Influence of Melatonin on Quality of Lifein Patients with Chronic Fatigue

and Late Melatonin Onset,

I;.~ M.G. Smits, MD, PillR. van Rooy

J. E. N agtegaal, PharmD

ABSTRACT. Medical Outcome Study Short Fonn-36 (MOS SF-36)qualities of life scores were studied in 38 chronic fatigue patients withlate melatonin onset before and after treatment with melatonin. Beforestart of the treatment, quality of life was assessed twice. Pre-treatmentscores were compared with each other and with the scores of 43 patientswith Delayed Sleep Phase Syndrome and of 1063 healthy subjects.Melatonin, 5 mg, was taken orally, 5 hours before baseline salivary en-dogenous dim light melatonin onset.

After mean (SO) treatment of 13.7 (0.8) weeks, quality of life scores"physical functioning," "energy/vitality," "bodily pain," and "generalhealth perception" improved (p values, respectively, 0.017, 0.002, 0.002and 0.009). In the pre-treatment period (mean [SO] interval: 6.5 [0.6]weeks) "social functioning" and "general health perception" improved(p = 0.013 and 0.010, respectively).

In the chronic fatigue patients the quality of life scores did not differfrom those of the Delayed Sleep Phase Syndrome patients, except for"physical functioning," "energy/vitality" and "general health percep-tion." These were significantly lower. All chronic fatigue patient'sscores were significantly lower than those of the healthy subjects exceptfor "health transition."

M. G. Smits and R. van Rooy are affiliated with the Hospital De Gelderse Vallei,Department of Neurology and Sleep-Wake Disorders, Ede, The Netherlands. J. E.Nagtegaal is affiliated with the Hospital Eemland, Department of Clinical Pharmacy,Amersfoort.

Address correspondence to: M. G. Smits, Hospital "Gelderse Vallei," Box 9025,6710 HN Ede, The Netherlands (E-mail: smitsm@zgv.n1).

Journal of Chronic Fatigue Syndrome, Vol. 10(3/4) 2002http://www .haworthpressinc. com/store/product. asp ?sku=J092

@ 2002 by The Haworth Press, Inc. All rights reserved. 25

26 JOURNAL OF CHRONIC FATIGUE SYNDROME

Chronic fatigue patients with late melatonin onset have a significantquality-of-life burden, similar to Delayed Sleep Phase Syndrome pa-tients. Several quality of life dimensions improved after treatment withmelatonin. [Article copies availableforafeefrom The Haworth Document De-livery Service.. 1-800-HA WORTH. E-mail address.. <getinfo@haworthpressinc.com> Website.. <http..//wwwHaworthPress.com> @2002 by The Haworth Press,Iric. All rights reserved.]

KEYWORDS. Melatonin, chronic fatigue, quality of life, SF-36, de-

layed sleep phase syndrome

INTRODUCTION

Circadian rhythms are generated and integrated by the hypothalamic "clock"and govern many important biological functions. These include the sleep wakecycle, feelings of alertness and tiredness, intellectual performance, concentra-tion and memory; body temperature and thermoregulatory changes in skinblood flow, as well as neuroendocrinic functions, including the secretion ofmelatonin; and the activity of the immune system (1,2). All these functions aredisturbed to some extent in Chronic Fatigue Syndrome (CFS) (1).

CFS-like symptoms of tiredness, poor concentration and depression maydevelop if circadian rhythms are disrupted experimentally, or by shiftworkingor jet-lag (3-6). The symptoms are also prominent in seasonal affective disor-der (SAD) (7), and Delayed Sleep Phase Syndrome (DSPS) (8), diseases char-acterized by a phase shifted circadian clock.

Endogenous melatonin, a hormone produced by the pineal gland during thedark phase of the day-night cycle, plays a major role in the synchronization ofcircadian rhythms (9). The circadian rhythm of melatonin is highly reproduc-ible and generally not easily altered (10). The endogenous 24-h melatonin pro-file is a reliable marker for circadian phase position. To assess differences incircadian phase position, it is not necessary to measure the complete 24-h pro-fIle. The time when melatonin starts to rise in dim light, the Dim LightMelatonin Onset (DLMO), is shown to be particularly convenient, as it canusually be obtained before sleep (11). In healthy subjects, DLMO usually oc-curs between 6 p.m. and 9:30 p.m. (12).

In DSPS patients DLMO is delayed. Melatonin, 5 mg, administered 5 hbefore individual DLMO, advances sleep-wake rhythm and DLMO. Further-more it makes these patients feel more refreshed in the morning (13) andincreases quality of life, assessed with the SF-36 health questionnaire (14).

Recently, we reported 10 DSPS patients, who had been misdiagnosed asCFS before the diagnosis of DSPS was made. With melatonin, 5 mg, adminis-

Preliminary Studies 27

tered 5 h before individual DLMO, their physical, functional, mental and gen-eral health scales of the MOS SF-36 health questionnaire improved significantly(15). Therefore, we decided to study the influence of melatonin treatment inchronic fatigue patients with delayed DLMO. To guide the design of a futurerandomized placebo-controlled trial in chronic fatigue patients with disturbedsleep and delayed melatonin onset, we performed an observational study (16)to see if improvement of Quality of Life occurs within three months of treat-ment with melatonin, 5 mg, administered 5 h before DLMO in chronic fatiguepatients.

METHODS

Study Protocol

Patients referred to the specialist Chronic Fatigue Syndrome out-patientclinic of the Gelderse Vallei hospital participated in the study. All patients withchronic fatigue studied fulfilled the following criteria of CFS: (1) persistentfatigue sufficient to impair daily activities for at least 1 year, and present for atleast 50% of the day during the preceding 6 months; (2) no coexistent physicalillness which could explain chronic fatigue; (3) no current or recent medica-tion which could interfere with sleep, mood or circadian rhythmicity (e.g.,hypnotics, antidepressants or steroids); (4) disrupted sleep patterns with loss ofrestorative sleep.

When the patient reported at the fIrst visit disturbances in the sleep-wakerhythm, an ambulatory polysomnography was performed at the patient's homeas described earlier (13). Furthermore endogenous salivary melatonin was as-sessed by collecting saliva at the patient's home in dim light, hourly from9 p.m. until 1 a.m. Melatonin was measured as described elsewhere (17).DLMO, defined as the time at which salivary melatonin reached 4 pg/ml, wascalculated as the linearly interpolated time of the fIrst sample above 4 pg/mlthat was preceded by a lower value (17,18).

At the second visit, six weeks after the fIrst visit, the results of these investi-gations were discussed with the patient. When sleep architecture was normal,DLMO occurred later than 21 :30, and when there were no contra indicationsfor melatonin treatment (13), patients were offered the possibility to be treatedwith orally melatonin, 5 mg, administered 5 h before individual DLMO. Themelatonin was mixed with microcrystalline cellulose in a gelatin capsule. Weused this high pharmacological dose because this dose was used in the pla-cebo-controlled studies on melatonin in DSPS (13,19,20). The patients weregiven oral and written information about melatonin. Melatonin is a not-li-censed drug in Europe. In the United States it has the status of a food supple-ment, which is freely available. Severe adverse effects have not yet been

28 JOURNAL OF CHRONIC FATIGUE SYNDROME

reported (21). The patients who wished to be treated received melatonin, 5 mg,administered 5 h before their individual DLMO. Three months later the resultswere evaluated at the third visit.

The patients completed a MOS SF-36 health questionnaire at the fIrst, sec-ond and third visit.

MOS SF -36 Questionnaire

The questionnaire which was used for measuring physical, functional, men-tal and social health is the Dutch version of the Medical Outcomes Study ShortForm-36 (MOS SF-36) (23,24). The MOS SF-36 questionnaire contains 36items, comprising eight scales and a one-item measure of the change in health.The scales are: physical functioning, social functioning, role disability due tophysical problems, role disability due to emotional problems, mental health,vitality, bodily pain and general health perceptions (22). The item scores of theMOS SF-36 questionnaire were summated to form scale scores and trans-formed to a 100 points scale. A higher score denotes a higher quality of health.The Dutch version of the SF-36 has a high validity and reliability compared tothe Nottingham Health Profile and can discriminate between healthy controlsand subjects who suffer from mild health problems (24). In patients with fa-tiguing illnesses the SF-36 is useful in assessing functional status (25).

The scores of the DSPS patients were compared to the Dutch population [arandom sample of n = 3000 taken from the Register of Population of which theresponse was n = 1063: 35% men, 65% women, between 18 and 89 years(mean: 44.1 years) (26)] and to scores of patients with DSPS (14) (Table 1).

The scores of the chronic fatigue patients before melatonin treatment werecompared with the scores of the same patients after treatment.

Statistics

The results were analyzed using the SPSS 10.0 package (SPSS Inc., Chi-cago, USA). A t-test for independent variables was used to test whether therewere differences between the MOS scores of the random Dutch sample and theDSPS patients before treatment with melatonin. A paired t -test was used to testthe differences of the SF-36 scores within the baseline and within the treatmentperiods. Pearsons correlations were calculated between the individual DLMOvalues and the MOS SF-36 scores.

To detect clinically meaningful differences of the quality of life before andafter treatment with melatonin, the effect sizes were calculated using themethod recommended by Kazis et al. (27), taking the mean change in a vari-able and dividing it by the baseline standard variable. An effect size of 1.0 isequivalent to the change of one standard deviation in the sample. As a bench-

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30 JOURNAL OF CHRONIC FATIGUE SYNDROME

mark for assessing the relative magnitude of a change, Cohen (28) identifiedan effect size of 0.2 as small, 0.5-0.8 as moderate and more than 0.8 as large.

RESULTS

Thirty-eight chronic fatigue patients, 27 women and 11 men, completed theMOS SF-36 questionnaires. Mean (SO) age was 35.8 (11.3) yr. Mean (SO)OLMO occurred at 22:51 (0:46) h. Mean (SO) interval between fIrst and sec-ond visit (baseline period) was 6.5 (0.6) weeks. Mean (SO) interval betweensecond and third visit (treatment period) was 13.7 (0.8) weeks.

The results of the MOS SF-36 scores are recorded. All scores of the chronicfatigue patients at the fIrst and second visit were significantly lower than thoseof the control population, except for "health transition." At the second visitmean score of this quality of life dimension did not differ significantly fromthe score of the healthy population (95% c.i. for the difference between means:-2.1 to 10.8).

The mean scores "physical functioning," "energy/vitality" and "generalhealth perception" of the CFS patients, recorded at the baseline visits 1 and 2were lower than those of the OSPS patients; at the second baseline visit thescore for "role physical" was higher in the CFS than in the OSPS patients(Table 2).

TABLE 2. Difference of MaS SF-36 Scores Between DSPS Patients andChronic Fatigue (CF) Patients at Visit 1 and Visit 2. Significant Differences ArePrinted in Bold.

Difference DSPS-CF visit 1 Difference DSPS-CF visit 2

Difference between 95% c.i. Difference between 95% c.i.sample means for the difference sample means for the difference

between means between means

Physical functioning 21.0 10.7-31.3 18.2 7.8-28.6

Social functioning -5.3 -20.0-9.37 -18.1 -31.4-4.8

Role physical -15.5 -35.4-4.37 -20.7 -40.8--0.6

Role emotional 1.9 -21.2-25.0 2.8 -17.0-22.6

Mental health -3.4 -11.0-4.2 -3.2 -25.5-19.1

Energy/vitality 13.8 6.6-21.1 9.9 2.3-17.5

Bodily pain 9.5 -2.7-21.7 7.1 -5.3-19.5

General health 25.3 17.6-33 20.3 12.4-28.2perception

Health transition -1.0 -13.2-11.2 -10.2 -22.1-1.72

Preliminary Studies 31

In the baseline period the scores "social functioning" and "general healthperception" increased significantly at the second visit relative to those at thefIrst visit. The effect sizes were moderate. In the treatment period, the scores"physical functioning," "energy/vitality," "bodily pain" and "general healthperception" increased significantly. The effect sizes were moderate.

DLMO did not correlate significantly with the MOS SF-36 scales at the fIrstvisit. DLMO correlated with "physical functioning" at the second visit (-0.435;P = 0.006) and third visit (-0.390; p = 0.016), as well as with "mental health"(-0.431; P = 0.007), "energy/vitality" (-0.382; P = 0.018) and "general healthperception" (-0.333; p = 0.041) at the third visit. DLMO correlated with thedifference of the score physical functioning between visit 1 and 2. DLMO didnot correlate with the changes of the other scores between visit 1 and 2 and be-tween visit 2 and 3.

DISCUSSION

In this observational study quality-of-life profIle of chronic fatigue patientswas generally similar to that of DSPS patients. The scores for "physical func-tioning," "energy/vitality" and "general health perception" were even moreimpaired. Furthermore, four out of the nine quality of life dimensions im-proved after three months treatment with melatonin 5 mg, administered 5 hbefore DLMO.

Several comments have to be given on these results, suggesting that mela-tonin might also be helpful for CFS patients with late melatonin onset.

Results of observational studies should not be used for defining evidencebased medical care (29). However when observational studies are well de-signed, they do not systematically overestimate the magnitude of the effects oftreatment as compared with those in randomized controlled trials (30,31). Fur-thermore, the relative long period between starting treatment and completingthe SF-36 questionnaire (32), the size effect of the treatment and the specificpattern of responses across the different health dimensions make it very un-\ike\y that the effects of melatonin treatment were caused by placebo treatment(33).

At present three operational case definitions have been presented for the di-agnosis of CFS. An American (34), which has been revised on two occasions(35,36), an Australian (37) and a British (38) definition. According to all,known physical causes for chronic fatigue have to be excluded. In our chronicfatigue patients, circadian rhythmicity was disturbed. Consequently the diag-nosis of CFS could not be made.

The pathophysiology of CFS is unknown. The late melatonin onset in ourpatients suggests that one of the possible causes of chronic fatigue might be a

32 JOURNAL OF CHRONIC FATIGUE SYNDROME

disturbed melatonin rhythm. The process of production and release of mela-tonin (summarized in Figure 1) is controlled by the endogenous biologicalclock, which is located in the suprachiasmatic nucleus (SCN) of the hypothala-mus (9). Suprachiasmatic projections regulate the pineal gland (PG) and rundorsal to the paraventricular nucleus of the hypothalamus and innervateparaventricular cells (39,40) that project through the medial forebrain bundleto intermediolateral cell column of the spinal cord (7,41). These nerve projec-tions stimulate preganglionic cells that innervate the superior cervical ganglia(SCG). These ganglia are of primary importance to the sympathetic innervationof the pineal gland (42) and mediate all known biochemical and physiologicalfunctions of the pineal gland. Postganglionic noradrenergic cells in the SCGproject to the pineal gland via the inferior carotid nerve and the coronary nerve(42).

A late DLMO can be due to defects of clock genes (43,44), enzymes in-volved in the melatonin synthesis (13), or neural connections between the ret-ina and pineal gland (45).

CFS is often preceded by viral infections. These viral infections could havedamaged the neural connections between retina and pineal gland, resulting inlate melatonin onset and disturbed circadian rhythm. Just as these connectionscan be damaged by a whiplash trauma, resulting in a chronic whiplash syn-drome with delayed sleep phase syndrome (45,46). Therefore, we hypothesize

FIGURE 1. Physiology of melatonin secretion.

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( ~Iation1prnf

prnf - postganglionic retinal nerve fibers GSCN - Supra Chiasmatic NucleusSCG = Superior Cervical Gaglion SCGPG = Pineal Gland

Preliminary Studies 33

that CFS-like disease could be caused by an encephalitis, which has damagedretinal-pineal neural connections resulting in delayed melatonin onset and de-layed circadian rhythms. Another possibility is that the late DLMO is the "out-come" of the CFS-like disorder. In that case, behavior of the chronic fatiguepatient expressed in a delayed sleep-wake rhythm, could secondarily result in adelayed DLMO.

Circadian rhythms can also be disturbed from childhood onset [resulting inchildhood onset delayed sleep phase syndrome (47)] or by shifting the sleep-wake rhythm by shiftwork [resulting in shiftwork maladaptation syndrome(48)] or rapid long-haul flights [resulting in jet-lag (49)]. Subsequently alsothese causes of disturbed circadian rhythm might provoke a CFS-like disease.

In healthy control subjects, DLMO, measured in blood, under strictly con-trolled circumstances, occurs before 21 :30 (11). In our patients saliva was col-lected at home. Light intensity and exact sampling at allocated times could notbe held under control and may have influenced results (50).

In our patients sleep architecture was nornlal, as judged by conventionalmethods. In future studies it is worthwhile to use more sophisticated analysessuch as Foumer analysis of alpha sleep (51).

Melatonin might be considered as an endogenous nonsteroidal anti-inflam-matory peptide in a manner similar to endorphins (14). This could explain whytreatment with melatonin improved the scale "bodily pain" in our chronic fa-

tigue patients.Sleep-wake and temperature rhythms are masked easily by daily activities

(52,53). Consequently, they can only be used to diagnose circadian rhythmdisorders using constant routine procedures in a sleep-lab. DLMO is a more ro-bust and more easily applicable method to diagnose circadian rhythm disorders.Therefore we did not study sleep-wake and temperature rhythms.

The present observational study suggests that it is worthwhile to analyzecircadian rhythms in CFS and CSF-like patients and to establish the efficacy ofmelatonin treatment with a placebo-controlled study. When in this study sleep,fatigue and cognitive functions are studied additionally, the mechanism atwhich melatonin works can be also evaluated.

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~ Preliminary Studies 35

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