Drug safety in a world of multimorbidity and polypharmacy

A new paper published today in the BMJ by Shin and colleagues has identified an increased risk of brain haemorrhage from the combined use of antidepressant medicines and non-steroidal anti-inflammatory drugs (NSAIDs). Colleagues from Glasgow and I discussed the clinical implications of this in an accompanying editorial.

These medicines are very commonly used. NSAIDs, which include products such as ibuprofen, are one of the top-twenty most frequently prescribed medications in UK primary care. Non-prescription use is also widespread, with many products available off the shelf in supermarkets and without oversight from a pharmacist. Antidepressants medication use is also commonplace, although in the UK these are prescription only medicines. Importantly, depression and chronic pain frequently co-exist: roughly a third of those with a painful condition also experience depression, and over a quarter of those suffering depression also complain of pain.

So the fact that these medications, in combination, appear to increase the risk of intracranial bleeding, will understandably raise concerns amongst both doctors and the public, particularly in the primary care environment. But is it that straightforward?

There is already an established risk of gastrointestinal bleeding with this combination of drugs, probably greater than the newly identified risk of intracranial haemorrhage. Yet it is likely many GPs (and probably other doctors) remain unaware of this problem, and it does not influence the majority of prescribing behaviour anyway. So does this new found problem matter, or will it be interpreted by many as simply relatively unfounded scaremongering? One should not, after all, lose sight of the fact that the 30-day risk of intracranial bleeding is still low – around 0.05%. And given the absolute benefits of antidepressants and NSAIDs are generally not easily quantified, and need to be interpreted in the wider psychosocial context, the balance of harm and benefit remains uncertain.

Doctors will also understandably ask what the alternatives are: there are limited options for chronic pain relief, and access to non-pharmacological psychological interventions in the NHS is generally poor. Patients’ quality of life will often be significantly diminished by stopping these medicines.

And there are several important unanswered questions remaining. What are the longer-term risks, beyond the first month examined by the current study? What is the risk of the drugs when used separately? And can these findings from an East-Asian population be generalized to the rest of the world, given what we know about ethnic variations in drug metabolism? There is a need for further research to answer these uncertainties.

Overall, the paper by Shin et al identifies a potential small risk of adverse consequences of combining two common drugs, but unresolved queries remain and many clinicians are likely to find themselves in the difficult position of trying to explain the uncertain balance of risks and benefits to patients. Importantly, these issues are very relevant to the safe and rational use of medicines more generally, within the broader context of an increasingly multimorbid population and high rates of polypharmacy.

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