Abstract and Introduction
Background: When opioid-induced constipation is treated with centrally acting opioid antagonists, there may be opioid withdrawal or aggravation of pain due to inhibition of μ-opioid analgesia. This led to the development of peripherally acting μ-opioid receptor antagonists (PAMORAs).
Aim: To evaluate the efficacy of available PAMORAs and other approved or experimental treatments for relieving constipation in patients with opioid-induced constipation, based on a systematic review and meta-analysis of published studies.
Methods: A search of MEDLINE, EMBASE and EBM Reviews Cochrane Central Register of Controlled Trials was completed in July 2019 for randomised trials compared to placebo. FDA approved doses or highest studied dose was evaluated. Efficacy was based on diverse endpoints, including continuous variables (the bowel function index, number of spontaneous bowel movements and stool consistency based on Bristol Stool Form Scale), or responder analysis (combination of >3 spontaneous bowel movements or complete spontaneous bowel movements plus 1 spontaneous bowel movement or complete spontaneous bowel movements, respectively, over baseline [so-called FDA endpoints]). Adverse effects evaluated included central opioid withdrawal, serious adverse events, abdominal pain and diarrhoea.
Results: We included 35 trials at low risk of bias enrolling 13 566 patients. All PAMORAs demonstrated efficacy on diverse patient response endpoints. There was greater efficacy with approved doses of the PAMORAs (methylnaltrexone, naloxegol and naldemidine), with lower efficacy or lower efficacy and greater adverse effects with combination oxycodone with naloxone, lubiprostone and linaclotide.
Conclusions: Therapeutic response in opioid-induced constipation is best achieved with the PAMORAs, methylnaltrexone, naloxegol and naldemidine, which are associated with low risk of serious adverse events.
Chronic pain occurs in association with cancer and non-cancer conditions. It has been estimated that 20% of patients presenting to physicians' offices in the United States with pain symptoms were prescribed opioids. Opioids are more effective than non-opioid analgesics in controlling moderate to severe pain. However, they also cause adverse effects such as physical dependence, tolerance, sedation, hyperalgesia and respiratory depression. Opioid-induced constipation is the most common gastrointestinal adverse effect,[4,5] causing a significant reduction in the quality of life.[6,7] Other common gastrointestinal effects of opioids are nausea, vomiting, abdominal pain, bloating and cramping.
The prevalence of opioid-induced constipation increases with increased duration of use of opioid analgesics. Treatment satisfaction with opioids decreases when opioid-induced constipation develops, and many patients tend to discontinue opioid therapy when they develop constipation. Mu-opioid receptors are expressed on enteric nerve cell bodies and facilitate potassium channel activation, membrane hyperpolarisation and inhibition of ongoing neural activity and transmitter release resulting in inhibition of motility and fluid secretion, including retardation of colonic transit.
The recommended outcome measures or assessment tools for opioid-induced constipation are as follows: stool consistency by Bristol Stool Form Scale, Bowel Function Index and Patient Assessment of Constipation Quality of Life. Bowel Function Index is a clinician assessment tool consisting of three variables rated by the patient from 0 to 100, based on the experience in previous 7 days: ease of defecation, feeling of incomplete bowel evacuation and personal judgment of constipation. A reference range of Bowel Function Index scores for nonconstipated patients is from 0 to 28.8. This provides a simple discrimination between constipated and nonconstipated patients on opioid therapy.
Four approaches are used for prophylaxis and treatment of opioid-induced constipation: first, over-the-counter agents[15,16] or agents approved for the treatment of chronic constipation specifically linaclotide, prucalopride and lubiprostone (the latter also approved for treatment of opioid-induced constipation); second, use of alternative opioids such as tapentadol (an enterally acting μ-opioid receptor agonist and norepinephrine reuptake inhibitor); third, use of a fixed combination of opioid and opioid antagonist such as oxycodone-naloxone and, fourth, use of peripherally acting mu-opioid receptor antagonists (PAMORAs).[18,19] The pharmacology of medications used in opioid-induced constipation appears in Box 1.[20–35] It is relevant to note that naloxone can enter the brain and it is theoretically conceivable that it may reverse analgesia or cause opiate withdrawal; however, the risk of this happening has not been assessed relative to other treatments used for opioid-induced constipation.
A systematic review by Luthra et al reviewed 27 randomised, controlled trials involving 9149 patients, based the analysis of efficacy on a dichotomous assessment of overall response to therapy (average of ≥3 bowel movements per week with an increase of ≥1 bowel movements per week over baseline) and concluded that naloxone was the best drug for treatment of patients with opioid-induced constipation, followed by naldemedine. However, the appraisal of the relative efficacy of diverse treatments appraised in network meta-analyses, specifically, is complicated by differences in distribution of the medication (based on bioavailability, lipophilic properties and penetration of the blood-brain barrier), receptor selectivity and potential for opioid withdrawal, as well as differences in trial design and endpoints. For example, the oral formulation of naloxone is widely distributed, has a narrow therapeutic index and can increase the risk of opioid withdrawal symptoms, whereas PAMORAs are extensively absorbed and excreted, do not cross the blood-brain barrier and are less likely to antagonise the analgesic effect of the opioid. Another significant confounder is variation of the primary or secondary outcome endpoints in the trials of opioid-induced constipation treatment; those endpoints included the Bowel Function Index, change in weekly number of spontaneous bowel movements and the U.S. Food and Drug Administration (FDA)-approved primary endpoint for constipation (three or more spontaneous bowel movements/week and an increase in one or more spontaneous bowel movements over baseline for ≥9 of 12 and ≥3 of the final 4 treatment weeks).
Nee et al performed a separate systematic review and meta-analysis that included 27 placebo-controlled trials (23 trials evaluated μ-opioid receptor antagonists, 3 lubiprostone and 1 prucalopride) with 5390 patients receiving a drug and 3491 receiving a placebo. Overall response to therapy was extracted in a dichotomous assessment using the original articles' prespecified outcome measure, or when unavailable, by extracting other clinically meaningful outcomes. Overall, using this dichotomous assessment, μ-opioid receptor antagonists, lubiprostone and prucalopride were superior to placebo for treatment of opioid-induced constipation, with overall NNT of 5 (95% CI, 4–7). Sensitivity analyses and meta-regression performed to account for heterogeneity showed treatment was more likely to be effective in study populations taking higher doses of opiates at baseline or refractory to laxatives. However, this systematic review and meta-analysis as well as the network meta-analysis conducted by Luthra et al did not provide detailed information on efficacy for the specific, diverse endpoints recommended for assessing efficacy in opioid-induced constipation treatment. The different conclusions reported by Luthra et al and Nee et al illustrate that the inferences from such analyses depend on the endpoints selected.
Adverse events of all of these medications can limit compliance. To date, studies have either combined all adverse events together or combined all opioids to address the risk of developing each adverse event.[39,40] Understanding the rates of each adverse event for each medication used for opioid-induced constipation can inform providers in the selection of individualised therapies.
The aim of this systematic review and meta-analysis was to evaluate multiple efficacy endpoints that address all aspects of bowel function and individual adverse effects of PAMORAs, μ-opioid antagonists and agents targeting chronic constipation in patients with opioid-induced constipation.
Aliment Pharmacol Ther. 2020;52(1):37-53. © 2020 Blackwell Publishing