User login
Original research
Debra L. Barton RN, PhD, AOCN, FAAN
Abstract
Sleep disorders are a substantial problem for cancer survivors, with prevalence estimates ranging from 23% to 61%. Although numerous prescription hypnotics are available, few are approved for long-term use or have demonstrated benefit in this circumstance. Hypnotics may have unwanted side effects and are costly, and cancer survivors often wish to avoid prescription drugs. New options with limited side effects are needed. The purpose of this trial was to evaluate the efficacy of a Valerian officinalis supplement for sleep in people with cancer who were undergoing cancer treatment. Participants were randomized to receive 450 mg of valerian or placebo orally 1 hour before bedtime for 8 weeks. The primary end point was area under the curve (AUC) of the overall Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes included the Functional Outcomes of Sleep Questionnaire, the Brief Fatigue Inventory (BFI), and the Profile of Mood States (POMS). Toxicity was evaluated with both self-reported numeric analogue scale questions and the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Questionnaires were completed at baseline and at 4 and 8 weeks. A total of 227 patients were randomized into this study between March 19, 2004, and March 9, 2007, with 119 being evaluable for the primary end point. The AUC over the 8 weeks for valerian was 51.4 (SD = 16), while that for placebo was 49.7 (SD = 15), with a P value of 0.6957. A supplemental, exploratory analysis revealed that several fatigue end points, as measured by the BFI and POMS, were significantly better for those taking valerian over placebo. Participants also reported less trouble with sleep and less drowsiness on valerian than placebo. There were no significant differences in toxicities as measured by self-report or the CTCAE except for mild alkaline phosphatase increases, which were slightly more common in the placebo group. This study failed to provide data to support the hypothesis that valerian, 450 mg, at bedtime could improve sleep as measured by the PSQI. However, exploratory analyses revealed improvement in some secondary outcomes, such as fatigue. Further research with valerian exploring physiologic effects in oncology symptom management may be warranted.
Article Outline
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]).
| VALERIAN (N = 102) | PLACEBO (N = 100) | P | |
|---|---|---|---|
| Gender | 0.387 | ||
| Female | 82 (80%) | 85 (85%) | |
| Age (years) | 0.546 | ||
| Mean (SD) | 59.5 (11.95) | 58.3 (12.71) | |
| Sleep scale group | 0.963 | ||
| Mildly impaired | 67 (66%) | 66 (66%) | |
| Moderately or severely impaired | 35 (34%) | 34 (34%) | |
| Sleep scale score | 0.841 | ||
| Mean (SD) | 6.6 (1.43) | 6.6 (1.69) | |
| Primary tumor site | 0.526 | ||
| Breast | 64 (63%) | 66 (67%) | |
| Colon | 9 (9%) | 5 (5%) | |
| Prostate | 3 (3%) | 1 (1%) | |
| Other | 25 (25%) | 27 (27%) | |
| Tumor status | 0.322 | ||
| Resected with no residual | 64 (64%) | 71 (71%) | |
| Resected with known residual | 17 (17%) | 12 (13%) | |
| Unresected | 19 (19%) | 13 (14%) | |
| Treatment type | 0.966 | ||
| Radiation therapy | 6 (5.9%) | 6 (6%) | |
| Parenteral chemotherapy | 38 (37%) | 39 (39%) | |
| Oral therapy | 40 (39%) | 40 (40%) | |
| Combined modality | 18 (18%) | 15 (15%) | |
| Concurrent radiation | 0.926 | ||
| Yes | 23 (23%) | 22 (22%) | |
| Concurrent cancer therapy | 0.679 | ||
| Yes | 56 (55%) | 52 (53%) | |
| Planned or concurrent hormone | 0.667 | ||
| Yes | 51 (51%) | 53 (54%) |
| VALERIAN (N = 101) | PLACEBO (N = 96) | P | |
|---|---|---|---|
| PSQI total1 | 0.695 | ||
| Mean (SD) | 41.3 (13.92) | 42.4 (14.97) | |
| POMS-SF total | 0.883 | ||
| Mean (SD) | 65.0 (14.28) | 63.9 (16.46) | |
| FOSQ total | 0.927 | ||
| Mean (SD) | 73.7 (16.07) | 72.8 (18.37) | |
| Fatigue Now | 0.285 | ||
| Mean (SD) | 45.7 (24.41) | 49.4 (25.00) | |
| Usual Fatigue | 0.216 | ||
| Mean (SD) | 46.8 (23.27) | 51.1 (24.73) | |
| Worst Fatigue | 0.522 | ||
| Mean (SD) | 35.2 (24.67) | 37.9 (26.37) | |
| Total Interference | 0.268 | ||
| Mean (SD) | 61.4 (25.05) | 57.1 (27.37) |
The primary end point of treatment effectiveness was measured using the normalized AUC calculated using baseline, week 4, and week 8 PSQI total scores. The Wilcoxon rank-sum test P value for the total PSQI score was nonsignificant (valerian AUC = 51.4, SD = 16; placebo AUC = 49.7, SD = 15; P = 0.696) (Figure 2). Similarly the FOSQ was not significantly different between groups either overall or on any subscale score.
Supplemental and exploratory analyses using changes from baseline, however, showed a significant difference in the change from baseline in the amount of sleep at night at week 4 (P = 0.008), favoring the valerian group. Change from baseline in the categorical value for sleep latency was also significantly different at week 4, where 10% of valerian patients indicated longer time to fall asleep compared to 28% on placebo and 43% of valerian patients reported less time to fall asleep compared to 32% on placebo (P = 0.03) (Table 3). The ITT analysis indicated that about 9% more patients experienced a success on valerian relative to placebo, but this was not statistically significant. When scores on the PSQI were divided into ≤5 and >5 (this latter group representing sleep problems), there were fewer patients in the valerian group having sleep problems by week 8 (64% vs 80%, P = 0.56).
| VALERIAN | PLACEBO | P | |
|---|---|---|---|
| Sleep quality | 0.199 | ||
| Week 4 | |||
| Worse | 2 (3%) | 5 (8%) | |
| Same | 33 (49%) | 37 (57%) | |
| Better | 33 (49%) | 23 (35%) | |
| Week 8 | 0.927 | ||
| Worse | 3 (5%) | 2 (3%) | |
| Same | 26 (41%) | 25 (42%) | |
| Better | 35 (55%) | 32 (54%) | |
| Sleep latency | 0.030 | ||
| Week 4 | |||
| Worse | 6 (10%) | 18 (28%) | |
| Same | 30 (48%) | 26 (40%) | |
| Better | 27 (43%) | 21 (32%) | |
| Week 8 | 0.072 | ||
| Worse | 3 (5%) | 11 (18%) | |
| Same | 28 (47%) | 29 (48%) | |
| Better | 27 (47%) | 21 (34%) | |
| Sleep duration | 0.244 | ||
| Week 4 | |||
| Worse | 6 (9%) | 10 (16%) | |
| Same | 26 (39%) | 29 (46%) | |
| Better | 34 (52%) | 24 (38%) | |
| Week 8 | 0.148 | ||
| Worse | 8 (13%) | 4 (7%) | |
| Same | 19 (31%) | 28 (48%) | |
| Better | 34 (56%) | 27 (46%) | |
| Sleep efficiency | 0.295 | ||
| Week 4 | |||
| Worse | 7 (12%) | 13 (22%) | |
| Same | 26 (43%) | 23 (39%) | |
| Better | 28 (46%) | 23 (39%) | |
| Week 8 | 0.758 | ||
| Worse | 11 (19%) | 9 (16%) | |
| Same | 19 (33%) | 22 (39%) | |
| Better | 28 (48%) | 25 (45%) | |
| Sleep disturbance | 0.738 | ||
| Week 4 | |||
| Worse | 9 (15%) | 11 (18%) | |
| Same | 41 (66%) | 40 (67%) | |
| Better | 12 (19%) | 9 (15%) | |
| Week 8 | 0.177 | ||
| Worse | 10 (16%) | 7 (13%) | |
| Same | 35 (57%) | 41 (73%) | |
| Better | 16 (26%) | 8 (14%) | |
| Daytime dysfunction | 0.114 | ||
| Week 4 | |||
| Worse | 6 (9%) | 13 (19%) | |
| Same | 42 (60%) | 40 (60%) | |
| Better | 22 (31%) | 14 (21%) | |
| Week 8 | 0.478 | ||
| Worse | 6 (10%) | 8 (13%) | |
| Same | 27 (43%) | 31 (50%) | |
| Better | 30 (48%) | 23 (37%) |
While the POMS AUC scores indicated no difference between treatment arms, the mean change from baseline at weeks 4 and 8 was significantly different for the Fatigue-Inertia subscale at weeks 4 (P = 0.004) and 8 (P = 0.02), with the valerian arm reporting better scores (Table 4). On the BFI, the valerian arm scored significantly better than the placebo arm in the mean change from baseline at weeks 4 and 8 on the Fatigue Now (P = 0.003 and P = 0.01, respectively) and Usual Fatigue (P = 0.02 and P = 0.046, respectively) items (Table 4).
| SIDE EFFECT | WEEK | VALERIAN | PLACEBO | P |
|---|---|---|---|---|
| BFI | ||||
| Fatigue Now | Week 4 | 13.2 | 1.5 | <0.01 |
| Week 8 | 22.1 | 10.5 | <0.01 | |
| Usual Fatigue | Week 4 | 12.8 | 4.2 | 0.02 |
| Week 8 | 19.4 | 10.0 | 0.05 | |
| Worst Fatigue | Week 4 | 11.2 | 3.2 | 0.03 |
| Week 8 | 14.8 | 12.4 | 0.65 | |
| Activity Interference | Week 4 | 6.2 | 4.1 | 0.75 |
| Week 8 | 12.3 | 10.8 | 0.75 | |
| POMS | ||||
| Anger-Hostility | Week 4 | 3.5 | 2.0 | 0.53 |
| Week 8 | 3.9 | 4.2 | 0.89 | |
| Vigor-Activity | Week 4 | 2.0 | -0.4 | 0.43 |
| Week 8 | 2.0 | 4.7 | 0.34 | |
| Depression-Dejection | Week 4 | 3.7 | 5.5 | 0.21 |
| Week 8 | 3.7 | 5.4 | 0.25 | |
| Confusion-Bewilderment | Week 4 | 4.8 | 2.6 | 0.26 |
| Week 8 | 5.3 | 3.4 | 0.79 | |
| Fatigue-Inertia | Week 4 | 13.9 | 2.8 | <0.01 |
| Week 8 | 17.5 | 9.2 | 0.02 | |
| TensionAnxiety | Week 4 | 6.3 | 5.6 | 0.85 |
| Week 8 | 9.2 | 8.9 | 0.54 | |
| Total score | Week 4 | 5.7 | 3.0 | 0.19 |
| Week 8 | 6.9 | 6.0 | 0.90 |
In terms of toxicity, there were no significant differences between arms for the self-reported side effect items (headache, trouble waking, nausea) at baseline, week 4, or week 8 (Table 5). The valerian arm change from baseline at both weeks 4 and 8 showed significant improvement in drowsiness (P = 0.04 and P = 0.03, respectively) and sleep problems (P = 0.005 and P = 0.03, respectively) compared to placebo (Table 5). The maximum severity over time for each self-reported toxicity resulted in no significant differences between arms. There was a significant difference in the CTCAE reporting of alkaline phosphatase, with the placebo arm having a higher incidence of grade 1 toxicity (P = 0.049).
| SIDE EFFECT | WEEK | VALERIAN | PLACEBO | P |
|---|---|---|---|---|
| Nausea | Week 4 | 3.0 | –2.1 | 0.07 |
| Week 8 | 3.4 | 0.0 | 0.06 | |
| Headache | Week 4 | 4.8 | 1.5 | 0.09 |
| Week 8 | 6.7 | 4.6 | 0.27 | |
| Trouble waking | Week 4 | 8.8 | 4.3 | 0.42 |
| Week 8 | 9.5 | 5.7 | 0.36 | |
| Drowsiness | Week 4 | 21.0 | 9.7 | 0.04 |
| Week 8 | 24.0 | 14.0 | 0.03 | |
| Sleep problems | Week 4 | 18.7 | 4.3 | <0.01 |
| Week 8 | 24.0 | 13.0 | 0.03 |
Discussion
This study failed to identify any significant improvements in sleep as measured by the overall PSQI or the FOSQ in this population. This corroborates data from a recent study by Taibi and colleagues,49 who evaluated 300 mg of valerian, taken half an hour before bed. They reported that valerian did not improve any self-reported or polysomnographic sleep outcomes significantly more than placebo. The Taibi et al. study has several possible limitations, including a small sample size (n = 16), a dose lower than that used in the majority of pilot trials with promising results, and a duration of only 15 days on the study agent.
The current study is one of the few randomized placebo-controlled trials evaluating pharmacological treatment of insomnia complaints among cancer patients. Most randomized trials of treatments directed at insomnia in cancer patients compare CBT with usual care or wait-list care and find it of substantial benefit.[50], [51], [52], [53], [54], [55], [56], [57], [58] and [59] One prior trial in terminal cancer patients evaluated intravenous agents for effectiveness, and another controlled trial found mirtazapine to be effective at improving sleep complaints in cancer patients with depression.[51] and [60] Otherwise, there are no other controlled trials assessing pharmacologic agents to primarily address sleep-related complaints in cancer patients.
While there was no significant improvement in sleep quality as assessed by the PSQI, there were consistent improvements in the secondary fatigue outcomes as measured by both the BFI and the POMS Fatigue-Inertia subscale. Although caution is required in interpreting these secondary results, the raw differences in change scores between the two arms are fairly large, often over 10 points (on a 100-point scale). In addition, several other secondary end points—change from baseline related to sleep latency, amount of sleep per night, improvement in sleep problems, and less drowsiness—all support the valerian arm outperforming placebo.
There are several hypotheses related to the inconsistencies in the results. The PSQI may measure different dimensions of well-being from the BFI or POMS, the former concentrating on sleep-quality measures, while the latter two concentrate on daytime symptoms. The correlation between sleep-quality and daytime symptoms may not be very strong in this study's population. Another possibility is that there was a beta-error. Some of the data were incomplete due to the patients' inability to complete the questionnaires appropriately. The power analysis suggested 100 patients per arm were required, and only about 60 per group provided data for analysis. Another hypothesis is that the effects of valerian were too modest and limited to one aspect, perhaps sleep latency, that were not detectable with multidimensional scales such as the PSQI or the FOSQ that look at impact on activity.
There were more patients who withdrew from the placebo arm early compared to the valerian arm. The reasons for this are not known. However, patients on this trial were getting active treatment for cancer, so numerous and varied reasons could explain early withdrawals including complications from treatment, increased fatigue, and worsening sleep problems.
In summary, this trial did not provide data to support that valerian is helpful in improving sleep during cancer treatment in this population. It is not clear whether valerian may have helpful physiologic activity supporting research in oncology symptom management related to fatigue. Perhaps further exploration is warranted.
Acknowledgments
This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-124477 (Mentorship Grant), CA-35431, CA-63848, CA-35195, CA-35133, CA-35267, CA-35269, CA-35103, CA-35101, CA-63849, CA-35119, CA-52352, CA-35448, CA-35103, CA-03011, CA-107586, CA-35261, CA-67575, CA-95968, CA-67753, and CA-35415. The content is solely the responsibility of the authors and does not necessarily represent the views of the National Cancer Institute or the National Institutes of Health.
References
1 J. Savard and C.M. Morin, Insomnia in the context of cancer: a review of a neglected problem, J Clin Oncol 19 (2001), pp. 895–908. View Record in Scopus | Cited By in Scopus (147)
2 J.R. Davidson, A.W. MacLean and M.D. Brundage et al., Sleep disturbance in cancer patients, Soc Sci Med 54 (2002), pp. 1309–1321. Article | 
3 D.S. Hu and P.M. Silberfarb, Management of sleep problems in cancer patients, Oncology (Williston Park) 5 (1991), pp. 23–27 discussion 28. View Record in Scopus | Cited By in Scopus (24)
4 L. Fiorentino and S. Ancoli-Israel, Insomnia and its treatment in women with breast cancer, Sleep Med Rev 10 (2006), pp. 419–429. Article |
5 J.J. Mao, K. Armstrong and M.A. Bowman et al., Symptom burden among cancer survivors: impact of age and comorbidity, J Am Board Fam Med 20 (2007), pp. 434–443. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (24)
6 A.H. Miller, S. Ancoli-Israel and J.E. Bower et al., Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer, J Clin Oncol 26 (2008), pp. 971–982. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (52)
7 J. Savard, J. Villa and H. Ivers et al., Prevalence, natural course, and risk factors of insomnia comorbid with cancer over a 2-month period, J Clin Oncol 27 (31) (2009), pp. 5233–5239. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (2)
8 G. Oxana, J. Palesh and K. Roscoe et al., Prevalence, demographics, and psychological associations of sleep disruption in patients with cancer: University of Rochester Cancer Center–Community Clinical Oncology Program, J Clin Oncol 8 (2) (2010), pp. 292–298.
9 D.C. Owen, K.P. Parker and D.B. McGuire, Comparison of subjective sleep quality in patients with cancer and healthy subjects, Oncol Nurs Forum 26 (1999), pp. 1649–1651. View Record in Scopus | Cited By in Scopus (26)
10 American Academy of Sleep Medicine, International Classification of Sleep Disorders: Diagnostic and Coding Manual (2nd ed.), American Academy of Sleep Medicine, Westchester, IL (2005).
11 A.K. Morin, C.I. Jarvis and A.M. Lynch, Therapeutic options for sleep-maintenance and sleep-onset insomnia, Pharmacotherapy 27 (2007), pp. 89–110. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (34)
12 T. Morgenthaler, M. Kramer and C. Alessi et al., Practice parameters for the psychological and behavioral treatment of insomnia: an update: An American Academy of Sleep Medicine report, Sleep 29 (2006), pp. 1415–1419. View Record in Scopus | Cited By in Scopus (81)
13 T. Roehrs and T. Roth, Sleep–wake state and memory function, Sleep 23 (suppl 3) (2000), pp. S64–S68. View Record in Scopus | Cited By in Scopus (6)
14 J. Payne, B. Piper and I. Rabinowitz et al., Biomarkers, fatigue, sleep, and depressive symptoms in women with breast cancer: a pilot study, Oncol Nurs Forum 33 (2006), pp. 775–783. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (23)
15 R.M. Benca, S. Ancoli-Israel and H. Moldofsky, Special considerations in insomnia diagnosis and management: depressed, elderly, and chronic pain populations, J Clin Psychiatry 65 (suppl 8) (2004), pp. 26–35. View Record in Scopus | Cited By in Scopus (44)
16 D.A. Katz and C.A. McHorney, The relationship between insomnia and health-related quality of life in patients with chronic illness, J Fam Pract 51 (2002), pp. 229–235. View Record in Scopus | Cited By in Scopus (145)
17 H.R. Colten, B.M. Altevogt and Institute of Medicine (U.S.) Committee on Sleep Medicine and Research, Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem, National Academies Press, Washington DC (2006).
18 F. Baker, M. Denniston and T. Smith et al., Adult cancer survivors: how are they faring?, Cancer 104 (2005), pp. 2565–2576. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (78)
19 F.C. Stiefel, A.B. Kornblith and J.C. Holland, Changes in the prescription patterns of psychotropic drugs for cancer patients during a 10-year period, Cancer 65 (4) (1990), pp. 1048–1053. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (39)
20 B. Ebert, K.A. Wafford and S. Deacon, Treating insomnia: current and investigational pharmacological approaches, Pharmacol Ther 112 (2006), pp. 612–629. Article |
21 H.J. Moller, Effectiveness and safety of benzodiazepines, J Clin Psychopharmacol 19 (1999), pp. 2S–11S. Full Text via CrossRef
22 J. Barbera and C. Shapiro, Benefit–risk assessment of zaleplon in the treatment of insomnia, Drug Saf 28 (2005), pp. 301–318. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (26)
23 A. Bellon, Searching for new options for treating insomnia: are melatonin and ramelteon beneficial?, J Psychiatr Pract 12 (2006), pp. 229–243. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (20)
24 T. Roth, D. Seiden and S. Sainati et al., Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia, Sleep Med 7 (2006), pp. 312–318. Article |
25 A.M. Holbrook, R. Crowther and A. Lotter et al., Meta-analysis of benzodiazepine use in the treatment of insomnia, CMAJ 162 (2000), pp. 225–233. View Record in Scopus | Cited By in Scopus (215)
26 N. Hall, Taking policy action to reduce benzodiazepine use and promote self-care among seniors, J Appl Gerontol 17 (1998), pp. 318–351. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (8)
27 L.C. Johnson and D.A. Chernik, Sedative-hypnotics and human performance, Psychopharmacology (Berl) 76 (1982), pp. 101–113. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (64)
28 W.A. Ray, M.R. Griffin and W. Downey, Benzodiazepines of long and short elimination half-life and the risk of hip fracture, JAMA 262 (1989), pp. 3303–3306.
29 A. Foy, D. O'Connell and D. Henry et al., Benzodiazepine use as a cause of cognitive impairment in elderly hospital inpatients, J Gerontol A Biol Sci Med Sci 50 (1995), pp. M99–M106. View Record in Scopus | Cited By in Scopus (73)
30 S.L. Gray, K.V. Lai and E.B. Larson, Drug-induced cognition disorders in the elderly: incidence prevention and management, Drug Saf 21 (1999), pp. 101–122. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (93)
31 L.E. Tune and F.W. Bylsma, Benzodiazepine-induced and anticholinergic-induced delirium in the elderly, Int Psychogeriatr 3 (1991), pp. 397–408. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (38)
32 P.J. Houghton, The scientific basis for the reputed activity of valerian, J Pharm Pharmacol 51 (1999), pp. 505–512. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (148)
33 G. Balderer and A.A. Borbely, Effect of valerian on human sleep, Psychopharmacology (Berl) 87 (1982), pp. 406–409.
34 P.D. Leathwood and F. Chauffard, Aqueous extract of valerian reduces latency to fall asleep in man, Planta Med 51 (1985), pp. 144–148. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (84)
35 P.D. Leathwood, F. Chauffard and E. Heck et al., Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man, Pharmacol Biochem Behav 17 (1982), pp. 65–71. Abstract |
36 H. Schulz, C. Stolz and J. Muller, The effect of valerian extract on sleep polygraphy in poor sleepers: a pilot study, Pharmacopsychiatry 27 (1994), pp. 147–151. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (67)
37 O. Lindahl and L. Lindwall, Double blind study of a valerian preparation, Pharmacol Biochem Behav 32 (1989), pp. 1065–1066. Abstract |
38 B. Hodgson and R. Kizior, Nursing Drug Handbook, Saunders, Philadelphia (2000).
39 C.A. Thompson, USP moves forward in providing information on botanical products, Am J Health Syst Pharm 55 (1998), pp. 527–530. View Record in Scopus | Cited By in Scopus (1)
40 H. Garges, I. Varia and P. Doraiswamy et al., Cardiac complications and delirium associated with valerian root withdrawal, JAMA 280 (1998), pp. 1566–1567. View Record in Scopus | Cited By in Scopus (75)
41 J.W. Budzinski, B.C. Foster and S. Vandenhoek et al., An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures, Phytomedicine 7 (2000), pp. 273–282. View Record in Scopus | Cited By in Scopus (176)
42 D.J. Buysse, C.F. Reynolds 3rd and T.H. Monk et al., The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research, Psychiatry Res 28 (1989), pp. 193–213. Abstract |
43 S. Curran, M. Andrykowsky and J. Studts, Short Form of the Profile of Mood States (POMS-SF): psychometric information, Psychol Assess 7 (1995), pp. 80–83. Abstract |
44 T.E. Weaver, A.M. Laizner and L.K. Evans et al., An instrument to measure functional status outcomes for disorders of excessive sleepiness, Sleep 20 (1997), pp. 835–843. View Record in Scopus | Cited By in Scopus (231)
45 T.R. Mendoza, X.S. Wang and C.S. Cleeland et al., The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory, Cancer 85 (1999), pp. 1186–1196. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (349)
46 S.R. Lipsitz, G.M. Fitzmaurice and E.J. Orav et al., Performance of generalized estimating equations in practical situations, Biometrics 50 (1994), pp. 270–278. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (90)
47 J. Cohen, Statistical Power Analysis for the Behavioral Sciences, Lawrence Erlbaum, Hillsdale, NJ (1988).
48 J. Sloan, T. Symonds and D. Vargas-Chanes et al., Practical guidelines for assessing the clinical significance of health-related quality of life changes within clinical trials, Drug Inform J 37 (2003), pp. 23–31. View Record in Scopus | Cited By in Scopus (80)
49 D.M. Taibi, M.V. Vitiello and S. Barsness et al., A randomized clinical trial of valerian fails to improve self-reported, polysomnographic, and actigraphic sleep in older women with insomnia, Sleep Med 10 (2009), pp. 319–328. Article |
50 A. Berger, B. Kuhn and J. Farr et al., Behavioral therapy intervention trial to improve sleep quality and cancer-related fatigue, Psychooncology 18 (2009), pp. 634–646. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (14)
51 E. Cankurtaran, E. Ozalp and H. Soygur et al., Mirtazapine improves sleep and lowers anxiety and depression in cancer patients: superiority over imipramine, Support Care Cancer 16 (2008), pp. 1291–1298. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (5)
52 C. Espie, L. Fleming and J. Cassidy et al., Randomized controlled clinical effectiveness trial of cognitive behavior therapy compared with treatment as usual for persistent insomnia in patients with cancer, J Clin Oncol 26 (28) (2008), pp. 4651–4658. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (37)
53 D. Epstein and S. Dirksen, Randomized trial of a cognitive-behavioral intervention for insomnia in breast cancer survivors, Oncol Nurs Forum 34 (5) (2007), pp. E51–E59. Full Text via CrossRef
54 J. Savard, S. Simard and I. Giguère et al., Randomized clinical trial on cognitive therapy for depression in women with metastatic breast cancer: psychological and immunological effects, Palliat Support Care 4 (3) (2006), pp. 219–237. View Record in Scopus | Cited By in Scopus (30)
55 J. Savard, S. Simard and H. Ivers et al., Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer, part I: Sleep and psychological effects, J Clin Oncol 23 (25) (2005), pp. 6083–6096. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (89)
56 J. Savard, S. Simard and H. Ivers, Randomized study on the efficacy of cognitive behavioral therapy for insomnia secondary to breast cancer, part II: Immunologic effects, J Clin Oncol 23 (25) (2005), pp. 6097–6106. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (32)
57 P. Sherwood, B. Given and C. Given et al., A cognitive behavioral intervention for symptom management in patients with advanced cancer, Oncol Nurs Forum 32 (6) (2005), pp. 1190–1198. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (22)
58 C. Quesnel, J. Savard and S. Simard et al., Efficacy of cognitive-behavioral therapy for insomnia in women treated for nonmetastatic breast cancer, J Consult Clin Psychol 71 (1) (2003), pp. 189–200. Abstract |
59 J. Davidson, J. Waisberg and M. Brundage et al., Nonpharmacologic group treatment of insomnia: a preliminary study with cancer survivors, Psychooncology 10 (2001), pp. 389–397. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (50)
60 N. Matsuo and T. Morita, Efficacy, safety, and cost effectiveness of intravenous midazolam and flunitrazepam for primary insomnia in terminally ill patients with cancer: a retrospective multicenter audit study, J Palliat Med 10 (5) (2007), pp. 1054–1062. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (7)
Original research
Debra L. Barton RN, PhD, AOCN, FAAN
Abstract
Sleep disorders are a substantial problem for cancer survivors, with prevalence estimates ranging from 23% to 61%. Although numerous prescription hypnotics are available, few are approved for long-term use or have demonstrated benefit in this circumstance. Hypnotics may have unwanted side effects and are costly, and cancer survivors often wish to avoid prescription drugs. New options with limited side effects are needed. The purpose of this trial was to evaluate the efficacy of a Valerian officinalis supplement for sleep in people with cancer who were undergoing cancer treatment. Participants were randomized to receive 450 mg of valerian or placebo orally 1 hour before bedtime for 8 weeks. The primary end point was area under the curve (AUC) of the overall Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes included the Functional Outcomes of Sleep Questionnaire, the Brief Fatigue Inventory (BFI), and the Profile of Mood States (POMS). Toxicity was evaluated with both self-reported numeric analogue scale questions and the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Questionnaires were completed at baseline and at 4 and 8 weeks. A total of 227 patients were randomized into this study between March 19, 2004, and March 9, 2007, with 119 being evaluable for the primary end point. The AUC over the 8 weeks for valerian was 51.4 (SD = 16), while that for placebo was 49.7 (SD = 15), with a P value of 0.6957. A supplemental, exploratory analysis revealed that several fatigue end points, as measured by the BFI and POMS, were significantly better for those taking valerian over placebo. Participants also reported less trouble with sleep and less drowsiness on valerian than placebo. There were no significant differences in toxicities as measured by self-report or the CTCAE except for mild alkaline phosphatase increases, which were slightly more common in the placebo group. This study failed to provide data to support the hypothesis that valerian, 450 mg, at bedtime could improve sleep as measured by the PSQI. However, exploratory analyses revealed improvement in some secondary outcomes, such as fatigue. Further research with valerian exploring physiologic effects in oncology symptom management may be warranted.
Article Outline
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]).
| VALERIAN (N = 102) | PLACEBO (N = 100) | P | |
|---|---|---|---|
| Gender | 0.387 | ||
| Female | 82 (80%) | 85 (85%) | |
| Age (years) | 0.546 | ||
| Mean (SD) | 59.5 (11.95) | 58.3 (12.71) | |
| Sleep scale group | 0.963 | ||
| Mildly impaired | 67 (66%) | 66 (66%) | |
| Moderately or severely impaired | 35 (34%) | 34 (34%) | |
| Sleep scale score | 0.841 | ||
| Mean (SD) | 6.6 (1.43) | 6.6 (1.69) | |
| Primary tumor site | 0.526 | ||
| Breast | 64 (63%) | 66 (67%) | |
| Colon | 9 (9%) | 5 (5%) | |
| Prostate | 3 (3%) | 1 (1%) | |
| Other | 25 (25%) | 27 (27%) | |
| Tumor status | 0.322 | ||
| Resected with no residual | 64 (64%) | 71 (71%) | |
| Resected with known residual | 17 (17%) | 12 (13%) | |
| Unresected | 19 (19%) | 13 (14%) | |
| Treatment type | 0.966 | ||
| Radiation therapy | 6 (5.9%) | 6 (6%) | |
| Parenteral chemotherapy | 38 (37%) | 39 (39%) | |
| Oral therapy | 40 (39%) | 40 (40%) | |
| Combined modality | 18 (18%) | 15 (15%) | |
| Concurrent radiation | 0.926 | ||
| Yes | 23 (23%) | 22 (22%) | |
| Concurrent cancer therapy | 0.679 | ||
| Yes | 56 (55%) | 52 (53%) | |
| Planned or concurrent hormone | 0.667 | ||
| Yes | 51 (51%) | 53 (54%) |
| VALERIAN (N = 101) | PLACEBO (N = 96) | P | |
|---|---|---|---|
| PSQI total1 | 0.695 | ||
| Mean (SD) | 41.3 (13.92) | 42.4 (14.97) | |
| POMS-SF total | 0.883 | ||
| Mean (SD) | 65.0 (14.28) | 63.9 (16.46) | |
| FOSQ total | 0.927 | ||
| Mean (SD) | 73.7 (16.07) | 72.8 (18.37) | |
| Fatigue Now | 0.285 | ||
| Mean (SD) | 45.7 (24.41) | 49.4 (25.00) | |
| Usual Fatigue | 0.216 | ||
| Mean (SD) | 46.8 (23.27) | 51.1 (24.73) | |
| Worst Fatigue | 0.522 | ||
| Mean (SD) | 35.2 (24.67) | 37.9 (26.37) | |
| Total Interference | 0.268 | ||
| Mean (SD) | 61.4 (25.05) | 57.1 (27.37) |
The primary end point of treatment effectiveness was measured using the normalized AUC calculated using baseline, week 4, and week 8 PSQI total scores. The Wilcoxon rank-sum test P value for the total PSQI score was nonsignificant (valerian AUC = 51.4, SD = 16; placebo AUC = 49.7, SD = 15; P = 0.696) (Figure 2). Similarly the FOSQ was not significantly different between groups either overall or on any subscale score.
Supplemental and exploratory analyses using changes from baseline, however, showed a significant difference in the change from baseline in the amount of sleep at night at week 4 (P = 0.008), favoring the valerian group. Change from baseline in the categorical value for sleep latency was also significantly different at week 4, where 10% of valerian patients indicated longer time to fall asleep compared to 28% on placebo and 43% of valerian patients reported less time to fall asleep compared to 32% on placebo (P = 0.03) (Table 3). The ITT analysis indicated that about 9% more patients experienced a success on valerian relative to placebo, but this was not statistically significant. When scores on the PSQI were divided into ≤5 and >5 (this latter group representing sleep problems), there were fewer patients in the valerian group having sleep problems by week 8 (64% vs 80%, P = 0.56).
| VALERIAN | PLACEBO | P | |
|---|---|---|---|
| Sleep quality | 0.199 | ||
| Week 4 | |||
| Worse | 2 (3%) | 5 (8%) | |
| Same | 33 (49%) | 37 (57%) | |
| Better | 33 (49%) | 23 (35%) | |
| Week 8 | 0.927 | ||
| Worse | 3 (5%) | 2 (3%) | |
| Same | 26 (41%) | 25 (42%) | |
| Better | 35 (55%) | 32 (54%) | |
| Sleep latency | 0.030 | ||
| Week 4 | |||
| Worse | 6 (10%) | 18 (28%) | |
| Same | 30 (48%) | 26 (40%) | |
| Better | 27 (43%) | 21 (32%) | |
| Week 8 | 0.072 | ||
| Worse | 3 (5%) | 11 (18%) | |
| Same | 28 (47%) | 29 (48%) | |
| Better | 27 (47%) | 21 (34%) | |
| Sleep duration | 0.244 | ||
| Week 4 | |||
| Worse | 6 (9%) | 10 (16%) | |
| Same | 26 (39%) | 29 (46%) | |
| Better | 34 (52%) | 24 (38%) | |
| Week 8 | 0.148 | ||
| Worse | 8 (13%) | 4 (7%) | |
| Same | 19 (31%) | 28 (48%) | |
| Better | 34 (56%) | 27 (46%) | |
| Sleep efficiency | 0.295 | ||
| Week 4 | |||
| Worse | 7 (12%) | 13 (22%) | |
| Same | 26 (43%) | 23 (39%) | |
| Better | 28 (46%) | 23 (39%) | |
| Week 8 | 0.758 | ||
| Worse | 11 (19%) | 9 (16%) | |
| Same | 19 (33%) | 22 (39%) | |
| Better | 28 (48%) | 25 (45%) | |
| Sleep disturbance | 0.738 | ||
| Week 4 | |||
| Worse | 9 (15%) | 11 (18%) | |
| Same | 41 (66%) | 40 (67%) | |
| Better | 12 (19%) | 9 (15%) | |
| Week 8 | 0.177 | ||
| Worse | 10 (16%) | 7 (13%) | |
| Same | 35 (57%) | 41 (73%) | |
| Better | 16 (26%) | 8 (14%) | |
| Daytime dysfunction | 0.114 | ||
| Week 4 | |||
| Worse | 6 (9%) | 13 (19%) | |
| Same | 42 (60%) | 40 (60%) | |
| Better | 22 (31%) | 14 (21%) | |
| Week 8 | 0.478 | ||
| Worse | 6 (10%) | 8 (13%) | |
| Same | 27 (43%) | 31 (50%) | |
| Better | 30 (48%) | 23 (37%) |
While the POMS AUC scores indicated no difference between treatment arms, the mean change from baseline at weeks 4 and 8 was significantly different for the Fatigue-Inertia subscale at weeks 4 (P = 0.004) and 8 (P = 0.02), with the valerian arm reporting better scores (Table 4). On the BFI, the valerian arm scored significantly better than the placebo arm in the mean change from baseline at weeks 4 and 8 on the Fatigue Now (P = 0.003 and P = 0.01, respectively) and Usual Fatigue (P = 0.02 and P = 0.046, respectively) items (Table 4).
| SIDE EFFECT | WEEK | VALERIAN | PLACEBO | P |
|---|---|---|---|---|
| BFI | ||||
| Fatigue Now | Week 4 | 13.2 | 1.5 | <0.01 |
| Week 8 | 22.1 | 10.5 | <0.01 | |
| Usual Fatigue | Week 4 | 12.8 | 4.2 | 0.02 |
| Week 8 | 19.4 | 10.0 | 0.05 | |
| Worst Fatigue | Week 4 | 11.2 | 3.2 | 0.03 |
| Week 8 | 14.8 | 12.4 | 0.65 | |
| Activity Interference | Week 4 | 6.2 | 4.1 | 0.75 |
| Week 8 | 12.3 | 10.8 | 0.75 | |
| POMS | ||||
| Anger-Hostility | Week 4 | 3.5 | 2.0 | 0.53 |
| Week 8 | 3.9 | 4.2 | 0.89 | |
| Vigor-Activity | Week 4 | 2.0 | -0.4 | 0.43 |
| Week 8 | 2.0 | 4.7 | 0.34 | |
| Depression-Dejection | Week 4 | 3.7 | 5.5 | 0.21 |
| Week 8 | 3.7 | 5.4 | 0.25 | |
| Confusion-Bewilderment | Week 4 | 4.8 | 2.6 | 0.26 |
| Week 8 | 5.3 | 3.4 | 0.79 | |
| Fatigue-Inertia | Week 4 | 13.9 | 2.8 | <0.01 |
| Week 8 | 17.5 | 9.2 | 0.02 | |
| TensionAnxiety | Week 4 | 6.3 | 5.6 | 0.85 |
| Week 8 | 9.2 | 8.9 | 0.54 | |
| Total score | Week 4 | 5.7 | 3.0 | 0.19 |
| Week 8 | 6.9 | 6.0 | 0.90 |
In terms of toxicity, there were no significant differences between arms for the self-reported side effect items (headache, trouble waking, nausea) at baseline, week 4, or week 8 (Table 5). The valerian arm change from baseline at both weeks 4 and 8 showed significant improvement in drowsiness (P = 0.04 and P = 0.03, respectively) and sleep problems (P = 0.005 and P = 0.03, respectively) compared to placebo (Table 5). The maximum severity over time for each self-reported toxicity resulted in no significant differences between arms. There was a significant difference in the CTCAE reporting of alkaline phosphatase, with the placebo arm having a higher incidence of grade 1 toxicity (P = 0.049).
| SIDE EFFECT | WEEK | VALERIAN | PLACEBO | P |
|---|---|---|---|---|
| Nausea | Week 4 | 3.0 | –2.1 | 0.07 |
| Week 8 | 3.4 | 0.0 | 0.06 | |
| Headache | Week 4 | 4.8 | 1.5 | 0.09 |
| Week 8 | 6.7 | 4.6 | 0.27 | |
| Trouble waking | Week 4 | 8.8 | 4.3 | 0.42 |
| Week 8 | 9.5 | 5.7 | 0.36 | |
| Drowsiness | Week 4 | 21.0 | 9.7 | 0.04 |
| Week 8 | 24.0 | 14.0 | 0.03 | |
| Sleep problems | Week 4 | 18.7 | 4.3 | <0.01 |
| Week 8 | 24.0 | 13.0 | 0.03 |
Discussion
This study failed to identify any significant improvements in sleep as measured by the overall PSQI or the FOSQ in this population. This corroborates data from a recent study by Taibi and colleagues,49 who evaluated 300 mg of valerian, taken half an hour before bed. They reported that valerian did not improve any self-reported or polysomnographic sleep outcomes significantly more than placebo. The Taibi et al. study has several possible limitations, including a small sample size (n = 16), a dose lower than that used in the majority of pilot trials with promising results, and a duration of only 15 days on the study agent.
The current study is one of the few randomized placebo-controlled trials evaluating pharmacological treatment of insomnia complaints among cancer patients. Most randomized trials of treatments directed at insomnia in cancer patients compare CBT with usual care or wait-list care and find it of substantial benefit.[50], [51], [52], [53], [54], [55], [56], [57], [58] and [59] One prior trial in terminal cancer patients evaluated intravenous agents for effectiveness, and another controlled trial found mirtazapine to be effective at improving sleep complaints in cancer patients with depression.[51] and [60] Otherwise, there are no other controlled trials assessing pharmacologic agents to primarily address sleep-related complaints in cancer patients.
While there was no significant improvement in sleep quality as assessed by the PSQI, there were consistent improvements in the secondary fatigue outcomes as measured by both the BFI and the POMS Fatigue-Inertia subscale. Although caution is required in interpreting these secondary results, the raw differences in change scores between the two arms are fairly large, often over 10 points (on a 100-point scale). In addition, several other secondary end points—change from baseline related to sleep latency, amount of sleep per night, improvement in sleep problems, and less drowsiness—all support the valerian arm outperforming placebo.
There are several hypotheses related to the inconsistencies in the results. The PSQI may measure different dimensions of well-being from the BFI or POMS, the former concentrating on sleep-quality measures, while the latter two concentrate on daytime symptoms. The correlation between sleep-quality and daytime symptoms may not be very strong in this study's population. Another possibility is that there was a beta-error. Some of the data were incomplete due to the patients' inability to complete the questionnaires appropriately. The power analysis suggested 100 patients per arm were required, and only about 60 per group provided data for analysis. Another hypothesis is that the effects of valerian were too modest and limited to one aspect, perhaps sleep latency, that were not detectable with multidimensional scales such as the PSQI or the FOSQ that look at impact on activity.
There were more patients who withdrew from the placebo arm early compared to the valerian arm. The reasons for this are not known. However, patients on this trial were getting active treatment for cancer, so numerous and varied reasons could explain early withdrawals including complications from treatment, increased fatigue, and worsening sleep problems.
In summary, this trial did not provide data to support that valerian is helpful in improving sleep during cancer treatment in this population. It is not clear whether valerian may have helpful physiologic activity supporting research in oncology symptom management related to fatigue. Perhaps further exploration is warranted.
Acknowledgments
This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-124477 (Mentorship Grant), CA-35431, CA-63848, CA-35195, CA-35133, CA-35267, CA-35269, CA-35103, CA-35101, CA-63849, CA-35119, CA-52352, CA-35448, CA-35103, CA-03011, CA-107586, CA-35261, CA-67575, CA-95968, CA-67753, and CA-35415. The content is solely the responsibility of the authors and does not necessarily represent the views of the National Cancer Institute or the National Institutes of Health.
References
1 J. Savard and C.M. Morin, Insomnia in the context of cancer: a review of a neglected problem, J Clin Oncol 19 (2001), pp. 895–908. View Record in Scopus | Cited By in Scopus (147)
2 J.R. Davidson, A.W. MacLean and M.D. Brundage et al., Sleep disturbance in cancer patients, Soc Sci Med 54 (2002), pp. 1309–1321. Article |
3 D.S. Hu and P.M. Silberfarb, Management of sleep problems in cancer patients, Oncology (Williston Park) 5 (1991), pp. 23–27 discussion 28. View Record in Scopus | Cited By in Scopus (24)
4 L. Fiorentino and S. Ancoli-Israel, Insomnia and its treatment in women with breast cancer, Sleep Med Rev 10 (2006), pp. 419–429. Article |
5 J.J. Mao, K. Armstrong and M.A. Bowman et al., Symptom burden among cancer survivors: impact of age and comorbidity, J Am Board Fam Med 20 (2007), pp. 434–443. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (24)
6 A.H. Miller, S. Ancoli-Israel and J.E. Bower et al., Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer, J Clin Oncol 26 (2008), pp. 971–982. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (52)
7 J. Savard, J. Villa and H. Ivers et al., Prevalence, natural course, and risk factors of insomnia comorbid with cancer over a 2-month period, J Clin Oncol 27 (31) (2009), pp. 5233–5239. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (2)
8 G. Oxana, J. Palesh and K. Roscoe et al., Prevalence, demographics, and psychological associations of sleep disruption in patients with cancer: University of Rochester Cancer Center–Community Clinical Oncology Program, J Clin Oncol 8 (2) (2010), pp. 292–298.
9 D.C. Owen, K.P. Parker and D.B. McGuire, Comparison of subjective sleep quality in patients with cancer and healthy subjects, Oncol Nurs Forum 26 (1999), pp. 1649–1651. View Record in Scopus | Cited By in Scopus (26)
10 American Academy of Sleep Medicine, International Classification of Sleep Disorders: Diagnostic and Coding Manual (2nd ed.), American Academy of Sleep Medicine, Westchester, IL (2005).
11 A.K. Morin, C.I. Jarvis and A.M. Lynch, Therapeutic options for sleep-maintenance and sleep-onset insomnia, Pharmacotherapy 27 (2007), pp. 89–110. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (34)
12 T. Morgenthaler, M. Kramer and C. Alessi et al., Practice parameters for the psychological and behavioral treatment of insomnia: an update: An American Academy of Sleep Medicine report, Sleep 29 (2006), pp. 1415–1419. View Record in Scopus | Cited By in Scopus (81)
13 T. Roehrs and T. Roth, Sleep–wake state and memory function, Sleep 23 (suppl 3) (2000), pp. S64–S68. View Record in Scopus | Cited By in Scopus (6)
14 J. Payne, B. Piper and I. Rabinowitz et al., Biomarkers, fatigue, sleep, and depressive symptoms in women with breast cancer: a pilot study, Oncol Nurs Forum 33 (2006), pp. 775–783. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (23)
15 R.M. Benca, S. Ancoli-Israel and H. Moldofsky, Special considerations in insomnia diagnosis and management: depressed, elderly, and chronic pain populations, J Clin Psychiatry 65 (suppl 8) (2004), pp. 26–35. View Record in Scopus | Cited By in Scopus (44)
16 D.A. Katz and C.A. McHorney, The relationship between insomnia and health-related quality of life in patients with chronic illness, J Fam Pract 51 (2002), pp. 229–235. View Record in Scopus | Cited By in Scopus (145)
17 H.R. Colten, B.M. Altevogt and Institute of Medicine (U.S.) Committee on Sleep Medicine and Research, Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem, National Academies Press, Washington DC (2006).
18 F. Baker, M. Denniston and T. Smith et al., Adult cancer survivors: how are they faring?, Cancer 104 (2005), pp. 2565–2576. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (78)
19 F.C. Stiefel, A.B. Kornblith and J.C. Holland, Changes in the prescription patterns of psychotropic drugs for cancer patients during a 10-year period, Cancer 65 (4) (1990), pp. 1048–1053. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (39)
20 B. Ebert, K.A. Wafford and S. Deacon, Treating insomnia: current and investigational pharmacological approaches, Pharmacol Ther 112 (2006), pp. 612–629. Article |
21 H.J. Moller, Effectiveness and safety of benzodiazepines, J Clin Psychopharmacol 19 (1999), pp. 2S–11S. Full Text via CrossRef
22 J. Barbera and C. Shapiro, Benefit–risk assessment of zaleplon in the treatment of insomnia, Drug Saf 28 (2005), pp. 301–318. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (26)
23 A. Bellon, Searching for new options for treating insomnia: are melatonin and ramelteon beneficial?, J Psychiatr Pract 12 (2006), pp. 229–243. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (20)
24 T. Roth, D. Seiden and S. Sainati et al., Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia, Sleep Med 7 (2006), pp. 312–318. Article |
25 A.M. Holbrook, R. Crowther and A. Lotter et al., Meta-analysis of benzodiazepine use in the treatment of insomnia, CMAJ 162 (2000), pp. 225–233. View Record in Scopus | Cited By in Scopus (215)
26 N. Hall, Taking policy action to reduce benzodiazepine use and promote self-care among seniors, J Appl Gerontol 17 (1998), pp. 318–351. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (8)
27 L.C. Johnson and D.A. Chernik, Sedative-hypnotics and human performance, Psychopharmacology (Berl) 76 (1982), pp. 101–113. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (64)
28 W.A. Ray, M.R. Griffin and W. Downey, Benzodiazepines of long and short elimination half-life and the risk of hip fracture, JAMA 262 (1989), pp. 3303–3306.
29 A. Foy, D. O'Connell and D. Henry et al., Benzodiazepine use as a cause of cognitive impairment in elderly hospital inpatients, J Gerontol A Biol Sci Med Sci 50 (1995), pp. M99–M106. View Record in Scopus | Cited By in Scopus (73)
30 S.L. Gray, K.V. Lai and E.B. Larson, Drug-induced cognition disorders in the elderly: incidence prevention and management, Drug Saf 21 (1999), pp. 101–122. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (93)
31 L.E. Tune and F.W. Bylsma, Benzodiazepine-induced and anticholinergic-induced delirium in the elderly, Int Psychogeriatr 3 (1991), pp. 397–408. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (38)
32 P.J. Houghton, The scientific basis for the reputed activity of valerian, J Pharm Pharmacol 51 (1999), pp. 505–512. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (148)
33 G. Balderer and A.A. Borbely, Effect of valerian on human sleep, Psychopharmacology (Berl) 87 (1982), pp. 406–409.
34 P.D. Leathwood and F. Chauffard, Aqueous extract of valerian reduces latency to fall asleep in man, Planta Med 51 (1985), pp. 144–148. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (84)
35 P.D. Leathwood, F. Chauffard and E. Heck et al., Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man, Pharmacol Biochem Behav 17 (1982), pp. 65–71. Abstract |
36 H. Schulz, C. Stolz and J. Muller, The effect of valerian extract on sleep polygraphy in poor sleepers: a pilot study, Pharmacopsychiatry 27 (1994), pp. 147–151. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (67)
37 O. Lindahl and L. Lindwall, Double blind study of a valerian preparation, Pharmacol Biochem Behav 32 (1989), pp. 1065–1066. Abstract |
38 B. Hodgson and R. Kizior, Nursing Drug Handbook, Saunders, Philadelphia (2000).
39 C.A. Thompson, USP moves forward in providing information on botanical products, Am J Health Syst Pharm 55 (1998), pp. 527–530. View Record in Scopus | Cited By in Scopus (1)
40 H. Garges, I. Varia and P. Doraiswamy et al., Cardiac complications and delirium associated with valerian root withdrawal, JAMA 280 (1998), pp. 1566–1567. View Record in Scopus | Cited By in Scopus (75)
41 J.W. Budzinski, B.C. Foster and S. Vandenhoek et al., An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures, Phytomedicine 7 (2000), pp. 273–282. View Record in Scopus | Cited By in Scopus (176)
42 D.J. Buysse, C.F. Reynolds 3rd and T.H. Monk et al., The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research, Psychiatry Res 28 (1989), pp. 193–213. Abstract |
43 S. Curran, M. Andrykowsky and J. Studts, Short Form of the Profile of Mood States (POMS-SF): psychometric information, Psychol Assess 7 (1995), pp. 80–83. Abstract |
44 T.E. Weaver, A.M. Laizner and L.K. Evans et al., An instrument to measure functional status outcomes for disorders of excessive sleepiness, Sleep 20 (1997), pp. 835–843. View Record in Scopus | Cited By in Scopus (231)
45 T.R. Mendoza, X.S. Wang and C.S. Cleeland et al., The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory, Cancer 85 (1999), pp. 1186–1196. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (349)
46 S.R. Lipsitz, G.M. Fitzmaurice and E.J. Orav et al., Performance of generalized estimating equations in practical situations, Biometrics 50 (1994), pp. 270–278. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (90)
47 J. Cohen, Statistical Power Analysis for the Behavioral Sciences, Lawrence Erlbaum, Hillsdale, NJ (1988).
48 J. Sloan, T. Symonds and D. Vargas-Chanes et al., Practical guidelines for assessing the clinical significance of health-related quality of life changes within clinical trials, Drug Inform J 37 (2003), pp. 23–31. View Record in Scopus | Cited By in Scopus (80)
49 D.M. Taibi, M.V. Vitiello and S. Barsness et al., A randomized clinical trial of valerian fails to improve self-reported, polysomnographic, and actigraphic sleep in older women with insomnia, Sleep Med 10 (2009), pp. 319–328. Article |
50 A. Berger, B. Kuhn and J. Farr et al., Behavioral therapy intervention trial to improve sleep quality and cancer-related fatigue, Psychooncology 18 (2009), pp. 634–646. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (14)
51 E. Cankurtaran, E. Ozalp and H. Soygur et al., Mirtazapine improves sleep and lowers anxiety and depression in cancer patients: superiority over imipramine, Support Care Cancer 16 (2008), pp. 1291–1298. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (5)
52 C. Espie, L. Fleming and J. Cassidy et al., Randomized controlled clinical effectiveness trial of cognitive behavior therapy compared with treatment as usual for persistent insomnia in patients with cancer, J Clin Oncol 26 (28) (2008), pp. 4651–4658. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (37)
53 D. Epstein and S. Dirksen, Randomized trial of a cognitive-behavioral intervention for insomnia in breast cancer survivors, Oncol Nurs Forum 34 (5) (2007), pp. E51–E59. Full Text via CrossRef
54 J. Savard, S. Simard and I. Giguère et al., Randomized clinical trial on cognitive therapy for depression in women with metastatic breast cancer: psychological and immunological effects, Palliat Support Care 4 (3) (2006), pp. 219–237. View Record in Scopus | Cited By in Scopus (30)
55 J. Savard, S. Simard and H. Ivers et al., Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer, part I: Sleep and psychological effects, J Clin Oncol 23 (25) (2005), pp. 6083–6096. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (89)
56 J. Savard, S. Simard and H. Ivers, Randomized study on the efficacy of cognitive behavioral therapy for insomnia secondary to breast cancer, part II: Immunologic effects, J Clin Oncol 23 (25) (2005), pp. 6097–6106. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (32)
57 P. Sherwood, B. Given and C. Given et al., A cognitive behavioral intervention for symptom management in patients with advanced cancer, Oncol Nurs Forum 32 (6) (2005), pp. 1190–1198. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (22)
58 C. Quesnel, J. Savard and S. Simard et al., Efficacy of cognitive-behavioral therapy for insomnia in women treated for nonmetastatic breast cancer, J Consult Clin Psychol 71 (1) (2003), pp. 189–200. Abstract |
59 J. Davidson, J. Waisberg and M. Brundage et al., Nonpharmacologic group treatment of insomnia: a preliminary study with cancer survivors, Psychooncology 10 (2001), pp. 389–397. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (50)
60 N. Matsuo and T. Morita, Efficacy, safety, and cost effectiveness of intravenous midazolam and flunitrazepam for primary insomnia in terminally ill patients with cancer: a retrospective multicenter audit study, J Palliat Med 10 (5) (2007), pp. 1054–1062. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (7)
Original research
Debra L. Barton RN, PhD, AOCN, FAAN
Abstract
Sleep disorders are a substantial problem for cancer survivors, with prevalence estimates ranging from 23% to 61%. Although numerous prescription hypnotics are available, few are approved for long-term use or have demonstrated benefit in this circumstance. Hypnotics may have unwanted side effects and are costly, and cancer survivors often wish to avoid prescription drugs. New options with limited side effects are needed. The purpose of this trial was to evaluate the efficacy of a Valerian officinalis supplement for sleep in people with cancer who were undergoing cancer treatment. Participants were randomized to receive 450 mg of valerian or placebo orally 1 hour before bedtime for 8 weeks. The primary end point was area under the curve (AUC) of the overall Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes included the Functional Outcomes of Sleep Questionnaire, the Brief Fatigue Inventory (BFI), and the Profile of Mood States (POMS). Toxicity was evaluated with both self-reported numeric analogue scale questions and the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Questionnaires were completed at baseline and at 4 and 8 weeks. A total of 227 patients were randomized into this study between March 19, 2004, and March 9, 2007, with 119 being evaluable for the primary end point. The AUC over the 8 weeks for valerian was 51.4 (SD = 16), while that for placebo was 49.7 (SD = 15), with a P value of 0.6957. A supplemental, exploratory analysis revealed that several fatigue end points, as measured by the BFI and POMS, were significantly better for those taking valerian over placebo. Participants also reported less trouble with sleep and less drowsiness on valerian than placebo. There were no significant differences in toxicities as measured by self-report or the CTCAE except for mild alkaline phosphatase increases, which were slightly more common in the placebo group. This study failed to provide data to support the hypothesis that valerian, 450 mg, at bedtime could improve sleep as measured by the PSQI. However, exploratory analyses revealed improvement in some secondary outcomes, such as fatigue. Further research with valerian exploring physiologic effects in oncology symptom management may be warranted.
Article Outline
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]).
| VALERIAN (N = 102) | PLACEBO (N = 100) | P | |
|---|---|---|---|
| Gender | 0.387 | ||
| Female | 82 (80%) | 85 (85%) | |
| Age (years) | 0.546 | ||
| Mean (SD) | 59.5 (11.95) | 58.3 (12.71) | |
| Sleep scale group | 0.963 | ||
| Mildly impaired | 67 (66%) | 66 (66%) | |
| Moderately or severely impaired | 35 (34%) | 34 (34%) | |
| Sleep scale score | 0.841 | ||
| Mean (SD) | 6.6 (1.43) | 6.6 (1.69) | |
| Primary tumor site | 0.526 | ||
| Breast | 64 (63%) | 66 (67%) | |
| Colon | 9 (9%) | 5 (5%) | |
| Prostate | 3 (3%) | 1 (1%) | |
| Other | 25 (25%) | 27 (27%) | |
| Tumor status | 0.322 | ||
| Resected with no residual | 64 (64%) | 71 (71%) | |
| Resected with known residual | 17 (17%) | 12 (13%) | |
| Unresected | 19 (19%) | 13 (14%) | |
| Treatment type | 0.966 | ||
| Radiation therapy | 6 (5.9%) | 6 (6%) | |
| Parenteral chemotherapy | 38 (37%) | 39 (39%) | |
| Oral therapy | 40 (39%) | 40 (40%) | |
| Combined modality | 18 (18%) | 15 (15%) | |
| Concurrent radiation | 0.926 | ||
| Yes | 23 (23%) | 22 (22%) | |
| Concurrent cancer therapy | 0.679 | ||
| Yes | 56 (55%) | 52 (53%) | |
| Planned or concurrent hormone | 0.667 | ||
| Yes | 51 (51%) | 53 (54%) |
| VALERIAN (N = 101) | PLACEBO (N = 96) | P | |
|---|---|---|---|
| PSQI total1 | 0.695 | ||
| Mean (SD) | 41.3 (13.92) | 42.4 (14.97) | |
| POMS-SF total | 0.883 | ||
| Mean (SD) | 65.0 (14.28) | 63.9 (16.46) | |
| FOSQ total | 0.927 | ||
| Mean (SD) | 73.7 (16.07) | 72.8 (18.37) | |
| Fatigue Now | 0.285 | ||
| Mean (SD) | 45.7 (24.41) | 49.4 (25.00) | |
| Usual Fatigue | 0.216 | ||
| Mean (SD) | 46.8 (23.27) | 51.1 (24.73) | |
| Worst Fatigue | 0.522 | ||
| Mean (SD) | 35.2 (24.67) | 37.9 (26.37) | |
| Total Interference | 0.268 | ||
| Mean (SD) | 61.4 (25.05) | 57.1 (27.37) |
The primary end point of treatment effectiveness was measured using the normalized AUC calculated using baseline, week 4, and week 8 PSQI total scores. The Wilcoxon rank-sum test P value for the total PSQI score was nonsignificant (valerian AUC = 51.4, SD = 16; placebo AUC = 49.7, SD = 15; P = 0.696) (Figure 2). Similarly the FOSQ was not significantly different between groups either overall or on any subscale score.
Supplemental and exploratory analyses using changes from baseline, however, showed a significant difference in the change from baseline in the amount of sleep at night at week 4 (P = 0.008), favoring the valerian group. Change from baseline in the categorical value for sleep latency was also significantly different at week 4, where 10% of valerian patients indicated longer time to fall asleep compared to 28% on placebo and 43% of valerian patients reported less time to fall asleep compared to 32% on placebo (P = 0.03) (Table 3). The ITT analysis indicated that about 9% more patients experienced a success on valerian relative to placebo, but this was not statistically significant. When scores on the PSQI were divided into ≤5 and >5 (this latter group representing sleep problems), there were fewer patients in the valerian group having sleep problems by week 8 (64% vs 80%, P = 0.56).
| VALERIAN | PLACEBO | P | |
|---|---|---|---|
| Sleep quality | 0.199 | ||
| Week 4 | |||
| Worse | 2 (3%) | 5 (8%) | |
| Same | 33 (49%) | 37 (57%) | |
| Better | 33 (49%) | 23 (35%) | |
| Week 8 | 0.927 | ||
| Worse | 3 (5%) | 2 (3%) | |
| Same | 26 (41%) | 25 (42%) | |
| Better | 35 (55%) | 32 (54%) | |
| Sleep latency | 0.030 | ||
| Week 4 | |||
| Worse | 6 (10%) | 18 (28%) | |
| Same | 30 (48%) | 26 (40%) | |
| Better | 27 (43%) | 21 (32%) | |
| Week 8 | 0.072 | ||
| Worse | 3 (5%) | 11 (18%) | |
| Same | 28 (47%) | 29 (48%) | |
| Better | 27 (47%) | 21 (34%) | |
| Sleep duration | 0.244 | ||
| Week 4 | |||
| Worse | 6 (9%) | 10 (16%) | |
| Same | 26 (39%) | 29 (46%) | |
| Better | 34 (52%) | 24 (38%) | |
| Week 8 | 0.148 | ||
| Worse | 8 (13%) | 4 (7%) | |
| Same | 19 (31%) | 28 (48%) | |
| Better | 34 (56%) | 27 (46%) | |
| Sleep efficiency | 0.295 | ||
| Week 4 | |||
| Worse | 7 (12%) | 13 (22%) | |
| Same | 26 (43%) | 23 (39%) | |
| Better | 28 (46%) | 23 (39%) | |
| Week 8 | 0.758 | ||
| Worse | 11 (19%) | 9 (16%) | |
| Same | 19 (33%) | 22 (39%) | |
| Better | 28 (48%) | 25 (45%) | |
| Sleep disturbance | 0.738 | ||
| Week 4 | |||
| Worse | 9 (15%) | 11 (18%) | |
| Same | 41 (66%) | 40 (67%) | |
| Better | 12 (19%) | 9 (15%) | |
| Week 8 | 0.177 | ||
| Worse | 10 (16%) | 7 (13%) | |
| Same | 35 (57%) | 41 (73%) | |
| Better | 16 (26%) | 8 (14%) | |
| Daytime dysfunction | 0.114 | ||
| Week 4 | |||
| Worse | 6 (9%) | 13 (19%) | |
| Same | 42 (60%) | 40 (60%) | |
| Better | 22 (31%) | 14 (21%) | |
| Week 8 | 0.478 | ||
| Worse | 6 (10%) | 8 (13%) | |
| Same | 27 (43%) | 31 (50%) | |
| Better | 30 (48%) | 23 (37%) |
While the POMS AUC scores indicated no difference between treatment arms, the mean change from baseline at weeks 4 and 8 was significantly different for the Fatigue-Inertia subscale at weeks 4 (P = 0.004) and 8 (P = 0.02), with the valerian arm reporting better scores (Table 4). On the BFI, the valerian arm scored significantly better than the placebo arm in the mean change from baseline at weeks 4 and 8 on the Fatigue Now (P = 0.003 and P = 0.01, respectively) and Usual Fatigue (P = 0.02 and P = 0.046, respectively) items (Table 4).
| SIDE EFFECT | WEEK | VALERIAN | PLACEBO | P |
|---|---|---|---|---|
| BFI | ||||
| Fatigue Now | Week 4 | 13.2 | 1.5 | <0.01 |
| Week 8 | 22.1 | 10.5 | <0.01 | |
| Usual Fatigue | Week 4 | 12.8 | 4.2 | 0.02 |
| Week 8 | 19.4 | 10.0 | 0.05 | |
| Worst Fatigue | Week 4 | 11.2 | 3.2 | 0.03 |
| Week 8 | 14.8 | 12.4 | 0.65 | |
| Activity Interference | Week 4 | 6.2 | 4.1 | 0.75 |
| Week 8 | 12.3 | 10.8 | 0.75 | |
| POMS | ||||
| Anger-Hostility | Week 4 | 3.5 | 2.0 | 0.53 |
| Week 8 | 3.9 | 4.2 | 0.89 | |
| Vigor-Activity | Week 4 | 2.0 | -0.4 | 0.43 |
| Week 8 | 2.0 | 4.7 | 0.34 | |
| Depression-Dejection | Week 4 | 3.7 | 5.5 | 0.21 |
| Week 8 | 3.7 | 5.4 | 0.25 | |
| Confusion-Bewilderment | Week 4 | 4.8 | 2.6 | 0.26 |
| Week 8 | 5.3 | 3.4 | 0.79 | |
| Fatigue-Inertia | Week 4 | 13.9 | 2.8 | <0.01 |
| Week 8 | 17.5 | 9.2 | 0.02 | |
| TensionAnxiety | Week 4 | 6.3 | 5.6 | 0.85 |
| Week 8 | 9.2 | 8.9 | 0.54 | |
| Total score | Week 4 | 5.7 | 3.0 | 0.19 |
| Week 8 | 6.9 | 6.0 | 0.90 |
In terms of toxicity, there were no significant differences between arms for the self-reported side effect items (headache, trouble waking, nausea) at baseline, week 4, or week 8 (Table 5). The valerian arm change from baseline at both weeks 4 and 8 showed significant improvement in drowsiness (P = 0.04 and P = 0.03, respectively) and sleep problems (P = 0.005 and P = 0.03, respectively) compared to placebo (Table 5). The maximum severity over time for each self-reported toxicity resulted in no significant differences between arms. There was a significant difference in the CTCAE reporting of alkaline phosphatase, with the placebo arm having a higher incidence of grade 1 toxicity (P = 0.049).
| SIDE EFFECT | WEEK | VALERIAN | PLACEBO | P |
|---|---|---|---|---|
| Nausea | Week 4 | 3.0 | –2.1 | 0.07 |
| Week 8 | 3.4 | 0.0 | 0.06 | |
| Headache | Week 4 | 4.8 | 1.5 | 0.09 |
| Week 8 | 6.7 | 4.6 | 0.27 | |
| Trouble waking | Week 4 | 8.8 | 4.3 | 0.42 |
| Week 8 | 9.5 | 5.7 | 0.36 | |
| Drowsiness | Week 4 | 21.0 | 9.7 | 0.04 |
| Week 8 | 24.0 | 14.0 | 0.03 | |
| Sleep problems | Week 4 | 18.7 | 4.3 | <0.01 |
| Week 8 | 24.0 | 13.0 | 0.03 |
Discussion
This study failed to identify any significant improvements in sleep as measured by the overall PSQI or the FOSQ in this population. This corroborates data from a recent study by Taibi and colleagues,49 who evaluated 300 mg of valerian, taken half an hour before bed. They reported that valerian did not improve any self-reported or polysomnographic sleep outcomes significantly more than placebo. The Taibi et al. study has several possible limitations, including a small sample size (n = 16), a dose lower than that used in the majority of pilot trials with promising results, and a duration of only 15 days on the study agent.
The current study is one of the few randomized placebo-controlled trials evaluating pharmacological treatment of insomnia complaints among cancer patients. Most randomized trials of treatments directed at insomnia in cancer patients compare CBT with usual care or wait-list care and find it of substantial benefit.[50], [51], [52], [53], [54], [55], [56], [57], [58] and [59] One prior trial in terminal cancer patients evaluated intravenous agents for effectiveness, and another controlled trial found mirtazapine to be effective at improving sleep complaints in cancer patients with depression.[51] and [60] Otherwise, there are no other controlled trials assessing pharmacologic agents to primarily address sleep-related complaints in cancer patients.
While there was no significant improvement in sleep quality as assessed by the PSQI, there were consistent improvements in the secondary fatigue outcomes as measured by both the BFI and the POMS Fatigue-Inertia subscale. Although caution is required in interpreting these secondary results, the raw differences in change scores between the two arms are fairly large, often over 10 points (on a 100-point scale). In addition, several other secondary end points—change from baseline related to sleep latency, amount of sleep per night, improvement in sleep problems, and less drowsiness—all support the valerian arm outperforming placebo.
There are several hypotheses related to the inconsistencies in the results. The PSQI may measure different dimensions of well-being from the BFI or POMS, the former concentrating on sleep-quality measures, while the latter two concentrate on daytime symptoms. The correlation between sleep-quality and daytime symptoms may not be very strong in this study's population. Another possibility is that there was a beta-error. Some of the data were incomplete due to the patients' inability to complete the questionnaires appropriately. The power analysis suggested 100 patients per arm were required, and only about 60 per group provided data for analysis. Another hypothesis is that the effects of valerian were too modest and limited to one aspect, perhaps sleep latency, that were not detectable with multidimensional scales such as the PSQI or the FOSQ that look at impact on activity.
There were more patients who withdrew from the placebo arm early compared to the valerian arm. The reasons for this are not known. However, patients on this trial were getting active treatment for cancer, so numerous and varied reasons could explain early withdrawals including complications from treatment, increased fatigue, and worsening sleep problems.
In summary, this trial did not provide data to support that valerian is helpful in improving sleep during cancer treatment in this population. It is not clear whether valerian may have helpful physiologic activity supporting research in oncology symptom management related to fatigue. Perhaps further exploration is warranted.
Acknowledgments
This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-124477 (Mentorship Grant), CA-35431, CA-63848, CA-35195, CA-35133, CA-35267, CA-35269, CA-35103, CA-35101, CA-63849, CA-35119, CA-52352, CA-35448, CA-35103, CA-03011, CA-107586, CA-35261, CA-67575, CA-95968, CA-67753, and CA-35415. The content is solely the responsibility of the authors and does not necessarily represent the views of the National Cancer Institute or the National Institutes of Health.
References
1 J. Savard and C.M. Morin, Insomnia in the context of cancer: a review of a neglected problem, J Clin Oncol 19 (2001), pp. 895–908. View Record in Scopus | Cited By in Scopus (147)
2 J.R. Davidson, A.W. MacLean and M.D. Brundage et al., Sleep disturbance in cancer patients, Soc Sci Med 54 (2002), pp. 1309–1321. Article |
3 D.S. Hu and P.M. Silberfarb, Management of sleep problems in cancer patients, Oncology (Williston Park) 5 (1991), pp. 23–27 discussion 28. View Record in Scopus | Cited By in Scopus (24)
4 L. Fiorentino and S. Ancoli-Israel, Insomnia and its treatment in women with breast cancer, Sleep Med Rev 10 (2006), pp. 419–429. Article |
5 J.J. Mao, K. Armstrong and M.A. Bowman et al., Symptom burden among cancer survivors: impact of age and comorbidity, J Am Board Fam Med 20 (2007), pp. 434–443. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (24)
6 A.H. Miller, S. Ancoli-Israel and J.E. Bower et al., Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer, J Clin Oncol 26 (2008), pp. 971–982. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (52)
7 J. Savard, J. Villa and H. Ivers et al., Prevalence, natural course, and risk factors of insomnia comorbid with cancer over a 2-month period, J Clin Oncol 27 (31) (2009), pp. 5233–5239. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (2)
8 G. Oxana, J. Palesh and K. Roscoe et al., Prevalence, demographics, and psychological associations of sleep disruption in patients with cancer: University of Rochester Cancer Center–Community Clinical Oncology Program, J Clin Oncol 8 (2) (2010), pp. 292–298.
9 D.C. Owen, K.P. Parker and D.B. McGuire, Comparison of subjective sleep quality in patients with cancer and healthy subjects, Oncol Nurs Forum 26 (1999), pp. 1649–1651. View Record in Scopus | Cited By in Scopus (26)
10 American Academy of Sleep Medicine, International Classification of Sleep Disorders: Diagnostic and Coding Manual (2nd ed.), American Academy of Sleep Medicine, Westchester, IL (2005).
11 A.K. Morin, C.I. Jarvis and A.M. Lynch, Therapeutic options for sleep-maintenance and sleep-onset insomnia, Pharmacotherapy 27 (2007), pp. 89–110. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (34)
12 T. Morgenthaler, M. Kramer and C. Alessi et al., Practice parameters for the psychological and behavioral treatment of insomnia: an update: An American Academy of Sleep Medicine report, Sleep 29 (2006), pp. 1415–1419. View Record in Scopus | Cited By in Scopus (81)
13 T. Roehrs and T. Roth, Sleep–wake state and memory function, Sleep 23 (suppl 3) (2000), pp. S64–S68. View Record in Scopus | Cited By in Scopus (6)
14 J. Payne, B. Piper and I. Rabinowitz et al., Biomarkers, fatigue, sleep, and depressive symptoms in women with breast cancer: a pilot study, Oncol Nurs Forum 33 (2006), pp. 775–783. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (23)
15 R.M. Benca, S. Ancoli-Israel and H. Moldofsky, Special considerations in insomnia diagnosis and management: depressed, elderly, and chronic pain populations, J Clin Psychiatry 65 (suppl 8) (2004), pp. 26–35. View Record in Scopus | Cited By in Scopus (44)
16 D.A. Katz and C.A. McHorney, The relationship between insomnia and health-related quality of life in patients with chronic illness, J Fam Pract 51 (2002), pp. 229–235. View Record in Scopus | Cited By in Scopus (145)
17 H.R. Colten, B.M. Altevogt and Institute of Medicine (U.S.) Committee on Sleep Medicine and Research, Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem, National Academies Press, Washington DC (2006).
18 F. Baker, M. Denniston and T. Smith et al., Adult cancer survivors: how are they faring?, Cancer 104 (2005), pp. 2565–2576. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (78)
19 F.C. Stiefel, A.B. Kornblith and J.C. Holland, Changes in the prescription patterns of psychotropic drugs for cancer patients during a 10-year period, Cancer 65 (4) (1990), pp. 1048–1053. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (39)
20 B. Ebert, K.A. Wafford and S. Deacon, Treating insomnia: current and investigational pharmacological approaches, Pharmacol Ther 112 (2006), pp. 612–629. Article |
21 H.J. Moller, Effectiveness and safety of benzodiazepines, J Clin Psychopharmacol 19 (1999), pp. 2S–11S. Full Text via CrossRef
22 J. Barbera and C. Shapiro, Benefit–risk assessment of zaleplon in the treatment of insomnia, Drug Saf 28 (2005), pp. 301–318. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (26)
23 A. Bellon, Searching for new options for treating insomnia: are melatonin and ramelteon beneficial?, J Psychiatr Pract 12 (2006), pp. 229–243. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (20)
24 T. Roth, D. Seiden and S. Sainati et al., Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia, Sleep Med 7 (2006), pp. 312–318. Article |
25 A.M. Holbrook, R. Crowther and A. Lotter et al., Meta-analysis of benzodiazepine use in the treatment of insomnia, CMAJ 162 (2000), pp. 225–233. View Record in Scopus | Cited By in Scopus (215)
26 N. Hall, Taking policy action to reduce benzodiazepine use and promote self-care among seniors, J Appl Gerontol 17 (1998), pp. 318–351. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (8)
27 L.C. Johnson and D.A. Chernik, Sedative-hypnotics and human performance, Psychopharmacology (Berl) 76 (1982), pp. 101–113. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (64)
28 W.A. Ray, M.R. Griffin and W. Downey, Benzodiazepines of long and short elimination half-life and the risk of hip fracture, JAMA 262 (1989), pp. 3303–3306.
29 A. Foy, D. O'Connell and D. Henry et al., Benzodiazepine use as a cause of cognitive impairment in elderly hospital inpatients, J Gerontol A Biol Sci Med Sci 50 (1995), pp. M99–M106. View Record in Scopus | Cited By in Scopus (73)
30 S.L. Gray, K.V. Lai and E.B. Larson, Drug-induced cognition disorders in the elderly: incidence prevention and management, Drug Saf 21 (1999), pp. 101–122. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (93)
31 L.E. Tune and F.W. Bylsma, Benzodiazepine-induced and anticholinergic-induced delirium in the elderly, Int Psychogeriatr 3 (1991), pp. 397–408. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (38)
32 P.J. Houghton, The scientific basis for the reputed activity of valerian, J Pharm Pharmacol 51 (1999), pp. 505–512. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (148)
33 G. Balderer and A.A. Borbely, Effect of valerian on human sleep, Psychopharmacology (Berl) 87 (1982), pp. 406–409.
34 P.D. Leathwood and F. Chauffard, Aqueous extract of valerian reduces latency to fall asleep in man, Planta Med 51 (1985), pp. 144–148. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (84)
35 P.D. Leathwood, F. Chauffard and E. Heck et al., Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man, Pharmacol Biochem Behav 17 (1982), pp. 65–71. Abstract |
36 H. Schulz, C. Stolz and J. Muller, The effect of valerian extract on sleep polygraphy in poor sleepers: a pilot study, Pharmacopsychiatry 27 (1994), pp. 147–151. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (67)
37 O. Lindahl and L. Lindwall, Double blind study of a valerian preparation, Pharmacol Biochem Behav 32 (1989), pp. 1065–1066. Abstract |
38 B. Hodgson and R. Kizior, Nursing Drug Handbook, Saunders, Philadelphia (2000).
39 C.A. Thompson, USP moves forward in providing information on botanical products, Am J Health Syst Pharm 55 (1998), pp. 527–530. View Record in Scopus | Cited By in Scopus (1)
40 H. Garges, I. Varia and P. Doraiswamy et al., Cardiac complications and delirium associated with valerian root withdrawal, JAMA 280 (1998), pp. 1566–1567. View Record in Scopus | Cited By in Scopus (75)
41 J.W. Budzinski, B.C. Foster and S. Vandenhoek et al., An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures, Phytomedicine 7 (2000), pp. 273–282. View Record in Scopus | Cited By in Scopus (176)
42 D.J. Buysse, C.F. Reynolds 3rd and T.H. Monk et al., The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research, Psychiatry Res 28 (1989), pp. 193–213. Abstract |
43 S. Curran, M. Andrykowsky and J. Studts, Short Form of the Profile of Mood States (POMS-SF): psychometric information, Psychol Assess 7 (1995), pp. 80–83. Abstract |
44 T.E. Weaver, A.M. Laizner and L.K. Evans et al., An instrument to measure functional status outcomes for disorders of excessive sleepiness, Sleep 20 (1997), pp. 835–843. View Record in Scopus | Cited By in Scopus (231)
45 T.R. Mendoza, X.S. Wang and C.S. Cleeland et al., The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory, Cancer 85 (1999), pp. 1186–1196. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (349)
46 S.R. Lipsitz, G.M. Fitzmaurice and E.J. Orav et al., Performance of generalized estimating equations in practical situations, Biometrics 50 (1994), pp. 270–278. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (90)
47 J. Cohen, Statistical Power Analysis for the Behavioral Sciences, Lawrence Erlbaum, Hillsdale, NJ (1988).
48 J. Sloan, T. Symonds and D. Vargas-Chanes et al., Practical guidelines for assessing the clinical significance of health-related quality of life changes within clinical trials, Drug Inform J 37 (2003), pp. 23–31. View Record in Scopus | Cited By in Scopus (80)
49 D.M. Taibi, M.V. Vitiello and S. Barsness et al., A randomized clinical trial of valerian fails to improve self-reported, polysomnographic, and actigraphic sleep in older women with insomnia, Sleep Med 10 (2009), pp. 319–328. Article |
50 A. Berger, B. Kuhn and J. Farr et al., Behavioral therapy intervention trial to improve sleep quality and cancer-related fatigue, Psychooncology 18 (2009), pp. 634–646. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (14)
51 E. Cankurtaran, E. Ozalp and H. Soygur et al., Mirtazapine improves sleep and lowers anxiety and depression in cancer patients: superiority over imipramine, Support Care Cancer 16 (2008), pp. 1291–1298. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (5)
52 C. Espie, L. Fleming and J. Cassidy et al., Randomized controlled clinical effectiveness trial of cognitive behavior therapy compared with treatment as usual for persistent insomnia in patients with cancer, J Clin Oncol 26 (28) (2008), pp. 4651–4658. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (37)
53 D. Epstein and S. Dirksen, Randomized trial of a cognitive-behavioral intervention for insomnia in breast cancer survivors, Oncol Nurs Forum 34 (5) (2007), pp. E51–E59. Full Text via CrossRef
54 J. Savard, S. Simard and I. Giguère et al., Randomized clinical trial on cognitive therapy for depression in women with metastatic breast cancer: psychological and immunological effects, Palliat Support Care 4 (3) (2006), pp. 219–237. View Record in Scopus | Cited By in Scopus (30)
55 J. Savard, S. Simard and H. Ivers et al., Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer, part I: Sleep and psychological effects, J Clin Oncol 23 (25) (2005), pp. 6083–6096. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (89)
56 J. Savard, S. Simard and H. Ivers, Randomized study on the efficacy of cognitive behavioral therapy for insomnia secondary to breast cancer, part II: Immunologic effects, J Clin Oncol 23 (25) (2005), pp. 6097–6106. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (32)
57 P. Sherwood, B. Given and C. Given et al., A cognitive behavioral intervention for symptom management in patients with advanced cancer, Oncol Nurs Forum 32 (6) (2005), pp. 1190–1198. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (22)
58 C. Quesnel, J. Savard and S. Simard et al., Efficacy of cognitive-behavioral therapy for insomnia in women treated for nonmetastatic breast cancer, J Consult Clin Psychol 71 (1) (2003), pp. 189–200. Abstract |
59 J. Davidson, J. Waisberg and M. Brundage et al., Nonpharmacologic group treatment of insomnia: a preliminary study with cancer survivors, Psychooncology 10 (2001), pp. 389–397. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (50)
60 N. Matsuo and T. Morita, Efficacy, safety, and cost effectiveness of intravenous midazolam and flunitrazepam for primary insomnia in terminally ill patients with cancer: a retrospective multicenter audit study, J Palliat Med 10 (5) (2007), pp. 1054–1062. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (7)