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We shouldn’t let diclofenac become the new lumiracoxib…

A new study on diclofenac and cardiac risk suggests that the risk-benefit analysis for this commonly used non-steroidal anti-inflammatory (NSAID) should now be regarded as completely unfavourable. The implication of such a scientific judgement is that it should be withdrawn from sale altogether, as a public health measure.

Removing a drug from sale is advocated for various reasons from time to time. Some, such as dextropropoxphene seem to be effective, but are found to be no more effective than much safer drugs. Others, such as sibutramine turn out to have unforeseen risks which become apparent with widespread use outside of clinical trials.

Others are harder to understand. Lumiracoxib was a highly effective NSAID which in numerous patients of mine was effective at improving serious musculoskeletal pain where no other drug had been useful. It was, quite literally, a hope for some patients who had none otherwise. The problem was that 8 people out of the 60,000 who took it suffered significant liver damage. Of the 8 cases reported to TGA, 2 survived with liver transplants and 2 died so there was no disputing the seriousness of the liver damage.

The issue for my patients however was that none of them had abnormal liver function tests, and they couldn’t see how the drug should be denied them when they were quite happy to take on the 1 in 7500 chance of serious toxicity.

Isn’t this fair enough?

Fans of lumiracoxib were quick to point out the case of clozapine. Clozapine is a very potent anti-psychotic drug which caused tremendous debate in the mid-1990s due to its ability to improve severe chronic psychosis in previously untreatable patients. Its big drawback was that it had a habit of knocking off peoples' bone marrow and stopping it producing white blood cells. It does this at a rate of around 1 in 100 people who take it. When regulators moved to ban it from sale, they were met with requests from doctors and patients to waive their legal protections and keep taking it, as the patients whose lives were being changed remarkably for the better were arguing that they would rather risk death than go back to the nightmare they had been living before starting clozapine. A reasonable accommodation was reached whereby the drug company paid for the ongoing costs of regular blood tests to monitor the white cell counts and patients taking clozapine were given standard educational materials and asked to consent in writing to the treatment.

Commonly used antibiotics like flucloxacillin and amoxycillin/clavulanic acid have much higher rates and raw numbers of serious liver injury, but have never been close to getting banned. A supreme irony is that diclofenac itself killed more people from liver failure in its first 5 years of use than lumiracoxib ever did!

Beside these figures, simply banning lumiracoxib for a rare and potentially avoidable side effect still rankles as an officious overreaction.

The diclofenac data reported above has been known (at least in the circles I hang out in) for quite a while. Even the Daily Mail in the UK - hardly known as a beacon of common sense - reported this back in 2011 in quite a balanced way. The reason nobody is kicking up too much is that diclofenac is used overwhelmingly for short-term relief from acute musculoskeletal pain, and the additional cardiac risk doesn’t kick in unless you are using it consistently over the medium to long term. It also has quite a short half-life compared to many other NSAIDs, and thus even a daily dose will mean you’re spending most of the time throughout the day without high levels of it in your system. And there are many, many people who benefit from intermittent bursts of diclofenac where little else helps.

The well-characterised excessive cardiac risk of diclofenac should mean that discussions about this risk are built into long-term decision-making about treatments. Potentially risky treatments should be reserved for severe or recalcitrant diseases, and consumers should be kept fully informed. Banning a useful but risky treatment shortchanges consumers as much as allowing them to be exposed to an overly risky one. Informed consent shouldn’t be replaced by bureaucratic paternalism.

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6 Comments sorted by

  1. Sue Ieraci

    Public hospital clinician

    Very pertinent article - thanks.

    As our risk-averse society develops less and less tolerance for imperfection, we are forcing regulators into more restrictive decisions - not always for the greater benefit.

    People who are suspicious pharmaceutical companies and orthodox medicine love the example of "Vioxx" (Rofecoxib) - one of the earlier cyclo-oxygenase (COX)-II inhibitors, which was effective for its core purpose, safer for gut bleeding that other NSAIDs, but caused an increase in cardiac…

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  2. Michael Tam

    Conjoint Senior Lecturer, and Staff Specialist in General Practice at UNSW Australia

    I agree somewhat that an outright ban seems somewhat of an over-reaction.

    However, I think we do need to address the issue that it remains one of the most widely used NSAIDs despite its apparent poor cardiovascular risk profile, and the fact that it is probably no more effective than any other NSAID. I have little faith that education in this area in itself will have much impact in changing clinical practice - as you mentioned Michael, the risk from diclofenac has been known for quite a while.

    Perhaps we need something like the black box warning system in Australia...

    1. Michael Vagg

      Clinical Senior Lecturer at Deakin University School of Medicine & Pain Specialist at Barwon Health

      In reply to Michael Tam

      The easiest thing to do would be for the TGA to make it prescription-only again and the PBS to introduce a streamlined Authority indication specifying that it should only be used where safer NSAIDs are clinically inappropriate.

      That's so crazy it just might work!

    2. Michael Tam

      Conjoint Senior Lecturer, and Staff Specialist in General Practice at UNSW Australia

      In reply to Michael Vagg

      That's certainly a option!

      I'm of the opinion though that we should aim for the least amount of regulation in achieving an outcome - it's less likely to lead to an unexpected effect. If we wanted to de-incentivise the use of diclofenac without a ban, we could just strip it of its PBS listing and making it available only as an S3 drug.

      People who really benefit from it, can still access it without too much fuss. On the other hand, there is a reasonably strong economic incentive to use other NSAIDs and it will no longer be sitting there openly on a pharmacy shelf. Also, it doesn't push the administrative burden onto GPs!


  3. Michael Woodhead

    logged in via Twitter

    I am told by clinical pharmacologists that the efficacy and cardiac risk of NSAIDs are both related to their COX-2 inhibitory activity. Diclofenac is one of the more potent (non-selective) COX-2 inhibitors. If you switch to a weaker drug such as naproxen, a higher dose will be needed for analgesia ... and this will confer the same cardiac risk. Paracetamol is also not without toxicity - a study in the BMJ this week notes it is responsible for about 120 deaths a year in the UK due to poisoning. All drugs have a risk-benefit ratio. If someone has severe pain they may be prepared to accept a small increase in cardiac risk for an analgesic that works, especially for short term treatment. The cardiac risk is dependent on duration of treatment - with rofecoxib it was only apparent after 3-5 years use.

    1. Michael Vagg

      Clinical Senior Lecturer at Deakin University School of Medicine & Pain Specialist at Barwon Health

      In reply to Michael Woodhead

      That's true Michael. That said, celecoxib and etorixocib which are the two COX-2 selective drugs available in Australia both have very low cardiac risk, and are also highly effective analgesics.

      Most of the 'league tables' of cardiac risk take equianalgesic dose equivalence into account when quantifying cardiac risk. I would completely agree with your comments about duration of exposure to NSAIDs being important. This is why many doctors (and well-informed consumers) are happy to trade off a very marginal increase in long-term CV risk for having a packet of tabs on the shelf that can effectively ease flareups of long-term pain.