levetiracetam for the treatment of hot flashes: a phase ii study

ORIGINAL ARTICLE

Levetiracetam for the treatment of hot flashes:a phase II study

Susan Thompson & Aditya Bardia & Angelina Tan &

Debra L. Barton & Lisa Kottschade & Jeff A. Sloan &

Brad Christensen & DeAnne Smith & Charles L. Loprinzi

Received: 15 February 2007 /Accepted: 16 May 2007 / Published online: 28 June 2007# Springer-Verlag 2007

AbstractGoals of work The objectives of this pilot trial were toassess the potential efficacy and safety of levetiracetam forthe treatment of hot flashes, a major cause of morbidityamong breast cancer survivors.Patients and methods Women, aged 18 years or more, witha history of breast cancer or those who wished to avoidestrogen because of a perceived increased risk of breastcancer, who were experiencing bothersome hot flashes(more than or equal to 14 times per week, for more than orequal to 1 month before study entry), were included.During the baseline week, general demographic character-istics, hot flash information, and quality of life data wereobtained. At the beginning of week 2, patients were startedon levetiracetam for a total of 4 weeks. Information abouthot flashes, quality of life, and toxicity were collectedduring these 4 weeks and compared with the baseline week.Main results After treatment with levetiracetam for 4 weeks(N=19), mean hot flash scores (frequency times mean

severity) were reduced by 57%, and mean hot flashfrequencies were reduced by 53%, compared to the baselineweek; both these reductions were greater than what wouldbe expected with a placebo (20–25% reduction). Therewere significant improvements in abnormal sweating (p=0.004), hot flash distress (p=0.0002), and satisfaction ofhot flash control (p=0.0001), when comparing data fromthe fourth week of treatment to the baseline week. Twenty-nine percent of the subjects did not complete the studybecause of treatment-related adverse events, with the mostfrequently reported side effects being somnolence, fatigue,and dizziness, usually with mild to moderate intensity.Conclusion The results of this pilot trial suggest thatlevetiracetam might be an effective therapy for the treatmentof hot flashes. Further data are needed to test this hypothesis,evaluating the efficacy and toxicity of this agent.

Keywords Hot flashes . Levetiracetam . Therapy

Introduction

Hot flashes are one of the earliest and most distressing aspectsof menopause [47]. They are known to occur in up to 75% ofmenopausal women [18, 45] and can significantly impairtheir general functional ability and overall quality of life [14,16, 19, 23, 52, 59]. Hot flashes generally occur naturally aspart of the aging process but can occur prematurelysecondary to surgery (oophorectomy), pelvic radiation, orpharmacological therapy (including chemotherapy and hor-monal therapy such as tamoxifen) [7, 38]. They are a majorcause of morbidity among breast cancer survivors [8, 27], asthese women have hot flashes that are often more frequent,longer, more severe, and more symptomatic than thoseexperiencing natural menopause [7, 9, 69].

Support Care Cancer (2008) 16:75–82DOI 10.1007/s00520-007-0276-1

Financial Disclosure: None

S. Thompson :D. L. Barton : L. Kottschade :B. Christensen :D. Smith : C. L. Loprinzi (*)Division of Medical Oncology, Mayo Clinic College of Medicine,200 First Street S.W.,Rochester, MN 55905, USAe-mail: [email protected]

A. BardiaDepartment of Medicine, Mayo Clinic College of Medicine,200 First Street S.W.,Rochester, MN 55905, USA

A. Tan : J. A. SloanDepartment of Biostatistics, Mayo Clinic College of Medicine,200 First Street S.W.,Rochester, MN 55905, USA

Traditionally, hormone replacement therapy (HRT),comprised of estrogens and/or progesterones, have beenused to treat hot flashes, and these agents can reduce hotflashes by about 80% [35, 48, 49]. However, there is recentconcern using HRT in healthy women as they appear toincrease the risk of cardiovascular events and breast cancer[5, 10–12, 24, 28, 29, 42, 46, 55, 60, 61, 70]. Thus, the useof alternate nonhormonal-based therapies has been sug-gested.

Hot flashes in women appear to be due to a dysfunctionof the central nervous system thermoregulatory centers as aresult of estrogen withdrawal [63]. This led to the investi-gation of various centrally acting agents, such as clonidine, asa potential hot flash mitigating agent. Currently, newertargeted antidepressants, such as paroxetine [66, 67] andvenlafaxine [17, 34], have been reported to be efficacious inreducing hot flashes in randomized control trials. In addition,gabapentin, an anticonvulsant, has also been reported to beefficacious in controlling hot flashes [33, 51]. However, moststudies suggest that these agents reduce hot flashes less thanwhat occurs with estrogen-based therapy, can have signifi-cant side effects, and are not efficacious in all women; thus,there is a need for better nonhormonal therapies to alleviatehot flashes.

Levetiracetam (Keppra®) is a popular oral anticonvul-sant used in the treatment of epilepsy [30, 62]. It alsoappears to have some analgesic properties, particularly forneuropathic pain [25]. Levetiracetam is usually bettertolerated than other common antiseizure medications, doesnot interfere with the metabolism of many other drugs, anddoes not require serum drug concentration measurementsfor dose adjustments [63]. The most frequently reportedadverse events include mild to moderate somnolence,dizziness, and fatigue [1, 56]. The usual starting dosage ofthis drug in adults is 500 mg twice a day and can beincreased by 1,000 mg/day every 2 weeks (two divideddoses) to a maximum recommended daily dosage of3,000 mg/day [56].

The efficacy of levetiracetam in reducing hot flashes has notpreviously been studied. Levetiracetam is a centrally actingagent and, thus, like other centrally acting agents that havebeen found to be efficacious in reducing hot flashes (such asgabapentin, paroxetine, and venlafaxine), levetiracetam has atheoretical potential to reduce hot flashes. Anecdotally, apatient with a history of breast cancer, suffering frompaclitaxel-induced neuropathy, was started on levetiracetam.Not only did her neuropathy improve greatly, but her hotflashes markedly diminished. She was very pleased with theapparent effect of this drug on her hot flashes, and herpromising findings encouraged the current study.

The purpose of this study was to evaluate the efficacy oflevetiracetam in reducing hot flashes among women. Theprimary study endpoint was to determine whether any

reduction in hot flash score activity would be beyond whatis expected with a placebo (20–25%). The secondaryobjective was to evaluate the adverse effects of levetiracetam.

Materials and methods

This was a phase II study designed to determine theefficacy of levetiracetam in the treatment of hot flashes. Themethodology of this trial was similar to other pilotinvestigations on hot flashes that have been conductedpreviously [3, 4, 31, 36]. The study protocol was approvedby the Mayo Foundation Institutional Review Board, and awritten consent was obtained from all participating women.

Study population

The study included women, aged 18 years or more, with ahistory of breast cancer (currently without any evidence ofmalignant disease) or women without a history of breastcancer, who wished to avoid estrogen because of aperceived increased risk of breast cancer. Other inclusioncriteria included bothersome hot flashes (more than or equalto 14 times per week and of sufficient severity to make thepatient desire therapeutic intervention), the presence of hotflashes for more than or equal to 1 month before studyentry, a life expectancy of more than or equal to 6 months, anegative serum pregnancy test done less than or equal to7 days before registration (for women of childbearingpotential), and an Eastern Cooperative Oncology Group(ECOG) performance status 0 or 1 [50].

The exclusion criteria included women with history ofallergic or other adverse reaction to levetiracetam, pregnantwomen, nursing women, women of childbearing potentialwho were unwilling to employ adequate contraception, ahistory of a seizure disorder, a creatinine greater than theupper normal limit, the current use of either eveningprimrose or ginkgo biloba (as there may be drug inter-actions), and those receiving any of the following current(less than or equal to 4 weeks before study entry) orplanned therapies: antineoplastic chemotherapy, androgens,estrogens, progestational agents, or gabapentin. Womenreceiving vitamin E, tamoxifen, raloxifene, or aromataseinhibitors were included if the patient had been on a stabledose for more than or equal to 4 weeks and planned tocontinue the same dose throughout the study period.Current use of other agents for treating hot flashes wasallowed as long as they were started more than 30 days beforestudy initiation and were to be continued throughout the studyperiod. Women receiving soy supplements were included, asthey have been shown to be ineffective against hot flashes incontrolled settings [41, 57, 72].

76 Support Care Cancer (2008) 16:75–82

Treatment

The eligible women were given a 4-week supply oflevetiracetam tablets (500 mg/tablet). The patients did notreceive any study medication during the first week(baseline week). During the next week, the patients wereinstructed to take one tablet of levetiracetam once daily atnight (first week of treatment). In the second treatmentweek, they were instructed to take one tablet in the morningand one tablet at night and in the third treatment week, onetablet in the morning and two tablets at night. During thefourth treatment week, the patients took two tablets in themorning and two tablets at night. Thus, the patients begantaking 500 mg/day during week 2 and titrated up to a totaldosage of 2,000 mg/day of levetiracetam. This titration is inaccordance with the product information by the drugmanufacturer [56]. It was decided to stop short of themaximally tolerated dose, to try to decrease toxicity. Afterthe last week of study treatment, the women were free todiscontinue or continue the treatment, based on theirpersonal preferences.

Treatment evaluation and follow-up

The primary endpoint, hot flash score, was measuredusing a prospective, daily hot flash diary where womenrecorded each hot flash and its severity. This diary hasbeen used in phase II and III hot flash trials with wellover 1,000 patients and has shown good reliability andvalidity [2, 65]. Eligible women were given a self-reportquestionnaire booklet containing an instruction sheet, hotflash definitions, the prospective 5-week hot flash diary, theProfile of Mood States, and various other numeric analoguescale questionnaires to evaluate side effects (symptom

Table 1 Baseline characteristics of the study population

Variable Total number(N=28)

Percentage (%)

Mean age (standard deviation) 53.0 (6.49) yearsECOG performance score0 28 100Current aromatase inhibitorYes 1 4No 27 96Current raloxifeneNo 28 100Current tamoxifenYes 3 11No 25 89Breast cancerYes 5 18No 23 82Number of hot flashes per day1: 2–3 1 42: 4–9 13 463: 10+ 14 50Hot flashes duration (months)1: <9 9 322: 9–18 3 113: >18 16 57

30 Patients Enrolled

Withdrew Before Treatment Initiation (N=2)

28 Patients Started Study

Refused Further Treatment; (N=8) Reason; time point:

Multiple side effects; week 2 Dizziness, drowsiness, fatigue; week 2 Nausea, vomiting, headache, dizziness; week 2 Dizziness; week 2 Drowsiness, joint aches, fatigue; week 3 Fatigue; week 4 Fatigue, rash, itching, arm numbness; week 5 Nausea, depressed mood; week 5

Did not complete the hot flash diary at the 5th week (N=1)

20 Patients Completed Study per Protocol and Evaluable for QOL and Side Effect endpoints

19 Patients Provided Complete Data for Hot Flash Efficacy Analysis

Fig. 1 Flowchart depicting participant enrollment and loss to follow-up

0

20

40

60

80

100

120

0 1 2 3 4

Week

Mea

n P

erce

nt

of

Bas

elin

e H

ot

Fla

sh S

core

an

d F

req

uen

cy

Frequency

Score

N= 26 26 19 2223

Fig. 2 Mean percent change in hot flash scores and frequency frombaseline week (0) to week 4 of treatment in the study population

Support Care Cancer (2008) 16:75–82 77

experience diary [SED]) and quality of life (self-assessmentscales [SAS] and a linear analogue self-assessment scale[LASA]). Information was also collected about baselinecharacteristics.

During the baseline week and the 4 weeks of treatment,patients were instructed to complete various questionnairesat roughly the same time each day. Hot flash diaries werecompleted daily, while the SED was completed weekly atthe end of each week. The SAS, LASA, and Profile ofMood States scale were completed at baseline and after4 weeks of treatment. A nurse coordinator contacted eachpatient by telephone weekly to document compliance, toencourage completion of the questionnaires, and to addressquestions.

Statistical analysis

Treatment effectiveness was measured using the hot flashfrequency (the average number of hot flashes per day foreach week) and the hot flash score. The latter wascalculated by summing the number of mild hot flashes,plus two times the number of moderate hot flashes, plusthree times the number of severe hot flashes, plus fourtimes the number of very severe hot flashes. Adverseeffects were computed as the mean change in adverseeffects after 4 weeks of treatment as compared to thebaseline, using the Wilcoxon signed rank test. The p valuesfor the percent of baseline scores were tested using 100minus the percentage. Nonparametric tests were usedwhenever applicable. A two-sided p value of 0.05 wasconsidered statistically significant.

Results

A total of 30 patients were enrolled on this trial between 5December 2005 and 23 August 2006. As outlined in Fig. 1,two patients withdrew after randomization but before takingany study medication. Eight patients stopped treatmentearly because of side effects. One patient did take the study

drug for the entire study duration but did not fill out the hotflash diary during the fifth week. Thus, complete quality oflife data and side effect data were available for 20 patients,and complete hot flash diary data were available for 19patients. Table 1 shows the patient characteristics for the 28eligible female patients who started the study medication.

Hot flash scores and frequencies significantly decreasedby 57 and 53%, respectively, from baseline to week 4, asdepicted in Fig. 2. The mean hot flash score decreased from13.6 per day during the baseline week to 5.9 per day duringthe fourth week of study treatment, and the median hotflash score decreased from a score of 11.9 to 4.6 per day,respectively (Table 2). Similarly, there was a reduction inthe mean and median hot flash frequency, as outlined inTable 2. The hot flash score decreased in most individualpatients, as is illustrated in Fig. 3.

There were significant improvements in responses toquestions regarding abnormal sweating (p=0.004), hotflash distress (p=0.0002), and satisfaction of hot flashcontrol (p=0.0001), when comparing data from the fourthweek of treatment to the baseline week. The mostfrequently reported treatment-related adverse events weresomnolence, fatigue, and dizziness, with mild to moderateintensity (Table 3). Some of these toxicities led to treatmentdiscontinuation, as is illustrated in Fig. 1.

Table 2 Change in various hot flashes scores, by week, among study population (N=19)

Hot flash variable Statistical method Baseline week Week 1 Week 2 Week 3 Week 4 Week 4 minusbaseline

p Valuea

Hot flash score Median 11.9 7.0 6.3 5.6 4.6 −7.3 0.0004Mean 13.6 8.9 8.5 7.4 5.9 −7.7

Hot flash frequency Median 7.6 5.0 5.3 5.3 4.1 −3.1 <0.0001Mean 8.3 5.8 5.8 5.0 3.8 −4.5

Number of severe/verysevere hot flashes

Median 0.1 0.0 0.0 0.0 0.0 0.0 0.14Mean 0.5 0.4 0.4 0.4 0.5 0.0

a For change from baseline at week 4

0

20

40

60

80

100

120

140

160

0 1 2 3 4

Week

Per

cen

tag

e o

f B

asel

ine

Fig. 3 Mean percent change in hot flash scores and frequency frombaseline week (0) to week 4 of treatment for the individual patients


Fifteen (75%) out of the 20 patients who completed thestudy stated that they were satisfied with hot flash control,and 8 of these 15 patients (53%) said that they planned tocontinue with levetiracetam.

Discussion

This is the first trial, to our knowledge, to report theefficacy of levetiracetam for mitigating hot flashes. Theresults of this pilot trial suggest that levetiracetam isefficacious in reducing hot flashes, by about 55%. Thedrug did appear to cause side effects, leading to itsdiscontinuation in about a third of patients. Approximatelythree fourths of the women who completed the study drugwere satisfied with its control for their hot flashes after1 month of treatment, but only half of these chose tocontinue taking levetiracetam after study completion. Inother words, 29% of the original patients enrolled in thetrial chose to continue the drug, and 71% (20 of 28 women)did not find the medication acceptable to continue becauseof side effects, inadequate hot flash control, or otherreasons.

The 55% reduction in hot flashes seen in this presenttrial is better than the 20–30% reduction usually seen with aplacebo [65]. The reduction is similar to that seen insimilarly conducted pilot trials conducted with other agents(venlafaxine, paroxetine, and gabapentin) that were subse-quently shown to be better than placebos in randomizeddouble-blinded clinical trials [17, 26, 34, 37, 51, 66](Fig. 4). It should be noted that levetiracetam, unlike otherdrugs such as paroxetine, is not metabolized through

cytochrome P450 enzyme and does not have any knowndrug interaction with tamoxifen.

With the present study suggesting that levetiracetammight be efficacious in reducing hot flashes, it is reasonableto muse about the potential mechanism of action for itspotential effect. Levetiracetam is a centrally acting agentthat binds to the synaptic vesicle protein SV2A in the brain[20, 40, 43]. The predominant effects of this binding toSV2A include inhibition of N-type calcium channels andallosteric modulation of gamma-aminobutyric acid (GABA)receptors [13, 39, 58]. This is similar to the effects seenwith gabapentin, another antiepileptic agent that reduceshot flashes [33, 51]. Gabapentin, a GABA analogue, isbelieved to mediate its effects by inhibiting the calcium

Table 3 Summary of weekly adverse effects (maximum grade per toxicity per patient)

Adverse effect Grade Baseline week Week 1 Week 2 Week 3 Week 4

Fatigue I 6 7 9 10 5II 0 1 0 0 0

Somnolence I 0 0 0 0 0II 0 5 3 1 3

Dizziness I 1 5 1 3 4II 0 2 0 0 0

Insomnia I 0 0 0 0 0II 0 2 0 0 0

Agitation I 1 0 1 1 0II 0 0 0 0 0

Depression I 0 0 0 0 0II 0 0 0 1 0

Rash/desquamation I 0 0 0 0 0II 0 0 0 1 0

Neurosensory I 0 0 0 0 0II 0 0 0 1 0

Ataxia I 0 0 0 0 0II 0 1 1 1 1

Fig. 4 Comparison of hot flash score reductions seen in a series ofpilot trials


channels in the brain [21, 44]. Thus, plausibly, bothlevetiracetam and gabapentin may potentially work throughsimilar mechanisms of action.

Some might consider this study to have a limitation bynoting that the sample was heterogenous, including womenwho had hot flashes associated with breast cancer treatmentas well as those with natural menopause. Nonetheless,available data suggest that hot flash treatments are equallyeffective in patients with, versus without, a history of breastcancer [65]. In addition, some might be concerned because50% of subjects in this trial had no severe or very severehot flashes. Nonetheless, patients with less severe hotflashes appear to respond to hot flash treatments in a similarmanner to those with more severe hot flashes [65]. Inaddition, some might be concerned, as the hot flashevaluations were done by a daily diary as opposed to aphysiologic measure of hot flashes. In response to this, hotflash diaries have been the time-honored standard formeasuring hot flashes in many studies [3, 4, 17, 22, 26,31, 33–37, 51, 53, 54, 57, 65–68, 71, 72]. While, in therecent past, new technology has led to the development ofinstruments designed to measure physiologic changesassociated with hot flashes, such as sweating [6, 64], atthis time, there are no convincing data that these toolsshould supplant the use of patient diaries, as a better meansof hot flash measurement [32].

The results of this pilot trial suggest that levetiracetammay possibly be an effective therapy for the treatment forhot flashes. However, understanding that at least one agent(black cohosh) looked promising on a pilot study [54] butdid not appear to be helpful in a subsequent placebo-controlled clinical trial [53], caution is in order.

Further study is needed to substantiate the utility andside effect profile of levetiracetam before it can be moredefinitively recommended for use in clinical practice.Ideally, this would be done in a placebo-controlled,double-blind, clinical trial.

Acknowledgment Funding source: This study was supported in partby a grant from the Susan G. Komen Foundation grant.

References

1. Abou-Khalil B (2005) Benefit–risk assessment of levetiracetamin the treatment of partial seizures. Drug Safety 28:871–890(Review)

2. Baker F, Denniston M, Zabora J, Polland A, Dudley WN (2002) APOMS short form for cancer patients: psychometric and structuralevaluation. Psychooncology 11:273–281

3. Barton DL, Loprinzi CL, Novotny P, Shanafelt T, Sloan J,Wahner-Roedler D, Rummans TA, Christensen B, Dakhill SR,Martin LS (2003) Pilot evaluation of citalopram for the relief ofhot flashes. J Support Oncol 1:47–51

4. Barton DL, Loprinzi CL, Quella SK et al (1998) Prospectiveevaluation of vitamin E for hot flashes in breast cancer survivors.J Clin Oncol 16:495–500

5. Bergkvist L, Adami HO, Persson I, Hoover R, Schairer C (1989)The risk of breast cancer after estrogen and estrogen-progestinreplacement. N Engl J Med 321:293–297

6. Carpenter JS (2005) Physiological monitor for assessing hotflashes. Clin Nurse Spec 19:8–10

7. Carpenter J, Adrykowski M, Cordova M et al (1998) Hot flashesin postmenopausal women treated for breast carcinoma. Cancer82:1682–1691

8. Carpenter J, Andrykowski M (1999) Menopausal symptoms inbreast cancer survivors. Oncol Nurs Forum 26:1311–1317

9. Carpenter JS, Johnson D, Wagner L, Andrykowski M (2002)Hot flashes and related outcomes in breast cancer survivorsand matched comparison women. Oncol Nurs Forum 29:E16–E25

10. Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE,Stampfer MJ, Hennekens C, Rosner B, Speizer FE (1995) The useof estrogens and progestins and the risk of breast cancer inpostmenopausal women. N Engl J Med 332:1589–1593

11. Collaborative Group on Hormonal Factors in Breast Cancer(1997) Breast cancer and hormone replacement therapy: collabo-rative reanalysis of data from 51 epidemiological studies of52,705 women with breast cancer and 108,411 women withoutbreast cancer. Lancet 350:1047–1059

12. Consensus Statement (1998) Treatment of estrogen deficiencysymptoms in women surviving breast cancer. The HormoneFoundation, Canadian Breast Cancer Research Initiative, NationalCancer Institute of Canada, Endocrine Society, and the Universityof Virginia Cancer Center and Woman’s Place. J Clin EndocrinolMetab 83:1993–2000 (Review)

13. Crowder KM, Gunther JM, Jones TA, Hale BD, Zhang HZ,Peterson MR et al (1999) Abnormal neurotransmission in micelacking synaptic vesicle protein 2A (SV2A). Proc Natl Acad SciUSA 96:15268–15273

14. Daly E, Gray A, Barlow D, McPherson K, Roche M, Vessey M(1993) Measuring the impact of menopausal symptoms on qualityof life. BMJ 307:836–840

15. Dew J, Eden J, Beller E et al (1998) A cohort study of hormonereplacement therapy given to women previously treated for breastcancer. Climacteric 1:137–142

16. Erlik Y, Tataryn IV, Meldrum DR et al (1981) Association ofwaking episodes with menopausal hot flushes. JAMA245:1741–1744

17. Evans ML, Pritts E, Vittinghoff E, McClish K, Morgan KS, JaffeRB (2005) Management of postmenopausal hot flushes withvenlafaxine hydrochloride: a randomized, controlled trial. ObstetGynecol 105:161–166

18. Feldman BM, Voda A, Gronseth E (1985) The prevalence of hotflash and associated variables among perimenopausal women. ResNurs Health 8(3):261–268 (Sept)

19. Finck G, Barton DL, Loprinzi CL et al (1998) Definitions of hotflashes in breast cancer survivors. J Pain Symptom Manage16:327–333

20. Fuks B, Gillard M, Michel P, Lynch B, Vertongen P, Leprince P etal (2003) Localization and photoaffinity labeling of thelevetiracetam binding site in rat brain and certain cell lines.Eur J Pharmacol 478:11–19

21. Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R,Woodruff GN (1996) The novel anticonvulsant drug, gabapentin(Neurontin), binds to the alpha2delta subunit of a calciumchannel. J Biol Chem 271:5768–5776

22. Goldberg RM, Loprinzi DL, O’Fallon JR et al (1994) Transdermalclonidine for ameliorating tamoxifen-induced hot flashes. J ClinOncol 12:155–158


23. Greendale G, Lee N, Arriola E (1999) The menopause. Lancet353:571–580

24. Greendale GA, Reboussin BA, Hogan P et al (1998) Symptomrelief and side effects of postmenopausal hormones: results fromthe postmenopausal estrogen/progestin interventions trial. ObstGynecol 92:982–988

25. Guay DR (2003) Oxcarbazepine, topiramate, zonisamide, andlevetiracetam: potential use in neuropathic pain. Am J GeriatrPharmacother 1:18–37 (Review)

26. Guttuso T Jr, Kurlan R, McDermott MP, Kieburtz K (2003)Gabapentin’s effects on hot flashes in postmenopausal women: arandomized controlled trial. Obstet Gynecol 101:337–345

27. Hoda D, Perez DG, Loprinzi CL (2003) Hot flashes in breastcancer survivors. Breast J 9:431–438 (Review)

28. Koster A (1990) Hormone replacement therapy: use patterns in51-year-old Danish women. Maturitas 12:345–356

29. Lacey JV Jr, Mink PJ, Lubin JH et al (2002) Menopausalhormone replacement therapy and risk of ovarian cancer. JAMA288:334–341

30. Leach JP (2004) Levetiracetam in the management of epilepsy.Hosp Med 65:740–744 (Review)

31. Loprinzi CL, Barton DL, Sloan JA et al (2002) Pilot evaluation ofgabapentin for treating hot flashes. Mayo Clin Proc 77:1159–1163

32. Loprinzi CL, Barton DL, Sloan JA (2006) Whose opinion counts?J Clin Oncol 24(33):5183–5185

33. Loprinzi CL, Kugler JW, Barton DL, Dueck AC, Tschetter LK,Nelimark RA et al (2007) Phase III trial of gabapentin alone or inconjunction with an antidepressant in the management of hotflashes in women who have inadequate control with an antide-pressant alone. J Clin Oncol 25:308–312

34. Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI,Barton DL, Novotny PJ, Dakhil SR, Rodger K, Rummans TA,Christensen BJ (2000) Randomized phase III controlled trial ofvenlafaxine in the management of hot flashes. Lancet 356:2059–2063

35. Loprinzi CL, Michalak JC, Quella SK et al (1994) Megesterolacetate for the prevention of hot flashes. N Engl J Med331:347–352

36. Loprinzi CL, Pisansky TM, Fonseca R et al (1998) Pilotevaluation of venlafaxine hydrochloride for the therapy of hotflashes in cancer survivors. J Clin Oncol 16:2377–2381

37. Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, MailliardJA, Halyard MY, Pruthi S, Novotny PJ, Rumman TA (2002)Phase III evaluation of fluoxetine for treatment of hot flashes. JClin Oncol 20(6):1578–1583

38. Loprinzi CL, Zahasky KM, Sloan JA, Novotny PJ, Quella SK(2000) Tamoxifen-induced hot flashes. Clin Breast Cancer1:52–56

39. Lukyanetz EA, Shkryl VM, Kostyuk PG (2002) Selectiveblockade of N-type calcium channels by levetiracetam. Epilepsia43:9–18

40. Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, BajjaliehSM, Matagne A et al (2004) The synaptic vesicle protein SV2A isthe binding site for the antiepileptic drug levetiracetam. Proc NatlAcad Sci USA 101:9861–9866

41. MacGregor CA, Canney PA, Patterson G, McDonald R, Paul J(2005) A randomised double-blind controlled trial of oral soysupplements versus placebo for treatment of menopausalsymptoms in patients with early breast cancer. Eur J Cancer41:708–714

42. Majumdar SR, Almasi EA, Stafford RS (2004) Promotion andprescribing of hormone therapy after report of harm by theWomen’s Health Initiative. JAMA 292:1983–1988

43. Margineanu DG, Klitgaard H (2000) Inhibition of neuronalhypersynchrony in vitro differentiates levetiracetam from classicalantiepileptic drugs. Pharmacol Res 42:281–285

44. Margineanu DG, Klitgaard H (2003) Levetiracetam has nosignificant gamma-aminobutyric acid-related effect on paired-pulse interaction in the dentate gyrus of rats. Eur J Pharmacol466:255–261

45. McKinlay SM, Jefferys M (1974) The menopausal syndrome. Br JPrev Soc Med 28:108–115

46. Moorhead T, Hannaford P, Warskyj M (1997) Prevalence andcharacteristics associated with use of hormone replacementtherapy in Britain. Br J Obstet Gynaecol 104(3):290–297

47. Morgante G, Farina M, Cianci A, La Marca A, Petraglia F,De Leo V (2004) Veralipride administered in combinationwith raloxifene decreases hot flushes and improves bonedensity in early postmenopausal women. Gynecol Endocrinol18:194–198

48. Nand SL, Webster MA, Baber R et al (1998) Menopausalsymptom control and side-effects on continuous estrone sulfateand three doses of medroxyprogesterone acetate. Climacteric1:211–218

49. Niespodziany I, Klitgaard H, Margineanu DG (2001) Levetir-acetam inhibits the high-voltage-activated Ca2+ current inpyramidal neurones of rat hippocampal slices. Neurosci Lett306:5–8

50. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE,McFadden ET, Carbone PP (1982) Toxicity and response criteriaof The Eastern Cooperative Oncology Group. Am J Clin Oncol5:649–655

51. Pandya KJ, Morrow GR, Roscoe JA, Zhao H, Hickok JT, Pajon E,Sweeney TJ, Banerjee TK, Flynn PJ (2005) Gabapentin for hotflashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial. Lancet 366:818–824

52. Pansini F, Albertazzi P, Bonaccorsi G et al (1994) The menopausaltransition: a dynamic approach to the pathogenesis of neuro-vegetative complaints. Eur J Obstet Gynecol Reprod Biol57:103–109

53. Pockaj BA, Gallagher JG, Loprinzi CL, Stella PJ, Barton DL,Sloan JA, Lavasseur BI, Rao RM, Fitch TR, Rowland KM,Novotny PJ, Flynn PJ, Richelson E, Fauq AH (2006) Phase IIIdouble-blind, randomized, placebo-controlled crossover trial ofblack cohosh in the management of hot flashes: NCCTG TrialN01CC1. J Clin Oncol 24:2836–2841

54. Pockaj BA, Loprinzi CL, Sloan JA, Novotny PJ, Barton DL,Hagenmaier A, Zhang H, Lambert GH, Reeser KA, Wisbey JA(2004) Pilot evaluation of black cohosh for the treatment of hotflashes in women. Cancer Investig 22:515–521

55. Porch JV, Lee IM, Cook NR, Rexrode KM, Burin JE (2002)Estrogen–progestin replacement therapy and breast cancer risk:the Women’s Health Study (United States). Cancer CausesControl 13:847–854

56. UCB Pharma (2005) Product information: KEPPRA(R) oralsolution, oral tablets, levetiracetam oral solution, oral tablets.UCB Pharma, Smyrna, GA

57. Quella SK, Loprinzi CL, Barton DL et al (2000) Evaluationof soy phytoestrogens for the treatment of hot flashes inbreast cancer survivors: an NCCTG trial. J Clin Oncol18:1068–1074

58. Rigo JM, Hans G, Nguyen L, Rocher V, Belachew S, MalgrangeB et al (2002) The anti-epileptic drug levetiracetam reverses theinhibition by negative allosteric modulators of neuronal GABAand glycine-gated currents. Br J Pharmacol 136:659–672

59. Roberts J, Chambers LF, Blake J et al (1992) Psychosocialadjustment in post-menopausal women. Can J Nurs Res 24:29–464

60. Ross RK, Paganini-Hill A, Wan PC, Pike MC (2000) Effectof hormone replacement therapy on breast cancer risk:estrogen versus estrogen plus progestin. J Natl Cancer Inst92:328–332


61. Rossouw JE, Anderson GL, Prentice RL et al (2002) WritingGroup for the Women’s Health Initiative Investigators. Risks andbenefits of estrogen plus progestin in healthy postmenopausalwomen: principal results from the Women’s Health Initiativerandomized controlled trial. JAMA 288:321–333

62. Sasa M (2006) A new frontier in epilepsy: novel antiepileptogenicdrugs. J Pharmacol Sci 100:487–494 (Review)

63. Shanafelt TD, Barton DL, Adjei AA, Loprinzi CL (2002)Pathophysiology and treatment of hot flashes. Mayo Clin Proc77:1207–1218 (Review)

64. Sievert LL, Freedman RR, Garcia JZ et al (2002) Measurement ofhot flashes by sternal skin conductance and subjective hot flashreport in Puebla, Mexico. Menopause 9:367–376

65. Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI,Windschitl H (2001) Methodologic lessons learned from hot flashstudies. J Clin Oncol 19:4280–4290

66. Stearns V, Beebe KL, Iyengar M, Dube E (2003) Paroxetinecontrolled release in the treatment of menopausal hot flashes: arandomized controlled trial. JAMA 289:2827–2834

67. Stearns V, Isaacs C, Crawford J et al (1997) A pilot trial assessingthe efficacy of paroxetine hydrochloride in controlling hot flashes.Breast Cancer Res Treat 46:23–113

68. Stearns V, Slack R, Greep N, Henry-Tilman R, Osborne M,Bunnell C, Ullmer L, Gallagher A, Cullen J, Gehan E, Hayes DF,Isaacs C (2005) Paroxetine is an effective treatment for hotflashes: results from a prospective randomized clinical trial. J ClinOncol 23:6919–6930

69. Stein KD, Jacobsen PB, Hann DM, Greenberg H, Lyman G(2000) Impact of hot flashes on quality of life among postmen-opausal women being treated for breast cancer. J Pain SymptomManage 19:436–445

70. Steinberg KK, Thacker SB, Smith SJ, Stroup DF, Zack MM,Flanders WD et al (1991) A meta-analysis of the effect of estrogenreplacement therapy on the risk of breast cancer. JAMA265:1985–1990

71. Suvanto-Luukkonen E, Koivunen R, Sundstrom H, Bloigu R,Karjalainen E, Haiva-Mallinen L, Tapanainen JS (2005) Citalo-pram and fluoxetine in the treatment of postmenopausal symp-toms: a prospective, randomized, 9-month, placebo-controlled,double-blind study. Menopause 12:18–26

72. Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T,Cummings SR (2003) Phytoestrogen supplements for the treat-ment of hot flashes: the Isoflavone Clover Extract (ICE) Study: arandomized controlled trial. JAMA 290:207–214


levetiracetam for the treatment of hot flashes: a phase ii study

Documents