Almost 40 years ago the antirheumatic and painkiller diclofenac came on the market. On account of many years of good therapeutic experiences, the prescription requirement for the medication for a 12.5-milligram dose was repealed in 2004. Since 2007 Diclofenac has also been available without prescription in a dosage of 25 milligrams per single dose. Non-prescription diclofenac preparations (maximum daily dose: 75 mg) for short-term self-medication (a maximum of four days) are approved for mild to moderate pain. Now scientists demand the withdrawal of diclofenac. How can that be?
Side effects like those of rofecoxib
Since its approval diclofenac has been the subject of numerous studies, the number of which is steadily increasing each year. Thus one finds in PubMed for the year 1990 145 studies that deal with diclofenac; in 2012 there were nearly four times as many, namely 538. In recent years diclofenac has again and again been associated with an increased risk of heart attacks and stroke. The fact that highly effective pain killers and anti-inflammatories also have side effects is no secret. Studies have shown, however, that with use of some nonsteroidal drugs (NSAIDs) such as rofecoxib, diclofenac or etoricoxib cardiovascular side effects occur more often than with others, such as with naproxen. The intake of diclofenac can lead to an increased risk of heart attack and stroke. Therefore its safety profile resembles that of the substance rofecoxib, better known as Vioxx, which in 2004 was taken off the market due to its cardiovascular-related side effects.
Known risks not relevant in practice
A study published in February 2013 in PLOS Medicine examined whether these long-acknowledged findings which form part of the risk profile of diclofenac are reflected in medical practice. This seems not to be the case: the authors examined sales data from 15 industrial, emerging and developing countries during 2011. This again reflected that diclofenac is the world’s best-selling NSAID by some distance. In these 15 countries diclofenac in total covers around 28 percent of sales in this drug class – almost as much as the three runners-up drugs (ibuprofen 11%, naproxen 9% and mefenamic acid 9%) combined.
Germany does not appear in the study, but in that country diclofenac is also often either prescribed or bought over the counter. Why is that? “There are aggressive marketing strategies by pharmaceutical companies behind it”, presumes Prof. Dr. Christoph Stein, medical director and chief physician of the Department of Anesthesiology of the Charité at the Benjamin Franklin Campus in Berlin.
National lists for guidance
When prescribing NSAIDs, physicians should keep the pre-existing conditions and the risk profile of their patients in mind. Especially with cardiovascular patients, physicians should either decide against NSAIDs or prescribe an NSAID which is associated with a relatively low cardiovascular risk, according to recommendations given by the WHO. Here, doctors can – such is the original plan – orient themselves using lists published by the WHO and also by many national authorities. For pharmacists this means, even in the non-prescription dispensing of low-dose diclofenac, informing about the possible risks and side effects.
Looking at the WHO list of essential medicines under the heading NSAIDs, ibuprofen and ASS can be found, but not diclofenac. Yet the current study showed that diclofenac appears in the national lists of 74 from 86 countries – naproxen, the apparently safer alternative, appears however only on 27 of the national lists. A farce according to the study authors: “The recommendations on the national lists of essential medicines should be based on a well-validated risk-benefit comparison and favour safe medicines”, say the scientists.
Diclofenac: abysmal risk profile
In their meta-analysis, the researchers examined the risk profile of various NSAIDs. Diclofenac and etoricoxib in particular, compared to ibuprofen and especially naproxen, fare poorly. Diclofenac thus does not seem to cause fewer gastrointestinal discomforts than other NSAIDs, but does lead more frequently to attacks and strokes. The scientists see in this compelling reasons to demand a worldwide withdrawal of authorisations for diclofenac.
Are there alternatives to diclofenac?
Yet diclofenac also offers a variety of advantages which are proven by the NSAID researchers: according to an in-vitro study from 1988 diclofenac possesses from among the common NSAIDs the highest potency. Clinical studies later confirmed that 25 mg diclofenac is as effective as 400 mg ibuprofen or 1000 mg of acetyl salicylic acid because diclofenac quickly moves into inflamed tissue, the active agent already after 30 minutes reaching its maximum level of effect. Even aspirin and ibuprofen, which require one to two hours for this process, cannot keep up. The apparently better tolerated naproxen, in comparison to these four NSAIDs, is with an uptake time of 2 to 4 hours in last place. Also with respect to risk of accumulation diclofenac seems to step ahead, because the substance is rapidly removed from the body. Thus, the elimination half-life of diclofenac is only one or two hours. Naproxen on other hand has a half-life of twelve to 25 hours.
Replacing diclofenac in practice with other NSAIDs is nevertheless something Prof. Stein is quite able to imagine: “The so-called ‘cons’ in the pharmacokinetics could be offset by a change in intake intervals. The so-called ‘potency’ is anyhow based mostly on in-vitro studies that do not allow conclusions on efficacy in clinical reality”, he says. NSAIDs, he adds, are inherently dangerous. “With all NSAIDs there exists an increased risk of cardiovascular side effects”, Professor Stein continues. For the chief surgeon, it is important alongside the prescription of NSAIDs to take into consideration the patient’s individual risk factors.
BfArM: Withdrawal from the market?
What do the authorities say about withdrawal from the market? The German Federal Institute for Drugs and Medical Devices (BfArM) upon request made by DocCheck on risk evaluation of diclofenac remarked as follows: “The known risks of diclofenac have in the past already led to contraindications, special warnings and precautions on use of diclofenac with patients carrying pre-existing cardiac conditions. At present diclofenac, with the participation of BfArM from the European Medicines Agency (EMA), is being reassessed. To what extent this will lead to other possible measures for the safety of patients we cannot yet conclusively say”. Whether the biggest selling NSAIDs may be withdrawn from the market remains to be seen.