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Chang Y, Wong CE, Chen WC, Hsu HH, Lee PH, Huang CC, Lee JS. Risk Factors for Postoperative Ileus Following Spine Surgery: A Systematic Review With Meta-Analysis. Global Spine J 2024; 14:707-717. [PMID: 37129361 PMCID: PMC10802551 DOI: 10.1177/21925682231174192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/03/2023] Open
Abstract
STUDY DESIGN Systematic review and meta-analysis. OBJECTIVES Postoperative ileus (POI) can negatively impact patient recovery and surgical outcomes after spine surgery. Emerging studies have focused on the risk factors for POI after spine surgery. This study aimed to review the available literature on risk factors associated with POI following elective spine surgery. METHODS Electronic databases were searched to identify relevant studies. Meta-analysis was performed using random-effect model. Risk factors for POI were summarized using pooled odds ratio (OR) with 95% confidence intervals (CI). RESULTS Twelve studies were included in the present review. Meta-analysis demonstrated males exhibited a higher risk of POI than females odds ratio (OR, 1.76; 95% CI, 1.54-2.01). Patients with anemia had a higher risk of POI than those without anemia (OR, 1.48; 95% CI, 1.04-2.11). Patients with liver disease (OR, 3.3; 95% CI, 1.2-9.08) had a higher risk of POI. The presence of perioperative fluid and electrolyte imbalances was a predictor of POI (OR, 3.24; 95% CI, 2.62-4.02). Spine surgery involving more than 3 levels had a higher risk of POI compared to that with 1-2 levels (OR, 1.82; 95% CI, 1.03-3.23). CONCLUSIONS Male sex and the presence of anemia and liver disease were significant patient factors associated with POI. Perioperative fluid and electrolyte imbalance and multilevel spine surgery significantly increased the risk of POI. In addition, through this comprehensive review, we identified several perioperative risk factors associated with the development of POI after spine surgery.
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Affiliation(s)
- Yu Chang
- Section of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital; College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-En Wong
- Section of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital; College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Cheng Chen
- Department of Orthopedics, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Taiwan Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hao-Hsiang Hsu
- Section of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital; College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Po-Hsuan Lee
- Section of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital; College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chi-Chen Huang
- Section of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital; College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jung-Shun Lee
- Section of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital; College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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King JW, Bennett ASW, Wood HM, Baker CC, Alsaadi H, Topley M, Vanner SA, Reed DE, Lomax AE. Expression and function of transient receptor potential melastatin 3 in the spinal afferent innervation of the mouse colon. Am J Physiol Gastrointest Liver Physiol 2024; 326:G176-G186. [PMID: 38084411 DOI: 10.1152/ajpgi.00230.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 12/05/2023] [Accepted: 12/06/2023] [Indexed: 01/27/2024]
Abstract
Abdominal pain is a cardinal symptom of inflammatory bowel disease (IBD). Transient receptor potential (TRP) channels contribute to abdominal pain in preclinical models of IBD, and TRP melastatin 3 (TRPM3) has recently been implicated in inflammatory bladder and joint pain in rodents. We hypothesized that TRPM3 is involved in colonic sensation and is sensitized during colitis. We used immunohistochemistry, ratiometric Ca2+ imaging, and colonic afferent nerve recordings in mice to evaluate TRPM3 protein expression in colon-projecting dorsal root ganglion (DRG) neurons, as well as functional activity in DRG neurons and colonic afferent nerves. Colitis was induced using dextran sulfate sodium (DSS) in drinking water. TRPM3 protein expression was observed in 76% of colon-projecting DRG neurons and was often colocalized with calcitonin gene-related peptide. The magnitudes of intracellular Ca2+ transients in DRG neurons in response to the TRPM3 agonists CIM-0216 and pregnenolone sulfate sodium were significantly greater in neurons from mice with colitis compared with controls. In addition, the percentage of DRG neurons from mice with colitis that responded to CIM-0216 was significantly increased. CIM-0216 also increased the firing rate of colonic afferent nerves from control and mice with colitis. The TRPM3 inhibitor isosakuranetin inhibited the mechanosensitive response to distension of wide dynamic range afferent nerve units from mice with colitis but had no effect in control mice. Thus, TRPM3 contributes to colonic sensory transduction and may be a potential target for treating pain in IBD.NEW & NOTEWORTHY This is the first study to characterize TRPM3 protein expression and function in colon-projecting DRG neurons. A TRPM3 agonist excited DRG neurons and colonic afferent nerves from healthy mice. TRPM3 agonist responses in DRG neurons were elevated during colitis. Inhibiting TRPM3 reduced the firing of wide dynamic range afferent nerves from mice with colitis but had no effect in control mice.
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Affiliation(s)
- James W King
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
- Department of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Aidan S W Bennett
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Hannah M Wood
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Corey C Baker
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Hanin Alsaadi
- Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada
| | - Max Topley
- Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada
| | - Stephen A Vanner
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
- Department of Medicine, Queen's University, Kingston, Ontario, Canada
| | - David E Reed
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
- Department of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Alan E Lomax
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
- Department of Medicine, Queen's University, Kingston, Ontario, Canada
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
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Gharibo C, Drewes AM, Breve F, Rekatsina M, Narvaez Tamayo MA, Varrassi G, Paladini A. Iatrogenic Side Effects of Pain Therapies. Cureus 2023; 15:e44583. [PMID: 37790027 PMCID: PMC10545448 DOI: 10.7759/cureus.44583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 09/02/2023] [Indexed: 10/05/2023] Open
Abstract
Pain regimens, particularly for chronic cancer and noncancer pain, must balance the important analgesic benefits against potential risks. Many effective and frequently used pain control regimens are associated with iatrogenic adverse events. Interventional procedures can be associated with nerve injuries, vascular injuries, trauma to the spinal cord, and epidural abscesses. Although rare, these adverse events are potentially catastrophic. Pharmacologic remedies for pain must also consider potential side effects that can occur even at therapeutic doses of over-the-counter remedies such as paracetamol (acetaminophen) or nonsteroidal anti-inflammatory drugs. Opioids are effective pain relievers but are associated with many side effects, some of which can be treatment limiting. A prevalent and distressing side effect of opioid therapy is constipation. Opioid-induced constipation is caused by binding to opioid receptors in the gastrointestinal system, making conventional laxatives ineffective. Peripherally acting mu-opioid receptor antagonists are a new drug class that offers the benefits of preserving opioid analgesia without side effects in the gastrointestinal system. An important safety concern, particularly among geriatric patients is the increasingly prevalent condition of polypharmacy. Many senior patients take five or more medications, including some that may be contraindicated in geriatric patients, duplicative of other drugs, have potential pharmacokinetic drug-drug interactions, or may not be the optimal choice for the patient's age and condition. Careful assessment of medications in the elderly, including possibly deprescribing with tapering of certain drugs, may be warranted but should be done systematically and under clinical supervision.
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Affiliation(s)
| | - Asbjørn M Drewes
- Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, DNK
| | - Frank Breve
- Pharmacy, Temple University, Philadelphia, USA
| | | | | | | | - Antonella Paladini
- Life, Health and Environmental Sciences (MESVA), University of L'Aquila, L'Aquila, ITA
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Ma Y, Zhang R, Cao X, Zhang L, Bao S, Ren J, Ma W. Effects of intraoperative esketamine addition on gastrointestinal function after benign gynaecological laparoscopic surgery: a double-blind, randomized controlled study. BMC Anesthesiol 2023; 23:220. [PMID: 37353773 PMCID: PMC10288755 DOI: 10.1186/s12871-023-02184-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 06/17/2023] [Indexed: 06/25/2023] Open
Abstract
BACKGROUND Gastrointestinal hypokinesis can occur transiently after benign gynecologic surgery. Opioids cause the side effect of postoperative gastrointestinal hypokinesis, but an opioid-sparing anaesthetic protocol based on esketamine reduces intraoperative opioid consumption. Therefore, this study hypothesised that an opioid-sparing anaesthetic protocol based on esketamine would shorten the gastrointestinal function recovery time after benign gynaecological laparoscopic surgery. METHODS This was a prospective randomized controlled double-blind study conducted in a single centre. All patients scheduled for elective benign laparoscopic gynaecological surgery at Xing'an Meng People's Hospital, Inner Mongolia Autonomous Region, from November 2021 to April 2022 were consecutively enrolled and randomly divided into the opioid-sparing anaesthesia group (Group OS) and the conventional anaesthesia group (Group C). Postoperative first exhaust time, feeding time and postoperative nausea and/or vomiting (PONV) were analyzed in both groups. RESULTS A total of 71 patients were enrolled in this study, including 35 in Group OS and 36 in Group C. The general condition, operative time, type of surgery, intraoperative bleeding, intraoperative fluid volume and intraoperative urine volume were not statistically different between the two groups. Compared with Group C, significantly shorter first postoperative flatus time (11 [8, 14] h vs. 14 [11, 18], p = 0.003) and anaesthesia resuscitation time (7 [6, 9] h vs. 9 [7, 11] h, p = 0.013)were observed in the OS group. The incidence of PONV in Group OS was significantly lower compared with Group C (11.4% vs. 41.7%, p = 0.007). CONCLUSION The esketamine-based opioid-sparing anaesthetic protocol can shorten the postoperative first flatus time after benign laparoscopic surgery in gynaecology, and reduce the incidence of PONV. In addition, the application of esketamine may reduce the postoperative opioid dose requirement of patients. TRIAL REGISTRATION This study was registered with the China Clinical Trials Registry (registration number: ChiCTR2100052528, 30/10/2021).
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Affiliation(s)
- Yuhua Ma
- Department of Anesthesiology, Xing'an Meng People's Hospital, Inner Mongolia Autonomous Region, Xing'an Meng, Inner Mongolia, 137400, China
| | - Ran Zhang
- Department of Anesthesiology, Peking University People's Hospital, Beijing, 100044, China.
| | - Xue Cao
- Department of Anesthesiology, Xing'an Meng People's Hospital, Inner Mongolia Autonomous Region, Xing'an Meng, Inner Mongolia, 137400, China
| | - Lin Zhang
- Department of Anesthesiology, Xing'an Meng People's Hospital, Inner Mongolia Autonomous Region, Xing'an Meng, Inner Mongolia, 137400, China
| | - Suozhu Bao
- Department of Anesthesiology, Xing'an Meng People's Hospital, Inner Mongolia Autonomous Region, Xing'an Meng, Inner Mongolia, 137400, China
| | - Jie Ren
- Department of Anesthesiology, Xing'an Meng People's Hospital, Inner Mongolia Autonomous Region, Xing'an Meng, Inner Mongolia, 137400, China
| | - Weiwei Ma
- Department of Anesthesiology, Xing'an Meng People's Hospital, Inner Mongolia Autonomous Region, Xing'an Meng, Inner Mongolia, 137400, China
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Graven-Nielsen CS, Knoph CS, Okdahl T, Høyer KL, Krogh K, Hellström PM, Drewes AM. Opioids in the Treatment of Chronic Idiopathic Diarrhea in Humans—A Systematic Review and Treatment Guideline. J Clin Med 2023; 12:jcm12072488. [PMID: 37048572 PMCID: PMC10094889 DOI: 10.3390/jcm12072488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/14/2023] [Accepted: 03/20/2023] [Indexed: 03/29/2023] Open
Abstract
In patients with chronic idiopathic diarrhea resistant to standard treatment, opioids are often used as rescue therapy. This systematic review investigated opioid effects on gut function in chronic diarrhea. PubMed and Embase were searched regarding effects of opioid agonists on the gastrointestinal tract in humans with chronic or experimentally induced diarrhea. A total of 1472 relevant articles were identified and, after thorough evaluation, 11 clinical trials were included. Generally, studies reported a reduction in stool frequency and an increase in transit time during treatment with the opioid receptor agonists loperamide, asimadoline, casokefamide, and codeine compared with placebo. Loperamide and diphenoxylate significantly improved stool consistency compared with placebo, whereas asimadoline showed no such effects. Compared with placebo, loperamide treatment caused less abdominal pain and urgency. Asimadoline showed no significant subjective improvements, but fedotozine was superior to placebo in reducing abdominal pain and bloating in selected patients. Only two relevant studies were published within the last 20 years, and standardized endpoint measures are lacking. Most trials included few participants, and further evidence is needed from larger, prospective studies. Likewise, consensus is needed to standardize endpoints for stool frequency, transit time, and consistency to conduct future meta-analyses on opioids in management of chronic idiopathic diarrhea.
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Wong AK, Grobler A, Le B. ENhANCE trial protocol: A multi-centre, randomised, phase IV trial comparing the efficacy of oxycodone/naloxone prolonged release (OXN PR) versus oxycodone prolonged release (Oxy PR) tablets in patients with advanced cancer. Contemp Clin Trials Commun 2022; 30:101036. [PMID: 36407843 PMCID: PMC9672918 DOI: 10.1016/j.conctc.2022.101036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 09/01/2022] [Accepted: 11/07/2022] [Indexed: 11/14/2022] Open
Abstract
Background Oxycodone is a frequently used opioid in cancer. Opioid-induced constipation (OIC) is common. Oxycodone/Naloxone Prolonged Release (OXN PR) contains naloxone, which mitigates OIC. Trials have either focused on non-cancer pain, or conducted before significant experience of using OXN PR. This trial aims to: demonstrate (1) analgesic equivalence between OXN PR and Oxycodone Prolonged Release (Oxy PR), and (2) superiority of constipation outcomes in OXN PR compared to Oxy PR in cancer pain. Unlike other trials, it will only include patients with at least moderate pain scores (≥4/10), allow usual laxatives, and exclude potential liver dysfunction. Methods This is a multi-centre, open-label, randomised, phase IV study of OXN PR vs Oxy PR in patients with cancer-related pain. The primary outcome is pain difference on Brief Pain Inventory-Short Form (BPI-SF) at 5 weeks. Secondary outcomes are comparison of other pain outcomes (BPI-SF) and neuropathic pain measures (Leeds Assessment of Neuropathic Symptoms & Signs (S-LANNS)), constipation (Bowel Function Index (BFI)), quality of life (EORTC-QLQ-C30), rescue analgesia use, total opioid dose, and total laxative dose over 5 weeks. Conclusion The comparison of analgesic efficacy between both arms, and superiority of constipation in the OXN PR arm will add new knowledge on the comparisons of both agents, and oxycodone independently. This trial will extend knowledge of the effectiveness, safety, and adverse effect profiles of both drugs in terms of pain, constipation, quality of life outcomes for patients with cancer pain, and provide clinicians with high quality data to guide decision making. Trial registration Name of the registry: ANZCTR Trial registration number ACTRN12619001282178 Date of registration 17/09/2019 URL of trial registry record https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377673&isReview=true Protocol version 2.1_28 August 2020
Opioid-induced constipation is the commonest side effect in cancer pain management. Oxycodone/naloxone prolonged release aims to reduce opioid-induced constipation. Trials have little focus on cancer pain, concurrent liver impairment, and laxatives. This trial evaluates these key problems practically to guide decision making.
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7
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Sabzi F, Rozbahani M, Heidar A, Faraji R. A rare case of volvulus after off-pump coronary artery bypass graft surgery in an opium addict patient revised. CASPIAN JOURNAL OF INTERNAL MEDICINE 2021; 12:S417-S420. [PMID: 34760096 PMCID: PMC8559659 DOI: 10.22088/cjim.12.0.417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 09/23/2020] [Accepted: 09/30/2020] [Indexed: 11/16/2022]
Abstract
Background: Volvulus of colon is a very rare phenomenon in post cardiac surgery course, and their predicting factor in most patients is unknown. Between colonic volvulus, splenic flexure is the rarest site for torsion in general population. The main symptoms are vague abdominal pain, vomiting and distension. The primary diagnostic images include plain chest x-ray, CT scan and colonoscopy. Case Presentation: We report the case of a 57-year -old opium male addict, who was. Admitted for abdominal pain, nausea, and vomiting five days after off-pump coronary artery bypass surgery (OPCAB). An abdominal x-ray reported a colonic volvulus. Exploratory laparotomy showed acute abdomen resulting from a gangrene of long segment of splenic flexure caused by volvulus. Conclusion: Gastrointestinal complication such as volvulus is an exceedingly rare complication of OPCAB, despite the absence of anatomic abnormalities only complete colonic malrotation as the result of mega colon and constipation, the main pathogenetic causes. This patient was unique because of careful literature search revealed that this case was the first reported volvulus that has been described so far.
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Affiliation(s)
- Feridon Sabzi
- Kermanshah Cardiovascular Research Centre, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Rozbahani
- Kermanshah Cardiovascular Research Centre, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Aghighe Heidar
- Kermanshah Cardiovascular Research Centre, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Reza Faraji
- Yazd Cardiovascular Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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8
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Muchhala KH, Jacob JC, Kang M, Dewey WL, Akbarali HI. The Guts of the Opioid Crisis. Physiology (Bethesda) 2021; 36:315-323. [PMID: 34431418 PMCID: PMC8813205 DOI: 10.1152/physiol.00014.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/10/2021] [Accepted: 06/10/2021] [Indexed: 01/09/2023] Open
Abstract
Bidirectional interactions of the gut epithelium with commensal bacteria are critical for maintaining homeostasis within the gut. Chronic opioid exposure perturbs gut homeostasis through a multitude of neuro-immune-epithelial mechanisms, resulting in the development of analgesic tolerance, a major underpinning of the current opioid crisis. Differences in molecular mechanisms of opioid tolerance between the enteric and central pain pathways pose a significant challenge for managing chronic pain without untoward gastrointestinal effects.
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Affiliation(s)
- Karan H Muchhala
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
| | - Joanna C Jacob
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
| | - Minho Kang
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
| | - William L Dewey
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
| | - Hamid I Akbarali
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
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De Giorgio R, Zucco FM, Chiarioni G, Mercadante S, Corazziari ES, Caraceni A, Odetti P, Giusti R, Marinangeli F, Pinto C. Management of Opioid-Induced Constipation and Bowel Dysfunction: Expert Opinion of an Italian Multidisciplinary Panel. Adv Ther 2021; 38:3589-3621. [PMID: 34086265 PMCID: PMC8279968 DOI: 10.1007/s12325-021-01766-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 04/28/2021] [Indexed: 12/14/2022]
Abstract
The prescribing and use of opioid analgesics is increasing in Italy owing to a profusion in the number and types of opioid analgesic products available, and the increasing prevalence of conditions associated with severe pain, the latter being related to population aging. Herein we provide the expert opinion of an Italian multidisciplinary panel on the management of opioid-induced constipation (OIC) and bowel dysfunction. OIC and opioid-induced bowel dysfunction are well-recognised unwanted effects of treatment with opioid analgesics that can profoundly affect quality of life. OIC can be due to additional factors such as reduced mobility, a low-fibre diet, comorbidities, and concomitant medications. Fixed-dose combinations of opioids with mu (μ) opioid receptor antagonists, such as oxycodone/naloxone, have become available, but have limited utility in clinical practice because the individual components cannot be independently titrated, creating a risk of breakthrough pain as the dose is increased. A comprehensive prevention and management strategy for OIC should include interventions that aim to improve fibre and fluid intake, increase mobility or exercise, and restore bowel function without compromising pain control. Recommended first-line pharmacological treatment of OIC is with an osmotic laxative (preferably polyethylene glycol [macrogol]), or a stimulant laxative such as an anthraquinone. A second laxative with a complementary mechanism of action should be added in the event of an inadequate response. Second-line treatment with a peripherally acting μ opioid receptor antagonist (PAMORA), such as methylnaltrexone, naloxegol or naldemedine, should be considered in patients with OIC that has not responded to combination laxative treatment. Prokinetics or intestinal secretagogues, such as lubiprostone, may be appropriate in the third-line setting, but their use in OIC is off-label in Italy, and should therefore be restricted to settings such as specialist centres and clinical trials.
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Affiliation(s)
- Roberto De Giorgio
- Department of Translational Medicine, University of Ferrara, Via Aldo Moro 8, 44124, Ferrara, Italy.
| | | | - Giuseppe Chiarioni
- Division of Gastroenterology of the University of Verona, Azienda Ospedaliera Universitaria Integrata (AOUI) Verona, Verona, Italy
- UNC Center for Functional GI and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | | | - Augusto Caraceni
- High-Complexity Unit of Palliative Care, Pain Therapy and Rehabilitation, IRCSS Foundation National Cancer Institute, Milan, Italy
| | - Patrizio Odetti
- Department of Geriatrics and Gerontology, University of Genoa, Genoa, Italy
| | - Raffaele Giusti
- High-Complexity Medical Oncology Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Franco Marinangeli
- Department of Anesthesiology, Pain Treatment, Intensive and Palliative Care, University of L'Aquila, L'Aquila, Italy
| | - Carmine Pinto
- High-Complexity Oncology Unit, Clinical Cancer Center, IRCCS Reggio Emilia, Reggio Emilia, Italy
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Alam MM, Emon NU, Alam S, Rudra S, Akhter N, Mamun MMR, Ganguly A. Assessment of pharmacological activities of Lygodium microphyllum Cav. leaves in the management of pain, inflammation, pyrexia, diarrhea, and helminths: In vivo, in vitro and in silico approaches. Biomed Pharmacother 2021; 139:111644. [PMID: 33945914 DOI: 10.1016/j.biopha.2021.111644] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 04/06/2021] [Accepted: 04/19/2021] [Indexed: 11/18/2022] Open
Abstract
Lygodium microphyllum Cav. (Family: Lygodiaceae) is a perennial, snake fern and an invasive weed in Florida and also known as old world climbing fern. This study is intended to evaluate the antipyretic, analgesic, anti-inflammatory, antidiarrheal and anthelmintic activity of methanol extract of Lygodium microphyllum Cav. leaves (MELM) by in vivo, in vitro and in silico approaches. In addition, Biovia, PyRx autoDock Vina, UCSF Chimera have been applied to investigate the docking study in order to evaluate the binding interaction and an online tool was used to explore the ADME/T properties of selected bioactive compounds. In acetic acid induced writhing study, MELM inhibited 44.28% and 56.61% of writhes at 200 and 400 (mg/kg) respectively compared to standard drug Diclofenac-Na (10 mg/kg) (74.42% inhibition). In anti-inflammatory experiment by formalin triggered licking method, MELM caused significant (p < 0.05) inhibition of licking in both early phase (42.97%, 63.30%) and late phase (43.35%, 63.03%) at the doses of 200 and 400 mg/kg respectively, whereas reference drug Ibuprofen inhibited paw licking 77.18% in early phase and 76.86% in late phase. MELM also showed promising antipyretic potential where the maximum reduction of fever was produced by MELM 400 mg/kg whose fever lowering capacity is close to the prescribe drug Indomethacin 4 mg/kg, i.p. In Castor oil triggered diarrhea method, MELM delayed the onset time of diarrhea, continuous persistence of wet feces, and decreased the weight of wet feces remarkably. Defection inhibition was achieved 27.56% and 51.72%, for MELM 200 and at 400 (mg/kg) respectively while loperamide 2 (mg/kg) yields 55.17% inhibition of the diarrheal defecation. In anthelmintic bioassay, MELM took 5.83 ± 0.83 and 41.67 ± 1.78 min respectively for paralyzing and death compared to standard drug albendazole; (paralysis time 4.00 ± 0.73 min and death time 31,00 ± 1.71 min). Isoeleutherol, isoquercetin and quercetin were found prominent in molecular docking study and ADME/T analysis verified their drug likeliness. The research validates the moderate analgesic, anti-inflammatory, and remarkable antipyretic, antidiarrheal, anthelmintic activities of the plant extract which can be used an alternative source of novel therapeutics.
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Affiliation(s)
- Md Munsur Alam
- Department of Pharmacy, Faculty of Science and Engineering, International Islamic University Chittagong, Chattogram 4318, Bangladesh
| | - Nazim Uddin Emon
- Department of Pharmacy, Faculty of Science and Engineering, International Islamic University Chittagong, Chattogram 4318, Bangladesh; Department of Public Health, School of Science and Technology, Bangladesh Open University, Gazipur 1705, Bangladesh
| | - Safaet Alam
- Department of Pharmacy, State University of Bangladesh, 77 Satmasjid road, Dhanmondi, Dhaka 1207, Bangladesh; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh.
| | - Sajib Rudra
- Department of Botany, Faculty of Biological Science, University of Chittagong, Chattogram 4331, Bangladesh
| | - Nahid Akhter
- Department of Pharmacy, Faculty of Science and Engineering, International Islamic University Chittagong, Chattogram 4318, Bangladesh
| | - Md Masudur Rahman Mamun
- Department of Pharmacy, Faculty of Science and Engineering, International Islamic University Chittagong, Chattogram 4318, Bangladesh
| | - Amlan Ganguly
- Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh
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Fernando H, Shaw JA, Myles PS, Peter K, Stub D. The opioid-P2Y12 inhibitor interaction: Potential strategies to mitigate the interaction and consideration of alternative analgesic agents in myocardial infarction. Pharmacol Ther 2021; 217:107665. [DOI: 10.1016/j.pharmthera.2020.107665] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 08/13/2020] [Indexed: 01/04/2023]
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12
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Lashgari NA, Roudsari NM, Zandi N, Pazoki B, Rezaei A, Hashemi M, Momtaz S, Rahimi R, Shayan M, Dehpour AR, Abdolghaffari AH. Current overview of opioids in progression of inflammatory bowel disease; pharmacological and clinical considerations. Mol Biol Rep 2021; 48:855-874. [PMID: 33394234 DOI: 10.1007/s11033-020-06095-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 12/16/2020] [Indexed: 02/01/2023]
Abstract
Inflammatory bowel diseases (IBD) belong to a subgroup of persistent, long-term, progressive, and relapsing inflammatory conditions. IBD may spontaneously develop in the colon, resulting in tumor lesions in inflamed regions of the intestine, such as invasive carcinoma. The benefit of opioids for IBD treatment is still questionable, thereby we investigated databases to provide an overview in this context. This review demonstrates the controversial role of opioids in IBD therapy, their physiological and pharmacological functions in attenuating the IBD symptoms, and in improving inflammatory, oxidative stress, and the quality of life factors in IBD subjects. Data were extracted from clinical, in vitro, and in vivo studies in English, between 1995 and 2019, from PubMed, Google Scholar, Scopus, and Cochrane library. Based on recent reports, there are promising opportunities to target the opioid system and control the IBD symptoms. This study suggests a novel approach for future treatment of functional and inflammatory disorders such as IBD.
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Affiliation(s)
- Naser-Aldin Lashgari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nazanin Momeni Roudsari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nadia Zandi
- Tehran University of Medical Sciences, Tehran, Iran
| | | | - Atiyeh Rezaei
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrnoosh Hashemi
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Roja Rahimi
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Shayan
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Hossein Abdolghaffari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran.
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
- Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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13
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Pitchumoni CS. Gastrointestinal Physiology and Aging. GERIATRIC GASTROENTEROLOGY 2021:155-200. [DOI: 10.1007/978-3-030-30192-7_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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14
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Medication use and polypharmacy in patients referred to a tertiary gastroenterology practice. ACTA ACUST UNITED AC 2020; 58:228-232. [PMID: 32543459 DOI: 10.2478/rjim-2020-0016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Indexed: 12/12/2022]
Abstract
Introduction. Commonly prescribed medications are associated with various gastrointestinal (GI) side effects but few data are available on prescription medication use and polypharmacy in a gastroenterology outpatient practice. We aimed to examine the prevalence of polypharmacy, defined as the simultaneous use of 5 or more medications.Methods. A descriptive correlational study of consecutive outpatient consultations in 988 patients referred to a tertiary gastroenterology practice. Main outcome measurements were frequency of prescription medication use and polypharmacy.Results. The most common GI symptoms were abdominal pain (72%), nausea (57%), and constipation (53%). The frequency of polypharmacy was 10%. Eighty percent of patients took at least one medication and 60% took two or more. The most frequently used medication classes were proton pump inhibitors (43%), followed by benzodiazepines (30%), selective serotonin-reuptake or norepinephrine-reuptake inhibitors (28%), non-steroidal anti-inflammatory drugs (27%), and opioids (21%).Conclusion. There was a higher use of prescription medicine including antidepressants, and a lower frequency of polypharmacy in our study cohort compared to the general population. The use of medications may have contributed to the symptoms leading to our study's population GI consultation.
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Katagiri N, Sakai R, Izutsu T, Kawana H, Sugino S, Kido K. Postoperative Pain Management in Patients With Ulcerative Colitis. Anesth Prog 2020; 67:158-163. [PMID: 32992337 DOI: 10.2344/anpr-67-01-06] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 11/14/2019] [Indexed: 12/26/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders of the gastrointestinal tract including ulcerative colitis (UC) and Crohn's disease. Pain management can be challenging in patients with IBD because there are limitations on the use of analgesics. Use of nonsteroidal anti-inflammatory drugs is not recommended in patients with IBD because there is risk of relapse of IBD and an overall increase in disease activity. Opioids, although frequently used for treating severe acute pain, can have additional risks and complications in patients with IBD such as ileus, toxic megacolon, and narcotic bowel syndrome. Furthermore, little information is available in the literature on pain management in these patients undergoing noncolorectal surgery. This report describes 2 patients with UC in whom postoperative pain following oral and maxillofacial surgery was managed by intravenous patient-controlled analgesia with pentazocine. Apart from the development of acute dystonia in 1 case that was likely due to the use of droperidol for prevention of postoperative nausea and vomiting, postoperative pain was well controlled by pentazocine in both patients without any complications or UC exacerbations.
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Affiliation(s)
- Norika Katagiri
- Department of Anesthesiology, Kanagawa Dental University Hospital, Yokosuka, Kanagawa, Japan
| | - Ryutaro Sakai
- Department of Anesthesiology, Kanagawa Dental University Hospital, Yokosuka, Kanagawa, Japan
| | - Takashi Izutsu
- Department of Oral and Maxillofacial Surgery, Yamagata Prefectural Central Hospital, Yamagata City, Yamagata, Japan
| | - Hiromasa Kawana
- Department of Oral and Maxillofacial Implantology, Kanagawa Dental University Hospital, Yokosuka, Kanagawa, Japan
| | - Shigekazu Sugino
- Department of Anesthesiology and Perioperative Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Kanta Kido
- Department of Anesthesiology, Kanagawa Dental University Hospital, Yokosuka, Kanagawa, Japan
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16
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Endoscopic ultrasound: a powerful tool to modify treatment algorithms in opioid-induced achalasia. Surg Endosc 2020; 35:4585-4594. [PMID: 32845401 DOI: 10.1007/s00464-020-07882-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 08/05/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Opioid use in the U.S. has increased dramatically over the last 15 years, recently being declared a public health emergency. Opioid use is associated with esophageal dysmotility lending to a confusing clinical picture compared to true achalasia. Patients exhibit symptoms and elicit diagnostic results consistent with esophageal motility disorders, in particular type III achalasia. Modified therapeutic strategies and outcomes become challenging. Differentiating true achalasia from opioid-induced achalasia is critical. Conventional surgical interventions, i.e., myotomy, are ineffective in the absence of true achalasia. We assess the utility of esophageal muscle layer mapping with endoscopic ultrasound (EUS) in distinguishing primary from opioid-induced achalasia. METHODS From 2016 to 2019, patients with abnormal manometry and suspected achalasia underwent esophagogastroduodenoscopy and EUS mapping of esophageal round muscle layer thickness. Maximum round layer thickness and length of round muscle layer thickness > 1.8 mm were collected and compared between opioid users and non-opioid users using Wilcoxon Rank sum test. RESULTS 45 patients were included: 12 opioid users, 33 non-opioid users. Mean age 56.8 years (range 24-93), 53.3% male patients. Mean BMI in the opioid-induced achalasia group was 30.2 kg/m2, mean BMI in the primary achalasia group 26.8 kg/m2 (p = 0.11). In comparing endoscopic maximum round layer thickness between groups, non-opioid patients had a thicker round muscle layer (2.7 mm vs 1.8 mm, p = 0.05). Length of abnormally thickened esophageal muscle (greater than 1.8 mm) also differed between the two groups; patients on opioids had a shorter length of thickening (4.0 cm vs 0.0 cm, p = 0.04). Intervention rate was higher in the non-opioid group (p = 0.79). Of the patients that underwent therapeutic intervention, symptom resolution was higher in the non-opioid group (p = 0.002), while re-intervention post-procedure for persistent symptomatology was elevated in the opioid subset (p = 0.06). Patients in the opioid group were less likely to undergo invasive treatment (Heller). As of 2017 all interventions in the opioid group have been endoscopic. CONCLUSION Endoscopic ultrasound is an essential tool that has improved our treatment algorithm for suspected achalasia in patients with chronic opioid usage. Incorporation of EUS findings into treatment approach may prevent unnecessary surgery in opioid users.
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17
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Seifi N, Safarian M, Nematy M, Rezvani R, Khadem-Rezaian M, Sedaghat A. Effects of synbiotic supplementation on energy and macronutrients homeostasis and muscle wasting of critical care patients: study protocol and a review of previous studies. Trials 2020; 21:221. [PMID: 32093741 PMCID: PMC7041281 DOI: 10.1186/s13063-020-4136-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 02/03/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND An extreme and persistent dysbiosis occurs among critically ill patients, regardless of the heterogeneity of disease. Dysbiosis in critically ill patients may make them prone to hospital-acquired infections, sepsis, multi-organ failure (MOF), energy homeostasis disturbance, muscle wasting, and cachexia. Modulation of gut microbiota through synbiotics can be considered as a potential treatment for muscle wasting and macronutrient homeostasis disturbances. METHODS This is a prospective, single-center, double-blind, parallel randomized controlled trial with the aim to evaluate the effects of synbiotic supplementation on energy and macronutrient homeostasis and muscle wasting in critically ill patients. A total of 40 hemodynamically stable, adult, critically ill patients who receive enteral nutrition via a nasogasteric tube (NGT) in the 24-48 h after admission to critical care will be included in this study. Eligible patients will be randomly assigned to receive Lactocare (ZistTakhmir) capsules 500 mg every 12 h or a placebo capsule, which contains only the sterile maize starch and is similar to synbiotic capsules for 14 days. The synbiotic and placebo capsules will be given through the nasogastric tube, separately from gavage, after feeding. DISCUSSION Gut microbiota modulation through synbiotics is proposed to improve clinical prognosis and reduce infectious complications, ventilator dependency, and length of ICU stay by improving energy and macronutrient homeostasis and reducing muscle protein catabolism. TRIAL REGISTRATION Iranian Registry of Clinical Trials, IRCT20190227042857N1. Registered on 17 March 2019.
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Affiliation(s)
- Najmeh Seifi
- Department of Nutrition, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Safarian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Nematy
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Rezvani
- Department of Nutrition, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khadem-Rezaian
- Department of community medicine, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Sedaghat
- Department of Anesthesiology, Mashhad University of Medical Sciences, Mashhad, Iran.
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18
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Al Momani L, Alomari M, Bratton H, Boonpherg B, Aasen T, El Kurdi B, Young M. Opioid use is associated with incomplete capsule endoscopy examinations: a systematic review and meta-analysis. Transl Gastroenterol Hepatol 2020; 5:5. [PMID: 32190773 PMCID: PMC7061196 DOI: 10.21037/tgh.2019.11.05] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 10/23/2019] [Indexed: 01/05/2025] Open
Abstract
BACKGROUND Capsule endoscopy (CE) is a non-invasive imaging modality designed to evaluate various small bowel pathologies. Failure to reach the cecum within the battery lifespan, termed incomplete examination, may result in inadequate testing and possibly delayed therapy. Several studies have attempted to evaluate the association between CE completion and opioid use. However, their results are conflicting. The aim of this meta-analysis is to evaluate the previously published literature on the association between opioid use and CE completion. METHODS We performed a comprehensive literature search in PubMed, PubMed Central, Embase, and ScienceDirect databases from inception through June 1, 2018, to identify all studies that evaluated the association between CE completion and opioid use. We included studies that presented an odds ratio (OR) with a 95% confidence interval (CI) or presented the data sufficient to calculate the OR with a 95% CI. Statistical analysis was performed using the comprehensive meta-analysis (CMA), version 3 software. RESULTS Five studies with a total of 1,614 patients undergoing CE in the inpatient (IP) and outpatient (OP) setting were included in this study, 349 of which had an incomplete CE (21.6%). The pooled OR for CE completion is 0.50 (95% CI: 0.38-0.66, I2=36.9%) in opioid users compared to non-users. No publication bias was found using Egger's regression test. CONCLUSIONS Our results indicate that patients on opioids are significantly less likely to have a complete CE examination compared to non-users. To our knowledge, this study represents the first meta-analysis to assess this association.
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Affiliation(s)
- Laith Al Momani
- Department of Internal Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Mohammad Alomari
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Hunter Bratton
- Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Boonphiphop Boonpherg
- Department of Internal Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Tyler Aasen
- Department of Gastroenterology, East Tennessee State University, Johnson City, TN, USA
| | - Bara El Kurdi
- Department of Internal Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Mark Young
- Department of Gastroenterology, East Tennessee State University, Johnson City, TN, USA
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19
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Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential. Br J Anaesth 2019; 123:637-654. [PMID: 31551115 DOI: 10.1016/j.bja.2019.07.026] [Citation(s) in RCA: 235] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 07/15/2019] [Accepted: 07/16/2019] [Indexed: 12/14/2022] Open
Abstract
The relationship between gut microbiota and neurological diseases, including chronic pain, has received increasing attention. The gut microbiome is a crucial modulator of visceral pain, whereas recent evidence suggests that gut microbiota may also play a critical role in many other types of chronic pain, including inflammatory pain, headache, neuropathic pain, and opioid tolerance. We present a narrative review of the current understanding on the role of gut microbiota in pain regulation and discuss the possibility of targeting gut microbiota for the management of chronic pain. Numerous signalling molecules derived from gut microbiota, such as by-products of microbiota, metabolites, neurotransmitters, and neuromodulators, act on their receptors and remarkably regulate the peripheral and central sensitisation, which in turn mediate the development of chronic pain. Gut microbiota-derived mediators serve as critical modulators for the induction of peripheral sensitisation, directly or indirectly regulating the excitability of primary nociceptive neurones. In the central nervous system, gut microbiota-derived mediators may regulate neuroinflammation, which involves the activation of cells in the blood-brain barrier, microglia, and infiltrating immune cells, to modulate induction and maintenance of central sensitisation. Thus, we propose that gut microbiota regulates pain in the peripheral and central nervous system, and targeting gut microbiota by diet and pharmabiotic intervention may represent a new therapeutic strategy for the management of chronic pain.
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20
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Raffa RB, Taylor R, Pergolizzi JV. Treating opioid‐induced constipation in patients taking other medications: Avoiding CYP450 drug interactions. J Clin Pharm Ther 2019; 44:361-371. [DOI: 10.1111/jcpt.12812] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/15/2019] [Accepted: 01/18/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Robert B. Raffa
- University of Arizona College of Pharmacy Tucson Arizona
- Temple University School of Pharmacy Philadelphia Pennsylvania
- Neumentum Inc Palo Alto California
- The NEMA Research Group Naples Florida
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21
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Pannemans J, Corsetti M. Opioid receptors in the GI tract: targets for treatment of both diarrhea and constipation in functional bowel disorders? Curr Opin Pharmacol 2018; 43:53-58. [PMID: 30189347 DOI: 10.1016/j.coph.2018.08.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 08/11/2018] [Accepted: 08/13/2018] [Indexed: 02/08/2023]
Abstract
Opioids have been used for centuries, mostly as a sedative and to treat pain. Currently, they are used on a global scale for the treatment of acute and chronic pain in diseases as osteoarthritis, fibromyalgia, and low back pain. Binding of opioids on opioid receptors can cause a range of different effects such as changes in stress response, analgesia, motor activity and autonomic functions. This review provide a synthetic summary of the most recent literature on the use of drugs acting on mu-receptors to treat two prevalent functional bowel disorders, presenting with opposite bowel habit. Eluxadoline and naloxegol, methylnaltrexone and naldemedine are recently FDA and/or EMA approved drugs demonstrated to be effective and safe for treatment respectively of irritable bowel syndrome subtype diarrhea and opioid induced constipation.
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Affiliation(s)
- J Pannemans
- Catholic University of Leuven, KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - M Corsetti
- NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.
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22
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Food pyramid for subjects with chronic pain: foods and dietary constituents as anti-inflammatory and antioxidant agents. Nutr Res Rev 2018; 31:131-151. [PMID: 29679994 DOI: 10.1017/s0954422417000270] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Emerging literature suggests that diet constituents may play a modulatory role in chronic pain (CP) through management of inflammation/oxidative stress, resulting in attenuation of pain. We performed a narrative review to evaluate the existing evidence regarding the optimum diet for the management of CP, and we built a food pyramid on this topic. The present review also describes the activities of various natural compounds contained in foods (i.e. phenolic compounds in extra-virgin olive oil (EVO)) listed on our pyramid, which have comparable effects to drug management therapy. This review included 172 eligible studies. The pyramid shows that carbohydrates with low glycaemic index should be consumed every day (three portions), together with fruits and vegetables (five portions), yogurt (125 ml), red wine (125 ml) and EVO; weekly: legumes and fish (four portions); white meat, eggs and fresh cheese (two portions); red or processed meats (once per week); sweets can be consumed occasionally. The food amounts are estimates based on nutritional and practical considerations. At the top of the pyramid there is a pennant: it means that CP subjects may need a specific customised supplementation (vitamin B12, vitamin D, n-3 fatty acids, fibre). The food pyramid proposal will serve to guide dietary intake with to the intent of alleviating pain in CP patients. Moreover, a targeted diet can also help to solve problems related to the drugs used to combat CP, i.e. constipation. However, this paper would be an early hypothetical proposal due to the limitations of the studies.
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23
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Mozaffari S, Nikfar S, Abdollahi M. Investigational opioid antagonists for treating opioid-induced bowel dysfunction. Expert Opin Investig Drugs 2017; 27:235-242. [DOI: 10.1080/13543784.2018.1420778] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Shilan Mozaffari
- Division of Pharmaceutical and Narcotic Affairs, Department of Food and Drug Affairs, Kurdistan University of Medical Science, Sanandaj, Iran
- Evidence-Based Medicine Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Shekoufeh Nikfar
- Evidence-Based Medicine Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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24
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de Boer HD, Detriche O, Forget P. Opioid-related side effects: Postoperative ileus, urinary retention, nausea and vomiting, and shivering. A review of the literature. Best Pract Res Clin Anaesthesiol 2017; 31:499-504. [DOI: 10.1016/j.bpa.2017.07.002] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 05/23/2017] [Accepted: 07/03/2017] [Indexed: 12/18/2022]
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25
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Akbarali HI, Dewey WL. The gut-brain interaction in opioid tolerance. Curr Opin Pharmacol 2017; 37:126-130. [PMID: 29145012 DOI: 10.1016/j.coph.2017.10.012] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 10/11/2017] [Accepted: 10/25/2017] [Indexed: 12/11/2022]
Abstract
The prevailing opioid crisis has necessitated the need to understand mechanisms leading to addiction and tolerance, the major contributors to overdose and death and to develop strategies for developing drugs for pain treatment that lack abuse liability and side-effects. Opioids are commonly used for treatment of pain and symptoms of inflammatory bowel disease. The significant effect of opioids in the gut, both acute and chronic, includes persistent constipation and paradoxically may also worsen pain symptoms. Recent work has suggested a significant role of the gastrointestinal microbiome in behavioral responses to opioids, including the development of tolerance to its pain-relieving effects. In this review, we present current concepts of gut-brain interaction in analgesic tolerance to opioids and suggest that peripheral mechanisms emanating from the gut can profoundly affect central control of opioid function.
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Affiliation(s)
- Hamid I Akbarali
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 E. Clay St., McGuire Hall 100, Richmond, VA 23298, USA.
| | - William L Dewey
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 E. Clay St., McGuire Hall 100, Richmond, VA 23298, USA
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26
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Müller-Lissner S, Bassotti G, Coffin B, Drewes AM, Breivik H, Eisenberg E, Emmanuel A, Laroche F, Meissner W, Morlion B. Opioid-Induced Constipation and Bowel Dysfunction: A Clinical Guideline. PAIN MEDICINE (MALDEN, MASS.) 2017; 18:1837-1863. [PMID: 28034973 PMCID: PMC5914368 DOI: 10.1093/pm/pnw255] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To formulate timely evidence-based guidelines for the management of opioid-induced bowel dysfunction. SETTING Constipation is a major untoward effect of opioids. Increasing prescription of opioids has correlated to increased incidence of opioid-induced constipation. However, the inhibitory effects of opioids are not confined to the colon, but also affect higher segments of the gastrointestinal tract, leading to the coining of the term "opioid-induced bowel dysfunction." METHODS A literature search was conducted using Medline, EMBASE, and EMBASE Classic, and the Cochrane Central Register of Controlled Trials. Predefined search terms and inclusion/exclusion criteria were used to identify and categorize relevant papers. A series of statements were formulated and justified by a comment, then labeled with the degree of agreement and their level of evidence as judged by the Strength of Recommendation Taxonomy (SORT) system. RESULTS From a list of 10,832 potentially relevant studies, 33 citations were identified for review. Screening the reference lists of the pertinent papers identified additional publications. Current definitions, prevalence, and mechanism of opioid-induced bowel dysfunction were reviewed, and a treatment algorithm and statements regarding patient management were developed to provide guidance on clinical best practice in the management of patients with opioid-induced constipation and opioid-induced bowel dysfunction. CONCLUSIONS In recent years, more insight has been gained in the pathophysiology of this "entity"; new treatment approaches have been developed, but guidelines on clinical best practice are still lacking. Current knowledge is insufficient regarding management of the opioid side effects on the upper gastrointestinal tract, but recommendations can be derived from what we know at present.
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Affiliation(s)
| | - Gabrio Bassotti
- Gastroenterology and Hepatology Section, Department of Medicine, University of Perugia School of Medicine, Piazza Università, 1, Perugia, Italy
| | - Benoit Coffin
- AP-HP Hôpital Louis Mourier, University Denis Diderot-Paris 7, INSERM U987, Paris, France
| | - Asbjørn Mohr Drewes
- Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Harald Breivik
- Department of Pain Management and Research, University of Oslo, Rikshospitalet, Oslo, Norway
| | - Elon Eisenberg
- Institute of Pain Medicine, Rambam Health Care Campus, The Technion, Israel Institute of Technology, Haifa, Israel
| | - Anton Emmanuel
- GI Physiology Unit, University College Hospital, Queen Square, London, UK
| | | | | | - Bart Morlion
- The Leuven Center for Algology and Pain Management, University of Leuven, KU Leuven, Leuven, Belgium
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27
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Esophageal bezoar due to karaya gum granules used as a laxative. Clin J Gastroenterol 2017; 10:437-441. [PMID: 28730320 DOI: 10.1007/s12328-017-0764-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 07/13/2017] [Indexed: 12/26/2022]
Abstract
Esophageal obstruction from soluble fiber laxatives, such as karaya gum, has been rarely reported in the literature. However, as such preparations are widely commercially available, it is important for gastroenterologists to be aware of their potential to form a bezoar in the esophagus due to swelling on contact with liquid. This report highlights such a case and discusses its challenging management.
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Leppert W, Woron J. The role of naloxegol in the management of opioid-induced bowel dysfunction. Therap Adv Gastroenterol 2016; 9:736-46. [PMID: 27582887 PMCID: PMC4984326 DOI: 10.1177/1756283x16648869] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
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.
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Affiliation(s)
| | - Jaroslaw Woron
- Department of Clinical Pharmacology, Jagiellonian University College of Medicine, Krakow, Poland,Department of Pain Treatment and Palliative Care, Jagiellonian University College of Medicine, Krakow, Poland
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Hussain Z, Rhee KW, Lee YJ, Park H. The Effect of DA-9701 in Opioid-induced Bowel Dysfunction of Guinea Pig. J Neurogastroenterol Motil 2016; 22:529-38. [PMID: 26932898 PMCID: PMC4930309 DOI: 10.5056/jnm15194] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 01/15/2016] [Accepted: 01/27/2016] [Indexed: 12/11/2022] Open
Abstract
Background/Aims Opioid induced bowel dysfunction (OIBD) is associated with decreased gastrointestinal (GI) propulsive activity due to intake of opioid analgesics. DA-9701, a novel prokinetic agent formulated with Pharbitis Semen and Corydalis Tuber has promising effects on GI motor function. Therefore, we aim to evaluate the prokinetic effects of DA-9701 in an OIBD model of guinea pig. Methods The ileal and distal colon muscle contraction in presence of different doses of DA-9701, morphine, and combination (morphine + DA-9701) was measured by tissue bath study. The prokinetic effect of DA-9701 was assessed by charcoal transit and fecal pellet output assay in an OIBD model of guinea pig. Results DA-9701 significantly increased the amplitude and area under the curve of ileal muscle contraction, while there was insignificant effect on the distal colon compared to the control. The maximal amplitude of ileal muscle contraction was acquired at a concentration of 10 μg/mL of DA-9701. In contrast, morphine significantly decreased the amplitude of ileal and distal colon muscle contraction compared to the control. Morphine delayed both upper (P < 0.01) and lower (P < 0.05) GI transit, and delayed GI transit was restored by the administration of DA-9701. Morphine induced reduction of contractility was significantly ameliorated by addition of DA-9701 in both ileal and distal colon muscles. Conclusions DA-9701 significantly increased the amplitude of contraction of the ileal muscle, however the distal colon muscle contraction was insignificant. Additionally, it restored delayed upper and lower GI transit in an OIBD model of guinea pig, and it might prove to be a useful candidate drug in a clinical trial for OIBD.
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Affiliation(s)
- Zahid Hussain
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang Won Rhee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Young Ju Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyojin Park
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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Gervais C, Ducrotté P, Piche T, Di Palma M, Jovenin N, Scotté F. [Constipation and cancer: Current strategies]. Bull Cancer 2016; 103:794-804. [PMID: 27341746 DOI: 10.1016/j.bulcan.2016.05.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Revised: 05/17/2016] [Accepted: 05/30/2016] [Indexed: 10/21/2022]
Abstract
Digestive disorders, in particular constipation, are symptoms very often reported by cancer patients as having a major impact on their quality of life. An accurate diagnosis of bowel delayed transit and defecation disorders is required to best adapt therapeutic management. Constipation associated with cancer may be related to several causes, which can be placed in three nosological categories that sometimes overlap: chronic constipation prior to cancer and having its own evolution; constipation related to the cancer condition, in particular the occlusive syndrome, and constipation induced by cancer therapies. The stricter application of diet and lifestyle measures is often necessary and sometimes sufficient. Laxative drug treatments come under various galenic forms and administration routes and must be selected according to the clinical features of constipation. Surgical management can be indicated in case of ileus or pelvic static disorders. In the case of refractory constipation induced by opioids and within the framework of palliative care to treat an advanced pathology, a peripheral morphinic antagonist can offer fast symptom relief. A way forward to improve the patients' quality of life could be to identify the contributing factors (in particular, genetic factors) to determine which patients are the more at risk and anticipate their management.
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Affiliation(s)
- Claire Gervais
- AP-HP, hôpital européen Georges-Pompidou, service d'oncologie médicale-unité fonctionnelle de soins de support, 20, rue Leblanc, 75015 Paris, France.
| | - Philippe Ducrotté
- CHU de Rouen, Inserm UMR 1073, hôpital Charles-Nicolle, service d'hépato-gastro-entérologie et nutrition, 1, rue de Germont, 76031 Rouen cedex, France
| | - Thierry Piche
- CHU de Nice, EA Inserm 6302, hôpital de l'Archet 2, service de gastro-entérologie et oncologie digestive, 151, route St-Antoine-de-Ginestière, CS 23079, 06202 Nice cedex 3, France
| | - Mario Di Palma
- Unicancer, Institut Gustave-Roussy, département ambulatoire, 114, rue Edouard-Vaillant, 94800 Villejuif cedex, France
| | - Nicolas Jovenin
- Unicancer, Institut Jean-Godinot, département d'oncologie médicale, 1, avenue du Général-Koenig, CS 80014, 51726 Reims cedex, France; Centre hospitalier de Saint-Dizier, cancérologie transversale, 1, rue Albert-Schweitzer, CS 10001, 52115 Saint-Dizier cedex, France; Clinique François I(er), service d'oncologie médicale, 12, rue François I(er), 52122 Saint-Dizier, France
| | - Florian Scotté
- AP-HP, hôpital européen Georges-Pompidou, service d'oncologie médicale-unité fonctionnelle de soins de support, 20, rue Leblanc, 75015 Paris, France
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Webster LR, Camilleri M, Finn A. Opioid-induced constipation: rationale for the role of norbuprenorphine in buprenorphine-treated individuals. Subst Abuse Rehabil 2016; 7:81-6. [PMID: 27366109 PMCID: PMC4913538 DOI: 10.2147/sar.s100998] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Buprenorphine and buprenorphine–naloxone fixed combinations are effective for managing patients with opioid dependence, but constipation is one of the most common side effects. Evidence indicates that the rate of constipation is lower when patients are switched from sublingual buprenorphine–naloxone tablets or films to a bilayered bioerodible mucoadhesive buccal film formulation, and while the bilayered buccal film promotes unidirectional drug flow across the buccal mucosa, the mechanism for the reduced constipation is unclear. Pharmacokinetic simulations indicate that chronic dosing of sublingually administered buprenorphine may expose patients to higher concentrations of norbuprenorphine than buprenorphine, while chronic dosing of the buccal formulation results in higher buprenorphine concentrations than norbuprenorphine. Because norbuprenorphine is a potent full agonist at mu-opioid receptors, the differences in norbuprenorphine exposure may explain the observed differences in treatment-emergent constipation between the sublingual formulation and the buccal film formulation of buprenorphine–naloxone. To facilitate the understanding and management of opioid-dependent patients at risk of developing opioid-induced constipation, the clinical profiles of these formulations of buprenorphine and buprenorphine-naloxone are summarized, and the incidence of treatment-emergent constipation in clinical trials is reviewed. These data are used to propose a potential role for exposure to norbuprenorphine, an active metabolite of buprenorphine, in the pathophysiology of opioid-induced constipation.
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Affiliation(s)
| | | | - Andrew Finn
- BioDelivery Sciences, Inc., Raleigh, NC, USA
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Dorn S, Lembo A, Cremonini F. Opioid-induced bowel dysfunction: epidemiology, pathophysiology, diagnosis, and initial therapeutic approach. ACTA ACUST UNITED AC 2016; 2:31-7. [PMID: 25207610 DOI: 10.1038/ajgsup.2014.7] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Opioids affect motor and sensory function throughout the gastrointestinal tract, and are frequently associated with a number of gastrointestinal symptoms including constipation, which impairs the quality of life and may limit the dose of opioid or result in discontinuation altogether. Patients with opioid-induced constipation should be assessed by careful history and physical examination, and in some cases where the diagnosis is unclear with select diagnostic tests. Few clinical studies have been conducted to assess the efficacy of various treatments. However, it is generally recommended that first-line therapy begin with opioid rotation, as well as with low-cost and low-risk approaches such as lifestyle changes, consumption of fiber-rich food, stool softeners, and laxatives.
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Affiliation(s)
- Spencer Dorn
- Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Anthony Lembo
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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[Bilateral hydronephrosis as a result of opioid-induced bowel spasm in a patient with an ileal conduit]. Urologe A 2016; 55:1347-1349. [PMID: 27146872 DOI: 10.1007/s00120-016-0096-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
A 47-year-old woman with spina bifida and an ileal conduit since childhood presented with left-sided flank pain, bilateral hydronephrosis and oliguria suspicious for a recurrent stenosis at the ureteral implantation site. Her history revealed a recent increase in her pain medication with opioids for treatment of neuropathic pain. After insertion of percutaneous nephrostomy on the left side and confirmation of the stenosis, open reimplantation of the ureter was already discussed with the patient. However after dose reduction of the opioid therapy hydronephrosis resolved. Thus opioid-induced bowel spasm was probably the cause for the obstruction.
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Drewes AM, Munkholm P, Simrén M, Breivik H, Kongsgaard UE, Hatlebakk JG, Agreus L, Friedrichsen M, Christrup LL. Definition, diagnosis and treatment strategies for opioid-induced bowel dysfunction–Recommendations of the Nordic Working Group. Scand J Pain 2016; 11:111-122. [DOI: 10.1016/j.sjpain.2015.12.005] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 12/12/2015] [Indexed: 02/07/2023]
Abstract
Abstract
Background and aims
Opioid-induced bowel dysfunction (OIBD) is an increasing problem due to the common use of opioids for pain worldwide. It manifests with different symptoms, such as dry mouth, gastro-oesophageal reflux, vomiting, bloating, abdominal pain, anorexia, hard stools, constipation and incomplete evacuation. Opioid-induced constipation (OIC) is one of its many symptoms and probably the most prevalent. The current review describes the pathophysiology, clinical implications and treatment of OIBD.
Methods
The Nordic Working Group was formed to provide input for Scandinavian specialists in multiple, relevant areas. Seven main topics with associated statements were defined. The working plan provided a structured format for systematic reviews and included instructions on how to evaluate the level of evidence according to the GRADE guidelines. The quality of evidence supporting the different statements was rated as high, moderate or low. At a second meeting, the group discussed and voted on each section with recommendations (weak and strong) for the statements.
Results
The literature review supported the fact that opioid receptors are expressed throughout the gastrointestinal tract. When blocked by exogenous opioids, there are changes in motility, secretion and absorption of fluids, and sphincter function that are reflected in clinical symptoms. The group supported a recent consensus statement for OIC, which takes into account the change in bowel habits for at least one week rather than focusing on the frequency of bowel movements. Many patients with pain receive opioid therapy and concomitant constipation is associated with increased morbidity and utilization of healthcare resources. Opioid treatment for acute postoperative pain will prolong the postoperative ileus and should also be considered in this context. There are no available tools to assess OIBD, but many rating scales have been developed to assess constipation, and a few specifically address OIC. A clinical treatment strategy for OIBD/OIC was proposed and presented in a flowchart. First-line treatment of OIC is conventional laxatives, lifestyle changes, tapering the opioid dosage and alternative analgesics. Whilst opioid rotation may also improve symptoms, these remain unalleviated in a substantial proportion of patients. Should conventional treatment fail, mechanism-based treatment with opioid antagonists should be considered, and they show advantages over laxatives. It should not be overlooked that many reasons for constipation other than OIBD exist, which should be taken into consideration in the individual patient.
Conclusion and implications
It is the belief of this Nordic Working Group that increased awareness of adverse effects and OIBD, particularly OIC, will lead to better pain treatment in patients on opioid therapy. Subsequently, optimised therapy will improve quality of life and, from a socio-economic perspective, may also reduce costs associated with hospitalisation, sick leave and early retirement in these patients.
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Affiliation(s)
- Asbjørn M. Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology , Aalborg University Hospital , Hobrovej Denmark
| | - Pia Munkholm
- NOH (Nordsjællands Hospital) Gastroenterology , Hillerød Denmark
| | - Magnus Simrén
- Department of Internal Medicine & Clinical Nutrition , Institute of Medicine, Sahlgrenska Academy, University of Gothenburg , Göteborg Sweden
| | - Harald Breivik
- Department of Pain Management and Research , Oslo University Hospital and University of Oslo , Rikshospitalet Norway
| | - Ulf E. Kongsgaard
- Department of Anaesthesiology, Division of Emergencies and Critical Care , Oslo University Hospital, Norway and Medical Faculty, University of Oslo , Rikshospitalet Norway
| | - Jan G. Hatlebakk
- Department of Clinical Medicine , Haukeland University Hospital , Bergen , Norway
| | - Lars Agreus
- Division of Family Medicine , Karolinska Institute , Stockholm , Sweden
| | - Maria Friedrichsen
- Department of Social and Welfare Studies , Faculty of Medicine and Health Sciences , Norrköping , Sweden
| | - Lona L. Christrup
- Department of Drug Design and Pharmacology , Faculty of Health Sciences, University of Copenhagen , københavn Denmark
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Wasilewski A, Lesniak A, Bujalska-Zadrozny M, Sadowski B, Fichna J, Sacharczuk M. The effect of opioid agonists and antagonists on gastrointestinal motility in mice selected for high and low swim stress-induced analgesia. Neurogastroenterol Motil 2016; 28:175-85. [PMID: 26510904 DOI: 10.1111/nmo.12704] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 09/16/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND The opioid system in the gastrointestinal (GI) tract plays an important physiological role, but is also responsible for the side effect of opioid drugs, including troublesome constipation in chronic pain treatment. The aim of this study was to characterize and validate a new mouse model to study the effects of opioid agonists and antagonists in the GI tract. METHODS Six-week-old male Swiss-Webster mice, divergently bred for high (HA) and low (LA) swim stress-induced analgesia (SSIA), were used in the study. To assess the influence of opioid agonists (morphine and loperamide) and antagonists (naloxone hydrochloride, NLX and naloxone methiodide, NLXM) on GI motility, whole GI transit (whole GIT) and upper GIT assays were conducted. To evaluate the expression of opioid receptors in the ileum and colon of HA and LA mice, immune staining was performed. KEY RESULTS The effect of morphine was more pronounced in HA line, whereas loperamide exerted a stronger effect in LA mice. Furthermore, NLX and NLXM differentially abolished the inhibitory action of the central and peripheral opioid system on whole and upper GIT in HA and LA mice. The differences in GI motility between HA and LA mice coexisted with parallel changes in the expression of opioid receptors in the ileum and colon. CONCLUSIONS & INFERENCES Differences in the activity of the endogenous opioid system are responsible for the vulnerability to changes in GI motility during treatment with opioids. Our findings validate the HA/LA model for further studies on opioids in the GI tract.
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Affiliation(s)
- A Wasilewski
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - A Lesniak
- Department of Neuropeptide Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.,Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
| | - M Bujalska-Zadrozny
- Department of Pharmacodynamics, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - B Sadowski
- Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Magdalenka, Poland
| | - J Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - M Sacharczuk
- Department of Neuropeptide Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.,Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Magdalenka, Poland
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Rumman A, Gallinger ZR, Liu LWC. Opioid induced constipation in cancer patients: pathophysiology, diagnosis and treatment. ACTA ACUST UNITED AC 2016. [DOI: 10.1080/23809000.2016.1131595] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Leppert W. Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:2215-31. [PMID: 25931815 PMCID: PMC4404965 DOI: 10.2147/dddt.s32684] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal (GI) symptoms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation, which significantly impair patients’ quality of life and may lead to undertreatment of pain. Traditional laxatives are often prescribed for OIBD symptoms, although they display limited efficacy and exert adverse effects. Other strategies include prokinetics and change of opioids or their administration route. However, these approaches do not address underlying causes of OIBD associated with opioid effects on mostly peripheral opioid receptors located in the GI tract. Targeted management of OIBD comprises purely peripherally acting opioid receptor antagonists and a combination of opioid receptor agonist and antagonist. Methylnaltrexone induces laxation in 50%–60% of patients with advanced diseases and OIBD who do not respond to traditional oral laxatives without inducing opioid withdrawal symptoms with similar response (45%–50%) after an oral administration of naloxegol. A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN) in one tablet (a ratio of 2:1) provides analgesia with limited negative effect on the bowel function, as oxycodone displays high oral bioavailability and naloxone demonstrates local antagonist effect on opioid receptors in the GI tract and is totally inactivated in the liver. OXN in daily doses of up to 80 mg/40 mg provides equally effective analgesia with improved bowel function compared to oxycodone administered alone in patients with chronic non-malignant and cancer-related pain. OIBD is a common complication of long-term opioid therapy and may lead to quality of life deterioration and undertreatment of pain. Thus, a complex assessment and management that addresses underlying causes and patomechanisms of OIBD is recommended. Newer strategies comprise methylnaltrexone or OXN administration in the management of OIBD, and OXN may be also considered as a preventive measure of OIBD development in patients who require opioid administration.
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Affiliation(s)
- Wojciech Leppert
- Chair and Department of Palliative Medicine, Poznan University of Medical Sciences, Poznan, Poland
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Gan TJ, Robinson SB, Oderda GM, Scranton R, Pepin J, Ramamoorthy S. Impact of postsurgical opioid use and ileus on economic outcomes in gastrointestinal surgeries. Curr Med Res Opin 2015; 31:677-86. [PMID: 25586296 DOI: 10.1185/03007995.2015.1005833] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVES To assess the incidence and economic impact of postoperative ileus (POI) following laparotomy (open) and laparoscopic procedures for colectomies and cholecystectomies in patients receiving postoperative pain management with opioids. METHODS Using the Premier research database, we retrospectively identified adult inpatients discharged between 2008 and 2010 receiving postsurgical opioids following laparotomy and laparoscopic colectomy and cholecystectomy. POI was identified through ICD-9 diagnosis codes and postsurgical morphine equivalent dose (MED) determined. RESULTS A total of 138,068 patients met criteria, and 10.3% had an ileus. Ileus occurred more frequently in colectomy than cholecystectomy and more often when performed by laparotomy. Ileus patients receiving opioids had an increased length of stay (LOS) ranging from 4.8 to 5.7 days, total cost from $9945 to $13,055 and 30 day all-cause readmission rate of 2.3 to 5.3% higher compared to patients without ileus. Patients with ileus received significantly greater MED than those without (median: 285 vs. 95 mg, p < 0.0001) and were twice as likely to have POI. MED above the median in ileus patients was associated with an increase in LOS (3.8 to 7.1 days), total cost ($8458 to $19,562), and readmission in laparoscopic surgeries (4.8 to 5.2%). Readmission rates were similar in ileus patients undergoing open procedures regardless of MED. CONCLUSIONS Use of opioids in patients who develop ileus following abdominal surgeries is associated with prolonged hospitalization, greater costs, and increased readmissions. Furthermore, higher doses of opioids are associated with higher incidence of POI. Limitations are related to the retrospective design and the use of administrative data (including reliance on ICD-9 coding). Yet POI may not be coded and therefore underestimated in our study. Assessment of pre-existing disease and preoperative pain management was not assessed. Despite these limitations, strategies to reduce opioid consumption may improve healthcare outcomes and reduce the associated economic impact.
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Affiliation(s)
- Tong J Gan
- Stony Brook University , Stony Brook, Long Island, NY , USA
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Bian X, Zhou R, Yang Y, Li P, Hang Y, Hu Y, Yang L, Wen D. Divergent Effect of Dezocine, Morphine and Sufentanil on Intestinal Motor Function in Rats. Int J Med Sci 2015; 12:848-52. [PMID: 26640403 PMCID: PMC4643074 DOI: 10.7150/ijms.12616] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 08/17/2015] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Opioid induced bowel dysfunction is the most common side effect of preoperatively administrated morphine, fentanyl and its derivative. However, the influence of dezocine on intestinal mobility is rarely reported. This study was designed to investigate the effects of dezocine, morphine and sufentanil on both intestinal smooth muscle contraction and propulsion in rats. METHODS Contractile tension and frequency of isolated rat small intestine smooth muscle were measured using tension transducer after incubation with different concentrations of dezocine, morphine and sufentanil. The propulsive rate of methylene blue in rat intestinal tract was measured 30 minutes after intraperitoneal injection of morphine, sufentanil and dezocine. Percent of change in contractile tension and contraction frequency compared to baseline level were calculated to evaluate muscle contraction. Propulsive rate of methylene blue was calculated as the percentage of methylene blue moving distance in intestinal tract compared to the length of the small intestine. RESULTS Morphine and sufentanil significantly increased the contractile tension of isolated small intestine smooth muscle at high doses. The contraction frequency did not change significantly among the 3 tested doses. Increasing the dose of dezocine from 1.7 mg.L(-1) to 10.2 mg.L(-1) did not change either the contractile tension or the contraction frequency. The propulsive rate of methylene blue in intestinal tract was significantly decreased after the treatment with morphine, sufentanil and dezocine (45.6%, 43.7%, and 42.1% respectively) compared to control group(57.1%), while the difference among the 3 drug groups were not significant. CONCLUSION Morphine and sufentanil may dose dependently increase the contractile tension and contraction ability of isolated rat small intestine smooth muscle, while dezocine has no significant effect on intestine smooth muscle contraction. However, all these opioids might impair small intestinal propulsion.
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Affiliation(s)
- Xiaocui Bian
- 1. Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China
| | - Renlong Zhou
- 1. Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China
| | - Yuting Yang
- 1. Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China
| | - Peiying Li
- 1. Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China
| | - Yannan Hang
- 1. Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China
| | - Youmin Hu
- 2. Laboratory Room for Physiology, Pathophysiology & Pharmacology, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China
| | - Liqun Yang
- 1. Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China
| | - Daxiang Wen
- 1. Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China
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Li JP, Wang XY, Gao CJ, Liao YH, Qu J, He ZY, Zhang T, Wang GD, Li YQ. Neurochemical phenotype and function of endomorphin 2-immunopositive neurons in the myenteric plexus of the rat colon. Front Neuroanat 2014; 8:149. [PMID: 25565974 PMCID: PMC4267282 DOI: 10.3389/fnana.2014.00149] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 11/22/2014] [Indexed: 12/20/2022] Open
Abstract
The distribution and activity of endomorphins (EMs), which are endogenous μ-opioid receptor (MOR) ligands in the gastrointestinal tract (GI), are yet to be elucidated. The current study aimed to shed light on this topic. EM2 was expressed in the enteric neurons in the myenteric plexus of the mid-colon. Of the EM2-immunoreactive (EM2-IR) neurons, 53 ± 4.6%, 26 ± 4.5%, 26 ± 2.8% and 49 ± 4.2% displayed immunopositive staining for choline acetyl transferase (ChAT), substance P (SP), vasoactive intestinal peptide (VIP) and nitric oxide synthetase (NOS), respectively. A bath application of EM2 (2 μM) enhanced spontaneous contractile amplitude and tension, which were reversed by β-FNA (an antagonist of MOR) but not NG-nitro-L-arginine methyl ether (L-NAME, a non-selective inhibitor of NOS) or VIP6-28 (an antagonist of the VIP receptor) in the colonic strips. EM2 significantly suppressed inhibitory junction potentials (IJPs) in 14 of the 17 examined circular muscle cells, and this effect was not antagonized by preincubation in L-NAME. EM2 was widely expressed in interneurons and motor neurons in the myenteric plexus and presynaptically inhibited fast IJPs, thereby enhancing spontaneous contraction and tension in the colonic smooth muscle.
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Affiliation(s)
- Jun-Ping Li
- Department of Anatomy, Histology and Embryology, K.K. Leung Brain Research Centre, The Fourth Military Medical UniversityXi’an, China
- Department of Anatomy, Histology and Embryology, Ningxia Medical UniversityYinchuan, China
| | - Xi-Yu Wang
- Department of Physiology and Cell Biology, Medical Center, Ohio State UniversityColumbus, OH, USA
| | - Chang-Jun Gao
- Department of Anatomy, Histology and Embryology, K.K. Leung Brain Research Centre, The Fourth Military Medical UniversityXi’an, China
| | - Yong-Hui Liao
- Department of Anatomy, Histology and Embryology, K.K. Leung Brain Research Centre, The Fourth Military Medical UniversityXi’an, China
| | - Juan Qu
- Department of Anatomy, Histology and Embryology, K.K. Leung Brain Research Centre, The Fourth Military Medical UniversityXi’an, China
| | - Zhong-Yi He
- Department of Anatomy, Histology and Embryology, Ningxia Medical UniversityYinchuan, China
| | - Ting Zhang
- Department of Anatomy, Histology and Embryology, K.K. Leung Brain Research Centre, The Fourth Military Medical UniversityXi’an, China
| | - Guo-Du Wang
- Department of Physiology and Cell Biology, Medical Center, Ohio State UniversityColumbus, OH, USA
| | - Yun-Qing Li
- Department of Anatomy, Histology and Embryology, K.K. Leung Brain Research Centre, The Fourth Military Medical UniversityXi’an, China
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Marciniak CM, Toledo S, Lee J, Jesselson M, Bateman J, Grover B, Tierny J. Lubiprostone vs Senna in postoperative orthopedic surgery patients with opioid-induced constipation: A double-blind, active-comparator trial. World J Gastroenterol 2014; 20:16323-16333. [PMID: 25473191 PMCID: PMC4239525 DOI: 10.3748/wjg.v20.i43.16323] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 06/05/2014] [Accepted: 07/25/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy of lubiprostone compared to Senna on bowel symptoms and constipation in post-operative orthopedic patients treated with opioids.
METHODS: In this double blind, randomized, active comparator trial, adults who required opioids for analgesia following orthopedic procedures and who were admitted in inpatient rehabilitation were randomized following baseline assessments to lubiprostone (Amitza®), orally twice a day or Senna (generic) two capsules administered daily for six days. Subjects were assessed using the patient assessment of constipation (PAC)-symptoms (PAC-SYM) and the PAC-quality of life (PAC-QOL) scales measured at baseline and Day 7; Subjects were assessed daily for secondary measures included the Bristol stool scale bowel consistency, specific bowel symptom score (Nausea, cramping, straining, completeness, abdominal pain, time per lavatory attempt, assistance needed), adverse events and rescue medications required. Function was measured using the functional independence measure (FIM) at admission and discharge; length of stay (LOS) and missed treatments due to gastrointestinal symptoms were also assessed.
RESULTS: 64 adults were enrolled; 56 participants (28 in each group) had baseline and follow up measures and were included in the intention to treat (ITT) analyses. 43 participants completed the study, 21 in the active lubiprostone and 22 in the active Senna group. The mean age of the participants was 71.5 years (SD = 11.4 years, range: 28-96 years). In the ITT analyses, participants showed significant improvement in bowel symptoms as measured by the PAC-SYM (mean ± SD, -0.28 ± 0.60, range: -1-2.33) and PAC-QOL (mean ± SD, 0.33 ± 0.81, range: -1.5-2.0) over time, but there were no significant differences between the lubiprostone and Senna groups in mean change in the PAC-SYM (-0.20 ± 0.60 vs -0.36 ± 0.61, P = 0.61 respectively) or the PAC-QOL (0.29 ± 0.76 vs 0.37 ± 0.87, P = 0.61 respectively). The mean change in each bowel symptom also did not significantly differ between treatment groups on ITT analyses, except for completeness of bowel movement, with the Senna group showing greater negative mean change in bowel movement completeness (-0.56 ± 1.01 vs -2.00 ± 1.41, P = 0.03) and for reduction of abdominal pain, favoring Senna (-0.14 ± 0.73 vs -0.73 ± 1.08, P = 0.04). Fifteen (75%) participants in the lubiprostone and in the Senna group requested rescue treatments. Participants made significant functional improvement from admission to discharge over a median LOS of 12 d, with a mean FIM change of 29.13 ± 13.58 and no significant between group differences (27.0 ± 9.2 vs 31.5 ± 16.6, P = 0.27).
CONCLUSION: Both lubiprostone and Senna improved constipation-related symptoms and QOL in opioid-induced constipation, with no significant between-group differences.
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Poulsen JL, Brock C, Olesen AE, Nilsson M, Drewes AM. Clinical potential of naloxegol in the management of opioid-induced bowel dysfunction. Clin Exp Gastroenterol 2014; 7:345-58. [PMID: 25278772 PMCID: PMC4179399 DOI: 10.2147/ceg.s52097] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Opioid-induced bowel dysfunction (OIBD) is a burdensome condition which limits the therapeutic benefit of analgesia. It affects the entire gastrointestinal tract, predominantly by activating opioid receptors in the enteric nervous system, resulting in a wide range of symptoms, such as reflux, bloating, abdominal cramping, hard, dry stools, and incomplete evacuation. The majority of studies evaluating OIBD focus on constipation experienced in approximately 60% of patients. Nevertheless, other presentations of OIBD seem to be equally frequent. Furthermore, laxative treatment is often insufficient, which in many patients results in decreased quality of life and discontinuation of opioid treatment. Novel mechanism-based pharmacological approaches targeting the gastrointestinal opioid receptors have been marketed recently and even more are in the pipeline. One strategy is prolonged release formulation of the opioid antagonist naloxone (which has limited systemic absorption) and oxycodone in a combined tablet. Another approach is peripherally acting, μ-opioid receptor antagonists (PAMORAs) that selectively target μ-opioid receptors in the gastrointestinal tract. However, in Europe the only PAMORA approved for OIBD is the subcutaneously administered methylnaltrexone. Alvimopan is an oral PAMORA, but only approved in the US for postoperative ileus in hospitalized patients. Finally, naloxegol is a novel, oral PAMORA expected to be approved soon. In this review, the prevalence and pathophysiology of OIBD is presented. As PAMORAs seem to be a promising approach, their potential effect is reviewed with special focus on naloxegol's pharmacological properties, data on safety, efficacy, and patient-focused perspectives. In conclusion, as naloxegol is administered orally once daily, has proven efficacious compared to placebo, has an acceptable safety profile, and can be used as add-on to existing pain treatment, it is a welcoming addition to the targeted treatment possibilities for OIBD.
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Affiliation(s)
- Jakob Lykke Poulsen
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark ; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Anne Estrup Olesen
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark ; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Matias Nilsson
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark ; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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43
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Holzer P. Pharmacology of Opioids and their Effects on Gastrointestinal Function. ACTA ACUST UNITED AC 2014. [DOI: 10.1038/ajgsup.2014.4] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Abstract
Opioid-induced bowel dysfunction (OIBD) is a potentially debilitating side effect of chronic opioid use. It refers to a collection of primarily gastrointestinal motility disorders induced by opioids, of which opioid-induced constipation (OIC) is the most common. Management of OIBD is difficult, and affected patients will often limit their opioid intake at the expense of experiencing more pain, to reduce the negative impact of OIBD on their quality of life. Effective pharmacologic therapy for OIC is considered an unmet need and several agents have recently been given priority review and approval for OIC. Furthermore, multiple agents currently in development show promise in treating OIC without significant impact on analgesia or precipitation of withdrawal symptoms. The approval and availability of such medications would represent a significant improvement in the management of OIC and OIBD in patients with chronic pain.
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Abramowitz L, Béziaud N, Labreze L, Giardina V, Caussé C, Chuberre B, Allaert FA, Perrot S. Prevalence and impact of constipation and bowel dysfunction induced by strong opioids: a cross-sectional survey of 520 patients with cancer pain: DYONISOS study. J Med Econ 2013; 16:1423-33. [PMID: 24102123 DOI: 10.3111/13696998.2013.851082] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE To describe the prevalence of opioid-induced constipation (OIC) in patients with cancer pain according to the Knowles-Eccersley-Scott symptom score (KESS), the different symptoms of opioid-induced bowel dysfunction (OIBD), and to assess the impact of OIBD on patient's quality-of-life. METHODS A cross-sectional observational study, using the KESS questionnaire and the physician's subjective assessment of constipation, and other questionnaires and questions on constipation, OIBD, and quality-of-life, carried out on 1 day at oncology day centres and hospitals. RESULTS Five hundred and twenty patients were enrolled at 77 centres in France; 61.7% of patients (n = 321) showed a degree of constipation that is problematic for the patient according to KESS (between 9-39). Even more patients, 85.7% (n = 438), were considered constipated according to the physician's subjective assessment-despite laxative use (84.7% of patients). Quality-of-life was significantly reduced in constipated vs non-constipated patients for both PAC-QoL (p < 0.0001 for total score and each dimension) and the SF-12 questionnaires (statistically significant for all dimensions except physical state and role physical). OIC and OIBD led to hospitalization (16% of patients), pain (75% of patients), and frequent changes in opioid and laxative treatment. KEY LIMITATIONS This cross-sectional study, in a selected population of cancer patients, has measured prevalence and impact of OIBD. Further confirmation could be sought through the use of longitudinal studies, and larger populations, such as non-cancer pain patients treated with opioids. CONCLUSIONS Cancer patients taking opioids for pain are very frequently constipated, even if they are prescribed laxatives. This leads to relevant impairments of quality-of-life.
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46
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Sharma A, Jamal MM. Opioid induced bowel disease: a twenty-first century physicians' dilemma. Considering pathophysiology and treatment strategies. Curr Gastroenterol Rep 2013; 15:334. [PMID: 23836088 DOI: 10.1007/s11894-013-0334-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The treatment of cancer-associated pain as well as chronic non-cancer-related pain (CNCP) is an increasingly relevant topic in medicine. However, it has long been recognized that opiates can adversely affect many organ systems, most notably the gastrointestinal system. These are referred to as the spectrum of "opioid-induced bowel dysfunction" (OBD) or what we will refer to as "opioid-induced bowel disease" (OIBD) which include constipation, nausea, vomiting, delayed gastric emptying, and gastro-esophageal reflux disease (GERD), and a newer entity known as narcotic bowel syndrome (NBS). Opioid analgesics are increasingly being used for the treatment of cancer pain, non-cancer-associated pain, and postoperative pain. As we achieve our goals towards pain control, we need to be cognizant of and competent in how to prevent and treat OIBD. The basis is due in part to µ-receptor activation, decreasing the peristaltic contraction and leading to sequelae of OIBD. Treatment beyond lifestyle interventional strategy will employ laxatives and stool softeners. However, studies performed while patients were already using laxativies and stool softeners have elicited the necessity of peripherally acting agents such as methylnaltrexone (MNTX) and alvimopan. Patients responded dramatically to both medications, but these studies were limited to patients that were deemed to have advanced illness. Lubiprostone, while different in its mechanism of action from MNTX and alvimopan, has proven effective and should be considered for use in OIBD. Further investigational research will promulgate more information and allow for better and more efficient treatment options for OIBD.
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Affiliation(s)
- Ankush Sharma
- Department of Internal Medicine, University of California Irvine Medical Center and Medical School, Orange, CA, USA,
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Paine P, McLaughlin J, Lal S. Review article: the assessment and management of chronic severe gastrointestinal dysmotility in adults. Aliment Pharmacol Ther 2013; 38:1209-29. [PMID: 24102305 DOI: 10.1111/apt.12496] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 02/27/2013] [Accepted: 08/30/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND The characterisation and management of chronic severe gastrointestinal (GI) dysmotility are challenging. It may cause intestinal failure requiring home parenteral nutrition (HPN). AIMS To review the presentation, aetiology, characterisation, management and outcome of chronic severe GI dysmotility, and to suggest a pragmatic management algorithm. METHODS PubMed search was performed up to December 2012 using appropriate search terms, restricted to human articles and reviewed for relevance. Segmental dysmotility, acute ileus, functional syndromes and non-English articles were excluded. Evidence and recommendations were evaluated using the GRADE system. RESULTS In total, 721 relevant articles were reviewed. A coherent and definitive picture is hampered by overlapping classification systems using multi-modal characterisation methods, subject to pitfalls and some requiring further validation. The literature is confined to case series with no randomised trials. Fewer than 20% undergo full thickness jejunal biopsy, which are otherwise labelled idiopathic. However, in studies with up to 80% biopsy rates, neuromuscular abnormalities may be found in 90%. Between 14% and 50% will require HPN, comprising 8-14% of all HPN patients, of which 2/3 are primary/idiopathic and 1/3 secondary, with scleroderma being the leading secondary cause. Ten-year mortality ranges from 13% to 35% and is worst in elderly scleroderma patients. Management includes limited treatments for secondary causes, prokinetics, symptom palliation, psychological support, nutrition, hydration and judicious surgery. CONCLUSIONS Severe dysmotility often remains idiopathic. It is rarely possible to alter disease trajectory; consequently, prognosis may be poor. Multi-disciplinary teams in a specialist setting can improve outcomes. Graded recommendations are enumerated and a pragmatic algorithm is suggested.
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Affiliation(s)
- P Paine
- Department of Gastroenterology, Salford Royal NHS Foundation Trust, Salford, UK; Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK
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Abstract
PURPOSE OF REVIEW Enteral nutrition has emerged as one of the most effective treatments in the early management of patients with acute pancreatitis. The original rationale for nutrition in acute pancreatitis, dating back to the mid-20th century, was to provide full nutritional requirements but avoid stimulating exocrine pancreatic secretion. The purpose of this article is to review the recent clinical studies of enteral nutrition in acute pancreatitis to revise the rationale and develop a contemporary conceptual framework for nutritional management of this disease. RECENT FINDINGS Several recent randomized controlled trials dispel the outdated concept of 'pancreatic rest', which equates with gut neglect, and offer 'gut rousing' as a preferred concept. The new concept postulates that gastrointestinal (dys)function has a discernible impact on the outcomes of patients with acute pancreatitis. Further, timely administration of appropriate intraluminal modalities prevents or mitigates the gastrointestinal dysfunction. SUMMARY Nutritional management in acute pancreatitis should aim primarily at maintaining the gastrointestinal function. Providing full nutritional requirements and avoiding pancreatic exocrine stimulation should be considered as secondary aims.
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Affiliation(s)
- Maxim S Petrov
- Department of Surgery, The University of Auckland, Auckland, New Zealand.
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49
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Christensen RD, Lambert DK, Baer VL, Gordon PV. Necrotizing enterocolitis in term infants. Clin Perinatol 2013; 40:69-78. [PMID: 23415264 DOI: 10.1016/j.clp.2012.12.007] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
This article is an overview of NEC in term neonates and also summarizes data from 52 cases within Intermountain Healthcare during the last 11 years. In all 52, NEC occurred among neonates already admitted to a neonatal intensive care unit for some other reason; thus, NEC invariably developed as a complication of treatment, not as a primary diagnosis. The authors speculate that the incidence of term NEC can be reduced by identifying neonatal intensive care unit patients at risk for NEC and applying appropriate-volume human milk feeding programs for these patients.
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Affiliation(s)
- Robert D Christensen
- The Women and Newborns Program, Intermountain Healthcare, Salt Lake City, Ogden, UT 84111, USA.
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Brock C, Olesen SS, Olesen AE, Frøkjaer JB, Andresen T, Drewes AM. Opioid-induced bowel dysfunction: pathophysiology and management. Drugs 2012; 72:1847-65. [PMID: 22950533 DOI: 10.2165/11634970-000000000-00000] [Citation(s) in RCA: 140] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Opioids are the most commonly prescribed medications to treat severe pain in the Western world. It has been estimated that up to 90% of American patients presenting to specialized pain centres are treated with opioids. Along with their analgesic properties, opioids have the potential to produce substantial side effects, such as nausea, cognitive impairment, addiction and urinary retention. In the gut, opioids exert their action on the enteric nervous system, where they bind to the myenteric and submucosal plexuses, causing dysmotility, decreased fluid secretion and sphincter dysfunction, which all leads to opioid-induced bowel dysfunction (OIBD). In the clinic, this is reported as nausea, vomiting, gastro-oesophageal reflux-related symptoms, constipation, etc. One of the most severe symptoms is constipation, which can be assessed using different scales for subjective assessment. Objective methods such as radiography and colonic transit time can also be used, together with manometry and evaluation of anorectal function to explore the pathophysiology. Dose-limiting adverse symptoms of OIBD can lead to insufficient pain treatment. Even though several treatment strategies are available, the side effects are still a major challenge. Traditional laxatives are normally prescribed but they are often insufficient to alleviate symptoms, especially those from the upper gastrointestinal tract. Newer prokinetics, such as prucalopride and lubiprostone, may be more effective in alleviating OIBD. Another treatment approach is co-administration of opioid antagonists, which either cannot cross the blood-brain barrier or selectively target opioid receptors in the gastrointestinal tract. However, although these new agents have proved to be more efficacious than placebo, clinical trials still need to prove their superiority to standard co-prescribed laxative regimes.
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Affiliation(s)
- Christina Brock
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.
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