To Lori Lemon, the doctors all seemed flabbergasted. She had come in to the Mayo Clinic in Jacksonville, Florida, to have a lipoma – a growth of soft fatty tissue under the skin – removed from her elbow. She needed to have the area around the lump numbed for the procedure, but that was proving inexplicably difficult.
“All the ways and all the different medications that they had at their disposal – none of them worked,” she says. Steven Clendenen, an anaesthesiologist at the clinic, confirms her story. “The nerves were flooded with local anaesthetic and at the time it didn’t work,” he recalls. Her physicians might have been surprised, but Lemon wasn’t. She’d had this problem, local anaesthetic resistance, for as long as she could remember. The first time she remembers it coming up was decades ago at the dentists, when she was about seven.
I just kind of screamed and was in tears the whole time – Lori Lemon
“They started working on me and I, being obedient, I just raised my hand and let ’em know, ‘I can feel this’,” she says. Another injection of the local anaesthetic had no effect. “Finally I just kind of screamed and was in tears the whole time.”
Clendenen, who had seen first-hand the effects this resistance had on his patient, decided to investigate further. He found a handful of stories scattered in the medical literature concerning strange cases where patients claimed local anaesthetic had no effect on them. It turns out that no-one really knows what’s going on in these patients – either in terms of what mechanisms cause the resistance, or what the best remedy may be. But a new genetic study of Lemon and her family may set us on the path to discovering the answer.
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.
Hard data is thin on the ground, however. Some existing articles probing the reasons for local anaesthetic resistance in EDS patients don’t delve into detail like this. “They haven’t been specific to say whether this is the infiltration technique or the nerve block technique [that has failed],” notes Joel Weaver, a dentist anaesthesiologist at Ohio State University. Weaver, like others, advocates more research into the issue.
Hakim says the work done by him and his colleagues has raised awareness among doctors and dentists that local anaesthetic resistance is a genuine problem. But many today have never heard of it and are sceptical, when first told, that it even exists.
It is a fact that Jenny Morrison, an EDS nurse and sufferer of the condition herself, is only too familiar with.
“It works for a few minutes and wears off very quickly,” she says. “In some people it doesn’t work at all, but for me it probably lasts about 10 minutes.”
Some of her patients have told her that their doctor or dentist simply won’t believe them when they say “local anaesthetic doesn’t work on me”. Ehlers-Danlos UK, a charity, has published some information that patients are able to show their doctor in order to explain the current medical understanding of the problem. But while Morrison says this can help, a real change in practitioners’ perceptions will probably only come about when a large, formal study confirms the existence of the phenomenon in a sizeable sample of patients. “I think until there’s that level of proof about it, it’s going to be very difficult to get doctors to accept it,” she says.
I sat through the entire heart catheterisation and felt every bit. That is no place a patient wants to be – Lori Lemon
Lori Lemon says this has been her experience, too. Besides the dentist and more recent procedures, she recalls other painful experiences involving surgery. She gives the example of a heart catheterisation, in which a long thin tube is threaded through the patient’s veins to the heart.
“I sat through the entire heart cath and felt every bit,” she says. “That, again, is no place a patient wants to be.”
But there’s something else surprising about Lemon’s case: she has never been diagnosed with EDS. Could there be other reasons for her resistance to the anaesthetics? This is what Steven Clendenen wondered when he first began to examine her medical history. His son Nathan, at Yale University School of Medicine, suggested there could be a genetic cause. The result of their team’s investigation is a new study hinting that anaesthetic resistance may be more prevalent than we previously thought.
They asked other members of Lemon’s family whether they experienced the same issue. It turned out that her mother and maternal half-sister shared the apparent resistance, though it wasn’t so pronounced, and yet her father did not. The next step was to analyse the family members’ genomes. When Clendenen and his colleagues did this, they discovered a genetic defect relating to a specific sodium channel in the body, known as sodium 1.5. The affected gene, called SCN5A, produces a protein called NaV1.5, which is a major component of this channel.
The type of mutation in question is known as a “missense” mutation, which means that one of the amino acids in the protein is different in people with this genetic quirk. As a result, the functionality of the protein can be affected. A similar mutation means that people with sickle-cell anaemia, for example, have abnormal haemoglobin – the protein designed to carry oxygen in their blood.
“We looked at the genetics of that and went, ‘wow’ – [her mother] had the same gene defect,” explains Clendenen. Her maternal half-sister did too, but her father, who reported no local anaesthetic resistance, didn’t.
But sodium 1.5 channels have only been studied in detail in heart tissue, not the peripheral nerves where local anaesthetic is applied. A chemical test, however, quickly showed that sodium 1.5 channels were present in peripheral nerves, so a genetic defect related to those channels could – in theory – inhibit anaesthetics in such areas of the body. It’s not clear what difference is caused by having this mutation, but it could make the sodium channels more likely to remain open, allowing signals to flow to the brain, despite the application of local anaesthetic. The anaesthetic usually inhibits the flow of sodium and therefore stops a pain signal being delivered from the nerve. But Clendenen admits the details of this mechanism still remain a mystery.
After presenting his paper at a recent conference, Clendenen says he was approached by several doctors who had stories of patients with as-yet unexplained resistance to local anaesthetics. He says one practitioner told him that he performed no fewer than five nerve blocks on the same patient – all to no avail.
Alan Hakim says the paper is “fascinating”. He points out that identifying the genetic differences potentially affecting ion channels in the nervous system could be useful for refining treatments for patients with the defect who suffer from anaesthetic resistance.
“It could be really quite powerful in terms of determining the type of medicine you might use and efficacy of it,” he says. However, Hakim emphasises that the sample size of the current study is limited to just one family – the result would need to be replicated elsewhere.
Clendenen says that the next step is to test more individuals who complain of local anaesthetic resistance to see if they share this genetic peculiarity. He also wants to examine the behaviour of local anaesthetics in cells containing the genetic defect in question.
Lemon is full of praise for his work and the Mayo clinic. While she emphasises how her condition has made her “frightful” of telling doctors that there might something wrong in case it requires surgery, she retains a sense of humour about it. “I feel like one of the X-Men,” she jokes, “that I have mutant genes.”
For those who have had to strain through invasive procedures at the doctor’s surgery without pain-relief, or undergo general anaesthetic just to have relatively routine dental work done, there might be fresh hope on the horizon. “This is really important to get that out there,” says Clendenen. “People don’t believe [these patients] and it’s very frustrating. Even some of my colleagues that I’ve talked to say, ‘I don’t believe it’.”
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