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Journal of Pharmacy Practice Apr 2022Opioid-induced constipation (OIC) treatment guidelines recommend over-the-counter laxatives as first-line therapy, followed by treatment with a peripherally-acting...
BACKGROUND
Opioid-induced constipation (OIC) treatment guidelines recommend over-the-counter laxatives as first-line therapy, followed by treatment with a peripherally-acting mu-opioid receptor antagonist (PAMORA) in refractory patients.
OBJECTIVE
To evaluate the ability of a pharmacist-driven OIC protocol to promote increased scheduled laxative use prior to escalation to PAMORA therapy.
METHODS
This retrospective, single-center cohort study evaluated patients 2 years pre- and post-protocol implementation. The primary outcome was the difference in the percentage of patients receiving 2 scheduled laxatives for ≥ 2 days prior to PAMORA therapy pre- and post-protocol. Secondary outcomes included difference in time to first bowel movement after PAMORA initiation, difference in total number of laxative/PAMORA doses administered, and difference in overall estimated total cost. Data was analyzed using chi-squared tests and Student's t tests.
RESULTS
Three-hundred patients were included (150 patients in the pre and post-protocol groups). In the pre-protocol group, 53 patients (35%) received 2 scheduled laxatives for 2 days prior to naloxegol/methylnaltrexone compared to 96 patients (64%) in the postprotocol group (p < 0.0001). One-thousand twenty-one scheduled laxative doses were given pre-protocol versus 1625 doses post-protocol. Average time to first bowel movement was similar between groups (17.7 hours vs 16.0 hours p = 0.441). Estimated total cost of OIC reversal therapy decreased from $20,896.95 to $13,405.47.
CONCLUSION
A pharmacist-driven OIC protocol is associated with an increase in the use of scheduled laxatives prior to PAMORA administration and decreased overall estimated total cost. A larger, prospective study is necessary to assess if this promotes more efficacious OIC.
Topics: Analgesics, Opioid; Cohort Studies; Constipation; Humans; Laxatives; Narcotic Antagonists; Opioid-Induced Constipation; Pharmacists; Prospective Studies; Retrospective Studies
PubMed: 35484871
DOI: 10.1177/0897190020966203 -
Current Treatment Options in Oncology Jul 2022Constipation is one of the most frequent problems in cancer patients, and its etiology is multifactorial. It leads to decreased quality of life and impedes optimal pain... (Review)
Review
Constipation is one of the most frequent problems in cancer patients, and its etiology is multifactorial. It leads to decreased quality of life and impedes optimal pain treatment. Despite the high prevalence, constipation is frequently underdiagnosed mainly because of lack of validated diagnostic criteria or widely accepted definition of constipation in cancer patients. All cancer patients should be evaluated regularly for constipation, and concomitant causes and risk factors were assessed. Opioids are responsible for a much of the secondary constipation in cancer patients. The management of constipation in cancer patients should be multifaceted, addressing dietary and behavioral issues and optimizing pharmacological interventions. Prevention of opioid-induced constipation (OIC) is pivotal, as treatment is often unsatisfactory or inefficient. Dietary and behavioral interventions should be considered. Non-pharmacological measures include hydration and nutrition, ensuring privacy during defecation, using a commode or footstool, and the availability of a caregiver. Abdominal massage may be of value. Traditional laxatives are recommended in prevention but not in the treatment of OIC. Peripherally acting mu-opioid receptor antagonists (PAMORA) appear the first choice in the treatment and an alternative to laxatives in some recent clinical practice guidelines in preventing OIC. Naldemedine, naloxegol, and methylnaltrexone are supported by quality evidence for OIC management. Naloxone or naltrexone, taken orally in combined formulations with opioids, may be valuable in preventing or reducing OIC symptoms.
Topics: Analgesics, Opioid; Constipation; Humans; Laxatives; Neoplasms; Opioid-Induced Constipation; Quality of Life
PubMed: 35441979
DOI: 10.1007/s11864-022-00976-y -
Advances in Therapy May 2022Opioid-induced constipation (OIC) prescription medications (OIC-Rx) like methylnaltrexone subcutaneous (SC) have shown efficacy in treating OIC in the emergency...
INTRODUCTION
Opioid-induced constipation (OIC) prescription medications (OIC-Rx) like methylnaltrexone subcutaneous (SC) have shown efficacy in treating OIC in the emergency department (ED). This study aimed to describe and compare healthcare resource utilization (HRU) and healthcare costs in ED patients with OIC receiving OIC-Rx versus those not receiving OIC-Rx.
METHODS
Adult patients with OIC during an ED encounter were identified from a hospital-based ED encounters database (2016-2019) and classified on the basis of receipt of OIC-Rx (OIC-Rx versus No OIC-Rx cohorts). Entropy balancing was used to reweight characteristics of the two cohorts. HRU and healthcare costs were measured and compared during the ED encounter and 30-day post-discharge period.
RESULTS
Among 11,135 patients in the OIC-Rx cohort (21,474 in the No OIC-Rx cohort), 93% received methylnaltrexone SC. Patients in the OIC-Rx cohort had 0.7 fewer inpatient days per OIC ED encounter and 64% decreased odds of being hospitalized versus the No OIC-Rx cohort (both p < 0.001). During the post-discharge period, the OIC-Rx cohort had 35% decreased odds of any re-encounter (p < 0.001). The OIC-Rx cohort had a $732 reduction in costs per OIC ED encounter versus the No OIC-Rx cohort (p < 0.001), driven by larger hospitals and patients with Medicare or Commercial insurance. During the post-discharge period, the OIC-Rx cohort had a $421 reduction in costs associated with any re-encounter versus the No OIC-Rx cohort (p = 0.004).
CONCLUSION
Patients receiving OIC-Rx in the ED had decreased odds of being hospitalized and fewer re-encounters in the 30-day post-discharge period versus patients who did not receive OIC-Rx, resulting in cost savings for insurance agencies and healthcare providers.
Topics: Adult; Aftercare; Aged; Analgesics, Opioid; Constipation; Emergency Service, Hospital; Humans; Medicare; Opioid-Induced Constipation; Patient Discharge; United States
PubMed: 35298784
DOI: 10.1007/s12325-022-02090-9 -
Journal of Medicinal Chemistry Mar 2022Opioid-induced constipation (OIC) is a common adverse effect of opioid analgesics. Peripherally acting μ opioid receptor antagonists (PAMORAs) can be applied in the...
Opioid-induced constipation (OIC) is a common adverse effect of opioid analgesics. Peripherally acting μ opioid receptor antagonists (PAMORAs) can be applied in the treatment of OIC without compromising the analgesic effects. NAP, a 6β-N-4-pyridyl-substituted naltrexamine derivative, was previously identified as a potent and selective MOR antagonist mainly acting peripherally but with some CNS effects. Herein, we introduced a highly polar aromatic moiety, for example, a pyrazolyl or imidazolyl ring to decrease CNS MPO scores in order to reduce passive BBB permeability. Four compounds , , , and , when administered orally, were able to increase intestinal motility during morphine-induced constipation in the carmine red dye assays. Among them, compound (p.o.) improved GI tract motility by 75% while orally administered NAP and methylnaltrexone showed no significant effects at the same dose. Thus, this compound seemed a promising agent to be further developed as an oral treatment for OIC.
Topics: Analgesics, Opioid; Constipation; Humans; Ligands; Naltrexone; Narcotic Antagonists; Opioid-Induced Constipation; Receptors, Opioid, mu
PubMed: 35255683
DOI: 10.1021/acs.jmedchem.1c02185 -
Journal of Visceral Surgery Mar 2022Postoperative constipation occurs relatively frequently, and can involve drug-related, surgical and lifestyle and dietary factors. Gastrointestinal motility can be...
Postoperative constipation occurs relatively frequently, and can involve drug-related, surgical and lifestyle and dietary factors. Gastrointestinal motility can be altered by inflammation, surgery, opioid medications, hypnotics, anti-secretory or anesthetic drugs or by functional modifications for which the physiopathology is not well defined. There are a number of laxatives available. These include bulk laxatives, osmotic laxatives and locally acting laxatives such as suppositories and enemas. Stimulant laxatives have a role to play in the short-term management of persistent constipation. 5-HT4 receptor antagonists are recommended in refractory constipation. Other specific therapeutic laxatives can be proposed such as methylnaltrexone in opioid-induced constipation or neostigmine in Ogilvie's syndrome. The prevention and/or early detection of iatrogenic constipation, whether postoperative or not, is essential and the knowledge how to improve patient comfort and reduce the duration of gastrointestinal motor disorders with specific drugs or other means is essential, particularly the postoperative period.
Topics: Analgesics, Opioid; Constipation; Digestive System Surgical Procedures; Humans; Iatrogenic Disease; Laxatives
PubMed: 35172956
DOI: 10.1016/j.jviscsurg.2021.12.003 -
Frontiers in Oncology 2021Opioids are administered to cancer patients in the period surrounding tumour excision, and in the management of cancer-associated pain. The effects of opioids on tumour... (Review)
Review
Opioids are administered to cancer patients in the period surrounding tumour excision, and in the management of cancer-associated pain. The effects of opioids on tumour growth and metastasis, and their consequences on disease outcome, continue to be the object of polarised, discrepant literature. It is becoming clear that opioids contribute a range of direct and indirect effects to the biology of solid tumours, to the anticancer immune response, inflammation, angiogenesis and importantly, to the tumour-promoting effects of pain. A common misconception in the literature is that the effect of opioid agonists equates the effect of the mu-opioid receptor, the major target of the analgesic effect of this class of drugs. We review the evidence on opioid receptor expression in cancer, opioid receptor polymorphisms and cancer outcome, the effect of opioid antagonists, especially the peripheral antagonist methylnaltrexone, and lastly, the evidence available of a role for opioids through non-opioid receptor mediated actions.
PubMed: 35004315
DOI: 10.3389/fonc.2021.792290 -
Trials Dec 2021Moderate to severe acute pancreatitis (AP) is associated with a high rate of complications and increased mortality, yet no targeted pharmacologic treatment currently...
Effects of the peripherally acting μ-opioid receptor antagonist methylnaltrexone on acute pancreatitis severity: study protocol for a multicentre double-blind randomised placebo-controlled interventional trial, the PAMORA-AP trial.
BACKGROUND
Moderate to severe acute pancreatitis (AP) is associated with a high rate of complications and increased mortality, yet no targeted pharmacologic treatment currently exists. As pain is a dominant symptom in AP, patients are exposed to excess levels of both endo- and exogenous opioids, which may have harmful effects on the course of AP. This trial investigates the effects of the peripherally acting μ-opioid receptor antagonist (PAMORA) methylnaltrexone on disease severity and clinical outcomes in patients with moderate to severe AP.
METHODS
PAMORA-AP is a multicentre, investigator-initiated, double-blind, randomised, placebo-controlled, interventional trial, which will be conducted at four referral centres for acute pancreatitis in Denmark. Ninety patients with early-onset AP (pain onset within 48 h) as well as predicted moderate to severe disease (two or more systemic inflammatory response syndrome criteria upon admission) will be prospectively included. Subsequently, participants will be randomised (1:1) to intravenous treatment with either methylnaltrexone or matching placebo (Ringer's lactate) during 5 days of admission. The primary endpoint will be the group difference in disease severity as defined and measured by the Pancreatitis Activity Scoring System (PASS) score 48 h after randomisation. Secondary endpoints include daily PASS scores; disease severity according to the Atlanta classification; quantification of need for analgesics, nutritional support, intravenous fluid resuscitation and antibiotics; duration of hospital admissions, readmission rates and mortality. Pain intensity and gut function will be self-reported using validated questionnaires. Exploratory endpoints include circulating levels of pro-and anti-inflammatory markers, polyethylene glycol recovery from the urine, circulating levels of blood markers of intestinal permeability, the prevalence of pancreatic complications on computed tomography (CT) scans, and colon transit time assessed using a CT-based radiopaque marker method.
DISCUSSION
This trial aims to evaluate the PAMORA methylnaltrexone as a novel targeted pharmacotherapy in patients with moderate to severe AP with the potential benefit of improved patient outcomes.
TRIAL REGISTRATION
ClinicalTrials.gov NCT04743570 . Registered on 28 January 2021. EudraCT 2020-002313-18.
Topics: Acute Disease; Humans; Multicenter Studies as Topic; Naltrexone; Narcotic Antagonists; Pancreatitis; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic; Research Design
PubMed: 34924020
DOI: 10.1186/s13063-021-05885-3 -
The Journal of Emergency Medicine Feb 2022Opioid-induced constipation (OIC) is a frequent consequence of opioid analgesia that may increase patient risk for emergency department visits and hospitalization.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Opioid-induced constipation (OIC) is a frequent consequence of opioid analgesia that may increase patient risk for emergency department visits and hospitalization. Methylnaltrexone is a peripherally acting µ-opioid receptor antagonist indicated for the treatment of OIC.
OBJECTIVE
To assess the safety and efficacy of a single methylnaltrexone dose.
METHODS
Results were pooled from three randomized, placebo-controlled methylnaltrexone (MNTX) studies in opioid-treated patients with advanced illness and OIC, despite treatment with conventional laxatives. Baseline assessments included demographics, disease/treatment characteristics, and functional levels. Efficacy endpoints included rescue-free laxation (RFL) rates within 4 and 24 h, time to first RFL, pain score change, and adverse events (AEs) after a single MNTX dose or placebo.
RESULTS
The analysis included 281 patients receiving MNTX and 237 receiving placebo. Mean age was 66.2 years for MNTX and 65.8 for placebo; ∼50% were men. The most frequent primary diagnosis was cancer (MNTX = 70.5%; placebo = 66.2%) and most (∼98%) were receiving at least one laxative at baseline. RFL occurred in 61.4% vs. 16.0%, and 72.1% vs. 40.1% MNTX vs. placebo patients, within 4 and 24 h of the initial dose, respectively. Relative to placebo, MNTX use reduced the time to first RFL, with most MNTX-treated patients achieving RFL within 2 h. Baseline and posttreatment pain scores were similar (p = 0.9556 vs. placebo for current and worst pain change from baseline), demonstrating that MNTX did not negatively affect opioid analgesia. Most AEs were gastrointestinal related and dissipated by the second dose.
CONCLUSIONS
Methylnaltrexone provides early RFL without compromising analgesia in patients receiving chronic opioid therapy.
Topics: Aged; Analgesics, Opioid; Constipation; Humans; Male; Naltrexone; Opioid-Induced Constipation; Quaternary Ammonium Compounds
PubMed: 34893381
DOI: 10.1016/j.jemermed.2021.10.012 -
Clinical and Experimental Pharmacology... Mar 2022Pain is responsible for inducing physical and mental stress, interfering negatively in patients' quality of life. Classic analgesic drugs, such as opioids and...
Pain is responsible for inducing physical and mental stress, interfering negatively in patients' quality of life. Classic analgesic drugs, such as opioids and non-steroidal anti-inflammatory drugs, are known for their wide range of adverse effects, making it important to develop new drugs. Thus, this study aimed to analyse the action of the hybrid compound cis- (±) -acetate of 4-chloro-6- (naphthalene-1-yl) -tetrahydro-2h-pyran -2-yl) methyl2- (2- [2,6-dichlorophenylamine] phenyl (LS19) under acute nociceptive conditions, and deepened the understanding of the responsible mechanisms. Male Swiss mice were evaluated in the acetic acid-induced abdominal writhing, formalin, tail flick, capsaicin- and glutamate-induced nociception, thermal stimulation in animals injected with capsaicin and rotarod tests besides the acute and subchronic toxicological evaluation. The compound showed effect on the acetic acid-induced abdominal writhing, formalin (both phases), tail flick, thermal stimulation in animals injected with capsaicin and capsaicin-induced nociception tests. In the study of the mechanism of action was observed reversion of the antihyperalgesic effect of the compound from the previous intraperitoneal and intrathecal administration of naloxone, nor-binaltorphimine, naltrindole, methylnaltrexone, 7-nitroindazole, L-NAME, ODQ, glibenclamide on the tail flick test. In the thermal stimulation in animals injected with capsaicin, the compound showed antinociceptive effect by oral and intraplantar routes, besides to reducing the levels of TNF-α, IL-1β and PGE in the paws previously administered with capsaicin. There were no signs of acute and subchronic intoxication with the compound. In summary, the compound LS19 presented spinal and local antihyperalgesic effect, demonstrating participation of the opioid/NO/cGMP/K+ ATP pathway and TRPV1 receptors and it demonstrated safety in its use in mice.
Topics: Animals; Humans; Male; Mice; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Capsaicin; Gene Expression Regulation; Glutamic Acid; Hot Temperature; Pain; Pyrans
PubMed: 34862806
DOI: 10.1111/1440-1681.13617 -
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