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Abstract

The effectiveness of nonsteroidal antiinflammatory drugs (NSAIDs) for the management of pain in osteoarthritis and other musculoskeletal diseases is well documented. The role of NSAIDs is less clear in the treatment of conditions involving soft tissue inflammation, including the airways, ear–nose–throat (ENT) system and urogenital tract. These conditions are often treated inappropriately with antibiotics. Morniflumate, the ß-morpholinoethyl ester of niflumic acid, is a member of the fenamate family of NSAIDs indicated for the treatment of inflammatory conditions (with or without pain) affecting airways, the ENT system, urogenital tract and the osteoarticular system. Morniflumate has a 30-year history of clinical use, particularly for the treatment of pain associated with paediatric ENT infection. This article reviews evidence supporting the efficacy and safety of morniflumate. Based on available evidence and the favourable tolerability profile emerging from extensive clinical use, morniflumate appears to be a valid and well-tolerated alternative to other NSAIDs, or to antibiotics, for the treatment of pain and other symptoms of soft tissue inflammation.

Keywords

Morniflumate niflumic acid NSAID soft tissue inflammation sore throat ENT

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) constitute a heterogeneous group of compounds and are among the most widely prescribed drugs worldwide for the relief of chronic and acute pain conditions.^1,2 Their primary mechanism of action is the inhibition of cyclo-oxygenase (COX), an enzyme responsible for the synthesis of proinflammatory prostaglandins.³ NSAIDs play a central role in the symptomatic treatment of inflammatory rheumatic conditions, mainly osteoarthritis and rheumatoid arthritis, but also including juvenile arthritis, psoriatic arthritis, rheumatic fever, gout, gouty arthritis and ankylosing spondylitis.⁴ Some NSAIDs are also indicated for the management of conditions involving inflammation of soft tissue, such as the upper and lower respiratory tract, ear–nose–throat (ENT) system, and urogenital tract.

Compared with the large body of evidence supporting the use of NSAIDs for musculoskeletal conditions, literature evaluating the effectiveness of NSAIDs in the treatment of soft-tissue inflammation is less extensive and conclusive. An exception to this is the management of pain associated with sore throat, which has been the object of several studies addressing the efficacy of NSAIDs (mostly ibuprofen, but also flurbiprofen, aceclofenac, diclofenac, nimesulide, tiaprofenic acid, and selective COX-2 inhibitors), analgesics–antipyretics (paracetamol and aspirin), and other types of drugs (corticosteroids, ambroxol).^5–22 Overall, these studies have demonstrated the efficacy of NSAIDs for the rapid relief of sore throat pain. Notably, in some of studies, NSAIDs were shown to be more effective pain relievers than paracetamol.^6,16,19,20 The availability of robust evidence supporting the effectiveness of NSAIDs is reflected in the current guidelines for the management of sore throat, which recommend either ibuprofen or paracetamol for the relief of acute sore-throat symptoms.^19,20,23

Respiratory tract infections, as well as other conditions involving soft-tissue inflammation, are a frequent cause of inappropriate prescribing of antibiotics.^11,24–27 The benefits of antibiotic treatment for respiratory diseases and sore throat are modest in the absence of a bacterial infection.^11,23 Various strategies have been suggested to limit the use of antibiotics, including delayed prescription and the use of alternative drugs.^24–27 The search for other therapeutic options has also led to reconsidering the role of available and well characterized NSAIDs as alternatives to antibiotics for the symptomatic treatment of airway and other soft-tissue infections.^11,19 A literature review investigating the effectiveness of nonantibiotic treatments for acute sore throat found that NSAIDs were a valid alternative to antibiotics.¹¹ The overprescription of antibiotics is also a matter of concern in the management of uncomplicated lower urogenital tract infections. Evidence is limited, but a meta-analysis of trials in patients with benign prostatic hyperplasia suggested that NSAIDs may be a valid alternative to antibiotics for the treatment of lower urinary tract symptoms.^11,28 In short-term treatment of acute pain associated with ENT infection, which is another condition often inadequately treated with antibiotics, COX-2 selective inhibitors were suggested as alternatives to antibiotics because of their improved gastrointestinal tolerability over traditional NSAIDs.²⁹

Niflumic acid (2-[3-(trifluoromethyl)-phenyl]aminonicotinic acid) is a member of the fenamate class of NSAIDs³⁰ originally developed for the treatment of rheumatic disorders.^31–33 Prodrugs with improved gastrointestinal tolerability, including morniflumate (the ß-morpholinoethyl ester of niflumic acid) are available.³⁴ Morniflumate is indicated for the treatment of inflammatory conditions (with or without pain, and also in the absence of fever) affecting the airways, ENT system, urogenital tract and osteo-articular system in adults.³⁴ In Italy, morniflumate is also indicated for the symptomatic treatment of pain associated with ENT and gastrointestinal inflammatory conditions in children.³⁴ Morniflumate is an extensively characterized NSAID that has been in use for over three decades in Italy (particularly for the treatment of upper respiratory tract infections in children), France, Belgium, Austria, Switzerland, Spain and Portugal; it has an overall favourable tolerability profile supported by clinical experience, data from clinical trials and the relatively small number of adverse drug reaction cases reported to pharmacovigilance authorities. Formulations for oral and rectal administration are available. Data on the safety and tolerability of morniflumate will be presented below.

The objective of the present article is to review data regarding the efficacy and safety of morniflumate and to critically assess the position of this drug in the management of inflammatory pain, with a focus on symptoms associated with respiratory tract, ENT and urogenital tract infections. The reviewed studies were identified by searching PubMed® using the terms “niflumic acid”, “morniflumate”, and variations of the preparation names including brand and chemical names, together with truncated variations of terms related to inflammatory pain, respiratory tract, ENT and urogenital infections. No language or date restrictions were applied. The search was conducted in January 2014. Articles identified were checked for relevance before retrieval. A manual check of reference lists of published review articles was conducted to identify further articles, and additional references were kindly provided by the drug manufacturer, Chiesi Farmaceutici S.p.A.

Pharmacological properties

The pharmacokinetics of niflumic acid and morniflumate has been investigated in both animal models and human subjects (below). As well as the selective inhibition of COX-2, these molecules have been found to exert effects on a variety of inflammatory pathways.

Pharmacokinetic profile

In both animal models and human subjects, niflumic acid was quickly absorbed, metabolized and excreted after a single oral dose.^35,36 Peak levels of niflumic acid were reached 2–3 h following drug administration.³⁵ Studies comparing the bioavailability of morniflumate versus niflumic acid in rats showed that orally administered morniflumate was rapidly absorbed in the gastrointestinal tract, and then rapidly hydrolyzed to niflumic acid in plasma.³⁴ The oral administration of niflumic acid resulted in peak plasma levels at 2 h, with a disappearance half-life of 5 h. Oral administration of morniflumate yielded peak plasma levels of niflumic acid at 30 min and a half-life of 5 h.³⁷ Niflumic acid was rapidly eliminated, mainly through renal excretion. The risk of morniflumate accumulation in body tissues should therefore be minimal. Rectally administered morniflumate was also rapidly absorbed, with peak plasma concentrations reached 5 h after administration.³⁷ Improved methods have been developed for the determination of niflumic acid in plasma after oral administration of morniflumate,^38,39 which will likely provide additional details regarding the pharmacokinetics of these compounds in humans.

Pharmacodynamic profile

Niflumic acid is a selective COX-2 inhibitor (IC₅₀ for human recombinant COX-1 and COX-2, 16 µM and 0.1 µM, respectively; K_i values, 2 µM and 0.02 µM, respectively),^40,41 with anti-inflammatory, antipyretic, and analgesic activities.

Niflumic acid inhibits other steps in the inflammatory process, including inhibiting the activity of 5-lipoxygenase, an enzyme responsible for the production of leukotrienes.³⁰ Niflumic acid is also a potent inhibitor of phospholipase A2, an enzyme that catalyses the first step in the production of proinflammatory compounds including prostaglandins.⁴² The inhibitory effect on multiple enzymes involved in the metabolism of arachidonic acid and in the synthesis of proinflammatory molecules may explain the marked anti-inflammatory activity of niflumic acid.

Niflumic acid is a potent, reversible blocker of Ca²⁺-activated Cl⁻ channels (CaCC),^43,44 activation of which is thought to play a role in the increased airway responsiveness to various stimuli in asthma.⁴⁵ This ability renders niflumic acid valuable for determining the mechanisms involved in mucous secretion from airway submucosal glands in animal models of cystic fibrosis,^46–48 histamine-induced interleukin (IL)-6 and IL-8 production,⁴⁹ and nociception.⁵⁰

Niflumic acid has also been found to be an activator of GPR (G-protein coupled receptor) 35, a protein implicated in a number of conditions including inflammatory pain, asthma, heart disease, cancer, and metabolic diseases, and regarded as a promising therapeutic target.⁵¹

Preclinical studies have shown that morniflumate has marked anti-inflammatory activity, comparable with niflumic acid.^34,37,52 Its antipyretic and analgesic activities were comparable with or superior to those of niflumic acid and other compounds, including aspirin and paracetamol.^34,52 In contrast to niflumic acid, morniflumate was not associated with gastrointestinal toxicity caused by local action on mucosa.^37,53 In rats, niflumic acid exerted a dose-dependent gastric ulcerogenic effect with UD₅₀ (i.e., dose of drug causing gastric ulcer in 50% of animals tested) of 177 µmol/kg, whereas no gastric damage was induced by morniflumate, even at a dose ∼80 times the UD₅₀ of niflumic acid (in molar terms). In addition, morniflumate was found to cause about five times fewer intestinal perforations than niflumic acid.³⁷ Morniflumate had a better therapeutic index in terms of anti-inflammatory, antipyretic and analgesic activity than other NSAIDs and paracetamol.⁵²

Therapeutic efficacy

Upper and lower airways

The efficacy of niflumic acid/morniflumate for the treatment of pharyngitis and tonsillitis has been evaluated in four randomized trials.^54–57 A randomized, placebo-controlled study was conducted in 231 adult patients with acute pharyngitis or acute tonsillitis with fever and dysphagia.⁵⁴ Patients were randomized to receive four capsules of 250 mg niflumic acid or placebo daily, in addition to phenoxymethylpenicillin (1.5 × 10⁶IU), for 4 to 5 days. After both 2 and 4 days, the patients receiving niflumic acid showed greater improvements in fever, pain, adenopathy, pharyngeal congestion, dysphagia and health-related quality-of-life (HRQoL) than those receiving placebo.⁵⁴ Similar results were obtained in a double-blind, placebo-controlled trial evaluating the efficacy of morniflumate suppositories plus phenoxymethylpenicillin versus phenoxymethylpenicillin alone in children with acute tonsillitis (n = 101).⁵⁵ Children were randomized to receive 400 mg morniflumate or placebo suppository twice daily for 4 days, in addition to phenoxymethylpenicillin (1.5 × 10⁶IU daily). Treatment response was evaluated by clinical examination after 2 and 4 days of treatment, and quantified using an intensity scale. Efficacy measures included the resolution of oropharyngeal pain, ENT congestion, fever, adenopathy size and sensitivity, and improvements in HRQoL and sleep duration. Patients treated with morniflumate had statistically significantly faster and greater overall improvements in all efficacy parameters than those in the placebo group. Notably, spontaneous pain decreased significantly more rapidly in the morniflumate group, despite being of comparable intensity at the start of treatment.⁵⁵

A rapid action on the local and systemic symptoms of pharyngotonsillitis was observed in a study conducted in 60 adults with acute pharyngotonsillitis with fever, randomized to morniflumate (700 mg orally, twice daily), nimesulide (100 mg orally, twice daily), or placebo. All patients received amoxicillin (1 g, twice daily).⁵⁶ The addition of an anti-inflammatory agent to the antibiotic therapy resulted in faster resolution of pain, local inflammation and fever compared with timings in the placebo group. Morniflumate was more effective than nimesulide on all efficacy measures (statistically significant after 3 days’ treatment).⁵⁶ Morniflumate (350 mg, twice daily) resulted in significantly faster resolution of pain, inflammation and fever than nimesulide (100 mg, twice daily) in a randomized study of 40 adults with acute viral pharyngotonsillitis.⁵⁷

Morniflumate is effective for the symptomatic treatment of acute bronchitis.^58,59 In a study conducted in 60 adults with acute bronchitis of suspected bacterial aetiology, the addition of an anti-inflammatory agent (morniflumate, 700 mg twice daily; or feprazone, 200 mg twice daily) to antibiotic treatment (amoxicillin, 1 g twice daily) resulted in a faster resolution of inflammatory symptoms than antibiotic monotherapy.⁵⁸ Morniflumate was significantly more effective than placebo in reducing cough intensity and frequency after 1 and 3 days’ treatment. Furthermore, after 3 days’ treatment, morniflumate was significantly more effective at reducing chest pain than both placebo and feprazone.⁵⁸ Morniflumate had a more effective and rapid action than placebo and an anti-inflammatory comparator (all in addition to antibiotic therapy) in patients with chronic bronchitis flare-ups, for all clinical parameters tested.⁵⁹

A randomized, controlled, single-blind trial compared the efficacy of morniflumate (700 mg, twice daily), flurbiprofen (100 mg, twice daily), and paracetamol (500 mg, three times daily) in 90 adult patients with acute upper airway viral infection.⁶⁰ The efficacy of morniflumate on fever was comparable with that of paracetamol and greater than with flurbiprofen, with statistically significant between- treatment differences during the first 2 days of treatment. The efficacy of both NSAIDs on oropharyngeal oedema and other inflammatory symptoms was comparable and significantly greater than that of paracetamol over the entire treatment course (7 days).⁶⁰ Similar results were obtained when comparing morniflumate with tiaprofenic acid and paracetamol in 60 adults with acute influenza with upper airway involvement.⁶¹

ENT system

The rapid resolution of pain and other inflammatory symptoms is a key objective in the treatment of ENT infections. A randomized, double-blind, placebo-controlled study evaluated the efficacy of morniflumate suppositories (400 mg daily) versus placebo in 79 infants (aged 6–18 months) with acute otitis media with fever. All patients also received amoxicillin (50 mg/kg, daily).⁶² The combination of morniflumate with antibiotic therapy resulted in significantly greater resolution of tympanic membrane abnormalities (after 2 days’ treatment), throat inflammation and nasal congestion, compared with antibiotic monotherapy. Overall clinical assessment confirmed significantly faster recovery in children treated with morniflumate than those treated with antibiotic alone.⁶² A randomized, controlled, single-blind study compared morniflumate (700 mg, twice daily) with flurbiprofen (100 mg, twice daily) or amoxicillin (1 g, twice daily) in 60 adults with otitis media with effusion.⁶³ Both anti-inflammatory treatments were rapidly effective, providing significant relief of tympanic inflammation, pain and other clinical parameters after 2 days’ treatment. The differences between antibiotic therapy and NSAIDs were statistically significant. Morniflumate was significantly more effective on tympanic inflammation than flurbiprofen after 5 days. In addition, audiometric and tympanometric parameters improved more rapidly (and more substantially) in patients treated with NSAIDs than antibiotics.⁶³ A randomized, placebo-controlled study of 100 adults with acute ENT inflammation (otitis media with effusion, rhinosinusitis, allergic rhinitis, pharyngolaryngitis, or tonsillitis) found that morniflumate (700 mg every 12 h) substantially improved objective symptoms (assessed on a scale from 0 [no symptoms] to 4 [very severe symptoms]) in all ENT conditions after 3 days, treatment compared with placebo.⁶⁴ Finally, a multicentre, double-blind, randomized study compared nimesulide combined with ß-cyclodextrin (to achieve faster analgesic and anti-inflammatory activities) with morniflumate in 316 patients with otitis externa, acute otitis media, or exacerbation of chronic otitis media.⁶⁵ Both treatments were effective in relieving pain due to otitis, with nimesulide and ß-cyclodextrin showing a faster onset of action and better tolerability than morniflumate.⁶⁵

Urogenital tract

Evidence of the efficacy of morniflumate on infections of the urogenital tract is limited to two observational studies.^66,67 In one, 35 patients with acute epididymo-orchitis received morniflumate suppositories (700 mg, twice daily) for a mean of 10 days.⁶⁶ With the exception of four patients, antibacterial agents and antibiotics were also prescribed. Treatment was effective for 26 of the 35 patients observed. In the majority of patients, resolution of pain and inflammatory symptoms was rapid and occurred over the first 3 days of treatment.⁶⁶ The other study involved 45 children who underwent surgery for vesicoureteral reflux and were given morniflumate suppositories (400 mg, twice daily, mean duration 8 days) to prevent inflammatory stenosis (a common complication).⁶⁷ Morniflumate prophylaxis was successful for the majority of children, with only 13% requiring corticosteroid treatment.

Safety and tolerability

Data on the safety and tolerability profiles of niflumic acid and morniflumate are provided by the clinical trials discussed above and from clinical practice.

Clinical trials

In clinical trials, morniflumate was generally well tolerated, with no occurrence of serious or unexpected adverse events.^{55–61,63,64,66,67} Reported adverse events were mostly gastrointestinal and of mild intensity; their frequency was low and similar between active and control treatments. Treatment was rarely discontinued or modified because of poor tolerability. In the study of children with acute tonsillitis,⁵⁵ treatment was discontinued in four patients in the morniflumate group (disease cured in one patient, adverse events in two patients, lack of efficacy in one patient) and one patient in the placebo group (adverse events). The treatment was well tolerated overall, with fewer adverse events occurring in the morniflumate group than in the placebo group. A favourable tolerability profile was reported for morniflumate in the two observational studies in adults and children with urogenital conditions discussed above, despite relatively prolonged treatment.^66,67

Postmarketing reports and surveillance

Niflumic acid and morniflumate have been in use for almost three decades with a good overall safety profile. In Italy, clinical experience with these NSAIDs is extensive. Postmarketing serious treatment-related adverse events are limited to isolated reports. Over a 10-year period, acute renal failure was observed in seven children with ENT disorders treated with niflumic acid.⁶⁸ In most cases, this acute renal failure was due to a hypersensitivity reaction to the drug. It should be noted that renal failure is a very rare adverse event associated with the NSAID family (a likely consequence of the inhibition of prostaglandins involved in the intrinsic autoregulation of renal function), as well as with other drug classes.^4,69–71 Reports of an association between Lyell’s syndrome (toxic epidermal necrolysis) and niflumic acid also have been published.^72,73 Severe skin adverse reactions (toxic epidermal necrolysis), although extremely rare, have also been associated with NSAID use, particularly oxicam derivatives.⁷⁴ A strong association between NSAIDs (mostly ibuprofen) and severe cutaneous infections, particularly in children with varicella, was reported in a French pharmacovigilance study aimed at defining the relationship between severe necrotizing soft tissue infection and NSAID use.⁷⁵ Cases of morniflumate induced angio-oedema and urticaria have been reported.⁷⁶ As with renal failure, urticaria and angio-oedema are rare adverse events that have been associated with NSAIDs (estimated frequency 0.1–0.3%).⁷⁷

A case–control study [cases n = 79, children admitted to the emergency department (ED) for mucocutaneous diseases; controls n = 162, children admitted to the ED for gastrointestinal lesions, neurological disorders or thrombocytopenia] conducted within the pharmacovigilance programme of an Italian children’s hospital, found that niflumic acid treatment resulted in a significantly increased risk of serious mucocutaneous events (odds ratio [OR] 4.9; 95% confidence intervals [CI] 1.9, 12.8).⁷⁸ These findings prompted the Italian Ministry of Health to write to paediatricians. A properly designed retrospective cohort study was conducted to investigate in detail the potential association between niflumic acid and the development of serious cutaneous adverse events.⁷⁹ This study investigated the incidence of severe and mild mucocutaneous reactions in a large paediatric cohort during the use of niflumic acid, other NSAIDs, or non-opioid analgesics. The cohort included 193 727 children (from computerized patient records of the Italian paediatrician network), 45 351 of whom received at least one of the study drugs. The most frequently prescribed drugs were niflumic acid, paracetamol and propionic acid derivatives (ketoprofen and flurbiprofen). This study found that niflumic acid was not associated with an increased risk of severe or mild mucocutaneous reactions in children, compared with other NSAIDs or paracetamol.⁷⁹ The cutaneous tolerability of morniflumate was further confirmed by another study designed to investigate its short-term tolerability, which found that oral challenge with 350 mg morniflumate did not elicit any serious adverse events in 112 adults with a history of cutaneous hypersensitivity reactions to other NSAIDs.⁸⁰

NSAID-related adverse events

Other known side effects of NSAIDs include gastrointestinal toxicity, cardiovascular events and liver damage.^4,71 A case–control study in children found a threefold increase in upper gastrointestinal complications with NSAID use, and a twofold increase with paracetamol and antibiotic use.⁸¹ Individual analysis of NSAIDs showed that niflumic acid (OR 1.6; 95% CI 0.8, 3.2) was associated with a lower risk of gastrointestinal events than ibuprofen (OR 3.7; 95% CI 2.3, 5.9) and paracetamol (OR 2.0; 95% CI 1.5, 2.6).

As a COX-2 selective inhibitor, niflumic acid can be expected to have better gastrointestinal tolerability than nonselective NSAIDs.⁸² This is supported by evidence from clinical studies^55,66,67 and clinical practice. In the early 2000s, COX-2 selective inhibitors were found to induce serious cardiovascular events, leading to the worldwide withdrawal of two drugs (rofecoxib and valdecoxib).^83,84 Considerable effort has since been devoted to assessing the safety profile of other COX-2 selective inhibitors and traditional NSAIDs.^85–89 These assessments have confirmed that COX-2 selective inhibitors are associated with a moderate increase in the risk of cardiovascular events, but this effect also appears to apply to nonselective NSAIDs.^87–89 Cardiovascular adverse events are now regarded more as a NSAID class effect rather than being specific to COX-2 selective inhibitors.^4,89 Based on these considerations, COX-2 selective inhibitors may be preferable to nonselective NSAIDs for the short-term treatment of acute symptoms associated with soft tissue inflammation, as their better gastrointestinal tolerability may outweigh the risk of cardiovascular events in this particular setting.

Several cases of severe liver disease have been reported with NSAID use, but epidemiological studies failed to show a consistently increased risk of hepatotoxicity.^90,91 A study based on Spanish and French pharmacovigilance databases, comparing the reporting of hepatic damage associated with NSAIDs, estimated a relatively low risk of liver injury for niflumic acid (reporting odds ratio [ROR] 0.77; 95% CI 0.63, 0.94).⁹¹ For comparison, the estimated ROR for paracetamol was 2.32 (95% CI 2.23, 2.42) and that for nimesulide was 1.22 (95% CI 0.69, 2.13).

Conclusions

The position of NSAIDs in the treatment of symptoms associated with soft tissue inflammation is less well defined than in its use in the management of pain caused by musculoskeletal diseases. Most of the evidence supporting the use of NSAIDs in this indication comes from studies investigating their efficacy on sore throat pain. Along with ibuprofen, NSAIDs including niflumic acid and its prodrug morniflumate have emerged as valid therapeutic options. Clinical trials and >30 years of use in clinical practice have demonstrated the efficacy of morniflumate for the symptomatic treatment of inflammatory conditions of the upper and lower airways, ENT system and urogenital tract. Morniflumate acts rapidly on pain and inflammatory symptoms: a feature that makes it particularly useful for the management of pain associated with sore throat and ENT conditions in children. The overall tolerability of this COX-2 selective inhibitor for short-term treatment is favourable. Concerns regarding the increased risk of severe mucocutaneous events induced by morniflumate use in children were not confirmed in a recent, well designed retrospective study of a large paediatric cohort. Clearly, these and other safety issues need to be further investigated and defined. Based on the available evidence, however, morniflumate appears to be a useful option for the symptomatic treatment of soft tissue inflammation and may be an effective alternative to antibiotics and other commonly used drugs in some instances.

Footnotes

Acknowledgements

Editorial assistance was provided by Lorenza Lanini, an independent medical writer, on behalf of HPS-Health Publishing & Services Srl. This assistance was funded by Chiesi Farmaceutici S.p.A.

Declaration of conflicting interests

Giovanni Cremonesi and Luca Cavalieri are employees of Chiesi Farmaceutici S.p.A.

References

Trelle

Reichenbach

Wandel

. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011; 342: c7086. doi: 10.1136/bmj.c7086.

Conaghan

. A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity. Rheumatol Int 2012; 32: 1491–1502.

McCarberg

Gibofsky

. Need to develop new nonsteroidal anti-inflammatory drug formulations. Clin Ther 2012; 34: 1954–1963.

Harirforoosh

Asghar

Jamali

. Adverse effects of nonsteroidal anti-inflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci 2013; 16: 821–847.

Nouri

. Nimesulide for treatment of acute inflammation of the upper respiratory tract. Clin Ther 1984; 6: 142–150.

Schachtel

Fillingim

Thodem

. Sore throat pain in the evaluation of mild analgesics. Clin Pharmacol Ther 1988; 44: 704–711.

Benarrosh

. Multicenter double blind study of tiaprofenic acid versus placebo in tonsillitis and pharyngitis in children. Arch Fr Pediatr 1989; 46: 541–546. [in French, English Abstract].

O’Brien

Meade

Falk

. Dexamethasone as adjuvant therapy for severe acute pharyngitis. Ann Emerg Med 1993; 22: 212–215.

Conti

. Comparative, randomized, parallel clinical study of the effectiveness and safety of aceclofenac vs. paracetamol in the treatment of viral pharyngoamygdalitis. Acta Otorrinolaringol Esp 1997; 48: 133–137. [in Spanish, English Abstract].

10.

Boureau

Pelen

Verriere

. Evaluation of ibuprofen vs paracetamol analgesic activity using a sore throat pain model. Clin Drug Investigation 1999; 17: 1–8.

11.

Thomas

Del Mar

Glasziou

. How effective are treatments other than antibiotics for acute sore throat? Br J Gen Pract 2000; 50: 817–820.

12.

Moore

Le Parc

van Ganse

. Tolerability of ibuprofen and paracetamol for the treatment of cold and flu symptoms and sore throat pain. Int J Clin Pract 2002; 56: 732–734.

13.

Gehanno

Dreiser

Ionescu

. Lowest effective single dose of diclofenac for antipyretic and analgesic effects in acute febrile sore throat. Clin Drug Investig 2003; 23: 263–271.

14.

Perrott

Piira

Goodenough

. Efficacy and safety of acetaminophen vs ibuprofen for treating children’s pain or fever: a meta-analysis. Arch Pediatr Adolesc Med 2004; 158: 521–526.

15.

de Mey

Peil

Kölsch

. Efficacy and safety of ambroxol lozenges in the treatment of acute uncomplicated sore throat. EBM-based clinical documentation. Arzneimittelforschung 2008; 58: 557–568.

16.

Pierce

Voss

. Efficacy and safety of ibuprofen and acetaminophen in children and adults: a meta-analysis and qualitative review. Ann Pharmacother 2010; 44: 489–506.

17.

Weckx

Ruiz

Duperly

. Efficacy of celecoxib in treating symptoms of viral pharyngitis: a double-blind, randomized study of celecoxib versus diclofenac. J Int Med Res 2002; 30: 185–194.

18.

Schachtel

McCabe

Berger

. Efficacy of low-dose celecoxib in patients with acute pain. J Pain 2011; 12: 756–763.

19.

Frye

Bailey

Blevins

. Clinical inquiries. Which treatments provide the most relief for pharyngitis pain? J Fam Pract 2011; 60: 293–294.

20.

ESCMID Sore Throat Guideline Group, Pelucchi

Grigoryan

Galeone

. Guideline for the management of acute sore throat. Clin Microbiol Infect 2012; 18(Suppl 1): 1–28.

21.

Russo

Bloch

de Looze

. Flurbiprofen microgranules for relief of sore throat: a randomized, double-blind trial. Br J Gen Pract 2013; 63: e149–e155.

22.

Schachtel

Aspley

Shephard

. Onset of action of a lozenge containing flurbiprofen 8.75 mg: a randomized, double-blind, placebo-controlled trial with a new method for measuring onset of analgesic activity. Pain 2014; 155: 422–428.

23.

Snellman L, Adams W, Anderson G, et al. Institute for Clinical Systems Improvement. Diagnosis and Treatment of Respiratory Illness in Children and Adults. Updated January 2013, www.icsi.org/_asset/1wp8x2/RespIllness.pdf (2013, accessed 22 January 2014).

24.

Spurling

Del Mar

Dooley

. Delayed antibiotics for respiratory infections. Cochrane Database Syst Rev 2007; 18: CD004417–CD004417.

25.

Llor

Moragas

Bayona

. Effectiveness of anti-inflammatory treatment versus antibiotic therapy and placebo for patients with non-complicated acute bronchitis with purulent sputum. The BAAP Study protocol. BMC Pulm Med 2011; 11: 38. doi: 10.1186/1471-2466-11-38.

26.

Altiner

Berner

Diener

. Converting habits of antibiotic prescribing for respiratory tract infections in German primary care—the cluster-randomized controlled CHANGE-2 trial. BMC Fam Pract 2012; 13: 124. doi: 10.1186/1471-2296-13-124.

27.

de la Poza Abad

Mas Dalmau

Moreno Bakedano

. Rationale, design and organization of the delayed antibiotic prescription (DAP) trial: a randomized controlled trial of the efficacy and safety of delayed antibiotic prescribing strategies in the non-complicated acute respiratory tract infections in general practice. BCM Fam Pract 2013; 14: 63. doi: 10.1186/1471-2296-14-63.

28.

Kahokehr

Vather

Nixon

. Non-steroidal anti-inflammatory drugs for lower urinary tract symptoms in benign prostatic hyperplasia: systematic review and meta-analysis of randomized controlled trials. BJU Int 2013; 111: 304–311.

29.

Passali

De Benedetto

Giordano

. Rationale of the use of COX-2 inhibitors in ENT pathologies. Clin Ter 2004; 155: 439–442. [in Italian, English Abstract].

30.

Civelli

Vigano

Acerbi

. Modulation of arachidonic acid metabolism by orally administered morniflumate in man. Agents Actions 1991; 33: 233–239.

31.

Vojtisek

Kanková

Pavelka

. Comparison of the effects of niflumic acid and aloxiprin in patients with progressive chronic rheumatoid arthritis in a double blind trial. Arzneimittelforschung 1975; 25: 1308–1311. [in German, English Abstract].

32.

Rejholec

. The long term treatment of rheumatoid arthritis with niflumic acid or indometazin in double blind controlled trial (author’s transl). Med Klin 1976; 71: 1188–1191. [in German, English Abstract].

33.

Raffaetà

Saponati

Terzuoli

. Controlled clinical study on the use of morniflumate in the treatment in inflammatory-degenerative diseases of the locomotor system. G Clin Med 1987; 68: 507–513. [in Italian, English Abstract].

34.

Flomax – Summary of Product Characteristics. Last revised, December 2012. https://farmaci.agenziafarmaco.gov.it/aifa/servlet/PdfDownloadServlet?pdfFileName=footer_000546_027244_RCP.pdf&retry=0&sys=m0b1l3.

35.

Lan

Chando

Weliky

. Metabolism of niflumic acid-14C: absorption, excretion and biotransformation by human and dog. J Pharmacol Exp Ther 1973; 186: 323–330.

36.

Houin

Tremblay

Bree

. The pharmacokinetics and availability of niflumic acid in humans. Int J Clin Pharmacol Ther Toxicol 1983; 21: 130–134.

37.

Schiantarelli

Cadel

Acerbi

. A gastroprotective anti-inflammatory agent: the beta-morpholinoethyl ester of niflumic acid (morniflumate). Agents Actions 1984; 14: 247–255.

38.

Bilecen

Schulte

Kaspar

. Detection of the non-steroidal anti-inflammatory drug niflumic acid in humans: a combined 19F-MRS in vivo and in vitro study. NMR Biomed 2003; 16: 144–151.

39.

Cho

Park

Lee

. Simultaneous determination of morniflumate and its major active metabolite, niflumic acid, in human plasma by high-performance liquid chromatography in stability and pharmacokinetic studies. Biomed Chromatogr 2013; 27: 1438–1443.

40.

Barnett

Chow

Ives

. Purification, characterization and selective inhibition of human prostaglandin G/H synthase 1 and 2 expressed in the baculovirus system. Biochim Biophys Acta 1994; 1209: 130–139.

41.

Johnson

Wimsatt

Buckel

. Purification and characterization of prostaglandin H synthase-2 from sheep placental cotyledons. Arch Biochem Biophys 1995; 324: 26–34.

42.

Jabeen

Singh

. Non-steroidal anti-inflammatory drugs as potent inhibitors of phospholipase A2: structure of the complex of phospholipase A2 with niflumic acid at 2.5 Angstroms resolution. Acta Crystallogr D Biol Crystallogr 2005; 61(Pt 12): 1579–1586.

43.

White

Aylwin

. Niflumic and flufenamic acids are potent reversible blockers of Ca2(+)-activated Cl- channels in Xenopus oocytes. Mol Pharmacol 1990; 37: 720–724.

44.

Rievaj

Davidson

Nadeem

. Allergic sensitization enhances anion current responsiveness of murine trachea to PAR-2 activation. Pflugers Arch 2012; 463: 497–509.

45.

Moura

Bezerra

de Moraes

. Increased responsiveness to 5-hydroxytryptamine after antigenic challenge is inhibited by nifedipine and niflumic acid in rat trachea in vitro. Clin Exp Pharmacol Physiol 2005; 32: 1119–1123.

46.

Ianowski

Choi

Wine

. Mucus secretion by single tracheal submucosal glands from normal and cystic fibrosis transmembrane conductance regulator knockout mice. J Physiol 2007; 580(Pt 1): 301–314.

47.

Khansaheb

Choi

Joo

. Properties of substance P-stimulated mucus secretion from porcine tracheal submucosal glands. Am J Physiol Lung Cell Mol Physiol 2011; 300: L370–L379.

48.

Shamsuddin

Quinton

. Surface fluid absorption and secretion in small airways. J Physiol 2012; 590(Pt 15): 3561–3574.

49.

Lim

Hwang

Chung

. Niflumic acid reduces histamine-induced interleukin-6 and -8 expression in human conjunctival epithelial cells. Ophthalmic Res 2013; 50: 192–196.

50.

García

Martínez-Rojas

Rocha-González

. Evidence for the participation of Ca(2+)-activated chloride channels in formalin-induced acute and chronic nociception. Brain Res 2014; 1579: 35–44.

51.

Jenkins

Brea

Smith

. Identification of novel species-selective agonists of the G-protein-coupled receptor GPR35 that promote recruitment of β-arrestin-2 and activate Gα13. Biochem J 2010; 432: 451–459.

52.

Cadel

Bongrani

Maiorino

. Morniflumato: attività antinfiammatoria, analgesica, antipiretica e tollerabilità: studio comparativo con una serie di antinfiammatori non steroidei. Clinica Europea 1990; 29: 12–26. [in Italian, English Abstract].

53.

Schiantarelli

Cadel

Folco

. Gastroprotective effects of morniflumate, an esterified anti-inflammatory drug. Arzneimittelforschung 1984; 34: 885–890.

54.

Sauvage

Ditisheim

Bessede

. Double-blind, placebo-controlled, multi-centre trial of the efficacy and tolerance of niflumic acid (‘Nifluril’) capsules in the treatment of tonsillitis in adults. Curr Med Res Opin 1990; 11: 631–637.

55.

Manach

Ditisheim

. Double-blind, placebo-controlled multicentre trial of the efficacy and tolerance of morniflumate suppositories in the treatment of tonsillitis in children. J Int Med Res 1990; 18: 30–36.

56.

Botti

Galetti

Oliani

. Efficacia e tollerabilità di morniflumato nel trattamento delle faringo-tonsilliti acute. Clinica Europea 1990; 29: 67–76. [in Italian, English Abstract].

57.

Poerio

Rampini

Moro

. Morniflumato del trattamento delle faringo-tonsilliti virali acute. Rivista di patologia e sperimentazione clinica 1992; 32: 28–32. [in Italian, English Abstract].

58.

Girbino

Oliani

Lauriello

. A new anti-inflammatory–analgesic–antipyretic for the treatment of acute disease of the bronchi. Riv Eur Sci Med Farmaco 1990; 12: 359–366. [in Italian, English Abstract].

59.

Melica

Donateo

Gerardi

. Un nuovo antiflogistico-analgesico-antipiretico, morniflumato, nel trattamento della bronchite cronica riacutizzata. Eur Rev Med Pharmacol Sci 1991; 13: 51–60. [in Italian, English Abstract].

60.

Ciaccia

Papi

Oliani

. Morniflumato: una nuova alternativa terapeutica per il trattamento delle affezioni virali acute delle vie aeree superiori. Giornale Italiano Malattie del Torace 1991; 45: 39–44. [in Italian, English Abstract].

61.

Marchioni

Livi

Oliani

. Treatment of acute inflammatory pathology of the upper airway with morniflumate. Riv Eur Sci Med Farmacol 1990; 12: 347–357. [in Italian, English Abstract].

62.

Portmann

Rohou

. Efficacy and tolerability of morniflumate in acute otitis in infants: results of a randomized study versus placebos. Rev Laryngol Otol Rhinol (Bord) 1990; 111: 507–510.

63.

Pretto

Oliani

Cimino

. Efficacia e tollerabilità di morniflumato nel trattamento della otite catarrale acuta e subacuta. Rivista Italiana di Otorinolaringologia Audiologia e Foniatria 1991; 11: 72–77. [in Italian, English Abstract].

64.

Libra

Arrabito

. Efficacia e tollerabilità di morniflumato in soggetti con flogosi dei distretti ORL. Reading in Otorinolaringoiatria 1992; 6: 1–4. [in Italian, English Abstract].

65.

Passali

Balli

Scotti

. Controlled, double-blind, randomized comparison of nimesulide ß-cyclodextrin and morniflumate in acute otitis. Curr Ther Res 2001; 62: 153–166.

66.

Mazemann

Biserte

. The beta-morpholino ethyl ester of niflumic acid in the treatment of orchi-epididymitis. Lille Med 1980; 25: 541–544. [in French, English Abstract].

67.

Mazeman

Biserte

Willot

. Beta-morpholinoethyl ester of niflumic acid following surgery for vesico-ureteral reflux in children. LARC Med 1982; 10: 915–916. [in French, English Abstract].

68.

Lantz

Cochat

Bouchet

. Short-term niflumic-acid-induced acute renal failure in children. Nephrol Dial Transplant 1994; 9: 1234–1239.

69.

Ravnskov

. Glomerular, tubular and interstitial nephritis associated with non-steroidal antiinflammatory drugs. Evidence of a common mechanism. Br J Clin Pharmacol 1999; 47: 203–210.

70.

John

Herzenberg

. Renal toxicity of therapeutic drugs. J Clin Pathol 2009; 62: 505–515.

71.

Harirforoosh

Jamali

. Renal adverse effects of nonsteroidal anti-inflammatory drugs. Expert Opin Drug Saf 2009; 8: 669–681.

72.

de Suremain

Le Roux

Smith-Xiberras

. Drug eruptions by niflumic acid. Arch Pediatr 1995; 2: 698. [in French, English Abstract].

73.

Raymond

Paillat

Gambert

. Lyell syndrome following administration of erythromycin-sulfafurazole and morniflumate. Arch Pediatr 1995; 2: 494–495. [in French, English Abstract].

74.

Ward

Archambault

Mersfelder

. Severe adverse skin reactions to nonsteroidal antiinflammatory drugs: a review of the literature. Am J Health Syst Pharm 2010; 67: 206–213.

75.

Souyri

Olivier

Grolleau

. Severe necrotizing soft-tissue infections and nonsteroidal anti-inflammatory drugs. Clin Exp Dermatol 2008; 33: 249–255.

76.

Matheu

Sierra

Gracia

. Morniflumate-induced urticaria-angioedema. Allergy 1998; 53: 812–813.

77.

Sánchez-Borges

Capriles-Hulett

Caballero-Fonseca

. NSAID-induced urticaria and angioedema: a reappraisal of its clinical management. Am J Clin Dermatol 2002; 3: 599–607.

78.

Menniti-Ippolito

Sagliocca

Da Cas

. Niflumic acid and cutaneous reactions in children. Arch Dis Child 2001; 84: 430–431.

79.

Sturkenboom

Nicolosi

Cantarutti

. Incidence of mucocutaneous reactions in children treated with niflumic acid, other nonsteroidal antiinflammatory drugs, or nonopioid analgesics. Pediatrics 2005; 116: e26–e33.

80.

Mero

Nettis

Aloia

. Short-term tolerability of morniflumate in patients with cutaneous hypersensitivity reactions to non-steroidal anti-inflammatory drugs. Int J Immunopathol Pharmacol 2013; 26: 247–250.

81.

Bianciotto

Chiappini

Raffaldi

. Drug use and upper gastrointestinal complications in children: a case-control study. Arch Dis Child 2013; 98: 218–221.

82.

Rainsford

. Anti-inflammatory drugs in the 21st century. Subcell Biochem 2007; 42: 3–27.

83.

Silverstein

Faich

Goldstein

. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284: 1247–1255.

84.

Graham

Campen

Hui

. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005; 365: 475–481.

85.

Public CHMP assessment report for medical products containing NSAID. Procedure No. EMEA/H/A-5.3/800, www.ema.europa.eu/docs/en_GB/document_library/Report/2010/01/WC500054344.pdf (2010, assessed 22 January 2014).

86.

Cannon

Curtis

FitzGerald

. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet 2006; 368: 1771–1781.

87.

Kearney

Baigent

Godwin

. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006; 332: 1302–1308.

88.

Roubille

Martel-Pelletier

Davy

. Cardiovascular adverse effects of anti-inflammatory drugs. Antiinflamm Antiallergy Agents Med Chem 2013; 12: 55–67.

89.

Patricio

Barbosa

Ramos

. Relative cardiovascular and gastrointestinal safety of non-selective non-steroidal anti-inflammatory drugs versus cyclo-oxygenase-2 inhibitors: implications for clinical practice. Clin Drug Investig 2013; 33: 167–183.

90.

Traversa

Bianchi

Da Cas

. Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs. BMJ 2003; 327: 18–22.

91.

Lapeyre-Mestre

de Castro

Bareille

. Non-steroidal anti-inflammatory drug-related hepatic damage in France and Spain: analysis from national spontaneous reporting system. Fundam Clin Pharmacol 2006; 20: 391–395.

Efficacy and Safety of Morniflumate for the Treatment of Symptoms Associated with Soft Tissue Inflammation

Abstract

Keywords

Introduction

Pharmacological properties

Pharmacokinetic profile

Pharmacodynamic profile

Therapeutic efficacy

Upper and lower airways

ENT system

Urogenital tract

Safety and tolerability

Clinical trials

Postmarketing reports and surveillance

NSAID-related adverse events

Conclusions

Footnotes

Acknowledgements

Declaration of conflicting interests

References