E CASE REPORT

Methylnaltrexone-Associated Bowel Perforation in

Postoperative Opioid-Induced Constipation and Ogilvie
Syndrome: A Case Report
Kevin A. Blackney, MD,* Nirav V. Kamdar, MD,† Chang Amber Liu, MD, MSc, FAAP,‡
and David A. Edwards, MD, PhD§

Pain management with opioids is often limited by medication side effects. One of the most
common and distressing side effects is opioid-induced constipation (OIC), a syndrome that is
now getting significant national attention. We report the case of an opioid-dependent 56-year-old
man who underwent lumbar decompression for spinal stenosis. Postoperatively, he developed
OIC and Ogilvie syndrome, then following treatment with methylnaltrexone experienced an acute
bowel perforation. We briefly review the recommended management of OIC as well as indica-
tions and contraindications of methylnaltrexone and similar new medications.  (A&A Practice.
2019;12:44–6.)

O
pioids are the most commonly prescribed medica-
tion for postoperative pain control, and their use
is increasing significantly in the outpatient set-
ting. Sales of prescription opioids quadrupled from 1999
to 2010, and while this trend has begun to reverse, as of
2015, opioid prescriptions were still 3 times more frequent
than in 1999.1 Opioid-induced constipation (OIC) is the
most frequent side effect reported in adults taking opioids,
occurring in 41%–80% of patients as a result of μ-opioid
receptor activation of the gastrointestinal (GI) tract.2,3
Rates of OIC, as well as hospital admissions due to OIC,
have increased in the United States since 2006.4 To patients,
OIC can be as distressing as the pain itself.5–7 OIC has even
garnered national media attention, now being advertised
on television and in print ads. Thus with increasing use of
opioids and aggressive advertising of OIC, prevention and
treatment of this side effect has become a larger factor in
pain management.
Methylnaltrexone is a derivative of naloxone and selec-
tively antagonizes opioid binding at the μ-opioid receptor.7–9
As a quaternary amine, it does not cross the blood-brain
barrier, so its action is restricted to the periphery including
tissues of the GI tract. Thus, it is an effective treatment for
OIC without affecting analgesia.7,10 Rarely, methylnaltrex-
one has been associated with bowel perforation.5
Here, we present the case of a 56-year-old opioid-
dependent man with a history of bowel perforation who
underwent lumbar spinal decompression and afterward
developed severe OIC and Ogilvie syndrome, also known
From the *Kaiser Permanente of Northern California, Oakland, California;
†David Geffen School of Medicine at UCLA/UCLA Health, Los Angeles,
California; ‡Harvard Medical School/Massachusetts General Hospital, Bos-
ton, Massachusetts; and §Vanderbilt University School of Medicine/Vander-
bilt University Medical Center, Nashville, Tennessee.
Accepted for publication May 31, 2018.
Funding: None.
The authors declare no conflicts of interest.
Address correspondence to Kevin A. Blackney, MD, The Permanente
Medical Group, Inc, Oakland Medical Center, Department of Anesthesia, 275
West MacArthur Blvd, Oakland, CA 94611. Address e-mail to KABlackney
@gmail.com.
Copyright © 2018 International Anesthesia Research Society
DOI: 10.1213/XAA.0000000000000840
as acute colonic pseudo-obstruction (ACPO), complicated
by bowel perforation after a single administration of meth-
ylnaltrexone. A written Health Insurance Portability and
Accountability Act authorization to use/disclose existing
protected health information was obtained.
DESCRIPTION OF THE CASE
A 56-year-old man was admitted for posterior lumbar decom-
pression of severe spinal stenosis. In addition to persistent low
back pain and opioid use, he had chronic obstructive pulmo-
nary disease and diverticulitis for which he had a subtotal
colectomy with anastomosis after bowel perforation 10 years
before. His outpatient opioid pain medications included oxy-
codone 10 mg by mouth (orally, per os) every 4 hours as needed
(PRN), and methadone 5 mg orally, per os 3 times daily. The
patient had been stable on this regimen with no constipation.
His posterior decompression operation was complicated
by a dural tear, which was repaired but necessitated he stay
flat in bed. Postoperative pain was initially managed by
restarting his home methadone and instituting low-dose
hydromorphone intravenously (IV) via patient-controlled
analgesia (PCA). Additionally, he was prescribed scheduled
docusate and sennosides with bisacodyl PRN. On post-
operative day (POD) 1, his back pain worsened; thus, his
PCA demand dose was increased. On POD2, his back pain
continued to be severe, so ketorolac 15 mg IV every 6 hours
PRN was added. Unfortunately, he also developed abdomi-
nal pain. Without improvement in overall pain on POD3,
an abdominal x-ray was obtained, a nasogastric tube was
placed, and the acute pain service (APS) was consulted.
On consultation, it was noted by the APS that the patient
had not had a bowel movement since the day before sur-
gery and postoperatively had refused docusate, received
sennosides only once, and had not received PRN bisacodyl.
The APS immediately instituted a multimodal pain regimen
to deescalate opioid use which included the addition of a
ketamine infusion at 2–5 µg/kg/min, acetaminophen every
6 hours, continued ketorolac every 8 hours, a switch of
methadone to 2.5 mg IV 3 times daily, and discontinuation
of hydromorphone PCA. The final abdominal x-ray report
showed ACPO; thus, it was advised to avoid methylnaltrex-
one given the ACPO and prior bowel anastomosis, and to

44 cases-anesthesia-analgesia.org January 15, 2019 • Volume 12 • Number 2

instead trial enemas. Unfortunately, before the diagnosis of
ACPO was made and the recommendations transmitted to
the consulting team, the patient received methylnaltrexone
12 mg subcutaneous for presumed simple OIC. One hour
later, the patient experienced severe abdominal cramping
and tearing pain; a repeat x-ray showed free air in the abdo-
men. He was taken urgently to the operating room for a
transverse colectomy and ileostomy for a perforated cecum.
DISCUSSION
With chronic opioid use, tolerance to the side effects of seda-
tion and respiratory depression develops, but tolerance to
constipation does not occur.3,6,8 The patient reported here
developed OIC only after the addition of hydromorphone,
exacerbated by immobility and limited diet in the post-
operative period. While randomized studies are limited,
it does appear that opioids have varying levels of associ-
ated constipation; thus, it was not unexpected that adding
hydromorphone could lead to new OIC.11 Additionally,
x-ray findings were suggestive of ACPO, which is a non-
mechanical obstruction of the large bowel. ACPO is a diag-
nosis of exclusion with imaging showing dilated loops of
bowel without evidence of volvulus or obstructing lesion.
The pathophysiology of ACPO is unknown, although rat
models have indicated a disruption of mediators such as
acetylcholine and nitric oxide within the enteric nervous
system causing uncoordinated contraction and relaxation.12
This proposed pathophysiology of ACPO mirrors that of
the pathophysiology of OIC.8 Thus, prevention and man-
agement of ACPO is also similar to OIC. Once present, man-
agement begins with the elimination of stimuli (ie, opioids),
decompression, fluids, and neostigmine IV in a monitored
setting.12 Thus, OIC and ACPO are possibly on the same
spectrum of disease processes.
To prevent OIC, common prophylactic measures are
used; a standard “bowel-regimen” consists of nonphar-
macologic agents (fiber, fluids), as well as stool softeners,
laxatives, and bowel stimulants.3,13 Occasionally, prophylac-
tic measures are inadequate and refractory constipation is
managed by using suppositories and enemas and reducing
or discontinuing causative medications.
The American Society of Interventional Pain Physicians
and the European Association for Palliative Care recom-
mend use of laxatives when initiating opioids for cancer
pain, although both note that evidence is lacking and 1 laxa-
tive is not superior to another.8,13 For patients taking opioids
for noncancer pain, there are no published guidelines or
recommendations; most patients are anecdotally prescribed
laxatives with different mechanisms of action except bulk-
ing agents that are contraindicated in OIC (Table  1).3,9,13,14
Although use of different classes of laxatives appears to
be synergistic, even with appropriate prophylactic bowel
regimens, only 50% of patients experience relief of OIC.3,14,15
Patients who are able to maintain physical activity, tolerate
oral fluid intake and fiber in their diet, are more often able to
avoid the constipating effects of chronic opioid use.13–15 Our
patient was not able to maintain these therapies because he
was confined to bed after dural tear repair.
When prophylactic measures fail, consideration for
more aggressive interventions, such as Peripherally Acting
Mu-Opioid Receptor Antagonists (PAMORA), are indicated.
January 15, 2019 • Volume 12 • Number 2 cases-anesthesia-analgesia.org 45
Table 1.  Laxatives to be Considered for
Prophylaxis of OIC
Laxative Class Mechanism of Action Example Medications
Stimulant Increases motility Sennosides, bisacodyl
Osmotic Retains water in the gut Polyethylene glycol,
lactulose
Detergent Increases luminal Docusate
secretions
Adapted from references 3, 13, 14. Abbreviation: OIC, opioid-induced
constipation.
The American Academy of Pain Medicine and the American
Gastroenterology Association recommend the use of the bowel
function index (BFI) to evaluate for the presence and severity
of OIC. The BFI is a 3-item questionnaire (1, ease of defecation;
2, sensation of incomplete bowel evacuation; 3, assessment of
overall constipation), with each item scored from 0 to 100. A
BFI score of ≥30 is recommended as an indication to initiate a
PAMORA or other newer-generation bowel agent.14
In 2008, methylnaltrexone was approved by the US Food
and Drug Administration (FDA) for treatment of OIC in
palliative care populations and adults with chronic noncan-
cer pain.7 Laxation occurs in 48% of patients within 4 hours
of administration of a single dose.7 Methylnaltrexone can
be administered via subcutaneous, IV, or oral, per os routes
in recommended doses of 8 mg for patients between 38 and
62 kg, 12 mg for 63–114 kg, and 0.15 mg/kg for patients
above these ranges.15 Higher doses may result in increased
abdominal pain but not improved or quicker resolution of
constipation.13 While methylnaltrexone is typically used
as a second-line agent, its use as a scheduled prophylactic
medication has shown superior control of OIC.10 The most
common side effects of methylnaltrexone are abdominal
pain (~21%–38%) and nausea (9%).6 With the continued
increase in opioid prescriptions and public awareness of
OIC, additional PAMORAs and other new classes of medi-
cations for OIC have been developed, each with side effects
and warnings (Table 2).2,3,8,15
Methylnaltrexone is the oldest PAMORA in use and thus
its risk profile for rare events is better understood. Bowel
perforation has been associated with the use of methylnal-
trexone in rare instances. While the mechanism for methyln-
altrexone-induced bowel perforation is unknown, clinicians
have been alerted to this association and encouraged to
report such cases to the FDA.5 We queried the FDA Adverse
Events Reporting System (FAERS) for reports of intestinal
perforation associated with methylnaltrexone, and, from
2010 to 2017, there are at least 6 reported cases. A previ-
ous FAERS query from 2008 to 2009 reported 7 additional
cases, with 4 that resulted in death with the causal mecha-
nism being disruptions in the integrity of the GI tract.5 Our
patient had several risk factors for bowel perforation: diver-
ticulitis and a distant history of bowel rupture requiring
anastomosis, OIC, and Ogilvie syndrome. Additionally, our
FAERS query also included the newer PAMORAs (Table 2).
As with methylnaltrexone, there are multiple reports of
intestinal perforation with these medications as well.
Patients on chronic narcotics, and those exposed to
opioids in the perioperative setting, are at risk for OIC.
Over-the-counter laxatives are frequently used for prophy-
laxis; however, there is limited evidence to support this
Table 2.  Medications Available to Treat OIC After Failed Prophylactic Measures
Drug Mechanism of Action
Alvimopan Peripheral μ-receptor antagonist, indicated for
restoration of bowel function following bowel
surgery only. FDA approved in 2008.
Naloxegol Peripheral μ-receptor antagonist, oral only. FDA
approved in 2015.
Naldemedine Peripheral μ-receptor antagonist, oral only. FDA
approved in 2017.
Prucalopride 5-HT4 agonist that increases the speed of colonic
transit. Not yet approved in the United States.
Lubiprostone Activates chloride channels to increase intestinal
fluid secretion.
Adapted from references 2, 15. Abbreviations: FDA, Food and Drug Administration; OIC, opioid-induced constipation.
intervention. When these fail, newer-generation medica-
tions for OIC are indicated but may carry significant risks.
Before the decision to use methylnaltrexone is made, a sur-
vey of risk factors should be done. E
DISCLOSURES
Name: Kevin A. Blackney, MD.
Contribution: This author helped review, draft, and edit the
manuscript.
Name: Nirav V. Kamdar, MD.
Contribution: This author helped review and edit the manuscript.
Name: Chang Amber Liu, MD, MSc, FAAP.
Contribution: This author helped review and edit the manuscript.
Name: David A. Edwards, MD, PhD.
Contribution: This author helped review and edit the manuscript.
This manuscript was handled by: BobbieJean Sweitzer, MD, FACP.
REFERENCES
1. Guy GP Jr, Zhang K, Bohm MK, et al. Vital signs: changes in
opioid prescribing in the United States, 2006-2015. MMWR
Morb Mortal Wkly Rep. 2017;66:697–704.
2. Sharma A, Jamal MM. Opioid induced bowel disease: a twenty-
first century physicians’ dilemma. Considering pathophysiol-
ogy and treatment strategies. Curr Gastroenterol Rep. 2013;15:334.
3. Nelson AD, Camilleri M. Chronic opioid induced constipation
in patients with nonmalignant pain: challenges and opportuni-
ties. Therap Adv Gastroenterol. 2015;8:206–220.
4. Sonu I, Triadafilopoulos G, Gardner JD. Persistent constipation
and abdominal adverse events with newer treatments for con-
stipation. BMJ Open Gastroenterol. 2016;3:e000094.
46   
cases-anesthesia-analgesia.org
Comment
Carries significant cardiovascular concerns with chronic use. Three reported
events of GI perforation.
Four reported events of GI perforation, but carries warning for use similar to
methylnaltrexone. 3% rate of opioid withdrawal symptoms.
Similar to naloxegol, no reported cases of bowel perforation, but carries
warning when used in patients with a history of diverticular disease, peptic
ulcer disease, or Crohn disease.
First in its class. Good safety profile, indicated for chronic constipation, but
shown effective for OIC as well.
Two reported events of GI perforation. Approved for chronic constipation,
constipation associated with irritable bowel syndrome and OIC.
5. Mackey AC, Green L, Greene P, Avigan M. Methylnaltrexone
and gastrointestinal perforation. J Pain Symptom Manage.
2010;40:e1–e3.
6. McCarberg BH. Overview and treatment of opioid-induced
constipation. Postgrad Med. 2013;125:7–17.
7. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for
opioid-induced constipation in advanced illness. N Engl J Med.
2008;358:2332–2343.
8. Leppert W. Emerging therapies for patients with symptoms
of opioid-induced bowel dysfunction. Drug Des Devel Ther.
2015;9:2215–2231.
9. Webster LR. Opioid-induced constipation. Pain Med.
2015;16(suppl 1):S16–S21.
10. Bull J, Wellman CV, Israel RJ, Barrett AC, Paterson C, Forbes
WP. Fixed-dose subcutaneous methylnaltrexone in patients
with advanced illness and opioid-induced constipation: results
of a randomized, placebo-controlled study and open-label
extension. J Palliat Med. 2015;18:593–600.
11. Dorn S, Lembo A, Cremonini F. Opioid-induced bowel
dysfunction: epidemiology, pathophysiology, diagnosis,
and initial therapeutic approach. Am J Gastroenterol Suppl.
2014;2:31–37.
12. Chudzinski AP, Thompson EV, Ayscue JM. Acute colonic pseu-
doobstruction. Clin Colon Rectal Surg. 2015;28:112–117.
13. Rauck RL. Treatment of opioid-induced constipation: focus on
the peripheral μ-opioid receptor antagonist methylnaltrexone.
Drugs. 2013;73:1297–1306.
14. Argoff CE, Brennan MJ, Camilleri M, et al. Consensus recom-
mendations on initiating prescription therapies for opioid-
induced constipation. Pain Med. 2015;16:2324–2337.
15. Ketwaroo GA, Cheng V, Lembo A. Opioid-induced bowel dys-
function. Curr Gastroenterol Rep. 2013;15:344.
A & A PRACTICE