Introduction
The importance of this review
Aims
Terminology
Methods
Search methods for identification of studies
Study ID | Indication | Participants | Dropout | PC/ITT analyses | Methodological assessment | Intervention | Duration of treatment | Main findings | Funding | ||
---|---|---|---|---|---|---|---|---|---|---|---|
Treatment
|
Control
|
Treatment
|
Control
|
Cochrane Handbook
|
Treatment vs Control
| ||||||
Buijs [36] | Venlafaxine versus clonidine for hot flashes in women with breast cancer | Venlafaxine/clonidine n = 30 | Clonidine/venlafaxine n = 30 | Venlafaxine period n = 15 | Clonidine period n = 5 | Yes/Yes | A-clear | Venlafaxine (75 mg × 1) Clonidine (0.05 mg x 2) Cross-over design. Randomized Double blind | 18 weeks - 2 × 8 weeks with 2 week wash out period | Venlafaxine and clonidine were equally effective in hot flash reduction. Main reasons for discontinuation were adverse effects, which were worse with venlafaxine | NR |
Biglia [39] | Gabapentin versus vitamin E for hot flashes and sleep quality in breast cancer patients | Gabapentin n = 60 | Vitamin E n = 55 | 29 | 25 | Yes/Yes | B-unclear. No allocation concealment or blinding | Gabapentin 900 mg/day vs Vitamin E 800 IU/day. Parallel group design, randomized but not blinded | 12 weeks + 12 week obs. | Gabapentin (900 mg) significantly reduced hot flash frequency and score, a non-significant reduction was seen in the vitamin E group | Not funded |
Boekhout [31] | Management of hot flashes in breast cancer patients with venlafaxine and clonidine | Venlafaxine n = 41 Clonidine n = 41 | Placebo n = 20 | Venlafaxine n = 6 Clonidine n = 13 | 3 | Yes/Yes | A-clear | Venlafaxine 75 mg/day vs Clonidine 0.1 mg/day vs placebo. Parallel group design. Stratified randomization. Double blind | 12 weeks | Venlafaxine and clonidine are effective treatments for hot flashes in breast cancer patients. A more immediate reduction was seen with venlafaxine, however hot flash scores were lower with clonidine at week 12 | NR |
Carpenter [32] | Dose-related efficacy of venlafaxine in the treatment of hot flashes in breast cancer patients | Venlafaxine 37.5/placebo n = 64. | Venlafaxine 75 mg/placebo n = 20 | 21 | 3 | Yes/Yes | A-clear | Venlafaxine low and high-dose groups randomized to 2 sequences each, 6 weeks treatment then 6 weeks placebo or visa versa. Cross-over design, randomized, double blind | 12 weeks | Venlafaxine resulted in modest decreases in hot flashes, only hot flash interference improved at the higher dose. Although adverse effects were mild most women discontinued venlafaxine long-term possibly due to treatments not outweighing benefits | National Institute of Nursing Research. USA |
Goldberg [38] | Transdermal clonidine for tamoxifen-induced hot flashes | Clonidine/placebo n = 55 | Placebo/clonidine n = 55 | 13 | 8 | No/Yes | A-clear | 4 weeks of transdermal clonidine (equivalent to 0.1 mg oral dose), the 4 weeks placebo or visa versa. Cross-over, randomized, double-blind design | 8 weeks | Clonidine significantly reduced hot flash frequency and severity, 4 different adverse effects were recorded | Public Health Service Grants. USA |
Liobl [42] | Venlafaxine versus clonidine for hot flashes in breast cancer patients | Venlafaxine n = 40 | Clonidine n = 40 | 9 | 7 | Yes/Yes | A-clear | Venlafaxine (37.5 mg x 2) Clonidine (0.075 mg x 2) Double-blind, randomized, cross-over design, only 39 patients were crossed over at week 4. | Part A = 4 weeks Part B (cross-over) = 8 weeks. No wash out period | Venlafaxine is significantly more effective in reducing the frequency of hot flashes in breast cancer patients than clonidine | NR |
Loprinzi [33] | Venlafaxine in management of hot flashes in survivors of breast cancer | 1.Venlafaxine 37.5 mg/day n = 56 2.Venlafaxine 75 mg/day n = 55 3.Venlafaxine 150 mg/day | Placebo n = 56 | 1. V(37.5 mg) n = 7 2.V(75 mg) n = 12 3. V(150 mg) n = 5 | 6 | Yes/Yes | A-clear | Venlafaxine, 3 doses, 37.5 mg, 75 mg and 150 mg vs placebo. Parallel group design, randomized, double blind | 4 weeks | Decrease in hot flash frequency was significant in all three venlafaxine doses compared to placebo. Four different adverse effects were significantly higher in 75 mg and 150 mg groups vs placebo | Public Health Service Grants. USA |
Maclaughlan [40] | Hypnotherapy versus gabapentin for the treatment of hot flashes in breast cancer survivors | Hypnoth. n = 13 | Gabapentin n = 14 | 4 | 6 | Yes/Yes | B- unclear (no blinding, small sample size) | Gabapentin 900 mg/day vs 3 x 1 hour hypnotic inductions, 1 week apart, instruction in self-hypnosis and home CD use. Parallel group design, randomized, non- blinded | 8 weeks | Hypnotherapy and gabapentin demonstrate efficacy in improving hot flashes, there were no significant differences between the 2 arms | Not funded |
Mao [41] | El.acupuncture versus gabapentin for hot flashes in breast cancer survivors | El.acup. n = 62 (real n = 30, sham n = 32) | Gabapentin 900 mg/day n = 58 (real n = 28, placebo n = 30) | El.acup n = 10 (real n = 6, sham n = 4) | Gaba n = 5 (real n = 1, placebo n = 4) | Yes/Yes | A-clear | Electroacupuncture (real and sham) versus gabapentin (real and placebo). Parallel group design, 4 arms, randomized, double-blind | 8 weeks, obs. at week 24 | Acupuncture produced larger placebo and smaller nocebo effects than the pills El.acup reduced HF by 47.8%, gabapentin by 39.4%, sham acup by 45% and placbo pills by 22.3% | 1. Pfizer 2. Genetech 3. Incyte 4. Millenium Pharmaceut 5. Bayer 6. Veridex 7. Calithera Biosciences 8. Glaxo.S.K. 9. Wyeth |
Pandya [37] | Clonidine for tamoxifen-induced hot flashes in breast cancer patients | Clonidine n = 99 | Placebo n = 99 | 26 | 23 | No/Yes | A-clear | Clonidine 0.1 mg before bed vs placebo. Parallel group design, randomized, double-blind | 8 weeks + 4 week obs | Clonidine significantly reduced frequency and severity of hot flashes | National Cancer Institute, Maryland, USA |
Pandya [34] | Gabapentin for hot flashes in women with breast cancer. Dose related efficacy and adverse effect profile was assessed | Gabapentin (300 mg) n = 139 Gabapentin (900 mg) n =144 | Placebo n = 137 | Gaba 300 mg n = 25 Gaba 900 mg n = 24 | 24 | Yes/Yes | A-clear | Gabapentin 300 mg/day vs 900 mg/day vs placebo. Parallel group design, randomized, double-blind | 8 weeks | Gabapentin is effective in the control of hot flashes at 900 mg/day, but not at 300 mg, measured at 8 weeks | US National Cancer Institute |
Walker [20] | Acupuncture versus venlafaxine for vasomotor symptoms in patients with hormone receptor positive breast cancer | Acupuncture n = 25 | Venlafaxine n = 25 | 1 | 5 | No/Yes | B-unclear (not possible to blind providers and participants, possibly affecting bias) | Acupuncture (16 treatments) vs venlafaxine (37.5 mg/day for 1 week, then 75 mg for 11 weeks) Parallel group design, randomized, not blinded | 12 weeks, observed for 1 year | Acupuncture and venlafaxine significantly and equally reduced hot flash symptoms. Eighteen incidents of adverse effects were seen in the venlafaxine group, there were none in the acupuncture group | Susan Komen Foundation |
Meta-analysis
Results
Outcome of the literature searches
Study ID | Number of participants | Total no. of AE (no. of participants with AE) | Type of AE | ||
---|---|---|---|---|---|
Treatment | Control | Treatment | Control | ||
Biglia [39] | Gabap. n = 60 | Vit E 55 | 17 (60) | 0 (55) | Somnolence, dizziness, dry mouth, nervousness, weight gain |
Boekhout [31] | Venl 41. Clon 41. | Placebo n = 20 | Venl 206 (41) Clon163 (41) | 82 (20) | Reduced appetite, nausea, sleepiness, dizziness, fatigue, dry mouth, sweating, constipation |
Buijs [36] | Venlafaxine n = 30 | Clonidine n = 30 | 27 (30) | 5 (30) | Headache, dizziness, dry mouth, mood disorder |
Carpenter [32] (high dose)* | Venlafaxine n = 9 | Placebo n = 9 | Dry mouth p = 0.002 vs placebo ** | NR | Dry mouth |
Carpenter [32] (low dose)* | Venlafaxine n = 26 | Placebo n = 26 | Constipation p = 0.001 headaches p = 0.007 dry mouth p = 0.001 vs placebo ** | NR | Constipation, headache, dry mouth |
Goldberg [38] | Clonidine n = 55 | Placebo n = 55 | dry mouth (p < .001) constipation (.02) itchiness (.01) | NR | Drowsiness, dry mouth, constipation, itching |
Loibl [42] | Venlafaxine n = 33 | Clonidine n = 31 | 38 (27) | 14 (27) | Loss of appetite, sleeplessness, nausea, drowsiness, tiredness, sweating, constipation, restless sleep, nervousness, moodiness, dry mouth |
Loprinzi [33] (High dose)* | Venlafaxine 150 mg n = 54 | Placebo n = 56 | 43(54) | 2 (56) | Decreased appetite, nausea, dry mouth, constipation |
Loprinzi [33] (Low dose) * | Venlafaxine 37.5 mg n = 56. | Placebo n = 56 | 14 (56) | 2 (56) | Decreased appetite, nausea, dry mouth, constipation |
Loprinzi [33](Medium dose)* | Venlafaxine 75 mg n = 55. | Placebo n = 56 | 18 (55) | 2 (56) | Decreased appetite, nausea, dry mouth, constipation |
Maclaughlan [40] | Gabapentine. n = 14 | Hypnotherapy n = 13 | 3 (24) | 0 (13) | Fatigue, vertigo |
Mao [41] | Gabapentin 900 mg/day = 28 | El.acupuncture = 30 | Gabapentin 13 (28) | 5 (30) | Bruising, constipation, dizziness, dry mouth, fatigue, headache, increased pain, drowsiness |
Pandya [37] | Clonidine n = 99 | Placebo 99 | 41 (99) | 21 (99) | Difficulty sleeping |
Pandya [34] (high dose) * | Gabapentine 900 mg n = 116 | Placebo n = 113 | 10 (120) | 6 (113) | Appetite, distress, drowsiness, fatigue, nausea, pain, memory, shortness of breath, sleep, vomiting |
Pandya [34] (low-dose study)* | Gabapentine 300 mg n = 114 | Placebo n = 119 | 6 (114) | 6 (113) | Appetite, distress, drowsiness, fatigue, nausea, pain, memory, shortness of breath, sleep, vomiting |
Walker [20] | Venlafaxine n= 25 | Acupuncture n=25 | 28 (25) | 0 (25) | Nausea, dry mouth, headache, difficulty sleeping, double vision, increased blood pressure, constipation, anxiety, lightheaded, jittery |
SUM | 627 (774) |
Study ID | Grade 1-5 (CTCAE) | ||||
---|---|---|---|---|---|
Treatment | |||||
G1 | G2 | G3 | G4 | G5 | |
Biglia [39] | 5 | 12 | |||
Boekhout [31] | V 104. Cl 93 | V. 102, Cl 70 | |||
Buijs [36] | 16 | 11 | |||
Carpenter [32] (high dose)* | |||||
Carpenter [32] (low dose)* | |||||
Goldberg [38] | |||||
Loibl [42] | 38 | ||||
Loprinzi [33] (High dose)* | 40 | 3 | |||
Loprinzi [33] (Low dose) * | 13 | 1 | |||
Loprinzi [33](Medium dose)* | 17 | 1 | |||
Maclaughlan [40] | 3 | ||||
Mao [41] | 13 | ||||
Pandya [37] | 41 | ||||
Pandya [34] (high dose) * | 10 | ||||
Pandya [34] (low-dose study)* | 6 | ||||
Walker [20] | 28 | ||||
SUM | 417 | 210 | 0 | 0 | 0 |
Study ID | Grade 1-5 (CTCAE) | ||||
---|---|---|---|---|---|
Control | |||||
G1 | G2 | G3 | G4 | G5 | |
Biglia [39] | 0 | ||||
Boekhout [31] | 40 | 42 | |||
Buijs [36] | 5 | ||||
Carpenter [32] (high dose)* | |||||
Carpenter [32] (low dose)* | |||||
Goldberg [38] | |||||
Loibl [42] | 14 | ||||
Loprinzi [33] (High dose)* | 2 | ||||
Loprinzi [33] (Low dose) * | 2 | ||||
Loprinzi [33](Medium dose)* | 2 | ||||
Maclaughlan [40] | |||||
Mao [41] | 5 | ||||
Pandya [37] | 21 | ||||
Pandya [34] (high dose) * | 6 | ||||
Pandya [34] (low-dose study)* | 6 | ||||
Walker [20] | 0 | ||||
SUM | 98 | 47 | 0 | 0 | 0 |