Effects of the peripherally acting μ-opioid receptor antagonist methylnaltrexone on acute pancreatitis severity: study protocol for a multicentre double-blind randomised placebo-controlled interventional trial, the PAMORA-AP trial

Abstract

Background Moderate to severe acute pancreatitis (AP) is associated with a high rate of complications and increased mortality, yet no targeted pharmacologic treatment currently exists. As pain is a dominant symptom in AP, patients are exposed to excess levels of both endo- and exogenous opioids, which may have harmful effects on the course of AP. This trial investigates the effects of the peripherally acting μ-opioid receptor antagonist (PAMORA) methylnaltrexone on disease severity and clinical outcomes in patients with moderate to severe AP. Methods PAMORA-AP is a multicentre, investigator-initiated, double-blind, randomised, placebo-controlled, interventional trial, which will be conducted at four referral centres for acute pancreatitis in Denmark. Ninety patients with early-onset AP (pain onset within 48 h) as well as predicted moderate to severe disease (two or more systemic inflammatory response syndrome criteria upon admission) will be prospectively included. Subsequently, participants will be randomised (1:1) to intravenous treatment with either methylnaltrexone or matching placebo (Ringer’s lactate) during 5 days of admission. The primary endpoint will be the group difference in disease severity as defined and measured by the Pancreatitis Activity Scoring System (PASS) score 48 h after randomisation. Secondary endpoints include daily PASS scores; disease severity according to the Atlanta classification; quantification of need for analgesics, nutritional support, intravenous fluid resuscitation and antibiotics; duration of hospital admissions, readmission rates and mortality. Pain intensity and gut function will be self-reported using validated questionnaires. Exploratory endpoints include circulating levels of pro-and anti-inflammatory markers, polyethylene glycol recovery from the urine, circulating levels of blood markers of intestinal permeability, the prevalence of pancreatic complications on computed tomography (CT) scans, and colon transit time assessed using a CT-based radiopaque marker method. Discussion This trial aims to evaluate the PAMORA methylnaltrexone as a novel targeted pharmacotherapy in patients with moderate to severe AP with the potential benefit of improved patient outcomes. Trial registration ClinicalTrials.govNCT04743570. Registered on 28 January 2021. EudraCT 2020-002313-18.

Acute Pancreatitis: Diagnosis and Treatment

“…RAPID-I has wide entry criteria, includes healthrelated quality of life and costs as outcomes, with follow-up of 3 months. The third is a Danish trial of the peripherally acting µ-opioid receptor antagonist methylnaltrexone, which counteracts inhibitory effects of opiates on gut function and immune responses, without affecting analgesia [266]. It is to be hoped these trials will be completed soon and that the international impetus for such trials will grow.…”

Opioid analgesia and severity of acute pancreatitis: An international multicentre cohort study on pain management in acute pancreatitis

“…As such, retrospective studies have shown that opioid treatment increased the risk of 30‐day mortality, invasive ventilation, vasopressor treatment, abdominal surgery, increased morphological severity of AP, and longer length of admission. 13 , 24 , 25 Furthermore, peripheral μ‐opioid receptor antagonists are currently being tested in patients with predicted severe and recurrent AP 7 , 26 due to their potential to counteract opioid‐induced alterations to the gastrointestinal and immune systems.…”

“…5 There are many potentially harmful effects of opioids on the human gastrointestinal tract, which could influence the course and outcome of AP . [6][7][8] Opioids can cause intestinal dysmotility, ileus, and bacterial overgrowth as well as increased intestinal permeability, which in turn might increase the risk of bacterial translocation, infected pancreatic necrosis, and worsen the severity of AP. 9 Furthermore, opioid administration may contribute to immunosuppression, which may promote infections.…”

Update on pain management in acute pancreatitis

“…Opioids also increase gut transit time which can cause bacterial overgrowth that can cause pain and bloating. Preclinical studies have shown that opioids can increase intestinal permeability, which is known to increase the translocation of bacteria and the risk of local and systemic infections, which might be promoted by opioid-induced immunosuppression [27]. It is customary to treat opioid induced intestinal dysmotility with laxatives although there is little evidence for r which specific laxative is most effective.…”

“…It is customary to treat opioid induced intestinal dysmotility with laxatives although there is little evidence for r which specific laxative is most effective. Recognizing that endogenous opioids, released in response to pain and visceral injury, also contribute to dysmotility means that laxatives might be required even when opioids are not prescribed [27]. There appears to be a role for peripherally acting μ-opioid receptor antagonists that have been shown to be effective in treating postoperative ileus and chronic constipation that share common mechanisms to that seen in opioid induced intestinal dysmotility [28].…”