Ibuprofen

By 2012 only 3.3% of eligible children (6-12 years old, FEV1 >60%) with CF in the USA were taking high dose ibuprofen (2012 CF Foundation Patient Registry)

1990 Konstan MW, Vargo KM, Davis PB.  Ibuprofen attenuates the inflammatory response to Pseudomonas aeruginosa in a rat model of chronic infection. Implications for anti-inflammatory therapy in cystic fibrosis. Am Rev Respir Dis 1990; 141:186-192.[PubMed]

Ibuprofen reduced inflammation in the rat lung and inhibited the release of the pro-inflammatory leukotriene B4 from the rat neutrophils in vitro. The authors suggested that the effect of antiinflammatory therapy and the known effect of alternate day steroids suggest that “anti- inflammatory therapy with ibuprofen should be considered for a new therapeutic strategy in CF”

Dr Konstan appears to have been working on ibuprofen in the treatment of CF for over 20 years. A small trial followed this 1990 paper in children with CF in 1991 which indicated no significant side effects but that the peak plasma concentration would need to be monitored for effective dosing (Konstan MW et al. J Pediatr 1991; 118:956-964.

1995 Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high dose ibuprofen in patients with cystic fibrosis. N Engl J Med 1995; 332:848-854.[PubMed]
This was a major study funded by the CF Foundation to determine the benefits of treating inflammation in the CF airways with long term oral ibuprofen. A double-blind trial involving 85 patients, five to 39 years of age, with mild lung disease who received oral ibuprofen or placebo twice daily for four years in doses to achieve peak plasma concentrations of 50 to 100 micrograms per ml. The patients on ibuprofen had a slower annual rate of change in FEV1 than the patients assigned to placebo (mean [+/- SE] slope, -2.17 +/- 0.57 percent vs. -3.60 +/- 0.55 percent in the placebo group; P = 0.02), and weight (as a percentage of ideal body weight) was better maintained in the former group (P = 0.02). Among the patients who took ibuprofen for four years and had at least a 70 percent rate of compliance, the annual rate of change in FEV1 was even slower (-1.48 +/- 0.69 percent vs. -3.57 +/- 0.65 percent in the placebo group, P = 0.03), and this group of patients also had a significantly slower rate of decline in forced vital capacity, the percentage of ideal body weight, and the chest-radiograph score. There was no significant difference between the ibuprofen and placebo groups in the frequency of hospitalization. One patient was withdrawn from the study because of conjunctivitis, and one because of epistaxis related to ibuprofen.

The authors concluded that in patients with CF and “mild” lung disease, high-dose ibuprofen, taken consistently for four years, significantly slows the progression of the lung disease without serious adverse effects.

Despite these results, the benefits of ibuprofen in this trial were not convincing to most clinicians. Subsequently the modest effect and frequent side effects prevented the widespread use of ibuprofen and the treatment never became popular even in the United States – only some 5% of patients on the CF Foundation’s registry reported taking the drug. For example Fennell PB et al (J Cyst Fibros 2007; 6:153-158.[PubMed]) reported half their patients stopped ibuprofen because of side effects (mainly gastrointestinal pain and bleeding) and the treatment had no effect on either the rate of pulmonary decline or hospitalisation rates in those who tolerated the drug.
Yet subsequent reports (below) from Michael Konstan remained supportive (Konstan MW et al, Am J Resp Crit Care Med 2007; 176:1084-1089. [PubMed]) and Larry Land’s separate Canadian study showed slower FVC but not FEV1 decline in the treated patients (Lands LC et al. J Pediatr 2007; 151:249-254. [PubMed]).  Despite these findings few clinicians in the UK now advise using long term ibuprofen.

An interesting and unrelated observational report suggested the recurrence of nasal polyps was reduced while patients were receiving ibuprofen (Lindstrom DR et al J Otolaryngol 2007; 36:309-314. [PubMed]).

2007 Lands LC, Milner R, Cantin AM, Manson D, Corey M. High-dose ibuprofen in cystic fibrosis: Canadian safety and effectiveness trial. J Pediatr 2007; 151:249-254. [PubMed]

The second major study on ibuprofen to assess the effectiveness and safety of high-dose ibuprofen when used as part of routine therapy in patients with CF – essentially to confirm the findings of Konstan (1995 above). 142 patients age 6 to 18 years with “mild” lung disease (FEV1 > 60% predicted) were randomized to receive either high-dose ibuprofen (70 subjects, 20 to 30 mg/kg/twice daily, adjusted to a peak serum concentration of 50 to 100 mug/mL) or placebo (72 subjects) for a 2-year period. The primary outcome was the annual rate of change in FEV1% predicted.

The patients in the high-dose ibuprofen group exhibited a significant reduction in the rate of decline of forced vital capacity percent predicted (0.07 +/- 0.51 vs -1.62 +/- 0.52; P = .03), but not of FEV1%. The ibuprofen group also spent fewer days in hospital after adjusting for age (1.8 vs 4.1 days per year; P = .07). A total of 11 patients (4 in the ibuprofen group and 7 in the placebo group) withdrew due to adverse events. The authors concluded that high-dose ibuprofen has a significant effect on slowing the progression of lung disease in CF and generally is well tolerated.

Although Michael Konstan’s original study on ibuprofen showed some slowing of deterioration of respiratory function (Konstan et al, 1995 above), this was unimpressive and few clinicians prescribed the drug on a long term basis, also because of the side effects. Here Larry Lands re-evaluates the use of ibuprofen and although finding some positive effects it is most unlikely that many clinicians will prescribe the treatment in view of the very modest advantages and definite side effects. As already noted it does appear to have an unexpected but favourable effect on nasal polyps (Lindstrom et al, 2007 below).

2007 Fennell PB, Quante J, Wilson K, Boyle M, Strunk R, Ferkol T. Use of high-dose ibuprofen in a pediatric cystic fibrosis center. J Cyst Fibros 2007; 6:153-158. [PubMed]
Despite its apparent benefits, high-dose ibuprofen has been infrequently prescribed for children with cystic fibrosis. Nearly half of the patients in this pediatric cystic fibrosis center who were prescribed with high-dose ibuprofen discontinued therapy due to adverse events, not because of poor adherence or patient choice. Neither use of high-dose ibuprofen nor its cessation resulted in a significant change in the rate of decline in pulmonary function or influenced hospitalization rates.

Further confirmation that ibuprofen has failed to make a significant contribution to CF care (also Konstan et al, 1995 above; Lands et al, 2007 above supporting the use of ibuprofen). Its benefits were modest, blood levels were required and the side effects relatively frequent.

2007 Lindstrom DR, Conley SF, Splaingard ML, Gershan WM. Ibuprofen therapy and nasal polyposis in cystic fibrosis patients. J Otolaryngol 2007; 36:309-314. [PubMed]
Twelve of 22 patients with CF were treated with high-dose ibuprofen therapy to benefit their pulmonary function. Twelve had nasal polyposis and all 12 patients had observed absence of nasal polyps at some point during their ibuprofen course; nasal polyps were present in five patients during ibuprofen therapy, and all resolved with increased ibuprofen doses. Polyps occurred in six of eight patients after ibuprofen therapy ceased. Five of the 12 patients required endoscopic sinus surgery for polyposis.

This is an interesting incidental finding that oral ibuprofen improves nasal polyposis. This could prove very helpful in the few patients with severe and recurring nasal polyposis which can be a very difficult problem.

2007 Konstan MW, Schluchter MD, Xue W, Davis PB. Clinical use of Ibuprofen is associated with slower FEV1 decline in children with cystic fibrosis. Am J Respir Crit Care 2007; 176:1084-1089. [PubMed]
High-dose ibuprofen in a 4-year controlled trial slowed FEV(1) decline in young subjects with cystic fibrosis, but the effectiveness of ibuprofen has not been assessed in a large group of patients treated clinically with this therapy. This study assessed the effect of ibuprofen therapy on FEV(1) decline in children and adolescents with cystic fibrosis, using observational data from the Cystic Fibrosis Foundation Patient Registry. The rate of decline in FEV(1) percent predicted over 2-7 years among patients age 6-17 years with FEV(1) > 60% predicted, and who were treated with ibuprofen (1,365), was compared with patients of similar age and disease severity who were not treated with this therapy (8,960). Multilevel repeated-measures mixed-regression models were used to estimate rates of decline, adjusting for characteristics and therapies that influenced FEV(1) decline. Adverse effects were compared among those treated versus not treated with ibuprofen.

FEV(1) declined less rapidly among patients treated with ibuprofen (difference, 0.60% predicted per year; 95% confidence interval, 0.31 to 0.89; P < 0.0001); a 29% reduction in slope based on an average decline of 2.08% predicted per year for patients not treated. Those treated with ibuprofen were more likely to have an episode of gastrointestinal bleeding requiring hospitalization, but the occurrence was rare in both groups (annual incidence, 0.37 vs. 0.14%; relative risk, 2.72; P < 0.001).

The authors concluded that slower rates of FEV(1) decline are seen in children and adolescents with cystic fibrosis who are treated with ibuprofen. They consider the apparent benefits of ibuprofen therapy outweigh the small risk of gastrointestinal bleeding.

This study from the CF Foundation Registry data confirms the slower decline of FEV1 in children treated with ibuprofen. However, despite a nuber of publications subsequent to Michael Konstan’s original 1995 study the treatment has not becomme popular.

Konstan still maintains that the benefits outweigh the risks (Konstan MW. Curr Opin Pulm Med 2008; 14:567-573. [PubMed]).

2013 Lands LC, Stanojevic S. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD001505. Oral non-steroidal anti-inflammatory drug therapy for cystic fibrosis. Update in Cochrane Database Syst Rev 2013;6:CD001505. [PubMed]
The reviewers identified six trials, of which four, including 287 participants aged five to 39 years with a maximum follow up of four years, were eligible for inclusion in the review. Two trials reporting effectiveness of ibuprofen in people with mild lung disease were from the same center and included some of the same participants. A third assessed piroxicam in participants with more severe impairment of respiratory function and the Trans-Canada trial compared ibuprofen to placebo for a period of two years. Three of the trials in this review were deemed to have good or adequate methodological quality, but variation in outcomes reported and their summary measures precluded calculation of pooled treatment estimates. Authors considered objective measures of lung function, nutritional status, radiological assessment of pulmonary involvement, intravenous antibiotic usage, hospital admissions, survival, frequency of all adverse effects and compliance with therapy. The addition of data from the Canadian trial showed evidence of a moderate absolute annual declinein per cent predicted forced expiratory volume in one second and forcedvital capacity in the placebo group than in the ibuprofen group. In one trial, long-term use of high-dose ibuprofen was associated with reduced intravenous antibiotic usage, improved nutritional and radiological pulmonary status. No major adverse effects were reported, but the power of the trials to identify clinically important differences in the incidence of adverse effects was low.

The reviewers concluded that high-dose ibuprofen can slow the progression of lung disease in people with CF, especially in children, and this suggests that strategies to modulate lung inflammation can be beneficial for people with CF.

However, in 2012 only 3.3% of children registered on the CFF database who were in the criteria to be presrcibed the medication (aged 6 – 12 yrs, FEV1 >60%) were receiving ibuprofen treatment.

2014 Lahiri T. Guillet A. Diehl S. Ferguson M. High-dose ibuprofen is not associated with increased biomarkers of kidney injury in patients with cystic fibrosis. Pediatr Pulmonol 2014; 49(2):148-53. [PubMed]
The authors examined the association of high-dose ibuprofen (IBU) with markers of acute kidney injury (AKI) in patients with CF. The effect of aminoglycoside (AG) exposure on AKI biomarkers was also examined. The AKI markers, kidney injury molecule-1 (KIM), N-acetyl-beta-glucosaminidase (NAG) and urine protein, normalised for creatinine, were chosen as they are more sensitive indicators of kidney injury than changes in serum creatinine. Urine samples from 52 patients, 26 from patients who were treated with IBU, were analysed. There was no significant association between IBU treatment and KIM-1, NAG or protein levels, compared to patients never treated with IBU. While there was an association between AG courses and KIM-1 levels, there were no differences in biomarker levels between IBU and non-IBU groups with respect to AG courses.

These preliminary results suggest that high dose ibuprofen treatment in patients with CF may be safe with respect to renal toxicity. Although relatively few patients are currently treated with IBU it is reassuring that the drug does not appear to contribute to renal injury which is an increasing problem with age in people with CF as a result of repeated course of IV aminoglycosides.

2016 Lands LC, Stanojevic S.  Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis.  Cochrane Database Syst Rev. 2016 Apr 7;4:CD001505. [Epub ahead of print] [PubMed]
The searches identified 10 trials; four are included (287 participants aged five to 39 years; maximum follow up of four years). Combined data from the two largest ibuprofen trials showed a significantly lower annual rate of decline for lung function in the ibuprofen group in younger children.  In one trial, long-term use of high-dose ibuprofen was associated with reduced intravenous antibiotic usage, improved nutritional and radiological pulmonary status. The authors concluded high-dose ibuprofen can slow the progression of lung disease in people with cystic fibrosis, especially in children, which suggests that strategies to modulate lung inflammation can be beneficial for people with cystic fibrosis.- Despite the logic of using an effective anti-inflammatory drug in a condition where chronic inflammation is destroying lung tissue, enthusiasm for the long-term use of ibuprofen remains low and ibuprofen is taken by less than 5% of the patients in the CFF

2016 Rymut SM; Kampman CM; Corey DA; Endres T; Cotton CU; Kelley TJ. Ibuprofen regulation of microtubule dynamics in cystic fibrosis epithelial cells. Am J Physiology – Lung Cellular & Molecular Physiology. 311(2):L317-27, 2016 Aug 01.[Pubmed]
High-dose ibuprofen, an effective anti-inflammatory therapy for the treatment of cystic fibrosis (CF), has been shown to preserve lung function in a pediatric population. Despite its efficacy, few patientsreceive ibuprofen treatment due to potential renal and gastrointestinal toxicity. The mechanism of ibuprofen efficacy is also unclear. The authors suggest that high-dose ibuprofen treatment enhances microtubule formation in CF cells likely through an AMPK-related pathway. These findings define a potential mechanism to explain the efficacy of ibuprofen therapy in CF.

~ Full details are in the complete summary. Very few people with CF are now treated with ibuprofen.

Konstan MW, Van Devanter DR, Sawicki GS, Pasta DJ, Foreman AJ, Neiman EA, Morgan WJ.  Association of High-Dose Ibuprofen Use, Lung Function Decline, and Long-Term Survival in Children with Cystic Fibrosis.Ann Am Thorac Soc. 2018 Jan 9. doi: 10.1513/AnnalsATS.201706-486OC. [Epub ahead of print]    [Pubmed]
A study of associations of high-dose ibuprofen treatment with the rate of FEV1 decline and mortality among children followed in the Epidemiologic Study of Cystic Fibrosis (ESCF) and subsequently in the US Cystic Fibrosis Foundation Patient Registry (CFFPR).  In a propensity-score matched cohort study of children with CF, the authors observed an association between high-dose ibuprofen use and both slower lung function decline and improved long-term survival. They suggest these results are consistent with the hypothesis that treatment-associated reduction of lung function decline in children with CF leads to improved survival.

– Despite the importance of inflammation in the causation of lung damage and the previous work on ibuprofen for people with CF by the leading author and others, ibuprofen is prescribed for very few patients and did not figure in the prescribed recommended therapies in the 2015 CFF patient registry; also less than 2 per cent of adults were taking ibuprofen treatment.

Varrassi G, Pergolizzi JV, Dowling P, Paladini A.  Ibuprofen Safety at the Golden Anniversary: Are all NSAIDs the Same? A Narrative Review.Adv Ther. 2019 Nov 8. doi: 10.1007/s12325-019-01144-9. [Epub ahead of print]  [Pubmed]

Ibuprofen first came to market about 50 years ago and rapidly moved to over-the-counter (OTC) sales. In April 2019, the National Agency for the Safety of Medicines and Health Products (ANSM) of France issued a warning for NSAID uses by patients with infectious diseases based on an analysis of 20 years of real-world safety data on ibuprofen and ketoprofen. Nevertheless, ibuprofen remains a mainstay in the analgesic armamentarium and with numerous randomized clinical trials, head-to-head studies, and decades of clinical experience. The authors offer a review of the safety of ibuprofen and how it may differ from other NSAIDs. Ibuprofen is associated with certain well-known gastrointestinal adverse effects that are related to dose and patient population. Among nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen has a comparatively low risk of cardiovascular adverse effects. It has been associated with renal and hepatic adverse effects, which appear to depend on dose, concomitant medications, and patient population. The association of ibuprofen with infections is more complex in that it confers risk in some situations but benefits in others, the latter in cystic fibrosis. Emerging interest in the literature is providing evidence of the role of ibuprofen as a possible endocrine disrupter as well as its potential antiproliferative effects for cancer cells. Taken altogether, ibuprofen has a favorable safety profile and is an effective analgesic for many acute and chronic pain conditions, although it-like other NSAIDs-is not without risk. After 50 years, evidence is still emerging about ibuprofen and its unique safety profile among NSAIDs. 

Dr Giustino Varassi is President of the World Institute of Pain and specialist in emergency medicine. Widely published on topics relating to pain.

– Ibuprofen has been recommended in cystic fibrosis as an anti-inflammatory (see Topics -> steroids and anti-inflammatories ->NSAID -> ibuprofen) but is not widely used.

Brian Cicali , Tao Long, Sarah Kim, Rodrigo Cristofoletti. Assessing the Impact of Cystic Fibrosis on the Antipyretic Response of Ibuprofen in Children: Physiologically-Based Modeling as a Candle in the Dark.  Br J Clin Pharmacol  2020 Apr 25.doi: 10.1111/bcp.14326. Online ahead of print. [Pubmed]

The goal of this study is to present the utility of quantitative modelling for extrapolation of drug safety and efficacy to underrepresented populations in controlled clinical trials. To illustrate this, the stepwise development of an integrated disease/pharmacokinetics/pharmacodynamics model of antipyretic efficacy of ibuprofen in children with cystic fibrosis (CF) is presented along with therapy optimization suggestions.
Published clinical trials, in vitro data and drug physiochemical properties were used to develop an ibuprofen-mediated antipyresis model for febrile children also having CF. Workflow included first developing a mechanistic absorption model using in vitro-in vivo extrapolation followed by physiologically-based pharmacokinetic (PBPK) modeling. The verified PBPK model was then scaled to pediatric patients with CF. Once verified, the PBPK model was linked to an indirect response model of antipyresis for simulation of the overall antipyretic efficacy of ibuprofen in CF children.
Model simulations showed therapeutic inequivalence between healthy children and pediatric patients with CF; C_max and AUC decreased by 39% (32-46%) and 44% (36-52%), respectively, in patients. Further and in agreement with literature reports, predicted pharmacodynamics time courses suggest a slower onset and faster offset of action in patients compared to healthy children, 30 and 60 minutes, respectively. Exploratory simulations suggest an increase in dosing frequency for CF children as a better therapeutic strategy.

The authors concluded model-informed approaches to leveraging knowledge obtained throughout the life cycle of drug development may play a key role in extrapolating drug efficacy and safety to underrepresented populations.

Dr Rodrigo Cristofoletti is Research Assistant Professor at the Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA