The unwanted sounds of tinnitus
Millions of people around the world suffer from tinnitus, yet there is not a single treatment that could alleviate the discomfort and pain caused to its victims. Aashruti Kak reviews the need for a ‘miracle’ drug
It is bliss for human race to have the ability to hear and comprehend innumerable sounds, but for certain less fortunate people among us, those afflicted with tinnitus, sound is nothing less than head exploding cacophony. Usually a symptom of an underlying condition, tinnitus has, since the beginning, been unresolved.
Many medical researchers believe that the static or the ringing that most patients hear could either be the sound of nerve firing or memory of a leftover sound. One cannot confidently pinpoint the cause of this condition due to the mystery surrounding its origin.
Speculated causes that have been thrown around range from infections of the eardrums or middle ear bones to blocking foreign bodies. But the one hypothesis that most treatments are based on is that tinnitus could be caused because of the damage to the microscopic hair endings of the auditory nerve in the inner ear. Also, in the ageing population, usually, the auditory nerves are impaired, leading to tinnitus.
Dr Ajay Swaroop, Senior Consultant, Sir Ganaga Ram Hospital, says, “Till date, we have no idea of what exactly is the cause of tinnitus, and what is the exact site in the brain or the ear, which is producing tinnitus. The pathophysiology as well as the etiology of the disease is totally obscure. Despite so many advances in medicine we still cannot pinpoint the exact cause of this unwanted sound. Since it is unknown, all sorts of empirical therapies are given.”
Amongst other causes, one possible cause is that there are certain drugs (ototoxic) that are toxic to the cochlea or the middle ear and have adverse effects on ear functions. Majority of such cases lead to deafness or vertigo. “There are some simple medicines like aspirin or salycilates can produce the ringing sensation. All the anti-tuberculosis drugs like isonicotinyl hydrazine or isoniazid (INH), p-aminosalicylic acid (PAS), rifampicin etc, all antibiotics like aminoglycosides can produce tinnitus. But, if we associate tinnitus with ototoxicity, we are assuming that it is a disease localised to the ear, which we have not agreed upon. So, all ototoxic drugs can produce tinnitus, but whether tinnitus is a part of ototoxicity is not clear,” says Swaroop.
Treating the ‘white noise’
|“A lot of companies are doing clinical trials but so far nothing has come out. The medications given for tinnitus have a lot of severe side effects because patients have to use these drugs for a very long time. This has become one of the major limiting factors in succeeding to treat tinnitus”
– Dr Ajay Swaroop Senior Consultant
Sir Ganaga Ram Hospital
Over decades, many treatments have been devised to beat the disease, and different approaches have been applied eg cognitive and electric therapies, magnetic brain stimulation, herbal therapies and drugs, but none have proven themselves to be effective enough. Swaroop says, “If a doctor treats five patients, and if even one of them improves, then it becomes a treatment. There is no scientific rationale behind any of these therapies.”
So far, the most promising and convincing therapy seems to be targeting the connection between brain activity and tinnitus, so much so, that in their search for the ideal medication for tinnitus, researchers now focus mostly on the correlation between the nerve cells and other drugs that act as neurotransmitters. “The basic assumption is that tinnitus is an abnormal wave formed in the brain; something similar to epilepsy and to pain, which means that there is some sort of hyperactivity of the brain that produces these unwanted sounds. Based on that, a majority of drugs are being used, which means that anti-epileptics have been tried to block the so-called epileptic passage, it has been partially successful; in 20-30 percent of patients it works,” says Swaroop.
For a normal brain function, the excitatory and the inhibitory neurotransmitters need to be balance, and in the case of tinnitus it is the imbalance between the two that causes the unwanted sounds. Since the most common excitatory neurotransmitters are glutamate and aspartate and the primary inhibitory neurotransmitter is GABA, researchers have decided to take these as their subjects.
There are many drugs that may not be formally indicated for tinnitus but have properties of altering the levels of various neurotransmitters. Swaroop explains, “There are certain medicines, known as GABA antagonists or benzodiazepines, which are being used keeping in mind that since in epilepsy and pain there is an increased secretion of this hormone, then anything that blocks it may also help in tinnitus. Local anaesthetics like lidocaine, zorcaine, xylocaine are also being used, again, to anaesthetise the brain. Their effect is similar to the reduction of nerve conduction as tinnitus is reduced, and it does work in certain cases. Then, of course, anti-depressants and everything else has also been tried.”
Some examples of the above are-memantine, ginkgo biloba extract, acamprosate calcium and caroverine. Memantine is an oral medication currently in use to treat Alzheimer’s disease. It blocks the N-methyl D-aspartate (NMDA) receptor used by glutamate. Ginkgo biloba extract is a powerful glutamate antagonist. Acamprosate calcium was approved last year by the Food and Drug Administration (US FDA) to treat alcohol dependence. Although it is not approved for its role as a glutamate antagonist to treat tinnitus but it can help in stabilising chemicals in the brain by balancing out the excitatory and the inhibitory neurotransmitters. Caroverine is also a glutamate antagonist and has been used in Austria for almost 40 years, under the trade name Spasmium-R, as an oral anti-spasmodic medication.
But, Swaroop maintains that the research being done is still not enough, considering the fact that firstly, it are not accurate, and secondly, tinnitus may just be more than just a physiological condition. He says, “Considering that the etiology of the disease is not clear, it is also psychosomatic, which means that there is a lot of psychological overlay in this condition. So, some patients that do appear to be improving may only be doing so because of their psychological state, when in actuality the medicine may not be working towards improvement. As far as I am concerned, the treatment for tinnitus is very unsatisfactory, there is no given standard or a protocol for treating tinnitus unlike most diseases where treatments are given as per established protocols.”
However, other treatments have been comparatively successful are surgically implanted electrodes and noninvasive magnetic stimulation, both intended to disrupt and possibly reset the faulty brain signals responsible for tinnitus. “Treatments that are much more effective in use are tinnitus maskers. These are small electrical devices, which produce sound at a given frequency, masking the sound that the patient hears. The disturbing sound is measured in terms of frequency and intensity, and equivalent amount of pure tone sounds are introduced. Basically, through this, the sounds are balanced. A lot of people have benefited from this,” informs Swaroop.
Another therapy, by the name of Tinnitus Retraining Therapy (TRT) has been of great help in treating various patients, as it involves psychotherapy, and background sounds are used to retrain the brain into accepting the sounds. “In certain cases where tinnitus is associated with deafness, we use hearing aids, which again, once external sound makes its way in, internal sounds are overlooked by the patient. Cochlear implants in severely deaf patients are also successful. Surprisingly, after an implant, the patient’s tinnitus improves. Even surgical treatment has been tried, in which you section the auditory nerve, but even this does not work in certain cases. This has given rise to the hypothesis that maybe whatever produces or causes tinnitus is totally different; it may not be in the nerve which is carrying the sound waves, but may be in the reticular formation of the brain,” says Swaroop.
|“Once we come out with the product, its success rate will be there for all to see along with its cost effectiveness, and patients will be comfortable with its use then the demand will rise. Since only Phafag AG has the rights to manufacture caroverine, once the drug is launched, we can approach bigger companies for co-manufacturing”
– Rajani G Patel Joint Managing Director
Caroverine is not available in the US or Canada for any purpose, as it has not been approved by the FDA. It is currently available only in Austria, Switzerland and Japan, and hopefully this year it will also be available in India. Lincoln Pharmaceuticals, an Ahmedabad based pharma company, will be marketing the drug in the country in collaboration with Phafag AG, a Swiss company based in Liechtenstein. Rajani G Patel, Joint Managing Director, Lincoln Pharma, informs, “We market various drugs for the ENT segment and while discussing with several doctors we discovered that a condition called tinnitus needed drugs for treatment in the country because there are none in the market for that purpose. Presently, there are two or three good anti-histamines but they do not have great results. As we are also into formulation development, we were suggested that we bring this drug to the market. Then we found out that a Swiss company called Phafag AG, based in Liechtenstein, is already working on clinical trials for this drug in India and we approached them. The company visited our plant, understood our marketing strength and soon after we signed an agreement to market their product.”
Phafag AG claims that according to certain physiological and morphological assessments in a study done by them, a low-dose and long-term caroverine treatment might protect against ‘impulse noise-induced hearing loss’. In the study, caroverine was delivered subcutaneously using an osmotic pump. As per the company, this kind of delivery has the advantage of avoiding systemic side effects. Many researchers, in their search for an effective treatment are also looking for a proper mode of drug delivery that will cause the least side effects.
Patel says, “We have already got the permission to import the raw material and to formulate and market caroverine in India is under consideration of the Drug Controller General of India (DCGI). We are waiting for that to happen within a month and then we can start the production in our factory.” According to him, the product needs to be properly priced to encourage acceptance by the patient population, because apart from the injection’s cost, the patient will have to pay the doctor’s fee as well as the infusion is to be given under a doctor’s supervision. “The cost per injectable infusion in Europe was Rs 2,000. So, after consulting doctors we realised that in order to conduct the trials and make the medicine accessible and affordable the price should be Rs 500-600 per infusion. This way, the whole treatment for a patient should come within Rs 2000,” he says.
Although, this is the first step towards bringing patients affected by tinnitus closer to better treatments, this seems to be the only step as no other pharma company has come forward to invest in the R&D or even in distributing the drug to the needy population. Patel believes that one has to have a positive outlook towards this situation. “It goes one step at a time. Once we come out with the product, its success rate will be there for all to see along with its cost effectiveness, and patients will be comfortable with its use then the demand will rise. Since only Phafag AG has the rights to manufacture caroverine, once the drug is launched, we can approach bigger companies for co-manufacturing,” he says.
The success rate of the drug is said to be 60-70 percent. The drug is to be given intravenously (IV), which gives a much better result; through eardrops and orally through capsules. Initially, a patient will be given the drug through IV for four to six hours, after which the patient has to take oral medication for five to six days to complete the treatment. Caroverine is already prevalent in the European market as an approved drug and has been marketed for 10 years already. Lincoln Pharma initially tried to import the consignments to India but the costs were too high to sustain, hence it was not financially viable.
What the future holds
Swaroop says that the problem is that even today we are not in a position to understand the actual etio-pathogenesis and the pharmacodynamics of the disease and that the success rate of all treatments is not even 30 percent. So no pharmaceutical company is willing to spend that much money on R&D for tinnitus. “I am sure people must be working, but it is a totally disappointing situation and every man is using his own personal judgments in treating patients. Tinnitus is a very debilitating problem. Patients face so many problems that they are usually on the verge of suicide, as a result, they have been referred to psychiatrists,” he says. He continues, “A lot of companies are doing clinical trials but so far nothing has come out. The medications given for tinnitus have a lot of severe side effects because patients have to use these drugs for a very long time. This has become one of the major limiting factors in succeeding to treat tinnitus.”
But, Swaroop feels very hopeful. “People are aware of the situation that with modernisation, the incidence of tinnitus is rising. Patients are coming to us as early as possible. I do not see any reason why there will not be a breakthrough. But right now, the most basic thing to do is find the focus of origination of the disease. Once that is achieved, it is just a question of time,” he concludes.