EM best conceptualized as a neurovascular neuropathic
pain condition? - New
http://www.erythromelalgia.org - The Erythromelalgia Association (TEA) is an international nonprofit organization made up of people with erythromelalgia, or their family members, or friends.
http://groups.yahoo.com/group/EM - This list was established (in January, 1999) to give people with erythromelalgia (aka "EM") a convenient way to communicate with each other about the disorder.
http://groups.yahoo.com/group/theredhots - A support group for people who suffer from facial flushing or blushing, along with redness, pain and burning. This includes people with severe rosacea or facial Erythromelalgia (EM).
This article submitted by Karl Granat on 2/16/99.
Email Address: KatlGra@aol.com
Form letter on Erythromelalgia:
Welcome!!! We wish to introduce you to our informal group on erythromelalgia (EM).
What is Erythromelalgia?
Erythromelalgia is a painful condition that has a very distinctive pattern of
symptoms.
It is diagnosed when the extremities are red, warm and painful- the pain is
often described as burning. This pain is only relieved by cooling (often in cold
water) or the elevation of the affected extremities.
New Research on Erythromelalgia
(Vol.
136 No. 3, March 2000-JAMA-Archives of Dermatology:-Erythromelalgia-A Mysterious Condition?here)
"Erythralgia" has also been used and in the German literature erythroprosopalgia (prosoponface) describes "facial EM.")
Summary: "No objective diagnostic criteria exist for applying the diagnosis of EM. Davis et al apply 3 inclusion criteria: red, hot, and burning extremities. Brown12 in 1932 added 3 criteria: induction and exacerbation of symptoms by warming, relief by cooling, and unresponsiveness to therapy. The last criterion today seems to be incorrect, since several reports describe patients with excellent responses to therapy.13-15 The 2 articles describing the prognosis of the condition also document cure in some patients.4, 16...
We, therefore, would strongly advise a strict assessment of the following 5 criteria proposed by Thompson et al18 before applying the diagnosis of EM, but we recognize the problems of using all criteria in the retrospective study by Davis et al. The criteria of Thompson et al are as follows: (1) burning extremity pain, (2) pain aggravated by warming, (3) pain relieved by cooling, (4) erythema of affected skin, and (5) increased temperature of affected skin...
Most textbooks consider EM as a disease entity. We have hypothesized that EM is not a disease, but a condition caused by one common pathophysiological response: skin microvascular shunting with a corresponding hypoxia...
According to our shunting hypothesis, symptoms are caused by tissue hypoxia, induced by maldistribution of skin microvascular blood flow with increased thermoregulatory flow and an inadequate nutritive perfusion...
We are of the opinion that EM is a model for maldistribution of blood flow. Erythromelalgia is a rare condition, but we are convinced that pathogenetic mechanisms of this condition can reveal mechanisms relevant for other large groups of patients with disturbances in distribution of microvascular blood perfusion, such as patients with diabetes mellitus, septic shock, multiorgan failure, scleroderma, or leg ulcers...
We think that recent publications, including the Mayo Clinic article, have shown that the condition is still a great challenge to further research, but that the condition is not more mysterious than most other more common medical conditions."
)
There has been a recent EM published in November 1998 by Dr.
Knut Kvernebo of Oslo, Norway. It appears to be the most comprehensive and
provocative research yet done on EM. We suggest that you find a copy of the
monograph for you an your physician to read the updated article HERE.
It was published in VASA, Journal of Vascular Diseases, Supplement 51 (39
pages), Nov. 1998. Title, Erythromelalgia; A condition caused by microvascular
arteriovenous shunting by Dr. Kurt Kvernebo. (This material should be available
in most medical libraries. Your local librarian may be able to get it for you.)
Dr. Kvernebo's primary thesis is that "tissue hypoxia causes a
compensatory arteriolar dilatation and thereby increased microvascular perfusion
pressures. The concomitant flow increase is, due to maldistribution, shunted
through AV shunts or 'physiological shunts', and leads to increased skin
temperature. When the temperature increases, the metabolic rate will increase
(about 130% for every 10 degrees centigrade.) The oxygen consumption will
increase accordingly, and hypoxia will be maintained.....all patients benefit
from cooling of affected skin. According to the presented hypothesis this is
because cooling decreases the metabolic rate and tissue oxygen
consumption." In common terms, the tissue gets caught in a vicious cycle
where the body cannot correct the EM because the extremity cannot get the
nutrients needed to repair itself.
Dr. Kvernebo has successfully treated several patients using a powerful
vasodilating drug, Prostaglandin E1 or PGE1. The patients have had remissions
from a few months to several years.
It is important to note that what Dr. Kvernebo described are the
physiological mechanisms which cause the red, hot skin and burning pain. He does
not believe that EM is a particular disease, but rather a painful condition
probably caused by a number of different underlying issues from patient to
patient.
The Erythromelalgia Group:
Our informal group (it really has no name that I know of) is made up of
people who have this disorder. We share information on treatments and ways to
cope with this disorder as we go on with our lives.
The group also gives each other support and information regarding new
treatments that may be recommended by our physicians (i.e. the epilepsy drug
Neurontin is now being used to try to treat the burning pain).
JOINING THE GROUP-
To join our group, please write a short introductory letter, with a short
history and a little about yourself. I will forward your letter to the rest of
the group. You will hear from others! Make sure that you keep your e-mail up to
date with the group if you don't include your phone number!
Good luck to you, and-- Welcome!!!
Karl Granat
For Information please contact:
Karl Granat Ph. (503) 364-7736
e-mail: KatlGra@aol.com
--Nitroprusside IS DANGEROUS!!! (IT HAS BEEN USED SUCCESSFULLY ONLY IN
PERIATRIC PATIENTS.
--Prostaglandin E1 as mentioned in the Oslo study is not now available in the
USA to our knowledge, but we are looking into obtaining the treatment here.
1. Aspirin (If you respond to this treatment- be sure and tell your Doctor
and monitor
your blood counts periodically.)
2. Combined therapy of: Amiltriptyline and Neurontin
3. Neurontin (300-900mg 3X daily)
4. Combined therapy of: Neurontin, trental, and tricyclic antidepressants
5. Combined therapy of: Beta blockers, trental, and tricyclic antidepressants
6. Cooling garmets (for the hands, feet, arms, legs)
7. Effexor
8. Zoloft
9. Spinal cord implant
10. Lumbar sympathetic block and total spinal block.
11. Propranolol 10 to 40 mg orally
12. 40 % urea in aquaphor.
13. The drug: pizotifene, an antiserotoninergic drug.
14. Biofeedback
15. Combined therapy of: prednisolone, vitamins, and analgesics.
16. Piroxicam
17. Trental
18. Capsaicin
19. Erythromycin
20. Zostrix cream
21. Dibenzyline
22. Acupuncture and herbal tea combination
23. Combined therapy of: Trental, Diltiazem, and baby aspirin.
24. Ephedrine 25 mg orally.
25. Methysergide 1 to 4 mg orally.
26. Lamictal
27. Stereotaxic destruction of VPL and CM and partial rhizotomy (extreme).
If your condition is secondary (like some who have high mercury levels) relief
may occur with a resolution of that condition.
Some of these treatments have led to a remission, total cure or at least have
given some relief to some people. Do others know of more?????? Please send them
to me and others.
CLINICAL REVIEW
Erythromelalgia: New theories and new therapies
Jay S. Cohen, MD LaJolla, California
J AM ACAD DERMATOL, VOLUME 43. NUMBER 5
From the Department of Psychiatry, University of California, San Diego.
Dr Cohen is a board member of The Erythromelalgia Association
and currently is with the Departments of Family and Preventive
Medicine and Psychiatry. C 2000 by the American Academy of Dermatology, Inc.
Erythromelalgia is a rare condition that has remained an enigma diagnostically and therapeutically for decades. It has been assumed that erythromelalgia, which is characterized by hot, red, intensely painful feet or hands, may be the opposite of Raynaud's phenomenon. However, new research suggests that these two disorders are more similar than dissimilar. Erythromelalgia usually follows a chronic, sometimes progressive and disabling course. New evidence suggests that this may not be a disease entity at all, but a syndrome of dysfunctional vascular dynamics; recent studies demonstrate that this dysfunction is reversible in some patients. This review article presents the latest theories and successful treatments for erythromelalgia, and data from a survey of members of The Erythromelalgia Association, which was formed to provide information about erythromelalgia to doctors and patients. (J Am Acad Dermatol 2000;43:841-7.)
Abbreviations used:
CRPS: complex regional pain syndrome, PGE: prostaglandin E, RP: Raynaud's phenomenon, TEA: The Erythromelalgia Association
The incidence and prevalence of erythromelalgia in the United States are unknown. Kvernebol estimates an incidence of 0.25/100,000 and a prevalence of 2/100,000 in Norway.
Erythromelalgia can be primary or secondary. Primary erythromelalgia begins spontaneously at any age. Secondary erythromelalgia has been reported with many disorders but most often with polycythemia, thrombocythemia, neuropathies, and autoimmune diseases 1-19 (Table 11-36). Unlike Raynaud's phenomenon (RP), patients with primary erythromelalgia do not typically experience autoimmune diseases in subsequent years.
The onset of erythromelalgia may be gradual with some cases remaining mild and unchanged for decades, or erythromelalgia may begin acutely, spreading or becoming disabling within weeks (Table 11).
DESCRIPTION
Erythromelalgia is characterized by intense burning pain, marked erythema, and increased skin temperature. Most patients experience erythromelalgia in the feet, but the hands may he the primary sites (Table 11). Although typically bilateral, erythromelalgia may be unilateral, especially in secondary cases. Severe erythromelalgia may spread up the legs or arms, from lower to upper limbs or vice versa, or to the face or ears (The Erythromelalgia Association [TEA] survey), typically bilaterally.
In mild cases, erythromelalgia's constellation of symptoms may be apparent only during a flare, which is characterized by acute erythema, heat, swelling, and pain. Flaring typically occurs late in the day and continues through the night, impairing sleep. Flaring is improved by elevating the affected limbs. In severe cases, patients elevate the limbs continuously. patients complain of severe tingling or neuropathy-like pain when flaring.
EFFECTS OF TEMPERATURE
Heat intolerance and relief with cooling are hallmarks of erythromelalgia. Exposure to warmth can trigger flaring and increase its severity. Patients quickly learn that their erythromelalgia is triggered at a specific temperature, which varies considerably between individuals.
Relief of pain with ice water immersion is so common that it is almost pathognomonic. Others buy air conditioners or blow fans across their affected areas. In severe cases, patients perform ice water immersions nearly constantly, which may trigger reactive flaring, and a vicious cycle can occur. Frequent immersion can lead to maceration of the skin, nonhealing ulcers, infection, necrosis, and amputation.4,37
Table 1. Disorders associated with erythromelaigia*
*A causal relationship has not been established for some of these conditions.
Table 11. Results of informal survey of TEA members
Total responses = 41 Age at which erythromelalgia appeared:
Mean age = 41.6
Age of onset per decade: 0-9 years old = 3 cases; 10-19 = 4; 20-29 = 6; 30-39 = 3; 40-49 = 8; 50-59 = 8; 60-69 = 4; 70-79 = 5.
( Many members had prodromal symptoms of burning pain, heat intolerance, or facial flushing for months or years before the appearance of characteristic vasomotor symptoms. )
Areas afflicted:
Lower limbs only or mainly = 21
Upper and lower limbs = 17
Face or ears also sometimes involved = 17
Unilateral or bilateral:
Bilateral = 40
Unilateral = I
Erythromelalgia episodic or active most of the time:
Episodic (worse in late afternoon, evening, nighttime)= 26
Active most of the time = 13
Red most of the time = 19
Episodic redness (with activity or flaring) = 14
Hardly any redness = 4
Pain:
Severe = 21
Moderate = 16
Mild = 4
Coolness in affected limbs when not flaring and in a cold environment:
Diagnosed with Raynaud's phenomenon = 4
No Raynaud's, but involved areas get colder than normal = 14
Erythromelaigia primary or secondary:
Primary = 26
Secondary = 13
Uncertain = 2
IMPACT ON NORMAL FUNCTIONING
Even mild erythromelalgia can greatly affect normal functioning and quality of life. Patients avoid warm weather and limit their activities to cool or airconditioned locations. Some move to cooler climates. Evening activities are avoided. Many patients cannot wear socks or closed shoes even in winter. In severe cases, patients become virtually housebound by continuous flaring and pain. Standing and even sitting with the legs down become increasingly intolerable, and constant elevation becomes necessary. Work and social functioning are disrupted, which in turn affects family functioning.
REACTIVE HYPEREMIA IN ERYTHROMELALGIA AND RP
Erythromelalgia has some similarities with RP. RP's most prominent symptom is the whiteness of digits from cold-induced vasoconstriction, but the greatest discomfort sometimes occurs with warming, which is described in terms that resemble erythromelalgia: intense heat, redness, vasodilation, and burning pain. It is hypothesized that similar dynamics underlie this aspect of RP and erythromelalgia: the hyperemia phase is more prominent in erythromelalgia, whereas the constriction phase is more prominent in RP. This might explain the puzzling reports of erythromelalgia and RP in the same patients. 28,38,39
Littleford, Khan, and Belch40 measured the skin temperature of patients with erythromelalgia, which, when not flaring, was lower than that of control subjects. This suggests a subclinical vasoconstriction during the day with subsequent reactive hyperemia at night. Littleford, Khan, and Belch state: "We believe that, in erythromelalgia, vasoconstriction precedes reactive hyperemia, similar to that seen in Raynaud's phenomenon." (p 588) This may explain why some patients have noticeably cool, yet still erythematous limbs during the day as their symptoms progress. Normal skin temperature may disappear entirely, and the affected areas go from cool during the day to hot at night. Other patients do not exhibit this diurnal variation; instead they display typical symptoms of erythromelalgia and heat intolerance continuously.
VASCULAR ABNORMALITIES IN ERYTHROMELALGIA
Blood perfusion through skin capillaries primarily serves nutritional needs, whereas arteriovenous anastomoses facilitate heat and temperature regulation.' Recent research suggests that in erythromelalgia, some precapillary sphincters may be constricted while the arteriovenous shunts are open, creating an imbalance of increased total perfusion yet deficient nutritive perfusion.1-4,17
The result is "the coexistence of hypoxia and hyperemia in affected skin."3 (p 191) The products of tissue hypoxia trigger increased local blood flow, worsening the redness, warmth, and pain. This may explain why higher ambient temperatures exacerbate symptoms of erythromelalgia.
DIAGNOSIS
Erythromelalgia's intermittence can make diagnosis difficult. Because symptoms typically appear late in the day, the patient may appear normal during daytime examinations. Confirmatory tests are lacking. Thus many patients are misdiagnosed or are undiagnosed for years. However, patients with erythromelalgia can usually provide good descriptions of their symptoms, from which a tentative diagnosis may be made. If doubt remains, immersing an affected area in hot water for 10 to 30 minutes sometimes (but not always) provokes flaring. Alternately, the patient can take pictures during a flare, or the patient can be directed to an after-hours facility for examination when flaring occurs.
Other telltale symptoms and signs may help in making the diagnosis. Some patients report tingling pain or exhibit allodynia during flaring. Severe cases may develop numbness in some digits. Several TEA members report curled or hyperextended toes, but it is not clear whether this association is causal or incidental. Skin injury from repeated immersion may be apparent.
Primary versus secondary erythromelalgia must be differentiated. In all new cases, underlying causes should be sought. Erythromelalgia may be an early sign of polycythemia or thrombocythemia,2,3.5-8,15 and appropriate laboratory studies should be performed periodically.
DIFFERENTIAL DIAGNOSIS
With a good history and classic findings, the diagnosis of erythromelalgia is easily made. Nevertheless, erythromelalgia may be confused with some types of complex regional pain syndrome (CRPSI, reflex sympathetic dystrophy). The latter also produces abnormal heat, erythema, and burning pain, and these patients sometimes soak affected limbs in ice water. Although CRPSI usually occurs after an injury some cases appear spontaneously. Conversely, although erythromelalgia typically occurs spontaneously, it can appear subsequent to injury. However, erythromelalgia usually is bilateral and spreads bilaterally. Pain is reduced or absent between flares.
The tingling and burning nature of erythromelalgia pain may resemble a neuropathy, and because burning pain sometimes precedes erythema for months, differentiation can he difficult. Secondary erythromelalgia is linked to several types of neuropathies,1,13,20,21 and skin biopsy specimen studies conducted by the Mayo Clinic have revealed "both small and large fiber neuropathies in a high proportion of patients."41 (p 1448) Electromyographic studies are usually normal for erythromelalgia not associated with neuropathies.
Menopausal symptoms and medication reactions may produce flushing or sensations of intense heat, but they do not cause the profound, localized redness and pain of erythromelalgia.
TREATMENT
The following therapies apply to primary erythromelalgia and to secondary erythromelalgia that is unresponsive to treatment of the underlying disorder.
Nonmedicinal approaches
Putt42 reported pain reduction in one patient using biofeedback. This approach provided modest benefit for 2 of 4 TEA members (Table 111). Hypnosis was reported as useful in 2 cases of erythromelalgia associated with hy ertension.10,43 Three nonhypertensive TEA members tried hypnosis with little benefit.
Table 111. Therapies used by members of the erythromelalgia association (TEA)
Standard capsaicin cream has been reported to help erythromelaigia,44 but often causes increased pain and redness. Robbins et al 45 have used high potency (10%) topical capsaicin, given with the patient under epidural anesthesia, for CRPS and neuropathic pain syndromes. This approach led to dramatic improvement in a TEA member with severe, incapacitating erythromelalgia for 40 years.
Oral medications
Isolated cases of remissions have been reported with propranolol (10 mg 3 times daily),46,47 clonazepam,16 cyproheptacline,48 methysergide,13 piroxicam,49pizotifen,50 and others, but TEA members report that these drugs usually do not work or, at best, work only modestly.
Aspirin. Early reports suggested that aspirin promptly relieved erythromelalgia, but this appears true only for cases involving thrombocythemia, polycythemia, or other blood dyscrasias.
Drugs inhibiting serotonin reuptake. Rudikoff and Jaffe5l reported 3 remissions achieved through use of venlafaxine and sertraline. Several TEA members have obtained substantial improvement with venlafaxine (18.75 to 75 mg twice daily), and others have improved with sertraline (25 to 200 mg/day) but no complete remissions have been achieved. Improvement has also been reported with paroxetine, fluoxetine, and tramadol. Some erythromelalgia patients are quite sensitive to these drugs and require very low doses initially
Tricyclic antidepressants. Herskovitz et al20 reported remission of secondary erythromelalgia in 1 patient using 75 mg of amitriptyline. Several TEA members use amitriptyline for pain reduction, but no remissions have occurred. Imipramine is also used.
Anticonvulsants. McGraw and Kosek52 reported a remission in a child using gabapentin. Gabapentin (400-3600 mg/day) reduces erythromelalgia pain for many TEA members, but no remissions have occurred. One TEA member has improved with carbamazepine used in combination; another did not respond to valproic acid.
Calcium antagonists. Belch2 recommends extended release nifedipine for some patients with erythromelalgia to attenuate the vasoconstriction phase of erythromelalgia, thereby lessening the reactive hyperemia1 Nifedipine may also improve nutritional capillary flow. Interestingly, calcium antagonists, including nifedipine, have also been implicated in the onset of erythromelalgia.25-28 One TEA member experienced mild improvement with nifedipine, but others experienced intolerable adverse effects. Five TEA members have obtained improvement with diltiazem (60 to 300 mg/day) without adverse effects, and one patient has achieved virtual remission. Several other patients did not respond to diltiazem.
Misoprostol. Prostaglandins can improve nutritive blood flow via relaxation of precapillary sphincters. Mork obtained improvement in 17 of 22 patients with erythromelalgia, including one remission, after 3 months of misoprostol compared with improvement in 5 of 22 with placebo (article in press). Doses up to 400 ug twice daily were used, in contrast to a usual dose of 200 ug 4 times daily for nonsteroidal anti-inflammatory drug-treated gastropathies. There is one report of misoprostol precipitating bilateral burning hand pain.53 Except for one patient, use of misoprostol among TEA members has generally been disappointing.
Medication combinations. Polypharmacy has helped some patients but not others.1,8,13,23 A 33-year-old TEA member who had to keep his legs elevated 22 hours a day obtained substantial relief with dibenzyline 10 mg twice daily, atenolol 50 mg twice daily, amitriptyline 25 mg 3 times daily, and pentoxifylline 400 mg 3 times daily (after starting with lower doses). Currently he reports even greater improvement with misoprostol and gabapentin. One TEA member has obtained considerable improvement with sertraline and diltiazem, and another with diltiazem and imipramine. Persons have benefited from gabapentin combined with imipramine, amitriptyline, or venlafaxine. Drug combinations may be worth considering when single agents do not adequately control symptoms.
Parenteral approaches
Nitroprusside infusions. Nitroprusside infusions have been helpful in some children and adolescents11,54 and may be the preferred treatment for severe erythromelalgia in these age groups. It is usually not effective in adults. One adult TEA member experienced increased pain and flaring with nitroprusside infusions.
Udocaine infusions. Kuhnert, Phillips, and Davis4l obtained a 90% reduction in pain and modest alleviation of redness in a man with long-term severe erythromelalgia. Improvement occurred with one lidocaine infusion and was maintained with oral mexiletine.
Prostaglandin infusions. Kvernebol and Belch2 have used prostaglandin E1 (PGE1) infusion because of its ability to improve nutritive blood flow. Kvernebol reported improvement in 8 of 9 patients, including 6 remissions, with one to three 72-hour PGE1 infusions. Belch2 used 6- to 8-hour infusions on 3 to 5 consecutive days. The dose was low initially and was increased according to the patient's tolerance and the appearance of mild signs of flushing. Belch states that there is no difference in efficacy between PGE1 and PGI 2 (prostacyclin), which is used more commonly in the United States. Two TEA members have received intravenous PGE1 therapy without improvement.
Invasive approaches
Sympathetic blocks and epidurals. Rauck et al4 reported remissions in 2 adolescent boys receiving epidural infusions of bupivacaine and opiates. One patient received an epidural for 9 days, then was sent home with medications. The second patient received an implanted pump device for 37 days, as well as oral medications and a nitroprusside infusion; his symptoms cleared gradually. The medical literature contains reports of 3 other remissions with epidurals.55-57 The oldest patient among these cases was 21 years old. Whether this procedure works for older patients with erythromelalgia is uncertain. Two TEA members, aged 45 and 67 years, received epidurals of 45 and 14 days, respectively, without significant improvement.
Zoppi et al8 performed 10 daily lumbar sympathetic blocks using alternate sides on 3 adult patients. Two patients obtained remissions; the third obtained partial improvement. Several TEA members have had a single unilateral sympathetic block, and either no effect was noted or erythema was worsened.
Sympathectomies. Zoppi et al58 reported mixed results with sympathectomies. In 1973, Postlethwaite59 reported "excellent" results with bilateral lumbar sympathectomies in 4 of 4 erythromelalgia cases. In 1999, Shiga et al60 reported a remission subsequent to bilateral thoracic sympathectomies in a patient with erythromelalgia of the hands. Belch2 has told the author that her group has obtained very good results with lower extremity sympathectomies in some patients, but others have not improved with this treatment, and a few have worsened. Belch supports doing sympathectomies if a diagnostic sympathetic block produces improvement.
Kvernebol described a patient made worse by a unilateral sympathectomy, and he considers sympathectomies contraindicated because he believes they increase thermoregulatory but not nutritive blood flow. However, Rauck et al4 described epidurals as maximizing blood flow of all types. One would theorize that if some erythromelalgia patients display vasoconstriction before reactive hyperemia, as indicated by the work of Littleford, Khan, and Belch,40 then thermoregulatory systems are involved. Moreover, the diurnal nature of erythromelalgia flaring may indicate autonomic involvement. The success of epidurals and sympathectomies supports this view, at least in some patients. Perhaps, as in RP, sympathetic and peripheral factors vary in importance in different patients with erythromelalgia.
Dorsal column stimulator. Graziotti and Goucke6l reported the control of intractable pain in one patient via a dorsal column stimulator. Two TEA members have obtained moderate pain relief from this method, but no improvement in erythema.
Neurosurgery. Two Russian physicians have reported remissions via neurosurgery.62,63 The author is not aware of similar work being done in North America or Western Europe.
DISCUSSION
The reversibility of erythromelalgia and its significance
It has now been amply demonstrated that erythromelalgia is a reversible condition in some patients. Once reversed, remissions may last months, years, or indefinitely. These remissions support the statement ofKalgaard, Seem, and Kvernebo3 that: "In our opinion erythromelalgia is not a separate disease entity but a pathophysiological response of the skin microcirculation." (p 195)
The hypothesis that erythromelalgia is a vicious cycle caused by a maldistribution of blood flow has gained plausibility via vascular studies and successful therapies that have been replicated. These therapies include nitroprusside infusions in children and adolescents, and prostaglandin and lidocaine infusions, 10% topical capsaicin, and bilateral sympathectomies in adults. None of these methods is consistently effective, suggesting multiple subtypes of erythromelalgia.
Different subtypes of erythromelalgia?
Belch2 has categorized3 subtypes: thrombocytosis/hyperviscosity, microvascular ischernia (vasoconstrictive), and vasodilatory.
Whereas most patients exhibit the vasoconstrictive/reactive-hyperemia type that responds to the infusion or invasive approaches mentioned above, the less common vasodilatory type will worsen with these therapies. Conversely, the latter may respond to the vasoconstriction of unselective beta blockers like propranolol, whereas the former will worsen with such treatment. To differentiate these types, Belch recommends vascular studies performed in warm and cool environments that include Doppler pressures, laser Doppler flowmetry, thermography, and tissue P02 monitoring. The Mayo Clinic often performs nerve biopsies.
Treatment considerations
The most useful oral medications for erythromelalgia appear to be gabapentin, venlafaxine, diltiazem, sertraline, amitriptyline, imipramine, paroxetine, fluoxetine, and some antihistamines (diphenhydramine, cyproheptadine), usually begun at low doses. Response is quite variable and remissions are infrequent but through careful trial and error, substantial benefit can be achieved with most patients. Oral medications should be tried initially, especially in mild erythromelalgia cases, but 10% capsaicin (under epiduralanesthesia), infusions, or invasive approaches may be necessary for intransigent and severe cases. The ideal therapeutic approach remains to be defined.
SUMMARY
Erythromelalgia is characterized by burning pain, marked erythema, swelling, and increased temperature in affected limbs. Symptoms are typically provoked by heat and reduced by cooling. The pathology underlying erythromelalgia appears to involve reduced nutritive blood flow coupled with increased arteriovenous shunting. This vascular dysfunction is potentially reversible even in long-term cases. Remissions have been reported with nitroprusside infusions or prolonged epidurals in children and adolescents, and with various medications, prostaglandin or lidocaine infusions, 10% topical capsaicin, and bilateral sympathectomies in adults. No single therapy has proved consistently effective, which supports the possibility that there are several subtypes of erythromelalgia. Although patients respond quite variably to medication therapy, careful trial and error often lead to substantial benefit. Patients and physicians can obtain information from a new organization, The Erythromelalgia Association (TEA),* which also runs an online support group.
*TEA, 4343 Roosevelt Way NE, #305, Seattle, WA 98105.Te1: 206-6320894. Fax: 206-632-1894.
E-mail: jeanmilt@cwix.com. Web site: www.erythromelaigia.org
ADDENDUM: After submission of this manuscript, 3 new articles on erythromelalgia have been published and are cited in MEDLINE:
Davis MD, O'Fallon WM, Rogers RS 111, Rooke TW. Natural history of erythromelalgia: presentation and outcome in 168 patients. Arch Dermatol 2000;136:330-6.
Mork C, Asker CL, Salerud EG, Kvernebo K. Microvascular arteriovenous shunting is a probable pathogenetic mechanism in erythromelalgia. J Invest Dermatol 2000;114:643-6.
Mork C, Kvernebo K. Erythromelalgia-a mysterious condition? Arch Dermatol 2000;136:406-9.
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14. Markel J. Erythromelalgia: a report of a case of its association
with chronic gout with relief of symptoms for two years after
intravenous administration of typhoid vaccine.
Arch Dermatol1938;38:73-4.
15. Drenth JP, Michiels JJ, van Joost T, Vuzevski VD. Secondary
erythermalgia in systemic lupus erythematosus.
J Rheumatol 1993;20:144-6.
16. Kraus A. Erythromelalgia in a patient with systemic lupus
erythematosustreated with clonazepam [letter].
J Rheumatol 1990;17:120.
17. Ratz JL, Bergfeld SF, Steck WD. Erythermalgia with vasculitis: a
review.) Am Acad Dermatol 1979;1:443-50.
18. Drench JP, Michiels JJ, Van Joost T, Vuzevski VD. Secondary
erythermalgia associated with an autoimmune disorder of
undetermined significance. Dermatology 1995;190:232-4.
19. Zheng ZM, Zhang JH, Hu JM, Liu SF, Zhu WP. Poxviruses isolated
from epidemic erythromelalgia in China [letter]. Lancet 1988;1:296.
20. Herskovitz S, Loh F, Berger AR, Kucherov M. Erythromelalgia:
association with hereditary sensory neuropathy and response
to amitriptyline. Neurology 1993;43:621-2.
21. Staub DB, Munger BL, Uno H, Dent C, Davis JS IV. Erythromelalgia
as a form of neuropathy. Arch Dermatol 1992;128:1654-5.
22. Collier J. The occurrence of erythromelalgia in disease of the
spinal cord: an account of ten cases. Lancet 1898;2:401-4.
23. Confino I, Passwell JH, Padeh S. Erythromelalgia following
influenza vaccine in a child. Clin Exp Rheumatol 1997;15:111-3.
24. Rabaud C, Barbaud A, Trechot R First case of erythromelalgia
related to hepatitis B vaccination.) Rheumatol 1999;26:233-4.
25. Fisher JR, Padnick MB, Olstein S. Nifedipine and erythromelalgia.
AnnIntern Med 1983;98:671-2.
26. Brodmerkel GJ Jr. Nifedipine and erythromelalgia [letter].
Ann. Intern Med 1983;99:415.
27. Grunwald Z. Painful edema, erythematous rash, and burning
sensation due to nifedipine [letter]. Drug Intel]
Clin Pharm 1982;16:492.
28. Sunahara JF, Gora-Harper ML, Nash KS. Possible erythromelalgia-like
syndrome associated with nifedipine in a patient with
Raynaud's phenomenon. Ann Pharmacother 1996;30:484-6.
30. Levesque H, Moore N, Wolfe LM, Courtois H. Erythromelalgia
induced by nicardipine (inverse Raynaud's phenomenon?).
Br Med J (Clinical Research Ed) 1989;298:1252-3.
31. Dupont E, Ilium F, Olivarius B de F. Bromocriptine and
erythromelalgia-like eruptions [letter]. Neurology 1983;33:670.
32. Wagner DR, Spengel F, Middeke M. Erythromelalgia unmasked
during norephedrine therapy: a case report. Angiology 1993;44:244-7.
33. Yosipovitch G, Rechavia E, Feinmesser M, David M. Adverse
cutaneous reactions to ticlopidine in patients with coronary
stents.J Am Acad Dermatol 1999;41:473-6.
34. Mork C, Kalgaard OM, Kvernebo K. Erythromelalgia as a
paraneoplasticsyndrome in a patient with abdominal cancer [letter].
Acta Derm Venereol 1999;79:394.
35. Levine AM, Gustafson PR. Erythromelalgia: case report and literature
review. Arch Phys Med Rehabil 1987;68:119-21.
36. Martin JC, Lacombe D, Lefebvre D, Bonafe JL,Taieb A, Maleville
J. Erythromelalgia: a familial case. Discussion on the role of mercury
[abstract]. Ann Dermatol Venereol 1994;121:309-14.
37. Kirby RL. Erythromelalgia-not so benign [letter]. Arch Phys
Med Rehabil 1987;68:389.
38. Slutsker GE. Coexistence of Raynaud's syndrome and erythromelalgia [letter].
Lancet 1990;335:853.
39. Lazareth I, Priollet P. Coexistence of Raynaud's syndrome and erythromelalgia [letter].
Lancet 1990;335:1286.
40. Littleford RC, Khan F, Belch JJ. Skin perfusion in patients with erythromelalgia.
Eur J Clin Invest 1999;29:588-93.
41. Kuhnert SM, Phillips WJ, Davis MD. Lidocaine and mexiletine
therapy for erythromelalgia. Arch Dermatol 1999;135:1447-9.
42. Putt AM. Erythromelalgia: a case for biofeedback. Nurs Clin North Am 1978;13:625-30.
43. Chakravarty K, Pharoah PD, Scott DG, Barker 5. Erythromelalgia: the role of hypnotherapy.
Postgrad Med J 1992;68:44-6.
44. Muhiddin KA, Gallen IW, Harries 5, Pearce VR. The use of capsaicin cream in a case
of erythromelalgia. Postgrad Med J 1994;70:841-3.
45. Robbins WR, Staats P5, Levine J, Fields HL, Allen RW, Campbell JN, et al.
Treatment of intractable pain with topical large-dose capsaicin: preliminary report.
Anesth Analg 1998;86:579-83.
46. Bada JL.Treatment of erythromelalgia with propranolol [letter].
Lancet 1977;2:412.
47. Serratrice G, Godde JL, Schiano A.Treatment of erythromelalgia with beta-blocking agents
[abstract]. Nouv Presse Med 1977;6: 3973.
48. Sakakibara R, Fukutake T, Kita K, Hattori T.Treatment of primary erythromelalgia with
cyproheptadine. J Auton New Syst 1996; 58:121-2.
49. Calderone DC, Finzi E. Treatment of primary erythromelalgia
with piroxicam.J Am Acad Dermatol 1991;24:145-6.
50. Guillet MH, Le Noach E, Milochau P, Sassolas B, Guillet G. Familial erythermalgia
treated with pizotifen [abstract]. Ann Dermatol Venereol 1995;122:777-9.
51. Rudikoff D, Jaffe IA. Erythromelalgia: response to serotonin reuptake inhibitors.)
Am Acad Dermatol 1997;37:281-3.
52. McGraw T, Kosek P Erythromelalgia pain managed with
gabapentin. Anesthesiology 1997;86:988-90.
53. Levesque H, Moore N. Erythromelalgia induced by nicardipine [letter]. Br Med J 1989;299:323.
54. Stone JD, Rivey MP, Allington DR. Nitroprusside treatment of erythromelalgia in an adolescent
female. Ann Pharmacother 1997;31:590-2.
55. D'Angelo R, Cohen IT, Brandom B. Continuous epidural infusion of bupivacaine
and fentanyl for erythromelalgia in an adolescent. Anesth Analg 1992;74:142-4.
56. Mohr M, Schneider K, Grosche M, Hildebrandt J. Cervical epidural infusion of morphine
and bupivacaine in severe erythromelalgia [abstract].
Anasthesiol Intensivmed Notfallmed Schmerzther 1994;29:371-4.
57. Takeda S,Tomaru T, Higuchi M. A case of primary erythromelalgia (erythermalgia)
treated with neural blockade [abstract]. Masui 1989;38:388-93.
58. Zoppi M, Zamponi A, Pagni E, Buoncristiano U. A way to understand erythromelalgia.
J Auton New Syst 1985;13:85-9.
60. Shiga T, Sakamoto A, Koizumi K, Ogawa R. Endoscopic thoracic sympathectomy
for primary erythromelalgia in the upper extremities. Anesth Analg 1999;88:865-6.
61. Graziotti PJ, Goucke CR. Control of intractable pain in erythromelalgia by using spinal
cord stimulation.) Pain Symptom Manage 1993;8:502-4.
62. Kandel El. Stereotactic surgery of erythromelalgia.
Stereotact Fund Neurosurg 1990;54-55:96-100.
63. Dash'ian GG, Sungurov EB. The surgical treatment of erythromelalgia by the
destruction of the inlet areas of the posterior spinal nerve roots [abstract].
Zh Vopr Neirokhir Im N N Burdenko 1995;2:14-5.
Erythromelalgia is a painful disorder of the extremities characterized by redness, swelling, a burning sensation, and an increase in skin temperature exacerbated by exposure to heat. 1 An early description was reported by Mitchell 2 in 1878. He coined the term erythromelalgia to denote the clinical features of redness (erythros), involvement of the extremities (melos), and the symptom of pain (algos). Later authors suggested the name “erythermalgia” to emphasize elevated temperature of the affected extremities, 3 and others have used the term “erythralgia.” 4 There have been two recent comprehensive reviews of erythromelalgia. 1,5
The pathophysiology of erythromelalgia is poorly understood but there is evidence that serotonin (5-HT) may be involved in at least some cases. 6,7 The warm, congested extremities suggest that vasodilation may be involved in its pathogenesis. 8,9 5-HT is a biogenic amine that influences vascular endothelium and platelet function. 10,11 The serotonin antagonists, methysergide 6,7 and pizotifen 12 have been reported to be effective in some cases of juvenile-onset erythromelalgia, further supporting a 5-HT mechanism.
It is believed that serotonin reuptake inhibitors are effective in the treatment of depression because of their ability to inhibit the reuptake of 5-HT in certain neuronal cells. 13 One of us (I. J.) recently reported the successful treatment of Raynaud’s phenomenon with serotonin reuptake inhibitors. 14 Although erythromelalgia has been called the “antithesis of Raynaud’s,” 8 there are cases of the coexistence of the two in the same patient. 15,16 It seemed reasonable, therefore, that serotonin reuptake inhibitors might be useful in the treatment of erythromelalgia.
CASE REPORTS
Case 1
A 63-year-old woman noted the abrupt onset of marked painful erythema of both feet that was so intense that it necessitated immersion of her feet in ice water. Her attacks were less frequent and less severe in the winter. Corticosteroids administered topically, intralesionally, and systemically, as well as ibuprofen, aspirin, nortriptyline, propranolol, and intravenous immunoglobulin were without benefit.
The feet showed marked plantar erythema, warmth, and tenderness. All routine blood studies including platelet count were within normal limits. Doppler studies, bone marrow studies, electromyography, tests of thyroid function, and all rheumatic serologies were negative.
Administration of venlafaxine, 37.5 mg twice daily, resulted in a rapid relief of her symptoms. She has had no major attacks in 14 months.
Case 2
A 68-year-old woman with chronic lymphocytic leukemia for 10 years had been treated with fludarabine. Six months previously, the patient suffered a right hip fracture that required internal fixation. Her postoperative course was complicated by staphylococcal sepsis and meningitis. Severe itching, burning pain, swelling, and marked redness of her feet and ankles occurred and was exacerbated by warmth and dependency. She was able to sleep only by use of a device that delivered ice cold water in plastic tubing wrapped around her feet. Her feet were bright red, warm, and edematous (Fig. 1) .
Fig. 1. Case 2. Right foot before treatment. Note marked erythema and swelling producing tightness and sheen of skin.
Pedal pulses and neurologic examination were normal. Complete blood cell count, including platelets, and all blood chemistries were normal. A biopsy specimen from the dorsum of the right foot revealed scattered foci of hydropic change in the epidermis. A mild perivascular infiltrate of predominantly mononuclear cells surrounded vessels of the superficial plexus in the dermis. No intravascular thrombi were noted.
There was no improvement of her symptoms with low-dose aspirin, indomethacin, cyproheptadine, amitriptyline, doxepin, prednisone, or propranolol. A right-sided lumbar sympathetic block failed to provide relief. The patient was given venlafaxine 37.5 mg twice daily. She noted marked improvement in her symptoms by the third day (Fig 2).
Fig. 2. Case 2. Feet after venlafaxine treatment. Erythema and swelling are markedly reduced. Erythematous macules on dorsa of feet were caused by folliculitis that resulted from repetitive use of cold water compresses.
Case 3
A 52-year-old woman had a 7-month history of swelling, redness, burning, and increased temperature of her hands and feet. Her symptoms were aggravated by warmth and relieved by ice. All treatments including aspirin had failed to relieve her discomfort. The hands and feet were blue-red, warm, and swollen. Routine hematologic studies including platelet count were normal. Scleroderma 70 and anticentromere antibodies were negative. A biopsy specimen of the dorsum of the right foot revealed minimal dermal fibrosis.
The patient was given fluoxetine 20 mg per day without benefit. She was then given sertraline 50 mg twice daily; marked improvement was noted after 3 days. Six months after successful treatment of her erythromelalgia she was found to have overt scleroderma.
DISCUSSION
All our patients experienced marked clinical improvement in their symptoms of erythromelalgia when given serotonin reuptake inhibitors. These patients were refractory to all other treatments. There has been no effective treatment for adult-onset idiopathic erythromelalgia. This is in contrast to erythromelalgia associated with thrombocytosis, which responds to aspirin, or erythromelalgia resulting from an underlying disease, which usually responds to treatment of the basic disorder.
5-HT is a vasoactive substance involved in central and peripheral neurotransmission and platelet function. It may cause vasoconstriction or vasodilation depending on the vessel involved and the integrity of the endothelium. 10
Two of our patients responded to venlafaxine, a serotonin reuptake inhibitor that also has an effect on the reuptake of norepinephrine. 17 To determine whether norepinephrine reuptake was necessary for a clinical response, we treated our third patient with fluoxetine, which blocks only serotonin reuptake. 13 She failed to respond and was then given sertraline, another serotonin reuptake inhibitor, that also blocks only serotonin reuptake. Because she responded, we conclude that blocking the reuptake of norepinephrine is not necessary for efficacy. We cannot explain why our third patient did not respond to fluoxetine but did respond to sertraline. A similar variability of response to serotonin reuptake inhibitors was seen in the treatment of Raynaud’s syndrome. 14
REFERENCES
1. Kurzrock R, Cohen P. Erythromelalgia: review of clinical characteristics and pathophysiology. Am J Med 1991;91:416-22. MEDLINE
2. Mitchell SW. On a rare vaso-motor neurosis of the extremities, and on the maladies with which it may be confounded. Am J Med Sci 1878;76:2-36.
3. Smith LA, Allen EV. Erythermalgia (erythromelalgia) of the extremities. A syndrome characterized by redness, heat and pain. Am Heart J 1938;16:175-88.
4. Zoppi M, Zamponi A, Pagni E, Buoncristiano U. A way to understand erythromelalgia. J Auton Nerv Syst 1985;13:85-9. MEDLINE
5. Drenth JPH, Michiels JJ. Erythromelalgia and erythermalgia: diagnostic differentiation. Int J Dermatol 1994;33:393-7. MEDLINE
6. Pepper H. Primary erythermalgia. Report of a patient treated with methysergide maleate. JAMA 1968;203:1066-7. MEDLINE
9. Ratz JL, Bergfeld WF, Steck WD. Erythermalgia with vasculitis: a review. J Am Acad Dermatol 1979;1:443-50. MEDLINE
10. Hollenberg NK. Serotonin and vascular responses. Ann Rev Pharmacol Toxicol 1988;28:41-59.
11. Vanhoutte PM, Van Nueten JM, Janssens WJ. The role of the endothelium in the cardiovascular response to serotonin. In: Paoletti R, Vanhoutte PM, Brunello N, Maggi FM, editors. Serotonin: from cell biology to pharmacology and therapeutics. Dordrecht: Kluwer Academic Publishers; 1990. p. 81-96.
12. H’Mila R, Samoud A, Souid M, Bourassine A, Ben Dridi MF. Erythermalgia: a rare acrosyndrome. Arch Fr Pediatr 1991;48:555-7. MEDLINE
13. Lemberger L, Bergstrom RF, Wolen RL, Farid NA, Enas GG, Aronoff GR. Fluoxetine: clinical pharmacology and physiologic disposition. J Clin Psychiatry 1985;46:(3, Sec. 2):14-9.
15. Slutsker GE. Coexistence of Raynaud’s syndrome and erythromelalgia [letter]. Lancet 1990;335:853. MEDLINE
16. Lazareth I, Priollet P. Coexistence of Raynaud’s syndrome and erythromelalgia [letter]. Lancet 1990; 335:1286. MEDLINE
17. Holliday SM, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression. Drugs 1995;49:280-94.
Department of Dermatology
Mt. Sinai School of Medicine, New York
Department of Medicine, College of Physicians and Surgeons,
Columbia University, New York
This article is referenced by these articles:
Erythromelalgia: New theories and new therapies
Journal of the American Academy of Dermatology
November 2000, part 1 • Volume 43 • Number 5
Jay S. Cohen, MD
Agree with authors that this patient should be followed for more than 6
months:
Endoscopic Thoracic Sympathectomy for Primary Erythromelalgia in the Upper Extremities
Toshiya Shiga, MD, PhD *, Atsuhiro Sakamoto, MD, PhD *, Kiyoshi Koizumi, MD, PhD , and Ryo Ogawa, MD, PhD *
*Department of Anesthesiology and Second Division of Surgery, Nippon Medical School, Tokyo, Japan
Anesth Analg 1999;88:865
REGIONAL ANESTHESIA AND PAIN MANAGEMENT
Introduction
Erythromelalgia, a rare syndrome of unknown cause, is characterized by burning pain, redness, edema, and increased skin temperature in the lower, upper, or both extremities (1,2). In addition to drug therapies (2–5), sympathetic blockade is effective in improving the symptoms (6–8). We report the successful outcome of treating primary erythromelalgia of the upper extremities with bilateral thoracic sympathectomy using a video-assisted thoracic surgical (VATS) technique.
Case Report
A 42-yr-old woman had been suffering from redness in distal site of both fingers since 1989. During the 2 yr before diagnosis of erythromelalgia, she began to notice severe burning pain in the fingers associated with edema. Her pain worsened after exertion that involved her hands but was alleviated markedly when she immersed them in cool water. Attacks of burning pain often occurred at night and sometimes lasted until early morning. Peripheral pulses were normal. Mechanical allodynia was absent in the affected areas. A diagnosis of erythromelalgia was made by a dermatologist she first consulted. Laboratory examination exhibited no symptoms of hypertension, diabetes, rheumatoid arthritis, systemic lupus erythematous, or gout. Red blood cell and platelet counts were within normal limits. She had no family history of relevant conditions. Thermography showed marked hyperthermia in the affected areas. Histopathological examination by punch skin biopsy from an affected area revealed thickening of the capillary blood vessel walls in the superficial epidermis, probably due to blood congestion; however, the findings were nonspecific. She received aspirin from a dermatologist but had no improvement in the symptoms and suffered side effects of nausea and vomiting. Therefore, the aspirin was discontinued, and the dermatologist consulted with us. Thoracic epidural blockade and stellate ganglion blockade afforded marked (Figure 1) but transient (a few days) pain relief. Because the patient desired lasting pain relief, we chose endoscopic thoracic sympathectomy (ETS) to attempt a more permanent sympathetic blockade.
Figure 1. results of seven repetitive, placebo-controlled, sympathetic blockade diagnostic tests. The effects of 0.125%–0.25% bupivacaine administration (thoracic epidural blockade and stellate ganglion blockade) were compared with those of saline placebo administration in a single-blinded fashion, assessed using a 100-mm visual analog scale (VAS). Values are numbers for placebo and mean ± SD for sympathetic blockade. Paired t-test was used to compare VAS scores before () administration of local anesthetics with those after () administration. ***P < 0.001 versus before administration of local anesthetics.
First, the patient underwent right ETS. In the operating room, an epidural catheter was inserted 2–3 cm cephalad at the T3 level. Anesthesia was induced with propofol (2 mg/kg), followed by vecuronium (1 mg/kg). Her trachea was intubated with a double-lumen endotracheal tube for differential ventilation. Anesthesia was maintained with sevoflurane, O2, and nitrous oxide (fraction of inspired oxygen [FIO2] 0.33), combined with intermittent 1% mepivacaine injection of approximately 3–6 mL via the epidural catheter. FIO2 was set at 1.0 during one-lung ventilation. The VATS procedure was performed using the standard technique (9). The sympathetic ganglia T2 and T3 over the second and third ribs were resected under thoracoscopic vision. The patient’s symptoms began to improve immediately after surgery. One week later, left ETS was performed in the same manner. Postoperative histopathological examination of resected samples confirmed the evidence of ganglia. Compensatory sweating appeared in the trunk after surgery. No major complications, such as Horner’s syndromes or pneumothoraces, developed. A few days after surgery, the epidural administration of local anesthetic was discontinued, as the patient had almost no more postoperative pain. Postoperative findings of thermography remained the same as those at admission. The patient was discharged 1 wk after the second surgery. At her 6-mo follow-up examination, she remained pain-free.
Discussion
Erythromelalgia can sometimes be confused with other disorders such, as complex regional pain syndrome (CRPS; formerly defined as reflex sympathetic dystrophy or causalgia) (10). Our patient had no history of recent trauma in the upper extremities, and her symptoms failed to meet the diagnostic criteria of CRPS (11). Because immersion of the affected fingers in ice water relieved the pain, it was easy to discriminate erythromelalgia from the above disorders. Furthermore, typical thermographic findings and histopathology confirmed the diagnosis of erythromelalgia (10,12). Erythromelalgia is classified into primary and secondary forms (10); in this case, primary erythromelalgia was diagnosed by the dermatologist by excluding any secondary cause.
This is the first report concerning the treatment of erythromelalgia by bilateral thoracic sympathectomy using the VATS technique. Over the past decade, ETS has become an established treatment for hand or axillary hyperhidrosis (9,13). However, extensive use of ETS for the treatment of chronic pain has not been well documented compared with its utility for treating hyperhidrosis; therefore, the decision to use ETS in such cases should be made restrictively. To determine whether ETS is indicated, a placebo-controlled diagnostic test using a temporary sympathetic blockade is mandatory. Because our patient showed a good response to this test, as assessed by using a visual analog scale, her pain seemed to be sympathetically maintained. Thus, permanent sympathetic blockade was considered appropriate. Several options were proposed. First, conventional chemical sympathetic blockade guided by roentgenography was considered because it is relatively noninvasive; however, its technical difficulty made us hesitate to choose it. Second, we determined that continuous infusion of epidural local anesthetics seemed to result in only transient pain relief. In our patient, sympathetic blockade with a single dose of local anesthetic was no longer effective beyond 3 days. Third, taking the risk-benefit ratio into consideration, a bilateral open thoracotomy procedure was considered too invasive. Therefore, we chose ETS because it is less invasive and more effective than these other techniques.
A concern may be raised about recurrence. Our patient has had no recurrence of symptoms 6 mo postsurgery. However, this observation time is too short to make conclusions with regard to long-term results. There are poor data on the long-term results of ETS in patients with chronic pain. Two groups reported the long-term recurrence of Raynaud’s syndrome treated with ETS to be approximately 50%–60% (14,15), whereas that of hyperhidrosis is almost 0%. In our patient, a much longer-term follow-up is required to rule out recurrence. Postoperative thermography was not significantly different from preoperative thermography, despite the pain relief and improvement in edema and redness. This suggests that sympathetic blockade is a nonspecific therapy for this disease, although erythromelalgia is considered to be sympathetically related.
We presented early successful results in the treatment of primary erythromelalgia with ETS and believe that this therapy may be effective for continuous pain relief and improvement in edema and redness.
References
1. Smith LA, Allen EV. Erythermalgia (erythromelalgia) of the extremities: a syndrome characterized by redness, heat, and pain. Am Heart J 1938;16:175–88.
2. Christensen CR, Stubbs DH. Erythromelalgia: a case study. Vasc Nurs 1996;14:18–20. [Medline]
3. Stone JD, Rivey MP, Allington DR. Nitroprusside treatment of erythromelalgia in an adolescent female. Pharmacother 1997;31:590–2. [Medline]
4. Rudikoff D, Jaffe IA. Erythromelalgia: response to serotonin reuptake inhibitors. J Am Acad Dermatol 1997;37:281–3. [Medline]
5. McGraw T, Kosek P. Erythromelalgia pain managed with gabapentin. Anesthesiology 1997;86:988–90. [Medline]
6. Takeda S, Tomaru T, Higuchi M. A case of primary erythromelalgia (erythermalgia) treated with neural blockade. Masui 1989;38:388–93. [Medline]
7. D’Angelo R, Cohen IT, Brandom BW. Continuous epidural infusion of bupivacaine and fentanyl for erythromelalgia in an adolescent. Anesth Analg 1992;74:142–4. [Medline]
9. Claes G, Drott C, Gothberg G. Thoracoscopy for autonomic disorders. Ann Thorac Surg 1993;56:715–6. [Abstract]
10. Kurzrock R, Cohen PR. Erythromelalgia: review of clinical characteristics and pathophysiology. Am J Med 1991;91:416–22. [Medline]
11. Stanton-Hicks M, Janig W, Hassenbusch S, et al. Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain 1995;63:127–33. [Medline]
12. Drenth JP, Vuzevski V, Van Joost T, et al. Cutaneous pathology in primary erythermalgia. Am J Dermatopathol 1996;18:30–4. [Medline]
13. Claes G, Drott C. Hyperhidrosis. Lancet 1994;343:247–8. [Medline]
14. Nicholson ML, Dennis MJ, Hopkinson BR. Endoscopic transthoracic sympathectomy: successful in hyperhidrosis but can the indications be extended? Surg Engl 1994;76:311–4. [Medline]
15. Sayers RD, Jenner RE, Barrie WW. Transthoracic endoscopic sympathectomy for hyperhidrosis and Raynaud’s phenomenon. Eur J Vasc Surg 1994;8:627–31. [Medline]
This article is referenced by these articles:
Erythromelalgia: New theories and new therapies
Journal of the American Academy of Dermatology
November 2000, part 1 • Volume 43 • Number 5
Jay S. Cohen, MD
http://www.bayareapainmedical.com/wwhatshot.html
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Area Pain Medical Associates welcomes physicians and other health care
professionals to this section of the website. Although it is open to anyone to
browse, the information is oriented towards physicians interested in developing
and attaining up to date information in pain medicine.
Lidocaine
is beneficial in the treatment of neuropathic pain states by blocking
conduction of sodium channels in peripheral and central neurons, and
therefore reducing spontaneous impulse firing.(i,ii)Furthermore, the effectiveness of intravenous lidocaine (IVL) in
producing analgesia is a predictor of the subsequent efficacy of oral
mexiletine both in the treatment of cardiac arrhythmias (iii)
and in the treatment of neuropathic pain.(iv)Although animal studies have shown that intravenous lidocaine
alleviates tactile allodynia in rats (v),
human studies have found no association between reduction in allodynia
and pain relief.(iv)Typically, IVL is administered to a target plasma lidocaine level
of 2-5 µg/ml.(vi,vii,viii)
There
are few reports of the use of lidocaine for treatment of neuropathic
pain states in children.Wallace
and others (ix)
used intravenous lidocaine to control pain after anti-GD2 antibody
therapy in children with neuroblastoma using IVL at 2 mg/kg over 30
minutes followed by 1 mg/kg/hr.Compared
with a morphine infusion (0.05-0.1 mg/kg/hr), lidocaine was associated
with improved mobility and decreased supplemental analgesic
requirements.Of note,
extended use of lidocaine infusions over 4 days was associated with an
increased incidence of nausea.
Our
clinical experience confirms that lidocaine is useful for treatment of
pediatric neuropathic conditions.We
routinely employ lidocaine as an adjunct medication for pain syndromes
refractory to conventional therapy, such as the pain of mucositis
following bone marrow transplantation and refractory cancer pain(x,xi),
and also in neuropathic pain states such as CRPS-1, CRPS-2,
erythromelalgia, and painful neuropathies to predict the efficacy of
mexiletine (see below).
Because
lidocaine pharmacokinetics are similar in children and adults, dosing
schedules for children should correlate reasonably with published
experience in adults.Lidocaine
plasma levels are readily available in most clinical laboratories, to
assure that infusions are delivering an effective dose without producing
toxicity. The most accurate way to deliver intravenous lidocaine is by a
computerized infusion, a technique utilized in our adult pain clinic, in
which our protocol calls for an initiating bolus of lidocaine equal to 1
mg/kg over 5 minutes, with subsequent infusion of lidocaine at a rate of
1 mg/kg/hr.Blood levels
are checked every 8 hours and the lidocaine infusion is adjusted to
target a blood level between 2-5 µg/ml.Patients with hepatic or renal insufficiency need dose
adjustments (halving the dosage of bolus or infusion) to prevent
toxicity.
Mexiletine
Originally
used as an oral cardiac antiarrhythmic analog of lidocaine, mexiletine
is used by most pain treatment centers as an oral analog to lidocaine to
treat neuropathic pain.The
original antiarrhythmic studies for lidocaine showed that it was a
useful predictor for the antiarrhythmic efficacy of mexiletine and
tocainide.Tocainide,
unfortunately, produces significant toxicity such as blood dyscrasias
and interstitial pneumonitis.Mexiletine,
on the other hand, is without such toxicity and is much better
tolerated.Dejgard and
others (xii)
reported a dose of mexiletine of up to 10 mg/kg daily to treat diabetic
neuropathy.Mexiletine was
used with at similar doses by Chabal and others in adults to treat
peripheral nerve injuries.(xiii)Chabal commented that most subjects required a daily dose of
mexiletine of 10 mg/kg for pain, while the usual range for treatment of
cardiac arrhythmias is between 10-15 mg/kg.
A
review of the pediatric literature shows no pharmacologic or
pharmacokinetic difference in the absorption or metabolism of mexiletine
between children and adults.Mexiletine
is frequently associated with untoward gastrointestinal side effects,
most commonly nausea and vomiting, as well as sedation, confusion,
difficulty concentrating, diploplia, blurred vision, and ataxia,
although gradual introduction of the drug and progressive escalation of
the dose is ordinarily successful in reducing this side effect, as
illustrated in Table 1.
Table
1.Mexiletine dosing
schedule for children.Mexiletine
is available as 150mg, 200mg, 250mg, and 300mg tablets.The target dose is 10-15 mg/kg.(xiv)
DAY
Morning
Mid-day
Bed-time
1
1
Tablet
2
1
Tablet
3
1
Tablet
4
1
Tablet
1
Tablet
5
1
Tablet
1
Tablet
6
1
Tablet
1
Tablet
7
1
Tablet
1
Tablet
1
Tablet
8
1
Tablet
1
Tablet
1
Tablet
9
1
Tablet
1
Tablet
1
Tablet
10
1
Tablet
1
Tablet
2
Tablets
11
1
Tablet
1
Tablet
2
Tablets
12
1
Tablet
1
Tablet
2
Tablets
13
1
Tablet
1
Tablet
2
Tablets
14
2
Tablets
1
Tablet
2
Tablets
15
2
Tablets
1
Tablet
2
Tablets
16
2
Tablets
1
Tablet
2
Tablets
17
2
Tablets
1
Tablet
2
Tablets
18+
2
Tablets
2
Tablets
2
Tablets
ANTICONVULSANTS
Carbamazepine
(Tegretol®)
Carbamazepine
is an older anti-epileptic used to treat neuropathic pain via sodium
channel blockade. Carbamazepine can be administered in oral
(100-200 mg) and suspension formulations (100 mg/5 ml).
Recommended dosing schedules for children > 6 years start at 10
mg/kg/day in two divided doses to a usual maintenance dose of 15-30
mg/kg/day in 2-4 divided doses per day. Blood levels (therapeutic
4-12 mcg/ml) can be obtained but do not necessarily correlate with
analgesia for neuropathic pain.
Metabolism
and adverse effects are significant with carbamazepine.
Carbamazepine is hepatically metabolized, limiting its usefulness
patients with hepatic insufficiency. Moreover, adverse effects are
common including hematologic – aplastic anemia, agranulocytosis;
cardiovascular – congestive heart failure, syncope, arrhythmias;
central nervous system – sedation, dizziness, fatigue, slurred speech,
ataxia; and even hepatitis.(xv) A complete blood count should be
obtained prior to initiating this antiepileptic and should be repeated
every 3-6 months. Although a classic agent for the management of
neuropathic pain, carbamazepine is no longer a first line drug,
particularly for a child or adult who may have hematologic alterations
or hepatic dysfunction.
Sodium
Valproate (Depakote®)
Valproic
acid is an anti-epileptic drug that has been used to treat neuropathic
pain states and associated mood disturbances. The drug also seems
effective for management of migraine headaches, but because of
significant side effects, valproate is not usually a first-line agent.
The
mechanism of action for valproate is unclear. The drug has a wide
spectrum of anticonvulsant applications, therefore multiple mechanisms
of action are proposed. Loscher describes at least three
mechanisms.(xvi) Valproate increases GABA synthesis and release,
which may partially explain efficacy in treating central pain.
Valproate also attenuates neuronal excitation induced by NMDA-type
glutamate receptors. NMDA receptors have some correlation with
centralization of neuropathic pain states or the “wind-up”
phenomenon. Moreover, valproate has direct effects on excitable
membranes and acts as a membrane stabilizer, similar to intravenous
lidocaine and mexiletine.
Valproate
is available in an oral tablet, syrup, and rectal suppository.
Dosing starts at 10-15 mg/kg/day to a maximum of 30-60 mg/kg/day.
The drug has a half-life in children of 6-18 hours with a peak effect in
4 hours after administration. Plasma concentration does not
correlate with toxicity, seizure control, or analgesia. Valproate
is protein-bound (80-95%) and metabolized by glucuronidation and other
oxidative pathways.
Adverse
effects can be significant. Typical toxic effects within the first
several months include anorexia, nausea/vomiting, sedation, and weight
gain or loss. Valproate may cause hepatotoxicity and hepatic
dysfunction in 5-30% of patients. Other less common adverse
effects include hyperammonemia, pancreatitis, and platelet dysfunction.
For these reasons, valproate is not a first-line agent. Liver
function tests should be performed prior to initiation of valproate
treatment and then every month for the next 6 months. Symptoms
such as malaise, lethargy, gastrointestinal symptoms, and easy bruising
may indicate liver dysfunction and lead to immediate laboratory
evaluation and discontinuation of the drug. (xvii)
Gabapentin
(Neurontin®)
Gabapentin
is a compound that was originally synthesized as a gaba-ergic drug to
treat spasticity.It was
later found to be more effective as a potent anticonvulsant for treating
partial seizures and generalized tonic-clonic seizures.(xviii,xix)At this time, the mechanism of action of this agent is unclear.Gabapentin may enhance extracellular GABA levels by reversing
GABA transport in a unique way.The
compound does not reduce voltage sensitive sodium channels or affect
NMDA receptors.On a
biochemical level, gabapentin may inhibit a branched chain amino acid
transferase ultimately producing a decreased level of glutamate, an
excitatory amino acid that may be important in nerve transmission.Increased activity of glutamate dehydrogenase and glutamic acid
decarboxylase has also been noted in gabapentin treated animals, further
decreasing levels of glutamate.
The
most remarkable clinical feature of gabapentin is its few and infrequent
side-effects or dose limiting factors.In fact, it is safe to say that of the many agents described in
this chapter for the management of pain, none has a more benign side
effect or toxicity profile.
Gabapentin
is not protein bound; therefore, distribution is not affected by
alterations in hepatic function.Gabapentin
is not metabolized, and therefore does not induce hepatic enzymes.Gabapentin elimination is entirely by renal excretion.Dosage must therefore be adjusted proportionally to the reduction
in creatinine clearance.
Side
effects are predominately limited to the central nervous system:
somnolence, dizziness, ataxia, nystagmus and tremor.These effects are dose related and are usually minor.
Dosage
for adults ranges from 300 mg/day to 5600 mg/day.Gabapentin has a biological half-life of 5-9 hours and therefore
is typically prescribed on a three times a day schedule.Higher dosages (for example, >20 mg/kg/day) require more
frequent administration because gastrointestinal absorption depends upon
an L-amino acid transporter in the gastrointestinal tract that may
become saturated at higher gabapentin dosages, producing diarrhea.
The
use of gabapentin has been well described in the pediatric literature,
using doses from 5-30 mg/kg for the management of seizure disorders.(xx,xxi)Behavioral side effects of gabapentin have been described in
children consisting of intensification of baseline behaviors including
tantrums, hyperactivity, oppositional behavior, fighting, and increased
anger.(xxii)A disinhibition theory similar to one seen with benzodiazepine
therapy has been postulated as the cause.
Gabapentin
has been unambiguously found to be beneficial in treating chronic
neuropathic pain syndromes in adults.Mellick (xxiii)
described the use of gabapentin in complex regional pain syndrome type
I, in which significant pain relief and possible reversal of the disease
process was found.Controlled
studies by Robotham (xxiv)
for postherpetic neuralgia and Backonja (xxv)
for neuropathy secondary to diabetes mellitus also suggest efficacy of
treatment in these neuropathic pain conditions.Backonja additionally found that gabapentin therapy had a
positive effect on mood.
In
the treatment of pain in the pediatric population, reports are few,
limited mostly to case reports and small series. (xxvi) Since the
initiation of use of gabapentin, however, its clinical utility has far
outpaced the published data. In part, this may be due to the
relative paucity of agents useful in neuropathic pain, and the
significant side effects of these agents. In our clinic,
gabapentin is frequently used as a first or second line agent for the
treatment of neuropathic pain, initially at 10mg/kg and gradually
escalating over several weeks to a maximum of 50mg/kg. The daily
dosage may be titrated up to 70 mg/kg/day depending on clinical response
and side effects. (xxvii)
TRICYCLIC ANTIDEPRESSANTS
Depression
and other psychological symptoms such as anxiety and anger accompany
many chronic pain conditions.Originally,
chronic pain patients were treated for depression and coincidentally
found significant pain relief independent of the mood altering affect of
antidepressant medication.Subsequent
studies by Max (xxviii)
and others (xxix,xxx)
showed statistically significant relief in treating neuropathic pain
syndromes.
Antidepressants
therefore have multiple uses in pain medicine.These agents are used to treat depression, anxiety, sleep
disturbance, and, of course, pain.
All
tricyclic antidepressants that have been tested have equal efficacy at
therapeutic dosages.While
most antidepressants take 4-6 weeks to reach their full antidepressant
effect, the onset of analgesic effect is less clear, but is almost
certainly much shorter than that for the antidepressant effect.
The
pharmacology of tricyclic antidepressants is well defined.The mechanism of action of tricyclic antidepressants is the
reuptake inhibition of serotonin and norepinephrine from synaptic
junctions in the central nervous system.Each TCA has varying degrees of effect on serotonin and
norepinephrine levels, depending upon whether the drug is a primary or
tertiary amine.
Tricyclic
antidepressants have a high first pass metabolism by the liver after
absorption from the gastrointestinal tract.They are highly protein bound in plasma to alpha-1 acid
glycoprotein.Tricyclic
antidepressants are lipophilic molecules, therefore accumulate in the
body’s fat stores; biologic half-lives are quite long (1-4 days).
In
patients, there is wide plasma TCA level variability due to genetic
polymorphism.TCAs are
metabolized by P450 2D6.The
biochemical activity of the drug metabolizing isozyme cytochrome P450
2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian
population (about 7-10% of Caucasians are so called "poor
metabolizers"); reliable estimates of the prevalence of reduced
P450 2D6 isozyme activity among Asian, African and other populations are
not yet available. Poor metabolizers have higher than expected plasma
concentrations of tricyclic antidepressants when given usual doses.
Depending on the fraction of drug metabolized by P450 2D6, the increase
in plasma concentration may be small, or quite large (8-fold increase in
plasma level of the TCA).
In
addition, certain drugs inhibit the activity of this isozyme and make
normal metabolizers resemble poor metabolizers. An individual who is
stable on a given dose of TCA may become abruptly toxic when given one
of these inhibiting drugs as concomitant therapy. The drugs that inhibit
cytochrome P450 2D6 include some that are not metabolized by the enzyme
(quinidine; cimetidine) and many that are substrates for P450 2D6 (many
other antidepressants, phenothiazines, and the type 1C antiarrhythmics
propafenone and flecainide).While
all the selective serotonin reuptake inhibitors (SSRIs), e.g.,
fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary
in the extent of inhibition. The extent to which SSRI-TCA interactions
may pose clinical problems will depend on the degree of inhibition and
the pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the coadministration of TCAs with any of the SSRIs and in
switching from one class to the other. Of particular importance,
sufficient time must elapse before initiating TCA treatment in a patient
being withdrawn from fluoxetine, given the long half-life of the parent
and active metabolite (at least 5 weeks may be necessary).
Typical
side effects of TCAs are dose-related and include:
Antihistaminic
(H1 and H2): sedation and increased gastric pH
Quinidine-like
effect: QRS widening, prolonged QTc. As early as 1990 in
“The Medical Letter” and as recently as 1997, reports of the
sudden death of children have raised concerns of life threatening
arrhythmias.(xxxi,xxxii) Sudden deaths in TCA-treated children
may be idiosyncratic. Desipramine and imipramine in particular seem
to produce greater changes in baseline EKG, specifically increased
QRS duration.
Amitriptyline(Elavil®)
Collins
(xxxiii)
retrospectively described eight children, ages 5-17 years, in whom
intravenous amitriptyline was effective in treating neuropathic pain,
depression, sleep disturbance, and as an adjuvant for opioid analgesia.The calculation of initial intravenous dosage for
‘amitriptyline naďve” children was 0.2mg/kg/day, with ultimate
doses of 0.05-2.4 mg/kg/day given intravenously.Side effects in addition to those listed above included dysphoria,
which might have been secondary to concurrent opioids, and
extrapyramidal effects that resolved with diphenhydramine.
While
children may be rapid metabolizers of amitriptyline, and therefore
require twice-daily dosing schedule, a single daily dose is usually
first used until a side effect profile is established for individual
patients.The most
prominent and consistent side effect is somnolence; therefore, the daily
dose is generally given before bedtime.A recommended initial dosage is 0.05 mg/kg/day, escalating over a
period of 3-4 weeks to approximately 0.5-1 mg/kg/day is generally
sufficient for pain management, although higher doses have been used in
the past for mood elevation. Amitriptyline may also be parenterally
administered as an intramuscular injection using about one-third to
one-half the oral dose.The
intramuscular preparation presently marketed may also be administered
intravenously over a period of 2 hours, to mimic the absorption of an
intramuscular injection.
The
utility of routine measurement of plasma drug levels in pain management
is dubious, because no correlation has been shown between plasma drug
levels and analgesia.However,
plasma levels may identify a rapid or slow metabolizer, confirm
patient/parent compliance with prescription, and optimization of dosage
prior to discontinuation of trial.(xxxiv)
Nortriptyline
(Pamelor®)
Nortriptyline
is a compound with virtually identical pharmacology to amitriptyline,
but because of the demethylation of the terminal amide group, the side
effect profile is superior to amitriptyline, particularly in regards to
its sedative and antimuscarinic effects.
While
published experience with nortriptyline is lacking in pediatrics,
experience shows that it is equally effective, and preferable when
daytime somnolence limits the use of amitriptyline.
Desiprimine
(Norpramin®)
Desipramine
has been reported to be associated with sudden death in several
pediatric cases; therefore, its use has been abandoned for the
management of pain in children.
Selective Serotonin Reuptake
Inhibitors (SSRI's)
While
most useful to treat clinical signs of depression complicating the
management of chronic pain, most SSRIs are less effective as specific
analgesics than TCAs, although Sindrup, et al. found some benefit in
using paroxetine (Paxil®) to treat diabetic neuropathies, especially
when patients could not tolerate the side-effects of tricyclic
antidepressants.(xxxv)The notable exception to the absence of analgesic properties with
this newest class of antidepressants is venlafaxine.
Venlafaxine
(Effexor®)
Venlafaxine
is a novel SSRI chemically unrelated to other SSRIs but chemically
similar to the opioid tramadol (Ultram®) (Figure 1).(xxxvi)
Figure
1. The
chemical structures of venlafaxine and tramadol demonstrating the
chemical similarity between these two antidepressant and analgesic
substances, respectively.
The mechanism of the antidepressant
action of venlafaxine in humans is believed to be the same as with other
SSRIs, associated with its potentiation of neurotransmitter activity in
the CNS as with other SSRIs: preclinical studies have shown that
venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are
potent inhibitors of neuronal serotonin and norepinephrine reuptake and
weak inhibitors of dopamine reuptake.
That
venlafaxine is analgesia is seen in studies in animals that show
that venlafaxine is effective in reversing chronic neuropathic pain
secondary to thermal hyperalgesia, and additionally is effective in
treating the hyperalgesia of neuropathic pain due to chronic sciatic
nerve constriction injury in rats.(xxxvii)
Venlafaxine-induced antinociception is
significantly inhibited by naloxone, nor-BNI and naltrindole but not by
beta-FNA or naloxonazine, implying involvement of kappa1- and delta-opioid
mechanisms.When adrenergic
and serotoninergic antagonists are used, yohimbine but not phentolamine
or metergoline, decreased antinociception elicited by venlafaxine,
implying a clear alpha2- and a minor alpha1-adrenergic mechanism of
antinociception.Therefore,
the antinociceptive effect of venlafaxine is mainly influenced by the
kappa- and delta-opioid receptor subtypes combined with the
alpha2-adrenergic receptor. These results suggest a potential use of
venlafaxine in the management of some pain syndromes.However, further research is needed in order to establish both
the exact clinical indications and the effective doses of venlafaxine
when prescribed for neuropathic pain. (xxxviii)
SPINAL ALPHA-AGONISTS
Clonidine (Duraclon Injection®)
Recent studies using clonidine in central
and peripheral blockade show that it is co-analgesic when used with
either local anesthetics or opioids in epidural, intrathecal, or
peripheral blocks.(xxxix,xl) Clonidine is thought to have
applications in the treatment of chronic pain, particularly neuropathic
pain. Finally, intrathecal administration of clonidine has been
shown to reduce intractable muscle spasms in patients with spinal cord
injuries.
Alpha-2 receptors are located on primary
afferent terminals (both peripheral and spinal endings) in the
superficial laminae of the dorsal horn of the spinal cord, and within
several brainstem nuclei. The analgesic effect of clonidine may be
at all three sites, with each site’s relative contribution to its
analgesic effect being unclear. Most studies support a direct and
primary spinal analgesic action of clonidine. Supportive data for
this conclusion are the facts that the relative potency of epidural
clonidine to intravenous clonidine is 2:1, clonidine has a lipophilicity
similar to fentanyl, the duration of analgesia of epidural clonidine is
3-5 hours, and that intrathecal administration of clonidine results in a
peak effect within 30-60 minutes and has duration of up to 6 hours.
Clonidine increases the release of
acetylcholine at the dorsal horn. This enhances sensory and motor
block of C and A-delta fibers by local anesthetics by increasing
potassium conductance.
Adverse effects of clonidine include:
Dose
dependent decrease in blood pressure. Action at the nucleus
tractus solitarius and locus coeruleus decrease peripheral
sympathetic tone. Further action at the lateral reticular
nucleus causes hypotension and an antiarrythmogenic action.
Neuraxial administration inhibits sympathetic preganglionic neurons
in the spinal cord, and heart rate may decrease secondary to a
depression in atrioventricular nodal conduction.
Sedation.
This side effect is localized to the activity in the locus coeruleus.
The sedation is dose dependent between 50-900 µg regardless of
route of administration. Clonidine has a rapid onset of
sedation within 20 minutes. In adults, an infusion of epidural
clonidine of 30 µg per hour does not produce more sedation than
epidural placebo or epidural morphine.
Endocrine
depression. Clonidine reduces but does not suppress
neurohormonal secretion.
Sudden
cessation of clonidine treatment, regardless of the route of
administration and including after prolonged epidural
administration, has, in some cases, resulted in symptoms such as
nervousness, agitation, headache, and tremor, accompanied or
followed by a rapid rise in blood pressure.
Clonidine
alone does not induce respiratory depression nor potentiate respiratory
depression from opioids.
With
regards to the pediatric literature, most studies have been performed
using clonidine in combination with a bupivacaine epidural analgesia in
the acute pain setting. Motsch (xli) studied a group of 40
children undergoing minor surgical procedures. He found that
combined caudal analgesia with bupivacaine and clonidine (5 µg/kg) was
superior to local anesthetic alone, as determined by both duration and
intensity of analgesia. However, children had decreased blood
pressure and sedation for the first three postoperative hours.
This observed effect is consistent with the known duration of epidural
clonidine in adults. Other authors have studied caudal
analgesia using bupivacaine and clonidine, 1-2 µg/kg, with bupivacaine.
This dose of clonidine was seen to decrease mean arterial pressure but
not to cause bradycardia or respiratory depression. (xlii,xliii,xliv)
The
experience in adult cancer patients with intractable pain suggests an
initial dose of 30-150 µg followed by a continuous infusion of 8-400 µg/day.
Extrapolation from experience in adults and our unpublished clinical
experience suggests an initial dose of epidural clonidine of 1-2 µg/kg
should also be appropriate either in the subarachnoid or epidural
spaces, followed by an infusion of local anesthetic and clonidine at
0.02-0.1 µg/kg/hr, titrating as needed to a maximum of 0.2 µg/kg/hr,
while observing for undesired hemodynamic effects or sedation.
Table
2.Summary of
unconventional analgesics useful in the management of pain in children.
Drug
Indications
and Uses
Pediatric
Dosing
Toxicity
and
Notes
Lidocaine
·Neuropathic pain
·Refractory visceral pain
150
µg/kg/hr
·Measure plasma level every 8-12 hr and maintain 2-5 µg/ml
Mexiletine
·See Lidocaine
See
Table 1
·See Table 1
Carbamazepine
·Neuropathic pain
·Migraine prophylaxis
15-30
mg/kg
·Blood dyscrasias
·Monitor plasma level and periodic CBC
Valproate
·Neuropathic pain
·Migraine prophylaxis
·Mood lability
10-60
mg/kg
·Blood dyscrasias; hepatotoxicity
·Dose divided BID.Monitor plasma level and periodic CBC and LFT
Gabapentin
·Neuropathic pain
·Migraine prophylaxis
5-30
mg/kg
·Dose divided TID or QID.Escalate dose over several weeks to target dose
Amitriptyline
Nortriptyline
Imipramine
·Neuropathic pain
·Migraine prophylaxis
0.05-2
mg/kg
·Escalate dose over several weeks to target dose.Dose given h.s.Obtain
screening ECG prior to use: contraindicated in prolonged QTc
Venlafaxine
·Chronic pain with depression
·Neuropathic pain
1-2
mg/kg
·Dose divided BID or TID
·Caution when used with TCAs or other SSRIs because of
reported arrhythmias
Clonidine
·Neuropathic pain
·Visceral pain
·Postoperative pain
0.05-0.2
µg/kg/hr
·By continuous epidural infusion
·May produce hypotension, bradycardia, somnolence
CAPSAICIN
Capsaicin is the chemical substance in chili peppers that creates their
spiciness and heat.
In 1997, a gene that encoded for a receptor specific for capsaicinoids
was identified. The capsaicin-gated vanilloid receptor 1 (VR1) is a
fatty acid receptor present only on C fibers, that when activated
produces desensitization or degeneration of the sensory afferent. This
phenomenon has led to the use of capsaicin for the management of chronic
pain states, particularly those associated with burning cutaneous
dysesthesias and mechanical allodynia. However, there are some
conditions for which capsaicin is ineffective, such as peripheral
neuropathy associated with the acquired immune deficiency syndrome
(AIDS) and neuropathic pain associated with nerve injury.
Overall, outcome studies show that the "number needed to
treat" (NNT) with capsaicin varies from 2.5 in painful diabetic
neuropathy, to 5.9 in other disorders. This is not an impressively
effective treatment modality, and the inconvenience of the necessity to
spread a cream over a large affected body surface.
Chronic application of capsaicin leads to
depletion of substance P from cutaneous C fibers, and ultimately
degeneration of C fibers, thus some degree of analgesia. However, acute
cutaneous application of capsaicin produces a complex sensation that
changes in intensity and quality as a function of time and is
characterized by sting, prick, burn and pain. The painful sensations and
inconvenience associated with acute application of capsaicin to affected
skin clearly limits its usefulness in pediatric pain medicine.
Furthermore, there are no published reports of the use of capsaicin in
children.
CONCLUSIONS
Nociceptive pain may be adequately
treated with conventional opioid and nonopioid analgesics, however many
neuropathic pain states are refractory to conventional analgesics.For these conditions, use of a number of drugs not traditionally
considered analgesics, and not developed by the pharmaceutical industry
for their analgesic properties is effective.These drugs are effective by virtue of their membrane stabilizing
effects or their additive or synergistic enhancement of endogenous
modulation of nociception in the central nervous system.
We are entering an era of new analgesic
drug development by the pharmaceutical industry, and it is likely that
in the next decade new compounds will be added to our armamentarium to
fight pain in novel molecular ways.As our understanding of the molecular mechanisms of pain evolve,
the category of unconventional analgesics will certainly expand.
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symptomatic treatment of painful neuropathy in patients with
diabetes mellitus. Journal of the American Medical Association
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xxvi.
Wheeler DS, Vaux KK, Tam DA. Use of gabapentin in the
treatment of childhood reflex sympathetic dystrophy. Pediatric
Neurology 2000; 22:220-1.
xxvii.
Bourgeois B. Antiepileptic drugs in pediatric practice.
Epilepsia 1995; 36:S34-45.
xxviii.
Max M, Kishore-Kumar R, Schafer S, et al. Efficacy of
desipramine in painful diabetic neuropathy: a placebo-controlled
trial. Pain 1991; 45:3-9.
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Vrethem M, Boivie J, Arnqvist H, et al. A comparison of
amitriptyline and maprotiline in the treatment of painful
polyneuropathy in diabetics and nondiabetics. Clinical Journal
of Pain 1997; 13-313-23.
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antidepressant in neuropathic pain. Pain
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xxxi.
Wilens T, Biederman J, Baldessarini RJ, et al. Cardiovascular
effects of therapeutic doses of tricyclic antidepressants in
children and adolescents. Journal of the American Academy of
Child and Adolescent Psychiatry 1996; 35:1491-1501.
xxxii.
Varley C, McClellan J. Case study:two additional sudden deaths
with tricyclic antidepressants. Journal of the American
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xxxiii.
Collins J, Kerner J, Sentivany S, et al. Intravenous
amitriptyline in pediatrics. Journal of Pain and Symptom
Management 1995;10:471-5.
xxxiv.
Richeimer S, Bajwa Z, Kahraman S, et al. Utilization patterns
of tricyclic antidepressants in a multidisciplinary pain clinic: a
survey. Clinical Journal of Pain 1997;13:324-9.
xxxv.
Sindrup S, Gram L, Brosen K, et al. The selective serotonin
reuptake inhibitor paroxetine is effective in the treatment of
diabetic neuropathy symptoms. Pain 1990; 42:135-44.
xxxvi.
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Hypotheses 1998; 51:167-8.
xxxvii.
Lang E, Hord AH, Denson D. Venlafaxine hydrochloride (Effexor)
relieves thermal hyperalgesia in rats with an experimental
mononeuropathy. Pain 1998; 68:151-5.
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Schreiber S, Backer MM, Pick CG. The antinociceptive effect of
venlafaxine in mice is mediated through opioid and adrenergic
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This section, edited by Charles B. Berde, MD, PhD, and
Michael C. Rowbotham, MD, presents timely topics in pain research and
treatment.
Testing the Autonomic
Nervous System
Paola Sandroni, MD, PhD
Department of Neurology, Mayo
Clinic,
Rochester, Minnesota, USA
The autonomic nervous system (ANS) is an
extensive neural network whose main role is to regulate the milieu intérieur
by controlling homeostasis and visceral functions. Although most functions
regulated by the ANS are out of conscious control, emotions and
somatosensory inputs profoundly influence the ANS. Observing the marked
vasomotor and sudomotor changes after traumatic nerve injury, it became
apparent long ago that the ANS plays an important role in pain modulation
and perception. Despite the debate on whether the role of the sympathetic
nervous system in generating and sustaining certain pain syndromes is
significant, specialists in pain management have sought tools for
investigating the ANS.
Anatomy
The ANS has components at every level of
the nervous system. The central component, also known as the central
autonomic network (CAN), includes the insula, medial prefrontal cortex,
hypothalamus, amygdala, ventrolateral medulla, nucleus of the tractus
solitarius (NTS), nucleus parabrachialis, periaqueductal gray, and the
circumventricular organs.
The insula, through its connection
with the hypothalamus, thalamus, parabrachial nucleus, and NTS, appears to
be a crucial visceral sensorimotor area. Activation of the insular cortex
induces hypertension, tachycardia, piloerection, pupillary dilatation, and
salivation, and alters gastrointestinal function. Stimulation of the
medial prefrontal cortex, which has connections with the amygdala,
hippocampus, thalamus, hypothalamus, parabrachial nucleus, and NTS, induces
bradycardia and hypotension and modulates gastric secretion.
The hypothalamus is the most
important ANS organ, controlling every vital function and integrating
neuroendocrine and autonomic systems. This is the site where the internal
and external worlds interface. The amygdala, intercalated between the
cerebral cortex, the hypothalamus, and the mesencephalic regions, plays a
major role by coloring with emotions all stimuli and generating responses
that include autonomic function modulation.
At the mesencephalic level, the nucleus
parabrachialis and periaqueductal gray (PAG) are integrative
relay areas. The PAG is also a crucial structure in pain modulation.
Brainstem regions of the medulla oblongata that control most reflex and
automatic cardiorespiratory functions include the ventrolateral medulla
and the NTS. Circumventricular organs, by sensing humoral
changes, participate in autonomic function modulation.
The peripheral components of the ANS are
the sympathetic and parasympathetic nervous systems. The
sympathetic system preganglionic neurons lie in the intermediolateral column
ofthe spinal cord: their axons synapse in the prevertebral and para-vertebral
ganglia from where postsynaptic fibers travel a relatively long distance to
innervate each organ.
The sympathetic is a diffuse system, able
to generate mass responses by epinephrine release from the adrenal medulla
by virtue of its high postganglionic:preganglionic fiber ratio and long
postganglionic fibers. Parasympathetic preganglionic neurons lie in cranial
and sacral nuclear groups. The parasympathetic nervous system acts
selectively because the preganglionic axons synapse in ganglia that lie in
close proximity to the effector organs and because the parasympathetic
postganglionic:preganglionic fiber ratio is much lower than in the
sympathetic nervous system. The sympathetic and parasympathetic systems
usually oppose each other, but in a few organs their effects are
synergistic.
Neurotransmitters
Acetylcholine (Ach) is the
"classic" neurotransmitter for preganglionic neurons in the
sympathetic and parasympathetic nervous systems. Sympathetic postganglionic
neurons release nor-epinephrine (NE), with the exception of sudomotor fiber
release of acetylcholine. Parasympathetic postganglionic neurons all release
Ach. A variety of neuropeptides and putative neurotransmitters coexist with
Ach- and NE-containing neurons at various levels of the CAN, the spinal
cord, and both pre- and postganglionic terminals. Neuropeptides and putative
neurotransmitters play an important role in visceral function and also
modulate a multitude of integrated functions, such as cognition, pain, and
locomotion. The most common are: cholecystokinin (CCK), substance P (SP),
somatostatin, enkephalins, neurokinins, nitric oxide (NO), vasoactive
intestinal peptide (VIP), neuropeptide Y (NPY), serotonin (5-HT), and
calcitonin gene-related peptide (CGRP). At the visceral level, purines,
prostaglandins (PGs), and other peptides (such as dynorphins) are also
present.
Clinical Investigations
Because of its many functions, a complete
assessment of the ANS is extremely complex. Each specialty has developed its
own test battery to assess those ANS functions most relevant to its field.
ANS testing is used most often by cardiologists, gastroenterologists,
urologists, and endocrinologists. Only recently have neurologists and pain
specialists become directly involved in developing ways to evaluate patients
with ANS dysfunction.
Because postganglionic fibers are
unmyelinated, they cannot be tested directly by conventional
neurophysiologic techniques, i.e., nerve conduction studies and
electromyography. Therefore, the only way to assess their function is
indirect, by evaluating the response elicited reflexly by appropriate
stimuli. Until very recently, autonomic tests were available only in a few
specialized centers. Now the equipment to measure noninvasively
cardiorespiratory and circulatory parameters and to measure sweat production
is commercially available. The cost of establishing a lab, however, is about
$66,000, and reimbursement remains a major problem. The testing is time
consuming, averaging 1 hour per patient. Furthermore, skilled technicians
and physicians trained in correctly interpreting the studies are few.
Adequate baseline acclimatization and proper positioning of subjects are
crucial. Efforts should be made to keep the patients as comfortable as
possible to limit pain-induced artifacts.
Drugs can have substantial effects on the
results of ANS testing and are a common cause of abnormal results. Patients
need to refrain from caffeine, nicotine, and alcohol at least 3 hours
prior to testing. All medications with adrenergic and anticholinergic
properties need to be discontinued at least 48 hours prior to the study (see
Table 1). Among the drugs commonly used for treatment of pain, tricyclic
antidepressants have the highest anticholinergic properties and can also
impact adrenergic transmission. Selective serotonin reuptake inhibitor (SSRI)
antidepressants can be continued, but mixed agents like venlafaxine and
trazodone should be stopped. Medications used to control nausea (such as
chlorpromazine) have weak anticholinergic effects and may have
antiadrenergic effect. Some sedatives with antihistaminic properties (diphenydramine)
may act as weak anticholinergics and should be stopped if possible. Agents
altering adrenergic transmission are used in pain control regimens. Besides
the obvious effect of beta-blockers and peripherally acting alpha-blockers,
centrally acting agents such as clonidine may significantly alter the
studies. Barbiturates, used in central pain syndromes, have beta-adrenergic
antagonist properties that are often forgotten, but only in specific
circumstances (such as in disorders of reduced orthostatic tolerance) are
these clinically relevant. Calcium channel blockers can alter cardiac
studies as well as studies of vaso-motor function. NSAIDs and steroids alter
vessel wall reactivity and should be stopped if the reason for the study is
orthostatic intolerance. Some muscle relaxants, such as cyclobenzaprine and
orphenadrine, have mild nicotinic anticholinergic properties. Muscle
relaxants usually have limited effects on autonomic testing, but ideally
patients should refrain from taking them 48 hours prior to testing. Topical
capsaicin, by inducing substance P release, causes neurogenic inflammation
altering vasomotor tone, and to a lesser extent, sudomotor tone. Capsaicin
should therefore be discontinued prior to testing.
Table
1. Medications and autonomic testing results
Medications
that significantly affect autonomic testing results
Muscle
relaxants have generally mild anticholinergic properties;
usually they do not affect significantly the studies
Opioids are vasodilators and by histamine
release can induce sweating. Opioids can be continued in patients who
chronically use stable doses of long-acting agents. Short-acting
preparations should be stopped, but withdrawal phenomena also affect
autonomic testing. Medications that can be continued include anticonvulsants
such as carbamazepine, valproic acid, and gabapentin, and membrane
stabilizers such as mexiletine and lithium.
Specific Tests (Table 2)
Table
2.Tests to assess autonomic function
Test Panel
Function
Assessed
Autonomic
Reflex Screen (ARS)
Tilt table
test
Deep breathing
Valsalva maneuver
QSART
Adrenergic
vasomotor function
Cardiovagal
Cardiovagal and adrenergic vasomotor
Postganglionic cholinergic sudomotor
CRPS
Screen
Temperature
measurements
RSO*
QSART*
TST
Index of
sympathetic vasomotor tone
Sudomotor and partially vasomotor
Postganglionic sudomotor (stimulated)
Thermoregulatory sudomotor pathways
*Performed
simultaneously in bilateral, symmetrical sites.
Quantitative Sudomotor Axon Reflex Test
(QSART)
A variety of methods have been described
to visualize sweat droplets, map sweat glands, and estimate sweat production
by the resulting modification in skin potentials. Most of these techniques
have become obsolete with the development of the QSART. QSART assesses the
integrity both of the axon reflex arch and of sweat glands in the dermis.
Postganglionic sympathetic sudo-motor fibers are activated by iontophoresis
of Ach into the skin. The impulse travels antidromically to the first
branching point and then travels orthodromically back to the skin to
activate the corresponding sweat glands.
The equipment needed to perform this test
consists of a 3-compartment capsule, a constant flow of N2 to
evaporate the sweat, a heat exchanger to detect the thermic change due to
moisture of the returning N2 flow, and a source of continuous
current for the iontophoresis.
Ach is iontophorized into one compartment
and sweat output is measured from a different compartment. A solution of 10%
Ach is injected into the first compartment and a constant current of 2 mA is
applied for 5 minutes. Sweat output is measured for 5 more minutes after
stimulus discontinuation. After a stable baseline is obtained, 4 sites are
tested simultaneously: medial distal forearm, proximal lateral leg, medial
distal leg, and dorsum of the foot.
Abnormalities that can be found include:
(1) reduced/absent output, frequently seen in small fiber neuropathies; and
(2) persistent sweat activity: a sustained output after stimulus
discontinuation indicates sweat gland overactivity. An excessive resting
sweat output has similar meaning. A shortened latency of sweat production
(<30 minutes) may be due to an exaggerated somatosympa-thetic reflex due
to reduced threshold for fiber activation. When these abnormalities are seen
in a painful neuropathy, the test is evidence of excessive sympathetic fiber
activity.
Sympathetic skin response, widely used in
the past, is still utilized where QSART is not available. By measuring
change in skin resistance following a random electric stimulation, it
provides an index of sweat production. However, this is non-thermoregulatory
sweat that occurs on the palms and soles, is of different pharmacological
and physiologic properties, and involves somatic afferents. Its sensitivity
and specificity are inferior to QSART.
Resting Sweat Output (RSO)
No stimulus is applied for this test.
Simultaneous recording is performed bilaterally in standard sites (upper
extremity: the medial distal forearm and hypothenar eminence; lower limb:
medial distal leg above the malleolus and dorsum of the foot). Sweat
production is measured as in QSART, but larger capsules are used. RSO is
recorded for 5 minutes, by which time a steady state is usually attained.
Measurement is made of the last minute of sweat production.
Thermoregulatory Sweat Test (TST)
The thermoregulatory sweat test assesses
the entire thermo-regulatory sudomotor pathway. It is a very useful
complement to the QSART for differentiating pre- vs. postganglionic
disorders. Neurologic disorders, drugs, and skin conditions are responsible
for most abnormal results. This test is based on the proportional sweat
production to a rise in core temperature. The temperature rise is sensed in
the hypothalamus, activating the sympathetic sudomotor pathways. After
appropriate acclimatization, the subject is disrobed and dusted with
alizarin red powder. When moist, the powder changes color from orange to
purple. A thermal probe is placed in the subject’s mouth (to monitor core
temperature) and another one on the skin (to monitor for excessive surface
heating that could cause injuries as well as induce non-thermoregulatory
sweat production mediated by pain). The subject enters a closed compartment
heated by infrared heating units that control humidity and ambient
temperature (respectively, 35–40% and 45–50°C). To generate the maximum
sweat response, subjects are heated to a core temperature 1 degree above
baseline or 38°C (whichever is greater). If profuse sweating occurs at a
lower temperature, the test is stopped. Subjects are then photographed and
by computer scanning the areas of anhidrosis/hypohidrosis are mapped and
expressed as percentage of body surface.
Abnormal TST results can be classified as
follows:
Hypo/anhidrosis can occur in
different patterns:
• Distal (involving toes, legs
below the knee, fingers, and in more advanced cases also the anterior lower
abdomen and forehead): typically seen in peripheral neuropathies.
• Focal: follows dermatomal or
peripheral nerve distribution. Also can be seen in isolated skin lesions.
• Segmental: usually larger
areas than focal ones, following sympathetic distribution (such a pattern
can be seen after sympathectomies).
• Regional: widespread
anhidrosis but <80% body surface bordering with hypohidrosis that
gradually evolves into normal areas.
• Global: diffuse, >80%
anhidrosis (usually an advanced stage of the prior pattern) such as can be
seen in multiple system atrophy (MSA) and progressive autonomic failure (PAF).
• Mixed: pattern not
classifiable into any of the above.
Hyperhidrosis can occur as well;
this can be classified as:
• Essential (idiopathic).
• Compensatory (perilesional),
associated with autonomic hyperreflexia.
Vasomotor Function
Tests to assess cardiovagal,
cardiosympathetic, and adrenergic vasomotor functions are based on reflex
arches originating from stretch receptors located in the lungs (Bainbridge
reflex) and low and high pressure receptors located in the atria and large
vessels (aorta, carotid arteries). The afferent branches synapse in the
ventrolateral medulla. The efferent branch of the reflex affects heart rate
and blood pressure and can be monitored beat-to-beat noninvasively by
photoplethysmographic technique utilizing a finger probe. An autonomic
screen includes 3 studies (deep breathing, Valsalva maneuver, tilt test),
the analysis of which allows for an adequate assessment of these functions.
Blood flow has been measured with
techniques such as Doppler probes. These are very sensitive, but prone to
artifact. Huge oscillations can be seen with even slight environmental
stimuli. An extremely controlled setting, experienced technician, and
cooperative subject are needed, making the technique impractical.
Indirect assessments of vasomotor function
by temperature measurement are much more popular. Infrared thermometry and
telethermography are widely used. Side-to-side comparison and pattern of
asymmetry are used in study analysis. Sensitivity and specificity are not
satisfactory, and in isolation these tests have limited clinical use.
The most common pain indication for
studies of vasomotor function is complex regional pain syndrome type I (CRPS
I), or reflex sympathetic dystrophy (RSD). Unfortunately, symptoms and signs
evolve over time and can have diurnal fluctuations. Attempts have been made
to stress patients to elicit asymmetries (such as ice water immersion).
These maneuvers are time consuming and painful to the patients;
somatosympathetic responses may be elicited that make interpretation
problematic. Since diagnosis relies on detection of asymmetries, a bilateral
syndrome is extremely difficult to diagnose, unless florid signs are
present.
Applications in Pain Evaluation
Autonomic testing is safe and reliable.
Two types of ANS screens are offered at the Mayo Clinic. In the screening
battery, a tilt table study, deep breathing, and Valsalva maneuver plus the
QSART are performed. In CRPS I patients, temperature measurements, RSO, and
QSART are performed. TST is often added to complement the screens.
Performing the screening battery in pain syndromes is useful if peripheral
neuropathy is suspected or to rule out associated conditions. No specific
pattern is associated with chronic pain per se. Highly significant
correlations have been found between the clinical and laboratory assessments
in CRPS I patients using this battery of tests.
ANS testing is valuable in assessment of
CRPS I and sympathetically maintained pain. In a prospective study, Willner
and colleagues showed that different patterns of abnormality of the QSART
could predict the response to sympathetic block in patients with CRPS I (Low
et al. 1996). In patients with burning feet and erythromelalgia, autonomic
tests have demonstrated subtle abnormalities suggesting selective
involvement of small fibers even when clinical examination and nerve
conduction studies are normal. When studying patients with postural
tachycardia syndrome, a higher than expected incidence of migraineurs was
found: further study revealed subtle adrenergic abnormalities suggesting
vasomotor lability in migraineurs. Other pain conditions have been
associated with reduced orthostatic tolerance, such as chronic fatigue
syndrome. Anecdotal reports of abnormal autonomic testing in fibromyalgia
have appeared; these data need confirmation.
Table
3. Indications for autonomic testing in some pain syndromes
Fibromyalgia
May detect
other conditions such as small neuropathy or a disorder of reduced
orthostatic tolerance.
Chronic
fatigue syndrome
May detect
a disorder of reduced orthostatic tolerance (such as postural
tachycardia syndrome).
Painful
neuropathies
Assess
degree of impairment of small fibers functions and presence of a
length dependent neuropathy.
CRPS
CRPS
screen, to detect asymmetry or abnormality of sympathetic functions.
Bibliography
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network: functional organization, dysfunction, and perspective. Mayo Clin
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Benarroch EE, Opfer-Gehrking T, Low PA.
Analysis of Valsalva maneuver in normal subjects. Ann Neurol 1989; 26:186A.
Chelimsky TC, Low PA, Naessens JM, et al.
The value of autonomic testing in RSD. Mayo Clin Proc 1995;70:1029–1040.
Dotson RM. Clinical neurophysiology
laboratory tests to assess the nociceptive system in humans. J Clin
Neurophysiol 1997; 14(1):32–45.
Freeman R, Komaroff AL. Does the chronic
fatigue syndrome involve the autonomic nervous system? Am J Med 1997;
102(4):357–364.
Low PA, Caskey PE, Tuck RR, Fealey RD,
Dyck PJ. Quantitative sudomotor axon reflex test in normal and neuropathic
subjects. Ann Neurol 1983; 14:573–580.
Low PA, Neumann C, Dyck PJ, Fealey RD,
Tuck RR. Evaluation of skin vasomotor reflexes by using laser Doppler
velocimetry. Mayo Clin Proc 1983; 58:583–592.
Low PA, Wilson PR, Sandroni P, Willner CL,
Chelimsky TC. Clinical characteristics of patients with RSD (SMP) in the
USA. In: Janig W, Stanton-Hicks M (Eds). Reflex Sympathetic Dystrophy: A
Reappraisal. Progress in Pain Research Management, Vol. 6. Seattle: IASP
Press, 1996, pp 49–66.
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Philadelphia: Lippincott-Raven, 1997, pp 383–390.
Pfeifer MA, Cook D, Brodsky J, et al.
Quantitative evaluation of cardiac parasympathetic activity in normal and
diabetic man. Diabetes 1982; 31:339–345.
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Pharmacologic dissection of components of the Valsalva maneuver in
adrenergic failure. J Appl Physiol 1991; 71:1563–1567.
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Philadelphia: Lippincott-Raven, 1997, pp 221–231.
Disclaimer: Timely topics in
pain research and treatment have been selected for publication, but the
information provided and opinions expressed have not involved any
verification of the findings, conclusions, and opinions by IASP®.
Thus, opinions expressed in the IASP Newsletter do not necessarily
reflect those of the Association or of the Officers and Councillors. No
responsibility is assumed by the Association for any injury and/or damage to
persons or property as a matter of products liability, negligence or
otherwise, or from any use or operation of any methods, products,
instruction, or ideas contained in the material herein. Because of the rapid
advances in the medical sciences, the publisher recommends that independent
verification of diagnoses and drug dosages should be made.
Raynauds & facial erythromelalgia
internet post - antidepressants can help or hurt?:
Doc
Spot
This feature is a regular
spot in our quarterly newsletter.
Members of the Association
can ask a question to Professor Belch via the Association.
Professor Belch is unable
to enter into any personal correspondence.
Professor Jill Belch
Q
I have Raynaud's and severe erythromelalgia in my feet, ears and cheeks.
I am taking one of the Prozac-type antidepressants (citalopram) which is
helping to ease my depression. But it has greatly increased the number
and severity of my erythro attacks so that I cannot sleep for the pain.
I have read that these antidepressants increase the amount of serotonin
among the nerves, but also constrict the blood vessels. Please can you
explain why this antidepressant is aggravating my erythro? I also have
severe erythro in my ears and cheeks so I can never put my face in the
sun.
A
Firstly, in terms of
your erythromelalgia, it is interesting that you feel you cannot put
your face in the sun because of problems with the ears and cheeks. Can
you clearly identify a link with sunlight exposure? If you are out in
the sun but have a hat over your ears do you get the same problem as if
the ears were exposed to sunlight? The reason I ask is that sometimes
people can develop photosensitivity, when they are actually allergic to
sunshine. There are effective barrier creams for this and therefore it
would be interesting to know if this is the case.
You ask about
antidepressants and erythromelalgia. One of the commonest causes of
erythromelalgia, ie hot burning pain, is a secondary reactive hyperaemia.
What happens is that the underlying problem is vasoconstriction. The
blood vessels constrict if not enough blood gets through and chemicals
are released from the tissues which are starved of blood. These
chemicals induce a vasodilatation (opening up the blood vessels) and
because this is induced by chemicals there is a burning pain associated.
Sometimes antidepressants can help erythromelalgia because they are
quite useful to control burning pain. Sometimes, however, they aggravate
it because they produce further vasoconstriction which results in
increased vasodilatory chemical release and worsening of the burning
pain symptoms.
Peter H. Gott, M.D. http://www.jewishworldreview.com
--
DEAR DR. GOTT: I have been diagnosed with erythromelalgia. What is this? Will a
special diet help my symptoms?
DEAR READER: This unusual ailment is marked by flushing, burning pain and
increased skin temperature of the feet and (sometimes) the hands. The cause is
unknown; however, some forms are associated with other diseases, such as blood
disorders, diabetes and hypertension.
Although symptoms are usually mild, in rare and severe cases they can be
disabling. Attacks of erythromelalgia are often triggered by changes in
environmental temperature.
Unfortunately, therapy is not consistently successful. Some patients'
symptoms can be relieved if their underlying diseases are brought under control;
for example, by reducing elevated blood sugar levels and lowering high blood
pressure. Other patients find relief by simply using daily aspirin, avoiding
temperature extremes and taking prescription medicine, such as ephedrine or
propranalol, that prevents flushing.
I am not aware of any diet that is beneficial. Perhaps you should review your
concerns with your doctor, who may recommend aspirin therapy as an economical
and effective first step.
Could you please e-mail any relevent information on the disease erythro
myalgia especially the causes, clinical features and management ?
A
Hi ... glad to help.
I think you mean 'erythromelalgia'. It is a rare syndrome of
paroxysmal vasodilation with burning pain, increased skin temperature, and
redness of the feet; less often of the hands.
It may occur in two forms, primary with no known etiology, or secondary .
The latter may occur in patients with myeloproliferative disorders,
hypertension, venous insufficiency, or diabetes mellitus.
The most notable clinical feature is attacks of burning pain in hot, red,
feet or hands. It is triggered by ambient temperatures of between 29 and 32
C in most patients. Trophic changes do not occur. Symptoms may remain mild
for years or may become so severe that total disability results. Diagnosis
is based on demonstration that the patient's complaints are related to
objectively increased skin temperature. Secondary types should be
differentiated from the rare primay disorder since correction of the
underlying disorder may relieve the symptoms.
Attacks can be avoided or aborted by rest, raising the affected
extremity, and applications of cold. Therapy is not always successful. In
the primary form. 600 mg. of aspirin 1 to 4 times per day, may produce
prompt, prolonged relief. Factors that produce vasodilation should be
avoided. Orally administered vasoconstrictors may also produce relief.
RSDS is often treated and evaluated by rheumatologists. You should have your
daughter evaluated by a pediatric rheumatologist or a pediatric orthopedist who
has experience with RSDS.
REFLEX SYMPATHETIC DYSTROPHY This disorder is a form of local causalgia,
usually involving a hand or foot but not corresponding to the anatomic
distribution of a peripheral nerve. A continuous burning pain and
hyperesthesia are associated with vasomotor instability in the affected zone,
resulting in increased skin temperature, erythema, and edema due to
vasodilatation and hyperhydrosis. In the chronic state, atrophy of skin
appendages, cool and clammy skin, and disuse atrophy of underlying muscle and
bone occur. More than one extremity is occasionally involved. The pain is
disabling and is exacerbated by the movement of an associated joint, though no
objective signs of arthritis are seen; immobilization provides some relief.
The most common preceding event is local trauma in the form of a contusion,
laceration, sprain, or fracture days or weeks earlier.
Several theories of pathogenesis have been proposed to explain this
phenomenon. The most widely accepted is reflexive overactivity of autonomic
nerves in response to injury, and regional sympathetic blockade often affords
temporary relief. Physiotherapy also is helpful. Some cases resolve
spontaneously after weeks or months, but others continue to be symptomatic and
require sympathectomy. A strong psychogenic component is suspected in some
cases but is difficult to prove.
Partial interruption of nerve conduction by injury, such as gunshot
wounds. Possible shunting of efferent sympathetic impulses into
sensory fibers at site of injury in a mixed nerve.
Reflex sympathetic dystrophy
RISK FACTORS
Trauma
DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
Rule out infection, hypertrophic scar, bone fragments, neuroma,
central nervous system tumor or syrinx
LABORATORY TESTS
none
PATHOLOGICAL FINDINGS
Partial or complete damage to afferent nerve pathways and probably
reorganized central pain pathways
Most common nerves involved are median and sciatic
Atrophy in affected muscles
Incomplete nerve plexus lesion
SPECIAL TESTS
none
IMAGING
Bone scan
DIAGNOSTIC PROCEDURES
Intravenous regional sympathetic block with guanethidine or
reserpine (this is a specialized anesthetic technique that may also be
therapeutic)
TREATMENT
APPROPRIATE HEALTH CARE
Outpatient, except for operative procedures or intravenous
sympathetic nerve blockade
GENERAL MEASURES
Treatment is empirical
Anesthetic blockade (chemical or surgical) of sympathetic nerve
function (transient relief suggests that chemical or surgical
sympathectomy will be helpful)
Intravenous regional sympathetic block with guanethidine or
reserpine by pain specialist or anesthetist
Physical therapy (essential during all phases of treatment)
Transcutaneous electric nerve stimulation (controversial)
Inject myofacial painful trigger points
Briskly rub the affected part several times per day
Acupuncture can be tried
Hypnosis
Relaxation training (alternate muscle relaxing and contracting)
Biofeedback
Discourage maladaptive behaviors
Refer the patient to a specialty pain clinic in difficult cases
SURGICAL MEASURES
Sympathectomy sometimes necessary
ACTIVITY
Maintain as high a level of physical and intellectual activity as
possible
DIET
No special diet
PATIENT EDUCATION
Stress staying active physically
Careful instructions about any prescribed medications
MEDICATIONS
DRUG(S) OF CHOICE
Following agents reported to be of benefit in some cases:
Prazosin, 1-8 mg orally in divided doses
Phenoxybenzamine 40-120 mg daily, orally in divided doses. The
initial dose should not exceed 10 mg.
Nifedipine 10-30 mg tid
Prednisone 60-80 mg/day orally, tapered over 2-4 weeks
Tricyclic antidepressants (see manufacturers recommended dose)
Anticonvulsants. (Require serum drug level monitoring, except
for clonazepam. Doses must be individualized.):
Carbamazepine 200-1000 mg/day orally
Phenytoin 100-300 mg/day orally
Clonazepam 1-10 mg/day orally
Valproic acid 750-2250 mg/day orally, maximum of 60 mg/kg
Skeletal muscle relaxant:
Baclofen 10-40 mg/day orally - may act synergistically with
carbamazepine and phenytoin
Contraindications: Refer to manufacturer's literature
Precautions: Refer to manufacturer's literature
Significant possible interactions: There are many with this group of
drugs. Refer to manufacturer's literature.
ALTERNATIVE DRUGS
Narcotics - only after all non-opioid therapies are exhausted
Other alpha-adrenergic blockers or dihydropyridine calcium channel
blockers may be tried though experience with them is limited
FOLLOW-UP
PATIENT MONITORING
Watch carefully for adverse reactions to medications
Several different forms of therapy may need to be tried
PREVENTION/AVOIDANCE
Mobilization following injury
Avoidance of nerve damage during surgical procedures
Splinting of an injured extremity for adequate period of time
Adequate analgesics during recovery from injuries
POSSIBLE COMPLICATIONS
Drug mishaps
Joint contractures
Contralateral spread of symptoms
EXPECTED COURSE/PROGNOSIS
Course - variable; chronic; remitting
Outlook only satisfactory, may need attempts at several treatment
modalities. No one form of therapy is superior to others. Failure to
respond to one form does not mitigate against success with another.
Those patients receiving work compensation for an injury or
secondary gain from family or friends are in a separate category and
may never get well
MISCELLANEOUS
ASSOCIATED CONDITIONS
Serious injury to bone and soft tissue
Herpes zoster
AGE-RELATED FACTORS
Pediatric: none
Geriatric: Painful perception is frequently worse in older patients.
Start with smaller than usual doses of drugs.
Others:
Postherpetic neuralgia is a result of partial or complete damage to
afferent nerve pathways
Pain occurring in dermatomes as a sequela of herpes zoster
SYNONYMS
Erythromelalgia, traumatic
Weir Mitchell causalgia
Minor causalgia
Reflex sympathetic dystrophy
Posttraumatic neuralgia
Sympathetically maintained pain
For additional information and support, check the RSDS Web site at http://rsds.org/
A refractory case of secondary erythermalgia successfully treated with
lumbar sympathetic ganglion block.
Br J Dermatol. 2000 Oct;143(4):868-72.
PMID: 11069475 [PubMed - indexed for MEDLINE]
Disorders of the autonomic nervous system. Chapter 7. Some disorders of
regional circulation.
Contemp Neurol Ser. 1974;(11):114-28. Review. No abstract
available.
PMID: 4615868 [PubMed - indexed for MEDLINE]
Lumbar sympathectomy. A retrospective study of 142 operations on 100
patients.
Br J Surg. 1973 Nov;60(11):878-9. No abstract available.
PMID: 4752732 [PubMed - indexed for MEDLINE]
Efficacy of sphenopalatine ganglion blockade in 66 patients suffering from
cluster headache: a 12- to 70-month follow-up evaluation.
J Neurosurg. 1997 Dec;87(6):876-80.
PMID: 9384398 [PubMed - indexed for MEDLINE]
Long-term results of sphenopalatine ganglioneurectomy for facial pain.
Am J Otolaryngol. 1987 May-Jun;8(3):171-4.
PMID: 3618907 [PubMed - indexed for MEDLINE]
http://www.emedicine.com/NEURO/topic517.htm
-Pathophysiology and Treatment of Migraine and Related Headache here-
"Cluster headache is an extremely severe, unilateral, orbital or
supraorbital pain associated with ipsilateral facial autonomic symptoms.
Pain also may radiate to the back of the neck, suboccipital area, and along
the carotid artery. Pain often is boring in nature, lasts from 15 minutes to
4 hours, and typically, patient is awakened in the middle of the night with
the headache. Tenderness of the temporal artery, facial flushing, and
elevated skin temperature on the ipsilateral side have been reported."
Cluster Headache (CH): Synonyms, Key Words, and Related Terms: Bing-Horton syndrome, histaminic cephalalgia, cluster migraine,
paroxysmal nocturnal cephalalgia, red migraine, erythromelalgia of the
head, sphenopalatine neuralgia, migrainous neuralgia
"The pathophysiology of CH is not understood entirely. Its typical periodicity has been attributed to hypothalamic (particularly suprachiasmatic nuclei) hormonal influences. CH pain is thought to be generated at the level of the pericarotid/cavernous sinus complex. This region receives sympathetic and parasympathetic input from the brain stem, possibly mediating occurrence of autonomic phenomena during an attack. The exact roles in CH of immunologic and vasoregulatory factors, as well as the influence of hypoxemia and hypocapnia, are still controversial...
- The association of prominent autonomic phenomena is a hallmark of CH.
Such signs include ipsilateral nasal congestion and rhinorrhea, lacrimation,
conjunctival hyperemia, facial diaphoresis, palpebral edema, and complete or
partial Horner syndrome (which may persist between attacks). Tachycardia is
a frequent finding.
A distinctive CH face is described as follows: leonine facial
appearance, multifurrowed and thickened skin with prominent folds, a broad
chin, vertical forehead creases, and nasal telangiectasias."
The antidepressant mirtazapine successfully treats refractory cluster
headache:
Researchers from the UK report the case of a 56 year old man who had an 11 year history of cluster headache which had proven refractory to treatment with calcium antagonists, lithium, dexamethasone, prednisolone and sumatriptan. However soon after starting a 6 week course of mirtazapine 30mg daily the patient experienced a rapid reduction in the number and severity of attacks. Nutt. D et al. Headache 39: 586-587 Per Inpharma 1999; 1215: 13 (27th Nov).
PET and MRA findings in cluster headache and MRA in
experimental pain.
May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ.
University Department of Clinical Neurology, Institute of Neurology,
National Hospital for Neurology and Neurosurgery, London, UK.
BACKGROUND: Cluster headache (CH), like migraine, is still regarded
as a vascular headache although in both conditions a CNS cause has been
suggested. OBJECTIVE: To examine neurovascular mechanisms in CH.
METHODS: The authors used functional imaging with PET to investigate 18
CH patients (25 to 62 years old). Ten were in the active period (nine
patients with induced attacks and one with spontaneous attack) and eight
were out of their bout. In addition, the authors studied spontaneous CH
and experimental pain in volunteers using MR angiography. RESULTS: When
an acute CH attack was triggered with nitroglycerin (NTG), activation
occurred in the ipsilateral posterior inferior hypothalamic gray, the
contralateral ventroposterior thalamus, the anterior cingulate cortex,
the ipsilateral basal ganglia, the right anterior frontal lobe, and both
insulae. In patients out of the bout who experienced only a mild NTG
headache, activation was seen bilaterally in the insulae and frontal
cortices, the anterior cingulate cortex, the right thalamus, and the
left basal ganglia, but not in the hypothalamic gray area. In addition,
the authors found a significant activation (vasodilatation) in the
region of the major basal arteries that was caused in part by NTG but
was also observed in the spontaneous case and could be induced by
capsaicin injection into the forehead. Therefore, the vasodilatation
is likely to be mediated by neural mechanisms involved in the acute CH
attacks that are present in every human being. CONCLUSIONS: Dilatation
of cranial vessels is not specific to any particular headache syndrome
but generic to cranial neurovascular activation, probably mediated by
the trigeminoparasympathetic reflex. These data confirm that CH is a CNS
disorder best considered as a form of neurovascular headache.
Institute of Neurology, The National Hospital for Neurology and
Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom. peterg@ion.ucl.ac.uk
Neuroimaging of primary headache syndromes, such as cluster headache and
migraine, has begun to provide a glimpse of the neuroanatomical and
physiological basis of the conditions. Although these headache types
have been widely described as vascular, there is now considerable
imaging and clinical evidence to suggest that they are primarily driven
from the brain. The shared anatomical and physiological substrate
for both of these clinical problems is the neural innervation of the
cranial circulation. Functional imaging with positron emission
tomography (PET) has shed light on the genesis of both syndromes,
documenting activation in the midbrain and pons in migraine, and in the
hypothalamic grey in cluster headache. These areas are involved not
simply as a response to first division nociceptive pain impulses but
specifically in each syndrome, probably in some permissive or
dysfunctional role. In a recent PET study in cluster headache, as well
as brain activation, tracer pooled in the region of the major basal
arteries. This is likely to be due to vasodilatation of these vessels
during the acute pain-attack and represents the first convincing
activation of neural vasodilator mechanisms in humans. The author
takes the view that the known physiology and pathophysiology of the
systems involved dictate that these disorders should be collectively
regarded as neurovascular headaches to place emphasis on the interaction
between nerves and vessels, which is the underlying characteristic
of these syndromes. Understanding this neurovascular relationship
facilitates an understanding of the pain mechanisms, while
characterising the CNS dysfunction will ultimately allow us to dissect
out the basic pathogenesis of these disorders. Copyright 2001 Wiley-Liss,
Inc.
Magnetic resonance angiography in facial and other
pain: neurovascular mechanisms of trigeminal sensation.
May A, Buchel C, Turner R, Goadsby PJ.
Headache Group, The National Hospital for Neurology and Neurosurgery,
Queen Square, London, UK.
For much of the twentieth century migraine and cluster headache have
been considered as vascular headaches whose pathophysiology was
determined by changes in cranial vascular diameter. To examine nociceptive
neural influences on the cranial circulation, the authors studied
healthy volunteers' responses to injection of the pain-producing
compound capsaicin in terms of the caliber of the internal carotid
artery. The study was conducted using magnetic resonance angiographic
techniques. Injection of capsaicin into the skin innervated by the
ophthalmic (first) division of the trigeminal nerve elicited 40% +/- 27%
(mean +/- SD) increase in vascular cross-sectional area in the right (ipsilateral)
internal carotid artery when compared with the mean baseline ( P <
0.001). Injection of capsaicin into the skin of the chin to stimulate
the mandibular (third) division of the trigeminal nerve and into the leg
led to a similar pain perception and failed to produce any significant
change in vessel caliber. The data suggest that there is a highly
functionally organized, somatotopically congruent trigeminal innervation
of the cranial vessels, with a potent vasodilator effect of the
ophthalmic division on the large intracranial vessels. The data are
consistent with the notion that pain drives changes in vessel caliber in
migraine and cluster headache, not vice versa. These conditions
therefore should be regarded as primary neurovascular headaches not as
vascular headaches.
Swedish Headache Clinic, Swedish Neurosciences Center, 1221 Madison,
Suite 1026, Seattle, WA 98104, USA. sheena.aurora@swedish.org
This last decade has seen remarkable progess made toward unraveling the
mystery of primary headache disorders like migraine and cluster. The vascular
theory has been superseded by recognition that neurovascular phenomena
seem to be the permissive and triggering factors in migraine and cluster
headache. This understanding has been achieved through new imaging
modalities such as positron emission tomography and functional magnetic
resonance imaging. Prior to these imaging techniques it was impossible
to study the primary headache disorders because these had no structural
basis. There is now an increasing body of evidence that the brain is
involved primarily in cluster and migraine and that vessel dilatation is
an epiphenomenon.
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