Donepezil

To evaluate the effectiveness of pharmacologic interventions used for fatigue in patients with cancer

Databases searched were PaPaS, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, Dissertation Abstracts International (DAI), metaRegister of Controlled Trials (mRCT) (January 2007–October 2009). Journals searched were British Journal of Cancer, Journal of Clinical Oncology, Journal of Pain and Symptom Management, and Journal of Palliative Medicine. The reference lists of all articles were checked for additional studies. Conference abstracts also were searched.

Search keywords were neoplasms, bone marrow transplantation, cancer, carcinoma, tumour, adenocarcinoma, leukemia, lymphoma, malignant, radiotherapy, fatigue, tired, weary, weariness, exhausted, lack or loss or lost energy or vigor, apathy or lassitude or lethargy, or feeling drained, sleepy, or sluggish.

Studies were included in the review if they

• Assessed drug therapy for the management of cancer-related fatigue (CRF) compared to placebo, usual care, or a nonpharmacologic intervention.
• Were randomized, controlled trials (single-blind and open-label were allowed).
• Included adult patients with a clinical diagnosis of cancer.

This review was an update of a previous review. The updated search retrieved 647 additional references. Of those, six additional studies met the inclusion criteria. The final sample of studies included was 31.

The review included 7,104 participants who received a drug intervention for CRF.

Psychostimulants

• Four trials examined methylphenidate, and one used dexamphetamine. These included 426 patients total.
• Evidence existed of a significant effect on fatigue with methylphenidate over placebo, and evidence supported the use of psychostimulants in the treatment of CRF.
• The standardized mean difference was positive, with a small effect and narrow confidence interval (CI) (total mean difference = –0.28; 95% CI [-0.48, -0.09]; Z = 2.83; p = 0.005).
• Fatigue was measured with the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) in all studies.

Erythropoietin and Darbepoetin

• Eleven studies were combined in total and demonstrated a positive effect. The weighted mean difference of studies using the FACT-F outcome measure in erythropoietin gave a score of 4.33, which was a clinically significant difference. The conclusion was limited to patients with anemia who were undergoing chemotherapy. Greater improvement was more likely in those with lower hemoglobin levels.
• In placebo-controlled trials of darbepoetin, the mean difference using the FACT-F score was -1.96, which was less than the minimally clinical significant difference.
• Combined analysis for both agents gave a mean difference score of 3.75, which was clinically significant. 
• Erythropoietin and darbepoetin cannot be recommended because of adverse events associated with these drugs.

Antidepressants/Paroxetine

• Two studies using paroxetine and a trial using sertraline were analyzed. Analysis showed no benefit for the treatment of CRF.

Progestational Steroids

• In studies that could be combined, no evidence existed to support continued use for the treatment of fatigue.
• The clinical significance of results of ibandronate were unclear.
• One study of etanercept during chemotherapy had statistically significant results, but the study had a small sample size and poor design. It was suggested that additional trials be conducted.
• One study of donepezil showed no benefit over placebo.

Four trials of methylphenidate provided evidence for use that was supportive but associated with a small effect size in a dose of 10–20 mg per day. Serious adverse events were minimal; however, clinicians need to review contraindications before prescribing. Additional large-scale trials were suggested using methylphenidate to further evaluate use in CRF. Erythropoietin and darbepoetin can no longer be recommended for CRF because of increased adverse events associated with these drugs. No current evidence exists to support the use of steroids.

• Reviewers found major limitations in the reporting of trials and multiple methods of measuring outcomes.
• Some outcomes in trials were not reported due to extensive missing data.
• These findings point to the need for improved research reporting to meet Consolidated Standards of Reporting Trials (CONSORT) guidelines and the benefit that could be derived from use of consistent methods of measuring outcomes.

To determine the efficacy of pharmacological treatment on nonspecific fatigue in palliative care, including patients with advanced cancer and other chronic conditions associated with fatigue.

Databases searched were EMBASE, PsychLit, CENTRAL, and MEDLINE. Reference lists of identified articles were reviewed for inclusion, and textbooks were handsearched. Conference proceedings of the American Society of Clinical Oncology (ASCO) from 2000 to 2008 and the 2005 meeting of the European Cancer Conference were included in the search.

An extensive listing of keywords and specific search methods per database are provided in the article.

Studies were included in the review if

• They were randomized, controlled trials
• The primary outcome was fatigue or related terms, such as asthenia
• Participants were 18 years or older
• The study included evaluation of the effect of pharmacologic treatment of fatigue with psychostimulants, amantadine, corticosteroids, donazepine, and antidepressants if used for the treatment of fatigue. 

Studies were excluded if they studied megestrol or focused on physiologic deficiencies, such as lack of hemoglobin and use of erythropoietin.

Initial searching provided 2,000 titles. Of those, 22 met the inclusion criteria. They included data from 11 drugs:  amantadine (6), pemoline (3), methylphenidate (3), dexamphetamine (2), paroxetine (2), acetyl-L-carnitine (2), testosterone (2), fluoxetine (1), donepezil (1), modafinil (1), and acetylsalicylic acid (1). If two or more studies of the same medication could be analyzed in the same subpopulation of patients, meta-analysis was performed. Meta-analysis was performed for amantadine, pemoline, methylphenidate, and modafinil.

• The final sample of 22 studies included 1,632 patients.
• Studies were performed in patients with multiple sclerosis (MS) (10), HIV (4), cancer (6), postpolio (1), and endstage chronic obstructive pulmonary disease (COPD) (1).

Most studies showed some beneficial effect; however, a substantial similar placebo effect was often observed.

Amantadine

• Meta-analysis was conducted for three (n = 154) studies comparing amantadine to placebo in patients with MS.
• Standard mean difference (SMD) favored amantadine (SMD = 1.68; 95% confidence interval [CI] [1.24,1.92]; Z = 12.76; p < 0.00001).
• No statistically significant heterogeneity existed.
• Study samples were generally small, and several methodologic weaknesses were seen.

Pemoline

• Pemoline was used in three studies on MS.
• Meta-analysis demonstrated no benefit (SMD = –0.11; 95% CI [–0.42, 0.2]; Z = 0.71; p = 0.48).
• There was significant heterogeneity among the studies.

Methylphenidate

• Two studies in patients with cancer were included.
• There was a slightly superior effect compared to placebo (SMD = 0.49; 95% CI [0.15, 0.83]; Z = 2.86; p = 0.004).
• There was significant heterogeneity.

Dextroamphetamine

• Two studies compared the drug to placebo in patients with cancer. No significant benefits were seen.

Paroxetine

• There were no significant effects demonstrated in one study in patients with COPD and one in patients with cancer.

Testosterone

• No significant effects were demonstrated in studies on HIV.

Acetyl-L-carnitine

• No significant effects were shown in one study on cancer and one on MS.

Modafinil

• Meta-analysis in two studies on MS showed no significant effect.

Donepezil

• One study in 142 patients with cancer showed no benefit compared to placebo.

Other

• Fluoxetine was inferior to testosterone in one study on HIV.
• Acetylsalicylic acid was associated with relief of fatigue compared to placebo in one study on MS.

Methylphenidate and amantadine showed promise for reducing fatigue in patients with advanced disease. Amantadine has not been studied in patients with cancer-related fatigue, but it has been shown to be effective in patients with MS. The meta-analysis included only a few studies and the evidence was weak, pointing to the need for additional research in this area. It is not clear whether amantadine would be useful for patients with cancer, as this has not been studied.

The analysis was performed only in palliative care populations and did not include studies of methylphenidate in patients with cancer during active treatment, which also have shown some efficacy. However, side effects included insomnia, anorexia, behavior change, and vertigo in studies reviewed with methylphenidate. In addition, although statistically significant, effect sizes were small. These findings suggest that use in patients with cancer, who also may experience anorexia and sleep disorders from other causes, has potential benefits that would need to be balanced with potential adverse effects. Carnitine, acetylsalicylic acid, and modafinil have been used in a few studies with positive results. These drugs warrant additional investigation to confirm efficacy in different patient populations with fatigue.

Patients received either donepezil or placebo (5 mg) orally every morning for seven days. A research nurse contacted patients by daily telephone calls to assess symptoms and treatment toxicity. Patients were evaluated at the clinic on day 8. Patients returned for a final assessment on day 15, and those who chose to continue taking donepezil were provided with a two-week supply of the drug. Fatigue outcomes were assessed at baseline, day 8, and day 15.

• N = 142; 103 patients were assessable for the final analysis
• MEAN AGE = 56 years
• FEMALES: 65%
• KEY DISEASE CHARACTERISTICS: Patients with advanced cancer, defined as locally recurrent or metastatic; the primary cancer site was most often breast.
• EXCLUSION CRITERIA: Women who were pregnant or lactating, use of tube feeding, cardiac complications, urinary incontinence, presence of concurrent nausea, vomiting, diarrhea, major contraindication to donepezil, major changes expected in the next seven days, administration of anticholinergic agents, hemoglobin less than 1 g/dL within four weeks before enrollment

• Patients were recruited from palliative care or pain clinics at the MD Anderson Cancer Center and the Lyndon B. Johnson General Hospital.

• Active treatment

• Prospective, open-label, pilot, double-blind, randomized, placebo-controlled trial
  • Donepezil intervention (N = 47)
  • Placebo (N = 56)

• Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F)

The donepezil intervention did not show any improvement in fatigue in comparison to the placebo, as no significant difference was seen between groups at baseline and on day 8 for FACIT-F fatigue intensity scores.

• Small sample size
• Intervention only lasted a week, so long-term effects of donepezil remain unknown.

Donepezil 5 mg every morning for seven days

• N = 27
• MEDIAN AGE = 52 years (range: 24–75 years)
• FEMALES: 67%
• KEY DISEASE CHARACTERISTICS: Mixed cancer diagnoses, including hematologic, gastrointestinal, lung, head and neck, and breast
• OTHER KEY SAMPLE CHARACTERISTICS: Median oral morphine-equivalent daily dose was 180 mg per day (range: 30–600)

• SETTING TYPE: Mixed inpatient and outpatient
• LOCATION: Academic cancer center

• PHASE OF CARE: Unclear

• Open label, prospective, non-randomized pilot study 
• No comparison/control group

• Edmonton Symptom Assessment Scale (ESAS)
• Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue)

Fatigue significantly was improved following a seven-day course of treatment with donepezil. Significant improvement was noted in anxiety, well-being, sleep problems, depression, and anorexia. Pain level was unchanged. Of the initial 27 patients enrolled in the study, 7 patients were discontinued from the study due to cellulitis (1 patient), concern about a possible drug-drug interaction (1 patient), transient arterial hypertension (1 patient), increasing muscle cramps (1 patient), and mild to moderate nausea (3 patients).

• Open-label trial without a comparison group
• Small sample size
• Short length of treatment and minimal follow-up to examine longer-term side effect profile

Participants initially were given donepezil 5 mg per day. After 6 weeks, dosage was increased to 10 mg per day for a total of 18 weeks. Treatment then was discontinued for a six-week washout period. Patients, therefore, served as their own control at two points (baseline and post-washout). After week 30, patients were given the choice to continue using donepezil at 10 mg per day. Patient outcomes were assessed at baseline and at week 6, 12, 24, and 30 (following the washout period).

• N = 35 enrolled (24 patients remained on the study and completed all assessments)
• MEDIAN AGE = 45 years
• KEY DISEASE CHARACTERISTICS: All had primary brain tumor, mostly low-grade glioma
• FEMALES: 46%
• OTHER KEY SAMPLE CHARACTERISTICS: 92% white, 8% black. Patients who remained on the study did not differ significantly at baseline from the patients who dropped out on the measures of sex, race, mood, and cancer-related quality of life. Patients remaining on the study were significantly younger than those who dropped out.
• EXCLUSION CRITERIA: Less than 18 years of age, life expectancy of less than 30 weeks, received partial or whole brain radiation less than six months before enrollment, imaging evidence of tumor progression in the previous three months, brain tumor treatment planned during course of study

• Wake Forest University School of Medicine in Winston-Salem, NC

• Active treatment

• Open-label, phase II clinical trial

• Profile of Mood States (POMS)

The donepezil intervention group demonstrated a significant improvement in fatigue from baseline to 24 months as shown by the POMS subscale for fatigue (p = 0.03).

• Lack of a neutral comparison group
• Possible that observed improvement is result of “practice effect,” as participants were required to fill out forms four times over a 7.5-month time period