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Originally published as JCO Early Release 10.1200/JCO.2006.07.5390 on December 4 2006 © 2007 American Society of Clinical Oncology. Phase III Trial of Gabapentin Alone or in Conjunction With an Antidepressant in the Management of Hot Flashes in Women Who Have Inadequate Control With an Antidepressant Alone: NCCTG N03C5
From the Mayo Clinic, Rochester; Metro-Minnesota Community Clinical Oncology Program, St Louis Park, MN; Illinois Oncology Research Association Community Clinical Oncology Program (CCOP), Peoria, IL; Cancer Consortium, Sioux Falls, SD; Michigan Cancer Consortium, Ann Arbor, MI; Missouri Valley Cancer Consortium, Omaha, NE; Upstate Carolina CCOP, Spartanburg, SC; Wichita Community Clinical Oncology Program, Wichita, KS; and the St Vincent Regional Cancer Center CCOP, Green Bay, WI. Address reprint requests to Charles L. Loprinzi, MD, Mayo Clinic, 200 First St, SW, Rochester, MN 55905; e-mail: cloprinzi{at}mayo.edu
PURPOSE: Despite the utility of newer antidepressants for alleviating hot flashes, antidepressants do not work adequately enough in many patients. Gabapentin is a nonhormonal agent that also can reduce hot flashes. No data have been available to address whether the combination of both agents would more effectively alleviate hot flashes, compared with gabapentin alone, in patients with inadequate hot flash control with an antidepressant alone. PATIENTS AND METHODS: This was a randomized trial in which 118 patients with inadequate hot flash control on an antidepressant were randomly assigned to receive both an antidepressant and gabapentin versus being weaned off the antidepressant and receiving gabapentin alone. Patients were observed for 5 weeks (including a baseline week in which patients continued on their current antidepressant without gabapentin) during which time they completed validated daily hot flash diaries. RESULTS: Ninety-one patients provided complete data at the 5-week assessment. Regardless of whether or not the antidepressant was continued when gabapentin was started, there was an approximately 50% median reduction in hot flash frequencies (54%; 95% CI, 34% to 70% for combined treatment v 49%; 95% CI, 26% to 58% for gabapentin alone) and scores (56%; 95% CI, 26% to 71% for combined treatment v 60%; 95% CI, 33% to 73% for gabapentin alone). CONCLUSION: Gabapentin seems to decrease hot flashes by approximately 50% in women with inadequate hot flash control who were using an antidepressant. This study saw no significant additional hot flash reduction from continuation of the antidepressant.
Hot flashes are a prominent problem in many women as they near midlife.1 For a long time, hormone replacement therapy was the standard therapy for this problem. Although this therapy clearly works, there are concerns with regards to the use of hormones.2,3 Pursuant to this, efforts have been asserted to find nonhormonal treatment options for hot flashes. In the recent past, several trials have demonstrated that newer antidepressants, such as venlafaxine and paroxetine, significantly reduce hot flashes compared with a placebo.4-10 As a result, these antidepressants have been commonly used in clinical practice. Nonetheless, these antidepressants do not adequately alleviate hot flashes in many women. Pursuant to this, a large number of women ask for alternative treatments for their hot flashes. Gabapentin is another nonhormonal, antiseizure medication that has recently been shown to moderately decrease hot flashes.11,12 It has been used in women who have inadequate hot flash control with antidepressants.13 Sometimes using two effective agents for a clinical problem produces additive or synergistic benefit, but other times, it does not. There has not been any available information to illustrate whether the combination of gabapentin and an antidepressant would be more helpful than either agent alone. The current clinical trial was developed to address the use of gabapentin in women with inadequate control of their hot flashes on an antidepressant. It set out to address whether or not it would be best to continue to use both agents versus switching to gabapentin alone.
Patients considered for this trial were women who had been receiving a stable dose of an antidepressant for treating hot flashes, but the antidepressant could not have been a monoamine oxidase inhibitor or a tricyclic antidepressant. These women must have had bothersome hot flashes despite the current use of the antidepressant to treat them. This criterion was defined by a patient-reported occurrence of at least 14 hot flashes per week, being of sufficient severity to make the patient desire additional therapy intervention. Eligible women had a history of breast cancer or concern about taking hormones because of a fear of breast cancer. Women were allowed to enter onto this study regardless of menopausal status; no specific information was collected regarding the menopausal status of individual participants. Eligible patients could not have received antineoplastic chemotherapy, androgens, estrogens, or progestational agents within the prior 4 weeks, and none of these could be planned during the subsequent 5 weeks. The patients could not have used gabapentin previously. Patients could not have been using clonidine, belladonna alkaloids, or dehydroepiandrosterone. They could have been using vitamin E or soy supplements as long as they had been on a stable dose for at least 1 month and planned to continue this during the study period. The patients could not have had any current evidence of malignant disease. They could have been using tamoxifen, raloxifene, or an aromatase inhibitor as long as these medications had been used for at least 4 weeks and as long as such patients were planning to continue use throughout the 5-week study period. Patients were not eligible if they had a history of renal insufficiency or a creatinine clearance of less than 60 mL/min. Patients were not eligible if they were known to be pregnant or nursing. Women of childbearing potential had to use adequate nonhormonal contraception, and a negative pregnancy test was required less than 7 days before registration.
After eligibility determination, patients were randomly assigned centrally by the North Central Cancer Treatment Group Randomization Office to one of two treatment arms based on the duration of the hot flash symptoms (< 9 v After random assignment, patients were asked to complete a validated prospective daily hot flash diary15 for 1 week while they were continuing the antidepressant that they had been receiving. The hot flash diary asked patients to record the number of mild, moderate, severe, and very severe hot flashes they experienced each day over the 7-day period. Starting with the first day of the second week, all patients were instructed to take gabapentin 300 mg at bedtime for 3 days, then twice daily for 3 days, and then 3 times a day for 22 days. During this time, the patient was to continue filling out the daily hot flash diary. Patients in one arm of the study continued to take their antidepressant at the same dosing schedule that they had been receiving it. In the other arm of the study, patients were to wean off their antidepressant over a 7- to 10-day period of time. Understanding that there were different scenarios regarding the antidepressants and doses that patients were taking, physician discretion was allowed regarding the titration off these antidepressants. This was permitted to be done in patients taking more than a minimal dose of antidepressants by having the patient decrease their dose by 50% for 7 days and then stop or by having the patient double the interval time between doses for four doses and then stop. Patients continued to complete the daily hot flash diaries during the 4-week treatment period. In addition, they completed a symptom experience diary on a weekly basis that inquired about symptoms experienced during the past week on numerical analog scales of 0 to 10. The symptoms evaluated in this symptom experience diary were appetite loss, sleepiness, nausea, dizziness, an undesirable increase in appetite, fatigue, mouth dryness, abnormal sweating, constipation, swelling of the hands or feet, undesirable weight gain, trouble sleeping, nervousness, negative mood changes, interest in sexual relations, difficulty achieving an orgasm, and rash. They also scored weekly, again on a 0 to 10 scale, how distressing their hot flash experience was and how satisfied they were with their control of hot flashes. In addition, the patients completed a linear analog self-assessment16 quality-of-life questionnaire on a weekly basis. This asked patients to identify, on a 0 to 10 numerical analog scale, their overall quality of life, mental (intellectual) well-being, physical well-being, emotional well-being, spiritual well-being, and level of social activity during the previous week. The hot flash diary and weekly questionnaires have been validated and used in multiple prior clinical trials.15 During the study period, if patients had symptoms that were attributed to gabapentin and were considered to be of unacceptable severity, the gabapentin dose could have been decreased by increments of 300 mg/d.
Statistical Methodology Secondary analyses included a Wilcoxon rank sum test comparing hot flash frequencies between arms, CIs constructed for the median reductions in hot flash frequency and score by arm, and plots of hot flash frequencies and scores over the study period by arm. Additionally, toxicity incidence rates were compared between arms using Fisher’s exact test; and changes from baseline in toxicity and quality-of-life scores were compared across arms using Wilcoxon rank sum tests. The impact of the missing data on conclusions was investigated. Analyses were first performed using all available data. Analyses were then performed on data sets with missing values imputed using the last value carried forward and the average value carried forward. Conclusions were consistent throughout. Results of the analyses using all available data are presented in the following section.
Between November 19, 2004, and July 29, 2005, 118 patients were entered onto this study. Five patients canceled their participation in the study before receiving any study medications, leaving 113 eligible patients. Baseline hot flash frequencies were available for 101 patients (89%), and week 4 frequencies were available for 91 patients (81%). Baseline hot flash scores were available for 99 patients (88%), and week 4 scores were available for 88 patients (78%). Baseline characteristics, as listed in Table 1, were well balanced across the treatment arms.
There were no significant differences in changes from baseline at week 4 of hot flash scores (P = .37) or hot flash frequencies (P = .61) between the two treatment arms. These are aptly illustrated in Figures 1 and 2. The median reduction in hot flash score at week 4 for the gabapentin arm was 60% (95% CI, 33% to 73%), and for the gabapentin plus antidepressant arm, it was 56% (95% CI, 26% to 71%). The median reduction in hot flash frequency at week 4 for the gabapentin arm was 49% (95% CI, 26% to 58%), and for the gabapentin plus antidepressant arm, it was 54% (95% CI, 34% to 70%).
As noted earlier, toxicities were mainly determined by patient-completed questionnaires. Of the 17 potential toxicity items in the symptom experience diary, no statistically significant differences between the two treatment arms, in terms of changes from baseline at each treatment week, were noted when a multiple testing adjustment18 was used. Nonetheless, Figure 3 illustrates that there was a trend for more dizziness seen in the patients who received gabapentin alone. This was a temporary effect seen primarily in the first week of therapy when the antidepressants were being weaned in the group receiving gabapentin alone.
There was also a trend for differences in nervousness and negative mood changes among the two treatment arms. This seemed to occur over a different time frame than was seen for the dizziness noted earlier, with differences being present in the later weeks of the study (Figs 4 and 5). Note, however, that the scales on these three figures range from –2 to +2, whereas the original item scores range from 0 to 10.
In terms of quality-of-life evaluations, there were no statistically significant differences in changes in linear analog self-assessment quality-of-life measures from baseline to week 4 for overall quality of life (P = .98) or for any of the subdomains of mental well-being (P = .27), physical well-being (P = .23), emotional well-being (P = .45), social activity (P = .82), or spiritual well-being (P = .77).
The data from this trial failed to demonstrate any suggestion that the combination of an antidepressant and gabapentin is more efficacious than gabapentin alone in patients who have inadequate control of hot flashes on an antidepressant. However, there were three toxicity items that suggest there may be slight differences in the symptoms experienced by patients on the two treatment regimens. The first of these, dizziness, seemed to be a temporary problem in the first week of the study, but this equilibrated over the later 3 weeks of the study. One explanation for this is that the dizziness is related to withdrawal from the antidepressant. Withdrawal symptoms are well described on the discontinuation of antidepressants.19 They seem to be more prominent when antidepressants are abruptly stopped, as opposed to being weaned down.19 It is suspected that this antidepressant withdrawal effect was the cause of this suggestive difference in toxicity. The nervousness and negative mood changes were seen over a different time frame. They were more apparent by the end of the 4-week treatment. It is suspected that nervousness and negative mood changes were from a positive antidepressant effect on nervousness and mood in those patients who continued their antidepressants. The strengths of this study include that it is a prospective, randomized trial involving multiple institutions using a rigorous methodology that has been the hallmark of numerous published studies that have clarified new effective agents for hot flashes. Limitations of this study include the lack of a placebo and a slight loss of power as a result of a higher than anticipated rate of missing data. It is possible that a larger sample size would have picked up a statistically significant difference between the two study arms, but it is likely to be a small difference that is not very clinically significant. One might argue that a limitation of this study might be that it only observed patients over a 3- to 4-week period of time after the antidepressant was stopped. This is in contrast to many studies of hormonal agents that have classically observed patients for 12 weeks. Nonetheless, there are good data to demonstrate that the results of 3 to 4 weeks of therapy with antidepressants and gabapentin are virtually the same as what is seen with 6 to 12 weeks of therapy.11,12,20 Thus, this suggests that 3 to 4 weeks of study was scientifically appropriate. The results from this trial, although not a placebo-controlled evaluation of gabapentin in patients with inadequate control of hot flashes on an antidepressant, do support that gabapentin decreases hot flashes by approximately 50%. This is in concert with the results seen in two placebo-controlled trials evaluating gabapentin11,12 and is more than the 20% to 30% reduction commonly observed with a placebo.15It is interesting that the reduction of hot flashes with gabapentin seems to be independent of whether the patient is currently receiving an antidepressant.13 With regards to the use of gabapentin in patients with inadequate control of hot flashes on an antidepressant in clinical practice, the data from this trial do support initiation of gabapentin in this situation. It could be argued that it would be reasonable to continue the patient on the antidepressant for another week or two after initiation of gabapentin and then discontinue it at that time, assuming that the antidepressant was being used for control of hot flashes and not for depression or mood changes. This delayed withdrawal of the antidepressant might be beneficial in that symptoms that might be attributable to antidepressant withdrawal might not be blamed on starting a new medication.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: Anthony J. Jaslowski, Merck, Pfizer Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: Charles L. Loprinzi, Debra L. Barton Provision of study materials or patients: Charles L. Loprinzi, John W. Kugler, Loren K. Tschetter, Robert A. Nelimark, Ernie Porteza Balcueva, Mark D. Carlson, Steven Fletcher Duane, Steven W. Corso, David B. Johnson, Anthony J. Jaslowski Collection and assembly of data: Charles L. Loprinzi, Paul J. Novotny, Amylou C. Dueck, Kelli N. Burger Data analysis and interpretation: Charles L. Loprinzi, Debra L. Barton, Amylou C. Dueck, Ernie Porteza Balcueva, Kelli N. Burger, Paul J. Novotny Manuscript writing: Charles L. Loprinzi, Debra L. Barton, Amylou C. Dueck, Paul J. Novotny Final approval of manuscript: Charles L. Loprinzi, John W. Kugler, Debra L. Barton, Amylou C. Dueck, Loren K. Tschetter, Robert A. Nelimark, Ernie Porteza Balcueva, Kelli N. Burger, Paul J. Novotny, Mark D. Carlson, Steven Fletcher Duane, Steven W. Corso, David B. Johnson, Anthony J. Jaslowski
Additional participating institutions include: Montana Cancer Consortium, Billings, MT 59101 (Patrick Cobb, MD); Carle Cancer Center Community Clinical Oncology Program (CCOP), Urbana, IL 61801 (Kendrith M. Rowland, MD); Iowa Oncology Research Association CCOP, Des Moines, IA 50309-1014 (Roscoe R. Morton, MD); Medcenter One Health Systems, Bismarck, ND 58506 (Edward J. Wos, DO); Meritcare Hospital CCOP, Fargo, ND 58122 (Preston D. Steen, MD); CentraCare Clinic, St Cloud, MN 56301 (Harold E. Windschitl, MD); Hematology & Oncology of Dayton, Inc, Dayton, OH 80224 (Howard M. Gross, MD); and Medical College of Georgia, Augusta, GA 30912 (Anand P. Jillella, MD).
published online ahead of print at www.jco.org on December 4, 2006. Supported in part by Public Health Service Grants No. CA-25224, CA-37404, CA-35103, CA-35103, CA-63848, CA-63849, CA-35267, CA-35113, CA-35119, CA-35431, CA-35195, CA-35101, CA-37417, and CA-35090. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. McKinlay SM, Jeffreys M: The menopausal syndrome. Br J Prev Soc Med 28:108-115, 1974[Medline] 2. Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321-333, 2002 3. Anderson GL, Limacher M, Assaf AR, et al: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA 291:1701-1712, 2004 4. Loprinzi CL, Kugler JW, Sloan JA, et al: Randomized phase III controlled trial of venlafaxine in the management of hot flashes. Lancet 356:2059-2063, 2000[CrossRef][Medline] 5. Evans ML, Pritts E, Vittinghoff E, et al: Management of postmenopausal hot flushes with venlafaxine hydrochloride: A randomized, controlled trial. Obstet Gynecol 105:161-166, 2005 6. Stearns V, Beebe KL, Iyengar M, et al: Paroxetine controlled release in the treatment of menopausal hot flashes: A randomized controlled trial. JAMA 289:2827-2834, 2003 7. Stearns V, Slack R, Greep N, et al: Paroxetine is an effective treatment for hot flashes: Results from a prospective randomized clinical trial. J Clin Oncol 23:6919-6930, 2005 8. Loprinzi CL, Sloan JA, Perez EA, et al: Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 20:1578-1583, 2002 9. Gordon PR, Kerwin JP, Green Boesen K, et al: Sertraline to treat hot flashes: A randomized controlled double-blind crossover trial in a general population. Menopause 13:568-575, 2006[CrossRef][Medline] 10. Kimmick GG, Lovato J, McQuellon R, et al: Randomized, double-blind, placebo-controlled, crossover study of sertraline (Zoloft) for the treatment of hot flashes in women with early stage breast cancer taking tamoxifen. Breast J 12:114-122, 2006[CrossRef][Medline] 11. Guttuso T Jr, Kurlan R, McDermott MP, et al: Gabapentin’s effects on hot flashes in postmenopausal women: A randomized controlled trial. Obstet Gynecol 101:337-345, 2003 12. Pandya KJ, Morrow GR, Roscoe J, et al: Gabapentin for hot flashes in 420 women with breast cancer: A randomized double-blind placebo-controlled trial. Lancet 366:818-824, 2005[CrossRef][Medline] 13. Loprinzi L, Barton DL, Sloan JA, et al: Pilot evaluation of gabapentin for treating hot flashes. Mayo Clin Proc 77:1159-1163, 2002[Medline] 14. Pocock S, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 31:103-115, 1975[CrossRef][Medline] 15. Sloan JA, Loprinzi CL, Novotny PJ, et al: Methodologic lessons learned from hot flash studies. J Clin Oncol 19:4280-4290, 2001 16. Bretscher M, Rummans T, Sloan J, et al: Quality of life in hospice patients: A pilot study. Psychosomatics 40:309-313, 1999 17. Cohen J: Statistical Power Analysis for the Behavioral Sciences. Hillsdale, NJ, Lawrence Erlbaum Associates Inc, 1988 18. Hochberg Y: A sharper Bonferroni procedure for multiple tests of significance. Biometrika 75:800-802, 1988 19. Bezchlibnyk-Butler KZ, Jeffries JJ: Clinical Handbook of Psychotropic Drugs. Cambridge, MA, Hogrefe & Huber, 2003, pp 2-42 20. Loprinzi CL, Levitt R, Barton D, et al: Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7. J Clin Oncol 24:1409-1414, 2006 Submitted June 15, 2006; accepted October 18, 2006. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
9 months), the average patient-reported frequency of hot flashes per day (two to three v four to nine v > nine per day), and the antidepressant that they were using (venlafaxine v paroxetine v other) by a dynamic allocation procedure that balanced the marginal distributions.
