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MsFLASH: Success, potential in treating bothersome menopause symptoms
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WASHINGTON — Findings from clinical intervention studies inside the Menopause Strategies: Finding Lasting Answers for Symptoms and Health, or MsFLASH, network reveal that several strategies showed success or potential in alleviating bothersome symptoms women experience during the menopause transition.
Presenters at the 25th annual meeting of The North American Menopause Society highlighted pharmacologic and behavioral interventions effective for sleep quality and quality of life and introduced a promising telehealth approach to help women in midlife.
Insomnia symptoms, self-reported sleep quality
Katherine A. Guthrie, PhD, of the Fred Hutchinson Cancer Research Center, a statistician who has been working with MsFLASH since its inception, presented findings from a pooled analysis of three randomized controlled studies.
“We’ve designed and conducted and hope to continue to do clinical trials, accommodating a wide scope of populations and types of interventions, not just medications,” Guthrie said. “Our first three trials were intended to treat hot flashes, but we systematically collected a number of secondary outcomes including mood, sleep and quality of life.”
The first (MsFLASH 01; n=200, 51% white) demonstrated the selective serotonin reuptake inhibitor (SSRI) escitalopram reduced hot flash frequency and severity vs. placebo after 8 weeks, Guthrie explained. The second (MsFLASH 02; n=334, 64% white) tested yoga, exercise and omega-3 supplementation in controls vs. placebo and showed no hot flash frequency reduction over 12 weeks. In the third (MsFLASH 03; n=328, 62% white), low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine both diminished hot flashes vs. placebo at 8 weeks.
Healthy women aged 40 to 62 years in menopause transition or postmenopausal, recruited overall from five US urban areas, were included in the trials; they all had at least 28 hot flashes per week, rated bothersome or severe, and none were receiving any treatment for hot flashes.
“We wanted to evaluate the impact of those interventions relative to each other — all vs. a control,” Guthrie said. “We are pooling individual-level data and taking advantage of the standardization of our methodology.”
The researchers compared both the baseline characteristics of participants and the placebo response on sleep measures across the trials, and then estimated the effect of each intervention on sleep measures over time relative to a pooled placebo group.
Insomnia Severity Index (ISI) measured insomnia based on a score range (0-28) and Pittsburgh Sleep Quality Index (PSQI) measured subjective sleep quality and sleep disturbances over a single month based on another range (0-21). Higher numbers indicated worse symptoms; both were similar across studies at baseline.
“It’s interesting that women were not recruited for these studies based on their sleep symptoms; they were recruited by hot flashes,” Guthrie said. “But they tended to have at least mild insomnia and many met the clinical threshold for poor sleep quality.”
The researchers looked at change from baseline in ISI and PSQI based on intent-to-treat analysis, using generalized linear models with adjustments for any differences between trials.
Compared with controls, the greatest decrease in ISI score at week 8 or 12 was seen with escitalopram (-2.1), followed by venlafaxine (-1.5), yoga (-1.4), exercise (-1.1) and estradiol (-1), relative to the pooled placebo group. Escitalopram helped the most for PSQI, while estradiol, venlafaxine, exercise and yoga also improved sleep quality.
“These three medications not only reduced vasomotor menopausal symptom frequency but are similarly beneficial for sleep outcomes,” Guthrie said. “Exercise and yoga unfortunately did not reduce hot flash frequency, at least in our studies, but were nearly as effective for sleep as these medications.”
Quality of life
Andrea Z. LaCroix, PhD, of the University of California, San Diego, where she is director of the Women’s Health Center for Excellence, presented the results on quality of life in menopausal and postmenopausal women using the same pooled data.
Andrea Z. LaCroix
“A lot of women have hot flashes, and they impact multiple domains of well-being,” LaCroix said. “It makes sense not just to evaluate the impact of treatments on frequency and severity, but on these domains.”
To the end of standardizing the trials to facilitate solid comparisons, the researchers selected a validated 29-item questionnaire covering VMS, psychosocial, physical and sexual domains. Domain scores ranged from 1 to 8, with higher numbers indicating more, and more bothersome, symptoms, and the total Menopause-related Quality of Life (MenQOL) score represented a composite formed by the average.
Questions addressed included: hot flashes, night sweats and sweating for VMS; anxiousness, memory and feeling “blue” for psychosocial; flatulence, bloating, pain, tiredness, sleeping, energy and weight gain for physical; and sexual desire, vaginal dryness and intimacy for sexual.
“After adjustments for baseline characteristics and outcome measures, the MenQOL scale responses in the placebo group were comparable across all trials,” LaCroix said. “Therefore, we pooled the placebo groups and used a single comparison for all the interventions.”
The pooled data for total MenQOL showed statistically significant score improvements with estradiol (–0.4) and escitalopram (–0.4), followed by yoga (–0.3); venlafaxine helped some, exercise did not help much and there was a worsening with omega-3, LaCroix said.
Estradiol showed significance for improving VMS (–1.2), and LaCroix said it is “nice to be able to tell patients that even low doses help.” VMS score improvements with escitalopram (–0.6) and yoga (–0.5) were also significant.
The most efficacious, and only statistically significant, intervention for psychosocial symptoms was escitalopram (–0.4), followed by venlafaxine.
In the physical domain, the intervention that showed scores improved most with was exercise, with significance seen for escitalopram, venlafaxine and yoga, as well (–0.1 for all). LaCroix said “even though exercise is not helping with menopause symptoms very much, it’s a great habit to cultivate for many aspects of health.”
Statistically significant improvement was seen in sexual domain scores with estradiol (–0.4) but slightly more with yoga (–0.5); LaCroix noted the yoga intervention was a gentle style with easy-to-do postures and breathing that is accessible for anyone.
“If you consider the effect of estradiol to be important, you should consider the effect of yoga to be just as important,” she said.
Telephone-delivered cognitive-behavioral intervention
Susan McCurry, PhD, of the University of Washington, said cognitive-behavioral interventions delivered via telephone could very well become the go-to insomnia treatment for women in midlife with vasomotor symptoms.
Susan McCurry
“We are hoping this is going to be the definitive trial on telephone-delivered cognitive-behavioral treatments for insomnia (CBT-I),” McCurry said of the MsFLASH 04 pilot study.
Menopause-related sleep disturbances, experienced by most women during the transition, place a substantial economic burden on both women and society, from mood shifts, anxiety and depression to fatigue and missed work days, McCurry said.
“Surprisingly, there are not a lot of evidence-based treatments to manage insomnia and hot flashes together in this population,” she said. “Many women don’t want to take sleep medicines or use hormone therapies to manage their symptoms.”
The researchers are currently evaluating the effects of a novel non-pharmacological CBT-I (n=55) vs. menopause education control (MEC; n=55) in women aged 40 to 65 years with comorbid insomnia symptoms and hot flashes.
Women with an ISI ≥12 (median in other MsFLASH trials), at least two hot flashes per day over 2 weeks, telephone availability for the intervention and written consent were included in the trial. Exclusion criteria were menstruation, excessive alcohol use, previous sleep disorder diagnosis and illness that would interfere with sleep/intervention.
Both groups receive six 20- to 30-minute individual sessions during 8 weeks (the first could be in-person), education and sleep monitoring based on logs. Masters’ level clinicians with no background experience in sleep medicine were brought on to serve as coaches.
CTB-I also gets sleep scheduling/goal setting and behavioral homework/problem-solving.
“It’s a very directive, but collaborative intervention,” McCurry said.
MEC gets only broad support.
“It’s designed to be very non-directive; we provide information we think menopausal women would be interested in … and encourage them to try some things and let us know how they work,” McCurry said.
ISI and PQSI are being used to assess symptom changes. Other outcomes being measured include self-reported sleep variables based on daily diary, hot flash bother and interference, symptoms of depression and anxiety, bodily pain and quality of life.
“We’re trying to create an intervention that, if it proves efficacious, would have the potential to be widely disseminated in primary care settings where most women who have insomnia and hot flash symptoms are seeking care,” McCurry said.
The investigators hypothesize the cognitive aspect of the CBT-I therapy would reduce nighttime arousal and rumination, whereas the behavioral aspect would re-regulate sleep schedules, McCurry said.
“Together, as we do this, we should see reduced nighttime wakefulness, less daytime fatigue and, ultimately, better mood, quality of life and, hopefully, reduced interference from the bothersome VMS,” she said.
The trial aims to evaluate: feasibility including recruitment, completion and delivery costs; treatment fidelity including training interventionists and participant response; and acceptability based on program evaluation.
At the time of the 25th annual NAMS meeting, 45 women in CBT-I and 47 in MEC had completed the sessions. Two women in each group withdrew after randomization but before ever seeing a coach, and four women in each group withdrew after the first session, McCurry said.
The last intervention is expected to end in early November, McCurry said.
“We should be able to have post-test data, hopefully, shortly thereafter, and 4 months after that see follow-up data,” she said. — by Allegra Tiver
For more information:
Guthrie KA. MsFLASH research network: Latest findings. Presented at: The North American Menopause Society Annual Meeting; Oct. 15-18, 2014; Washington, D.C.
Disclosure: The MsFLASH network was supported by a cooperative agreement issued by the National Institute of Aging in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development, the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Research on Women’s Health. MsFLASH-04 Pilot study supported by the Fred Hutchinson Cancer Research Center.