Inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), is one of the most challenging gastrointestinal (GI) conditions to treat. Patients with IBD are often complex and frequently have both a significant GI and non-GI clinical burden. The ultimate goal in treating IBD is to induce remission, which has several subtypes, including clinical, endoscopic, and deep remission. The clinical course is typically not straightforward, with patients encountering relapses throughout their lifetime. A patient with uncontrolled IBD can report multiple symptoms including abdominal pain, diarrhea, and GI bleeding (GIB), many of which necessitate visits to both their primary gastroenterologist as well as the emergency department (ED). Patients whose symptoms cannot be adequately controlled in the outpatient setting may ultimately require inpatient hospitalization.
Upon their initial and subsequent evaluation, patients may receive pain medications in the form of opioids. Non-steroidal anti-inflammatory drugs (NSAIDs) are typically not an option for patients with IBD based on the possibility of exacerbating their GI symptoms. Initiation of opioid use during a flare of symptoms can eventually lead to chronic opioid use (COU), which can have detrimental effects on a patient’s IBD as well as their overall clinical health. In recent years there has been an emphasis on limiting opioid use in all patients, based on the opioid crisis.
When evaluating a patient with IBD who reports worsening symptoms, it is critical to determine if there is any potential overlap with irritable bowel syndrome (IBS)-like symptoms. This overlap can be present in over 30% of patients with IBD, making the diagnosis extremely challenging.1 This determination could drastically change how a patient is managed, as those patients with symptoms thought to be related to IBS are treated more conservatively and without steroids, opioids, or significant testing. Evaluation with C-reactive protein (CRP), fecal calprotectin (FCP), contrast enhanced imaging (eg, computed tomography [CT], magnetic resonance enterography [MRE]), and colonoscopy can assist in making this determination.
A study conducted by Pauly et al evaluated 47,164 patients with new CD and found that 3.8% of patients were diagnosed with new COU during a two year follow up period.2 The patients most at risk for developing COU included women, those of advanced age, and those with a history of multiple surgeries, endoscopies, or hospitalizations. Patients who had a history of psychiatric disorders, arthritis, chronic pain, and history of prior opioid use before being diagnosed with CD were more likely to develop COU after their CD was diagnosed. Patients who continue to have inadequate disease control will continue to be at risk for COU.
Patients with IBD who eventually develop COU are at increased risk of mortality, longer hospital length of stay, and worse surgical outcomes.3,4 Li et al reviewed 1331 patients with CD who underwent a total of 1461 abdominal operations and found that 18.3% of these surgeries were performed on patients receiving preoperative narcotics. Compared with those not, patients receiving preoperative narcotics were more likely to develop postoperative complications (52.8% vs 40.8%, respectively; P <.001) and have a longer mean length of stay (11.2 vs 7.7 days, respectively; P <.001). This study highlights the need to have patients off of narcotics heading into surgery or to possibly consider surgical intervention before patients develop COU.
There has been a trend within IBD management to support more aggressive treatments, especially in patients with worsening symptoms, biomarkers (eg, labs and stool) and endoscopic findings.5 In 2017, Colombel et al published their findings from a phase 3 Effect of Tight Control Management on CD (CALM) study, which evaluated “tight control” versus standard clinical management in patients with moderate to severe CD without any prior exposure to immunomodulators or biologics. The tight control group used a treatment algorithm driven by the Crohn Disease Activity Index (CDAI), FCP, CRP and prednisone use while the clinical management group used an algorithm driven by CDAI and prednisone use only. Patients who eventually received treatment did so with adalimumab and possibly azathioprine. The primary endpoint was mucosal healing, which was defined as Crohn Disease Endoscopic Index of Severity (CDEIS) < 4, along with absence of deep ulcerations at 48 weeks post randomization. This primary endpoint was achieved in more patients in the tight control group compared with the standard management group (46% vs 30%; adjusted risk difference, 16.1%; P =.010). In addition, the tight control group had more patients achieve deep remission, biological remission, and steroid-free remission. There were no significant differences found between the groups in terms of adverse events reported.5
The CALM study and idea of tight control in patients with IBD is further complicated when patients have COU. Patients with COU can eventually develop symptoms similar to an IBD flare.6 In addition, patients who are withdrawing from opioids can also present with IBD-like symptoms. These “flares” may lead to patients receiving treatment with biologics and being labeled as primary non-responders, which would subsequently alter their treatment plan and could lead to limited treatment options in the future.
Recently, a group led by Rhudy et al conducted a study aimed at determining if COU is associated with early discontinuation of biologics regardless of disease severity.3 A database of commercial claims within the United States was reviewed using a retrospective cohort design. The records of 16,624 patients with IBD who were receiving their first biologic were reviewed, of which 1768 (10.6%) patients were identified as having COU. COU was defined as having at least a 90-day supply of outpatient opioid prescriptions in a 6 month period without any 30-day gaps in opioid coverage. Patients meeting the COU definition used more mean biologic agents when compared with the control group (1.51 vs 1.37; P <.0001). Fewer patients in the COU group continued biologic therapies until the end of the study period (16.2% vs 33.5%; P <.0001). Patients in the COU group had fewer mean days on first-line (555 vs 600 days; P <.0001) and second line agents (404 vs 433 days; P =.0003) but there was no significant difference for third through fifth line agents.
In addition, patients in the COU group were more likely to be non-persistent with biologic therapy (hazard ratio [HR] 1.23; 95% CI, 1.16-1.31). Patients with COU were more likely to receive adalimumab, golimumab, certolizumab, and ustekinumab compared with the control group. The COU group had significantly higher numbers of ED visits, hospital admissions, steroid treatments, abdominal surgeries, endoscopic procedures and comorbidities (fistula, arthritis, malnutrition).
The underlying pathophysiology to explain why COU may lead to worse outcomes is not entirely understood, but may be attributed to the development of narcotic bowel syndrome (NBS).6 Patients with IBD and COU are at risk for developing the “classic” symptoms associated with opioid use, such as constipation. However, NBS is characterized by chronic abdominal pain that worsens with continued or escalating doses of narcotics. Enhanced pain perception may be related to activation of excitatory antianalgesic pathways, including those involving dynorphin, cholecystokinin, and glial cells.
- Halpin S, Ford AC. Prevalence of symptoms meeting criteria for irritable bowel syndrome in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2012;107(10):1474-82. doi: 10.1038/ajg.2012.260.
- Pauly NJ, Michailidis L, Kindred MG, et al. Predictors of chronic opioid use in newly diagnosed crohn’s disease. Inflamm Bowel Dis. 2017;23(6):1004-1010. doi: 10.1097/MIB.0000000000001087.
- Rhudy C, Perry CL, Singleton M, Talbert J, Barrett TA. Chronic opioid use is associated with early biologic discontinuation in inflammatory bowel diseasehttps://pubmed.ncbi.nlm.nih.gov/33497484/. Aliment Pharmacol Ther. 2021;53(6):704-11. doi: 10.1111/apt.16269.
- Li Y, Stocchi L, Cherla D, Liu X, Remzi FH. Association of preoperative narcotic use with postoperative complications and prolonged length of hospital stay in patients with crohn disease. JAMA Surg. 2016;151(8):726-34. doi: 10.1001/jamasurg.2015.5558.
- Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet. 2017;390(10114):2779-2789. doi: 10.1016/S0140-6736(17)32641-7.
- Grunkemeier DMS, Cassara JE, Dalton CB, Drossman DA. The narcotic bowel syndrome: clinical features, pathophysiology, and management. Clin Gastroenterol Hepatol. 2007;5(10):1126-39. doi: 10.1016/j.cgh.2007.06.013.