Methods and compositions for treating pain

Abstract

The invention features combinations of dopaminergic agents and analgesic agents useful for treating pain. In particular, the combinations feature a low ratio of dopaminergic agent to analgesic agent. The dopaminergic agent can be an agonist of the dopamine receptor D1-like family or the dopamine receptor D2-like family. Such combinations potentiate analgesia to 1) alleviate acute pain, 2) prevent the transition from acute pain to chronic pain, and 3) manage chronic pain.

1 . A pharmaceutical composition comprising a dopaminergic agent and an analgesic agent in a ratio of about 1:1000 to about 1:2. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . The composition of  claim 1 , wherein the composition comprises the dopaminergic agent and the analgesic agent in a ratio of about 1:150 to about 1:15. 
     
     
         5 . The composition of  claim 1 , wherein the dopaminergic agent is a dopamine receptor agonist or a precursor thereof or is a D1 agonist, a D2 agonist, or a combination thereof. 
     
     
         6 . (canceled) 
     
     
         7 . The composition of  claim 5 , wherein the D1 agonist is levodopa, the D2 agonist is pramipexole or carbidopa, or the dopaminergic agent comprises levodopa and carbidopa. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . The composition of  claim 1 , wherein the analgesic agent is paracetamol, an anticonvulsant, or a non-steroidal anti-inflammatory drug (NSAID). 
     
     
         11 . (canceled) 
     
     
         12 . The composition of  claim 10 , wherein:
 i) the anticonvulsant is selected from the group consisting of pregabalin, lamotrigine, topiramate, oxcarbazepine, tiagabine, levetiracetam, zonisamide, phenytoin, carbamazepine, gabapentin, and ethosuximide; or   ii) the NSAID is selected from the group consisting of naproxen, aceclofenac, acemetacin, acetaminophen, aloxiprin, aspirin, benorilate, bromfenac, celecoxib, deracoxib, diclofenac, diflunisal, ethenzamide, etodolac, etofenamate, etoricoxib, fenbufen, fenoprofen, flufenamic acid, flurbiprofen, lonazolac, lornoxicam, ibuprofen, indomethacin, isoxicam, kebuzone, ketoprofen, ketorolac, licofelone, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizol, mofebutazone, naproxen, nabumetone, niflumic acid, nimesulide, oxaprozin, oxyphenbutazone, parecoxib, phenidone, phenylbutazone, piroxicam, propacetamol, propyphenazone, rofecoxib, salicylamide, sulfinpyrazone, sulindac, suprofen, tiaprofenic acid, tenoxicam, tolmetin, or valdecoxib.   
     
     
         13 - 15 . (canceled) 
     
     
         16 . The composition of  claim 12 , wherein the analgesic agent is naproxen, and wherein:
 i) the dopaminergic agent is levodopa and the ratio of levodopa to naproxen is about 1:20;   ii) the dopaminergic agent is levodopa and the ratio of levodopa to naproxen is about 1:100;   iii) the dopaminergic agent is pramipexole and the ratio of pramipexole to naproxen is about 1:150;   iv) the dopaminergic agent is pramipexole or carbidopa; or   v) the dopaminergic agent is carbidopa and levodopa, and the ratio of carbidopa to levodopa to naproxen is about 1:4:80, respectively.   
     
     
         17 - 21 . (canceled) 
     
     
         22 . The composition of  claim 1 , wherein the composition comprises an amount of the dopaminergic agent in the range of about 0.001 mg to about 1000 mg, an amount of the analgesic agent in the range of about 0.01 mg to about 5000 mg, an additional therapeutic agent, or a pharmaceutically acceptable carrier or excipient. 
     
     
         23 - 26 . (canceled) 
     
     
         27 . The composition of  claim 1 , wherein the composition is:
 i) formulated to be administered intravenously, intramuscularly, intravitreally, ocularly, intraocularly, itraorbitally, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, intratumorally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, orally, topically, by inhalation, by injection, by implantation, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in creams, or in lipid compositions;   ii) a liquid;   iii) a solid   iv) formulated for sustained release; or   v) is present in or on an implanted device.   
     
     
         28 - 31 . (canceled) 
     
     
         32 . A method of reducing pain in a subject, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a dopaminergic agent and an analgesic agent in a ratio of about 1:1000 to about 1:2. 
     
     
         33 . The method of  claim 32 , wherein:
 i) the subject is at risk for experiencing pain;   ii) the dopaminergic agent comprises a D1 agonist, a D2 agonist, or a combination thereof;   iii) the analgesic agent is an NSAID, paracetamol, or an anticonvulsant;   iv) the pain is acute pain;   v) the dopaminergic agent comprises a D1 agonist;   vi) the pain is chronic pain;   vii) the dopaminergic agent and the analgesic agent are administered at least once or twice per day, week, month, or year;   viii) the ratio of the dopaminergic agent to the analgesic agent is between about 1:100 and 1:4;   ix) the dopaminergic agent or the analgesic agent is administered in an amount of about 0.01 mg to about 10,000 mg per dose;   x) the dopaminergic agent or the analgesic agent is administered in an amount of about 20 mg to about 500 mg per dose;   xi) the dopaminergic agent or the analgesic agent is administered for a period of time effective to reduce pain;   xii) the dopaminergic agent of the analgesic agent further comprise a pharmaceutically acceptable carrier or excipient;   xiii) the method further comprises administering an additional therapeutic agent, wherein the additional therapeutic agent comprises an antiemetic agent, an antidepressant, an anti-inflammatory agent, a chemotherapeutic agent, a steroid, or a muscle relaxant; or   xiv) the subject is a human.   
     
     
         34 - 36 . (canceled) 
     
     
         37 . The method of  claim 32 , wherein:
 i) the analgesic agent is an anticonvulsant selected from the group consisting of pregabalin, lamotrigine, topiramate, oxcarbazepine, tiagabine, levetiracetam, zonisamide, phenytoin, carbamazepine, gabapentin, and ethosuximide;   ii) the analgesic agent is an NSAID selected from the group consisting of naproxen, aceclofenac, acemetacin, acetaminophen, aloxiprin, aspirin, benorilate, bromfenac, celecoxib, deracoxib, diclofenac, diflunisal, ethenzamide, etodolac, etofenamate, etoricoxib, fenbufen, fenoprofen, flufenamic acid, flurbiprofen, lonazolac, lornoxicam, ibuprofen, indomethacin, isoxicam, kebuzone, ketoprofen, ketorolac, licofelone, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizol, mofebutazone, nabumetone, niflumic acid, nimesulide, oxaprozin, oxyphenbutazone, parecoxib, phenidone, phenylbutazone, piroxicam, propacetamol, propyphenazone, rofecoxib, salicylamide, sulfinpyrazone, sulindac, suprofen, tiaprofenic acid, tenoxicam, tolmetin, and valdecoxib;   iii) the administering occurs prior to the onset of acute pain; or   iv) the administering occurs after the onset of acute pain.   
     
     
         38 - 41 . (canceled) 
     
     
         42 . The method of  claim 32 , wherein the pain is acute pain, and wherein the administering occurs no earlier than two months prior to the onset of the acute pain or no later than 3 months after the onset of the acute pain. 
     
     
         43 - 49 . (canceled) 
     
     
         50 . The method of  claim 33 , wherein the D1 agonist is levodopa. 
     
     
         51 . The method of  claim 42 , wherein:
 i) the subject is additionally at risk for developing chronic pain; or   ii) the method prevents the transition from said acute pain to chronic pain.   
     
     
         52 . (canceled) 
     
     
         53 . The method of  claim 51 , wherein the dopaminergic agent comprises levodopa and carbidopa. 
     
     
         54 . The method of  claim 53 , wherein the ratio of levodopa to carbidopa to the analgesic agent is about 1:4:80, respectively. 
     
     
         55 . (canceled) 
     
     
         56 . The method of  claim 32 , wherein the pain is chronic pain and wherein:
 i) the chronic pain is peripheral neuropathic pain, post-herpetic neuralgia, diabetic neuropathic pain, neuropathic cancer pain, failed back-surgery syndrome, trigeminal neuralgia, phantom limb pain, central neuropathic pain, multiple sclerosis related pain, Parkinson disease-related pain, post-stroke pain, post-traumatic spinal cord injury pain, pain from dementia, musculoskeletal pain, osteoarthritic pain, fibromyalgia syndrome, inflammatory pain, rheumatoid arthritis, endometriosis, migraine, cluster headache, tension headache syndrome, facial pain, headache caused by other diseases, visceral pain, interstitial cystitis, irritable bowel syndrome, chronic pelvic pain syndrome, lower back pain, neck and shoulder pain, burning mouth syndrome, or complex regional pain syndrome;   ii) the ratio of the dopaminergic agent to the analgesic agent is between about 1:600 and 1:30;   iii) the dopaminergic agent comprises a D2 agonist; or   iv) the administering is for a period of time of at least 4 months.   
     
     
         57 - 59 . (canceled) 
     
     
         60 . The method of  claim 56 , wherein the D2 agonist is pramipexole or carbidopa. 
     
     
         61 - 65 . (canceled) 
     
     
         66 . The method of  claim 33 , wherein the additional therapeutic agent is administered:
 i) at a different time from the dopaminergic agent or the analgesic agent;   ii) at the same time as the dopaminergic agent or the analgesic agent;   iii) through a different route from the dopaminergic agent or the analgesic agent; or   iv) through the same route as the dopaminergic agent or the analgesic agent.   
     
     
         67 - 80 . (canceled) 
     
     
         81 . A kit comprising the pharmaceutical composition of  claim 1 , wherein the kit further comprises instructions for administering said composition to a subject at risk of acute or chronic pain, having acute or chronic pain, or at risk of transitioning from acute pain to chronic pain. 
     
     
         82 . (canceled)