Clin Rheumatol. 2000;19(1):9-13. Links
The effect of melatonin in patients with fibromyalgia: a pilot study.Citera G, Arias MA, Maldonado-Cocco JA, Lázaro MA, Rosemffet MG, Brusco LI, Scheines EJ, Cardinalli DP.
Rheumatology Section, Instituto de Rehabilitación Psicofísica and Department of Physiology, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
The aim of the study was to determine the possible effect of melatonin treatment on disturbed sleep, fatigue and pain symptoms observed in fibromyalgia (FM) patients. Twenty-one consecutive patients with FM were included in an open 4-week-duration pilot study. Before and after treatment with melatonin 3 mg at bedtime, patients were evaluated using tender point count by palpation of 18 classic anatomical regions, pain score in four predesignated areas, pain severity on a 10 cm visual analogue scale (VAS), sleep disturbances, fatigue, depression, anxiety, and patient and physician global assessments, also by a VAS. Urine 6-sulphatoxymelatonin levels (aMT-6S) were measured in the patients and 20 age- and sex-matched controls. Nineteen patients completed the study. One patient withdrew because of migraine and another was lost to follow-up. At day 30, median values for the tender point count and severity of pain at selected points, patient and physician global assessments and VAS for sleep significantly improved with melatonin treatment. Other variables improved but did not reach statistical significance. Adverse events were mild and transient. Lower levels of aMT-6S were found in FM patients compared with normal median controls (+/-SD, 9.16 +/- 7.9 microg/24 h vs 16.8 +/- 12.8 microg/24 h) (p = 0.06). Although this is an open study, our preliminary results suggest that melatonin can be an alternative and safe treatment for patients with FM. Double-blind placebo controlled studies are needed.
J. Pineal Res. 2006; 40:98–99
COMMENTARY
Melatonin therapy in fibromyalgia
The fibromyalgia syndrome (FMS) is a chronic, widespread
pain disorder of unknown etiology, mainly accompanied by
fatigue, disturbed sleep and depression. The American
College of Rheumatology (ACR) criteria for FMS requires
that a patient has both a history of chronic widespread pain
for at least 3 months and the finding of pain in 11 of 18
possible tender points on examination [1]. Using the ACR
criteria, the prevalence of FMS in industrialized countries
ranges from 0.5% to 4% in the population, being 11 times
more frequent in women.
Factors that may contribute to the development of FMS
include [2, 3]: (i) familial component, suggestive of a genetic
factor; (ii) environmental factors, including stressors such
as physical trauma, infections, psychological stress, endocrine
disorders, and autoimmune diseases. Cytokines such
as interleukin (IL)-1a, IL-6, and tumor necrosis factoralpha
have been shown to be related to neuropathic pain,
and they are released by activated immune cells during
inflammation; (iii) endocrine alterations including those of
the hypothalamo-pituitary axis (HPA) and changes in the
sympathetic nervous system; (iv) neurotransmitter alterations
including increased substance P and decreased
norepinephrine and serotonin levels; and (v) psychological
factors.
Fibromyalgia syndrome is, at present, an incurable
disease, and it should be consider a chronic illness. Current
pharmacological treatment of FMS depends on the severity
of the symptoms and include antidepressants, anti-inflammatory
drugs, anti-epileptic drugs, sedative hypnotics,
muscle relaxants, and opiates [3].
In an atempt to ameliorate some of the FMS symptoms
including insomnia and thus improve chronic stress in
these individuals, melatonin was given orally to four FMS
patients. One patient was a 22-yr-old male, and the other
three were females between the ages of 47–55 yr. All
patients were receiving medication including chronic
analgesics, antidepressants, sedative hypnotics, and in
one case opioids. Melatonin was given at doses of
6 mg/day at night, 60 min before the expected sleeping
time. After 15 days of treatment with melatonin, all
patients developed a sleep/wake cycle that was considered
normal. They also mentioned a significant reduction of
pain. At this time, the patients were taken off hypnotics.
Thirty days after the initiation of melatonin, other
medications were withdrawn and thereafter they only
took melatonin. They currently report feeling very well,
have a normal sleep/wake cycle, normal diurnal activity,
lack of pain and fatigue and claim significant improvement
of the behavioral symptoms including lack of
depression. At this time, none of them take any drug
other than melatonin. These four patients have been on
melatonin therapy for 3–15 months.
A previous study revealed that 3 mg melatonin daily for
30 days significantly improved the tender point count,
severity of pain, global physician assessments and sleep [4].
Our experience, with 6 mg melatonin daily and more than
1 yr of treatment in some cases, suggests that chronic
melatonin therapy may be highly beneficial in relieving the
overall symptoms in FMS patients.
How is melatonin benefiting FMS patients? Melatonin
has multiple actions including modulation of the sleep/
wake cycle and benzodiazepine-like effects [5]. Thus,
melatonin administration improves sleep and rest, and
decreases anxiety derived from sleeplessness. Additionally,
melatonin also synchronizes neurotransmitter circadian
rhythms including those of c-aminobutyric acid, benzodiazepine,
dopamine, and glutamate [5, 6]. Data from the
literature are inconsistent regarding melatonin levels and its
circadian rhythm in FMS patients. Although it is unknown
whether there is an alteration in the neurotransmitter and/
or melatonin rhythms in FMS patients, we have reported
that when the latter is altered, providing melatonin therapy
reduces abnormal brain physiology [7]. Thus, one effect of
melatonin in FMS may be the normalization of the
neurotransmitter rhythms and the sleep/wake cycle. Also,
melatonin has anti-stress properties and influences the HPA
axis, which may account for some of its effects in FMS.
Furthermore, new data regarding the anti-inflammatory
role of melatonin [8], as well as its inhibition of the
macrophage/monocyte activation including the reduction
of both inducible nitric oxide synthase and proinflammatory
cytokines may be of benefit in FMS. Finally, as altered
muscle physiology may participate in the pathophysiology
of FMS, the actions of melatonin in terms of its ability to
enhance mitochondrial bioenergetics [9–11] may be pertinent
to its beneficial effects in these patients. While reduced
levels of melatonin have been reported in FMS women [12],
alterations in its circadian rhythm seem to be not a primary
cause of FMS.
Taken together, the observed effects in these patients
along with the minimal side effects of melatonin, and the
fact that melatonin reduces the toxicity and increases the
efficacy of many drugs [13], suggest that melatonin alone or
in combination with other therapies may be of significant
benefit in the pharmacological management of FMS.
