From the desk of:

Medical Report on Effective Non-Hormonal Hot Flash Treatments
(For your Health Care Practitioner/Doctor; prepared 6/21/11) From the Menopause Therapy Center; Thomas Guttuso, Jr., MD; Assistant Professor of Neurology; University at Buffalo; Buffalo, NY; 716-932-6080, option 3. Question: Which non-hormonal hot flash therapies have been shown to provide clinically
meaningful & significant long-term benefit in post-menopausal women? Answer: Gabapentin and Oxybutynin ER
The gold-standard hot flash therapy remains hormone replacement therapy (HRT); however, the
NIH-sponsored Women’s Health Initiative (WHI) study results published in 2002 linked HRT
use in older women to increased rates of breast cancer, heart disease, stroke, and deSubgroup analysis of the WHI study also showed increased rates of stroke in younger women,
who are more likely to be experiencing hot flash the synthetic hormone tibolone is as
effective as HRT for reducing hot flashes but is also associated with increased rates of str
Although HRT currently remains the only FDA-approved hot flash therapy, well-designed and
peer-reviewed studies have shown gabapentin and oxybutynin ER to be safe and effective non-
hormonal treatments for hot flashes.
These 2 therapies will very likely provide long-term benefit in treating hot flashes as they are
the only 2 compounds currently available that have shown clinically meaningful efficacy in
randomized controlled trials (RCTs) for at least 8 weeks of treatment (Table 1). The length of
the RCT treatment period is critical in order to be able to generalize the results long-terFDA actually recommends a 12 week study period for hot flash RCTs supporting this
indi
Table 1: Daily Hot Flash Frequency Treatment Effects During Final Treatment Week. Pandya et aclonidine 0.1mg qd (n=194) A “clinically meaningful” daily hot flash frequency treatment effect is considered to be about -2/day. Table 1 shows gabapentin and oxybutynin ER to be clinically meaningful hot flash treatments. Although HRT is considered the “gold standard” hot flash therapy, gabapentin 800mg tid was shown to have equivalent efficacy and tolerability to conjugated estrogen To make an appointment with Dr. Guttuso, call 716-932-6080, option 3. (Premarin) 0.625mg qd after 12 weeks of treatme other hand, desvenlafaxine was clearly shown to be less effective than hormonal therain a comparative trial. Also, recent studies have shown increased blood pressure and heart attacks in women with hot flashes taking desvenlafaxine. Oxybutynin ER has not yet been directly compared to hormonal therapy. Gabapentin has also been reported to provide satisfactory benefit in a patient whose hot flashes were resistant to HR Effective non-hormonal hot flash therapy doses: Gabapentin 300-800mg tid; Oxybutynin ER 15mg qd Gabapentin (Neurontin) is FDA-approved for treating seizures and neuropathic pain. Its unique
mechanism of action stems from its interaction with voltage-dependent calcium channels in the
CNS and P the older seizure medications, there is no need to check gabapentin
serum levels. Gabapentin also does not have any drug-drug interactions because it is only
minimally bound to serum proteins and it is not metabolized but is excreted in the urine in its
original forentin’s principal side effects in hot flash patients are sleepiness (20%),
dizziness (13%), and peripheral edema (7%), which usually are mild and last for 1-2 weeks
before resolving. The sleepiness side effect can often be advantageous in patients most bothered
by night sweats simply by giving a higher dose at bedtime or sometimes only giving a dose at
bedtime if daytime hot flashes are not bothersome. In 2008, the FDA reported that the use of any
anticonvulsant increases the risk for suicidal thoughts and behaviors by 0.2%.
The following start-up dosing regimen was used in the initial gabapentin hot flash RCand has
also been most effective for my hot flash patients:
“Gabapentin 300mg capsules:
1 capsule qhs x 3 days; then 1 capsule bid x 3 days; then 1 capsule tid (last dose qhs)”.

This slow titration greatly minimizes any possible gabapentin-related side effects. If after 1
week at this dose the patient is still being bothered by hot flashes, repeat the titration up to 2
capsules tid (1,800mg/day). About 86% of patients who respond to gabapentin will be satisfied
at 1,800mg/day or l The maximum recommended daily dose for gabapentin is 3,600mg/day;
however, in my experience, if a patient has not responded to a dose of 900mg tid (2,700mg/day),
they will not respond to higher doses. If side effects are bothersome, the 100mg gabapentin
capsules and/or a slower titration can be used. Also, gabapentin tends to be most effective and
best tolerated if a larger dose is given at bedtime, especially for patients with frequent night
sweats. I have found that the most common effective final dosing regimen for gabapentin to be
300mg qAM, 600mg q2PM, and 600mg qhs.
Oxybutynin ER (Ditropan XL) is FDA-approved for treating overactive bladder/urge
incontinence. The only RCT performed with oxybutynin ER has only been published in abstract
form as of 1ertheless, it was a well-designed study with a 12 week treatment period.
The treatment effect for 15mg qd appears to be quite robust (Table 1). The main side effects
reported were dry mouth (52%), dyspepsia (12%), and diarrhea (10%). The recommended
dosing is 5mg qd x 1 week, then 10mg qd x 1 week, then 15mg qd. The distinct advantage of
oxybutynin ER over gabapentin is its qd dosing.
To make an appointment with Dr. Guttuso, call 716-932-6080, option 3. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. Jama 2002;288:321-33. 2. Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, Ko M, LaCroix AZ, Margolis KL, Stefanick ML. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. Jama 2007;297:1465-77. 3. Cummings SR, Ettinger B, Delmas PD, Kenemans P, Stathopoulos V, Verweij P, Mol-Arts M, Kloosterboer L, Mosca L, Christiansen C, Bilezikian J, Kerzberg EM, Johnson S, Zanchetta J, Grobbee DE, Seifert W, Eastell R. The Effects of Tibolone in Older Postmenopausal Women. N Engl J Med 2008;359:697-708. 4. Guttuso T, Evans M. Minimum Trial Duration to Reasonably Assess Long-Term Efficacy of Nonhormonal Hot Flash Therapies. J Womens Health (Larchmt) 2010;19:699-702. 5. U.S. Department of Health and Human Services FDA. Guidance for Industry: Estrogen and estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms- recommendations for clinical evaluation, 1/2003. Available at: Accessed 1 September 2010. 6. 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. 7. 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. 8. 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. 9. Simon JA, LaGuardia KD. Extended-release oxybutynin relieves vasomotor symptoms in healthy postmenopausal women. Obstet Gynecol 2007;109:76S. 10. Speroff L, Gass M, Constantine G, Olivier S. Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized controlled trial. Obstet Gynecol 2008;111:77-87. 11. Freeman EW, Guthrie KA, Caan B, Sternfeld B, Cohen LS, Joffe H, Carpenter JS, Anderson GL, Larson JC, Ensrud KE, Reed SD, Newton KM, Sherman S, Sammel MD, LaCroix AZ. Efficacy of escitalopram for hot flashes in healthy menopausal women: a randomized controlled trial. Jama 2011;305:267-74. 12. Reddy SY, Warner H, Guttuso T, Jr., Messing S, Digrazio W, Thornburg L, Guzick DS. Gabapentin, Estrogen, and Placebo for Treating Hot Flushes: A Randomized Controlled Trial. Obstet Gynecol 2006;108:41-8. 13. European Medicines Agency EMEA. Withdrawal assessment report for Pristiqs. Available at: Guttuso T, Jr. Hot flashes refractory to HRT and SSRI therapy but responsive to gabapentin therapy. J Pain Symptom Manage 2004;27:274-6. 15. Taylor CP. The biology and pharmacology of calcium channel (alpha)2(delta) proteins. Pfizer Satellite Symposium to the 2003 Society for Neuroscience Meeting. Sheraton New Orleans Hotel, New Orleans, LA November 10, 2003. CNS Drug Rev 2004;10:183-8. 16. Accessed 31 August 2009. Financial Conflict: Dr. Guttuso is the inventor on US Patent 6,310,098, which is owned by the University of Rochester, covering the use of gabapentin and related compounds for treating hot flashes. Dr. Guttuso does not receive royalties on the sales of generic gabapentin or brand name Neurontin. To make an appointment with Dr. Guttuso, call 716-932-6080, option 3.

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