Gastrointestinal Adverse Effects of Opioids
Systemic opioids are often the mainstay of treatment for acute and chronic pain. Their use is frequently limited by intolerable adverse effects, which can include constipation, nausea, and vomiting. Constipation affects >50% of patients with metastatic malignancies receiving pain medication and 30% of patients receiving chronic opioid treatment for nonmalignant pain.1,2 Severe constipation can reduce the value of effective pain relief by >30%.3 Nausea occurs in 8-35% of patients, whereas vomiting occurs in 14-40%.4 The successful use of opioids thus relies on balancing analgesia with adverse effect management. Potentially new therapies may reduce the side effects of opiates and may provide useful adjunct therapy for the patient undergoing chronic pain treatment.
The three main opioid receptor classes ?, d, and k mediate their peripheral and central actions. All belong to the family of G-protein coupled receptors, which reduce intracellular cAMP by inhibiting adenylate cyclase activity.5 The ?1-receptors are the principal mediators of analgesia via their central actions, whereas the ?2-receptors act mostly in the periphery, producing gastrointestinal dysfunction.6 Opioid k-receptors are more abundant in the periphery, and can also mediate analgesia and bowel dysfunction whereas d-receptors may also play a role in analgesia.6 Opioid m-receptors predominate on neurons in the submucosal plexus, whereas k-receptors predominate in the myenteric plexus.6 These receptors exert effects locally and centrally to delay intestinal transit by inducing non-propulsive contractions of the longitudinal muscles, decreasing segmentation of the circular muscles, delaying gastric emptying, preventing intestinal fluid secretion, increasing fluid re-absorption in the colon by decreasing transit time and increasing net solute absorption, and inhibiting ileocecal sphincter and defecation reflexes.7,8 The adverse effects of nausea and vomiting are predominantly centrally m-receptor mediated due to direct opioid action on the chemoreceptor trigger zone (CTZ) at the area postrema of the medulla, enhanced by delayed gastric emptying, impaired motility, and stimulation of gastrointestinal mechanoreceptors.8
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