WO2011145062A1 - Treatment of tinnitus and related auditory dysfunctions - Google Patents

Treatment of tinnitus and related auditory dysfunctions Download PDF

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WO2011145062A1
WO2011145062A1 PCT/IB2011/052173 IB2011052173W WO2011145062A1 WO 2011145062 A1 WO2011145062 A1 WO 2011145062A1 IB 2011052173 W IB2011052173 W IB 2011052173W WO 2011145062 A1 WO2011145062 A1 WO 2011145062A1
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tinnitus
naltrexone
auditory
treatment
related
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PCT/IB2011/052173
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French (fr)
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Andréia APARECIDA DE AZEVEDO
Ricardo Rodrigues Figueiredo
Dirk De Ridder
Matteo De Nora
Berthold Langguth
Ana Belén ELGOYEN
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Link Research & Grants Corporation
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Abstract

The invention provides naltrexone for use in the treatment of tinnitus and related auditory dysfunctions by oral administration as tablets, capsules, powder or a solution or by parenteral administration of naltrexone through intramuscular, intravenous, subcutaneous or intrathecal injection, or infusion, preferably in an amount from 5-60 mg/day, preferably in a long-term treatment over 2 or 8 weeks or more.

Description

Treatment of Tinnitus and Related Auditory Dysfunctions

Field of the Invention

This invention relates to the treatment of tinnitus and related common auditory dysfunctions such as hyperacusis, auditory hallucinations, misophonia, phonophobia and central auditory processing disorders.

Background of the Invention

Tinnitus

Tinnitus is the phantom sensation of hearing in the absence of external sounds. Two main types can be identified: (1) objective tinnitus, which is caused by sounds generated somewhere in the body; (2) subjective tinnitus, which is the perception of meaningless sounds without any physical sound being present. Objective tinnitus is rare and is caused by a sound in the body, such as turbulent flow of blood or muscle contractions in the head. Such tinnitus can be heard by an observer in contrast to subjective tinnitus, which can only be heard by the individual who has the tinnitus. Subjective tinnitus is the most prevalent type of tinnitus. Tinnitus sounds can take a variety of forms such as buzzing, ringing, whistling, hissing or a range of other sounds. For some people it can even sound like music or singing. It can be a benign sound or it can prevent its sufferers from sleep or the ability to do intellectual work. All degrees of subjective tinnitus occur in between these extremes. Tinnitus is also related to other symptoms, such as hyperacusis, auditory hallucinations, misophonia, phonophobia and central auditory processing disorders. Affective disorders, such as anxiety and depression, often accompany severe tinnitus and that form of tinnitus can lead to suicide. Tinnitus is most likely related to altered neuronal activity which leads to plastic changes in the central auditory pathway derived from a distorted input. However, the mechanisms underlying the different forms of tinnitus remain incompletely understood.

Tinnitus often occurs as a result of dysfunction of the hearing system, such as from noise exposure, presbyacusis or from administration of specific pharmacologic agents. It can also be caused as the result of ear or head injuries, some diseases of the ear, ear infections and emotional stress. Perhaps the most common source of chronic tinnitus is exposure to loud sound. The noise causes permanent damage to the sound-sensitive cells of the cochlea, a spiral shaped organ in the inner ear. Carpenters, pilots, soldiers, rock musicians, street repair-workers are among those people whose jobs put them at risk. But also recreational use of sound, like MP3 players at maximal volume can produce damage. In addition, a long list of drugs can induce tinnitus. In some cases the causative agent remains unknown. One in 10 adults have clinically significant tinnitus (regular prolonged spontaneous tinnitus lasting 5 minutes or more), and for 1 in 100 adults tinnitus severely affects their ability to lead a normal life. Estimates indicate that 13 million people in western Europe and the USA currently seek medical advice for their tinnitus. Over 4 million prescriptions are written each year for tinnitus relief but these are all for off-label drugs from a wide variety of therapeutic classes and most are associated with considerable side effects.

The greatest medical need arises from the 1 to 3% of the population that is severely affected by tinnitus, with major negative impact on quality of life. Despite the significant clinical need for effective treatment of tinnitus, there is currently no single FDA- or EMEA-approved drug on the market. For the majority of tinnitus sufferers that seek medical advice, the treatment goals are aimed at symptomatic relief, since causally oriented therapeutic strategies are lacking. The most frequently used therapies consist of auditory stimulation and cognitive behavioral treatment aimed at improving habituation and coping strategies.

Since tinnitus is a subjective phenomenon, assessment of tinnitus severity and measurement of treatment outcome is challenging. A comprehensive evaluation includes the assessment of (1) tinnitus loudness, either by visual analogue scales or by psycho acoustic measurements and (2) tinnitus severity, which is usually assessed by validated questionnaires. However, since psychoacoustic measures of tinnitus loudness have shown only limited test-retest reliability and only a low correlation with perceived tinnitus severity or annoyance there is increasing consensus among clinical researchers, that psycho acoustic tests are only of limited value for outcome measurement.

There exist many different forms of tinnitus, which differ in both in their pathomechanisms and in their response to specific treatments. In light of this heterogeneity the description of treatment results from every single treated patient provides more information than just the mean improvement of the whole group. It is of particular interest whether there are patients in which the tinnitus completely disappears during treatment. There are several therapeutic approaches to alleviate tinnitus, however, they have limited results and most patients are left unsatisfied. This includes: 1. counselling which can help the patient to cope with his tinnitus; 2. if tinnitus is accompanied by hearing loss, a hearing aid can help with tinnitus management; 3. sound therapy, also known as sound enrichment; 4. Tinnitus Retraining Therapy, a combination of counseling and sound therapy; 5. cognitive -behavioral therapy; 6. repetitive transcranial magnetic stimulation; 7. epidural cortical stimulation with implantable electrodes and 8. a series of off-label drugs like antidepressants, anxiolytics, anesthetics, anticonvulsants, analgesics, antiarrythmics, herbal medicines, anticoagulants, sedative-hypnotics, antihistaminergic compounds, antipsychotics, antioxidants, vasodilators, among others.

Specifically, the following proposals have been made in the patent literature, but have not been proven for widespread use:

US patent 4,735,968 discloses a method of treating tinnitus with aminoxyacetic acid (ADAA) administered orally. US patent 4,954,486 proposed treating tinnitus symptoms with furosemide. US Patent 4,956,391 discloses procaine and a complexing agent for treating individuals addicted to narcotics and reducing the effect of tinnitus and ageing. US patent 5,668,117 proposed treatment of tinnitus with a carbonyl trapping agent in combination with antidepressants or antianxiety medications; anti-convulsants; lidocaine; aminooxyacetic acid; praxilene; aniracetam; piracetam; 13-cisretionic acid; and 13-trans-retinoic acid. US patent 5,716,961 discloses the treatment of tinnitus using specific neuroprotective agents. US patent 5,863,927 proposed to treat tinnitus with dextromethorphan in combination with a debrisoquin hydroxylase inhibitor. US patent 6,358,540 disclosed the treatment of tinnitus with an herbal composition. US Patent 6,465,442 discloses treating tinnitus by topically administrating in the ear a muscarinic agent or opioid agent. US patents 6,656,172 and 6,969,383 proposed treatment of tinnitus using a catheter to infuse a therapeutic agent for example an agent comprising a local anesthetic such as lidocaine, or a GABA agonist. US patent 6,713,490 discloses a c o m p o u n d w h i c h i s ( R )-6[2-[4-(3-fiuorophenyl)-4-hydroxy-l-piperidibyl]-l - hydroxyethyl]-3,4-dihydro-2(lH)-quinolinone inter alia for the treatment of tinnitus. US patent 6,770,661 disclosed various aryl substituted pyridines inter alia as antitinnitus agent.

US patent application 2002/0039599 discloses the treatment of small intestinal bacterial growth (SIBO) by depressing the bacterial population of nutrients. This is said to treat SIBO-caused conditions inter alia tinnitus. The same patent application describes the administration of a large group of pharmaceutically active agents including opioid antagonists such as naltrexone in order to enhance digestion. US patent application 2003/0069318 discloses a combination of an analgesic agent such as lidocaine and bupitacaine HC1 and an oil, for the treatment of tinnitus. US patent application 2004/0204409 describes bicyclic amide compounds that can be used to treat various conditions including tinnitus, or possibly administered for the treatment of pain in combination with opioid analgesics including naltrexone. US patent application 2004/0266989 describes certain peptides which can be used in combination with naltrexone for the treatment of gastrointestinal disorders, or these peptides can be used in other combination therapy treatments for treating tinnitus. US patent application 2007/0105863 describes guinoline and octahydropyridopyrazine derivatives used to antagonize opioid receptors, to treat various symptoms including tinnitus and impaired hearing. US patent application 2008/003301 1 describes deuterium derivatives of paroxetine that can be used in combination with vestipitant for the treatment of tinnitus, or in combination with naltrexone for the treatment of alcohol dependence. Naltrexone

Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. Naltrexone, and its active metabolite 6-β- naltrexol, are competitive antagonists at μ- and κ-opioid receptors, and to a lesser extent at δ-opioid receptors. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia and Depade. In some countries including the United States, an extended-release formulation is marketed under the trade name Vivitrol.

The blockade of opioid receptors is the basis behind its action in the management of opioid dependence-it reversibly blocks or attenuates the effects of opioids. It is licensed for use orally as adjunctive therapy in the treatment of detoxified formerly opioid- dependent individuals (after around 10 days of being opiate free). The oral bioavailability of naltrexone ranges from 5 to 40%, with peak plasma levels reached within 1 h. The effectiveness of oral naltrexone for preventing relapse to opioid addiction has been systematically reviewed with dosing regimens ranging from 50-100 mg oral naltrexone daily to thrice weekly dosing (100-100-150 mg). It blocks the pleasurable and euphoric effects of heroin and other opiates. It works to help former opioid-dependent individuals to stay off drugs through the knowledge that these drugs will produce no positive effects. It does not increase motivation to stay abstinent and thus if people choose not to take the dose regularly it will not work. Thus, the usefulness of naltrexone in opioid dependence is very limited by the low retention in treatment. It temporarily blocks substance intake but does not affect craving. Even if sustained-release preparations of naltrexone have shown rather promising results, it remains a treatment only for a small part of the opioid-dependent population, usually the ones with an unusually stable social situation and motivation. Naltrexone is sometimes used for rapid detoxification ("rapid detox") regimens for opioid dependence. The principle of rapid detoxification is to induce opioid-receptor blockage while the patient is in a state of impaired consciousness, so as to attenuate the withdrawal symptoms experienced by the patient. Rapid detoxification under general anaesthesia involves an unconscious patient and requires intubation and external ventilation. The main use of naltrexone is for the treatment of alcohol dependence. The mechanism of action of naltrexone in alcohol dependence is not fully understood, but as an op io id-receptor antagonist its action is likely to be due to the modulation of the dopaminergic mesolimbic pathway which ethanol is believed to activate. The standard regimen is one 50 mg tablet per day. In 1994, the Food and Drug Administration (FDA) approved naltrexone for the treatment of alcohol dependence based on data from two relatively small (total N = 167) studies. In those studies, recently abstinent, alcohol- dependent individuals who received naltrexone (50 mg/day), compared with their counterparts who got placebo, were less likely to relapse during the treatment period of 12 weeks. Nevertheless, 5 months after treatment, the relapse rates for the naltrexone and placebo groups were similar. A multi-center COMBINE study has recently proven the usefulness of naltrexone in an ordinary, primary care setting, without adjunct psychotherapy. The majority of the data confirm that naltrexone is an efficacious medication for treating alcohol dependence. The therapeutic treatment effect size is, however, small, and poor pill-taking compliance can be associated with poor clinical outcome.

Three extended-release formulations of naltrexone for deep intramuscular injection have been developed— Vivitrol® (Alkermes, Inc., Cambridge, MA, USA), Naltrel® (Drug Abuse Sciences, Inc., Paris, France), and Depotrex® (Biotek, Inc., Woburn, MA, USA).

Vivitrol, formerly Vivitrex, was approved by the FDA on April 13, 2006 for the treatment of alcoholism. This version is made by Alkermes, and will be jointly marketed by Cephalon, Inc. The medication is administered by intra-muscular injection and lasts for up to 30 days. Depot formulations of naltrexone may offer some advantages such as increased compliance over the oral formulations. This advantage has, however, been difficult to demonstrate in randomized controlled trials but might become more apparent when these depot formulations are used in generic practices. Depot formulations do not appear to be more efficacious than the oral formulations, and with one of these— Vivitrol®— no therapeutic effect in women has been demonstrated. The adverse events profiles of depot formulations of naltrexone that have been reported in randomized controlled trials appear similar in frequency and intensity to those observed for the oral formulation. The different depot formulations do appear to be similar in characteristics and profile, and more clinical information about which one to select to treat a particular alcohol-dependent patient, if all are approved by the FDA, shall be needed.

Low-dose naltrexone (LDN) where the drug is used in doses approximately one- tenth those used for drug/alcohol rehabilitation purposes, has been proposed for the treatment and prophylaxis of various bodily disorders

(http://www.lowdosenaltrexone.org/). Accumulating evidence suggests that LDN can promote health supporting immune -modulation which may reduce various oncogenic and inflammatory autoimmune processes. Since LDN can upregulate endogenous opioid activity, it may also have a role in promoting stress resilience, exercise, social bonding, and emotional well-being, as well as amelioration of psychiatric problems such as autism and depression. Low dose naltrexone (LDN) is being used by some as an "off-label" experimental treatment for certain immunologically-related disorders, including HIV/AIDS, multiple sclerosis (in particular, the primary progressive variant) Parkinson's disease, cancer, fibromyalgia, autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, Hashimoto's thyroiditis, and central nervous system disorders. Naltrexone in combination with bupropion is being investigated for the treatment of obesity.

Naltrexone patenting and marketing.

A non-verified history of naltrexone marketing and patenting can be found in the following webpage: http://newsgroups.derkeiler.corn/Archive/Alt/alt.support.mult- sclerosis/2008-09/msg00153.html.

Despite many suggestions for tinnitus treatment discussed above, there remains a need for an effective treatment of tinnitus that could be widely accepted. Rationale for the use of naltrexone for tinnitus patients

There is growing evidence that tinnitus is related to changes in neural transmission in the inner ear but also in many parts of the auditory pathway, including the dorsal cochlear nucleus, inferior colliculus, thalamus and auditory cortex. However tinnitus- related changes of neural activity are not restricted to the auditory system. Also non- auditory brain areas such as frontal or limibic areas are involved in tinnitus pathophysiology. Naltrexone acts on μ- and κ-opioid receptors, and to a lesser extent at δ- opioid receptors. These receptors are localized in many brain areas, including cortex, thalamus (μ-receptor), hypothalamus (κ-receptor) and amygdala (δ- receptor). Furthermore μ-, K- and δ-Opioid receptors are located in the cochlea, where they interact with NMDA receptors which in turn have been claimed to be involved in tinnitus generation. At the level of the inferior colliculus modulation of gabaergic inhibitory activity by μ- and κ- opioid receptor blockade has been demonstrated. In summary naltrexone can exert a modulatory effect on neuronal activity both in the cochlea, and in the central auditory pathways. Furthermore it acts on non-auditory brain areas, involved in emotional and attentional aspects of tinnitus. Among other brain structures naltrexone modulates the dopaminergic mesolimbic pathway, which is thought to be involved in tinnitus distress. Naltrexone also results in upregulation of endogenous opioid activity, which may promote stress resilience, social bonding, and emotional well-being.

Summary of the Invention

According to one aspect, the invention provides naltrexone for use in the treatment of tinnitus and related auditory dysfunctions by oral administration or by parenteral administration through intramuscular, intravenous, subcutaneous or intrathecal injection or infusion.

Another aspect of the invention is the use of naltrexone in the manufacture of a medicament for the treatment of tinnitus and related auditory dysfunctions by oral administration or by parenteral administration through intramuscular, intravenous, subcutaneous or intrathecal injection or infusion. Yet another aspect of the invention is a method of treating tinnitus and related auditory dysfunctions in a mammal, comprising orally administrating or parenterally administrating by intramuscular, intravenous, subcutaneous or intrathecal injection or infusion, to a mammal in need of such treatment, naltrexone in an amount sufficient to alleviate the symptoms of tinnitus or associated auditory dysfunctions.

In all of these aspects, the oral administration of about 1-150 mg/day of naltrexone to a subject suffering from tinnitus and related auditory dysfunctions provides alleviating affect, the most effective dosage being from 5-60 mg/day, administered usually in doses 1- 3 times per day. Excellent results have been achieved with a naltrexone dosage of 50 mg/day. Using parenteral administration through intramuscular, intravenous, subcutaneous or intrathecal injection or infusion it may be possible to use a reduced dosage and better avoid side-effects. The naltrexone is conveniently administered in tablet form but it can also be administered orally as capsules, as a powder or in solution and as a solution for injection or infusion. The administrated form can contain the usual pharmaceutically acceptable carriers, excepients or diluents. Tablets or capsules can be designed for several times a day administration, or extended release for once-a-day administration.

The treatment according to the invention is in principle a long-term treatment extending over 2 weeks or more, or preferably over 4, 8 or even 12 weeks or more. In some patients positive effects were seen already after shorter treatment durations. In the below-described trials the treatment of tinnitus with naltrexone was weaned off after 12 weeks and tinnitus then got worse in some patients. It is noteworthy that the structure of the molecule naltrexone has been shown to be safe for long-term administration. Moreover, naltrexone is on the market already for a long time, and its tolerability and side effects are well known. As shown by the tests reported below, naltrexone has a positive effect on tinnitus severity and on tinnitus loudness in the tested subjects, it is safe to administer and though common side effects (like nausea and vomiting) may be experienced, it is tolerated well by most subjects. Similar results are expected for associated auditory dysfunctions. Generally, according to the invention, naltrexone is effective for the treatment of an auditory dysfunction selected from tinnitus, hyperacusis, auditory hallucinations, misophonia, phonophobia and central auditory processing disorders.

The time of tinnitus onset was not a predictive variable to positive outcome; subjects suffering for over 20 years had positive results as well as subjects who had it for less than a year.

The duration of positive results is yet to be determined.

The invention will further be described by way of example in the tests reported below for tinnitus.

Brief Description of the Drawings

Figures 1 to 6 are graphs showing the Tinnitus Handicap Inventory and the results of other tests on various patients.

Description and Results of Trial Tests

The aim of this trial was to assess safety and efficacy of naltrexone in the treatment of tinnitus.

From April to September 2009, 18 patients suffering from chronic subjective tinnitus were recruited for this trial. Clinical and demographic characteristics of the patients are given in Table 1. Table 1: Clinical and demographic characteristics of tinnitus patients

Figure imgf000013_0001

Medication

The patients received Naltrexone tablets 50 mg once a day orally at noon for 12 weeks.

Assessment

Systematic assessment of the case history was performed with the TRI Sample case History Questionnaire. Tinnitus severity was assessed at Baseline, after 2 weeks, 4 weeks, 8 weeks, 12 weeks of treatment and 4 weeks after end of treatment by using the Tinnitus Handicap Inventory (scores 0-100), a "Tinnitus Problem" numeric rating scale (1-5), five numeric rating scales covering different aspects of tinnitus ("Tinnitus numeric rating scales; sum-score 0-50) and a clinical global improvement (CGI) scale (scores 1-7). Further assessments included quality of life and depression scales. At baseline and at week 12 audiologic examinations were performed including pure -tone audiometry, tinnitus pitch matching and minimal masking levels.

Results

Fourteen patients completed the trial. Two patients underwent the baseline assessment but then decided not to start drug treatment. Two patients stopped drug treatment because of side effects. Both patients experienced nausea and vomiting, one patient additionally stomach ache. Symptoms resolved completely after treatment was stopped. All further data refer to those 14 patients, who completed treatment as planned (per protocol analysis).

Improvement of tinnitus (according to CGI) was reported by nine patients. In five of these nine patients tinnitus remitted completely during the naltrexone treatment. In one patient the tinnitus stopped after few days of treatment, in one patient after 2 weeks, in one after 4 weeks and in two patients after 8 weeks of treatment. After stopping naltrexone, tinnitus started again in one patient, however on a lower level than before treatment. The complete remission of tinnitus was reflected by a complete or near complete reduction of the scores in the different used assessment instruments (Figures 1 ,2). The tinnitus duration in those patients in which tinnitus remitted completely ranged between 3 months and 9 years.

Figure 1 shows the Tinnitus Handicap Inventory Scores of the five patients, in which tinnitus stopped (complete responders).

Figure 2 shows the sum of five numeric tinnitus rating scales of the five patients in which tinnitus stopped (complete responders). Figure 3 shows the Tinnitus Handicap Inventory Scores of the four patients, in which tinnitus improved (partial responders).

Figure 4 shows the sum of five numeric tinnitus rating scales of the four patients in which tinnitus improved (partial responders). Figure 5 shows the mean values of all tests for the whole group, namely the Tinnitus handicap Inventory and the sum of the numeric rating scales.

Figure 6 shows a graph of Tinnitus problem and clinical global improvement (CGI) for the whole group.

Claims

CLAIMS :
1. Naltrexone for use in the treatment of tinnitus and related auditory dysfunctions by oral administration or by parenteral administration through intramuscular, intravenous, subcutaneous or intrathecal injection or infusion.
2. Naltrexone according to claim 1 in a form for administration to a subject suffering from tinnitus or related auditory dysfunctions in an amount of 1-150 mg/day.
3. Naltrexone according to claim 2 for administration in an amount of 5-60 mg/day.
4. Naltrexone according to claim 1 , 2 or 3 in the form of tablets, capsules, powder or solution.
5. Naltrexone according to any preceding claim for a long-term treatment of tinnitus and related auditory dysfunctions extending over 2 weeks or more, preferably 8 weeks or more.
6. Naltrexone according to any preceding claim for use in the treatment of an auditory dysfunction selected from tinnitus, hyperacusis, auditory hallucinations, misophonia, phonophobia, and central auditory processing disorders.
7. Use of naltrexone in the manufacture of a medicament for the treatment of tinnitus and related auditory dysfunctions by oral administration or by parenteral administration through intramuscular, intravenous, subcutaneous or intrathecal injection or infusion.
8. The use according to claim 7 of naltrexone for administration to a subject suffering from tinnitus or related auditory disorders in an amount of 1-150 mg/day.
9. The use according to claim 8 for administration in an amount of 5-60 mg/day.
10. The use according to claim 8 or 9 wherein the naltrexone is in the form of tablets, capsules, powder or solution.
1 1. The use according to claim 7, 8, 9 and 10 for a long-term treatment of tinnitus and related auditory dysfunctions extending over 2 weeks or more, preferably 8 weeks or more.
12. The use according to any one of claims 7 to 1 1 for the treatment of an auditory dysfunction selected from tinnitus, hyperacusis, auditory hallucinations, misophonia, phonophobia, and central auditory processing disorders.
13. A method of treating tinnitus and related auditory disorders in a mammal, comprising orally administering or parentarally administering by intramuscular, intravenous, subcutaneous or intrathecal injection or infusion, to a mammal in need of such treatment, naltrexone in an amount sufficient to alleviate the symptoms of tinnitus or related auditory disorder.
14. The method of claim 13, comprising administering naltrexone to the mammal in an amount of 1-150 mg/day.
15. The method of claim 14, comprising administering naltrexone to the mammal in an amount of 5-60 mg/day.
16. The method of claim 13, wherein the naltrexone is administered in the form of tablets, capsules, powder or solution.
17. The method of claim 13, for a long-term treatment of tinnitus and related auditory disorders extending over 2 weeks or more.
18. The method of claim 17 for a long-term treatment extending over 8 weeks or more.
19. The method of claim 13 of treating of an auditory disfunction selected from tinnitus, hyperacusis, auditory hallucinations, misophonia, phonophobia, and central auditory processing disorders.
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