Treatment of tinnitus with acamprosate

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Slide 1 :

TREATMENT OF TINNITUS WITH ACAMPROSATE Andréia Azevedo,MD Ricardo Figueiredo,MD,MSc OTOSUL,Volta Redonda,RJ Faculdade de Medicina de Valença,RJ BRASIL www.otosul.com.br otosul@otosul.com.br

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TINNITUS “ the perception of sound or noise in the absence of internal or external sound stimulation”

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EPIDEMIOLOGY 1 to 32 % of population 35 to 50 milhões (USA) 10 to 12 % of > 65 ys 75 to 80 % of hearing losses 1- Ahmad,N; Seidman,M: Tinnitus in the older adult, Drugs and Aging, 2004,21(5): 297-305 2- Adams, PF; Hendershot,GE: Current estimatesfrom the National Health Interview Survey,1996 3- McFadden,D. Tinnitus:Facts,Theories and Tretaments.Washington,D.C.:National Academy Press 1982;1-150.

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“DEAFERENTATION” NIHL PRESBYCUSIS SCHWANNOMA METABOLICS AUTO-IMUNE OTHERS Pujol et al

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EXCITATORY INFLUENCES OF INNER EAR INHIBITORY INFLUENCES OF INNER EAR ELECTRICAL ACTIVITY AT CENTRAL AUDITORY PATHWAYS NEUROPLASTICITY TONOTOPICAL REORGANIZATION TINNITUS

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NEUROTRANSMITTERSinner ear Puel et al

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FEEDBACK REGULATIONneurotransmitters at inner ear Mazurek et al, 2007

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NMDA RECEPTORS AND EXCITOTOXICITY AT AUDITORY PATHWAYS, NMDA RECEPTORS ARE NOT INVOLVED IN PHYSIOLOGYCAL TRANSMISSION THEY MAY BE OVEREXPRESSED IN SITUATIONS SUCH AS NOISE EXPOSURE AND ISCHAEMIA THEY ARE VERY PERMEABLE TO CALCIUM IONS, THAT GET INTO NEURAL TERMINATIONS WATER FOLLOWS CALCIUM, LEADING TO NEURON SWELLING AND RUPTURE REPEATED EVENTS MAY DESTROY NEURON DEFINITIVELY AND SPREAD THROUGH CENTRAL AUDITORY PATHWAYS

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EXCITOTOXICITY Pujol et al

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TINNITUS AND NEUROTRANSMITTERS CHEMICAL IMBALANCES BETWEEN EXCITATORY AND INHIBITORY NEUROTRANSMITTERS AT PERIPHERIC AND CENTRAL AUDITORY PATHWAYS MAY BE INVOLVED IN MANY TINNITUS SUBTYPES. MAIN NEUROTRANSMITTERS INVOLVED ARE GLUTAMATE (exc), GABA (inh),DOPAMINE, SEROTONIN, ACHETYLCHOLINE(exc/inh). PHARMACOLOGICALLY ACTING AT THESE NEUROTRANSMITTERS MAY HELP MANY TINNITUS PATIENTS A COMPLEMENTARY METHOD THAT COULD HELP TO IDENTIFY THE IMBALANCED NEUROTRANSMITTER COULD BE OF GREAT VALUE

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TINNITUS TREATMENT WITH PIRIBEDIL GUIDED BY ECoCH AND AOE(Azevedo, Figueiredo, Oliveira, 2008, to be published)supported by a grant of Tinnitus Research Initiative Extratympanical ECoCh Modified “Tip-trode” eletrode(Azevedo) Piribedil, a dopamine agonist that acts at D2 receptors at inner ear lateral efferents 56 pts, double-blinded, cross-over Improvements compared with ECoCh THI and VAS

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GENERAL RESULTSWilcoxon test THI VAS

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RESULTSpacients with double-peak (DP) at the CAPMann-Whitney test piribedil placebo

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Azevedo, Figueiredo, Mello 2008 project granted by Tinnitus Research Initiative CAP DOUBLE-PEAK

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SP AND CAP DURATIONSpearman coefficient

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CONCLUSIONS Pacients with ECoCh evidence of neural hyperactivity at the synapsis with the IHC have better response to piribedil This may be due to Lateral Efferent System Dysfunction Does tinnitus results from hyperactivity ONLY at the Central Auditory Pathways ? ECoCh could be helpful at tinnitus drug treatment rationalization Azevedo,Figueiredo e Oliveira, 2008

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ACAMPROSATE Analog of homotaurine, a GABA-ergic agonist Active at post-synaptic GABA B receptors Antagonizes the effects of Glutamate Inhibits NMDA Interactions with both the glutamatergic and GABAergic systems in the Cochlea and Central Auditory Pathways

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Double blind studyAzevedo and Figueiredo,2005 50 tinnitus patients Transmission and Mixed hearing loss excluded. TMJ Disorders excluded Audiometer- Amplaid 177 Amplaid 750 to the timpanometry.

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TINNITUS CLASSIFICATION Age Gender Etiology Time Kind of tinnitus’ noise Hearing loss level Tinnitus Score (VAS)

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Tinnitus groups PLACEBO 25 patients Prescription: 03 times a day 30,60 and 90 days later In each visit :side effects, score changes,... ACAMPROSATE 25 patients Prescription:acamprosate 333 mg 03 times a day. 30,60 and 90 days later In each visit :side effects, score changes,...

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STUDY RESULTS Age –35 to 82 yrs (avg 60) Symptom’s time: 1 to 420 months (avg 101,78 months). Gender: 58% M, 42% F Tinnitus feature:creak-62%,whistle-46% 16% had more than one sound

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TINNITUS AETIOLOGY

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TINNITUS- Results 58 % bilateral 72 % ininterrupted 64 % with associated symptoms

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Study results Side Effects: Acamprosate 12% Placebo group 20% ACAMPROSATE side effects were all mild (stomach ache, chocking)

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TINNITUS SCALE EVOLUTION

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Improve Percentual Acamprosate 86,9 % improved 47,8 % superior than 50% of improvement in the score Other drugs Egb 761- 57,5 % CBMZ- 50 % Clonazepam- 32 % Nimodipine- 16,13 % Baclofen- 9,7 % Caroverine- 63 % Trimetazidine- 89 % Piribedil- 92,6 %

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Conclusion: Acamprosate has a double action mechanism in both peripheric and central auditory pathways and it is a safe drug to be in our therapeutic arsenal for tinnitus.

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NMDA Blockers Flupirtine – no effects (Salembier,2006) Memantine – no effects, maybe with longer periods treatment (Figueiredo,Langguth,Oliveira,Azevedo,2008) Acamprosate – good perspective (Azevedo and Figueiredo,2005;Martinez, 2007) Gacyclidine and Neramexane – future perspectives

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REFERENCES Azevedo AA, Figueiredo RR.Tinnitus treatment with acamprosate: double-blind study.Rev Bras Otorrinolaringol (Engl Ed). 2005 Sep-Oct;71(5):618-23. Azevedo AA, Figueiredo RR. Treatment of tinnitus with acamprosate. Prog Brain Res. 2007;166:273-7. Review. Martínez AP. Tratamiento del tinnitus en hipoacusias neurosensoriales de curvas descendentes por modulación de los neurotransmisores con el uso de acamprosato:Experiencia clínica. Rev. Otorrinolaringol. Cir. Cabeza Cuello 2007; 67: 13-19 Figueiredo RR, Langguth B, Oliveira PM, Azevedo AA.Tinnitus treatment with memantine.Otolaryngol Head Neck Surg. 2008 Apr;138(4):492-6. Salembier L, De Ridder D, Van Heyning PH. The use of flupirtine in treatment of tinnitus. Acta Otolaryngol Suppl. 2006 Dec;(556):93-5.

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