Erythromelalgia Pain Research Articles

Locus revealed: Painlessness via loss of NaV1.7 at central terminals of sensory neurons

How genetic loss of the sodium channel NaV1.7 results in painlessness is puzzling. MacDonald etal. (2021) demonstrate that instead of impairing peripheral excitability, NaV1.7 channels at central terminals of pain-sensing afferents play a pivotal role in the balance between pain and analgesia.

Novel treatment modality in a case of resistant erythromelalgia

<p>Erythromelalgia presents with redness, pain and warmth of the extremities, which is exacerbated by warming and relieved by cooling. Treatment of pain in erythromelalgia can be difficult, and often polypharmacy is utilized. No single therapy has been found to provide complete relief for any patient. Therefore, a multidisciplinary approach is required to treat pain and its significant negative impact across many domains of functioning. A 21 year old male diagnosed case of primary erythromelalgia since 5 years, presented multiple times with recurrent pain and erythema in bilateral lower limbs. Patient was treated initially with oral antibiotics, tramadol and prednisolone, without relief. Aspirin, amitriptyline, pregabalin, carbamazepine, atenolol were later added which gave him partial relief. Epidural caudal catheter with daily infusion of anesthesia was added along with topical buprenorphine patch when conservative polypharmacy failed to provide complete relief and later unilateral lumbar sympathectomy was done as a last resort. Adding pentoxifylline and compression therapy improved the patient’s condition drastically and complete remission is in progress. The patient required a multidisciplinary approach for pain management and surgical intervention was required due to his refractory nature. However, this also does not give complete relief and thus a combination of both medical and surgical methods is required for best control of symptoms.</p>

Erythromelalgia – A dramatic pain of genetic origin, revealing pain mechanisms with implications for neuropathic pain in general

The name erythromelalgia was coined by Silas Weird Mitchell who also described causalgia) in 1878. In 2004 erythromelalgia ecame the first human neuropathic pain disorder known to be aused by an ion channel mutation, in the gene SCN9A encodng the voltage-gated sodium channel -subunit of NaV1.7. This oltage gated sodium channel is expressed in C-fibres of periphral nerves and in nerves of the sympathetic autonomic nervous ystem. Vaso-dilatation causes the red skin of erythromelalagia. A imilar painful disease, secondary eythromelalgia, can be caused by ide-effects ofmedication, e.g. verapamil and nifedipin. The attacks f erythromelalgia pain, lasting from hours to months, arise from yperexcitability of nociceptive C-fibres and their neurons in the orsal root ganglia and autonomic ganglia, and can be precipitated y exertion, heating of the affected extremities, or pressure to the

Douleurs chroniques et anesthésie locorégionale chez l’enfant

Chronic pain is usually underestimated in children, due to lack of knowledge and its specific signs. In addition to suffering, chronic pain causes a physical, psychological, emotional, social, and financial burden for the child and his family. Practitioners may find themselves in a situation of failure with depletion of medical resources. Some types of chronic pain are refractory to conventional systemic treatment and may require the use of regional anesthesia. Cancer pain is common in children and its medical management is sometimes insufficient. It is accessible to neuroaxial or peripheral techniques of regional anesthesia if it is limited to an area accessible to one of these techniques and no contraindications (e.g., thrombopenia) are present. Complex regional pain syndrome 1 is not rare in children and adolescents, but it often goes undiagnosed. Regional anesthesia may contribute to the treatment of complex regional pain syndrome 1, mainly in case of recurrence, because it provides rapid effective analgesia and allows rapid implementation of intensive physiotherapy. These techniques have also shown interest in phantom limb pain after limb amputation, but they remain controversial for erythromelalgia pain or chronic abdominopelvic pain. Finally, the treatment of postdural puncture headache due to cerebrospinal fluid leak can be treated by performing an epidural injection of the patient's blood, called a blood-patch. Finally, the management of children with chronic pain should be multidisciplinary (pediatrician, physiotherapist, psychologist, surgeon, anesthesiologist) to support the child and her problem in its entirety.

Top-Accessed Article: Combination Gel of 1% Amitriptyline and 0.5% Ketamine to Treat Refractory Erythromelalgia Pain

Sandroni P, Davis MP. Combination gel of 1% amitriptyline and 0.5% ketamine to treatrefractoryerythromelalgiapain:anewtreatmentoption?ArchDermatol.2006; 142(3):283-286. Erythromelalgia is a rare skin disorder characterized by severe burning pain, warmth, and erythema that is aggravated by heat and exercise. It is considered to be a neurovascular disorder associated with a small nerve fiber neuropathy and alteredvoltage-gatedsodiumchannels.Inrecentyears,neuromodulatingagents,such as gabapentin and pregabalin, as well as topical lidocaine, were found to be useful therapies. However, there are cases of erythomelalgia that remain resistant to these conventionaltherapiesandcauseextremesuffering.SandroniandDavisreportusing a novel treatment featuring combination gel of 1% amitryptiline hydrochloride and 0.5% ketamine hydrochloride in lecithin pluronic organogel applied 4 to 5 times a day in 5 patients with intractable erythromelalgia. In 4 of these patients, a significant response was noted, with the improvement rate ranging from 50% to 95%. The rationale for this combination can be explained by specific pathways that aretargeted.KetamineisanN-methyl-Daspartate(NMDA)receptorantagonistand a modulator of glutamatergic receptors. This is important since NMDA and glutamate are known to play a key role in neuropathic pain. Amitriptyline is a tricyclic antidepressant, which helps reduces pain in various disorders owing to its ability to block voltage-gated sodium ion channels. While topical application in limited body areas in this study did not lead to systemic absorption, the safety profile of thispreparationhasnotbeenfullyassessed.Nonetheless,thisanecdotalreportholds

Imaging the neural correlates of neuropathic pain and pleasurable relief associated with inherited erythromelalgia in a single subject with quantitative arterial spin labelling

We identified a patient with severe inherited erythromelalgia secondary to an L858F mutation in the voltage-gated sodium channel Nav1.7. The patient reported severe ongoing foot pain, which was exquisitely sensitive to limb cooling. We confirmed this heat hypersensitivity using quantitative sensory testing. Additionally, we employed a novel perfusion imaging technique in a simple block design to assess her baseline erythromelalgia pain vs cooling relief. Robust activations of key pain, pain-affect, and reward-related centres were observed. This combined approach allowed us to confirm the presence of a temperature-sensitive channelopathy of peripheral neurons and to investigate the neural correlates of tonic neuropathic pain and relief in a single subject.

Experience with oral mexiletine in primary erythromelalgia in children

Primary erythromelalgia is characterized by burning pain, redness, and warmth in the extremities. We present two cases of primary erythromelalgia both of whom presented with a history of several months of severe burning pain in both hands and feet. Both patients had received multiple pain medications with no improvement in symptoms. Pain was relieved by putting affected parts in ice cold water, which resulted in immersion injury of the affected parts. Both patients stopped taking part in school and social activities. We tried oral mexiletine, a class Ib antiarrythmic agent, in view of its reported role in various chronic painful conditions. Dramatic improvement was observed with its use. Both patients improved after several weeks of use, and there were fewer soaking episodes. We observed no adverse effects with mexilitine therapy.

Mutation I136V Alters Electrophysiological Properties of the NaV1.7 Channel in a Family with Onset of Erythromelalgia in the Second Decade

BackgroundPrimary erythromelalgia is an autosomal dominant pain disorder characterized by burning pain and skin redness in the extremities, with onset of symptoms during the first decade in the families whose mutations have been physiologically studied to date. Several mutations of voltage-gated Na+ channel NaV1.7 have been linked with primary erythromelalgia. Recently, a new substitution NaV1.7/I136V has been reported in a Taiwanese family, in which pain appeared at later ages (9–22 years, with onset at 17 years of age or later in 5 of 7 family members), with relatively slow progression (8–10 years) to involvement of the hands. The proband reported onset of symptoms first in his feet at the age of 11, which then progressed to his hands at the age of 19. The new mutation is located in transmembrane segment 1 (S1) of domain I (DI) in contrast to all NaV1.7 mutations reported to date, which have been localized in the voltage sensor S4, the linker joining segments S4 and S5 or pore-lining segments S5 and S6 in DI, II and III.ResultsIn this study, we characterized the gating and kinetic properties of I136V mutant channels in HEK293 cells using whole-cell patch clamp. I136V shifts the voltage-dependence of activation by -5.7 mV, a smaller shift in activation than the other erythromelalgia mutations that have been characterized. I136V also decreases the deactivation rate, and generates larger ramp currents.ConclusionThe I136V substitution in NaV1.7 alters channel gating and kinetic properties. Each of these changes may contribute to increased excitability of nociceptive dorsal root ganglion neurons, which underlies pain in erythromelalgia. The smaller shift in voltage-dependence of activation of NaV1.7, compared to the other reported cases of inherited erythromelalgia, may contribute to the later age of onset and slower progression of the symptoms reported in association with this mutation.

Combination Gel of 1% Amitriptyline and 0.5% Ketamine to Treat Refractory Erythromelalgia Pain

A 17-year-old white woman presented with a 2-year history of increasingly frequent episodes of erythromelalgia involving her hands, feet, and lower legs (Figure). She described the discomfort as “throbbing, burning, stinging.” Her symptoms occurred daily. The episodes involved her feet about 10 to 15 times during the day and involved her hands slightly less frequently. Whenever her feet got warm at night, erythromelalgia developed. These episodes were extremely painful. Generally, the erythema and pain occurred independently in the hands and feet. The symptoms were precipitated in her hands and feet by exercise; for example, walking precipitated the symptoms in her feet and legs, and writing precipitated them in her hands. Occasionally, the symptoms occurred when she was at rest, and they occasionally were worse at night. The symptoms lasted from minutes to up to 2 hours. She relieved the symptoms by cooling the affected area with ice and by raising the symptomatic limbs above the level of her heart. At night, she would stick her feet out of bed to relieve the symptoms and, during warm weather, used a fan.

Control of intractable pain in erythromelalgia by using spinal cord stimulation

A 69-yr-old woman with severe, long-standing erythromelalgia possibly secondary to multiple deep-vein thromboses, was treated with transcutaneous electrical nerve stimulation for the burning pain in her legs and feet. Problems developed, and she was subsequently successfully managed with spinal cord stimulation. The relief was reproduced after a 6-mo period of no stimulation by reestablishing spinal cord stimulation.