Gabapentin

Gabapentin

PEP Topic 
Hot Flashes
Description 

Gabapentin is in a class of medications called anticonvulsants. Gabapentin treats seizures by decreasing excitement in the brain. Gabapentin has been studied for its effect in patients with cancer who have neuropathic pain or symptoms of peripheral neuropathy. It changes the way the body senses pain. It has also been studied for its effect on anxiety, chemotherapy-induced nausea and vomiting, and hot flashes.

 

Likely to Be Effective

Research Evidence Summaries

Biglia, N., Sgandurra, P., Peano, E., Marenco, D., Moggio, G., Bounous, V., … Sismondi, P. (2009). Non-hormonal treatment of hot flushes in breast cancer survivors: Gabapentin vs. vitamin E. Climacteric, 12, 310–318.

doi:10.1080/13697130902736921
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Study Purpose:

  • Assess efficacy and tolerability of gabapentin 900 mg/day compared to vitamin E for the control of vasomotor symptoms.
  • Secondary objective to evaluate effect of the treatments on quality of sleep and other aspects of quality of life (QOL).

Intervention Characteristics/Basic Study Process:

Patients were randomized to gabapentin 900 mg/day or vitamin E 800 IU/day for 12 weeks.

Sample Characteristics:

The study population included 115 adult postmenopausal women with history of breast cancer experiencing eight or more hot flushes per day. Sixty women completed the study. 

  • Median age: 50 years
  • Inclusion: Previous breast cancer surgically treated one year prior; no evidence of systemic disease; eight or more hot flushes per day; postmenopausal status; adjuvant tamoxifen, aromatase inhibitors or gonadotropin releasing hormone (GnRH) analogs allowed if started at least two months prior.
  • Exclusion: Use of any antidepressant treatment, progestagens, or other medication to treat hot flashes within three months; concomitant chemotherapy; uncontrolled hypertension; impaired renal or hepatic function or diabetes.

Setting:

Oncology Department University of Turin, Italy

Study Design:

Non–placebo-controlled, non-blinded trial

Measurement Instruments/Methods:

  • Hot flush diary completed daily
  • Pittsburgh Sleep Quality Index (PSQI)
  • Menopause Rating Scale (MRS) 
  • SF-36 Health Survey

Results:

Hot flush frequency and score decreased by 57.05% and 66.87%, respectively (p < 0.05) in the gabapentin group. Hot flush frequency and score were reduced by 10.02% and 7.28% respectively (p > 0.05) in the vitamin E group. Gabapentin improved the quality of sleep (PSQI score reduction: 21.33%, p < 0.05).

Limitations:

  • Small sample size
  • High dropout rate

Bordeleau, L., Pritchard, K. I., Loprinzi, C. L., Ennis, M., Jugovic, O., Warr, D., . . . Goodwin, P. J. (2010). Multicenter, randomized, cross-over clinical trial of venlafaxine versus gabapentin for the management of hot flashes in breast cancer survivors. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 28(35), 5147-5152.

doi:10.1200/JCO.2010.29.9230
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Study Purpose:

Evaluate the efficacy of venlafaxine versus gabapentin for hot flashes in breast cancer survivors

Intervention Characteristics/Basic Study Process:

Patients were randomly assigned to receive venlafaxine for 4 weeks, then after a 2-4 week washout receive gabapentin for 4 weeks, or to have the medications in the reverse order.    Patients were given venlafaxine 37.5 mg daily for 7 days and then 75 mg daily for 21 days.  Gabapentin was given at 300 mg at bedtime for 3 days, then 2 times daily for 3 days, then 3 times daily for 22 days.  Patients completed a hot flash diary daily.  At baseline, and at the end of each study period, they completed a symptom rating and study questionnaires.

Sample Characteristics:

  • N = 58
  • AGE   Median 55, range 39.6 - 78.7
  • MALES (%)          FEMALES (%)100%
  • KEY DISEASE CHARACTERISTICS
    • All had previous breast cancer and were from 0-20 years since diagnosis. 
    • All had history of bothersome hot flashes. 
    • 79% had hormonal therapy. 
    • 18% had previous treatment for hot flashes.

Setting:

  • SITE  Multi-site 
  • SETTING TYPE  Outpatient 
  • LOCATION Canada

Phase of Care and Clinical Applications:

PHASE OF CARE Late effects and survivorship

Study Design:

Crossover RCT

Measurement Instruments/Methods:

  • SF -36
  • Hot flash severity on VAS
  • Hot flash diary
  • Quality of Life Questionnaire

Results:

Only 38 patients completed all 4 weeks of both drugs, and 12% of those initially entered dropped out.  Of patients who provided data regarding drug preference, the majority preferred venlafaxine (p = .01).   There were no significant differences between treatments on hot flash outcomes, and hot flash scores were reduced from baseline in both groups (p<.001).  Venlaxafine was associated with loss of appetite (p<.01), nausea ( p = .02), constipation (p =.05), and fewer negative mood changes (p = .003).  Gabapentin was associated with more dizziness ( p = .005) and increased appetite (p<.001).  Hot flash scores in all subjects increased during the 2-4 weeks off therapy.  There were no serious adverse effects of the medications.

Conclusions:

  • Both gabapentin and venlaxafine reduced hot flash severity in these patients. 
  • Each medication was associated with (differing) side effects. 
  • More patients preferred venlaxafine.

Limitations:

  • Small sample (< 100)
  • Risk of bias (no blinding)
  • Subject withdrawals ≥ 10%
  • Other limitations/*explanation  It is not clear if patients or observers were blinded to treatment assignments. Subjects not stratified based on age.

Nursing Implications:

The findings suggest that either venlafaxine or gabapentin can be effective in reducing hot flash symptoms in breast cancer survivors.  More patients preferred venlafaxine.  Both drugs have side effects.

Loprinzi, C. L., Kugler, J. W., Barton, D. L., Dueck, A. C., Tschetter, L. K., Nelimark, R. A., . . . Jaslowski, A. J. (2007). 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. Journal of Clinical Oncology, 25, 308-312.

doi:10.1200/JCO.2006.07.5390
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Study Purpose:

To determine the effectiveness of Gabapentin in combination with an antidepressant for the treatment of hot flashes.

Intervention Characteristics/Basic Study Process:

Women must have been on a stable dose of antidepressant for the tx of hot flashes. In week one, patients completed a hot flash diary. In the second week, patients took 300 mg gabapentin at bedtime for 3 days, then twice daily for 3 days, then 3 times a day for 22 days. In one arm of the study patients remained on their previous dose of antidepressant and in the other arm patients weaned off antidepressants over 7-10 days and physician discretion was allowed. Patients completed a daily hot flash diary for 4 week and a weekly symptom assessment.

Sample Characteristics:

N  113       AGE   median 53.5
FEMALES  100
KEY DISEASE CHARACTERISTICS breast cancer survivors

Setting:

SITE  Single site    SETTING TYPE  Outpatient    LOCATION USA

Phase of Care and Clinical Applications:

PHASE OF CARE Late effects and survivorship

Study Design:

RCT

Measurement Instruments/Methods:

Daily hot flash diary
Numeric analog symptom scale 
0-10 hot flash distress
Linear analog self assessment QOL questionnaire

Results:

Both groups experienced a reduction in hot flashes: gabapentin = 60% reduction (95% CI, 33%-73%) and gabapentin plus antidepressant = 56% reduction (95% CI, 26%-71%)No difference between groups in hot flash scores or frequency from baseline to 4 weeks in either arm. No difference in toxicities reported by either arm. No difference in QOL in either arm.

Conclusions:

This trial failed to demonstrate that the combination of gabapentin with antidepressants is more effective to reduce the number of hot flashes experienced by breast cancer survivors.

Limitations:

Risk of bias (no control group)

Risk of bias (no blinding)

Risk of bias(sample characteristics)

Other limitations/*explanation  All breast cancer patients, no placebo arm

Nursing Implications:

The combination of gabapentin plus antidepressant does not appear to be an effective regimen to decrease hot flashes in breast cancer survivors

Loprinzi, C.L., Sloan, J., Stearns, V., Slack, R., Iyengar, M., Diekmann, B., … Novotny, P. (2009). Newer antidepressants and gabapentin for hot flashes: An individual patient pooled analysis. Journal of Clinical Oncology, 27, 2831–2837.

doi:10.1200/JCO.2008.19.6253
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Study Purpose:

Efficacy and side-effects of three relatively low gabapentin doses in comparison to placebo.

Intervention Characteristics/Basic Study Process:

Randomized to:

  • Placebo for 28 days, or
  • Gabapentin 300 mg at bedtime for 28 days, or
  • Gabapentin 300 mg at bedtime for 7 days then 300 mg twice a day for 7 days then 300 mg three times a day for 14 days

Sample Characteristics:

  • Men undergoing androgen deprivation therapy for prostate cancer with at least 14 hot flashes per week.
  • N = 223; 214 completed the study.
  • Mean age: 70 years old
  • Inclusion: Men with a history of prostate cancer on a program of androgen ablation hormone therapy four weeks prior study and planning continuation of therapy during study; bothersome hot flashes of at least 14 times per week with hot flashes present at least 1 month prior study entry; Antidepressant use at least one month prior study with continuation during study trial.
  • Exclusion: Renal insufficiency; concurrent therapies, including antineoplastic chemotherapy, androgens, estrogens, or progestational agents; previous therapy with gabapentin

Setting:

Outpatient oncology centers

Study Design:

Double-blind, placebo-controlled.

Measurement Instruments/Methods:

Hot flash frequencies and severities were recorded daily for a baseline week and for four weeks while taking the study medication; symptom experience diaries were completed weekly for five weeks; 30-item Profile of Mood States–Brief was completed at the end of the baseline week and the end of four weeks of treatment.

Results:

By the fourth treatment week, mean hot flash scores decreased from baseline in the placebo group by 4.1 units. They also decreased in the three increasing dose gabapentin groups by 3.2, 4.6, and 7.0 units. No significant difference was reported in the three combined gabapentin arms versus placebo: Wilcoxon rank-sum p values for change in hot flash scores and frequencies after four weeks of treatment were 0.10 and 0.02 comparing the highest dose gabapentin arm to the placebo arm, respectively.

Limitations:

Short follow-up period

Moraska, A. R., Atherton, P. J., Szydlo, D. W., Barton, D. L., Stella, P. J., Rowland, K. M.,Jr, . . . Loprinzi, C. L. (2010). Gabapentin for the management of hot flashes in prostate cancer survivors: a longitudinal continuation Study-NCCTG Trial N00CB. The Journal of Supportive Oncology, 8(3), 128-132.

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Study Purpose:

Examined efficacy and toxicity of gabapentin when taken for additional 8 weeks after previous study, where it was compared 3 different doses of gabapentin with placebo for treatment of hot flashes due to androgen deprivation therapy

 

Intervention Characteristics/Basic Study Process:

Self completed report by participants

Sample Characteristics:

  • N :  Evaluable 147, data for 117 
  • AGE: Mean 69.4 years old
  • MALES: (%) 100% males    FEMALES: (%) NO
  • KEY DISEASE CHARACTERISTICS: Prostate cancer  
  • OTHER KEY SAMPLE CHARACTERISTICS:  
    • Men with history of prostate cancer, on stable androgen deprivation therapy,  experiencing troublesome hot flashes
    • No renal insufficiency or previous used of gabapentin or concurrent use of any other chemotherapy or hormone treatment
       

Setting:

SITE: Mutli-site    
 

Phase of Care and Clinical Applications:

PHASE OF CARE: Transition phase after initial treatment

APPLICATIONS: Late Effects & Survivorship; End of Life and Palliative Care
 

Study Design:

Observational, open label, and uncontrolled design continuation of randomized study

Measurement Instruments/Methods:

  • Patients received a booklet containing instructions     
  • Patients received a set of hot flash diaries to be completed daily
  • Patients received symptoms experience diaries to be completed weekly, addressing adverse effects: decreased appetite, nausea, dry mouth, dizziness, fatigue, trouble walking or balance problems, muscle pain, difficulty with concentration, constipation, sleepiness/sleep problems, blurred vision, anxiety, and mood changes; also included quality of life and satisfaction with hot flash control (0 none to 10 worst)
  • Quality of Life measured by the Profile of Mood States-Brief (POMS-B)- baseline week and after he 4 weeks of treatment
     

Results:

 600 mg/d  of gabapentin moderately decreased the hot flash score without substantial toxicities.  All groups decreased hot flash scores and frequency at similar levels. Appetite loss and constipation were not increased. Troubled sleeping and nervousness scores were better in the placebo group.

Conclusions:

  • Gabapentin moderately decreases hot flash scores and frequencies without important toxicities over 8 weeks. 
  • Doses of 600-900 mg/d of gabapentin show better results for treating hot flashes than 300 mg/d.

Limitations:

  •  Continuation phase:  observational, open label, and uncontrolled

Nursing Implications:

  • Results from the study should be cautiously generalized because of patient subjective ratings.
  • The study was not controlled or randomized.
  • There was some possible recruitment bias for those patients with better adherence to medical instructions.

Pandya, K.J., Morrow, G.R., Roscoe, J.A., Zhao, H., Hickok, J.T., Pajon, E., … Flynn, P.J. (2005). Gabapentin for hot flashes in 420 women with breast cancer: A randomised double-blind placebo-controlled trial. Lancet, 366, 818–824.

doi:10.1016/S0140-6736(05)67215-7
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Study Purpose:

Assess efficacy of gabapentin in controlling hot flashes in women with breast cancer

Intervention Characteristics/Basic Study Process:

Patients were randomized to placebo, gabapentin 300 mg/day, or gabapentin 300 mg three times a day for eight weeks.

Sample Characteristics:

  • Women with breast cancer having an average of two or more hot flashes per day (N = 420).
  • Evaluable data for 371 patients at four weeks (119 placebo, 123 gabapentin 300 mg, and 129 gabapentin 900 mg) and 347 at eight weeks (113 placebo, 114 gabapentin 300 mg, 120 gabapentin 900 mg).
  • Mean age: 55 years old
  • Inclusion: Adult women with history of breast cancer and were having an average of two or more hot flashes per day; adjuvant tamoxifen use was permitted
  • Exclusion: Currently receiving chemotherapy; use of venlafaxine, clonidine, or anticonvulsants not permitted; pregnancy, breastfeeding, use of steroidal contraception, coronary insufficiency, recent history of myocardial infarction, symptomatic cardiac disease, peripheral or cerebrovascular disease, stroke, syncope, or symptomatic hypotension; hepatic dysfunction (aspartate aminotransferase concentration above twice the upper limit of normal or bilirubin concentration above the upper limit of normal), renal dysfunction (serum creatinine concentration above 1–25 times the upper limit of normal); allergy to gabapentin

Setting:

University community clinic oncology program

Study Design:

Randomized, double-blind, placebo-controlled multi-institutional trial.

Measurement Instruments/Methods:

  • Hot flash diary one week prior to study and during weeks 4 and 8 of treatment
  • Symptom inventory pretreatment, weeks 4 and 8 of treatment.

Results:

Decreases in hot flash severity scores between baseline and weeks 4 and 8, respectively were: 21% and 15% in the placebo group; 33% and 31% in the group assigned gabapentin 300 mg; and 49% and 46% in the group assigned gabapentin 900 mg. The differences between the groups were significant (p = 0.0001 at four weeks and p = 0.007 at eight weeks by analysis of covariance for overall treatment effect).

Conclusions:

Gabapentin was effective in control of hot flashes at a dose of 900 mg/day but not at a dose of 300 mg/day.

Limitations:

  • Long-term use of gabapentin not assessed 
  • Withdrawal rate of 12% at four weeks and 17% at eight weeks

Systematic Review/Meta-Analysis

Frisk, J. (2010). Managing hot flushes in men after prostate cancer--a systematic review. Maturitas, 65(1), 15-22.

doi:10.1016/j.maturitas.2009.10.017
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Purpose:

To describe hot flushes in men with prostate cancer and their treatment methods.

TYPE OF STUDY Systematic review

Search Strategy:

DATABASES MEDLINE, ISI Web of Knowledge, Cinahl & PsycINFO

KEYWORDS  Prostate cancer, androgen deprivation therapy, vasomotor symptoms, hot flashes treatment

INCLUSION CRITERIA All studies were randomized controlled studies (RCT) that addressed hot flashes (HF) in men with any stage of prostate cancer, treated with androgen deprivation therapy either medically or surgically. The studies addressed treatment for hot flashes where the main outcomes were frequency of hot flushes, distress from hot flushes, or hot flash score.

EXCLUSION CRITERIA Studies were limited to human studies and publications appearing between 1966 - 2009. Excluded were reviews & meta-analysis.

Literature Evaluated:

TOTAL REFERENCES RETRIEVED: 252

METHOD OF STUDY EVALUATION The Jadad score was used to assess the quality of the randomized controlled trial (RCT), on a five-point scale, and the QUORUM guidelines for systematic review were considered.

This summary did not include the measures that were used by the participants in reporting their hot flashes: i.e, diaries, skin temperature measurements, QOL surveys.
 

Sample Characteristics:

FINAL NUMBER STUDIED INCLUDED; N = 5   TOTAL SAMPLE SIZE: N = : 328 men were analyzed.   SAMPLE RANGE ACROSS STUDIES : Sample sizes ranged from 12 - 177.

KEY SAMPLE CHARACTERISTICS: Samples included men with prostate cancer who had undergone surgical or medical castration and were currently experiencing hot flushes.
 

Phase of Care and Clinical Applications:

PHASE OF CARE Active Treatment

APPLICATIONS Late Effects and Survivorship; Elderly Care
 

Results:

In the five studies analyzed, the treatments that were studied included cyproterone acetate (CA), megestrol acetate (MA), gabapentin, transdermal clonidine, and diethylstilbestrol (DES). Unfortunately, none of the studies analyzed the same treatment. Because the studies looked at different interventions to relieve hot flushes (HF) in castrated men with prostate cancer, it was not possible to combine the studies to strengthen the outcomes. The studies' outcomes demonstrated varying degrees of success in relieving the hot flushes: Cyproterone acetate 100 mg, once per day, yielded 75% fewer HF than placebo  (p<0.001), and 100% of men on CA had a 50% or greater reduction of mean number of HF, compared to placebo group. Megestrol acetate  20 mg, twice per day, yielded an 80% reduction of the  median number of HF compared to a 19% reduction in the placebo group (p<0.001), an 87% reduction of median HF score vs. a 16% reduction for placebo (p<0.001), and a 50% or greater reduction of median number of HF (p<0.001) reported by 79% of MA group and 12% of placebo group. Gabapentin (4 schedules) achieved a 45.5% reduction of the median number of HF with 900mg gabapentin per day vs. 21.5% with placebo (p=0.02). Transdermal clonidine demonstrated no difference between the  treated group and placebo. Diethylstilbestrol (1 mg) yielded a 100% reduction in the median number of HF vs.13% with placebo. 100% of DES and 14% of placebo reported a 50% or greater reduction of the median number of HF.

Conclusions:

The systematic review of studies on treatment approaches to managing hot flushes in men after castration for prostate cancer showed very few such studies. Only five RCT studies were identified, and none of them analyzed the same treatment approach. Several of the studies that were presented demonstrated successful treatment approaches, including DES as the most effective, followed closely by MA and CA. However, these medications are linked to side effects that are not well tolerated by all patients.

Limitations:

Only five RCT studies were identified, and none of them analyzed the same treatment approach. 

Nursing Implications:

Large randomized placebo controlled studies are needed to clarify the data and provide clearer direction to managing HF in men who have been castrated as a treatment for prostate cancer. The summary, although providing insight for possible medical management, addressed only briefly the drop-out rates due to side effects. Further investigations of the drop-out subgroup could explore correlations among the medications to reveal unacceptable side effects  in managing the participants’ hot flash symptoms. Further investigations comparing medications used and providing more specific information about measurements of QOL and hot flash reporting by participants are warranted.

Rada, G., Capurro, D., Pantoja, T., Corbalán, J., Moreno, G., Letelier, L. M., & Vera, C. (2010). Non-hormonal interventions for hot flushes in women with a history of breast cancer. Cochrane Database of Systematic Reviews, (9) CD004923.

doi: 10.1002/14651858.CD004923.pub2
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Purpose:

To assess the efficacy of non-hormonal interventions for the treatment of hot flushes in women with a history of breast cancer

TYPE OF STUDY Combined systematic review and meta analysis

Search Strategy:

  • DATABASES: CENTRAL, CINAHL, PsycINFO, LILACS, MEDLINE, EMBASE, WHO clinical trials registry combined with hand search of reference lists of reviews, included articles, conference proceedings and contacts with experts.
  • KEYWORDS:  Detailed key words by database listed in appendix - all included randomized controlled trials of therapies for vasomotor symptoms (hot flashes, night sweats) in women with breast cancer
  • INCLUSION CRITERIA: Randomized controlled clinical trials of non-hormonal interventions pertaining to women of any age experiencing hot flashes and with or without a history of breast cancer.  Studies that included women without a history of breast cancer were accepted if data on these cases was presented separately or if these women constituted <20% of the study population  
  • EXCLUSION CRITERIA: Studies of hormonal interventions and hormone-like interventions including plant phytoestrogens, black cohosh, and tibolone
  • METHOD OF STUDY EVALUATION: Evaluated studies according to the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2; Two persons evaluated each study and extracted information about the studies onto forms; Bias in studies was assessed and noted.
     

Literature Evaluated:

TOTAL REFERENCES RETRIEVED : N =1012


 

Sample Characteristics:

  • FINAL NUMBER OF STUDIES INCLUDED: N = 16    
  • KEY SAMPLE CHARACTERISTICS: All women with breast cancer and reporting vasomotor symptoms. There were inconsistencies in inclusion criteria related to number or severity of hot flashes required for inclusion.

Phase of Care and Clinical Applications:

APPLICATIONS Late Effects and Survivorship

Results:

  • Outcomes inconsistently reported across studies 
  • Outcomes included hot flash frequency, severity, bother, interference, hot flash composite scores (frequency x severity). 
  • Secondary outcomes were also inconsistently reported and included side effects, recurrence risk, and health-related quality of life

Conclusions:

  • Clonidine is effective but may have intolerable side effects.
  • Gabapentin and SSRIs/SNRIs may be effective but must be weighed against side effects, cost, dosing, and absolute benefit.
  • Vitamin E should not be recommended as it was not effective.
  • Evidence for other non-pharmacological therapies is limited.

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