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Opioid-induced bowel disorders and narcotic bowel syndrome in patients with chronic non-cancer pain
Neurogastroenterology & Motility
Abstract
Opioids are used increasingly in the management of moderate-to-severe chronic non-cancer pain (CNCP). Opioid-induced bowel disorders (OBD) markedly impact health-related quality of life (HRQoL) and frequently limit medically indicated opioid pharmacotherapy. We assessed the risk factors, and effect of OBD on HRQoL in CNCP patients. We also estimated the likely prevalence of narcotic bowel syndrome (NBS). These effects have been reported in cancer patients but not in CNCP previously.
Ambulatory CNCP patients (n = 146) taking regularly scheduled opioids were invited to complete the Bowel-Disease-Questionnaire and a pain-sensitive HRQoL instrument. The Rome-II criteria were used to define bowel disorders. Narcotic bowel syndrome was defined as presence of daily severe to very-severe abdominal pain of more than 3 months duration requiring more than 100 mg of morphine equivalent per day.
Ninety-eight patients (69%) returned the survey. Respondents had taken opioids for 10 days to 10 years (median 365 days) at a median daily dose of 127.5 mg morphine-equivalent (range 7.5-600 mg). Constipation prevalence was 46.9% (95% CI 36.8-57.3), nausea 27% (95% CI 17.2-35.3), vomiting 9% (95% CI 17.2-35.3), and gastro-esophageal reflux disease 33% (95% CI 23.5-42.9). Chronic abdominal pain was reported by 58.2% (95% CI 53.2-73.9) and 6.4%, (95% CI 2.4-13.5) fulfilled the criteria of NBS. Prevalence of constipation increased with duration of treatment. Health-related quality of life was low in patients with chronic abdominal pain.
Bowel disorders including chronic abdominal pain and NBS are common in patients taking opioids for CNCP. Decreased HRQoL in patients with CNCP is driven by chronic abdominal pain.
... 11,[14][15][16] Besides over-the-counter analgesics, opioids are frequently prescribed for the management of chronic pain in IBD. 17,18 Although the use of opioids in noncancer-related chronic pain is controversial, 17 their prescription for non-cancer-related pain has increased dramatically in recent years. 19 This has led to problems with excessive use of prescription opioids, and a sharp increase in deaths related to (prescription-) opioid overdose in recent years. ...
... Most opioids block pain sensation via inhibition of dand j-opioid receptors; they typically also antagonize l-opioid receptors on intestinal neurons, resulting in reduced gastrointestinal motility and promoting constipation, 31 which is one of the major gastrointestinal problems upon opioid use and might also be linked to the increased risk of infection upon opioid use in IBD patients. 17,22 Tramadol, in contrast, has a low affinity to l-opioid receptors and consequently affects gastrointestinal motility only mildly, 32 which might make it a promising drug to manage pain in patients with gastrointestinal symptoms. ...
Application of dextran sodium sulfate (DSS) is often used to induce experimental colitis. Current state of the art is to refrain from the use of analgesics due to their possible interaction with the model. However, the use of analgesics would be beneficial to reduce the overall constraint imposed on the animals. Here, we analyzed the effect of the analgesics Dafalgan (paracetamol), Tramal (tramadol) and Novalgin (metamizole) on DSS-induced colitis. To study the effect of those analgesics in colitis mouse models, acute and chronic colitis was induced in female C57BL6 mice by DSS administration in the drinking water. Analgesics were added to the drinking water on days four to seven (acute colitis) or on days six to nine of each DSS cycle (chronic colitis). Tramadol and paracetamol had minor effects on colitis severity. Tramadol reduced water uptake and activity levels slightly, while mice receiving paracetamol presented with a better overall appearance. Metamizole, however, significantly reduced water uptake, resulting in pronounced weight loss. In conclusion, our experiments show that tramadol and paracetamol are viable options for the use in DSS-induced colitis models. However, paracetamol seems to be slightly more favorable since it promoted the overall wellbeing of the animals upon DSS administration without interfering with typical readouts of colitis severity.
... Schmerzen gehören zu den häufigsten Symptomen bei Patienten mit CIPO, und ihre Therapie kann schwierig sein. Dennoch darf der Einsatz von Opioiden zur Schmerztherapie bei Patienten mit GIT-Motilitätsstörungen allenfalls mit großer Zurückhaltung erfolgen, weil diese die Motilitätsstörung und häufig auch die Beschwerden aggravieren [119,120]. Opioide führen zu sehr starken Veränderungen der gastrointestinalen Motilität mit oft chaotischen Motilitätsmustern und Verlangsamung des intestinalen Transits bereits bei Gesunden [105,121,122]. Initial vorhandene oder im Verlauf auftretende funktionelle abdominelle Schmerzen werden bei einem relevanten Prozentsatz von Patienten nicht gebessert, sondern verschlechtert [119,120,123]. ...
... Opioide führen zu sehr starken Veränderungen der gastrointestinalen Motilität mit oft chaotischen Motilitätsmustern und Verlangsamung des intestinalen Transits bereits bei Gesunden [105,121,122]. Initial vorhandene oder im Verlauf auftretende funktionelle abdominelle Schmerzen werden bei einem relevanten Prozentsatz von Patienten nicht gebessert, sondern verschlechtert [119,120,123]. Entsprechend deletär können die Wirkungen von Opioiden auf den gastrointestinalen Transit und die Symptomatik bei vorbestehender schwerer Motilitätsstörung sein. ...
... 1,2 The reported prevalence of OIC is typically around 50% among patients taking opioids for chronic cancer pain and non-cancer pain. [3][4][5][6][7] In one prospective study in cancer patients, about half developed OIC within 2 weeks of beginning opioid therapy. 7 Unlike other adverse effects associated with opioid therapy, OIC persists unabated over time, even with use of laxatives. ...
... -PLR, naldemedine 0.2 mg n = 221, placebo n = 226; PLR, naldemedine 0.2 mg n = 315, placebo n = 308. BM, bowel movement; BMI, body mass index; BSS, Bristol Stool Scale; ITT, intent to treat; MED, morphine equivalent dose; non-PLR, non-poor laxative responder; OIC, opioid-induced constipation; PLR, poor laxative responder; SBM, spontaneous bowel movement; SD, standard deviation.6 journals.sagepub.com/home/tag ...
Background
Two studies demonstrated the efficacy and safety of naldemedine in adult patients with chronic non-cancer pain and opioid-induced constipation (OIC). However, no studies have compared the efficacy of peripherally acting µ-opioid receptor antagonists in patients with adequate and inadequate responses to prior OIC therapy with laxatives. This post hoc analysis of integrated data from the two previous studies compared the efficacy of naldemedine in patients who were unsuccessfully treated with laxatives [poor laxative responders (PLRs)] with those who either did not receive laxatives >30 days prior to screening or those who only received rescue laxative at or after screening (non-PLRs).
Methods
Patients with OIC were randomized to once-daily treatment with naldemedine 0.2 mg or placebo. The primary efficacy endpoint was the proportion of responders [⩾3 spontaneous bowel movements (SBMs)/week and an increase from baseline of ⩾1 SBM/week for ⩾9 weeks of the 12-week treatment period and ⩾3 weeks of the final 4 weeks of the 12-week treatment period]. Additional endpoints included change in SBM frequency, change in frequency of SBMs without straining, proportion of complete SBM (CSBM) responders, change in CSBM frequency, and time to first SBM. Treatment-emergent adverse events (TEAEs) were assessed.
Results
The analysis included 538 (317 PLRs, 221 non-PLRs) and 537 (311 PLRs, 226 non-PLRs) patients in the naldemedine and placebo arms, respectively. There were significantly more responders in the naldemedine PLR (46.4%; p < 0.0001) and non-PLR (54.3%; p = 0.0009) subgroups versus the placebo groups (30.2% and 38.9%, respectively). In both the PLR and non-PLR subgroups, naldemedine treatment was superior to placebo on all additional endpoints. Overall incidence of TEAEs in the PLR subgroups treated with naldemedine or placebo was similar.
Conclusion
This integrated analysis further supports the efficacy and tolerability of naldemedine in the treatment of OIC and demonstrates a consistent effect in both PLR and non-PLR subgroups.
[ClinicalTrials.gov identifier: NCT01965158 and NCT01993940]
... Side effects to morphine treatment include nausea and vomiting, abdominal pain, and constipation, which collectively are referred to as "opioid-induced bowel dysfunction." Although tolerance develops toward many of the effects of morphine, including analgesia, constipation remains resistant to tolerance such that in many cases patients choose to limit or discontinue opioid treatment (Moore and McQuay, 2005;Holzer et al., 2009;Tuteja et al., 2010). Consistent with the persistence of morphine-induced constipation in humans, tolerance to morphine-induced retardation of colonic transit does not develop in either moderate (5.5-fold) or high (52fold) antinociceptive tolerance mice . ...
... Notwithstanding the prevalence, suffering, and economic burden of chronic pain, opiate-based therapy remains underused largely as a result of adverse side effects. Clinical reports suggest that, of the several adverse effects of long-term opiate use, constipation is one of the most debilitating (Grond et al., 1994;Kurz and Sessler, 2003;Droney et al., 2008;Tuteja et al., 2010). Studies in several species, including the mouse and guinea pig, have demonstrated that morphine alters gastrointestinal motility and produces constipation via its effect on -opioid receptors (Roy et al., 1998;Sternini et al., 2004). ...
Morphine, the most often used analgesic for chronic pain, is associated with severe side‐effects including nausea, abdominal pain, constipation. Development of tolerance is the major drawback of morphine that limits its clinical efficacy. Tolerance develops to many of the effects of morphine but not to constipation. Previous findings from our lab suggest that tolerance to chronic morphine develops in the ileum but not in the colon. β‐arrestin 2 is implicated with development of tolerance to morphine. Anti‐nociceptive tolerance is associated with uncoupling of GPCRs following binding of β‐arrestin 2 to GRK‐phosphorylated opioid receptors. In the present study we elucidate the role of β‐arrestin 2 in differential response to chronic morphine in the colon and ileum. We identified 4 out of 13 known β‐arrestin 2 splice variants (ARRB2‐006, 005, 013 and 001) in the colon and ileum by RNA‐seq. RT‐PCR analysis confirmed the presence of these variants in both tissues. The mRNA expression of each of the four β‐arrestin 2 variants was 10‐fold higher in the ileum as compared to the colon. On chronic morphine treatment, the expression of all the β‐arrestin 2 variants decreased in the ileum by 80% but remained unchanged in the colon. Furthermore, the mRNA expression levels of GRK5 and GRK6 decreased in the ileum on chronic morphine treatment by about 50‐70% but not in the colon. We, thus, hypothesize that down regulation of β‐arrestin 2 and GRK 5/6 is associated with development of tolerance in the ileum.
Grant Funding Source : Supported by NIH DA024009 and DK046367
... Gastrointestinal events such as bloating, nausea, and constipation are frequent complaints of opioid therapy due to the expression of muand delta-opioid receptors in the gastrointestinal tract, including the myenteric plexus (Auerbach's plexus), which regulates gut motility, and the submucosal plexus (Meissner's plexus), which is responsible for the secretion and absorption of water and electrolytes [2,3]. Opioid-induced constipation (OIC) is the most common type of opioid-induced bowel dysfunction, occurring in 47-94% of patients receiving opioids for cancer pain [4,5] and 41-57% of patients for chronic noncancer pain [1,6]. While OIC is understudied in a context of dependence, recent reports indicate that 60-90% of patients receiving opioid substitution therapy experience gastrointestinal symptoms and associated decreases in QoL, but only a small proportion of these individuals seek healthcare for their constipation symptoms [7,8]. ...
... In clinical practice, it is common (across care settings) for physicians to leave the subject of OIC unaddressed until a patient or caregiver specifically denotes the development of constipation symptoms. As outlined in the introduction, the prevalence of OIC among individuals who use opioids is high (41-87%) [1,[4][5][6][7], regardless of treatment purpose. One study indicated that patients were equally bothered by constipation from weak and strong opioids, despite a lower severity of physical symptoms and effect on QoL associated with the former [3]. ...
Introduction: Despite the essential utility of opioids for the clinical management of pain, opioid-induced constipation (OIC) remains an important obstacle in clinical practice. In patients, OIC hinders treatment compliance and has negative effects on quality of life. From a clinician perspective, the diagnosis and management of OIC are hampered by the absence of a clear, universal diagnostic definition across disciplines and a lack of standardization in OIC treatment and assessment.
Methods: A multidisciplinary panel of physician experts who treat OIC was assembled to
identify a list of ten corrective actions—five ‘‘things to do’’ and five ‘‘things not to do’’—for the diagnosis and management of OIC, utilizing the Choosing Wisely methodology.
Results: The final list of corrective actions to improve the diagnosis and clinical management of OIC emphasized a need for: (i) better physician and patient education regarding OIC; (ii) systematic use of diagnostically validated approaches to OIC diagnosis and assessment (i.e., Rome IV criteria and Bristol Stool Scale, respectively) across various medical contexts; and (iii) awareness about appropriate, evidence-based treatments for OIC including available peripheral mu-opioid receptor antagonists (PAMORAs).
Conclusions: Physicians who prescribe longterm opioids should be forthcoming with patients about the possibility of OIC and be adequately versed in the most recent guideline recommendations for its management.
... The prevalence of constipation symptoms increased with the duration of opioid therapy; health-related quality of life was low in those with chronic abdominal pain [48]. In a survey of opioid patients, of those respondents who met the Rome IV qualifications for OIC (n=951), more than half reported their most frequent symptoms were: straining to defecate, a sensation of blockage, abdominal bloating, hard or lumpy stools, feeling of incomplete evacuation, stomach cramps, rectal burning during or after bowel movements, and hemorrhoids. ...
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.
... [2][3][4][5][6] Opioid-induced constipation (OIC) is a common and bothersome side effect of chronic opioid use and is estimated to occur in 40-80% of patients. [7][8][9] OIC results from the binding of opioids to μ-opioid receptors located in the enteric nervous system leading to decreased gastrointestinal motility, reduced intestinal fluid and electrolyte secretion and increased reabsorption, and sphincter dysfunction. [10][11][12] OIC commonly persists with chronic opioid use, whereas other adverse effects such as nausea and vomiting lessen over time. ...
Objective:
This study evaluates the onset, magnitude, and consistency of improvement of opioid-induced constipation (OIC) symptoms with naloxegol treatment.
Methods:
This was a pooled analysis of two Phase 3, double-blind, randomized, placebo-controlled studies (KODIAC-04/05, NCT01309841/NCT01323790) in patients with chronic non-cancer pain and OIC treated with naloxegol 25mg or 12.5mg daily. This analysis assessed improvements in response rates, frequency of spontaneous bowel movement (SBM) and complete SBMs (CSBM), OIC constipation symptoms (straining, stool consistency), time to first post-dose SBM and CSBM, and onset of adverse events over the 12-week period.
Subjects:
The population of 1337 subjects had a mean age of 52 years and mean duration of opioid use of 3.6 years at baseline. Mean SBM frequency was 1.4/week.
Results:
Naloxegol 25mg and 12.5mg demonstrated significantly higher response rates vs placebo (PBO) [41.9% (P < 0.001), 37.8% (P = 0.008), 29.4% respectively]. Rapid (within 1 week) and sustained (over 12 weeks) symptom improvement was significantly greater for naloxegol vs PBO (P < 0.05). Both doses showed statistically significant and clinically meaningful improvements in straining, stool consistency, number of SBMs and CSBMs/wk. Significantly shorter times to first post-dose SBM and CSBM were observed with naloxegol vs PBO (SBM HR: 25mg = 1.90, 12.5mg= 1.60; CSBM HR: 25mg = 1.42, 12.5mg = 1.36; P < 0.001 for each regimen). Adverse events occurred more frequently in the naloxegol 25mg group and were most frequently reported during the first week.
Conclusion:
In patients with chronic non-cancer pain, naloxegol 25mg and 12.5mg demonstrated significantly higher response rates and rapid and sustained improvements in OIC symptoms compared with PBO.
... Opioids further influence gastrointestinal function by increasing sphincter tone [9]. Increased sphincter tone can affect the lower esophageal sphincter, leading to gastroesophageal reflux disease characterized by heartburn, regurgitation, and chest discomfort [10]. Additionally, increased sphincter tone in the anal region can result in difficulty with defecation, contributing to constipation and straining during bowel movements. ...
Opioid therapy plays a crucial role in the management of acute and chronic pain, with opioids being widely prescribed worldwide. However, alongside the analgesic benefits, the use of opioids is associated with a range of adverse effects, including opioid-induced bowel dysfunction. Opioid-induced bowel dysfunction refers to a constellation of gastrointestinal symptoms caused by the effects of opioids on the gastrointestinal tract. These symptoms primarily manifest as constipation, but can also include abdominal pain, bloating, nausea, and vomiting. Opioid-induced bowel dysfunction poses a significant clinical challenge, as it can severely affect patients' quality of life. Non-pharmacological approaches alone are rarely sufficient to counteract the adverse effects of opioid therapy. The primary pharmacological agents used in opioid-induced bowel dysfunction management are laxatives, which should be chosen according to individual patient needs. Patients with poorly controlled symptoms can benefit from new pharmacological approaches, particularly peripheral mu-opioid receptor antagonists. By better understanding the underlying mechanisms, clinical manifestations, diagnostic criteria, and management strategies, healthcare professionals can optimize patient care, minimize complications, and improve patients' overall well-being.
... In the US this may be the result of increase in using narcotics for chronic nonmalignant painful disorders, and the development of maladaptive therapeutic interactions around its use. NBS has been reported in 6.4% of non-cancer patients on longterm opioid therapy (Tuteja et al 2010). Health-related quality of life was low in these patients. ...
This report describes the latest concepts of pathomechanisms of pain as a basis for management and development of new pharmacotherapies for pain. Major segments of the pain market are arthritis, neuropathic pain and cancer pain. Because pain is a subjective sensation, it is difficult to evaluate objectively in clinical trials. Various tools for pain measurement are described, including brain imaging.
Most of the currently used analgesic drugs fall into the categories of opioids and nonsteroidal antiinflammatory drugs such as COX-2 inhibitors. Non-opioid analgesics include ketamine, a N-methyl-D-aspartate receptor antagonist. Adjuvant analgesics include antidepressants and antiepileptic drugs used for the treatment of neuropathic pain. Management of pain is multidisciplinary and includes both pharmacological and non-pharmacological methods such as acupuncture, transcutaneous electrical nerve stimulation and surgery. Various pain syndromes require different approaches in management, for example, the main category of drugs for migraine are triptans such as sumatriptan.
Drug delivery is an important consideration in pain treatment. Controlled release preparations provide a steady delivery of analgesics. Well-known non-injection methods such astransdermal, pulmonary and intranasal application have been used. Topical analgesics and local anesthetics are also available. Devices such as implanted pumps are used for delivery of drugs such as opioids intrathecally (introduction into spinal subarachnoid space by lumbar puncture) in patients with cancer pain.
The wide variety of drugs in development includes opioid receptor ligands, bradykinin antagonists, mPGES-1 inhibitors, glutamate receptor antagonists, substance P and neurokinin receptor antagonists, norepinephrine transporter inhibitors,P2X2 neuron receptor antagonists and nitric oxide-based analgesics. A number of cannabinoids are also in development for pain. Fish-derived tetrodotoxin was initially focused on indication of opiate addiction withdrawal but is found to have an analgesic action as well. Cone shells contain therapeutically useful peptides including the conotoxins, and one such peptide, ziconotide, has been approved. Various cell and gene therapies are also being developed for the management of pain.
Advances in molecular and biological techniques are markedly advancing our undestanding of pain. Understanding the pathophysiology of pain is an important factor in discovery of rational therapies for pain. Advances in pharmacogenomics and pharmacogenetics are enabling the development of personalized approaches to the management of pain.
Over 500 companies have been identified to be involved in developing or marketing pain therapeutics and 173 of these are profiled in the report along with 156 collaborations. These are a mix of pharmaceutical companies and biotechnology companies.
The worldwide analgesic markets were analyzed for the year 2020 and projected to 2030. Calculations are based on the epidemiology of various painful conditions and the development of analgesic drugs and devices. Unfulfilled needs for analgesics are identified and strategies are outlined to develop markets for analgesic drugs. The report is supplemented with 78 tables, 25 figures, and 600 selected references to the literature.
... Opioids are also known to cause frequent adverse effects in the gastrointestinal tract including nausea, vomiting, and constipation. The effects of opioids on esophageal function are now increasing in recognition [3][4][5][6]. In this review, we discuss the current literature on opioid-induced esophageal dysfunction (OIED) including pathophysiology, diagnosis, and management. ...
Purpose of Review
The purpose of this review is to discuss the pathophysiology, clinical presentation, and diagnosis of opioid-induced esophageal dysfunction (OIED) and describe the limited data available on its management.
Recent Findings
OIED is defined by chronic opioid use, esophageal symptoms, and specific manometric abnormalities. Larger retrospective studies show that patients with OIED present with significant esophageal symptoms particularly dysphagia. High-resolution esophageal manometry findings in OIED include distal esophageal spasm, esophagogastric junction outflow obstruction, achalasia type III, and hypercontractile esophagus. OIED is more prevalent in patients taking the stronger opioids oxycodone and hydrocodone compared to tramadol, and OIED is more frequent at higher 24-h morphine equivalent doses. Limited retrospective data suggest holding opioids may reverse manometric findings.
Summary
OIED is a clinico-manometric diagnosis which causes significant esophageal symptoms. Management of OIED is not well defined. Based on limited retrospective studies, complete opioid cessation or dose reduction is the current treatment recommendation. Future prospective studies are needed to guide management strategies.
... 25 Furthermore, information necessary for diagnosing Narcotic Bowel Syndrome was not included in the survey; however, previous studies have suggested that may be found in up to 6% of patients on chronic opioids. 26,27 When comparing the use of prescription pain medications in the Canadian RFGES survey sample to such use by respondents from ...
Background
Using data from the Rome Foundation Global Epidemiology Study examining prevalence of disorders of gut–brain interaction (DGBI) in 33 countries, this study explored the prevalence of all 22 disorders in Canada. It examined differences related to geography and sociodemographic factors, health impact and compared these findings to other countries.
Methods
The Rome Foundation survey was conducted through the Internet, targeting 2000 Canadian participants. The survey used the validated ROME IV diagnostic questionnaire to identify the 22 DGBI and an in‐depth supplemental questionnaire that included quality assurance techniques.
Key Results
There were 2029 respondents with a mean age of 48 years and 50% females. Diagnostic criteria for at least one of the 22 DGBI were met by 41.3%, similar to other countries. Functional constipation, functional diarrhea, and unspecified functional bowel disorders were most common. Irritable bowel syndrome prevalence was 4.2% using Rome IV and 10.1% using ROME III criteria. DGBI were associated with poorer quality of life and increased psychological symptom scores. Prevalence of DGBI ranged from 48% in Quebec to 36% in British Columbia. Prescription pain medication was reported by 17% with DGBI compared to 9% without DGBI and correlated negatively with mental health and physical well‐being. Quebecers and francophones were in limited number but reported higher DGBI prevalence and symptom severity compared to others.
Conclusions & Inferences
A large proportion of Canadians suffer from DGBI which seriously impact their well‐being. Findings highlight the need for further research and education, including understanding whether significant regional and cultural differences contribute to DGBI.
... The gastric symptoms are spastic achalasia-like esophageal dysmotility, gastric hypomobility and paralytic ileus, generalized visceral congestion or cramp, nausea, vomiting, constipation, anorexia and a loss of weight. Nausea and vomiting were seen in 9% to 27% of patients [87,95,99,21,[122][123][124][125][126][127]. The vesical symptoms are urinary urgency or retention [21]. ...
Dans le monde, environ 271 millions d’adultes, soit 5,5 % des personnes âgées de 14 à 64 ans, auraient déjà consommé des drogues illicites au cours de leur vie (UNODC, 2019). Le nombre de consommateurs augmente avec des usages souvent problématiques. En parallèle, le développement permanent de nouvelles molécules rend le diagnostic d’exposition difficile. Le manque de connaissances concrètes sur la composition et les dosages en principes actifs de ces produits pose un risque sanitaire important, voire mortel. Au cours de la dernière décennie, la spectrométrie de masse à haute résolution a suscité un intérêt croissant dans le domaine de la toxicologie analytique. L'objectif principal de la présente étude a été d'évaluer l'apport analytique de la spectrométrie de masse haute résolution en QTOF pour l'identification et la gestion de l'exposition aux substances psychoactives. Pour cela, nous avons comparé une méthode de criblage toxicologique par QTOF avec une méthode par spectrométrie infrarouge en analysant des produits provenant directement de consommateurs de drogues. En combinant des approches in vivo, in silico et in vitro, ainsi que d’autres méthodes comme la RMN et l’IR, nous avons évalué l’apport du QTOF pour l’identification des nouveaux produits de synthèse et la mise en évidence de nouveaux biomarqueurs d’exposition. Enfin, nous avons évalué son intérêt en pratique clinique pour l’identification de cannabinoïdes de synthèse dans les départements d’Outre-mer et en France métropolitaine. Ces différents apports sont particulièrement intéressants dans le domaine de la toxicologie analytique et clinique, notamment pour l'identification de nouvelles substances psychoactives et de nouveaux métabolites.
... 52 The overall prevalence of opioid induced constipation for non-cancer abdominal pain is up to 50%, which increases with duration of treatment. 53 Patients with opioid induced constipation have poorer quality of life. 54 Long-term opioid use (>3 months) in chronic, non-cancer pain does not confer benefit, with patients exposed to deleterious tolerance, addiction, premature death 55 and narcotic bowel syndrome, 56 adding to the burden of disease. ...
Patients diagnosed with hypermobile Ehlers-Danlos syndrome and hypermobile spectrum disorders are increasingly presenting to secondary and tertiary care centres with gastrointestinal (GI) symptoms and nutritional issues. Due to the absence of specific guidance, these patients are investigated, diagnosed and managed heterogeneously, resulting in a growing concern that they are at increased risk of iatrogenic harm. This review aims to collate the evidence for the causes of GI symptoms, nutritional issues and associated conditions as well as the burden of polypharmacy in this group of patients. We also describe evidence-based strategies for management, with an emphasis on reducing the risk of iatrogenic harm and improving multidisciplinary team care.
... Reportedly, 15-64% of patients receiving strong opioid analgesic treatment experience constipation [7][8][9][10][11], and the cumulative incidence of opioidinduced constipation (OIC) in Japan has been reported to be as high as 79%, which has been observed in patients with breast cancer [12]. Prolonged opioid administration is largely associated with OIC [13] and the prophylactic administration of laxatives is important, as drug tolerance in patients with OIC is low [14]. OIC is worth investigating as the symptoms associated with constipation (abdominal pain, bloating, and appetite loss) may reduce the quality of life (QOL) of these patients. ...
Simple Summary
Opioids are used in cancer pain management, however, their continuous use may not be tolerable owing to adverse effects such as constipation, sleepiness, nausea, and respiratory depression. Opioid-induced constipation reduces the quality of life of patients, and osmotic laxatives are conventionally recommended for preventing opioid-induced constipation. Recently, naldemedine, a peripherally acting μ-opioid receptor antagonist, can be used to safely and effectively treat opioid-induced constipation based on its etiological mechanism, without affecting central analgesia. In this study, we compared the effectiveness of magnesium oxide with that of naldemedine in preventing opioid-induced constipation. Naldemedine significantly prevented deterioration in the quality of defecation (the Japanese Patient Assessment of Constipation Quality of Life and complete spontaneous bowel movement) and reduced gastrointestinal adverse effects, mainly nausea, compared with magnesium oxide during 12-week administration.
Abstract
Opioid-induced constipation (OIC) may occur in patients receiving opioid treatment, decreasing their quality of life (QOL). We compared the effectiveness of magnesium oxide (MgO) with that of naldemedine (NAL) in preventing OIC. This proof-of-concept, randomized controlled trial (registration number UMIN000031891) involved 120 patients with cancer scheduled to receive opioid therapy. The patients were randomly assigned and stratified by age and sex to receive MgO (500 mg, thrice daily) or NAL (0.2 mg, once daily) for 12 weeks. The change in the average Japanese version of Patient Assessment of Constipation QOL (JPAC-QOL) from baseline to 2 weeks was assessed as the primary endpoint. The other endpoints were spontaneous bowel movements (SBMs) and complete SBMs (CSBMs). Deterioration in the mean JPAC-QOL was significantly lower in the NAL group than in the MgO group after 2 weeks. There were fewer adverse events in the NAL group than in the MgO group. Neither significant differences in the change in SBMs between the groups nor serious adverse events/deaths were observed. The CSBM rate was higher in the NAL group than in the MgO group at 2 and 12 weeks. In conclusion, NAL significantly prevented deterioration in constipation-specific QOL and CSBM rate compared with MgO.
... †Significant difference vs. day 1 data from morphine-pelleted mice, as indicated by a significant treatment x time interaction in the two-way, repeated-measures ANOVA with Bonferroni's test (P < 0.05). opioid-induced constipation was prevalent in 17% of patients receiving methadone maintenance treatment for at least 3 yr, whereas in a separate clinical trial 79% of the patient population on opioids for 2-10 yr suffered from constipation (75,76). These differences in the rate and extent of tolerance underlie opioid overdose, as tolerance develops at a faster rate to the euphoric and analgesic effects than to respiratory depression by opioids. ...
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.
... 26 Patients who use opioids long term are at risk for development of narcotic bowel syndrome, which often is under-recognized and occurs in approximately 6 % of this population. 27 Narcotic bowel syndrome is characterized by chronic or frequently recurring paradoxic increases in abdominal pain, despite continued or escalating dosages of opioids. It is associated with significant impairment in quality of life. ...
Description:
The purpose of this expert review is to summarize approaches to management of pain in disorders of gut-brain interaction. This review focuses specifically on approaches to pain that persists if first-line therapies aimed at addressing visceral causes of pain are unsuccessful. The roles of a therapeutic patient-provider relationship; non-pharmacological and pharmacological therapies; and avoidance of opioids are discussed.
Methods:
This is not a formal systematic review but is based upon a review of the literature to provide best practice advice statements. No formal rating of the quality of evidence or strength of recommendation is carried out.
... Complications due to opioid administration concern all medical practitioners (90)(91)(92)(154)(155)(156)(157)(158)(159)(160)(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171)(172). Commonly known side effects of opioids include constipation, pruritus, respiratory depression, nausea, vomiting, delayed gastric emptying, sexual dysfunction (154), muscle rigidity and myoclonus (173,174), sleep disturbance (175), pyrexia, diminished psychomotor performance (152,153), cognitive impairment (176), hyperalgesia (2,154,165,177), dizziness, and sedation, all reflecting the effects of opioids on multiple organ systems (178). ...
Background: Opioids have been utilized for thousands of years to treat pain and their use continues to escalate. It is estimated that 90% of the patients who present to pain centers and receive treatment in such facilities are on opioids. However, in contrast to increasing opioid use and the lack of evidence supporting long-term effectiveness in chronic non-cancer pain, is the escalating misuse of prescription opioids, including abuse and diversion. There is also uncertainty about the incidence and clinical salience of multiple, poorly characterized adverse drug events, including endocrine dysfunction, immunosuppression, infectious disease, opioidinduced hyperalgesia, overdoses, deaths, and psychosocial and economic implications. Study Design: A comprehensive review of the literature. Objective: The objective of this comprehensive review is to evaluate the clinical effectiveness and safety of chronic opioid therapy in chronic non-cancer pain. Methods: A comprehensive review of the literature relating to chronic opioid therapy in chronic non-cancer pain. The literature was collected from various electronic and other sources. The literature that was evaluated included randomized trials, observational studies, case reports, systematic reviews, and guidelines. Outcome Measures: Pain relief was the primary outcome measure. The secondary outcome measures were functional improvement and adverse effects. Short-term effectiveness was considered to be less than 6 months; long-term effectiveness was considered to be at least one year. Results: Given the complexity and widespread nature of opioid therapy, there is a paucity of qualitative and/or quantitative literature. The available evidence is weak for pain relief combined with improvement in functional status. Only one drug, tramadol, is effective for pain relief and improvement of functional status. Limitations: This is a narrative review without application of methodologic quality assessment criteria. Even so, a paucity of literature exists concerning both controlled and observational literature for multiple drugs and multiple conditions of chronic non-cancer pain. Conclusions: This comprehensive review illustrates the lack of literature on long-term opioid therapy; thus, opioid therapy should be provided with great restraint and caution, based on the weak evidence available. Key words: Chronic non-cancer pain, opioids, opioid effectiveness, adverse effects, morphine, hydrocodone, hydromorphone, fentanyl, tramadol, methadone, oxycodone
... Original research first declared in 2016 as a new category in the Rome IV criteria. 1 2 OIC affects up to 41%-57% of patients with pain, [3][4][5][6][7][8][9][10] and up to 87% of patients with pain and cancer. [10][11][12][13] Opioids are prescribed to patients with cancer for the control of pain. ...
Objectives
Naloxegol is a peripherally acting µ-opioid receptor antagonist (PAMORA) for treatment of opioid-induced constipation (OIC). The main objective was to analyse the long-term efficacy, quality of life (QOL) and safety of naloxegol in patients with cancer in a real-world study.
Methods
This one-year prospective study included patients older than 18 years, with active oncological disease who were under treatment with opioids for pain control and Karnofsky≥50 and OIC with inadequate response to treatment with laxative (s). All the patients received treatment with naloxegol according to clinical criteria. The main efficacy objectives were measured by the patient assessment of constipation QOL questionnaire (PAC-QOL), the PAC symptoms (PAC-SYM), the response rate at day 15, and months 1-3-6-12, and global QOL (EuroQoL-5D-5L).
Results
A total of 126 patients (58.7% males) with a mean age of 61.5 years (95% CI 59.4 to 63.7) were included. PAC-SYM and PAC-QOL total score and all their dimensions improved from baseline (p<0.0001). At 12 months, 77.8% of the patients were responders to naloxegol treatment. Global QOL was conserved from baseline. A total of 28 adverse reactions, mainly gastrointestinal were observed in 15.1% of the patients (19/126), being 75% (21) mild, 17.9% (5) moderate and 7.1% (2) severe. Most adverse reactions (67.9%) appeared the first 15 days of treatment.
Conclusion
The results of this first long-term and real-world-data study in patients with cancer, showed the sustained efficacy and safety of naloxegol for the treatment of OIC in this group of patients.
... The most prevalent form of OIBD is opioid-induced constipation (OIC) which occurs in up to 87% of patients with pain related TA B L E 1 The Rome IV diagnostic criteria for opioid-induced constipation 1. New, or escalating, symptoms of constipation when initiating, changing, or increasing opioid therapy that must include 2 or more of the following: A Straining during more than one-quarter of defecations B Lumpy or hard stools (BSFS 1-2) more than one-quarter of the time C Sensation of incomplete evacuation more than one-quarter of the time D Sensation of anorectal blockage/obstruction in more than onequarter of defecations E Manual maneuvers to facilitate more than one-quarter of defecations F Fewer than three spontaneous bowel movements per week 2. Loose stools rarely present without the use of laxatives to cancer, although rates are approximately 50% in those with noncancer pain. [106][107][108] OIC is associated with reduced work productivity and quality of life, yet remains underdiagnosed. [109][110][111] The Rome IV criteria define OIC as a change in bowel habit or defecatory patterns, in comparison with normal following initiation, alteration, or an escalation in opioid therapy, see Table 1. ...
BACKGROUND
Chronic constipation is a prevalent disorder that affects patients' quality of life and consumes resources in healthcare systems worldwide. In clinical practice, it is still considered a challenge as clinicians frequently are unsure as to which treatments to use and when. Over a decade ago, a Neurogastroenterology & Motility journal supplement devoted to the investigation and management of constipation was published (2009; 21 (Suppl.2)). This included seven articles, disseminating all themes covered during a preceding 2‐day meeting held in London, entitled “Current perspectives in chronic constipation: a scientific and clinical symposium.” In October 2018, the 3rd London Masterclass, entitled “Contemporary management of constipation” was held, again over 2 days. All faculty members were invited to author two new review articles, which represent a collective synthesis of talks presented and discussions held during this meeting.
PURPOSE
This article represents the first of these reviews, addressing epidemiology, diagnosis, clinical associations, pathophysiology, and investigation. Clearly, not all aspects of the condition can be covered in adequate detail; hence, there is a focus on particular “hot topics” and themes that are of contemporary interest. The second review addresses management of chronic constipation, covering behavioral, conservative, medical, and surgical therapies.
... Spinal cord stimulation suppresses the visceral response to colon distension in an animal model and therefore may be an effective therapy for chronic pelvic pain of visceral origin. There has been success reported in one study of 35 patients in whom the catheter tip was situated at the T5 position for a median of 9 days (range [4][5][6][7][8][9][10][11][12][13][14]. 134 The Cochrane database concludes that more studies are needed. ...
Adult patients with severe chronic small intestinal dysmotility are not uncommon and can be difficult to manage. This guideline gives an outline of how to make the diagnosis. It discusses factors which contribute to or cause a picture of severe chronic intestinal dysmotility (eg, obstruction, functional gastrointestinal disorders, drugs, psychosocial issues and malnutrition). It gives management guidelines for patients with an enteric myopathy or neuropathy including the use of enteral and parenteral nutrition.
... Además, un número creciente de estudios informa de dolor abdominal persistente en pacientes con uso crónico de opioides, además de la posible disfunción intestinal inducida por opioides que se manifiesta con dolor abdominal, estreñimiento, náuseas, gases, íleo paralítico, contracción de la vesícula biliar y reflujo gastroesofágico. Y también pueden producir síndrome de intestino narcótico, definido como dolor abdominal crónico o recurrente frecuentemente tratado con dosis altas de opioides (7)(8)(9). ...
Chronic abdominal pain of benign origin can be disabling and significantly reduces the quality of life of some patients. Common treatment includes the chronic use of opioids that have also been linked with causing different sources of pain, so alternative pharmacological treatments should be considered instead. However, when these are not effective, insufficient, or cause intolerable adverse effects, interventional pain management should be considered. In this field, the inhibition of splanchnic nerves, which is a technique that can be used to control cancer pain, could play an important role in the treatment of chronic pain of benign origin, despite the lack of solid evidence in its applicability. As far as we know, it is the first time that this procedure has been performed in Ecuador and this report suggests that it can offer positive results even after the effect of the drugs used has ended.
... In patients with various cancers in Japan, the cumulative incidence of opioidinduced constipation (OIC) is lung, 48%; pancreatic, 53%; colon, 60%; breast, 79%; stomach, 71%; esophageal, 60%, prostate, 50%; bladder, 50%; and others, 59% [13]. Long duration of opioid therapy is largely responsible for OIC [14], and drug tolerance against OIC is rarely established, so preventive administration of laxatives is important [15]. ...
Background:
Patients taking opioids are known to develop opioid-induced constipation (OIC), which reduces their quality of life. The aim of this study is to compare magnesium oxide with naldemedine and determine which is more effective in preventing OIC.
Methods:
This proof-of-concept, prospective, randomized controlled trial commenced in Japan in March 2018. Initially, a questionnaire-based survey will be conducted targeting adult patients with cancer who concomitantly commenced opioid treatment and OIC prevention treatment. Patients will then be randomly allocated to a magnesium oxide group (500 mg thrice daily) or a naldemedine group (0.2 mg once daily). Each drug will be orally administered for 12 weeks. The primary endpoint is defined as any improvement in scores on the Japanese version of Patient Assessment of Constipation Quality of Life questionnaire (JPAC-QOL) from baseline to 2 weeks of treatment.
Discussion:
The primary endpoint is change in JPAC-QOL score from baseline to 2 weeks of intervention. The key secondary endpoint will be change in spontaneous bowel movements at 2 and 12 weeks of intervention. This study will determine whether magnesium oxide or naldemedine is more effective for the prevention of OIC.
Trial registration:
University Hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000031891. Registered March 25, 2018.
Purpose
Naloxegol has been shown to be an efficient alternative to treat opioid‐induced constipation (OIC). This study aimed at describing the characteristics of naloxegol users and assessing patterns of naloxegol use and associated factors.
Methods
This drug utilization cohort study used observational registry data on patients newly prescribed naloxegol in four European countries. Patient characteristics and patterns of naloxegol use and associated factors were described.
Results
A total of 17 254 naloxegol users were identified across the countries. Their median age was 56–71 years, and each country had a majority of women (ranging 57.5%–62.9%). Multiple comorbidities, including cancer, were common. Natural opium alkaloids and osmotically acting laxatives (excluding saline) were the most frequently used opioids and laxatives. Overall prior use of opioids ranged from 91.9% to 99.6% and overall prior use of laxatives ranged from 69.9% to 92.4%. Up to 77.7% had prior use of medications with interaction potential, and up to 44.5% used them concurrently with naloxegol. Naloxegol was discontinued by 55.1%–90.9% of users, typically during the first 30 days. Approximately 10%–30% switched to or augmented the treatment with another constipation medication or restarted naloxegol after discontinuation. Augmentation with another constipation medication was relatively common, suggesting that naloxegol was used for multifactorial constipation.
Conclusion
The present study reflects real‐world clinical use of naloxegol, including in vulnerable patient groups. Some naloxegol users lacked laxative or regular opioid use within six months before index date or used naloxegol concomitantly with medications presenting an interaction potential.
Severe chronic small bowel dysmotility occurs when there is a failure to propel the gut luminal contents without there being an organic obstructing lesion. Patients with dysmotility are challenging to manage both as the diagnosis can be difficult to make since other contributing factors (e.g. opioid/cyclizine, abdominal surgery, psychosocial problems and malnutrition) can all cause/exacerbate dysmotility. There are overlapping diagnostic sub-categories which include chronic intestinal pseudo-obstruction (CIPO) defined by a dilated small bowel and non-CIPO which does not. Enteric dysmotility is a sub-category of non-CIPO with abnormal small bowel manometry or transit. Histopathologically, CIPO patients are more likely to have a myopathy whilst non-CIPO/enteric dysmotility are more likely to have a neuropathy, and these may be either primary or secondary as part of a systemic disease. Most patients however will not receive a histopathological diagnosis and are termed idiopathic. The management starts with determining and ordering the primary symptoms/problems and assessing the contributing factors. Mechanical obstruction is excluded (CT abdomen with oral contrast) and a nutritional assessment made. If malnourished or at risk of becoming so nutritional treatment should be started taking into account the risks of refeeding problems. Tests for the underlying aetiology are performed and include excluding hypothyroidism, coeliac disease, diabetes, hypokalaemia or hypercalcaemia, thymoma or other neoplastic condition [chest X-ray (or CT/PET CT)]. Antibodies for connective disorders and those associated with paraneoplastic conditions are performed along with tests for mitochondrial disorders. If none of these are positive a full thickness jejunal biopsy may be considered on a careful risk/benefit analysis, bearing in mind that the results rarely lead to any change in management or outcome at present. The patient may be taking medication that slows gut transit or is very malnourished both of which affect tests of motility (e.g. mamometry and isotope studies). These patients should not be given a definite diagnosis, but rather one of probable/possible or working diagnosis of dysmotility. The primary symptoms/problems are addressed (e.g. pain, distention, vomiting, constipation, malnutrition/bacterial overgrowth, psycho-social issues and quality of life). Bacterial overgrowth may be treated by giving rotating courses of antibiotics and supplements of fat soluble vitamins may be needed. Surgical options (full thickness jejunal biopsy/enteral tube/venting stoma/resection/transplantation) may be considered. Regular MDTs, which include psychological and pain team input should review and reconsider the diagnosis as the clinical situation changes. Opioid medication and cyclizine (especially intravenously) should be avoided due to associated harms.
Opioids are well known to cause adverse effects on the gastrointestinal tract including nausea, vomiting, and constipation. Data regarding how opioids affect the esophagus are more limited. Opioid‐induced esophageal dysfunction (OIED) is a clinical syndrome defined by chronic opioid use (≥3 months), esophageal symptoms (mainly dysphagia), and esophageal motility abnormalities diagnosed by manometry including achalasia type III, hypercontractile esophagus, distal esophageal spasm, and esophagogastric junction outflow obstruction. Up until now, the effect of opioids on esophageal motility assessed by the functional lumen imaging probe (FLIP) had not been described. In this issue of NGM, Patel et al. report that FLIP assessment in patients with esophageal symptoms showed that chronic opioid users have a significant increase in repetitive retrograde contractions, but no significant reduction in distensibility at the esophagogastric junction compared to non‐users. Additionally, perceptive symptoms were higher, and quality of life metrics were lower in the chronic opioid users. This review article will discuss our current understanding of OIED and provide context for this latest study in chronic opioid users. Further investigation with larger prospective studies is needed to understand the pathophysiology, diagnosis, and management of OIED.
Background
Guidelines recommend to prescribe a laxative with an opioid to prevent constipation. We aimed to determine the adherence by general practitioners (GPs) to this recommendation and to explore which GP- and patient related factors were associated with it from the perspective of the GP.
Methods
We conducted an observational study using GPs’ prescription data from the Nivel Primary Care Database combined with a questionnaire asking for reasons of non-adherence. The proportion of first opioid prescriptions prescribed together with a laxative was determined as primary outcome. Possible explanatory factors such as the quality of registration, the level of collaboration with the pharmacy, familiarity with the recommendation and use of a clinical decision support system were explored, as were the self-reported reasons for non-adherence (classified as either GP-related or patient-related). We assessed the association of factors with the primary outcome using univariable multilevel logistic regression analysis.
Results
The recommendation was measured in 195 general practices. The median proportion of first opioid prescriptions prescribed together with a laxative in these practices was 54% (practice range 18–88%). None of the determinants was consistently associated with the primary outcome. GPs from 211 practices filled out the questionnaire and the most frequently mentioned reason not to prescribe a laxative was that the patient has laxatives in stock, followed by that the patient doesn’t want a laxative; both were patient-related factors.
Conclusion
There was room for improvement in following the guideline on laxative prescribing in opioid use. A main reason seemed to be that the patient refuses a laxative. Improvement measures should therefore focus on communication between GPs and patients on the relevance of co-using a laxative with opioids. Future studies need to establish the effect of such improvement measures, and determine whether reasons for non-adherence to the guideline changed over time.
Introduction:
Opioid-induced constipation (OIC) is the most common adverse effect of opioid therapy, but it is underdiagnosed and undertreated. Last year, a survey among Italian healthcare providers revealed important differences in the clinical management of OIC across physician specialties, the need of standardization of diagnosis and treatment, and the urgency of further education. Herein, we submitted an updated version of the survey to the same cohort of experts to evaluate potential progress.
Methods:
The online survey included 15 questions about OIC. Responses were analyzed descriptively and aggregated by physician specialty.
Results:
A total of 190 physicians completed the survey. Most respondents (65%) did not feel adequately educated about OIC despite general consensus regarding interest in the topic and acknowledgement of OIC impact on patients' QoL and adherence to opioid therapy. Overall, 55-77% of physicians regularly evaluated intestinal function or OIC symptoms in patients receiving opioid therapy, with one-third of respondents implementing it in the past year. Even though the most common method for assessment was still patient diary, the use of specific scales underwent a small but significant increase compared to the previous year, with major implementation in the use of Rome IV criteria. As regards first-line treatment, most respondents (49%) preferred macrogol prophylaxis followed by macrogol plus another laxative. For second-line treatment, we revealed a growth in the prescription of peripherally acting mu-opioid receptor antagonists (PAMORAs), with 46% of all the respondents having increased their use during the past year.
Conclusions:
Despite some limitations, our study demonstrated a slow but important step closer to standardization of diagnosis and treatment of OIC. Further educational and training efforts should be put in place to favor best evidence-based clinical practice.
Increased interest in cannabis as a potential treatment and/or adjuvant therapy for inflammatory bowel disease (IBD) has been driven by patients with refractory disease seeking relief as well those who desire alternatives to conventional therapies. Available data have shown a potential role of cannabis as a supportive medication, particularly in pain reduction; however, it remains unknown whether cannabis has any impact on the underlying inflammatory process of IBD. The purpose of this review article is to summarize the available literature concerning the use of cannabis for the treatment of IBD and highlight potential areas for future study.
The purpose of this review is to highlight the impact of common medications on esophageal motility. Esophageal motility is mediated through a complex network of neural innervation. Opioids lead to excitatory esophageal motor abnormalities termed opioid-induced esophageal dysfunction or OIED. Prokinetics have mixed effects on esophageal motility. Nitrates and calcium channel blockers relax esophageal smooth muscle, but they are limited clinically due to side effects. Sildenafil also relaxes smooth muscle, but it is costly. Peppermint oil may reduce distal esophageal spasm. Anticholinergics, selective serotonin reuptake inhibitors, estrogen, and cannabis need further study to evaluate their effects on esophageal motility.
The following areas will be discussed in relation to opioid-related side effects and approaches to their management in the cancer patient.
Background and aim
Opioid receptors agonists have been demonstrated to impair lower esophageal sphincter (LES) relaxation and induce spastic esophageal dysmotility, but little was known for their impact on distension-induced secondary peristalsis. The aim of the study was to investigate the hypothesis whether acute administration of codeine can influence physiological characteristics of primary and secondary peristalsis in healthy adults.
Methods
Eighteen healthy volunteers (13 men, mean age 27.5 years, aged 20-43 years) underwent high resolution manometry (HRM) with a catheter containing an injection port in mid-esophagus. Secondary peristalsis was performed with 10 and 20 mL rapid air injections. Two different sessions including acute administration of codeine (60 mg) or the placebo were randomly performed.
Results
Codeine significantly increased 4-second integrated relaxation pressure (IRP-4s) (P = 0.003) and shortens distal latency (DL) (P = 0.003) of primary peristalsis. The IRP-4s of secondary peristalsis was also significantly higher after codeine than the placebo during air injections with 10 mL (P = 0.048) and 20 mL (P = 0.047). Codeine significantly increased the frequency of secondary peristalsis during air injections with 10 mL than the placebo (P = 0.007), but not for air injection with 20 mL (P = 0.305).
Conclusions
In addition to impair LES relaxation and reduce distal latency of primary peristalsis, codeine impairs LES relaxation of secondary peristalsis and increases secondary peristaltic frequency. Our study supports the notion in human esophagus that the impact of opioids on peristaltic physiology appears to be present in both primary and secondary peristalsis.
Background:
Opioid-induced constipation (OIC) remains an important clinical obstacle despite the availability of several guidelines and pharmacological options for its management. Here, we surveyed common practices and perceptions about OIC among physicians who prescribe opioids in Italy.
Methods:
The online survey included 26 questions about OIC. Responses were analyzed descriptively and aggregated by physician specialty.
Results:
A total of 501 physicians completed the survey. Most respondents (67%) did not feel adequately educated about OIC despite general consensus regarding interest in the topic. Overall, 62-75% of physicians regularly evaluated intestinal function or OIC symptoms in patients receiving opioid therapy. The most common method for assessment was patient diary; few physicians used a validated instrument such as the Rome IV criteria. Psychiatrists and addiction specialists showed the lowest interest and poorest practices. Most respondents (78%) preferred macrogol prophylaxis followed by macrogol plus another laxative for first-line treatment of OIC symptoms. Peripheral-acting mu opioid receptor antagonists (PAMORAs) were not widely used among physicians; 61% had never prescribed a PAMORA for OIC.
Conclusion:
Our findings reveal important differences in clinical practice for OIC across physician specialties. Additional formative efforts are necessary to improve awareness about best practices in OIC.
In treating chronic and acute pain, opioids are widely used. Although they do provide analgesia, their usage does come with adverse events (AEs). One of the most burdensome is opioid-induced bowel dysfunction, and more specifically opioid-induced constipation (OIC). The pathogenesis of these AEs is well known as the consequence of the action of opioids on m-receptors in the enteric nervous system. In recent years, medicines counteracting this specific action at the receptors have been registered for clinical use: the
peripherally acting μ-opioid receptor antagonists (PAMORAs). The knowledge of their comparative efficacy and tolerability is very important for physicians and patients in opioid therapy. This systematic review of the existing literature on PAMORAs aimed to study the relative clinical advantages and disadvantages.
The most important data banks, including “PubMed,” “Embase,” “CT.gov,” “ICTRP” and “CINAHL” were used to find the published material on PAMORAs. The selected publications were examined to systematically analyze the efficacy and safety of the four existing PAMORAs.
All of the medications are superior to placebo in reducing OIC. There are few published data on alvimopan used to treat OIC, and it is only indicated for the treatment of post-abdominal surgery ileus. Methylnaltrexone is studied mainly in its subcutaneous (SC) formulation. When used in its oral formulation, it seems more rapid than naloxegol and placebo in the reduction of OIC. Naldemedine is able to produce more spontaneous bowel movements (SBMs) when compared to alvimopan and naloxegol.
Tolerability was found to be similar for all of them. In particular, they affect the gastrointestinal tract (GI), with flatulence and diarrhea, especially at high dosages. For some of them, nasopharyngitis and abdominal pain were observed as treatment adverse effects (TEAs). Several cardiovascular TEAs were reported after methylnaltrexone use, but it is not clear whether they were consequences of the drug or related to the general conditions of the patients.
Considering the existing data, naloxegol and naldemedine seem to be the best choices, with a higher number of spontaneous bowel movements following naldemedine administration.
Background and aims:
Constipation and abdominal pain are commonly encountered in opioid-induced bowel dysfunction (OBD). The underlying mechanisms are incompletely understood, and treatments are not satisfactory. As OBD patients often have fecal retention, we aimed to determine whether fecal retention plays a pathogenic role in the development of constipation and abdominal pain in OBD, and if so to investigate the mechanisms.
Methods:
A rodent model of OBD was established by daily morphine treatment at 10 mg/kg for 7 days. Bowel movements, colonic muscle contractility, visceromotor response to colorectal distention, and cell excitability of colon-projecting dorsal root ganglion neurons were determined in rats fed in normal pellet food, or in clear liquid diet.
Results:
Morphine treatment (Mor) reduced fecal outputs starting on day 1, and caused fecal retention afterwards. Compared to controls, Mor rats demonstrated suppressed muscle contractility, increased neuronal excitability and visceral hypersensitivity. Expression of cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) was up-regulated in smooth muscle of the distended colon in Mor rats. However, prevention of fecal retention by feeding rats with clear liquid diet blocked up-regulation of COX-2 and NGF, restored muscle contractility, and attenuated visceral hypersensitivity in Mor rats. Moreover, inhibition of COX-2 improved smooth muscle function and fecal outputs, whereas anti-NGF antibody administration attenuated visceral hypersensitivity in Mor rats.
Conclusions:
Morphine-induced fecal retention is an independent pathogenic factor for motility dysfunction and visceral hypersensitivity in OBD rats. Liquid diet may have therapeutic potential for OBD by preventing fecal retention-induced mechano-transcription of COX-2 and NGF.
Objectives:
Constipation and opioid-induced constipation (OIC) are common with limited treatment options. We investigated whether a noninvasive method of auricular vagal nerve stimulation (aVNS) could be used for treating OIC and explored its potential mechanisms and neural pathways in a rodent model of OIC.
Materials and methods:
Sprague-Dawley were chronically implanted with one pair of auricular electrodes for aVNS. Sixteen rats were treated with loperamide for a week while another 16 rats received bilateral vagotomy, then randomly treated with aVNS or sham-aVNS for a week. In addition, eight normal rats were implanted with a polyethylene catheter in the proximal colon for assessing whole colon transit.
Results:
1) The number of fecal pellets and water content in feces increased after aVNS, compared with sham-aVNS. 2) aVNS accelerated colon transit and whole gut transit, compared with sham-aVNS. 3) In colon tissues, aVNS increased the protein expression of choline acetyltransferase, glial cell line-derived neurotrophic factor and the c-kit expression in myenteric interstitial cells of Cajal but decreased the protein expression of neural nitric oxide synthase (p < 0.05 for all, vs. sham-VNS). 4) The prokinetic effects of aVNS were abolished by both subdiaphragmatic vagotomy and atropine. 5) aVNS increased the c-fos expression in both nucleus tractus solitarius and dorsal motor nucleus of vagus, and increased vagal efferent activity (p < 0.05, vs. sham-VNS).
Conclusions:
aVNS improves OIC by enhancing colon motility and restoring enteric neural functions mediated via the central and vagal efferent pathway.
Results: Part 2 of the guidelines on responsible opioid prescribing provides the following recommendations for initiating and maintaining chronic opioid therapy of 90 days or longer. 1. A) Comprehensive assessment and documentation is recommended before initiating opioid therapy, including documentation of comprehensive history, general medical condition, psychosocial history, psychiatric status, and substance use history. (Evidence: good) B) Despite limited evidence for reliability and accuracy, screening for opioid use is recommended, as it will identify opioid abusers and reduce opioid abuse. (Evidence: limited) C) Prescription monitoring programs must be implemented, as they provide data on patterns of prescription usage, reduce prescription drug abuse or doctor shopping. (Evidence: good to fair) D) Urine drug testing (UDT) must be implemented from initiation along with subsequent adherence monitoring to decrease prescription drug abuse or illicit drug use when patients are in chronic pain management therapy. (Evidence: good) 2. A) Establish appropriate physical diagnosis and psychological diagnosis if available prior to initiating opioid therapy. (Evidence: good) B) Caution must be exercised in ordering various imaging and other evaluations, interpretation and communication with the patient; to avoid increased fear, activity restriction, requests for increased opioids, and maladaptive behaviors. (Evidence: good) C) Stratify patients into one of the 3 risk categories – low, medium, or high risk. D) A pain management consultation, may assist non-pain physicians, if high-dose opioid therapy is utilized. (Evidence: fair) 3. Essential to establish medical necessity prior to initiation or maintenance of opioid therapy. (Evidence: good) 4. Establish treatment goals of opioid therapy with regard to pain relief and improvement in function. (Evidence: good) 5. A) Long-acting opioids in high doses are recommended only in specific circumstances with severe intractable pain that is not amenable to short-acting or moderate doses of long-acting opioids, as there is no significant difference between long-acting and short-acting opioids for their effectiveness or adverse effects. (Evidence: fair) B) The relative and absolute contraindications to opioid use in chronic non-cancer pain must be evaluated including respiratory instability, acute psychiatric instability, uncontrolled suicide risk, active or history of alcohol or substance abuse, confirmed allergy to opioid agents, coadministration of drugs capable of inducing life-limiting drug interaction, concomitant use of benzodiazepines, active diversion of controlled substances, and concomitant use of heavy doses of central nervous system depressants. (Evidence: fair to limited) 6. A robust agreement which is followed by all parties is essential in initiating and maintaining opioid therapy as such agreements reduce overuse, misuse, abuse, and diversion. (Evidence: fair) 7. A) Once medical necessity is established, opioid therapy may be initiated with low doses and short-acting drugs with appropriate monitoring to provide effective relief and avoid side effects. (Evidence: fair for short-term effectiveness, limited for long-term effectiveness) B) Up to 40 mg of morphine equivalent is considered as low dose, 41 to 90 mg of morphine equivalent as a moderate dose, and greater than 91 mg of morphine equivalence as high dose. (Evidence: fair) C) In reference to long-acting opioids, titration must be carried out with caution and overdose and misuse must be avoided. (Evidence: good) 8. A) Methadone is recommended for use in late stages after failure of other opioid therapy and only by clinicians with specific training in the risks and uses. (Evidence: limited) B) Monitoring recommendation for methadone prescription is that an electrocardiogram should be obtained prior to initiation, at 30 days and yearly thereafter. (Evidence: fair) 9. In order to reduce prescription drug abuse and doctor shopping, adherence monitoring by UDT and PMDPs provide evidence that is essential to the identification of those patients who are non-compliant or abusing prescription drugs or illicit drugs. (Evidence: fair) 10. Constipation must be closely monitored and a bowel regimen be initiated as soon as deemed necessary. (Evidence: good) 11. Chronic opioid therapy may be continued, with continuous adherence monitoring, in well-selected populations, in conjunction with or after failure of other modalities of treatments with improvement in physical and functional status and minimal adverse effects. (Evidence: fair) Disclaimer: The guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a “standard of care.” Key words: Chronic pain, persistent pain, non-cancer pain, controlled substances, substance abuse, prescription drug abuse, dependency, opioids, prescription monitoring, drug testing, adherence monitoring, diversion
Background: Opioid abuse has continued to increase at an alarming rate since the 1990s. As documented by different medical specialties, medical boards, advocacy groups, and the Drug Enforcement Administration, available evidence suggests a wide variance in chronic opioid therapy of 90 days or longer in chronic non-cancer pain. Part 1 describes evidence assessment. Objectives: The objectives of opioid guidelines as issued by the American Society of Interventional Pain Physicians (ASIPP) are to provide guidance for the use of opioids for the treatment of chronic non-cancer pain, to produce consistency in the application of an opioid philosophy among the many diverse groups involved, to improve the treatment of chronic non-cancer pain, and to reduce the incidence of abuse and drug diversion. The focus of these guidelines is to curtail the abuse of opioids without jeopardizing non-cancer pain management with opioids. Results: 1) There is good evidence that non-medical use of opioids is extensive; one-third of chronic pain patients may not use prescribed opioids as prescribed or may abuse them, and illicit drug use is significantly higher in these patients. 2) There is good evidence that opioid prescriptions are increasing rapidly, as the majority of prescriptions are from non-pain physicians, many patients are on long-acting opioids, and many patients are provided with combinations of long-acting and short-acting opioids. 3) There is good evidence that the increased supply of opioids, use of high dose opioids, doctor shoppers, and patients with multiple comorbid factors contribute to the majority of the fatalities. 4) There is fair evidence that long-acting opioids and a combination of long-acting and shortacting opioids contribute to increasing fatalities and that even low-doses of 40 mg or 50 mg of daily morphine equivalent doses may be responsible for emergency room admissions with overdoses and deaths. 5) There is good evidence that approximately 60% of fatalities originate from opioids prescribed within the guidelines, with approximately 40% of fatalities occurring in 10% of drug abusers. 6) The short-term effectiveness of opioids is fair, whereas the long-term effectiveness of opioids is limited due to a lack of long-term (> 3 months) high quality studies, with fair evidence with no significant difference between long-acting and short-acting opioids. 7) Among the individual drugs, most opioids have fair evidence for short-term and limited evidence for long-term due to a lack of quality studies. 8) The evidence for the effectiveness and safety of chronic opioid therapy in the elderly for chronic non-cancer pain is fair for short-term and limited for long-term due to lack of high quality studies; limited in children and adolescents and patients with comorbid psychological disorders due to lack of quality studies; and the evidence is poor in pregnant women. 9) There is limited evidence for reliability and accuracy of screening tests for opioid abuse due to lack of high quality studies. 10) There is fair evidence to support the identification of patients who are non-compliant or abusing prescription drugs or illicit drugs through urine drug testing and prescription drug monitoring programs, both of which can reduce prescription drug abuse or doctor shopping. Disclaimer: The guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a “standard of care.” Key words: Chronic pain, persistent pain, non-cancer pain, controlled substances, substance abuse, prescription drug abuse, dependency, opioids, prescription monitoring, drug testing, adherence monitoring, diversion
This article addresses the management of chronic constipation and opioid-induced constipation. Apart from increasing dietary fiber, there are several classes of medications that can be used for treatment of constipation, and these include osmotic and secretory laxatives, agents that impede the re-absorption of endogenous bile acids resulting in stimulation of motor and secretory functions in the colon, and agents that stimulate the motor function of the colon thereby propelling stool towards the rectum. Several drug classes are also available for the treatment of opioid-induced constipation including peripherally active mu-opioid receptor antagonists, and some of the same secretory agents and prokinetics that are used for chronic constipation. For both of these indications, there have recently been studies that compared efficacy and safety of the available drugs through network meta-analyses, which are also summarized in this article.
Purpose:
The purpose of this study was to identify the prevalence of constipation in hospitalized patients, along with sociodemographic and clinical variables associated with its occurrence.
Design:
Observational, cross-sectional study.
Subjects and settings:
The study sample comprised 343 adult patients hospitalized at a University Hospital in Sao Paulo, Brazil.
Methods:
Point-prevalence data were collected on the same day each month over a 4-month period. Data were collected via interviews, physical examination, medical record review, and completion of a data collection form that queried sociodemographic data and incorporated the Bowel Function in the Community instrument. Patients were classified as constipated if they met 2 or more of the Rome III criteria. Logistic regression analyses were used to identify clinical or sociodemographic factors associated with constipation.
Results:
Fifty-one patients had constipation, reflecting a point-prevalence of 14.8% (95% CI, 11.49-19.02). The prevalence of constipation was 15% in females (n = 29) and 14.7% in males (n = 22). Multivariable logistic regression showed that use of laxatives (OR = 9.98; 95% CI, 3.539-29.666) was associated with a higher likelihood of constipation.
Conclusion:
The prevalence of constipation in hospitalized adult patients was lower than that in previous studies. Patients using laxatives were more likely to experience constipation.
Background
Opioid‐induced esophageal dysfunction (OIED) is a recognized complication of chronic opioid use. However, the impact of acute opioid administration on esophageal motility remains unclear.
Methods
Opioid naïve patients with high‐resolution manometry (HRM) <480 min following esophagogastroduodenoscopy (EGD) (opioid‐HRM) and a control group with HRM <36 h prior to EGD between January 1, 2016, and November 10, 2018, from a single institution were identified. EGDs were performed exclusively with versed and fentanyl.
Key Results
One hundred and seventy‐four patients were identified, with 83 (47.7%) opioid‐HRM and 91 (52.3%) controls. Mean time from EGD to HRM was 229 (78–435) min. Baseline clinical features and HRM indications were similar between opioid‐HRM and controls. Chicago classification v3.0 defined HRM findings were similar between groups. Major motility disorders as defined by the Chicago classification v3.0 occurred at a similar frequency among opioid‐HRM and controls (27.7% vs. 36.3%, p = 0.23). Mean distal contractile integrity (DCI) was higher in opioid‐HRM (1939.3 ± 1318.9 vs. 1792.2 ± 2062.3 mmHg∙cm∙s, p = 0.043), but maximum DCI, distal latency, and integrated relaxation pressure did not differ between groups. Subgroup analysis assessing time and dose dependency did not identify differences in individual manometric parameters and Chicago classification v3.0 diagnosis between patients with HRM <240 min after EGD, >240 min after EGD, ≥125 mcg of IV fentanyl, <125 mcg IV fentanyl and controls.
Conclusions and Inferences
Same‐day acute opioid administration did not affect HRM findings in opioid naïve patients. Studies assessing the pathophysiology of and duration‐dependent relationship with opioids in OIED are needed.
The elderly are particularly prone to developing upper gastrointestinal disturbances. Changes are due to the aging process, diabetes, cardiovascular risk factors, and neurologic issues. Medications used to treat these underlying conditions can cause gastrointestinal symptoms. Dysphagia is common and can be oropharyngeal and/or esophageal. Gastroparesis is due to either medications such opiates, or due to neurologic sequala of diabetes, cerebrovascular accidents, or neurologic diseases such as Parkinson's disease. Given limitations in many commonly used prokinetics with a wide range of side effect profiles including neurologic and cardiac, the focus of treatment should be on symptom management with dietary changes.
Background and aims
Quantitative sensory testing (QST) has been previously used to study pain in chronic pancreatitis (CP) but included methods that are not suitable for clinical purposes. The aims of this study were to determine if pancreatic QST (P-QST) can differentiate patients into distinct pain phenotypes and to determine the association of these with their clinical pain and psychiatric comorbidities.
Methods
A multicenter cross-sectional study was conducted where patients completed validated questionnaires assessing quality of life (QoL), depression and anxiety scores as well as clinical pain symptoms followed by P-QST which included a cold pressor test, repetitive pin prick stimuli and pressure stimulation of the upper abdominal (T10) and control dermatomes. P-QST categorized patients into pain phenotypes based on a previously established nomogram. QoL, clinical pain and psychiatric assessment scores were compared across these groups.
Results
A total of 179 patients were enrolled with a mean age of 54.1±13.6 years among whom 59% were males and 42% had an alcohol etiology. P-QST showed no hyperalgesia in 91 (51%), segmental hyperalgesia in 50 (28%) and widespread hyperalgesia in 38 (21%) patients. Patients with widespread hyperalgesia had significantly higher pain intensity scores (P = .03) and rates of constant pain (P = .002) as well as decreased QoL (P < .001) and physical functioning (P =.03) in comparison with the other two pain phenotypes. In contrast, psychiatric comorbidities were similar across all groups.
Conclusion
P-QST may serve as novel unbiased pain assessment tool in CP as it categorizes patients into distinct pain phenotypes independent of their psychiatric comorbidities.
Acute and chronic gastrointestinal (GI) problems are common in the setting of alcohol, tobacco, and prescription and recreational drug use. Excessive alcohol use is associated with injury to all parts of the gastrointestinal tract. Alcohol-related liver disease, alcohol-related pancreatitis, and gastrointestinal cancer are important causes of morbidity and mortality related to excessive alcohol use. Tobacco use is associated with gastroesophageal reflux, peptic ulceration, gastrointestinal cancer, and Crohn’s disease but appears to protect against ulcerative colitis. Opioids have important effects on gastrointestinal secretion and motility. Narcotic bowel syndrome may develop in the setting of escalating doses of opioid analgesia. Cannabis use is associated with both relief of nausea and vomiting associated with chemotherapy and adverse gastrointestinal effects. Cannabinoid hyperemesis syndrome should be considered in the setting of heavy cannabis use and recurrent vomiting. The body packing syndrome is sporadically encountered at hospitals near international transport hubs and can be challenging when encountered.
The infectious disease (ID) physician can play an important role in the evidence-based treatment of both opioid use disorder (OUD) and addiction-related infections. A comprehensive ID consultation will include substance-related screening, diagnosis, and initiation of medications for OUD—extended-release naltrexone, buprenorphine, and methadone. This care can be integrated into the treatment of common and uncommon OUD-related infections. Providers should understand patient-centered concepts for persons who use drugs such as acute pain, opioid-related conditions, and reduction of unplanned disposition. Team-based integration of ID and OUD management can improve care and reduce treatment interruptions.
Purpose of review:
Opioid medications are a pillar of acute and chronic analgesia, though their use is often accompanied by side-effects, such as opioid-induced constipation. Unfortunately, tolerance rarely develops to this untoward side effect. This review presents the background, evidence, and indications for the use of Naldemedine (Brand name Symproic 0.2 mg tablets) to treat opioid-induced constipation.
Recent findings:
Opioids are often used for the treatment of acute and chronic analgesia. Outside of the central effect they exert, they also interact with peripheral receptors, resulting in opioid-induced constipation, the commonest of side effects of chronic opioid usage. Complications include colonic distention, ileus, perforation, and can progress to other serious bowel complications, which can result in hospitalization and fatal events.For the most part, laxatives and other anti-constipation therapies are often inefficient and require intervention directed at the root cause, such as peripheral mu receptor agonists, including methylnaltrexone, naloxegol, and naldemedine. Naldemedine is the most recent to gain FDA approval of the group.An antagonist of Mu, Kappa, and Delta peripheral receptors, Naldemedine, is the only drug to counteract all three receptor classes. It was shown to be both safe and effective when compared with placebo. No data exists to compare its efficacy to that of other members of the group.
Summary:
Opioids are frequently used in the management of acute and chronic pain. The most common of the side effects is opioid-induced constipation, secondary to the peripheral activity of opioids. Naldemedine is an FDA-approved, once-daily oral tablet that counteracts this side effect by antagonizing mu, kappa, and delta-opioid receptors and has been shown to be safe and effective. Further investigation including head-to-head clinical trials are required to evaluate the relative efficacy of naldemedine compare with other peripheral opiate receptor antagonists.
A 36-item short-form (SF-36) was constructed to survey health status in the Medical Outcomes Study. The SF-36 was designed for use in clinical practice and research, health policy evaluations, and general population surveys. The SF-36 includes one multi-item scale that assesses eight health concepts: 1) limitations in physical activities because of health problems; 2) limitations in social activities because of physical or emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. The survey was constructed for self-administration by persons 14 years of age and older, and for administration by a trained interviewer in person or by telephone. The history of the development of the SF-36, the origin of specific items, and the logic underlying their selection are summarized. The content and features of the SF-36 are compared with the 20-item Medical Outcomes Study short-form.
Opioid prescription use is increasing. Narcotic bowel syndrome (NBS) refers to chronic abdominal pain aggravated by narcotic use. Despite increasing narcotic use, NBS may be under-recognized. The aim of this study was to assess whether gastrointestinal (GI) symptoms in the community are associated with chronic narcotic use and estimate the likely prevalence of NBS.
Validated self-report GI symptom questionnaires were mailed to 4,898 randomly selected people in the community. The medical charts of all respondents were reviewed to identify participants who had used narcotics and to determine whether they were taking an opioid for > 5 weeks for the treatment of chronic pain (malignant or nonmalignant). NBS was defined as abdominal pain developing in those taking chronic narcotics. The associations between GI symptoms and chronic narcotics use were assessed using logistic regression analysis.
A total of 2,913 respondents returned a completed questionnaire (overall response rate 59%, mean age 62, 52% female); 117 participants (4.1%, 95% confidence interval (CI): 3.3, 4.5) were taking narcotics. Five participants (0.17%; 95% CI: 0.06, 0.40%) met the criteria for NBS. Participants using narcotics had an increased use of laxatives (17 vs. 8% in those not using narcotics, P < 0.05). GI symptom reporting was more common in participants on narcotics, although the adjusted (for age, gender, somatic symptom complaints, and use of laxatives) odds ratios (ORs) were significantly increased only for frequent abdominal pain and stool frequency.
NBS may be relatively uncommon. Those on narcotics report additional GI symptoms (abdominal pain and stool frequency) and use more laxatives.
In contrast to the use of opioids for the treatment of acute and chronic cancer pain, the administration of chronic opioid therapy for pain not due to malignancy remains controversial. We describe 100 patients who were chronically given opioids for treatment of nonmalignant pain. Most patients experienced neuropathic pain or back pain. We used sustained-release dihydrocodeine, buprenorphine, and sustained-release morphine. Pain reduction was measured with visual analogue scales (VAS), and the Karnofsky Performance Status Scale was used to assess the patient's function. Good pain relief was obtained in 51 patients and partial pain relief was reported by 28 patients. Only 21 patients had no beneficial effect from opioid therapy. There was a close correlation between the sum and the peak VAS values (r = 0.983; p less than 0.0001) and pain reduction was associated with an increase in performance (p less than 0.0001). The most common side effects were constipation and nausea. There were no cases of respiratory depression or addiction to opioids. Our results indicate that opioids can be effective in chronic nonmalignant pain, with side effects that are comparable to those that complicate the treatment of cancer pain.
A 36-item short-form (SF-36) was constructed to survey health status in the Medical Outcomes Study. The SF-36 was designed for use in clinical practice and research, health policy evaluations, and general population surveys. The SF-36 includes one multi-item scale that assesses eight health concepts: 1) limitations in physical activities because of health problems; 2) limitations in social activities because of physical or emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. The survey was constructed for self-administration by persons 14 years of age and older, and for administration by a trained interviewer in person or by telephone. The history of the development of the SF-36, the origin of specific items, and the logic underlying their selection are summarized. The content and features of the SF-36 are compared with the 20-item Medical Outcomes Study short-form.
To compare patients' preference for transdermal fentanyl or sustained release oral morphine, their level of pain control, and their quality of life after treatment.
Randomised, multicentre, international, open label, crossover trial.
35 centres in Belgium, Canada, Denmark, Finland, the United Kingdom, the Netherlands, and South Africa.
256 patients (aged 26-82 years) with chronic non-cancer pain who had been treated with opioids.
Patients' preference for transdermal fentanyl or sustained release oral morphine, pain control, quality of life, and safety assessments. Results: Of 212 patients, 138 (65%) preferred transdermal fentanyl, whereas 59 (28%) preferred sustained release oral morphine and 15 (7%) expressed no preference. Better pain relief was the main reason for preference for fentanyl given by 35% of patients. More patients considered pain control as being "good" or "very good" with fentanyl than with morphine (35% v 23%, P=0.002). These results were reflected in both patients' and investigators' opinions on the global efficacy of transdermal fentanyl. Patients receiving fentanyl had on average higher quality of life scores than those receiving morphine. The incidence of adverse events was similar in both treatment groups; however, more patients experienced constipation with morphine than with fentanyl (48% v 29%, P<0.001). Overall, 41% of patients experienced mild or moderate cutaneous problems associated with wearing the transdermal fentanyl patch, and more patients withdrew because of adverse events during treatment with fentanyl than with morphine (10% v 5%). However, within the subgroup of patients naive to both fentanyl and morphine, similar numbers of patients withdrew owing to adverse effects (11% v 10%, respectively).
Transdermal fentanyl was preferred to sustained release oral morphine by patients with chronic non-cancer pain previously treated with opioids. The main reason for preference was better pain relief, achieved with less constipation and an enhanced quality of life.
Although its inclusion in medical research is relatively recent and its interpretation is often variable, quality of life is increasingly being recognized as one of the most important parameters to be measured in the evaluation of medical therapies, including those for pain management. Pain, when it is not effectively treated and relieved, has a detrimental effect on all aspects of quality of life. This negative impact has been found to span every age and every type and source of pain in which it has been studied. Effective analgesic therapy has been shown to improve quality of life by relieving pain. Opioid analgesics, cyclooxygenase (COX)-2 inhibitors (or coxibs), and several adjuvant analgesics for neuropathic pain have been demonstrated to significantly improve quality-of-life scores in patients with pain. Coxibs provide effective, well-tolerated analgesia without some of the issues faced with opioids-benefits that should translate into improved quality of life. Recent studies have demonstrated that the COX-2 inhibitor rofecoxib significantly improves quality of life in patients with osteoarthritis and chronic, lower back pain. Quality-of-life measurements, especially symptom distress scales, can also be used as sensitive means of differentiating one agent from another in the same class. In future pharmacotherapeutic research, quality of life should be included as an outcome domain as are the traditionally measured variables of efficacy and safety. In particular, future studies of coxibs should include symptom distress scores as important quality-of-life measurements, to identify meaningful differences between this new class of analgesics and nonselective nonsteroidal anti-inflammatory drugs.
Common pain conditions appear to have an adverse effect on work, but no comprehensive estimates exist on the amount of productive time lost in the US workforce due to pain.
To measure lost productive time (absence and reduced performance due to common pain conditions) during a 2-week period.
Cross-sectional study using survey data from the American Productivity Audit (a telephone survey that uses the Work and Health Interview) of working adults between August 1, 2001, and July 30, 2002.
Random sample of 28 902 working adults in the United States.
Lost productive time due to common pain conditions (arthritis, back, headache, and other musculoskeletal) expressed in hours per worker per week and calculated in US dollars.
Thirteen percent of the total workforce experienced a loss in productive time during a 2-week period due to a common pain condition. Headache was the most common (5.4%) pain condition resulting in lost productive time. It was followed by back pain (3.2%), arthritis pain (2.0%), and other musculoskeletal pain (2.0%). Workers who experienced lost productive time from a pain condition lost a mean (SE) of 4.6 (0.09) h/wk. Workers who had a headache had a mean (SE) loss in productive time of 3.5 (0.1) h/wk. Workers who reported arthritis or back pain had mean (SE) lost productive times of 5.2 (0.25) h/wk. Other common pain conditions resulted in a mean (SE) loss in productive time of 5.5 (0.22) h/wk. Lost productive time from common pain conditions among active workers costs an estimated 61.2 billion dollars per year. The majority (76.6%) of the lost productive time was explained by reduced performance while at work and not work absence.
Pain is an inordinately common and disabling condition in the US workforce. Most of the pain-related lost productive time occurs while employees are at work and is in the form of reduced performance.
To assess the reliability of an augmented SF-36 instrument, the Treatment Outcomes in Pain Survey ("TOPS"), in patients treated in two pain management programs, and present norms for initial values and treatment-related improvements.
Prospective case series at two sites with longitudinal follow-up.
Multidisciplinary, comprehensive outpatient pain treatment centers in university hospitals in Salt Lake City and Boston.
Nine hundred and forty seven adult outpatients with a range of socioeconomic, demographic, and ethnic characteristics, all referred for evaluation and treatment of chronic pain.
Usual practice multidisciplinary pain treatment.
TOPS prior to pain treatment and 5-week nominal follow-up. Means and standard deviations of baseline and follow-up results. Psychometric results for reliability (Cronbach alpha), validity (item discriminant validity, validity coefficients), and related statistical precision measures for group and individual designs.
Several measures were precise enough to permit following individual patients in standard clinic treatment, of which the Total Pain Experience dimension was the most powerful. Similar psychometrics were observed in the Boston and Salt Lake City sites. The Pain Symptom, Objective Family/Social Disability, Objective Work Disability, and Upper Body Functional Limitations scales were validated.
The TOPS was designed to satisfy several models of clinical pain treatment. It successfully monitored treatment based on those models. Not all patients improve with treatment, but most do. The TOPS can be administered in a variety of ways, but we found paper and pencil administration with computer scanning of results quick and efficient for making the data available to clinicians as part of treatment.
The accuracy of the TOPS is sufficient to monitor the response of individual patients during multidisciplinary treatment of chronic pain. The TOPS provides needed documentation (e.g., to third-party payors) of the aggregate value of multidisciplinary outpatient treatment of chronic pain as well as its benefit for individual patients.
Opioids are used increasingly for chronic non-cancer pain. Controversy exists about their effectiveness and safety with long-term use. We analysed available randomised, placebo-controlled trials of WHO step 3 opioids for efficacy and safety in chronic non-cancer pain. The Oxford Pain Relief Database (1950-1994) and Medline, EMBASE and the Cochrane Library were searched until September 2003. Inclusion criteria were randomised comparisons of WHO step 3 opioids with placebo in chronic non-cancer pain. Double-blind studies reporting on pain intensity outcomes using validated pain scales were included. Fifteen randomised placebo-controlled trials were included. Four investigations with 120 patients studied intravenous opioid testing. Eleven studies (1025 patients) compared oral opioids with placebo for four days to eight weeks. Six of the 15 included trials had an open label follow-up of 6-24 months. The mean decrease in pain intensity in most studies was at least 30% with opioids and was comparable in neuropathic and musculoskeletal pain. About 80% of patients experienced at least one adverse event, with constipation (41%), nausea (32%) and somnolence (29%) being most common. Only 44% of 388 patients on open label treatments were still on opioids after therapy for between 7 and 24 months. The short-term efficacy of opioids was good in both neuropathic and musculoskeletal pain conditions. However, only a minority of patients in these studies went on to long-term management with opioids. The small number of selected patients and the short follow-ups do not allow conclusions concerning problems such as tolerance and addiction.
Adverse events of opioids may restrict their use in non-cancer pain. Analysis of the incidence of common adverse events in trials conducted in non-cancer pain has usually been limited to opioids used to treat severe pain according to the WHO three-step ladder. To examine the incidence of common adverse events of opioids in non-cancer pain, a systematic review and meta-analysis of information from randomised trials of all opioids in non-cancer pain was undertaken. Studies used were published randomised trials of oral opioid in non-cancer pain, with placebo or active comparator. Thirty-four trials with 5,546 patients were included with 4,212 patients contributing some information on opioid adverse events. Most opioids used (accounting for 90% of patients) were for treating moderate rather than severe pain. Including trials without a placebo increased the amount of information available by 1.4 times. Because of clinical heterogeneity in condition, opioid, opioid dose, duration, and use of titration, only broad results could be calculated. Use of any oral opioid produced higher rates of adverse events than did placebo. Dry mouth (affecting 25% of patients), nausea (21%), and constipation (15%) were the most common adverse events. A substantial proportion of patients on opioids (22%) withdrew because of adverse events. Because most trials were short, less than four weeks, and because few titrated the dose, these results have limited applicability to longer-term use of opioids in clinical practice. Suggestions for improved studies are made.
Treatment for constipation depends on an assessment of the underlying physiological mechanisms. Several distinct mechanisms are proposed: delayed colonic transit associated with decreased peristaltic motility, increased segmenting (impeding) contractions, decreased rectal tone associated with magarectum, pelvic floor dyssynergia (anismus), and hypochondriacal constipation. It is recommended that the diagnostic assessment include, in addition to the history and physical examination, a psychological symptom checklist, colonoscopy or barium enema, whole gut and segmental transit time, rectal manometry, and (if colectomy is contemplated) a small bowel motility. If available, a 24-hour colon motility is also helpful. Experience suggests that a physiological cause of constipation will be found in only half of patients; the extent to which psychological mechanisms account for complaints of constipation in the remaining 50% is unknown. Conservative treatment for delayed colonic transit includes 30 g daily of fibre and moderate exercise. For constipation related to increased segmenting contractions, no treatment is of proven efficacy but increased fibre and exercise are recommended. For pelvic floor dyssynergia, biofeedback training appears to be the most effective treatment, although additional research is needed. Megarectum with associated encopresis, largely confined to children and geriatric patients, can be treated by habit training in which the patient is required to attempt to defaecate at a regular time of day rather than in response to urge. Hypochondriacal constipation may be treated by reassuring and educating the patient, combined when necessary with antidepressant medications. The chronic use of stimulant laxatives may be justified in some patients, but this should be supervised by a physician, and it is suggested that the frequency of administration not exceed two times per week. Colectomy should be used reluctantly because this is a radical, irreversible treatment for a non-life-threatening disorder, and it is associated with a high complication rate. Guidelines for the use of colectomy are proposed.
In this editorial, we review the narcotic bowel syndrome, its etiology, presentation, and treatment. We suggest this is an often overlooked diagnosis in many clinical settings.
Opioid treatment for postoperative or chronic pain is frequently associated with adverse effects, the most common being dose-limiting and debilitating bowel dysfunction. Postoperative ileus, although attributable to surgical procedures, is often exacerbated by opioid use during and following surgery. Postoperative ileus is marked by increased inhibitory neural input, heightened inflammatory responses, decreased propulsive movements and increased fluid absorption in the gastrointestinal tract. The use of opioids for chronic pain is characterised by a constellation of symptoms including hard dry stools, straining, incomplete evacuation, bloating, abdominal distension and increased gastroesophageal reflux.
The current management of opioid-induced bowel dysfunction among patients receiving opioid analgesics consists primarily of nonspecific ameliorative measures. Intensive investigations into the mode of action of opioids have characterised three opioid receptor classes — μ, δ and κ — that mediate the myriad of peripheral and central actions of opioids. Activation of μ-opioid receptors in the gastrointestinal tract is responsible for inhibition of gut motility, whereas receptors in the central nervous system mediate the analgesic actions of opioids. Blocking peripheral opioid receptors in the gut is therefore a logical therapeutic target for managing opioid-induced bowel dysfunction.
Available opioid antagonists such as naloxone are of limited use because they are readily absorbed, cross the blood-brain barrier, and act at central opioid receptors to reverse analgesia and elicit opioid withdrawal. Methylnaltrexone and alvimopan are recently developed opioid antagonists with activity that is restricted to peripheral receptors. Both have recently shown the ability to reverse opioid-induced bowel dysfunction without reversing analgesia or precipitating central nervous system withdrawal signs in non-surgical patients receiving opioids for chronic pain. In addition, recent clinical studies with alvimopan suggest that it may normalise bowel function without blocking opioid analgesia in abdominal laparotomy patients with opioid-related postoperative ileus.
Objectives: To compare patients' preference for transdermal fentanyl or sustained release oral morphine, their level of pain control, and their quality of life after treatment.
Design: Randomised, multicentre, international, open label, crossover trial.
Setting: 35 centres in Belgium, Canada, Denmark, Finland, the United Kingdom, the Netherlands, and South Africa.
Participants: 256 patients (aged 26-82 years) with chronic non-cancer pain who had been treated with opioids.
Main outcome measures: Patients' preference for transdermal fentanyl or sustained release oral morphine, pain control, quality of life, and safety assessments.
Results: Of 212 patients, 138 (65%) preferred transdermal fentanyl, whereas 59 (28%) preferred sustained release oral morphine and 15 (7%) expressed no preference. Better pain relief was the main reason for preference for fentanyl given by 35% of patients. More patients considered pain control as being “good” or “very good” with fentanyl than with morphine (35% v 23%, P=0.002). These results were reflected in both patients' and investigators' opinions on the global efficacy of transdermal fentanyl. Patients receiving fentanyl had on average higher quality of life scores than those receiving morphine. The incidence of adverse events was similar in both treatment groups; however, more patients experienced constipation with morphine than with fentanyl (48% v 29%, P<0.001). Overall, 41% of patients experienced mild or moderate cutaneous problems associated with wearing the transdermal fentanyl patch, and more patients withdrew because of adverse events during treatment with fentanyl than with morphine (10% v 5%). However, within the subgroup of patients naive to both fentanyl and morphine, similar numbers of patients withdrew owing to adverse effects (11% v 10%, respectively).
Conclusion: Transdermal fentanyl was preferred to sustained release oral morphine by patients with chronic non-cancer pain previously treated with opioids. The main reason for preference was better pain relief, achieved with less constipation and an enhanced quality of life.
What is already known on this topic
What is already known on this topic The clinical use of potent opioids in the treatment of chronic non-cancer pain is supported by retrospective, survey data and small randomised controlled trials showing efficacy and safety
Studies with transdermal fentanyl have shown efficacy and preference over sustained release oral morphine in the treatment of cancer pain
Background:
Narcotic bowel syndrome is characterized by chronic or recurrent abdominal pain associated with escalating doses of narcotic pain medications. It may occur in as many as 4% of all patients taking opiates, and yet few physicians are aware that the syndrome exists.
Objectives:
The objectives of this case report are to raise awareness of narcotic bowel syndrome among emergency physicians, as well as review the clinical features, diagnosis, pathophysiology, and emergency department (ED) management of the syndrome.
Case report:
We report a case of narcotic bowel syndrome diagnosed in a 24-year-old woman after > 1 year of ED visits for recurrent abdominal pain of unknown origin.
Conclusions:
It is particularly important for emergency physicians to be familiar with this syndrome, as many patients with narcotic bowel syndrome seek evaluation and treatment in the ED. Although the diagnosis is unlikely to be made in the ED, timely referral for evaluation of this syndrome may help patients to receive definitive treatment for their recurrent and chronic pain.
This multinational, Internet-based survey was designed to assess the prevalence, frequency, severity, and impact of opioid-induced bowel dysfunction (OBD) in patients receiving opioid therapy for chronic pain and taking laxatives.
In total, 322 patients taking daily oral opioids and laxatives completed the 45-item questionnaire. At the time of the survey, 45% of patients reported <3 bowel movements per week. The most prevalent opioid-induced side effects were constipation (81%) and straining to pass a bowel movement (58%). Those side effects considered most bothersome by patients were (in order of rank) constipation, straining, fatigue, small or hard bowel movements, and insomnia.
Most of the OBD symptoms specified in the questionnaire were experienced by the majority of patients >or=4 times a week. Constipation was the OBD symptom that was most often reported as severe. Most patients reported that their OBD symptoms had at least a moderate negative impact on their overall quality of life and activities of daily living. A third of patients had missed, decreased or stopped using opioids in order to make it easier to have a bowel movement.
The survey findings confirm that OBD occurs frequently, despite the use of laxatives, in individuals taking daily oral opioids for chronic pain. These gastrointestinal symptoms add to the burden already experienced by chronic pain patients, negatively impacting quality of life and, in some cases, affecting opioid treatment itself.
Although functional gastrointestinal symptoms are seen frequently by internists and are the commonest reason for patients to be referred to gastroenterologists, no validated self-report questionnaire is available for their diagnosis. To differentiate among non-ulcer dyspepsia, the irritable bowel syndrome, organic gastrointestinal disease, and health, we developed a self-report questionnaire. Our bowel disease questionnaire, which evaluated 46 symptom-related items was completed prospectively by 361 subjects before their clinical evaluation as outpatients. Of these subjects, 115 were categorized ultimately as having functional bowel disease (non-ulcer dyspepsia or the irritable bowel syndrome), 101 were categorized ultimately as having organic gastrointestinal disease, and 145 were healthy persons having routine periodic examinations for whom no additional diagnoses were made. All diagnoses were based on independent clinical evaluations, not on the patients' responses to the questionnaire. The bowel disease questionnaire was acceptable and easily completed; it elicited symptoms in a highly reliable manner and was shown to be a valid measure of functional bowel complaints. Our questionnaire discriminated non-ulcer dyspepsia from irritable bowel syndrome with a sensitivity of 75% and a specificity of 72%, and it discriminated functional bowel disease from organic disease and health with sensitivities of 85% and 83%, and specificities of 60% and 76%, respectively. We believe that this questionnaire is an additional and useful diagnostic tool for identifying patients with functional gastrointestinal symptoms.
We describe the cases of five patients having a syndrome of chronic abdominal pain, vomiting, weight loss, and features of intestinal pseudo-obstruction associated with prolonged use or abuse of narcotic analgesics. In each patient, abdominal complaints were originally attributed to either mechanical bowel obstruction or an underlying gastrointestinal disorder often involving prior abdominal surgery. Symptoms resolved rapidly in all patients when narcotic administration was stopped. Clonidine therapy was used to alleviate symptoms of narcotic analgesic withdrawal. The narcotic bowel syndrome is a clinically important and frequently unrecognized cause of chronic abdominal pain.
Patients with chronic abdominal pain without an organic basis present a difficult management problem. Some of these patients may be prescribed opiates initially which may result in requiring progressively higher doses for pain relief. In this clinical setting, the suspicion of narcotic bowel syndrome should be borne in mind. With appropriate treatment and counselling, further invasive investigations including laparotomy may be avoided and resolution of symptoms can be achieved with clonidine. This case report demonstrates such a typical clinical scenario and discusses the possible aetiology and pathophysiology of narcotic bowel syndrome as well as the role of clonidine in controlling opiate withdrawal symptoms.
Chronic gastrointestinal (GI) symptoms are believed to be common in the general population, but Australian data are lacking. A valid instrument is required to assess GI symptoms adequately and determine their prevalence in the community.
To test the feasibility, reliability and concurrent validity of a self-report Bowel Symptom Questionnaire (BSQ) as a measure of GI symptoms, and obtain preliminary data on the prevalence of symptoms in an Australian population-based sample.
Outpatients (n = 63), volunteers (n = 163) and a random sample (n = 99) of the Penrith population, Sydney, completed the BSQ. Feasibility was evaluated in 264 subjects. Reliability was measured by a test-retest procedure (n = 43), while concurrent validity was documented by comparing self-report data with an independent interview (n = 20). The response rate in the population mail survey was 68%. Prevalence data on bowel symptoms in the community sample (n = 99) were age and gender standardised to the Australian population.
The majority of subjects found the BSQ easy to complete (97%) and understand (97%); 90% completed the questionnaire in half an hour or less. Reliability (median kappa 0.70, interquartile range 0.20) and concurrent validity (median kappa 0.79, interquartile range 0.26) of GI symptoms were both very acceptable. The internal consistency of all GI symptom scales was good (Cronbach's Alpha range 0.51-0.74). The prevalence of the irritable bowel syndrome (defined as abdominal pain and disturbed defaecation based on two or more of the Manning criteria) was 17.2% (95% CI: 10-25%).
The BSQ was well accepted and easy to understand; it provided reliable and valid data on GI symptoms and should prove useful in large scale epidemiological studies in Australia.
The use of opioid analgesics for chronic non-cancer pain is controversial. Some surveys report good pain relief and improvement in performance while others suggest a poor outcome with a propensity to psychological dependence or addiction.
We undertook a randomised double-blind crossover study to test the hypothesis that oral morphine relieves pain and improves the quality of life in patients with chronic regional pain of soft tissue or musculoskeletal origin who have not responded to codeine, anti-inflammatory agents, and antidepressants. Morphine was administered as a sustained-release preparation in doses up to 60 mg twice daily and compared with benztropine (active placebo) in doses up to 1 mg twice daily over three-week titration, six-week evaluation, and two-week washout phases. Pain intensity, pain relief, and drug liking were rated weekly and psychological features, functional status, and cognition were assessed at baseline and at the end of each evaluation phase.
After dose titration in the 46 patients who completed the study, the mean daily doses of drugs were morphine 83.5 mg and benztropine 1.7 mg. On visual analogue scales, the morphine group showed a reduction in pain intensity relative to placebo in period I (p = 0.01) and this group also fared better in a crossover analysis of the sum of pain intensity differences from baseline (p = 0.02). No other significant differences were detected.
In patients with treatment-resistant chronic regional pain of soft-tissue or musculoskeletal origin, nine weeks of oral morphine in doses up to 120 mg daily may confer analgesic benefit with a low risk of addiction but is unlikely to yield psychological or functional improvement.
Gastroesophageal reflux is considered a common condition, but detailed population-based data on reflux in the United States are lacking. The aim of this study was to determine the prevalence and clinical spectrum of gastroesophageal reflux in Olmsted County, Minnesota.
A reliable and valid self-report questionnaire was mailed to an age- and sex-stratified random sample of 2200 Olmsted County residents aged 25-74 years.
The prevalence per 100 of heartburn and/or acid regurgitation experienced at least weekly was 19.8 (95% confidence interval [95% CI], 17.7-21.9). Heartburn and acid regurgitation were associated with noncardiac chest pain (odds ratio [OR], 4.2; 95% CI, 2.9-6.0), dysphagia (OR, 4.7; 95% CI, 2.9-7.4), dyspepsia (OR, 3.1; 95% CI, 1.9-5.0), and globus sensation (OR, 1.9; 95% CI, 1.0-3.6) but not with asthma, hoarseness, bronchitis, or a history of pneumonia. Among subjects with reflux symptoms, 1.0% reported an episode of hematemesis and 1.3% had a past esophageal dilatation.
Symptoms of reflux are common among white men and women who are 25-74 years of age. Heartburn and acid regurgitation are significantly associated with chest pain, dysphagia, dyspepsia, and globus sensation. The percentage of patients reporting complications is low, but the absolute number is probably considerable given the high prevalence of the condition in the community.
Opioids are the major class of analgesics used in the management of moderate to severe cancer pain, and constipation is a common side effect of opioid administration. While monitoring for quality-assurance, nurses found that 95% of patients interviewed on a 28-bed oncology unit of a Midwestern hospital reported constipation as the major side effect of their opioid regimen for pain control. Through the efforts of a nursing research utilization committee, a protocol to prevent opioid-induced constipation in patients with cancer was developed and implemented.
Opioid bowel dysfunction (OBD) is a common adverse effect associated with opioid therapy. OBD is commonly described as constipation; however, it is a constellation of adverse gastrointestinal (GI) effects, which also includes abdominal cramping, bloating, and gastroesophageal reflux. The mechanism for these effects is mediated primarily by stimulation of opioid receptors in the GI tract. In patients with pain, uncontrolled symptoms of OBD can add to their discomfort and may serve as a barrier to effective pain management, limiting therapy, or prompting discontinuation. Patients with cancer may have disease-related constipation, which is usually worsened by opioid therapy. However, OBD is not limited to cancer patients. A recent survey of patients taking opioid therapy for pain of noncancer origin found that approximately 40% of patients experienced constipation related to opioid therapy (<3 complete bowel movements per week) compared with 7.6% in a control group. Of subjects who required laxative therapy, only 46% of opioid-treated patients (control subjects, 84%) reported achieving the desired treatment results >50% of the time. Laxatives prescribed prophylactically and throughout opioid therapy may improve bowel movements in many patients. Nevertheless, a substantial number of patients will not obtain adequate relief of OBD because of its refractory nature. Naloxone and other tertiary opioid receptor antagonists effectively reduce the symptoms of constipation in opioid-treated patients. However, because they also act centrally, they may provoke opioid withdrawal symptoms or reverse analgesia in some patients. There are 2 peripherally selective opioid receptor antagonists, methylnaltrexone and ADL 8-2698 (Adolor Corporation, Exton, PA, USA), that are currently under investigation for their use in treating OBD. Early studies confirm that they are effective at normalizing bowel function in opioid-treated patients without entering the central nervous system and affecting analgesia. With a better understanding of the prevalence of OBD and its pathophysiology, a more aggressive approach to preventing and treating OBD is possible and will likely improve the quality of life of patients with pain.
Efficacy, long-term effectiveness and safety of opioids in chronic non-tumor associated pain syndromes (NTAS) are still under debate. The study (MONTAS) was performed by physicians and psychologists as a multicenter prospective, randomized, double-blind placebo-controlled crossover trial, followed by an open long-term study. Patients were enrolled only when pain relief from specific defined pretreatment was insufficient. Patients were randomly assigned to group I receiving sustained-release morphine (doses: 20mg/d titrated appropriately to a maximum of 180mg/d) in the first week, placebo in the second week or group II receiving study medication in reverse order. The primary endpoint was defined as: (i) adequate pain relief (pain intensity of less than 50% of pretreatment intensity or less than 5 on a 11 point Numerical Rating Scale) and (ii) pain rated as tolerable and (iii) adverse effects rated as tolerable. Full responders (all criteria fulfilled under morphine) and partial responders (less pain relief, but tolerable side effects) were offered continuation of treatment with oral morphine in an open long-term study (LAMONTAS), to be published later. Forty-nine patients of 997 patients screened fulfilled the inclusion criteria for MONTAS and were enrolled. Mean pain intensity in all patients was reduced by morphine from 7.8 to 5.2 (NNT: 2.2); in 17 (35.4%) responders from 7.4 to 2.9, in 17 (35.4%) partial responders from 7.8 to 5.6 and in 14 (29.2%) non-responders from 8.2 to 7.7. Pain reduction correlated with improvement of physical function. Pain disability, depression score, mood and exercise endurance improved, particularly in responders. Gastrointestinal complaints increased, central nervous system-related complaints were reduced. Efficacy and safety of morphine in NTAS were demonstrated in this randomized-controlled trial. Pretreatment failure was the indication for trying morphine treatment; predictive factors for responsiveness could not be identified.
Opioid treatment for postoperative or chronic pain is frequently associated with adverse effects, the most common being dose-limiting and debilitating bowel dysfunction. Postoperative ileus, although attributable to surgical procedures, is often exacerbated by opioid use during and following surgery. Postoperative ileus is marked by increased inhibitory neural input, heightened inflammatory responses, decreased propulsive movements and increased fluid absorption in the gastrointestinal tract. The use of opioids for chronic pain is characterised by a constellation of symptoms including hard dry stools, straining, incomplete evacuation, bloating, abdominal distension and increased gastroesophageal reflux. The current management of opioid-induced bowel dysfunction among patients receiving opioid analgesics consists primarily of nonspecific ameliorative measures. Intensive investigations into the mode of action of opioids have characterised three opioid receptor classes -mu, delta and kappa- that mediate the myriad of peripheral and central actions of opioids. Activation of mu-opioid receptors in the gastrointestinal tract is responsible for inhibition of gut motility, whereas receptors in the central nervous system mediate the analgesic actions of opioids. Blocking peripheral opioid receptors in the gut is therefore a logical therapeutic target for managing opioid-induced bowel dysfunction. Available opioid antagonists such as naloxone are of limited use because they are readily absorbed, cross the blood-brain barrier, and act at central opioid receptors to reverse analgesia and elicit opioid withdrawal. Methylnaltrexone and alvimopan are recently developed opioid antagonists with activity that is restricted to peripheral receptors. Both have recently shown the ability to reverse opioid-induced bowel dysfunction without reversing analgesia or precipitating central nervous system withdrawal signs in non-surgical patients receiving opioids for chronic pain. In addition, recent clinical studies with alvimopan suggest that it may normalise bowel function without blocking opioid analgesia in abdominal laparotomy patients with opioid-related postoperative ileus.
Physicians and other healthcare professionals may often be faced with the need to change opioids during the course of a patient's opioid analgesic care due to a number of clinical reasons. The act of converting opioid analgesics, for many physicians, nurses, and pharmacists, who do not receive adequate training, remains a challenging and often uncomfortable aspect of pain treatment. Part of the challenge clinicians face is secondary to the relatively weak literature evidence base that exists to support the equianalgesic ratios provided in textbooks, journals, and other medical resources. Another aspect involves the lack of a widely recognized treatment algorithm or guideline to assist clinicians with opioid conversion. The final decision on which opioid dose to prescribe must involve a thorough clinical assessment to minimize the risk of prescribing inappropriate opioid doses over or under the patient's actual need. The purpose of this paper is to provide the clinician with an approach for dealing with the conversion between opioid analgesics that is standardized, yet allows for individualized results to meet unique patient needs. We present a 5-step process as a guide for clinicians faced with the need to change a patient's opioid regimen. This approach may help to build a comfort level when dealing with the clinical challenges of converting from one opioid to another.
To meet the growing demand for objective outcomes measurement during treatment of chronic pain, we developed an instrument to track outcomes of individual patients.
In a 2-phase study, existing and novel outcomes instruments were applied in an interdisciplinary pain management program. In the initial phase, 408 patients were administered the Short Form 36-item questionnaire and during phase 2, 437 patients (87 of whom were followed) were given an expanded (191-item) questionnaire.
When applied to individual patients, the Short Form 26-item questionnaire lacked measurement reliability for assessment of treatment outcomes and sensitivity to upper extremity or facial pathology, and failed to separate limitations of work versus everyday activity. A novel group of scales derived from responses to 61 questions, including the Short Form 36-item questionnaire, proved sufficiently reliable for routine follow-up of individual chronic pain patients.
This new Treatment Outcomes in Pain Survey allows assessment of individual patient outcomes, and aggregate or individual clinician performance, during interdisciplinary treatment of chronic pain.
Dispositions for genes encoding opioid receptors may explain some variability in morphine efficacy. Experimental studies show that morphine and morphine-6-glucuronide are less effective in individuals carrying variant alleles caused by the 118 A > G polymorphism in the mu-opioid receptor gene (OPRM1). The purpose of the study was to investigate whether this and other genetic polymorphisms in OPRM1 influence the efficacy of morphine in cancer pain patients.
We screened 207 cancer pain patients on oral morphine treatment for four frequent OPRM1 gene polymorphisms. The polymorphisms were the -172 G > T polymorphism in the 5'untranslated region of exon 1, the 118 A > G polymorphism in exon 1, and the IVS2 + 31 G > A and IVS2 + 691 G > C polymorphisms, both in intron 2. Ninety-nine patients with adequately controlled pain were included in an analysis comparing morphine doses and serum concentrations of morphine and morphine metabolites in the different genotypes for the OPRM1 polymorphisms. Results: No differences related to the -172 G > T, the IVS2 + 31 G > A and the IVS2 + 691 G > C polymorphisms were observed. Patients homozygous for the variant G allele of the 118 A > G polymorphism (n = 4) needed more morphine to achieve pain control, compared to heterozygous (n = 17) and homozygous wild-type (n = 78) individuals. This difference was not explained by other factors such as duration of morphine treatment, performance status, time since diagnosis, time until death, or adverse symptoms.
Patients homozygous for the 118 G allele of the mu-opioid receptor need higher morphine doses to achieve pain control. Thus, genetic variation at the gene encoding the mu-opioid receptor contributes to variability in patients' responses to morphine.
The effectiveness of physical activity in the management of constipation remains controversial. We examined the associations among physical activity, constipation, and quality of life (QoL) in a population of employed adults to determine whether the risk of constipation is related to physical activity.
A total of 1,069 employees (age range 24-77) of the Veterans Affairs (VA) Black Hills Health Care System were mailed validated questionnaires (response rate 72%), inquiring about bowel habits, QoL (SF 36), and physical activity (modified Baecke questionnaire). Constipation was defined using the Rome I criteria.
One hundred and forty (19.4%, 95% CI 16.2-22.4) employees reported constipation. The average total physical activity and all subscales of physical activity were not significantly different in subjects with and without constipation (all p > or = 0.2). Subjects with constipation had lower QoL scores than subjects without constipation, and physical activity was positively correlated with physical functioning and health perception.
Physical activity appears to be unrelated to the risk of constipation in employed adults, but higher physical activity was associated with improved QoL. Recommendations to increase physical activity may not alter symptoms of constipation but may improve overall well-being.
Patients with irritable bowel syndrome (IBS) report lower health-related quality of life (QoL) as compared to healthy controls. The aims of this analysis were to describe which IBS symptoms were rated on a daily diary as most distressing/severe by IBS women, and determine which IBS symptoms were most predictive of lower QoL and have the greatest impact on daily life.
This report is a secondary analysis of prospective and retrospective symptom severity and impact data, collected on 242 women with IBS, aged 18-48, who were studied between 1997 and 2004.
On the daily diary, intestinal gas was the most frequent IBS symptom with subjects reporting at least minimal intestinal gas on 74% of days and moderate or worse severity on 27% of days. Abdominal pain occurred at least minimally on 62% of days. Diarrhea was the least common. Across women, abdominal pain was most strongly related to life impact variables and QoL, followed by intestinal gas and bloating. Analysis of day-to-day variation within women showed that abdominal pain was most strongly correlated with daily life impact variables and constipation had the weakest correlation. While diarrhea had a lower correlation with life impact, this was due to the low prevalence of diarrhea. When it occurs, diarrhea has a large impact. Partial correlation analysis showed that the impact of diarrhea is independent of abdominal pain.
Abdominal pain is the most disruptive IBS symptom. Diarrhea also has an independent and significant impact when it occurs, especially in those with diarrhea-predominant IBS.
As a result of the undesired action of opioids on the gastrointestinal (GI) tract, patients receiving opioid medication for chronic pain often experience opioid-induced bowel dysfunction (OBD), the most common and debilitating symptom of which is constipation. Based on clinical experience and a comprehensive MEDLINE literature review, this paper provides the primary care physician with an overview of the prevalence, pathophysiology and burden of OBD. Patients with OBD suffer from a wide range of symptoms including constipation, decreased gastric emptying, abdominal cramping, spasm, bloating, delayed GI transit and the formation of hard dry stools. OBD can have a serious negative impact on quality of life (QoL) and the daily activities that patients feel able to perform. To relieve constipation associated with OBD, patients often use laxatives chronically (associated with risks) or alter/abandon their opioid medication, potentially sacrificing analgesia. Physicians should have greater appreciation of the prevalence, symptoms and burden of OBD. In light of the serious negative impact OBD can have on QoL, physicians should encourage dialogue with patients to facilitate optimal symptomatic management of the condition. There is a pressing need for new therapies that act upon the underlying mechanisms of OBD.
Narcotic bowel syndrome (NBS) is a subset of opioid bowel dysfunction that is characterized by chronic or frequently recurring abdominal pain that worsens with continued or escalating dosages of narcotics. This syndrome is underrecognized and may be becoming more prevalent. In the United States this may be the result of increases in using narcotics for chronic nonmalignant painful disorders, and the development of maladaptive therapeutic interactions around its use. NBS can occur in patients with no prior gastrointestinal disorder who receive high dosages of narcotics after surgery or acute painful problems, and among patients with functional gastrointestinal disorders or other chronic gastrointestinal diseases who are managed by physicians who are unaware of the hyperalgesic effects of chronic opioids. The evidence for the enhanced pain perception is based on the following: (1) activation of excitatory antianalgesic pathways within a bimodal opioid regulation system, (2) descending facilitation of pain at the rostral ventral medulla and pain facilitation via dynorphin and cholecystokinin activation, and (3) glial cell activation that produces morphine tolerance and enhances opioid-induced pain. Treatment involves early recognition of the syndrome, an effective physician-patient relationship, graded withdrawal of the narcotic according to a specified withdrawal program, and the institution of medications to reduce withdrawal effects.
BACKGROUND Bloating is common, but its significance as a marker of underlying disease has not been defined. AND AIMS: We report on risk factors for bloating, its relationship to physical activity and quality of life (QOL), and its predictive value for functional bowel disorders.
This is a cross-sectional population-based study of 1,069 employees of the Veterans Affairs Black Hills Health Care System. The validated Bowel Disease Questionnaire was used to identify subjects with abdominal bloating and other bowel disorders. The association of bloating with QOL was assessed using the SF36 (Short-Form 36) questionnaire. Physical activity was assessed using the modified Baecke questionnaire.
The response rate was 72% (723 of 1,069). Bloating was reported by 21% of all subjects (95% confidence interval [CI] 17.7-23.7), 64% with irritable bowel syndrome (IBS), 35% with non-IBS constipation, 23% with non-IBS diarrhea, and 42% with dyspepsia. Functional bloating (i.e., bloating in the absence of other bowel disorders) was reported by 7% of subjects (95% CI 5.2-9.0). Of those with bloating, 28% had IBS, 25% non-IBS constipation, 8% non-IBS diarrhea, and 30% dyspepsia. The positive and negative predictive values of bloating in the diagnosis of functional bowel disorder were 66% and 87%, respectively. The only risk factors were smoking and high-dose aspirin. Bloating was not associated with physical activity. QOL on all subscales of SF36 was lower in subjects with bloating than those without bloating.
Bloating is a common symptom in otherwise healthy adults, and is often associated with but not predictive of functional bowel disorders. Smoking and high-dose aspirin are associated with bloating while physical activity is not.
Opioids are widely prescribed for non-cancer pain conditions (NCPC), but there have been no large observational studies in actual clinical practice assessing patterns of opioid use over extended periods of time. The TROUP (Trends and Risks of Opioid Use for Pain) study reports on trends in opioid therapy for NCPC in two disparate populations, one national and commercially insured population (HealthCore plan data) and one state-based and publicly-insured (Arkansas Medicaid) population over a six year period (2000-2005). We track enrollees with the four most common NCPC conditions: arthritis/joint pain, back pain, neck pain, headaches, as well as HIV/AIDS. Rates of NCPC diagnosis and opioid use increased linearly during this period in both groups, with the Medicaid group starting at higher rates and the HealthCore group increasing more rapidly. The proportion of enrollees receiving NCPC diagnoses increased (HealthCore 33%, Medicaid 9%), as did the proportion of enrollees with NCPC diagnoses who received opioids (HealthCore 58%, Medicaid 29%). Cumulative yearly opioid dose (in mg. morphine equivalents) received by NCPC patients treated with opioids increased (HealthCore 38%, Medicaid 37%) due to increases in number of days supplied rather than dose per day supplied. Use of short-acting Drug Enforcement Administration Schedule II opioids increased most rapidly, both in proportion of NCPC patients treated (HealthCore 54%, Medicaid 38%) and in cumulative yearly dose (HealthCore 95%, Medicaid 191%). These trends have occurred without any significant change in the underlying population prevalence of NCPC or new evidence of the efficacy of long-term opioid therapy and thus likely represent a broad-based shift in opioid treatment philosophy.
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