Carnitine/L-Carnitine

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.

Carnitine is hypothesized to be key in the energy metabolism and regulation of adenosine triphosphate (ATP) promotion and a protective effect of mitochondrial metabolism. Carnitine deficits are common in cancer patients and other chronically ill persons.
 

L-carnitine supplementation was given in dose levels of 250 mg/day. Dose levels were planned to increase by 500 mg until the target dose of 3000 mg/day was reached.

Of 645 adult patients, 13% met following inclusion criteria:

• Age of at least 18 years
• Greater than 3 month life expectancy
• Self-reported fatigue was moderate to severe for at least one week
• Carnitine deficiency
• Karnofsky Performance Status (KPS) of 50% or greater.

Patients were excluded from the study if they had severe disease, brain tumor, or stroke; were unable to complete the assessment tools; had started erythropoietin within less than 3 months; had received radiotherapy or chemotherapy within one week prior to the study; or were unable to consent.

Hospice and Cancer Center

The study used an open-label, dose-finding, safety design, with dose cohorts of three.

• Brief Fatigue Inventory (BFI)
• Center for Epidemiological Studies Depression Scale (CESD)
• Quality of sleep
• Epworth Sleepiness Scale (ESS)
• KPS

• Of the patients, 83% reported fatigue with a significant decrease in BFI score after one week (p = .009).
• CESD decreased (p = 0.028).
• ESS decreased (p = 0.015).
• No significant change occurred in KPS.
• Dose was safely escalated to 1750 mg/d.

• The study had a small sample size.
• Hospice patients often have multiple medical problems. 
• Three higher dose levels were not reached.
• Treatment length was short (one week). 
• The effect of prolonged use is unknown.
• No monitoring of dietary carnitine was performed.
• It is unknown if L-carnitine supplementation accelerates cancer or interferes with the effects of certain agents.

Cost of supplements and monitoring levels of L-carnitine is unknown.

Carnitine deficiency is among the many metabolic disturbances that may contribute to fatigue in patients with cancer. Administration of exogenous L-carnitine may hold promise as a treatment for this symptom. Carnitine was prepared by the institutional pharmacy at a concentration of 1 g/mL. The drug was administered in two daily doses for seven days. After the intervention period, patients were allowed to continue L-carnitine supplementation if desired. Patient outcomes were evaluated at baseline and on day seven.

• In total, 27 patients (37% female) with advanced cancer were included.
• Mean age was 59.7 years.
• The majority of patients were Caucasian (59%).
• The most common diagnosis was breast cancer (22%).
• Most patients reported severe fatigue (70%), and all were carnitine-deficient.
• Patients were excluded from the study if they had hemoglobin levels less than 9 g/dL, had increased risk of seizure or heart failure, were receiving current treatment (chemotherapy, radiotherapy, or recombinant erythropoietin), or had renal insufficiency.

Beth Israel Medical Center Continuum Hospice Care, Jacob Perlow Hospice, or the Cancer Center

Patients were undergoing the active treatment phase of care.

The study was an open-label, phase I/II clinical trial.

Brief Fatigue Inventory (BFI)

Patients who received the L-carnitine intervention experienced a significant decline in fatigue (p < 0.001) as BFI scores decreased from baseline (66.1 [standard deviation (SD) = 12]) to one week after treatment to (39.7 [SD = 26]).

• Of the 85 patients who were eligible for study, 47 elected not to participate, the most common reason being that patients were interested in trials that aimed to treat their condition and were less interested in symptom management studies.
• The study lacked a neutral comparison group.
• The assessment of side effects did not rely on validated measures, and a range of potential safety measurements, such as repeated liver function tests, were not performed.

To determine the efficacy of L-carnitine supplementation for fatigue in patients with cancer.

Patients were randomized to receive 1 g of L-carnitine liquid twice daily for four weeks or placebo.  For weeks five to eight, all patients received L-carnitine in an open-label extension. Outcome measures were assessed at baseline and at weeks four and eight.

• In total, 237 patients (42% male, 58% female) were included.
• Age was not reported.
• Disease types were not reported.
• About 80% of patients were currently receiving chemotherapy and 18% were receiving radiotherapy. Slightly less than one-third were receiving antidepressants. 

• Multisite 
• Outpatient 
• United States

Patients were undergoing the active antitumor treatment phase of care.

The study was a randomized, double-blind, placebo-controlled, phase III trial followed by a four-week open-label extension.

• Brief Fatigue Inventory (BFI)
• Center for Epidemiologic Studies Depression Scale (CESD)
• Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
• Eastern Cooperative Oncology Group (ECOG) performance status
• Blood sample analysis for plasma carnitine and acylcarnitine
   

The group receiving L-carnitine had a greater increase in plasma carnitine levels. At week four, one-third of those on placebo were carnitine-deficient, compared to 11% of those who were receiving carnitine (p ≤ 0.001). BFI scores improved significantly in both groups by approximately one point (p < 0.001). There were no differences between groups in fatigue, depression, or pain. Over time, there was a significant decrease in the proportion of patients with severe fatigue, pain, and depression; however, there were no significant differences between groups. There were few high-grade toxicities. In one patient, the cause of death was possibly related to treatment.

Supplementation of 1 g of L-carnitine did not improve fatigue, pain, or depression in these patients.

Of the patients, 25% to 30% had missing outcome data; however, power analysis showed that the sample size was sufficient.

The findings showed that dietary supplementation with L-carnitine did not improve fatigue, depression, or pain in patients with cancer. Nurses can advise patients that this approach has not been shown to be helpful, as these results provide strong evidence that L-carnitine is not effective for these symptoms.

Carnitine is a cofactor required for cell energy production that serves as the primary fuel source for heart and skeletal muscles. Cancer-related anorexia/cachexia syndrome (CACS) and oxidative stress (OS) are two prominent features in patients with advanced cancer; therefore, L-carnitine supplementation was tested in patients with advanced cancer. Based on the current knowledge of carnitine use, patients took three doses (2 g) of L-carnitine orally each day for four weeks. Patient outcomes were evaluated at baseline (T0), week two (T1), and week four (T2).

• Twelve patients with locally advanced or metastatic disease were included.
• Mean age was 60 years (range 42–73).
• The majority of patients were women (n = 10) with mixed tumor sites (most common being gynecological cancer), and most were receiving concomitant chemotherapy (n = 10). 
• Patients were excluded if they had an Eastern Cooperative Oncology Group (ECOG) performance status of greater than 2, had insulin-dependent diabetes mellitus, or were pregnant.

Patients were undergoing the active treatment phase of care.

The study was an open-label, nonrandomized trial. 

Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF)

The L-carnitine intervention resulted in improved fatigue outcomes. The observed decline in MFSI-SF fatigue scores was statistically significance at both T1 (p < 0.05) and T2 (p < 0.001) in comparison to the baseline scores. Mean MFSI-SF scores at T0, T1, and T2 were 25.40 (standard deviation [SD] = 13.91), 16.93 (SD = 11.92), and 12.05 (SD = 12.56), respectively. Evaluation of subscales showed a statistically significant difference from T0 to T1 for the General subscale (p < 0.05) and the Physical subscale (p < 0.05).

• The study had a small sample size. 
• The study lacked a neutral comparison group.

L-carnitine is essential for glucose and lipid turnover and has a role in maintaining energy metabolism.

A high daily fractionated dose ​L-carnitine 2-g solution was given twice daily (BID) for seven days. Ifosfamide and cisplatin cause increased renal excretion and alter the usual enzyme pathways, potentially causing asthenia with impaired energy metabolism.

The study included 50 nonanemic adults with stage IV solid tumors receiving combination chemotherapy, including ifosfamide or cisplatin, with palliative treatment intent.

Not described

The study used a prospective, nonrandomized, single-arm trial, open-label, pre-/posttest design.

Functional Assessment of Cancer Therapy-Fatigue (FACT-F), 13 items with ratings from zero to four

All 50 patients were evaluable; 20 patients had fatigue at the first cycle and 30 had fatigue at the second cycle. L-carnitine levels were greater than 30 μm in 100% of the patients, and it was well tolerated. Fatigue was ameliorated in 90% (n = 45) with L-carnitine (p < 0.001). Of the nonresponders, three patients were stable and two got worse.

• The study had a small sample size.
• The study used a nonrandomized design.
• No comparison group was included.
• L-carnitine depletion may not be the primary cause of fatigue experienced by these patients.
• L-carnitine could be resupplied through diet, which was not monitored.
• Urinary loss of L-carnitine may be asymptomatic.

Cost of supplements and monitoring levels of L-carnitine is unknown.

All patients received basic treatment with polyphenols (300 mg/day) from alimentary sources (e.g., onions, apples, oranges, red wine, and green tea) or supplementary tablets. Patients also received antioxidant agents (a-lipoic acid and carbocisteine), as well as vitamins A, C, and E, orally. All patients then were randomized to one of the following five treatment arm interventions:

1. Progestational agent medroxyprogesterone acetate (MPA) 500 mg/day or megestrol acetate (MA) 320 mg/day
2. Oral supplementation of eicosapentaenoic acid (EPA)-enriched nutritional supplements, with docosahexaenoic acid, high-calorie, and high-protein content
3. L-carnitine 4 g/day, orally
4. Thalidomide 200 mg/day, orally
5. MPA or MA plus pharmacologic nutritional support, L-carnitine, and thalidomide.

The planned treatment duration was four months. Patient outcomes were evaluated at 4, 8, 16, and 24 weeks.

• The sample was comprised of 125 adult patients with cancer and cancer cachexia (mean age = 69.1 years [range 35–80]).
• The male/female ratio was 74/51.
• A majority (83%) of patients experienced more than 5% weight loss before study entry and were stage IV (94.4%).
• Patients had varied diagnoses, the most common being lung (14.4%) and breast (14.4%) cancer.
• Patients were excluded if they were women of child-bearing age, had significant comorbidities, had a mechanical obstruction to feeding, underwent medical treatments that induced significant changes to body metabolism or weight, or had contradiction to MPA or MA.

Policlinico Universitario and Ospedale Oncologico Regionale, Cagliari, Italy

The study was a randomized, phase II, two-center clinical trial with five treatment arms.

Multidimensional Fatigue Symptom Inventory–Short Form (MFSI-SF)

When comparing baseline and posttreatment measures, statistically significant improvements in fatigue outcomes were observed in the L-carnitine treatment arm (p = 0.039) and the MPA/MA plus pharmacologic nutritional support, L-carnitine, and thalidomide arm (p = 0.015). Fatigue worsened significantly in patients receiving EPA-enriched oral supplementation treatment (p = 0.051).

• No placebo arm was included because an approved drug for cancer cachexia treatment was available at the time of study (MPA or MA).
• The results were from an interim report.