M Underwood,^1* D Ashby,² D Carnes,¹ E Castelnuovo,¹ P Cross,¹ G Harding,¹ E Hennessy,² L Letley,³ J Martin,³ S Mt-Isa,² S Parsons,¹ A Spencer,⁴ M Vickers³ and K Whyte¹

¹ Centre for Health Sciences, Barts and The London, School of Medicine and Dentistry, Queen Mary University of London, UK
² The Wolfson Institute of Preventive Medicine, Barts and The London, School of Medicine and Dentistry, Queen Mary University of London, UK
³ Medical Research Council, General Practice Research Framework, London, UK
⁴ Department of Economics, Queen Mary University of London, UK

* Corresponding author

Background

Both oral and topical non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat knee pain. However, oral NSAIDs are associated with gastric, renovascular and respiratory adverse effects, which are a particular risk for older people. If oral and topical NSAIDs are equally effective for chronic knee pain, and topical preparations produce fewer adverse effects than oral preparations, they may be preferred to oral preparations, even if they appear more expensive to purchase. Patient preference for route of administration may be an important factor influencing patient perception of effectiveness of the medication.

Objective

The objective of the study was to determine whether GPs should advise their older patients with chronic knee pain to use topical or oral NSAIDs.

Design

An equivalence study was designed to compare the effect of advice to use preferentially oral or topical ibuprofen (an NSAID) on knee pain and disability, NSAID-related adverse effects and NHS/societal costs, using a randomised controlled trial (RCT) and a patient preference study (PPS). Reasons for patient preferences for topical or oral preparations, and attitudes to adverse effects, were explored in a qualitative study.

Setting

The setting was 26 general practices in the UK.

Participants

Participants comprised 585 people with knee pain, aged 50 years or over; 44% were male, mean age 64 years. The RCT had 282 participants: 144 in the oral group and 138 in the topical group. The PPS had 303 participants: 79 in the oral group and 224 in the topical group.

Intervention

The intervention was advice to use preferentially oral or topical NSAIDs for knee pain.

Main outcome measures

The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcome measures were the Short Form with 36 Items (SF-36), perceived troublesomeness of knee pain, satisfaction with health status, major adverse effects (unplanned hospital admissions and deaths) and minor adverse events over 12 months. The health economic analysis measured the comparative cost per quality-adjusted life-year (QALY) from both an NHS and a societal perspective over 24 months.

Results

Clinical outcomes

Changes in the global WOMAC score at 12-months were equivalent in both studies: topical – oral, RCT difference = 2 [95% confidence interval (CI) –2 to 6], PPS difference = 1 (95% CI –4 to 6). There were no differences in the secondary outcomes, except for a suggestion, in the RCT, that those in the topical group were more likely to have more severe overall pain and disability as measured by the chronic pain grade, and more likely to report changing treatment because of inadequate pain relief.

Adverse effects

There were no differences in the rate of major adverse effects. There were some differences in the number of minor adverse effects. In the RCT, 17% and 10% in the oral and the topical group, respectively, had a defined respiratory adverse effect (95% CI of difference –17% to –2.0%); after 12 months, the change in serum creatinine was 3.7 mmol/l (95% CI 0.9 to 6.5) less favourable in the oral than in the topical group, and 11% of those in the oral group reported changing treatment because of adverse effects compared with 1% in the topical group (p = 0.02). None of these differences were seen in the PPS.

Economic analysis

Oral NSAIDs cost the NHS £191 and £72 more per participant over 1 year in the RCT and PPS, respectively. In the RCT the cost per QALY in the oral group, from an NHS perspective, was in the range £9000–12,000. In the PPS it was £2564 over 1 year, but over 2 years the oral route was dominant, that is, more cost-effective.

Qualitative studies

Patient preference for medication type was affected by previous experience of medication (including adverse reactions), other illness, pain elsewhere, anecdotes, convenience, severity of pain and perceived degree of degeneration. Lack of understanding about knee pain and the action of medication led to increased tolerance of symptoms. Symptoms such as indigestion, sensitive stomach and poor general well-being were normalised as an effect of age rather than medication. Potentially important symptoms may inadvertently have been disregarded, increasing participants' risk of suffering a major adverse effect.

Interpretation

Clinical outcomes in the two groups were similar in almost every measure at every time-point. This finding was consistent across the RCT and PPS, suggesting that the two treatment strategies are either equally effective or equally ineffective. Although it is inconclusive, those in the RCT oral group appeared to have more minor adverse effects. Rigorous safety exclusion criteria meant that the impact of adverse effects on NHS costs and health utility may have been underestimated. Since the absolute differences in NHS costs and health utility were small, the cost per QALY may have been very sensitive to any such underestimate. In the PPS, participants with more severe widespread pain chose oral rather than topical ibuprofen. Furthermore, there was little difference in defined adverse effect rates in those who chose oral NSAIDs and those who were randomised to them, even though the PPS oral group took substantially more oral NSAIDs and were older than those in the RCT.

Conclusions

Advice to use either oral or topical preparations has an equivalent effect on knee pain, but oral NSAIDs appear to produce more minor adverse effects than topical NSAIDs. Generally, these results support advising older people with knee pain to use topical rather than oral NSAIDS. However, for patients who prefer oral NSAID preparations rather than a topical NSAID, particularly those with more widespread or severe pain, the oral route is a reasonable treatment option, provided that patients are aware of the risks of potentially serious adverse effects from oral medication.

Implications for healthcare

The evidence suggests that advice to use topical NSAIDs in preference to oral NSAIDs for treating knee pain in older people may be appropriate.

Recommendations for research

Further research is recommended in the following areas.

• Developing and testing strategies to change prescribing behaviour and ensure that older patients are aware of the potential risks and benefits of using NSAIDs.
• Observational studies to estimate rates of different predefined minor adverse effects associated with the use of oral NSAIDs in older people.
• Long-term studies of topical NSAIDs in those for whom oral NSAIDs are not appropriate, for example the very elderly.

Publication

Underwood M, Ashby D, Carnes D, Castelnuovo E, Cross P, Harding G, et al. Topical or oral ibuprofen for chronic knee pain in older people. The TOIB study. Health Technol Assess 2008;12(22).

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