Adverse Events of the Long-Term Use of Opioids for Chronic Non-cancer Pain: A Narrative Review.

BACKGROUND: The long-term use of opioids for chronic non-cancer pain (CNCP) has drawn more attention and debate. Although opioids are frequently used to treat chronic pain, their effectiveness and safety over extended periods are still unknown. OBJECTIVES: The purpose of this review is to provide an overview of what is currently known about the adverse events of long-term use of opioids in CNCP. It also delivers patient-centered strategies designed to mitigate these risks. METHODS: We conducted a literature search in PubMed, MEDLINE, EMBASE, and Web of Science databases. Search terms included CNCP, pain pathophysiology, opioid pharmacodynamics, opioid prescribing trends, guidelines for opioid use, and opioid side effects.  Results: Our review highlights that while opioids may provide short-term relief from CNCP, their effectiveness diminishes over time due to the development of opioid tolerance. This tolerance often leads to increased dosages, which can subsequently result in opioid dependence. Additionally, long-term opioid therapy is associated with a spectrum of adverse effects, including constipation, drowsiness, respiratory depression, and potential for drug interactions. Furthermore, our review indicates that alternative pain management strategies play a crucial role in controlling CNCP. They offer significant benefits with fewer adverse events. These strategies include non-opioid medications, physical therapy, cognitive-behavioral therapy (CBT), various interventional procedures, injection therapy, and acupuncture. CONCLUSION: Using opioids to manage CNCP presents several challenges. Given these challenges, alternative treatments are being considered as viable options. Moreover, it is crucial to customize treatment plans to align with the patients' specific health requirements, existing conditions, and potential risks to ensure the best possible outcomes.

Navigating opioid use in chronic noncancer pain conditions: A case series on pseudoaddiction.

Opioid prescriptions for chronic non-cancer pain raise concerns of addiction risks. Understanding the nuanced intersection of chronic pain and opioid use is crucial in clinical settings. We present four case studies from two tertiary care hospitals illustrating the phenomenon of "pseudoaddiction" in CNCP referred to addiction specialists for management. Each case involves complex pain presentations like pancreatitis, avascular necrosis, and SLE intertwined with escalating opioid demands. Management involved psychoeducation, CBT, and opioid substitution, resulting in reduced pain and need for opioids. Differentiating between addiction and uncontrolled pain is crucial for tailored management, emphasizing individualized care for improved outcomes.

A novel observation: effect of anionic gelatin nanoparticle on stromal cells.

Biocompatible nanoparticles are very popular in health science research. Biomolecule carriers for wound healing and tissue engineering are two main applications among many others. In many instances, these structures come in direct vicinity of cells and govern cell behaviour and responses. In this study, gelatin nano/submicron structures were synthesized by binary nonsolvent aided coacervation (BNAC) method at pH ranging from 3 to 11 with an intention to employ in skin tissue regeneration. Effect of pH over morphology and the surface composition with respect to its ionic composition were studied. Further, the initial toxicity was assessed against peripheral blood mononuclear cells (PBMC). pH 7 was found to be the optimum for synthesis of gelatin nanoparticles (GNPs) with minimum particle size. Positive cell viability of 103.14% for GNPs synthesized at pH 7 was observed. It may be due to the minimum difference between cumulative negative and positive charge (CNCP) ratio of 1.19. Finally, effect of the gelatin nanoparticles over L929 mouse fibroblast cells was assessed through MTT assay. It has resulted in 122.77% cell viability.

Update on the role of naldemedine in opioid-induced constipation in patients with chronic noncancer pain.

Chronic noncancer pain (CNCP) affects up to 20% of adults and can interfere with activities of daily living. Up to 4% of adults in the United States receive chronic opioid therapy and up to 57% of patients on long-term opioids for CNCP report opioid-induced constipation (OIC). OIC is essentially constipation occurring after starting opioid treatment. While laxatives are traditionally the first-line therapy for OIC, 81% of patients taking daily laxatives and opioids still reported OIC and considered that it negatively affected their quality of life. Naldemedine is a peripherally acting µ-opioid receptor antagonists (PAMORA) approved for the treatment of OIC in patients with CNCP. This article reviews the mechanism of action, efficacy, and safety of naldemedine in CNCP patients. Naldemedine improves OIC in patients with CNCP by acting as an opioid receptor antagonist in the gastrointestinal tract. It does not interfere with the analgesic properties of opioids or cause withdrawal symptoms since these effects are centrally mediated, and naldemedine does not cross the blood brain barrier. Naldemedine showed significant and sustained improvement in frequency of bowel movements, quality of life, and constipation-related symptoms. It is generally well tolerated with a higher incidence of gastrointestinal adverse events of mild or moderate severity such as diarrhea, abdominal pain, or vomiting compared to placebo. While there are no randomized, controlled trials that compare head-to-head pharmacological therapies used for treatment of OIC, network meta-analysis shows that naldemedine has an overall good benefit-risk profile compared to the other approved medications.

The impact of an easy access drug supply management policy law on the consumption and abuse of opioids in Catalonia: A population-based study.

BACKGROUND: Over the last two decades, the rise in opioid prescription has worsened health outcomes worldwide, increasing both levels of abuse and mortality rates. In order to reduce the scale of this public health problem, new policies have been implemented in many countries. In 2012, Spain adopted new legislation on opioid prescription (the ROE law), which meant that practitioners no longer needed to obtain extra authorisation in order to prescribe strong opioids. The objective of the paper is to assess the impact of this law on opioid use and abuse in Catalonia, Spain. METHODS: We established two measures of the use of strong and weak opioids: DDDs, and abuse. We used benzodiazepines and antidepressants as controls, and adjusted for age, sex, drug co-payment level, death or near death, cancer diagnosis, morbidity group, and type of prescription. The data were obtained from administrative and dispensing drug databases in a population of 7.5 million inhabitants. We estimated two-way fixed effects using difference in difference models. RESULTS: The ROE law impacted reducing the monthly use of strong opioids by 0.903 DDDs, representing a 3.15% decrease in the mean monthly use of strong opioids. However, abuse rose 1.86 times compared with the average pre-ROE value, which represents an increase of 11,190 months of opioid abuse (i.e., an 11.33% of all monthly opioids use). CONCLUSION: The abolition of the duplicate prescription programme for strong opioids led to a reduction in the average monthly use of strong opioids, but an increase in abuse.

Dropout associated with osteopathic manual treatment for chronic noncancerous pain in randomized controlled trials.

CONTEXT: Reviews exploring harm outcomes such as adverse effects (AE), all cause dropouts (ACD), dropouts due to inefficacy, and dropouts due to AE associated with osteopathic manipulative treatment (OMT) or osteopathic manual therapy (OMTh) are scant. OBJECTIVES: To explore the overall AE, ACD, dropouts due to inefficacy, and AE in chronic noncancerous pain (CNCP) patients receiving OMTh through a systematic review of previous literature. METHODS: For this systematic review and meta-analysis, the authors searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Physiotherapy Evidence Database (PEDro), EMCare, and Allied and Complementary Medicine Database (AMED), and Ostmed.Dr, as well as the bibliographical references of previous systematic reviews evaluating OMTh for pain severity, disability, quality of life, and return to work outcomes. Randomized controlled trials with CNCP patients 18 years or older with OMTh as an active or combination intervention and the presence of a control or combination group were eligible for inclusion. In this sub-study of a previous, larger systematic review, 11 studies (n=1,015) reported data that allowed the authors to perform meta-analyses on ACD and dropouts due to AE. The risk of bias (ROB) was assessed with the Cochrane ROB tool and the quality of evidence was determined with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: The pooled analysis showed that ACD was not significantly different for visceral OMTh (vOMTh) vs. OMTh control (odds ratio [OR]=2.66 [95% confidence interval [[CI]], 0.28, 24.93]) or for OMTh vs. standard care (OR=1.26 [95% CI, 0.84, 1.89]; I2=0%). Single study analysis showed that OMTh results were nonsignificant in comparison with chemonucleolysis, gabapentin, and exercise. OMTh in combination with gabapentin (vs. gabapentin alone) and OMTh in combination with exercise (vs. exercise alone) showed nonsignificant ACD. Dropouts due to AE were not significantly different, but the results could not be pooled due to an insufficient number of studies. CONCLUSIONS: Most articles did not explicitly report AEs, ACD rates, or dropouts due to AEs and inefficacy. The limited data available on dropouts showed that OMTh was well tolerated compared with control interventions, and that the ACD and dropouts due to AEs were not significantly different than comparators. Future trials should focus on explicit reporting of dropouts along with beneficial outcomes to provide a better understanding of OMTh efficacy.

Patient Engagement Survey Regarding Future Double-Blinded, Randomized Controlled Trial of Tapering of Chronic Opioid Therapy.

Objective: There is a lack of evidence regarding tapering opioid medications in patients with chronic non-cancer pain. The purpose of this survey was to gather perspectives on future research into opioid tapering from utilizers of chronic opioid therapy (COT) or other people affected by chronic noncancer pain. Methods: The survey was distributed in paper form to patients on COT and via an online platform to patients self-enrolled in the chronic pain patient engagement group. The survey included a layman's description of a possible tapering trial of opioid medications and elicited binary responses regarding willingness to participate and reasoning as well as qualitative freeform responses. Thematic analysis was performed to identify themes in narrative responses. Results: A total of 190 surveys were returned with 72.1% of all respondents answering positively regarding their willingness to participate in a proposed study. The most common reasons for participating in the study included concerns regarding opioid dependence, adding to society's knowledge of opioid medications, and determining if the respondent would personally receive benefit from opioid medications. Patients recently on COT felt it was important to be able to withdraw from the study and return to usual care at any time (41.8% for recent COT and 15.5% for no recent COT, P < .05). The most common reason for unwillingness to participate was that respondents did not feel they had enough information to feel comfortable participating. The narrative responses showed a group of respondents felt COT was the only answer to their or their loved ones' chronic pain and that a study would demonstrate the need to continue these medications long-term. There were also stories of side effects and dependence with decreasing effectiveness of opioids for pain control. When prompted to comment on study design, respondents indicated the study should include alternative pain management options. This was accompanied by responses with the assumption that pain will worsen as opioid medications are decreased. Conclusion: Patient concerns regarding opioid medications and discontinuation reflect the lack of evidence available to prescribers. There appears to be patient support for future research into the effects of tapering opioid medications.

Consideraciones para el uso de tramadol en dolor crónico no oncológico en atención primaria de salud (APS)

Introducción: tramadol es un analgésico opioide usado frecuentemente para el manejo del dolor crónico no oncológico (DCNO). En Chile, es parte del arsenal farmacológico de los centros de atención primaria para el tratamiento de patologías como artrosis de cadera y rodilla. Es considerado seguro y efectivo, sin embargo, existen reportes de efectos adversos serios por polimorfismos hepáticos, interacciones farmacológicas, intoxicaciones, adicción y muerte. La dosis óptima de tramadol es paciente dependiente. Por esto, es necesario contar con orientaciones específicas para prescribir tramadol de manera segura y eficaz según las características de cada paciente. Materiales y métodos: se revisaron guías actualizadas, revisiones sistemáticas y guías de sociedades internacionales sobre el uso de opioides en DCNO y el uso de tramadol en patologías de DCNO como artrosis, lumbago crónico, dolor neuropático y fibromialgia. Resultados: tramadol no está indicado en el tratamiento de cuadros de dolor primario como fibromialgia y en DCNO secundario es un fármaco de segunda línea o no está recomendado. En dolor crónico neuropático (DCN) es segunda línea de tratamiento. En osteoartritis de cadera, rodilla y mano, se reporta efecto analgésico modesto. Sopesar riesgos versus beneficios en estos pacientes. En artritis reumatoide y lumbago crónico se desaconseja su uso. Conclusiones: tramadol es un medicamento seguro y efectivo si se indica, administra, supervisa y descontinúa adecuadamente. Sin embargo, puede asociarse a interacciones farmacológicas, efectos secundarios serios, conductas de abuso y usos ilícitos, por lo que es necesario conocer y manejar adecuadamente su farmacología e indicaciones.

Introduction: Tramadol is an opioid pain medicine commonly used for chronic non-cancer pain (CNCP) management. In Chile, it is part of the pharmacological arsenal available in primary care centers for treating specific CNCP pathologies, such as hip and knee arthrosis. Tramadol is considered a safe and effective drug. Nevertheless, there are reports of serious adverse effects of tramadol, such as poisoning, addiction, and death, probably caused by liver polymorphisms and drug interaction. The optimal dose of tramadol is patient-specific. Specific knowledge is needed to prescribe tramadol in a safe and effective way according to the patient's medical backward. Methods: We review updated guidelines, systematic reviews, and guidelines from international societies about the use of opioids and tramadol in CNCP pathologies such as osteoarthritis, chronic low back pain, neuropathic pain, and fibromyalgia. Results: Tramadol has no role in primary pain treatment, such as fibromyalgia, but is a second-line drug for chronic neuropathic pain (CNP) and some secondary pain syndromes. Tramadol has a modest analgesic effect in osteoarthritis patients. Clinicians should always weigh the risks and benefits before prescribing tramadol. Tramadol use is discouraged in rheumatoid arthritis and chronic lumbago. Conclusions: Tramadol is a safe and effective drug if correctly indicated, administered, supervised, and discontinued. However, it may be associated with pharmacological interactions, serious side effects, abuse behaviors, and illicit uses, and it is necessary that clinicians know and manage its pharmacology and indications appropriately.

Study of antidiabetic activity of two novel Schiff base derived dibromo and dichloro substituted compounds in streptozotocin-nicotinamide-induced diabetic rats: pilot study

Abstract Schiff bases are aldehyde-or ketone-like chemical compounds in which an imine or azomethine group replaces the carbonyl group. Such compounds show various beneficial biological activities, such as anti-inflammation and antioxidants. The present study addresses comprehensiveevaluation of antidiabetic effect of two novel dibromides and dichlorides substituted Schiff bases substituted Schiff bases (2,2'-[1,2-cyclohexanediylbis (nitriloethylidyne)]bis[4-chlorophenol] (CNCP) and 2, 2'-[1,2-cyclohexanediylbis(nitriloethylidyne)]bis[4-bromophenol] (CNBP) with two different doses, high (LD) and low (LD) in streptozotocin and nicotinamide induced diabetic rats. The rats were separated into normal, untreated, treated and reference groups. Except for the normal group, diabetes traits were induced in the rest animals. Insulin level was measured, and the effect of the compounds on biochemical parameters of liver function and lipid profile were evaluated. High glucose and decreased insulin level are observed in the groups. The histological evaluation confirms that the hepatic architecture in the treated animals with a low dose of CNCP is quite similar to that of the normal hepatic structure and characterized by normal central vein, hepatocytes without any fatty alterations and mild red blood cell infiltration. CNCP (LD) and CNBP (HD) are more successful in enhancing cell survival in the diabetic rat's liver and can be responsible for causing much healthier structure and notable morphology improvement.

A Model for Improving Adherence to Prescribing Guidelines for Chronic Opioid Therapy in Rural Primary Care.

OBJECTIVE: To describe the steps taken and results obtained by a rural primary care practice to effectively implement opioid prescribing guidelines. PATIENTS AND METHODS: Between December 1, 2014, and May 30, 2017, a quality improvement project was undertaken. Elements included prescribing registries, a nurse coordinator, and an Opioid Use Review Panel. Clinic workflow was redesigned to more consistently incorporate these and other guideline recommendations into practice. The effect on opioid prescribing was measured as well as patient outcomes. RESULTS: There were 462 patients meeting inclusion criteria before implementation. At the conclusion, 16 patients (3%) had died, 9 patients (2%) were no longer seeing clinicians participating in the project, and 2 patients (0.4%) had transitioned to hospice or long-term care facilities. Of the remaining 435 patients, 96 (22.1%; 95% CI, 18.4-26.2) had decreased prescribing below the threshold for inclusion or were no longer receiving opioid prescriptions. Originally, 64 patients (13.9%; 95% CI, 11.0-17.3) were using average daily doses equal to or greater than 90 morphine milligram equivalents. After implementation, 54 of 435 patients (12.4%; 95% CI, 9.6-15.8) were still using equal to or greater than 90 morphine milligram equivalents per day after accounting for death or loss to follow-up. CONCLUSION: A change in clinic process to implement guidelines for prescribing of chronic opioid therapy was completed. It was associated with a decrease in the number of patients using chronic opioid therapy, primarily at lower doses. This was accomplished in a rural practice with very limited resources in pain medicine, psychiatry, and addiction medicine.