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Oncology Nursing Forum Nov 2020A systematic review and meta-analysis was conducted to inform the development of national clinical practice guidelines on the management of cancer constipation. (Meta-Analysis)
Meta-Analysis
PROBLEM IDENTIFICATION
A systematic review and meta-analysis was conducted to inform the development of national clinical practice guidelines on the management of cancer constipation.
LITERATURE SEARCH
PubMed®, Wiley Cochrane Library, and CINAHL® were searched for studies published from May 2009 to May 2019.
DATA EVALUATION
Two investigators independently reviewed and extracted data from eligible studies. The Cochrane Collaboration risk-of-bias tool was used, and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to assess the certainty of the evidence.
SYNTHESIS
For patients with cancer and opioid-induced constipation, moderate benefit was found for osmotic or stimulant laxatives; small benefit was found for methylnaltrexone, naldemedine, and electroacupuncture. For patients with cancer and non-opioid-related constipation, moderate benefit was found for naloxegol, prucalopride, lubiprostone, and linaclotide; trivial benefit was found for acupuncture.
IMPLICATIONS FOR PRACTICE
Effective strategies for managing opioid-induced and non-opioid-related constipation in patients with cancer include lifestyle, pharmacologic, and complementary approaches.
SUPPLEMENTAL MATERIAL CAN BE FOUND AT HTTPS
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Topics: Analgesics, Opioid; Constipation; Gastrointestinal Agents; Humans; Neoplasms
PubMed: 33063777
DOI: 10.1188/20.ONF.E211-E224 -
Neuroscience Oct 2020The present study was performed to determine neuronal loci and individual molecular mechanisms responsible for remifentanil-induced hyperalgesia. The effect of...
The present study was performed to determine neuronal loci and individual molecular mechanisms responsible for remifentanil-induced hyperalgesia. The effect of methylnaltrexone (MNX) on remifentanil-induced behavioral hyperalgesia was assessed to distinguish contributions of the peripheral and/or central nervous system to remifentanil-induced hyperalgesia. Phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) in the dorsal root ganglion (DRG) neurons after remifentanil infusion, and the effect of a p38MAPK inhibitor on remifentanil-induced hyperalgesia were analyzed to investigate involvement of p38MAPK in the peripheral mechanisms of remifentanil-induced hyperalgesia. Spinal levels of prodynorphin mRNA after remifentanil infusion, and the effect of the BK2 bradykinin receptor antagonist on remifentanil-induced hyperalgesia were investigated to assess potential spinal mechanisms. The effects of MNX and BK2 antagonists on remifentanil-induced exacerbation of post-incisional hyperalgesia were also investigated using behavioral analysis. Remifentanil infusion induced hyperalgesia in the early (4 h to 2 days) and late (8-14 days) post-infusion periods. MNX inhibited hyperalgesia only during the early post-infusion period. p38MAPK phosphorylation was observed in the DRG neuron, and the p38MAPK inhibitor inhibited hyperalgesia during the early post-infusion period. Prodynorphin expression increased in the spinal cord, and a BK2 antagonist inhibited hyperalgesia during the late post-infusion period. Remifentanil-induced exacerbation of incisional hyperalgesia was inhibited by MNX and the BK2 antagonist. The present study demonstrated that remifentanil activates peripheral and spinal neurons to promote chronologically distinctive hyperalgesia. p38MAPK phosphorylation in the DRG neuron leads to peripherally-driven hyperalgesia during the early post-infusion period, while spinal dynorphin-bradykinin signaling promotes hyperalgesia during the late post-infusion period.
Topics: Analgesics, Opioid; Animals; Ganglia, Spinal; Hyperalgesia; Piperidines; Rats; Rats, Sprague-Dawley; Remifentanil; Spinal Cord
PubMed: 32818602
DOI: 10.1016/j.neuroscience.2020.08.014 -
Journal of Gastrointestinal Surgery :... Jan 2021Postoperative ileus (POI) and constipation are common secondary effects of opioids and carry significant clinical and economic impacts. μ-Opioid receptors mediate... (Review)
Review
Postoperative ileus (POI) and constipation are common secondary effects of opioids and carry significant clinical and economic impacts. μ-Opioid receptors mediate opioid analgesia in the central nervous system (CNS) and gastrointestinal-related effects in the periphery. Peripherally acting μ-opioid receptor antagonists (PAMORAs) block the peripheral effects of opioids in the gastrointestinal tract, while maintaining opioid analgesia in the CNS. While most are not approved for POI or postoperative opioid-induced constipation (OIC), PAMORAs have a potential role in these settings via their selective effects on the μ-opioid receptor. This review will discuss recent clinical trials evaluating the safety and efficacy of PAMORAs, with a focus on alvimopan (Entereg) and methylnaltrexone (Relistor) in patients with POI or postoperative OIC. We will characterize potential factors that may have impacted the efficacy observed in phase 3 trials and discuss future directions for the management and treatment of POI.
Topics: Analgesics, Opioid; Constipation; Humans; Ileus; Narcotic Antagonists; Postoperative Complications
PubMed: 32779081
DOI: 10.1007/s11605-020-04671-x -
Psychopharmacology Bulletin Jul 2020Opioid medications are a pillar of acute and chronic analgesia, though their use is often accompanied by side-effects, such as opioid-induced constipation.... (Review)
Review
PURPOSE OF REVIEW
Opioid medications are a pillar of acute and chronic analgesia, though their use is often accompanied by side-effects, such as opioid-induced constipation. Unfortunately, tolerance rarely develops to this untoward side effect. This review presents the background, evidence, and indications for the use of Naldemedine (Brand name Symproic 0.2 mg tablets) to treat opioid-induced constipation.
RECENT FINDINGS
Opioids are often used for the treatment of acute and chronic analgesia. Outside of the central effect they exert, they also interact with peripheral receptors, resulting in opioid-induced constipation, the commonest of side effects of chronic opioid usage. Complications include colonic distention, ileus, perforation, and can progress to other serious bowel complications, which can result in hospitalization and fatal events.For the most part, laxatives and other anti-constipation therapies are often inefficient and require intervention directed at the root cause, such as peripheral mu receptor agonists, including methylnaltrexone, naloxegol, and naldemedine. Naldemedine is the most recent to gain FDA approval of the group.An antagonist of Mu, Kappa, and Delta peripheral receptors, Naldemedine, is the only drug to counteract all three receptor classes. It was shown to be both safe and effective when compared with placebo. No data exists to compare its efficacy to that of other members of the group.
SUMMARY
Opioids are frequently used in the management of acute and chronic pain. The most common of the side effects is opioid-induced constipation, secondary to the peripheral activity of opioids. Naldemedine is an FDA-approved, once-daily oral tablet that counteracts this side effect by antagonizing mu, kappa, and delta-opioid receptors and has been shown to be safe and effective. Further investigation including head-to-head clinical trials are required to evaluate the relative efficacy of naldemedine compare with other peripheral opiate receptor antagonists.
Topics: Analgesics, Opioid; Constipation; Humans; Naltrexone; Narcotic Antagonists; Opioid-Induced Constipation
PubMed: 32733114
DOI: No ID Found -
BMJ Supportive & Palliative Care Sep 2020Opioid-induced constipation (OIC) is common and can significantly affect quality of life. Naloxegol and methylnaltrexone are peripherally acting µ-opioid receptor...
Opioid-induced constipation (OIC) is common and can significantly affect quality of life. Naloxegol and methylnaltrexone are peripherally acting µ-opioid receptor antagonists (PAMORAs) which are effective for the management of OIC. We report on a case in the palliative care setting where a patient with established OIC had an inadequate response to naloxegol but an effective and immediate response to methylnaltrexone at the dose recommended for her weight. This is the first reported case of two PAMORAs used concomitantly.
Topics: Analgesics, Opioid; Female; Humans; Middle Aged; Morphinans; Naltrexone; Narcotic Antagonists; Opioid-Induced Constipation; Palliative Care; Polyethylene Glycols; Quality of Life; Quaternary Ammonium Compounds
PubMed: 32709705
DOI: 10.1136/bmjspcare-2019-002172 -
The Clinical Journal of Pain Sep 2020The objective of this study was to provide an overview of opioid-induced constipation (OIC) and its influence on disease burden and quality of life (QOL). (Review)
Review
Opioid-induced Constipation: A Review of Health-related Quality of Life, Patient Burden, Practical Clinical Considerations, and the Impact of Peripherally Acting μ-Opioid Receptor Antagonists.
OBJECTIVE
The objective of this study was to provide an overview of opioid-induced constipation (OIC) and its influence on disease burden and quality of life (QOL).
METHODS
This is a narrative review.
RESULTS
For many patients, opioid-related side effects, the most common being OIC, have the potential to significantly impair patients' QOL. Patients with OIC often experience substantial overall burden (ie, increases in anxiety and depression, impairments in activities of daily living, low self-esteem, feelings of embarrassment) and economic burden (ie, higher health care costs, more frequent doctor visits, increased out-of-pocket medication costs), which often causes patients to modify or discontinue opioid treatment despite the analgesic benefits. OIC occurs when opioids bind to peripheral μ-opioid receptors in the gastrointestinal tract. Currently, 4 Food and Drug Administration (FDA)-approved medications are available for OIC, 3 of which are peripherally acting µ-opioid receptor antagonists (PAMORAs). PAMORAs block µ-opioid receptors in the gastrointestinal tract without affecting the central analgesic effects of the opioid and thus provide a targeted approach to OIC management. Two PAMORAs, naldemedine and methylnaltrexone, have shown significant improvements in QOL based on the Patient Assessment of Constipation Symptoms questionnaire relative to placebo. Along with pharmacologic management for OIC, health care providers should institute comprehensive communication strategies with patients to ensure OIC is effectively recognized and managed.
DISCUSSION
OIC has both physical and psychological impacts on patients. PAMORAs provide effective relief of OIC while also improving QOL. To augment the pharmacologic management of OIC, proactive counseling approaches between physicians and patients may help relieve some of the patient burden associated with OIC and lead to improved outcomes.
Topics: Activities of Daily Living; Analgesics, Opioid; Humans; Narcotic Antagonists; Opioid-Induced Constipation; Quality of Life
PubMed: 32554978
DOI: 10.1097/AJP.0000000000000852 -
Pharmacological Research Sep 2020Stimulation of opioid receptors is widely used for relieving cancer pain in patients with advanced cancer. The expression of tissue opioid receptors varies depending on... (Review)
Review
Stimulation of opioid receptors is widely used for relieving cancer pain in patients with advanced cancer. The expression of tissue opioid receptors varies depending on the types of cancer and it is regulated by several factors. This review provides a focused overview of the current evidence for the role of opioid receptors in modulating cancer progression, a discussion of the proposed underlying mechanisms and the pharmacological activity of opioid agonists and antagonists. Conflicting evidence from preclinical and clinical studies suggests the possible involvement of opioid receptor agonists in both the development and suppression of human cancer. Some retrospective clinical studies also show a possible detrimental effect on long-term patient outcomes. Among the opioid receptor agonists, morphine has been extensively studied in various cancer types. Moreover, various pathological processes of human cancer are affected by opioid receptor agonists, such as tumour growth, angiogenesis and immunosuppression. These findings highlight the functional value of opioid receptors in human cancer, and a potential double role of opioid receptor agonists and antagonists in human cancer treatment.
Topics: Analgesics, Opioid; Animals; Antineoplastic Agents; Cancer Pain; Disease Progression; Humans; Narcotic Antagonists; Neoplasms; Receptors, Opioid; Signal Transduction
PubMed: 32504831
DOI: 10.1016/j.phrs.2020.104938 -
Pain Medicine (Malden, Mass.) Nov 2020To assess the efficacy and safety of peripherally acting mu-opioid receptor antagonists (PAMORAs) for the treatment of opioid-induced constipation (OIC). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To assess the efficacy and safety of peripherally acting mu-opioid receptor antagonists (PAMORAs) for the treatment of opioid-induced constipation (OIC).
METHODS
Randomized controlled trials (RCTs) were searched for OIC therapy comparing PAMORAs with placebo. Both a pairwise and network meta-analysis were performed. The surface under the cumulative ranking area (SUCRA) was used to determine the efficacy and safety of OIC treatment using different PAMORAs.
RESULTS
The primary target outcome was a response that achieves an average of three or more bowel movements (BMs) per week. In the network meta-analysis, four PAMORAs (naldemedine, naloxone, methylnaltrexone, and alvimopan) showed a better BM response than the placebo. Naldemedine was ranked first (odds ratio [OR] = 2.8, 95% credible interval [CrI] = 2-4.5, SUCRA = 89.42%), followed by naloxone (OR = 2.9, 95% CrI = 1.6-5.3, SUCRA = 87.44%), alvimopan (OR = 2.2, 95% CrI = 1.3-3.5, SUCRA = 68.02%), and methylnaltrexone (OR = 1.7, 95% CrI = 1.0-2.8, SUCRA = 46.09%). There were no significant differences in safety found between the PAMORAs and the placebo.
CONCLUSIONS
We found that PAMORAs are effective and can be safely used for the treatment of OIC. In network meta-analysis, naldemedine and naloxone appear to be the most effective PAMORAs for the treatment of OIC.
Topics: Analgesics, Opioid; Constipation; Humans; Narcotic Antagonists; Network Meta-Analysis; Opioid-Induced Constipation; Receptors, Opioid, mu
PubMed: 32488259
DOI: 10.1093/pm/pnaa152 -
Alimentary Pharmacology & Therapeutics Jul 2020When opioid-induced constipation is treated with centrally acting opioid antagonists, there may be opioid withdrawal or aggravation of pain due to inhibition of... (Meta-Analysis)
Meta-Analysis
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.
Topics: Analgesics, Opioid; Constipation; Humans; Laxatives; Narcotic Antagonists; Randomized Controlled Trials as Topic; Receptors, Opioid, mu; Treatment Outcome
PubMed: 32462777
DOI: 10.1111/apt.15791 -
Journal of Neuroscience Research Jan 2022Opioids are effective analgesics in the management of severe pain. However, tolerance, leading to dose escalation and adverse effects are significant limiting factors in...
Opioids are effective analgesics in the management of severe pain. However, tolerance, leading to dose escalation and adverse effects are significant limiting factors in their use. The role of peripheral opioid receptors in analgesia has been discussed especially under inflammatory conditions. The results from pharmacological and conditional knockout studies together do not provide a clear picture of the contribution of peripheral opioid receptors on antinociceptive tolerance and this needs to be evaluated. Therefore, we studied whether the peripherally restricted opioid receptor antagonist, methylnaltrexone (MNTX), could prevent morphine tolerance without attenuating the antinociceptive effect of morphine. Male Sprague-Dawley rats were treated for 7 days with increasing subcutaneous doses of morphine (5-30 mg/kg) and were coadministered saline, MNTX (0.5 or 2 mg/kg), or naltrexone (NTX; 2 mg/kg). Nociception was assessed with tail-flick, hotplate, and von Frey tests. Morphine, MNTX, and NTX concentrations in the plasma, brain, and spinal cord were measured by liquid chromatography-tandem mass spectrometry. In acute coadministration, NTX, but not MNTX, abolished the acute antinociceptive effects of morphine in all nociceptive tests. The antinociceptive tolerance after repeated morphine administration was also prevented by NTX but not by MNTX. MNTX penetrated to the spinal cord and the brain to some extent after repeated administration. The results do not support the use of MNTX for preventing opioid tolerance and also suggest that morphine tolerance is mediated by central rather than peripheral opioid receptors in the rat.
Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Tolerance; Male; Morphine; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, mu
PubMed: 32459013
DOI: 10.1002/jnr.24638