Clonidine

Clonidine

PEP Topic 
Hot Flashes
Description 

Clonidine is in a class of medications called centrally acting alpha-agonist hypotensive agents. It is a sympatholytic that decreases heart rate and cardiac output and relaxes the blood vessels. Clonidine comes as a tablet to take by mouth. Clonidine has been studied for its effect in treatment of hot flashes. 

Effectiveness Not Established

Research Evidence Summaries

Boekhout, A. H., Vincent, A. D., Dalesio, O. B., van den Bosch, J., Foekema-Tons, J. H., Adriaansz, S., . . . Schellens, J. H. (2011). Management of hot flashes in patients who have breast cancer with venlafaxine and clonidine: a randomized, double-blind, placebo-controlled trial. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 29(29), 3862-3868.

doi:10.1200/JCO.2010.33.1298
Print

Study Purpose:

Evaluate the efficacy of venlaxafine and clonidine for hot flashes in patients with breast cancer

Intervention Characteristics/Basic Study Process:

Patients were randomly assigned to receive 75 mg venlafaxine,  0.1 mg clonidine, or placebo daily.  Subjects were stratified by age, duration of hot flashes, concurrent endocrine therapy, and previous chemotherapy.   Patients were treated for 12 weeks.  Hot flash scores at week 12 were compared among the three groups.

Sample Characteristics:

N  80 AGE   Median = 49, range 28-71

MALES (%)          FEMALES (%)100%

KEY DISEASE CHARACTERISTICS 31% had age related symptoms, and 99% were post menopausal after breast cancer treatment.  52% received endocrine treatment
 

Setting:

SITE  Multi-site  SETTING TYPE  Outpatient  LOCATION Netherlands

Phase of Care and Clinical Applications:

PHASE OF CARE Late effects and survivorship

Study Design:

 Double blind placebo controlled RCT

Measurement Instruments/Methods:

  • Daily diary of frequency and severity of hot flashes - mild, moderate, severe categorization and calculation of daily hot flash scores
  • Groningen Sleep Quality Index
  • Hospital Anxiety and Depression Score
  • Sexual Activity Questionnaire
     

Results:

Hot flash scores were lower in the clonidine group than the placebo group at week 12 ( p = .03), and lower in the venlaxafine group than placebo, though not statistically significant ( p = .07).  Over the 12-week period, reduction in the venlaxafine group was 41% ( P<.001), 26% in the clonidine group ( p=.045), and 29% in the placebo group (p<.001).  Those on venlaxafine tended to have some loss of appetite ( p = .003) as well as symptoms of nausea.  Sleep and sexual function were not different between the two treatment groups.  At week 12, anxiety and depression scores were higher in the venlafaxine than the clonidine group. (p = .03).  Significantly lower hot flash scores began in the venlafaxine group compared to placebo in weeks 1-4 (p =.01), and in the clonidine group, lower scores began compared to placebo in weeks 5-8 ( p = .04)

Conclusions:

Both venlafaxine and clonidine were slightly more effective than placebo in reducing hot flash symptoms in this group of patients. However, over the 12 weeks, all study groups showed significant reduction in symptoms.

Limitations:

  • Questionable protocol fidelity
  • Other limitations/*explanation  Authors state that the final sample was underpowered.  It is noted that not all patients were compliant with the medications, but is not clearly stated how compliant they were or were not.  No information is given regarding any missing diary data, and reliability of diary and self-report of severity of hot flashes is not clear.  Follow up period was relatively short, so longer term efficacy is not clear.

Nursing Implications:

Findings suggest that venlafaxine and clonidine may be of benefit in reducing hot flash symptoms in women with breast cancer. However, further research is needed for support, because placebo group also showed reduction in hot flashes. Some patients did have side effects from these medications; patients should be monitored for nausea, changes in appetite, anxiety, and depression if these medications are used.

Buijs, C., Mom, C.H., Willemse, P.H., Marike Boezen, H., Maurer, J.M., Wymenga, A.N., … Mourits, M.J. (2009). Venlafaxine versus clonidine for the treatment of hot flashes in breast cancer patients: A double-blind, randomized cross-over study. Breast Cancer Research and Treatment, 115, 573–580.

doi:10.1007/s10549-008-0138-7
Print

Study Purpose:

Comparison of venlafaxine versus clonidine for the treatment of hot flashes with regard to side effects, efficacy, QOL, and sexual functioning in patients with breast cancer.

Intervention Characteristics/Basic Study Process:

Patients randomly assigned to receive venlafaxine for eight weeks, followed by a wash-out period of two weeks, then eight weeks of clonidine or vice versa

Sample Characteristics:

N = 60 (30 assigned to venlafaxine and 30 to clonidine). Patients with a primary or metastatic breast cancer age 60 years or younger, allowed antitumor hormonal treatment if started one month prior and continued taking throughout treatment period.

Study Design:

Double-blind, randomized, cross-over study.

Measurement Instruments/Methods:

Assessment took place before the start of each drug, then at 2, 8, 12, 18 weeks after treatment began. Six questionnaires were used to compare the drugs' effects on adverse events, efficacy, QOL, and sexual functioning: daily diary on hot flashes, hot flash–related daily interface questionnaire, Medical Outcomes Study Short Form (SF-36), sexual activity questionnaire, and Zung Self-Rating Depression Scale.

Results:

Forty patients completed all treatments, 12 patients only one treatment, 8 patients neither. Dropout rates during venlafaxine were 15 out of 59, versus clonidine, 5 out of 53. Withdrawal rateswere not affected by sequence of treatment. Efficacy: After eight weeks, no difference was seen between the two drugs in reduction of hot flash scores: median 49% for venlafaxine and 55% for clonidine. The drug that the patient received first caused the greatest reduction in hot flash score.

Limitations:

Statistics: based on the testing used to calculate the number of patients needed to detect differences, the sample size was too small to detect difference, which may be the reason no statistical difference was  found between the interventions.

Goldberg, R.M., Loprinzi, C.L., O’Fallon, J.R., Veeder, M.H., Miser, A.W., Mailliard, J.A., … Burnham, N.L. (1994). Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. Journal of Clinical Oncology, 12, 155–158.

Print

Study Purpose:

The study evaluated transdermal clonidine for alleviating tamoxifen-induced hot flashes in women with a history of breast cancer.

Intervention Characteristics/Basic Study Process:

Four weeks of transdermal clonidine (equivalent to a daily oral dose of 0.1mg) was followed by four weeks of placebo patches or vice versa. Patches were changed weekly.

Sample Characteristics:

The study enrolled 116 women with a mean age of 54 years who were receiving tamoxifen for breast cancer experiencing hot flashes and requesting intervention; experiencing hot flashes for longer than one month and at least seven per week. One hundred ten (110) of the 116 completed the study. Participants were stratified by age, duration of hot flash symptoms, and the average frequency and severity of hot flashes.

Study Design:

This was a randomized, double-blind, crossover prospective study.

Measurement Instruments/Methods:

The study employed the following measures:

  • Daily self-administered patient questionnaires
  • Weekly questionnaires
  • Nurse assessment every two to three weeks for compliance, toxicity profile, and standard questions
  • Hot flash severity and frequency measures and combined hot flash score

Results:

The study showed a statistically significant decrease in hot flashes (frequency and severity) (p < .0001), and clinically moderate decreases in frequency (20%) and severity (10%). Toxicities included dry mouth (p < .001) and constipation (p < .02).

Limitations:

Small study size limited the value of the outcomes.

Loibl, S., Schwedler, K., von Minckwitz, G., Strohmeier, R., Mehta, K.M., & Kaufmann, M. (2007). Venlafaxine is superior to clonidine as treatment of hot flashes in breast cancer patients—A double-blind, randomized study. Annals of Oncology, 18, 689–693.

doi:10.1093/annonc/mdl478
Print

Study Purpose:

Compare venlafaxine to another nonhormonal agent in the treatment of hot flashes in patients with breast cancer

Intervention Characteristics/Basic Study Process:

Patients were randomized to receive 0.075 mg clonidine twice daily or venlafaxine 37.5 mg twice daily for four weeks then crossover.

Sample Characteristics:

  • Women with breast cancer experiencing hot flashes at least 14 times per week (N = 80). 64 patients completed study 
  • Majority older than age 50 years 
  • 40 randomized to each group.
    • 33 received clonidine, 31 received venlafaxine 
    • 9 stopped early because of side-effects
    • 7 withdrew
  • Inclusion:
    • Adult women with primary breast cancer experiencing hot flashes at least 14 times per week or must have been seeking help for hot flashes. Hot flashes present at least four weeks before study entry.
    • Predefined menopausal status as not required.
    • Tamoxifen, gonadotropin-releasing agonists, and aldose reductase inhibitors  allowed as long as the patients had been on such therapy for at least a month and were planning to continue therapy during study.
    • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Exclusion:
    • Previous treatment with venlafaxine and clonidine as well as estrogens, progestagens, or androgens for hot flashes
    • Current treatment with hypertensive or antidepressant agents, other nonhormonal agents for hot flashes such as black cohosh, isoflavones, and vitamin E 
    • Patients with hypertension or hypotension, peripheral or cardiovascular diseases, or symptomatic cardiac diseases

Setting:

University hospital setting

Study Design:

Double-blind, randomized study

Measurement Instruments/Methods:

  • Self-reported one-week hot flash and other symptom questionnaire assessed one week before start of treatment and end of treatment.
    • Hot flashes: frequency and severity
    • Symptoms assessed: Loss of appetite, mouth dryness, nausea, tiredness, constipation, restless sleep, nervousness, sweating, dizziness, mood disorder, diarrhea, sleeplessness

Results:

At end of week 4, the median hot flash frequency dropped by 7.6 hot flashes per day for patients receiving venlafaxine and 4.85 hot flashes for those receiving clonidine (p = .025). Nausea was significantly greater with venlafaxine compared with clonidine. Mouth dryness, constipation, and restless sleep were reported more with clonidine but the difference was not statistically significant.

Limitations:

  • Small sample size with less than 100 participants 
  • Short follow-up period

Pandya, K.J., Raubertas, R.F., Flynn, P.J., Hynes, H.E., Rosenbluth, R.J., Kirshner, J.J., … Morrow, G.R. (2000). Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: A University of Rochester Cancer Center community clinical oncology program study. Annals of Internal Medicine, 132, 788–793.

doi: 10.7326/0003-4819-132-10-200005160-00004
Print

Study Purpose:

The study evaluated oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes.

Intervention Characteristics/Basic Study Process:

Participants received oral clonidine hydrochloride 0.1 mg daily or placebo at bedtime for eight weeks.

Sample Characteristics:

The study enrolled 198 postmenopausal women (mean age 71 years) with breast cancer taking tamoxifen and stratified by time since menopause (less than three years, more than three years), duration of tamoxifen use (less than one year; longer than one year), and baseline frequency of hot flashes (less than 10 per day, more than 10 per/day). One hundred forty-nine (149) completed the study. Of the participants, 99 received clonidine and 99 received the placebo.

  • Inclusion criteria:
    • Postmenopausal women who had been receiving adjuvant tamoxifen therapy for breast cancer for at least one month and reported at least one hot flash per day
    • Normal hepatic and renal function
  • Exclusion criteria:
    • Premenopausal women 
    • Women receiving concurrent chemotherapy or endocrine therapy for breast cancer, hypertension therapy or concurrent treatment with monoamine oxidase inhibitors; L-dopa, piribedil, tricyclic antidepressants, or sedatives
    • Coronary insufficiency, recent history of myocardial infarction (within three months), symptomatic cardiac disease, peripheral or cerebrovascular disease, syncope, or symptomatic hypotension
    • Allergy or adverse reaction to clonidine

Setting:

A community oncology clinic conducted the study.

Study Design:

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

Measurement Instruments/Methods:

Measures included:

  • Daily hot flash diary for one week at baseline, during the weeks 4 and 8 during treatment, and four weeks after the end of treatment
  • Symptom checklist

Results:

One hundred forty-nine (149) of 198 completed 12 weeks of follow-up (73 in clonidine group and 76 in placebo group.) Oral clonidine was shown to be effective. The mean decrease in hot flash frequency was greater in the clonidine group after week 4 (37% to 20%) and week 8 (38% to 24%). The clonidine group had more difficulty with sleep (41%–21%). A significant difference was seen in the mean change in QOL scale (p = 0.02) at 8 weeks.

Limitations:

Limitations included:

  • Evaluation for eight weeks
  • No evaluation of long-term effectiveness

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
Print

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
Print

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.

Menu