Opioids are the most commonly prescribed medication for postoperative pain control, and their use is increasing significantly in the outpatient setting. 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 selectively 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, methylnaltrexone 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 as acute colonic pseudo-obstruction (ACPO), complicated by bowel perforation after a single administration of methylnaltrexone. 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 decompression of severe spinal stenosis. In addition to persistent low back pain and opioid use, he had chronic obstructive pulmonary disease and diverticulitis for which he had a subtotal colectomy with anastomosis after bowel perforation 10 years before. His outpatient opioid pain medications included oxycodone 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 postoperative 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 abdominal 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 surgery 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 methylnaltrexone given the ACPO and prior bowel anastomosis, and to 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 abdomen. He was taken urgently to the operating room for a transverse colectomy and ileostomy for a perforated cecum.
With chronic opioid use, tolerance to the side effects of sedation 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 postoperative period. While randomized studies are limited, it does appear that opioids have varying levels of associated 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 nonmechanical obstruction of the large bowel. ACPO is a diagnosis 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 management of ACPO is also similar to OIC. Once present, management 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 nonpharmacologic agents (fiber, fluids), as well as stool softeners, laxatives, and bowel stimulants.3,13 Occasionally, prophylactic 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 recommend use of laxatives when initiating opioids for cancer pain, although both note that evidence is lacking and 1 laxative 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 bulking 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. 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 noncancer 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 medications 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 methylnaltrexone in rare instances. While the mechanism for methylnaltrexone-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 previous FAERS query from 2008 to 2009 reported 7 additional cases, with 4 that resulted in death with the causal mechanism being disruptions in the integrity of the GI tract.5 Our patient had several risk factors for bowel perforation: diverticulitis 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 prophylaxis; however, there is limited evidence to support this intervention. When these fail, newer-generation medications for OIC are indicated but may carry significant risks. Before the decision to use methylnaltrexone is made, a survey of risk factors should be done.
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.
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