Cause and genetics of local anesthetic resistance

Whole-exome sequencing of a family with local anesthetic resistance. – PubMed – Minerva Anestesiol. 2016 Oct

Many people with EDS experience eventually discover that local anesthetic doesn’t work on them.

This seems so improbable that doctors simply cannot believe it and cause their patients much suffering when they slice into the skin for some procedure for which it should be numbed.

Local anesthetics (LA) work by blocking sodium conductance through voltage-gated sodium channels.  

Complete local anesthetic resistance is infrequent, and the cause is unknown. Genetic variation in sodium channels is a potential mechanism for local anesthetic resistance.

A patient with a history of inadequate loss of sensation following LA administration underwent an ultrasound-guided brachial plexus nerve block with a complete failure of the block. We hypothesized that LA resistance is due to a variant form of voltage-gated sodium channel.


Whole-Exome Sequencing. The patient and her immediate family provided consent for exome sequencing, and they were screened with a questionnaire to identify family members with a history of LA resistance.

Exome sequencing results for four individuals were referenced to the 1000 Genomes Project and the NHLBI ESP to identify variants associated with local anesthetic resistance present in less than 1% of the general population and located in functional regions of the genome.

These variants are far more common in people who inherit other aspects of EDS as well.


Exome sequencing of the four family members identified one genetic variant in the voltage-gated sodium channel shared by the three individuals with LA resistance but not present in the unaffected family member. Specifically, we noted the A572D mutation in the SCN5A gene encoding for Nav1.5.


We identified a genetic variant that is associated with LA resistance in the gene encoding for Nav1.5.

We also demonstrate that Nav1.5 is present in human peripheral nerves to support the plausibility that an abnormal form of the Nav1.5 protein could be responsible for the observed local anesthetic resistance.

Here are more posts about this phenomenon:

I wrote an article about my own experience with this:

If you have the time and inclination, you can also help university researchers by filling out this survey:

3 thoughts on “Cause and genetics of local anesthetic resistance

  1. lavenderandlevity

    I once pulled my own baby tooth as a child because the dentist was taking so long and I felt it all. He didn’t believe it and I just wanted it over as fast as possible so I grabbed his hand with the tool and just yanked for all I was worth. The adults all laughed at the silly kid…but it never changed. I’ve always been in serious pain under local anesthetic.

    Liked by 1 person

    1. Zyp Czyk Post author

      Perhaps you can bring this article with you next time you need local anesthetic for some procedure. I think they can try different types of anesthetic to find one that could work for you.

      This is truly a case where a doctor has to believe the patient despite all they’ve been taught and experienced so far in their career. I can understand how hard it would be for a doctor to believe us, so documentation is needed.

      Liked by 3 people

  2. Pingback: People who can’t go numb from local anesthetic | EDS and Chronic Pain News & Info

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