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Anesthesiology/Local anesthetic resistance, especially lidocaine and other -caine derivatives


I read your 2012 Q&A on resistance to local anesthesia along with your linked blog article on sodium channels. [ ]

As one of those people with a consistent record of resistance to local anesthetics particularly of the -caine variety, I took it for granted this was a known subset. Seeing in the comments how often people are dismissed when they say they have this, even to the point that procedures and surgeries continue over their protestations of pain, has been a reality check for me.

In any case, especially as the 2012 question referenced a dad and daughter both not responding to -caine drugs, I wanted to comment on a known subset of people who would present exactly like that: Ehlers-Danlos Syndrome, especially the Hypermobile type and to a lesser degree the Classic or other non-vascular types. Here's one study that confirmed the reality of -caine resistance in EDS:

EDS is an umbrella disorder meaning a genetic mutation causes the body to either make one of the types of collagen incorrectly or to use a type of collagen incorrectly. Which of the currently-known 36 types of collagen is affected is determined by the particular gene mutation and that in turn affects which parts of the body are structurally defective at a cellular level. Vascular EDS is the most well-known and well-studied type because the affected collagen builds major arteries like the aorta and a weakness leads to a sudden unexpected death. There are many non-vascular EDS types that do not affect life expectancy, with Hypermobile and Classic being the most common. Current estimates put EDS incidence at 1:5000 realistically and 1:2500 when aggressive identification is used. It's really common, especially in it's more mild forms, so I'd expect doctors to experience these patients' complaints frequently even if they don't label them correctly.

Collagen is the building block for all the body's structures. Instead of forming a tightly knit weave like a denim that can bend and flex while keeping it's strength and shape as it is supposed to, the EDS mutation causes the affected collagen to instead form a loose and stretchy weave, more like a knit fabric. Some like to compare it to a stretched out rubberband or to old elastic on underwear. The current literature says this is autosomal dominant (50/50 chance of being passed on, with child always having the same disorder as parent) and that half of cases show up out of the blue (de novo) with no family history.

Most of the Hypermobile EDS people are misdiagnosed as having fibromyalgia (one EDS expert says half of all fibro cases have underlying EDS), chronic regional pain syndrome, osteoarthritis, or similarly accurate but small window pictures into their full situation. While in some ways this is beneficial as it doesn't open them to genetic bias in employment, medical care, fertility management, and non-protected insurances like life and disability, it tends to limit their access to appropriate pain management and comprehensive care (though plenty do not see improvement in these areas even with the diagnosis). For example, a fibromyalgia dx often restricts opioid management while EDS responds quite well to opioids. On the flip side, many people with EDS are given steroid injections for their joint pain without informed consent explaining that the steroids break down collagen and could, in the long term, exacerbate their underlying collagen disorder that is causing the pain.

Many people with EDS also find that they have drug metabolism variances, like CYP450 differences (although it isn't clear if there's a higher incidence or a higher discovery rate in this subset more likely to need chronic pain management); some report that OTCs like Zyrtec put them to sleep while others can tolerate 3x the dose of narcotics with little benefit or effect. -Caine resistance (especially lidocaine in dental settings) is a textbook hallmark that should immediately trigger suspicion of EDS, though not all EDS patients are affected by it. A generalized dysautonomia is a frequent occurrence in EDS, especially, again, with the Hypermobile type and then Classical and other non-vascular types to a lesser degree, with the most common situation being sluggish parasympathetics (mistaken for constipation, slow stomach emptying, low libido, etc) and overreactive sympathetics (mistaken for orthostatic hypotension, sometimes identified as the more confined POTS, but largely unaddressed). Most with EDS are unaware of their recurrent subluxations and/or dislocations, if they occur based on type. Research is just beginning to emerge that also links mast cell activation disorder with EDS.

The skin elasticity associated with some types of EDS can lead to a youthful or glowing appearance, which can unfortunately work against patients when seeking a diagnosis for an invisible, poorly researched, genetic/cellular level disorder that isn't on most doctors' radars. A subset of EDS patients are also marfanoid, being tall and thin with long limbs. One of the hallmarks of the non-vascular types is hypermobility, adding to the impression of health with older patients often retaining high degrees of flexibility. It appears that women seek and/or obtain a diagnosis more often than men, even though both should be equally affected. It is possible that male hormones provide some sort of protective effect, especially as there's strong anecdotal evidence for increased comorbidity of endocrine disorders like hypothyroidism, PCOS, and diabetes. A tall, thin, youthful-looking, flexible woman (while not the only face of EDS, a common presenting one) who is complaining of rare and/or random and seemingly unconnected issues is highly unlikely to be taken seriously.  Many instead experience doctors dismissing the issue as women's histrionics/psychiatric issues, leading to a higher incidence of anxiety diagnosis even though research shows when the autonomic dysregulation (neurological expression) is controlled for that those with dysautonomia actually have comparable or lower incidences of anxiety (psychological maladaption) than the general population. [ and and Stress, Catecholamines, and Cardiovascular Disease by Dr. David S. Goldstein (New York:  Oxford UP 1995, pp. 40-41).]

Due to the amount of crossover between non-vascular types seen in many families, there's speculation that it might be a multigenic disorder with varying levels of expression, but there really isn't much known at this point. There's simply not enough research into the body parts affected and how they interact, much less the disorders of them. That's why your calcium channel discussion is of particular interest to me: it is possible that the local anesthetic resistance seen in EDS could help elucidate the next level of research, connecting the frequent drug metabolism issues and general dysautonomia and the currently unresearched hormonal interactions to the structural changes that are already identified in EDS.

I'd like to encourage you to:
-Listen for stories that sound like EDS in your patients
-Feel the skin of all patients (the volar forearm is a great location) to take note of texture and elasticity so you start identifying patterns
-Share information about EDS and anesthetic management with your colleagues
-Write more accurate case reports and/or other peer reviewed articles about anesthetic and/or pain management of EDS to broaden the base of knowledge
-Try to recognize chronic generalized dysautonomia symptoms in patients
-Check biases against those with medical complaints who appear anxious or who appear healthy/youthful by cultural standards
-Continue to question and research anesthetic resistance, especially in the EDS population, as this could lead to both practical and foundational explosions in information that will help many, many people

I'd particularly be interested in following your musings on the possible pathways of anesthetic resistance when EDS is taken into account!

Your emphasis is on EDS is appreciated.  my case report is a report of suspected LA resistance in a patient with no other symptoms consistent with EDS.  There are a number of reasons why my patient may have not responded to the  LA injection one of which is resistance.  My goal was to focus on this entity (resistance), not increase awareness about EDS.  I feel like the case was report was accurate in its limited focus and for it's intended audience.

I, however will look into your discussion of EDS and look for ways in which anesthesiologist can better prepare for these types of patients.

Thanks again
Dr Russell


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Rex Russell


Any question dealing with general anesthesia issues. With particular emphasis on regional anesthesia.


I am a board certified anesthesiologist, graduated from residency in 2004 from Johns Hopkins Hospital. I have since worked as an anesthesiologist first in the Air Force for three years and then most recently in Texas in Private Practice.

Texas Medical Association Texas society of Anesthesiologists American Society of Anesthesiologists

BS, BYU MD, U of Texas, Galveston Intern-St. Joe's Hospital, Phx, AZ Internal Medicine Residency-Johns Hopkins Hospital, Baltimore, MD

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