The Use of Valeriana officinalis (Valerian) in Improving Sleep in Patients Who Are Undergoing Treatment for Cancer: A Phase III Randomized, Placebo-Controlled, Double-Blind Study (NCCTG Trial, N01C5)

Disordered sleep has been found to be common in cancer survivors and to contribute to fatigue and impaired overall functioning. The true prevalence and incidence of sleep disorders in the oncology population is not well documented, though reports range from 23% to 61%.^{[1], [2], [3], [4], [5], [6], [7] and [8]} Some research suggests that sleep–wake disturbances are more prevalent in patients with cancer than in other populations.⁹ In addition, Miller and colleagues⁶ suggest that a disturbed sleep–wake cycle may well be a main predictor of, and contributor to, other symptoms such as fatigue, depressed mood, and cognitive dysfunction. Evaluating and improving sleep may have broad ramifications for cancer survivors.

Insomnia is present when there is repeated difficulty initiating or maintaining sleep or impairment in sleep quality that occurs despite adequate time and opportunity for sleep, and there is some form of daytime impairment as a result.¹⁰ Secondary insomnia is denoted when insomnia is prominent and develops in the setting of another primary medical or psychiatric illness or in the setting of a separate sleep disorder such as sleep apnea.^{[10], [11] and [12]} Sleep disturbance can be associated with poor work performance, increased anxiety and depression, poor cognitive functioning, and impairment of overall quality of life (QOL).^{[13], [14], [15] and [16]} A recent Institute of Medicine report highlighted the severe costs to individuals and society of untreated insomnia.¹⁷

Davidson and colleagues² conducted a cross-sectional descriptive study in six malignant disease clinics from a regional cancer center in Canada. Those surveyed included patients with breast, gastrointestinal, gynecological, genitourinary, lung, and nonmelanoma skin cancers. Insomnia was defined as a report of trouble sleeping on at least 7 of the previous 28 nights, interfering with daytime functioning. More patients who had treatment within the past 6 months reported insomnia, use of sleeping pills, sleeping more than usual, or fatigue. There were no differences based on type of cancer or treatment. Baker and colleagues¹⁸ surveyed 752 adult patients who had been diagnosed with 1 of the 10 most commonly occurring cancers to identify which problems cancer survivors experience in dealing with their cancer and its treatment 1 year after diagnosis. Sleep difficulties ranked fifth on the list and were reported by 48% of the sample.

Fatigue is related to sleep disturbance. Although cancer-related fatigue is not necessarily relieved by sleep or rest, insomnia and sleep disturbances clearly contribute to fatigue issues. Fatigue and sleep disturbances are undoubtedly interwoven symptoms and may be difficult to separate. It is not known how much variance in fatigue is explained by sleep problems or in what situations sleep is a major contributor.

Pharmacological Treatments for Insomnia

Because sleep complaints are common, hypnotics are among the most commonly prescribed medications for cancer patients, being prescribed for insomnia in up to 44% of patients.¹⁹ Agents most commonly used are benzodiazepine receptor agonists, including true benzodiazepines, such as flurazepam, triazolam, quazepam, estazolam, and temazepam, and the nonbenzodiazepine agents zolpidem (Ambien^®), zaleplon (Sonata^®), and eszopiclone (Lunesta^®), which decrease subjective time to sleep onset, improve sleep efficiency, decrease the number of awakenings, and increase total sleep duration.^{[20], [21], [22] and [23]} Eszopiclone, extended-release formulations of zolpidem (Ambien), and ramelteon (a melatonin receptor agonist) are approved for prolonged use in patients with chronic insomnia;²⁴ but other hypnotics lack well-established effectiveness and safety data for use beyond brief intervals in situational insomnia or as part of a combined approach using cognitive-behavioral therapy (CBT) and brief pharmacological therapy.

In general, improvements in various sleep end points with pharmacologic therapy have been modest, with mean differences in sleep latency being about 15 minutes, wake after sleep onset improving by about 26 minutes, and total sleep time improving by about 40 minutes.^{[22], [24] and [25]} Although subjective improvements are often noted, hypnotic medications are associated with a number of risks, including residual next-day hypersomnia, dizziness, lightheadedness, impaired mental status, and increased risk of falls and hip fractures, especially in elderly patients when taking longer-acting hypnotics.^{[26], [27], [28], [29], [30] and [31]} Clearly, better options to improve sleep are still needed.

The Use of Valeriana officinalis for Sleep

Valeriana officinalis is a perennial herb found in North America, Europe, and Asia. In the United States, it is primarily sold as a sleeping aid, while in Europe it is used for restlessness, tremors, and anxiety. There are three main chemicals that are thought to be the active components of the plant. These are the essential oils valerenic acid and valenol, valepotriates, and a few alkaloids. Herbal extracts of V. officinalis can be ground root, aqueous or aqueous-alcoholic extracts using 70% ethanol and herb-to-extract ratios of 4–7:1. Single recommended doses range from 400 to 900 mg at bedtime.³² Most sleep studies have used 400 or 450 mg for their trials, with a couple of dose-finding trials showing that 900 mg was not significantly better than 450 mg.^{[33] and [34]} The main impact of valerian from those studies has been on sleep latency (time to fall asleep), and this has improved more in patients who had reported a longer time to fall asleep and who considered themselves poor sleepers.^{[33], [34], [35], [36] and [37]}

Most reviews proclaim V. officinalis to be a safe herb with no drug interactions, the only adverse event being daytime sedation at higher doses.^{[38] and [39]} Anecdotal reports of side effects include headaches, nausea, heart palpitations, and benzodiazepine-like withdrawal symptoms when stopping the agent.⁴⁰ Some concern has been raised as to whether valerian might interfere with cytochrome P-450 metabolism. An article by Budzinski and colleagues reviews numerous herbs and quantitates their interaction with cytochrome P-450.⁴¹ Out of 21 herbs tested, V. officinalis ranked at the bottom of interaction potential, rating a 15 out of a possible 16 (1 being the highest, 16 being the lowest).

The cost of V. officinalis, compared to other prescription sleep aids, is less, with a 1-month supply costing around $10 per month. By contrast, zolpidem, for example, costs over $80 per month.

Therefore, based on the favorable toxicity profile, low cost, and promising but limited pilot data, this current trial was designed to evaluate 450 mg of valerian at bedtime for sleep disturbance.

Methods

The primary purpose of this trial was to assess the effect of a standardized preparation of valerian in improving sleep in patients undergoing therapy for cancer. Secondary goals were to assess its safety as well as effect on anxiety, fatigue, and activities of daily living.

Patients eligible for this trial included adults diagnosed with cancer and receiving therapy (radiation, chemotherapy, oral antitumor agents, or endocrine therapy). Patients had to report difficulty sleeping of 4 or more on a scale of 0–10, had to have a life expectancy ≥6 months, and had to have an Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0 or 1. They could not have an abnormally elevated serum glutamic-oxaloacetic transaminase (SGOT) and/or alkaline phosphatase. Patients were excluded for prior use of valerian for sleep, use of other prescription sleep aids in the past 30 days, or a diagnosis of obstructive sleep apnea or primary insomnia per Diagnostic and Statistical Manual, 4th edition (DSM-IV), criteria. Pregnant and nursing women were also excluded, as were patients with known sleep disturbance etiologies such as nighttime hot flashes, uncontrolled pain, and/or diarrhea.

Participants were randomized to receive 450 mg of oral valerian or placebo, to be taken 1 hour before bedtime for 8 weeks. The valerian used was pure ground, raw root, from one lot and standardized to contain 0.8% valerenic acid. Valerian capsules and matching placebo, a gelatin capsule, were supplied by Hi-Health (Scottsdale, AZ). Both valerian and placebo were stored in the same containers so that the placebo would acquire some of the valerian smell. Self-report booklets were completed at baseline and at weeks 4 and 8 and contained the Pittsburgh Sleep Quality Index (PSQI),⁴² the Profile of Moods States (POMS),⁴³ the Functional Outcomes of Sleep Questionnaire (FOSQ),⁴⁴ and the Brief Fatigue Inventory (BFI).⁴⁵ Assessments were scored according to the appropriate algorithms, and total and subscale scores were transformed to a 0–100 scale, with 100 being best. Self-reported symptoms were recorded weekly using a self-report numeric analogue scale, called the Symptom Experience Diary (SED). Toxicity was also assessed every 2 weeks during a clinical research associate/nurse phone call using the Common Terminology Criteria for Adverse Events (CTCAE, v 3.0).

The primary end point was the normalized (averaged) area under the curve (AUC) of the PSQI between the two arms, compared using the Kruskal-Wallis test. Secondary analyses compared AUC scores of other assessments and toxicity incidence. Toxicity comparisons were performed using the chi-squared test or the Kruskal-Wallis test, as appropriate. As an intent-to-treat (ITT) analysis, using chi-squares tests, patients were categorized as a success if there was a 10-point improvement in the assessment score at week 4 or 8 and a failure if there was no improvement or data were missing.

All hypothesis testing was carried out using a two-sided alternative hypothesis and a 5% Type I error rate. A two-sample t-test with 100 patients per group provided 94% power to detect 50% times the standard deviation (SD) of the end point under study.⁴⁶ This effect size is considered moderate and has been declared the minimally clinically significant difference for QOL end points.^{[47] and [48]}

Results

A total of 227 patients were randomized into this study between March 19, 2004, and March 9, 2007. The consort diagram depicts the flow of data (Figure 1). Twenty-three patients withdrew before starting the study treatment. Primary end-point data were available on 119 patients (62 receiving valerian and 57 receiving placebo). Baseline characteristics and baseline patient reported outcomes were well balanced between arms with no statistically significant differences ([Table 1] and [Table 2]).