Borgeat, A

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University of ZurichZurich Open Repository and ArchiveWinterthurerstr. 190CH-8057 Zurichhttp://www.zora.uzh.chYear: 2008Opioid-induced constipation: avoiding the perils and pitfalls Borgeat, ABorgeat, A (2008). Opioid-induced constipation: avoiding the perils and pitfalls. Paineurope, 1:6.Postprint available at:http://www.zora.uzh.chPosted at the Zurich Open Repository and Archive, University of Zurich.http://www.zora.uzh.chOriginally published at:Paineurope 2008, 1:6.Borgeat, A (2008). Opioid-induced constipation: avoiding the perils and pitfalls. Paineurope, 1:6.Postprint available at:http://www.zora.uzh.chPosted at the Zurich Open Repository and Archive, University of Zurich.http://www.zora.uzh.chOriginally published at:Paineurope 2008, 1:6.Low-dose opioids and constipationOpioid-induced constipation: avoiding the perils and pitfallsAlain Borgeat, Head of the Department of Anaesthesiology,  Orthopaedic University Hospital Balgrist, SwitzerlandChronic pain is a serious issue in many Western countries. In Europe its incidence ranges from 30 per cent in Norway to 11 per cent in Spain. Long-term treatment with opioids has usually been prescribed for chronic pain associated with cancer, but recent evidence has shown the benefits of this class of drugs in the treatment of chronic neuropathic pain of diverse aeti-ologies. Considering the new indications of long-term opioid therapy, it is nowadays difficult to imagine the practice of chronic pain therapy without their use. Although µ-opioid agonists provide effective analgesia they also produce a large number of other undesirable effects. Among them gastrointestinal dysfunction (nausea, vomiting and constipation) is of particular concern since its occurrence increases patients’ distress and enhances the level of pain. Tolerance commonly develops to most of the effects of opioids on the gastrointestinal tract, but constipa-tion often persists. Constipation is consid-ered by many patients to be the most debilitating adverse effect associated with opioid therapy. Physiopathology of opioid-induced constipationThe interaction between opioids and the GI tract is complex and is mainly mediated by the µ-opioid receptor, although ∂- and k-receptors are also implicated to a certain extent. The GI tract is innervated by the enteric nervous system which comprises the myenteric plexus, located between cir-cular and longitudinal smooth muscle lay-ers of the bowel and the submucosal plexus, located in the submucosa. Enteric neurons are responsible for the synthesis and release of opioid peptides (encephalins) and their transmitters. These mediators participate in co-ordination of the contrac-tile process under physiological conditions and can decrease intestinal motility in cases of inflammation, trauma or stress. The binding of opioids to the µ-receptor leads to the inhibition of excitatory and inhibitory neurotransmitter release. The consequences are interruption of the co-ordinated rhythmic contractions required for intestinal motility and decrease of propulsive peristaltic activity. Some areas of the GI tract show increased tone and spasms, thereby delaying gastric empty-ing and further slowing intestinal trans-port. Opioid binding also inhibits secretion while increasing absorption of fluids. The net result is the formation of dry, hard stools that are difficult to pass. Opioid tolerance and constipationWith repeated exposure to morphine, tol-erance does not develop to constipation as it does to other effects such as anal-gesia, nausea and vomiting or pruritus. It has been suggested that upregulation of the drug efflux protein P-glycoprotein is required for tolerance development. Studies have demonstrated that morphine induces P-glycoprotein upregulation in the brain, but it does not upregulate  intestinal P-glycoprotein.1Handling opioid-induced constipation Constipation management is an important issue as patients suffering from opioid-induced constipation have decreased lev-els of activity, miss more work and have decreased health-related quality of life scores. Apart from instituting a prophylac-tic laxative regimen, the physician does not have many options for resolving this A hazardous journey: tackling opioid-induced constipation without losing effective pain control can be a difficult undertakingproblem. On the one hand reducing the opioid dosage may increase levels of pain, and on the other hand if constipation becomes more severe the patient may decide to stop the opioid treatment. Like Ulysses in Greek mythology, the physician must decide how to navigate the narrow strait between Scylla the six-headed mon-ster and Charybdis the whirlpool. Ulysses was smart enough to successfully sail between these two dangers, although he lost a few crew members along the way. Decreasing the morphine dosage is not the best way to move forward as the dose of opioids that induces constipation is much smaller than that required for anal-gesia. Opioid-induced constipation is seen even with a single administration of morphine. Even a low dose of morphine (0.05mg/kg) was shown to increase oral to caecum transit time by 40 per cent.2 Reducing the severity of constipation by lowering the morphine dosage requires a dramatic reduction of opioid which will probably result in an increased pain severity for the patient, thereby increas-ing the patient’s distress. Conditions for a vicious circle are set up. The only viable reason to decrease opioid dosage in this setting would be the suspicion of opioid-induced hyperalgesia. To escape from this dilemma some steps need to be undertaken. The first is not to give in to temptation to reduce the mor-phine dosage. Control of the pain is a high priority and it should remain efficient. Moreover, we know that this measure is unlikely to reduce the severity of the con-stipation. The second step is to plan a pro-phylactic laxative regimen, which should be started at the time opioid therapy begins.References1. Tan-No K, Niijima F, Nakagawasai O, et al. Development of tolerance to the inhibitory effect of loperamide on gastrointestinal transit in mice. Eur J Pharm Sci 2003;20:357-63.2. Yuan CS, Foss JF, Osinski J, et al. The safety and efficacy of oral methylnaltrexone in preventing morphine-induced delay in oral-cecal transmit time. Clin Pharmacol Ther 1997;61:467-75.iStockIN MY OPINION6 paineurope  2008: Issue 1

Opioid-induced constipation: avoiding the perils and pitfalls

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Opioid-induced constipation: avoiding the perils and pitfalls

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