Venlafaxine

To examine the efficacy of two doses of venlafaxine:  37.5 mg (low-dose study) or 75 mg (high-dose study) to treat hot flashes after breast cancer.

Women were scheduled for 14 weekly visits. Weeks 1 and 2 provided baseline information, and weeks 3 to 14 included six weeks of treatment and six weeks of placebo.

Outcomes were hot flash (frequency, severity, and bother), hot flash impact on daily life, negative effect, fatigue, sleep, and quality of life (QOL).

The sample was comprised of breast cancer survivors:  57 in the low-dose study and 20 in the high-dose study.

University cancer clinics in the southeastern and midwestern United States

Patients were undergoing the long-term follow-up phase of care.

The study included two randomized, double-blind, placebo-controlled, crossover trials.

• Adherence was measured by capsule counts and weekly written verification.
• Sternal skin conductance monitor
• Electronic event markers and written diaries used for self-reporting hot flashes
• Profile of Mood States–Short Form (POMS-SF)
• Positive and Negative Affect Scale (PANAS)
• Center for Epidemiologic Studies Depression Scale (CESD)
• Diagnostic and Statistical Manual of Mental Disorders (DSM)
• Hamilton Rating Scale–Depression (HRSD)
• Pittsburgh Sleep Quality Index (PSQI) 
• Medical Outcomes Survey (MOS)

Venlafaxine resulted in modest decreases in hot flashes, but only hot flash interference improved differentially at the higher dose. The timing of the effect of venlafaxine on hot flashes varied by dose.

Only women with a 50% or greater decrease in physiologic hot flashes experienced significant improvement in fatigue, sleep quality, and QOL. Although side effects were mild, most patients discontinued venlafaxine long-term.

• The sample was racially and ethnically homogeneous.
• The study had a small sample size.
• Treatment time was limited.
• The study lacked pharmacogenetic data.
• In assessing hot flashes, subjective hot flash measures are prone to placebo effects, and subjective hot flash measures and secondary outcome measures may both be subject to a positive reporting bias.
• A study psychologist verified the absence of depressive symptoms, which could confound data if present.
• Trained study nurses are required.

To evaluate the efficacy of optimizing hot flash (HF) treatment, as determined by sleep and quality of life (QOL) measurements, by combining the hypnotic agent zolpidem with a selective-serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) in a randomized, placebo-controlled, double-blind clinical trial.

All women were evaluated for current use of SSRIs/SNRIs for the treatment of HFs. If currently on an SSRI/SNRI for HFs, they were instructed to continue use. If they were nonusers, they were started on venlafaxine 75 mg per day. They were then randomized to receive zolpidem 10 mg each evening or placebo each evening for five weeks. Patients were evaluated at baseline and at the end of the study.

• The study enrolled 53 women with a mean age of 51.1 years (range 29.6–65.3 years).
• The women were being treated for breast cancer or were being managed for increased risk of breast cancer. 
• Adjuvant endocrine therapies were used by 71% of the women, with 29 taking tamoxifen.
• The level of perceived sleep disturbance was high.
• Patients reported HFs and awakenings, part of a clinical insomnia syndrome that was attributed to the HFs.
• Median time since diagnosis was 27.2 months (interquartile range 13.7–49.9 months).
• Patients must have completed therapy more than three months prior to enrollment.
• Menopause status varied.
• Women with primary sleep disorders or psychiatric disorders were excluded.

• Multisite
• Outpatient clinics
• Boston, Massachusetts

Patients were undergoing the long-term follow-up phase of care.

The study was a randomized, placebo-controlled, double-blind clinical trial. 

• Objective and subjective sleep HF measures:  sleep questionnaire, sleep diary, actigraphy using an actigraphic watch (Actiwatch-Score, Mini Mitter  Co, Inc. Bend, Oregon), skin temperature using the sterna lskin-conductance monitor (Biolog ambulatory recorder, UFI, Morro Bay, California), 7-day North Central Cancer Treatment Group Daily Vasomotor Symptom Diary    
• Beck Depression Inventory (BDI)
• Period of time awake after sleep onset (WASO) as determined by the actigraphic watch
• Pittsburgh Sleep Quality Index (PSQI)
• Quality of Life Inventory (QOLI)

Due to the high percentage of drop-outs in the placebo arm, the investigators changed the way they evaluated the results.  First, they identified the number of people who completed the study and showed improvement in sleep scores. The proportion of women completing the study varied by treatment assignment; 88% (22/25) of those who received zolpidem completed the therapy, whereas 57% (16/28) of those receiving placebo did so. Responders were those who completed the study AND showed improvement in their sleep scores. Forty percent (10) of the women taking zolpidem responded, whereas 14% (4) of the placebo group responded. Sleep improved in more women in the zolpidem arm than the placebo arm. The investigators looked at the differences in outcome measures between the two groups that completed the therapy. Measurements of PSQI scores and WASO time were significantly worse in the placebo arm. PSQI scores improved by 15% in the zolpidem arm and worsened by 26% in the placebo arm. The same was true with WASO time, which improved by 9% in the zolpidem arm and worsened by 2% in the placebo arm. In addition, patients in the zolpidem arm showed improvement in their QOL scores, whereas those on placebo showed a decrease in QOL scores. No change occurred in depressive symptoms in either group.

Zolpidem appears to improve a patient’s perception of nighttime HFs, perhaps by allowing her to sleep through the HF. Sleep scores improved, as did QOL in patients who augmented SSRIs with zolpidem for HFs. No change occurred in objective measurements of the number of HFs. Treatments targeting sleep may be an important supplemental strategy to optimize well-being.

• The study had a small sample size.
• The study had a high drop-out rate.
• The study had a heterogeneous sample.

Sleep disturbances due to HFs are among the most commonly reported symptoms in patients with breast cancer.  Augmenting SSRIs/SNRIs with zolpidem may improve perception of nighttime HFs and, in turn, improve sleep and QOL. Further study is required.