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  Pharmaceutical Patents  

 

Title:  Methods for enhancing therapeutic effects of a neurotoxin
United States Patent: 
7,824,694
Issued: 
November 2, 2010

Inventors:
 First; Eric R. (Boston, MA), Irvine; Ryan A. (Los Angeles, CA)
Assignee:
  Allergan, Inc. (Irvine, CA)
Appl. No.:
 11/330,893
Filed:
 January 12, 2006


 

Executive MBA in Pharmaceutical Management, U. Colorado


Abstract

The present invention relates to methods for enhancing the therapeutic effects of a neurotoxin, e.g., a botulinum toxin, where the methods comprise a "wash-down" (e.g., a decreased intake) of a current pain medication and an administration of a neurotoxin. In some embodiments, the present inventions relates to methods for enhancing the therapeutic effects of a neurotoxin for treating pain, e.g., headache pain.

Description of the Invention

SUMMARY

The present invention meets this need and provides methods for enhancing the therapeutic use of neurotoxin, e.g., botulinum toxin, for treating various conditions, such as pain and headache pain. The therapeutic effect of the neurotoxin is enhanced by, for example, being administered at a lower dose/frequency but still achieving the same or better therapeutic end result.

In some embodiments, the methods of the present invention comprise the steps of decreasing a dose of at least one current headache medication that is being used by the patient to a lower dose ("wash-down"), and locally administering a neurotoxin to the patient.

In some embodiments, the wash-down may be prior to the step of administering the neurotoxin. Further, the wash-down period may occur within about an amount of time equal to that required to achieve the current dose relative to the lower dose. In some embodiments, the amount of time required to achieve the current dose is provided by a product instruction insert of the medication.

In some embodiments, the wash-down is to reduce the pain medication in the blood circulation of the patient to about 5% (or more) of the original level prior to wash-down. In some embodiments, the wash-down is to reduce the pain medication in the blood circulation of the patient to about 10% (or more) of the level prior to wash-down. In some embodiments, the wash-down is to reduce the pain medication in the blood circulation of the patient to about 25% (or more) of the level prior to wash-down. In some embodiments, the wash-down is to reduce the pain medication in the blood circulation of the patient to about 50% (or more) of the level prior to wash-down.

For patients who are on prophylactic pain medications, the wash-down step of the prophylactic pain medication is such that there is still residual prophylactic pain medication in the patient's circulatory system. For example, in some embodiments, the wash-down is to reduce the prophylactic pain medication in the blood circulation of the patient to about 5% (or more) of the original level prior to wash-down. In some embodiments, the wash-down is to reduce the prophylactic pain medication in the blood circulation of the patient to about 10% (or more) of the level prior to wash-down. In some embodiments, the wash-down is to reduce the prophylactic pain medication in the blood circulation of the patient to about 25% (or more) of the level prior to wash-down. In some embodiments, the wash-down is to reduce the prophylactic pain medication in the blood circulation of the patient to about 50% (or. more) of the level prior to wash-down.

After the administration of the neurotoxin, the methods comprise an optional step of increasing the dose of the lowered headache dose.

The term "neurotoxin" employed herein refers to one or more of a toxin made by a bacterium, for example, a Clostridium botulinum, Clostridium butyricum, Clostridium beratti, Clostridium tetani. In some embodiments, the neurotoxin is a botulinum toxin. The botulinum toxin may be a botulinum toxin type A, type B, type C.sub.1, type D, type E, type F, or type G. In some embodiments, the neurotoxin is a botulinum toxin type A. Unless stated otherwise, the dose of the neurotoxin referenced herein is equivalent to that of a botulinum toxin type A. The assays required to determine equivalency to the therapeutic effectiveness of botulinum toxin type A at a certain dosage are well established.

DESCRIPTION

The present invention is based, in part, upon the discovery that a reduction in the administration of a pain medication prior to the administration of a neurotoxin, or prior to the therapeutic onset of the neurotoxin after its administration, can enhance the therapeutic effects of the neurotoxin. The therapeutic effect of the neurotoxin is enhanced by, for example, being administered at a lower dose/frequency but still achieving the same or better therapeutic end result.

As stated above, the term "neurotoxin" refers to one or more of a toxin made by a bacterium, for example, a Clostridium botulinum, Clostridium butyricum, Clostridium beratti, Clostridium tetani. In some embodiments, the neurotoxin is a botulinum toxin. The botulinum toxin may be a botulinum toxin type A, type B, type C.sub.1, type D, type E, type F, or type G. In some embodiments, the neurotoxin is a botulinum toxin type A. Unless stated otherwise, the dose of the neurotoxin referenced herein is equivalent to that of a botulinum toxin type A. In some embodiments, the neurotoxin dose suitable for the present invention may be from about 1 Units to about 1,000 Units (in terms of unit equivalency to botulinum toxin type A).

In some embodiments, the methods of the present invention can enhance the therapeutic effects of a neurotoxin for its use in preventing and/or treating a headache pain. The methods comprise the steps of decreasing at least one current dose of a headache medication being used by the patient to a lower dose ("wash-down"), and locally administering a neurotoxin to the patient.

The wash-down may be prior to the step of administering the neurotoxin. In some embodiments, the wash-down occurs within about an amount of time equal to that required to achieve the current dose relative to the lower dose. In some embodiments, the amount of time required to achieve the current dose is provided by a product instruction insert of the medication. Further, the wash-down step may involve decreasing the current dose via a titration process. In some embodiments, the titration process is in reverse of a dosing regimen used by the patient to achieve the current dose.

In some embodiments, the titration process is in reverse of a dosing regimen provided by a product instruction insert of the medication to achieve the current dose. For example, the titration schedule as provided by the product insert for topiramate is 25-50 mg nightly for one week. Subsequently, at weekly intervals, the dose is increased by 25-50 mg/day and taken in two divided doses. The reverse of this titration process would be, at weekly intervals, reduction of 25-50 mg/day, until the initial dose (25-50 mg/day) is reached.

In some embodiments, the wash-down occurs within about an amount of time equal to about 1 to 5 times a half-life of the medication. For example, the wash-down may occur within about an amount of time equal to 2 times a half-life of the medication, 2.5 times a half-life of the medication, or 3 times a half-life of the medication. In some embodiments, the wash-down occurs within about an amount of time equal to about 2 hours to 6 weeks.

The lower dose with reference to the wash-down may be the initial dose or a factor of the minimum effective dose (dose at which the patient first reported effectiveness) of the medication. For example, the lower dose may be about 0.10 to about 0.90 that of a minimum effective dose. In some embodiments, the lower dose may be about 0.10 to about 0.80, or about 0.10 to about 0.30,.that of a minimum effective dose. In some embodiments, the lower dose may be about 0.75 that of a minimum effective dose.

In some embodiments, the wash-down step is to achieve a plasma level of less than 75% of the headache medication being washed-down, prior to the administration of a neurotoxin. In some embodiments, the wash-down step is to achieve a plasma level of less than 50% of the headache medication being washed-down. In some embodiments, the wash-down step is to achieve a plasma level of less than 25% of the headache medication being washed-down.

Although plasma level of a headache medication may be useful in determining the appropriate time at which to administer a neurotoxin, it is also possible to wash-down the pain medication only to a level that may be tolerated by the patient, and then administer the neurotoxin. For example, a method in accordance with the present invention comprises lowering the dose of the pain medication (wash-down) to a level where the patient would be able to tolerate a headache pain, and then administering a neurotoxin.

Although the wash-down step can be practiced prior to the administration of a neurotoxin, in some embodiments, the wash-down step may begin at or after the step of administration of a neurotoxin. In some embodiments, the wash-down step may be prior to the onset of the therapeutic effect of the neurotoxin. The onset of the therapeutic affect of the neurotoxin may be determined by an improvement of a diseased condition by about 1% to about 25%. For example, an onset of the therapeutic affect of the neurotoxin for the treatment of a headache pain may be determined by a reduction of the pain by about 1% to about 25%.

In some embodiments, the wash-down may be proceeded via a stepwise process. For example, there are situations where a reduction to a particular pain medication dose is not immediately achievable because the patient is not able to tolerate the pain at that particular lower dose. An application of a stepwise wash-down may be effective in a situation like this. A stepwise wash-down comprises a wash-down and an administration of a neurotoxin in alternation, for as many times as needed. For example, a stepwise wash-down in accordance with the present invention comprises the following steps in order: (1) decreasing a dose of a pain medication by 10%, (2) administering a neurotoxin, (3) decreasing the dose of the pain medication by another 10%, (4) administering the neurotoxin, etc.

FIG. 1 (see Original Patent) shows an exemplary scheme for a stepwise wash-down. Since the stepwise wash-down allows for a smaller reduction in the dose of the pain medication, it may be more appropriate for some patients. Further, as the dose of the pain medication is sequentially decreased, the dose of the neurotoxin administration may also sequentially decrease.

In some embodiments, the wash-down step comprises decreasing the dose of all the pain medications that the patient is currently taking. In some embodiments, the wash-down step comprises decreasing the dose of only some of the pain medications.

In some embodiments, the wash-down step comprises decreasing the dose of only the prophylactic pain medication, and still allowing the patient to continue with the acute pain medication at full dose. In some embodiments, the wash-down step comprises decreasing the dose of only the acute pain medication, and allowing the patient to continue with the prophylactic pain medication at full dose. In some embodiments, the wash-down step comprises decreasing the dose of both the prophylactic and the acute pain medications.

The current pain medication that may be washed-down in accordance with the present invention include a prophylactic headache medication and/or an acute pain medication. In some embodiments, only the prophylactic pain medication is washed-down. In some embodiments, only the prophylactic pain medication is washed-down.

Medications that may be used as a prophylactic or acute headache medication include a beta-blocker, anti-epileptic agent, calcium channel blocker, sodium channel blocker, chloride enhancing agent, serotonin antagonists, selective serotonin re-uptake inhibitor, amitriptyline, tricyclic anti-depressant, valproic acid and derivatives, nonsteroidal anti-inflammatory drug and combinations thereof.

In some embodiments, a calcium channel blocker selected from the group consisting of topiramate, gabapentin, levetiraceltam, zonisamide, ethosuximide, lamotrigine, oxcarbazepine, pregabalin and combinations thereof. In some embodiments, a sodium channel blocker selected from the group consisting of topiramate, carbamazepine, oxcarbazepine, phenytoin, valproate, lamotrigine and combinations thereof. In some embodiments, a chloride-enhancing agent selected from the group consisting of gabapentin, levetiracetam and tiagabine. In some embodiments, the current headache medication is a aspirin (acetylsalicylic acid) or acetaminophen.

The methods of the present invention are effective in treating pain arising from a tension headache, a migraine headache, a cluster headache and/or a sinus headache. Further, the methods of the present invention are effective in treating pain arising from a chronic headache, an episodic headache and/or an acute headache.

In preventing or treating a headache pain in a patient in need thereof, the neurotoxin may be locally administered to a head muscle, face muscle, an upper neck muscle, or a combination thereof. More specifically, the neurotoxin may be administered locally to a frontalis muscle, a glabellar muscle, a masseter muscle, a temporalis muscle, a occipitalis muscle, a trapezius muscle, a semispinali muscle, a splenius muscle, a corrugator muscle, a procerus muscle, or a combination thereof.

According to our invention, the neurotoxin (such as botulinum toxinserotype A, B, C.sub.1, D, E, F or G) can be injected locally (e.g. intramuscular injection) into or in the vicinity where a patient is experiencing the pain to thereby suppress the pain or prevent its occurrence. In some embodiments, the neurotoxin can be administered intradermally and/or subdermally. Further, the neurotoxin can be administered at one or multiple sites. Table 1 and FIGS. 2A and 2B (see Original Patent) show an exemplary injection scheme of a neurotoxin (e.g. botulinum toxin) in accordance with the present invention.

In some embodiments, the methods of the present invention reduces the frequency of the headache pain by more than about 10% to about 95% as compared to the frequency and/or intensity of headache pain treated with a neurotoxin that is not accompanied by a wash-down. For example, patients being treated with methods of the present invention would experience more than 15, preferably more than 20, headache-free days out of 30 days. In some embodiments, the therapeutic effects provided by the neurotoxin can persist for a relatively long period of time, for example, for more than two months, and potentially for several years.

In some embodiments, the methods of the present invention reduces the intensity of the headache pain by more than about 10% to about 95% as compared to the intensity of headache treated with a neurotoxin that is not accompanied by a wash-down.

After the wash-down and administration of the neurotoxin, the 20 methods of the present invention optionally comprise the step of increasing the lower dose of the headache medication ("wash-up"). In some embodiments, the wash-up occurs at about when the neurotoxin begins to alleviate the pain. For example, the wash-up can occurs at about 5 to 14 days after the administration of the neurotoxin. In some embodiments, the wash-up further decreases the frequency and/or intensity of the headache pain.

For patients who are concurrently using a pain medication, and who are also being administered a neurotoxin for the treatment of conditions other than headache pain, the wash-down step of the present invention would also be effective to enhance the therapeutic effects of the neurotoxin in treating those conditions. For example, patients who are concurrently using a pain medication, and are being administered a neurotoxin for the treatment of a neuromuscular disorder, an autonomic nervous system disorder and/or non-headache pain may also benefit from the present invention.

In some embodiments, the method for treating a neuromuscular disorder, autonomic disorder and/or non-headache pain comprises a wash-down step. The wash-down may be prior to the administration of a neurotoxin or prior to the onset of the therapeutic effect of the neurotoxin.

The neuromuscular disorders and conditions that may be treated with the present method include: for example, strabismus, blepharospasm, spasmodic torticollis (cervical dystonia), oromandibular dystonia and spasmodic dysphonia (laryngeal dystonia). Muscle spasm conditions that may be treated with the present method include those arising from: post-stroke spasticity, cerebral palsy, spinal cord injury, brain injury, and multiple sclerosis. Autonomic nervous system disorders may also be treated with the present methods include: glandular malfunctioning (e.g., excessive sweating and excessive salivation) and respiratory malfunctioning (chronic obstructive pulmonary disease and asthma). Non-headache pain that may be treated with the present methods include: pain caused by muscle tension, or spasm, or pain that is not associated with muscle spasm; articular and non-articular pain arising from a joint; including; rheumatoid arthritis, acute crystal-induced arthritis, refractory sacroiliac joint pain related to ankylosing spondylitis or other spondyloarthropathies, juvenile rheumatoid arthritis, osteoarthritis, rotator cuff tendinitis, frozen shoulder, and other causes of shoulder pain, lateral epicondylitis (tennis elbow), femoral trochanteric pain syndromes (ie, bursitis), and periarticular knee pain including; anserine bursitis, synovial plicas, bone pain, in particular, metastatic bone cancer pain; neuropathic pain (e.g., post-herpetic pain), peripheral neuropathy (e.g. diabetic peripheral neuropathy), de Quervain's tenosynovitis, plantar fasciitis, carpal tunnel syndrome, tarsal tunnel syndrome, phantom pain and myofascial pain. With regards to pain that is not associated with muscle spasm, Foster et al. in U.S. Pat. No. 5,989,545 discloses that a botulinum toxin conjugated with a targeting moiety may be administered centrally (intrathecally) to alleviate pain. The disclosure of Foster et al. is incorporated in its entirety by reference herein.

In some embodiments, the present invention excludes the treatment of myofascial pain. In some embodiments, the present invention includes the treatment of myofascial pain, with a proviso that the wash-down of the pain medication is at the most 13 days prior to the injection of the neurotoxin. It is surprisingly discovered that a wash-down period of 13 days or less will allow for an effective treatment of myofascial pain. In some embodiments, the methods for reducing myofascial pain includes a wash-up.

In some embodiments, the method for treating a smooth muscle disorder,glandular disorder and/or non-headache pain comprises a wash-down step. The wash-down may be prior to the administration of a neurotoxin or prior to the onset of the therapeutic effect of the neurotoxin.

The smooth muscle disorders and conditions that may be treated with the present method include: for example, interstitial cystitis, detrusor external sphincter dyssynergia, overactive bladder, (neurogenic incontinence) detrusor hyperreflexia; detrusor sphincter dyssynergia and urinary retention, non-neurogenic bladder conditions and other bladder and urethral conditions such as; idiopathic conditions of hypercontraction of the urethral sphincter or for cases in which lowering urethral resistance may improve voiding function (eg, bladder hypocontractility). The glandular disorders that may be treated with the present method include: for example; benign prostatic hypertrophy.

With respect to applying the present methods for treating pain in general, our invention is preferably practiced by administering a botulinum toxin directly to a location where a patient is or is predisposed to experience pain. Without wishing to be bound by theory a physiological mechanism can be proposed for the efficacy of the present invention. It is known that muscles have a complex system of innervation and sensory output. Thus, anterior motor neurons located in each segment of the anterior horns of the spinal cord gray matter give rise to efferent alpha motor neurons and efferent gamma motor neurons that leave the spinal cord by way of the anterior roots to innervate skeletal (extrafusal) muscle fibers. The alpha motor neurons cause contraction of extrafusal skeletal muscle fibers while the gamma motor neurons innervate the intrafusal fibers of skeletal muscle. As well as excitation by these two type of efferent anterior motor neuron projections, there are additional, afferent sensory neurons which project from muscle spindle and golgi tendon organs and act to transmit information regarding various muscle parameter status to the spinal cord, cerebellum and cerebral cortex. These afferent motor neurons which relay sensory information from the muscle spindle include type Ia and type II sensory afferent neurons. See e.g. pages 686-688 of Guyton A.C. et al., Textbook of Medical Physiology, W.B. Saunders Company 1996, ninth edition.

Significantly, it has been determined that a neurotoxin, i.e., a botulinum toxin, can act to reduce transmission of sensory information from muscle type la afferent neurons. Aoki, K., Physiology and pharmacology of therapeutic botulinum neurotoxins, in Kreyden, O., editor, Hyperhidrosis and botulinum toxin in dermatology, Basel, Karger; 2002; 30: pages 107-116, at 109-110. And it has been hypothesized that botulinum toxin can have a direct effect upon muscle cell sensory afferents and modify signals from these afferents to the central nervous system. See e.g. Brin, M., et al., Botulinum toxin type A: pharmacology, in Mayer N., editor, Spasticity: etiology, evaluation, management and the role of botulinum toxin, 2002; pages 110-124, at 112-113; Cui, M., et al., Mechanisms of the antinociceptive effect of subcutaneous BOTOX.RTM.. inhibition of peripheral and central nociceptive processing, Naunyn Schmiedebergs Arch Pharmacol 2002; 365 (supp 2): R17; Aoki, K., et al., Botulinum toxin type A and other botulinum toxin serotypes: a comparative review of biochemical and pharmacological actions, Eur J. Neurol 2001: (suppl 5); 21-29. Thus, it has been demonstrated that botulinum toxin can cause an altered sensory output from muscle to CNS and brain.

Importantly, the sensory neurons from which afferent output is to be inhibited by a method according to the present invention need not be located on or within a muscle, but can be in an intradermal or subdermal location.

Thus, pain can be due to sensory input from afferent facial area neurons. Administration of a botulinum toxin to a facial muscles or skin to reduce sensory output from the muscle can result in alleviation of and prevention of pain.

It is our hypothesis, as may be the case in the treatment of a migraine headache with a neurotoxin, that signals transmitted by afferent pain nerves in or on muscle tissue (i.e. muscle spiridle fibers and muscle pain fibers) or as a part of sensory structures in the skin or subdermally induce the pain sensation. That is, afferent signal from muscles or skin structures provide sensory information to the brain which then leads to the generation of pain. Thus, a local administration of a neurotoxin, e.g., a botulinum toxin, to muscle spindle fibers, pain fibers or other sensors in or in the vicinity of a muscle can act to alter the neural signal afferent output from these muscles to the brain and thereby decrease the sensation of pain.

Important elements of our invention are firstly that is practiced by use of a local administration of low dose of a neurotoxin, e.g., a botulinum toxin. The selected low dose may not cause a muscle paralysis. Secondly, the invention can be practiced by local administration of the low dose of the botulinum toxin to the muscle or to the muscle group which initiates the pain sensation.

The amount of the neurotoxin administered according to a method within the scope of the disclosed invention can vary according to the particular characteristics of the pain being treated, including its severity and other various patient variables including size, weight, age, and responsiveness to therapy. To guide the practitioner, typically, no less than about 1 unit and no more than about 25 units of a botulinum toxin type A (such as BOTOX.RTM.) is administered per injection site (i.e. to each muscle portion injected), per patent treatment session. For a botulinum toxin type A such as Xeomin.RTM., no less than about 1 unit and no more about 25 units of the botulinum toxin type A are administered per injection site, per patent treatment session. For a botulinum toxin type A such as DYSPORT.RTM., no less than about 2 units and no more about 125 units of the botulinum toxin type A are administered per injection site, per patent treatment session. For a botulinum toxin type B such as MYOBLOC.RTM., no less than about 40 units and no more about 1500 units of the botulinum toxin type B are administered per injection site, per patent treatment session. Less than about 1, 1, 2 or 40 units (of BOTOX.RTM., Xeomin.RTM., DYSPORT.RTM. and MYOBLOC.RTM. respectively) can fail to achieve a desired therapeutic effect, while more than about 25, 25, 125 or 1500 units (of BOTOX.RTM.), Xeomin.RTM., DYSPORT.RTM. and MYOBLOC.RTM. respectively) can result in significant muscle hypotonicity, weakness and/or paralysis.

More preferably: for BOTOX.RTM. no less than about 2 units and no more about 20 units of a botulinum toxin type A; for DYSPORT.RTM. no less than about 4 units and no more than about 100 units, and; for MYOBLOC.RTM., no less than about 80 units and no more than about 1000 units are, respectively, administered per injection site, per patent treatment session.

Even more preferably: for BOTOX.RTM. no less than about 5 units and no more about 15 units of a botulinum toxin type A; for DYSPORT.RTM. no less than about 20 units and no more than about 75 units, and; for MYOBLOC.RTM., no less than about 200 units and no more than about 750 units are, respectively, administered per injection site, per patent treatment session. It is important to note that there can be multiple injection sites (i.e. a pattern of injections) for each patient treatment session.

Generally, the total amount of BOTOX.RTM., DYSPORT.RTM. or MYOBLOC.RTM., suitable for administration to a patient according to the methods of the invention disclosed herein should not exceed about 300 units, about 1,500 units or about 15,000 units respectively, per treatment session.

The enhancement of therapeutic effect of a neurotoxin for treating the various conditions discussed herein is an improvement of the condition by more than about 5%, preferably more than about 20%, even more preferably more than 50%, as compared to using the same treatment with a neurotoxin but without a wash-down step.

Although examples of routes of administration and dosages are provided, the appropriate route of administration and dosage are generally determined on a case by case basis by the attending physician. Such determinations are routine to one of ordinary skill in the art (see for example, Harrison's Principles of Internal Medicine (1998), edited by Anthony Fauci et al., 14.sup.th edition, published by McGraw Hill). For example, the route and dosage for administration of a neurotoxin according to the present disclosed invention can be selected based upon criteria such as the solubility characteristics of the neurotoxin chosen as well as the intensity of pain perceived.

The present invention also includes the use of (a) Clostridial neurotoxins obtained or processed by bacterial culturing, toxin extraction, concentration, preservation, freeze drying, and/or reconstitution; and/or (b) modified or recombinant neurotoxins, that is neurotoxins that have had one or more amino acids or amino acid sequences deliberately deleted, modified or replaced by known chemical/biochemical amino acid modification procedures or by use of known host cell/recombinant vector recombinant technologies, as well as derivatives or fragments of neurotoxins so made. These neurotoxin variants retain the ability to inhibit neurotransmission between or among neurons, and some of these variants may provide increased durations of inhibitory effects as compared to native neurotoxins, or may provide enhanced binding specificity to the neurons exposed to the neurotoxins. These neurotoxin variants may be selected by screening the variants using conventional assays to identify neurotoxins that have the desired physiological effects of inhibiting neurotransmission.

Botulinum toxins for use according to the present invention can be stored in lyophilized, vacuum dried form in containers under vacuum pressure or as stable liquids. Prior to lyophilization the botulinum toxin can be combined with pharmaceutically acceptable excipients, stabilizers and/or carriers, such as albumin. The Iyophilized material can be reconstituted with saline or water to create a solution or composition containing the botulinum toxin to be administered to the patient.

Although the composition may only contain a single type of neurotoxin, such as botulinum toxin type A, as the active ingredient to suppress neurotransmission, other therapeutic compositions may include two or more types of neurotoxins, which may provide enhanced therapeutic treatment of a headache. For example, a composition administered to a patient may include botulinum toxin type A and botulinum toxin type B. Administering a single composition containing two different neurotoxins may permit the effective concentration of each of the neurotoxins to be lower than if a single neurotoxin is administered to the patient while still achieving the desired therapeutic effects. The composition administered to the patient may also contain other pharmaceutically active ingredients, such as, protein receptor or ion channel modulators, in combination with the neurotoxin or neurotoxins. These modulators may contribute to the reduction in neurotransmission between the various neurons. For example, a composition may contain gamma aminobutyric acid (GABA) type A receptor modulators that enhance the inhibitory effects mediated by the GABA.sub.A receptor. The GABA.sub.A receptor inhibits neuronal activity by effectively shunting current flow across the cell membrane. GABA.sub.A receptor modulators may enhance the inhibitory effects of the GABA.sub.A receptor and reduce electrical or chemical signal transmission from the neurons. Examples of GABA.sub.A receptor modulators include benzodiazepines, such as diazepam, oxaxepam, lorazepam, prazepam, alprazolam, halazeapam, chordiazepoxide, and chlorazepate. Compositions may also contain glutamate receptor modulators that decrease the excitatory effects mediated by glutamate receptors. Examples of glutamate receptor modulators include agents that inhibit current flux through AMPA, NMDA, and/or kainate types of glutamate receptors. The compositions may also include agents that modulate dopamine receptors, such as antipsychotics, norepinephrine receptors, and/or serotonin receptors. The compositions may also include agents that affect ion flux through voltage gated calcium channels, potassium channels, and/or sodium channels. Thus, the compositions used to treat pain can include one or more neurotoxins, such as botulinum toxins, in addition to ion channel receptor modulators that may reduce neurotransmission.

The neurotoxin may be administered by any suitable method as determined by the attending physician. The methods of administration permit the neurotoxin to be administered locally to a selected target tissue. Methods of administration include injection of a solution or composition containing the neurotoxin, as described above, and include implantation of a controlled release system that controllably releases the neurotoxin to the target tissue. Such controlled release systems reduce the need for repeat injections. Diffusion of biological activity of a botulinum toxin within a tissue appears to be a function of dose and can be graduated. Jankovic J., et al Therapy With Botulinum Toxin, Marcel Dekker, Inc., (1994), page 150. Thus, diffusion of botulinum toxin can be controlled to reduce potentially undesirable side effects that may affect the patient's cognitive abilities. For example, the neurotoxin can be administered so that the neurotoxin primarily effects neural systems believed to be involved in the generation of pain and/or inflammation, and does not have negatively adverse effects on other neural systems.

A polyanhydride polymer, Gliadel.RTM. (Stolle R & D, Inc., Cincinnati, OH) a copolymer of poly-carboxyphenoxypropane and sebacic acid in a ratio of 20:80 has been used to make implants, and has been intracranially implanted to treat malignant gliomas. Polymer and BCNU can be co-dissolved in methylene chloride and spray-dried into microspheres. The microspheres can then be pressed into discs 1.4 cm in diameter and 1.0 mm thick by compression molding, packaged in aluminum foil pouches under nitrogen atmosphere and sterilized by 2.2 megaRads of gamma irradiation. The polymer permits release of carmustine over a 2-3 week period, although it can take more than a year for the polymer to be largely degraded. Brem, H., et al, Placebo-Controlled Trial of Safety and Efficacy of Intraoperative Controlled Delivery by Biodegradable Polymers of Chemotherapy for Recurrent Gliomas, Lancet 345; 1008-1012:1995.

Implants useful in practicing the methods disclosed herein may be prepared by mixing a desired amount of a stabilized neurotoxin (such as non-reconstituted BOTOX.RTM.) into a solution of a suitable polymer dissolved in methylene chloride. The solution may be prepared at room temperature. The solution can then be transferred to a Petri dish and the methylene chloride evaporated in a vacuum desiccator. Depending upon the implant size desired and hence the amount of incorporated neurotoxin, a suitable amount of the dried neurotoxin incorporating implant is compressed at about 8000 p.s.i. for 5 seconds or at 3000 p.s.i. for 17 seconds in a mold to form implant discs encapsulating the neurotoxin. See e.g. Fung L. K. et al., Pharmacokinetics of Interstitial Delivery of Carmustine 4-Hydroperoxycyclophosphamide and Paclitaxel From a Biodegradable Polymer Implant in the Monkey Brain, Cancer Research 58;672-684:1998.

Local administration of a Clostridial toxin, such as a botulinum toxin, can provide a high, local therapeutic level of the toxin. A controlled release polymer capable of long term, local delivery of a Clostridial toxin to a target muscle permits effective dosing of a target tissue. A suitable implant, as set forth in U.S. Pat. No. 6,306,423 entitled "Neurotoxin Implant", allows the direct introduction of a chemotherapeutic agent to a target tissue via a controlled release polymer. The implant polymers used are preferably hydrophobic so as to protect the polymer incorporated neurotoxin from water induced decomposition until the toxin is released into the target tissue environment.

The amount of a neurotoxin selected for local administration to a target tissue according to the present disclosed invention can be varied based upon criteria such as the severity of the pain or type of headache being treated, the extent of muscle tissue to be treated, solubility characteristics of the neurotoxin toxin chosen as well as the age, sex, weight and health of the patient. For example, the extent of the area of muscle tissue influenced is believed to be proportional to the volume of neurotoxin injected, while the quantity of the suppressant effect is, for most dose ranges, believed to be proportional to the concentration of a Clostridial toxin administered. Methods for determining the appropriate route of administration and dosage are generally determined on a case by case basis by the attending physician. Such determinations are routine to one of ordinary skill in the art (see for example, Harrison's Principles of Internal Medicine (1998), edited by Anthony Fauci et al., 14.sup.th edition, published by McGraw Hill).

Significantly, a method within the scope of the present invention can provide improved patient function. "Improved patient function" can be defined as an improvement measured by factors such as a reduced pain, reduced time spent in bed, increased ambulation, healthier attitude, more varied lifestyle and/or healing permitted by normal muscle tone. Improved patient function is synonymous with an improved quality of life (QOL). QOL can be assessed using, for example, the known SF-12 or SF-36 health survey scoring procedures. SF-36 assesses a patient's physical and mental health in the eight domains of physical functioning, role limitations due to physical problems, social functioning, bodily pain, general mental health, role limitations due to emotional problems, vitality and general health perceptions. Scores obtained can be compared to published values available for various general and patient populations.
 

Claim 1 of 36 Claims

1. A method for alleviating a headache pain for a patient in need thereof, the method comprising the steps of: (a) decreasing at least one current dose of a headache medication being used by the patient to a lower dose via a titration process in reverse of a dosing regimen used by the patient to achieve the current dose, the decreasing of the headache medication to a lower dose being a wash-down, and then (b) locally administering a therapeutically effective amount of a botulinum neurotoxin to the patient subsequent to the wash-down, thereby alleviating the headache pain.
 

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