Venlafaxine

Effexor-XR is an SSNRI (Selective Serotonin Norepinepherine Reuptake Inhibitor) with a similar side effect profile to SSRIs including a reportedly difficult withdrawal on the internet similar to Paroxetine if not tapered properly. More info for consumers & medical professionals at: http://www.rxlist.com (with forum board of users) & the company's website http://www.effexorxr.com . Also worth visiting http://www.effexor-xr-side-effects-withdrawal.com (informed consent is important).

Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. [In Process Citation]

Loprinzi CL; Kugler JW; Sloan JA; Mailliard JA; La Vasseur BI; Barton DL; Novotny PJ; Dakhil SR; Rodger K; Rummans TA; Christensen BJ
Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. cloprinzi@mayo.edu.

BACKGROUND: Hot flashes can be troublesome, especially when hormonal therapy is contraindicated. Preliminary data have suggested that newer antidepressants, such as venlafaxine, can diminish hot flashes. We undertook a double-blind, placebo-controlled, randomised trial to assess the efficacy of venlafaxine in women with a history of breast cancer or reluctance to take hormonal treatment because of fear of breast cancer. METHODS: Participants were assigned placebo (n=56) or venlafaxine 37.5 mg daily (n=56), 75 mg daily (n=55), or 150 mg daily (n=54). After a baseline assessment week, patients took the study medication for 4 weeks. All venlafaxine treatment started at 37.5 mg daily and gradually increased in the 75 mg and 150 mg groups. Patients completed daily hot-flash questionnaire diaries. The primary endpoint was average daily hot-flash activity (number of flashes and a score combining number and severity). Analyses were based on the women who provided data throughout the baseline and study weeks. FINDINGS: 191 patients had evaluable data for the whole study period (50 placebo, 49 venlafaxine 37.5 mg, 43 venlafaxine 75 mg, 49 venlafaxine 150 mg). After week 4 of treatment, median hot flash scores were reduced from baseline by 27% (95% CI 11-34), 37% (26-54), 61% (50-68), and 61% (48-75) in the four groups. Frequencies of some side-effects (mouth dryness, decreased appetite, nausea, and constipation) were significantly higher in the venlafaxine 75 mg and 150 mg groups than in the placebo group. INTERPRETATION: Venlafaxine is an effective non-hormonal treatment for hot flashes, though the efficacy must be balanced against the drug's side-effects. Confirmation of the results of this 4-week study awaits the completion of three ongoing randomised studies to assess the effects of other related antidepressants for the treatment of hot flashes.

Language: English
MEDLINE Indexing Date: 200012
Publication Type: MEDLINE RECORD IN PROCESS
Publication Type: Journal Article
Grant ID: CA-25224; CA-35113; CA-37404
PreMedline Identifier: 0011145492
Unique NLM Identifier: 21017708
Journal Code: ; AIM

Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors.

Loprinzi CL; Pisansky TM; Fonseca R; Sloan JA; Zahasky KM; Quella SK; Novotny PJ; Rummans TA; Dumesic DA; Perez EA
Department of Oncology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. cloprinzi@mayo.edu.

PURPOSE: Hot flashes can be a prominent clinical problem for breast cancer survivors and men who undergo androgen-deprivation therapy. Anecdotal information suggested a low dose of a relatively new antidepressant, venlafaxine, could abrogate this clinical problem. MATERIALS AND METHODS: This study included 28 consecutive assessable patients entered onto a phase II clinical trial. Hot flash data were collected by daily diary questionnaires during a 1-week baseline period and then for 4 weeks, during which time patients received venlafaxine 12.5 mg orally twice daily. RESULTS: Fifty-eight percent of patients who completed the study had a greater than 50% reduction in hot flash scores (frequency times severity) during the fourth treatment week as compared with the baseline week. Median weekly hot flash scores were reduced by 55% from baseline during the fourth week of venlafaxine therapy. Therapy was generally well tolerated and appeared to alleviate fatigue, sweating, and trouble sleeping. CONCLUSION: Venlafaxine appears to represent an efficacious new method to alleviate hot flashes. Further evaluation of this compound for alleviating hot flashes is indicated.

Major Subject Heading(s)	Minor Subject Heading(s)	CAS Registry / EC Numbers
Antidepressive Agents, Second-Generation [therapeutic use] Antineoplastic Agents [adverse effects] Cyclohexanols [therapeutic use] Hot Flashes [drug therapy] Serotonin Uptake Inhibitors [therapeutic use] .	Adult Hot Flashes [chemically induced] Middle Age Pilot Projects Prospective Studies Questionnaires Treatment Outcome	0 (Antidepressive Agents, Second-Generation) 0 (Antineoplastic Agents) 0 (Cyclohexanols) 0 (Serotonin Uptake Inhibitors) 93413-69-5 (venlafaxine)

Language: English
MEDLINE Indexing Date: 199810
Publication Type: CLINICAL TRIAL; JOURNAL ARTICLE
Unique NLM Identifier: 98329828
Journal Code: M; X

OBJECTIVE: To determine if increases in core body temperature preceding most hot flashes are caused by increased metabolic rate, peripheral vasoconstriction, or central noradrenergic activation. DESIGN: Laboratory physiological study. SETTING: University medical center. PATIENT(S): Fourteen healthy, postmenopausal women reporting frequent hot flashes. INTERVENTION(S): Data were recorded for 3 hours in a temperature- and humidity-controlled room. MAIN OUTCOME MEASURE(S): Core body temperature, mean skin temperature, respiratory exchange ratio, sternal skin conductance, plasma 3-methoxy-4-hydroxyphenylglycol, and vanillylmandelic acid. RESULT(S): Twenty-nine physiologically defined hot flashes were recorded. Increases in core body temperature, measured with an ingested radiotelemetry capsule, preceded 76% of the flashes. Increased metabolic rate began after increased core temperature. Peripheral vasoconstriction did not occur. Plasma levels of 3-methoxy-4-hydroxyphenylglycol, a metabolite of brain norepinephrine, increased significantly, whereas vanillylmandelic acid, a peripheral metabolite, did not. CONCLUSION(S): Core body temperature elevations preceding menopausal hot flashes are not driven by peripheral vasoconstriction or increased metabolic rate, but probably by a central noradrenergic mechanism.

Major Subject Heading(s)	Minor Subject Heading(s)	CAS Registry / EC Numbers
Body Temperature Regulation [physiology] Hot Flashes [physiopathology] Menopause [physiology] Norepinephrine [physiology] Vasoconstriction [physiology]	Analysis of Variance Galvanic Skin Response Hot Flashes [metabolism] Middle Age	51-41-2 (Norepinephrine)

Language: English
MEDLINE Indexing Date: 199810
Publication Type: CLINICAL TRIAL; JOURNAL ARTICLE
Grant ID: AG-05233-AG-NIA
Unique NLM Identifier: 98359419
Journal Code: M

Erythromelalgia: Response to serotonin reuptake inhibitors
Journal of The American Academy of Dermatology
August 1997 • Volume 37 • Number 2
Donald Rudikoff, MD
Israeli A. Jaffe, MD, FACP

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

7. Catchpole BN. Erythromelalgia. Lancet 1964;1:909-11.

8. Mandell F, Folkman J, Matsumoto S. Erythromelalgia. Pediatrics 1977;59:45-8. 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.

14. Jaffe IA. Serotonin reuptake inhibitors in Raynaud’s phenomenon [letter]. Lancet 1995;345:1378. MEDLINE

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

* Unlike TCAs & other SSRIs such as fluoxetine (Prozac), SSNRI Venlafaxine (Effexor) & SSRI sertraline (Zoloft) do have more affect on the dopamine system which may account for the difference in response or it may be totally idiosyncratic. As a more natural alternative, SAM-e boosts levels of both serotonin and dopamine as well, while stabilizing noradrenaline levels.

Warnings: The information above is provided for educational purposes and may not be construed as a medical prescription or as a substitute for the advice of your physicians.