IBUPROFEN

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 One patient was withdrawn from the study because of conjunctivitis, and one because of epistaxis related to ibuprofen.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 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]
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]). So few clinicians in the UK now advise using ibuprofen.

Professor Michael Konstan (figure 37) is Director of the Leroy Matthews Cystic fibrosis Centre, Cleveland and particularly identified as being associated with this study. He is a leading figure involved in CF in the USA and heavily involved in both research and patient care.

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). It s 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 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). CONCLUSIONS: Slower rates of FEV(1) decline are seen in children and adolescents with cystic fibrosis who are treated with ibuprofen. 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 number of publications subsequent to Michael Konstan's original 1995 study the treatment never became popular.