Treatment of hot flashes in patients with breast cancer •
Updated 2013 Feb 04 06:25:00 AM: cognitive behavioral therapy and/or physical exercise may improve treatment-induced menopausal symptoms in women with breast cancer (J Clin Oncol 2012 Nov 20) view updateShow more updates
Related Summaries: • •
Breast cancer (list of topics) Breast cancer in women
Overview: •
medications associated with reduced frequency and severity of hot flashes include o antidepressants
•
antidepressants with supporting evidence include
venlafaxine (Effexor) 37.5 mg/day, 75 mg/day, or 150 mg/day, based on multiple trials (level 2 [mid-level] evidence)
fluoxetine (Prozac) 20 mg/day, based on 1 trial (level 2 [midlevel] evidence)
paroxetine (Paxil) 10 mg/day or 20 mg/day, based on 1 trial (level 2 [mid-level] evidence)
some antidepressants may reduce efficacy of tamoxifen
paroxetine use during tamoxifen treatment may increase risk of breast cancer-related death (level 2 [mid-level] evidence)
paroxetine, fluoxetine, and bupropion inhibit metabolism of tamoxifen to more active metabolites via cytochrome P450 2D6 (CYP2D6) enzyme, and might decrease the anticancer effect (level 3 [lacking direct] evidence)
o
clonidine 0.1 mg/day (level 2 [mid-level] evidence)
o
megestrol acetate 20 mg orally twice daily (level 1 [likely reliable] evidence)
o
gabapentin (Neurontin) 300 mg 3 times daily (level 2 [mid-level] evidence)
psychologic therapies which may reduce hot flash impact on daily life include
o
cognitive behavioral therapy (level 2 [mid-level] evidence)
o
hypnosis (level 2 [mid-level] evidence)
•
acupuncture might reduce frequency of hot flashes in women with breast cancer, but evidence inconsistent (level 2 [mid-level] evidence)
•
phytoestrogen/soy supplementation appears ineffective for treatment of hot flashes in women with history of breast cancer (level 2 [mid-level] evidence)
Medications • some nonhormonal pharmacologic treatments associated with reduced frequency and severity of hot flashes (level 2 [mid-level] evidence) o based on Cochrane review of trials without intention-to-treat analysis o
systematic review of 16 randomized trials comparing nonhormonal treatment vs. placebo in woman with hot flashes and history or high risk of breast cancer
o
15 trials lacked intention-to-treat analysis; meta-analysis not possible due to heterogeneity of outcome reporting
o
pharmacologic treatments found to significantly reduce frequency and severity of hot flashes (compared to placebo)
venlafaxine 37.5 mg, 75 mg, or 150 mg (3 trials)
fluoxetine 20 mg (1 trial)
paroxetine 10 mg or 20 mg (1 trial)
clonidine 0.1 mg transdermally or orally (2 trials)
gabapentin 900 mg (1 trial summarized below)
o
no significant difference in frequency or severity of hot flashes comparing sertraline 50 mg vs. placebo in 1 underpowered trial with 39 women or vitamin E 800 units vs. placebo in 1 trial with 104 women
o
most nonpharmacologic interventions did not significantly reduce frequency or severity of hot flashes (interventions included homeopathy, magnetic device, acupuncture); inconsistent evidence for effect of relaxation therapy in 2 trials
o
Reference - Cochrane Database Syst Rev 2010 Sep 8;(9):CD004923
Antidepressants:
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some antidepressants may reduce efficacy of tamoxifen o paroxetine use during tamoxifen treatment may increase risk of breast cancer-related death (level 2 [mid-level] evidence)
based on population-based cohort study
2,430 women ≥ 66 years old treated with tamoxifen for breast cancer also treated with single selective serotonin reuptake inhibitor were followed for breast cancer progression for mean 2.38 years
374 (15.4%) died of breast cancer
analysis adjusted for multiple potential confounders including age, tamoxifen treatment duration, timing of initiation of tamoxifen to breast cancer, comorbidities, socioeconomic status, and other medications which might affect cytochrome P450 2D6 (CYP2D6) system
adjusted risk of breast cancer-related death increased with increasing proportion of time on tamoxifen during which patient also treated with paroxetine (p < 0.05)
24% increased risk with paroxetine treatment for 25% of tamoxifen duration
54% increased risk with paroxetine treatment for 50% of tamoxifen duration
91% increased risk with paroxetine treatment for 75% of tamoxifen duration
paroxetine also associated with increased risk of overall mortality (p = 0.03)
13% increased risk of death with paroxetine treatment for 25% of tamoxifen duration
28% increased risk of death with paroxetine treatment for 50% of tamoxifen duration
46% increased risk of death with paroxetine treatment for 75% of tamoxifen duration
no significant association observed with increasing time on other antidepressants for risk of either breast cancer-related death or overall mortality
estimated paroxetine use for 41% of tamoxifen treatment would result in 1 additional breast cancer death within 5 years of tamoxifen cessation for every 19.7 patients treated
o
some antidepressants inhibit metabolism of tamoxifen to more active metabolites via CYP2D6 enzyme, and might decrease the anticancer effect (level 3 [lacking direct] evidence)
based on literature search of effects on CYP2D6 enzyme activity without clinical outcomes
antidepressants that inhibit CYP2D6
•
Reference - BMJ 2010 Feb 8;340:c693 full-text, editorial can be found in BMJ 2010 Feb 8;340:c783 (commentary can be found in BMJ 2010 Mar 10;340:c1319)
paroxetine
fluoxetine
bupropion
antidepressants that do not appear to inhibit CYP2D6
venlafaxine
desvenlafaxine
mirtazapine
Reference - J Clin Psychiatry 2009 Dec;70(12):1688
venlafaxine o
venlafaxine may reduce frequency and severity of hot flashes (level 2 [mid-level] evidence)
based on randomized trial without intention-to-treat analysis
221 women having ≥ 14 hot flashes/day with history of breast cancer or reluctance to take hormonal replacement therapy for fear of breast cancer were randomized to 1 of 4 oral interventions
venlafaxine 37.5 mg/day for 28 days
venlafaxine 37.5 mg/day for 7 days, then 75 mg/day for 21 days
venlafaxine 37.5 mg/day for 7 days, then 75 mg/day for 7 days, then 150 mg/day for 14 days
placebo for 28 days
191 women (86%) who completed study included in analysis
o
venlafaxine associated with decreased hot flash frequency and severity for all dosing regimens (p < 0.001)
reduction in hot flash severity scores
27% with placebo
37% with 37.5 mg maximum-dose regimen
61% with 75 mg and 150 mg maximum dosing regimens
side effects included mouth dryness, decreased appetite, nausea, and constipation
mouth dryness significantly increased with 150-mg dose compared to 75-mg and 150-mg doses
Reference - Lancet 2000 Dec 16;356(9247):2059, editorial can be found in Lancet 2000 Dec 16;356(9247):2025, commentary can be found in Am Fam Physician 2001 Jun 15;63(12):2460
venlafaxine may reduce hot flashes in women with history of breast cancer (level 2 [mid-level] evidence)
based on randomized trial without intention-to-treat analysis
102 women with history of breast cancer and ≥ 2 hot flashes/day randomized to 1 of 3 treatments for 12 weeks
venlafaxine 75 mg/day orally
clonidine 0.1 mg/day orally
placebo
78% of patients evaluated at week 12
daily hot flash score was sum of scores for individual hot flashes (rated on a 1-4 scale with higher numbers indicating increased severity)
median daily hot flash scores during week 12
7.6 for venlafaxine (p = 0.07 vs. placebo, not significant vs. clonidine)
7.5 for clonidine (p = 0.03 vs. placebo)
10.9 for placebo
median daily hot flash scores during weeks 1-4
o
6.6 for venlafaxine (p = 0.01 vs. placebo, not significant vs. clonidine)
10.3 for clonidine (not significant vs. placebo)
12.1 for placebo
venlafaxine associated with higher rates of nausea and constipation compared to placebo (p ≤ 0.04) and higher rate of appetite loss compared to clonidine (p = 0.003)
Reference - J Clin Oncol 2011 Oct 10;29(29):3862
venlafaxine associated with greater patient preference compared with gabapentin in breast cancer survivors with hot flashes (level 2 [midlevel] evidence)
based on randomized crossover trial without blinding
66 postmenopausal breast cancer survivors with ≥ 14 bothersome hot flashes/week in past month randomized to venlafaxine vs. gabapentin for 4 weeks and crossed over to other treatment after 2-week washout period
significantly more women preferred venlafaxine (68% vs. 32%, p = 0.01)
reduction in hot flash scores by 66% in both groups
venlafaxine associated with increased nausea, appetite loss, constipation, and reduced negative mood changes (p < 0.05 for each)
gabapentin associated with increased dizziness and appetite (p < 0.05)
Reference - J Clin Oncol 2010 Dec 10;28(35):5147
Clonidine: •
clonidine 0.1 mg/day may reduce tamoxifen-induced hot flashes (level 2 [midlevel] evidence) o based on randomized trial with high loss to follow-up o
194 postmenopausal women taking tamoxifen for breast cancer were randomized to clonidine 0.1 mg/day orally vs. placebo for 8 weeks with follow-up at 12 weeks
o
77% completed study
o
mean decrease in hot flash frequency comparing clonidine vs. placebo
•
37% vs. 20% at 4 weeks (95% CI for difference 7%-27%)
38% vs. 24% at 8 weeks (95% CI for difference 3%-27%)
24% vs. 14% at 12 weeks (p = 0.09)
o
Reference - Ann Intern Med 2000 May 16;132(10):788, commentary can be found in BMJ 2000 Jun 17;320(7250):1680, Am Fam Physician 2000 Nov 1;62(9):2115
o
commentary that use of clonidine limited by toxicity can be found in ACP J Club 2001 Jan-Feb;134(1):24
clonidine may reduce hot flashes in women with history of breast cancer (level 2 [mid-level] evidence) o
based on randomized trial without intention-to-treat analysis
o
102 women with history of breast cancer and ≥ 2 hot flashes/day randomized to 1 of 3 treatments for 12 weeks
venlafaxine 75 mg/day orally
clonidine 0.1 mg/day orally
placebo
o
78% of patients evaluated at week 12
o
daily hot flash score was sum of scores for individual hot flashes (rated on a 1-4 scale with higher numbers indicating increased severity)
o
median daily hot flash scores during week 12
o
7.6 for venlafaxine (p = 0.07 vs. placebo, not significant vs. clonidine)
7.5 for clonidine (p = 0.03 vs. placebo)
10.9 for placebo
median daily hot flash scores during weeks 1-4
6.6 for venlafaxine (p = 0.01 vs. placebo, not significant vs. clonidine)
10.3 for clonidine (not significant vs. placebo)
12.1 for placebo
o
venlafaxine associated with higher rates of nausea and constipation compared to placebo (p ≤ 0.04) and higher rate of appetite loss compared to clonidine (p = 0.003)
o
Reference - J Clin Oncol 2011 Oct 10;29(29):3862
Megestrol acetate: •
megestrol acetate reduces hot flashes in women with breast cancer (level 1 [likely reliable] evidence) o based on randomized crossover trial o
100 women with breast cancer (and 66 men with surgical or medical orchiectomy) with bothersome hot flashes for ≥ 1 month were randomized to megestrol acetate 20 mg vs. placebo orally twice daily for 4 weeks each
o
3 women withdrew before starting medication or were considered ineligible
o
80% women used tamoxifen
o
80 women and 60 men provided usable data for efficacy analysis
o
comparing megestrol acetate vs. placebo
o
o
median frequency of hot flashes (as percent of baseline) in women 26% vs. 73% (p < 0.001)
median frequency of hot flashes (as percent of baseline) in men 20% vs. 81% (p < 0.001)
median severity of hot flashes (as percent of baseline) in women 17% vs. 73% (p < 0.001)
median severity of hot flashes (as percent of baseline) in men 13% vs. 84% (p < 0.001)
in intention-to-treat analysis comparing megestrol acetate vs. placebo
50% reduction in hot flashes in women in 71% vs. 24% (p < 0.001, NNT 3)
50% reduction in hot flashes in men in 79% vs. 12% (p < 0.001, NNT 2)
Reference - N Engl J Med 1994 Aug 11;331(6):347 full-text
Gabapentin: •
gabapentin 300 mg 3 times daily may reduce severity and frequency of hot flashes in patients with breast cancer (level 2 [mid-level] evidence)
o
based on randomized trial with allocation concealment not stated
o
420 women with breast cancer having ≥ 2 hot flashes/day (mean 8.5-8.8 hot flashes/day) were randomized to placebo vs. gabapentin 100 mg vs. gabapentin 300 mg orally 3 times daily for 8 weeks, all patients had 3-day titration period to maintain blinding
o
patients kept 1-week symptom diaries at baseline, 4 weeks (completed in 88.3%), and 8 weeks (completed in 82.6%)
o
gabapentin 900 mg/day associated with (p < 0.0001 vs. placebo)
o
o
26% decrease in hot flash frequency
30% decrease in hot flash severity
gabapentin 300 mg/day associated with (vs. placebo)
12% decrease in hot flash frequency (p = 0.04)
nonsignificant trend toward decreased hot flash severity (13%, p = 0.09)
Reference - Lancet 2005 Sep 3;366(9488):818 full-text, commentary can be found in ACP J Club 2006 Mar-Apr;144(2):41, Am Fam Physician 2006 Mar 15;73(6):1100
Phytoestrogen/Soy Supplementation • phytoestrogen/soy supplementation appears ineffective for treatment of hot flashes in women with history of breast cancer (level 2 [mid-level] evidence) o based on 4 randomized trials with methodologic limitations o
o
randomized trial with allocation concealment not stated
62 postmenopausal women with history of breast cancer randomized to phytoestrogens 114 mg/day vs. placebo 3 tablets orally twice daily for 3 months each in crossover trial with 2-month washout
56 patients (90%) completed trial
no significant differences in hot flashes, other menopausal symptoms, or quality of life; 45% preferred phytoestrogen while 27% preferred placebo (not significant)
Reference - Obstet Gynecol 2003 Jun;101(6):1213 full-text
randomized trial with high dropout rate
157 postmenopausal women with moderate hot flashes and history of early-stage breast cancer treatment were randomized to soy beverage containing isoflavone 90 mg vs. placebo rice beverage
o
o
o
123 women (78%) completed trial
no significant differences in number of hot flashes or hot flash scores
both groups had mild gastrointestinal side effects but soy beverage associated with greater frequency and severity
Reference - J Clin Oncol 2002 Mar 15;20(6):1449 full-text, editorial can be found in J Clin Oncol 2002 Mar 15;20(6):1436, commentary can be found in J Clin Oncol 2002 Jul 1;20(13):3040
randomized trial with allocation concealment not stated
177 women with substantial hot flashes and history of breast cancer were randomized to soy tablets containing isoflavone 50 mg orally 3 times daily vs. placebo for 4 weeks before crossover to opposite treatment for additional 4 weeks
soy tablet not associated with significant improvement in hot flash frequency or severity
Reference - J Clin Oncol 2000 Mar;18(5):1068 full-text, commentary can be found in J Clin Oncol 2000 Jul;18(14):2792
randomized trial with inadequate statistical power
72 women with resected breast cancer and menopausal symptoms (sweats and flushes) were randomized to soy supplementation consisting of isoflavone 70 mg/day vs. placebo for 3 months
most women were taking tamoxifen
both soy and placebo groups improved, but no significant difference in menopausal symptom scores between groups
Reference - Eur J Oncol 2005 Mar;41(5):708
DynaMed commentary -- despite animal research suggesting dietary soy, isoflavone, or phytoestrogen intake may interfere with tamoxifen (level 3 [lacking direct] evidence); observational studies suggest increased dietary intake is not associated with increase (and may be associated with decrease) in risk for breast cancer recurrence or mortality in women with breast cancer (level 2 [mid-level] evidence)
Psychologic Therapies Cognitive behavioral therapy: •
cognitive behavioral therapy may reduce severity of hot flashes and night sweats following breast cancer treatment (level 2 [mid-level] evidence)
•
o
based on randomized trial without intention-to-treat analysis
o
96 women (mean age 54 years) with problematic hot flushes and night sweats (≥ 10 episodes/week) after breast cancer treatment were randomized to cognitive behavioral therapy plus usual care vs. usual care alone and followed for 26 weeks
o
cognitive behavioral therapy consisted of psychoeducation, paced breathing, and cognitive and behavioral management strategies conducted during 1 group session/week for 6 weeks
o
9% did not complete treatment and were excluded from analyses
o
treatment response assessed as ≥ 2-point decrease in hot flash problem rating scale (range 0-10 with higher scores indicating worse symptoms)
o
comparing cognitive behavioral therapy plus usual care vs. usual care alone
treatment response at 9 weeks in 65% vs. 38% (p < 0.05, NNT 4)
treatment response at 26 weeks in 78% vs. 33% (p < 0.05, NNT 3)
o
cognitive behavioral therapy associated with improved sleep, general health, and reduced depression at weeks 9 and 26 (p < 0.05 for all)
o
no significant differences in hot flash or night sweat frequency, or somatic symptoms at weeks 9 or 26
o
Reference - MENOS 1 trial (Lancet Oncol 2012 Mar;13(3):309 full-text), editorial can be found in Lancet Oncol 2012 Mar;13(3):227, commentary can be found in Lancet Oncol 2012 May;13(5):e188
cognitive behavioral therapy and/or physical exercise may improve treatmentinduced menopausal symptoms in women with breast cancer (level 2 [midlevel] evidence) o
based on randomized trial without intention-to-treat analysis
o
422 women < 50 years old with nonmetastatic breast cancer and treatmentinduced menopausal symptoms (hot flashes, night sweats, and/or vaginal dryness) were randomized to 1 of 4 treatments and followed for 6 months
cognitive behavioral therapy (CBT) consisting of six 90-minute sessions once weekly focusing on menopausal symptoms
physical exercise consisting of home-based, individualized, and selfdirected exercise program 2.5-3 hours per week for 12 weeks
CBT plus physical exercise
wait-list control
o
all women were premenopausal at diagnosis, had received adjuvant chemotherapy (completed 4 months to 5 years prior) or hormonal therapy, and were disease-free at baseline
o
30%-42% in active treatment groups completed ≥ 4 CBT sessions and/or ≥ 24 physical exercise sessions
o
19% were lost to follow-up and excluded from analyses
o
compared to control
o
CBT alone and CBT plus physical exercise each associated with significant improvements in hot flashes and night sweat severity (absolute differences about 1 point on 30-point scale), endocrine symptoms (absolute differences about 4 points on 72-point scale), lower urinary tract symptoms, and sexual activity
physical exercise alone associated with significant improvements in endocrine symptoms (absolute differences about 4 points on 72-point scale), lower urinary tract symptoms, and bodily pain
Reference - J Clin Oncol 2012 Nov 20;30(33):4124, editorial can be found in J Clin Oncol 2012 Nov 20;30(33):4059
Hypnosis: •
hypnosis may be associated with symptom improvement in women with hot flashes and history of breast cancer (level 2 [mid-level] evidence) o based on small randomized trial without attention control o
60 female survivors of breast cancer with ≥ 14 hot flashes/week for ≥ 1 month were randomized to hypnosis intervention 5 times weekly vs. no intervention
o
51 women (85%) completed study
o
hypnosis associated with significant improvements in self-reported anxiety, depression, hot flash interference in daily activities, and sleep
o
women with hypnosis reported to have 68% decrease in hot flash score (frequency and severity) from baseline (p < 0.001), but no comparison to control group
o
Reference - J Clin Oncol 2008 Nov 1;26(31):5022 full-text
Acupuncture • acupuncture might reduce frequency of hot flashes in women with breast cancer, but evidence inconsistent (level 2 [mid-level] evidence) o based on systematic review with heterogeneity
•
o
systematic review of 6 trials evaluating acupuncture for treatment of hot flashes in 281 women with breast cancer
o
acupuncture associated with reduced frequency of hot flashes vs. sham acupuncture (p = 0.05) in 3 trials with 189 patients, but analysis limited by significant heterogeneity (p = 0.02) with benefit in 1 trial and no significant difference in 2 trials
o
1 trial found no significant differences comparing acupuncture vs. venlafaxine
o
1 trial found no significant differences comparing acupuncture vs. applied relaxation
o
1 trial found hormone therapy more effective than electroacupuncture
o
Reference - Breast Cancer Res Treat 2009 Jun;115(3):497
acupuncture may be as effective as venlafaxine for reducing hot flashes, with fewer adverse effects (level 2 [mid-level] evidence) o
based on small randomized trial
o
50 patients with breast cancer randomized to acupuncture vs. venlafaxine for 12 weeks and followed for 1 year
o
comparing acupuncture vs. venlafaxine
0 vs. 18 incidences of adverse events (such as nausea, headache, difficulty sleeping, and dizziness) reported (p ≤ 0.002)
no significant differences in hot flashes, depressive symptoms, and other quality-of-life measures, but both groups showed improvement
o
most women in acupuncture group reported improvement in energy, clarity of thought, and sense of well-being
o
Reference - J Clin Oncol 2010 Feb 1;28(4):634 full-text
Other Interventions • stellate-ganglion block reported to reduce frequency of hot flashes and night awakenings (level 3 [lacking direct] evidence) o based on case series o
13 women in remission from breast cancer with severe hot flashes and night awakenings were treated with stellate-ganglion block and followed for 12 weeks
o
5 patients had 1 block, 8 patients had 2 blocks
o
mean symptom frequency per week at baseline vs. 2 weeks vs. 12 weeks
hot flashes 79.4 vs. 49.9 (p = 0.0002) vs. 8.1 (p < 0.0001)
night awakenings 19.5 vs. 7.3 (p < 0.0001) vs. 1.4 (p < 0.0001)
o
no adverse effects reported
o
Reference - Lancet Oncol 2008 Jun;9(6):523
Guidelines and Resources Guidelines: United States guidelines: •
American College of Obstetricians and Gynecologists (ACOG) practice bulletin 126 on management of gynecologic issues in women with breast cancer can be found in Obstet Gynecol 2012 Mar;119(3):666 or at National Guideline Clearinghouse 2012 Apr 23:36055, commentary can be found in ACOG News Release 2012 Feb 21
Central and South American guidelines: •
Seguro Social Costa Rica (CCSS) guideline on treatment of breast cancer (Guía de Práctica Clínica para el Tratamiento del Cáncer de Mama) can be found at CCSS 2012 PDF ZIP [Spanish], patient version can be found at CCSS 2012 PDF ZIP [Spanish]
Review articles: •
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review of hot flashes can be found in Mayo Clin Proc 2002 Nov;77(11):1207, editorial can be found in Mayo Clin Proc 2002 Nov;77(11):1155, commentary can be found in Mayo Clin Proc 2003 Mar;78(3):379 (corrections can be found in Mayo Clin Proc 2003 May;78(5):656 and in Mayo Clin Proc 2004 Aug;79(8):1088) review of antidepressants for management of hot flushes can be found in Pharmacotherapy 2009 Nov;29(11):1357
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review of alternatives to hormone replacement therapy for menopausal symptoms can be found in Lancet 2005 Jul 30;366(9483):409
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review of nonhormonal therapies for hot flashes in menopause can be found in Am Fam Physician 2006 Feb 1;73(3):457, editorial can be found in Am Fam Physician 2006 Feb 1;73(3):396
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review of follow-up of patients with early breast cancer can be found in N Engl J Med 2007 Jun 14;356(24):2505, commentary can be found in N Engl J Med 2007 Sep 6;357(10):1052, Am Fam Physician 2007 Dec 15;76(12):1864
MEDLINE search:
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to search MEDLINE for (hot flash OR hot flush OR vasomotor symptoms) with targeted search (Clinical Queries for therapy articles), click here
Patient Information • handout of nonhormonal options for hot flashes can be found in Am Fam Physician 2006 Feb 1;73(3):467 • handout for what to take for hot flashes after breast cancer from US News Health ICD-9/ICD-10 Codes ICD-9 codes: •
627.4 states associated with artificial menopause
ICD-10 codes: •
N95.3 states associated with artificial menopause
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