Protracted Tinnitus after Discontinuation of Long-Term Therapeutic Use of Benzodiazepines
New England Journal of Medicine315: 854-8591988
USOA BUSTO, PharmD, LUIS FORNAZZARI MD, FRCP(C), AND CLAUDIO A. NARANJO, MD
Pharmacy Department and Neurology Program; Clinical Institute of the Addiction Research Foundation, Clinical Pharmacology Program, Clinical Institute Addiction Research Foundation and Faculty of Pharmacy, Department of Medicine and Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
The presence of protracted tinnitus after discontinuation of long-term therapeutic doses of diazepam (≤3O mg/day) is described in three patients. In one of these patients, the association of the tinnitus appearance with the drug discontinuation was documented in a double-blind, randomized, crossover single case study. Objective confirmation of drug use or of abstinence was performed by obtaining plasma benzodiazepine concentrations. The findings provide further documentation that sensory disturbances of short-and long-term duration are among the most distinctive clinical features of the benzodiazepine withdrawal syndrome. (J Clin Psychopharmacol 1988;8:359-362)
Benzodiazepines are the most widely prescribed psychotropic drugs.(1-3) A mild abstinence syndrome may appear after discontinuation of long-term therapeutic doses of benzodiazepine4 and is characterized, among other symptoms, by poor appetite, gastrointestinal disturbances, insomnia, and tremor. Anxiety and tension are also reported by some patients.(4-6) Sensory disturbances, such as paresthesia, hypersensitivity to touch, photophobia, blurred vision, and hyperacusis, have also been observed during withdrawal.(4-7) Tinnitus has been occasionally reported after withdrawal from benzodiazepines. However, as with most withdrawal symptoms, it usually resolves within a few days after drug discontinuation.(5)
The long-term consequences of withdrawal of benzodiazepines from therapeutic doses are not well characterized. We report three cases of protracted tinnitus associated with benzodiazepine withdrawal in patients without tinnitus prior to the time the patients began to use benzodiazepines. In one of these patients, we were able to perform a single case, double-blind, randomized experiment comparing the effect of diazepam and placebo on the occurrence and severity of the tinnitus.
A 57-year-old retired salesman was seen at the Addiction Research Foundation Clinical Institute for treatment of diazepam dependence. He had been using 25 to 30 mg of diazepam per day for 3 years. He was first prescribed diazepam 10 years before assessment (5 mg/day) to diminish anxiety over business meetings. He had slowly increased the dose over the years. Now he felt dependent on diazepam and wanted treatment to discontinue use. He denied use of alcohol, nicotine, or other drugs. The general physical and neurological examinations and routine laboratory tests were normal. Urine and blood screens were positive only for benzodiazepines.
He participated in the outpatient treatment of benzodiazepine dependence offered at our hospital. Briefly described, the treatment consisted of a gradual taper from the 30 mg/day diazepam over a 2-month period and concurrent weekly cognitive behavioral therapy. Follow-ups were performed at 1, 3, 6, and 12 months after discharge.4 When diazepam was reduced to 5 mg/day, he complained of tinnitus (without hearing loss), nausea, abdominal pain, anorexia, and anxiety. He reported that this was the first time he had experienced tinnitus in his life, and he described it as a high-pitched ringing in the ear (both sides) being the worst in silence and in bed. Neurological examination, EEG, and CT scan performed at the time were normal. Ear, nose, and throat examination revealed normal cochlear and vestibular functions.
The patient was successfully detoxified from diazepam. Blood and urine concentrations were low at the end of the treatment and negative at the 3-month follow-up. At the 6-month follow-up, the gastrointestinal symptoms had resolved, but the tinnitus persisted. With due informed consent, we conducted a double-blind, randomized controlled study as follows:
After a baseline period of 7 days, the patient received identical capsules of either diazepam or placebo in increasing doses weekly The severity of the tinnitus was blindly assessed by one of us (L.F.) with a standardized scale.(8) The patient also assessed his tinnitus daily as "no change," "better," or "worse." Both the neurologist and the patient were blind to the order and dose of diazepam/placebo.
The results of this experimental procedure are summarized in Figure 1. An inverse correlation between the total plasma diazepam concentration and the severity of the tinnitus as measured by the scale was observed. In addition, each time the patient received placebo he assessed his tinnitus as "worse" while during the weeks he received diazepam he assessed the tinnitus as "a little better" when receiving lower doses (weeks 4 and 5) and "much better" when receiving the highest diazepam dose (week 6):
The patient was offered to continue on low doses of benzodiazepines to diminish the tinnitus but he chose to remain abstinent. At the 1 year follow-up, he still had some tinnitus but he was able to cope with it.
A 34-year-old man had been using diazepam for 8 years for anxiety, but he felt the drug was not helping him and wanted to discontinue its use. At admission, he was taking 10 mg/day. He denied present abuse of any other drugs. He smoked approximately one package of cigarettes per day. He had used street drugs in the past (ages 21 to 25) and abused alcohol (two bottles of wine a day) for several years. He had completely stopped drinking alcohol 6 months before the present visit and had been abstinent since. Physical examination and laboratory tests at assessment were all normal. Urine and blood screens were negative for all drugs except benzodiazepines. He also participated in the outpatient treatment of benzodiazepine dependence.4 He was successfully detoxified and blood and urine screens were negative 6 weeks after starting on the program. He objectively remained abstinent from benzodiazepines and other drugs for the full 1-year follow-up period, documented by plasma benzodiazepine concentrations.
Four days after discontinuation of diazepam, he complained of tinnitus ("ears buzzing"), neck stiffness, headache, and insomnia. These symptoms were attributed to diazepam withdrawal and had resolved at the 1-month follow-up with the exception of neck stiffness and tinnitus, which were still present 3 months later. No obvious cause for the tinnitus was found on neurological examination and the patient had no history of previous tinnitus. At a 6-month follow-up appointment, the tinnitus was only occasional and of short duration. One year later, all symptoms had completely cleared up except mild and occasional anxiety and tension relieved by exercise and relaxation techniques.
A 49-year-old male computer programmer using 5 to 20 mg of diazepam daily for 12 years presented to the Clinical Institute of the Addiction Research Foundation with memory impairment, difficulty in concentration, and severe tinnitus upon diazepam discontinuation.
His use of benzodiazepines had started 12 years before admission to decrease his anxiety over work stress and had been almost constant. He was a social drinker and a smoker, but he denied use of any other drugs. Physical examination and laboratory tests were normal. Urine and blood screen were negative for all drugs except benzodiazepines. Neurological evaluation and CT scan were normal. He maintained that the main reason for not being able to achieve abstinence from benzodiazepines was a high-pitched, very intense ringing in both ears that began each time the diazepam dose was reduced. The tinnitus disappeared 15 minutes after a dose of diazepam was ingested, but reappeared approximately 4 hours after every dose. The tinnitus was present during the day and did not affect his night sleep. The patient refused treatment mainly because of the incapacitating tinnitus.
The withdrawal syndrome after discontinuation of long-term therapeutic doses of benzodiazepines is now adequately documented.(4, 5) This syndrome most typically comprises a combination of anxiety symptoms, such as increased tension, tremor, sweating, difficulty in concentration, palpitations, and nonanxiety symptoms, such as involuntary movements, sensory disturbances, photosensitivity, and hyperacusis.(4, 5) Most symptoms occur mainly within the first 2 weeks after drug discontinuation and are most pronounced 3 to 7 days after discontinuing the medication, depending on the half-life of the drug.(5, 6) The withdrawal reaction usually subsides over the next 2 to 4 weeks.(5) Thus, the type and time course of some of the symptoms experienced by patients described here are consistent with a benzodiazepine withdrawal reaction.(9)
Tinnitus is a symptom characterized by the perception of abnormal sounds in the ear. It is described as a ringing, buzzing, blowing, whistling, humming, beating, sounding, or roaring sound.(10) Tinnitus may be associated with deafness of either conductive middle ear or sensorineural cochlear type and is frequently associated with otosclerosis.(10) Tinnitus is often associated with disorders of the cochlea and may be the result of either an increase in the spontaneous firing rate of primary auditory nerve fibers caused by hyperactivity of hair cells in the cochlea(11) or a decrease in the spontaneous activity of the system.(12, 13) Most common identifiable causes of tinnitus are otological (acoustic trauma, blunt trauma, otosclerosis, Meniere's disease, and ear infections),(8) but medical (diabetes mellitus, thyroid disease, hyperlipidemias, allergies, systemic lupus erythematosus, syphilis) and neurological causes (vascular malformations, vascular tumors, meningitis, strokes, contusions, demyelinating diseases, cerebellopontine angle tumor) should be included in the differential diagnosis.(14) In our patients these causes were ruled out.
Tinnitus is a symptom that has also been associated with the concurrent use of a number of drugs(15, 16) such as aspirin, quinine, aminoglycoside antibiotics, and tricyclic antidepressants and in some instances with benzodiazepine withdrawal.(4, 17) However, most studies on benzodiazepine dependence show that the symptoms usually disappear by the fourth week.(4-6) Thus, protracted tinnitus seems to be an uncommon manifestation of withdrawal. Other cochlear symptoms have been described after benzodiazepine discontinuation. For example, four cases of hyperacusis during the first 2 weeks of withdrawal among 22 patients withdrawing from benzodiazepines have been reported.(17) Two to 4 weeks after drug discontinuation, only two patients continued to complain of the same symptoms. At 12 weeks follow-up, there was one case of persistent hyperacusis in that study. The authors do not provide further details on this case.(17)
The three cases described here provide evidence for an uncommon consequence of long-term therapeutic benzodiazepine use after drug discontinuation. In one of the cases, a strong association between diazepam withdrawal and tinnitus was established. The probability that the tinnitus was related to the diazepam withdrawal was assessed using the Adverse Drug Reaction Probability Scale, which gave a score of 11.(9) This score means that the tinnitus was definitely related to benzodiazepine withdrawal. Alternative causes were systematically ruled out.
The long-term management of these cases is difficult but may include the use of very low doses of benzodiazepines, particularly if the tinnitus is impairing the quality of life. More appropriately, gradual tapering of benzodiazepines in long-term users may help to minimize short-term symptomatology.(4) Because the indications for long-term therapeutic use of benzodiazepines are few, careful assessment, in each individual case of the reasons for long-term use of benzodiazepines seems indicated in all patients.
1. Baler MB, Manheimer DI, Mellinger GD, Uhlenhuth EH. A cross-national comparison of anti-anxiety/sedative drug use. Curr Med Res Opin 1984;8(suppl 4):5-20.2. Mellinger G, Balter MB. Prevalence and patterns of use of psychotherapeutic drugs. Results from a 1979 national survey of American adults. International Seminar on the Epidemiological Impact of Psychotropic Drugs, Milan, June 24-26, 1981.3. Marks J, ed. The benzodiazepines: use, overuse, misuse, abuse? 2nd ed. Lancaster, UK: MTP Press Ltd., 1985.4. Busto U, Sellers EM, Naranjo CA, et al. Withdrawal reactions after long-term therapeutic use of benzodiazepines. N Engl J Med 1986;315:854-9.5. Petursson H, Lader M, eds. Dependence on tranquilizers. Oxford, UK: Oxford University Press, 1984.6. Owen RT, Tyrer P. Benzodiazepine dependence: a review of the evidence. Drugs 1983;25:385-98.7. Cappell HD, Sellers EM, Busto U. Benzodiazepines as drugs of abuse and dependence. In: Cappell HD, Sellers EM, eds. Recent advances in the treatment of alcohol and drug abuse problems. New York: Plenum Press, 1986:56-114.8. Lechtenberg R, Shulman A. The neurologic implications of tinnitus. Arch Neurol 1984;41:718-21.9. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts E, Janecek E, Domecq C, Greenblatt DJ. A method for estimating the probability of adverse drug reactions. Clin Pharmacol T 1981;30:239-45.10. Dejong NR. Case taking and the neurologic examination. Baker AB, Baker LH, eds. Clinical neurology, vole 1. New York Harper & Row, 1975:1-83.11. Möller AR. Pathophysiology of tinnitus. Ann Otol Rhino Laryngol 1984;93:39-43.12. Kiang NYS, Moxon EC, Levine RA. Auditory nerve activity cats with normal and abnormal cochleas. CIBA Foundation Symposium. London: Churchill, 1970:241-73.13. Harrison RV. The effects of hair cell damage on cochlear function. PhD Thesis. Staffordshire: University of Keele, 1978.14. House JW. Management of the tinnitus patient. Ann Otol Rhino Laryngol 1981;90:597-601.15. Dukes MNG, ed. Meyler's side effects of drugs. Amsterdam: El cerpta Medica, 1975.16. Brown DR, Penny JE, Henley CM, Hodges KB, Kupetz SA, Glen DW, Jobe PC. Ototoxic drugs and noise. In: Evered D, Lawrense G, eds. Tinnitus. London: Pitman Books Ltd., 1981:151-71.17. Petursson H, Lader M. Benzodiazepine withdrawal. In: Dependence on tranquilizers. Oxford, UK: Oxford University Press, 1984:37-62.
Address requests for reprints to:Dr. Usoa Busto, Pharmacy Department,Addiction Research Foundation,33 Russell Street, Toronto,Ontario M5S 2S1, Canada.
The views expressed in this article are those of the authors and do not necessarily reflect those of the Addiction Research Foundation.