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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 -
Therapeutic Advances in Chronic Disease Mar 2016Currently opioids are the most frequently used medications for chronic noncancer pain. Opioid-induced constipation is the most common adverse effect associated with... (Review)
Review
Currently opioids are the most frequently used medications for chronic noncancer pain. Opioid-induced constipation is the most common adverse effect associated with prolonged use of opioids, having a major impact on quality of life. There is an increasing need to treat opioid-induced constipation. With the recent approval of medications for the treatment of opioid-induced constipation, there are several therapeutic approaches. This review addresses the clinical presentation and diagnosis of opioid-induced constipation, barriers to its diagnosis, effects of opioids in the gastrointestinal tract, differential tolerance to opiates in different gastrointestinal organs, medications approved and in development for the treatment of opioid-induced constipation, and a proposed clinical management algorithm for treating opioid-induced constipation in patients with noncancer pain.
PubMed: 26977281
DOI: 10.1177/2040622315627801 -
Anesthesiology Mar 2016Opioids have long been regarded as the most effective drugs for the treatment of severe acute and chronic pain. Unfortunately, their therapeutic efficacy and clinical...
BACKGROUND
Opioids have long been regarded as the most effective drugs for the treatment of severe acute and chronic pain. Unfortunately, their therapeutic efficacy and clinical utility have been limited because of central and peripheral side effects.
METHODS
To determine the therapeutic value of peripheral μ-opioid receptors as a target for neuropathic pain treatment, the authors examined the effects of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a hydrophilic, peripherally acting μ-opioid receptor agonist, in male and female rats with spinal nerve ligation-induced neuropathic pain. The authors also utilized behavioral, pharmacologic, electrophysiologic, and molecular biologic tools to characterize DALDA's possible mechanisms of action in male rats.
RESULTS
DALDA, administered subcutaneously, had 70 times greater efficacy for inhibiting thermal (n = 8 to 11/group) than mechanical hypersensitivity (n = 6 to 8/group) in male rats. The pain inhibitory effects of DALDA on mechanical and heat hypersensitivity were abolished in animals pretreated with systemic methylnaltrexone (n = 7 to 9/group), a peripheral μ-opioid receptor antagonist. In the spinal wide-dynamic range neurons, systemic DALDA inhibited C-fiber-mediated, but not A-fiber-mediated, response in neuropathic male rats (n = 13). In primary sensory neurons, DALDA inhibited the capsaicin-induced [Ca2+] increase more than the β-alanine-induced [Ca] increase (n = 300); capsaicin and β-alanine activate subpopulations of neurons involved in the signaling of heat and mechanical pain, respectively. DALDA-treated rats (n = 5 to 8/group) did not exhibit motor deficits and locomotor impairment suggesting that it does not induce central side effects.
CONCLUSIONS
These findings suggest that DALDA may represent a potential alternative to current opioid therapy for the treatment of neuropathic pain and is likely to be associated with minimal adverse effects.
Topics: Analgesics, Opioid; Animals; Female; Male; Neuralgia; Opioid Peptides; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu
PubMed: 26756519
DOI: 10.1097/ALN.0000000000000993 -
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 -
Journal of Pain Research 2015Subcutaneous methylnaltrexone is efficacious and well tolerated for opioid-induced constipation (OIC) but may theoretically disrupt opioid-mediated analgesia.
BACKGROUND
Subcutaneous methylnaltrexone is efficacious and well tolerated for opioid-induced constipation (OIC) but may theoretically disrupt opioid-mediated analgesia.
METHODS
Opioid use, pain intensity, and opioid withdrawal (Objective Opioid Withdrawal Scale [OOWS] and Subjective Opiate Withdrawal Scale [SOWS] scores) were reported in a randomized, double-blind trial with an open-label extension (RCT) and an open-label trial (OLT) evaluating safety in adults with chronic noncancer pain. In the RCT, patients taking ≥50 mg of oral morphine equivalents daily with <3 rescue-free bowel movements weekly received methyl naltrexone 12 mg once daily (n=150), every other day (n=148), or placebo (n=162) for 4 weeks, followed by open-label methylnaltrexone 12 mg (as needed [prn]; n=364) for 8 weeks. In the OLT, patients (n=1,034) on stable opioid doses with OIC received methylnaltrexone 12 mg prn for up to 48 weeks.
RESULTS
Minimal fluctuations of median morphine equivalent dose from baseline (BL) were observed in the RCT double-blind period (BL, 154.8-161.0 mg/d; range, 137.1-168.0 mg/d), RCT open-label period (BL, 156.3-174.6; range, 144.0-180.0) and OLT (BL, 120 mg/d; range, 117.3-121.1 mg/d). No significant change from BL in pain intensity score occurred in any group at weeks 2 or 4 (both P≥0.1) of the RCT double-blind period, and scores remained stable during the open-label period and in the OLT (mean change, -0.2 to 0.1). Changes from BL in OOWS and SOWS scores during the double-blind period were not significantly impacted by methylnaltrexone exposure at weeks 2 or 4 (P>0.05 for all).
CONCLUSION
Methylnaltrexone did not affect opioid-mediated analgesia in patients with chronic noncancer pain and OIC.
PubMed: 26586963
DOI: 10.2147/JPR.S88203 -
Pain Medicine (Malden, Mass.) Dec 2015Aims of this consensus panel were to determine (1) an optimal symptom-based method for assessing opioid-induced constipation in clinical practice and (2) a threshold of... (Review)
Review
OBJECTIVE
Aims of this consensus panel were to determine (1) an optimal symptom-based method for assessing opioid-induced constipation in clinical practice and (2) a threshold of symptom severity to prompt consideration of prescription therapy.
METHODS
A multidisciplinary panel of 10 experts with extensive knowledge/experience with opioid-associated adverse events convened to discuss the literature on assessment methods used for opioid-induced constipation and reach consensus on each objective using the nominal group technique.
RESULTS
Five validated assessment tools were evaluated: the Patient Assessment of Constipation-Symptoms (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL), Stool Symptom Screener (SSS), Bowel Function Index (BFI), and Bowel Function Diary (BF-Diary). The 3-item BFI and 4-item SSS, both clinician administered, are the shortest tools. In published trials, the BFI and 12-item PAC-SYM are most commonly used. The 11-item BF-Diary is highly relevant in opioid-induced constipation and was developed and validated in accordance with US Food and Drug Administration guidelines. However, the panel believes that the complex scoring for this tool and the SSS, PAC-SYM, and 28-item PAC-QOL may be unfeasible for clinical practice. The BFI is psychometrically validated and responsive to changes in symptom severity; scores range from 0 to 100, with higher scores indicating greater severity and scores >28.8 points indicating constipation.
CONCLUSIONS
The BFI is a simple assessment tool with a validated threshold of clinically significant constipation. Prescription treatments for opioid-induced constipation should be considered for patients who have a BFI score of ≥30 points and an inadequate response to first-line interventions.
Topics: Analgesics, Opioid; Constipation; Drug Administration Schedule; Drug Prescriptions; Humans; Practice Guidelines as Topic; Surveys and Questionnaires; United States
PubMed: 26582720
DOI: 10.1111/pme.12937 -
BMJ Clinical Evidence Sep 2015Constipation is a common adverse effect of opioids. As an example, constipation is reported in 52% of people with advanced malignancy, and this figure rises to 87% in... (Review)
Review
INTRODUCTION
Constipation is a common adverse effect of opioids. As an example, constipation is reported in 52% of people with advanced malignancy, and this figure rises to 87% in people who are terminally ill and taking opioids. There is no reason to believe that people with chronic non-malignant disease who are prescribed opioids will be any less troubled by this adverse effect.
METHODS AND OUTCOMES
We conducted a systematic overview and aimed to answer the following clinical question: What are the effects of opioid antagonists for constipation in people prescribed opioids? The population we studied included people with any condition, although most studies were in people with cancer pain. We searched Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review).
RESULTS
At this update, searching of electronic databases retrieved 162 studies. After deduplication and removal of conference abstracts, 84 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 47 studies and the further review of 37 full publications. Of the 37 full articles evaluated, two systematic reviews and one RCT were included at this update. We performed a GRADE evaluation for three PICO combinations.
CONCLUSIONS
In this systematic overview we categorised the efficacy for three interventions based on information relating to the effectiveness of alvimopan, methylnaltrexone, and naloxone.
Topics: Analgesics, Opioid; Constipation; Gastrointestinal Agents; Humans; Naloxone; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds; Treatment Outcome
PubMed: 26360669
DOI: No ID Found -
Journal of Pharmacology &... 2015Opioid-induced constipation (OIC) is one of the most troublesome and the most common effects of opioid use leading to deterioration in quality of life of the patients...
Opioid-induced constipation (OIC) is one of the most troublesome and the most common effects of opioid use leading to deterioration in quality of life of the patients and also has potentially deleterious repercussions on adherence and compliance to opioid therapy. With the current guidelines advocating liberal use of opioids by physicians even for non-cancer chronic pain, the situation is further complicated as these individuals are not undergoing palliative care and hence there cannot be any justification to subject these patients to the severe constipation brought on by opioid therapy which is no less debilitating than the chronic pain. The aim in these patients is to prevent the opioid-induced constipation but at the same time allow the analgesic activity of opioids. Many drugs have been used with limited success but the most specific among them were the peripherally acting mu opioid receptor antagonists (PAMORA). Methylnaltrexone and alvimopan were the early drugs in this group but were not approved for oral use in OIC. However naloxegol, the latest PAMORA has been very recently approved as the first oral drug for OIC. This article gives an overview of OIC, its current management and more specifically the development and approval of naloxegol, including pharmacokinetics, details of various clinical trials, adverse effects and its current status for the management of OIC.
PubMed: 26312011
DOI: 10.4103/0976-500X.162015 -
Scientific Reports Jun 2015Interactions between cancer cells and stromal cells in the tumour microenvironment play a key role in the control of invasiveness, metastasis and angiogenesis....
Interactions between cancer cells and stromal cells in the tumour microenvironment play a key role in the control of invasiveness, metastasis and angiogenesis. Macrophages display a range of activation states in specific pathological contexts and alternatively activated (M2) macrophages can promote tumour aggressiveness. Opioids are able to modulate tumour growth and metastasis. We tested whether morphine modulates the activation of macrophages induced by (i) interleukin-4 (IL-4), the prototypical M2 polarization-inducing cytokine, or (ii) coculture with breast cancer cells. We showed that IL-4 causes increased MMP-9 production and expression of the alternative activation markers arginase-1 and MRC-1. Morphine prevented IL-4-induced increase in MMP-9 in a naloxone- and methylnaltrexone-reversible fashion. Morphine also prevented IL-4-elicited alternative activation of RAW264.7 macrophages. Expression of MMP-9 and arginase-1 were increased when RAW264.7 were subjected to paracrine activation by 4T1 cells, and this effect was prevented by morphine via an opioid receptor-mediated mechanism. Morphine further decreased 4T1 breast cancer cell invasion elicited by co-culture with RAW264.7. Reduction of MMP-9 expression and alternative activation of macrophages by morphine was confirmed using mouse bone marrow-derived macrophages. Taken together, our results indicate that morphine may modulate tumour aggressiveness by regulating macrophage protease production and M2 polarization within the tumour microenvironment.
Topics: Animals; Arginase; Bone Marrow Cells; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Coculture Techniques; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-4; Macrophage Activation; Macrophages; Mammary Glands, Animal; Matrix Metalloproteinase 9; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Naltrexone; Quaternary Ammonium Compounds; Receptors, Cell Surface; Receptors, Immunologic; Signal Transduction
PubMed: 26078009
DOI: 10.1038/srep11389 -
Cancer Aug 2015Mu opioids are among the most widely used drugs for patients with cancer with both acute and chronic pain as well as in the perioperative period. Several retrospective... (Review)
Review
Mu opioids are among the most widely used drugs for patients with cancer with both acute and chronic pain as well as in the perioperative period. Several retrospective studies have suggested that opioid use might promote tumor progression and as a result negatively impact survival in patients with advanced cancer; however, in the absence of appropriate prospective validation, any changes in recommendations for opioid use are not warranted. In this review, the authors present preclinical and clinical data that support their hypothesis that the mu opioid receptor is a potential target for cancer therapy because of its plausible role in tumor progression. The authors also propose the hypothesis that peripheral opioid antagonists such as methylnaltrexone, which reverses the peripheral effects of mu opioids but maintains centrally mediated analgesia and is approved by the US Food and Drug Administration for the treatment of opioid-induced constipation, can be used to target the mu opioid receptor.
Topics: Animals; Humans; Mice; Molecular Targeted Therapy; Naltrexone; Narcotic Antagonists; Neoplasms; Quaternary Ammonium Compounds; Receptors, Opioid, mu
PubMed: 26043235
DOI: 10.1002/cncr.29460