Cyproheptadine

Cyproheptadine

PEP Topic 
Anorexia
Description 

Cyproheptadine is an antihistamine marketed for the treatment of various allergic problems. Cyproheptadine is a serotonin and histamine antagonist with sedative and anticholinergic effects. In early clinical trials, cyproheptadine was noted to cause unexpected weight gain. It has been marketed in Europe as a drug for weight gain and evaluated for anorexia.

Effectiveness Not Established

Guideline/Expert Opinion

Desport, J.C., Gory-Delabaere, G., Blanc-Vincent, M.P., Bachmann, P., Beal, J., Benamouzig, R., . . . Senesse, P. (2003). Standards, options and recommendations for the use of appetite stimulants in oncology (2000). British Journal of Cancer, 89(Suppl. 1), S98–S100.

doi: 10.1038/sj.bjc.6601090
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Purpose & Patient Population:

To review the literature on the use of appetite stimulants in oncology by a multidisciplinary group established by the French National Federation of Cancer Centers

Type of Resource/Evidence-Based Process:

The group conducted a literature search of four databases (MEDLINE, CancerLit, Embase, and the Cochrane Library) using search phrases: appetite stimulants, anorexia/drug therapy, cachexia/drug, or appetite associated with neoplasms. The search yielded 55 reports of randomized controlled trials (RCTs) published between 1990–1999 that evaluated the appetite-stimulating effect of corticosteroids, synthetic progestogens, or other drugs. 

The group defined standards, options, and recommendations for the use of appetite stimulants.

  • Standards: Clinical situations for which there exist strong indications or contraindications for a particular intervention.
  • Options: Situations for which there are several alternatives without clear superiority of one choice over another.
  • Recommendations: Additional information to enable the available options to be ranked using explicit criteria with an indication of the level of evidence.

They also defined the level of evidence. 

  • A: High-standard, meta-analysis, or several high-standard RCTs with consistent results.
  • B: Good-quality evidence from randomized trials or prospective or retrospective studies with consistent results.
  • C: Weak methodology of studies or inconsistent results.
  • D: Lack of scientific data or case study reports only.
  • Expert Agreement: Data do not exist for the method concerned, but the experts are unanimous in their judgment.

The primary outcome used in analysis of study results was anorexia. Secondary outcomes were improved quality of life, increase in body weight, increased food consumption, decrease in nausea and/or vomiting, and improvement in anthropometric and biologic parameters.

Guidelines & Recommendations:

Corticosteroids

Corticosteroids were found to be effective appetite stimulants. Their level of evidence was B1 (good-quality evidence from randomized trials), but optimal dose and scheduling information was lacking.

Synthetic Progestogens

Megesterol acetate: Effective appetite stimulant (level B1) and beneficial effect on body weight (level B1). Minimum effective dose is 160 mg/day (level B1). Optimal dose is 480 mg/day (level C). No greater efficacy was seen with doses higher than 480 mg/day (level B1).*

Medroxyprogesterone acetate: Effective appetite stimulant (level B1). Effect on weight was not confirmed (level C). The group recommended more clinical trials to establish optimal dose and duration of therapy.

Cyproheptadine: May be an appetite stimulant, but adverse effects were reported (level C).

Dronabinol, metoclopramide, nandrolone, pentoxifylline: No appetite-stimulating effects were shown (level C). These should be used only in the setting of RCTs.

Hydrazine sulfate: Not an appetite stimulant (level A).

Nursing Implications:

Corticosteroids and progestogens can be used in the treatment of anorexia in patients with cancer, especially in patients with advanced disease and with any type of cancer. Hydrazine sulfate should not be used.

* Data from trials completed after 1999 establish the safety and efficacy of higher doses of megesterol acetate.

Research Evidence Summaries

Kardinal, C.G., Loprinzi, C.L., Schaid, D.J., Hass, A.C., Dose, A.M., Athmann, L.M., . . . Schray, M.F. (1990). A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. Cancer, 65(12), 2657–2662.

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Intervention Characteristics/Basic Study Process:

  • Cyproheptadine 8 mg by mouth three times daily versus placebo
  • Patients stratified for
    • Primary disease site: lung, gastrointestinal, or other
    • Chemotherapy: CDDP or non-CDDP
    • Amount of RT: whole or upper abdomen

Sample Characteristics:

  • N = 293 evaluable patients (143 cyproheptadine, 150 placebo)
  • KEY DISEASE CHARACTERISTICS: The three groups entered had the following key disease characteristics.
  1. Advanced malignant disease with no definite planned cytotoxic therapy with weight loss of five pounds over two months and intake less than 20 calories/kg
  2. Same as 1 but patients receiving chemo or immunotherapy
  3. Same as 1 but receiving upper abdominal or whole abdominal RT with planned dose greater than 2500 cGy
  • EXCLUSION CRITERIA: Tube feeding or parenteral nutrition; life expectancy less than six weeks; ascites, pedal edema; mechanical obstruction; brain tumors; glaucoma; urinary hesitancy; concomitant treatment with steroids, progestational agents, and MAOI inhibitors

 

Study Design:

  • Randomized, placebo-controlled, double-blinded clinical trial

Measurement Instruments/Methods:

  • Percentage of weight change from baseline values (Patients’ weights were monitored monthly by HCP, and patients were asked to weigh themselves weekly at home.)
  • Patient appetite questionnaire
  • Food intake questionnaire
  • Perceived drug benefits and toxicities (e.g., lethargy, sedation, nausea, dry mouth)

Results:

  • Appetite improved
    • 64% of cyproheptadine
    • 50% of placebo
    • P = 0.02
  • Average maximum weight gain
    • Cyproheptadine: 0.9 pounds
    • Placebo: 0.5 pounds
    • P = 0.78
  • Average weight loss
    • Cyproheptadine: 4.5 pounds
    • Placebo: 4.9 pounds
    • P = 0.72
  • Toxicities: Lethargy, dizziness, dry mouth

Conclusions:

Cyproheptadine in patients with advanced malignant disease showed mild appetite enhancement but no significant weight enhancing effect.

Limitations:

  • Patients remained in the study for a short time. The median time in the study was 34 days with cyproheptadine and 39 days with placebo. Only 25% of the patients entered still were participating in it after three months. 
  • The intervention was done late in the disease trajectory.

Systematic Review/Meta-Analysis

Yavuzsen, T., Davis, M.P., Walsh, D., LeGrand, S., & Lagman, R. (2005). Systematic review of the treatment of cancer-associated anorexia and weight loss. Journal of Clinical Oncology, 23, 8500–8511.

doi: 10.1200/JCO.2005.01.8010
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Search Strategy:

Studies were included in the review if they reported on

  • Adult patients older than 18 years of age
  • Patients with nonhematologic malignancies
  • Patients with anorexia or symptoms of anorexia, such as lack of appetite, weight loss, poor performance status, and decreased quality of life.

Literature Evaluated:

The review involved only prospective, randomized controlled trials (RCTs; double- and single-blind or unblended and phase III trials). The quality of studies was assessed using the validated scale published by Jadad et al. (1996).

Sample Characteristics:

There were 55 studies reviewed that met the eligibility criteria.

Results:

Androgenic steroids
Androgenic steroids were studied in two studies involving 512 patients; no significant benefit was demonstrated.
 
Cannabinoids
Cannabinoids were studied in one RCT involving 469 patients; they did not confer an additional benefit.
 
Corticosteroids
Six studies investigated the use of corticosteroids in 647 patients. Some improvements in appetite were found; however, dosage and type of steroid varied such that optimal dose and duration of therapy could not be determined.
 
Cyproheptadine
Two studies investigated the use of cyproheptadine in 344 patients; these investigations had conflicting outcomes.
 
Eicosapentaenoic acid (EPA)
Three studies investigated the use of EPA in 689 patients; these reported conflicting results.
 
Erythropoietin (EPO)
EPO was investigated in two studies involving 417 patients. In one investigation, EPO was administered in combination with a COX-2 inhibitor with and without a specialized nutritional program. The intent-to-treat analysis was negative. No differences in food intake were noted.
 
Ghrelin
Ghrelin was investigated in one RCT involving seven patients; differences between groups were noted, but long-term safety data on the agent are not available.
 
Hydrazine sulfate
Five studies investigated the use of hydrazine sulfate in 796 patients. Multicenter RCTs in patients with lung and colon cancers did not demonstrate any benefit when compared to a placebo.
 
Interferon
Interferon was investigated in one study involving 57 patients; no differences were found.
 
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs were investigated in two trials involving 417 patients; these investigations failed to demonstrate a benefit in the NSAID arm.
 
Pentoxyfilline
One study investigated the use of pentoxyfilline in 70 patients and found no benefit. Melatonin was investigated in two studies involving 186 patients; these did not demonstrate any improvement in appetite or intake.
 
Progestins
Twenty-nine studies reviewed the safety and efficacy of progestins: 23 examined megesterol acetate (MA), and six investigated medroxyprogesterone acetate (MPA). Results favored progestins over placebo and found that side effects were tolerable. Ten studies assessed the influence of MA on quality of life; these demonstrated that the effect of MA on quality of life was minimal.
 
Prokinetics
Two studies investigated prokinetics for anorexia in a total of 55 patients. No improvement in caloric intake or appetite was noted.
 
Thalidomide
Thalidomide has not been investigated in prospective RCTs.

Conclusions:

Multiple RCTs have been conducted to investigate the safety and efficacy of pharmacologic agents to stimulate appetite. Only two therapeutic interventions for cancer-related anorexia demonstrated enough evidence to support their use in patients with cancer: corticosteroids and progestins. Other studies had mixed outcomes, positive results in only a single randomized trial, or were not placebo-controlled.

There is strong evidence supporting the use of progestins in patients with cancer, of which the most commonly reported drugs were MA and MPA. There was increased weight with both progestins; there was also evidence of a dose-response, but higher doses did not confer any additional benefit with regard to appetite. Metaclopromide is effective for nausea and early satiety but has not been shown to directly stimulate appetite.

The RCTs did not show sufficient evidence to justify the use of dronabinol, EPA, EPO, ghrelin, interferon, melatonin, nandrolone, NSAIDs, or pentoxyfilline in cancer-related anorexia. Cyproheptadine is a weak appetite stimulant, but side effects are limiting.

Nursing Implications:

The optimal dose, start time, and duration of treatment for many appetite stimulants are still unknown. A more systematic approach to research methodology is needed. In addition, uniform outcome measures to better assess the value of various appetite stimulants are needed. These should include subjective ratings of appetite and associated symptoms (e.g.,  early satiety) and objective measures (e.g., food consumed, weight gain, weight loss).


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