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Diclofenac — a useful drug that may now be entering its twilight years

By Jenny Bryan

Diclofenac has been prescribed widely but recently there has been emerging evidence of its cardiovascular side effects. Jenny Bryan investigates


Well into its fourth decade on pharmacy shelves, the non-steroidal anti-inflammatory drug diclofenac (Voltarol) remains a popular choice of treatment for a range of musculoskeletal disorders. But concerns about its cardiovascular (CV) side effects in humans and its links to a rapid decline in vulture populations in India have kept diclofenac in the headlines at a time when most drugs of its age have dropped below the news radar.

Earlier this year, an extensive analysis of CV events with individual NSAIDs concluded that diclofenac carries a CV risk comparable to that of the cyclo-oxygenase 2 (COX2) inhibitor rofecoxib,1 which led to its withdrawal in 2004.

The review authors recommended that diclofenac should be removed from the World Health Organization Essential Medicines Lists (EMLs), and the European Medicines Agency (EMA) is currently reviewing treatment guidance for the drug.
“GPs are aware of the increased risk of myocardial infarction and stroke with diclofenac, and clinical commissioning groups send reminders to those who continue to prescribe more than other local practices and advice about putting patients on naproxen rather than diclofenac.

However, some patients don’t like naproxen as much as diclofenac so, having discussed the risks with them, I think we still need the option of prescribing diclofenac in a small number of cases,” explains Louise Warburton, president of the Primary Care Rheumatology Society, GP with a special interest in rheumatology and musculoskeletal medicine, Shropshire Community Health NHS Trust, and Telford and Wrekin CCG board member.

Chemists at work

Impressed by the early success of the first NSAIDs, phenylbutazone, mefenamic acid, ibuprofen and indometacin, during the 1960s, chemists at the Swiss pharmaceutical company, Ciba-Geigy (now Novartis) set about finding an “antirheumatic” agent with similar properties.2 They wanted a molecule that was weakly acidic with two aromatic rings twisted in relation to each other.2 Receptor modelling was still in its infancy but the researchers postulated that the twisted ring structure was essential to fit the cyclo-oxygenase receptor site, and hence inhibit the activity of the enzyme for prostaglandin synthesis. Of more than 200 analogues tested by Ciba-Geigy, it was diclofenac that proved to have the most useful pharmacological properties.2

Musculoskeletal role

In an early clinical trial, diclofenac 100mg per day was shown to produce more relief from pain and stiffness and improved joint mobility in a larger number of patients with osteoarthritis than naproxen 500mg.3

It also appeared to be better tolerated. In another early study, diclofenac appeared superior to indometacin in rheumatoid arthritis.4

The drug was launched in the UK in 1979 and a growing body of clinical trials accumulated so that, by the mid-1980s, diclofenac was confirmed as at least as effective as other NSAIDs in the treatment of rheumatoid and osteoarthritis,5,6 with safety comparable to that of ibuprofen and naproxen, and fewer adverse reactions than other NSAIDs.7

Additional formulations — slow release tablets, suppositories, intramuscular injections and gels — followed and indications were extended to a wide range of painful and inflammatory conditions, including ankylosing spondilitis, acute gout, frozen shoulder, low back pain, strains and sprains, and dental and other minor surgery.

“By the time I started in rheumatology in 1992, diclofenac was well established as the NSAID of choice. It was seen as a ‘mid range’ NSAID that wasn’t as potent as indometacin but better tolerated, and a little more effective than ibuprofen. It was also very well marketed, so that was probably part of the reason for its popularity,” recalls Dr Warburton.

Entering the skin

Nearly two decades after diclofenac’s introduction, further clinical research demonstrated the efficacy of 3 per cent diclofenac in 2.5 per cent hyaluronic acid (HA) gel for the topical treatment of actinic keratosis (AK), the epidermal skin lesions which may progress to squamous cell carcinoma. In a series of studies, diclofenac HA gel applied twice daily for 60 or 90 days, produced significant reductions and, in many cases, complete clearance of lesions.8 

Few comparative studies have been carried out on AK treatments but a recent network meta-analysis of data used in a Cochrane review showed that patients using diclofenac were less likely to achieve complete clearance of AK lesions than with the other commonly used topical agents, 5-FU, imiquimod and ingenol mebutate.9 Because skin reactions are common with AK treatments, tolerability and duration of treatment are also likely to play a role in choice of therapy. In the Cochrane review, treatment withdrawal due to adverse events was more common with diclofenac than with imiquimod.10

Cardiovascular concerns

During most of the time since diclofenac was launched, safety guidance has focused on the risk of gastrointestinal side effects with it and other NSAIDs. But it was the withdrawal of rofecoxib that led to a review of CV events with other NSAIDs.

In 2006, a meta analysis of data from randomised, placebo-controlled trials of COX2 and traditional NSAIDs showed a 42 per cent relative increase in the incidence of serious vascular events (1.2 per cent/year versus 0.9 per cent/year; rate ratio 1.42, 95 per cent confidence interval 1.13 to 1.78; P=0.003) in patients using a selective COX2 inhibitor.11 Overall, the risk for COX2 inhibitors and traditional NSAIDs was similar, but further analysis showed that the rate ratio for vascular events, compared with placebo, was 0.92 (0.67 to 1.26) for naproxen, 1.51 (0.96 to 2.37) for ibuprofen, and 1.63 (1.12 to 2.37) for diclofenac. The same year, warnings about the potential for CV events were added to NSAID prescribing information.

In 2011, a systematic review of community-based controlled observational studies, which included nearly 200,000 CV events and recorded outcomes in over 2.7 million NSAID users, again identified differences in CV risk between agents.12 The highest overall risks occurred with rofecoxib, 1.45 (95 per cent CI 1.33 to 1.59), and diclofenac, 1.40 (1.27 to 1.55), and the lowest with ibuprofen, 1.18 (1.11 to 1.25), and naproxen, 1.09 (1.02 to 1.16).

Earlier this year, the same authors again reviewed CV risk and related this to NSAID use in 15 low, middle and high income countries, including England.1 Diclofenac and the COX2 Inhibitor, etoricoxib, accounted for one-third of NSAID use across the 15 countries, and diclofenac was by far the most commonly used NSAID. Using 2011 prescribing data for England, the researchers showed that diclofenac was the single most prescribed NSAID.1 As well as urging that diclofenac should be removed from EMLs, they suggested there were strong arguments for its marketing authorisations to be revoked worldwide.

In October 2012, the EMA published the results of a review of recently published CV safety data for NSAIDs. It concluded that the evidence confirmed findings from previous safety reviews and that these were adequately reflected in current treatment advice for naproxen and ibuprofen. However, as the latest evidence showed a small but consistent increase in CV risk for diclofenac compared with other NSAIDs, similar to the risk of COX2 inhibitors, the Pharmacovigilance Risk Assessment Committee of the EMA was tasked with assessing all available data on diclofenac to see if treatment advice should be updated. Recommendations are expected soon.

Vulture crisis

Around the same time that the CV effects of diclofenac were being identified, the drug’s likely impact on the Asian vulture population was widely reported. Numbers declined rapidly during the 1990s and early 2000s so that, by 2007, the Indian population of white backed vultures was 0.1 per cent of previous levels and long-billed and slender billed vulture populations were down to 3.2 per cent of earlier levels.13 The dramatic mortality was attributed largely to renal failure caused by exposure to diclofenac in livestock carcasses on which the birds fed. Although not the most endearing species, vultures are important environmental scavengers and, since veterinary use of diclofenac was stopped in the region in 2006, the decline in vulture numbers has slowed.13

Twilight years

Latest prescribing data show that the message is getting through about the potential disadvantages of diclofenac to human users. Prescription Cost Analysis data for England show a reduction in oral diclofenac prescriptions from 4.7 million in 2011 to 3.2 million in 2012, with an accompanying increase in oral naproxen prescriptions from 4.2 million in 2011 to 5.7 million in 2012.  Oral ibuprofen prescriptions remained the same, at around 4.6 million.

“Diclofenac has been a very useful drug, but it is probably nearing the end of its useful life, and the cardiovascular issues may have put the final nail in its coffin,” concludes Dr Warburton. “But there are advantages to keeping a range of treatment options available since evidence can change. Look what happened to the COX2 inhibitors. We never know how new concerns will affect our remaining NSAIDs in the future.”

 

References

1 McGettigan P, Henry D. Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS Medicine 2013;10:e1001388.
2 Sallmann AR. The history of diclofenac. American Journal of Medicine 1986;80:29–33.
3 Siraux P. Diclofenac (Voltaren) for the treatment of osteo-arthrosis: a double-blind comparison with naproxen. Journal of International Medical Research 1977;5:169–74.
4 Dürrigl T, Vitaus M, Pucar I et al. Diclofenac sodium (Voltaren): results of a multi-centre comparative trial in adult-onset rheumatoid arthritis. Journal of International Medical Research 1975;3:139–44.
5 Caldwell JR. Efficacy and safety of diclofenac sodium in rheumatoid arthritis. Experience in the United States. American Journal of Medicine 1986;80:43–7.
6 Altman R. International experiences with diclofenac in osteoarthritis. American Journal of Medicine 1986;80:48–52.
7 Catalano MA. Worldwide safety experience with diclofenac. American Journal of Medicine 1986;80:81–7.
8 Jarvis B, Figgitt DP. Topical 3% diclofenac in 2.5% hyaluronic acid gel: a review of its use in patients with actinic keratoses. American Journal of Clinical Dermatology 2003;4:203–13.
9 Gupta AK, Paquet M. Network meta-analysis of the outcome “participant complete clearance” in non-immunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review. British Journal of Dermatol 2013 Mar 29. doi: 10.1111/bjd.12343. [Epub ahead of print].
10 Gupta AK, Paquet M, Villanueva E et al. Interventions for actinic keratoses. Cochrane Database of Systematic Review 2012 Dec 12;12:CD004415. doi.
11 Kearney PM, Baigent C, Godwin J et al. 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;332:1302–8.
12 McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Medicine 2011;8:e1001098.
13 Prakash V, Bishwakarma MC, Chaudhary A et al. The population decline of Gyps vultures in India and Nepal has slowed since veterinary use of diclofenac was banned. PLoS One 2012;7:e49118. doi: 10.1371/journal.pone.0049118. Epub 2012 Nov 7.

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11121261

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