Effect of Melatonin Plus Zinc Supplementation on Fatigue Perception in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial

Jesús Castro-Marrero, Maria-Cleofé Zaragozá, Irene López-Vílchez, José Luis Galmés, Begoña Cordobilla, Sara Maurel, Joan Carles Domingo, José Alegre-Martín, Jesús Castro-Marrero, Maria-Cleofé Zaragozá, Irene López-Vílchez, José Luis Galmés, Begoña Cordobilla, Sara Maurel, Joan Carles Domingo, José Alegre-Martín

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem, and profoundly debilitating condition, probably of multifactorial etiology. No effective approved drugs are currently available for its treatment. Several studies have proposed symptomatic treatment with melatonin and zinc supplementation in chronic illnesses; however, little is known about the synergistic effect of this treatment on fatigue-related symptoms in ME/CFS. The primary endpoint of the study was to assess the effect of oral melatonin plus zinc supplementation on fatigue in ME/CFS. Secondary measures included participants' sleep disturbances, anxiety/depression and health-related quality of life. A proof-of-concept, 16-week, randomized, placebo-controlled, double-blind trial was conducted in 50 ME/CFS patients assigned to receive either oral melatonin (1 mg) plus zinc (10 mg) supplementation (n = 24) or matching placebo (n = 26) once daily. Endpoint outcomes were evaluated at baseline, and then reassessed at 8 and 16 weeks of treatment and 4 weeks after treatment cessation, using self-reported outcome measures. The most relevant results were the significant reduction in the perception of physical fatigue in the Mel-Zinc group at the final treatment follow-up versus placebo (p < 0.05), and the significant improvement in the physical component summary at all follow-up visits in the experimental group. Urinary 6-sulfatoxymelatonin levels were significantly elevated though the treatment in experimental group vs. placebo (p < 0.0001); however, no significantly differences were observed for zinc concentration among participants. Our findings suggest that oral melatonin plus zinc supplementation for 16 weeks is safe and potentially effective in reducing fatigue and improving the quality of life in ME/CFS. This clinical study was registered on ClinicalTrials.gov (NCT03000777).

Keywords: chronic fatigue syndrome; fatigue; melatonin; myalgic encephalomyelitis; quality of life; sleep quality; zinc.

Conflict of interest statement

M.C.-Z., I.L.-V., and J.L.G. are employees of the Laboratorios Viñas, S.A. The funders declare that they had no role in the analysis, interpretation or presentation of data. J.C.-M. received financial support from the Laboratorios Viñas, S.A. to conduct this study. The rest of the authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Consolidated Standards of Reporting Trials (CONSORT) flow diagram.
Figure 2
Figure 2
Summarized study schedule at each visit throughout the clinical trial.
Figure 3
Figure 3
Changes in the FIS-40 domain scores during the intervention study. Each bar indicates the mean FIS-40 item scores ± SEM compared by a paired Student’s t-test, where appropriate, for intragroup analysis and by a Wilcoxon’s signed rank test for intergroup analysis. (A) Physical functioning domain; (B) Cognitive domain; (C) Psychological domain; (D) Total FIS-40 score. The significance threshold was set at * p < 0.05 and ** p < 0.01. No significant differences in any FIS-40 domain scores were observed between the intervention groups in the rest of study visits. Lower scores indicate an improvement in the fatigue perception among participants. Abbreviations: Mel-Zinc, Melatonin plus Zinc group; FIS-40, 40-item fatigue index scale.

References

    1. Nishishinya B., Requeijo C., Roque M., Salas C., Urrutia G. Evaluación y Abordaje de Síndrome de Fatiga Crónica. Actualización de Las Evidencias Científicas. Agència de Qualitat i Avaluació Sanitàries de Catalunya. Departament de Salut. Generalitat de Catalunya; Barcelona, Spain: 2017. Centro Cochrane Iberoamericano y Agència de Qualitat i Avaluació Sanitàries de Catalunya.
    1. Castro-Marrero J., Zaragozá M.C., González-Garcia S., Aliste L., Sáez-Francàs N., Romero O., Ferré A., Fernandez de Sevilla T., Alegre J. Poor self-reported sleep quality and health-related quality of life in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J. Sleep Res. 2018;27:e12703. doi: 10.1111/jsr.12703.
    1. Fisk J.D., Ritvo P.G., Ross L., Haase D.A., Marrie T.J., Schlech W.F. Measuring the functional impact of fatigue: Initial validation of the fatigue impact scale. Clin. Infect. Dis. 1994;18:S79–S83. doi: 10.1093/clinids/18.Supplement_1.S79.
    1. Alonso J., Prieto L., Antó J.M. La versión española del SF-36 Health Survey (Cuestionario de Salud SF-36): Un instrumento para la medida de los resultados clínicos. Med. Clin. 1995;104:771–776.
    1. Herrero M.J., Blanch J., Peri J.M., De Pablo J., Pintor L., Bulbena A. A validation study of the hospital anxiety and depression scale (HADS) in a Spanish population. Gen. Hosp. Psychiatr. 2003;25:277–283. doi: 10.1016/S0163-8343(03)00043-4.
    1. Castro-Marrero J., Sáez-Francàs N., Santillo D., Alegre J. Treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis: All roads lead to Rome. Br. J. Pharmacol. 2017;174:345–369. doi: 10.1111/bph.13702.
    1. Maes M., Twisk F.N. Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: Disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS. Neuroendocrinol. Lett. 2009;30:677–693.
    1. Werbach M.R. Nutritional Strategies for Treating Chronic Fatigue Syndrome. Altern Med. Rev. 2000;52:93–108.
    1. Alraek T., Lee M.S., Choi T.Y., Cao H., Liu J. Complementary and alternative medicine for patients with CFS: A systematic review. BMC Complement. Altern. Med. 2011;11:87. doi: 10.1186/1472-6882-11-87.
    1. Castro-Marrero J., Zaragozá M.C., Domingo J.C., Martinez-Martinez A., Alegre J., von Schacky C. Low omega-3 index and polyunsaturated fatty acid status in patients with chronic fatigue syndrome/myalgic encephalomyelitis Prostaglandins Leukot. Essent. Fatty Acids. 2018;139:20–24. doi: 10.1016/j.plefa.2018.11.006.
    1. Sánchez A., Calpena A.C., Clares B. Evaluating the oxidative stress in inflammation: Role of melatonin. Int. J. Mol. Sci. 2015;16:16981–17004. doi: 10.3390/ijms160816981.
    1. Cambras T., Castro-Marrero J., Zaragozá M.C., Díez-Noguera A., Alegre J. Circadian rhythm abnormalities and autonomic dysfunction in patients with chronic fatigue syndrome/myalgic encephalomyelitis. PLoS ONE. 2018;13:e0198106. doi: 10.1371/journal.pone.0198106.
    1. Bonaventura P., Benedetti G., Albarède F., Miossec P. Zinc and its role in immunity and inflammation. Autoimmun. Rev. 2015;14:277–285. doi: 10.1016/j.autrev.2014.11.008.
    1. Prasad A.S. Zinc is an antioxidant and anti-inflammatory agent: Its role in human health. Front. Nutr. 2014;1:14. doi: 10.3389/fnut.2014.00014.
    1. Nowak G., Szewczyk B., Pilc A. Zinc and depression. An update. Pharmac. Rep. 2005;57:713–719.
    1. Maksoud R., Balinas C., Holden S., Cabanas H., Staines D., Marshall-Gradisnik S. A systematic review of nutraceutical interventions for mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome. J. Transl. Med. 2021;19:81. doi: 10.1186/s12967-021-02742-4.
    1. Bjørklund G., Dadar M., Pen J.J., Chirumbolo S., Aaseth J. Chronic fatigue syndrome: Suggestions for a nutritional treatment in the therapeutic approach. Biomed. Pharmacother. 2019;109:1000–1007. doi: 10.1016/j.biopha.2018.10.076.
    1. Fukuda K., Strauss S.E., Hickie I., Sharpe M.C., Dobbins J.G., Komaroff A. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann. Intern. Med. 1994;121:953–959. doi: 10.7326/0003-4819-121-12-199412150-00009.
    1. Milton J.S. Estadística para Biología y Ciencias de la Salud. 2nd ed. Interamericana-McGraw-Hill; Madrid, Spain: 1994. p. 466.
    1. Buysse D.J., Reynolds C.F., Monk T.H., Berman S.R., Kuepfer D.J. The Pittsburgh sleep quality index: A new instrument for psychiatric practice and research. Psychiatry Res. 1989;28:193–213. doi: 10.1016/0165-1781(89)90047-4.
    1. Marrugat J., Vila J., Pavesi M., Sanz F. Estimación del tamaño de la muestra en la investigación clínica y epidemiológica. Med. Clin. 1998;111:267–276.
    1. Foley H.M., Steel A.E. Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence. Complement. Ther. Med. 2019;42:65–81. doi: 10.1016/j.ctim.2018.11.003.
    1. Cummings J.E., Kovacic J.P. The ubiquitous role of zinc in health and disease. J. Vet. Emerg. Crit. Care. 2009;19:215–240. doi: 10.1111/j.1476-4431.2009.00418.x.
    1. Swardfager W., Herrmann N., Mazereeuw G., Goldberger K., Harimoto T., Lanctôt K.L. Zinc in depression: A meta-analysis. Biol. Psychiatry. 2013;74:872–878. doi: 10.1016/j.biopsych.2013.05.008.
    1. Maes M., Mihaylova I., De Ruyter M. Lower serum zinc in chronic fatigue syndrome: Relationships to immune dysfunction and relevance for the oxidative stress status in CFS. J. Affect. Disord. 2006;90:141–147. doi: 10.1016/j.jad.2005.11.002.
    1. Acuna-Castroviejo D., Escames G., Reiter R.J. Melatonin therapy in fibromyalgia. J. Pineal Res. 2006;40:98–99. doi: 10.1111/j.1600-079X.2005.00278.x.
    1. La Rubia M., Rus A., Molina F., del Moral M.L. Is fibromyalgia-related oxidative stress implicated in the decline of physical and mental health status. Clin. Exp. Rheumatol. 2013;31:S121–S127.
    1. Korszun A., Sackett-Lundeen L., Papadopoulus E., Brucksch C., Masterson L., Engelberg N.C., Haus E., Demitrack M.A., Crofford L. Melatonin levels in women with fibromyalgia and chronic fatigue syndrome. J. Rheumatol. 1999;26:2675–2680.
    1. Castro-Marrero J., Sáez-Francàs N., Segundo M.J., Calvo N., Faro M., Aliste L., Fernández de Sevilla T., Alegre J. Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome: A randomized, controlled, double-blind trial. Clin. Nutr. 2016;35:826–834. doi: 10.1016/j.clnu.2015.07.010.
    1. van Heukelom R.O., Prins J.B., Smits M.G., Bleijenberg G. Influence of melatonin on fatigue severity in patients with chronic fatigue syndrome and late melatonin secretion. Eur. J. Neurol. 2006;13:55–60. doi: 10.1111/j.1468-1331.2006.01132.x.
    1. Pardini M., Cordano C., Benassi F., Mattei C., Sassos D., Guida S., Serrati C., Primavera A., Amore M., Cocito L., et al. Agomelatine but not melatonin improves fatigue perception: A longitudinal proof-of-concept study. Eur. Neuropsychopharmacol. 2014;24:939–944. doi: 10.1016/j.euroneuro.2014.02.010.
    1. Starreveld D.E.J., Daniels L.A., Valdimarsdottir H.B., Redd W.H., de Geus J.L., Ancoli-Israel S., Lutgendorf S., Korse C.M., Kieffer J.M., van Leeuwen F.E., et al. Light therapy as a treatment of cancer-related fatigue in (non-) Hodgkin lymphoma survivors (SPARKLE trial): Study protocol of a multicenter randomized controlled trial. BMC Cancer. 2018;18:880. doi: 10.1186/s12885-018-4746-2.
    1. Steur L.M.H., Kaspers G.J.L., Van Someren E.J.W., Van Eijkelenburg N.K.A., Van der Sluis I.M., Dors N., Van den Bos C., Tissing W.J.E., Grootenhuis M.A., Van Litsenburg R.R.L. Sleep-wake rhythm disruption is associated with cancer-related fatigue in paediatric acute lymphoblastic leukaemia. Sleep. 2020;43:zsz320. doi: 10.1093/sleep/zsz320.
    1. Hemati K., Kadijani A.A., Sayehmiri F., Mehrzadi S., Zabihiyeganeh M., Hosseinzadeh A., Mirzaei A. Melatonin in the treatment of fibromyalgia symptoms: A systematic review. Complement. Ther. Clin. Pract. 2020;38:101072. doi: 10.1016/j.ctcp.2019.101072.
    1. Adamczyk-Sowa M., Sowa P., Adamczyk J., Niedziela N., Misiolek H., Owczarek M., Zwirska-Korczala K. Effect of melatonin supplementation on plasma lipid hydroperoxides, homocysteine concentrations and chronic fatigue syndrome in multiple sclerosis patients treated with interferons-beta and mitoxantrone. J. Physiol. Pharmacol. 2016;67:235–242.
    1. Adamczyk-Sowa M., Pierzchala K., Sowa P., Polaniak R., Kukla M., Hartel M. Influence of melatonin supplementation on serum antioxidative properties and impact of the quality of life in multiple sclerosis patients. J. Physiol. Pharmacol. 2014;65:543–550.
    1. de Figueiredo Ribeiro S.M., Moreno Braga C.B., Maris Peria F., Zangiacomi Martinez E., Ribeiro da Rocha J.J., Carvalho Cunha S.F. Effects of zinc supplementation on fatigue and quality of life in patients with colorectal cancer. Einstein. 2017;15:24–28. doi: 10.1590/s1679-45082017ao3830.
    1. Rondanelli M., Opizzi A., Monteferrario F., Antoniello N., Manni R., Klersy C. The effect of melatonin, magnesium and zinc on primary insomnia in long-term care facility residents in Italy: A double-blind, placebo-controlled clinical trial. J. Am. Geriatr. Soc. 2011;59:82–90. doi: 10.1111/j.1532-5415.2010.03232.x.
    1. Celer M., Mogulkoc R., Baltaci A.K., Dervis Dasdelen D. The effects of zinc and melatonin on muscle ischaemia-reperfusion injury in rat. Cell. Mol. Biol. 2018;64:1–4. doi: 10.14715/cmb/2018.64.3.1.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться