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`Title of Invention
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`USE OF ZOLEDRONIC ACID AND RELATED COMPOUNDS FOR THE
`TREATMENT OF PAIN
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`The invention was made by an agency of the United States Government or under a contract with an agency of the United
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`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (11-08)
`Approved for use through 09/30/2010 OMB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
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`/Herriot Tabuteau/
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`Date (YYYY-MM-DD)
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`2013-02-14
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`Herriot
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`Tabuteau
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`

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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Utility Patent Application (Provisional)
`
`USE OF ZOLEDRONIC ACID AND RELATED COMPOUNDS FOR THE TREATMENT OF PAIN
`
`Inventor: Herriot Tabuteau
`
`Correspondence Address:
`Herriot Tabuteau
`401 East 64th Street, Apt. 4D
`New York, NY 10065
`
`BACKGROUND OF THE INVENTION
`Complex regional pain syndrome type I (CRPS-I), also known as reflex sympathetic dystrophy
`(RSD)„ and complex regional pain syndrome type II (CRPS-H), also known as causalgia, are debilitating
`pain syndromes. They are characterized by severe pain in a limb accompanied by allodynia,
`hyperalgesia, edema, changes in skin blood flow and abnormal sudomotor activity.
`These disorders are often difficult to treat and there exists a need for additional therapeutic
`options.
`
`DESCRIPTION OF THE INVENTION
`Disclosed are pharmaceutical compositions and methods for the treatment of any type of pain
`including, but not limited to, postoperative pain, cancer pain, arthritic pain, lumbosacral pain,
`musculoskeletal pain, neuropathic pain, chronic pain, etc.
`Disclosed are pharmaceutical compositions and methods for the treatment of complex regional
`pain syndrome type I and type II (CRPS-I and CRPS-II).
`One embodiment is a pharmaceutical composition comprising pamidronate„ neridronate,
`olpadronate, alendronate, incadronate, ibandronate, risedronate, zoledronate or another
`bisphosphonate compound for the treatment of pain.
`Another embodiment is a pharmaceutical composition comprising pamidronate, neridronate,
`olpadronate, alendronate, incadronate, ibandronate, risedronate, zoledronate or another
`bisphosphonate compound for the treatment of CRPS-I and CRPS-II.
`The terms pamidronate, neridronate, olpadronate, alendronate, incadronate, ibandronate,
`risedronate, zoledronate, or another bisphosphonate compound, as used in this application refer to
`these compounds or their pharmaceutically acceptable salts, and any of their polymorphic forms.
`Other names for pamidronate, neridronate, olpadronate, alendronate, incadronate,
`ibandronate, risedronate, and zoledronate may include but are not limited to pamidronic acid,
`neridronic acid, olpadronic acid, alendronic acid, incadronic acid, ibandr nic add, risedronic acid, and
`zoledronic add, respectively.
`Another embodiment is a method for the treatment of treatment of pain comprising
`administering to an individual pamidronate, neridronate, olpadronate, alendronate, incadronate,
`ibandronate, risedronate, zoledronate or another bisphosphonate compound.
`Yet another embodiment is a method for the treatment of treatment of CRPS-I and CRPS-H
`comprising administering to an individual pamidronate, neridronate, olpadronate, alendronate,
`incadronate, ibandronate, risedronate, zoledronate or another bisphosphonate compound.
`
`Page 1 of 8
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`4
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`Any suitable route of administration may be employed for providing an individual with an
`effective dosage of the pamidronate, neridronate, olpadronate, alendronate, incadronate, ibandronate,
`risedronate, zoledronate or another bisphosphonate compound. For example, oral, rectal, parenteral,
`transdermal, sublingual, subcutaneous, intrathecal, intramuscular and the like may be employed as
`appropriate.
`Dosage forms for the pamidronate, neridronate, olpadronate, alendronate, incadronate,
`ibandronate, risedronate zoledronate or another bisphosphonate compound in the present
`embodiments include but are not limited to tablets, coated tablets, cachets, capsules, caplets, troches,
`dispersions, sustained release formulations, suspensions, solutions, patches and the like.
`In addition to the common dosage forms set forth above, the pamidronate, neridronate,
`olpadronate, alendronate, incadronate, ibandronate, risedronate, zoledronate or another
`bisphosphonate compound may also be administered by controlled release or sustained release means
`and/or delivery devices.
`The effective amount of pamidronate, neridronate, olpadronate, alendronate, incadronate,
`ibandronate, risedronate , zoledronate or another bisphosphonate compound in the treatment of pain,
`CRPS-1 and CRPS-II will vary depending on various factors known to the treating physicians, such as the
`severity of the condition to be treated, route of administration, formulation and dosage forms, physical
`characters of the pamidronate, neridronate, olpadronate, alendronate, incadronate, ibandronate,
`risedronate , zoledronate or another bisphosphonate compound used, and age, weight and response of
`the individual patients.
`In some embodiments the daily oral dose of pamidronate is about 10 mg to about 1,000 mg,
`about 50 mg to about 500 mg, about 100 mg to about 500 mg, or about 150 mg to about 300 mg. In
`some embodiments the parenteral dose of pamidronate is about 5 mg to about 500 mg, about 5 mg to
`about 200 rng, or about 10 mg to about 150 mg.
`In some embodiments the daily oral dose of neridronate is about 10 mg to about 1,000 mg,
`about 50 mg to about 500 mg, about 100 mg to about 500 mg, or about 150 rng to about 300 mg. In
`some embodiments the parenteral dose of neridronate is about 5 rng to about 500 mg, about 5 rng to
`about 200 rng, or about 10 mg to about 150 mg.
`In some embodiments the daily oral dose of olpadronate is about 0.5 mg to about 400 mg,
`about 1 mg to about 300 rng, about 5 mg to about 100 rng, or about 2 mg to about 50 mg. In some
`embodiments the parenteral dose of olpadronate is about 1 rng to about 100 mg, about 1 rng to about
`40 mg, or about 2 mg to about 30 mg.
`In some embodiments the daily oral dose of alendronate is about 0.5 mg to about 400 mg,
`about 1 mg to about 200 mg, about 5 mg to about 100 mg, or about 2 mg to about 50 mg. In some
`embodiments the parenteral dose of alendronate is about 1 mg to about 100 mg, about 1 mg to about
`40 mg, or about 2 mg to about 30 mg.
`In some embodiments the daily oral dose of incadronate is about 0.5 mg to about 400 mg, about
`1 mg to about 300 mg, about 5 mg to about 100 mg, or about 2 mg to about 50 mg, In some
`embodiments the parenteral dose of incadronate is about 1 mg to about 100 mg, about 1 mg to about
`40 mg, or about 2 mg to about 30 rng.
`In some embodiments the daily oral dose of ibandronate is about 0.25 mg to about 100 mg,
`about 0.5 rng to about 50 mg, about 2.5 mg to about 50 mg, or about 1 mg to about 25 mg. In some
`embodiments the parenteral dose of ibandronate is about 0.5 mg to about 50 mg, about 0.5 mg to
`about 20 mg, or about 1 mg to about 15 rng.
`In some embodiments the daily oral dose of risedronate is about 0.25 mg to about 100 mg,
`about 0.5 rng to about 50 mg, about 2.5 mg to about 50 mg, or about 1 mg to about 25 mg. In some
`embodiments the parenteral dose of risedronate is about 0.25 rng to about 25 mg, about 0.25 mg to
`about 10 mg, or about 0.5 mg to about 7.5 mg.
`
`Page 2 of 8
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`In some embodiments the daily oral dose of zoledronate is about 0.005 mg to about 20 mg,
`about 0.1 mg to about :10 mg, about 0.5 mg to about 10 mg, or about 0.2 mg to about 5 mg. in some
`embodiments the parenterai dose of zoledronate is about 0.25 mg to about 25 mg, about 0.25 mg to
`about 10 mg, or about 0.5 mg to about 7.5 mg.
`Some embodiments include orally administering zoledronic acid in a form such as the disodium
`salt. Any suitable amount of zoledronic acid or disodium salt of zoledronic acid may be used, such as
`about 10 mg to about 500 mg, about 20 mg to about 200 mg, about 50 mg to about 150 mg, about 50
`mg, about 100 mg, or about 150 mg. In some embodiments, the oral zoledronic acid is administered
`daily, weekly, monthly, once a year, or twice a year. The oral zoledronic acid, or disodium salt thereof,
`may be administered in combination with about 0.1 to about 10 mg of zoledronic acid, or a salt thereof,
`administered intravenously. In some embodiments, about 50 mg, about 100 mg, or about 150 mg of the
`disodium salt of zoledronic acid is administered orally in combination with 1 mg intravenous zoledronic
`acid.
`
`Some oral dosage forms comprising zoledronic acid or a salt thereof may have enteric coatings.
`In some embodiments, the pamidronate, neridronate, olpadronate, alendronate„ incadronate,
`ibandronate, risedronate , zoledronate or another bisphosphonate compound can be given weekly,
`monthly, every two or three months, once a year or twice a year.
`In some embodiments the weekly oral dose of pamidronate is about 70 mg to about 7„000
`about 350 mg to about 3„500 mg, about 700 mg to about 3„500 mg„ or about 1,000 mg to about 2„000
`mg. In some embodiments the monthly oral dose of pamidronate is about 300 mg to about 30,000 mg,
`about 1,500 mg to about 15,000 mg, about 3,000 mg to about 15,000 mg, or about 4,000 mg to about
`8,000 mg.
`In some embodiments the weekly oral dose of neridronate is about 70 mg to about 7,000 mg,
`about 350 mg to about 3500 mg, about 700 mg to about 3,500 mg, or about 1,000 mg to about 2,000
`mg. In some embodiments the monthly oral dose of neridronate is about 300 mg to about 30,000 mg,
`about 1,500 mg to about 15,000 mg, about 3,000 mg to about 15,000 mg, or about 4,000 mg to about
`8,000 mg.
`In some embodiments the weekly oral dose of olpadronate is about 3.5 mg to about 2,800 mg,
`about 7 mg to about 2,100 rng, about 35 mg to about 700 rng, or about 15 mg to about 350 mg. In some
`embodiments the monthly oral dose of olpadronate is about 15 mg to about 11,000 mg, about 30 rng to
`about 8,500 rng, about 150 rng to about 2,800 mg, or about 60 mg to about 1,500 mg.
`In some embodiments the weekly oral dose of alendronate is about 3.5 mg to about 2,800 mg,
`about 7 mg to about 2,100 mg, about 35 mg to about 700 mg, or about 15 mg to about 350 mg. In some
`embodiments the monthly oral dose of alendronate is about 15 mg to about 11,000 mg, about 30 mg to
`about 8,500 mg, about :150 mg to about 2,800 mg, or about 60 mg to about 1,500 mg.
`In some embodiments the weekly oral dose of incadronate is about 3.5 mg to about 2,800 mg,
`about 7 mg to about 2,100 mg, about 35 mg to about 700 mg, or about 15 mg to about 350 mg. In some
`embodiments the monthly oral dose of incadronate is about 15 mg to about 11„000 mg, about 30 mg to
`about 8,500 mg, about 150 mg to about 2,800 mg, or about 60 mg to about 1,500 mg.
`In some embodiments the weekly oral dose of ibandronate is about 1.75 mg to about 700 mg,
`about 3.5 mg to about 350 mg, about 18 mg to about 350 mg, or about 7 mg to about 175 mg. In some
`embodiments the monthly oral dose of ibandronate is about 7 mg to about 2,800 mg, about 15 mg to
`about 1,500 mg, about 70 mg to about 1,500 mg, or about 30 mg to about 700 mg.
`In some embodiments the weekly oral dose of risedronate is about 1.75 mg to about 700 mg,
`about 3.5 mg to about 350 mg, about 18 mg to about 350 mg, or about 7 rng to about 175 mg. In some
`embodiments the monthly oral dose of risedronate is about 7 mg to about 2,800 mg, about 15 rng to
`about 1,500 mg, about 70 mg to about 1,500 mg, or about 30 mg to about 700 mg.
`
`Page 3 of 8
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`In some embodiments the weekly oral dose of zoledronate is about 1 mg to about 500 mg,
`about 10 mg to about 250 mg, about 20 mg to about 150 mg, or about 30 mg to about 100 mg. In some
`embodiments the monthly oral dose of zoledronate is about 1 mg to about 1,000 mg, about 10 mg to
`about 600 mg, about 50 mg to about 500 mg, or about 100 mg to about 500 mg.
`The dose of pamidronate, neridronate, olpadronate„ alendronate, incadronate, ibandronate,
`risedronate, zoledronate or another bisphosphonate compound may be administered in a single or
`divided dose.
`
`Example 1. Treatment of complex regional pain syndrome with zoledronic acid.
`
`The effect of zoledronic acid in a rat fracture model of complex regional pain syndrome (CRPS) is
`examined. Tibia fracture and cast immobilization of rats to produce the CRPS model is performed as
`described in Wei et al. J Neuroinflammation 2012; 9: 181. This paper is attached as Exhibit A. The
`resulting animals are treated with vehicle (placebo) or varying doses of orally administered zoledronic
`acid according to the table below. The animals are tested for nociception (pain) also as described in Wei
`et al. 2012 (Exhibit A) and sometimes using other methods, When the experiment is done, the animals
`treated with zoledronic acid display less nociception including less mechanical allodynia and
`unweighting than the placebo-treated animals. The animals treated with zoledronic acid display less
`edema than the placebo-treated animals.
`
`Table of Doses
`
`Animals 1-5
`
`Vehicle (placebo)
`
`Animals 6-10
`
`0.1 mcg/kg/day
`
`Animals 11-15
`
`0.2 mcg/kg/day
`
`Animals 16-20
`
`0.5 mcg/kg/day
`
`Animals 21-25
`
`1 mcg/kg/day
`
`Animals 26-30
`
`5 rncg/kg/day
`
`Animals 31-35
`
`10 mcg/kg/day
`
`Animals 36-40
`
`20 mcg/kg/day
`
`Animals 41-45
`
`40 mcg/kg/daY
`
`Animals 46-50
`
`60 mcg/kg/daY
`
`Animals 51-55
`
`100 mcg/kg/day
`
`Animals 56-60
`
`500 mcg/kg/day
`
`Animals 61-65
`
`Animals 66-70
`
`1000 mcg/kg/day
`2000 mcg kg day
`
`Animals 71-75
`
`4000 mcg keday
`
`Animals 76-80
`
`6000 mcg/kg/day
`
`Animals 81-85
`
`2.5 mcg/kg once
`
`Animals 86-90
`
`25 mcg/kg once
`
`Animals 91-95
`
`250 mcg/kg once
`
`Animals 96-100
`
`2500 mcg/kg once
`
`Animals 101-105
`
`25000 mcg/kg once
`
`Animals 106-110
`
`50000 mcg/kg once
`
`Animals 111-115
`
`100000 mcg/kg once
`
`Page 4 of 8
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`

`Animals 116420
`
`0.7 mcg/kg once weekly
`
`Animals 121425
`
`1.4 mcg/kg once weekly
`
`Animals 126430
`
`3.5 mcg/kg once weekly
`
`Animals 131-135
`
`7 mcg/kg once weekly
`
`Animals 136-140
`
`35 mcg/kg once weekly
`
`Animals 141-145
`
`70 mcg/kg once weekly
`
`Animals 146-150
`
`140 mcg/kg once weekly
`
`Animals 151-155
`
`280 mcg/kg once weekly
`
`Animals 156-160
`
`420 mcg/kg once weekly
`
`Animals 161-165
`
`700 mcg/kg once weekly
`
`Animals 166-170
`
`3500 mcg/kg once weekly
`
`Animals 171-175
`
`7000 mcg/kg once weekly
`
`Animals 176-180
`
`14000 mcg/kg once weekly
`
`Animals 181-185
`
`28000 mcg/kg once weekly
`
`Animals 186-190
`
`42000 mcg/kg once weekly
`
`Example 2. Treatment of complex regional pain syndrome with zoledronic acid.
`
`The experiment is conducted as in Example 1, except that the doses are administered
`intravenously. When the experiment is done, the animals treated with zoledronic acid display less
`nociception including less mechanical allodynia and unweighting than the placebo-treated animals. The
`animals treated with zoledronic acid display less edema than the placebo-treated animals.
`
`Example 3. Treatment of complex regional pain syndrome with zoledronic acid.
`
`The experiment is conducted as in Example 1, except that the doses are administered
`subcutaneously. When the experiment is done, the animals treated with zoledronic acid display less
`nociception including less mechanical allodynia and unweighting than the placebo-treated animals. The
`animals treated with zoledronic acid display less edema than the placebo-treated animals.
`
`Example 4. Treatment of complex regional pain syndrome with zoledronic acid.
`
`The experiment is conducted as in Example 1, except that the doses are administered
`intrathecally. When the experiment is done, the animals treated with zoledronic acid display less
`nociception including less mechanical allodynia and unweighting than the placebo-treated animals. The
`animals treated with zoledronic acid display less edema than the placebo-treated animals.
`
`Example 5. Treatment of complex regional pain syndrome with zoledronic acid.
`
`The experiment is conducted as in Example 1, except that the doses are administered
`intraperitoneally. When the experiment is done, the animals treated with zoledronic acid display less
`nociception including less mechanical allodynia and unweighting than the placebo-treated animals. The
`animals treated with zoledronic acid display less edema than the placebo-treated animals.
`
`Example 6. Treatment of complex regional pain syndrome with zoledronic acid.
`
`Page 5 of 8
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`

`

`The experiment is conducted as in Example 1, except that the daily doses are administered on
`days 1, 2, 5, 7, 9, 12, 14, 16 and 19. When the experiment is done, the animals treated with zoledronic
`acid display less nociception including less mechanical allodynia and unweighting than the placebo-
`treated animals. The animals treated with zoledronic acid display less edema than the placebo-treated
`animals.
`
`CLAIMS
`
`1, A pharmaceutical composition comprising either parnidronate, neridronate, olpadronate,
`alendronate, incadronate, ibandronate, risedronate, zoledronate or another bisphosphonate
`compound for the treatment of pain.
`2. A method for the treatment of pain comprising administering to an individual either
`pamidronate, neridronate, olpadronate, alendronate, incadronate, ibandronate, risedronate,
`zoledronate or another bisphosphonate compound.
`3. The composition according to claim 1 where the weekly oral dose of pamidronate is about 1,000
`mg to about 2,000 mg.
`4. The composition according to claim 1 where the weekly oral dose of neridronate is about 1,000
`mg to about 2,000 mg.
`5. The composition according to claim 1 where the weekly oral dose of alendronate is about 15 mg
`to about 350 mg.
`6. The composition according to claim 1 where the weekly oral dose of incadronate is about 15 mg
`to about 350 mg.
`7. The composition according to claim 1 where the weekly oral dose of olpadronate is about 15 mg
`to about 350 mg.
`8. The composition according to claim 1 where the weekly oral dose of ibandronate is about 7 mg
`to about 175 mg.
`9. The composition according to claim 1 where the weekly oral dose of risedronate is about 7 mg
`to about 17.5 mg.
`10. The composition according to claim 1 where the weekly oral dose of zoledronate is about 10 mg
`to about 250 mg.
`11. The method according to claim 2 where the weekly oral dose of pamidronate is about 1,000 mg
`to about 2,000 mg.
`12. The method according to claim 2 where the weekly oral dose of neridronate is about 1,000 mg
`to about 2,000 mg.
`13. The method according to claim 2 where the weekly oral dose of alendronate is about 15 mg to
`about 350 mg.
`14. The method according to claim 2 where the weekly oral dose of incadronate is about 15 mg to
`about 350 mg.
`15, The method according to claim 2 where the weekly oral dose of olpadronate is about 15 mg to
`about 350 mg.
`16, The method according to claim 2 where the weekly oral dose of ibandronate is about 7 mg to
`about :1.75 mg.
`17, The method according to claim 2 where the weekly oral dose of risedronate is about 7 mg to
`about 175 mg.
`18, The method according to claim 2 where the weekly oral dose of zoledronate is about 10 mg to
`about 250 mg.
`
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`19. A pharmaceutical composition comprising either pamidronate, neridronate, olpadronate,
`alendronate„ incacironate, ibandronate, risedronate, zoledronate or another bisphosphonate
`compound for the treatment of CRPS-lor CRPS-H.
`20. A method for the treatment of CRP5-1 or CRPS-H comprising administering to an individual either
`pamidronate, neridronate, olpadronate, alendronate, incadronate, ibandronate, risedronate,
`zoledronate or another bisphosphonate compound.
`21. The composition according to claim 19 where the weekly oral dose of pamidronate is about
`1,000 mg to about 2,000 mg.
`22. The composition according to claim 19 where the weekly oral dose of neridronate is about 1,000
`mg to about 2,000 mg.
`23. The composition according to claim 19 where the weekly oral dose of alendronate is about 15
`mg to about 350 mg.
`24. The composition according to claim 19 where the weekly oral dose of incadronate is about 15
`mg to about 350 mg.
`25. The composition according to claim 19 where the weekly oral dose of olpadronate is about 15
`mg to about 350 mg.
`26, The composition according to claim 19 where the weekly oral dose of ibandronate is about 7 mg
`to about 175 mg,
`27, The composition according to claim 19 where the weekly oral dose of risedronate is about 7 mg
`to about 175 mg,
`28, The composition according to clairn 19 where the weekly oral dose of zoledronate is about 10
`mg to about 250 mg.
`29, The method according to claim 20 where the weekly oral dose of pamidronate is about 1,000
`mg to about 2,000 mg.
`30, The method according to claim 20 where the weekly oral dose of neridronate is about 1,000 mg
`to about 2,000 mg.
`31. The method according to claim 20 where the weekly oral dose of alendronate k about 15 mg to
`about 350 mg.
`32. The method according to claim 20 where the weekly oral dose of incadronate is about 15 mg to
`about 350 mg.
`33. The method according to claim 20 where the weekly oral dose of olpadronate is about 15 mg to
`about 350 mg.
`34. The method according to claim 20 where the weekly oral dose of ibandronate is about 7 mg to
`about 175 mg.
`35. The method according to claim 20 where the weekly oral dose of risedronate is about 7 mg to
`about 175 mg.
`36. The method according to claim 20 where the weekly oral dose of zoledronate is about 10 mg to
`about 250 mg.
`
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`EXHIBIT A
`EXHIBIT A
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`Page 8 of 8
`Page 8 of 8
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`Wei et at Journal of Neuroinflammation 2012, 9:181
`http:llwww.jneurointlarrirnation.com/content/9/1/181
`
`JOURNAL. OF
`NEUROINFLAMMATION
`
`Keratinocyte expression of inflammatory
`mediators plays a crucial role in substance
`P-induced acute and chronic pain
`
`Tzuping Wei', Tian-Zhi Guo', Wen-Wu Li (cid:9)
`
`Saiyun Hou l , Wade S Kingery' and John David Clark2'3*
`
`Abstract
`
`Tibia fracture in rats followed by cast immobilization leads to nociceptive, trophic, vascular and bone-related
`changes similar to those seen in Complex Regional Pain Syndrome (CRPS). Substance P (SP) mediated neurogenic
`inflammation may be responsible for some of the signs of CRPS in humans. We therefore hypothesized that SP
`acting through the SP receptor (NK1) leads to the CRPS-like changes found in the rat model. In the present study,
`we intradermally injected rats with SP and monitored hindpaw mechanical allodynia, temperature, and thickness as
`interieukin 6 (IL-6), and nerve growth
`well as tissue levels of tumor necrosis factor-a (TNIF-a), interleukin 1 R (IL-.1 (cid:9)
`factor-i3 (NGF) for 72 h. Anti-NGF antibody was utilized to block the effects of SP-induced NGF up-regulation.
`Fracture rats treated with the selective NK1 receptor antagonist LY303870 prior to cast removal were assessed for
`BrdU, a DNA synthesis marker, incorporation in skin cells to examine cellular proliferation. Bone microarchitecture
`was measured using micro computed tomography (pal. We observed that: (1) SP intraplantar injection induced
`mechanical allodynia, warmth and edema as well as the expression of nociceptive mediators in the hindpaw skin
`of normal rats, (2) LY303870 administered intraperitoneally after fracture attenuated allodynia, hindpaw unweighting,
`warmth, and edema, as well as cytokine and NGF expression, (3) LY303870 blocked fracture-induced epidermal
`thickening and BrdU incorporation after fracture; (4) anti--NGF antibody blocked SP-induced allodynia but riot
`warmth or edema, and (5) LY303870 had no effect on bone microarchitecture. Collectively our data indicate that
`SP acting through NK1 receptors supports the nociceptive and vascular components of CRPS, but riot the
`bone-related changes.
`
`Introduction
`Complex regional pain syndrome (CRPS) is a painful,
`disabling and often chronic condition affecting the ex-
`tremities and is a frequent sequela of tibial and radial
`fractures [1]. Previously we described a distal tibial frac-
`ture model in rats that exhibits chronic unilateral hind-
`limb warmth, edema, facilitated spontaneous protein
`extravasation, allodynia, postural unweighting, and per--
`articular osteoporosis [2]. These post-fracture changes
`closely resemble the clinical presentation of patients
`with acute CRPS,
`
`*Correspondence: diclark@stanford.edu
``Anesthesiology Service, Veterans .Affai