METHODS OF TREATING CHRONIC PAIN

RELATED APPLICATION(S)

This application claims the benefit of U.S. Provisional Application No. 60/906,381, filed on March 12, 2007. The entire teachings of the above application are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Pain is associated with a variety of different underlying illnesses or injuries and is a leading cause of morbidity worldwide. Chronic pain, which can result from neuropathic damage, visceral injury or chronic inflammation, is often endured by patients over many years or decades. Consequently, patients suffering from chronic pain often develop emotional problems that can lead to depression, anxiety and loss of mental function. In the United States alone, chronic pain is estimated to cause a loss of more than 250 million working days per year.

Many medications that are currently used to treat pain are associated with undesirable side effects, toxicity and/or addictive properties. For example, morphine and related opioids, which are used to treat moderate to severe pain, have limited therapeutic use due to side effects, such as constipation, respiratory depression, tolerance, and abuse potential. Furthermore, most analgesics in current use are not effective for treating chronic pain. Neuropathic pain is a type of chronic pain that results from damage to the peripheral or central nervous system, and is often refractory to traditional analgesics, such as non-steroidal anti-inflammatory compounds. It is estimated that at least 5% of patients undergoing surgery suffer significant neuropathic pain that lasts for years. As a result, neuropathic pain results in enormous morbidity and economic costs.

Visceral pain is a type of chronic pain that results from damage to or inflammation of the viscera (e.g., colon, pancreas, reproductive organs, gastrointestinal (GI) tract) and is associated with diseases such as Crohn's disease, pancreatitis, colitis, and irritable bowel syndrome (IBS). Current analgesics are only moderately effective in treating these disorders. For example, nonsteroidal anti-

inflammatory drugs have adverse effects on the GI tract (e.g., gastric erosion, peptic ulcer formation, inflammation of the duodenum and colon) and, therefore, have limited therapeutic use for treating visceral pain.

Arthritis, a musculoskeletal disorder resulting from chronic inflammation, is the leading cause of disability in the United States. Forty million Americans, representing 15% of the population, have some form of arthritis, and that figure is expected to increase to 59.4 million (18.2%) by the year 2020, an increase of 57% in the number of persons affected. Arthritis patients make more than 315 million physician visits and are hospitalized more than 8 million times a year. Arthritis costs the nation $65 billion annually in medical costs and lost productivity. Osteoarthritis (OA), or degenerative joint disease, is the most common type of arthritis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to treat osteoarthritis, but long-term use can lead to gastric ulcers, kidney damage, hearing loss and even inhibit cartilage formation. Fibromyalgia syndrome (FMS) is the most frequent cause of chronic pain, estimated to affect 2% of the population. FMS is characterized by a generalized heightened perception of sensory stimuli. Patients with FMS display abnormalities in pain perception in the form of both allodynia (pain with innocuous stimulation) and hyperalgesia (increased sensitivity to painful stimuli). Most anti-inflammatory analgesics, including NSAIDs, which are widely used for treating pain in general, are not very effective as a treatment for fibromyalgia. Although various drugs including muscle relaxants, opioid analgesics and anti-anxiety agents have undergone trial use for the treatment of fibromyalgia, the efficacy of these drugs differs greatly among individuals and no general effect has been recognized for any of these drugs.

Clearly, there is an urgent need for new agents that can effectively alleviate and treat the symptoms of chronic pain without producing undesirable side effects.

SUMMARY OF THE INVENTION

The present invention provides methods of treating chronic pain, in particular, neuropathic pain, chronic visceral pain, chronic inflammatory pain and pain resulting from fibromyalgia syndrome, comprising administering Dimebon™

antihistamine agent (i.e., "Dimebon") to a subject in need of such treatment. "Dimebon" is currently used as a commercial name for the small molecule 3, 6- dimethyl-9-(2-methyl-pyridyl-5)-ethyl-l,2,3,4-tetrahydro-γ- carboline dihydrochloride, which is referred to hereinafter by the acronym "DETCD." In one embodiment, the invention is a method of treating chronic pain in a subject in need thereof, comprising administering DETCD to the subject, wherein the chronic pain is not headache pain. Types of chronic pain that are suitable for treatment using this method include, but are not limited to, neuropathic pain, chronic visceral pain, chronic inflammatory pain and pain associated with fibromyalgia syndrome. In a certain embodiment, the chronic pain includes one or more symptoms selected from the group consisting of burning sensation, hyperpathia, dysaethesia, and allodynia.

In one embodiment, DETCD is administered to the subject at a dosage of about 20 mg per unit dose. In a further embodiment, DETCD is administered at a dosage of about 60 mg per day.

In a certain embodiment, DETCD is administered to the subject orally. For oral administration, DETCD can be provided to the subject in the form of a liquid, tablet or capsule.

In another embodiment, DETCD is administered to the subject parenterally, intravenously, subcutaneously, intramuscularly, intracranially, intraorbitally, ophthalmically, intraventricularly, intracapsularly, intraspinally, intracisternally, intraperitoneally, or intranasally. In a particular embodiment, DETCD is administered to the subject via a gel, skin patch, powder, nasal drop, nasal spray or aerosol. In a particular embodiment, the invention is a method of treating chronic pain in a subject in need thereof, comprising administering DETCD in combination with an agent selected from the group consisting of an antidepressant agent, an anticonvulsant agent, an antiarrhythmic agent, an anesthetic agent, an NMDA antagonist, and a narcotic. In one embodiment, the agent and DETCD are administered to the subject at the same time. In another embodiment, the agent is administered prior to or after DETCD is administered to the subject.

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In another embodiment, the invention is a method of treating neuropathic pain in a subject in need thereof, comprising administering DETCD to the subject. In a particular embodiment, the neuropathic pain is selected from the group consisting of pain resulting from post herpetic neuralgia, pain resulting from peripheral neuropathy, pain resulting from trigeminal neuralgia, phantom limb pain, pain resulting from reflex sympathetic dystrophy, pain resulting from causalgia, pain resulting from anesthesia dolorosa, pain resulting from intercoastal neuralgia, posttraumatic localized pain, pain resulting from HIV neuropathy, pain resulting from diabetic neuropathy, pain resulting from Fabry's disease, pain resulting from trauma, pain resulting from tic doleroux, pain resulting from toxic poisoning, pain resulting from chemotherapy and pain resulting from complex regional pain syndrome.

In yet another embodiment, the invention is a method of treating chronic visceral pain in a subject in need thereof, comprising administering DETCD to the subject. In a particular embodiment, the chronic visceral pain is selected from the group consisting of pain resulting from Crohn's disease, pain resulting from pancreatitis, pain resulting from colitis, and pain resulting from irritable bowel syndrome (IBS).

In a certain embodiment, the invention is a method of treating chronic inflammatory pain in a subject in need thereof, comprising administering DETCD to the subject. In one embodiment, the chronic inflammatory pain is pain resulting from arthritis. In a further embodiment, the arthritis is osteoarthritis or rheumatoid arthritis.

In a particular embodiment, the invention is a method of treating fibromyalgia syndrome in a subject in need thereof, comprising administering DETCD to the subject.

In a further embodiment, the invention is a method of preventing headache pain in a subject in need thereof, comprising administering a therapeutically- effective amount of DETCD to the subject. In a particular embodiment, the headache pain is migraine headache pain.

DETAILED DESCRIPTION OF THE INVENTION

Dimebon™ antihistamine agent (i.e., 3, 6-dimethyl-9-(2-methyl-pyridyl-5)- ethyl-l,2,3,4-tetrahydro-γ-carboline dihydrochloride) ("DETCD"), a proprietary

drug of Medivation, Inc., San Francisco, CA, is an FDA-approved, small molecule drug having a broad spectrum of pharmacological properties (Mashkovsky, M.D., "Medicinal Drugs" Vol. l-12th Edition, Moscow, Meditzina Publishers, 1993, p.383). DETCD has been used as an antihistamine in Russia for over two decades and has recently been demonstrated to have clinical efficacy in the treatment of Alzheimer's disease in humans (Bachurin, S., et al., Ann. N Y Acad. Sci. 939:425- 435 (2001); Bachurin, S.O., Ann. N Y Acad Sci. 993:334-349 (2003); Grigorev V.V., Bull. Exp. Biol. Med. /3<5(5):474-477 (2003)). Studies indicate that DETCD exhibits calcium blocking activity and neuroprotective properties (Lermontova, N.N., et al, Bull. Exp. Biol. Med. 132(5): 1079-1083 (2001)), reduces mitochondrial swelling induced by Aβ (Shevtsova, E.F., et al, Vestn. Ross. Ahad. Med. Nauk. P: 13-7 (2005)), and acts as an inhibitor of cholinesterases and NMDA receptors (Bachurin, S., et al., Ann. N Y Acad. Sci. 939:425-35 (2001); Grigorev V.V., Bull. Exp. Biol. Med. 73<5(5):474-477 (2003)). However, unlike several NMDA receptor blockers (e.g., MK-801), DETCD has few adverse side effects and low toxicity (Golubeva, M.I., Farmakol Toksikol. 8(3): 114-119 (1995); Proinova, V.A., Farmakol Toksikol. 45(6):89-93 (1985)). While the efficacy of DETCD in the treatment of allergies and neurodegenerative disorders has been investigated, a role for DETCD in the treatment of different types of chronic pain has not been described. The present invention is based upon the inventor's conception that DETCD can be used effectively and safely to treat chronic pain.

Accordingly, the present invention provides methods of treating chronic pain in a subject comprising administering DETCD to the subject, provided that the chronic pain is not headache pain. As used herein, the term "chronic pain" means pain that persists longer than the normal course of time associated with a particular type of underlying injury or disorder. Chronic pain can be associated with a chronic disorder or an injury (e.g., trauma, surgery) and is often resistant to medical treatment. Chronic pain can be spontaneous (e.g., ongoing background pain) or evoked by environmental stimuli (e.g., contact with a noxious or non-noxious agent, weather conditions that cause a subject to experience pain). Symptoms of chronic pain include allodynia, burning sensation, dysaesthesia, hyperalgesia, hyperesthesia,

hyperpathia, and neuralgia, among others. In some cases, chronic pain persists for at least 3 months. In other cases, chronic pain persists for at least 6 months.

Suitable types of chronic pain which can be treated by the methods of the invention include, but are not limited to, pain associated with one or more of the following disorders or injuries: chronic inflammation (e.g., arthritis, neuritis), neuropathy (e.g., mononeuropathy, polyneuropathy), visceral disorders or injuries, burns, cancer, musculoskeletal disorders, trauma (e.g., back injury, head injury), myofascial pain syndrome (e.g., fibromyalgia), repetitive stress injury, sciatica, shingles, sports injury, spinal stenosis, post-operative injury, temperomandibular disorders, arachnoiditis, and vascular disease or injury. Particularly suitable types of chronic pain that are treatable by the methods described herein include, but are not limited to, neuropathic pain, chronic visceral pain, chronic inflammatory pain and pain resulting from fibromyalgia syndrome.

As used herein, the term "neuropathic pain" refers to pain initiated or caused by nerve damage or dysfunction of neurons. Such damage or dysfunction can occur in the peripheral (e.g., post-herpetic neuralgia) or central nervous system (e.g., spinal cord injury, stroke) and may be caused by a variety of factors, including infectious disease (e.g., HIV neuropathy), metabolic and pathological conditions (e.g., diabetes, Fabry's disease), trauma (e.g., phantom limb pain, pain from incomplete anesthesia, reflex sympathetic dystrophy, complex regional pain syndrome, causalgia), toxicity (e.g., lead poisoning, chemotherapy), primary lesions, surgery and idiopathic causes (e.g., trigeminal neuralgia, tic doleroux). Neuropathic pain is often characterized by spontaneous pain and hypersensitivity to innocuous as well as noxious stimuli, and persistent symptoms (e.g., pain, burning sensation, hyperpathia, dysaethesia, allodynia). Particularly suitable types of neuropathic pain that may be treated by the methods of the invention include, but are not limited to, pain resulting from post herpetic neuralgia, pain resulting from peripheral neuropathy, pain resulting from trigeminal neuralgia, phantom limb pain, pain resulting from reflex sympathetic dystrophy, pain resulting from causalgia, pain resulting from anesthesia dolorosa, pain resulting from intercoastal neuralgia, post-traumatic localized pain, pain resulting from HIV neuropathy, pain resulting from diabetic neuropathy, pain resulting from Fabry's disease, pain resulting from trauma, pain resulting from tic

doleroux, pain resulting from toxic poisoning, pain resulting from chemotherapy and pain resulting from complex regional pain syndrome. Other types of neuropathic pain that may be treated by the methods of the invention include neuropathic back pain (e.g., neuropathic lower back pain), among others. The term "visceral pain," as used herein, means pain caused by damage to, disorders of, or inflammation of one or more internal organs of the body (e.g., colon, pancreas, intestines, reproductive organs). Visceral pain can be associated with disease, for example, Crohn's disease, pancreatitis, colitis, or irritable bowel syndrome (IBS). Visceral pain originates from body organs and internal cavities. The scarcity of nociceptors in these areas produces a pain that is usually more aching and of a longer duration than somatic pain. Visceral pain is extremely difficult to localize, and several injuries to visceral tissue exhibit "referred" pain, where the sensation is localized to an area completely unrelated to the site of injury. Particularly suitable types of chronic visceral pain that can be treated by the methods of the invention include, but are not limited to, pain resulting from Crohn's disease, pain resulting from pancreatitis, pain resulting from colitis, and pain resulting from IBS. In addition, chronic visceral pain resulting from interstitial cystitis (e.g., painful bladder syndrome) can also be treated by the methods of the invention.

As used herein, the term "chronic inflammatory pain" refers to pain caused by tissue injury and the resulting inflammatory process in non-visceral tissue, including bone. Chronic inflammatory pain includes, without limitation, pain caused by arthritis and arthritic conditions, such as osteoarthritis, rheumatoid arthritis, gout and ankylosing spondylitis. Particularly suitable types of chronic inflammatory pain that may be treated by the methods of the invention include, but are not limited to, pain resulting from arthritis (e.g., osteoarthritis, rheumatoid arthritis) and arthritic conditions.

"Fibromyalgia syndrome" or "FMS" refers to a widespread musculoskeletal pain and fatigue disorder for which the cause is still unknown (i.e., an idiopathic condition). Pain associated with fibromyalgia includes pain in the soft fibrous tissues in the body, such as muscles, ligaments, and tendons. FMS is often characterized by muscle aches that include feelings of pulled or overworked

muscles. Fibromyalgia symptoms can also include muscle twitches and burning sensations.

As used herein, the term "headache" means any acute recurring or chronic pain of the head wherein the pain is localized above the eyes or the ears, at the back of the head (occipital locations), or in the back of the upper neck. The term "headache" includes both primary headaches (e.g., migraine headache, cluster headache, tension headache) and secondary headaches (e.g., headaches caused by an underlying disease, condition or injury). Examples of suitable types of chronic headache pain that can be treated by the methods of the invention include intractable headache pain and interictal headache pain (e.g., pain resulting from interictal migraine headaches).

As used herein, a "subject" can be either a human or non-human animal. In a preferred embodiment, the subject is a human. A "subject in need thereof refers to a subject who has chronic pain, or a subject who is at risk for developing chronic pain due to, for example, injury, disease or an idiopathic condition.

According to the methods of the invention, chronic pain can be treated in a subject by administering DETCD (e.g., a therapeutically-effective amount of Dimebon™) to the subject. As used herein, the terms "treat," "treating," or "treatment," mean to manage or counteract one or more symptoms of chronic pain to the extent that the chronic pain is improved according to a clinically-acceptable standard. In some cases, the symptoms of chronic pain may be improved or relieved by treating a disease, pathological condition, injury or disorder that is causing the chronic pain.

As used herein, the term "treatment" encompasses active treatment (i.e., treatment directed specifically toward improvement of a disease, pathological condition, injury or disorder underlying chronic pain); causal treatment (i.e., treatment directed toward removal of the cause of the disease, pathological condition, or disorder underlying chronic pain); palliative treatment (i.e., treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder underlying chronic pain); preventive treatment (i.e., treatment directed to prevention of the disease, pathological condition, or disorder underlying chronic pain); supportive treatment (i.e., treatment employed to

supplement another specific therapy directed toward the improvement of the disease, pathological condition, or disorder underlying chronic pain); and symptomatic treatment (i.e., treatment directed toward constitutional symptoms of the disease, pathological condition, or disorder underlying chronic pain). In some embodiments, treatment of chronic pain by administration of

DETCD can produce a variety of clinico-pathological effects, including sensory effects (e.g., decreased intensity or perception of pain), emotional effects (e.g., improved cognitive abilities, reduced anxiety, reduced depression), neurological effects (e.g., inhibition of neurodegeneration or loss of gray matter), neuroimmunological effects and enhancement of endogenous pain relieving pathways. The enhancement of endogenous pain relieving pathways is particularly useful for the treatment of neuropathic pain and fibromyalgia.

As used herein, the term "effective amount" or "therapeutically-effective amount," when referring to DETCD means an amount of DETCD that is sufficient to treat the chronic pain, for example, by ameliorating symptoms associated with the chronic pain, preventing or delaying the onset of the chronic pain, and/or also lessening the severity, duration or frequency of the symptoms of chronic pain, as described above. Thus, an effective amount of DETCD is a quantity which will result in a therapeutic or prophylactic benefit for the subject. The effective amount will vary depending on such factors as, for example, the route of administration, the condition of the subject, and the nature and/or extent of the chronic pain. Such factors can be determined by those skilled in the art.

The term "effective amount" or "therapeutically-effective amount" also means the total amount of DETCD that is sufficient to show a meaningful benefit to the subject, thereby producing a healing, curative, prophylactic, stabilizing, or ameliorative effect in the treatment of chronic pain.

Conventional pharmaceutical practice can be employed to provide suitable formulations (e.g., compositions) containing DETCD for administration to subjects. Such formulations typically include one or more excipients or carriers (e.g., pharmaceutically acceptable organic or inorganic carrier substances which do not deleteriously react with the active compound and are not deleterious to the recipient thereof). Suitable pharmaceutically acceptable carriers include, but are not limited

to, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, and polyvinylpyrrolidone. The pharmaceutical formulations can be sterilized and, if desired, mixed with auxiliary agents (e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings, aromatic substances) that do not deleteriously react with the active compounds.

For the methods of the present invention, oral administration of DETCD is preferred, although any other appropriate route of administration can be employed. For example, parenteral, intravenous, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraocular, topical, transdermal, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, or aerosol administration of DETCD can be employed in the methods of the invention. Therapeutic formulations comprising DETCD may be in the form of liquid solutions or suspensions, which are particularly suitable for intravenous administration. For oral administration, suitable formulations include liquids, tablets, and capsules. For intranasal administration, suitable formulations include powders, nasal drops or sprays, and aerosols. If desired, slow release or extended release delivery systems may be utilized. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients (e.g., lactose), may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops. DETCD can be administered to a subject before, during or after the onset of the chronic pain. According to the methods of the present invention, formulations comprising DETCD may be provided to a subject in a single administration or in multiple administrations, given either simultaneously or over an extended period of time. DETCD can be administered periodically at regular intervals (e.g., bimonthly,

monthly, biweekly, weekly, twice weekly, daily, twice per day or three times or more often per day), depending on the nature and extent of the chronic pain.

The administration interval for a single individual (i.e., subject) need not be a fixed interval, but can be varied over time, depending on the needs of the individual. For example, during the manifestation of symptoms of chronic pain, or if already present symptoms worsen, the interval between doses can be decreased.

The administration of DETCD can take place daily, weekly or monthly, using single or divided doses. In one embodiment, DETCD is administered to a subject at a frequency of about once per day to about three times per day. Administration can take place at any time of day, for example, in the morning, the afternoon or evening.

For the treatment of chronic pain (e.g., neuropathic pain) associated with, or caused by, surgery, DETCD can be administered to a subject before, during and/or after a surgical procedure. Thus, DETCD can be administered pre-operatively, intraoperatively, post-operatively, or perioperatively.

The dosage of DETCD that is administered to a subject should be sufficient to treat the chronic pain, or one or more symptoms thereof, without producing significant toxic or undesirable side effects. One of skill in the art will recognize that the amount of DETCD administered to the individual will depend on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs as well as the degree, severity and type of chronic pain and/or underlying condition. The precise dose to be employed may also depend on the route of administration. The skilled artisan will be able to determine appropriate dosages depending on these and other factors using standard clinical techniques. In vitro or in vivo assays may optionally be employed to identify optimal dosage ranges. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. The amount of an agent of the present invention will also depend on the disease state or condition being treated along with the above clinical factors and the route of administration of the compound. For example, in times of severe chronic pain, or if the symptoms of chronic pain worsen, the amount of DETCD administered to the subject can be increased.

Optimal administration rates for a given protocol can be readily ascertained by those skilled in the art using conventional dosage determination tests. In general, a suitable effective dose of DETCD will be in the range of from 0.01 to 100 milligrams per kilogram of bodyweight of recipient per day, particularly in the range of from 0.01 to 20 milligrams per kilogram bodyweight of recipient per day, more particularly in the range of 0.05 to 4 milligrams per kilogram bodyweight of recipient per day. The desired dose can be administered once daily, or in several sub-doses (e.g., 2 to 4 sub-doses) administered at appropriate intervals throughout the day, or other appropriate schedule. Such doses or sub-doses may be administered as unit dosage forms, e.g., containing from about 5 to 500 milligrams of DETCD per unit dosage, more particularly from about 20 mg to about 200 mg per unit dosage. For example, DETCD may be administered to a subject in a dosage of about 5, 10, 20, 40, 60 80, 100, or 200 mg of DETCD per unit dose.

The interchangeable terms "unit dose" and "unit dosage" when used in reference to DETCD refer to a physically discrete unit suitable as a unitary dosage for the subject, each unit containing a predetermined quantity of DETCD calculated to produce the desired therapeutic effect, in association with the required diluent; i.e., carrier or vehicle. In addition to the ingredients mentioned above, the formulations of the present invention may also include other agents that are conventionally used in the art in the type of formulation to be administered.

In one embodiment of the invention, chronic pain in a subject is treated by administering DETCD to the subject in a dosage of about 20 mg per unit dose. In a particular embodiment, DETCD is administered in a dosage of about 60 mg per day (e.g., in 20 mg unit dosages three times per day). Other suitable protocols for administration of DETCD to human subjects are described in U.S. Patent Nos. 6,187,785 and 7,071,206, the contents of which are incorporated herein by reference.

In certain embodiments of the invention, DETCD is administered to a subject in combination with one or more additional agents (e.g., analgesics) or medical interventions that are suitable for treating chronic pain. Particularly suitable agents that can be administered with DETCD for the treatment of chronic pain (e.g., neuropathic pain, chronic visceral pain, chronic inflammatory pain, pain associated

with fibromyalgia) include, but are not limited to, antidepressant agents, anticonvulsant agents, antiarrhythmic agents, anesthetic agents, NMDA antagonists, and narcotics.

Exemplary antidepressants include venlafaxine, tricyclic antidepressants (e.g., amitriptyline and desipramine), and SSRIs (e.g., paroxetine). Other suitable antidepressants include elavil and duloxetine. Exemplary anticonvulsants include phenytoin, carbamazepine, and gabapentin/pregabalin. An exemplary anesthetic is lidocaine, and exemplary antiarrhythmics include tocainide and mexiletine.

Exemplary narcotics include morphine, fentanyl, oxycodone, and tramadol. Exemplary NMDA antagonists include memantine and ketamine. Other compounds that may be administered with DETCD include, for example, quinolones and capsaicin.

For the treatment of neuropathic pain, additional suitable agents or medical interventions that may be used in combination with DETCD include, for example, direct injection of local anesthetics near or at the affected nerve, topical applications

(e.g., capsaicin patch, lidoderm patch), and surgery to remove the affected nerve.

Additional examples of suitable agents or medical interventions that may be used in combination with DETCD for the treatment of visceral pain include spinal cord stimulators and acupuncture. Such agents or medical interventions can be administered to the subject with

DETCD concurrently, either in separate formulations or within the same formulation. Alternatively, the agent or medical intervention can be administered either prior to or after DETCD is administered to the subject. The agent or medical intervention may also be administered both before and after administration of DETCD.

The relevant teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.