Darlington, Cynthia L.

Smith, Paul F.

Zheng, Yiwen

English

PubMed

Paul F. Smith

Yiwen Zheng

Cynthia L. Darlington

Frontiers - Publisher Connector

of the study appeared to have more severe 
tinnitus to begin with. Another was that 
the study was potentially underpowered 
statistically due to the inclusion of sev-
eral different types of tinnitus, some of 
which might not have responded to the 
drug (Møller, 1997). The possibility that 
the study was underpowered was carefully 
acknowledged by the authors themselves, 
who performed power calculations for dif-
ferent scenarios (Westerberg et al., 1996). 
In addition, Westerberg et al. (1996) appar-
ently used racemic baclofen (i.e., a mixture 
of the l- and d-isomers of baclofen, also 
known as R- and S-isomers), which was 
the only licensed form in 1996 (Szczepaniak 
and Møller, 1995), and d-baclofen has been 
reported to be less potent than l-baclofen 
in reducing tone- and click-evoked hyper-
excitability in neurons of the inferior colli-
culus (Szczepaniak and Møller, 1995, 1996).
In fact, a number of studies have 
reported that d-baclofen can reduce the 
effects of l-baclofen. This has been reported 
in the trigeminal nucleus (Terrence et al., 
1983; Fromm et al., 1990), but not in the 
hippocampus or neocortex (Howe and 
Zieglgänsberger, 1986). In the spinal cord, 
d-baclofen has been reported to antago-
nize the effects of l-baclofen (Sawynok 
and Dickson, 1984, 1985). In a double 
blind crossover trial with 15 patients suf-
fering from trigeminal neuralgia, in 9 
patients l-baclofen was reported to be five 
times more effective in relieving the symp-
toms than racemic baclofen (Fromm and 
Terrence, 1987). In addition, the adverse 
side effects of l-baclofen were better tol-
erated than those of the racemic baclofen 
(Fromm and Terrence, 1987). Although the 
idea that d-baclofen is an antagonist, at least 
at some GABA
B
 receptors, is still unresolved 
(Froestl, 2010), at the very least it can be 
concluded that its agonist effects are much 
less potent than l-baclofen, which appears 
to be the case in the inferior colliculus 
(Szczepaniak and Møller, 1995, 1995). This 
Revisiting baclofen for the treatment of severe  
chronic tinnitus
Paul F. Smith*, Yiwen Zheng and Cynthia L. Darlington
Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago Medical School, and Brain Health Research Centre, University of Otago, 
Dunedin, New Zealand
*Correspondence: paul.smith@stonebow.otago.ac.nz
Subjective tinnitus is a phantom sensation 
of sound, which has been estimated to occur 
in 25.3% of people in the USA, with 7.9% 
experiencing it frequently (Shargorodsky 
et al., 2010). Drugs are one of a number 
of potential treatment avenues for severe 
chronic tinnitus. However, to date, there is 
relatively little agreement about which par-
ticular drugs might be best used to alleviate 
the condition (see Darlington and Smith, 
2007; Hoekstra et al., 2011 for reviews).
On the assumption that chronic tinnitus 
is associated with neuronal hyperactivity at 
different levels of the central auditory path-
ways, such as the dorsal cochlear nucleus, the 
inferior colliculus, and the auditory cortex 
(see Moller, 2000; Eggermont and Roberts, 
2004; Eggermont, 2005; Kaltenbach, 2006; 
Roberts et al., 2010 for reviews; see Dong 
et al., 2010; Middleton et al., 2011; Vogler 
et al., 2011; Wang et al., 2011 and Mulders 
and Robertson, 2011 for recent examples), 
drugs that increase inhibitory neuro-
transmission or block excitatory neuro-
transmission, are often used. Aside from 
anti-epileptic drugs, which are an obvious 
choice, the anti-spasticity agent and GABA
B
 
receptor agonist, baclofen, has also been 
used occasionally.
Unfortunately, as Hoekstra et al. (2011) 
concluded in a recent review, the evidence 
supporting the efficacy of anti-epileptic 
drugs in treating tinnitus is not very con-
vincing. Even less convincing is the evi-
dence supporting the use of baclofen. The 
only published clinical trial of baclofen in 
patients with tinnitus, yielded inconsistent 
results. The patients’ subjective ratings of 
tinnitus were significantly reduced follow-
ing drug administration compared to before 
drug administration; however, there was 
no significant difference compared to the 
placebo group (Westerberg et al., 1996). 
Nonetheless, interest in the possible use of 
baclofen to treat tinnitus remained (Møller, 
1997). One potential problem with the trial 
was that the patients in the baclofen arm 
raises the possibility that the use of racemic 
baclofen to treat tinnitus, as was the case in 
the study by Westerberg et al. (1996), may 
have actually undermined the effects of 
the l-baclofen. An obvious question is why 
racemic baclofen would be manufactured 
if there was evidence that d-baclofen is less 
potent than l-baclofen? One consideration 
is probably that racemic baclofen is easier to 
manufacture, because the separation of the 
l- and d-isomers requires additional steps.
The potential utility of l-baclofen, as 
opposed to d-baclofen or racemic baclofen, 
is supported by a recent study in which we 
found that l-baclofen dose-dependently 
reduced the behavioral signs of chronic tin-
nitus in an animal model caused by acoustic 
trauma (Zheng et al., 2012). Although the 
lowest effective dose for clear suppression 
of tinnitus was 3 mg/kg, using the dose 
adjustment calculation employed by the 
FDA to calculate human equivalent doses 
(Regan-Shaw et al., 2007), this was approxi-
mately equivalent to 34.1 mg/day for a 70-kg 
adult. This is above the effective dose of 
6–12 mg of l-baclofen reported by Fromm 
and Terrence (1987) for the treatment of 
trigeminal neuralgia but is lower than the 
twice daily 20 or 30 mg doses of racemic 
baclofen employed by Westerberg et al. 
(1996) in patients with tinnitus, which were 
the highest doses used in the second and 
third weeks of their study (in the first week 
they used 10 mg twice daily). Therefore, the 
effective dose of l-baclofen in our animal 
model study was within the dose range 
of racemic baclofen that has been used in 
humans.
While baclofen is not likely to be a 
drug of first choice for tinnitus due to 
its adverse side effects, such as sedation, 
confusion, and dizziness (Jorns and 
Zakrzewska, 2007), the significance of 
the potential underestimation of GABAB 
receptor  agonists for the treatment of 
tinnitus, extends beyond baclofen itself. 
Arbaclofen placarbil is a novel l- (or r-) 
www.frontiersin.org March 2012 | Volume 3 | Article 34 | 1
OpiniOn Article
published: 09 March 2012
doi: 10.3389/fneur.2012.00034
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Received: 08 February 2012; accepted: 21 February 2012; 
published online: 09 March 2012.
Citation: Smith PF, Zheng Y and Darlington CL (2012) 
Revisiting baclofen for the treatment of severe chronic tin-
nitus. Front. Neur. 3:34. doi: 10.3389/fneur.2012.00034
This article was submitted to Frontiers in Neuro-otology, a 
specialty of Frontiers in Neurology.
Copyright © 2012 Smith, Zheng and Darlington. This is 
an open-access article distributed under the terms of the 
Creative Commons Attribution Non Commercial License, 
which permits non-commercial use, distribution, and repro-
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mic baclofen prevented these new GABA
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for their efficacy against tinnitus.
Acknowledgments
This research was supported by grants 
from the Jean Cathie Estate and the New 
Zealand Neurological Foundation grant to 
Paul F. Smith, Yiwen Zheng, and Cynthia 
L. Darlington.
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Frontiers in Neurology | Neuro-otology  March 2012 | Volume 3 | Article 34 | 2
Smith et al. Tinnitus and baclofen


Revisiting Baclofen for the Treatment of Severe Chronic Tinnitus

Paul eSmith

Yiwen eZheng

Cynthia eDarlington

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Revisiting Baclofen For The Treatment Of Severe Chronic Tinnitus.

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Revisiting Baclofen for the Treatment of Severe Chronic Tinnitus

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