Do NSAIDs affect bone healing rate, delay union, or cause non-union: an updated systematic review and meta-analysis.

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) may potentially delay or cause non-union of fractures by inhibiting prostaglandin synthesis. However, studies have shown conflicting results. This systematic review and meta-analysis aim to synthesize current evidence on the potential influence of NSAIDs on bone healing. Methods: We conducted a comprehensive search of PubMed, Embase, and Cochrane CENTRAL databases for studies published up to 25 July 2023. Specific keywords included "NSAID," "nonsteroidal anti-inflammatory drug," "cyclooxygenase-2 inhibitor," "bone healing," "non-union," "pseudoarthrosis," "delayed union," and "atrophic bone." Eligible studies included prospective, retrospective, and case-controlled studies assessing the correlation between NSAID use and bone healing outcomes. The leave-one-out approach was used to test the robustness of the meta-analysis results. Results: A total of 20 studies with 523,240 patients were included in the analysis. The mean patient age ranged from 6.7 to 77.0 years, with follow-up durations from 3 to 67 months. The meta-analysis revealed no significant difference in non-union or delayed union between NSAID users and non-users [pooled adjusted odds ratio (OR) = 1.11; 95% confidence interval (CI): 0.99-1.23]. Initial analysis identified a significant association between NSAID usage and an increased risk of reoperation, but this association became insignificant upon sensitivity analysis (crude OR = 1.42; 95% CI: 0.88-2.28). Discussion: NSAIDs may have a minimal impact on non-union or delayed union risks. However, caution is advised due to the limited number of studies and the absence of a specific focus on NSAID types and dosages. Further research is necessary to better understand the implications of NSAID use on bone healing.

Radiofrequency Ablation (RFA) for Osteoid Osteoma in an 11-Year-Old Male Child With Sickle Cell Trait: A Case Report.

Osteoid osteoma is a benign bone tumor that typically presents with nocturnal pain alleviated by nonsteroidal anti-inflammatory medications. The coexistence of osteoid osteoma with sickle cell anemia, a hereditary hemoglobinopathy characterized by vaso-occlusive crises and bone infarcts, poses diagnostic and therapeutic challenges due to overlapping clinical and radiological features. This condition primarily involves the long bones of the lower extremities, particularly the femur and tibia. Despite its benign nature, osteoid osteoma can significantly impact a patient's quality of life due to persistent and intense pain, often leading to substantial sleep disturbances and functional limitations.

A Case of Ketorolac-Induced Aseptic Meningitis.

Drug-induced aseptic meningitis is a rare condition that occurs because of an adverse reaction to medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics. Unlike bacterial or viral meningitis, aseptic meningitis is not caused by an infection, but rather by an inflammatory response. This condition creates a challenge since patients with aseptic meningitis often present with classic clinical meningeal symptoms, including fever, headache, and neck stiffness. We present a case of a patient with NSAID-induced aseptic meningitis and highlight the importance for healthcare providers to have a high index of suspicion for drug-induced aseptic meningitis in patients presenting with symptoms of meningitis with negative cerebrospinal fluid analysis and culture.

Effect of pulsed radiofrequency to the suprascapular nerve (SSN) in treating frozen shoulder pain: A randomised controlled trial.

BACKGROUND: Treatment for frozen shoulder (FS) focuses on pain control and restoring movement and strength through physical therapy. We aimed to evaluate the efficacy of pulsed radiofrequency (PRF) lesioning of the suprascapular nerve for the treatment of FS pain. METHODS: Forty patients with FS were enrolled and randomly assigned into the intervention group (n = 20) that received PRF and a control group (n = 20) which received medical treatment (NSAIDs). Patients were followed-up for a total of three months. The primary outcome was the pain intensity, measured by the Numeric Pain Rating Scale (NRS). The secondary outcomes included shoulder range of motion (ROM) evaluation measured by simple shoulder test (SST); Likert-type-based patient satisfaction scale; and any adverse events (AEs) throughout the treatment period. All results were measured at baseline, at the end of one week, four weeks and 12 weeks after treatment. RESULTS: At 12 weeks post-procedure, the intervention group significantly improved their pain (NRS dropped to 2.80 ± 0.5) and there was significant improvement in range of motion (SST from 6.55% ± 2.0% to 76.50% ± 6.5) compared to control group. CONCLUSIONS: PRF lesioning of the SSN is a fast and effective modality in treating frozen shoulder pain and improving ROM for three months.

Non-steroidal anti-inflammatory drugs, renin-angiotensin system blockade or diuretics and risk of acute kidney injury: A case-crossover study.

BACKGROUND: Aging-related physiological changes, such as decline in renal function, not only exacerbates pre-existing comorbidities but also escalate the susceptibility to adverse events. Previous studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI), and the concomitant use of renin-angiotensin system blockade or diuretics may further potentiate the risk. However, studies evaluating the risk of AKI associated with NSAIDs (including routes, concomitant use of different NSAIDs, categories (traditional NSAIDs or COX-2 inhibitors), and cumulative doses of NSAIDs) are limited, particularly the risk of AKI associated with the dual or triple combination of NSAIDs with renin-angiotensin system blockade (RAS blockades) and/or diuretics. METHODS: A case-crossover study utilized two sets of longitudinal data from Taiwan's National Health Insurance Research Database (NHIRD). Newly admitted patients with a primary AKI diagnosis were included, with the index date defined as the first admission date. The 1-7 days and 181-187 days prior to the index date served as the case and control periods. Exposure to NSAIDs and co-exposures of RAS blockade and/or diuretics were assessed in both periods. Multivariable conditional logistic regression models, adjusting for potential confounders, estimated adjusted odds ratios (aORs) and 95 % confidence intervals (CIs) for AKI associated with NSAIDs, dual, or triple combinations. Sensitivity analyses explored result robustness by varying case and control period lengths. RESULTS: The study included 1,284 newly diagnosed AKI patients. NSAIDs showed a 3.55-fold increased risk of AKI (aOR: 3.55; 95 % CI 2.70-4.65), with similar risks for traditional NSAIDs and COX-2 inhibitors. Use of multiple NSAIDs, parenteral dosage forms, and higher cumulative doses increased AKI risk. Dual combination with either RAS blockade or diuretics resulted in a 2.90-fold (aOR: 2.90; 95 %CI 1.47-5.70) and 12.68-fold (aOR: 12.68; 95 %CI 6.15-26.12) risk, respectively. The highest risk occurred with triple combination (aOR: 29.22; 95 %CI 12.82-66.64). CONCLUSIONS: NSAIDs, including both non-selective NSAIDs and COX2 inhibitors, elevate the risk of AKI. Increased AKI risk is linked to using multiple NSAIDs, the parenteral dosage form, and higher cumulative doses. Dual combination of RAS blockade with NSAIDs or diuretics with NSAIDs, as well as triple therapy, heightens the risk, with the latter associated with the highest risk of AKI.

Subacute Thyroiditis Masquerading as Fever of Unknown Origin.

Subacute thyroiditis (SAT) is an inflammatory disease of the thyroid gland. It can present with overlapping features of other etiology of thyroiditis. It can present with thyroid enlargement and systemic symptoms such as fever as well as neck pain and may be confused with infectious thyroiditis. It can be difficult to diagnose and present as fever of unknown origin (FUO). A good history, physical examination, laboratory investigation, as well as imaging may aid in the correct diagnosis and prevent the inappropriate use of antibiotics. Treatment is usually with nonsteroidal anti-inflammatory drugs (NSAIDs) as well as corticosteroids. We herein present a case of SAT presenting as FUO. We highlighted the importance of proper clinical evaluation, the importance of thyroid imaging, and how to differentiate other forms of thyroiditis.

Challenges in Drug and Hymenoptera Venom Hypersensitivity Diagnosis and Management in Mastocytosis.

Mastocytosis is a myeloproliferative neoplasm characterized by abnormal proliferation and activation of clonal mast cells typically bearing the KITD816V mutation. Symptoms manifest due to the release of bioactive mediators and the tissue infiltration by neoplastic mast cells. Mast cell activation symptoms include flushing, pruritus, urticaria, abdominal cramping, diarrhea, wheezing, neuropsychiatric symptoms, and anaphylaxis. Up to 50% of patients with mastocytosis report a history of provoked and unprovoked anaphylaxis, with Hymenoptera venom and drugs the most common culprits. NSAIDs, antibiotics, vaccines, perioperative medications, and radiocontrast media are often empirically avoided without evidence of reactions, depriving patients of needed medications and placing them at risk for unfavorable outcomes. The purpose of this review is to highlight the most common agents responsible for adverse drug reactions in patients with mastocytosis, with a review of current epidemiology, diagnosis, and management of drug hypersensitivity and Hymenoptera venom allergy.

Nonsteroidal Anti-inflammatory Medications in Cranial Neurosurgery: Balancing Opioid-Sparing Analgesia with Bleeding Risk.

Postcraniotomy pain is a common problem frequently encountered by neurosurgeons. This is typically managed with opioids; however, opioids have been shown to increase intracranial pressure by way of hypercapnia and straining from the associated constipation. Additionally, opioids can confound and mask the neurologic examination of postcraniotomy patients, as well as be the nidus for a potential opioid addiction. Thus, alternative solutions for opioids have been a major topic of investigation within the neurosurgical community. Nonsteroidal anti-inflammatory drugs (NSAIDs) present as a potential solution due to their nonaddictive and analgesic properties, but utilization of NSAIDs in neurosurgical patients has been controversial given that NSAIDs alter platelet function. The degree to which NSAIDs alter platelet function and bleeding time to a clinically relevant manner has remained controversial, although several well-designed studies concluded that the utilization of NSAIDs in post-craniotomy patients does not increase the risk of postoperative bleeding. Herein, we review the pharmacology, efficacy, and safety of NSAIDs with a particular emphasis on NSAID use for postintracranial neurosurgical procedure pain management.

Opioid analgesics for nociceptive cancer pain: A comprehensive review.

Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the authors evaluated the efficacy and toxicities of opioid analgesics compared with placebo, other opioids, nonopioid analgesics, and nonpharmacologic treatments for background cancer pain (continuous and relatively constant pain present at rest), and breakthrough cancer pain (transient exacerbation of pain despite stable and adequately controlled background pain). They found a paucity of placebo-controlled trials for background cancer pain, although tapentadol or codeine may be more efficacious than placebo (moderate-certainty to low-certainty evidence). Nonsteroidal anti-inflammatory drugs including aspirin, piroxicam, diclofenac, ketorolac, and the antidepressant medicine imipramine, may be at least as efficacious as opioids for moderate-to-severe background cancer pain. For breakthrough cancer pain, oral transmucosal, buccal, sublingual, or intranasal fentanyl preparations were identified as more efficacious than placebo but were more commonly associated with toxicities, including constipation and nausea. Despite being recommended worldwide for the treatment of cancer pain, morphine was generally not superior to other opioids, nor did it have a more favorable toxicity profile. The interpretation of study results, however, was complicated by the heterogeneity in the study populations evaluated. Given the limited quality and quantity of research, there is a need to reappraise the clinical utility of opioids in people with cancer pain, particularly those who are not at the end of life, and to further explore the effects of opioids on immune system function and quality of life in these individuals.

Editorial: Optimizing opioid prescriptions in the emergency department.

Optimizing opioid prescriptions in the emergency department is essential to address the opioid pandemic while ensuring patient wellbeing. This requires a comprehensive approach that includes exploring alternatives to opioids for pain management, identifying individuals at risk for opioid addiction, implementing evidence-based guidelines, and involving doctors in the management of opioid addiction.

Different Patterns of Response in Hypersensitivity Reactions to Arylpropionic Acid Derivatives.

BACKGROUND: Ibuprofen and other arylpropionic acid derivatives (APs) are among the most consumed nonsteroidal anti-inflammatory drugs worldwide at all age ranges; however, little is known about drug hypersensitivity reactions (DHRs) they induce. OBJECTIVE: To characterize in detail patients reporting DHRs to APs. METHODS: We prospectively evaluated patients with symptoms suggestive of AP-DHRs and analyzed their clinical characteristics, reported reactions, and diagnostic approaches. RESULTS: Six hundred sixty-two patients confirmed as hypersensitive to APs were included: 489 with cross-reactive reactions (CRs) (73.86%) and 173 with selective reactions (SRs) (26.13%). The percentage of subjects reporting reactions to ibuprofen and dexketoprofen was higher in CRs (P = .005 and P = .01, respectively), whereas naproxen and ketoprofen were more frequently involved in SRs (P = .0002 and P = .00001, respectively). The most frequent symptoms induced by ibuprofen, dexketoprofen, and naproxen were isolated angioedema and urticaria, combined or not with angioedema in both CRs and SRs. The result of nasal provocation test with lysine acetylsalicylate was positive in 156 cases (77.14% in patients showing exclusively respiratory symptoms, and in 68.18% of those with both cutaneous and respiratory involvement). To confirm diagnosis, drug provocation test with acetylsalicylic acid was required in 246 CR patients (50.3%), whereas in 28 SR patients (16.18%) drug provocation test with the culprit AP was required. CONCLUSIONS: Skin is the organ most commonly involved in AP-DHRs, with ibuprofen and dexketoprofen inducing most frequently CRs, and naproxen and ketoprofen SRs. More studies are necessary to clarify the underlying mechanism in DHRs induced by APs.

Ketoprofen as an emerging contaminant: occurrence, ecotoxicity and (bio)removal.

Ketoprofen, a bicyclic non-steroidal anti-inflammatory drug commonly used in human and veterinary medicine, has recently been cited as an environmental contaminant that raises concerns for ecological well-being. It poses a growing threat due to its racemic mixture, enantiomers, and transformation products, which have ecotoxicological effects on various organisms, including invertebrates, vertebrates, plants, and microorganisms. Furthermore, ketoprofen is bioaccumulated and biomagnified throughout the food chain, threatening the ecosystem function. Surprisingly, despite these concerns, ketoprofen is not currently considered a priority substance. While targeted eco-pharmacovigilance for ketoprofen has been proposed, data on ketoprofen as a pharmaceutical contaminant are limited and incomplete. This review aims to provide a comprehensive summary of the most recent findings (from 2017 to March 2023) regarding the global distribution of ketoprofen in the environment, its ecotoxicity towards aquatic animals and plants, and available removal methods. Special emphasis is placed on understanding how ketoprofen affects microorganisms that play a pivotal role in Earth's ecosystems. The review broadly covers various approaches to ketoprofen biodegradation, including whole-cell fungal and bacterial systems as well as enzyme biocatalysts. Additionally, it explores the potential of adsorption by algae and phytoremediation for removing ketoprofen. This review will be of interest to a wide range of readers, including ecologists, microbiologists, policymakers, and those concerned about pharmaceutical pollution.

Novel Molecular Consortia of Cannabidiol with Nonsteroidal Anti-Inflammatory Drugs Inhibit Emerging Coronaviruses' Entry.

The COVID-19 pandemic provoked a global health crisis and highlighted the need for new therapeutic strategies. In this study, we explore the potential of the molecular consortia of cannabidiol (CBD) and non-steroidal anti-inflammatory drugs (NSAIDs) as novel antiviral dual-target agents against SARS-CoV-2/COVID-19. CBD is a natural compound with a wide range of therapeutic activities, including antiviral and anti-inflammatory properties, while NSAIDs are commonly used to mitigate the symptoms of viral infections. Chemical modifications of CBD with NSAIDs were performed to obtain dual-target agents with enhanced activity against SARS-CoV-2. The synthesised compounds were characterised using spectroscopic techniques. The biological activity of three molecular consortia (CBD-ibuprofen, CBD-ketoprofen, and CBD-naproxen) was evaluated in cell lines transduced with vesicular stomatitis virus-based pseudotypes bearing the SARS-CoV-1 or SARS-CoV-2 spike proteins or infected with influenza virus A/Puerto Rico/8/34. The results showed that some CBD-NSAID molecular consortia have superior antiviral activity against SARS-CoV-1 and SARS-CoV-2, but not against the influenza A virus. This may suggest a potential therapeutic role for these compounds in the treatment of emerging coronavirus infections. Further studies are needed to investigate the efficacy of these compounds in vivo, and their potential use in clinical settings. Our findings provide a promising new approach to combatting current and future viral emergencies.

Assessment of Platelet Function by Automated Light Transmission Aggregometry.

Light transmission aggregometry (LTA) has long been the historical "gold standard" of platelet function testing and is typically performed in specialized hemostasis laboratories due to its manual and labor intensive process. However, newer automated testing provides a means of standardization and ability to perform the testing in routine laboratories. Here we describe the measurement of platelet aggregation in the CS-Series™ (Sysmex Corporation, Kobe, Japan) and CN-Series™ (Sysmex Corporation, Kobe, Japan) routine blood coagulation analyzers. Differences in the methods for both analyzers are further described. For the CS-5100™ analyzer, the final diluted concentrations of the agonists are prepared by manual pipetting from reconstituted agonist solutions. These prepared dilutions are eight times concentrated with respect to the final working concentration of the agonists and appropriately diluted within the analyzer to achieve the desired concentration of agonists prior to testing. For the CN-6000™ analyzer, the dilutions of agonists and the final working concentrations are automatically prepared by the auto-dilution feature in the analyzer.

Modulating disease phenotype in a songbird: A role for inflammation in disease tolerance?

Individual animals vary greatly in their responses to infection, either killing off the invading pathogen (resistance) or minimizing the per-pathogen costs of infection on host fitness (tolerance). Though we understand little about the physiological drivers of tolerance in wild animals, phenotypically, it manifests as milder clinical signs of disease. Here, we use a well-described disease system, finch mycoplasmosis, to evaluate the role of inflammation in disease tolerance. House finches (Haemorhous mexicanus) infected with the bacterial pathogen Mycoplasma gallisepticum (MG) develop conjunctival pathology that satisfies the cardinal signs of inflammation. We report on a captive trial performed in 2016 and replicated in 2018 that tested whether chemotherapeutics, specifically nonsteroidal anti-inflammatory drugs (NSAIDs), can reduce lesion severity, thus pushing individuals toward more tolerant phenotypes. Though birds treated with NSAIDs in the first trial developed milder pathology per unit pathogen load, we found no effect of treatment in the second trial, perhaps due to natural variation in baseline tolerance within the source population across years. Second-trial control birds developed markedly milder pathology than first-year controls, suggesting that the effect of trial swamped the effect of treatment in this study. Moving forward, using birds from a population in which the disease is absent or only recently emerged-and so tolerance has not yet been selected for-may better elucidate the role of pro-inflammatory mediators in disease tolerance.

Interactions between NSAIDs, opioids and the gut microbiota - Future perspectives in the management of inflammation and pain.

The composition of intestinal microbiota is influenced by a number of factors, including medications, which may have a substantial impact on host physiology. Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics are among those widely used medications that have been shown to alter microbiota composition in both animals and humans. Although much effort has been devoted to identify microbiota signatures associated with these medications, much less is known about the underlying mechanisms. Mucosal inflammation, changes in intestinal motility, luminal pH and bile acid metabolism, or direct drug-induced inhibitory effect on bacterial growth are all potential contributors to NSAID- and opioid-induced dysbiosis, however, only a few studies have addressed directly these issues. In addition, there is a notable overlap between the microbiota signatures of these drugs and certain diseases in which they are used, such as spondyloarthritis (SpA), rheumatoid arthritis (RA) and neuropathic pain associated with type 2 diabetes (T2D). The aims of the present review are threefold. First, we aim to provide a comprehensive up-to-date summary on the bacterial alterations caused by NSAIDs and opioids. Second, we critically review the available data on the possible underlying mechanisms of dysbiosis. Third, we review the current knowledge on gut dysbiosis associated with SpA, RA and neuropathic pain in T2D, and highlight the similarities between them and those caused by NSAIDs and opioids. We posit that drug-induced dysbiosis may contribute to the persistence of these diseases, and may potentially limit the therapeutic effect of these medications by long-term use. In this context, we will review the available literature data on the effect of probiotic supplementation and fecal microbiota transplantation on the therapeutic efficacy of NSAIDs and opioids in these diseases.

Angiotensin-Converting Enzyme Inhibitors and Other Medications Associated With Angioedema.

Angioedema is a localized swelling of the dermis, subcutaneous tissues, and/or submucosal tissues caused by fluid extravasation into these tissues. Angioedema is associated with certain vasoactive molecules and is typically mediated by histamine or bradykinin. It manifests clinically as facial edema, swelling of the extremities and urogenital area, and potential involvement of the larynx, leading to dyspnea and inspiratory stridor, which can become life-threatening. Histamine-mediated angioedema is associated with urticaria and pruritus and will show classic signs of allergic (type 1 hypersensitivity) reactions. Bradykinin-mediated angioedema is often familial (hereditary angioedema) and is more often associated with gastrointestinal symptoms (abdominal pain, nausea, vomiting, diarrhea), edema of the extremities and trunk, and a lack of urticaria and pruritus. Angiotensin-converting enzyme inhibitors (ACEIs) are a class of medications commonly prescribed for hypertension, heart failure, and diabetic nephropathy. ACEIs are associated with an increased risk of angioedema, which can range from a mild reaction to severe and life-threatening. ACEI-induced angioedema is a bradykinin-mediated reaction that can occur in individuals with a genetic predisposition. Other medications, such as angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs, and certain antibiotics, most notably those in the beta-lactam class, can also cause drug-induced angioedema. The present investigation describes current knowledge of the pathophysiology, epidemiology, clinical manifestations, predisposing factors, and management of drug-induced angioedema.

Virtual Care in Nephrology: An In-Depth Retrospective Analysis of Outcomes Using the Reset Kidney Health Model.

The advent of virtual healthcare has reshaped patient management paradigms across various medical domains. This analysis examines the potential effectiveness of treating chronic kidney disease (CKD) using Reset Kidney Health's virtual, multidisciplinary, and integrated care approach. The pilot study concentrated on evaluating the impact of this care model on the estimated Glomerular Filtration Rate (eGFR) of CKD patients over an eight-month period. The analyses showed that a majority of patients managed with the Reset Kidney Health Model experienced stability or improvements in their kidney function, as measured by eGFR. While this pilot study has several limitations, these early results suggest the potential benefits of digital healthcare innovations in chronic disease management and provide an argument for the broader integration of virtual care strategies in healthcare systems. These initial findings could lay the groundwork for further research into effectively integrating digital healthcare in chronic disease management.

Potential effects, diagnosis, and management of De Quervain Tenosynovitis in the aesthetics community: A Brief Review, Case Example, and Illustrative Exercises.

Background: Aesthetics is a demanding and growing specialty. More providers are injecting daily at a high volume. De Quervain's tenosynovitis (DQT) is a well-known syndrome involving the hand in the orthopedic and rehabilitation space. The prediction is that DQT will soon become well known to aesthetic injectors. DQT presents with swollen tendons that run along the thumb side of the wrist and attach to the base of the thumb. This is a result of repetitive motion or overuse of the thumb, most often of the dominant hand. This causes pain to the thumb and wrist area, making it difficult to complete daily tasks and perform injections on patients. Objective: This article's goal is to increase awareness among providers of the signs and symptoms of DQT and to be proactive in preventing this condition. A home exercise program has been created to focus on strengthening and conditioning the hand of injectors. Methods: A systematic literature search of the PubMed database was completed. Results: There is a positive correlation between industry demand, increased daily injecting, and the probability of injectors developing DQT. The pain caused by this syndrome can affect the daily lives and work performance of injectors. Proper body ergonomics, including stretching and strengthening the thumb, can be used to reduce pain caused by DQT. Limitations: There was no case study or testing done on groups of people, which limits the results of this review.