Tinnitus, the phantom perception of sounds, is a highly prevalent disorder. Although a wide variety of drugs have been investigated off label for the treatment of tinnitus, there is no approved pharmacotherapy. We report an open-label exploratory pilot study to assess the effect of muscle relaxants acting on the central nervous system on tinnitus patients. Cyclobenzaprine at high (30 mg) and low doses (10 mg), orphenadrine (100 mg), tizanidine (24 mg) and eperisone (50 mg) were administered to a maximum of 20 patients per group over a 12-week period. High-dose cyclobenzaprine resulted in a significant reduction in the Tinnitus Handicap Inventory (THI) score between baseline and week 12 in the intention-to-treat sample. On the other hand, other treatments were not effective. These results were confirmed in an explorative analysis where baseline corrected THI and Clinical Global Impression scores at week 12 were compared between groups. The present open trial presents a new promising pharmacotherapy for tinnitus that should be validated in placebo-controlled double-blind trials.

Abdul-Baqi KJ: Objective high-frequency tinnitus of middle-ear myoclonus. J Laryngol Otol 2004;118:231–233.
Aston-Jones G, Bloom FE: Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli. J Neurosci 1981;1:887–900.
Barnes CD, Fung SJ, Gintautas J: Brainstem noradrenergic system depression by cyclobenzaprine. Neuropharmacology 1980;19:221–224.
Bauer CA, Turner JG, Caspary DM, Myers KS, Brozoski TJ: Tinnitus and inferior colliculus activity in chinchillas related to three distinct patterns of cochlear trauma. J Neurosci Res 2008;86:2564–2578.
Bayar N, Boke B, Turan E, Belgin E: Efficacy of amitriptyline in the treatment of subjective tinnitus. J Otolaryngol 2001;30:300–303.
Bezerra Rocha CA, Sanchez TG, Tesseroli de Siqueira JT: Myofascial trigger point: a possible way of modulating tinnitus. Audiol Neurotol 2008;13:153–160.
Bjorne A: Tinnitus aereum as an effect of increased tension in the lateral pterygoid muscle. Otolaryngol Head Neck Surg 1993;109:969.
Blackshear MA, Friedman RL, Sanders-Bush E: Acute and chronic effects of serotonin (5-HT) antagonists on serotonin binding sites. Naunyn Schmiedebergs Arch Pharmacol 1983;324:125–129.
Browning R, Jackson JL, O’Malley PG: Cyclobenzaprine and back pain: a meta-analysis. Arch Intern Med 2001;161:1613–1620.
Cabitza P, Randelli P: Efficacy and safety of eperisone in patients with low back pain: a double blind randomized study. Eur Rev Med Pharmacol Sci 2008;12:229–235.
Cacace AT: Hearing loss and tinnitus prevention initiatives: partnerships for success. Am J Audiol 2006;15:99–100.
Cacace AT, Cousins JP, Parnes SM, McFarland DJ, Semenoff D, Holmes T, Davenport C, Stegbauer K, Lovely TJ: Cutaneous-evoked tinnitus. II. Review of neuroanatomical, physiological and functional imaging studies. Audiol Neurotol 1999;4:258–268.
Chau C, Barbeau H, Rossignol S: Effects of intrathecal alpha1- and alpha2-noradrenergic agonists and norepinephrine on locomotion in chronic spinal cats. J Neurophysiol 1998;79:2941–2963.
Chikamori Y, Sasa M, Fujimoto S, Takaori S, Matsuoka I: Locus coeruleus-induced inhibition of dorsal cochlear nucleus neurons in comparison with lateral vestibular nucleus neurons. Brain Res 1980;194:53–63.
Cohen J: Statistical Power Analysis for the Behavioral Sciences. Hillsdale, Erlbaum, 1988.
Commissiong JW, Karoum F, Reiffenstein RJ, Neff NH: Cyclobenzaprine: a possible mechanism of action for its muscle relaxant effect. Can J Physiol Pharmacol 1981;59:37–44.
Cullington H: Tinnitus evoked by finger movement: brain plasticity after peripheral deafferentation. Neurology 2001;56:978.
Darlington CL, Smith PF: Drug treatments for tinnitus. Prog Brain Res 2007;166:249–262.
Dehmel S, Cui YL, Shore SE: Cross-modal interactions of auditory and somatic inputs in the brainstem and midbrain and their imbalance in tinnitus and deafness. Am J Audiol 2008;17:S193–S209.
De Ridder D, Elgoyhen AB, Romo R, Langguth B: Phantom percepts: tinnitus and pain as persisting aversive memory networks. Proc Natl Acad Sci USA 2011;108:8075–8080.
De Ridder D, Heijneman K, Haarman B, van der Loo E: Tinnitus in vascular conflict of the eighth cranial nerve: a surgical pathophysiological approach to ABR changes. Prog Brain Res 2007;166:401–411.
De Ridder D, Ryu H, Moller AR, Nowe V, Van de Heyning P, Verlooy J: Functional anatomy of the human cochlear nerve and its role in microvascular decompressions for tinnitus. Neurosurgery 2004;54:381–388, discussion 388–390.
De Ridder D, Verstraeten E, Van der Kelen K, De Mulder G, Sunaert S, Verlooy J, Van de Heyning P, Moller A: Transcranial magnetic stimulation for tinnitus: influence of tinnitus duration on stimulation parameter choice and maximal tinnitus suppression. Otol Neurotol 2005;26:616–619.
Desaphy JF, Dipalma A, De Bellis M, Costanza T, Gaudioso C, Delmas P, George AL Jr, Camerino DC: Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine. Pain 2009;142:225–235.
Dobie RA: A review of randomized clinical trials in tinnitus. Laryngoscope 1999;109:1202–1211.
Dohrmann K, Weisz N, Schlee W, Hartmann T, Elbert T: Neurofeedback for treating tinnitus. Prog Brain Res 2007;166:473–485.
Eggermont JJ: Pathophysiology of tinnitus. Prog Brain Res 2007;166:19–35.
Eggermont JJ, Roberts LE: The neuroscience of tinnitus. Trends Neurosci 2004;27:676–682.
Elgoyhen AB, Langguth B: Pharmacological approaches to the treatment of tinnitus. Drug Discov Today 2010;15:300–305.
Gallinat J, Senkowski D, Wernicke C, Juckel G, Becker I, Sander T, Smolka M, Hegerl U, Rommelspacher H, Winterer G, Herrmann WM: Allelic variants of the functional promoter polymorphism of the human serotonin transporter gene is associated with auditory cortical stimulus processing. Neuropsychopharmacology 2003;28:530–532.
Goodey R: Tinnitus treatment: state of the art. Prog Brain Res 2007;166:237–246.
Helfer TM, Jordan NN, Lee RB, Pietrusiak P, Cave K, Schairer K: Noise-induced hearing injury and comorbidities among postdeployment US army soldiers: April 2003 through June 2009. Am J Audiol 2011;20:33–41.
Honda M, Nishida T, Ono H: Tricyclic analogs cyclobenzaprine, amitriptyline and cyproheptadine inhibit the spinal reflex transmission through 5-HT2 receptors. Eur J Pharmacol 2003;458:91–99.
Hunskaar S, Donnell D: Clinical and pharmacological review of the efficacy of orphenadrine and its combination with paracetamol in painful conditions. J Int Med Res 1991;19:71–87.
Ishizuki M, Yanagisawa M: Antinociceptive effects of tizanidine, diazepam and eperisone in isolated spinal cord-tail preparations of newborn rat. Pain 1992;48:101–106.
Jastreboff PJ, Jastreboff MM: Tinnitus retraining therapy: a different view on tinnitus. ORL J Otorhinolaryngol Relat Spec 2006;68:23–29, discussion 29–30.
Jones BE, Yang TZ: The efferent projections from the reticular formation and the locus coeruleus studied by anterograde and retrograde axonal transport in the rat. J Comp Neurol 1985;242:56–92.
Kaltenbach JA: The dorsal cochlear nucleus as a participant in the auditory, attentional and emotional components of tinnitus. Hear Res 2006;216–217:224–234.
Kaltenbach JA, Godfrey DA: Dorsal cochlear nucleus hyperactivity and tinnitus: are they related? Am J Audiol 2008;17:S148–S161.
Kino Y, Tanabe M, Honda M, Ono H: Involvement of supraspinal imidazoline receptors and descending monoaminergic pathways in tizanidine-induced inhibition of rat spinal reflexes. J Pharmacol Sci 2005;99:52–60.
Kleinjung T, Steffens T, Sand P, Murthum T, Hajak G, Strutz J, Langguth B, Eichhammer P: Which tinnitus patients benefit from transcranial magnetic stimulation? Otolaryngol Head Neck Surg 2007;137:589–595.
Kobayashi H, Hasegawa Y, Ono H: Cyclobenzaprine, a centrally acting muscle relaxant, acts on descending serotonergic systems. Eur J Pharmacol 1996;311:29–35.
Kornhuber J, Parsons CG, Hartmann S, Retz W, Kamolz S, Thome J, Riederer P: Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies. J Neural Transm Gen Sect 1995;102:237–246.
Koskinen J, Paavolainen M, Raivio M, Roschier J: Otological manifestations in temporomandibular joint dysfunction. J Oral Rehabil 1980;7:249–254.
Kuttila S, Kuttila M, Le Bell Y, Alanen P, Suonpaa J: Recurrent tinnitus and associated ear symptoms in adults. Int J Audiol 2005;44:164–170.
Landgrebe M, Langguth B, Zeman F, Koller M: Methodology of clinical trials for tinnitus; in Moller A, Langguth B, De Ridder D, Kleinjung T (eds): Textbook of Tinnitus. New York, Springer, 2011a, pp 199–212.
Landgrebe M, Zeman F, Koller M, Eberl Y, Mohr M, Reiter J, Staudinger S, Hajak G, Langguth B: The Tinnitus Research Initiative (TRI) database: a new approach for delineation of tinnitus subtypes and generation of predictors for treatment outcome. BMC Med Inform Decis Mak 2011b;10:42.
Landy S, Altman CA, Xie F: Time to recovery in patients with acute painful musculoskeletal conditions treated with extended-release or immediate-release cyclobenzaprine. Adv Ther 2011;28:295–303.
Langguth B, Goodey R, Azevedo A, Bjorne A, Cacace A, Crocetti A, Del Bo L, De Ridder D, Diges I, Elbert T, Flor H, Herraiz C, Ganz Sanchez T, Eichhammer P, Figueiredo R, Hajak G, Kleinjung T, Landgrebe M, Londero A, Lainez MJ, Mazzoli M, Meikle MB, Melcher J, Rauschecker JP, Sand PG, Struve M, Van de Heyning P, Van Dijk P, Vergara R: Consensus for tinnitus patient assessment and treatment outcome measurement: Tinnitus Research Initiative meeting, Regensburg, July 2006. Prog Brain Res 2007;166:525–536.
Langguth B, Hajak G, Kleinjung T, Pridmore S, Sand P, Eichhammer P: Repetitive transcranial magnetic stimulation and chronic tinnitus. Acta Otolaryngol Suppl 2006;556:102–105.
Langguth B, Landgrebe M, Kleinjung T, Sand P, Hajak G: Tinnitus and depression. World J Biol Psychiatry 2011;12:489–500.
Langguth B, Salvi R, Elgoyhen AB: Emerging pharmacotherapy of tinnitus. Expert Opin Emerg Drugs 2009;14:687–702.
Leite FM, Atallah AN, El Dib R, Grossmann E, Januzzi E, Andriolo RB, da Silva EM: Cyclobenzaprine for the treatment of myofascial pain in adults. Cochrane Database Syst Rev 2009;3:CD006830.
Levine RA, Abel M, Cheng H: CNS somatosensory-auditory interactions elicit or modulate tinnitus. Exp Brain Res 2003;153:643–648.
Lofland JH, Szarlej D, Buttaro T, Shermock S, Jalali S: Cyclobenzaprine hydrochloride is a commonly prescribed centrally acting muscle relaxant, which is structurally similar to tricyclic antidepressants (TCAs) and differs from amitriptyline by only one double bond. Clin J Pain 2001;17:103–104.
Malanga GA, Ruoff GE, Weil AJ, Altman CA, Xie F, Borenstein DG: Cyclobenzaprine ER for muscle spasm associated with low back and neck pain: two randomized, double-blind, placebo-controlled studies of identical design. Curr Med Res Opin 2009;25:1179–1196.
Mazurek B, Olze H, Haupt H, Szczepek AJ: The more the worse: the grade of noise-induced hearing loss associates with the severity of tinnitus. Int J Environ Res Public Health 2010;7:3071–3079.
Melcher JR, Sigalovsky IS, Guinan JJ Jr, Levine RA: Lateralized tinnitus studied with functional magnetic resonance imaging: abnormal inferior colliculus activation. J Neurophysiol 2000;83:1058–1072.
Mico JA, Ardid D, Berrocoso E, Eschalier A: Antidepressants and pain. Trends Pharmacol Sci 2006;27:348–354.
Moller AR: Tinnitus: presence and future. Prog Brain Res 2007a;166:3–16.
Moller AR: Tinnitus and pain. Prog Brain Res 2007b;166:47–53.
Moller AR, Rollins PR: The non-classical auditory pathways are involved in hearing in children but not in adults. Neurosci Lett 2002;319:41–44.
Murai K, Tyler RS, Harker LA, Stouffer JL: Review of pharmacologic treatment of tinnitus. Am J Otol 1992;13:454–464.
Orzechowski RF, Currie DS, Valancius CA: Comparative anticholinergic activities of 10 histamine H1 receptor antagonists in two functional models. Eur J Pharmacol 2005;506:257–264.
Patterson MB, Balough BJ: Review of pharmacological therapy for tinnitus. Int Tinnitus J 2006;12:149–159.
Pinchoff RJ, Burkard RF, Salvi RJ, Coad ML, Lockwood AH: Modulation of tinnitus by voluntary jaw movements. Am J Otol 1998;19:785–789.
Rajkowski J, Majczynski H, Clayton E, Aston-Jones G: Activation of monkey locus coeruleus neurons varies with difficulty and performance in a target detection task. J Neurophysiol 2004;92:361–371.
Rocha CA, Sanchez TG: Myofascial trigger points: another way of modulating tinnitus. Prog Brain Res 2007;166:209–214.
Rubinstein B: Tinnitus and craniomandibular disorders – is there a link? Swed Dent J Suppl 1993;95:1–46.
Salembier L, De Ridder D, Van de Heyning PH: The use of flupirtine in treatment of tinnitus. Acta Otolaryngol Suppl 2006;556:93–95.
Sanchez TG, da Silva Lima A, Brandao AL, Lorenzi MC, Bento RF: Somatic modulation of tinnitus: test reliability and results after repetitive muscle contraction training. Ann Otol Rhinol Laryngol 2007;116:30–35.
Sanchez TG, Guerra GC, Lorenzi MC, Brandao AL, Bento RF: The influence of voluntary muscle contractions upon the onset and modulation of tinnitus. Audiol Neurotol 2002;7:370–375.
Sayers AC, Burki HR, Eichenberger E: The pharmacology of 5-chloro-4-(2-imidazolin-2- yl-amino)-2,1,3-benzothiadiazole (DS 103-282), a novel myotonolytic agent. Arzneimittelforschung 1980;30:793–803.
Schlee W, Hartmann T, Langguth B, Weisz N: Abnormal resting-state cortical coupling in chronic tinnitus. BMC Neurosci 2009a;10:11.
Schlee W, Mueller N, Hartmann T, Keil J, Lorenz I, Weisz N: Mapping cortical hubs in tinnitus. BMC Biol 2009b;7:80.
Schlee W, Weisz N, Bertrand O, Hartmann T, Elbert T: Using auditory steady state responses to outline the functional connectivity in the tinnitus brain. PLoS One 2008;3:e3720.
Simpson JJ, Davies WE: A review of evidence in support of a role for 5-HT in the perception of tinnitus. Hear Res 2000;145:1–7.
Smits M, Kovacs S, de Ridder D, Peeters RR, van Hecke P, Sunaert S: Lateralization of functional magnetic resonance imaging (fMRI) activation in the auditory pathway of patients with lateralized tinnitus. Neuroradiology 2007;49:669–679.
Sullivan M, Katon W, Russo J, Dobie R, Sakai C: A randomized trial of nortriptyline for severe chronic tinnitus. Effects on depression, disability, and tinnitus symptoms. Arch Intern Med 1993;153:2251–2259.
Thompson AM, Moore KR, Thompson GC: Distribution and origin of serotoninergic afferents to guinea pig cochlear nucleus. J Comp Neurol 1995;351:104–116.
Van de Heyning P, Vermeire K, Diebl M, Nopp P, Anderson I, De Ridder D: Incapacitating unilateral tinnitus in single-sided deafness treated by cochlear implantation. Ann Otol Rhinol Laryngol 2008;117:645–652.
Vio MM, Holme RH: Hearing loss and tinnitus: 250 million people and a US$10 billion potential market. Drug Discov Today 2005;10:1263–1265.
Wallhausser-Franke E, Cuautle-Heck B, Wenz G, Langner G, Mahlke C: Scopolamine attenuates tinnitus-related plasticity in the auditory cortex. Neuroreport 2006;17:1487–1491.
Watemberg NM, Roth KS, Alehan FK, Epstein CE: Central anticholinergic syndrome on therapeutic doses of cyproheptadine. Pediatrics 1999;103:158–160.
Westerberg BD, Roberson JB Jr, Stach BA: A double-blind placebo-controlled trial of baclofen in the treatment of tinnitus. Am J Otol 1996;17:896–903.
Wolf C, Schunack W: Synthesis and pharmacology of combined histamine H1-/H2-receptor antagonists containing diphenhydramine and cyproheptadine derivatives. Arch Pharm (Weinheim) 1996;329:87–94.
Yang M, Zhou M, He L, Chen N, Zakrzewska JM: Non-antiepileptic drugs for trigeminal neuralgia. Cochrane Database Syst Rev 2011;1:CD004029.
Zeman F, Koller M, Figueiredo R, Aazevedo A, Rates M, Coelho C, Kleinjung T, de Ridder D, Langguth B, Landgrebe M: Tinnitus handicap inventory for evaluating treatment effects: which changes are clinically relevant? Otolaryngol Head Neck Surg 2011;145:282–287.
Zhou J, Shore S: Projections from the trigeminal nuclear complex to the cochlear nuclei: a retrograde and anterograde tracing study in the guinea pig. J Neurosci Res 2004;78:901–907.
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