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Patient Preference and Adherence 2017Opioid-induced constipation (OIC), a prevalent and distressing side effect of opioid therapy, does not reliably respond to treatment with conventional laxatives. OIC can... (Review)
Review
Opioid-induced constipation (OIC), a prevalent and distressing side effect of opioid therapy, does not reliably respond to treatment with conventional laxatives. OIC can be a treatment-limiting adverse event. Recent advances in medications with peripherally acting μ-opioid receptor antagonists, such as methylnaltrexone, naloxegol, and alvimopan, hold promise for treating OIC and thus extending the benefits of opioid analgesia to more chronic pain patients. Peripherally acting μ-opioid receptor antagonists have been clinically tested to improve bowel symptoms without compromise to pain relief, although there are associated side effects, including abdominal pain. Other treatment options include fixed-dose combination products of oxycodone analgesic together with naloxone.
PubMed: 28176913
DOI: 10.2147/PPA.S78042 -
Nature Medicine Feb 2017Opioid pain medications have detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). Tolerance and OIH counteract opioid analgesia...
Opioid pain medications have detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). Tolerance and OIH counteract opioid analgesia and drive dose escalation. The cell types and receptors on which opioids act to initiate these maladaptive processes remain disputed, which has prevented the development of therapies to maximize and sustain opioid analgesic efficacy. We found that μ opioid receptors (MORs) expressed by primary afferent nociceptors initiate tolerance and OIH development. RNA sequencing and histological analysis revealed that MORs are expressed by nociceptors, but not by spinal microglia. Deletion of MORs specifically in nociceptors eliminated morphine tolerance, OIH and pronociceptive synaptic long-term potentiation without altering antinociception. Furthermore, we found that co-administration of methylnaltrexone bromide, a peripherally restricted MOR antagonist, was sufficient to abrogate morphine tolerance and OIH without diminishing antinociception in perioperative and chronic pain models. Collectively, our data support the idea that opioid agonists can be combined with peripheral MOR antagonists to limit analgesic tolerance and OIH.
Topics: Analgesia; Analgesics, Opioid; Animals; Chronic Pain; Disease Models, Animal; Drug Tolerance; Gene Deletion; Hyperalgesia; Long-Term Potentiation; Mice; Mice, Knockout; Microglia; Morphine; Naltrexone; Nociception; Nociceptors; Pain, Postoperative; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Signal Transduction; Spinal Cord
PubMed: 28092666
DOI: 10.1038/nm.4262 -
Hospital Pharmacy Nov 2016Each month, subscribers to receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to...
Each month, subscribers to receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of publishes selected reviews in this column. For more information about , contact Wolters Kluwer customer service at 866-397-3433. The November 2016 monograph topics are apaziquone, crisaborole, irinotecan liposome, plecanatide, and telotristat. The Safety MUE is on methylnaltrexone PO.
PubMed: 27928191
DOI: 10.1310/hpj5110-847 -
Annals of Oncology : Official Journal... Nov 2016Methylnaltrexone (MNTX), a peripherally acting μ-opioid receptor (MOR) antagonist, is FDA-approved for treatment of opioid-induced constipation (OIC). Preclinical data... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Methylnaltrexone (MNTX), a peripherally acting μ-opioid receptor (MOR) antagonist, is FDA-approved for treatment of opioid-induced constipation (OIC). Preclinical data suggest that MOR activation can play a role in cancer progression and can be a target for anticancer therapy.
PATIENTS AND METHODS
Pooled data from advanced end-stage cancer patients with OIC, despite laxatives, treated in two randomized (phase III and IV), placebo-controlled trials with MNTX were analyzed for overall survival (OS) in an unplanned post hoc analysis. MNTX or placebo was given subcutaneously during the double-blinded phase, which was followed by the open-label phase, allowing MNTX treatment irrespective of initial randomization.
RESULTS
In two randomized, controlled trials, 229 cancer patients were randomized to MNTX (117, 51%) or placebo (112, 49%). Distribution of patients' characteristics and major tumor types did not significantly differ between arms. Treatment with MNTX compared with placebo [76 days, 95% confidence interval (CI) 43-109 versus 56 days, 95% CI 43-69; P = 0.033] and response (laxation) to treatment compared with no response (118 days, 95% CI 59-177 versus 55 days, 95% CI 40-70; P < 0.001) had a longer median OS, despite 56 (50%) of 112 patients ultimately crossing over from placebo to MNTX. Multivariable analysis demonstrated that response to therapy [hazard ratio (HR) 0.47, 95% CI 0.29-0.76; P = 0.002) and albumin ≥3.5 (HR 0.46, 95% CI 0.30-0.69; P < 0.001) were independent prognostic factors for increased OS. Of interest, there was no difference in OS between MNTX and placebo in 134 patients with advanced illness other than cancer treated in these randomized studies (P = 0.88).
CONCLUSION
This unplanned post hoc analysis of two randomized trials demonstrates that treatment with MNTX and, even more so, response to MNTX are associated with increased OS, which supports the preclinical hypothesis that MOR can play a role in cancer progression. Targeting MOR with MNTX warrants further investigation in cancer therapy.
CLINICAL TRIALS NUMBER
NCT00401362, NCT00672477.
Topics: Adult; Aged; Analgesics, Opioid; Constipation; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Laxatives; Male; Middle Aged; Naltrexone; Neoplasms; Quaternary Ammonium Compounds; Receptors, Opioid, mu
PubMed: 27573565
DOI: 10.1093/annonc/mdw317 -
Therapeutic Advances in Gastroenterology Sep 2016Opioid-induced constipation (OIC) and other gastrointestinal (GI) symptoms of opioid-induced bowel dysfunction (OIBD) significantly deteriorate patients' quality of life... (Review)
Review
Opioid-induced constipation (OIC) and other gastrointestinal (GI) symptoms of opioid-induced bowel dysfunction (OIBD) significantly deteriorate patients' quality of life and may lead to noncompliance with opioid schedule and undertreatment of pain. Although traditional oral laxatives are the first-line treatment of OIC, they do not address OIBD pathophysiology, and display numerous adverse effects. OIC treatment includes prokinetics (lubiprostone), opioid switch, and changing route of opioid administration. Targeted management of OIBD comprises the use of purely peripherally acting μ-opioid receptor antagonists (PAMORA): naloxegol and methylnaltrexone. Naloxegol (NKTR-118) is a polymer conjugate of the opioid antagonist naloxone. The polyethylene glycol limits naloxegol capacity to cross the blood-brain barrier (BBB). Naloxegol is substrate for the P-glycoprotein (P-gp) transporter. The central nervous system penetration of naloxegol is negligible due to reduced permeability and its increased efflux across the BBB, related to P-gp transporter. Naloxegol antagonizes μ- and κ-opioid receptors and displays low affinity to δ-opioid receptors in the GI tract, thereby decreasing OIBD symptoms without reversing central analgesic effects. Naloxegol is metabolised through CYP3A4 to six metabolites, with the majority of the dose (68%) excreted with faeces and less (16%) with urine. The dose of naloxegol equals 25 mg administered orally once daily on a fasting condition. Mild or moderate hepatic impairment has no impact on naloxegol dosing; naloxegol was not studied and is not recommended in patients with hepatic failure. Dose reduction (12.5 mg once daily) and caution is recommended in patients with moderate-to-severe renal impairment. Efficacy (bowel movement in 42-49% of patients not responsive to laxatives) and safety of naloxegol were confirmed in studies conducted in patients with OIC and nonmalignant pain. Naloxegol may be useful for cancer patients with OIC, although studies in this population are lacking.
PubMed: 27582887
DOI: 10.1177/1756283X16648869 -
Ugeskrift For Laeger Aug 2016The evidence for treatment of constipation in palliative care patients is poor. The condition of these patients is often complex, and results from studies performed in... (Review)
Review
The evidence for treatment of constipation in palliative care patients is poor. The condition of these patients is often complex, and results from studies performed in other patient groups cannot be extrapolated unconditionally. However, macrogol (polyethylene glycol), lactulose and sodium picosulphate seem to be well tolerated, and methylnaltrexone could be used in opioid-induced constipation, if the patients are not at risk from gastrointestinal perforation. The patients should be offered quiet and private surroundings, and attention should be payed to securing an optimal body position for defecation.
Topics: Analgesics, Opioid; Constipation; Defecation; Evidence-Based Medicine; Humans; Laxatives; Palliative Care; Posture
PubMed: 27550785
DOI: No ID Found -
BMJ Open Gastroenterology 2016Clinical trials of several new treatments for opioid-induced constipation (OIC), chronic idiopathic constipation (CIC) and constipation-predominant irritable bowel...
BACKGROUND
Clinical trials of several new treatments for opioid-induced constipation (OIC), chronic idiopathic constipation (CIC) and constipation-predominant irritable bowel syndrome (IBS-C) have focused on differences between subjects relieved of constipation with placebo and active treatment. Patients and clinicians however, are more interested in the probability these treatments provide actual relief of constipation and its associated symptoms.
METHODS
We searched the medical literature using MEDLINE and Cochrane central register of controlled trials. Randomised, placebo-controlled trials that examined the use of methylnaltrexone, naloxegol, lubiprostone, prucalopride or linaclotide in adults with OIC, CIC and IBS-C were eligible for inclusion. The primary efficacy measure was relief of constipation. Adverse event data for abdominal symptoms were also analysed.
KEY RESULTS AND FINDINGS
25 publications were included in our analyses. The proportion of constipated individuals with active treatment was significantly lower than the proportion with placebo; however, in 15 of these 20 trials analysed, a majority of patients remained constipated with active treatment. Analyses of adverse event data revealed that the percentage of participants who experienced abdominal pain, diarrhoea and flatulence with active treatment was higher than that with placebo in the majority of trials analysed.
CONCLUSIONS
Newer pharmacological treatments for constipation are superior to placebo in relieving constipation, but many patients receiving active treatment may remain constipated. In addition, all 5 of the treatments studied are accompanied by no change or a possible increase in the prevalence of abdominal symptoms, such as abdominal pain, diarrhoea and flatulence.
PubMed: 27486521
DOI: 10.1136/bmjgast-2016-000094 -
Drugs & Aging Aug 2016Constipation is a common and often debilitating condition in the elderly, which may be caused by underlying disease conditions, structural abnormalities in the bowel,... (Review)
Review
Constipation is a common and often debilitating condition in the elderly, which may be caused by underlying disease conditions, structural abnormalities in the bowel, and a variety of medications such as anticholinergics, antidepressants, and opiates. In this review, we focus on opioid-induced constipation (OIC), which is often underrecognized and undertreated in the elderly. When opioid therapy is initiated, healthcare providers are encouraged to evaluate risk factors for the development of constipation as part of a thorough patient history. To this end, the patient assessment should include the use of validated instruments, such as the Bristol Stool Scale and Bowel Function Index, to confirm the diagnosis and provide a basis for evaluating treatment outcomes. Healthcare providers should use a stepwise approach to the treatment of OIC in the elderly. Conventional laxatives are a first-line option and considered well tolerated with short-term use as needed; however, evidence is lacking to support their effectiveness in OIC. Moreover, because of the risk of adverse events and other considerations, such as chewing difficulties and swallowing disorders, conventional oral laxatives may be inappropriate for the treatment of OIC in the elderly. Thus, the availability of new pharmacologic agents such as the peripherally acting µ-opioid receptor antagonists methylnaltrexone and naloxegol, which target the underlying causes of OIC, and the secretagogue lubiprostone may provide more effective treatment options for elderly patients with OIC.
Topics: Aged; Analgesics, Opioid; Constipation; Health Personnel; Humans; Laxatives; Naltrexone; Narcotic Antagonists; Pain; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Treatment Outcome
PubMed: 27417446
DOI: 10.1007/s40266-016-0381-2 -
BMJ Open Jul 2016Gastrointestinal dysmotility and constipation are common problems in intensive care patients. The majority of critical care patients are sedated with opioids to... (Randomized Controlled Trial)
Randomized Controlled Trial
Protocol for a randomised control trial of methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients (MOTION).
INTRODUCTION
Gastrointestinal dysmotility and constipation are common problems in intensive care patients. The majority of critical care patients are sedated with opioids to facilitate tolerance of endotracheal tubes and mechanical ventilation, which inhibit gastrointestinal motility and lead to adverse outcomes. Methylnaltrexone is a peripheral opioid antagonist that does not cross the blood-brain barrier and can reverse the peripheral side effects of opioids without affecting the desired central properties. This trial will investigate whether methylnaltrexone can reverse opioid-induced constipation and gastrointestinal dysmotility.
METHODS
This is a single-centre, multisite, double-blind, randomised, placebo-controlled trial. 84 patients will be recruited from 4 intensive care units (ICUs) within Imperial College Healthcare NHS Trust. Patients will receive intravenous methylnaltrexone or placebo on a daily basis if they are receiving opioid infusion to facilitate mechanical ventilation and have not opened their bowels for 48 hours. All patients will receive standard laxatives as per the clinical ICU bowel protocol prior to randomisation. The primary outcome of the trial will be time to significant rescue-free laxation following randomisation. Secondary outcomes will include tolerance of enteral feed, gastric residual volumes, incidence of pneumonia, blood stream and Clostridium difficile infection, and any reversal of central opioid effects.
ETHICS AND DISSEMINATION
The trial protocol, the patient/legal representative information sheets and consent forms have been reviewed and approved by the Harrow Research Ethics Committee (REC Reference 14/LO/2004). An independent Trial Steering Committee and Data Monitoring Committee are in place, with patient representation. On completion, the trial results will be published in peer-reviewed journals and presented at national and international scientific meetings.
TRIAL REGISTRATION NUMBER
2014-004687-37; Pre-results.
Topics: Adult; Analgesics, Opioid; Blood-Brain Barrier; Constipation; Critical Care; Female; Gastrointestinal Motility; Humans; Laxatives; Male; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds
PubMed: 27412108
DOI: 10.1136/bmjopen-2016-011750 -
British Journal of Nursing (Mark Allen...Up to 40% of patients taking opioids develop constipation. Opioid-induced constipation (OIC) may limit the adequate dosing of opioids for pain relief and reduce quality... (Review)
Review
Up to 40% of patients taking opioids develop constipation. Opioid-induced constipation (OIC) may limit the adequate dosing of opioids for pain relief and reduce quality of life. Health professionals must therefore inquire about bowel function in patients receiving opioids. The management of OIC includes carefully re-evaluating the necessity, type and dose of opioids at each visit. Lifestyle modification and alteration of aggravating factors, the use of simple laxatives and, when essential, the addition of newer laxatives or opioid antagonists (naloxone, naloxegol or methylnaltrexone) can be used to treat OIC. This review discusses the recent literature regarding the management of OIC and provides a rational approach to assessing and managing constipation in individuals receiving opioids.
Topics: Analgesics, Opioid; Chronic Pain; Constipation; Disease Management; Enema; Fluid Therapy; Humans; Laxatives; Narcotic Antagonists
PubMed: 27231750
DOI: 10.12968/bjon.2016.25.10.S4