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BJA Advance Access published online on June 2, 2008
British Journal of Anaesthesia, doi:10.1093/bja/aen137
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2008. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

I.V. ropivacaine compared with lidocaine for the treatment of tinnitus

H. Kallio1,*, M. L. Niskanen1, M. Havia2, P. J. Neuvonen3, P. H. Rosenberg1 and E. Kentala2

1 Department of Anaesthesiology and Intensive Care Medicine
2 Audiology Unit, Department of Otorhinolaryngology
3 Department of Clinical Pharmacology, Eye Hospital, Helsinki University Central Hospital—Anaesthesia, Haartmanstr. 4, PO Box 220, Helsinki 00029, HUS, Finland

* Corresponding author. E-mail: helena.kallio{at}hus.fi

Accepted for publication March 25, 2008.


   Abstract
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 Abstract
Introduction
 Methods
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 Discussion
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 References
 
Background: I.V. lidocaine has been used to ameliorate tinnitus, but in general its effect has been limited. The longer acting local anaesthetic ropivacaine may be more effective.

Methods: A total of 19 randomized, double-blind, cross-over study patients suffering from chronic tinnitus were given a 30 min i.v. infusion of ropivacaine or lidocaine 1.5 mg kg–1 at an interval of 2–3 months. The intensity of tinnitus was evaluated on tinnitus handicap inventory (THI) scale and on the visual analogue scale (VAS). Plasma ropivacaine and lidocaine concentrations were determined.

Results: In both treatments, the infusion decreased the VAS score significantly. At the end of infusion, a ≥50% reduction in VAS score was observed in five patients by ropivacaine and in one patient by lidocaine, but this effect was sustained for 1 h only in three patients. However, the THI scores did not differ significantly within or between treatments. On the post-infusion day, three patients after ropivacaine and five after lidocaine treatment had ≥30% improvement in the THI score. Four weeks later, one patient after ropivacaine and two after lidocaine had a ≥30% reduction in the THI score. One patient developed seizures soon after ropivacaine infusion from which he recovered uneventfully. His plasma concentration of ropivacaine was 1817 ng ml–1. The highest individual ropivacaine and lidocaine concentrations were 3483 and 1680 ng ml–1, respectively.

Conclusions: Temporary clinically significant alleviation of tinnitus was observed only in a few individuals after both i.v. ropivacaine and lidocaine. The toxicity of ropivacaine limits its usefulness.

Keywords: anaesthetic techniques, i.v. infusion; anaesthetics local, lidocaine; anaesthetics local, ropivacaine; toxicity, local anaesthetics


   Introduction
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 Abstract
 Introduction
Methods
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Subjective tinnitus is a phantom auditory sensation without external sound. In 2% of the population, tinnitus affects the quality of their lives.1 The treatment of choice for tinnitus is retraining therapy,2 but there is a group of patients who does not get sufficient alleviation with it. Certain similarities exist between tinnitus and chronic pain,3 and they can be ameliorated with the same pharmacological agents, such as tricyclic antidepressants,4 anticonvulsants,5 and the local anaesthetic lidocaine at anticonvulsant doses.6 With an i.v. infusion of lidocaine 1.5 mg kg–1, the duration of the relief of tinnitus has been observed most variable, from no effect to several weeks.7

Lidocaine has also been administered intratympanically for the treatment of tinnitus because it may also be generated from the cochlea.8 Intratympanic administration of relatively high topical concentrations has provided temporary relief in a few individuals,9 but associated with side-effects such as nausea, vomiting, and vertigo. In any case, the i.v. route has remained the common route of lidocaine administration in tinnitus. Other local anaesthetics have not been studied for the treatment of tinnitus. We therefore compared the effect of i.v. ropivacaine with that of lidocaine for the treatment of tinnitus.


   Methods
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 Methods
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Twenty patients suffering from tinnitus were recruited from the audiology department of Helsinki University Hospital. The study was approved by the Ethics Committee of the hospital and the National Agency for Medicines, and the patient volunteers gave their written informed consent. They all had moderate or severe tinnitus that had lasted on an average for 124 months (range, 12–360 months). To be eligible, they had to be otherwise in good health with no neurological or cardiac disease. One patient had medication for high arterial pressure. The patient characteristics are presented in Table 1. All subjects had audiometry and otoacoustic emissions done before the infusion. The most common causes of the tinnitus were noise trauma (n=8) and sensorineural hearing loss (n=6).


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  		Table 1 Characteristics of patients and their tinnitus symptoms. Mean values or per cent distribution are indicated under the columns

 
A randomized (sealed envelopes), double-blind, cross-over design was followed for the study, and a total dose of 1.5 mg kg–1 of lidocaine or ropivacaine was given i.v. over 30 min with an infusion pump (Perfusor® Space, B. Braun Melsungen, Germany). The dose (1.5 mg ml–1) of lidocaine was the same as that has been generally used in studies on the treatment of tinnitus.7 8 As there are no published studies on the use of i.v. ropivacaine for the treatment of tinnitus, we chose the same dose as used for lidocaine, considering that comparable doses up to a maximum of 150 mg i.v. have been administered safely in volunteers,10–12 and a dose of 2 mg kg–1 i.v. has been found not to be ototoxic in rabbits.13 The infusions were given into a peripheral vein by an anaesthesiologist and a nurse in the post-anaesthesia care unit of the university ear–nose–throat hospital. All of the infusions were started at 3–4 p.m. Monitoring during infusion and 1 h thereafter included ECG, non-invasive arterial pressure, and pulse oximetry. The time interval between the two infusions was 2–3 months.

We used self-evaluating scores of the tinnitus handicap inventory (THI, 0–100, higher number for greater handicap)14 to evaluate the handicap of tinnitus and reported scores on visual analogue scale (VAS, 0 indicating no tinnitus, 10 indicating the worst imaginable degree of tinnitus) to evaluate its intensity. A 30% reduction on the THI scale and a 50% reduction in VAS scores were considered clinically significant. THI and VAS scores were evaluated immediately before the infusion, at 9 p.m. on the evening of the infusion day (about 4 h after the treatment) and thereafter on Days 1, 3, and 5, and weekly until 4 weeks after the infusion. In addition, VAS score was recorded immediately and 1 h after the infusion. The patients returned their THI evaluation sheets by mail.

The cubital vein opposite to the arm of the infusion was cannulated for timed blood samples, and 10 ml of blood sample was obtained before the infusion, 15 min after the start and at the end of infusion (30 min after the start), and 30 and 60 min after the end of the infusion into 10 ml EDTA tubes (Venoject®, Terumo Europe NV, Leuven, Belgium). The blood samples were centrifuged within 2 h and plasma was separated and stored at –70°C until analysed. Lidocaine and ropivacaine plasma concentrations were assayed by liquid chromatography.15 The quantification limit for both was ~1 ng ml–1. The intra-day coefficient of variation (CV) for lidocaine (n=8) was 2.3% at 104.5 ng ml–1 and 1.1% at 1135 ng ml–1. The CV for ropivacaine (n=7) was 1.8% at 509 ng ml–1 and 1.9% at 1552 ng ml–1.

The values of VAS and THI are reported as median (range) and are compared using Wilcoxon's test for between the treatments and Friedman's test for within the treatments. Binominal data are given as numbers and percentages and were compared using the {chi}2 test or Fisher's exact test. A value of P<0.05 was considered statistically significant. SigmaStat® (version 3.5, Systat Software, Inc., Point Richmond, CA, USA) was used to perform analyses.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 References
 
The characteristics of the patients and their tinnitus symptoms are shown in Table 1. Fourteen patients had documented hearing loss in audiometry and 13 of them had deviant responses in otoacoustic emissions. The occurrence of hearing loss or presence of spontaneous emissions did not predict the relief of tinnitus by the local anaesthetic treatment. One patient (no. 12) was unwilling to continue in the study after the first treatment session (ropivacaine) during which she had some numbness of the upper extremities. Her VAS values and local anaesthetic concentrations from that session are included in the analyses. Thus, complete data sets were obtained from 19 patients.

Immediately after six infusion sessions (five ropivacaine and one lidocaine), marked relief ({Delta}VAS≥50%) of tinnitus was seen. This degree of relief was sustained for >1 h after two ropivacaine treatments. In three patients, the tinnitus VAS score was temporarily increased by ≥30% at the end of ropivacaine infusion, when their plasma ropivacaine concentrations were 2216–2679 ng ml–1.

Significantly less tinnitus (VAS score) was reported 1 h after ropivacaine treatment in comparison with the score 1 h after lidocaine treatment (P=0.048, Wilcoxon's test). Four weeks after ropivacaine treatment, patients reported significantly more tinnitus than 1 or 4 h after ropivacaine treatment (P=0.003, Friedman's test). At other time points, the intensity of tinnitus (VAS or THI) did not differ significantly between or within the ropivacaine and lidocaine treatments (Table 2, Figs 1 and 2). Only one patient after ropivacaine infusion and two after lidocaine infusion had >30% reduction in the THI after 4 weeks.


Figure 1
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  		Fig 1 Tinnitus handicap inventory sum scores (0–100) in 19 patients after ropivacaine infusion. The open circles depict the assessment times and their mean values (bold line).

 


Figure 2
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  		Fig 2 The individual tinnitus handicap inventory sum scores (0–100) in 19 patients after lidocaine infusion. The open circles depict the assessment times and their mean values (bold line).

 


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  		Table 2 Visual analogue scale (VAS) and tinnitus handicap inventory (THI) scores of tinnitus (a few missing values), measured before and after the infusion of ropivacaine or lidocaine 1.5 mg kg–1. Delta ({Delta}) values (comparisons with scores before infusion). Percentages of patients with more than 50% decrease in VAS score and more than 30% decrease of THI. Some clinically insignificant differences occurred in VAS scores (*P=0.048 with Wilcoxon's test, {dagger},{ddagger}P=0.003 with Friedman's test). THI scores did not differ significantly between or within the treatments

 
One patient (no. 11, male 100 kg) lost his consciousness and developed tonic–clonic convulsive activity in his extremities a few minutes after the completion of ropivacaine (150 mg) infusion, soon after the 30 min venous blood sampling. He was ventilated by mask using 100% O2, and the convulsions were abolished with diazepam 5 mg i.v. repeated four times. He had no oxygen desaturation and his cardiovascular variables remained stable. He recovered in 10 min and was rather tired with moderate numbness of all extremities. There were no significant changes in the intensity of his tinnitus, other than that a distinct lower frequency sound had ceased. In the second infusion with lidocaine 150 mg about 2 months later, this patient experienced no adverse effects and no effect on tinnitus, either.

Seven patients after ropivacaine and four after lidocaine experienced tiredness after the end of the infusion. Five patients after ropivacaine infusion, including the one with convulsions, had temporary numbness in different parts of the body, one in the area surrounding the mouth. Lidocaine infusion caused numbness of the upper extremities in two patients. In the telephone interview on the following day, five patients after ropivacaine infusion and two after lidocaine infusion complained of dizziness.

The total plasma concentrations of ropivacaine and lidocaine are shown in Figures 3 and 4. In general, the highest concentration of both drugs was observed at the end of infusion. However, the decline after the infusion was markedly faster with lidocaine. The highest individual ropivacaine concentration was 3483 ng ml–1 (no. 15, male 103 kg). He had no adverse effects and the intensity of tinnitus stayed stable (VAS score 6). The highest individual concentration of lidocaine was 1680 ng ml–1, in a patient (no. 1, male 97 kg), who obtained a temporary reduction in the intensity of tinnitus (baseline VAS score 2 and after infusion VAS score 1) without adverse effects.


Figure 3
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  		Fig 3 Total individual plasma concentrations (ng ml–1) of ropivacaine and their mean values (bold line) in 20 patients. Ropivacaine was infused i.v. 1.5 mg kg–1 in 30 min.

 


Figure 4
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  		Fig 4 Total plasma concentrations (ng ml–1) of lidocaine and their mean values (bold line) in 19 patients. Lidocaine was infused i.v. 1.5 mg kg–1 in 30 min.

 
The plasma concentrations of ropivacaine declined slowly (Fig. 3). For instance, in patient with convulsions, the concentration of ropivacaine 30 min after the infusion (1890 ng ml–1) was still at the same level as at the time of the end of infusion (1817 ng ml–1). Still 1 h after infusion, the concentration (1493 ng ml–1) had not declined very much. In another patient (no. 18; male, 98 kg), circumoral numbness and difficulty in talking was associated with a high plasma ropivacaine concentration (3128 ng ml–1). His tinnitus was ameliorated at the end of infusion to be returned to the level before infusion in 1 h (VAS scores 5–2–4).


   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 References
 
Previously reported, occasional long-lasting effects by lidocaine on tinnitus were also seen in the present study.6–8 However, a 30 min infusion of ropivacaine or lidocaine in a dose of 1.5 mg kg–1 had no long-lasting significant effect on tinnitus. A clinically significant reduction in the intensity of tinnitus occurred only in a few patients at the end of infusion, or 60 min later.

Clinically, lidocaine has been used as an antiarrhythmic in ventricular dysrhythmias,16 as an anticonvulsant for the treatment of epileptic seizures17 and occasionally for the treatment of neuropathic pain18 and various types of severe headache.19 20 Independent of the targeted i.v. therapy, there is always a risk of systemic toxicity.21 The popularity of lidocaine for the therapy of cardiac and neurological disorders has been based on its relatively wide therapeutic window (dose/concentration producing wanted effect vs dose/concentration producing systemic toxicity).

In spite of similar local anaesthetic mechanisms of action, ropivacaine has not been shown to be therapeutically applicable in any of the situations mentioned above. The reason for this is its significantly greater anaesthetic potency and systemic toxicity compared with lidocaine22 making it very difficult to titrate safe dose without toxicity. In fact, in our study, we encountered one possible case of pre-toxic symptoms (circumoral numbness) after having infused 147 mg of ropivacaine in a 98 kg patient, and one obvious systemic toxicity reaction (seizures) after having infused 150 mg of ropivacaine in a 100 kg patient. The ropivacaine concentration in plasma in the former patient (3128 ng ml–1) was the second highest individual value. However, considering that the free fraction of ropivacaine in plasma is usually approximately 5%, the extrapolated unbound ropivacaine concentration would be 156 ng ml–1, which is less than half of the level shown to result in mild toxic symptoms in healthy volunteers.11 In the latter patient, the ropivacaine plasma concentration (1817 ng ml–1) in the blood sample obtained immediately before the start of the seizures was not excessively high, suggesting that there may be large interindividual differences between seizure threshold among patients and, perhaps, among patients with concomitant neural disturbance (tinnitus). The plasma ropivacaine concentration 30 min after the end of infusion was still at the same level as or even slightly higher than at the end of infusion. This suggested slow clearance and an unusual redistribution of ropivacaine during convulsions and initial recovery.

In conclusion, the efficacy of i.v. ropivacaine and lidocaine 1.5 mg kg–1 in the treatment of tinnitus is weak, short lasting, and occasional. I.V. ropivacaine 1.5 mg kg–1 infused in 30 min is not suitable for the treatment of tinnitus. One case of clear systemic toxicity (seizures) and another of mild pre-toxic symptoms after ropivacaine treatment further support our view. A clinically significant, temporary effect by i.v. lidocaine on tinnitus was observed only in a few patients but its safety was better than that of ropivacaine.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
References
 
This study was supported by the Special Governmental subsidy for Health Sciences Research (EVO), Finland.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 References
 
1 Axelsson A, Ringdahl A. Tinnitus – a study of its prevalence and characteristics. Br J Audiol (1989) 23:53–62.[Medline]

2 Herraiz C, Hernandez FJ, Toledano A, Aparicio JM. Tinnitus retraining therapy: prognosis factors. Am J Otolaryngol (2007) 28:225–9.[CrossRef][Web of Science][Medline]

3 Møller AR. Similarities between chronic pain and tinnitus. Am J Otol (1997) 18:577–85.[Web of Science][Medline]

4 Dobie RA, Sakai CS, Sullivan MD, Katon WJ, Russo J. Antidepressant treatment of tinnitus patients: report of a randomized clinical trial and clinical prediction of benefit. Am J Otol (1993) 14:18–23.[Web of Science][Medline]

5 Espir M, Illingworth R, Ceranic B, Luxon L. Paroxysmal tinnitus due to a meningioma in the cerebellopontine angle. J Neurol Neurosurg Psychiatry (1997) 62:401–3.[Abstract/Free Full Text]

6 Baguley DM, Jones S, Wilkins I, Axon PR, Moffat DA. The inhibitory effect of intravenous lidocaine infusion on tinnitus after translabyrinthine removal of vestibular schwannoma: a double-blind, placebo-controlled, crossover study. Otol Neurotol (2005) 26:169–76.[CrossRef][Web of Science][Medline]

7 Kalcioglu MT, Bayindir T, Erdem T, Ozturan O. Objective evaluation of the effects of intravenous lidocaine on tinnitus. Hear Res (2004) 199:81–8.[Web of Science]

8 Simpson JJ, Davies WE. Recent advances in the pharmacological treatment of tinnitus. Trends Pharmacol Sci (1999) 20:12–8.[CrossRef][Medline]

9 Laurikainen EA, Johansson RK, Kileny PR. Effects of intratympanically delivered lidocaine on the auditory system in humans. Ear Hear (1996) 17:49–54.[CrossRef][Web of Science][Medline]

10 Scott DB, Lee A, Fagan D, et al. Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg (1989) 69:563–9.[Abstract/Free Full Text]

11 Knudsen K, Beckman Suurküla M, Blomberg S, Sjövall J, Edvardsson N. Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth (1997) 78:507–14.[Abstract/Free Full Text]

12 Stewart J, Kellett N, Castro D. The central nervous system and cardiovascular effects of levobupivacaine and ropivacaine in healthy volunteers. Anesth Analg (2003) 97:412–6.[Abstract/Free Full Text]

13 Arikan OK, Muluk NB, Budak B, et al. Effects of ropivacaine on transient-evoked otoacoustic emissions: a rabbit model. Eur Arch Otorhinolaryngol (2006) 263:421–5.[CrossRef][Medline]

14 Newman CW, Jacobson GP, Spitzer JB. Development of the Tinnitus Handicap Inventory. Arch Otolaryngol Head Neck Surg (1996) 122:143–8.[Abstract/Free Full Text]

15 Arvidsson T, Askemark Y, Halldin MM. Liquid chromatographic bioanalytical determination of ropivacaine, bupivacaine and major metabolites. Biomed Chromatogr (1999) 13:286–92.[CrossRef][Web of Science][Medline]

16 Rea RS, Kane-Gill SL, Rudis MI, et al. Comparing intravenous amiodarone or lidocaine, or both, outcomes for inpatients with pulseless ventricular arrhythmias. Crit Care Med (2006) 34:1617–23.[CrossRef][Web of Science][Medline]

17 DeToledo JC. Lidocaine and seizures. Ther Drug Monit (2000) 22:320–2.[CrossRef][Web of Science][Medline]

18 Carroll I, Gaeta R, Mackey S. Multivariate analysis of chronic pain patients undergoing lidocaine infusions: increasing pain severity and advancing age predict likelihood of clinically meaningful analgesia. Clin J Pain (2007) 23:702–6.[Web of Science][Medline]

19 Hand PJ, Stark RJ. Intravenous lignocaine infusions for severe chronic daily headache. Med J Austr (2000) 172:157–9.

20 Matharu MS, Cohen AS, Goadsby PJ. SUNCT syndrome responsive to intravenous lidocaine. Cephalalgia (2004) 24:985–92.[CrossRef][Web of Science][Medline]

21 de Jong RH, Ronfeld RA, DeRosa RA. Cardiovascular effects of convulsant and supraconvulsant doses of amide local anesthetics. Anesth Analg (1982) 61:3–9.[Abstract/Free Full Text]

22 Rosenberg PH, Veering BTh, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth Pain Med (2004) 29:564–75.[CrossRef][Web of Science][Medline]


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