Can Tricyclic Antidepressants Cause Tinnitus?

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UKMi Q&A 2.5 Can tricyclic antidepressants cause tinnitus?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp Date prepared: 28th October 2014

Background

Tinnitus is a condition characterised by a ringing, buzzing or other noise in the ear that is not due to an external cause. It may be continuous or intermittent.

Answer

Tinnitus has been described following administration of various tricyclic antidepressants (TCAs). It is an infrequently reported event. For example in 1987, a retrospective chart review of 475 patients taking TCAs revealed 5 who developed tinnitus during therapy (about 1% of the patients) (1). None of them had any previous history of otologic disorders. In these patients, the condition developed after 2 –3 weeks of imipramine treatment at daily doses of imipramine ranging from 150mg to 250mg. Interestingly, the condition disappeared completely in every case despite continued use of imipramine and without any specific treatment for the tinnitus. The time from first detection of tinnitus to disappearance ranged from 2 to 4 weeks. The same authors later briefly described a sixth case of occupational tinnitus which was made worse by imipramine (2). Symptoms returned to baseline within 3 weeks despite continuing imipramine at the same dose.

An isolated case describes a woman taking 100mg imipramine daily who developed tinnitus after one week at this dose (3). When the daily dose was increased to 150mg, the tinnitus persisted initially but after 4 weeks at this dose it diminished. Therapy was interrupted for a short period (not specified) since the patient was in a clinical trial and it is implied that the tinnitus resolved during this time. When imipramine was re-introduced at 150mg daily there was no tinnitus.

A series of four patients with imipramine-associated tinnitus was described in 1980 (4). The daily doses causing this reaction ranged from 50mg to 150mg. In one case the reaction began only “2 or 3 days” after starting imipramine 50mg daily. The time to onset for the other cases is not given. In all patients, the imipramine dose was reduced and this led to abolition in three and improvement in the fourth. In this last case, changing from imipramine 75 - 150mg per day to desipramine 100 - 150mg per day was effective and tinnitus resolved and did not return. No details are given for resolution times, but the descriptions of each case suggest that improvement was rapid.

Tinnitus has been reported with other TCAs. In one case report, a patient developed the reaction after two weeks of therapy with amitriptyline (5). Tinnitus began 2 days after the dose was increased to 150mg daily. The patient could not tolerate the tinnitus and amitriptyline was stopped. Tinnitus resolved within 7 days, but returned when the drug was re-introduced at a lower dose (50mg daily for 2 weeks). A second case linked to amitriptyline has also been described in which tinnitus and other symptoms occurred about 30 minutes after a 150mg dose and lasted for 2 – 3 hours (6). These resolved when the regimen was altered to 50mg three times daily, thus avoiding peak levels. A more recent case report describes a woman who developed sudden-onset unilateral tinnitus whilst taking amitriptyline 10mg for 3 days for neuralgic foot pain (7). Symptoms gradually improved but had failed to resolve at 7 month follow-up despite treatment cessation.

Tinnitus has also been reported in one patient, with a history of transient tinnitus, who complained of tinnitus 3 days after starting trimipramine 50mg for depression (8). Tinnitus persisted when the dose was increased to 100mg and was exacerbated when the trimipramine was changed after 6 weeks to amitriptyline 50mg. Only very limited improvement was seen with alternative treatments including citalopram, mirtazapine, lithium carbonate and non-pharmacological therapies.

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Other cases of tinnitus associated with individual TCAs have been described involving doxepin (9) and protriptyline (10). In both reports the reaction seemed to be dose-related and in the case involving doxepin it resolved “in a few weeks” despite continued therapy at the causative dose level (150 – 175mg per day). This patient did not report tinnitus on imipramine (150mg per day) which she had taken previously. In the case linked to protriptyline, tinnitus improved when the dose was reduced, but only resolved when protriptyline was stopped and desipramine was substituted.

Tricyclic antidepressants are not licensed for tinnitus treatment but it is interesting to note that a number of small clinical trials have successfully investigated tricyclic antidepressants as a treatment for tinnitus [for examples see refs (11) and (12)]. Tinnitus is frequently associated with depression and these may work directly on the tinnitus by acting on receptors in the central auditory pathway, and/or indirectly by treating depression (13,14). However, the authors of a recent Cochrane review concluded that there is no high quality evidence on the effect of tricyclic antidepressant drugs in the treatment of tinnitus, with no evidence that tricyclic antidepressants are effective or ineffective in the management of this condition (13).

Summary

The limited published data suggest that this reaction is dose-related, but may subside quite quickly even if the antidepressant is continued. If this is not effective, or the tinnitus is distressing, a dose reduction or selection of a different antidepressant is recommended. There are two published case reports of tinnitus persisting after TCA cessation.

Limitations This is not a common reaction so data available are limited.

References (1) Tandon R, Grunhaus L, Greden JF. Imipramine and tinnitus. J Clin Psychiatry 1987; 48: 109- 11. (2) Tandon R, Grunhaus L, Greden JF. Reply to “Imipramine and Tinnitus” letter. J Clin Psychiatry 1987; 48: 496-7. (3) Laird LK and Lydiard RB. Imipramine-related tinnitus (letter). J Clin Psychiatry 1989; 50: 146. (4) Racy J and Ward-Racy EA. Tinnitus in imipramine therapy. Am J Psychiatry 1980; 137: 854-5. (5) Feder R. Tinnitus associated with amitriptyline (letter). J Clin Psychiatry 1990; 51: 85-6. (6) Miles SW. Amitriptyline side effect (letter). N Z Med J 1980; 92: 66-7. (7) Mendis D and Johnston M. An unusual case of prolonged tinnitus following low-dose amitriptyline. J Psychophamacol 2008; 22: 574-5. (8) Langguth, B, Landgrebe M, Wittmann M et al. Persistent tinnitus induced by tricyclic antidepressants. J Psychopharmacol 2010; 24: 1273-5. (9) Golden RN, Evans DL, Nau CH. Doxepin and tinnitus. South Med J 1983; 76: 1204-5. (10)Evans DL and Golden RN. Protriptyline and tinnitus. J Clin Psychopharmacol 1981; 1: 404-6. (11)Bayar N, Böke B, Turan E et al. Efficacy of amitriptyline in the treatment of subjective tinnitus. J Otolaryngol 2001; 30:300-3. (12)Sullivan M, Katon W, Russo J et al. A randomized trial of nortriptyline for severe chronic tinnitus. Effects on depression, disability, and tinnitus symptoms. Arch Intern Med 1993; 153: 2251-9. (13)Baldo P, Doree C, , Molin P, McFerran D, Cecco S. Antidepressants for patients with tinnitus. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD003853. DOI: 10.1002/14651858.CD003853.pub3. Accessed via http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003853.pub3/abstract on 28th October 2014 (14)Anon. Tinnitus. Drug and Therapeutics Bulletin 2013; 51: 20-24.

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Quality Assurance

Prepared by Marc Miell (based on earlier work by Dr Simon Wills and Kate Pickett), Lead Medicines Information Pharmacist, Wessex Drug and Medicines Information Centre, University Hospital Southampton NHS Foundation Trust

Date Prepared 28th October 2014

Checked by Kate Pickett (based on the Q&A previously checked by Sue Gough), Lead Pharmacist – Formulary and Medicines Q&As, Wessex Drug and Medicines Information Centre, University Hospital Southampton NHS Foundation Trust

Date of check 10th December 2014

Search strategy  Embase (via NICE Evidence Search): *TINNITUS/ and exp TRICYCLIC ANTIDEPRESSANT AGENT/  Medline (via NICE Evidence Search): exp ANTIDEPRESSIVE AGENTS, TRICYCLIC/ and exp TINNITUS/  Micromedex (DrugDex). Accessed via http://www.micromedexsolutions.com  Cochrane Database. Accessed via http://www.thecochranelibrary.com/  BNF October 2014. Accessed via http://www.medicinescomplete.com/mc/bnf/current/  Martindale. The Complete Drug Reference. Accessed via http://www.medicinescomplete.com