Turn down the heat!
Treating hot flashes
Amanda Place, PharmD, BCACP
St Vincent Joshua Max Simon
Primary Care Center
September 2014
I HAVE NO ACTUAL OR POTENTIAL
CONFLICT OF INTEREST IN RELATION TO
THIS PROGRAM OR PRESENTATION.
Objectives
Describe both symptoms and possible
mechanisms of hot flashes
 Discuss benefits and risks of estrogencontaining products in the treatment of hot
flashes
 Identify the utility of and evidence supporting
non-estrogen treatment alternatives
 Define the role of complementary and
alternative medicine therapies in the treatment
of hot flashes

What is a hot flash?
Sudden sensation of heat (face, neck and chest)
 Skin flushing, sweating
 May be accompanied by anxiety, irritation
 Often followed by chills

J Support Oncol 2006;4:315-320
Ann N Y Acad Sci 1990;592:52-86
Prevalence
70-80% of women will experience hot flashes
 Average duration: 2-5 years
 15-20% of women may have ongoing hot flashes
 Greater severity in patients with chemical or
surgical menopause, or premature menopause
(<40 yrs of age)

Am J Epidemiol 2000; 152:463
Am J Public Health 2006; 96: 1226
Arch Intern Med. 2008;168(8):840-846
Pathophysiology
Exact mechanism for vasomotor flushing not
yet identified
 Several proposed mechanisms

◦ Decrease in hormones
◦ Changes in the hypothalamus
◦ Other factors implicated
 Prostaglandins
 Endorphins
 Neurotransmitters
Acta Oncologica 2002;41:269-75 Ann Pharmacother1997;31:915-7
ONF 2002;29: 33-40
Ann Pharmacother2002;36:433-6
Contributing Factors

Modifiable
◦
◦
◦
◦
◦
BMI
Smoking
Avoidance of triggers
Exercise
Depression/anxiety

Difficult to modify
◦ Cause of menopause
◦ Genetics
◦ Socioeconomic factors
Am J Epidemiol 2000; 152:463
Am J Public Health 2006; 96: 1226
Assessment Tools
Patient history and recall
 Hot flash diary
 Validated tools:

◦
◦
◦
◦
Hot Flash Score
Greene Climacteric Score
Modified Kupperman Index
Utian Quality of Life Scale
Menopause 2002; 9(6):402-410
J Clin Oncol 2001; 19:4280-4290
Maturitas 2012 March;71(3):213-216
Treatment Options
Lifestyle
modifications
Hormonal
Therapies
SSRI/SNRI
Gabapentin
Clonidine
CAM
modalities
Endocr Pract 2011;17 (suppl 6)
Menopause 2012;19(3):257-271
Climacteric 2014;17:1-16
Lifestyle Modification







Decrease BMI
Decrease caffeine
Modify or eliminate alcohol use
Increase exercise
Improve dietary habits
Layered clothing
Stress reduction/paced respirations
Menopause 2004;11:11
Menopause 2012;20(2):179-184
Menopause 2012;19(7):749-759
Estrogen Replacement (ET)

Considered most effective agent
Agent
Initial dose
Conjugated
0.3 mg
equine estrogens
(CEE)
17βEstradiol
0.5 mg
Transdermal
0.025 mg
estradiol
Estradiol gel
0.5 mg
High dose
1.25 mg
2 mg
0.1 mg
1.5 mg
Endocr Pract 2011;17(Suppl 6)
Menopause 2012;19(3):257-271
Climacteric 2014;17:1-16
ET Risks and Benefits
Benefits
Risks
Vasomotor symptoms
Vaginal symptoms
Sexual function
Coronary heart disease
Stroke
Venous thromboembolism
Urinary tract health
Osteoporosis
Quality of life
Endometrial cancer
Breast cancer
Effect of ET on ovarian cancer, lung cancer, mood,
dementia, and mortality remain mixed.
Endocr Pract 2011;17(Suppl 6)
Menopause 2012;19(3):257-271
Climacteric 2014;17:1-16
ET Considerations







Transdermal =  risk
Duration of use
Appropriate dose
Need for progestin
Choice of progestin
Taper vs. stop
Bioidentical ET
Menopause 2010;17:946-954
Menopause 2006;13:370-376
Endocr Pract 2011;17(Suppl 6)
Menopause 2012;19(3):257-271
Assessment question
According to data from the Women’s Health
Initiative, which of the following is a benefit of
using estrogen to treat hot flashes?
1. Increase or maintenance of bone mass
2. Decrease in cardiovascular risk because of
increase in good cholesterol
3. Decrease in the risk of endometrial cancer
4. All of the above
Assessment question
A 50 yo female would like to start estrogen
therapy for hot flashes. She has no allergies and no
significant medical or surgical history. Which would
be a good initial choice for her?
1.
2.
3.
4.
Estradiol 0.025 mg/24 hr transdermal patch once
weekly
Estradiol 0.5 mg /norethindrone acetate 0.1 mg daily
CEE 0.625 mg/medroxyprogesterone 2.5 mg daily
Estradiol cream 0.1 mg/gm: 2 gm intravaginally once
daily at bedtime
Bazedoxifene/CEE (Duavee)

Tissue-selective estrogen complex
Indications
Precautions/
warnings
Dose
Cost

Vasomotor symptoms, prevention of
postmenopausal osteoporosis
Refer to CE
CEE 0.45 mg and bazedoxifene 20 mg
≈$140 per month
Safety data for up to 2 years
Lexi-Comp, Inc. (Lexi-DrugsTM ). Lexi-Comp, Inc.;
Version1.13.0 Accessed July 28th, 2014
Menopause 2009;16(6):1116-1124
Menopause 2012;19(4):479-485
Clinical study limitations





Small sample sizes
Outcomes based on patient-reported data
Many studies focus on patients with breast
cancer history
Large placebo effect: 20-30% reductions in hot
flash score/frequency
Limited duration of trials
Non-estrogen therapies
Menopause 2008;15:655
Progestational agents
Megestrol
acetate
• 20-80 mg daily
Medroxyprogesterone
acetate
• 400 mg depot
Norethindrone
acetate
• 10 mg daily
N Engl J Med 1994;331(6);347
J Clin Oncol 2008;26(10):1650
J Clin Oncol 2006;24(9):1409
Ann Oncol 2002;13(6):883
Progestational agents
Weight gain
Adrenal
suppression
Bone loss
Clotting risk
Breast cancer
risk
SSRIs/SNRIs
Mechanism: increases available
neurotransmitters
 Doses differ if only treating hot flashes
 Serotonin syndrome risks
 Product selection:

◦
◦
◦
◦
Drug interactions
Cost
Evidence
Co-morbid conditions
Paroxetine

®
(Brisdelle )
Approved 2013
Trial #1 at 4 wks
VMS frequency vs placebo
↓ 1.2 /day
Trial #2 at 4 wks
Trial #1 at 12 wks
Trial #2 at 12 wks
↓ 1.3/day
↓ 0.9/day
↓ 1.7/day

Cost ~$150/month
Brisdelle PI, Noven Therapeutics, LLC, Miami, FL
Other antidepressants
Drug
Daily Dose
Outcomes
Fluoxetine
20 mg
↓ monthly hot flash
score
Sertraline
50-100 mg
↓ weekly frequency
Citalopram**
20-40 mg
↓ hot flash scores
Escitalopram
10-20 mg
↓ daily frequency
Venlafaxine
37.5-75 mg ER
↓ hot flash scores
Desvenlafaxine
100 mg
↓ daily frequency
Duloxetine
60 mg
↓ VMS
** showed efficacy as an add-on to HRT as well
References provided at end of presentation
Antidepressant safety
T/F May inhibit platelet aggregation
T/F May be associated with bone loss/fracture
risk
T/F Don’t need to be tapered when used for hot
flashes
T/F May decrease the efficacy of antibiotics
T/F May decrease the efficacy of tamoxifen
T/F May increase risk of suicidality
Antidepressant pearls
Which one must have a wash-out?
fluoxetine
 Which ones should be cross-tapered?
paroxetine or venlafaxine
 Which one to choose if a patient takes
clopidogrel?
citalopram or venlafaxine
 Which one causes the MOST hypertension?
venlafaxine

The gabas





Mechanism: GABA vs. Norepinephrine
Lower doses than used in neuropathic pain
Drug interactions: CNS depressants
Monitoring: renal function
Adverse effects: drowsiness, dizziness, rash,
peripheral edema, weight gain
Gabapentin dose range
J Clin Oncol 2009; 27:2831-2837
Gabapentin ER interrupted

FDA declined approval in May 2013
Trial
VMS change VMS change @
@ 4 weeks
12 weeks
Breeze 1: 1200 mg
↓ 0.96/day
↓ 0.56/day**
Breeze 1: 1800 mg
↓ 1.51/day
↓ 1.53/day
Breeze 2: 1200 mg
↓ 1.61/day
↓ 1.56/day
Breeze 2: 1800 mg
↓ 1.51/day
↓ 1.12/day
Breeze 3: 1800 mg
↓ 1.69/day
↓ 1.14/day
** not statistically significant
www.clinicaltrials.gov accessed 2/13/14
Pregabalin

Not seeking FDA approval
Daily dose
75 mg BID
150 mg BID

Change in hot flash
frequency
↓ 1.7/day
↓ 2.0/day
Cost: pregabalin = gabapentin x 10
J Clin Oncol 28:641-647
Gabas’ safety
T/F
These should not be used in pts with
NYHA class 3 HF
T/F These drugs should be dose adjusted for
hepatic function
T/F Since these agents are hepatically
metabolized, they have many drug interactions
T/F Dizziness/somnolence may go away over
time
Gabas’ pearls

Possible to direct switch
Gabapentin
0-900 mg per day
901-1500 mg per day
Pregabalin
150 mg per day
225 mg per day
1501-2100 mg per day 300 mg per day

Gabapentin dosing regimen may differ from pain
dosing:
◦ 600-900 mg hs vs. 300 mg TID
Pain Med. 2010; 11(3): 456-465
Clonidine
Mechanism: decreases available
neurotransmitters
 Dose range: 0.1 to 0.2 mg per day- oral or
transdermal
 Drug interactions: antihypertensives, SNRIs
 Adverse effects: drowsiness, dizziness, fatigue,
dry mouth, orthostatic hypotension,
dermatologic reactions with transdermal form

Obst Gynecol 1982;60:583-586
J Clin Oncol 1994;12:1155-158
Comparator Trials








(Gabapentin = estrogen) >placebo
Venlafaxine preferred vs gabapentin
Gabapentin = gabapentin + SSRI/SNRI
MPA = megestrol
Fluoxetine = citalopram = placebo
MPA > venlafaxine
Venlafaxine > clonidine
(Estradiol ≈ venlafaxine) > placebo
JAMA Intern Med 2014;174(7):1058-1066
J Clin Oncol 2010;28:147-5152
Ann Oncol 2002;13:883-888
J Clin Oncol 2006:24:1409
Obstet Gynecol 2006;108:41-48
J Clin Oncol 2007;25:308-312
Menopause 2005;12(1):18-26
Ann Oncol 2007;18:689-693
Assessment question
Which of the following drug classes have
NOT shown efficacy in the treatment of
hot flashes:
1. Estrogens
2. Dihydropyridine calcium channel
blockers
3. α-2-δ ligands
4. Serotonin/norepinephrine reuptake
inhibitors
Assessment question
A 47 yo female with a strong family of breast cancer
would like to start drug treatment for hot flashes. She
takes tamoxifen 20 mg and a multivitamin daily. Blood
pressure at most recent visit was 114/74 mm Hg.
What would you recommend?
1.
2.
3.
4.
Paroxetine 7.5 mg daily
Estradiol 0.5 mg/norethindrone acetate 0.1 mg daily
Clonidine 0.1 mg/24 hr transdermal patch weekly
Gabapentin 300 mg in the morning and 600 mg before
bedtime
CAM Hormonal agents







Alfalfa
Black Cohosh
Chasteberry
DHEA
Dong Quai
Flaxseed
Hops






Kudzu
Licorice
Panax Ginseng
Red clover
Soy
Wild Yam
CAM Hormonal agents







Alfalfa
Black Cohosh
Chasteberry
DHEA
Dong Quai
Flaxseed
Hops






Kudzu
Licorice
Panax Ginseng
Red clover
Soy
Wild Yam
CAM Treatments for Hot Flashes
Likely safe
Possibly safe
Flaxseed
Soy foods
Black Cohosh
Soy extracts
Insufficient
evidence
Chasteberry
Ginkgo
Vitamin E
Alfalfa
DHEA (short term)
Hops
Kudzu
Licorice
Valerian
Possibly
ineffective
Evening Primrose
oil
Dong Quai (short term)
Red Clover
Wild Yam
Panax Ginseng
Effective
Likely effective
Possibly
effective
Adapted from Natural Medicines
ComprehensiveDatabase-Accessed
5/17/2010
CAM Hormonal agents
General cautions:
◦
◦
◦
◦
Unknown or questionable estrogenic activity
Standardization of products/preparations
Consistent quality of products
Lack of high quality evidence
Acupuncture
Difficult to determine a true “placebo”
group
 Differing disciplines of acupuncture
 Pt expectations
 Lack of understanding about physiologic
effects of acupuncture

Menopause 2010;17(2):228-230
Menopause 2009;16:1065-1073
Conclusions
Choice of agent should be made with
patient-specific variables as a guide.
 Patient expectations may impact efficacy.
 Different agents or combinations may
need to be tried to achieve desired
benefit.

Turn down the heat!
Treating hot flashes
Amanda Place, PharmD, BCACP
St Vincent Joshua Max Simon
Primary Care Center
September 2014
Slide 17 References

Obst Gynecol 1982;60:583-586

J Clin Oncol 1994;12:155-158

J Clin Oncol 2002;20:1578-1583

Lancet 2000;356:2059-2063

J Clin Oncol 2010;28:3278-3283

JAMA 2001;305(3):267-274

J Clin Oncol 2009;27:2831-2837

Drugs 2011;71(3):287-304

Pharmacotherapy 2009;29(11):1357-1374