Methylnaltrexone for the Management of Unwanted Peripheral Opioid Effects
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DRUG EVALUATION Methylnaltrexone for the management of unwanted peripheral opioid effects Peter Holzer For many a patient suffering from moderate to severe pain, opioid analgesics offer the Medical University of Graz, Research Unit of anxiously sought-after relief, but at a high price. While the pain is wearing off, distressful Translational constipation, abdominal discomfort, nausea and urinary retention ensue. These unwanted Neurogastroenterology, effects have been difficult to deal with, and the laxatives that are usually prescribed Institute of Experimental and Clinical Pharmacology, ameliorate constipation in no more than 50% of the patients receiving opiates. A new Universitätsplatz 4, treatment concept emerged from the development of opioid receptor antagonists with a A-8010 Graz, Austria peripherally restricted site of action. One of these treatments is methylnaltrexone, which Tel.: +43 316 380 4500 Fax: +43 316 380 9645 clinical trials have shown to be of benefit in opioid-induced constipation, postoperative [email protected] ileus and urinary retention, while analgesia remains unabated. The drug is well tolerated and holds great promise in freeing opioid therapy of some of its most-feared adverse aspects. In 2008, methylnaltrexone (RelistorTM) was approved in the USA, Canada and Europe for the treatment of opioid-induced constipation in patients with advanced illness. Opioids denominate exogenous and endogenous the bowel, anorexia, nausea and vomiting, as well compounds that activate the principal µ-, κ- and as interference with oral drug administration and δ-opioid receptors. The term opioid has been absorption [1,2]. The symptoms associated with derived from opium, which refers to the dried OBD can profoundly impair the quality of life, latex collected from the unripe seed capsules of and in some patients can be so severe that they Papaver somniferum. Due to its efficacy, opium prefer to discontinue analgesic therapy rather has been used since ancient times to treat pain than experience the discomfort of OBD [1,3]. and diarrhea – the major opioid alkaloids being Unlike other adverse effects of chronic opioid morphine and codeine. Despite many attempts therapy, such as sedation, nausea and vomiting, to develop other strong pain medications, opioid which often resolve with continued use, OBD analgesics have remained the mainstay of therapy generally persists throughout treatment [1]. in many patients with moderate to severe pain. The distressing nature of OBD is underscored Unfortunately, adverse effects can severely com- by the frequency of its occurrence. Since GI promise the therapeutic benefit offered by these function is impaired by subanalgesic opioid drugs [1]. In the periphery, these unwanted doses, OBD affects 40–90% of patients taking effects of opioids comprise gastrointestinal (GI) opioids for chronic pain [1,4]. There are data in stasis, urinary retention and pruritus, and can be the literature that indicate that the distress of disabling to a degree that opioid treatment needs OBD can rival that of pain associated with the to be reduced or even abandoned. underlying disease [1]. Although less well studied, urinary retention Opioid-induced bowel dysfunction, owing to impaired micturition is another side prolongation of postoperative ileus & effect of opioid therapy, and a significant source urinary retention of morbidity. Studies in postoperative patients In the GI tract, the adverse effects of opioids indicate that total urinary retention requiring Keywords: constipation, manifest themselves primarily in constipation, catheterization may develop in 3.8–18.1% of methylnaltrexone, opioid characterized by a reduction of defecation fre- the patients, the use of patient-controlled anal- analgesics, opioid-induced quency, hard, dry stools, fecal impaction, incom- gesia with morphine being a significant risk fac- bowel dysfunction, opioid-induced urinary plete evacuation, defecation-associated straining, tor [4,5]. Partial urinary retention is thought to retention, peripherally abdominal bloating and distention, abdominal be an even more frequent adverse reaction to restricted opioid receptor discomfort and pain, and increased gastro- opioid therapy. antagonists, postoperative ileus esophageal reflux. Collectively, these symptoms Another unwanted condition related to opioid are embodied in the term opioid-induced bowel medication is postoperative ileus (POI), which part of dysfunction (OBD), which may lead to second- occurs most commonly following abdominal or ary complications such as pseudo-obstruction of pelvic surgery. POI is characterized by bowel 10.2217/14750708.5.4.531 © 2008 Future Medicine Ltd ISSN 1475-0708 Therapy (2008) 5(4), 531–543 531 DRUG EVALUATION – Holzer distention, lack of bowel sounds, accumulation via the Gi/Go subtypes of G-proteins to various of gas and fluid in the GI lumen, intolerance of cellular transduction processes [10,11]. Studies in solid food, nausea, vomiting and delayed passage isolated tissues from the human intestine show of flatus and stool [1,6,7]. Motor stasis occurs in that µ-, κ- and δ-opioid receptors contribute to all segments of the digestive tract, the colon usu- opiate-induced inhibition of muscle activity [1,2]. ally being most severely affected, and lasts on Propulsive motility in the rat intestine is blocked average 3–7 days [4]. Opioid analgesics have an by µ- and δ-opioid receptor agonists [12], whereas adverse influence on postoperative GI motility, peristalsis in the guinea-pig intestine is sup- as their use for postoperative analgesia delays pressed by activation of µ- and κ-opioid recep- recovery of normal bowel function [1,4]. tors [16]. Although these data indicate that OBD is mediated by opioid receptors in the gut [1,2], Mechanisms of action of opioid-induced there are experimental data to show that intra- inhibition of GI function & micturition cerebral injection of opioid analgesics also delays The effect of opioid analgesics on the GI tract is intestinal transit [17]. However, opiate-induced thought to reflect the action of endogenous opi- blockade of gut motility correlates better with oid peptides on GI physiology. Both endogenous opiate concentrations in the gut than with opiate and exogenous opioids modify GI function by concentrations in the brain [18]. In addition, the interaction with µ-, κ- and δ-opioid receptors, all N-methyl quaternary analogs of naloxone and of which are present in the enteric nervous sys- naltrexone, which do not cross the blood–brain tem [8–11]. Opioid receptor agonists can interrupt barrier, are able to fully antagonize the effects of both excitatory and inhibitory enteric pathways morphine in the canine and rat intestine [1,18]. It governing muscle activity [2,11]. For this reason, follows that the adverse influence of opiates on the net effect on motility can be quite diverse. GI function results primarily from interaction Suppression of excitatory neural pathways results with opioid receptors in the gut. in suppression of acetylcholine release and peri- The pathophysiology of prolonged POI staltic contractions, whereas blockade of inhibi- involves inflammatory, immunological, muscu- tory neural pathways results in depression of lar and neurogenic mechanisms [7,19,20]. Post- nitric oxide release from inhibitory motor neu- operative pain control with opioids is thought to rons, disinhibition of GI muscle activity, eleva- exacerbate POI, as the time required for resolu- tion of resting muscle tone and nonpropulsive tion of POI following colectomy is related to the motility patterns [2,9,11–13]. dose of morphine administered [21]. In addition, Depending on whether interruption of excita- it is assumed that the GI opioid system contrib- tory or inhibitory neural pathways is prevailing, utes to the condition [2,8]. muscle relaxation or spasm will ensue in response The pathophysiology of opioid-induced uri- to opiate administration. As a result, opioid nary retention is not completely understood. receptor agonists inhibit gastric emptying, Opioids decrease the force of detrusor contrac- increase pyloric muscle tone, induce pyloric and tion, decrease the sensation of bladder filling, duodenojejunal phasic pressure activity, disturb but probably do not increase sphincter tone [22]. the migrating myoelectrical complex, delay tran- These adverse effects involve opioid actions in sit through the small and large intestine and ele- the CNS and, possibly, in the periphery [23–25]. vate the resting anal sphincter pressure [1,2,11]. The halt in propulsive motility combines with Unmet needs in the current inhibition of GI ion and fluid transport. management of unwanted opioid Through prolonged contact of the intestinal effects in the periphery contents with the mucosa and interruption of The frequency and distress of OBD profoundly prosecretory enteric reflexes, opioids attenuate impairs the quality of life, and often necessitates the secretion of electrolytes and water, and facili- rescue treatment, which is difficult to achieve. tate the net absorption of fluid [12,14,15]. The There are two main approaches to the patient experiences constipation, hard, dry stools pharmacological management of OBD: nonspe- and abdominal discomfort. cific treatment with laxatives, and specific treat- In considering pharmacological opportunities ment with opioid receptor antagonists (Box 1). to manage OBD, it is important to know the Softening, stimulant and osmotic laxatives are opioid receptor subtypes responsible for this most