Alan Hakim and his colleagues at University College Hospital in London were some of the first scientists to bring these cases to light. Hakim was helping to run a clinic for people with Ehlers-Danlos Syndrome (EDS), a group of very rare genetic diseases characterised by defects in connective tissue, leading to joint hypermobility, skin that bruises easily and fatigue.

But Hakim found that some of these patients reported resistance to local anaesthesia. Instead of going numb, they were having to endure the pain. “It became obvious to us that it was a question we should ask every patient we see in the clinic,” recalls Hakim, who co-authored a short report about the findings in 2005.

Eleven years after writing about the problem, Hakim says there has still been no formal medical investigation into the causes for local anaesthetic resistance in these cases, although there are a few theories. One hypothesis is that their tissue is slightly different from non-EDS patients and that might affect how the anaesthetic is absorbed. Local anaesthetics work by disrupting sodium channels. These channels conduct positively charged sodium ions – and with them the feeling of pain – to nerve cells. But there are still some questions over the nuts and bolts of this process. Filling in the details of that mechanism might explain why some patients find certain drugs – say, articaine instead of lidocaine – work better than others. One theory proposed for the heightened efficacy of articaine, for example, is that it is more soluble in fat (lipids) and therefore diffuses better through each nerve’s membrane.

It’s also possible that the patients’ nerves may be in slightly different places from the norm, with some evidence that dentists can overcome the problems by changing the location of the injection. Sometimes local anaesthetic is injected into the tissue under the skin, known as infiltration, and sometimes it is injected into or next to a nerve, what’s called a nerve block. In the latter case, the anaesthetic gets distributed directly to nerve cells further down the nervous system from the block. A dentist might use a nerve block if he or she is going to do a significant amount of drilling, for example, since more nerves will be affected and the anaesthetic will not have to diffuse through so much tissue to reach them.