, Camilleri M.
Opioids and the gut: pharmacology and current clinical
experience. Neurogastroenterol Motil. 2004;16(4):383-394.
15. Thomas JR, Cooney GA, Slatkin NE. Palliative care and
pain: new strategies for managing opioid bowel dysfunction.
J Palliat Med. 2008;(11 suppl 1):S1-S19.
16. Yuan CS, Foss JF, O’Connor M, et al. Methylnaltrexone
prevents morphine-induced delay in oral-cecal transit time
without affecting analgesia: a double-blind randomized
placebo-controlled trial. Clin Pharmacol Ther. 1996;59(4):
469-475.
REPORT
17. Manchikanti L, Singh A. Therapeutic opioids: a ten-year
perspective on the complexities and complications of the
escalating use, abuse, and non-medical use of opioids.
Pain Physician. 2008;11(2 suppl):S63-S88.
24. Mercandante S, Casuccio A, Fulfaro F, et al. Switching from
morphine to methadone to improve analgesia and tolerability
in cancer patients: a prospective study. J Clin Oncol.
2001;19(11):2898-2904.
18. Rosti G, Gatti A, Costantini A, et al. Opioid-related bowel
dysfunction: prevalence and identification of predictive factors
in a large sample of Italian patients on chronic treatment.
Eur Rev Med Pharmacol Sci. 2010;14(12):1045-1050.
25. Vissers KP, Besse K, Hans G, et al. Opioid rotation in the
management of chronic pain: where is the evidence?
Pain Pract. 2010;10(2):85-93.
19. Quigley C. The role of opioids in cancer pain. BMJ. 2005;
331(7520):825-829.
20. Sykes NP. The relationship between opioid use and laxative use in terminally ill cancer patients. Palliat Med.
1998;12(5):375-382.
21. Slatkin N, Thomas J, Lipman AG, et al. Methylnaltrexone
for treatment of opioid-induced constipation in advanced
illness patients. J Support Oncol. 2009;7(1):39-46.
22. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11(2 suppl):
S105-S120.
23. Schaefer DC, Cheskin LJ. Constipation in the elderly.
Am Fam Physician. 1998;58(4):907-914.
26. Narabayashi M, Saijo Y, Takenoshita S, et al; Advisory
Committee for Oxycodone Study. Opioid rotation from
oral morphine to oral oxycodone in cancer patients with
intolerable adverse effects: an open-label trial. Jpn J Clin
Oncol. 2008;38(4):296-304.
27. Relistor (methylnaltrexone bromide) subcutaneous injection
[prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals, Inc; 2012.
28. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone
for opioid-induced constipation in advanced illness.
N Engl J Med. 2008;358(22):2332-2343.
29. Slatkin NE, Lynn R, Su C, et al. Characterization of abdominal pain during methylnaltrexone treatment of opioid-induced
constipation in advanced illness: a post hoc analysis of two
clinical trials. J Pain Symptom Manage. 2011;42(5):754-760.
Disclosures: Dr. Brenner reported that he has served as a consultant for Perrigo and has served as a consultant for and on the speakers’ bureau of
Salix Pharmaceuticals. Dr. Pergolizzi reported that he has served as a consultant for, on the speakers’ bureau of, and received honorarium from Endo
Pharmaceuticals, Johnson & Johnson, Purdue Pharma, and Salix Pharmaceuticals. He has also served as a consultant for and received honorarium from
Kirax Corporation.
Copyright © 2013, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction,
in whole or in part, in any form.
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Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing,
Salix, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph,
and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.
11
Adverse Reactions from all Doses in DoubleBlind, Placebo-Controlled Clinical Studies
of RELISTOR*
The following is a brief summary only; see
full Prescribing Information for complete
product information.
INDICATIONS AND USAGE
RELISTOR is indicated for the treatment of opioidinduced constipation in patients with advanced illness
who are receiving palliative care, when response
to laxative therapy has not been sufficient. Use of
RELISTOR beyond four months has not been studied.
CONTRAINDICATIONS
RELISTOR is contraindicated in patients with known
or suspected mechanical gastrointestinal obstruction.
WARNINGS AND PRECAUTIONS
Severe or Persistent Diarrhea
If severe or persistent diarrhea occurs during treatment,
advise patients to discontinue therapy with RELISTOR
and consult their physician.
Intestinal Perforation
Rare cases of gastrointestinal (GI) perforation have
been reported in advanced illness patients with
conditions that may be associated with localized or
diffuse reduction of structural integrity in the wall
of the GI tract (i.e., cancer, peptic ulcer, Ogilvie’s
syndrome). Perforations have involved varying regions
of the GI tract (e.g., stomach, duodenum, or colon).
Use RELISTOR with caution in patients with known
or suspected lesions of the GI tract. Advise patients
to discontinue therapy with RELISTOR and promptly
notify their physician if they develop severe,
persistent, and/or worsening abdominal symptoms.
Peritoneal Catheters
The use of RELISTOR has not been studied in
patients with peritoneal catheters.
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in
the clinical trials of a drug may not reflect the rates
observed in clinical practice.
The safety of RELISTOR was evaluated in two,
double-blind, placebo-controlled trials in patients
with advanced illness receiving palliative care:
Study 1 included a single dose, double blind,
placebo-controlled period, whereas Study 2
included a 14-day multiple dose, double-blind,
placebo-controlled period. The most common
adverse reactions (>5%) in patients receiving
RELISTOR are shown in the table above.
Adverse
Reaction
RELISTOR
N = 165
Placebo
N = 123
Abdominal Pain
47 (28.5%)
12 (9.8%)
Flatulence
22 (13.3%)
7 (5.7%)
Nausea
19 (11.5%)
6 (4.9%)
Dizziness
12 (7.3%)
3 (2.4%)
Diarrhea
9 (5.5%)
3 (2.4%)
Hyperhidrosis
11 (6.7%)
8 (6.5%)
* Doses: 0.075, 0.15, and 0.30 mg/kg/dose
The rates of discontinuation due to adverse events
during the double-blind placebo controlled clinical
trials (Study 3 and Study 4) were comparable
between RELISTOR (1.2%) and placebo (2.4%).
Postmarketing Experience
In addition to adverse events reported from clinical
trials, the following adverse events have been
identified during post-approval use of RELISTOR.
Because they are reported voluntarily from a
population of unknown size, estimates of frequency
cannot be made. These events have been chosen
for inclusion due to either their seriousness,
frequency of reporting or causal connection to
RELISTOR, or a combination of these factors.
Gastrointestinal
Cramping, perforation, vomiting
General Disorders and Administrative Site Disorders
Diaphoresis, flushing, malaise, pain
DRUG INTERACTIONS
Drugs Metabolized by Cytochrome P450 Isozymes
In in vitro drug metabolism studies methylnaltrexone
bromide did not significantly inhibit the activity of
cytochrome P450 (CYP) isozymes CYP1A2, CYP2A6,
CYP2C9, CYP2C19 or CYP3A4, while it is a weak
inhibitor of CYP2D6. In a clinical drug interaction
study in healthy adult male subjects, a subcutaneous
dose of 0.30 mg/kg of methylnaltrexone bromide
did not significantly affect the metabolism of
dextromethorphan, a CYP2D6 substrate.
Drugs Renally Excreted
The potential for drug interactions between
methylnaltrexone bromide and drugs that are
actively secreted by the kidney has not been
investigated in humans.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B
Reproduction studies have been performed in
pregnant rats at intravenous doses up to about
14 times the recommended maximum human
subcutaneous dose of 0.3 mg/kg based on the body
surface area and in pregnant rabbits at intravenous
doses up to about 17 times the recommended
maximum human subcutaneous dose based on the
body surface area and have revealed no evidence
of impaired fertility or harm to the fetus due to
methylnaltrexone bromide. There are no adequate
and well-controlled studies in pregnant women.
Because animal reproduction studies are not always
predictive of human response, methylnaltrexone
bromide should be used during pregnancy only if
clearly needed.
Labor and Delivery
Effects of RELISTOR on mother, fetus, duration of
labor, and delivery are unknown. There were no
effects on the mother, labor, delivery, or on offspring
survival and growth in rats following subcutaneous
injection of methylnaltrexone bromide at dosages
up to 25 mg/kg/day.
Nursing Mothers
Results from an animal study using [3H]-labeled
methylnaltrexone bromide indicate that
methylnaltrexone bromide is excreted via the milk
of lactating rats. It is not known whether this drug is
excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised
when RELISTOR is administered to a nursing woman.
Pediatric Use
Safety and efficacy have not been established in
pediatric patients.
Geriatric Use
In the phase 2 and 3 double-blind studies, a
total of 77 (24%) patients aged 65-74 years (54
methylnaltrexone bromide, 23 placebo) and a total
of 100 (31.2%) patients aged 75 years or older
(61 methylnaltrexone bromide, 39 placebo) were
enrolled. There was no difference in the efficacy
or safety profile of these elderly patients when
compared to younger patients. Therefore, no dose
adjustment is recommended based on age.
Renal Impairment
No dose adjustment is required in patients with mild
or moderate renal impairment. Dose reduction by
one-half is recommended in patients with severe
renal impairment (creatinine clearance less than
30 mL/min as estimated by Cockcroft-Gault). No
studies were performed in patients with end-stage
renal impairment requiring dialysis.
Hepatic Impairment
No dose adjustment is required for patients with
mild or moderate hepatic impairment. The effect of
severe hepatic impairment on the pharmacokinetics
of methylnaltrexone bromide has not been studied.
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