News in non-hormonal treatment of menopausal symptoms
June 30, 2010 News
in non-hormonal treatment of menopausal symptoms
Jaime Urdinola MD
Medical Association Andes-AK 9116 20 CS 326 - Bogotá DC Colombia
☎ 571/2152300 e-mail: jaimeurdinolamd@gmail.com
blogger: www.urdinolamenopausia.blogspot.com - www.urdinolamenopausia2.blogspot.com
Symposium / Luncheon on Women's Health and Menopause
Andes Medical Association - Board Room - First Floor
Wednesday, June 30, 2010
Introduction
vasomotor symptoms are common in the menopausal transition period. informing up to 57% of hot flashes and 50% in postmenopausal 1. Most women (60%) are experienced for 7 years, although 15% still exist for more than 15 years 2. And traditionally have been treated effectively with hormone therapy (HT), the only therapy approved for this purpose. Obviously today, after the publication of the WHI (Women's Health Initiative) in 2 002, there is concern about possible adverse effects of HRT on the breast and uterus. For this reason, is currently being evaluated today by treatments SERM (Selective Oestrogen Receptor Modulators) through estrogen agonist or antagonist effects, alone or in combination with estrogen as is the case bazedoxifene and hormonal therapies Action on central nervous system (CNS) to the alleviation of vasomotor symptoms, such as various antidepressants and the use of gabapentin and clonidine. The dietary herbal supplements such as soy and "black cohosh" or radúnculo have shown mixed results and inconclusive in controlled clinical studies placebo. In study also finds a Chinese herbal therapy directed at β receptor, the compound MF-101.
MF-101-Selective Estrogen Receptor β
selective agonists can stimulate estrogen receptors or receptor α or β receptor inducing estrogenic effects specific tissue, thereby providing a safe alternative compared to the TH. MF-101 is derived from 22 herbs that are traditionally used in Chinese medicine for treating menopausal symptoms. Preclinical studies and one Phase II liquiritigenina made to date and chalcone isolated active compounds (found in alcazuz licorice or English) show selectivity for the estrogen receptor β without induction of proliferative events, growth of cancer cells in the breast or uterine growth stimulation 3. To confirm its safety and efficacy results are expected Phase III studies, which were planned for the year 2 009.
For those women who can not take estrogen or who choose not to use them, but persistent symptoms of moderate to severe intensity, the current options for management of vasomotor symptoms are centrally acting antidepressants, and gabapentin and clonidine.
Neuroactive agents
Most studies have been conducted in women with breast cancer or at increased risk for this problem. Apparently, increased serotonergic activity in the CNS reduces hot flashes, possibly through a fading effect of the suspension at the central level of opioid peptides or reducing noradrenergic activity. We have studied the inhibitors of serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, citalopram and mirtazapine, as well as inhibitors of norepinephrine reuptake (SSNI) such as venlafaxine and its metabolite desvenlafaxine, and gabapentin. Venlafaxine
, desvenlafaxine, paroxetine, and clonidine appear be those that produce more relief and reduction of vasomotor symptoms between 50 and 67%. The effects are apparent after 4 weeks and the answer seems to be stable up to 12 weeks. However, the extent of relief over time, the doses needed for maximum benefit and whether the impact varies according to specific medication use, are questions not yet fully clarified 4 . Concomitant use of MAO inhibitors (MAOI), thioridazine, warfarin is contraindicated with SSRIs. Adverse effects in patients treated for depression include asthenia, sweating, nausea, decreased appetite, somnolence, insomnia and dizziness. Also, can inhibit cytochrome P450 enzyme CYP2D6, which contraindicated use in patients receiving tamoxifen for breast cancer, it will reduce your metabolism up to 60% at its most active, endoxifen. The power described for the inhibition of this enzyme varies between paroxetine (the highest), fluoxetine, sertraline, citalopram and venlafaxine (the lowest). Venlafaxine
A double-masked, placebo-controlled randomized (n = 191, efficacy evaluable for 4 weeks) at doses of 37.5, 75 or 150 mg in women with a history of breast cancer or who refused to receiving HT. In the end, women with placebo showed a decrease of 27%, 37% with 37.5 mg and 61% with 75 and 150 mg, the latter being no more effective dose of 75 mg and associated with an increase in dry mucous membranes, anorexia, nausea and constipation 5 . An open study 6 continuation reported a sustained reduction in hot flashes and other randomized controlled 7 (n = 80, 12 weeks) in postmenopausal women receiving 37.5 Initial mg and 75 mg after 1 second. week for 11 weeks, found that the severity was not statistically decreased significant, but its effects on daily living were significantly improved (p = 0,001). 93% of patients in the venlafaxine group chose to continue treatment.
desvenlafaxine
metabolite of venlafaxine demonstrated in a randomized controlled trial (n = 458, postmenopausal women) at a dose of 100/150 mg / day, a significant reduction in the number of hot flashes at week 4 and 12 , up 66.6% at week 12 compared with placebo, 50.8% 8. Most adverse events were reported in the first week than with placebo, as appropriate titration of the dose appears to improve initial tolerance and decrease the adverse event reporting. Fluoxetine
Discussed in doses of 20 mg in a randomized double-masked (n = 81 for 4 weeks, tamoxifen and raloxifene permitted by previous breast cancer). The rates of hot flashes decreased 50% vs. placebo 9 and analysis were crossed vs index improved. placebo (p <0.02).
Citalopram vs
was studied. Fluoxetine (n = 150, 9 months) in a randomized controlled trial, beginning with 10 mg and increasing to 20 mg at 4 weeks and 30 mg at 6 months . There were no differences significant relief, between treatment and placebo groups, although a positive trend for the SSRI. Insomnia was significantly improved with citalopram 10 . Paroxetine
twice in a multicenter randomized controlled trial (n = 165 for 6 weeks, raloxifene, tamoxifen and vitamin E allowed), women who received paroxetine CR at doses of 12.5 and 25 mg had a reduction in 62. 2 and 64.6%, vs. a reduction of 37.8% in the placebo group 11.
Clonidine has been studied in oral and transdermal 12.13 , the oral dose of 0.1 mg / day vs. placebo (n = 194 for 8 weeks) in patients with breast cancer receiving tamoxifen, a decrease of 38% vs. 20% for placebo. Adverse effects were dry mouth, drowsiness, constipation and dizziness, which decreased by using the patch given as a dose escalation.
Gabapentin is approved as an anticonvulsant and for the treatment of postherpetic neuralgia. Serves as an agonist of γ-amino acid butíricoy is believed to affect the temperature regulation through its link a calcium channel. Randomized controlled studies suggest that its efficacy is superior to placebo. In one study (n = 59, allowing antiestrogens, clonidine or antidepressants) at a dose of 900 mg, were reduced hot flushes 54% vs. 31% with placebo (p = 0.01) 14. In another open study with higher doses of 900 mg reduced hot flashes was higher, however 50% of patients reported at least one adverse event vs. 27.6% in the placebo group. 13.3% was suspended due to drowsiness, dizziness or skin rash. In another large study, randomized controlled trial with doses of 300 and 900 mg (n = 420 patients, 371, measurable, with a history of breast cancer) 15, the index of severity of hot flashes declined 21% in week 4 and 15% at week 8 vs. placebo with 300 mg of gabapentin, and 49 and 46% respectively with a dose of 900 mg. The latter dose is significant in reducing the frequency of heat waves and their severity. It should be emphasized however, that although gabapentin appears to be effective, adverse effects are significant and longest published study has only 12 weeks.
Conclusion Venlafaxine, desvenlafaxine, paroxetine, gabapentin and clonidine as trandérmica oral and currently appear most promising agents for non-hormonal treatment for vasomotor symptoms. Awaiting results of tests on the compound MF-101, β-receptor agonist. References
1 - Gold EB, Colvin A, Avis N, Bromberger J, Greendale GA, Powell L, Sternfeld B, Matthews K. Longitudinal analysis of the Association Between Vasomotor Symptoms and race / ethnicity across the menopausal transition: study of women's health across the nation. Am J Public Health. 2006, 96:1226-35.
2 - Kronenberg F. Hot flashes: epidemiology and physiology. Ann NY Acad Sci 1990, 592:52-86.
3 - Stovall DW, Pinkerton JV. MF-101, an estrogen receptor beta agonist for the treatment of vasomotor symptoms in peri- and postmenopausal women. Curr Opin Investig Drugs. 2009; 10: 365-71.
4- Pinkerton JV, Stovall DW, Kightlinger R. Advances in the treatment of menopausal symptoms. Women's Health. 2009; 5: 361-384.
5- Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, Novotny PJ, Dakhil SR, Rodger K, Rummans TA, Christensen BJ. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet. 2000; 356: 2059-63.
6- Barton D, La VB, Loprinzi C, Novotny P, Wilwerding MB, Sloan J. Venlafaxine for the control of hot flashes: results of a longitudinal continuation study. Oncol Nurs Forum. 2002; 29: 33-40.
7- Evans ML, Pritts E, Vittinghoff E, McClish K, Morgan KS, Jaffe RB. Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol. 2005 ; 105: 161-6.
8- Archer DF, Dupont CM, Constantine GD, Pickar JH, Olivier S; Study 319 Investigators. Desvenlafaxine for the treatment of vasomotor symptoms associated with menopause: a double-blind, randomized, placebo-controlled trial of efficacy and safety. Am J Obstet Gynecol. 2009 Mar;200: 238.e1-238.e10.
9- Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard JA, Halyard MY, Pruthi S, Novotny PJ, Rummans TA. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol. 2002 15; 20: 1578-83.
10- Suvanto-Luukkonen E, Koivunen R, Sundström H, Bloigu R, Karjalainen E, Häivä-Mällinen L, Tapanainen JS. Citalopram and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebo-controlled, double-blind study. Menopause. 2005; 12: 18-26.
11- Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003 ; 289: 2827-34.
12- Pandya KJ, Raubertas RF, Flynn PJ, Hynes HE, Rosenbluth RJ, Kirshner JJ, Pierce HI, Dragalin V, Morrow GR. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med. 2000; 132: 788-93.
13- Goldberg RM, Loprinzi CL, O'Fallon JR, Veeder MH, Miser AW, Mailliard JA, Michalak JC, Dose AM, Rowland KM Jr, Burnham NL. Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol. 1994; 12: 155-8. Erratum in: J Clin Oncol 1996; 14: 2411.
14- Guttuso T Jr, Kurlan R, McDermott MP, Kieburtz K. Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2003; 101: 337-45.
15- Pandya KJ, Morrow GR, Roscoe JA, Zhao H, Hickok JT, Pajon E, Sweeney TJ, Banerjee TK, Flynn PJ. Gabapentin for hot flashes in 420 Women with breast cancer: a Randomised double-blind placebo-controlled trial. Lancet. 2005, 366: 818-24.
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