Development of Peripheral Opioid Antagonists: New Insights Into Opioid Effects

Department of Anesthesia and Critical Care, University of Chicago, 5841 S Maryland Ave, MC 4028, Chicago, IL 60637, USA.
Mayo Clinic Proceedings (Impact Factor: 6.26). 11/2008; 83(10):1116-30. DOI: 10.4065/83.10.1116
Source: PubMed


The recent approval by the US Food and Drug Administration of 2 medications--methylnaltrexone and alvimopan--introduces a new class of therapeutic entities to clinicians. These peripherally acting mu-opioid receptor antagonists selectively reverse opioid actions mediated by receptors outside the central nervous system, while preserving centrally mediated analgesia. Methylnaltrexone, administered subcutaneously, has been approved in the United States, Europe, and Canada. In the United States, it is indicated for the treatment of opioid-induced constipation in patients with advanced illness (eg, cancer, AIDS) who are receiving palliative care, when response to laxative therapy has not been sufficient. Alvimopan, an orally administered medication, has been approved in the United States to facilitate recovery of gastrointestinal function after bowel resection and primary anastomosis. Clinical and laboratory studies performed during the development of these drugs have indicated that peripheral receptors mediate other opioid effects, including decreased gastric emptying, nausea and vomiting, pruritus, and urinary retention. Laboratory investigations with these compounds suggest that opioids affect fundamental cellular processes through mechanisms that were previously unknown. These mechanisms include modifications of human immunodeficiency virus penetration, tumor angiogenesis, vascular permeability, and bacterial virulence.

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    • "Another strategy may be coadministration of COX-2 inhibitors which may have an opioid sparing effect [109] and simultaneously inhibit the adverse effects of opioids on renal hemodynamics. Opioid-induced peripheral effects can also be antagonized by coadministration of peripherally selective opioid receptor antagonists [110]. Before advancing to clinical use, however, newer strategies need to be tested for potential adverse effects on the pathophysiology of SCD using validated transgenic mouse models of SCD. "
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    ABSTRACT: Pain is a hallmark of sickle cell disease (SCD) and its treatment remains challenging. Opioids are the major family of analgesics that are commonly used for treating severe pain. However, these are not always effective and are associated with the liabilities of their own. The pharmacology and multiorgan side effects of opioids are rapidly emerging areas of investigation, but there remains a scarcity of clinical studies. Due to opioid-induced endothelial-, mast cell-, renal mesangial-, and epithelial-cell-specific effects and proinflammatory as well as growth influencing signaling, it is likely that when used for analgesia, opioids may have organ specific pathological effects. Experimental and clinical studies, even though extremely few, suggest that opioids may exacerbate existent organ damage and also stimulate pathologies of their own. Because of the recurrent and/or chronic use of large doses of opioids in SCD, it is critical to evaluate the role and contribution of opioids in many complications of SCD. The aim of this review is to initiate inquiry to develop strategies that may prevent the inadvertent effect of opioids on organ function in SCD, should it occur, without compromising analgesia.
    01/2015; 2015:1-10. DOI:10.1155/2015/540154
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    • "A phase III trial of 485 patients reported a nonsignificant increase in the proportion of patients experiencing spontaneous bowel movement in the alvimopan group (63%) compared to the placebo group (56%) [36]. Another study of patients with chronic cancer pain did not find any increase in the frequency of bowel movements with doses of 0.5 mg to 1 mg twice daily [37]. Consequent to these disappointing phase III data, further development of alvimopan to treat OIC was discontinued [38]. "
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    ABSTRACT: Although opioids offer potent analgesia for severe acute and chronic noncancer pain, adverse gastrointestinal effects potentially undermine their clinical utility. In particular, between 40% and 95% of patients develop opioid-induced constipation (OIC). Therefore, there is a consensus that patients should commence laxatives at the start of opioid therapy and continue throughout treatment. Nevertheless, laxatives are not routinely coprescribed with opioids. Even when concurrent laxatives are prescribed, approximately half the patients treated for OIC do not achieve the desired improvement. Moreover, laxatives do not target the underlying cause of OIC (opioid binding to the μ -receptors in the enteric system) and as such are not very effective at managing OIC. The failure of lifestyle modification and laxatives to treat adequately many cases of OIC led to the concurrent use of peripherally acting opioid antagonists (such as methylnaltrexone bromide and naloxone) to reduce the incidence of gastrointestinal adverse events without compromising analgesia. Judicious use of the various options to manage OIC should allow more patients to benefit from opioid analgesia. Therefore, this paper reviews the causes, consequences, and management of OIC to help clinicians optimise opioid analgesia.
    Gastroenterology Research and Practice 05/2014; 2014:141737. DOI:10.1155/2014/141737 · 1.75 Impact Factor
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    • "Recently, it was demonstrated that the μ-opioid receptor regulates cancer progression in animal models (Moss and Rosow 2008; Wang et al. 2009; Singleton and Moss 2010). The μ-opioid receptor-knockout mice were shown not to develop significant tumors when injected with Lewis lung cancer cells as did the wild-type controls (Mathew et al. 2009). "
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    ABSTRACT: Morphine is considered the "gold standard" for relieving pain and is currently one of the most effective drugs available clinically for the management of severe pain associated with cancer. In addition to its use in the treatment of pain, morphine appears to be important in the regulation of neoplastic tissue. Although morphine acts directly on the central nervous system to relieve pain, its activities on peripheral tissues are responsible for many of the secondary complications. Therefore, understanding the impact, other than pain control, of morphine on cancer treatment is extremely important. The effect of morphine on tumor growth is still contradictory, as both growth-promoting and growth-inhibiting effects have been observed. Accumulating evidence suggests that morphine can affect proliferation and migration of tumor cells as well as angiogenesis. Various signaling pathways have been suggested to be involved in these extra-analgesic effects of morphine. Suppression of immune system by morphine is an additional complication. This review provides an update on the influence of morphine on the growth and migration potential of tumor cells.
    Archiv für Experimentelle Pathologie und Pharmakologie 09/2011; 384(3):221-30. DOI:10.1007/s00210-011-0672-4 · 2.47 Impact Factor
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