Drugs for tinnitus can be vetted through clinical trials, but the evidence remains thin regarding their efficacy.
Compared with other treatments of tinnitus symptoms, drug therapy—the use of medications or supplements to relieve tinnitus suffering—is easier to test using randomized clinical trials.
A randomized clinical trial (RCT) is an experiment in which patients with a particular condition receive one of two or more treatments, with the choice of treatment determined at random. Those receiving a placebo become the control group. Sometimes, one treatment (often new) is compared with another (often an older or better-established treatment), rather than comparing it to a placebo. In an RCT, neither the patient nor the doctor can decide which treatment a patient will receive, and “double blinding” means neither actually knows. If the numbers of patients in each treatment group are large enough, and if the differences in outcome are large enough, it may be possible to conclude with some statistical confidence that one treatment is better than another.
Fewer Subjects, Better Results?
In most RCTs, each patient gets only one treatment. But “crossover” RCTs are particularly attractive for reversible, relatively brief treatments given to patients with stable disorders—such as for most treatments for tinnitus. In this type of study, each patient receives both treatments, but in randomly determined order, with a “washout” period interposed between the active and placebo periods.
Crossover RCTs require far fewer patients. Obviously, the number of patients getting each treatment is twice what it would be in an ordinary RCT. More importantly, each patient acts as his own control, so differences among individuals are much less important.
Plus, a simple design solution for drug treatments has emerged: Restrict the RCT to patients who have claimed benefit in a preliminary open trial of the drug. For instance, in one study, ginkgo biloba was given to 80 tinnitus patients, 21 of whom claimed benefit. Twenty of the 21 were then entered into a crossover RCT in which each patient received both ginkgo and a placebo, in randomly selected order.
There was no outcome difference between ginkgo and placebo. This negative result was more compelling and much less expensive than would have been a negative trial of all 80 patients.
Do Drug Treatments Work?
Using the criteria of RCTs, we can review some results of drug therapy for the relief of tinnitus symptoms.
Antiarrhythmics: The ability of injected doses of lidocaine, which is also a local anesthetic, to temporarily eliminate or at least change tinnitus sensation was probably discovered by accident, but was later documented in well-controlled trials. Since this drug can’t be taken by mouth, many investigators turned to tocainide, which after oral administration is converted to lidocaine in the liver. Several RCTs were done, but as a group they failed to show that this drug had any effect on tinnitus sensation of suffering. In addition, tocainide—whose numerous side effects included severe rash, heart damage, and dizziness—is no longer available in the United States. Topical lidocaine can be driven through the tympanic membrane (eardrum) by electrical current, but two RCTs failed to show significant relief of tinnitus.
Anticonvulsants: This is a class of drugs normally used to treat epilepsy. Drugs such as carbamazepine have effects on neural tissue that are somewhat similar to those of the antiarrythmics; they selectively inhibit neural activity. Also, some can relieve chronic pain, a condition often compared to tinnitus. But RCTs using carbamazepine and aminooxyacetic acid have failed to demonstrate any benefit at subtoxic doses. These drugs have very serious side effects and require frequent medical monitoring.
Benzodiazepines: This class of anti-anxiety drugs includes diazepam (Valium) and alprazolam (Xanax); most have tranquilizing as well as anticonvulsant effects, with great potential for dependency and abuse. Alprazolam was shown in a single RCT to reduce tinnitus sensation (loudness), but tinnitus suffering was not measured, and double blindness was not properly maintained. Other studies with benzodiazepines have failed to show statistically significant benefit and have suggested that tinnitus may rebound after these drugs are stopped. (See, however, a 2012 study using clonazepam, in “Recent Results,” below.)
Antidepressants: A 2012 Cochrane review of six tinnitus clinical trials using antidepressants recommended further study, noting “trial quality was generally low.” The four trials involving three tricyclic antidepressants (amitriptyline, nortriptyline, and trimipramine) did not show enough statistical evidence for improvement. One trial involving paroxetine (Paxil), a selective serotonin reuptake inhibitor, was deemed high quality but also showed no benefit, except possibly for a subgroup that received higher doses. The benefits from trazodone, a serotonin antagonist and reuptake inhibitor, were also not statistically significant. Side effects including dry mouth, sedation, and sexual dysfunction were common.
Ginkgo biloba: Extracts of the leaves of the ginkgo biloba tree have been used in Chinese herbal medicine for centuries and are frequently used in the United States and Europe as well. A Cochrane review suggested that ginkgo may have genuine benefit in treating cognitive impairment and dementia; it is also popular for treating both tinnitus and dizziness in France and Germany. But most English-language publications of RCTs using ginkgo for tinnitus fail to prove any benefit.
Miscellaneous drugs (and zinc): Many unrelated drugs have been tried in single RCTs, sometimes for no apparent reason. These include melatonin, baclofen, lamotrigine, misoprostol, nicotinamide, betahistine, cinnizarine, cyclandelate, flunarizine, caroverine, and eperisone, plus a homeopathic preparation containing salicylate, quinine, conine, and ascaridole. None was shown to reduce tinnitus suffering, although both cyclandelate (a vasodilator) and eperisone (an antispasmodic) slightly reduced tinnitus match levels (its loudness).
Zinc, a dietary supplement, was ineffective in one RCT but said to be helpful (using a locally developed tinnitus questionnaire) in another. The latter study, from Turkey, included several older patients with low blood zinc levels.
Can Any Drugs Be Recommended?
To date, evidence is weak for drugs to treat tinnitus. But since insomnia is often a component of tinnitus suffering, it is likely that any drug or supplement (or other regimen) that improves sleep will reduce tinnitus suffering. The same logic applies to other tinnitus-related conditions such as depression and anxiety, explaining why antidepressants and anti-anxiety drugs have shown to be of some benefit, even if not statistically relevant. — With reporting by Yishane Lee, Editor, Hearing Health Magazine
Robert A. Dobie, M.D., is a clinical professor of otolaryngology at the University of Texas, San Antonio, and the University of California, Davis. This article is adapted from his chapter “Clinical Trials and Drug Therapy for Tinnitus” in “Tinnitus: Theory and Management,” edited by James B. Snow, Jr., M.D. It appears here with permission from Dobie, Snow, and PMPH-USA, the publisher.
A crossover RCT whose results were published in the Journal of Neurology, Neurosurgery & Psychiatry in 2012 concluded that clonazepam (Klonopin), a benzodiazepine, significantly improved tinnitus loudness, duration, and annoyance for a large proportion of tinnitus patients. The drug was compared with ginkgo biloba, which was found to be ineffective. The effectiveness of clonazepam was dependent on a carefully controlled and monitored dosing schedule, with side effects of drowsiness or dizziness reported in many patients.
Recent research has also found that certain medications are effective against tinnitus in the animal model. Vigabatrin, a type of enzyme inhibitor, reversibly eliminated tinnitus in rats, according to a 2007 study. Retigabine, an epilepsy drug, was reported this May to prevent tinnitus in mice (see “Hearing Headlines,” page 8). —James A. Kaltenbach, Ph.D.