Case Study Treating Recurrent Postmenopausal Vasomotor Symptoms in a Patient with a Positive Family History for Breast Cancer Christine Leong, Jennifer Lake Objective: To report a case of recurrent hot flashes unresponsive to gabapentin in a postmenopausal patient with a positive family history of breast cancer. Case Summary: A 69-year-old Caucasian female experienced a recurrence of debilitating hot flashes for the past eight months. More recently, she failed a two-month trial of gabapentin 600 mg by mouth at bedtime after she previously received effective hormone replacement therapy (HRT) seven years ago with near-complete resolution of her symptoms. The patient had a sister and a niece who developed breast cancer in their 40s. Discussion: The treatment of postmenopausal hot flashes in a patient with a positive family history of breast cancer represents a clinical challenge for many clinicians. This case is an example in which gabapentin was ineffective in the treatment of severe hot flashes in a postmenopausal woman. The risks and benefits of HRT compared with nonhormonal alternatives were assessed. Conclusion: In this case, a two-month trial of gabapentin 600 mg/day failed to demonstrate efficacy in reducing the severity, frequency, and duration of hot flashes. Controlled trials are necessary to evaluate the safety and efficacy of other therapeutic alternatives. Key words: Gabapentin, Hormone replacement therapy, Hot flashes, Menopause, Vasomotor. AbbreviationS: CEE = Conjugated estrogen, HRT = Hormone replacement therapy, IBS = Irritable bowel syndrome. Consult Pharm 2015;30:38-44.

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Introduction Hot flashes, a common adverse outcome during menopause, are widely known to cause a significant impairment in quality of life.1-3 They are characterized by a sudden wave of heat, often with profuse sweating, that typically lasts for a few minutes, but can re-emerge up to several times per day.1-3 Most postmenopausal women (60%) experience hot flashes intermittently for fewer than 7 years.1 However, up to 15% may experience hot flashes that persist for 15 or more years, and as many as 50% of women who stop hormone replacement therapy (HRT) will have a recurrence of vasomotor symptoms.1,2 Estrogen-based therapy has well-documented efficacy in resolving vasomotor symptoms in menopausal women.1,2,4,5 Adverse effects, such as cardiovascular events and breast cancer, have made HRTs a less favorable option in certain patient populations.6,7 Moreover, the best treatment approach for patients with a family history of breast cancer experiencing a recurrence of hot flashes—but have already received a course of HRT in the past—is also unclear. Nonhormonal pharmacotherapy, including certain antidepressant agents, gabapentin (an anticonvulsant), clonidine, and Bellergal Spacetabs (belladonna, ergotamine tartate, phenobarbital; available in Canada), have been studied as alternatives for vasomotor symptom relief when HRT is contraindicated or not desired.1 However, their use is limited to small randomized controlled trials, and their adverse effect profile is often undesirable for older patients. We describe a case in which gabapentin was ineffective for the treatment of hot flashes in a postmenopausal woman and in which the efficacy and safety of re-initiating HRT was assessed.

Case Report A 69-year-old Caucasian woman with a medical history significant for depression, anxiety, insomnia, osteoporosis, irritable bowel syndrome (IBS), environmental allergies, and intermittent genital herpes presented to a Canadian family medicine clinic with a recurrence of debilitating vasomotor symptoms seven years after the initial occurrence. Her previous occurrence was treated with HRT for two years with almost complete resolution of symptoms.

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Vasomotor Symptoms in a Patient with a Family History for Breast Cancer

The patient reported having had a hysterectomy in the past and a positive family history for breast cancer; her sister and niece developed breast cancer in their 40s (type unknown). The patient described her current hot flashes as a sudden sensation of heat followed by profuse sweating that occurred multiple times (more than six per day) on a daily basis. The patient reported the severity of vasomotor symptoms as a 9-10 out of 10 on a numeric rating scale (1 = best symptoms, 10 = worst symptoms). Duration of each episode varied from minutes to hours. The patient reported waking up throughout the night, drenched in sweat; that sometimes occurred during the day as well. There were no triggers identified. She was initiated on a trial of gabapentin 100 mg by mouth at bedtime in March 2012. The dose was increased by 100 mg every week up to 600 mg by mouth at bedtime. After two months of treatment, the patient had “no beneficial effect” in severity, frequency, or duration of hot flashes and was “at wits’ end” with her symptoms. She had significant reduction in quality of life, including impacting her sleep and daily functioning. She requested reinitiation of HRT to improve her vasomotor symptoms at the time. The patient’s current medications included: • Amitriptyline 75 mg by mouth daily for depression and anxiety • Zopiclone 5 mg by mouth at bedtime when needed for insomnia • Risedronate 35 mg by mouth weekly for osteoporosis prevention • Pantoprazole 40 mg by mouth daily for IBS • Mometasone furoate intranasal 50 mcg daily • Ciclesonide 50 mcg intranasal daily prn for allergies • Acyclovir 400 mg by mouth three times daily when needed for intermittent genital herpes The patient has no known allergies, but an intolerance to duloxetine 30 mg by mouth daily, which she tried in July 2011 for depression but stopped taking it after five days secondary to intolerable sweating and dizziness from its use.

After a literature review of the alternatives for treating postmenopausal vasomotor symptoms, and a thorough assessment of the risk and benefits of each agent as they pertain to the patient, the patient and the team decided to reinitiate HRT. A trial of conjugated estrogens (CEE) 0.625 mg by mouth daily was initiated in May 2012. The risk and benefits of reinitiating HRT compared with other alternatives were discussed. Improvement of vasoactive symptoms was assessed two weeks following initiation of treatment. The patient was advised to monitor and report any changes in her breasts to her physician (e.g., enlargement, lumps, tenderness, pain, nipple discharge). Follow-up at two months showed resolution of the vasomotor symptoms, but long-term follow-up is unavailable to assess safety issues.

Discussion The patient expressed significant impairment in quality of life secondary to severe, intolerable hot flashes, and failed a two-month trial of gabapentin 600 mg by mouth at bedtime. All nonhormonal options for postmenopausal hot flashes have been supported by randomized controlled trials of relatively small numbers demonstrating a reduction in the severity, frequency, and duration of hot flashes compared with placebo (Table 1).4,8-15 Anticholinergic effects and other side effects that mimic vasomotor symptoms also limit these options. In addition, natural health products such as black cohosh, oil of evening primrose, dong quai, and ginseng have insufficient evidence supporting their use in reducing hot flashes.16-19 There is also a lack of strong evidence in efficacy for phytoestrogen supplements such as soy and red clover for mitigating vasomotor symptoms.17,18 Given the lack of standardized formulations, variability in dosage strengths, and lack of well-designed controlled trials for natural health products, the use of such agents was not considered for the current case patient. Gabapentin is an anticonvulsant approved by the Food and Drug Administration and Health Canada as adjunctive treatment for epilepsy.20,21 It is also used off-label for the treatment of neuropathic pain (including diabetic neuropathy, postherpetic neuralgia), fibromyalgia, restless

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Case Study

Table 1. Pharmacotherapy Alternatives That Were Considered for the Treatment of Postmenopausal Vasomotor Symptoms Alternative

Efficacy

Safety and Case Comments

HT: Estrogen plus Progestin5 (for intact uterus)

Demonstrated effectiveness for menopause-related vasomotor symptoms and their consequences (e.g., diminished sleep quality, irritability, difficulty concentrating, quality of life)5

Breast cancer relative risk 30% after 5 years

Cochrane review found a 75% reduction in the frequency of hot flashes with the treatment of HT compared with placebo27

Risk appears to be significant only in women who have a gap of ≤ 5 years between menopause and initiation of HT Risk for more invasive breast cancer (0.42%/year vs 0.34%/year) and for mortality (0.03%/year vs 0.01%/year) from breast cancer increased with estrogen plus progestin (11-year follow-up)

HT: Estrogen5 0.625 mg by mouth daily (to 1.25 mg daily)

Desired effects seen in 1-2 weeks5

Estrogen monotherapy for 7 years associated with a very small reduction in risk of breast cancer but in women with high body mass index

Clonidine (Dixarit) 0.05 mg by mouth twice daily

Indicated as a nonhormonal option for hot flashes in Canada

Occasional reports of further depressive episodes; careful supervision necessary

1 RCT (n =194) in tamoxifen-associated hot flashes in postmenopausal women with breast cancer, clonidine 0.1 mg by mouth/day reduced hot flash frequency at 4 weeks (37% vs 20%) and 8 weeks (38% vs 24%), and increased quality of life score, compared with placebo11

Side effects: mild, and diminish with continued therapy: dry mouth, dizziness, constipation, sedation

MOA: Reduces response of peripheral vessels to vasoconstrictor/ dilator stimuli

1 RCT (n = 29): reduction in frequency, severity, duration of flushing attacks at 8 weeks reported in 80%, 73%, and 67% for transdermal clonidine vs 36%, 29%, 21% placebo12 1 randomized double-blind cross-over: in women with breast cancer history receiving tamoxifen, transdermal clonidine reduced hot flash frequency (by 20% baseline) and severity (by 10% baseline) but increased dry mouth, constipation, drowsiness13

Drug interactions: Orthostatic regulation disturbances may be aggravated with concomitant TCAs with alpha-blocking properties; withdrawal of higher doses of clonidine may lead to excess catecholamines (caution with TCAs that increase these neurotransmitters); TCAs may reduce effect of clonidine, concurrent amitriptyline, and clonidineenhanced corneal lesions in rats Not ideal for patient given current amitriptyline use with very limited data supporting efficacy, despite approved indication for menopausal-associated vasomotor symptoms

1 systematic review reported 3 positive and 3 negative double-blind, placebo-controlled RCT (n ranged from 12 to 100) for clonidine in postmenopausal women with vasomotor symptoms10 Remission should be achieved in 2-4 weeks. If no benefit, discontinue and reassess

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Vasomotor Symptoms in a Patient with a Family History for Breast Cancer

Table 1. Pharmacotherapy Alternatives That Were Considered for the Treatment of Postmenopausal Vasomotor Symptoms (continued) Alternative

Efficacy

Safety and Case Comments

Venlafaxine (Effexor) Start 37.5 mg/ day and increase up to 75 mg/day after 1 week.

1 RCT (n = 191): In breast cancer survivors, venlafaxine 75 mg and 150 mg dose significantly reduced hot flash score by > 60% compared with placebo

Increase side effects without additional benefit above venlafaxine 75 mg

No significant difference was observed with venlafaxine 37.5 mg compared with placebo14

Patient failed trial of duloxetine (an SNRI) for depression. Limited data to support efficacy in menopausal-induced hot flashes. Patient is stable on amitriptyline. Concurrent use with amitriptyline increases risk for serotonin syndrome

1 RCT (n = 165): Paroxetine CR 12.5 mg and 25 mg dose reduced hot flashes by 50%-60% at 6 weeks15

Side effects: nausea, anticholinergic, sweating

Discontinuation: by 25% per week MOA: SNRI Paroxetine CR (Paxil CR) MOA: SSRI

Long-term benefit not known Gabapentin Start 300 mg daily, then increase to 300 mg TID over 3-7 days. Discontinuation: done over a 1-week period MOA: GABA analogue. Exact MOA unclear. Modulation of calcium channels thought to influence adrenergic and serotonergic pathways of the pituitaryhypothalamus responsible for thermoregulation.23 Bellergal (belladonna, ergotamine, phenobarbital)

RCT (n = 420): 900 mg/d in 3 divided doses, reduced hot flash severity (~50% vs 20%) at 4 and 8 weeks24 RCT: 900 mg/day in 3 divided doses reduced hot flash frequency and severity by 54% compared with placebo at 12 weeks in women with breast cancer25

Side effects: increased blood pressure, agitation, sweating, nausea, sleep disturbance

Anticholinergic effects in this population not desired. Limited data to support efficacy. Patient is stable on amitriptyline. Concurrent use with amitriptyline increases risk for serotonin syndrome Side effects: dizziness, light-headedness Although dose studied demonstrating efficacy was 300 mg 3 times a day, patient found no benefit after trial of gabapentin 600 mg HS over 2 months

Reduced frequency of hot flashes by 45% and a hot flash composite score by 31% to 71%26

Clinical trials show small benefit compared with placebo29

Side effects: dry mouth, constipation, sedation Trials show only small benefit compared with placebo. Limited by intolerable side effects

Abbreviations: CI = Confidence interval, CR = Controlled release, HS = At bedtime, HT = Hormone therapy, MOA = Mechanism of action, RCT = Randomized controlled trial, RR= Relative risk, SNRI = Serotonin norepinephrine reuptake inhibitor, SSRI = Selective serotonin reuptake inhibitor, TCA = Tricyclic antidepressant. Source: References 5, 10-15, 23-27, 29.

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Case Study legs syndrome, anxiety, alcohol dependence, and vasomotor symptoms.22 The mechanism of action of gabapentin in the management of vasomotor symptoms is not known, but it has been proposed to act on the thermoregulatory center of the hypothalamus.23 Gabapentin at a dose of 300 mg-2,400 mg by mouth per day (most commonly used was 300 mg-900 mg by mouth per day) for 4-12 weeks has been studied in randomized controlled trials and open-label studies in patients with hot flashes as a result of menopause or anticancer therapy.24-26 Gabapentin was found to reduce the frequency of hot flashes by approximately 45% and a hot-flash composite score (which comprised the weekly number of mild, moderate, severe, and very severe hot flashes) by 31%-71%.26 One meta-analysis determined that gabapentin at 900 mg per day was found to have a combined weighted mean decrease in the daily frequency of hot flashes of -2.05 (95% confidence interval [CI] -2.80 to -1.30).26 However, it is difficult to assess the clinical meaning of this value in a patient experiencing several episodes of hot flashes a day. Although all studies identified found an improvement in the frequency and severity of hot flashes with the use of gabapentin, these studies were of small sample size (range 11 to 420 women).24-26 Gabapentin 600 mg per day was not demonstrated to be effective in terms of reducing the severity, frequency, and duration of hot flashes for this patient with debilitating postmenopausal vasomotor symptoms after a two-month trial. Possible reasons for inefficacy could include inadequate dose or noncompliance. However, adherence was judged as not an issue for this patient. A trial of two months was deemed an appropriate length of time for determining the efficacy of gabapentin in the treatment of vasomotor symptoms in a clinical setting. However, it is possible that a treatment duration of up to 12 weeks may be necessary to observe a benefit. In earlier studies, an approximate 30% reduction in hot flashes was observed with gabapentin 300 mg daily at four weeks.26 Given the patient’s debilitating vasomotor symptoms, alternative treatment was explored at two months instead of dose titration.

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The risk-benefit ratio for reintroducing HRT (CEE alone) was assessed for this case patient. HRTs have been demonstrated to be the most effective option for moderateto-severe menopausal-induced vasomotor symptoms.1,5 One Cochrane Review reported a weekly reduction in hot flashes of approximately 18 per week (95% CI -23 to -13), which was equivalent to a 75% (95% CI 64-82) reduction in the frequency of hot flashes with the treatment of HRT compared with placebo.27 HRT also significantly reduced the severity of hot flashes compared with placebo (odds ratio [OR] = 0.13, 95% 0.07-0.23).27 An increased risk of breast cancer was observed with the long-term use of HRT.5 However, this risk was seen in patients receiving continuous progestin therapy for more than five years.5 In addition, the risk of breast cancer with estrogen alone was not found to be increased after seven years of continuous use.5 A more recent publication of the two Women’s Health Initiative hormone-therapy trials—with extended postintervention follow-up—report that invasive breast cancer risk was not higher in those receiving CEE 0.625 mg per day compared with placebo among women without an intact uterus aged 50 to 79 years of age. (Hazard ratio [HR] = 0.79, 95% CI 0.61-1.02; median follow-up 7.2 years for CEE alone).28 The average age of the population studied was 63.6 years (45.4% were between 60 and 69 years of age), 75.1% were Caucasian, 49.8% had menopause that initiated 20 or more years ago, and 35.5% had a past use of hormone therapy (approximately 52% had never used hormone therapy).28 Absolute risk of adverse events per 10,000 women per year taking CEE alone ranged from 19 fewer cases for those 50-59 years of age to 51 excess cases for those 70-79 years of age.28 The current case patient had a prior history of HRT exposure (continuous treatment for two years). There are limited data in the current literature that examined the risks of reinitiating HRT in older patients. Moreover, the patient is at higher risk for breast cancer given that she has a history of late-onset menopause and a first-degree relative with breast cancer. However, these risk factors are not an absolute contraindication for HRT.1

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Vasomotor Symptoms in a Patient with a Family History for Breast Cancer

Summary HRTs continue to demonstrate efficacy in alleviating symptoms of severe postmenopausal hot flashes; however, more data are needed for evaluating the safety of intermittent use in patients with recurrent vasomotor symptoms and risk factors for breast cancer. A two-month trial of gabapentin 600 mg per day did not demonstrate to be effective in ameliorating severe hot flashes in this postmenopausal patient.

Christine Leong, PharmD is assistant professor, faculty of pharmacy, Apotex Centre, University of Manitoba, Winnipeg, Manitoba, Canada. Jennifer Lake, PharmD, is assistant professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada, and pharmacist, Women’s College Hospital, Toronto. For correspondence: Christine Leong, PharmD, 750 McDermot Avenue, Winnipeg, Manitoba, R3E 0T5, Canada; Phone: 204-3185276; Fax: 204-474-7617; E-mail: [email protected]. Disclosure: No funding was received for the development of this manuscript. The authors have no potential conflicts of interest. © 2015 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2015.38.

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Case Study 19. Herbal medicines for menopausal symptoms. Drug Ther Bull 2009;47:2-6. 20. Neuronton prescribing information. New York, NY: Pfizer Inc; December 2012. Available at http://labeling.pfizer.com/ShowLabeling. aspx?id=630. Accessed December 3, 2013. 21. Neuronton® product monograph. Kirkland, Quebec: Pfizer Canada Inc; February 21, 2013. Available at http://www.pfizer.ca/en/our_ products/products/monograph/128. Accessed December 3, 2013. 22. Gabapentin. Lexi-Drugs. Lexicomp. November 25, 2013. Available at http://online.lexi.com.proxy2.lib.umanitoba.ca/lco/action/doc/retrieve/ docid/patch_f/6961#f_uses. Accessed December 3, 2013. 23. Taylor CP, Gee NS, Su TZ et al. A summary of mechanistic hypothesis of gabapentin pharmacology. Epilepsy Res 1998;29:233-49. 24. Pandya KJ, Morrow GR, Roscoe JA et al. Gabapentin for hot flashes in 420 women with breast cancer: a randomized double-blind placebocontrolled trial. Lancet. 2005;366:818-24.

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25. Guttuso T Jr, Kurlan R, McDermott MP et al. Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 2003;101:337-45. 26. Brown JN, Wright BR. Use of gabapentin in patients experiencing hot flashes. Pharmacotherapy 2009;29:74-81. 27. Maclennan AH, Broadbent JL, Lester S et al. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004:CD002978. 28. Manson JE, Chlebowski RT, Stefanick ML et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA 2013;310:1353-68. 29. Bergmans MG, Merkus JM, Corbey RS et al. Effect of Bellergal Retard on climacteric complaints: a double-blind, placebo-controlled study. Maturitas 1987;9:227-34.

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Treating recurrent postmenopausal vasomotor symptoms in a patient with a positive family history for breast cancer.

To report a case of recurrent hot flashes unresponsive to gabapentin in a postmenopausal patient with a positive family history of breast cancer...
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