WO2005107467A2 - Compositions including opioids and methods of their use in treating pain - Google Patents

Compositions including opioids and methods of their use in treating pain Download PDF

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WO2005107467A2
WO2005107467A2 PCT/US2005/015044 US2005015044W WO2005107467A2 WO 2005107467 A2 WO2005107467 A2 WO 2005107467A2 US 2005015044 W US2005015044 W US 2005015044W WO 2005107467 A2 WO2005107467 A2 WO 2005107467A2
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opioid
combination
bupropion
pain
administered
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PCT/US2005/015044
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French (fr)
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WO2005107467A3 (en
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Harry Jefferson Leighton
David Borsook
Stephen Ashley Lawton
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Descartes Therapeutics, Inc.
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Publication of WO2005107467A3 publication Critical patent/WO2005107467A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof

Definitions

  • Pain is a complex response that has been functionally categorized into sensory, autonomic, motor, and affective components.
  • the sensory aspect includes information about stimulus location and intensity while the adaptive component may be considered to be the activation of endogenous pain modulation and motor planning for escape responses.
  • the affective component appears to include evaluation of pain unpleasantness and stimulus threat as well as negative emotions triggered by memory and context of the painful stimulus.
  • Extensive electrophysiological research in animals has defined likely neuroanatomical substrates for some of the sensory attributes of pain, such as localization and intensity, and some of the adaptive responses, such as descending analgesia.
  • Pain conditions can be divided into chronic and acute.
  • Chronic pain includes neuropathic pain (e.g., post surgical and postherpetic neuralgia) and chronic inflammatory pain (e.g., arthritis), or pain of unknown origin (e.g. fibromyalgia) while acute pain usually follows non-neural tissue injury (e.g., tissue damage from surgery or inflammation, or migraine).
  • opioids are frequently used as analgesics in pain management, with mo ⁇ hine being the most widely used.
  • mo ⁇ hine has a number of side effects along with its therapeutic potential. These side effects include respiratory depression, decreased gastrointestinal motility resulting in severe constipation, urinary retention, sedation, nausea, and vomiting. In addition, tolerance and dependence frequently occur which can limit its clinical use. Certain combinations, such as acetaminophen and oxycodone (Percocet), are known to provide additive analgesic effects, but more active analgesic combinations are in great demand particularly if they can offer lower dosages, with reduced expected side effects and toxicity.
  • acetaminophen and oxycodone Percocet
  • compositions for treatment of pain or nociception and methods of their use include the combination of two or more drugs, such as an opioid (e.g., delta, kappa, or mu), a non-steroidal anti-inflammatory drug (NSAID) or acetaminophen, and a dopaminergic agent.
  • opioid e.g., delta, kappa, or mu
  • NSAID non-steroidal anti-inflammatory drug
  • acetaminophen acetaminophen
  • dopaminergic agent e.g., acetaminophen
  • these drug combinations may be administered alone (i.e., treatment is accomplished using a composition that consists of or consists essentially of the drug combination itself), or the drug combinations may be administered in conjunction with yet additional compounds.
  • the invention features a method of treating pain or nociception by administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of a combination of (i) an opioid (e.g., a delta, kappa, or mu opioid) and (ii) a dopaminergic agent (e.g., bupropion).
  • a subject e.g., a human
  • a dopaminergic agent e.g., bupropion
  • the combination may also include an NSAID or acetaminophen.
  • the invention also features a method of reducing the side effects of opioid treatment of pain or nociception by administering to a subject (e.g., a human) in need thereof a combination of (i) an opioid (e.g., a delta, kappa, or mu opioid) and (ii) a dopaminergic agent (e.g., bupropion), wherein said combination is administered in a therapeutically effective amount to treat pain or nociception, and wherein a side effect associated with the opioid is reduced.
  • the combination further includes an NSAID or acetaminophen.
  • Opioid side effects include, without limitation, nausea, emesis, sedation, mental confusion, lightheadedness, hyperalgesia, urinary retention, respiratory depression, pruritus, miosis, hallucinations, constipation, myoclonic seizures, euphoria, excitation, dysphoria, hypotension, tolerance, and dependence.
  • the invention features a pharmaceutical composition including (i) an opioid, such as a delta, kappa, or mu opioid, (e.g., in a subtherapeutically effective amount) and (ii) a dopaminergic agent (e.g., bupropion).
  • the composition may also include an NSAID or acetaminophen.
  • a pharmaceutically acceptable carrier may be included in the composition.
  • the invention also features a kit including (i) the combination of an opioid, such as a delta, kappa, or mu opioid, (e.g., in a subtherapeutically effective amount) and a dopaminergic agent (e.g., bupropion), and (ii) instructions for administering said combination to treat pain or nociception.
  • the combination may further include an NSAID or acetaminophen.
  • the instructions direct, for example, the administration 0.001 to 25 mg/kg per day, e.g., 0.005 to 10 mg/kg per day, of the opioid.
  • opioids include but are not limited to alfentanil, allylprodine, alphaprodine, anileridine, benzylmo ⁇ hine, bezitramide, bupreno ⁇ hine, buto ⁇ hanol, clonitazene, codeine, cyclazocine, desomo ⁇ hine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromo ⁇ hine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmo ⁇ hine, etonitazene, fentanyl, heroin, hydrocodone, hydromo ⁇ hone, hydroxypethidine, isomethadone, ketobemidone, levallo ⁇ han, levo
  • delta opioids include delto ⁇ hin I and II, DALDA, DPDPE/DADLE, [D-Ala 2 , D-Leu 5 ]-enkephalin, SNC80, SNC162, SNC121, DSLET, BW373U86, FIT, and SB205607.
  • Exemplary kappa opioids include bremazocine, [Arg 6 ]-dyno ⁇ hin A (1-13), GR 89696, ICI-204,448, naloxone benzoylhydrazone, U-50488 methane sulfonate, (-)-trans-(lS,2S)-U-50488, (+)- trans-(lR,2R)-U-50488, U-62066, and U-69593.
  • Exemplary mu opioids include endomo ⁇ hin-1, endomo ⁇ phin-2, DAMGO, etonitazene, fentanyl, moiphine, and oxymo ⁇ hone.
  • dopaminergic agents examples include those that act as a dopamine precursor, monoamine oxidase inhibitor, catechol-O-methyl transferase (COMT) inhibitor, dopamine releaser, dopamine reuptake inhibitor, postsynaptic dopamine receptor agonist, and presynaptic dopamine receptor antagonist.
  • Dopaminergic agents also include tricyclic antidepressants. Specific dopaminergic agents are described herein. Tricyclic antidepressants may also be used in combination with opioids in the compositions and methods described herein in the absence of any dopaminergic activity by the tricyclic antidepressant. Suitable tricyclic antidepressants are known in the art.
  • NSAIDs useful in the invention include aspirin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, and rofecoxib.
  • NSAIDs include those compounds active against cyclooxygenase 1 (COX 1) and 2 (COX 2) as well as those active against COX 2 selectively.
  • the combination of opioid and dopaminergic agent is mo ⁇ hine and levodopa, mo ⁇ hine and bupropion (e.g., at about a 1 to 15 ratio), or mo ⁇ hine and imipramine (e.g., at about a 1 to 10).
  • Additional combinations include oxycodone, acetaminophen, and bupropion; hydrocodone, acetaminophen, and bupropion; and tramadol, acetaminophen, and bupropion. Pain may be chronic (e.g., neuropathic) or acute.
  • the opioid may also be administered in a subtherapeutically effective amount.
  • Dosages for the opioid include 0.001 to 25 mg/kg per day, e.g., 0.005 to 10 mg/kg per day.
  • acute pain is meant pain of short duration that resolves completely and follows direct stimuli such as trauma (e.g., resulting from acute injury or surgery), inflammation, or burns. Typically, acute pain ceases when the stimulus is removed or the injured tissue has healed.
  • chronic pain is meant persistent pain that is not caused by an acute stimulus. Most commonly, chronic pain results from a pathological condition such as infection, arthritis, chronic injury (e.g., sprain), cancer, and neuropathic pain. Such pain may persist long after the inciting event.
  • dopaminergic agent is meant a compound that increases dopaminergic function by any mechanism.
  • exemplary agents increase the synthesis of dopamine (e.g., dopamine precursors like levodopa (L-DOPA)), prevent the breakdown of dopamine (e.g., monoamine oxidase inhibitors (such as pargyline, deprenyl (R or S), Ro 16-6491, clorgyline, hydralazine, hydroxylamine, ipronazid, 6-methoxy- tetrahydro-9H-pyrido-indole, nialamide, quinacrine, Ro 41-1049, semicarbazide, or tranylcypromine) or catechol-O-methyl transferase (COMT) inhibitors (such as tropolone, 3,5-dinitrocatechol, or RO 41-0960)), stimulate the release of dopamine (e.g., amphetamine, amantadine, or apomo
  • Dopaminergic agents also include tricyclic antidepressants, such as amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, or trimipramine. Additional information on mechanisms for increasing dopaminergic function is found, for example, in Cooper et al. The Biochemical Basis ofNeuropharmacology, 7 th ed. OxfordrNew York 1996, hereby incoiporated by reference. Additional agents are provided in the Cell Signaling & Neuroscience Catalog (Sigma-RBI, 2004-2005), hereby inco ⁇ orated by reference. Dopaminergic agents include free bases, free acids, or pharmaceutically acceptable salts of the compounds.
  • Neuroneuropathic pain is meant pain caused by peripheral nerve or central nervous system damage (e.g., stroke or spinal cord trauma).
  • Neuropathic pain may include, without limitation, a burning sensation, hype ⁇ athia, dysaethesia, allodynia, or phantom pain.
  • neuropathic pain examples include infective (e.g., post he ⁇ etic neuralgia and HIV neuropathy), metabolic (e.g., diabetic neuropathy and Fabry's disease), toxic (e.g., from lead or chemotherapy), traumatic/stretch injury (e.g., post incisional, trauma, phantom limb pain, and reflex sympathetic dystrophy/complex regional pain syndrome/causalgia), and idiopathic (e.g., trigeminal neuralgia/tic douloureux).
  • infective e.g., post he ⁇ etic neuralgia and HIV neuropathy
  • metabolic e.g., diabetic neuropathy and Fabry's disease
  • toxic e.g., from lead or chemotherapy
  • traumatic/stretch injury e.g., post incisional, trauma, phantom limb pain, and reflex sympathetic dystrophy/complex regional pain syndrome/causalgia
  • idiopathic e.
  • nociception is meant the stimulus-response process involving the stimulation of peripheral pain-carrying nerve fibers and the transmission of impulses along peripheral nerves of the central nervous system where the stimulus is perceived as pain.
  • opioid and “NSAID” include free bases, free acids, or pharmaceutically acceptable salts of the compounds.
  • pharmaceutically acceptable salt represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • treating is meant the medical management of a patient with the intent that a cure, amelioration, or prevention of pain or nociception will result.
  • This term includes active treatment, that is, treatment directed specifically toward improvement of pain or nociception, and also includes causal treatment, that is, treatment directed toward removal of the cause of the pain or nociception.
  • this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of an underlying disease; preventive treatment, that is, treatment directed to prevention of pain or nociception; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of pain or nociception.
  • treating also includes symptomatic treatment, that is, treatment directed toward constitutional symptoms of an underlying disease.
  • terapéuticaally effective amount is meant an amount of an agent sufficient to produce a healing, curative, prophylactic, stabilizing, or ameliorative effect in the treatment of pain or nociception.
  • consisting essentially of is meant that a combination or composition includes the listed drug components, and may include other agents that do not contribute to the pain-treating effect of the combination or composition.
  • FIGURE 1 is a graph of the percent maximum effectiveness for nociception in the Hargreaves heat test for imipramine alone, mo ⁇ hine alone, and the two drugs combined.
  • FIGURE 2 is a graph of the percent maximum effectiveness for nociception in the Hargreaves heat test for bupropion alone, mo ⁇ hine alone, and the two drugs combined.
  • FIGURE 3 is a graph of the percent maximum effectiveness for nociception in the Hargreaves heat test for levodopa alone, moiphine alone, and the two drugs combined.
  • the invention features combinations of opioids, dopaminergic agents, and optionally NSAIDs or acetaminophen, useful for the treatment of pain, e.g., neuropathic or acute pain. Such combinations were found in in vivo animal models to he su ⁇ risingly effective in treating pain.
  • Opioids are potent analgesics that may be used to treat various types of pain. At dosages typically employed, these compounds often cause severe side effects that reduce their utility.
  • Side effects include nausea, emesis, sedation, mental confusion, lightheadedness, hyperalgesia, urinary retention, respiratory depression, pruritus, miosis, hallucinations, constipation, myoclonic seizures, euphoria, excitation, dysphoria, and hypotension. It is also possible to develop a tolerance for the effects of opioids, and use of opioids may lead to dependence. As indicated above, the invention features the use of opioids in combination with a dompaminergic agent.
  • Opioids that may be used in the present invention include alfentanil, allylprodine, alphaprodine, anileridine, benzylmo ⁇ hine, bezitramide, bupreno ⁇ hine, buto ⁇ hanol, clonitazene, codeine, cyclazocine, desomo ⁇ hine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromo ⁇ hine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmo ⁇ hine, etonitazene, fentanyl, heroin, hydrocodone, hydromo ⁇ hone, hydroxypethidine, isomethadone, ketobemidone, levallo ⁇ han
  • Opioids may be selective or non-selective.
  • Selective opioids are, for example, delta (e.g., ⁇ 1 or ⁇ 2 ), kappa, or mu agonists.
  • Exemplary delta opioids include delto ⁇ hin I and II, DALDA, DPDPE/DADLE, [D-Ala 2 , D-Leu 5 ]- enkephalin, SNC80, SNC162, SNC121, DSLET, BW373U86, FIT, and SB205607.
  • Exemplary kappa opioids include bremazocine, [Arg 6 ]-dyno ⁇ hin A (1-13), GR 89696, ICI-204,448, naloxone benzoylhydrazone, U-50488 methane sulfonate, (-)-trans-(lS,2S)-U-50488, (+)-trans-(lR,2R)-U-50488, U-62066, and U-69593.
  • Exemplary mu opioids include endomo ⁇ hin-1, endomo ⁇ hin-2, DAMGO, etonitazene, fentanyl, mo ⁇ hine, and oxymo ⁇ hone.
  • NSAIDs useful in the invention include aspirin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, and rofecoxib.
  • Dopaminergic agents that may be used in the present invention include those that increase the synthesis of dopamine (e.g., levodopa, either alone or in combination with carbidopa), prevent the breakdown of dopamine (e.g., monoamine oxidase inhibitors (such as pargyline, deprenyl (R or S), Ro 16-6491, clorgyline, hydralazine, hydroxylamine, ipronazid, 6-methoxy-tetrahydro-9H- pyrido-indole, nialamide, quinacrine, Ro 41-1049, semicarbazide, or tranylcypromine) or catechol-O-methyl transferase (COMT) inhibitors (such as tropolone, 3,5-dinitrocatechol, or RO 41-0960)), stimulate the release of dopamine (e.g., amphetamine, amantadine, or apomo ⁇ hine), inhibit the reuptake of
  • Tricyclic antidepressants such as amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, or trimipramine.
  • Tricyclic antidepressants may also be used in combination with opioids in the compositions and methods described herein in the absence of any dopaminergic activity by the tricyclic antidepressant. Suitable tricyclic antidepressants are known in the art.
  • compositions for administration to patients.
  • Oral administration is preferred, but any other appropriate route of administration may be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, transdermal, or aerosol administration.
  • Therapeutic formulations may be in the form of liquid solutions or suspensions (as, for example, for intravenous administration); for oral administration, formulations may be in the form of liquids, tablets, or capsules; and for intranasal formulations, in the form of powders, nasal drops, or aerosols.
  • Formulations for parenteral administration may, for example, contain excipients, sterile water, saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydro genated naphthalenes. 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 a compound.
  • one agent is formulated for fast release, while the other is formulated for slow release.
  • 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, for example, lactose, or 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, or as a gel.
  • two or more drugs are administered, they may supplied in separate formulations or the same formulation. Appropriate pharmaceutical carriers may be employed depending on the formulation used.
  • the pharmacokinetic profiles for each agent can also be suitably matched.
  • the combinations of drugs are administered together they are given in a ratio that produces the desired therapeutic effect.
  • the ratio by weight may be between 0.01 to 1 and 100 to 1 dopaminergic agent to opioid, e.g., approximately 10 to 1 imipramine to mo ⁇ hine, approximately 15 to 1 bupropion to mo ⁇ hine, or greater than 8 to 1 levodopa to mo ⁇ hine.
  • the dopaminergic agent and opioid combinations (and NSAID or acetaminophen if present) will be given at a dosage up to conventional dosage levels for such drugs.
  • Some standard dosages of opioids are codeine 30 mg-60 mg I.M.
  • opioids are known in the art, e.g., in the Merck Manual of Diagnosis & Therapy (17th Ed. MH Beers et al., Merck & Co.) and Physicians ' Desk Reference 2003 (57 th Ed. Medical Economics Staff et al., Medical Economics Co., 2002).
  • the opioid e.g., mo ⁇ hine
  • a lower dosage level i.e., a subtherapeutically effective amount
  • Such a reduction typically lessens the side effects caused by the opioid.
  • Suitable dosage levels depend on the analgesic effect desired and the specific opioid, but typically dosages are approximately 0.001 to 25 mg/kg per day, e.g., 0.005 to 10 mg/kg per day.
  • the compound may be administered up to six times per day, e.g., one to four times per day.
  • the drug combinations are given for extended periods of time, e.g., at least one week, one month, three months, six months, or one year.
  • extended periods of time e.g., at least one week, one month, three months, six months, or one year.
  • Example 1 To demonstrate that the dopaminergic agents imipramine, bupropion, and levodopa in combination with mo ⁇ hine provide improved analgesia, these drugs were administered to animals, and pain treatment was assayed by the Hargreaves Plantar Test, a standard test for identifying analgesic activity. Imipramine, bupropion, and mo ⁇ hine were purchased from Sigma Aldrich Chemical Co. (St. Louis, MO). These drugs were made up fresh for each experiment and were dissolved in 0.9% sodium chloride. Sprague-Dawley male rats were purchased from Harlan (Indianapolis, IN) and housed in animal facilities with controlled humidity, temperature, and on a 12h: 12h, light: dark cycle.
  • Rats were housed for at least 48 h prior to use to allow acclimation to the facility, and handled to minimize stress. At the time of use, rats weighed approximately 175-250 g. Rats were placed into a plexiglass chamber and allowed to habituate for 20- 30 minutes. An infrared beam was aimed at the plantar hind paw, either left or right, and the length of time it took for the rat to lift his hindpaw from the glass was the withdrawal latency. A timer automatically measured this latency. To prevent any tissue damage, the infrared beam was shut off after 20 seconds. Rats were treated with different doses of the dopaminergic agent subcutaneously, followed by mo ⁇ hine subcutaneously.
  • Figures 1-3 show that the combination of an opioid and a dopaminergic agent exhibited a su ⁇ risingly synergistic effect on treatment of nociception, thereby lowering the dose of opioid necessary to achieve a therapeutic effect. Equivalent reduction of the opioid in humans will reduce the side effects associated with opioid administration.

Abstract

The invention features compositions for treatment of pain or nociception and methods of their use. The compositions include the combination of two or more drugs, such as an opioid (e.g., delta, kappa, or mu), a non-steroidal anti-inflammatory drug (NSAID) or acetaminophen, and a dopaminergic agent. These drug combinations may be administered alone (i.e., treatment is accomplished using a composition that consists of or consists essentially of the drug combination itself), or the drug combinations may be administered in conjunction with yet additional compounds.

Description

COMPOSITIONS INCLUDING OPIOIDS AND METHODS OF THEIR USE IN TREATING PAIN
BACKGROUND OF THE INVENTION The invention relates to the treatment of pain or nociception and pharmaceutical compositions. Pain is a complex response that has been functionally categorized into sensory, autonomic, motor, and affective components. The sensory aspect includes information about stimulus location and intensity while the adaptive component may be considered to be the activation of endogenous pain modulation and motor planning for escape responses. The affective component appears to include evaluation of pain unpleasantness and stimulus threat as well as negative emotions triggered by memory and context of the painful stimulus. Extensive electrophysiological research in animals has defined likely neuroanatomical substrates for some of the sensory attributes of pain, such as localization and intensity, and some of the adaptive responses, such as descending analgesia. Other regions activated by painful stimuli have also been identified which may be involved in the affective response; however, the neural substrates for the motivational and emotional response to pain remain a topic of debate. In general, pain conditions can be divided into chronic and acute. Chronic pain includes neuropathic pain (e.g., post surgical and postherpetic neuralgia) and chronic inflammatory pain (e.g., arthritis), or pain of unknown origin (e.g. fibromyalgia) while acute pain usually follows non-neural tissue injury (e.g., tissue damage from surgery or inflammation, or migraine). There are many drugs that are known to be useful in the treatment or management of pain. Opioids are frequently used as analgesics in pain management, with moφhine being the most widely used. Unfortunately, moφhine has a number of side effects along with its therapeutic potential. These side effects include respiratory depression, decreased gastrointestinal motility resulting in severe constipation, urinary retention, sedation, nausea, and vomiting. In addition, tolerance and dependence frequently occur which can limit its clinical use. Certain combinations, such as acetaminophen and oxycodone (Percocet), are known to provide additive analgesic effects, but more active analgesic combinations are in great demand particularly if they can offer lower dosages, with reduced expected side effects and toxicity.
SUMMARY OF THE INVENTION In general, the invention features compositions for treatment of pain or nociception and methods of their use. The compositions include the combination of two or more drugs, such as an opioid (e.g., delta, kappa, or mu), a non-steroidal anti-inflammatory drug (NSAID) or acetaminophen, and a dopaminergic agent. These drug combinations may be administered alone (i.e., treatment is accomplished using a composition that consists of or consists essentially of the drug combination itself), or the drug combinations may be administered in conjunction with yet additional compounds. In one aspect, the invention features a method of treating pain or nociception by administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of a combination of (i) an opioid (e.g., a delta, kappa, or mu opioid) and (ii) a dopaminergic agent (e.g., bupropion). The combination may also include an NSAID or acetaminophen. The invention also features a method of reducing the side effects of opioid treatment of pain or nociception by administering to a subject (e.g., a human) in need thereof a combination of (i) an opioid (e.g., a delta, kappa, or mu opioid) and (ii) a dopaminergic agent (e.g., bupropion), wherein said combination is administered in a therapeutically effective amount to treat pain or nociception, and wherein a side effect associated with the opioid is reduced. In an alternative embodiment, the combination further includes an NSAID or acetaminophen. Opioid side effects include, without limitation, nausea, emesis, sedation, mental confusion, lightheadedness, hyperalgesia, urinary retention, respiratory depression, pruritus, miosis, hallucinations, constipation, myoclonic seizures, euphoria, excitation, dysphoria, hypotension, tolerance, and dependence. In another aspect, the invention features a pharmaceutical composition including (i) an opioid, such as a delta, kappa, or mu opioid, (e.g., in a subtherapeutically effective amount) and (ii) a dopaminergic agent (e.g., bupropion). The composition may also include an NSAID or acetaminophen. In addition, a pharmaceutically acceptable carrier may be included in the composition. The invention also features a kit including (i) the combination of an opioid, such as a delta, kappa, or mu opioid, (e.g., in a subtherapeutically effective amount) and a dopaminergic agent (e.g., bupropion), and (ii) instructions for administering said combination to treat pain or nociception. The combination may further include an NSAID or acetaminophen. The instructions direct, for example, the administration 0.001 to 25 mg/kg per day, e.g., 0.005 to 10 mg/kg per day, of the opioid. Exemplary opioids include but are not limited to alfentanil, allylprodine, alphaprodine, anileridine, benzylmoφhine, bezitramide, buprenoφhine, butoφhanol, clonitazene, codeine, cyclazocine, desomoφhine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromoφhine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmoφhine, etonitazene, fentanyl, heroin, hydrocodone, hydromoφhone, hydroxypethidine, isomethadone, ketobemidone, levalloφhan, levoφhanol, levophenacylmoφhan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, moφhine, myrophine, nalbuphine, narceine, nicomoφhine, norlevoφhanol, normethadone, naloφhine, normoφhine, noφipanone, opium, oxycodone, oxymoφhone, papaveretum, pentazocine, pethidine, phenadoxone, phenomoφhan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, and tilidine. Exemplary delta opioids include deltoφhin I and II, DALDA, DPDPE/DADLE, [D-Ala2, D-Leu5]-enkephalin, SNC80, SNC162, SNC121, DSLET, BW373U86, FIT, and SB205607. Exemplary kappa opioids include bremazocine, [Arg6]-dynoφhin A (1-13), GR 89696, ICI-204,448, naloxone benzoylhydrazone, U-50488 methane sulfonate, (-)-trans-(lS,2S)-U-50488, (+)- trans-(lR,2R)-U-50488, U-62066, and U-69593. Exemplary mu opioids include endomoφhin-1, endomoιphin-2, DAMGO, etonitazene, fentanyl, moiphine, and oxymoφhone. Examples of dopaminergic agents include those that act as a dopamine precursor, monoamine oxidase inhibitor, catechol-O-methyl transferase (COMT) inhibitor, dopamine releaser, dopamine reuptake inhibitor, postsynaptic dopamine receptor agonist, and presynaptic dopamine receptor antagonist. Dopaminergic agents also include tricyclic antidepressants. Specific dopaminergic agents are described herein. Tricyclic antidepressants may also be used in combination with opioids in the compositions and methods described herein in the absence of any dopaminergic activity by the tricyclic antidepressant. Suitable tricyclic antidepressants are known in the art. NSAIDs useful in the invention include aspirin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, and rofecoxib. NSAIDs include those compounds active against cyclooxygenase 1 (COX 1) and 2 (COX 2) as well as those active against COX 2 selectively. In various embodiments, the combination of opioid and dopaminergic agent is moφhine and levodopa, moφhine and bupropion (e.g., at about a 1 to 15 ratio), or moφhine and imipramine (e.g., at about a 1 to 10). Additional combinations include oxycodone, acetaminophen, and bupropion; hydrocodone, acetaminophen, and bupropion; and tramadol, acetaminophen, and bupropion. Pain may be chronic (e.g., neuropathic) or acute. The opioid may also be administered in a subtherapeutically effective amount. Dosages for the opioid include 0.001 to 25 mg/kg per day, e.g., 0.005 to 10 mg/kg per day. By "acute pain" is meant pain of short duration that resolves completely and follows direct stimuli such as trauma (e.g., resulting from acute injury or surgery), inflammation, or burns. Typically, acute pain ceases when the stimulus is removed or the injured tissue has healed. By "chronic pain" is meant persistent pain that is not caused by an acute stimulus. Most commonly, chronic pain results from a pathological condition such as infection, arthritis, chronic injury (e.g., sprain), cancer, and neuropathic pain. Such pain may persist long after the inciting event. By "dopaminergic agent" is meant a compound that increases dopaminergic function by any mechanism. Exemplary agents increase the synthesis of dopamine (e.g., dopamine precursors like levodopa (L-DOPA)), prevent the breakdown of dopamine (e.g., monoamine oxidase inhibitors (such as pargyline, deprenyl (R or S), Ro 16-6491, clorgyline, hydralazine, hydroxylamine, ipronazid, 6-methoxy- tetrahydro-9H-pyrido-indole, nialamide, quinacrine, Ro 41-1049, semicarbazide, or tranylcypromine) or catechol-O-methyl transferase (COMT) inhibitors (such as tropolone, 3,5-dinitrocatechol, or RO 41-0960)), stimulate the release of dopamine (e.g., amphetamine, amantadine, or apomoφhine), inhibit the reuptake of dopamine (e.g., amfonelic acid, BTCP, β-CFT, β-CIT, 4',4"-difluoro-3α- (diphenylmethoxy) tropane, 4'-chloro-3α-diphenylmethoxytopane, GBR-12683, GBR-12909, GBR-12935, GBR-12935, GBR-13069, GBR-13098, GYKI 52895, benztropine, amphetamine, mazindol, nomifensine, indatraline, or bupropion), agonize a postsynaptic dopamine receptor (e.g., A-77636), or antagonize a presynaptic dopamine receptor (autoreceptor) (e.g., (+)-UH232 or (+)-AJ76). Dopaminergic agents also include tricyclic antidepressants, such as amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, or trimipramine. Additional information on mechanisms for increasing dopaminergic function is found, for example, in Cooper et al. The Biochemical Basis ofNeuropharmacology, 7th ed. OxfordrNew York 1996, hereby incoiporated by reference. Additional agents are provided in the Cell Signaling & Neuroscience Catalog (Sigma-RBI, 2004-2005), hereby incoφorated by reference. Dopaminergic agents include free bases, free acids, or pharmaceutically acceptable salts of the compounds. By "neuropathic pain" is meant pain caused by peripheral nerve or central nervous system damage (e.g., stroke or spinal cord trauma). Neuropathic pain may include, without limitation, a burning sensation, hypeφathia, dysaethesia, allodynia, or phantom pain. Exemplary types of neuropathic pain include infective (e.g., post heφetic neuralgia and HIV neuropathy), metabolic (e.g., diabetic neuropathy and Fabry's disease), toxic (e.g., from lead or chemotherapy), traumatic/stretch injury (e.g., post incisional, trauma, phantom limb pain, and reflex sympathetic dystrophy/complex regional pain syndrome/causalgia), and idiopathic (e.g., trigeminal neuralgia/tic douloureux). By "nociception" is meant the stimulus-response process involving the stimulation of peripheral pain-carrying nerve fibers and the transmission of impulses along peripheral nerves of the central nervous system where the stimulus is perceived as pain. The terms "opioid" and "NSAID" include free bases, free acids, or pharmaceutically acceptable salts of the compounds. The term "pharmaceutically acceptable salt" represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. By "treating" is meant the medical management of a patient with the intent that a cure, amelioration, or prevention of pain or nociception will result. This term includes active treatment, that is, treatment directed specifically toward improvement of pain or nociception, and also includes causal treatment, that is, treatment directed toward removal of the cause of the pain or nociception. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of an underlying disease; preventive treatment, that is, treatment directed to prevention of pain or nociception; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of pain or nociception. The term "treating" also includes symptomatic treatment, that is, treatment directed toward constitutional symptoms of an underlying disease. By "therapeutically effective amount" as used herein, is meant an amount of an agent sufficient to produce a healing, curative, prophylactic, stabilizing, or ameliorative effect in the treatment of pain or nociception. By "consisting essentially of is meant that a combination or composition includes the listed drug components, and may include other agents that do not contribute to the pain-treating effect of the combination or composition. Other features and advantages will be apparent from the following description and the claims.
BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 is a graph of the percent maximum effectiveness for nociception in the Hargreaves heat test for imipramine alone, moφhine alone, and the two drugs combined. FIGURE 2 is a graph of the percent maximum effectiveness for nociception in the Hargreaves heat test for bupropion alone, moφhine alone, and the two drugs combined. FIGURE 3 is a graph of the percent maximum effectiveness for nociception in the Hargreaves heat test for levodopa alone, moiphine alone, and the two drugs combined. DETAILED DESCRIPTION OF THE INVENTION The invention features combinations of opioids, dopaminergic agents, and optionally NSAIDs or acetaminophen, useful for the treatment of pain, e.g., neuropathic or acute pain. Such combinations were found in in vivo animal models to he suφrisingly effective in treating pain. Opioids are potent analgesics that may be used to treat various types of pain. At dosages typically employed, these compounds often cause severe side effects that reduce their utility. Side effects include nausea, emesis, sedation, mental confusion, lightheadedness, hyperalgesia, urinary retention, respiratory depression, pruritus, miosis, hallucinations, constipation, myoclonic seizures, euphoria, excitation, dysphoria, and hypotension. It is also possible to develop a tolerance for the effects of opioids, and use of opioids may lead to dependence. As indicated above, the invention features the use of opioids in combination with a dompaminergic agent. Opioids that may be used in the present invention include alfentanil, allylprodine, alphaprodine, anileridine, benzylmoφhine, bezitramide, buprenoφhine, butoφhanol, clonitazene, codeine, cyclazocine, desomoφhine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromoφhine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmoφhine, etonitazene, fentanyl, heroin, hydrocodone, hydromoφhone, hydroxypethidine, isomethadone, ketobemidone, levalloφhan, levoφhanol, levophenacylmoφhan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, moφhine, myrophine, nalbuphine, narceine, nicomoφhine, norlevoφhanol, nonnethadone, naloφhine, normoφhine, noφipanone, opium, oxycodone, oxymoφhone, papaveretum, pentazocine, pethidine, phenadoxone, phenomoφhan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, and tilidine. Opioids may be selective or non-selective. Selective opioids are, for example, delta (e.g., δ1 or δ2), kappa, or mu agonists. Exemplary delta opioids include deltoφhin I and II, DALDA, DPDPE/DADLE, [D-Ala2, D-Leu5]- enkephalin, SNC80, SNC162, SNC121, DSLET, BW373U86, FIT, and SB205607. Exemplary kappa opioids include bremazocine, [Arg6]-dynoφhin A (1-13), GR 89696, ICI-204,448, naloxone benzoylhydrazone, U-50488 methane sulfonate, (-)-trans-(lS,2S)-U-50488, (+)-trans-(lR,2R)-U-50488, U-62066, and U-69593. Exemplary mu opioids include endomoφhin-1, endomoφhin-2, DAMGO, etonitazene, fentanyl, moφhine, and oxymoφhone. NSAIDs useful in the invention include aspirin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, and rofecoxib. Dopaminergic agents that may be used in the present invention include those that increase the synthesis of dopamine (e.g., levodopa, either alone or in combination with carbidopa), prevent the breakdown of dopamine (e.g., monoamine oxidase inhibitors (such as pargyline, deprenyl (R or S), Ro 16-6491, clorgyline, hydralazine, hydroxylamine, ipronazid, 6-methoxy-tetrahydro-9H- pyrido-indole, nialamide, quinacrine, Ro 41-1049, semicarbazide, or tranylcypromine) or catechol-O-methyl transferase (COMT) inhibitors (such as tropolone, 3,5-dinitrocatechol, or RO 41-0960)), stimulate the release of dopamine (e.g., amphetamine, amantadine, or apomoφhine), inhibit the reuptake of dopamine (e.g., amfonelic acid, BTCP, β-CFT, β-CIT, 4',4"-difluoro-3α- (diphenylmethoxy) tropane, 4'-chloro-3α-diphenylmemoxytopane, GBR-12683, GBR-12909, GBR-12935, GBR-12935, GBR-13069, GBR-13098, GYKI 52895, benztropine, amphetamine, mazindol, nomifensine, indatraline, or bupropion), agonize a postsynaptic dopamine receptor (e.g., A-77636), or antagonize a presynaptic dopamine receptor (autoreceptor) (e.g., (+)-UH232 or (+)-AJ76). Other dopaminergic agents are tricyclic antidepressants, such as amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, or trimipramine. Tricyclic antidepressants may also be used in combination with opioids in the compositions and methods described herein in the absence of any dopaminergic activity by the tricyclic antidepressant. Suitable tricyclic antidepressants are known in the art.
Administration Conventional pharmaceutical practice is employed to provide suitable foπnulations or compositions for administration to patients. Oral administration is preferred, but any other appropriate route of administration may be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, transdermal, or aerosol administration. Therapeutic formulations may be in the form of liquid solutions or suspensions (as, for example, for intravenous administration); for oral administration, formulations may be in the form of liquids, tablets, or capsules; and for intranasal formulations, in the form of powders, nasal drops, or aerosols. Methods well known in the art for making formulations are described, for example, in Remington: The Science and Practice of Pharmacy (20th ed.) ed. A.R. Gennaro, 2000, Lippincott, Philadelphia, PA. Formulations for parenteral administration may, for example, contain excipients, sterile water, saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydro genated naphthalenes. 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 a compound. In one embodiment, one agent is formulated for fast release, while the other is formulated for slow release. 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, for example, lactose, or 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, or as a gel. When two or more drugs are administered, they may supplied in separate formulations or the same formulation. Appropriate pharmaceutical carriers may be employed depending on the formulation used. By using different formulation strategies for different agents, the pharmacokinetic profiles for each agent can also be suitably matched. When the combinations of drugs are administered together they are given in a ratio that produces the desired therapeutic effect. In particular, the ratio by weight may be between 0.01 to 1 and 100 to 1 dopaminergic agent to opioid, e.g., approximately 10 to 1 imipramine to moφhine, approximately 15 to 1 bupropion to moφhine, or greater than 8 to 1 levodopa to moφhine. The dopaminergic agent and opioid combinations (and NSAID or acetaminophen if present) will be given at a dosage up to conventional dosage levels for such drugs. Some standard dosages of opioids are codeine 30 mg-60 mg I.M. or 60 mg-120 mg p.o.; fentanyl 50 mcg-100 meg I.V. or 25 mcg-100 mcg/hr transdermal patch; hydrocodone /acetaminophen 5 mg-20 mg; hydromoiphone 1 mg I.V, 1 mg-2.0 mg I.M. or 4 mg-6 mg p.o.; levoφhanol 1 mg-2 mg I.M. or 2 mg-4 mg p.o.; meperidine 50 mg- 100 mg I.M. or 10 mg-25 mg I.V.; moφhine 2 mg-4 mg I.V. or 8 mg-12 mg I.M.; methadone 5 mg-10 mg I.M. or 5 mg-10 mg p.o.; oxycodone 5 mg-15 mg p.o.; oxymoφhone 0.5 mg-0.75 mg I.V. or 1.0 mg-1.5 mg I.M.; and tramadol 50 mg- 100 mg p.o. Other standard dosages for opioids are known in the art, e.g., in the Merck Manual of Diagnosis & Therapy (17th Ed. MH Beers et al., Merck & Co.) and Physicians ' Desk Reference 2003 (57th Ed. Medical Economics Staff et al., Medical Economics Co., 2002). Preferably, the opioid, e.g., moφhine, is given at a lower dosage level (i.e., a subtherapeutically effective amount) than is commonly prescribed because of a synergistic effect of the dopaminergic agent. Such a reduction typically lessens the side effects caused by the opioid. Suitable dosage levels depend on the analgesic effect desired and the specific opioid, but typically dosages are approximately 0.001 to 25 mg/kg per day, e.g., 0.005 to 10 mg/kg per day. The compound may be administered up to six times per day, e.g., one to four times per day. For chronic conditions, the drug combinations are given for extended periods of time, e.g., at least one week, one month, three months, six months, or one year. One particular example of drug combinations according to the invention is now described. This example is intended to illustrate the invention and is not intended to be limiting.
Example 1 To demonstrate that the dopaminergic agents imipramine, bupropion, and levodopa in combination with moφhine provide improved analgesia, these drugs were administered to animals, and pain treatment was assayed by the Hargreaves Plantar Test, a standard test for identifying analgesic activity. Imipramine, bupropion, and moφhine were purchased from Sigma Aldrich Chemical Co. (St. Louis, MO). These drugs were made up fresh for each experiment and were dissolved in 0.9% sodium chloride. Sprague-Dawley male rats were purchased from Harlan (Indianapolis, IN) and housed in animal facilities with controlled humidity, temperature, and on a 12h: 12h, light: dark cycle. Rats were housed for at least 48 h prior to use to allow acclimation to the facility, and handled to minimize stress. At the time of use, rats weighed approximately 175-250 g. Rats were placed into a plexiglass chamber and allowed to habituate for 20- 30 minutes. An infrared beam was aimed at the plantar hind paw, either left or right, and the length of time it took for the rat to lift his hindpaw from the glass was the withdrawal latency. A timer automatically measured this latency. To prevent any tissue damage, the infrared beam was shut off after 20 seconds. Rats were treated with different doses of the dopaminergic agent subcutaneously, followed by moφhine subcutaneously. The rats were tested 30, 60, 90, and 120 minutes after moφhine was administered. Data were normalized by calculating withdrawal latency values as the percent of the maximum possible effect. Figures 1-3 show that the combination of an opioid and a dopaminergic agent exhibited a suφrisingly synergistic effect on treatment of nociception, thereby lowering the dose of opioid necessary to achieve a therapeutic effect. Equivalent reduction of the opioid in humans will reduce the side effects associated with opioid administration.
Other Embodiments All publications, patents, and patent applications mentioned in this specification are hereby incoφorated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incoφorated by reference. While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the appended claims. Other embodiments are in the claims. What is claimed is:

Claims

CLAIMS 1. A method of treating pain or nociception, said method comprising administering to a subject in need thereof a combination of (i) an opioid (ii) a non- steroidal anti-inflammatory drug (NSAID) or acetaminophen, and (iii) a dopaminergic agent, wherein said combination is administered in a therapeutically effective amount.
2. The method of claim 1, wherein said opioid is alfentanil, allylprodine, alphaprodine, anileridine, benzylmoφhine, bezitramide, buprenoφhine, butoφhanol, clonitazene, codeine, cyclazocine, desomoφhine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromoφhine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmoφhine, etonitazene, fentanyl, heroin, hydrocodone, hydromoφhone, hydroxypethidine, isomethadone, ketobemidone, levalloφhan, levoφhanol, levophenacylmoφhan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, moiphine, myrophine, nalbuphine, narceine, nicomoφhine, norlevoφhanol, nonnethadone, naloφhine, normoφhine, noφipanone, opium, oxycodone, oxymoφhone, papaveretum, pentazocine, pethidine, phenadoxone, phenomoφhan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, or tilidine.
3. The method of claim 1, wherein said NSAID is aspirin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, or rofecoxib.
4. The method of claim 1, wherein said dopaminergic agent is a dopamine precursor, monoamine oxidase inhibitor, catechol-O-methyl transferase (COMT) inhibitor, dopamine releaser, dopamine reuptake inhibitor, postsynaptic dopamine receptor agonist, or presynaptic dopamine receptor antagonist.
5. The method of claim 4, wherein said dopamine precursor is levodopa.
6. The method of claim 4, wherein said monoamine oxidase inhibitor is pargyline, deprenyl (R or S), Ro 16-6491, clorgyline, hydralazine, hydroxylamine, ipronazid, 6-methoxy-tetrahydiO-9H-pyrido-indole, nialamide, quinacrine, Ro 41- 1049, semicarbazide, or tranylcypromine.
7. The method of claim 4, wherein said catechol-O-methyl transferase (COMT) inhibitor is tropolone, 3,5-dinitrocatechol, or RO 41-0960.
8. The method of claim 4, wherein said dopamine releaser is amphetamine, amantadine, or apomoφhine.
9. The method of claim 4, wherein said dopamine reuptake inhibitor is amfonelic acid, BTCP, β-CFT, β-CIT, 4',4"-difluoro-3α-(diphenylmethoxy) tropane, 4'-chloro-3α-diρhenylmethoxytoρane, GBR-12683, GBR-12909, GBR- 12935, GBR-12935, GBR-13069, GBR-13098, GYKI 52895, benztropine, amphetamine, mazindol, nomifensine, indatraline, or bupropion.
10. The method of claim 4, wherein said postsynaptic dopamine receptor agonist is A-77636.
11. The method of claim 4, wherein said presynaptic dopamine receptor antagonist (+)-UH232 or (+)-AJ76.
12. The method of claim 1, wherein said dopaminergic agent is a tricyclic antidepressant.
13. The method of claim 12, wherein said tricyclic antidepressant is amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, or himipramine.
14. The method of claim 1, wherein said pain is chronic pain.
15. The method of claim 14, wherein said chronic pain is neuropathic pain.
16. The method of claim 1, wherein said pain is acute pain.
17. The method of claim 1, wherein said opioid is administered in a subtherapeutically effective amount.
18. The method of claim 1, wherein said combination is (i) oxycodone, (ii) acetaminophen, and (iii) bupropion.
19. The method of claim 1, wherein said combination is (i) hydrocodone, (ii) acetaminophen, and (iii) bupropion.
20. The method of claim 1, wherein said combination is (i) tramadol, (ii) acetaminophen, and (iii) bupropion.
21. The method of claim 1, wherein said subject is a human.
22. The method of claim 1, wherein 0.001 to 25 mg/kg per day of said opioid is administered.
23. The method of claim 22, wherein 0.005 to 10 mg/kg per day of said opioid is administered.
24. A method of reducing the side effects of opioid treatment, said method comprising administering to a subject in need thereof a combination of (i) an opioid (ii) a non-steroidal anti-inflammatory drug (NSAID) or acetaminophen, and (iii) a dopaminergic agent, wherein said combination is administered in a therapeutically effective amount to treat pain or nociception, and wherein a side effect associated with said opioid is reduced.
,
25. The method of claim 24, wherein said side effect is nausea, emesis, sedation, mental confusion, lightheadedness, hyperalgesia, urinary retention, respiratory depression, pruritus, miosis, hallucinations, constipation, myoclonic seizures, euphoria, excitation, dysphoria, hypotension, tolerance, or dependence.
26. The method of claim 24, wherein said combination is (i) oxycodone, (ii) acetaminophen, and (iii) bupropion.
27. The method of claim 24, wherein said combination is (i) hydrocodone, (ii) acetaminophen, and (iii) bupropion.
28. The method of claim 24, wherein said combination is (i) tramadol, (ii) acetaminophen, and (iii) bupropion.
29. The method of claim 24, wherein said subject is a human.
30. The method of claim 24, wherein 0.001 to 25 mg/kg per day of said opioid is administered.
31. The method of claim 30, wherein 0.005 to 10 mg/kg per day of said opioid is administered.
32. A phannaceutical composition comprising (i) an opioid, (ii) a non- steroidal anti-inflammatory drag (NSAID) or acetaminophen, and (iii) a dopaminergic agent.
33. The phannaceutical composition of claim 32, further comprising a pharmaceutically acceptable carrier.
34. The pharmaceutical composition of claim 32, wherein said opioid is present in a subtherapeutically effective amount.
35. The pharmaceutical composition of claim 32, wherein said combination comprises (i) oxycodone, (ii) acetaminophen, and (iii) bupropion.
36. The pharmaceutical composition of claim 32, wherein said combination comprises (i) hydrocodone, (ii) acetaminophen, and (iii) bupropion.
37. The pharmaceutical composition of claim 32, wherein said combination comprises (i) tramadol, (ii) acetaminophen, and (iii) bupropion.
38. A kit comprising (a) combination of (i) an opioid, (ii) a non-steroidal anti-inflammatory drug (NSAID) or acetaminophen, and (iii) a dopaminergic agent, and (b) instructions for administering said combination to treat pain or nociception.
39. The kit of claim 38, wherein said opioid is present in a subtherapeutically effective amount.
40. The kit of claim 38, wherein said combination comprises (i) oxycodone, (ii) acetaminophen, and (iii) bupropion.
41. The kit of claim 38, wherein said combination comprises (i) hydrocodone, (ii) acetaminophen, and (iii) bupropion.
42. The kit of claim 38, wherein said combination comprises (i) tramadol, (ii) acetaminophen, and (iii) bupropion.
43. The kit of claim 38, wherein said instructions comprise administering 0.001 to 25 mg/kg per day of said opioid.
44. The kit of claim 40, wherein said instructions comprise administering 0.005 to 10 mg/kg per day of said opioid.
45. A method of treating pain or nociception, said method comprising administering to a subject in need thereof a combination of (i) a delta or kappa opioid and (ii) a dopaminergic agent, wherein said combination is administered in a therapeutically effective amount.
46. The method of claim 45, wherein said delta opioid is deltoφhin I and II, DALDA, DPDPE/DADLE, [D-Ala2, D-Leu5]-enkephalin, SNC80, SNC162, SNC121, DSLET, BW373U86, FIT, or SB205607.
47. The method of claim 45, wherein said kappa opioid is bremazocine, [Arg6]-dynoφhin A (1-13), GR 89696, ICI-204,448, naloxone benzoylhydrazone, U-50488 methane sulfonate, (-)-trans-(lS,2S)-U-50488, (+)-trans-(lR,2R)-U- 50488, U-62066, or U-69593.
48. The method of claim 45, wherein said dopaminergic agent is a dopamine precursor, monoamine oxidase inhibitor, catechol-O-methyl transferase (COMT) inhibitor, dopamine releaser, dopamine reuptake inhibitor, postsynaptic dopamine receptor agonist, or presynaptic dopamine receptor antagonist.
49. The method of claim 48, wherein said dopamine precursor is levodopa.
50. The method of claim 48, wherein said monoamine oxidase inhibitor is pargyline, deprenyl (R or S), Ro 16-6491, clorgyline, hydralazine, hydroxylamine, ipronazid, 6-methoxy-tetrahydro-9H-pyrido-indole, nialamide, quinacrine, Ro 41- 1049, semicarbazide, or tranylcypromine.
51. The method of claim 48, wherein said catechol-O-methyl transferase (COMT) inhibitor is tropolone, 3,5-dinitiOcatechol, or RO 41-0960.
52. The method of claim 48, wherein said dopamine releaser is amphetamine, amantadine, or apomoφhine.
53. The method of claim 48, wherein said dopamine reuptake inhibitor is amfonelic acid, BTCP, β-CFT, β-CIT, 4',4"-difluoro-3α-(diphenylmethoxy) tropane, 4'-chloro-3α-diρhenylmethoxytoρane, GBR-12683, GBR-12909, GBR- 12935, GBR-12935, GBR-13069, GBR-13098, GYKI 52895, benztropine, amphetamine, mazindol, nomifensine, indatraline, or bupropion.
54. The method of claim 48, wherein said postsynaptic dopamine receptor agonist is A-77636.
55. The method of claim 48, wherein said presynaptic dopamine receptor antagonist (+)-UH232 or (+)-AJ76.
56. The method of claim 45, wherein said dopaminergic agent is a tricyclic antidepressant.
57. The method of claim 56, wherein said tricyclic antidepressant is amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, or trimipramine.
58. The method of claim 45, wherein said pain is chronic pain.
59. The method of claim 58, wherein said chronic pain is neuropathic pain.
60. The method of claim 45, wherein said pain is acute pain.
61. The method of claim 45, wherein said delta or kappa opioid is administered in a subtherapeutically effective amount.
62. The method of claim 45, wherein said subject is a human.
63. A method of reducing the side effects of opioid treatment, said method comprising administering to a subject in need thereof a combination of (i) a delta or kappa opioid and (ii) a dopaminergic agent, wherein said combination is administered in a therapeutically effective amount to treat pain or nociception, and wherein a side effect associated with said delta or kappa opioid is reduced.
64. The method of claim 63, wherein said side effect is nausea, emesis, sedation, mental confusion, lightheadedness, hyperalgesia, urinary retention, respiratory depression, pruritus, miosis, hallucinations, constipation, myoclonic seizures, euphoria, excitation, dysphoria, hypotension, tolerance, or dependence.
65. The method of claim 63, wherein said delta opioid is deltoφhin I and
II, DALDDAA,, DDPPDDPPEE//DDAADDLLEE,, [[DD--AAllaa22,, DD--LLeeuu55]]--eeιnkephalin, SNC80, SNC162 SNC121, DSLET, BW373U86, FIT, or SB205607.
66. The method of claim 63, wherein said kappa opioid is bremazocine, [Arg6]-dynoφhin A (1-13), GR 89696, ICI-204,448, naloxone benzoylhydrazone, U-50488 methane sulfonate, (-)-trans-(lS,2S)-U-50488, (+)-trans-(lR,2R)-U- 50488, U-62066, or U-69593.
67. The method of claim 63, wherein said dopaminergic agent is bupropion.
68. The method of claim 63 wherein said subject is a human.
69. The method of claim 63, wherein 0.001 to 25 mg/kg per day of said delta or kappa opioid is administered.
70. The method of claim 69, wherein 0.005 to 10 mg/kg per day of said delta or kappa opioid is administered.
71. A pharmaceutical composition comprising (i) a delta or kappa opioid and (ii) a dopaminergic agent.
72. The phannaceutical composition of claim 71, further comprising a phannaceutically acceptable earner.
73. The pharmaceutical composition of claim 71, wherein said opioid is present in a subtherapeutically effective amount.
74. The pharmaceutical composition of claim 71, wherein said delta opioid is deltoφhin l and II, DALDA, DPDPE/DADLE, [D-Ala2, D-Leu5]-enkephalin, SNC80, SNC162, SNC121, DSLET, BW373U86, FIT, or SB205607.
75. The pharmaceutical composition of claim 71, wherein said kappa opioid is bremazocine, [Arg6]-dynoφhin A (1-13), GR 89696, ICI-204,448, naloxone benzoylhydrazone, U-50488 methane sulfonate, (-)-tτans-(lS,2S)-U- 50488, (+)-trans-(lR,2R)-U-50488, U-62066, or U-69593.
76. The pharmaceutical composition of claim 71, wherein said dopaminergic agent is bupropion.
77. A kit comprising (i) combination of a delta or kappa opioid and a dopaminergic agent, and (ii) instructions for administering said combination to treat pain or nociception.
78. The kit of claim 77, wherein said delta opioid is deltoφhin I and II, DALDA, DPDPE/DADLE, [D-Ala2, D-Leu5]-enkephalin, SNC80, SNC162, SNC121, DSLET, BW373U86, FIT, or SB205607.
79. The kit of claim 77, wherein said kappa opioid is bremazocine, [Arg6]- dynoφhin A (1-13), GR 89696, ICI-204,448, naloxone benzoylhydrazone, U- 50488 methane sulfonate, (-)-tτans-(lS,2S)-U-50488, (+)-trans-(lR,2R)-U-50488, U-62066, or U-69593.
80. The kit of claim 77, wherein said dopaminergic agent is bupropion.
81. The kit of claim 77, wherein said instructions comprise administering 0.001 to 25 mg/kg per day of said delta or kappa opioid.
82. The kit of claim 81, wherein said instructions comprise administering 0.005 to 10 mg/kg per day of said delta or kappa opioid.
83. A method of treating pain or nociception, said method comprising administering to a human in need thereof a combination of (i) an opioid and (ii) bupropion, wherein said combination is administered in a therapeutically effective amount.
84. The method of claim 83, wherein said opioid is alfentanil, allylprodine, alphaprodine, anileridine, benzylmoφhine, bezitramide, buprenoφhine, butoiphanol, clonitazene, codeine, cyclazocine, desomoφhine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromoφhine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmoφhine, etonitazene, fentanyl, heroin, hydrocodone, hydromoφhone, hydroxypethidine, isomethadone, ketobemidone, levalloiphan, levoφhanol, levophenacylmoφhan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, moiphine, myrophine, nalbuphine, narceine, nicomoφhine, norlevoφhanol, nonnethadone, naloφhine, nonnoφhine, noipipanone, opium, oxycodone, oxymoφhone, papaveretum, pentazocine, pethidine, phenadoxone, phenomoφhan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, or tilidine.
85. The method of claim 83, wherein said pain is chronic pain. \
86. The method of claim 85, wherein said chronic pain is neuropathic pain.
87. The method of claim 83, wherein said pain is acute pain.
88. The method of claim 83, wherein said opioid is administered in a subtherapeutically effective amount.
89. The method of claim 83, wherein said opioid is moφhine.
90. The method of claim 88, wherein said combination comprises between about 15:1 and 5:1 bupropion to moiphine.
91. The method of claim 83, wherein 0.001 to 25 mg/kg per day of said opioid is administered.
92. The method of claim 91, wherein 0.005 to 10 mg/kg per day of said opioid is administered.
93. The method of claim 83, wherein said method comprises administering to a human in need thereof a combination consisting essentially of (i) an opioid and (ii) bupropion, wherein said combination is administered in a therapeutically effective amount.
94. A method of reducing the side effects of opioid treatment, said method comprising administering to a subject in need thereof a combination of (i) an opioid and (ii) bupropion, wherein said combination is administered in a therapeutically effective amount to treat pain or nociception, and wherein a side effect associated with said opioid is reduced.
95. The method of claim 94, wherein said side effect is nausea, emesis, sedation, mental confusion, lightheadedness, hyperalgesia, urinary retention, respiratory depression, pruritus, miosis, hallucinations, constipation, myoclonic seizures, euphoria, excitation, dysphoria, hypotension, tolerance, or dependence.
96. The method of claim 94, wherein said opioid is moφhine.
97. The method of claim 96, wherein said combination comprises between about 15: 1 and 5:1 bupropion to moiphine.
98. The method of claim 94, wherein said subject is a human.
99. The method of claim 94, wherein 0.001 to 25 mg/kg per day of said opioid is administered.
100. The method of claim 99, wherein 0.005 to 10 mg/kg per day of said opioid is administered.
101. The method of claim 94, wherein said method comprises administering to said subject a combination consisting essentially of (i) an opioid and (iii) bupropion, wherein said combination is administered in a therapeutically effective amount.
102. A pharmaceutical composition comprising (i) an opioid and (ii) bupropion.
103. The pharmaceutical composition of claim 102, further comprising a pharmaceutically acceptable carrier.
104. The pharmaceutical composition of claim 102, wherein said opioid is present in a subtherapeutically effective amount.
105. The pharmaceutical composition of claim 102, wherein said opioid is moφhine.
106. The pharmaceutical composition of claim 105, comprising between about 15:1 and 5:1 bupropion to moφhine.
107. The pharmaceutical composition of claim 102, wherein said composition consists essentially of (i) an opioid and (ii) bupropion.
108. A kit comprising a (i) combination of an opioid and bupropion, and (ii) instructions for administering said combination to treat pain or nociception.
109. The kit of claim 108, wherein said opioid is present in a subtherapeutically effective amount.
110. The kit of claim 108, wherein said opioid is moφhine.
111. The kit of claim 110, wherein said combination comprises between about 15: 1 and 5:1 bupropion to moφhine.
112. The kit of claim 108, wherein said instructions comprise administering 0.001 to 25 mg/kg per day of said opioid.
113. The kit of claim 112, wherein said instructions comprise administering 0.005 to 10 mg/kg per day of said opioid.
114. The kit of claim 108, wherein said kit comprises a (i) combination consisting essentially of an opioid and bupropion, and (ii) instructions for administering said combination to treat pain or nociception.
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