P
`WORLD magi;
`INTERNATKENIL APPLICATION PUBLISHEI
`
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`.
`w ‘m 1H ‘1!
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`i
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`
`(51) International Patent Classification 6 :
`
`,
`
`9602251A1.
`
`A61K 31/485
`
`..*- uauumu rumication Date:
`
`1 February 1996 (01.02.96)
`
`(21) International Application Number:
`
`PCP/US95/09974
`
`(22) International Filing Date:
`
`18 July 1995 (18.07.95)
`
`(81) Designated States: AU, CA, 1?, European patent (AT, BE,
`CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC. NL, PT,
`SE).
`
`Published
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(30) Priority Data:
`08/276,966
`
`19 July 1994 (19.07.94)
`
`US
`
`(71) Applicant: ALBERT EINSTEIN COLLEGE OF MEDICINE
`0F YESHIVA UNIVERSITY, a division of YESI-IIVA
`UNIVERSITY [US/US]; 1300 Morris Park Avenue, Bronx,
`NY 10461 (US).
`
`(72) Inventors: CRAIN, Stanley, M.; 10 Linden Terrace, Leonia,
`NJ 07605 (US). SHEN, Ke—Fei; 144-30 Sanford Avenue,
`Flushing, NY 11355 (US).
`
`(74) Agents: GEORGE, Kenneth, P. et al.; Amster, Rothstein &
`Ebenstein, 90 Park Avenue. New York, NY 10016 (US).
`
`opioid receptor antagonist of the invention and a bimodally-acting opioid agonist.
`
`(54) Title: METHOD OF SMULTANEOUSLY ENHANCING ANALGESIC POTENCY AND A'I'I'ENUATING DEPENDENCE
`LIABILITY CAUSED BY EXOGENOUS AND ENDOGENOUS OPIOID AGONISTS
`
`(57) Abstract
`
`This invention relates to a method of selectively enhancing the analgesic potency of morphine and other clinically used bimodally-
`acting opioid agonists and simultaneously attenuating development of physical dependence, tolerance and other undesirable side effects
`caused by the chronic administration of said bimodally-acting opioid agonists comprising the co-administration of a bimodally-acting opioid
`agonist which activates both inhibitory and excitatory opioid receptor-mediated functions of neurons in the nociceptive (pain) pathways of
`the nervous system and an opioid receptor antagonist which selectively inactivates excitatory opioid receptor-mediated side effects. This
`invention also relates to a method of using excitatory opioid receptor antagonists alone to block the undesirable excitatory side effects of
`endogenous bimodally-acting opioid agonists which may be markedly elevated during chronic pain. This invention further relates to a method
`of long-term treatment of previously detoxified opiate, cocaine and alcohol addicts utilizing said excitatory opioid receptor antagonists, either
`alone or in combination with low-dose methadone. to prevent protracted physical dependence, and to compositions comprising an excitatory
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`Viet Nam
`
`Mailman”in
`Malawi
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Slovenia
`Slovakia
`Senegal
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`United States of America
`Uzbekistan'
`
`AT
`AU
`33
`BE
`BF
`BG
`3.]
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`
`Austria
`Australia.
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`COte d'lvoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`

`

`WO 96/02251
`
`PCT/US95/09974
`
`METHOD OF SIMULTANEOUSLY ENHANCING ANALGESIC POTENCY
`AND ATTENUATING DEPENDENCE LIABILITY CAUSED BY
`EXOGENOUS AND ENDOGENOUS OPIOID AGONISTS
`
`Statement of Government Iflterest
`
`This invention was made with government support
`
`under NIDA research grant number DA 02031. As such,
`
`the
`
`government has certain rights in the invention.
`
`10
`
`CROSS-BEFEBENCE TO RELATED APPLICATIONS
`
`This Application is a Continuation-In-Part of
`
`Application Serial No. 08/097,460 filed July 27, 1993,
`
`entitled METHOD OF
`
`SIMULTANEOUSLY ENHANCING ANALGESIC
`
`15
`
`POTENCY AND ATTENUATING DEPENDENCE LIABILITY CAUSED BY
`
`MORPHINE AND OTHER OPIOID AGONISTS, currently pending,
`
`which is a Continuation-In-Part of Application Serial No.
`
`07/947,690 filed September 19, 1992, entitled A METHOD OF
`
`IDENTIFICATION OF NON-ADDICTIVE OPIOID ANALGESICS AND THE
`
`20
`
`USE OF SAID ANALGESICS FOR TREATMENT OF OPIOID ADDICTION,
`
`currently pending.
`
`D OF
`
`NV N
`
`O
`
`This invention relates to a method of enhancing
`
`25
`
`the analgesic (inhibitory) effects of bimodally-acting
`
`including morphine, codeine and other
`opioid agonists,
`clinically used opioid analgesics, while at the same time
`
`attenuating anti—analgesic effects, physical dependence,
`
`tolerance, hyperexcitability, hyperalgesia,
`
`and other
`
`30
`
`undesirable (excitatory) side effects typically caused by
`
`chronic
`
`use
`
`of
`
`bimodally-acting
`
`(excitatory
`
`and
`
`35
`
`the term
`inhibitory) opioid agonists. As used. herein,
`"opioid" refers to compounds which bind to specific opioid
`receptors and have agonist
`(activation) or antagonist
`(inactivation) effects at these receptors, such as opioid
`alkaloids,
`including
`the
`agonist morphine
`and
`the
`antagonist
`naloxone,
`and opioid peptides,
`including
`enkephalins, dynorphins and endorphins. As used herein,
`the term "opiate" refers to drugs derived from opium or
`
`40
`
`related analogs.
`
`

`

`WO 96/02251
`
`PCTIUS95/09974
`
`—2-
`
`In the instant invention, a very low dose of a
`
`selective
`
`excitatory opioid
`
`receptor
`
`antagonist
`
`is
`
`combined with a reduced dose of a bimodally-acting opioid
`
`agonist
`
`so
`
`as
`
`to enhance
`
`the degree
`
`of
`
`analgesia
`
`(inhibitory effects) and attenuate undesired side effects
`
`(excitatory effects).
`
`Opioid analgesia results from
`
`activation (by opioid agonists)
`
`of
`
`inhibitory opioid
`
`receptors on neurons in the nociceptive (pain) pathways of
`
`the
`
`peripheral
`
`and
`
`central
`
`nervous
`
`systems.
`
`The
`
`undesirable
`
`side
`
`effects,
`
`including
`
`anti-analgesic
`
`actions,
`
`hyperexcitability
`
`and
`
`hyperalgesia,
`
`the
`
`development of physical dependence,
`
`and some 'types of
`
`tolerance result from sustained activation (by bimodally-
`
`acting opioid agonists) of excitatory opioid receptors on
`
`neurons
`
`in the nociceptive
`
`(pain)
`
`pathways
`
`of
`
`the
`
`peripheral and central nervous systems.
`
`In addition,
`
`in
`
`the instant invention,
`
`long-term administration of ultra-
`
`low doses of the excitatory opioid receptor antagonists of
`
`the invention, either alone or
`
`in combination with low
`
`doses of conventional bimodally-acting opioid agonists,
`
`provides effective maintenance treatment of previously
`
`detoxified opiate, alcohol and cocaine addicts.
`
`AKGO
`
`OF
`
`NV
`
`Morphine
`
`or
`
`other
`
`bimodally—acting
`
`opioid
`
`agonists are administered to relieve severe pain due to
`
`the fact
`
`that
`
`they have analgesic effects mediated by
`
`their
`
`activation of
`
`inhibitory opioid receptors
`
`on
`
`nociceptive neurons (see North, Igeggs figuzgsgi,, Vol. 9,
`
`pp. 114-117 (1986) and Crain and Shen, Trends Ehazmacgl.
`
`§ci., Vol. 11, pp. 77-81 (1990)).
`
`However, bimodally-
`
`acting opioid agonists also activate opioid excitatory
`
`receptors on nociceptive neurons, which attenuate the
`
`analgesic potency of
`
`the opioids
`
`and result
`
`in the
`
`development of physical dependence thereon and increased
`
`tolerance thereto (see Shen and Grain, Brain Res., Vol.
`
`597, pp. 74-83
`
`(1992)),
`
`as well as hyperexcitability,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`

`W0 96/0225 1
`
`PCTIU595109974
`
`_3—
`
`hyperalgesia and other undesirable
`
`(excitatory)
`
`side
`
`effects. As a result, a long-standing need has existed to
`
`develop
`
`a method
`
`of
`
`both
`
`enhancing
`
`the
`
`analgesic
`
`(inhibitory) effects of bimodally-acting opioid agonists
`
`and limiting the undesirable (excitatory) side effects
`
`caused by such opioid agonists.
`
`The grandparent Patent Application for
`
`the
`
`instant
`
`invention, Serial No. 07/947,690,
`
`relates to a
`
`specific group of opioid agonists for use as low/non-
`
`addictive analgesics and for
`
`the treatment of opioid
`
`addiction.
`
`In the grandparent Application, it is stated
`
`that this group of opioid agonists binds to and activates
`
`inhibitory but not excitatory opioid receptors.
`
`In
`
`contrast, morphine and most other opioid alkaloids and
`
`peptides elicit
`
`bimodal effects
`
`by binding to and
`
`activating
`
`both
`
`excitatory
`
`and
`
`inhibitory
`
`opioid
`
`receptors.
`
`To date,
`
`no method has been discovered or
`
`developed whereby
`
`two
`
`opioid
`
`compounds
`
`are
`
`co—
`
`administered,
`
`one of which binds
`
`to and acts
`
`as
`
`a
`
`selective agonist at inhibitory opioid receptors to cause
`
`analgesia and the other of which binds to and acts as a
`
`selective antagonist at excitatory opioid receptors so as
`
`to attenuate undesirable side effects caused by the
`
`administration of bimodally-acting opioid agonists while
`
`simultaneously enhancing the analgesic effects of said
`
`bimodally-acting opioid agonists.
`
`It is therefore an object of this invention to
`
`provide a method of enhancing the analgesic potency of
`
`morphine and other bimodally-acting opioid agonists by
`
`blocking their anti—analgesic side effects.
`
`It is a further object of
`
`this invention to
`
`provide a method of attenuating physical dependence,
`
`tolerance,
`
`hyperexcitability,
`
`hyperalgesia
`
`and other
`
`undesirable
`
`side
`
`effects
`
`caused
`
`by
`
`the
`
`chronic
`
`administration of bimodally-acting opioid agonists.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`

`W0 96/0225 1
`
`PCTIU595/09974
`
`—4_
`
`It
`
`is another object of
`
`this invention to
`
`provide a method for maintenance treatment of previously
`
`detoxified opiate, cocaine and alcohol addicts utilizing
`
`ultra—low doses
`
`of
`
`an
`
`excitatory
`
`opioid
`
`receptor
`
`antagonist, either alone or in combination with long-term
`administration of low doses of methadone.
`
`It is yet another object of this invention to
`
`provide a composition which enhances the analgesic effects
`
`of bimodally—acting opioid agonists while simultaneously
`
`attenuating undesirable side effects caused by said opioid
`
`agonists,
`
`including
`
`physical
`
`dependence,
`
`tolerance,
`
`hyperexcitability and hyperalgesia.
`
`It is still a further object of this invention
`
`to provide a composition which is useful for treatment of
`
`opiate, cocaine and alcohol addicts.
`
`§HMMAB¥_QE_IHE_LEEEEIIQE
`
`This
`
`invention is directed to a method of
`
`selectively enhancing the analgesic potency of morphine
`
`and other conventional bimodally-acting opioid agonists
`
`and simultaneously attenuating undesirable side effects,
`
`including physical dependence,
`
`caused by the chronic
`
`administration of said opioid agonists. Morphine and
`
`other
`
`bimodally-acting
`
`(inhibitory/excitatory)
`
`opioid
`
`agonists
`
`bind to and activate both
`
`inhibitory and
`
`excitatory opioid receptors on nociceptive neurons which
`
`mediate pain. Activation of inhibitory receptors by said
`
`agonists causes analgesia.
`
`Activation of excitatory
`
`receptors by said agonists
`
`results in anti-analgesic
`
`effects, hyperexcitability, hyperalgesia,
`
`as well
`
`as
`
`development of physical dependence and tolerance and other
`
`undesirable side effects.
`
`A series of antagonists which
`
`bind to excitatory opioid receptors (e.g., diprenorphine,
`
`naltrexone and naloxone)
`
`selectively block excitatory
`
`opioid receptor
`
`functions of nociceptive types of DRG
`
`neurons at 1,000 to 10,000-fold lower concentrations than
`
`are required to block inhibitory opioid receptor functions
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`

`WO 96/02251
`
`PCT/U895109974
`
`-5—
`
`in these neurons.
`
`The co-administration of a bimodally—
`
`acting opioid agonist together with an ultra-low dose of
`
`an opioid antagonist which binds
`
`to and inactivates
`
`excitatory, but not inhibitory, opioid receptors results
`
`in the blocking of excitatory anti-analgesic side effects
`
`of
`
`said opioid agonists
`
`on
`
`these neurons,
`
`thereby
`
`resulting in enhanced analgesic potency.
`
`This enhanced
`
`analgesic potency permits
`
`the use of
`
`lower doses of
`
`morphine or other conventional opioid analgesics.
`
`The
`
`preferred
`
`excitatory
`
`opioid
`
`receptor
`
`antagonists of
`
`the invention include naltrexone and
`
`naloxone,
`
`in addition to etorphine, dihydroetorphine, and
`
`diprenorphine which are disclosed in parent U.s. Patent
`
`Application Serial No. 08/097,460 and similarly acting
`
`opioid alkaloids and opioid peptides.
`
`Prior hereto,
`
`clinical uses of naloxone
`
`and naltrexone have been
`
`formulated to be administered at much higher doses (e.g.
`
`50 mg), which block inhibitory opioid receptor functions
`
`mediating analgesia in addition to blocking excitatory
`
`opioid receptors.
`
`These high doses of antagonist are
`
`required as an antidote for acute opiate agonist overdose
`
`(e.g., respiratory depression). However,
`
`in the instant
`
`invention,
`
`long-term oral administration of ultra-low
`
`doses of naltrexone (for example about 1 ug) alone or in
`
`combination with low doses of methadone (e.g. mg) prevents
`
`protracted physical dependence which underlies resumption
`
`of drug abuse in previously detoxified opiate, cocaine and
`
`alcohol addicts. This is in contrast to clinical use of
`
`naltrexone prior hereto, wherein large (50 mg)
`
`tablets
`
`(Trexan) are administered, which produce dysphoria and
`
`other aversive side effects, and long-term treatment with
`
`high
`
`doses
`
`of methadone which
`
`result
`
`in physical
`
`dependence on methadone.
`
`The opioid agonists of
`
`the invention include
`
`morphine or'other bimodally-acting (inhibitory/excitatory)
`
`opioid alkaloids or opioid peptides that are in clinical
`
`use as analgesics,
`
`including codeine,
`
`fentanyl analogs,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`

`WO 96102251
`
`PCT[U895/09974
`
`-6-
`
`pentazccine, buprenorphine, methadone and endorphins.
`
`Further,
`
`in
`
`chronic
`
`pain
`
`patients,
`
`the
`
`excitatory opioid receptor antagonists of the invention
`
`are administered alone in ultra-low doses to enhance the
`
`analgesic potency and decrease the dependence liability of
`
`endogenous
`
`(as opposed to exogenous) opioid peptides,
`
`including enkephalins, dynorphins and endorphins, so as to
`
`facilitate physiologic mechanisms which normally regulate
`
`opioid responsivity and nociceptive systems.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`The above brief description, as well as further
`
`objects and features of
`
`the present
`
`invention, will be
`
`more
`
`fully understood by
`
`reference to the following
`
`detailed description of the presently preferred, albeit
`
`illustrative, embodiments of the present
`
`invention when
`
`taken in conjunction with the accompanying drawings
`
`wherein:
`
`Figure 1 represents the structural formulae of
`
`the bimodally-acting opioid agonist morphine
`
`and the
`
`preferred excitatory opioid receptor antagonists of the
`
`invention, naltrexone and naloxone. Naltrexone is the N-
`
`cyclopropylmethyl congener of naloxone;
`
`Figure 2 represents the direct inhibitory effect
`
`of etorphine on the action potential duration (APD) of
`
`nociceptive types of
`
`sensory neurons and the blocking
`
`effect of etorphine on
`
`the excitatory response
`
`(APD
`
`prolongation) elicited by morphine. Acute application of
`
`low (pM-nM) concentrations of etorphine to naive dorsal
`
`root ganglion
`
`(DRG)
`
`neurons elicits dose-dependent,
`
`naloxone-reversible inhibitory shortening of the APD.
`
`In
`
`contrast, morphine
`
`and other bimodally-acting opioid
`
`agonists elicit excitatory APD prolongation at these low
`
`concentrations which can be selectively blocked by <pM
`
`levels of etorphine,
`
`resulting in unmasking of potent
`
`inhibitory APD shortening by nM morphine;
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`

`WO 96102251
`
`PCTlUS95/09974
`
`-7-
`
`Figure 3
`
`represents dose-response curves of
`
`different
`
`opioids,
`
`showing
`
`that
`
`etorphine
`
`and
`
`dihydroetorphine elicit only inhibitory dose-dependent
`
`shortening of the APO of DRG neurons at all concentrations
`
`tested (fM-uM).
`
`In contrast, dynorphin A (as well as
`
`morphine and other bimodally-acting opioids) elicit dose-
`
`dependent
`
`excitatory
`
`APD
`
`prolongation
`
`at
`
`low
`
`concentrations
`
`(fM-nM)
`
`and
`
`requires
`
`much
`
`higher
`
`concentrations
`
`(about 0.1-1 MM)
`
`to shorten the APD,
`
`thereby resulting a bell-shaped, dose—response curve;
`
`Figures
`
`4A and
`
`48
`
`represent
`
`the
`
`selective
`
`blocking of excitatory APB-prolonging effects elicited by
`
`morphine in DRG neurons by co-administration of a low (pH)
`
`concentration of diprenorphine,
`
`thereby unmasking potent
`
`dose-dependent
`
`inhibitory
`
`APD
`
`shortening
`
`by
`
`low
`
`concentrations of morphine (comparable to the inhibitory
`
`potency of etorphine).
`
`In contrast, co—treatment with a
`
`higher (nM) concentration of DPN blocks both inhibitory as
`
`well as excitatory opioid effects;
`
`Figure 5 represents similar selective blocking
`
`of excitatory APD-prolonging effects elicited by morphine
`
`in DRG neurons when co-administered with a
`
`low (pH)
`
`concentration of naltrexone,
`
`thereby unmasking potent
`
`inhibitory APD
`
`shortening by
`
`low concentrations
`
`of
`
`morphine.
`
`In contrast, a higher
`
`(pH) concentration of
`
`naltrexone blocks both inhibitory as well as excitatory
`
`opioid effects; and
`
`Figure 6 represents the assay procedure used to
`
`demonstrate
`
`that
`
`selective antagonists at excitatory
`
`opioid receptors prevents
`
`development
`
`of
`
`tolerance]
`
`dependence during chronic co-treatment of DRG neurons with
`
`morphine.
`
`DEIAILED QESCRIPTION OF IHE INVENTION
`
`This
`
`invention is directed to a method of
`
`selectively enhancing the analgesic effect caused by the
`
`administration of a bimodally-acting opioid agonist and
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`

`

`W0 96/0225 1
`
`PCTIU595109974
`
`_8—
`
`simultaneously attenuating undesirable side effects caused
`
`by the chronic administration of said bimodally-acting
`
`opioid agonists.
`
`This
`
`is performed. by simultaneously
`
`inactivating excitatory opioid.receptor-mediated functions
`
`and
`pathways
`(pain)
`in the nociceptive
`neurons
`of
`activating inhibitory opioid receptor-mediated functions
`
`of nociceptive neurons.
`
`Low doses of a bimodally-acting
`
`opioid
`
`agonist
`
`and
`
`an
`
`excitatory
`
`opioid
`
`receptor
`
`antagonist are co-administered.
`
`The bimodally-acting
`
`opioid
`
`agonist
`
`binds
`
`to
`
`inhibitory
`
`receptors
`
`on
`
`nociceptive neurons so as to activate inhibitory opioid
`
`receptor-mediated functions,
`
`including analgesia,
`
`and
`
`concomitantly activates excitatory opioid. receptors on
`
`nociceptive neurons.
`
`The excitatory opioid receptor
`
`antagonist binds to excitatory receptors on said neurons
`
`and
`
`thereby inactivates
`
`excitatory opioid receptor—
`
`mediated functions,
`
`including anti-analgesic effects,
`
`physical dependence and tolerance to the opioid agonist,
`
`hyperexcitability and hyperalgesia.
`
`Alternatively,
`
`the excitatory opioid receptor
`
`antagonists of
`
`the invention can be used to pretreat
`
`patients prior to administering bimodally-acting exogenous
`
`opioids thereto, or used alone to enhance the analgesic
`
`potency
`
`and
`
`decrease
`
`the
`
`dependence
`
`liability of
`
`endogenous
`
`opioid
`
`peptides
`
`including
`
`enkephalins,
`
`dynorphins and endorphins, which are markedly unregulated
`
`in chronic pain patients.
`
`In addition, this invention is directed to the
`
`use of said excitatory opioid receptor antagonists and
`
`opioid agonists for maintenance treatment of previously
`
`detoxified opiate addicts. Because addiction to cocaine
`
`and alcohol are also mediated by specific opioid-sensitive
`
`brain cell networks (see Gardner, et a1. Substance Abuse
`
`2ed. pp. 70-99 (1992)) and because addiction to cocaine is
`
`mediated by specific opioid-sensitive brain cell networks,
`
`the method of the invention for treating opiate addicts
`
`can also be used for the treatment of cocaine or alcohol
`
`10
`
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`_9—
`
`addicts.
`
`Further,
`
`this invention is directed to a
`
`composition comprising an excitatory opioid receptor
`
`antagonist and a bimodally-acting opioid agonist.
`
`The
`
`inventors have discovered that certain
`
`compounds act as excitatory opioid receptor antagonists,
`
`that is,
`
`they bind to and inactivate excitatory opioid
`
`receptors on neurons in the nociceptive pathways.
`
`The
`
`excitatory opioid receptor antagonists of the invention
`
`are preferably selected from ‘the group consisting of
`
`naloxone,
`
`naltrexone,
`
`diprenorphine,
`
`etorphine
`
`and
`
`dihydroetorphine.
`
`One of the excitatory opioid receptor
`
`antagonists
`
`of
`
`the
`
`invention,
`
`naltrexone,
`
`can
`
`be
`
`administered orally at very low doses.
`
`For example,
`
`naltrexone can be administered at a level as low as 1 pg
`
`and will have selective antagonist action at excitatory,
`
`but not
`
`inhibitory, opioid receptors.
`
`All previous
`
`clinical use of naltrexone, as well as naloxone, has been
`
`at much higher
`
`(2 mg) doses which results in antagonist
`
`actions at both inhibitory as well as excitatory opioid
`
`receptors.
`
`In addition, since the antagonists enhance the
`
`analgesic potency of the agonists,
`
`the agonists become
`
`effective when administered at markedly'
`
`reduced doses
`
`which would otherwise be sub—analgesic.
`
`The alkaloid opioid receptor antagonists of the
`
`invention inactivate mu, delta, kappa and other subtypes
`
`of
`
`excitatory
`
`opioid
`
`receptors.
`
`Etorphine
`
`and
`
`dihydroetorphine have very similar chemical structures and
`
`are
`
`potent
`
`analgesics which
`
`selectively
`
`activate
`
`inhibitory but not excitatory opioid receptors (see Shen
`
`and Grain, §;§1n_3§§;, Vol. 636, pp.
`
`286—297
`
`(1994)).
`
`Naltrexone, naloxone (see Figure l) and diprenorphine have
`
`slightly different chemical structures than etorphine and
`
`dihydroetorphine, which results in their acting as general
`
`opioid receptor antagonists at all types of inhibitory and
`
`excitatory opioid receptors (see Shen and Crain, again
`
`Resp, Vol. 491, pp. 227-242 (1989) and fir;in_3§§&, Vol.
`
`636,
`
`(1994)).
`
`Nevertheless,
`
`at
`
`very
`
`low
`
`(pH)
`
`10
`
`15
`
`20
`
`25
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`
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`

`WO 96/02251
`
`PCTlUS95/09974
`
`-10-
`
`concentrations,
`
`these
`
`compounds
`
`are all
`
`capable
`
`of
`
`selectively binding to and acting as antagonists at
`
`excitatory,
`
`but not
`
`inhibitory,
`
`opioid receptors
`
`on
`
`nociceptive DRG neurons.
`
`The bimodally-acting opioid. agonists of
`
`this
`
`invention preferably include morphine, codeine, methadone,
`
`pentazocine, buprenorphine, fentanyl analogs, endorphins,
`
`and
`
`other
`
`opioid
`
`alkaloids
`
`and
`
`opioid
`
`peptides.
`
`Typically,
`
`the opioid agonists of the invention are mu,
`
`10
`
`delta, kappa or epsilon opioid receptor agonists, and are
`
`capable of binding to inhibitory opioid receptors on
`
`neurons in the pain pathway. When these bimodally-acting
`
`agonists bind to inhibitory opioid receptors, they thereby
`
`activate inhibitory opioid receptor-mediated functions,
`
`15
`
`including analgesia.
`
`As
`
`discussed
`
`below,
`
`the
`
`inventors
`
`have
`
`discovered by studies of nociceptive DRG neurons that
`
`certain
`
`compounds
`
`(the
`
`excitatory
`
`opioid
`
`receptor
`
`antagonists of the invention), when used for pretreatment
`
`or when co-administered with bimodally-acting opioid
`
`agonists, are capable at very low dosages of enhancing the
`
`analgesic effects of the bimodally—acting opioid
`
`agonists at least 100-1000 fold by inactivating excitatory
`
`anti-analgesic
`
`side effects
`
`of
`
`said agonists.
`
`In
`
`addition,
`
`the excitatory opioid receptor antagonists of
`
`the invention prevent development of opioid tolerance and
`
`dependence which are mediated by sustained activation of
`
`excitatory opioid receptor functions.
`
`In addition,
`
`the excitatory opioid receptor
`
`antagonists of the invention can be administered either
`
`alone or in conjunction with low, sub—analgesic doses of
`
`inhibitory
`
`opioid
`
`receptor
`
`agonists
`
`for
`
`long-term
`
`maintenance treatment of previously detoxified opiate,
`
`cocaine and alcohol addicts to prevent protracted physical
`
`dependence (see Goldberg, et a1.
`
`(1969) and Grain, et a1.
`
`(1992)), which underlies resumption of drug abuse.
`
`20
`
`25
`
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`
`35
`
`

`

`WO 96/02251
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`
`The long-term treatment of detoxified addicts
`
`with selective antagonists blocks sustained activation of
`
`excitatory opioid receptor functions by endogenous opioid
`
`peptides.
`
`These peptides are present
`
`in the brain at
`
`concentrations that are well above the markedly reduced
`
`threshold required to activate chronic morphine-sensitized
`
`excitatory opioid receptors, thereby blocking the cellular
`
`mechanism proposed
`
`to underlie protracted physical
`
`dependence.
`
`Further,
`
`the excitatory opioid receptor
`
`10
`
`antagonists can be administered alone to chronic pain
`
`patients to enhance the analgesic potency and decrease the
`
`dependence
`
`liability of
`
`endogenous opioid peptides,
`
`including enkephalins, dynorphins and. endorphins which
`
`normally regulate nociceptive (pain) sensitivity and which
`
`15
`
`are elevated during chronic pain.
`
`20
`
`25
`
`Ordinarily, most conventional bimodally-acting
`
`opioid agonists are administered clinically in milligram
`
`dosages.
`
`By co-administering bimodally-acting opioid
`
`agonists with the excitatory opioid receptor antagonists
`
`of the invention, it is possible to achieve an analgesic
`
`effect with 10-100 times lower doses of the bimodally-
`
`acting opioid agonist
`
`than when said opioid agonist
`
`is
`
`administered alone. This is because the excitatory opioid
`
`receptor
`
`antagonists
`
`of
`
`the
`
`invention
`
`enhance
`
`the
`
`analgesic effects of the bimodally-acting opioid agonists
`
`by attenuating the anti-analgesic excitatory side effects
`
`of said opioid agonists. Hence, bimodally-acting opioid
`
`agonists which are administered with the excitatory opioid
`
`receptor antagonists of the invention are administered in
`
`30
`
`an amount 10-100 times
`
`less than the amount of
`
`that
`
`bimodally—acting opioid agonist which has typically been
`
`administered for analgesia.
`
`According to the present invention,
`
`the dose of
`
`excitatory opioid receptor antagonist to be administered
`
`35
`
`is loo—1000 times less than the dose of bimodally-acting
`
`opioid agonist to be administered,
`
`for example, about 1
`
`microgram of
`
`said antagonist
`
`together with 100-1000
`
`

`

`WO 96/02251
`
`PCT/US95/09974
`
`micrograms of said agonist.
`
`These estimates of dosages
`
`are based on
`
`studies of nociceptive DRG neurons
`
`in
`
`culture.
`
`The excitatory opioid receptor antagonists, as
`
`well
`
`as
`
`the
`
`inhibitory
`
`opioid
`
`agonists,
`
`can
`
`be
`
`administered
`
`orally,
`
`sublingually,
`
`intramuscularly,
`
`subcutaneously
`
`or
`
`intravenously.
`
`Naltrexone
`
`is
`
`particularly useful since it can be administered orally at
`
`1 ug doses, has long-lasting action and has been safely
`
`used in treatment of opiate addiction at 50 mg doses,
`
`several times per week for several years (see Greenstein
`
`et al., gubst. Abuse, 2d ed.
`
`(1992) and Gonzales et al.,
`
`nggg, Vol. 35, pp. 192-213 (1988)).
`
`The co-administration of the opioid agonists and
`
`excitatory opioid receptor antagonists of the invention
`
`simultaneously
`
`activates
`
`inhibitory
`
`functions
`
`of
`
`nociceptive
`
`neurons mediating
`
`pain
`
`and
`
`inactivates
`
`excitatory functions of
`
`the same or other nociceptive
`
`neurons.
`
`In order to demonstrate this, electrophysiologic
`
`studies on the effects of opioids on nociceptive types of
`
`mouse
`
`sensory DRG neurons
`
`in tissue cultures were
`
`performed.
`
`It is shown below that this bimodal modulation
`
`is mediated by activating putative excitatory opioid
`
`receptors
`
`in
`
`addition
`
`to
`
`previously
`
`characterized
`
`inhibitory opioid receptors on sensory neurons.
`
`It is shown that at low pM—nM concentrations,
`
`nearly all bimodally-acting opioids,
`
`including morphine,
`
`enkephalins, dynorphins, endorphins and specific mu, delta
`
`and. kappa opioid. agonists, elicit. naloxone-reversible,
`
`dose-dependent
`
`excitatory
`
`effects manifested
`
`by
`
`prolongation of
`
`the calcium-dependent component of
`
`the
`
`action potential duration (APD) of DRG neurons.
`
`In
`
`contrast, the same opioids generally elicit inhibitory APD
`
`shortening effects when applied at higher concentrations
`
`(0.1-1 nu) .
`
`The excitatory opioid effects on sensory neurons
`
`have been shown to be mediated by opioid receptors that
`
`are coupled via a cholera-toxin-sensitive stimulatory GTP-
`
`10
`
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`W0 96/0225 1
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`
`binding
`
`protein,
`
`Gs,
`
`to
`
`adenylate
`
`cyclase/cyclic
`
`AMP/protein kinase A-dependent
`
`ionic conductances that
`
`prolong the APD (resembling, for example, beta-adrenergic
`
`receptors).
`
`(See Grain and Shen, Trends Pharmacol. Sci.,
`
`Vol.
`
`110,
`
`pp.
`
`77-81
`
`(1990)).
`
`On
`
`the other hand,
`
`inhibitory opioid effects are mediated by opioid receptors
`
`that are coupled via pertussis toxin-sensitive inhibitory
`
`G proteins: Gi to the adenylate cyclase/cyclic AMP system
`and Go
`to ionic conductances
`that
`shorten the APD
`
`(resembling,
`
`for' example, alphaz-adrenergic: receptors).
`
`Shortening by opioids of the action potential of primary
`
`sensory neurons has generally been considered to be a
`
`useful model of their inhibition of calcium influx and
`
`transmitter release at presynaptic terminals in the dorsal
`
`spinal
`
`cord,
`
`thereby
`
`accounting
`
`for
`
`opioid-induced
`
`analgesia in viyg.
`
`(See North, Iggng§_flguggsgi;, Vol. 9,
`
`pp. 114-117 (1986) and Grain and Shen,
`
`II§QQ§_£hg;m3991;
`
`593;, Vol. 11, pp. 77-81 (1990)).
`
`Similarly, the delayed repolarization associated
`
`with the observed opioid-induced prolongation of action
`
`potential has been interpreted as evidence of excitatory
`
`effects of opioids on nociceptive types of sensory neurons
`
`(see Shen and Grain, J
`
`N
`
`'
`
`,
`
`(1994,
`
`in press)) that
`
`may result
`
`in enhanced calcium influx and transmitter
`
`release at presynaptic terminals. This could account for
`
`some
`
`types of hyperalgesia and. hyperexcitatory states
`
`elicited by opioids in_yigg (see Crain and Shen,
`
`re s
`
`Ehgxmaggl. Sci., Vol.11, pp. 77—81 (1990); Shen and Crain,
`
`n;ain_3g§L, Vol. 491, pp. 227-242 (1989); and Shen and
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`Grain, J. Neurosci.
`
`(1994)).
`
`Chronic treatment of DRG neurons with typical
`
`bimodally-acting (excitatory/inhibitory) opioids (e.g., 1
`
`MM D-alaz-D-leu5 enkephalin (DADLE) or morphine for 1 week)
`
`results
`
`in tolerance
`
`to the usual
`
`inhibitory APD-
`
`35
`
`shortening effects of high concentrations of these opioids
`
`and supersensitivity to the excitatory APB-prolonging
`
`effects of these opioid agonists, as well as the opioid
`
`

`

`WO 96/02251
`
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`
`antagonist, naloxone (see Grain and Shen, Brain ges., Vol.
`
`575, pp. 13—24 (1992) and Shen and Grain, figgig_g§§;, Vol.
`
`597, pp. 74-83 (1992)).
`
`It has been suggested that the
`
`latter electrophysiologic effects and related biochemical
`
`5
`
`adaptations
`
`are cellular manifestations
`
`of physical
`
`dependence
`
`that may underlie some aspects of opiate
`
`addiction (see Shen and Grain, grain Be§., Vol. 597, pp.
`
`74-83 (1992) and Terwilliger et a1., Brain Res., Vol. 548,
`
`pp. 100-110 (1991)).
`
`10
`
`In contrast to bimodally-acting opioids, it has
`
`been discovered by the inventors that the opioid alkaloids
`
`etorphine (see Bentley and Hardy, Ergc. Chem. Soc., pp.
`
`220
`
`(1963)
`
`and Blane et al.,
`
`321;.
`
`J. Enarmacol.
`
`Qhemother.,
`
`Vol.
`
`30,
`
`pp.
`
`11-22
`
`(1967))
`
`and
`
`15 dihydroetorphine (see Bentley and Hardy, J. Amer. Chem.
`
`599;, Vol. 89, pp. 3281-3286 (1967)) uniquely elicit dose-
`
`dependent,
`
`naloxone—reversible
`
`inhibitory effects
`
`on
`
`sensory neurons
`
`in DRG-spinal cord explants,
`
`even at
`
`concentrations as low as 1 pM,
`
`and show no excitatory
`
`20 effects at lower concentrations (see Shen and Grain, Brain
`
`Beep, Vol. 636, pp. 286-297 (1994)).
`
`In addition,
`
`these
`
`potent
`
`inhibitory opioid receptor agonists also display
`
`unexpected
`
`antagonist
`
`effects
`
`at
`
`excitatory opioid
`
`receptors on DRG neurons.
`
`Acute pretreatment of DRG
`
`25 neurons with etorphine or dihydroetorphine,
`
`at
`
`low
`
`concentrations (<pM) which do not alter the APD, block the
`
`excitatory APB-prolonging effects of morphine and other
`
`bimodally-acting opioids
`
`and
`
`unmask
`
`inhibitory APD-
`
`shortening' effects which. normally require much higher
`
`30
`
`concentrations. The potent inhibitory effect of etorphine
`
`and dihydroetorphine may be due
`
`to their
`
`selective
`
`activation
`
`of
`
`inhibitory
`
`opioid
`
`receptor—mediated
`
`functions while simultaneously inactivating excitatory
`
`opioid receptor-mediated functions in sensory neurons.
`
`In
`
`35 contrast, bimodally-acting opioids activate excitatory as
`
`well as
`
`inhibitory opioid receptors
`
`on DRG neurons,
`
`thereby decreasing the net
`
`inhibitory effectiveness of
`
`

`

`WO 96/02251
`
`PCT/US95/09974
`
`these
`
`agonists,
`
`resembling
`
`the
`
`attenuation of
`
`the
`
`inhibitory potency of systemic morphine by the "anti-
`
`analgesic" (excitatory) effect of dynorphin A release in
`
`spinal cord in mice (see Fujimoto et a1. , Neuro
`
`a acol. ,
`
`Vol. 29, pp. 609- 617,
`
`(1990)).
`
`The inventors have discovered that at ultra—low
`
`(pM)
`
`concentrations,
`
`naloxone
`
`and naltrexone act
`
`as
`
`selective antagonists at excitatory opioid receptors on
`
`DRG neurons,
`
`thereby unmasking potent inhibitory effects
`
`of
`
`bimodally-acting
`
`opioid
`
`agonists.
`
`At
`
`nM
`
`concentrations,
`
`naloxone blocks
`
`both
`
`inhibitory APD
`
`shortening in DRG neurons by uM opioid agonists as well as
`
`excitatory APD prolongation by pM-nM opioids. Systematic
`
`tests with lower concentrations of naloxone have revealed
`
`that pM naloxone acts selectively as an antagonist at
`
`excitatory opioid recepto