Novel Insights of Effects of Pregabalin on Neural Mechanisms of Intracortical Disinhibition in Physiopathology of Fibromyalgia: An Explanatory, Randomized, Double-Blind Crossover Study

Alícia Deitos, Matheus Dorigatti Soldatelli, Jairo Alberto Dussán-Sarria, Andressa Souza, Iraci Lucena da Silva Torres, Felipe Fregni, Wolnei Caumo, Alícia Deitos, Matheus Dorigatti Soldatelli, Jairo Alberto Dussán-Sarria, Andressa Souza, Iraci Lucena da Silva Torres, Felipe Fregni, Wolnei Caumo

Abstract

Background: The fibromyalgia (FM) physiopathology involves an intracortical excitability/inhibition imbalance as measured by transcranial magnetic stimulation measures (TMS). TMS measures provide an index that can help to understand how the basal neuronal plasticity state (i.e., levels of the serum neurotrophins brain-derived neurotrophic factor (BDNF) and S100-B protein) could predict the effect of therapeutic approaches on the cortical circuitries. We used an experimental paradigm to evaluate if pregabalin could be more effective than a placebo, to improve the disinhibition in the cortical circuitries in FM patients, than in healthy subjects (HS). We compared the acute intragroup effect of pregabalin with the placebo in FM patients and healthy subjects (HS) on the current silent period (CSP) and short intracortical inhibition (SICI), which were the primary outcomes. Pain scores and the pain pressure threshold (PPT) were secondary outcomes. Methods: This study included 27 women (17 FM and 10 HS), with ages ranging from 19 to 65 years. In a blinded, placebo-controlled clinical trial, participants were randomized to receive, in a cross-over manner, oral pregabalin of 150 mg or a placebo. The cortical excitability pain measures were assessed before and 90 min after receiving the medication. Results: A generalized estimating equation (GEE) model revealed that in FM, pregabalin increased the CSP by 14.34% [confidence interval (CI) 95%; 4.02 to 21.63] and the placebo reduced the CSP by 1.58% (CI 95%; -57 to 25.9) (P = 0.00). Pregabalin reduced the SICI by 8.82% (CI 95%, -26 to 46.00) and the placebo increased it by 19.56% (CI 95%; 8.10 to 59.45; P = 0.02). Pregabalin also improved the pain measures. In the treatment group, the BDNF-adjusted index was positively correlated and the serum S100-B negatively correlated with the CSP, respectively. However, in the HS, pregabalin and the placebo did not induce a statistically significant effect in either intracortical excitability or pain measures. Conclusion: These results suggest that pregabalin's effect on cortical neural networks occurs, particularly under basal neuronal hyperexcitability, because its impact on the cortical excitability and the pain measures was observed only in the FM group. This indicates that pregabalin increased the CSP to induce inhibition in specific neural networks, while it increased the SICI to improve the excitability in other neurobiological systems. Trial registration in clinicaltrials.gov Identifier: NCT02639533.

Keywords: BDNF; S100B; cortical silent period; fibromyalgia; short intracortical inhibition.

Figures

FIGURE 1
FIGURE 1
Experimental design – cross-over, assessments, and interventions in each one of two sessions. The period between each course was 1 week. Abbreviations: B-PCS, Brazilian Portuguese version of the pain catastrophizing scale; VAS, visual analog scale; STAI-E-T, state-trait anxiety inventory; BDI II, beck depression inventory II; FIQ, fibromyalgia impact questionnaire; PPT, pain pressure threshold; QST, quantitative sensory testing; MINI, mini-international neuropsychiatric interview; VASS, visual analog sleepiness scale; BDNF, brain-derived neurotrophic factor; S100B, S100 calcium-binding protein B; TMS, transcranial magnetic stimulation; TMS measures include motor threshold (MT), motor evoked potential (MEP), short intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP).
FIGURE 2
FIGURE 2
Flowchart showing recruitment and progress through the study.
FIGURE 3
FIGURE 3
(A,B) Percentage of change from pre- to post-intervention. Bars indicate the mean and the standard error of the mean (SEM). The groups are identified by letters: FM group treated with pregabalin (a) and placebo (b). HS group treated with pregabalin (c) and placebo (d). All comparisons were performed by using a GEE model, followed by the Bonferroni correction for post hoc multiple comparisons. Post hoc differences between groups are indicated via superscript letters.

References

    1. Amorim P. (2000). Mini International Neuropsychiatric Interview (MINI): validação de entrevista breve para diagnóstico de transtornos mentais. Rev. Bras. Psiquiatr. 22 106–115. 10.1590/S1516-44462000000300003
    1. Ballinger G. A. (2004). Using generalized estimating equations for longitudinal data analysis. Organ. Res. Methods 7 127–150. 10.1177/1094428104263672
    1. Barger S. W., Van Eldik L. J. (1992). S100 beta stimulates calcium fluxes in glial and neuronal cells. J. Biol. Chem. 267 9689–9694.
    1. Beck A. T., Steer R. A., Ball R., Ranieri W. (1996). Comparison of beck depression inventories -IA and -II in psychiatric outpatients. J. Pers. Assess. 67 588–597. 10.1207/s15327752jpa6703_13
    1. Bertolazi A. N., Fagondes S. C., Hoff L. S., Dartora E. G., da Silva Miozzo I. C., de Barba M. E. F., et al. (2011). Validation of the Brazilian Portuguese version of the Pittsburgh sleep quality index. Sleep Med. 12 70–75. 10.1016/j.sleep.2010.04.020
    1. Bockbrader H. N., Radulovic L. L., Posvar E. L., Strand J. C., Alvey C. W., Busch J. A., et al. (2010). Clinical pharmacokinetics of pregabalin in healthy volunteers. J. Clin. Pharmacol. 50 941–950. 10.1177/0091270009352087
    1. Brown B. W. (1980). The crossover experiment for clinical trials. Biometrics 36 69–79. 10.2307/2530496
    1. Caipa A., Alomar M., Bashir S. (2018). TMS as tool to investigate the effect of pharmacological medications on cortical plasticity. Eur. Rev. Med. Pharmacol. Sci. 22 844–852. 10.26355/EURREV_201802_14321
    1. Caumo W., Deitos A., Carvalho S., Leite J., Carvalho F., Dussán-Sarria J. A., et al. (2016). Motor cortex excitability and BDNF levels in chronic musculoskeletal pain according to structural pathology. Front. Hum. Neurosci. 10:357. 10.3389/fnhum.2016.00357
    1. Coghill R. C., Sang C. N., Maisog J. M., Iadarola M. J. (1999). Pain intensity processing within the human brain: a bilateral, distributed mechanism. J. Neurophysiol. 82 1934–1943. 10.1152/jn.1999.82.4.1934
    1. Di Lazzaro V., Oliviero A., Pilato F., Saturno E., Dileone M., Mazzone P., et al. (2004). The physiological basis of transcranial motor cortex stimulation in conscious humans. Clin. Neurophysiol. 115 255–266. 10.1016/j.clinph.2003.10.009
    1. Di Lazzaro V., Pilato F., Dileone M., Ranieri F., Ricci V., Profice P., et al. (2006). GABAA receptor subtype specific enhancement of inhibition in human motor cortex. J. Physiol. 575(Pt 3), 721–726. 10.1113/jphysiol.2006.114694
    1. Galhardoni R., Correia G. S., Araujo H., Yeng L. T., Fernandes D. T., Kaziyama H. H., et al. (2015). Repetitive transcranial magnetic stimulation in chronic pain: a review of the literature. Arch. Phys. Med. Rehabil. 96 S156–S172. 10.1016/j.apmr.2014.11.010
    1. Geers A. L., Helfer S. G., Weiland P. E., Kosbab K. (2006). Expectations and placebo response: a laboratory investigation into the role of somatic focus. J. Behav. Med. 29 171–178. 10.1007/s10865-005-9040-5
    1. Gomes-Oliveira M. H., Gorenstein C., Neto F. L., Andrade L. H., Wang Y. P. (2012). Validation of the Brazilian Portuguese Version of the beck depression inventory-II in a community sample. Rev. Bras. Psiquiatr. 34 389–394. 10.1016/j.rbp.2012.03.005
    1. Grizzle J. E. (1965). The two-period change-over design and its use in clinical trials. Biometrics 21 467–480. 10.2307/2528104
    1. Kaipper M. B., Chachamovich E., Hidalgo M. P. L., da Silva Torres I. L., Caumo W. (2010). Evaluation of the structure of Brazilian State-Trait Anxiety Inventory using a Rasch psychometric approach. J. Psychosom. Res. 68 223–233. 10.1016/j.jpsychores.2009.09.013
    1. Kim S.-H., Lee Y., Lee S., Mun C.-W. (2013). Evaluation of the effectiveness of pregabalin in alleviating pain associated with fibromyalgia: using functional magnetic resonance imaging study. PLoS One 8:e74099. 10.1371/journal.pone.0074099
    1. Kuczewski N., Fuchs C., Ferrand N., Jovanovic J. N., Gaiarsa J.-L. L., Porcher C. (2011). Mechanism of GABAB receptor-induced BDNF secretion and promotion of GABAA receptor membrane expression. J. Neurochem. 118 533–545. 10.1111/j.1471-4159.2011.07192.x
    1. Kujirai T., Caramia M. D., Rothwell J. C., Day B. L., Thompson P. D., Ferbert A., et al. (1993). Corticocortical inhibition in human motor cortex. J. Physiol. 471 501–519. 10.1113/jphysiol.1993.sp019912
    1. Lang N., Sueske E., Hasan A., Paulus W., Tergau F. (2006). Pregabalin exerts oppositional effects on different inhibitory circuits in human motor cortex: a double-blind, placebo-controlled transcranial magnetic stimulation study. Epilepsia 47 813–819. 10.1111/j.1528-1167.2006.00544.x
    1. Latremoliere A., Woolf C. J. (2009). Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J. Pain 10 895–926. 10.1016/j.jpain.2009.06.012
    1. Maclure M. (1991). The case-crossover design: a method for studying transient effects on the risk of acute events. Am. J. Epidemiol. 133 144–153. 10.1093/oxfordjournals.aje.a115853
    1. Marques A. P., Santos A. M. B., Matsutani L. A., Lage L. V. (2006). Validation of the Brazilian version of the Fibromyalgia Impact Questionnaire (FIQ). Rev. Bras. Reumatol. 46 24–31.
    1. McDonnell M. N., Orekhov Y., Ziemann U. (2006). The role of GABAB receptors in intracortical inhibition in the human motor cortex. Exp. Brain Res. 173 86–93. 10.1007/s00221-006-0365-2
    1. Mease P. J., Clauw D. J., Arnold L. M., Goldenberg D. L., Witter J., Williams D. A., et al. (2005). Fibromyalgia syndrome. J. Rheumatol. 322270–2277.
    1. Micheva K. D., Buchanan J., Holz R. W., Smith S. J. (2003). Retrograde regulation of synaptic vesicle endocytosis and recycling. Nat. Neurosci. 6 925–932. 10.1038/nn1114
    1. Molendijk M. L., Bus B. A., Spinhoven P., Penninx B. W., Kenis G., Prickaerts J., et al. (2011). Serum levels of brain-derived neurotrophic factor in major depressive disorder: state–trait issues, clinical features and pharmacological treatment. Mol. Psychiatry 16 1088–1095. 10.1038/mp.2010.98
    1. Pascual-Leone A., Valls-Solé J., Wassermann E. M., Hallett M. (1994). Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain 117 847–858. 10.1093/brain/117.4.847
    1. Rossi S., Hallett M., Rossini P. M., Pascual-Leone A., Safety of Tms Consensus Group. (2009). Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin. Neurophysiol. 120 2008–2039. 10.1016/j.clinph.2009.08.016
    1. Salerno A., Thomas E., Olive P., Blotman F., Picot M. C., Georgesco M. (2000). Motor cortical dysfunction disclosed by single and double magnetic stimulation in patients with fibromyalgia. Clin. Neurophysiol. 111 994–1001. 10.1016/S1388-2457(00)00267-4
    1. Schestatsky P., Stefani L. C., Sanches P. R., Silva Junior D. P., da Torres I. L. S., Dall-Agnol L., et al. (2011). Validation of a Brazilian quantitative sensory testing (QST) device for the diagnosis of small fiber neuropathies. Arq. Neuro Psiquiatr. 69 943–948. 10.1590/S0004-282X2011000700019
    1. Sehn F., Chachamovich E., Vidor L. P., Dall-Agnol L., de Souza I. C., Torres I. L., et al. (2012). Cross-cultural adaptation and validation of the brazilian portuguese version of the pain catastrophizing scale. Pain Med. 13 1425–1435. 10.1111/j.1526-4637.2012.01492.x
    1. Selinfreund R. H., Barger S. W., Pledger W. J., Van Eldik L. J. (1991). Neurotrophic protein S100 beta stimulates glial cell proliferation. Proc. Natl. Acad. Sci. U.S.A. 88 3554–3558. 10.1073/pnas.88.9.3554
    1. Siebner H. R., Dressnandt J., Auer C., Conrad B. (1998). Continuous intrathecal baclofen infusions induced a marked increase of the transcranially evoked silent period in a patient with generalized dystonia. Muscle Nerve 21 1209–1212. 10.1002/(SICI)1097-4598(199809)21:9<1209::AID-MUS15>;2-M
    1. Staud R., Spaeth M. (2008). Psychophysical and neurochemical abnormalities of pain processing in fibromyalgia. CNS Spectr. 13 12–17. 10.1017/S109285290002678X
    1. Tanga F. Y., Raghavendra V., Nutile-McMenemy N., Marks A., DeLeo J. A. (2006). Role of astrocytic S100β in behavioral hypersensitivity in rodent models of neuropathic pain. Neuroscience 140 1003–1010. 10.1016/j.neuroscience.2006.02.070
    1. van Elswijk G., Kleine B. U., Overeem S., Stegeman D. F. (2007). Expectancy induces dynamic modulation of corticospinal excitability. J. Cogn. Neurosci. 19 121–131. 10.1162/jocn.2007.19.1.121
    1. Vidor L., Torres I. L., Medeiros L., Dussán-Sarria J., Dall’Agnol L., Deitos A., et al. (2014). Association of anxiety with intracortical inhibition and descending pain modulation in chronic myofascial pain syndrome. BMC Neurosci. 15:42. 10.1186/1471-2202-15-42
    1. Warmenhoven F., van Rijswijk E., Engels Y., Kan C., Prins J., van Weel C., et al. (2012). The Beck Depression Inventory (BDI-II) and a single screening question as screening tools for depressive disorder in Dutch advanced cancer patients. Support. Care Cancer 20 319–324. 10.1007/s00520-010-1082-8
    1. Werhahn K. J., Kunesch E., Noachtar S., Benecke R., Classen J. (1999). No title. J. Physiol. 517(Pt 2), 591–597. 10.1111/j.1469-7793.1999.0591t.x
    1. Wolfe F., Clauw D. J., Fitzcharles M.-A., Goldenberg D. L., Hauser W., Katz R. S., et al. (2011). Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR preliminary diagnostic criteria for fibromyalgia. J. Rheumatol. 38 1113–1122. 10.3899/jrheum.100594
    1. Wolfe F., Smythe H. A., Yunus M. B., Bennett R. M., Bombardier C., Goldenberg D. L., et al. (1990). The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. report of the multicenter criteria committee. Arthritis Rheum. 33 160–172. 10.1002/art.1780330203
    1. Woolf C. J. (2011). Central sensitization: implications for the diagnosis and treatment of pain. Pain 152(Suppl.), S2–S15. 10.1016/j.pain.2010.09.030
    1. Yunus M. B. (2007). Fibromyalgia and overlapping disorders: the unifying concept of central sensitivity syndromes. Semi. Arthritis Rheum. 36 339–356. 10.1016/j.semarthrit.2006.12.009
    1. Zanette S. A., Dussan-Sania J. A., Souza A., Deitos A., Torres I. L. S., Caumo W. (2014). Higher serum S100B and BDNF levels are correlated with a lower pressure-pain threshold in fibromyalgia. Mol. Pain 10:46. 10.1186/1744-8069-10-46
    1. Ziemann U. (2004). TMS and drugs. Clin. Neurophysiol. 115 1717–1729. 10.1016/j.clinph.2004.03.006
    1. Ziemann U., Lönnecker S., Steinhoff B. J., Paulus W. (1996a). Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann. Neurol. 40 367–378. 10.1002/ana.410400306
    1. Ziemann U., Lönnecker S., Steinhoff B. J., Paulus W. (1996b). The effect of lorazepam on the motor cortical excitability in man. Exp. Brain Res. 109 127–135.
    1. Ziemann U., Reis J., Schwenkreis P., Rosanova M., Strafella A., Badawy R., et al. (2015). TMS and drugs revisited 2014. Clin. Neurophysiol. 126 1847–1868. 10.1016/j.clinph.2014.08.028

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