-
Journal of Pharmacy Practice Dec 2018Opioid receptors are distributed throughout the central and peripheral nervous systems and on many nonneuronal cells. Therefore, opioid administration induces effects... (Review)
Review
Opioid receptors are distributed throughout the central and peripheral nervous systems and on many nonneuronal cells. Therefore, opioid administration induces effects beyond analgesia. In the enteric nervous system (ENS), stimulation of µ-opioid receptors triggers several inhibitory responses that can culminate in opioid-induced bowel dysfunction (OBD) and its most common side effect, opioid-induced constipation (OIC). OIC negatively affects patients' quality of life (QOL), ability to work, and pain management. Although laxatives are a common first-line OIC therapy, most have limited efficacy and do not directly antagonize opioid effects on the ENS. Peripherally acting µ-opioid receptor antagonists (PAMORAs) with limited ability to cross the blood-brain barrier have been developed. The PAMORAs approved by the U S Food and Drug Administration for OIC are subcutaneous and oral methylnaltrexone, oral naloxegol, and oral naldemedine. Although questions of cost-effectiveness and relative efficacy versus laxatives remain, PAMORAs can mitigate OIC and improve patient QOL. PAMORAS may also have applications beyond OIC, including reducing the increased cardiac risk or potential tumorigenic effects of opioids. This review discusses the burden of OIC and OBD, reviews the mechanism of action of new OIC therapies, and highlights other potential opioid-related side effects mediated by peripheral opioid receptors in the context of new OIC therapies.
Topics: Analgesics, Opioid; Animals; Constipation; Humans; Narcotic Antagonists; Pain; Quality of Life; Receptors, Opioid, mu
PubMed: 28946783
DOI: 10.1177/0897190017732263 -
Therapeutics and Clinical Risk... 2016Opioid-induced constipation (OIC) is a frequent adverse event that impairs patients' quality of life. This article evaluates the objective plus subjective efficacy and...
INTRODUCTION
Opioid-induced constipation (OIC) is a frequent adverse event that impairs patients' quality of life. This article evaluates the objective plus subjective efficacy and the safety of methylnaltrexone (MNTX) in OIC patients.
METHODS
Randomized controlled trials from a recent systematic review were included. In addition, a PubMed search was conducted for January 2014 to December 21, 2015. We included randomized controlled trials with adult OIC patients, MNTX as study drug, and OIC as primary outcome. Results were categorized in three outcome types: objective outcome measures (eg, time to laxation), patient-reported outcomes (eg, straining), and global burden measures (eg, constipation distress). Dichotomous meta-analyses with risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using RevMan 5.3. Only comparisons between MNTX and placebo were made.
RESULTS
We included seven studies with 1,860 patients. A meta-analysis revealed that patients under MNTX had considerably more rescue-free bowel movement within 4 hours after the first dose (RR 3.74, 95% CI 2.87 to 4.86; five studies, n=938; I (2)=0). Results of the review indicated that patients under MNTX had a higher stool frequency and needed less time to laxation compared with placebo. Moreover, patients receiving MNTX tended to have better values in patient-reported outcomes and global burden measures. Meta-analyses on safety revealed that patients under MNTX experienced more abdominal pain (RR 2.38, 95% CI 1.75 to 3.23; six studies, n=1,412; I (2)=60%) but showed a nonsignificant tendency in nausea (RR 1.27, 95% CI 0.90 to 1.78; six studies, n=1,412; I (2)=12%) and diarrhea (RR 1.45, 95% CI 0.94 to 2.24; five studies, n=1,258; I (2)=45%). The incidence of MNTX-related serious adverse events was 0.2% (4/1,860).
CONCLUSION
MNTX has been shown to be effective and safe. Future randomized controlled trials should consequently incorporate objective outcome measures, patient-reported outcomes, and global burden measures, and research the efficacy of MNTX in other populations, for example, patients under opioids after surgical procedures.
PubMed: 27042082
DOI: 10.2147/TCRM.S80749 -
Journal of Pain Research 2021Methylnaltrexone inhibits opioid-induced constipation (OIC) by binding to peripheral µ-opioid receptors without impacting central opioid receptor mediated analgesia....
Subcutaneous Methylnaltrexone for Treatment of Opioid-Induced Constipation in Cancer versus Noncancer Patients: An Analysis of Efficacy and Safety Variables from Two Studies.
PURPOSE
Methylnaltrexone inhibits opioid-induced constipation (OIC) by binding to peripheral µ-opioid receptors without impacting central opioid receptor mediated analgesia. This analysis compared methylnaltrexone efficacy and safety among advanced illness patients with and without active cancer and OIC.
PATIENTS AND METHODS
This post hoc analysis included two multicenter, randomized, double-blind, placebo-controlled studies in adults with advanced illness and OIC who received subcutaneous methylnaltrexone. Efficacy endpoints included the proportion of patients achieving rescue-free laxation (RFL), time to RFL, weekly laxations within 24 hours after dosing, rescue laxative use, and pain scores. Adverse events were monitored for safety.
RESULTS
After pooling, 178 patients received methylnaltrexone (n = 116 with cancer) and 185 received placebo (n = 114 with cancer). Median baseline daily opioid morphine equivalents (mg/d) were higher in cancer (methylnaltrexone: 180; placebo: 188) versus noncancer patients (methylnaltrexone: 120; placebo: 80). The proportions of patients achieving RFL within 4 hours after ≥2 of the first 4 doses were significantly greater with methylnaltrexone (cancer: 56.9%; noncancer: 58.1%) versus placebo (cancer: 5.3%; noncancer: 11.3%; < 0.0001). The median time to laxation within 24 hours after the first methylnaltrexone dose was significantly shorter in cancer and noncancer patients versus placebo (cancer: 0.96 vs 22.53 hours, < 0.0001; noncancer: 1.25 vs >24 hours, = 0.0002). The mean number of weekly laxations within 24 hours after dosing by week 2 was significantly higher in methylnaltrexone- vs placebo-treated cancer and noncancer patients (cancer: 7.9 vs 4.9, < 0.0001; noncancer: 8.4 vs 5.0, < 0.0001). Methylnaltrexone reduced rescue laxative use without impacting pain scores. Consistent with previous data, methylnaltrexone was well tolerated in cancer and noncancer patients, and the AE profile did not suggest symptoms of opioid withdrawal.
CONCLUSION
Methylnaltrexone reduced RFL time in advanced-illness patients with and without active cancer, while maintaining pain control with opioid treatment despite higher baseline opioid use among cancer patients.
PubMed: 34512008
DOI: 10.2147/JPR.S312731 -
Anesthesiology Oct 1997
Topics: Gastric Emptying; Humans; Naltrexone; Narcotic Antagonists; Narcotics; Quaternary Ammonium Compounds
PubMed: 9357871
DOI: 10.1097/00000542-199710000-00003 -
Regional Anesthesia and Pain Medicine 2016In patients with chronic noncancer pain, subcutaneous methylnaltrexone for opioid-induced constipation (OIC) was examined in a randomized controlled trial (RCT) followed... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
In patients with chronic noncancer pain, subcutaneous methylnaltrexone for opioid-induced constipation (OIC) was examined in a randomized controlled trial (RCT) followed by an open-label extension (OLE). This study examined the reproducibility of RCT findings by analyzing data from placebo-treated patients who crossed over to methylnaltrexone.
METHODS
Adults with less than 3 weekly rescue-free bowel movements (RFBMs), taking 50 mg or more of an oral morphine equivalent per day, were randomized to receive methylnaltrexone 12 mg or placebo for 4 weeks, followed by open-label methylnaltrexone 12 mg as needed for 8 weeks.
RESULTS
A total of 134 placebo-treated patients (median morphine equivalent dose, 150 mg/d; mean of 1.1 RFBM per week) crossed over to methylnaltrexone in OLE. During the RCT, 9.7% of placebo-treated patients experienced an RFBM within 4 hours of first dose and 9.0% of all placebo injections resulted in an RFBM within 4 hours compared with 45.9% and 34.5%, respectively, with methylnaltrexone treatment in the OLE. When expressed as percentage of patients experiencing 3 or more RFBMs per week and a 1-RFBM increase over baseline, weekly values ranged from 35% to 40% during placebo treatment; at week 5 of OLE methylnaltrexone, this percentage increased to more than 70% and remained relatively stable throughout the OLE. The most common adverse events during methylnaltrexone treatment were abdominal pain (9.7% vs 1.5% for placebo) and nausea (5.2% vs 6.7%).
CONCLUSIONS
Findings during placebo treatment further establish the profile of OIC and support that little or no gastrointestinal tolerance develops across time. Findings under open-label conditions established the reproducibility and durability of methylnaltrexone for OIC.
Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Chronic Pain; Constipation; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Treatment Outcome; Young Adult
PubMed: 26650429
DOI: 10.1097/AAP.0000000000000341 -
The Cochrane Database of Systematic... Jun 2018Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events of treatment for pain in cancer and in palliative care, resulting in increased morbidity and reduced quality of life.This is an update of two Cochrane reviews. One was published in 2011, Issue 1 on laxatives and methylnaltrexone for the management of constipation in people receiving palliative care; this was updated in 2015 and excluded methylnaltrexone. The other was published in 2008, Issue 4 on mu-opioid antagonists (MOA) for OIBD. In this updated review, we only included trials on MOA (including methylnaltrexone) for OIBD in people with cancer and people receiving palliative care.
OBJECTIVES
To assess the effectiveness and safety of MOA for OIBD in people with cancer and people receiving palliative care.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, and Web of Science to August 2017. We also searched clinical trial registries and regulatory websites. We contacted manufacturers of MOA to identify further data.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that assessed the effectiveness and safety of MOA for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease they experienced.
DATA COLLECTION AND ANALYSIS
Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across the trials. Our primary outcomes were laxation, impact on pain relief, and adverse events. Impact on pain relief was a primary outcome because a possible adverse effect of MOAs is a reduction in pain relief from opioids. We assessed the evidence on these outcomes using GRADE.
MAIN RESULTS
We identified four new trials for this update, bringing the total number included in this review to eight. In total, 1022 men and women with cancer irrespective of stage or at a palliative care stage of any disease were randomised across the trials. The MOAs evaluated were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared with MOA with a placebo or with the active intervention administered at different doses or in combination with other drugs. The trial of naldemedine and the two of naloxone in combination with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. The four trials on methylnaltrexone were undertaken in palliative care where most participants had cancer. All trials were vulnerable to biases; four were at a high risk as they involved a sample of fewer than 50 participants per arm.In the trial of naldemedine compared to placebo in 225 participants, there were more spontaneous laxations over the two-week treatment for the intervention group (risk ratio (RR) 1.93, 95% confidence intervals (CI) 1.36 to 2.74; moderate-quality evidence). In comparison with higher doses, lower doses resulted in fewer spontaneous laxations (0.1 mg versus 0.2 mg: RR 0.73, 95% CI 0.55 to 0.95; 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89; moderate-quality evidence). There was moderate-quality evidence that naldemedine had no effect on opiate withdrawal. There were five serious adverse events. All were in people taking naldemedine (low-quality evidence). There was an increase in the occurrence of other (non-serious) adverse events in the naldemedine groups (RR 1.36, 95% CI 1.04 to 1.79, moderate-quality evidence). The most common adverse event was diarrhoea.The trials on naloxone taken either on its own, or in combination with oxycodone (an opioid) compared to oxycodone only did not evaluate laxation response over the first two weeks of administration. There was very low-quality evidence that naloxone alone, and moderate-quality evidence that oxycodone/naloxone, had no effect on analgesia. There was low-quality evidence that oxycodone/naloxone did not increase the risk of serious adverse events and moderate-quality evidence that it did not increase risk of adverse events.In combined analysis of two trials of 287 participants, we found methylnaltrexone compared to placebo induced more laxations within 24 hours (RR 2.77, 95% CI 1.91 to 4.04. I² = 0%; moderate-quality evidence). In combined analysis, we found methylnaltrexone induced more laxation responses over two weeks (RR 9.98, 95% CI 4.96 to 20.09. I² = 0%; moderate-quality evidence). The proportion of participants who had a rescue-free laxation response within 24 hours of the first dose was 59.1% in the methylnaltrexone arms and 19.1% in the placebo arm. There was moderate-quality evidence that the rate of opioid withdrawal was not affected. Methylnaltrexone did not increase the likelihood of a serious adverse event; there were fewer in the intervention arm (RR 0.59, 95% CI 0.38 to 0.93; I² = 0%; moderate-quality evidence). There was no difference in the proportion of participants experiencing an adverse event (RR 1.17, 95% CI 0.94 to 1.45; I² = 74%; low-quality evidence). Methylnaltrexone increased the likelihood of abdominal pain and flatulence.Two trials compared differing methylnaltrexone schedules of higher doses with lower doses. For early laxation, there was low-quality evidence of no clear difference between doses on analgesia and adverse events. Both trials measured laxation response within 24 hours of first dose (trial one: RR 0.82, 95% CI 0.41 to 1.66; trial two: RR 1.07, 95% CI 0.81 to 1.42).
AUTHORS' CONCLUSIONS
In this update, the conclusions for naldemedine are new. There is moderate-quality evidence to suggest that, taken orally, naldemedine improves bowel function over two weeks in people with cancer and OIBD but increases the risk of adverse events. The conclusions on naloxone and methylnaltrexone have not changed. The trials on naloxone did not assess laxation at 24 hours or over two weeks. There is moderate-quality evidence that methylnaltrexone improves bowel function in people receiving palliative care in the short term and over two weeks, and low-quality evidence that it does not increase adverse events. There is a need for more trials including more evaluation of adverse events. None of the current trials evaluated effects in children.
Topics: Constipation; Defecation; Female; Gastrointestinal Agents; Humans; Intestinal Diseases; Male; Nalbuphine; Naloxone; Naltrexone; Narcotic Antagonists; Neoplasms; Opioid-Related Disorders; Oxycodone; Palliative Care; Piperidines; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic; Receptors, Opioid, mu
PubMed: 29869799
DOI: 10.1002/14651858.CD006332.pub3 -
Anticancer Research Aug 2009Methylnaltrexone, a novel peripherally acting opioid receptor antagonist, is used to treat opiate-induced constipation in cancer patients. Its effects on the activities...
BACKGROUND
Methylnaltrexone, a novel peripherally acting opioid receptor antagonist, is used to treat opiate-induced constipation in cancer patients. Its effects on the activities of chemotherapeutic agents, however, have not been evaluated. In this study, the effect of methylnaltrexone on the action of 5-fluorouracil (5-FU) was tested in three human cancer cell lines.
MATERIALS AND METHODS
Treatment was for 72 h and the effects on cell proliferation were measured in human SW-480 colorectal cancer cells, MCF-7 breast cancer cells and non-small cell lung cancer cells in vitro. The apoptotic effect was analyzed by using flow cytometry. The cell cycle and expression of cyclin A were assayed after staining with propidium iodide and cyclin A-fluorescein isothiocyanate.
RESULTS
5-FU decreased the cancer cell growth significantly in all three cancer cell lines in a concentration-dependent manner and methylnaltrexone enhanced the actions of 5-FU. Compared to 5-FU 10 muM alone on SW-480 cells (63.5+/-1.1%), on MCF-7 cells (58.3+/-3.1%), or on non-small cell lung cancer cells (81.3+/-1.6%), 5-FU 10 muM plus methylnaltrexone 1.0 muM reduced cancer cell growth in all three cell lines to 50.2+/-2.9% for SW-480 cells (p<0.05), 50.0+/-1.7% for MCF-7 cells (p<0.05) and 68.7+/-2.2% for lung cancer cells (p<0.01). Methylnaltrexone alone also showed anti-proliferative activity in the three cell lines. Methylnaltrexone at 1.0 muM, reduced SW-480 cell growth to 81.9+/-3.7% (p<0.01), MCF-7 cell growth to 85.9+/-2.4% (p<0.01) and lung cancer cell growth to 85.5+/-2.2% (p<0.01). Apoptosis was not induced by treatment of SW-480 cells with 1.0 or 10 muM methylnaltrexone for 48 h. However, methylnaltrexone increased the number of cells in the G(1)-phase and decreased the expression of cyclin A.
CONCLUSION
At its therapeutic concentrations for opioid-induced constipation, methylnaltrexone does not attenuate and in fact may enhance the tumoricidal activity of 5-FU. Enhanced 5-FU activity may be attributed to the distinct pathways of 5-FU and methylnaltrexone, an effect that could give methylnaltrexone a complementary role in the treatment of cancer with chemotherapeutic agents.
Topics: Antimetabolites, Antineoplastic; Apoptosis; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Proliferation; Colorectal Neoplasms; Cyclin A; Drug Synergism; Drug Therapy, Combination; Flow Cytometry; Fluorescein-5-isothiocyanate; Fluorouracil; Humans; Lung Neoplasms; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Tumor Cells, Cultured
PubMed: 19661297
DOI: No ID Found -
Journal of Drug Assessment 2013This phase 2 study evaluated the safety and activity of intravenous methylnaltrexone on the duration of postoperative ileus in patients undergoing segmental colectomy.
OBJECTIVE
This phase 2 study evaluated the safety and activity of intravenous methylnaltrexone on the duration of postoperative ileus in patients undergoing segmental colectomy.
METHODS
Adults (aged 18 years or older) with American Society of Anesthesiologists physical status of I, II, or III who underwent segmental colectomy, including partial colectomy, sigmoidectomy, cecectomy, or anterior proctosigmoidectomy, via laparotomy with general anesthesia, received intravenous methylnaltrexone 0.30 mg/kg or placebo every 6 h beginning within 90 min after end of surgery. Treatment continued until 24 h after the patient tolerated solid foods, was discharged, or for 7 d maximum. Efficacy endpoints included measures of gastrointestinal recovery and time to discharge eligibility.
RESULTS
A total of 65 patients (methylnaltrexone, n = 33; placebo, n = 32) were randomized. Mean time to first bowel movement was accelerated by 20 h (p = 0.038) and time to discharge eligibility was accelerated by 33 h (p = 0.049) with methylnaltrexone vs placebo. Opioid use was similar between groups until postoperative day 4, then fluctuated in the placebo group. Methylnaltrexone was generally well tolerated.
CONCLUSIONS
In this study, intravenous methylnaltrexone significantly decreased time to postoperative bowel recovery and eligibility for hospital discharge by ∼1 d, with an adverse event profile similar to placebo. These were two of several exploratory endpoints; not all efficacy endpoints showed a significant difference between methylnaltrexone and placebo. The efficacy results in this trial were not seen in two subsequent large-scale studies.
PubMed: 27536446
DOI: 10.3109/21556660.2013.838169 -
Cancer Cell International Nov 2021Morphine, a µ-opioid receptor (MOR) agonist, has been shown to be related to the activity of cancer cells, and a higher morphine dosage reduces the survival time of...
BACKGROUND
Morphine, a µ-opioid receptor (MOR) agonist, has been shown to be related to the activity of cancer cells, and a higher morphine dosage reduces the survival time of patients with lung cancer. However, the effect of morphine on the malignant behavior of lung cancer cells remains unclear. The aim of this study was to investigate the specific molecular mechanism by which morphine regulates the malignant biological behavior of non-small cell lung cancer.
METHODS
Immunofluorescence staining and Western blot analyses were performed to detect MOR expression. H460 non-small cell lung cancer cells were used in this study, and cell proliferation, the cell cycle and apoptosis were evaluated using Cell Counting Kit-8 (CCK-8) and flow cytometry assays, respectively. Cell migration and invasion were detected using wound healing and Transwell assays. The effect of morphine on lung cancer development in vivo was examined by performing a xenograft tumor assay following morphine treatment.
RESULTS
Morphine promoted the growth of H460 cells both in vivo and in vitro. Morphine enhanced cell migration and invasion, modified cell cycle progression through the S/G transition and exerted an antiapoptotic effect on H460 cells. Additionally, morphine increased Rous sarcoma oncogene cellular homolog (Src) phosphorylation and activated the phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. Treatment with the MOR antagonist methylnaltrexone (MNTX) and the Src inhibitor protein phosphatase 1 (PP1) reduced the phosphorylation induced by morphine. Furthermore, MNTX, PP1, and the PI3K/AKT inhibitor deguelin reversed the antiapoptotic effect of morphine on lung cancer cells.
CONCLUSION
Morphine promotes the malignant biological behavior of H460 cells by activating the MOR and Src/mTOR signaling pathways.
PubMed: 34823532
DOI: 10.1186/s12935-021-02334-8 -
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