Melatonin

To evaluate the impact of melatonin on survivors of breast cancer with data analysis of secondary quality-of-life outcomes (sleep, mood, hot flashes)

Participants were randomized using 1:1 randomization format and received four months of 3 mg melatonin or placebo nightly at 9 pm.

• N = 85
• MEAN AGE: 59 years
• RANGE: 38-81 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Stage I-III primary nonmetastatic breast cancer, ductal carcinoma in situ, lobular carcinoma in situ, completed with active treatment (surgery, radiation, chemotherapy, and hormonal therapy) 60 days prior to enrollment.
• OTHER KEY SAMPLE CHARACTERISTICS: There was no history of other cancers except nonmelanoma skin cancer; no night-shift work; no active seizures with medication; and no beta-blocker, warfarin, hormonal therapy, black cohosh, flaxseed, soy, or sleep-aid use. There was also no melatonin use 30 days prior to enrollment.

• SITE: Single site
• SETTING TYPE: Outpatient
• LOCATION: Dana-Farber/Harvard Cancer Center, Boston, MA

PHASE OF CARE: Transition phase after active treatment

• Secondary analysis of the effect of melatonin on sleep, mood, and hot flashes
• Original study was a double-blind, placebo-controlled, randomized trial

• Subjective measures included Pittsburgh Sleep Quality Index (PSQI) (19-item scale)
• Center for Epidemiologic Studies Depression (CES-D) (20-item scale)
• North Center Cancer Treatment Group hot flash diary (frequency and intensity of hot flashes over seven days, and severity [1 = mild to 4 = very severe]).
• Diary data summed but number of and severity of hot flashes per day, calculation of hot flash score using frequency and severity

No baseline differences in characteristics were noted between groups (n = 48 melatonin; n = 46 placebo). Sleep outcomes included significant improvement in sleep quality, daytime dysfunction, and PSQI total scores in treatment versus placebo. Overall change of sleep over time using all time points, which was adjusted for multiple comparisons, showed overall high PSQI global scores in placebo group (1.67) (95% CI [0.67, 2.66]), indicating worse sleep quality. CES-D scores did not change over time. Hot flash frequency decreased over time for both treatment groups. Only grade 1-2 toxicities were reported.

The use of oral 3 mg of melatonin showed minimal side effects with possible impact on the improvement of subjective sleep quality. There was no exclusion for prior sleep disorders, limiting understanding of MOA of melatonin and preexisting sleep disorders. Sleep was a secondary outcome of this study and needs larger RCT trials to verify results.

• Small sample (less than 100)
• Details of randomization process are missing.
• Melatonin dose is often started low and increased as needed; yet the rationale for a stable 3 mg dose of melatonin in this study is unclear
• Underpowered for evaluation of effect on hot flashes

Oral 3 mg melatonin is potentially a safe and effective treatment for sleep disturbances in survivors of breast cancer with baseline poor sleep quality. However, additional larger scale-studies in which sleep is the primary variable outcome are needed using objective and subjective measures of sleep.

To determine the effectiveness of melatonin on postoperative cognitive function and sleep quality in women who underwent breast cancer surgery

The intervention group received 6 mg of melatonin orally one hour before bedtime one week prior to surgery through 12 weeks postoperatively. The control group received a placebo medication packaged by the hospital pharmacy with the same instructions. Both the placebo and melatonin were labeled and administered identically. Neuropsychological testing was conducted within one week preoperatively and after two and 12 weeks postoperatively. Sleep assessments were collected three days preoperatively to eight days postoperatively (short-term) and 2–12 weeks postoperatively (long-term).

• N = 54 (intervention 28, placebo 26)  
• MEAN AGE = 51 years (intervention), 60 years (placebo)
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Women who were 30–75 years old undergoing a lumpectomy or mastectomy and were American Society of Anesthesiologists classes I–III
• OTHER KEY SAMPLE CHARACTERISTICS: Exclusions included patients who were pregnant; depression as indicated by the Major Depression Inventory; current chemotherapy; patients taking SSRIs, antithrombotic agents, MAO inhibitors, calcium channel blockers, or insulin; patients with pre-existing neurologic diseases, sleep apnea, another sleep disorder, kidney disease, autoimmune disorders, or an allergy to melatonin

• SITE: Single-site    
• SETTING TYPE: Multiple settings    
• LOCATION: Herlev Hospital Department of Breast Surgery, Copenhagen, Denmark

• PHASE OF CARE: Active antitumor treatment

Double-blinded, randomized, controlled study

• Mini-Mental State Examination (MMSE)
• International Studies of Postoperative Cognitive Dysfunction (ISPOCD) Test Battery
  • Visual verbal learning test 
  • Concept shifting task
  • Letter-digit coding test 
  • Stroop color-word test
• Sleep diary (sleep latency, number of awakenings, total sleep, sleep efficiency) 
• Sleep Visual Analog Scale (VAS)
• Major Depression Scale (MDS)

There were no statistically significant differences between group characteristics. There was no evidence of cognitive impairment two weeks postoperatively in either group; however, there was a decline in cognitive performance (as a composite z-score) in the placebo group, 6.3%, compared to no decline in the intervention group (p = .38). Perioperative sleep efficiency was significantly greater for the intervention group (p = .02). Postoperative total sleep time was greater in the intervention group (p = .03). Side-effect frequency was similar for both groups; however, there was a difference in types of effects reported. Intervention side effects included dizziness (14%), headache (10%), and paresthesias (10%), and the placebo group experienced headache (27%), difficulty falling asleep (13%), and nausea (13%).

Although cognitive impairment was not found to be a significant problem in this sample, subjects who received melatonin had greater sleep efficiency and total sleep time postoperatively than those in the placebo group. In addition, subjects who received melatonin tended to have less cognitive decline although it was not statistically significant.

• Small sample (< 100)
• Subject withdrawals ≥ 10%
• Other limitations/explanation: More subjects in the placebo group withdrew (n = 10) than in the intervention group (n = 1).

Melatonin may be useful as an intervention to reduce cognitive difficulties and improve sleep, but further study is warranted.

To conduct a randomized, double-blind, placebo-controlled efficacy study evaluating the effects of oral melatonin in improving sleep in patients with cancer experiencing symptoms of insomnia

The investigators randomized participants who consented into group A (melatonin) or group B (placebo) using a fishbowl technique. Melatonin (3 mg) or placebo (multivitamin tablet) was provided by a pharmacist. Tablets were similar in color (light yellow) and shape, and were wrapped in similar envelopes and given to participants. Instructions were to take tablets two hours prior to bedtime every day for 14 days. The Athens Insomnia Scale (AIS) was given by phone or in person on days 1, 7, and 14. Patients and evaluators were blinded to the drug group, and the group was revealed to research staff at the end of the study. Results were compared using a paired t test.

• N = 50    
• MALES: 13% (group A), 13% (group B); FEMALES: 12% (group A),12% (group B)
• CURRENT TREATMENT: Other
• KEY DISEASE CHARACTERISTICS: Any patients with cancer with sleep complaints were included. No specific exclusion criteria were noted.

• SITE: Single site   
• SETTING TYPE: Outpatient    
• LOCATION: India

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Palliative care

Prospective, randomized, double-blind, placebo-controlled study

The AIS self-assessment psychometric tool for measurement of sleep difficulty is an eight-item scale, and the first five items assess sleep induction, nighttime awakenings, final awakening, total sleep duration, and sleep quality. The remaining three items assess daytime well-being, functional capacity, and sleepiness. Items are scaled using 0–3 ratings, from 0 (no problem) to 3 (no sleep at all). The scale cut-off is 10 to predict outcomes.

Power for a sample size of 25 was verified (90% and alpha = 5%). No significant differences in demographic characteristics of age and sex existed (p > 0.05). Each group had one dropout. The sample was predominantly stage 1 (44% [group A], 40% [group B]) and stage 2 (32% [group A], 36% [group B]), and stage 3–4 was 24% in each group. The majority of subjects (54%) had head and neck cancer (e.g., tongue, larynx) followed by cervix cancer (12%), and 14% had ovarian, gastrointestinal, breast, and sarcomas. Group A had significantly improvements in sleep (p < 0.05) on the AIS at week 1 with intragroup improvements in group A in week 2 (p = 0.00001). The percent change in sleep improvement within group A was significant (p = 0.0001) but not significant in group B (p > 0.05).

The use of 3 mg of melatonin two hours prior to bedtime is an effective nonpharmacological treatment for increasing sleep induction and sleep quality in patients with cancer experiencing insomnia.

• Small sample (< 100)
• Measurement validity/reliability questionable
• Questionable protocol fidelity

Additional large-scale randomized studies are needed to determine efficacy. Melatonin has emerging data to support the nonpharmacological treatment of sleep problems in patients with cancer.

To conduct a secondary data analysis from the MELODY trial to determine if 6 mg of oral melatonin administered at bedtime pre- and postsurgery would improve objective and subjective sleep outcomes in patients with breast cancer

The original study design was a randomized, double-blind, placebo-controlled trial to test the effect of melatonin on depressive symptoms. Participants randomized to melatonin or placebo taken at bedtime for three days prior to surgery and continued until 12 weeks postoperative. Secondary data points for sleep are described in this article. No baseline sleep assessment was reported, and time points of subjective and objective data collection were preoperative night 2/3, preoperative night 1, postoperative night 1/2/3, postoperative night 4/5/6, and night before histology information, normally two weeks postoperative.

• N = 48  
• MEAN AGE = 55 years
• AGE RANGE = 34–74 years 
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Nonmetastatic breast cancer 
• OTHER KEY SAMPLE CHARACTERISTICS: All participants were surgical patients scheduled for mastectomy or lumpectomy with sentinel node dissection with and without axillary dissection.

• SITE: Single site    
• SETTING TYPE: Not specified    
• LOCATION: Herlev Hospital, Copenhagen, Denmark

• PHASE OF CARE: Active antitumor treatment

• Secondary analysis of effect of melatonin on subjective and objective sleep  pre- and postsurgery

Subjective measures included visual analog scale for subjective sleep quality (0 mm = best possible sleep and 100 mm = worst sleep). The Karolinska sleepiness scale (KS) was used to assess level of sleepiness using nine-point scale (1 = very alert, 10 = very sleepy). No psychometric properties were provided. Objective sleep actigraphy data were guided with a sleep diary for parameters of efficiency, time in bed, total sleep time, wake after sleep onset (WASO), latency, and awakenings. Actigraphy was recorded for the entire study period.

Evaluation of objective sleep outcomes from actigraphy revealed no significant differences for preoperative sleep or wake outcome variables postoperatively and prehistology. Sleep efficiency was higher in the treatment group (p < 0.03). WASO was significantly lower in the postoperative times of 1/2/3 and 4/5/6 in the melatonin group (p < 0.03). No significant differences were found in the subjective measurements (sleep, pain, KSS) preoperatively and postoperatively.

Use of oral 6 mg of melatonin one hour before bed significantly increased efficiency in the three postoperative time points, and WASO decreased during the postoperative time points. However, subjective sleep and pain did not improve. Melatonin use needs to be further evaluated as this study had several limitations.

• Small sample (less than 100)
• Measurement validity/reliability questionable
• Findings not generalizable
• Questionable protocol fidelity
• Subject withdrawals of 10% or greater
• Appropriateness of study statistical plan is questionable.
• The active and placebo groups differed on the duration of surgery and anesthesia; since one of the three-day sleep periods included postoperative nights one, two, and three, the duration of anesthesia may have affected sleep and other outcomes in the first postoperative night, which should have been accounted for or addressed in the Limitations section.
• The rationale for 6 mg dose is missing.

Nurses need to inquire about pre- and postoperative use of any medications to understand and counsel patients and family members on evidence that would support the use of the medication. Melatonin may be helpful to improve sleep, but additional studies are needed.

To determine if oral melatonin administered at night would reduce fatigue and improve sleep in patients with advanced cancer treated in a palliative care facility

This was a two-part trial. In part one, patients received either melatonin (20 mg) or placebo followed by a washout of two days, then crossed over and received the opposite of the first week of treatment. Part two was an open-label study of patients who completed part one and chose to continue melatonin. Study questionnaires were completed at the beginning and end of each treatment period (days 1, 7 ,10, and 17). In part two, study measures were obtained weekly. Patients were randomly assigned to the order in which they received melatonin or placebo.

• N = 34 by ITT analysis  
• MEAN AGE = 64.5 years
• AGE RANGE = 35–84 years
• MALES: 38%, FEMALES: 62%
• KEY DISEASE CHARACTERISTICS: Breast and lung cancer were most common. All had advanced disease.

• SITE: Single site  
• SETTING TYPE: Inpatient  
• LOCATION: Denmark

• PHASE OF CARE: Active antitumor treatment

• Randomized, placebo-controlled, crossover trial

• Multidimensional Fatigue Inventory (MFI)
• EORTC Cancer Quality of Life Core 15 for palliative care patients (EORTC-QLQ-C15-PAL)

No significant differences were noted in patient outcomes between the placebo and melatonin groups.

Melatonin administration did not improve fatigue, insomnia, or other symptoms in patients with advanced cancer.

• Small sample (less than 100)
• Subject withdrawals 10% or greater
• Multiple and frequent use of the same measurement tools

This study did not show any improvement in fatigue or sleep as a result of melatonin.