Non-steroidal anti-inflammatory drugs (NSAIDs) for chronic non-cancer pain in children and adolescents.

BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as important.We designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions.As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) from genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, as well as for other unknown reasons.Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat pain, reduce fever, and for their anti-inflammation properties. They are commonly used within paediatric pain management. Non-steroidal anti-inflammatory drugs are currently licensed for use in Western countries, however they are not approved for infants under three months old. The main adverse effects include renal impairment and gastrointestinal issues. Common side effects in children include diarrhoea, headache, nausea, constipation, rash, dizziness, and abdominal pain. OBJECTIVES: To assess the analgesic efficacy and adverse events of NSAIDs used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, as well as online clinical trial registries. SELECTION CRITERIA: Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing any NSAID with placebo or an active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE and created three 'Summary of findings' tables. MAIN RESULTS: We included seven studies with a total of 1074 participants (aged 2 to 18 years) with chronic juvenile polyarthritis or chronic juvenile rheumatoid arthritis. All seven studies compared an NSAID with an active comparator. None of the studies were placebo controlled. No two studies investigated the same type of NSAID compared with another. We were unable to perform a meta-analysis.Risk of bias varied. For randomisation and allocation concealment, one study was low risk and six studies were unclear risk. For blinding of participants and personnel, three studies were low risk and four studies were unclear to high risk. For blinding of outcome assessors, all studies were unclear risk. For attrition, four studies were low risk and three studies were unclear risk. For selective reporting, four studies were low risk, two studies were unclear risk, and one study was high risk. For size, three studies were unclear risk and four studies were high risk. For other potential sources of bias, seven studies were low risk. Primary outcomesThree studies reported participant-reported pain relief of 30% or greater, showing no statistically significant difference in pain scores between meloxicam and naproxen, celecoxib and naproxen, or rofecoxib and naproxen (P > 0.05) (low-quality evidence).One study reported participant-reported pain relief of 50% or greater, showing no statistically significant difference in pain scores between low-dose meloxicam (0.125 mg/kg) and high-dose meloxicam (0.25 mg/kg) when compared to naproxen 10 mg/kg (P > 0.05) (low-quality evidence).One study reported Patient Global Impression of Change, showing 'very much improved' in 85% of ibuprofen and 90% of aspirin participants (low-quality evidence). Secondary outcomesAll seven studies reported adverse events. Participants reporting an adverse event (one or more per person) by drug were: aspirin 85/202; fenoprofen 28/49; ibuprofen 40/45; indomethacin 9/30; ketoprofen 9/30; meloxicam 18/47; naproxen 44/202; and rofecoxib 47/209 (very low-quality evidence).All seven studies reported withdrawals due to adverse events. Participants withdrawn due to an adverse event by drug were: aspirin 16/120; celecoxib 10/159; fenoprofen 0/49; ibuprofen 0/45; indomethacin 0/30; ketoprofen 0/30; meloxicam 10/147; naproxen 17/285; and rofecoxib 3/209 (very low-quality evidence).All seven studies reported serious adverse events. Participants experiencing a serious adverse event by drug were: aspirin 13/120; celecoxib 5/159; fenoprofen 0/79; ketoprofen 0/30; ibuprofen 4/45; indomethacin 0/30; meloxicam 11/147; naproxen 10/285; and rofecoxib 0/209 (very low-quality evidence).There were few or no data for our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning as defined by validated scales; and quality of life as defined by validated scales (very low-quality evidence).We rated the overall quality of the evidence (GRADE rating) for our primary and secondary outcomes as very low because there were limited data from studies and no opportunity for a meta-analysis. AUTHORS' CONCLUSIONS: We identified only a small number of studies, with insufficient data for analysis.As we could undertake no meta-analysis, we are unable to comment about efficacy or harm from the use of NSAIDs to treat chronic non-cancer pain in children and adolescents. Similarly, we cannot comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life.We know from adult randomised controlled trials that some NSAIDs, such as ibuprofen, naproxen, and aspirin, can be effective in certain chronic pain conditions.

Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3.

The efficiency of drug research and development has paradoxically declined over the last decades despite major scientific and technological advances, promoting new cost-effective strategies such as drug repositioning by systematic screening for new actions of known drugs. Here, we performed a screening for positive allosteric modulators (PAMs) at melanocortin (MC) receptors. The non-steroidal anti-inflammatory drug fenoprofen, but not the similar compound ibuprofen, presented PAM activity at MC3, MC4, and MC5 receptors. In a model of inflammatory arthritis, fenoprofen afforded potent inhibition while ibuprofen was nearly inactive. Fenoprofen presented anti-arthritic actions on cartilage integrity and synovitis, effects markedly attenuated in Mc3r-/- mice. Fenoprofen displayed pro-resolving properties promoting macrophage phagocytosis and efferocytosis, independently of cyclooxygenase inhibition. In conclusion, combining repositioning with advances in G-protein coupled receptor biology (allosterism) may lead to potential new therapeutics. In addition, MC3 PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases.

A supramolecular topical gel derived from a non-steroidal anti-inflammatory drug, fenoprofen, is capable of treating skin inflammation in mice.

A new series of bioconjugates derived from a non-steroidal anti-inflammatory drug (NSAID), namely fenoprofen, has been synthesised by amidation with various biogenic molecules such as ß-alanine, aminocaproic acid and tyramine with the aim of converting the NSAID into a supramolecular gelator for plausible biomedical applications. One such bioconjugate (2) showed gelation ability with methylsalicylate (MS) and 1% menthol in methyl salicylate (MMS) solvents. These gels were characterized by table top rheology, high resolution-transmission electron microscopy (HR-TEM) and dynamic rheology. Gelator 2 was found to be biostable both in proteolytic enzymes and in blood serum of BALB/c mouse under physiological conditions. It was also found to be biocompatible, as revealed by the methyl thiazolyldiphenyl tetrazolium bromide (MTT) assay in mouse macrophage RAW 264.7 and mouse myoblast C2C12 cells. The anti-inflammatory response (prostaglandin E2 assay, denoted PGE2 assay) of 2 was comparable to that of the parent drug fenoprofen calcium salt. Finally, a topical gel formulation of 2 displayed in vivo self-delivery application in treating imiquimod (IMQ) induced skin inflammation in BALB/c mice.

Enhanced analgesic properties and reduced ulcerogenic effect of a mononuclear copper(II) complex with fenoprofen in comparison to the parent drug: promising insights in the treatment of chronic inflammatory diseases.

Analgesic and ulcerogenic properties have been studied for the copper(II) coordination complex of the nonsteroidal anti-inflammatory drug Fenoprofen and imidazole [Cu(fen)2(im)2] (Cu: copper(II) ion; fen: fenoprofenate anion from Fenoprofen, im: imidazole). A therapeutic dose of 28 mg/kg was tested for [Cu(fen)2(im)2] and 21 mg/kg was employed for Fenoprofen calcium, administered by oral gavage in female mice to compare the therapeutic properties of the new entity. The acetic acid induced writhing test was employed to study visceral pain. The percentage of inhibition in writhing and stretching was 78.9% and 46.2% for the [Cu(fen)2(im)2] and Fenoprofen calcium, respectively. This result indicates that the complex could be more effective in diminishing visceral pain. The formalin test was evaluated to study the impact of the drugs over nociceptive and inflammatory pain. The complex is a more potent analgesic on inflammatory pain than the parent drug. Ulcerogenic effects were evaluated using a model of gastric lesions induced by hypothermic-restraint stress. Fenoprofen calcium salt caused an ulcer index of about 79 mm(2) while the one caused by [Cu(fen)2(im)2] was 22 mm(2). The complex diminished the development of gastric mucosal ulcers in comparison to the uncomplexed drug. Possible mechanisms of action related to both therapeutic properties have been discussed.

Local infiltration analgesia for postoperative pain after hip arthroplasty: a systematic review and meta-analysis.

UNLABELLED: Postoperative pain after hip arthroplasty (HA) is very common and severe. Currently, use of routine analgesic methods is often accompanied by adverse events (AEs). Local infiltration analgesia (LIA) for controlling pain has been a therapeutic option in many surgical procedures. However, its analgesic efficacy in HA and its safety remain unclear. Data from 9 randomized controlled trials, involving 760 participants, comparing the effect of LIA with that of placebo infiltration or no infiltration on patients undergoing HA were retrieved from an electronic database, and the pain scores, analgesic consumption, and AEs were analyzed. Effects were summarized using weighted mean differences, standardized mean differences, or odds ratio with fixed or random effect models. There was strong evidence of an association between LIA and reduced pain scores at 4 hours at rest (P < .00001) and with motion (P < .00001), 6 hours with motion (P = .02), and 24 hours at rest (P = .01), and decreased analgesic consumption during 0 to 24 hours (P = .001) after HA. These analgesic efficacies for LIA were not accompanied by any increased risk for AEs. However, the current meta-analysis did not reveal any associations between LIA and the reduced pain scores or analgesic consumption at other time points. The results suggest that LIA can be used for controlling pain after HA because of its efficacy in reducing pain scores and thus can reduce analgesic consumption on the first day without increased risk of AEs. PERSPECTIVE: This is the first pooled database meta-analysis to assess the analgesic effects and safety of LIA in controlling pain after HA. The derived information offers direct evidence that LIA can be used for patients undergoing HA because of its ability to reduce pain scores and analgesic consumption without any additional AEs.

Non-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery.

BACKGROUND: Cystoid macular oedema (CMO) is the accumulation of fluid in the central retina (the macula) due to leakage from dilated capillaries. It is the most common cause of poor visual outcome following cataract surgery. The exact cause is unclear. Acute CMO, defined as oedema of less than four months duration, often resolve spontaneously. CMO that persists for four months or more is termed chronic CMO. Different types of non-steroidal anti-inflammatory agents (NSAIDs) are used in the treatment of CMO which may be delivered topically or systemically. OBJECTIVES: To examine the effectiveness of NSAIDs in the treatment of CMO following cataract surgery. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 7), MEDLINE (January 1950 to August 2011), EMBASE (January 1980 to August 2011), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to August 2011), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (August 2011) and ClinicalTrials.gov (www.clinicaltrials.gov) (August 2011). We searched the reference lists of identified trials. We searched conference abstracts (sessions related to cataract) in The Association for Research in Vision and Ophthalmology (ARVO) 1975 to 2011. We contacted experts in the field and NSAIDs manufacturers for details on published and unpublished trials.There were no language or date restrictions in the search for trials. The electronic databases were last searched on 5 August 2011. SELECTION CRITERIA: We included randomised controlled trials evaluating the effects of NSAIDs in the treatment of CMO following cataract surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. Since considerable heterogeneity was observed between studies we did not conduct meta-analyses. MAIN RESULTS: Seven trials involving a total of 266 participants were included. Four trials studied the effects of NSAIDs in chronic CMO while the other three examined the effect of NSAIDs in acute CMO. Of the studies examining chronic CMO, one study enrolled 120 participants, but the remainder had 34 or fewer participants. Four different NSAIDs were used and administered in different ways. Indomethacin was used orally and was found to be ineffective for chronic CMO in one trial. Topical fenoprofen appeared effective but not statistically significantly so for chronic CMO in another small trial. Treatment with topical 0.5% ketorolac for chronic CMO was found to be effective in two trials. Three trials examined the effect of topical NSAIDs on acute CMO. The comparisons among these studies were of an NSAID to placebo, prednisolone or another NSAID. The study design differed between the studies in other important aspects thus they could not be combined in a meta-analysis. AUTHORS' CONCLUSIONS: This review found two trials which showed that topical NSAID (0.5% ketorolac tromethamine ophthalmic solution) has a positive effect on chronic CMO and two trials which revealed no significant difference between comparative groups. As such, the effects of NSAIDs in acute and chronic CMO remain unclear and needs further investigation.

Anti-nociceptive activity and toxicity evaluation of Cu(II)-fenoprofenate complexes in mice.

The proposed curative properties of copper(II)-non-steroidal anti-inflammatory drugs (NSAIDs) have led to the development of numerous copper(II)-NSAID complexes with enhanced anti-inflammatory activity. In this work, the antinociceptive and toxic effects of two new coordination complexes: Cu2(fen)4(caf)2 [fen: fenoprofenate anion; caf: caffeine] and Cu2(fen)4(dmf)2 [dmf: N-N'-dimethylformamide] were evaluated in mice. The antinociceptive effect was evaluated with two models: acetic acid-induced writhing response and formalin test. For the sub-acute exposure, the complexes were added to the diet at different doses for 28days. Behavioral and functional nervous system parameters in a functional observational battery were assessed. Also, hematological, biochemical and histopathological studies were performed. Cu2(fen)4(caf)2 and Cu2(fen)4(dmf)2 significantly decreased the acetic acid-induced writhing response and the licking time on the late phase in the formalin test with respect to the control and fenoprofen salt groups. The sub-acute exposure to Cu2(fen)4(caf)2 complex increased the motor activity, the number of rearings and the arousal with respect to the control and fenoprofen salt groups. These impaired parameters in mice exposed to Cu2(fen)4(caf)2 can be attributable to the presence of caffeine as stimulating agent. On the other hand, all exposed groups decreased the urine pools in the functional observational battery and increased the plasmatic urea. These effects could be due to the decrease in the glomerular filtration caused by NSAIDs. In conclusion, both complexes Cu2(fen)4(dmf)2 and Cu2(fen)4(caf)2 were more potent antinociceptive agents than fenoprofen salt. Sub-acute exposure to different doses of these complexes did not produce significant changes in the parameters that evaluate toxicity.

Joint space measurement in hand radiographs using computerized image analysis.

OBJECTIVE: To compare computerized joint space (JS) measurements with conventional joint space narrowing (JSN) scores in patients with mild rheumatoid arthritis. METHODS: Serial paired hand and wrist radiographs from 34 patients with classic rheumatoid arthritis were evaluated. Purpose-written software automatically measured the JS on test images and standard clinical hand radiographs; JSN was scored "blind" by 6 observers. RESULTS: The software proved reliable. JS values differed significantly (men > women; metacarpophalangeal > proximal interphalangeal joints), declining with disease duration more than with age; JSN scores correlated poorly and varied more. CONCLUSION: Computerization permits sensitive JS measurement and should be of benefit in studies of early joint disease.

Calcific tendinitis of the flexors of the forefoot.

We report a case of calcific tendinitis in the flexor tendons of the forefoot. A 33-year-old woman presented with a two-day history of foot pain but she recalled no direct trauma to the foot. Physical examination revealed redness, warmth, and tenderness on the plantar surface of the foot near the head of the first metatarsal. Radiographs showed a small focus of calcification in the flexor tendons of the great toe, diagnostic of calcific tendinitis. The patient was treated with supportive therapy and recovered.

Efficacy of fenoprofen in the treatment of primary dysmenorrhea.

We compared fenoprofen calcium, 200 mg; fenoprofen calcium, 400 mg; aspirin, 650 mg; and a placebo in 85 women for the relief of primary dysmenorrhea in a double-blind, clinical trial. The usefulness of these drugs was judged from data obtained over four consecutive menstrual periods on: restriction of daily activity, pain intensity scores, need for rescue analgesics, withdrawal due to lack of efficacy, and adverse events. Both fenoprofen, 200 mg, and fenoprofen, 400 mg, offered significant (P less than .01) pain relief when compared to placebo and aspirin. Analyses of data on 1, 2 and 3 indicated that aspirin was not significantly different from placebo. The aspirin-treated group reported the greatest number of adverse reactions, but the differences between the four groups were not statistically significant. Our study lends support to the concept of a "plateau analgesic effect" of nonsteroidal antiinflammatory drugs (NSAIDs): fenoprofen, 200 mg, appears to be as effective as fenoprofen, 400 mg. When this type of drug fails to provide relief for a woman suffering from primary dysmenorrhea, switching to another NSAID may be more appropriate than increasing the dosage and the probability of dosage-related side effects.

Fenoprofen calcium versus aspirin in the treatment of acute inflammatory soft-tissue injuries.

The efficacy and safety of fenoprofen calcium (Nalfon, Dista, Indianapolis, IN) and aspirin for treating acute inflammatory soft tissue injuries were compared in a 3 to 10-day randomized, double-blind, parallel study of 100 patients with bruise (1), bursitis (33), ligamentous strain (8), myofascitis (43), and tendinitis (15). Forty-seven of the 50 aspirin-treated and 48 of the 50 fenoprofen-treated patients were evaluable. Results of the study showed that fenoprofen calcium and aspirin were equally effective in treating acute inflammatory soft-tissue injuries; however, adverse experiences occurred in fewer patients and at a lower frequency with fenoprofen calcium therapy. In global assessments, 73% of the patients rated fenoprofen therapy as very good or good compared to 64% of the patients who received aspirin therapy. There were no significant differences in the clinician's and the patients' global assessments of therapy. The study suggests that fenoprofen calcium is effective for use in treating soft-tissue injuries since it is better tolerated than aspirin when given in equally effective doses.

Dose response to fenoprofen calcium using placebo and codeine as controls.

This paper evaluates the dose-response relationship of several doses of fenoprofen calcium, between 12.5 and 300 mg, and their relationship to 60 mg of codeine sulfate and placebo. Three separate parallel studies are included in this evaluation, including a total of 867 patients. The types of pain were cesarean section, episiotomy wound, uterine cramping, and general surgery. This paper shows that a significant increasing relationship exists between efficacy and dose of fenoprofen, suggesting that relatively larger doses of fenoprofen will achieve greater amounts of efficacy.

Mild analgesics and the accident and emergency department--cost and safety more important than potency?

A prospective controlled trial involving over 1000 patients did not reveal any difference between four drugs commonly used in accident and emergency departments for the relief of mild to moderate pain. There were no significant variations in therapeutic effect, side-effects or patient compliance. When considering the supply of analgesics which may be no more potent than those available without prescription from retail chemists, cost and safety are more important than analgesic effect. By restricting the choice of analgesics available, the accident and emergency department should be able to increase awareness among its staff of the actions and side-effects of a small number of prescribed drugs and to contain costs.

Peripherally acting analgesics.

The therapeutic effect of aspirin and the other nonsteroidal anti-inflammatory drugs derives from the peripheral inhibition of prostaglandin synthetase. Aspirin produces irreversible inhibition, whereas the inhibition triggered by the other nonsteroidal anti-inflammatory drugs is reversible. Despite proved analgesic efficacy, use of aspirin and the nonsteroidal anti-inflammatory drugs may be accompanied by a wide range of side effects of a potentially serious nature. For relief of pain, there appears to be no clear-cut superiority of one nonsteroidal anti-inflammatory drug over another, and patients who fail to respond to one class of nonsteroidal anti-inflammatory drugs may respond to a representative of another class. As with aspirin, it is difficult to demonstrate the superiority of higher doses of these agents over the lower doses. The side-effect profile of non-narcotic analgesics favors acetaminophen, presumably because its inhibition of prostaglandin synthetase occurs centrally. Acetaminophen does not appear to have the same potential for toxicity that is seen with aspirin and other nonsteroidal anti-inflammatory drugs. At dosages up to 4 g per day, acetaminophen compares favorably in analgesic potency to aspirin and other nonsteroidal anti-inflammatory drugs, and it should be considered the treatment of choice for mild-to-moderate pain. Safe conditions for the analgesic use of nonsteroidal anti-inflammatory drugs in children and pregnancy have not been established. Because it is virtually free of side effects, acetaminophen may be the mild analgesic of choice for the pregnant patient. It has been used safely for years in children. Only a limited number of analgesic studies have been conducted in children. The results of analgesic studies carried out in adults are generally recognized as applicable to pain relief in children.