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.

Carborane Analogues of Fenoprofen Exhibit Improved Antitumor Activity.

Fenoprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID) against rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis and gout. Like other NSAIDs, fenoprofen inhibits the synthesis of prostaglandins by blocking both cyclooxygenase (COX) isoforms, COX-1 the "house-keeping" enzyme and COX-2 the induced isoform from pathological stimuli. Unselective inhibition of both COX isoforms results in many side effects, but off-target effects have also been reported. The steric modifications of the drugs could afford the desired COX-2 selectivity. Furthermore, NSAIDs have shown promising cytotoxic properties. The structural modification of fenoprofen using bulky dicarba-closo-dodecaborane(12) (carborane) clusters and the biological evaluation of the carborane analogues for COX inhibition and antitumor potential showed that the carborane analogues exhibit stronger antitumor potential compared to their respective aryl-based compounds.

Enteric coating of fenoprofen calcium reduces gastrointestinal microbleeding.

The effects of plain and enteric-coated fenoprofen calcium (Nalfon, Dista, Indianapolis, Ind.) on gastrointestinal microbleeding were studied in 32 normal male volunteers in a randomized, open-label, parallel trial at two inpatient research facilities. A 1-week placebo (baseline) period preceded 2 weeks of fenoprofen therapy (enteric coated or plain, 600 mg q.i.d.). Fecal blood loss was measured by 51Cr-tagged erythrocyte assay and averaged over days 4 to 7 (baseline) and 11 to 14 and 18 to 21 (active therapy). At one center gastrointestinal irritation was evaluated endoscopically before and after active therapy. Endoscopy showed both formulations to cause mucosal damage not evident by subject-reported symptoms. Four of the 16 subjects developed asymptomatic duodenal ulcers. Mean daily fecal blood loss was significantly lower (P = 0.03) with enteric-coated (mean +/- SD, 1.104 +/- 0.961 ml/day) than with plain fenoprofen calcium (mean +/- SD, 1.686 +/- 0.858 ml/day), suggesting that tolerance of fenoprofen can be improved with administration in an enteric-coated form.

Fenoprofen, aspirin, and gold induction in rheumatoid arthritis.

Fenoprofen calcium (2,400 mg/day) or aspirin (3,900 mg/day) was administered in double-blind fashion to 20 rheumatoid patients during 6 months of gold induction therapy, and to 20 rheumatoid patients not receiving gold. Among both the gold-treated and nongold-treated patients, the fenoprofen and aspirin groups improved equally in all but one parameter of disease activity. Fenoprofen and aspirin did not differ significantly in the observed prevalences of abdominal discomfort, guaiac-positive stools, or peptic ulcers. Aspirin was associated with significantly higher mean serum glutamic oxaloacetic transaminase (SGOT) levels than fenoprofen, but only among patients undergoing gold induction. Comparison of efficacy parameters between patients treated with gold and patients treated with oral drugs alone revealed significant differences favoring gold.

T and B lymphocyte subsets in fenoprofen nephropathy.

Renal failure due to combined acute interstitial nephritis and minimal-change glomerulopathy is reported in two patients after fenoprofen therapy. In the interstitial infiltrates, T lymphocytes predominated over B lymphocytes in a ratio of four to one. The majority of B lymphocytes present were IgE-bearing cells. Among the T cells, the ratio of cytotoxic/suppressor cells to helper-inducer cells was three to one. Repeated renal biopsy in one patient after steroid-induced clinical remission demonstrated resolution of the inflammatory infiltrate and restoration of normal glomerular foot processes. The theoretic and practical implications of these findings are discussed.

Fenoprofen nephropathy: lipoid nephrosis and interstitial nephritis. A possible T-lymphocyte disorder.

Five patients are presented, each of whom had an acute idiosyncratic reaction to fenoprofen calcium (Nalfon) characterized by acute renal failure and marked proteinuria. Renal pathology was similar in all patients. Light microscopy revealed marked lymphocytic inflammatory infiltrates and normal glomeruli. Immunofluorescent staining was minimal or absent. Electron microscopy showed fusion of podocytes in otherwise normal glomeruli. Two patients were studied using T-cell and B-cell specific fluorescent staining, which revealed that the interstitial infiltrates were composed exclusively of T-lymphocytes. This finding is considered in relation to prior experimental and theoretic work. It is suggested that the various clinical and pathologic findings in fenoprofen nephropathy are all manifestations of a disordered cell-mediated immunity.

Interstitial nephritis, proteinuria, and renal failure caused by nonsteroidal anti-inflammatory drugs. Immunologic characterization of the inflammatory infiltrate.

Nine patients with the unusual combination of renal failure, nephrotic-range proteinuria, and biopsy-proved interstitial nephritis are described. Six of these patients had received nonsteroidal anti-inflammatory agents (three fenoprofen, one ibuprofen, one zomepirac, and one tolmetin). The remaining three patients had no history of exposure to drugs known to cause interstitial nephritis. Immunologic characterization of the infiltrating cells with monoclonal antibodies showed that the majority of cells in most cases were cytotoxic T cells, although some B cells were present in all cases. Giant collecting duct cells were seen in half the patients with drug exposure but in none of the others. Otherwise, there were no conspicuous morphologic differences between patients with and without drug exposure. Many of the patients had associated glomerular abnormalities. Only the zomepirac and tolmetin recipients showed pure interstitial disease. The three fenoprofen recipients and the zomepirac and tolmetin recipients regained normal renal function after the drug was discontinued. The combination of renal failure, nephrotic range proteinuria, and interstitial nephritis is one form of nephrotoxicity observed in patients treated with nonsteroidal anti-inflammatory agents. However, this lesion, which may be mediated by cytotoxic T cells, may also be seen rarely in patients with no apparent drug exposure.

Effects of nonsteroidal anti-inflammatory drugs on prostaglandins and renal function.

In the past 15 years, there has been an explosion in the number of nonsteroidal anti-inflammatory drugs on the market. Along with this explosion have come increasing reports of the physiologic and pathologic changes seen in the kidneys. This report reviews the effects of prostaglandins on the kidney and the physiologic changes that result when prostaglandin synthesis is blocked. The world literature on renal complications of nonsteroidal anti-inflammatory drugs is reviewed and 274 cases of acute renal disease associated with their use are reported. The following cases are described: nephrotic syndrome (34); acute interstitial nephritis (51); acute tubular necrosis (29); papillary necrosis (53); poor perfusion with renal failure (40); acute glomerulitis or vasculitis (13); and unspecified renal failure (102). Fenoprofen appeared to be more nephrotoxic than other nonsteroidal anti-inflammatory drugs and resulted in multiple renal lesions in the same patient.

Fenoprofen: a review of its pharmacological properties and therapeutic efficacy in rheumatic diseases.

Fenoprofen1 (dl-2-[3-phenoxyphenyl]propionic acid) is a new non-steroidal anti-inflammatory, antipyretic, analgesic agent advocated for use in rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis and gout. Published data suggest that in rheumatoid arthritis, fenoprofen 2.4 g daily is comparable in effectiveness with moderate doses of aspirin (3.6 to 4 g daily), but generally causes fewer and milder side-effects at the dosages used. In published comparisons with other non-steroidal anti-inflammatory agents of the same chemical group, it is closely comparable with naproxen in effectiveness but tends to cause more minor side-effects than naproxen. However, as no one of the non-steroidal anti-inflammatory agents is the most suitable drug for all patients requiring such therapy, fenoprofen should be considered along with the other drugs of its type in the initial treatment of the arthritic patient. Fenoprofen has compared favourably with phenylbutazone in osteoarthrosis of the hips and with aspirin in osteoarthrosis of the shoulders, hips, knees and spine. Its exact place in the management of gout and ankylosing spondylitis remains to be determined.

Renal failure associated with fenoprofen.

The nonsteroidal anti-inflammatory drugs used in treating various arthritides have been implicated in decreased renal function. We describe two patients who had acute renal failure that was apparently secondary to fenoprofen and was associated with a tubulointerstitial nephritis and nephrotic syndrome. The complication resolved when the use of the drug was discontinued.

Drug-induced acute interstitial nephritis with granulomas.

To shed more light on the immunopathogenesis of drug-induced acute interstitial nephritis, a combined histologic, immunopathologic, and ultrastructural study of renal biopsy specimens from nine patients with drug-induced renal disease was performed. None of the patients had pre-existing renal disease or evidence of sarcoidosis or tuberculosis. The principal drugs included a hydrochlorothiazide-triamterene combination (Dyazide), hydrochlorothiazide, fenoprofen, and furosemide and triamterene. Renal insufficiency developed approximately four to ten weeks after initiation of drug therapy. In all cases, withdrawal of the drug(s) with or without steroid therapy resulted in restoration of normal or near-normal renal function. Histologically, all biopsy specimens showed acute interstitial nephritis characterized by an intense but patchy mononuclear cell interstitial infiltrate consisting of lymphocytes, monocytes, and plasma cells, modest numbers of eosinophils, patchy tubular atrophy, interstitial edema, and normal glomeruli. All biopsy specimens contained interstitial (and, in two cases, perivascular) non-caseating granulomas, which were numerous in one case, moderate in four cases, and rare in the remainder. Direct immunofluorescence was negative for IgG, IgM, IgA, C1q, C4, and C3 along glomerular and tubular basement membranes. Immunoperoxidase staining for lysozyme (performed in three cases) demonstrated many positive cells in the infiltrate. In two cases in which granulomas were present in prepared sections, the epithelioid and multinucleated giant cells did not stain for lysozyme. Electron microscopy of the granulomas in two cases revealed that the epithelioid and giant cells had "secretory" features characteristic of hypersensitivity granulomas. These findings provide further evidence for the participation of cell-mediated immunity in the pathogenesis of at least some cases of drug-induced acute interstitial nephritis.

Fenoprofen-induced immune hemolysis. Difficulties in diagnosis and complications in compatibility testing.

A 70-year-old man developed severe immune intravascular hemolysis and renal failure following ingestion of fenoprofen, a nonsteroidal, anti-inflammatory drug. The patient's red blood cells were sensitized with both IgG and C3d. The serum reacted with normal red blood cells in the presence and absence of the drug. Addition of albumin to the serum inhibited the reactivity with both neat and drug-treated serum. These atypical serologic findings for drug-related immune hemolytic anemia were explained by (1) the measurement of fenoprofen by high performance liquid chromatography (HPLC) in the neat serum; and (2) solid-phase adsorption studies showing that albumin can bind drug, leading to the disappearance of agglutination when albumin is added. This case demonstrates the utility of drug levels and adsorption techniques to confirm the diagnosis of drug-induced immune hemolytic anemia despite the anomalous serologic results which obscured the diagnosis and management of the patient.

Evaluating interactions between fenoprofen and propoxyphene: analgesia and adverse reports by postepisiotomy patients.

Groups of 30 postepisiotomy patients were administered single oral doses of fenoprofen calcium (0, 200, 400, or 600 mg acid equivalent) and/or propoxyphene napsylate (0, 50, 100, or 150 mg). The complete block design permits analysis of variance with determination of orthogonal medication contrasts. Evaluation of the analgesia scores indicates that both drugs were effective. In comparison with the appropriate placebo control, propoxyphene is associated with an increase in elicited adverse reports and fenoprofen is associated with a decrease in adverse reports. The two drugs are additive when given together.

Pure red cell aplasia associated with fenoprofen.

A 69-year-old man developed pure red cell aplasia after taking fenoprofen for ten months. The erythroid defect fully reversed after the drug was discontinued and could not be attributed to the patient's previously treated lung carcinoma. This case represents the third example of erythroid aplasia associated with an anti-inflammatory agent and the first instance due to fenoprofen.

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.

Analgesic efficacy and acceptability of fenoprofen combined with paracetamol and compared with dihydrocodeine tartrate in general practice.

A single-blind between-patient study in general practice was made to examine the acceptability and analgesic efficacy of a combination of fenoprofen (200 mg) and paracetamol (500 mg) given 3 to 4 times daily for a period of 4 to 14 days in the treatment of acute and chronic pain. The combination was compared with dihydrocodeine tartrate (30 mg) in two groups of 75 patients suffering from a wide variety of presenting conditions, including osteo-arthritis, spondylitis, lumbago, sciatica, non-articular rheumatism and trauma. Clinical and patient assessment indicated that the combination was an effective analgesic combination, significantly better in success rate than dihydrocodeine tartrate and with a much lower incidence of side-effects (13% of patients receiving fenoprofen and paracetamol reported side-effects compared to 37% for the dihydrocodeine group). The combination demonstrated particular success in the treatment of non-articular rheumatism.

Oral manifestations of drug therapies in the geriatric patient.

Oral manifestations of drug therapies in the geriatric patient must be considered in a multifactorial approach. A logical pattern of individual "normality" must be perceived, and variation from this pattern, with the aid of both physical examination and adequate drug history, will enable the clinician to interpret protean manifestations of untoward actions of chemotherapeutic agents in and about the oral cavity.

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.