Search Results (34)

Opioid-induced constipation (OIC) represents a prevalent adverse effect of opioid analgesics, affecting 60–90% of patients and significantly compromising quality of life. This review delineates the multifactorial pathogenesis of OIC. Peripheral μ-opioid receptor (MOR) activation suppresses enteric neuronal excitability, inhibits intestinal motility and secretion, and impairs rectoanal function. Notably, the colon appears to exhibit a distinctive lack of tolerance to opioids. Enteric glial cell activation has been implicated in neuroinflammation, while interstitial cells of Cajal show impaired pacemaker function. Central mechanisms are increasingly recognized to involve the brain–gut axis. Furthermore, opioid-induced barrier disruption, microbiota dysbiosis, and LPS/TLR4-mediated inflammation are proposed to interact and may contribute to a self-reinforcing cycle. Animal models have been instrumental in dissecting these mechanisms. However, they present limitations in reproducibility, clinical phenotype fidelity, and translational validity, particularly regarding microbiome composition and neuroimmune responses. Future research should prioritize the development of standardized, physiologically relevant animal models incorporating multi-omics approaches, and validate mechanism-based therapeutic strategies, including peripherally acting MOR antagonists and microbiota-targeted interventions, for precision management of OIC. Full article

Background/Objectives: Opioid-induced constipation (OIC) is a frequent adverse effect of opioid therapy. In contrast to other opioid-related side effects, OIC usually does not improve over time and significantly impairs the quality of life of affected patients. Despite its high prevalence, OIC remains underdiagnosed and undertreated in clinical practice, which has been demonstrated in several European countries. Healthcare data indicates that approximately 2.3 million people in Germany received potentially OIC-inducing opioids in 2023, the majority being patients with chronic non-cancer pain. Methods: An interdisciplinary board of experts in gastroenterology, pain medicine, neurology, oncology, and palliative care developed consensus-based recommendations to improve the diagnosis and management of OIC. Fifteen statements were drafted according to current national German and international guidelines and literature and subsequently discussed. Out of the fifteen statements, twelve statements remained, which achieved consensus with at least 90% agreement. Results: The consensus statements address key aspects of OIC management, including pathophysiology, patient education, diagnosis, prevention, treatment and structured follow-up. Following the statements, a practical treatment algorithm was developed to facilitate clinical implementation. Use of validated tools such as the Bowel Function Index (BFI) for diagnosis and monitoring, early initiation of laxative therapy and timely escalation to mechanism-oriented therapy with peripherally acting μ-opioid receptor antagonists (PAMORAs) in cases of inadequate response have been recommended by the panel. Accordingly, treatment should follow an approach with the following steps: (1) Laxative, (2) switch to PAMORA, (3) rotation of PAMORA, and (4) combination of PAMORA with laxative. In Europe, the PAMORAs methylnaltrexone, naloxegol and naldemedine are approved for the treatment of OIC. Conclusions: This consensus paper provides both evidence-based and practice-oriented recommendations for the systematic management of OIC. By promoting patient education, early recognition, structured evaluation and stepwise treatment escalation, the presented statements and algorithm aim to improve patient outcomes and quality of life under opioid therapy including better adherence to opioid therapy. Full article

Background: Mu opioid receptors (MORs) in peripheral tissues mediate adverse effects of opioids that impair health-related quality of life (HRQoL) and may stimulate cancer progression via mitogenic signaling. Naloxegol, a peripherally acting MOR antagonist (PAMORA), is approved for opioid-induced constipation. Safety and efficacy of naloxegol have not been evaluated concurrently with systemic cancer therapy. Methods: We conducted a randomized, double-blind, placebo-controlled trial of naloxegol in patients with advanced lung adenocarcinoma starting first-line systemic therapy. Results: Only 50 patients were enrolled; the trial was terminated early due to slow accrual. Two of the three components of the feasibility primary endpoint were not met (accrual and PRO completion). At 6 months, FACT-L emotional well-being was better with naloxegol (p = 0.0113). There were trends towards better Trial Outcome Index (p = 0.0505) and physical well-being (p = 0.0628) with naloxegol. Bowel function favored naloxegol for constipation (p = 0.0223), rectal pain during defecation (p = 0.0075), and abdominal pain from constipation (p = 0.0113). Adverse event frequency and severity, PRO-CTCAE, urinary hesitancy, pain scores, and progression-free and overall survival were comparable between naloxegol and placebo. Conclusions: Naloxegol appears to be safe and tolerable, with a signal of improved HRQoL and previously unappreciated benefit for emotional well-being, without adverse clinical outcomes. Our findings should be confirmed in larger studies. ClinicalTrials.gov ID: NCT03087708. Full article

Cervicofacial actinomycosis is a well-recognized infectious disease caused by Actinomyces, a Gram-positive filamentous bacterium. In contrast, Nocardia, a morphologically similar, hyphae-forming organism, is an exceedingly rare cause of cervicofacial abscesses, and even more uncommon associated osteomyelitis of mandible. We present such a case involving a kidney transplant recipient who presented with opioid-induced constipation, along with left jaw pain and swelling. CT scan of the soft tissue in the neck revealed a complex cervicofacial abscess with enhancement of underlying mandible. Culture growth and RNA sequencing of USG-guided aspirate identified a Nocardia species closely related to N. beijingensis/exalbida. The patient initially received broad-spectrum antibiotics, including ceftriaxone, imipenem, and trimethoprim-sulfamethoxazole (TMP-SMX). Imipenem was later discontinued in view of new-onset unexplained encephalopathy and replaced with linezolid, which was subsequently switched to minocycline following thrombocytopenia development. Minocycline therapy was intended for a total of 12 months. TMP-SMX was avoided long-term due to avoid nephrotoxicity risk in kidney transplant patients. On six-month follow-up, the patient showed clinical and radiological improvement; minocycline was discontinued after additional six months. This case highlights the importance of considering Nocardia as a differential diagnosis in immunosuppressed patients presenting with cervicofacial symptoms, especially following orofacial surgery or trauma. Early recognition, prompt diagnosis, and appropriate antibiotic therapy with adequate bone penetration seem crucial for optimal management and may help avoid the need for surgical intervention. Full article

Magnesium (Mg²⁺) has gained oncologists’ attention due to its wide range of biological functions and frequent use as a complementary or integrative agent. This review outlines Mg’s actions, its complex role in carcinogenesis and tumor risk, and clinical issues. Mg²⁺ is essential in numerous biochemical processes, including adenosine triphosphate production, cellular signal transduction, DNA, RNA and protein synthesis, and bone formation. Pertinent full-text articles were thoroughly examined, and the most relevant ones were selected for inclusion in this review. There is conflicting scientific evidence about the relationship between Mg²⁺ changes and cancer risk, apart from colorectal cancer. Chronic Mg²⁺ deficiency leads to immune dysfunctions and enhanced baseline inflammation associated with oxidative stress related to various age-associated morbidities and cancer. On the other hand, Mg²⁺ deficiency is associated with drug or chemotherapy-related hypomagnesemia, postoperative pain, cachexia, opioid-induced constipation, normal tissue protection from radiation damage, and prevention of nephrotoxicity. A balanced diet usually provides sufficient Mg²⁺, but supplementation may be necessary in some clinical settings. Full article

Endogenous opioids, such as Endomorphin-2, are not typically associated with severe constipation, unlike pharmaceutical opioids, which induce opioid-induced constipation (OIC) by activating μ-opioid receptors in the gastrointestinal tract. In this study, we present a mathematical model, which integrates the serotonergic and opioid pathways, simulating the interaction between serotonin and opioid signaling within the enteric nervous system (ENS). The model explores the mechanisms underlying OIC, with a focus on the change in adenylyl cyclase (AC) activity, cAMP accumulation, and the distinct functionalities of Endomorphin-2 compared to commonly used pharmaceutical opioids. We study the effects of Morphine, Fentanyl, and Methadone and contrast them with Endomorphin-2. Our findings reveal that opioids do not perturb the signaling of serotonin, but only the activity of AC, suggesting that serotonin levels have no influence on improving opioid-induced constipation. Furthermore, this study reveals that the primary difference between endogenous and pharmaceutical opioids is their degradation rates. This finding shows that modulating opioid degradation rates significantly improves cAMP recovery. In conclusion, our insights steer towards exploring opioid degrading enzymes, localized to the gut, as a strategy for mitigating OIC. Full article

Naldemedine, a peripherally acting μ-opioid receptor antagonist, is used to treat opioid-induced constipation (OIC). However, it causes diarrhea as an adverse effect. This retrospective study aimed to investigate whether the occurrence of diarrhea was dependent on the timing of naldemedine treatment initiation. Inpatients who were initially treated with naldemedine at the Department of Respiratory Medicine, NHO Iwakuni Medical Center, Japan, between 1 December 2017 and 31 March 2021 were included in this study and divided into the simultaneous combination group, in which naldemedine was introduced at the same time as strong opioid analgesics, and the non-simultaneous combination group, in which naldemedine was introduced after the initiation of treatment with strong opioid analgesics. This study included 45 patients, 15 (33.3%) of whom developed diarrhea. Among the patients in the simultaneous combination group and non-simultaneous combination group, diarrhea occurred in 2 (11.1%) and 13 (48.1%) patients, respectively. Multivariate logistic regression analysis revealed that the delayed introduction of naldemedine was significantly associated with the development of diarrhea (odds ratio: 6.68, 95% confidence interval: 1.220–36.700, p = 0.028). Our analysis reveals that the simultaneous administration of naldemedine and oxycodone may prevent the development of diarrhea associated with naldemedine use for OIC. Full article

Objective: The aim of the NALOPOOL project was to assess the efficacy and safety of naloxegol in patients with cancer pain who exhibited opioid-induced constipation (OIC) and were treated under real-world conditions. Methods: We pooled individual patient data from three multicenter observational studies conducted with naloxegol in patients with cancer who exhibited OIC and were prescribed naloxegol under real-world conditions. Efficacy outcomes were evaluated after 4 weeks of treatment. All analyses were performed via a visit-wise approach. Heterogeneity was assessed via Cochran’s Q-test or Levene’s test. Results: Spontaneous bowel movements (SBM) response (≥3 SBM per week and an increase of ≥1 from baseline; three studies) was reported in 223 of 314 evaluable patients (71%, 95% CI 66–76); clinically relevant improvement in the Patient Assessment of Constipation Quality-of-Life Questionnaire (>0.5 points; three studies) occurred in 179 of 299 evaluable patients (60%, 95% CI 56–74) and in the Patient Assessment of Constipation Symptoms (>0.5 points; two studies) was reported in 131 of 190 evaluable patients (69%, 95% CI 62–76); and clinically relevant improvement in the Bowel Function Index (score ≥ 12 points at the endpoint; two studies;) was reported in 133 of 195 evaluable patients (68%, 95% CI 62–75). No significant heterogeneity was found for any efficacy outcome. The pooled proportion of patients who discontinued the drug owing to adverse reactions was 6.1% (95% CI 3.8% to 8.4%). Conclusions: Our results support the use of naloxegol for the management of OIC in patients with cancer pain who do not respond to laxative treatment. Full article

Background: Chronic constipation is a well-recognized complication which is caused by hard and/or infrequent defecation. According to estimates, constipation presents as a chronic illness affecting 16% of adults globally, who deal with insufficient bowel movements that cause discomfort, bloating, or a sensation of incomplete bowel. Objectives: This review looks at the many local and systemic factors that contribute to the pathogenesis of the causative, including dietary habits, genetic factors, colon function and absorption, social and economic factors, lifestyle, and biological and drug factors. Results: Appropriate diagnostic and management modalities are the cornerstone in the management of patients with chronic constipation. However, there are still controversies regarding the timing of these diagnostic and management approaches. This condition is common and reduces the quality of life of patients and represents a burden on any healthcare system. In clinical practice, it remains problematic, as physicians are most of the time indecisive on which therapy to administer and at what time. Conclusions: Constipation management is a new topic that was introduced over a decade ago and the purpose of this study is to shed some light onto the practice, problems and modern day techniques that can be used to treat constipation in patients, primarily through behavioural, conservative, medical, and surgical means. Additionally, this particular management is to be used in conjunction with an algorithm designed to enhance and support clinical practice. Full article

Opioid-induced constipation (OIC) is a very common and troublesome gastrointestinal side effect following the use of opioids. Despite existing international guidelines, OIC is largely underdiagnosed and undertreated. ECHO OIC is a European project designed to improve the diagnosis and management of OIC at the primary care level. The next phase of the ECHO OIC project is to review and adapt the proposed European pathway at national level, considering the local patient journey and clinical practice. A multidisciplinary group of 12 Italian experts reviewed and discussed the European path and formulated a seven-step guide for the practical management of OIC that is also easily applicable in primary care: 1. When prescribing long-term opioids, the physician should inform the patient of the possibility of the onset of OIC; 2. At opioid prescription, doctors should also prescribe a treatment for constipation, preferably macrogol or stimulant laxatives; 3. The patient should be evaluated for OIC within the second week of initiating opioid treatment, by clinical history and Rome IV criteria; 4. In the presence of constipation despite laxatives, prescription of a PAMORA (Peripherally Acting Mu Opioid Receptor Antagonist) should be considered; 5. When prescribing a PAMORA, prescribing information should be carefully reviewed, and patients should be accurately instructed for appropriate use; 6. Efficacy and tolerability of the PAMORA should be monitored regularly by Bowel Function Index, considering a cut-off of 30 for the possible step-up of OIC treatment; 7. After 4 weeks of treatment, if the efficacy of PAMORA is deemed inadequate, discontinuation of the PAMORA, addition of an anti-constipation drugs, change of opioid type, or referral to a specialist should be considered. Spreading knowledge about the OIC problem as much as possible to the health community is crucial to obtain not only an early treatment of the condition but also to promote its prevention. Full article

Background: Kratom is a substance that alters one’s mental state and is used for pain relief, mood enhancement, and opioid withdrawal, despite potential health risks. In this study, we aim to analyze the social media discourse about kratom to provide more insights about kratom’s benefits and adverse effects. Also, we aim to demonstrate how algorithmic machine learning approaches, qualitative methods, and data visualization techniques can complement each other to discern diverse reactions to kratom’s effects, thereby complementing traditional quantitative and qualitative methods. Methods: Social media data were analyzed using the latent Dirichlet allocation (LDA) algorithm, PyLDAVis, and t-distributed stochastic neighbor embedding (t-SNE) technique to identify kratom’s benefits and adverse effects. Results: The analysis showed that kratom aids in addiction recovery and managing opiate withdrawal, alleviates anxiety, depression, and chronic pain, enhances mood, energy, and overall mental well-being, and improves quality of life. Conversely, it may induce nausea, upset stomach, and constipation, elevate heart risks, affect respiratory function, and threaten liver health. Additional reported side effects include brain damage, weight loss, seizures, dry mouth, itchiness, and impacts on sexual function. Conclusion: This combined approach underscores its effectiveness in providing a comprehensive understanding of diverse reactions to kratom, complementing traditional research methodologies used to study kratom. Full article

Opioids are commonly used for the management of severe chronic cancer pain. Their well-known pharmacological effects on the gastrointestinal system, particularly opioid-induced constipation (OIC), are the most common limiting factors in the optimization of analgesia, and have led to the wide use of laxatives and/or peripherally acting mu-opioid receptor antagonists (PAMORAs). A growing interest has been recently recorded in the possible effects of opioid treatment on the gut microbiota. Preclinical and clinical data, as presented in this review, showed that alterations of the gut microbiota play a role in modulating opioid-mediated analgesia and tolerability, including constipation. Moreover, due to the bidirectional crosstalk between gut bacteria and the central nervous system, gut dysbiosis may be crucial in modulating opioid reward and addictive behavior. The microbiota may also modulate pain regulation and tolerance, by activating microglial cells and inducing the release of inflammatory cytokines and chemokines, which sustain neuroinflammation. In the subset of cancer patients, the clinical meaning of opioid-induced gut dysbiosis, particularly its possible interference with the efficacy of chemotherapy and immunotherapy, is still unclear. Gut dysbiosis could be a new target for treatment in cancer patients. Restoring the physiological amount of specific gut bacteria may represent a promising therapeutic option for managing gastrointestinal symptoms and optimizing analgesia for cancer patients using opioids. Full article

In the palliative care population, prescription opioids are often considered viable pain relief options. However, in this complex patient population, the adverse effects of opioid medications should be identified and managed without delay. Common adverse effects can include constipation, nausea, somnolence, dizziness, vomiting, and pruritus. Less common adverse effects can include potentially lethal respiratory depression and cardiovascular effects. Critical aspects of safe opioid prescribing are recognition of side effects and knowledge of effective management strategies; prompt management is necessary for uninterrupted pain relief. Most complications are managed with general approaches such as dose reduction, opioid rotation, alternate routes of administration, and symptomatic management. The only opioid-induced complication for which US Food and Drug Administration-approved treatments currently exist is constipation. Treating laxative-refractory opioid-induced constipation (OIC) with peripherally acting mu-opioid receptor antagonists (PAMORAs), which block gastrointestinal opioid receptors, can restore gastrointestinal motility and fluid secretion. This narrative review discusses key complications of prescription opioid treatment and their management in the palliative care setting. Full article

Severe cancer pain substantially affects patients’ quality of life, increasing the burden of the disease and reducing the disability-adjusted life years. Although opioid analgesics are effective, they may induce opioid-induced bowel dysfunction (OIBD). Oxycodone/naloxone combination therapy has emerged as a promising approach to mitigate opioid-induced constipation (OIC) while providing effective pain relief. This review provides an updated analysis of the literature of the last decade regarding the use of oxycodone/naloxone in the management of severe cancer pain. Through a comprehensive search of databases, studies focusing on the efficacy, safety, and patient experience of oxycodone/naloxone’s prolonged release in severe cancer pain management were identified. Furthermore, the literature discusses the mechanism of action of naloxone in mitigating OIC without compromising opioid analgesia. Overall, the evidence suggests that oxycodone/naloxone combination therapy offers a valuable option for effectively managing severe cancer pain while minimizing opioid-induced constipation, thereby improving patients’ quality of life. However, further research is needed to optimize dosing regimens, evaluate long-term safety, and assess patient outcomes in diverse cancer populations. Full article

Background: Opioid-induced constipation (OIC) is a pervasive and distressing side effect of chronic opioid therapy in patients with cancer pain, significantly impacting their quality of life. Peripherally acting μ-opioid receptor antagonists (PAMORAS) were developed for treatment-resistant OIC but most studies were conducted with non-cancer patients. Objective: to discuss two oral formulations of PAMORAs, naldemedine and naloxegol, and to review available evidence of the effectiveness of these drugs for OIC in cancer patients. Methods: a comprehensive search to identify primary literature for either naldemedine or naloxegol for OIC in cancer patients. Results: Only three prospective randomized, double-blind, placebo-controlled clinical trials for naldemedine enrolling cancer patients were identified; the results of a subgroup analysis of two of those studies and two non-interventional post marketing surveillance studies of these trials are also reported here. For naloxegol, only two randomized controlled trials were identified; both were unsuccessful in enrolling sufficient patients. An additional four prospective non-interventional observational studies with naloxegol were found that enrolled cancer patients. There were significantly higher rates of responders in the PAMORA groups than in the placebo groups. The most common side effect for both PAMORAs was diarrhea. Limitations: All studies were industry-funded, and given that only three trials were randomized controlled studies, the overall quality of the studies was lacking. Conclusion: Naldemedine or naloxegol appeared safe and useful in the treatment of OIC in cancer patients and may improve their quality of life. Larger-scale randomized placebo-controlled studies of PAMORAs in cancer patients would strengthen existing evidence. Full article