Treating tinnitus patients,tinnitus zentrum chemnitz m?llerstra?e,ear pain and blowing nose vertigo - Step 2

Author: admin, 16.08.2014
Kaneko, Megumi et al., Intrathecally Administered Gabapentin Inhibits Formalin-Evoked Nociception and the Expression of Fos-Like Immunoreactivity in the Spinal Cord of the Rat, J. FIELD OF THE INVENTIONThis invention relates to a method for treating severe tinnitus.BACKGROUND OF THE INVENTIONTinnitus is the perception of ringing, hissing, or other sounds in the ears or head when no external sound is present. Inner ear disorders that increase hearing sensitivity (such as SCD) can cause pulsatile tinnitus. There are some very large blood vessels -- the carotid artery and the jugular vein -- that are very close to the inner ear (see diagram above).
This is a congenital anomaly in which the internal carotid can present as a middle ear mass. Dural Arteriovenous fistulae (DAVF) cause loud noises, synchronous with the pulse, that can often be heard by others with a stethescope, or sometimes by simply putting one's ear next to the person's head. To be certain there is no DAVF at all, 6 vessel DSA is suggested by the interventional radiologists.
Radiosurgery is mainly reserved for cases that persist after embolization, but some authors use the opposite order -- radiosurgery first, followed by a clean up embolization (e.g. Recurrence of fistulae may appear, possibly due to release of growth factors associated with local tissue hypoxia, following occlusion of the DAVF.
It may seem silly to say this, but in our opinion, it is generally not worth taking on a significant risk of having a stroke to attempt to get rid of a noise in one's head with embolization.
The method of the present invention comprises implanting a catheter into a patient and administering a drug formulation or fluid comprising a therapeutic agent intrathecally into the patient's cerebrospinal fluid. The method of claim 1, wherein the solvent comprises an effective amount of NaCl to make the drug formulation isotonic. The method of claim 1, wherein the drug formulation is substantially free of preservatives. The method of claim 1, wherein the at least one therapeutic agent comprises a GABAB agonist.
The method of claim 10, wherein the infusing baclofen comprises a daily dose between 20 and 2000 mcg. The method of claim 10, wherein the infusing baclofen comprises a daily dose between 50 and 1500 mcg. The method of claim 10, wherein the infusing baclofen comprises a daily dose between 100 and 1000 mcg. The method of claim 1, wherein the at least one therapeutic agent comprises a thyrotropin-releasing hormone. The method of claim 1, wherein the at least one therapeutic agent comprises sodium valproate. The method of claim 1, wherein the at least one therapeutic agent comprises a GABAA agonist.
The method of claim 1, wherein the distal end of the catheter is placed in subarachnoid space between fifth thoracic and first cervical vertebrae. The method of claim 1, wherein the distal end of the catheter is placed in subarachnoid space between fifth lumbar and fifth thoracic vertebrae. The method of claim 26, wherein the gabapentin delivered comprises a daily dose between 1 and 200 mg. The method of claim 26, wherein the gabapentin delivered comprises a daily dose between 1 and 150 mg. The method of claim 26, wherein the gabapentin delivered comprises a daily dose between 2 and 60 mg. The method of claim 26, wherein the distal end of the catheter is placed in the subarachnoid space between fifth thoracic and first cervical vertebrae. The method of claim 26, wherein the distal end of the catheter is placed in the subarachnoid space between fifth lumbar and fifth thoracic vertebrae. The method of claim 35, wherein the solvent comprises an effective amount of NaCl to make the drug formulation isotonic. The method of claim 39, wherein the distal end of the catheter is placed in the subarachnoid space between fifth thoracic and first cervical vertebrae. The method of claim 39, wherein the distal end of the catheter is placed in the subarachnoid space between fifth lumbar and fifth thoracic vertebrae. The method of claim 42, wherein the solvent comprises an effective amount of NaCl to make the drug formulation isotonic. The method of claim 46, wherein the distal end of the catheter is placed in the subarachnoid space between fifth thoracic and first cervical vertebrae.
The method of claim 46, wherein the distal end of the catheter is placed in the subarachnoid space between fifth lumbar and fifth thoracic vertebrae. The method of claim 49, wherein the solvent comprises an effective amount of NaCl to make the drug formulation isotonic. Method for treating tinnitus, the method comprising of: intrathecally administering drug formulation comprising at least one therapeutic agent and a solvent in an amount effective to treat tinnitus. The Audio Laser-Kliniken is treating amd, tinnitus and other inner ear disorders with laser. If the carotid fails to develop correctly during fetal life, the inferior tympanic artery enlarges to take it's place. DAVF recieve blood through meningeal arteries or meningeal branches of cerebral arteries and drain directly through a dural sinus or venous channel tributary of a venous sinus through dilated deep veins (Signorelli et al, 2014). The Cognard states that type I and II DAVFs drain directly into dural sinuses, the difference being antegrade flow in the type I, and retrograde flow in the type II. Successful treatment requires occlusion of the venous recipient, as occlusion of the arteries alone can be associated with recruitment of more venous drainage (Adamczyk et al, 2012). Surgery is sometimes preferred for fistulae draining into the superior sagittal or dominant transverse sinus when embolization might result in an undesirable sacrifice of the dural venous sinus.
Eggermont, “Effects of salicylate on neural activity in cat primary auditory cortex.” Hearing Research, 1996, pp.
Accordingly, other possibilities for vascular tinnitus include dehiscence (missing bone) of the jugular bulb -- an area in the skull which contains the jugular vein, and an aberrantly located carotid artery.
It enters the skull through it's own foramen, courses through the medial part of the middle ear, and then rejoins the petrous ICA (Branstetter and Weissman, 2006). DAVF are thought to be acquired and are associated with intracranial surgery, ear infection, tumor, hypercoagulability, puerperium, and trauma.
According to De Keukeleire et al (2011), Type I DAVs are low risk and need be treated only if symptoms are intolerable. The reason for this order is that embolization might obscure the target for the radiosurgery if performed first. According to the American Tinnitus Association, over 50 million Americans experience tinnitus to some degree and of these, approximately 12 million people have tinnitus to a distressing degree.Approximately 2 million Americans have tinnitus to the point where they are so seriously debilitated that they cannot function on a “normal” day-to-day basis and some may commit suicide.
An enlarged jugular bulb on the involved side is common in persons with venous type pulsatile tinnitus.
Radiosurgery by itself has a low succes rate as the only treatment (Signorellli et al, 2014). To avoid conflicts of interest, ideally the expert should work for another medical insitution. McGeer, “Age Changes in the Human for Some Enzymes Associated with Metabolism of the Catecholamines, GABA and Acetycholine.” Neurobiology of Aging, 1975, pp. Trans venous embolization is a good option when arterial feedrs are too numerous, and when the venous drainage of the DAVF can be sacrifised.
It is also a poor choice for those with hemmorage, because it is slow acting (1-3 years), and more hemmorage might occur while waiting for the blood vessels to close.
The risk of hemmorage increases with direct drainage into cortical veins (Signorelli et al, 2014).


On the other hand, radiosurgery is likely a more durable long term treatment than embolization alone. It is this severely affected population, which is only poorly managed with therapies available today, that may benefit from intrathecal pharmacotherapy proposed in the current investigation.In terms of population percentages, approximately 17% of the general population, and 33% of the elderly population suffer from tinnitus.
Most of the therapies that are presently available attempt to minimize the patients' awareness of the tinnitus symptoms or reduce their emotional reaction to their condition.Rational treatment for the small proportion of patients with a reversible cause for their tinnitus involves correcting the underlying condition.
In its simplest form, masking consists of self-exposure to background noise such as, radio, television, or recorded music.
People with normal hearing and severe tinnitus can wear a small hearing-aid-like device that produces background (masking) noise in the affected ear. Patients with concomitant impaired hearing and tinnitus sometimes benefit (both their hearing and tinnitus) from use of a conventional hearing aid.PsychotherapyLimbic structures of the brain may be involved in the neural plastic changes associated with tinnitus. Supportive of this notion is the observation that the perceived amplitude of the tinnitus often does not correspond to the overall severity of the condition.
For example, some patients with tinnitus of a relatively low volume are extremely disturbed, whereas others with high volume tinnitus are relatively unaffected by it. Habituation is a psychological technique that trains patients to ignore or minimize their emotional reaction to tinnitus.
Habituation is traditionally defined as the disappearance of reactions to sensory stimuli because of repetitive exposure and the lack of positive or negative reinforcement.
The most popular version of this therapy, tinnitus retraining therapy, has been developed and popularized by Dr.
Treatments tend to be more successful for mild and moderate forms of tinnitus and for cases of shorter duration.Psychoactive DrugsThe drugs most commonly used to manage tinnitus are antidepressants (especially tricyclics) and anxiolytics (valium, alprazolam, buspirone), although they have limited efficacy.
Anxiolytics and antidepressants affect the secondary psychological sequelae of tinnitus, rather than the perception of the noise itself. The neural plasticity associated with tinnitus may involve the formation of new neural connections between the auditory and limbic systems of the brain. Most agents have been administered orally, although several clinical trials attempting to directly administer agents into the ear have also failed to show efficacy.
Unlike other commonly prescribed oral medications that tend to manage only the emotional symptoms associated with tinnitus, lidocaine actually reduces or eliminates the noise.
Lidocaine ameliorates tinnitus in approximately 60-80% of sufferers, a result that has been replicated in numerous well-controlled clinical trials. The efficacy of IV lidocaine is greater than the efficacy produced by auditory nerve transection (approximately 50%), suggestive of a central mechanism of lidocaine action. However, locally administered lidocaine (to the ear or cochlea) has been relatively ineffective.
In addition, locally administered lidocaine to the ear has been associated with significant vestibular side effects such as vertigo and nausea. Tinnitus patients effectively treated with IV lidocaine in the short term, usually experience a return of their symptoms shortly after the medication has been stopped.
Intravenous lidocaine (bolus administration) has a short duration of action (10-20 minutes) and is metabolized rapidly by the liver (terminal half life of 1.5 to 2 hours in humans).
Lidocaine used in the treatment of cardiac arrhythmias is typically diluted with saline, and administered as a precisely-metered IV infusion.
Unfortunately in tinnitus patients with healthy heart rhythms, IV lidocaine can induce potentially life-threatening cardiac arrhythmias. If administered orally, lidocaine is ineffective due to a major first pass effect.BaclofenTinnitus is associated with abnormal spontaneous neural activity at multiple levels within the central auditory pathways.
Gamma-amino-butyric acid (GABA) is the main inhibitory neurotransmitter of the mammalian CNS.
An example of a GABAB-receptor agonist is baclofen, which mimics in part the effects of GABA.Several studies have correlated age-related changes in the concentrations of GABA and GABAB-binding sites in the Inferior Colliculus (“IC”), the major auditory midbrain structure.
Age-related decreases in the enzyme responsible for GABA synthesis (glutamic acid decarboxylase) have been reported in the IC of both rats and humans. Age changes in the human for some enzymes associated with metabolism of the catecholamines, GABA and acetycholine. In rats, age-related decreases in the levels of GABA and the number of GABAB-binding sites within the IC have also been reported. These biochemical findings may explain why tinnitus is more prevalent among the elderly.In addition to age-related biochemical changes, the inferior colliculus also shows changes in function (increased spontaneous activity) in response to noise exposure or injury to the peripheral auditory system, results commonly associated with tinnitus in humans. In rats, IV baclofen inhibited noise-induced electrical potentials recorded directly from IC neurons. An additional observation suggestive of the inhibitory role of GABA in the normal auditory system comes from clinical reports of auditory hallucinations that are sometimes experienced with baclofen withdrawal in humans. The authors conducted a randomized, double-blinded study after anecdotal reports described patients who experienced beneficial subjective reduction in tinnitus while taking oral baclofen.
Not all of the patients had severe tinnitus, and for some, tinnitus was not their primary complaint.
Oral baclofen therapy was associated with significant side effects that included sedation, confusion, dizziness, GI upset, and weakness, the combination of which caused 25% of the enrolled patients to drop out of the trial.These side effects are also associated with oral baclofen used to treat spasticity but are typically not a problem when baclofen is administered intrathecally to treat spasiticity. By acting at GABAA receptors, benzodiazepines act to inhibit neuronal activity and have proven to be useful in decreasing neuronal hyperactivity associated with epilepsy and anxiety.Benzodiazepines are also commonly used in anesthesiology as tranquilizers. In addition to quelling the hyperactive neurons associated with tinnitus, these agents may offer the added benefit of decreasing anxiety, a common comorbidity associated with severe tinnitus. Two drugs in the benzodiazepine family are midazolam and alprazolam, both of which may be useful in the management of tinnitus.GabapentinGabapentin is a GABA-agonist-like drug. Because it does not bind directly to GABA receptors, it is not a true pharmacologic GABA agonist.
On the other hand, it is known that gabapentin produces inhibitory effects like GABA on selective neuronal populations and thus has been useful in treating several diseases characterized by hyperactivity of central neurons including epilepsy and neuropathic pain. Since the pathophysiology of chronic severe tinnitus appears to be similar to neuropathic pain (plastic neural changes leading to central facilitation of synaptic transmission), many drugs that are effective for neuropathic pain may be effective for tinnitus.
Indeed, reports both in animal models and humans suggest that oral gabapentin may be useful in reducing tinnitus.
Because gabapentin does not readily penetrate the blood-brain barrier, intrathecal delivery should produce higher more effective concentrations of gabapentin in the CNS.Thyrotropin-releasing hormone (TRH)TRH, a peptide neurotransmitter in the CNS, has been suggested as a useful agent for treating both mood disorders and epilepsy by acting primarily to inhibit the activity of glutamine-containing neurons. Glutamine is the major excitatory neurotransmitter of the CNS and may be associated with increased activity of the central auditory neurons involved in tinnitus.
The loss of GABA-containing neurons with aging, results in an increased activity of glutamine-containing neurons that may be controlled by supplying exogenous TRH.Sodium ValproateSodium valproate is another agent that is used to treat central diseases of the nervous system associated with increased neuronal activity. Clinically it is used to treat both epilepsy and as a mood stabilizer to treat bipolar disorder. 5,676,655 discloses a method for implanting a neural prosthetic drug delivery apparatus into a target zone of a patient's brain for reducing or eliminating the effects of tinnitus. The apparatus includes a catheter that is inserted into the patient's auditory cortex or thalamus. The catheter microinfuses drugs that suppress or eliminate abnormal neural activity into geometrically separate locations of the patient's cortex or thalamus, thereby reducing or eliminating the effects of tinnitus. The patent, however, deals with drug delivery directly into brain tissue or into specific anatomical structures, i.e. There are a number of disadvantages to intraparenchymal drug delivery to treat severe tinnitus. For example, intraparenchymal drug delivery is relatively invasive and requires a highly trained neurosurgeon to implant the catheter into the brain tissue or specific anatomical structure.SUMMARY OF THE INVENTIONOne or more of the above-mentioned deficiencies in the art are satisfied by the method of the present invention of intrathecal drug delivery for the treatment of severe tinnitus. One embodiment of the invention involves the use of a drug formulation infused intrathecally to treat tinnitus. For example, a catheter is implanted into a patient, the catheter having a proximal end and a distal end.


The distal end of the catheter is adapted to infuse the drug formulation intrathecally into a patient's cerebrospinal fluid. The drug formulation may comprise a solvent and at least one therapeutic agent such as baclofen, gabapentin, sodium valproate, a benzodiazepine such as midazolam or alprazolam, or a thyrotropin-releasing hormone.In one embodiment of the invention, the proximal end of the catheter is coupled to an implantable pump and the distal end of the catheter is inserted into the subarachnoid space of a patient's spinal column. The implantable pump is operated to deliver a fluid that may comprise a therapeutic agent such as gabapentin, sodium valproate, or a thyrotropin-releasing hormone. 2 is a diagrammatic illustration of the location of a patient's inferior colliculus and the flow of cerebrospinal fluid in the subarachnoid space.FIG. 3 is diagrammatic illustration of a catheter implanted in a patient according to an embodiment of the present invention.FIG.
4 is a diagrammatic illustration of an implanted catheter and pump in accordance with an embodiment of the present invention.FIG. 5 is a diagrammatic illustration of a catheter implanted in a patient's subarachnoid space for the delivery of a therapeutic agent or agents into the cerebrospinal fluid.DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTSAs illustrated in FIG.
1, the central auditory pathways comprise, the inferior colliculus 1, the auditory cortex 2, the dorsal acoustic stria 102, the cochlear nuclei 104, the geniculate nucleus 106, the nucleus of the lateral lemniscus 108, the superior olivary nuclei 110, and the intermediate acoustic stria 112.
Experimental evidence suggests that the dorsal cochlear nuclei 104, the inferior colliculus 1, and the auditory cortex 2, as shown in FIGS. These major auditory structures are relatively shallow brain structures that lie in close proximity to the subarachnoid space 3 as shown in FIG. 2.The inferior colliculus 1 lies on the dorsal surface of the midbrain 4 and rostral (cephalad) to the fourth ventricle 5 and dorsal to the cerebral aqueduct of Sylvius 8.
The superficial surface of the inferior colliculus 1 is bathed in cerebrospinal fluid (CSF) 6 that exits the foramina of Magendie and Luschka to flow around the brainstem and cerebellum. 2 indicate cerebrospinal fluid 6 flow.The subarachnoid space 3 is a compartment within the central nervous system that contains cerebrospinal fluid 6. The cerebrospinal fluid 6 is produced in the ventricular system of the brain and communicates freely with the subarachnoid space 3 via the foramina of Magendie and Luschka.As previously discussed in the background of the invention, available evidence suggests that tinnitus arises within the central auditory structures of the brain, and that those structures represent an important target for therapeutic agents.
Given the limited efficacy of other treatments, intrathecal delivery of therapeutics into the cerebrospinal fluid 6 in accordance with the present invention offers the potential to reduce the perception of tinnitus in a large portion of severely affected patients who currently have very limited options.The therapeutic agent or agents may include baclofen, gabapentin, sodium valproate, a benzodiazepine such as midazolam or alprazolam, or a thyrotropin-releasing hormone. Each of the agents may be combined with a solvent to form a drug formulation that may be administered intrathecally to a patient. In addition, the drug formulation may comprise an effective amount of NaCl to make the drug formulation isotonic. The drug formulation may have a pH between 4 and 9 and more preferably a pH between 5 and 7. Also, the drug formulation may be substantially free of preservatives and may contain cyclodextrin acting as an excipient to increase solubility.Intrathecal delivery of therapeutics into the cerebrospinal fluid is less invasive than intraparenchymal (direct tissue) delivery of therapeutics.
In addition, intrathecal delivery of therapeutics may not require the need for a neurosurgeon as the delivery of the therapeutics does not require delivery to a direct brain target. Numerous other physicians may be qualified to insert a catheter into the lumbar subarachnoid space of the spinal column in order to initiate intrathecal therapeutic delivery.Referring to FIG.
The device 30 has a port 34 into which a hypodermic needle can be inserted through the skin to inject a quantity of therapeutic agent.
The therapeutic agent is delivered from device 30 through a catheter port 37 into a catheter 38. Catheter 38 is positioned so that the distal tip 39 of catheter 38 is positioned in the subarachnoid space 3 between the fourth cervical vertebrae (C4) 52 and the seventh cervical vertebrae (C7) 54, as shown in FIG. The distal tip 39 can be placed in a multitude of locations to deliver a therapeutic agent into the cerebrospinal fluid of the patient. In one embodiment, the distal tip 39 of catheter 38 is inserted in the subarachnoid space 3 between the fourth cervical vertebrae (C4) 52, and the seventh cervical vertebrae (C7) 54, to allow for relatively high therapeutic dose infusion concentrations in the intracranial CSF compartment near the inferior colliculus 1 while minimizing spinal exposure.
In other embodiments, the distal tip 39 of the catheter 38 is inserted in the subarachnoid space 3 between the fifth thoracic (T5) 49 (FIG.
4) and the first cervical vertebrae (C1) 56, or in the subarachnoid space 3 between the fifth lumbar (L5) 48 (FIG.
3, delivery of a therapeutic agent into the CSF to treat severe tinnitus can be accomplished by simply injecting the therapeutic agent via port 34 to catheter 38.A higher concentration of baclofen delivered intrathecally into the CSF in accordance with the present invention can provide improved reduction of the perception of tinnitus in a large proportion of severely effected patients. Baclofen is a zwitterionic, hydrophilic molecule that does not readily penetrate the blood-brain barrier.
The enhanced efficacy and reduced side effects associated with baclofen delivered intrathecally provides higher concentrations of baclofen in CSF than baclofen delivered orally. For example, pharmacokinetic data shows that baclofen levels in the cisternal CSF, at the base of the brain, after lumbar intrathecal administration are approximately 20-30 times higher in the CSF than levels after oral administration to treat spasticity. The higher concentration reduces the amount of time between pump reservoir refills whereas the lower concentrations may allow for a greater amount of volume to be delivered intrathecally. In addition, the daily dosage of baclofen to be administered may depend upon the particular treatment protocol to be administered. Unlike baclofen, which is a selective GABAB agonist, muscimol is a selective GABAA agonist that inhibits neuronal activity by activating chloride channels leading to neuronal hyperpolarization.In addition, a GABAA agonist family of therapeutics, benzodiazepines, may also be intrathecally delivered into the CSF as a therapeutic agent alone or in combination with other therapeutic agents.
The benzodiazepines may be comprised of the therapeutics midazolam or alprazolam.A GABA-agonist-like drug, gabapentin, may also be administered intrathecally in the treatment of tinnitus.
In addition, the daily dosage of gabapentin to be administered may depend upon the particular treatment protocol. 4, an implantable medical device known as an implantable therapeutic pump 40 is implanted into a patient.
The location of pump implantation is one in which the implantation interferes as little as practicable with patient activity, such as subcutaneous in the lower abdomen.
The proximal end 35 of a catheter 38 is connected to the implantable therapeutic pump outlet.
The catheter 38 is a flexible tube with a lumen typically running the length of the catheter 38. The distal end 33 of catheter 38 is positioned to infuse a fluid into the target area of CSF of the patient. The pumped fluid may comprise a therapeutic agent such as gabapentin, sodium valproate, or a thyrotropin-releasing hormone.
In addition, the pumped fluid may comprise an effective amount of NaCl to make the drug formulation isotonic.The target area of CSF of the patient may be the subarachnoid space 3 between the fourth cervical vertebrae (C4) 52 and seventh cervical vertebrae (C7) 54, as shown in FIG. In addition, other target areas of the CSF of the patient may include the subarachnoid space 3 between the fifth thoracic (T5) 49 (FIG. 4) and the first cervical vertebrae (C1) 56, or the subarachnoid space 3 between the fifth lumbar (L5) 48 (FIG. The implantable therapeutic pump 40 is operated to discharge a predetermined dosage of the pumped fluid into the CSF of the patient.The implantable therapeutic pump 40 contains a microprocessor 42 or similar device that can be programmed to control the amount of fluid delivery. A controlled amount of fluid comprising therapeutics may be delivered over a specified time period. With the use of the implantable therapeutic pump 40, different dosage regimens may be programmed for a particular patient.
Additionally, different therapeutic dosages can be programmed for different combinations of fluid comprising therapeutics.
Those skilled in the art will recognize that a programmed implantable therapeutic pump 40 allows for starting conservatively with lower doses and adjusting to a more aggressive dosing scheme, if warranted, based on safety and efficacy factors.The embodiments of the invention, and the invention itself, are now described in such full, clear, concise and exact terms to enable a person of ordinary skill in the art to make and use the invention. To particularly point out and distinctly claim the subject matters regarded as invention, the following claims conclude this specification. To the extent variations from the preferred embodiments fall within the limits of the claims, they are considered to be part of the invention, and claimed.



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