Rev. Bras. Reumatol. vol.55 número6

w w w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Original

article

The

importance

of

lactic

acid

in

migraines

and

fibromyalgia

夽

Guido

Assis

Cachuba

de

Sá

Ribeiro

_,

_Rosana

_Hermínia

_Scola

,

Elcio

Juliato

Piovesan

,

Darley

Rugeri

Wollmann

Junior

_,

_Eduardo

_dos

_Santos

_Paiva

_,

Claudio

Leinig

Pereira

da

Cunha

,

Lineu

Cesar

Werneck

a_{InternalMedicineandHealthSciencesPost-GraduationProgram,UniversidadeFederaldoParaná(UFPR),Curitiba,PR,Brazil} b_{Neuromuscular/Neurology,HospitaldeClínicas,UniversidadeFederaldoParaná(UFPR),Curitiba,PR,Brazil}

c_{HeadacheUnit/Neurology,HospitaldeClínicas,UniversidadeFederaldoParaná(UFPR),Curitiba,PR,Brazil} d_{Cardiology/InternalMedicine,HospitaldeClínicas,UniversidadeFederaldoParaná(UFPR),Curitiba,PR,Brazil} e_{Rheumatology/InternalMedicine,HospitaldeClínicas,UniversidadeFederaldoParaná(UFPR),Curitiba,PR,Brazil}

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Articlehistory:

Received20February2014 Accepted17February2015 Availableonline8September2015

Keywords:

Chronicmigraine Episodicmigraine Lacticacid Fibromyalgia

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b

s

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c

t

Background:Lacticacidisabyproductofbothmusclemetabolismandthecentralnervous system.Changesinmetabolismarerelatedtovariousphysiologicalandpathological con-ditions.Theaimofthisstudywastodeterminetherelationshipbetweenmigraineand fibromyalgiawiththelevelsoflacticacidintheblood.

Methods:Westudy93patientsdividedintofivegroups:(1)patientswithfibromyalgia(n=20); (2) episodic migraine(n=20);(3) chronicmigraine (n=20); (4)fibromyalgiaand episodic migraine(n=13);and(5)fibromyalgiaandchronicmigraine(n=20),and20 healthy sub-jects(controlgroup).Bloodlevelsoflacticacidweremeasuredatfourdifferenttimepoints: atrest,duringaerobicexercise,duringanaerobicphysicalactivityandwhilerestingafter anaerobicexercise.

Results:Lacticacidincreasedinallgroupsduringanaerobicphysicalactivitywithout pre-dominanceforeithergroup.Duringaerobicphysicalactivity,allgroupsincreasedlacticacid levels,buttheincreasewasmoreexpressiveinthechronicmigrainegroupandthechronic migrainewithfibromyalgiagroupwithoutstatisticalsignificance.

Conclusions: We didnot foundabnormalitiesinvolvingthe metabolism oflactic acidin episodicandchronicmigrainewithorwithoutfibromyalgia.

©2015ElsevierEditoraLtda.Allrightsreserved.

夽

ThestudywasconductedattheNeurology,CardiologyandRheumatologyServices,HospitaldeClínicas,UniversidadeFederaldo Paraná(UFPR),Curitiba,PR,Brazil.

∗ _{Correspondingauthor.}

E-mail:lineu.werneck@hc.ufpr.br(L.C.Werneck).

http://dx.doi.org/10.1016/j.rbre.2015.08.012

A

importância

de

ácido

láctico

na

enxaqueca

e

na

fibromialgia

Palavras-chave:

Enxaquecacrônica Enxaquecaepisódica Ácidoláctico Fibromialgia

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e

s

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m

o

Introduc¸ão: Oácidolácticoéumsubprodutodometabolismomuscularedosistemanervoso central.Asalterac¸õesnometabolismoestãorelacionadascomdiversascondic¸ões fisiológ-icasepatológicas.Oobjetivodesteestudofoideterminararelac¸ãoentreaenxaquecaea fibromialgiacomosníveisdeácidolácticonosangue.

Métodos: Foramestudados93pacientes,divididosemcincogrupos:1)fibromialgia(n=20); 2)enxaquecaepisódica(n=20);3)enxaquecacrônica(n=20);4)fibromialgiaeenxaqueca episódica(n=13);e 5)fibromialgiae enxaquecacrônica (n=20), além de20 indivíduos saudáveis(grupocontrole).Osníveissanguíneosdeácidolácticoforammedidosemquatro momentos:emrepouso,duranteoexercícioaeróbico,duranteaatividadefísicaanaeróbica eduranteodescansodepoisdoexercícioanaeróbico.

Resultados: O ácido láctico aumentou em todos os grupos durante a atividade física anaeróbica,sempredominânciaemqualquergrupo.Duranteaatividadefísicaaeróbica, todososgruposapresentaramumaumentonosníveisdeácidoláctico,masesseaumento foimaisexpressivonosgruposdeenxaquecacrônicaeenxaquecacrônicacomfibromialgia, semsignificânciaestatística.

Conclusões: Nãoforamencontradasanormalidadesqueenvolvessemometabolismodo ácidolácticonaenxaquecaepisódicaecrônica,napresenc¸aounãodefibromialgia.

©2015ElsevierEditoraLtda.Todososdireitosreservados.

Introduction

Migraineisachronicneurologicaldisorderwithhigh preva-lenceand severe impacton apatient’s quality oflife.This disorderhasgeneticcharacteristicsthatmodulatea dysfunc-tioninbrainelectricalactivity.Thisneurologicalconditionis characterizedbyrecurrentepisodesofheadachewith unilat-eralthrobbingcharacteristicsofmoderatetostrongseverity thatworsenswithphysicalactivity.Thisworseningis associ-atedwithvomiting,nausea,phonophobiaandphotophobia.1,2

Many biochemical changes can beobserved duringand

betweenmigraineattacks.Lacticacidlevels,forexample,may be altered, exhibiting an increase compared with patients

with tension-type headache and healthy controls.3 _These

datasuggest thatmigrainepatientshaveanabnormalityin mitochondrialmetabolism.Itwasdemonstratedthatlactate levelswithinthevisualoccipitalcortexiselevatedinmigraine patientsduringtheinter-ictalperiodand couldsuggestthe presenceofanaerobicglycolysisincorticalregions.4_However,

other studies have notconfirmed these changes and,as a

result,donotsupportthishypothesis.5

Lacticacidusuallyincreasesduringhigh-intensityphysical activityandisrelatedtoadeclineinmusclestrengthandpain generationduringexercise.6–8_{Additionally,theincreasein} lac-ticacidobservedduringexercisehasbeenshowntotrigger migraineattackswithaura.9,10 _{Despitethis causal} relation-ship,lacticacidisnotconsideredanalgogenicsubstance.11

Fibromyalgia is a chronic pain condition of unknown

etiology characterized by widespread spontaneous muscle

pain and tenderness to palpation. The diagnostic criteria

usedforfibromyalgia comesfrom the American Collegeof

Rheumatology2009and2010.12,13_{Fibromyalgiacanalso} dis-playco-morbidities,suchaspsychiatricdisordersandother

pain syndromes. Thecorrelationbetweenfibromyalgia and

migraine variesfrom22 to50% ofcases.14 _{Thisassociation} contributes to a decreased quality of life forpatients and enhances thepresenceofco-morbidities.The pathophysio-logicalrelationshipbetweenthesetwodisordershasnotyet beenestablishedinthemedicalliterature.

Patientswithfibromyalgiamayexperiencehigh levelsof lactic acid atrest15,16 _{or during aerobicphysical activity.}17 However,otherstudiesshowthatchangesinglycolysisand lactic acid at rest or during physical activity were slight increasedamongfibromyalgiapatients.18,19

Theratiooflacticacidproductioninpatientswithmigraine andfibromyalgia,aswellastheinfluenceofthismetabolite inthepathophysiologyofthesediseases,iscontroversialor nonexistent.Thegoalofthisstudyistodeterminewhether themetabolismoflacticacidchangedinepisodicmigraineor chronicmigraine,withorwithoutassociatedfibromyalgia.

Patients

and

methods

We selected from out-patient headache clinic cases with

chronicandepisodicmigrainewhowerealsosufferingfrom fibromyalgia and from the out-patient rheumatology clinic forpatientswithonlyfibromyalgia.Allpatientswithchronic

and episodic migraine met the criteria proposed by the

Medications

Aportionofpatientscontinuouslyusedoneormoreofthe fol-lowingmedications:selectiveinhibitorsofserotoninuptake (n=23), tricyclic antidepressants (n=20), selective

recep-tor of serotonin inhibitors, norepinephrine and dopamine

(n=5), antipsychotics/dopamine blockers (n=6), benzodi-azepines (n=14), sleep inducers (n=1), muscle relaxants (n=19),anti-inflammatorydrugs(n=9),antimalarials(n=2), antihistaminesforallergy(n=4),statins(n=3),protonpump blockers(n=6),anticonvulsants(n=10),angiotensin convert-ing enzyme inhibitors (n=10), diuretics (n=10), oral anti-coagulants(n=1), alendronate (n=1), levothyroxine (n=15), metformin,insulinandorlistat(n=4).

Symptomsduringtesting

Thetestswereperformeddespitethepainfulmuscle symp-tomsinpatientswithfibromyalgia.Thepatientswithepisodic

migraine underwent the test only if they were free of a

headachecrisisforatleastfivedays.Patientswithchronic migraineweretestedduringperiodsoflowerheadache inten-sity.

Exercisestresstesting

Thepatientsunderwentexercisestresstestingusinga tread-millwith progressiveincrementsofeffort and whileusing thesoftwareMicromedErgoPC13.Initially,thepatientshadan electrocardiogramatrest(baselinecontrolphase)followedby exerciseswithameandurationof30min.Thetreadmillwas inaflatposition,startedatspeedsof2.0mphandincreased

by 1.0mph every minute until reaching 9.0mph. The test

wasdividedintodifferentstages:aerobic,anaerobicexercise andrestpostexercise.Todifferentiatebetweenaerobicand anaerobicexercise,weusedtheKarvonenformula(220minus subjectage=maximumheartratefortheage).Weconsidered aerobicmetabolicactivitywhentheheartratewasbetween 50and69%ofthepredictedvaluefoundintheKarvonen for-mulafortheageandanaerobicexercisewhentheheartrate wasfrom70%to85%ofthepredictedmaximum.Allsubjects sustainedtheexerciseatthenecessaryheartrateforatleast 3min.19_{Allsubjectswereconsideredtobesedentary.}

Lacticaciddetermination

Lacticacidwasdeterminedbycapillarybloodsamplesviaa transdermalskinpunchoftheleftindexfingeratfourtime points: (1) restingbaseline beforeexercise; (2) after10min ofaerobicactivity;(3)after3minofanaerobicactivity;and (4)after6minofrestfollowinganaerobicexercise.Adropof bloodwasplacedonaspecificpapertape(RocheDiagnostics Brazil)andintroducedintoadeviceforreflectancephotometry (AccutrendLactate,Roche Diagnostica, Brazil),which auto-maticallydeterminedthelevelsoflacticacid.

Ethicsstudy

All patients signed an informed consent form.The

proce-duresinthis studywereapprovedbythe ethicscommittee

forhumanresearchattheHospitaldeClinicas,Universidade FederaldoParaná.

Statisticalanalysis

Inadditiontodescriptivestatisticaltests,weusedthet-test forindependentsamples(homogenizationofcases)andthe

Mann–WhitneyUtestformakingcomparisonsbetweenthe

levelsoflacticacidinthevariousstagesofthestudy(p<0.05 forstatisticalsignificance).Toconfirmtheresultsweapplied theBonferronicorrection.Statisticalanalysisandplotswere doneusingtheSPSSsoftwareversion11.0(Chicago,IL).

Results

Studysubjects

Thestudysubjectsweregroupedbyage,weight,heightand bodymassindex(BMI).Allsubjectsandcontrolswerefemales. Patientsweredividedintosixgroups:GroupI–thehealthy subjects using no medication (n=20); Group II – patients withonlyfibromyalgia(n=20);GroupIII–patientswithonly episodic migraine (n=20); Group IV – patients with only chronicmigraine(n=20);GroupV–patientswith fibromyal-giaplusepisodicmigraine(n=13);andGroupVI–patientswith fibromyalgiapluschronicmigraine(n=20)(Table1).Allgroups weresimilar,andtherewasnostatisticallysignificant differ-encebetweenthemwithrespecttoage,weight,heightorbody massindex(BMI)(Table1).

Lacticacidbloodlevels

Thelacticacidwasmeasuredin113casesinfouroccasions (452 analyses): the baseline phase, aerobic phase, anaero-bic phase and rest after physical activity. The lactic acid

average of all groups underwent elevation during

anaer-obic activity and remained high during the rest period.

Comparison of all subjects lactic acid level at the

base-line phase (2.70±1.32mmol/L) with the anaerobic phase

(3.81±1.81mmol/L)showedasignificantincrease(p=0.0001). The lactic acid level at the baseline phasecompared with the post-exercise rest (3.28±1.34mmol/L)was also signifi-cant(p=0.001).Theaerobicphaselacticacidalsoincreased (3.01±2.20mmol/L)but wasnotsignificantlydifferentfrom thebaseline(p=0.125)(Fig.1).

No significant difference was found between aerobic

exercises when compared with the baseline phase in all

groups.Anaerobicexerciseincreasedthelacticacidcompared with baselineinthe controlgroup(p=0.0001),fibromyalgia group (p=0.0001) and chronic migraine group (p=0.008). In the post-exercise rest group, the lactic acid remained ele-vated in the control group (p=0.008) and the fibromyalgia group(p=0.003).Inthegroupsofepisodicmigraine,chronic migraine, fibromyalgia plus episodic migraine and chronic migraineplusfibromyalgia,thelevelsoflacticacidremained slightlyelevatedornearthebasalcontrolwithoutstatistical significance(Table2).

Table1–Subjectscharacteristicsofthecontrols,fibromyalgiaandmigrainecases.

Group Numberofcasesa _{Age(years-old)}

Mean±SD Min–max

Weight(kg) Mean±SD

Min–max

Height(m) Mean±SD Min–max

Bodyindex mass Mean±SD

Min–max

Controls 20 42.60±9.36

(22–56)

66.75±9.15 (53–84)

1.64±0.76 (1.53–1.80)

24.95±3.90 (18.59–34.17) Fibromyalgia 20 47.35±6.33

(32–57)

65.75±12.38 (46–90)

1.60±0.54 (1.49–1.70)

25.65±4.98 (18.81–34.07) Episodicmigraine 20 37.75±10.54

(21–59)

65.95±12.68 (46–90)

1.62±0.67 (1.50–1.76)

25.24±5.21 (17.85–35.15) Chronicmigraine 20 39.15±12.13

(26–67)

65.15±11.88 (45–100)

1.60±0.78 (1.47–1.79)

25.71±5.34 (20.00–42.16) Episodicmigraine

plusfibromyalgia

13 46.92±8.64 (30–62)

71.08±4.70 (65–80)

1.61±0.55 (1.53–1.72)

27.33±2.35 (23.87–30.86) Chronicmigraine

plusFibromyalgia

20 44.30±6.45 (31–57)

66.45±12.39 (44–92)

1.61±0.73 (1.50–1.76)

25.56±4.16 (19.04–31.59)

SD,standarddeviation;min,minimal;max,maximal.

a _{Allcaseswerefemales.}

Table2–Lacticacidlevelsatrestandthetypeofexercisesphases.

Group Numberofcases Rest(mmol/L)

Mean±SD

Aerobic (mmol/L) Mean±SD

Anaerobic (mmol/L) Mean±SD

Restpost exercise (mmol/L) Mean±SD

Controls 20 2.39±0.88 2.82±2.41 3.64±1.31 3.34±1.24

Fibromyalgia 20 2.33±1.08 2.38±1.71 4.32±1.96 3.37±1.56

Episodicmigraine 20 2.93±1.38 3.22±2.70 3.22+0.96 3.25±1.39

Chronicmigraine 20 2.79±1.25 3.40±1.91

p=0.048a

4.21±1.56 3.44±1.19

Episodicmigraineplusfibromyalgia 13 2.40±0.83 2.05±0.81 4.15±3.40 3.05±1.60 Chronicmigraineplusfibromyalgia 20 3.23±1.95 3.87±2.53

p=0.042a

3.43±1.48 3.16±1.27

SD,standarddeviation.

a _{StatisticalsignificanceinrelationtothecontrolgroupbeforeBonferroniCorrection(Mann–WhitneyUtest).}

thephasesofanaerobicexerciseandrestafterexercisephase. Intheaerobicphasewefoundthatthelevelsoflacticacid increasedinthechronicmigrainegroup(p=0.048)andchronic migraineplusfibromyalgiagroup(p=0.042)whencompared withtheothergroups.However,ifweappliedtheBonferroni correction,thisstatisticalsignificancedisappears(Table2).

Nopatientswithfibromyalgiareportedincreasedofmuscle paininallphasesoftheexercise.Allpatientswithmigraine andcontrolshadnonewcomplaintsrelatedtestsduringthe study.

Discussion

Thelactic acid blood level increasedduring exercise, with theskeletalmusclebeingthelargest productionsite.20 _The increase inlactic acid production occurs after anincrease

of glycogenolysis and glycolysis. These changes promote

a reversal ofsystemic genesis of energy, increasing circu-lating levels of catecholamines and altering the systemic glucose metabolism.21,22 _{The energy source in the central}

nervous system (CNS) originates from glucose and lactic

acid.Thelatterservesasenergysourceafterovercomingthe

blood–brainbarrierorwhenbeingproduceddirectlyinglial cells.23_{IntheCNS,lacticacidisessentialformaintainingthe} metabolicinteractionsbetweenastrocytesandneurons,and itsincreasesinlacticacidinfluenceneuronalactivityinthe hypothalamusandthesolitarytract.24,25

Thediffusionoflactic acid isknowntobemediatedby transporters,suchasmonocarboxylatetransporters1(MCT1) and 2(MCT2), allowinggreater ATPsynthesis, closure ofK channels and neuronal depolarization.26 _{The sub-forms of}

MCT1 and MCT2 are expressed in the sites of lactic acid

production (muscle and glialcells) and local of utilization (astrocytes,bloodvessels,hippocampus,cerebellum,cerebral cortexandhypothalamus).27_{Inhumans,theamountof} intra-cellular lactate is determined by the balance between the amountproducedinthecellfromincreasedglycolysis (physi-calactivity)andthequantitytransportedoutofthecellorinto themitochondria(influencedbyMCT1).Acutephysical activ-ityalterstheexpressionofMCT1inthefirstminutes,andthis changeismaintainedwithin24hoursafterexercise.28

A central mechanism that may alter lactate removalis

4.0

3.5

3.0

2.5

Rest Aerobic Anaerobic

Lactic acid levels (mmoles/I)

Rest post anaerobic

Fig.1–Lacticacidlevelsandresponsetothetypeof exercisesin113femalecases(controls20;fibromyalgia20; episodicmigraine20;chronicmigraine20;episodic migraineplusfibromyalgia13;andchronicmigraineplus fibromyalgia20).

function, peripheral blood flow and the elevation of

cat-echolamine levels (norepinephrine and epinephrine).29

However,themainremovalcapacityoflactateduring exer-ciseisdetermined bytheactionofcellularMCT1, whichis expressedinlargeamountsinthefirstminutesfollowingthe onsetofphysicalactivity.Thisrelationshipoccurssuchthat theincreasedamountofcirculatingMCT1isdirectlyrelated tothereductionofthelevelsofmusclelacticacid.30,31

Conclusion

In conclusion our groups ofchronic migraine and chronic

migraineplusfibromyalgiashowedsignificantincreased lev-elsoflacticacidduringaerobicphysicalactivityinrelationto thecontrols.However,theydidnotreachastatistical signifi-cancelevelafterBonferronicorrection.Theincreasedlevels

seems to be more dependent on the presence of chronic

migrainethanfibromyalgiaandmaybeduetotheincreased production,bythedecreasedmetabolismoflacticacidorto theseveralmedicationsusedbythepatients.Ourfindings can-notsupportthesuggestionofabnormalmetabolismoflactic acidinpatientswithepisodicandchronicmigraineassociated withfibromyalgia.Nocausalrelationshipbetweenmigraine, fibromyalgiaandlacticacidproductionwasfound.

Funding

ThisworkwassupportedbygrantsfromFundac¸ãoAraucária,

CNPq,CAPES.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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