Methods for treating fibromyalgia by administering a therapeutically effective amount of a botulinum toxin to a patient with fibromyalgia.

SUMMARY OF THE INVENTION

In accordance with the present invention, there are provided methods for treating fibromyalgia. These methods may include administering locally a therapeutically effective amount of a Clostridial toxin to a peripheral location on a body of a patient afflicted with fibromyalgia. The peripheral location of local administration is not a locus of pain. For example, the peripheral location may be on the body of a patient about one centimeter or more from the locus of pain. In one embodiment, the locus of pain is a fibromyalgia tender point.

In one embodiment of the present invention, a dermatome may include both the locus of pain, for example, where a pain associated with fibromyalgia is perceived by the patient to originate, and the peripheral location where the therapeutically effective amount of a Clostridial toxin is administered.

In another embodiment, the peripheral location where an effective amount of Clostridial neurotoxin is administered is in the head of the patient. For example, the neurotoxin may be administered to the facial area and/or cranial area of the head. In this embodiment, where an effective amount of Clostridial neurotoxin is administered in the head of the patient, the locus of pain to be treated is not in the head. For example, the locus of pain may be at a fibromyalgia tender point.

Further in accordance with the present invention, there are provided methods for treating pain which may include administering locally a therapeutically effective amount of a Clostridial toxin to a peripheral location on a body of a patient. The site of local administration is other than a locus of pain. A dermatome may include both a locus of pain and a site of local administration. In one embodiment, the locus of pain may be at a fibromyalgia tender point. In one embodiment, a patient has at least eleven loci of pain.

Further in accordance with the present invention, there are provided methods for treating fibromyalgia. These methods may include administering locally a therapeutically effective amount of a Clostridial toxin to a dermatome of a patient afflicted with fibromyalgia. This dermatome may substantially include a locus of pain. The local administering is not at a locus of pain. In one embodiment of the invention, the locus of pain is at one or more fibromyalgia tender points.

Methods for treating pain are within the scope of the invention. These methods may administering locally a therapeutically effective amount of a Clostridial toxin at a location in a dermatome other than a locus of pain. This dermatome also includes a locus of pain. The locus of pain may be at a fibromyalgia tender point.

Further in accordance with the present invention, there are provided methods for treating fibromyalgia pain. These methods include a step of administering a therapeutically effective amount of botulinum toxin type A to a dermatome. This dermatome may include a site where the pain is perceived by the patient to originate.

Still further in accordance with the present invention, there are provided methods for treating pain which is perceived to originate at fibromyalgia tender point. These methods include a step of administering a therapeutically effective amount of botulinum toxin type A to a location in a dermatome other than where the pain is perceived to originate. This dermatome includes the site where the pain is perceived to originate. A toxin used in accordance with the present invention may be botulinum toxin type A, B, C.sub.1, C.sub.2, D, E, F, G or fragments of these toxins or derivatives of these toxins. In one embodiment of the present invention, the toxin may be a mixture or combination of these botulinum toxins.

The location where the therapeutically effective amount of a toxin is administered and the site where a pain is perceived by the patient to originate may have neuronal processes that project from the same spinal sensory nerve root.

Further in accordance with the present invention, a toxin may be administered, for example, subcutaneously or intramuscularly. Further, the toxin may be administered with a needle or by needleless injection.

In one embodiment of the present invention, there is provided a method for treating fibromyalgia which may include administering locally a therapeutically effective amount of a botulinum toxin type A to a dermatome of a patient afflicted with fibromyalgia. The dermatome substantially encompasses a locus of pain and the locus of pain is at a fibromyalgia tender point. The local administration is not at the locus of pain.

In one embodiment of the present invention, there is provided a method for treating pain which may include administering locally a therapeutically effective amount of a botulinum toxin type A to a dermatome of a patient. The patient has a locus of pain which is at a fibromyalgia tender point, wherein the dermatome substantially encompasses the locus of pain, and wherein the local administration is not to the locus of pain.

My invention also includes a method for treating fibromyalgia by administering a botulinum toxin to a patient with fibromyalgia. As stated, the botulinum toxin can be a botulinum toxin type A, B, C, D, E, F or G. The botulinum toxin can be administered subcutaneously or intramuscularly.

Another embodiment of my invention is a method for treating a fibromyalgia pain by administering a botulinum toxin to a patient with fibromyalgia. The botulinum toxin administering being carried out at a first location. This first location is anatomically distinct from and/or anatomically distant from a second location. Similarly, any part of an arm is not anatomically contiguous with any part of a leg, and vice versa. "Anatomically distinct" means that the functional anatomy of the first and second locations is not contiguous, in a functional anatomical sense. For example, all parts of a leg, or all parts of an arm are anatomically contiguous. But any part of the head or any part of the neck is not anatomically contiguous to any part of a leg, arm or back. "Anatomically distant" is a synonym for anatomically distinct. At the second location the patient has a fibromyalgia pain which is alleviated by the administration of the botulinum toxin at the first location. The first location can be a peripheral location and the second location can be a locus of pain. Preferably, the first location is the head or neck of the patient.

DESCRIPTION OF THE INVENTION

The present invention is based upon the discovery that a botulinum toxin can be used to effectively treat fibromyalgia. In one embodiment, the invention relates to methods for treating pain associated with fibromyalgia and pain associated with fibromyalgia tender points.

It has been reported that botulinum toxin is ineffective to treat fibromyalgia, see Paulson et al, Mov Dis 11(4), 459 (1996) and Childers et al, Musculoskeletal Rehabilitation 10, 89-96 (1998). In these reports, botulinum toxin was injected into the site of fibromyalgia associated pain (shoulder muscles). George Paulson, co-author of one above cited article, has stated; "Based on our experience, we suggest that patients with fibromyalgia are unlikely to benefit from botulinum toxin injection" (Paulson et al).

Methods for treating a symptom of fibromyalgia (including pain) by non-systemic administration of a therapeutic amount of neurotoxin are within the scope of the present invention. In one broad embodiment of this invention, a neurotoxin is administered to a site on the body of a patient other than a site where the pain to be treated is perceived to originate. For example, a neurotoxin may be administered to a site other than a tender point to be treated in association with fibromyalgia.

The locations of fibromyalgia tender points are shown in FIG. 1. Pain may be perceived to originate from these locations in a fibromyalgia patient. The pain may be centered at these, or other sites and may be accompanied by an emanating diffuse pain. In one embodiment, pain may be perceived to originate at a location on a body if the location is pain sensitive when firm, even pressure is applied.

Preferably, the neurotoxin used to practice a method within the scope of the present invention is a Clostridial toxin, or fragments thereof, or derivatives thereof. For example, botulinum toxin serotypes A, B, C, D, E, F or G may be used. Because of reasons including its high potency in humans and ready availability, the botulinum toxin preferably used is botulinum toxin type A.

Without wishing to be limited to any theory or mechanism of operation, it is hypothesized that pain pathways and/or pain feedback loops are influenced by neurotoxins, for example, botulinum toxins, administered in accordance with the present invention. For example, neurotoxins may act through the afferent nerve pathways to block the release of pain transmitters, for example, substance P. This mechanism of operation may be related to that by which peripheral administration of botulinum toxin is known to alleviate pain associated with migraine headache, see Binder, U.S. Pat. No. 5,714,468; Yue, U.S. Pat. No. 5,863,552; First, U.S. Pat. No. 6,063,768; Yue, U.S. Pat. No. 5,707,642; Sanders, U.S. Pat. No. 5,766,606; and Aoki, U.S. Pat. No. 6,113,915. The disclosure of these patents is herein incorporated in its entirety by reference.

In support of this theory, treatment of pain by intraspinal administration of botulinum toxin has been proposed. See Aoki et al, U.S. Pat. No. 6,136,551 and Foster et al, U.S. Pat. No. 5,989,545. The disclosure of these patents is herein incorporated in its entirety by reference. Further, neurotoxins, for example, botulinum toxin type A, have been shown to be retrogradely transported to the spinal cord following injection of the toxin into either the hind limb or forelimb of a rat (Habermann, Naunyn-Schmiedeberg's Arch Pharmacol. 281, 47-56 (1974), incorporated herein in its entirety by reference). In this study, dialyzed, radiolabeled botulinum toxin (about 0.2 ug/ml) was injected into either the left gastronemius or the left foreleg of rats in a volume of 0.2 ml/100 g body weight. All animals were killed and their spinal cords removed and radiolabeled botulinum toxin was quantitated. The results suggest that botulinum toxin ascends to the spinal area by retrograde transport (FIG. 2). Further, Wiegand et al, Naunyn-Schmiedeberg's Arch Pharmacol 292, 161165 (1976), incorporated herein in its entirety by reference, have also shown that radiolabeled botulinum toxin travels to the spinal cord after intramuscular injection. Wiegand et al state that: "obviously the [radiolabeled botulinum toxin] reaches the spinal cord by neural ascent via the ventral roots." Several findings by Wiegand et al support this hypothesis. For example, after injection of the labeled toxin, a gradient of radiolabel was found to form in the sciatic nerve. In addition, a significant level of radioactivity was found in the ventral roots giving rise to the innervation of the injected muscle. Also, this radioactivity was localized exclusively within the axons of the neurons. Further, a ligature of the left ventral root prevented the radiolabeled botulinum from reaching the corresponding segment of the spinal cord half segment.

The idea that botulinum toxins move through the afferent nerve pathways by retrograde transport is further supported by the distant effect botulinum toxin may have when administered by intramuscular or subcutaneous injection. For example, there is electrophysiological evidence that botulinum toxin type A can effect muscle spindle output, by the Ia afferent signal, Filippi et al, Acta Otolaryngologica 113, 400-404 (1993). Remote effects of botulinum toxins at distant body parts have been reported by Nix et al (Neurology 42, 602-606 (1992)). In addition, it has been proposed that the mode of action of botulinum type A on focal dystonias is through the afferent pathways in addition to the well-known effect at the alpha motor neuron nerve terminals, Giladi, J of Neuro Sci 152, 132-135 (1997). Each of these publications is incorporated herein in its entirety by reference. It is possible that part of the mechanism of action of botulinum toxin in treating focal dystonias is that retrograde transport of the toxin to the spinal area takes place and inhibition of the release of pain producing substances results, for example, inhibition of substance P release. In support of this, botulinum toxins have been shown to markedly inhibit the release of substance P in neuron cell cultures, Welch et al, Toxicon 38, 245-258 (2000). The ability of a neurotoxin, for example, a botulinum toxin, to inhibit the release of a pain producing substance at a location in the body distant to the site of administration of the toxin is important for at least one theory of operation of the present invention.

Without wishing to limit the invention to any theory or mechanism of operation, it is hypothesized that the afferent nerve pathways innervating the tissue at the point of origin of certain types of pain, for example pain associated with fibromyalgia, may be effected in a manner so as to disallow the effect of a neurotoxin, for example, a botulinum toxin, on the release of pain producing substances. For example, the ability of a botulinum toxin to move by retrograde transport in afferent pathways may be blocked. The present invention allows for bypassing a blockage by administration of the neurotoxin to a location that is not at or near the site of pain origin. For example, the neurotoxin may be administered to a location on a body other than a site on the body where a pain is centered. The toxin may then move by retrograde transport up the afferent neural pathway and into the spine where a local or regional inhibition of release of pro-nociceptive mediators, for example substance P, may take place. Release of nociceptive mediators into the dorsal root that leads to innervation of the site of pain may be inhibited resulting in a subsidence of pain, for example, subsidence of pain at the origin of the pain. Further, it may be preferable to administer the neurotoxin to a region of a body that is innervated by the same dorsal root that innervates the site of pain to be treated. Doing so may allow for the most direct route for the toxin to reach the sensory neurotransmitters associated with the site of pain.

The data of Habermann and Weigand et al show a segmental distribution of botulinum toxin accumulation in the spinal cord of rats after intramuscular injection. The distribution was determined by the innervation of the muscles which were injected with the toxin. The graphs of FIGS. 2a and 2b show the accumulation of radioactivity in the spinal cord following injection of the toxin. Graph 2a shows the results for injection into the hind limb and graph 2b shows the results for injection into the forelimb. The X-axis of each graph represents the segment of the rat's spinal cord examined for radioactive deposit. It can be seen that an injection of the labeled toxin into the hind limb causes radioactivity to appear in lumbar segment 2 of the cord, whereas an injection into the forelimb results in deposit of radioactivity in cervical segments 6 and 7 of the cord.

Segments of a human body innervated by a single dorsal root are known as dermatomes (FIG. 3). Since one dorsal root may innervate a single dermatome, a neurotoxin, for example, a botulinum toxin, may be administered to a location at or near a dermatome encompassing a site of pain to be treated. In one embodiment of the invention, the neurotoxin is administered to a dermatome that encompasses the site, or point of origin, of pain to be treated, for example, a fibromyalgia tender point. In this embodiment, the neurotoxin is administered to a location on the body of the patient that is not at or near the site of pain origin.

Dermatomal boundaries may overlap as is shown in FIG. 4. Therefore administration of toxin into a dermatome that does not encompass the site of pain origin to be treated may be effective. Therefore, in one embodiment of the invention, the neurotoxin is administered to a dermatome that is adjacent to the dermatome which contains the site of pain origin. In another embodiment of the invention, the neurotoxin is administered to a dermatome that is one or more dermatomes away from the dermatome which contains the site of pain origin.

In one broad embodiment, the neurotoxin may be administered to a site on the body of a patient that is about 0.1 centimeters or more from the site of pain origin. In another embodiment, the neurotoxin may be administered to a location on the body of a patient that is about 1 centimeter or more from the site of pain origin. In another embodiment, the neurotoxin is administered to a location on the body of a patient that is about 4 centimeters or more from the site of pain origin. In still another embodiment of the invention, the neurotoxin is administered to a location on the body of a patient that is about 8 centimeters or more from the site of pain origin. In still another embodiment of the invention, the neurotoxin is administered to a location that is about 0.1 centimeter to less than about 200 centimeters from the site of pain origin. In still another embodiment of the invention, the neurotoxin is administered to a location that is about 1 centimeter to less than about 6 centimeters from the site of pain origin. In still another embodiment of the invention, the neurotoxin is administered to a location that is about 3 centimeter to about less than about 100 centimeters from the site of pain origin.

Generally, the dose of neurotoxin to be administered will vary with the age, presenting condition and weight of the patient to be treated. The potency of the neurotoxin will also be considered. Toxin potency is expressed as a multiple of the LD.sub.50 value for a mouse. One "unit" of toxin can be defined as the amount of toxin that kills 50% of a group of mice that were disease-free prior to inoculation with the toxin. For example, commercially available Botulinum toxin A typically has a potency such that one nanogram contains about 40 mouse units. The potency, or LD.sub.50 in humans of the Botulinum toxin A product supplied by Allergan, Inc. under the registered trademark "BOTOX" is believed to be about 2,730 mouse units.

The neurotoxin can be administered in a dose of about 0.1 units up to about 1,000 units. In one embodiment, individual dosages of about 15 units to about 30 units are used. In another embodiment, individual dosages of about 30 units to about 60 units are used. In still another embodiment, individual dosages of about 60 units to about 180 units are used. Generally, the neurotoxin will be administered as a composition at a dosage that is proportionally equivalent to about 2.5 cc/100 units. Those of ordinary skill in the art will know, or can readily ascertain, how to adjust these dosages for neurotoxin of greater or lesser potency.

Preferably, the lowest therapeutically effective dosage will be injected into the patient. The lowest therapeutic dosage is that dosage which results in detection by the patient of a reduction in the occurrence and/or magnitude of pain experienced by the patient, for example, pain experience by a patient which is associated with fibromyalgia.

Methods for assessing or quantifying the amount of pain experienced by a patient are well known to those skilled in the art. For example, a patient can be given a pain assessment test in which the patient quantifies the degree of pain based on a scale. One example would be assigning the patient's pain a number based on a scale of 1 to 10, where a "10" would indicate the worst degree of pain the patient might imagine. A pain measure of 4 from an original pain score of 8 would be a 50% reduction in pain. Thus, the amount of conjugate required to achieve that 50% reduction in pain could be considered 1 U of the botulinum toxin component-targeting moiety conjugate. Alternatively, the patient's pain may be measured as the duration of pain. One unit of the conjugate of the invention would accordingly reduce the duration of pain by 50%. In addition, a number of physiological measures, such as heart rate, respiratory rate, blood pressure, and diaphoresis, may be used alone or together with the patientive methods described above, to quantify the amount of the patient's pain.

In an initial treatment, a low dosage may be administered at one site to determine the patient's sensitivity to, and tolerance of, the neurotoxin. Additional injections of the same or different dosages will be administered as necessary. For example, if pain predominates in the shoulder region (FIG. 1), the patient may receive about 40 units in the cervical region, for example, in dermatome C7. In one embodiment, the patient receives 40 units in the C7 dermatome of the cervical region and may also receive 40 units of the neurotoxin in the C8 and/or C6 dermatomes.

In one embodiment, the site of injection is intramuscular. However, for some indications, extramuscular injection may be the most efficacious route of administration as well as a route which avoids the risk of trauma to muscle tissue. Such injection may, for example, be made subcutaneously or, preferably, perivascularly (to produce infiltration of the neurotoxin into innervated tissue). In one embodiment, the site for injection of the neurotoxin is in or near the extramuscular regions.

The neurotoxins may be administered by, for example, injection using a needle or by needleless injection.

In needleless injection delivery methods, microprojectile drug particles may be coated with a neurotoxin and then discharged into the skin from an external delivery device. Depending on the discharge velocity and the distance from the injection site, the drug particles penetrate through the stratum corneum to different layers of the epidermis, dermis and underlying muscle. As the microprojectiles penetrate through epidermal and dermal cells, or are deposited in these cells, the neurotoxin is released. Individual layers of skin cells or underlying muscle cells may be targeted for the microprojectiles.

For intramuscular injections using a needle, to ensure that the neurotoxin is delivered to the target site without substantial systemic distribution, electromyographical ("EMG") injection may be used. A preferred technique for EMG injection is to introduce the neurotoxin through a monopolar hollow bore needle (commonly, one which is coated with a non-stick surface such as "TEFLON.RTM.", a trademarked product of DuPont Nemours, of Massachusetts). The needle is placed through the skin and into the target site of a muscle, preferably at a neuromuscular junction. Once the needle has been inserted, the most active site of the muscle can be determined by observation of the EMG signal. Those of ordinary skill in the art will know of, or can readily ascertain, other suitable techniques for administering EMG injections.

The injections will be repeated as necessary. As a general guideline, Botulinum toxin A administered into or near muscle tissue according to the method of the invention has been observed to produce flaccid paralysis at target site muscles for up to about 3 to about 6 months. Reduction of pain, for example, pain associated with fibromyalgia, in patients who received the neurotoxins of the invention extramuscularly may persist for extended periods of time. However, botulinum toxin type A in particular is expected to be most effective when administered according to the method of the invention at about 3 month intervals.
 

Claim 1 of 11 Claims

1. A method for treating fibromyalgia, the method comprising the step of subcutaneously or intramuscularly administering a therapeutically effective amount of a botulinum toxin to treat a patient with fibromyalgia, the botulinum toxin administering being carried out at a first location which first location is anatomically distinct from and/or anatomically distant from a second location, at which second location the patient has a fibromyalgia pain which is alleviated by the administration of the botulinum toxin at the first location, wherein the first location and the second location are within a same dermatome, thereby treating fibromyalgia.

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