Efficacy and Safety of Peripherally Acting μ-Opioid Receptor Antagonist (PAMORAs) for the Management of Patients With Opioid-Induced Constipation: A Systematic Review

Abstract

In treating chronic and acute pain, opioids are widely used. Although they do provide analgesia, their usage does come with adverse events (AEs). One of the most burdensome is opioid-induced bowel dysfunction, and more specifically opioid-induced constipation (OIC). The pathogenesis of these AEs is well known as the consequence of the action of opioids on m-receptors in the enteric nervous system. In recent years, medicines counteracting this specific action at the receptors have been registered for clinical use: the peripherally acting μ-opioid receptor antagonists (PAMORAs). The knowledge of their comparative efficacy and tolerability is very important for physicians and patients in opioid therapy. This systematic review of the existing literature on PAMORAs aimed to study the relative clinical advantages and disadvantages.The most important data banks, including "PubMed," "Embase," "CT.gov," "ICTRP" and "CINAHL" were used to find the published material on PAMORAs. The selected publications were examined to systematically analyze the efficacy and safety of the four existing PAMORAs.All of the medications are superior to placebo in reducing OIC. There are few published data on alvimopan used to treat OIC, and it is only indicated for the treatment of post-abdominal surgery ileus. Methylnaltrexone is studied mainly in its subcutaneous (SC) formulation. When used in its oral formulation, it seems more rapid than naloxegol and placebo in the reduction of OIC. Naldemedine is able to produce more spontaneous bowel movements (SBMs) when compared to alvimopan and naloxegol.Tolerability was found to be similar for all of them. In particular, they affect the gastrointestinal tract (GI), with flatulence and diarrhea, especially at high dosages. For some of them, nasopharyngitis and abdominal pain were observed as treatment adverse effects (TEAs). Several cardiovascular TEAs were reported after methylnaltrexone use, but it is not clear whether they were consequences of the drug or related to the general conditions of the patients.Considering the existing data, naloxegol and naldemedine seem to be the best choices, with a higher number of spontaneous bowel movements following naldemedine administration.

Factors associated with non-response to naldemedine for opioid-induced constipation in cancer patients: A subgroup analysis

“…Naldemedine is a PAMORA, and the mechanism of action suggests that efficacy may be greater for a shorter duration of opioid exposure. Administration of naldemedine from the initiation of opioids may also reduce the risk of developing the opioid-withdrawal symptoms that can be seen when naldemedine is started during opioid administration [22,23]. On the other hand, the factor "naldemedine prescription within 2 days of opioid initiation" was not extracted as a significant factor in the present study.…”

Opioids and Falls Risk in Older Adults: A Narrative Review

“…According to Screening Tool to Alert to Right Treatment (START) criteria, strong opioids should be used for severe pain or when treatment with paracetamol, NSAIDs or mild and moderate opioids are ineffective [24]. In addition, laxatives or peripherally acting μ-opioid receptor antagonists such as oral naloxone should be used regularly with opioids to avoid constipation [27]. Sometimes vomiting may also require a therapeutic approach.…”

A Survey of the Incidence of Constipation in Patients with Chronic Non-cancer Pain Using Opioid Analgesics in Japan

“…The role of peripheral μ-opioid receptors in tramadol-induced constipation is adequately described in a preclinical study in rodents [ 28 ]. Consequently, the co-administration of a peripherally acting μ-opioid receptor antagonist with negligible systemic availability, such as methylnaltrexone, naldemedine and naloxegol, presents a novel approach for selectively and locally antagonizing the gastrointestinal effects of opioids without compromising systemic analgesia [ 29 , 30 ] and is strongly recommended by the American Gastroenterological Association Institute guidelines on the medical management of OIC [ 31 ]. Such pharmacological treatment of OIC will support a holistic multidisciplinary approach with a combination of medications, exercise and psychotherapy for the management of chronic pain.…”