Author(s): Sabine Bader [*] 2 , Thorsten Dürk 1 , Gerhild Becker 1
constipation; methylnaltrexone; opioid; palliative care; peripherally acting μ-opioid receptor antagonist
Opioids are the drugs of choice and the therapeutic cornerstone for the treatment of severe chronic and acute pain in malignant and nonmalignant pain, during anesthesia for surgery and in critical care [1-3] . Opioid receptors are distributed all over the body where they mediate multiple functions of endogenous opioids in various physiological processes that are not fully understood and are under intense scrutiny. This complexity explains the risk for multiple side effects of analgesic opioids. Sedation, nausea, pruritus, urinary retention and constipation have to be controlled in order to use these important drugs to their full potential. As one of their main side effects, opioid-induced bowel dysfunction (OIBD) occurs in up to 90% of patients with chronic pain on opioids, especially in advanced illnesses [4,5] . In contrast to sedation and nausea, patients do not develop clinically relevant tolerance for this syndrome during a long-term therapy. Opioids activate µ-receptors in the enteric neuron system. This interrupts autonomous pathways by reducing the release of acetylcholine and other excitatory transmitters that control reactive enteric muscle contractions responsible for coordinated propulsory activity. They also directly influence ion flux, leading to increased fluid absorption and decreased intestinal secretion, which dries out the stool. Uncoordinated colonic spasms and increased anal sphincter tonus also lead to constipation, while less tonus at the esophageal sphincter and higher antral tonus cause reflux and retarded gastric emptying. Consequently, patients on narcotics can suffer from reflux esophagitis, increased risk of aspiration and prolonged feces transit. This leads to hard stools, incomplete evacuation, abdominal bloating and discomfort by accumulation of gas and secretions. Consecutive nausea and vomiting may interfere with the administration and absorption of other medication and contribute to anorexia, especially in the severely ill. Patients' quality of life can be impaired to a point where they prefer inadequate pain control to the agonizing side effect of the analgesic. For surgical patients or patients in critical care, opioids can cause similar problems by comparable pathophysiological mechanisms [6,7] . Esophageal reflux and consecutive aspiration of stomach content can cause pain and pulmonary complications. Opioids enhance the risk of postoperative ileus (POI), a major multifactorial complication that deteriorates outcome especially after abdominal surgery  .
Body of review
Overview of the market
Current therapies for OIBD are unspecific and mainly aimed at constipation. For long-term analgesic therapy with opioids, these include stool softeners, osmotic agents and stimulant laxatives, which are applied prophylactically according to pain management guidelines  . They do not always succeed in sufficiently controlling the problem [5,9] and, in case of advanced illness, the study-based evidence for their efficacy is sparse  . For the prevention of POI and treatment of constipation in patients on opioids in critical care, there is also a lack of evidence about potential medical treatment [11,12] .
The underlying mechanism of OIBD involves the activation of µ-receptors in the plexus myentericus, the complex neural net of the gut [13-16] . Physiological µ-agonists...