USRE36547E - Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists - Google Patents

Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists Download PDF

Info

Publication number
USRE36547E
USRE36547E US08/782,452 US78245296A USRE36547E US RE36547 E USRE36547 E US RE36547E US 78245296 A US78245296 A US 78245296A US RE36547 E USRE36547 E US RE36547E
Authority
US
United States
Prior art keywords
opioid
bimodally
excitatory
acting
morphine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US08/782,452
Inventor
Stanley M. Crain
Ke-fei Shen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Albert Einstein College of Medicine
Com Affiliation Inc
Original Assignee
Albert Einstein College of Medicine
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/097,460 external-priority patent/US5472943A/en
Priority claimed from US08/276,966 external-priority patent/US5512578A/en
Application filed by Albert Einstein College of Medicine filed Critical Albert Einstein College of Medicine
Priority to US08/782,452 priority Critical patent/USRE36547E/en
Application granted granted Critical
Publication of USRE36547E publication Critical patent/USRE36547E/en
Anticipated expiration legal-status Critical
Assigned to COM AFFILIATION, INC. reassignment COM AFFILIATION, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIVERSITY
Assigned to ALBERT EINSTEIN COLLEGE OF MEDICINE, INC. reassignment ALBERT EINSTEIN COLLEGE OF MEDICINE, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: COM AFFILIATION, INC.
Assigned to ALBERT EINSTEIN COLLEGE OF MEDICINE reassignment ALBERT EINSTEIN COLLEGE OF MEDICINE MERGER AND CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: ALBERT EINSTEIN COLLEGE OF MEDICINE, ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/94Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
    • G01N33/9486Analgesics, e.g. opiates, aspirine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/94Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00Screening for compounds of potential therapeutic value
    • G01N2500/10Screening for compounds of potential therapeutic value involving cells

Definitions

  • This invention relates to a method of enhancing the analgesic (inhibitory) effects of bimodally-acting opioid agonists, including morphine, codeine and other clinically used opioid analgesics, while at the same time attenuating anti-analgesic effects, physical dependence, tolerance, hyperexcitability, hyperalgesia, and other undesirable (excitatory) side effects typically caused by chronic use of bimodally-acting (excitatory and inhibitory) opioid agonists.
  • 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.
  • opioid alkaloids including the agonist morphine and the antagonist naloxone
  • opioid peptides including enkephalins, dynorphins and endorphins.
  • opioidate refers to drugs derived from opium or related analogs.
  • 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.
  • 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, Trends Neurosci., Vol. 9, pp. 114-117 (1986) and Crain and Shen, Trends Pharmacol. Sci., Vol. 11, pp. 77-81 (1990)).
  • bimodally-acting opioid agonists also activate opioid excitatory receptors on nociceptive neurons, which attenuates the analgesic potency of the opioids and results in the development of physical dependence thereon and increased tolerance thereto (see Shen and Crain, Brain Res., Vol. 597, pp.
  • the grandparent Patent Application for the instant invention Ser. 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.
  • this group of opioid agonists bind to and activate inhibitory but not excitatory opioid receptors.
  • morphine and most other opioid alkaloids and peptides elicit bimodal effects by binding to and activating both excitatory and inhibitory opioid receptors.
  • 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 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 in these neurons.
  • excitatory opioid receptors e.g., diprenorphine, naltrexone and naloxone
  • 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 Ser. No. 08/097,460 and similarly acting opioid alkaloids and opioid peptides.
  • naloxone and naltrexone 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).
  • naltrexone for example about 1 ⁇ g
  • methadone e.g. mg
  • long-term oral administration of ultra-low doses of naltrexone prevents protracted physical dependence which underlies resumption of drug abuse in previously detoxified opiate, cocaine and alcohol addicts.
  • methadone e.g. mg
  • 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, pentazocine, buprenorphine, methadone and endorphins.
  • 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.
  • FIG. 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;
  • FIG. 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.
  • 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;
  • FIG. 3 represents dose-response curves of different opioids, showing that etorphine and dihydroetorphine elicit only inhibitory dose-dependent shortening of the APD of DRG neurons at all concentrations tested (fM- ⁇ M).
  • dynorphin A (as well as morphine and other bimodally-acting opioids) elicits dose-dependent excitatory APD prolongation at low concentrations (fM-nM) and requires much higher concentrations (about 0.1-1 ⁇ M) to shorten the APD, thereby resulting in-a bell-shaped dose-response curve;
  • FIGS. 4A and 4B represent the selective blocking of excitatory APD-prolonging effects elicited by morphine in DRG neurons by co-administration of a low (pM) concentration of diprenorphine, thereby unmasking potent dose-dependent inhibitory APD shortening by low concentrations of morphine (comparable to the inhibitory potency of etorphine).
  • a low concentration of diprenorphine thereby unmasking potent dose-dependent inhibitory APD shortening by low concentrations of morphine (comparable to the inhibitory potency of etorphine).
  • co-treatment with a higher (nM) concentration of DPN blocks both inhibitory as well as excitatory opioid effects;
  • FIG. 5 represents similar selective blocking of excitatory APD-prolonging effects elicited by morphine in DRG neurons when co-administered with a low (pM) concentration of naltrexone, thereby unmasking potent inhibitory APD shortening by low concentrations of morphine.
  • a higher ( ⁇ M) concentration of naltrexone blocks both inhibitory as well as excitatory opioid effects;
  • FIG. 6 represents the assay procedure used to demonstrate that selective antagonists at excitatory opioid receptors prevent development of tolerance/dependence during chronic co-treatment of DRG neurons with morphine.
  • This invention is directed to a method of selectively enhancing the analgesic effect caused by the administration of a bimodally-acting opioid agonist and 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 of neurons in the nociceptive (pain) pathways and activating inhibitory opioid receptor-mediated 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.
  • 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.
  • 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 al. Substance Abuse 2 ed. pp. 70-99 (1992)), and because addiction to cocaine and alcohol are 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 addicts. Further, this invention is directed to a composition comprising an excitatory opioid receptor antagonist and a bimodally-acting opioid agonist.
  • the excitatory opioid receptor antagonists of the invention are preferably selected from the group consisting of naloxone, naltrexone, diprenorphine, etorphine and dihydroetorphine.
  • naltrexone can be administered orally at very low doses.
  • naltrexone can be administered at a level as low as 1 ⁇ g and will have selective antagonist action at excitatory, but not inhibitory, opioid receptors.
  • naltrexone As well as naloxone, has been at much higher (>mg) doses which results in antagonist actions at both inhibitory as well as excitatory opioid receptors.
  • 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.
  • 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 Crain, Brain Res., Vol. 636, pp. 286-297 (1994)).
  • Naltrexone, naloxone (see FIG. 1) 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, Brain Res., Vol. 491, pp.
  • 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.
  • the opioid agonists of the invention are mu, 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, including analgesia.
  • 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.
  • 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.
  • 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 al. (1969) and Crain, et al. (1992)), which underlies resumption of drug abuse.
  • the long-term treatment of detoxified addicts with selective antagonists blocks sustained activation of excitatory opioid receptor functions by endogenous opioid peptides.
  • endogenous opioid 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.
  • the excitatory opioid receptor 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 are elevated during chronic pain.
  • bimodally-acting opioid agonists are administered clinically in milligram dosages.
  • bimodally-acting opioid agonists are administered with the excitatory opioid receptor antagonists of the invention in an amount 10-100 times less than the amount of that bimodally-acting opioid agonist which has typically been administered for analgesia.
  • the dose of excitatory opioid receptor antagonist to be administered is 100-1000 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 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 ⁇ g 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., Subst. Abuse, 2d ed. (1992) and Gonzales et al., Drugs, 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.
  • opioids 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.
  • 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.
  • 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-binding protein, Gs, to adenylate cyclase/cyclic AMP/protein kinase A-dependent ionic conductances that prolong the APD (resembling, for example, beta-adrenergic receptors).
  • Gs cholera-toxin-sensitive stimulatory GTP-binding protein
  • 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, alpha 2 -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 vivo. (See North, Trends Neurosci., Vol. 9, pp. 114-117 (1986) and Crain and Shen, Trends Pharmacol. Sci., Vol. 11, pp. 77-81 (1990)).
  • DRG neurons Chronic treatment of DRG neurons with typical bimodally-acting (excitatory/inhibitory) opioids (e.g., 1 ⁇ M D-ala 2 -D-leu 5 enkephalin (DADLE) or morphine for 1 week) results in tolerance to the usual inhibitory APD-shortening effects of high concentrations of these opioids and supersensitivity to the excitatory APD-prolonging effects of these opioid agonists, as well as the opioid antagonist, naloxone (see Crain and Shen, Brain Res., Vol. 575, pp. 13-24 (1992) and Shen and Crain, Brain Res., Vol. 597, pp. 74-83 (1992)).
  • typical bimodally-acting (excitatory/inhibitory) opioids e.g., 1 ⁇ M D-ala 2 -D-leu 5 enkephalin (DADLE) or morphine for 1 week
  • 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.
  • bimodally-acting opioids activate excitatory as well as inhibitory opioid receptors on DRG neurons, thereby decreasing the net inhibitory effectiveness of 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 al., Neuropharmacol., Vol. 29, pp. 609-617, (1990)).
  • naloxone and naltrexone act as selective antagonists at excitatory opioid receptors on DRG neurons, thereby unmasking potent inhibitory effects of bimodally-acting opioid agonists.
  • naloxone blocks both inhibitory APD shortening in DRG neurons by ⁇ M 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 receptors.
  • naloxone i.t.
  • naloxone i.t.
  • 100 fg of naloxone was required to significantly reduce analgesia mediated by direct i.t. injection of morphine or k opioid agonists (see Fujimoto et al., J. Pharm. Exp. Ther., Vol. 251, pp. 1045-1052 (1989)).
  • Co-administration of low (pM) concentrations of etorphine during chronic treatment of DRG neurons with ⁇ M levels of morphine is effective in preventing development of the opioid excitatory supersensitivity and tolerance that generally occurs after sustained exposure to bimodally-acting opioids.
  • Acute application of 1 fM dynorphin A(1-13) or 10 nM naloxone to DRG neurons chronically exposed to 3 ⁇ M morphine together with 1 pM etorphine (for greater than 1 week) did not evoke the usual excitatory APD prolongation observed in chronic morphine-treated cells, even when tested up to 6 hours after return to BSS. Furthermore, there was little or no evidence of tolerance to the inhibitory APD-shortening effects of ⁇ M morphine.
  • Acute application of fM dynorphin A-(1-13) or fM morphine, as well as 1 nM naloxone to DRG neurons chronically exposed to 1 ⁇ M morphine together with 1 pM naloxone or naltrexone (for 1-10 weeks) did not evoke the usual excitatory APD prolongation observed in chronic morphine-treated cells (see Crain et al., (1992) and Shen et al., (1992)) tested after washout with BSS. Furthermore, there was no evidence of tolerance to the usual inhibitory effects of ⁇ M opioids.
  • Chronic co-treatment of nociceptive types of DRG neurons with morphine together with ultra-low (pM) concentrations of naltrexone or naloxone can therefore prevent the cellular manifestations of tolerance and dependence that generally occur in chronic morphine-treated DRG neurons.
  • This data for naltrexone and naloxone on chronic morphine-treated nociceptive DRG neurons provides evidence that the formulation of opioid analgesic preparations comprising ultra-low doses of these excitatory opioid receptor antagonists and morphine (or codeine) will result in enhanced analgesic potency and low dependence liability.
  • Etorphine and dihydroetorphine are the first compounds determined by the inventors by electrophysiologic analyses on DRG neurons to have specific antagonist action on excitatory opioid receptor functions when applied at ultra-low (pM) concentrations. This is in contrast to their well-known agonist action at inhibitory opioid receptors when applied at higher concentrations.
  • DRG dorsal root ganglion
  • the experiments described herein were carried out on dorsal root ganglion (DRG) neurons in organotypic explants of spinal cord with attached DRGs from 13-day-old fetal mice after 3 to 5 weeks of maturation in culture.
  • the DRG-cord explants were grown on collagen-coated coverslips in Maximow depression-slide chambers.
  • the culture medium consisted of 65% Eagle's minimal essential medium, 25% fetal bovine serum, 10% chick embryo extract. 2 mM glutamine and 0.6% glucose.
  • NGF-7S nerve growth factor
  • the culture coverslip was transferred to a recording chamber containing about 1 ml of Hanks' balanced salt solution (BSS).
  • BSS Hanks' balanced salt solution
  • the bath solution was supplemented with 4 mM Ca 2+ and 5 mM Ba 2+ (i.e., Ca,Ba/BSS) to provide a prominent baseline response for pharmacological tests.
  • Intracellular recordings were obtained from DRG perikarya selected at random within the ganglion.
  • the micropipettes were filled with 3M KCl (having a resistance of about 60-100 megohms) and were connected via a chloridized silver wire to a neutralized input capacity preamplifier (Axoclamp 2A) for current-clamp recording.
  • 3M KCl having a resistance of about 60-100 megohms
  • Drugs were applied by bath perfusion with a manually operated, push-pull syringe system at a rate of 2-3 ml/min. Perfusion of test agents was begun after the action potential and the resting potential of the neuron reached a stable condition during >4 minute pretest periods in control Ca, Ba/BSS. Opioid-mediated changes in the APD were considered significant if the APD alteration was >10% of the control value for the same cell and was maintained for the entire test period of 5 minutes. The APD was measured as the time between the peak of the APD and the inflection point on the repolarizing phase. The following drugs were used in this and the following Examples: etorphine, diprenorphine and morphine (gifts from Dr.
  • Opioid alkaloids and peptides were generally prepared as 1 mM solutions in H 2 O and then carefully diluted with BSS to the desired concentrations, systematically discarding pipette tips after each successive 1-10 or 1-100 dilution step to ensure accuracy of extremely low (fM-pM) concentrations.
  • Intracellular recordings were made from small- and medium-size DRG neuron perikarya (about 10-30 ⁇ m in diameter) which generate relatively long APDs (greater than 3 msec in Ca/Ba BSS) and which show characteristic responsiveness to opioid agonists and other properties of primary afferent nociceptive neurons as occur in vivo.
  • Acute application of selective inhibitory opioid receptor agonists, e.g., etorphine to these DRG neurons shortens the APD in 80-90% of the cells tested, whereas low concentrations of bimodally-acting (excitatory/inhibitory) opioids, e.g., morphine, dynorphin, enkephalins, prolong the APD in these same cells.
  • the opioid responsiveness of DRG neurons was analyzed by measuring the opioid-induced alterations in the APD of DRG perikarya.
  • FIG. 2 shows that acute application of low (pM-nM) concentrations of etorphine to naive DRG neurons elicits dose-dependent, naloxone-reversible inhibitory shortening of the action potential duration (APD).
  • dynorphin and many other bimodally-acting opioid agonists, e.g., morphine, DADLE
  • FIG. 3 shows excitatory APD prolongation at these low concentrations (see FIG. 3), which can be selectively blocked by ⁇ pM levels of etorphine, as well as by diprenorphine or naltrexone (see FIGS. 4 and 5).
  • FIG. 3 shows that acute application of low (pM-nM) concentrations of etorphine to naive DRG neurons elicits dose-dependent, naloxone-reversible inhibitory shortening of the action potential duration (APD).
  • dynorphin and many other bimodally-acting opioid agonist
  • FIG. 2A record 1 shows the action potential (AP) generated by a DRG neuron in balanced salt solution containing 5 mM Ca 2+ and 5 mM Ba 2+ (BSS).
  • AP response in this record (and in all records below) is evoked by a brief (2 msec) intracellular depolarizing current pulse.
  • FIG. 2A records 2-5 show that APD is not altered by bath perfusion with 1 fM etorphine (Et) but is progressively shortened in 1 pM, 1 nM and 1 ⁇ M concentrations (5 minute test periods).
  • FIG. 2A record 6 shows that APD returns to control value after transfer to BSS (9 minute test).
  • FIG. 2B records 1 and 2 show that APD of another DRG neuron is shortened by application of 1 nM etorphine (2 minute test).
  • FIG. 2B record 3 shows that APD returns to control value after transfer to 10 nM naloxone (NLX).
  • FIG. 2B records 4 and 5 show that APD is no longer shortened by 1 nM or even 1 ⁇ M etorphine when co-perfused with 10 nM naloxone (5 minute test periods).
  • FIG. 2C records 1 and 2 show that APD of another DRG neuron is prolonged by application of 3 nM morphine.
  • FIG. 2C record 3 shows that APD returns to control value by 5 minutes after washout
  • FIG. 2C record 4 shows that application of 1 pM etorphine does not alter the APD.
  • FIG. 2C record 5 shows that APD is no longer prolonged by 3 nM morphine when co-perfused with 1 pM etorphine and instead is markedly shortened to a degree which would require a much higher morphine concentration in the absence of etorphine. Similar results were obtained by pretreatment with 1 pM diprenorphine (see FIG. 4), with 1 pM naltrexone (FIG. 5) or 1 pM naloxone. Records in this and subsequent Figures are from DRG neurons in organotypic DRG-spinal cord explants maintained for 3-4 weeks in culture.
  • FIG. 3 shows dose-response curves demonstrating that etorphine (Et) ( ⁇ ) and dihydroetorphine (DHE) ( ⁇ ) elicit only inhibitory dose-dependent shortening of the APD of DRG neurons at all concentrations tested (fM- ⁇ M).
  • dynorphin A (1-13) (Dyn) (X) (as well as morphine and other bimodally-acting opioids) elicits dose-dependent excitatory APD prolongation at low concentrations (fM-nM) and generally requires much higher concentrations (about 0.1-1 ⁇ M) to shorten the APD, thereby resulting in a bell-shaped dose-response curve.
  • These potent inhibitory effects of etorphine and dihydroetorphine on DRG neurons at low concentrations are in sharp contrast to the excitatory APD-prolonging effects observed in similar tests with morphine and a wide variety of mu, delta and kappa opioids. None of the DRG neurons tested with different concentrations of etorphine or dihydroetorphine showed prominent APD prolongation.
  • DRG neurons were pretreated with etorphine at low concentrations (fM-pM) that evoked little or no alteration of the APD. Subsequent addition of nM concentrations of morphine.
  • etorphine which has been considered to be a "universal" agonist at mu, delta and kappa opioid receptors (see Magnan et al., Naunyn-Schmiedeberg's Arch. Pharmacol., Vol. 319, pp. 197-205 (1982)), has potent antagonist actions at mu, delta and kappa excitatory opioid receptors on DRG neurons, in addition to its well-known agonist effects at inhibitory opioid receptors.
  • fM-pM etorphine
  • fM-nM levels of bimodally-acting opioids now showed potent inhibitory APD-shortening effects (5 out of 9 cells) (see FIG. 2C and FIG. 4). This is presumably due to unmasking of inhibitory opioid receptor-mediated functions in these cells after selective blockade of their excitatory opioid receptor functions by etorphine.
  • Example 1 Mouse DRG-cord explants, grown for >3 weeks as described in Example 1, were tested with the opioid antagonists, diprenorphine, naltrexone and naloxone. Electrophysiological recordings were made as in Example 1.
  • naloxone and diprenorphine were previously shown to block, at nM concentrations, both inhibitory APD shortening of DRG neurons by ⁇ M opioid agonists as well as excitatory APD prolongation by nM opioids. Tests at lower concentrations have revealed that pM diprenorphine, as well as pM naloxone or naltrexone, act selectively as antagonists at mu, delta and kappa excitatory opioid receptors, comparable to the antagonist effects of pM etorphine and dihydroetorphine.
  • FIG. 4 shows that excitatory APD-prolonging effects elicited by morphine in DRG neurons are selectively blocked by co-administration of a low (pM) concentration of diprenorphine, thereby unmasking potent dose-dependent inhibitory APD shortening by low concentrations of morphine.
  • FIG. 4A records 1-4 show that APD of a DRG neuron is progressively prolonged by sequential bath perfusions with 3 fM, 3 pM and 3 nM morphine (Mor).
  • FIG. 4A record 5 shows that APD of this cell is only slightly shortened after increasing morphine concentration to 3 ⁇ M.
  • FIG. 4 shows that excitatory APD-prolonging effects elicited by morphine in DRG neurons are selectively blocked by co-administration of a low (pM) concentration of diprenorphine, thereby unmasking potent dose-dependent inhibitory APD shortening by low concentrations of morphine.
  • FIG. 4A records 1-4 show that A
  • FIG. 4A records 6 and 7 show that after transfer to BSS, the APD is slightly shortened during pretreatment for 17 minutes with 1 pM diprenorphine (DPN).
  • FIG. 4A records 8-11 show that after the APD reached a stable value in DPN, sequential applications of 3 fM, 3 pM, 3 nM and 3 ⁇ M Mor progressively shorten the APD, in contrast to the marked APD prolongation evoked by these same concentrations of Mor in the absence of DPN (see also FIG. 2C).
  • FIG. 2C shows that
  • FIG. 5 shows that excitatory APD-prolonging effects elicited by morphine in DRG neurons ( ⁇ ) are also selectively blocked by co-administration of a low (pM) concentration of naltrexone (NTX), thereby unmasking potent dose-dependent inhibitory APD shortening by low concentrations or morphine (X).
  • NTX naltrexone
  • pretreatment with a higher ( ⁇ M) concentration of NTX blocks both inhibitory as well as excitatory effects of morphine ( ⁇ ) (similar blockade occurs with 1 nM NTX).
  • FIG. 6 outlines the assay procedure used for testing the effectiveness of these and other antagonists at excitatory opioid receptors in preventing development of tolerance/dependence during chronic co-treatment of DRG neurons with morphine.
  • morphine and other clinically used bimodally-acting opioid agonists showed markedly increased potency in evoking the inhibitory effects on the action potential of sensory neurons which are generally considered to underlie opioid analgesic action in vivo.
  • the combined use of a relatively low dose of one of these selective excitatory opioid receptor antagonists, together with morphine or other bimodally-acting mu, delta or kappa opioid agonists will markedly enhance the analgesic potency of said opioid agonist, and render said opioid agonist comparable in potency to etorphine or dihydroetorphine, which, when used alone at higher doses, are >1000 times more potent than morphine in eliciting analgesia.
  • the sustained use of a relatively low clinical dose of one of these selective excitatory opioid receptor antagonists e.g., about 1 microgram of naltrexone, naloxone, etorphine, dihydroetorphine or diprenorphine, in combination with 100-1000 micrograms of morphine or other conventional bimodally-acting opioid analgesics will result in analgesia comparable to that elicited by said analgesics when administered alone in >10 milligram doses and will attenuate or even prevent development of tolerance, physical dependence and other undesirable excitatory side effects generally associated with said analgesics.
  • administration of ⁇ g doses of these excitatory opioid receptor antagonists alone will enhance the analgesic effects of endogenous opioid peptides and thereby decrease chronic pain.
  • Ultra-low doses (about 1 ⁇ g) of naltrexone.
  • Ultra-low dose naltrexone selectively blocks resumption of the sustained activation of excitatory opioid receptor functions that are required for the development of protracted opioid dependence as well as opioid-mediated cocaine and alcohol dependence without inducing dysphoria or other adverse side effects caused by high-dose naltrexone blockade of inhibitory opioid receptor functions.
  • ultra-low dose (about 1 ⁇ g) naltrexone can be administered long-term in combination with low-dose methadone to provide effective treatment for addiction.

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 opioid receptor antagonist of the invention and a bimodally-acting opioid agonist.

Description

STATEMENT OF GOVERNMENT INTEREST
This invention was made with government support under NIDA research grant number DA 02031. As such, the government has certain rights in the invention.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a Continuation-In-Part of application Ser. No. 08/097,460 filed Jul. 27, 1993, entitled METHOD OF SIMULTANEOUSLY ENHANCING ANALGESIC POTENCY AND ATTENUATING DEPENDENCE LIABILITY CAUSED BY MORPHINE AND OTHER OPIOID AGONISTS, .[.currently pending,.]. .Iadd.now issued as U.S. Pat. No. 5,472,943, .Iaddend.which is a Continuation-In-Part of application Ser. No. 07/947,690 filed Sep. 19, 1992, entitled A METHOD OF IDENTIFICATION OF NON-ADDICTIVE OPIOID ANALGESICS AND THE USE OF SAID ANALGESICS FOR TREATMENT OF OPIOID ADDICTION, now abandoned.
FIELD OF THE INVENTION
This invention relates to a method of enhancing the analgesic (inhibitory) effects of bimodally-acting opioid agonists, including morphine, codeine and other clinically used opioid analgesics, while at the same time attenuating anti-analgesic effects, physical dependence, tolerance, hyperexcitability, hyperalgesia, and other undesirable (excitatory) side effects typically caused by chronic use of bimodally-acting (excitatory and inhibitory) opioid agonists. As used herein, the term "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 related analogs.
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.
BACKGROUND OF THE INVENTION
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, Trends Neurosci., Vol. 9, pp. 114-117 (1986) and Crain and Shen, Trends Pharmacol. Sci., Vol. 11, pp. 77-81 (1990)). However, bimodally-acting opioid agonists also activate opioid excitatory receptors on nociceptive neurons, which attenuates the analgesic potency of the opioids and results in the development of physical dependence thereon and increased tolerance thereto (see Shen and Crain, Brain Res., Vol. 597, pp. 74-83 (1992)), as well as hyperexcitability, 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, Ser. 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 bind to and activate 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.
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 antagonists, 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.
SUMMARY OF THE INVENTION
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 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 Ser. 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 μg) 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 results 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, pentazocine, 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:
FIG. 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;
FIG. 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;
FIG. 3 represents dose-response curves of different opioids, showing that etorphine and dihydroetorphine elicit only inhibitory dose-dependent shortening of the APD of DRG neurons at all concentrations tested (fM-μM). In contrast, dynorphin A (as well as morphine and other bimodally-acting opioids) elicits dose-dependent excitatory APD prolongation at low concentrations (fM-nM) and requires much higher concentrations (about 0.1-1 μM) to shorten the APD, thereby resulting in-a bell-shaped dose-response curve;
FIGS. 4A and 4B represent the selective blocking of excitatory APD-prolonging effects elicited by morphine in DRG neurons by co-administration of a low (pM) 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;
FIG. 5 represents similar selective blocking of excitatory APD-prolonging effects elicited by morphine in DRG neurons when co-administered with a low (pM) concentration of naltrexone, thereby unmasking potent inhibitory APD shortening by low concentrations of morphine. In contrast, a higher (μM) concentration of naltrexone blocks both inhibitory as well as excitatory opioid effects; and
FIG. 6 represents the assay procedure used to demonstrate that selective antagonists at excitatory opioid receptors prevent development of tolerance/dependence during chronic co-treatment of DRG neurons with morphine.
DETAILED DESCRIPTION OF THE 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 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 of neurons in the nociceptive (pain) pathways and activating inhibitory opioid receptor-mediated 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 al. Substance Abuse 2 ed. pp. 70-99 (1992)), and because addiction to cocaine and alcohol are 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 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 μg 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 (>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 Crain, Brain Res., Vol. 636, pp. 286-297 (1994)). Naltrexone, naloxone (see FIG. 1) 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, Brain Res., Vol. 491, pp. 227-242 (1989) and Brain Res., Vol. 636, (1994)). Nevertheless, at very low (pM) 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, 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, 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 al. (1969) and Crain, et al. (1992)), which underlies resumption of drug abuse.
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 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 are elevated during chronic pain.
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 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 is 100-1000 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 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 μg 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., Subst. Abuse, 2d ed. (1992) and Gonzales et al., Drugs, 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 μM).
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-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 Crain and Shen, Trends Pharmacol. Sci., Vol. 11, 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, alpha2 -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 vivo. (See North, Trends Neurosci., Vol. 9, pp. 114-117 (1986) and Crain and Shen, Trends Pharmacol. Sci., 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 Crain, J. Neurosci., (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 vivo (see Crain and Shen, Trends Pharmacol. Sci., Vol. 11, pp. 77-81 (1990); Shen and Crain, Brain Res., Vol. 491, pp. 227-242 (1989); and Shen and Crain, J. Neurosci. (1994).
Chronic treatment of DRG neurons with typical bimodally-acting (excitatory/inhibitory) opioids (e.g., 1 μM D-ala2 -D-leu5 enkephalin (DADLE) or morphine for 1 week) results in tolerance to the usual inhibitory APD-shortening effects of high concentrations of these opioids and supersensitivity to the excitatory APD-prolonging effects of these opioid agonists, as well as the opioid antagonist, naloxone (see Crain and Shen, Brain Res., Vol. 575, pp. 13-24 (1992) and Shen and Crain, Brain Res., Vol. 597, pp. 74-83 (1992)). It has been suggested that the latter electrophysiologic effects and related biochemical adaptations are cellular manifestations of physical dependence that may underlie some aspects of opiate addiction (see Shen and Crain, Brain Res., Vol. 597, pp. 74-83 (1992) and Terwilliger et al., Brain Res., Vol. 548, pp. 100-110 (1991)).
In contrast to bimodally-acting opioids, it has been discovered by the inventors that the opioid alkaloids etorphine (see Bentley and Hardy, Proc. Chem. Soc., pp. 220 (1963) and Blane et al., Brit. J. Pharmacol. Chemother., Vol. 30, pp. 11-22 (1967)) and dihydroetorphine (see Bentley and Hardy, J. Amer. Chem. Soc., 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 effects at lower concentrations (see Shen and Crain, Brain Res.,, 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 neurons with etorphine or dihydroetorphine, at low concentrations (<pM) which do not alter the APD, block the excitatory APD-prolonging effects of morphine and other bimodally-acting opioids and unmask inhibitory APD-shortening effects which normally require much higher 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 contrast, bimodally-acting opioids activate excitatory as well as inhibitory opioid receptors on DRG neurons, thereby decreasing the net inhibitory effectiveness of 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 al., Neuropharmacol., 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 μM 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 receptors. In DRG neurons where fM-nM morphine elicited dose-dependent excitatory APD prolongation, subsequent tests on the same neurons in the presence of 1 pM naloxone showed a complete block of opioid excitatory effects, and in some of the cells inhibitory APD shortening was evoked at these low (fM-nM) morphine concentrations. Similar unmasking of potent inhibitory effects of low concentrations of morphine was obtained in another series of DRG neurons tested with fM-nM morphine in the presence of pM naltrexone, whereas higher concentrations of naltrexone (nM-μM) blocked both inhibitory as well as excitatory opioid effects (see FIG. 5).
The selective antagonist action of ultra-low dose naloxone at excitatory opioid receptors is consonant with in vivo data where 0.1 fg of naloxone (i.t.) enhanced a type of behavioral (tail-flick) analgesia in mice shown to be mediated by an endogenous dynorphin A-(1-17) anti-analgesic system, whereas 100 fg of naloxone (i.t.) was required to significantly reduce analgesia mediated by direct i.t. injection of morphine or k opioid agonists (see Fujimoto et al., J. Pharm. Exp. Ther., Vol. 251, pp. 1045-1052 (1989)).
Co-administration of low (pM) concentrations of etorphine during chronic treatment of DRG neurons with μM levels of morphine is effective in preventing development of the opioid excitatory supersensitivity and tolerance that generally occurs after sustained exposure to bimodally-acting opioids. Acute application of 1 fM dynorphin A(1-13) or 10 nM naloxone to DRG neurons chronically exposed to 3 μM morphine together with 1 pM etorphine (for greater than 1 week) did not evoke the usual excitatory APD prolongation observed in chronic morphine-treated cells, even when tested up to 6 hours after return to BSS. Furthermore, there was little or no evidence of tolerance to the inhibitory APD-shortening effects of μM morphine.
If etorphine was acting simply as an agonist at inhibitory opioid receptors, it might be predicted that the addition of 1 pM etorphine together with a 106 -fold higher concentration of morphine would have a negligible effect on chronic morphine-treated DRG neurons or would augment development of cellular signs of dependence. However, the results obtained are accounted for by the potent antagonist action of etorphine at excitatory opioid receptors during chronic morphine treatment, thereby preventing development of opioid excitatory supersensitivity and tolerance, just as occurs during chronic opioid treatment of DRG neurons in the presence of cholera toxin-B sub-unit (see Shen et al., Brain Res., Vol. 575, pp. 13-24 (1992)), which selectively interferes with GM1 ganglioside regulation of excitatory opioid receptor functions (see Shen et al., Brain Res., Vol. 531, pp. 1-7 (1990) and Shen et al., Brain Res., Vol. 559, pp. 130-138 (1991)).
Similarly, co-administration of ultra-low (pM) concentrations of naloxone or naltrexone during chronic treatment of DRG neurons with μM levels of morphine was effective in preventing development of the opioid excitatory supersensitivity and tolerance that generally occurs after sustained exposure to bimodally-acting opioids. Acute application of fM dynorphin A-(1-13) or fM morphine, as well as 1 nM naloxone to DRG neurons chronically exposed to 1 μM morphine together with 1 pM naloxone or naltrexone (for 1-10 weeks) did not evoke the usual excitatory APD prolongation observed in chronic morphine-treated cells (see Crain et al., (1992) and Shen et al., (1992)) tested after washout with BSS. Furthermore, there was no evidence of tolerance to the usual inhibitory effects of μM opioids.
Chronic co-treatment of nociceptive types of DRG neurons with morphine together with ultra-low (pM) concentrations of naltrexone or naloxone can therefore prevent the cellular manifestations of tolerance and dependence that generally occur in chronic morphine-treated DRG neurons. This data for naltrexone and naloxone on chronic morphine-treated nociceptive DRG neurons provides evidence that the formulation of opioid analgesic preparations comprising ultra-low doses of these excitatory opioid receptor antagonists and morphine (or codeine) will result in enhanced analgesic potency and low dependence liability.
The unmasking by pM naloxone or naltrexone of potent inhibitory (APD-shortening) effects of low pM-nM concentrations of morphine in DRG neurons accounts for the paradoxical enhancement by low-dose naloxone of: (1) morphine analgesia in humans (see Gillman et al., Intern. J. Neurosci., Vol. 48, pp. 321-324 (1989); Gillman et al., J. Nuerol. Sciences, Vol. 49, pp. 41-49 (1981); and South African J. Science Vol. 83, pp. 560-563 (1987); (2) buprenorphine analgesia in humans and animals (see Pederson et al., Brit. J. Anaesth., Vol. 57, pp. 1045-1046 (1985); Schmidt et al., Anesthesia, Vol. 40, pp. 583-586 (1985); and Bergman et al., Arch. Int. Pharmacodyn., Vol. 291, pp. 229-237 (1988)); and (3) pentazocine analgesia in humans (see Levine et al., J Clin, Invest., Vol. 82, pp. 1574-1577 (1988).
EXAMPLE 1
The effects of etorphine and dihydroetorphine on nociceptive types of DRG neurons in culture are described in Example 1. Etorphine and dihydroetorphine are the first compounds determined by the inventors by electrophysiologic analyses on DRG neurons to have specific antagonist action on excitatory opioid receptor functions when applied at ultra-low (pM) concentrations. This is in contrast to their well-known agonist action at inhibitory opioid receptors when applied at higher concentrations.
Etorphine and Dihydroetorphine Act as Potent Selective Antagonists at Excitatory Opioid Receptors on DRG Neurons Thereby Enhancing Inhibitory Effects of Bimodally-Acting Opioid Agonists
Methods (Used in This and Following Examples): The experiments described herein were carried out on dorsal root ganglion (DRG) neurons in organotypic explants of spinal cord with attached DRGs from 13-day-old fetal mice after 3 to 5 weeks of maturation in culture. The DRG-cord explants were grown on collagen-coated coverslips in Maximow depression-slide chambers. The culture medium consisted of 65% Eagle's minimal essential medium, 25% fetal bovine serum, 10% chick embryo extract. 2 mM glutamine and 0.6% glucose. During the first week in vitro the medium was supplemented with nerve growth factor (NGF-7S) at a concentration of about 0.5 μg/ml, to enhance survival and growth of the fetal mouse DRG neurons.
In order to perform electrophysiologic procedures, the culture coverslip was transferred to a recording chamber containing about 1 ml of Hanks' balanced salt solution (BSS). The bath solution was supplemented with 4 mM Ca2+ and 5 mM Ba2+ (i.e., Ca,Ba/BSS) to provide a prominent baseline response for pharmacological tests. Intracellular recordings were obtained from DRG perikarya selected at random within the ganglion. The micropipettes were filled with 3M KCl (having a resistance of about 60-100 megohms) and were connected via a chloridized silver wire to a neutralized input capacity preamplifier (Axoclamp 2A) for current-clamp recording. After impalement of a DRG neuron, brief (2 msec) depolarizing current pulses were applied via the recording electrode to evoke action potentials at a frequency of 0.1 Hz. Recordings of the action potentials were stored on a floppy disc using the P-clamp program (Axon Instruments) in a microcomputer (IBM AT-compatible).
Drugs were applied by bath perfusion with a manually operated, push-pull syringe system at a rate of 2-3 ml/min. Perfusion of test agents was begun after the action potential and the resting potential of the neuron reached a stable condition during >4 minute pretest periods in control Ca, Ba/BSS. Opioid-mediated changes in the APD were considered significant if the APD alteration was >10% of the control value for the same cell and was maintained for the entire test period of 5 minutes. The APD was measured as the time between the peak of the APD and the inflection point on the repolarizing phase. The following drugs were used in this and the following Examples: etorphine, diprenorphine and morphine (gifts from Dr. Eric Simon); dihydroetorphine (gift from Dr. B.-Y. Qin, China and United Biomedical, Inc.); naloxone (Endo Labs); naltrexone, DADLE, dynorphin and other opioid peptides (Sigma).
Opioid alkaloids and peptides were generally prepared as 1 mM solutions in H2 O and then carefully diluted with BSS to the desired concentrations, systematically discarding pipette tips after each successive 1-10 or 1-100 dilution step to ensure accuracy of extremely low (fM-pM) concentrations.
Results: Intracellular recordings were made from small- and medium-size DRG neuron perikarya (about 10-30 μm in diameter) which generate relatively long APDs (greater than 3 msec in Ca/Ba BSS) and which show characteristic responsiveness to opioid agonists and other properties of primary afferent nociceptive neurons as occur in vivo. Acute application of selective inhibitory opioid receptor agonists, e.g., etorphine, to these DRG neurons shortens the APD in 80-90% of the cells tested, whereas low concentrations of bimodally-acting (excitatory/inhibitory) opioids, e.g., morphine, dynorphin, enkephalins, prolong the APD in these same cells. Relatively small numbers of large DRG neurons (about 30-50 μm in diameter) survive in DRG-cord explants (about 10-20%) and show much shorter APDs (about 1-2 msec in Ca/Ba BSS), with no clear-cut inflection or "hump" on the falling phase of the spike. The APD of these large DRG neurons is not altered by exogenous opioids.
The opioid responsiveness of DRG neurons was analyzed by measuring the opioid-induced alterations in the APD of DRG perikarya. A total of 64 DRG neurons (from 23 DRG-cord explants) were studied for sensitivity to progressive increases in the concentration of etorphine (n=30) or dihydroetorphine (n=38). Etorphine rapidly and dose-dependently shortened the APD in progressively larger fractions of DRG cells at concentrations from 1 fM (30% of cells; n=26) to 1 μM (80% of cells; n=16) (see FIGS. 2 and 3).
FIG. 2 shows that acute application of low (pM-nM) concentrations of etorphine to naive DRG neurons elicits dose-dependent, naloxone-reversible inhibitory shortening of the action potential duration (APD). In contrast, dynorphin (and many other bimodally-acting opioid agonists, e.g., morphine, DADLE) elicit excitatory APD prolongation at these low concentrations (see FIG. 3), which can be selectively blocked by <pM levels of etorphine, as well as by diprenorphine or naltrexone (see FIGS. 4 and 5). FIG. 2A record 1 shows the action potential (AP) generated by a DRG neuron in balanced salt solution containing 5 mM Ca2+ and 5 mM Ba2+ (BSS). AP response in this record (and in all records below) is evoked by a brief (2 msec) intracellular depolarizing current pulse. FIG. 2A records 2-5 show that APD is not altered by bath perfusion with 1 fM etorphine (Et) but is progressively shortened in 1 pM, 1 nM and 1 μM concentrations (5 minute test periods). FIG. 2A record 6 shows that APD returns to control value after transfer to BSS (9 minute test). FIG. 2B records 1 and 2 show that APD of another DRG neuron is shortened by application of 1 nM etorphine (2 minute test). FIG. 2B record 3 shows that APD returns to control value after transfer to 10 nM naloxone (NLX). FIG. 2B records 4 and 5 show that APD is no longer shortened by 1 nM or even 1 μM etorphine when co-perfused with 10 nM naloxone (5 minute test periods).
FIG. 2C records 1 and 2 show that APD of another DRG neuron is prolonged by application of 3 nM morphine. FIG. 2C record 3 shows that APD returns to control value by 5 minutes after washout FIG. 2C record 4 shows that application of 1 pM etorphine does not alter the APD. FIG. 2C record 5 shows that APD is no longer prolonged by 3 nM morphine when co-perfused with 1 pM etorphine and instead is markedly shortened to a degree which would require a much higher morphine concentration in the absence of etorphine. Similar results were obtained by pretreatment with 1 pM diprenorphine (see FIG. 4), with 1 pM naltrexone (FIG. 5) or 1 pM naloxone. Records in this and subsequent Figures are from DRG neurons in organotypic DRG-spinal cord explants maintained for 3-4 weeks in culture.
FIG. 3 shows dose-response curves demonstrating that etorphine (Et) (□) and dihydroetorphine (DHE) (⋄) elicit only inhibitory dose-dependent shortening of the APD of DRG neurons at all concentrations tested (fM-μM). In contrast, dynorphin A (1-13) (Dyn) (X) (as well as morphine and other bimodally-acting opioids) elicits dose-dependent excitatory APD prolongation at low concentrations (fM-nM) and generally requires much higher concentrations (about 0.1-1 μM) to shorten the APD, thereby resulting in a bell-shaped dose-response curve. Data were obtained from 11 neurons for the etorphine tests, 13 for the DHE tests and 35 for the dynorphin tests; 5, 8 and 9 neurons were tested (as in FIG. 2) with all four concentrations of etorphine, DHE and dynorphin, respectively (from fM to μM). For sequential dose-response data on the same neuron, the lowest concentrations (e.g., 1 fM) were applied first.
Dihydroetorphine was even more effective (n=38; FIG. 3). Naloxone (10 nM) prevented the etorphine- and dihydroetorphine-induced APD shortening which was previously elicited in the same cells (n=12. FIG. 2B). These potent inhibitory effects of etorphine and dihydroetorphine on DRG neurons at low concentrations are in sharp contrast to the excitatory APD-prolonging effects observed in similar tests with morphine and a wide variety of mu, delta and kappa opioids. None of the DRG neurons tested with different concentrations of etorphine or dihydroetorphine showed prominent APD prolongation.
The absence of excitatory APD-prolonging effects of etorphine and dihydroetorphine on DRG neurons could be due to low binding affinity of these opioid agonists to excitatory opioid receptors. Alternatively, these opioids might bind strongly to excitatory receptors, but fail to activate them, thereby functioning as antagonists. In order to distinguish between these two modes of action, DRG neurons were pretreated with etorphine at low concentrations (fM-pM) that evoked little or no alteration of the APD. Subsequent addition of nM concentrations of morphine. DAGO, DADLE or dynorphin to etorphine-treated cells no longer evoked the usual APD prolongation observed in the same cells prior to exposure to etorphine (n=11; see FIG. 2C). This etorphine-induced blockade of opioid excitatory effects on DRG neurons was often effective for periods up to 0.5-2 hours after washout (n=4).
These results demonstrate that etorphine, which has been considered to be a "universal" agonist at mu, delta and kappa opioid receptors (see Magnan et al., Naunyn-Schmiedeberg's Arch. Pharmacol., Vol. 319, pp. 197-205 (1982)), has potent antagonist actions at mu, delta and kappa excitatory opioid receptors on DRG neurons, in addition to its well-known agonist effects at inhibitory opioid receptors. Pretreatment with dihydroetorphine (fM-pM) showed similar antagonist action at excitatory opioid receptor mediating nM opioid-induced APD prolongation (n=2). Furthermore, after selective blockade of opioid excitatory APD-prolonging effects by pretreating DRG neurons with low concentrations of etorphine (fM-pM), which showed little or no alteration of the APD, fM-nM levels of bimodally-acting opioids now showed potent inhibitory APD-shortening effects (5 out of 9 cells) (see FIG. 2C and FIG. 4). This is presumably due to unmasking of inhibitory opioid receptor-mediated functions in these cells after selective blockade of their excitatory opioid receptor functions by etorphine.
EXAMPLE 2
Diprenorphine, Naloxone and Naltrexone, at Low Concentrations, Show Potent Selective Antagonist Action at Excitatory Opioid Receptors
Drug tests: Mouse DRG-cord explants, grown for >3 weeks as described in Example 1, were tested with the opioid antagonists, diprenorphine, naltrexone and naloxone. Electrophysiological recordings were made as in Example 1.
Results: The opioid receptor antagonists naloxone and diprenorphine were previously shown to block, at nM concentrations, both inhibitory APD shortening of DRG neurons by μM opioid agonists as well as excitatory APD prolongation by nM opioids. Tests at lower concentrations have revealed that pM diprenorphine, as well as pM naloxone or naltrexone, act selectively as antagonists at mu, delta and kappa excitatory opioid receptors, comparable to the antagonist effects of pM etorphine and dihydroetorphine. In the presence of pM diprenorphine, morphine (n=7) and DAGO (n=7) no longer elicited APD prolongation at low (pM-nM) concentrations (see FIG. 4A). Instead, they showed progressive dose-dependent APD shortening throughout the entire range of concentrations from fM to μM (see FIG. 4B), comparable to the dose-response curves for etorphine and dihydroetorphine (see FIG. 3 and FIG. 2C). This unmasking of inhibitory opioid receptor-mediated APD-shortening effects by pM diprenorphine occurred even in the presence of 106 -fold higher concentrations of morphine (see FIG. 4A. records 11 vs. 5).
FIG. 4 shows that excitatory APD-prolonging effects elicited by morphine in DRG neurons are selectively blocked by co-administration of a low (pM) concentration of diprenorphine, thereby unmasking potent dose-dependent inhibitory APD shortening by low concentrations of morphine. FIG. 4A records 1-4 show that APD of a DRG neuron is progressively prolonged by sequential bath perfusions with 3 fM, 3 pM and 3 nM morphine (Mor). FIG. 4A record 5 shows that APD of this cell is only slightly shortened after increasing morphine concentration to 3 μM. FIG. 4A records 6 and 7 show that after transfer to BSS, the APD is slightly shortened during pretreatment for 17 minutes with 1 pM diprenorphine (DPN). FIG. 4A records 8-11 show that after the APD reached a stable value in DPN, sequential applications of 3 fM, 3 pM, 3 nM and 3 μM Mor progressively shorten the APD, in contrast to the marked APD prolongation evoked by these same concentrations of Mor in the absence of DPN (see also FIG. 2C). FIG. 4B dose-response curves demonstrate similar unmasking by 1 pM DPN of potent dose-dependent inhibitory APD shortening by morphine (□) in a group of DRG neurons (n=7), all of which showed only excitatory APD prolongation responses when tested prior to introduction of DPN (X). Note that the inhibitory potency of morphine in the presence of pM DPN becomes comparable to that of etorphine and dihydroetorphine (see FIG. 3). In contrast, pretreatment with a higher (nM) concentration of DPN blocks both inhibitory as well as excitatory effects of morphine ().
FIG. 5 shows that excitatory APD-prolonging effects elicited by morphine in DRG neurons (∘) are also selectively blocked by co-administration of a low (pM) concentration of naltrexone (NTX), thereby unmasking potent dose-dependent inhibitory APD shortening by low concentrations or morphine (X). In contrast, pretreatment with a higher (μM) concentration of NTX blocks both inhibitory as well as excitatory effects of morphine (□) (similar blockade occurs with 1 nM NTX). These dose-response curves are based on data from 18 neurons, all of which showed only excitatory APD prolongation responses when tested prior to introduction of NTX. The inhibitory potency of morphine in the presence of pM NTX becomes comparable to that of etorphine and dihydroetorphine (see FIG. 3).
EXAMPLE 3
Chronic Co-treatment of DRG Neurons with Morphine and Ultra-low-dose Naloxone or Naltrexone Prevents Development of Opioid Excitatory Supersensitivity ("Dependence") and Tolerance
Co-administration of ultra-low (pM) concentrations of naloxone or naltrexone during chronic treatment of DRG neurons with μM levels of morphine was effective in preventing development of opioid excitatory supersensitivity and tolerance which generally occurs after sustained exposure to bimodally-acting opioids. Acute application of fM dynorphin A-(1-13) or fM morphine (n=21), as well as 1 nM naloxone (n=11), to DRG neurons chronically exposed to 1 μM morphine together with 1 pM naloxone or naloxone or naltrexone (for 1-10 weeks) did not evoke the usual excitatory APD prolongation observed in chronic morphine-treated cells tested after washout with BSS (see FIG. 6). Furthermore, there was no evidence of tolerance to the usual inhibitory effects of μM opioids (n=6) (FIG. 6).
These results are consonant with previous data that blockade of sustained opioid excitatory effects by cholera toxin-B sub-unit during chronic morphine treatment of DRG neurons prevents development of tolerance and dependence. (See Shen and Crain, Brain Res., Vol. 597, pp. 74-83 (1992)). This toxin sub-unit selectively interferes with GMl ganglioside regulation of excitatory opioid receptor functions (see Shen and Crain, Brain Res., Vol. 531, pp. 1-7 (1990) and Shen et al., Brain Res., Vol. 559, pp. 130-138 (1991)).
Similarly, in the presence of pM etorphine, chronic μM morphine-treated DRG neurons did not develop signs of tolerance or dependence. FIG. 6 outlines the assay procedure used for testing the effectiveness of these and other antagonists at excitatory opioid receptors in preventing development of tolerance/dependence during chronic co-treatment of DRG neurons with morphine.
Excitatory Opioid Receptor Antagonists Enhance Analgesic Potency and Reduce Dependence Liability and Other Side Effects of Morphine or Other Conventional Opioid Analgesics When Administered in Combination
Electrophysiological studies on DRG neurons in culture indicated that pretreatment with low fM-pM concentrations of naltrexone, naloxone, diprenorphine, etorphine or dihydroetorphine is remarkably effective in blocking excitatory APD-prolonging effects of morphine or other bimodally-acting opioid agonists by selective antagonist actions at mu, delta and kappa excitatory opioid receptors on these cells. In the presence of these selective excitatory opioid receptor antagonists, morphine and other clinically used bimodally-acting opioid agonists showed markedly increased potency in evoking the inhibitory effects on the action potential of sensory neurons which are generally considered to underlie opioid analgesic action in vivo.
These bimodally-acting opioid agonists became effective in shortening, instead of prolonging, the APD at pM-nM (i.e., 10-12 -10-9 M) concentrations, whereas 0.1-1 μM (i.e., 10-7 -10-6 M) levels were generally required to shorten the APD (FIGS. 4B and 5). Selective blockade of the excitatory side effects of these bimodally-acting opioid agonists eliminates the attenuation of their inhibitory effectiveness that would otherwise occur. Hence, according to this invention, the combined use of a relatively low dose of one of these selective excitatory opioid receptor antagonists, together with morphine or other bimodally-acting mu, delta or kappa opioid agonists, will markedly enhance the analgesic potency of said opioid agonist, and render said opioid agonist comparable in potency to etorphine or dihydroetorphine, which, when used alone at higher doses, are >1000 times more potent than morphine in eliciting analgesia.
Co-administration of one of these excitatory opioid receptor antagonists at low (pM) concentration (10-12 M) during chronic treatment of sensory neurons with 10-6 M morphine or other bimodally-acting opioid agonists (>1 week in culture) prevented development of the opioid excitatory supersensitivity, including naloxone-precipitated APD-prolongation, as well as the tolerance to opioid inhibitory effects that generally occurs after chronic opioid exposure. This experimental paradigm was previously utilized by the inventors on sensory neurons in culture to demonstrate that co-administration of 10-7 M cholera toxin-B sub-unit, which binds selectively to GMl ganglioside and thereby blocks excitatory GMl-regulated opioid receptor-mediated effects, but not opioid inhibitory effects (see Shen and Crain, Brain Res., Vol. 531, pp. 1-7 (1990)), during chronic opioid treatment prevents development of these plastic changes in neuronal sensitivity that are considered to be cellular manifestations related to opioid dependence/addiction and tolerance in vivo (see Shen and Crain, Brain Res., Vol. 597, pp. 74-83 (1992)).
Hence, according to this invention, the sustained use of a relatively low clinical dose of one of these selective excitatory opioid receptor antagonists, e.g., about 1 microgram of naltrexone, naloxone, etorphine, dihydroetorphine or diprenorphine, in combination with 100-1000 micrograms of morphine or other conventional bimodally-acting opioid analgesics will result in analgesia comparable to that elicited by said analgesics when administered alone in >10 milligram doses and will attenuate or even prevent development of tolerance, physical dependence and other undesirable excitatory side effects generally associated with said analgesics. Furthermore, administration of μg doses of these excitatory opioid receptor antagonists alone will enhance the analgesic effects of endogenous opioid peptides and thereby decrease chronic pain.
Treatment of Detoxified Opiate Addicts
Long-term maintenance treatment of previously detoxified opiate, cocaine and alcohol addicts to prevent protracted dependence is carried out by long-term oral administration of ultra-low doses (about 1 μg) of naltrexone. Ultra-low dose naltrexone selectively blocks resumption of the sustained activation of excitatory opioid receptor functions that are required for the development of protracted opioid dependence as well as opioid-mediated cocaine and alcohol dependence without inducing dysphoria or other adverse side effects caused by high-dose naltrexone blockade of inhibitory opioid receptor functions. Alternatively, ultra-low dose (about 1 μg) naltrexone can be administered long-term in combination with low-dose methadone to provide effective treatment for addiction.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of various aspects of the invention. Thus, it is to be understood that numerous modifications may be made in the illustrative embodiments and other arrangements may be devised without departing from the spirit and scope of the invention.

Claims (32)

We claim:
1. A method for selectively enhancing the analgesic potency of a bimodally-acting opioid agonist and simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects associated with the administration of said bimodally-acting opioid agonist, comprising administering to a subject an analgesic or sub-analgesic amount of said bimodally-acting opioid agonist and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of said bimodally-acting opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of said bimodally-acting opioid agonist.
2. The method of claim 1 wherein the excitatory opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, etorphine, diprenorphine, dihydroetorphine, and similarly acting opioid alkaloids and opioid peptides.
3. The method of claim 1 wherein the bimodally-acting opioid agonist is selected from the group consisting of morphine, codeine, fentanyl analogs, pentazocine, buprenorphine, methadone, enkephalins, dynorphins, endorphins and similarly acting opioid alkaloids and opioid peptides.
4. The method of claim 1 wherein the amount of the excitatory opioid receptor antagonist administered is at least 100-1000 fold less than the amount of the bimodally-acting opioid agonist administered.
5. The method of claim 2 wherein the excitatory opioid receptor antagonist is naltrexone.
6. The method of claim 3 wherein the bimodally-acting opioid agonist is morphine.
7. The method of claim 3 wherein the bimodally-acting opioid agonist is codeine.
8. The method of claim 1 wherein the mode of administration is selected from the group consisting of oral, sublingual, intramuscular, subcutaneous and intravenous.
9. The method of claim 1 wherein the opioid receptor antagonist is naltrexone, and is administered orally.
10. A method for treating a detoxified opiate, cocaine or alcohol addict so as to prevent protracted dependence thereon comprising administering to the detoxified addict over a long term an amount of an excitatory opioid receptor antagonist which does not block but instead enhances the analgesic effect of morphine and other bimodally-acting opioid agonists.
11. The method of claim 10 wherein the antagonist is administered in combination with a sub-analgesic amount of a long-lasting bimodally-acting opioid agonist.
12. The method of claim 11 wherein the opioid agonist is methadone.
13. The method of claim 10 wherein the excitatory opioid receptor antagonist is selected from the group consisting of naloxone, naltrexone, etorphine, dihydroetorphine, diprenorphine, and similarly acting opioid alkaloids and opioid peptides.
14. The method of claim 13 wherein the excitatory opioid receptor antagonist is naltrexone.
15. The method of claim 11 wherein the bimodally-acting opioid agonist is methadone and the excitatory opioid receptor antagonist is naltrexone.
16. A composition comprising an analgesic or sub-analgesic amount of a bimodally-acting opioid agonist and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of said bimodally-acting opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of said bimodally-acting opioid agonist.
17. The composition of claim 16 wherein the excitatory opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, etorphine, diprenorphine, dihydroetorphine, and similarly acting opioid alkaloids and opioid peptides.
18. The composition of claim 16 wherein the bimodally-acting opioid agonist is selected from the group consisting of morphine, codeine, fentanyl analogs, pentazocine, methadone, buprenorphine, enkephalins, dynorphins, endorphins and similarly acting opioid alkaloids and opioid peptides.
19. The method of claim 1 wherein the bimodally-acting opioid agonist is morphine and the excitatory opioid receptor antagonist is naltrexone.
20. The method of claim 3 wherein the bimodally-acting opioid agonist is methadone.
21. The composition of claim 16 wherein the amount of the excitatory opioid receptor antagonist is at least 100-1000 fold less than the amount of the bimodally-acting opioid agonist.
22. The composition of claim 17 wherein the excitatory opioid receptor antagonist is naltrexone.
23. The composition of claim 18 wherein the bimodally-acting opioid agonist is morphine.
24. The composition of claim 18 wherein the bimodally-acting opioid agonist is methadone.
25. The composition of claim 16 wherein the bimodally-acting opioid agonist is morphine and the excitatory opioid receptor antagonist is naltrexone.
26. A method for treating pain in a subject comprising administering to said subject an analgesic or sub-analgesic amount of a bimodally-acting opioid agonist and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of said bimodally-acting opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of said bimodally-acting opioid agonist.
27. The method of claim 26 wherein the bimodally-acting opioid agonist is selected from the group consisting of morphine, codeine, fentanyl analogs, pentazocine, methadone, buprenorphine, enkephalins, dynorphins, endorphins and similarly acting opioid alkaloids and opioid peptides.
28. The method of claim 26 wherein the excitatory opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, etorphine, diprenorphine and dihydroetorphine, and similarly acting opioid alkaloids and opioid peptides.
29. The method of claim 26 wherein amount of the excitatory opioid receptor antagonist administered is at least 100-1000 fold less than the amount of the bimodally-acting opioid agonist administered.
30. The method of claim 26 wherein the excitatory opioid receptor antagonist is naltrexone.
31. The method of claim 26 wherein the bimodally-acting opioid receptor agonist is morphine.
32. The method of claim 26 wherein the bimodally-acting opioid agonist is morphine and the excitatory opioid receptor antagonist is naltrexone.
US08/782,452 1992-09-21 1996-01-13 Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists Expired - Lifetime USRE36547E (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US08/782,452 USRE36547E (en) 1992-09-21 1996-01-13 Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US94769092A 1992-09-21 1992-09-21
US08/097,460 US5472943A (en) 1992-09-21 1993-07-27 Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists
US08/276,966 US5512578A (en) 1992-09-21 1994-07-19 Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists
US08/782,452 USRE36547E (en) 1992-09-21 1996-01-13 Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US08/097,460 Continuation-In-Part US5472943A (en) 1992-09-21 1993-07-27 Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists
US08/276,966 Reissue US5512578A (en) 1992-09-21 1994-07-19 Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists

Publications (1)

Publication Number Publication Date
USRE36547E true USRE36547E (en) 2000-02-01

Family

ID=27378386

Family Applications (1)

Application Number Title Priority Date Filing Date
US08/782,452 Expired - Lifetime USRE36547E (en) 1992-09-21 1996-01-13 Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists

Country Status (1)

Country Link
US (1) USRE36547E (en)

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6525062B2 (en) 2000-06-09 2003-02-25 The Regents Of The University Of California Method of treating pain using nalbuphine and opioid antagonists
US6528271B1 (en) 1997-06-05 2003-03-04 Duke University Inhibition of βarrestin mediated effects prolongs and potentiates opioid receptor-mediated analgesia
US6541021B1 (en) 1999-03-18 2003-04-01 Durect Corporation Devices and methods for pain management
US20030073714A1 (en) * 2001-08-06 2003-04-17 Christopher Breder Opioid agonist formulations with releasable and sequestered antagonist
US20030088236A1 (en) * 1999-03-18 2003-05-08 Johnson Randolph Mellus Implantable devices and methods for treatment of pain by delivery of fentanyl and fentanyl congeners
US20030091635A1 (en) * 2001-09-26 2003-05-15 Baichwal Anand R. Opioid formulations having reduced potential for abuse
US20030129234A1 (en) * 2001-07-06 2003-07-10 Penwest Pharmaceuticals Company Methods of making sustained release formulations of oxymorphone
US6608075B2 (en) 1997-11-03 2003-08-19 The University Of Chicago Use of methylnaltrexone and related compounds
US20030158220A1 (en) * 1997-11-03 2003-08-21 Foss Joseph F. Use of methylnaltrexone and related compounds to treat chronic opioid use side effects
US20030187010A1 (en) * 1997-11-03 2003-10-02 Foss Joseph F. Use of methylnaltrexone and related compounds to treat chronic opioid use side effects
US20030222908A1 (en) * 2002-06-03 2003-12-04 Microsoft Corporation Dynamic wizard interface system and method
US20040029905A1 (en) * 2000-11-30 2004-02-12 Gruenenthal Gmbh Use of weak opioids and mixed opioid agonists/antagonists for treatment of urinary incontinence
EP1392265A2 (en) * 2000-10-30 2004-03-03 Pain Therapeutics, Inc. Inhibitors of abc drug transporters at the blood-brain barrier
US6713488B2 (en) 2000-03-15 2004-03-30 Sadee Wolfgang Neutral antagonists and use thereof in treating drug abuse
US20040101899A1 (en) * 1999-11-30 2004-05-27 Corixa Corporation Compositions and methods for the therapy and diagnosis of breast cancer
US20040102476A1 (en) * 2002-11-25 2004-05-27 Chan Tai Wah High concentration formulations of opioids and opioid derivatives
US20040171968A1 (en) * 2001-07-13 2004-09-02 Koji Katsuki Analyzing apparatus, piercing element integrally installed body for temperature measuring device with analyzing apparatus, and body fluid sampling apparatus
US20040224907A1 (en) * 2001-10-19 2004-11-11 Pasternak Gavril W. Compositions and methods for reversal of drug resistance
US20040266806A1 (en) * 2003-04-08 2004-12-30 Sanghvi Suketu P. Pharmaceutical formulation
US20050004155A1 (en) * 2003-04-08 2005-01-06 Boyd Thomas A. Use of methylnaltrexone to treat irritable bowel syndrome
US20050038062A1 (en) * 2003-04-14 2005-02-17 Burns Lindsay H. Methods and materials for the treatment of pain comprising opioid antagonists
US20050063909A1 (en) * 2001-08-06 2005-03-24 Euro-Celtique, S.A. Oral dosage form comprising a therapeutic agent and an adverse-effect agent
US20060009478A1 (en) * 2003-10-15 2006-01-12 Nadav Friedmann Methods for the treatment of back pain
US20060026702A1 (en) * 2002-03-19 2006-02-02 Duke University Phosphoinositide 3-kinase mediated inhibition of GPCRs
US7026329B2 (en) 1992-09-21 2006-04-11 Albert Einstein College Of Medicine Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
US20060188944A1 (en) * 1997-06-05 2006-08-24 Barak Lawrence S Methods of assaying receptor activity
US20060205753A1 (en) * 2005-01-20 2006-09-14 Israel Robert J Use of methylnaltrexone and related compounds to treat post-operative gastrointestinal dysfunction
US20060258696A1 (en) * 2005-03-07 2006-11-16 Jonathan Moss Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US20070014820A1 (en) * 2003-01-23 2007-01-18 Dana Litmanovitz Opioid formulations
US20070099946A1 (en) * 2005-05-25 2007-05-03 Doshan Harold D Synthesis of R-N-methylnaltrexone
US20070098794A1 (en) * 2001-07-06 2007-05-03 Haui-Hung Kao Oxymorphone controlled release formulations
US20070212414A1 (en) * 2006-03-08 2007-09-13 Penwest Pharmaceuticals Co. Ethanol-resistant sustained release formulations
US20070265293A1 (en) * 2005-05-25 2007-11-15 Boyd Thomas A (S)-N-methylnaltrexone
WO2008027442A2 (en) * 2006-08-30 2008-03-06 Theraquest Biosciences, Llc Abuse deterrent oral pharmaceutical formulations of opioid agonists and method of use
US20080064743A1 (en) * 2006-09-08 2008-03-13 Wyeth Dry powder compound formulations and uses thereof
US20080194611A1 (en) * 2005-06-03 2008-08-14 Alverdy John C Modulation of Cell Barrier Dysfunction
US20080261991A1 (en) * 2007-02-12 2008-10-23 Dmi Biosciences, Inc. Reducing Side Effects of Tramadol
US20080262094A1 (en) * 2007-02-12 2008-10-23 Dmi Biosciences, Inc. Treatment of Comorbid Premature Ejaculation and Erectile Dysfunction
US20080274119A1 (en) * 2005-03-07 2008-11-06 The University Of Chicago Use of Opioid Antagonists to Attenuate Endothelial Cell Proliferation and Migration
US7528175B2 (en) 2004-10-08 2009-05-05 Inverseon, Inc. Method of treating airway diseases with beta-adrenergic inverse agonists
US20090124650A1 (en) * 2007-06-21 2009-05-14 Endo Pharmaceuticals, Inc. Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instructions on Effects of Alcohol
US7541151B2 (en) 1997-06-05 2009-06-02 Duke University Single-cell biosensor for the measurement of GPCR ligands in a test sample
US20090203722A1 (en) * 2000-05-05 2009-08-13 Pain Therapeutics, Inc. Novel compositions and methods for enhancing potency or reducing adverse side effects of opiold agonists
US20100099699A1 (en) * 2007-03-29 2010-04-22 Wyeth Peripheral opioid receptor antagonists and uses thereof
US20100120813A1 (en) * 2008-09-30 2010-05-13 Wyeth Peripheral opioid receptor antagonists and uses thereof
US20100168119A1 (en) * 2008-11-05 2010-07-01 Pharmorx, Inc. Compositions and methods for minimizing or reducing agonist-induced desensitization
US20110021551A1 (en) * 2008-03-21 2011-01-27 Jonathan Moss TREATMENT WITH OPIOID ANTAGONISTS AND mTOR INHIBITORS
US20110100099A1 (en) * 2008-02-06 2011-05-05 Progenics Pharmaceuticals, Inc. Preparation and use of (r),(r)-2,2'-bis-methylnaltrexone
US20110190331A1 (en) * 2007-03-29 2011-08-04 Avey Alfred A Peripheral opioid receptor antagonists and uses thereof
US8309122B2 (en) 2001-07-06 2012-11-13 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US8518962B2 (en) 2005-03-07 2013-08-27 The University Of Chicago Use of opioid antagonists
US9102680B2 (en) 2007-03-29 2015-08-11 Wyeth Llc Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof
US9278094B2 (en) 2013-01-30 2016-03-08 Pharmorx Therapeutics, Inc. Treatments for depression and other diseases with a low dose agent
US9539221B2 (en) 2003-10-09 2017-01-10 Egb Advisors, Llc Method of treating airway diseases with β-adrenergic inverse agonists
US9662325B2 (en) 2005-03-07 2017-05-30 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3332950A (en) * 1963-03-23 1967-07-25 Endo Lab 14-hydroxydihydronormorphinone derivatives
US4760069A (en) * 1985-09-23 1988-07-26 Nova Pharmaceutical Corporation Oximes of oxymorphone, naltrexone and naloxone as potent, selective opioid receptor agonists and antagonists
US4769372A (en) * 1986-06-18 1988-09-06 The Rockefeller University Method of treating patients suffering from chronic pain or chronic cough
US4882335A (en) * 1988-06-13 1989-11-21 Alko Limited Method for treating alcohol-drinking response
US4889860A (en) * 1985-09-23 1989-12-26 Nova Pharmaceutical Corporation Oximes of oxymorphone, naltrexone and naloxone as potent, selective opioid receptor agonists and antagonists
US5075341A (en) * 1989-12-01 1991-12-24 The Mclean Hospital Corporation Treatment for cocaine abuse
US5086058A (en) * 1990-06-04 1992-02-04 Alko Ltd. Method for treating alcoholism with nalmefene
US5096715A (en) * 1989-11-20 1992-03-17 Alko Ltd. Method and means for treating alcoholism by extinguishing the alcohol-drinking response using a transdermally administered opiate antagonist
WO1994006426A1 (en) * 1992-09-21 1994-03-31 Qin Bo Yi Methods for identifying and using low/non-addictive opioid analgesics
US5317022A (en) * 1991-02-04 1994-05-31 Alkaloida Chemical Company Ltd. Pharmaceutical composition and use
US5321012A (en) * 1993-01-28 1994-06-14 Virginia Commonwealth University Medical College Inhibiting the development of tolerance to and/or dependence on a narcotic addictive substance
US5352680A (en) * 1992-07-15 1994-10-04 Regents Of The University Of Minnesota Delta opioid receptor antagonists to block opioid agonist tolerance and dependence
WO1995003804A1 (en) * 1993-07-27 1995-02-09 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Methods of enhancing opiate analgesic potency or detoxifying an opiate addict

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3332950A (en) * 1963-03-23 1967-07-25 Endo Lab 14-hydroxydihydronormorphinone derivatives
US4760069A (en) * 1985-09-23 1988-07-26 Nova Pharmaceutical Corporation Oximes of oxymorphone, naltrexone and naloxone as potent, selective opioid receptor agonists and antagonists
US4889860A (en) * 1985-09-23 1989-12-26 Nova Pharmaceutical Corporation Oximes of oxymorphone, naltrexone and naloxone as potent, selective opioid receptor agonists and antagonists
US4769372A (en) * 1986-06-18 1988-09-06 The Rockefeller University Method of treating patients suffering from chronic pain or chronic cough
US4882335A (en) * 1988-06-13 1989-11-21 Alko Limited Method for treating alcohol-drinking response
US5096715A (en) * 1989-11-20 1992-03-17 Alko Ltd. Method and means for treating alcoholism by extinguishing the alcohol-drinking response using a transdermally administered opiate antagonist
US5075341A (en) * 1989-12-01 1991-12-24 The Mclean Hospital Corporation Treatment for cocaine abuse
US5086058A (en) * 1990-06-04 1992-02-04 Alko Ltd. Method for treating alcoholism with nalmefene
US5317022A (en) * 1991-02-04 1994-05-31 Alkaloida Chemical Company Ltd. Pharmaceutical composition and use
US5352680A (en) * 1992-07-15 1994-10-04 Regents Of The University Of Minnesota Delta opioid receptor antagonists to block opioid agonist tolerance and dependence
WO1994006426A1 (en) * 1992-09-21 1994-03-31 Qin Bo Yi Methods for identifying and using low/non-addictive opioid analgesics
US5321012A (en) * 1993-01-28 1994-06-14 Virginia Commonwealth University Medical College Inhibiting the development of tolerance to and/or dependence on a narcotic addictive substance
WO1995003804A1 (en) * 1993-07-27 1995-02-09 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Methods of enhancing opiate analgesic potency or detoxifying an opiate addict

Non-Patent Citations (96)

* Cited by examiner, † Cited by third party
Title
Arts, et al., Pharm. Biochemistry Behavior, 46:623 629 (1993). *
Arts, et al., Pharm. Biochemistry Behavior, 46:623-629 (1993).
Bentley and Hardy, J. American Chem. Soc., 89:3281 3286 (1967). *
Bentley and Hardy, J. American Chem. Soc., 89:3281-3286 (1967).
Bentley and Hardy, Proc. Chem. Soc., p. 220 (1963). *
Bergman, et al., Arch. Int. Pharmacodyn., 291:229 237 (1988). *
Bergman, et al., Arch. Int. Pharmacodyn., 291:229-237 (1988).
Blane, et al., Brit. J. Pharmacol. Chemother., 30:11 22 (1967). *
Blane, et al., Brit. J. Pharmacol. Chemother., 30:11-22 (1967).
Bo Yi, Quin, New Drugs and Clinical Remedies, 12:119 123 (1992) and English translation thereof. *
Bo-Yi, Quin, New Drugs and Clinical Remedies, 12:119-123 (1992) and English translation thereof.
Buchsbaum, et al., Nature, 270:620 622 (1977). *
Buchsbaum, et al., Nature, 270:620-622 (1977).
Budd, K., Ballieres Clin. Anesthesiology, 1:993 1011 (1987). *
Budd, K., Ballieres Clin. Anesthesiology, 1:993-1011 (1987).
Cappell, et al., Pharmacology Biochemistry & Behavior, 34:425 427 (1989). *
Cappell, et al., Pharmacology Biochemistry & Behavior, 34:425-427 (1989).
Crain and Shen, J. Pharmacol. Exp. Ther., 260:182 186 (1992). *
Crain and Shen, J. Pharmacol. Exp. Ther., 260:182-186 (1992).
Crain and Shen, Trends Pharmacol. Sci., 11:77 81 (1990). *
Crain and Shen, Trends Pharmacol. Sci., 11:77-81 (1990).
Crain, et al., Brain Research, 455:99 109 (1988). *
Crain, et al., Brain Research, 455:99-109 (1988).
Fujimoto, et al., J. Pharm. Exp. Ther., 251:1045 1052 (1989). *
Fujimoto, et al., J. Pharm. Exp. Ther., 251:1045-1052 (1989).
Fujimoto, et al., Neuropharmacol., 29:609 617 (1990). *
Fujimoto, et al., Neuropharmacol., 29:609-617 (1990).
Gardner, Substance Abuse, 2d ed., pp. 70 99 (1992). *
Gardner, Substance Abuse, 2d ed., pp. 70-99 (1992).
Gillman and Lichtigfield, South African Med. J., 70:650 651 (1986). *
Gillman and Lichtigfield, South African Med. J., 70:650-651 (1986).
Gillman, et al., European J. Pharmacol., 61: 175 177 (1980). *
Gillman, et al., European J. Pharmacol., 61: 175-177 (1980).
Gillman, et al., Intern. J. Neurosci., 48:321 324 (1989). *
Gillman, et al., Intern. J. Neurosci., 48:321-324 (1989).
Gillman, et al., J. Neurol. Sciences, 49:41 49 (1981). *
Gillman, et al., J. Neurol. Sciences, 49:41-49 (1981).
Gillman, et al., South African J. Science, 83:560 563 (1987). *
Gillman, et al., South African J. Science, 83:560-563 (1987).
Goldberg, et al., Science, 166:1548 1549 (1969). *
Goldberg, et al., Science, 166:1548-1549 (1969).
Gonzales, et al., Drugs, 35:193 213 (1988). *
Gonzales, et al., Drugs, 35:193-213 (1988).
Greenstein, et al., Subst. Abuse, 2d ed., pp. 562 573 (1992). *
Greenstein, et al., Subst. Abuse, 2d ed., pp. 562-573 (1992).
Holmes and Fujimoto, Anesth. Analg., 77:1166 1173 (1993). *
Holmes and Fujimoto, Anesth. Analg., 77:1166-1173 (1993).
Horan, et al., J. Pharm. Exp. Therapeutics, 265:1446 1454 (1993). *
Horan, et al., J. Pharm. Exp. Therapeutics, 265:1446-1454 (1993).
Kayser, et al., Brain Research, 371:37 41 (1986). *
Kayser, et al., Brain Research, 371:37-41 (1986).
Lange, et al., Toxicol. Applied Pharm., 54:177 186 (1980). *
Lange, et al., Toxicol. Applied Pharm., 54:177-186 (1980).
Lasagna, Proc. Royal Soc. Med., 58(11):978 983 (1965). *
Lasagna, Proc. Royal Soc. Med., 58(11):978-983 (1965).
Levine, Brain Research, 365:377 378 (1986). *
Levine, Brain Research, 365:377-378 (1986).
Levine, et al., J. Clin. Invest., 82:1574 1577 (1988). *
Levine, et al., J. Clin. Invest., 82:1574-1577 (1988).
Levine, Nature, 278:740 741 (1979). *
Levine, Nature, 278:740-741 (1979).
Magnan, et al., Nauyn Schmiedelberg s Arch. Pharmacol., 319:197 205 (1982). *
Magnan, et al., Nauyn-Schmiedelberg's Arch. Pharmacol., 319:197-205 (1982).
Miaskowski and Levine, Brain Research, 596:41 45 (1992). *
Miaskowski and Levine, Brain Research, 596:41-45 (1992).
North, Trends Neurosci., 9:114 117 (1986). *
North, Trends Neurosci., 9:114-117 (1986).
Pederson, et al., Brit. J. Anaesth., 57:1045 1046 (1985). *
Pederson, et al., Brit. J. Anaesth., 57:1045-1046 (1985).
Schmidt, et al., Anesthesia, 40:583 586 (1985). *
Schmidt, et al., Anesthesia, 40:583-586 (1985).
Shen and Crain, Brain Res., 636:286 297 (1994). *
Shen and Crain, Brain Res., 636:286-297 (1994).
Shen and Crain, Brain Research, 491:227 242 (1989). *
Shen and Crain, Brain Research, 491:227-242 (1989).
Shen and Crain, Brain Research, 531:1 7 (1990). *
Shen and Crain, Brain Research, 531:1-7 (1990).
Shen and Crain, Brain Research, 575:13 24 (1992). *
Shen and Crain, Brain Research, 575:13-24 (1992).
Shen and Crain, Brain Research, 597:74 83 (1992). *
Shen and Crain, Brain Research, 597:74-83 (1992).
Shen and Crain, J. Neurosci., 14:5570 5579 (1994). *
Shen and Crain, J. Neurosci., 14:5570-5579 (1994).
Shen and Crain, Regulatory Peptides, in press (1993). *
Shen, et al., Brain Research, 559:130 138 (1991). *
Shen, et al., Brain Research, 559:130-138 (1991).
Taiwo, et al., J. Pharm. Exp. Therapeutics, 249:97 100 (1989). *
Taiwo, et al., J. Pharm. Exp. Therapeutics, 249:97-100 (1989).
Takemori, et al., J. Pharm. Exp. Therapeutics, 266:121 124 (1993). *
Takemori, et al., J. Pharm. Exp. Therapeutics, 266:121-124 (1993).
Terwillinger, et al., Brain Research, 548:100 110 (1991). *
Terwillinger, et al., Brain Research, 548:100-110 (1991).
Vaccarino, et al., Pain, 36:103 109 (1989). *
Vaccarino, et al., Pain, 36:103-109 (1989).
Wang, et al., Chinese J. Pharm. Toxicol., 6:36 40 (1992) and English translation thereof. *
Wang, et al., Chinese J. Pharm. Toxicol., 6:36-40 (1992) and English translation thereof.

Cited By (121)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7026329B2 (en) 1992-09-21 2006-04-11 Albert Einstein College Of Medicine Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
US7572888B2 (en) 1997-06-05 2009-08-11 Duke University Methods of assaying receptor activity and constructs useful in such methods
US6528271B1 (en) 1997-06-05 2003-03-04 Duke University Inhibition of βarrestin mediated effects prolongs and potentiates opioid receptor-mediated analgesia
US7138240B2 (en) 1997-06-05 2006-11-21 Duke University Methods of assaying receptor activity
US20060188944A1 (en) * 1997-06-05 2006-08-24 Barak Lawrence S Methods of assaying receptor activity
US7541151B2 (en) 1997-06-05 2009-06-02 Duke University Single-cell biosensor for the measurement of GPCR ligands in a test sample
US6770449B2 (en) 1997-06-05 2004-08-03 Duke University Methods of assaying receptor activity and constructs useful in such methods
US20040162307A1 (en) * 1997-11-03 2004-08-19 Foss Joseph F. Use of methylnaltrexone and related compounds to induce laxation in chronic opioid users
US20100087472A1 (en) * 1997-11-03 2010-04-08 Foss Joseph F Use of methylnaltrexone and related compound to treat constipation in chronic opioid users
US20040162306A1 (en) * 1997-11-03 2004-08-19 Foss Joseph F. Use of methylnal trexone and related compounds to treat constipation in chronic opioid users
US6608075B2 (en) 1997-11-03 2003-08-19 The University Of Chicago Use of methylnaltrexone and related compounds
US20030158220A1 (en) * 1997-11-03 2003-08-21 Foss Joseph F. Use of methylnaltrexone and related compounds to treat chronic opioid use side effects
US20030187010A1 (en) * 1997-11-03 2003-10-02 Foss Joseph F. Use of methylnaltrexone and related compounds to treat chronic opioid use side effects
US20040162308A1 (en) * 1997-11-03 2004-08-19 Foss Joseph F. Use of methylnaltrexone and related compounds for treatment of constipation caused by endogenous opioids
US20040167148A1 (en) * 1997-11-03 2004-08-26 Foss Joseph F. Oral use of methylnaltrexone and related compounds to treat constipation in chronic opioid users
US20040167147A1 (en) * 1997-11-03 2004-08-26 Foss Joseph F. Oral use of methylnaltrexone and related compounds to induce laxation in chronic opioid users
US20050048117A1 (en) * 1997-11-03 2005-03-03 Foss Joseph F. Use of methylnaltrexone and related compounds
US20050106205A1 (en) * 1999-03-18 2005-05-19 Gillis Edward M. Implantable devices and methods for treatment of pain by delivery of fentanyl and fentanyl congeners
US6835194B2 (en) 1999-03-18 2004-12-28 Durect Corporation Implantable devices and methods for treatment of pain by delivery of fentanyl and fentanyl congeners
US6689373B2 (en) 1999-03-18 2004-02-10 Durect Corporation Devices and methods for pain management
US20050129737A1 (en) * 1999-03-18 2005-06-16 Johnson Randolph M. Devices and methods for pain management
US20030088236A1 (en) * 1999-03-18 2003-05-08 Johnson Randolph Mellus Implantable devices and methods for treatment of pain by delivery of fentanyl and fentanyl congeners
US6541021B1 (en) 1999-03-18 2003-04-01 Durect Corporation Devices and methods for pain management
US20040101899A1 (en) * 1999-11-30 2004-05-27 Corixa Corporation Compositions and methods for the therapy and diagnosis of breast cancer
US6713488B2 (en) 2000-03-15 2004-03-30 Sadee Wolfgang Neutral antagonists and use thereof in treating drug abuse
US20090203722A1 (en) * 2000-05-05 2009-08-13 Pain Therapeutics, Inc. Novel compositions and methods for enhancing potency or reducing adverse side effects of opiold agonists
US6525062B2 (en) 2000-06-09 2003-02-25 The Regents Of The University Of California Method of treating pain using nalbuphine and opioid antagonists
US20030096832A1 (en) * 2000-06-09 2003-05-22 Regents Of The University Of California Method of treating pain using nalbuphine and opioid antagonists
US20030149066A1 (en) * 2000-06-09 2003-08-07 The Regents Of The University Of California Method of treating pain using nalbuphine and opioid antagonists
US20030207905A1 (en) * 2000-06-09 2003-11-06 The Regents Of The University Of California Method of treating pain using nalbuphine and opioid antagonists
EP1392265A2 (en) * 2000-10-30 2004-03-03 Pain Therapeutics, Inc. Inhibitors of abc drug transporters at the blood-brain barrier
US20040029905A1 (en) * 2000-11-30 2004-02-12 Gruenenthal Gmbh Use of weak opioids and mixed opioid agonists/antagonists for treatment of urinary incontinence
US7008939B2 (en) * 2000-11-30 2006-03-07 Gruenenthal Gmbh Use of weak opioids and mixed opioid agonists/antagonists for treatment of urinary incontinence
US20030129234A1 (en) * 2001-07-06 2003-07-10 Penwest Pharmaceuticals Company Methods of making sustained release formulations of oxymorphone
US7276250B2 (en) 2001-07-06 2007-10-02 Penwest Pharmaceuticals Company Sustained release formulations of oxymorphone
US20030129230A1 (en) * 2001-07-06 2003-07-10 Penwest Pharmaceuticals Company Sustained release formulations of oxymorphone
US8309122B2 (en) 2001-07-06 2012-11-13 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US8329216B2 (en) 2001-07-06 2012-12-11 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US20070098794A1 (en) * 2001-07-06 2007-05-03 Haui-Hung Kao Oxymorphone controlled release formulations
US20040171968A1 (en) * 2001-07-13 2004-09-02 Koji Katsuki Analyzing apparatus, piercing element integrally installed body for temperature measuring device with analyzing apparatus, and body fluid sampling apparatus
US20030073714A1 (en) * 2001-08-06 2003-04-17 Christopher Breder Opioid agonist formulations with releasable and sequestered antagonist
US7914818B2 (en) * 2001-08-06 2011-03-29 Purdue Pharma L.P. Opioid agonist formulations with releasable and sequestered antagonist
US8518443B2 (en) 2001-08-06 2013-08-27 Purdue Pharma, L.P. Opioid agonist formulations with releasable and sequestered antagonist
US9949930B2 (en) 2001-08-06 2018-04-24 Purdue Pharma L.P. Opioid agonist formulations with releasable and sequestered antagonist
US8231901B2 (en) 2001-08-06 2012-07-31 Purdue Pharma L.P. Opioid agonist formulations with releasable and sequestered antagonist
US8815287B2 (en) 2001-08-06 2014-08-26 Purdue Pharma L.P. Opiod agonist formulations with releasable and sequestered antagonist
USRE45822E1 (en) 2001-08-06 2015-12-22 Purdue Pharma L.P. Oral dosage form comprising a therapeutic agent and an adverse-effect agent
US20050063909A1 (en) * 2001-08-06 2005-03-24 Euro-Celtique, S.A. Oral dosage form comprising a therapeutic agent and an adverse-effect agent
US20070140975A1 (en) * 2001-09-26 2007-06-21 Penwest Pharmaceuticals Co. Opioid formulations having reduced potential for abuse
US20030091635A1 (en) * 2001-09-26 2003-05-15 Baichwal Anand R. Opioid formulations having reduced potential for abuse
US20040224907A1 (en) * 2001-10-19 2004-11-11 Pasternak Gavril W. Compositions and methods for reversal of drug resistance
US20060026702A1 (en) * 2002-03-19 2006-02-02 Duke University Phosphoinositide 3-kinase mediated inhibition of GPCRs
US20030222908A1 (en) * 2002-06-03 2003-12-04 Microsoft Corporation Dynamic wizard interface system and method
US20110136847A1 (en) * 2002-11-25 2011-06-09 Tai Wah Chan High Concentration Formulations of Opioids and Opioid Derivatives
US20040102476A1 (en) * 2002-11-25 2004-05-27 Chan Tai Wah High concentration formulations of opioids and opioid derivatives
US20070014820A1 (en) * 2003-01-23 2007-01-18 Dana Litmanovitz Opioid formulations
US8552025B2 (en) 2003-04-08 2013-10-08 Progenics Pharmaceuticals, Inc. Stable methylnaltrexone preparation
US20050004155A1 (en) * 2003-04-08 2005-01-06 Boyd Thomas A. Use of methylnaltrexone to treat irritable bowel syndrome
US20040266806A1 (en) * 2003-04-08 2004-12-30 Sanghvi Suketu P. Pharmaceutical formulation
US10376584B2 (en) 2003-04-08 2019-08-13 Progenics Pharmaceuticals, Inc. Stable pharmaceutical formulations of methylnaltrexone
US20100261746A1 (en) * 2003-04-08 2010-10-14 Progenics Pharmaceuticals, Inc. Pharmaceutical formulation
US9669096B2 (en) 2003-04-08 2017-06-06 Progenics Pharmaceuticals, Inc. Stable pharmaceutical formulations of methylnaltrexone
US20100261745A1 (en) * 2003-04-08 2010-10-14 Progenics Pharmaceuticals, Inc. Pharmaceutical formulation
US20100261744A1 (en) * 2003-04-08 2010-10-14 Progenics Pharmaceuticals, Inc. Pharmaceutical formulation
US20050038062A1 (en) * 2003-04-14 2005-02-17 Burns Lindsay H. Methods and materials for the treatment of pain comprising opioid antagonists
US9539221B2 (en) 2003-10-09 2017-01-10 Egb Advisors, Llc Method of treating airway diseases with β-adrenergic inverse agonists
US20060009478A1 (en) * 2003-10-15 2006-01-12 Nadav Friedmann Methods for the treatment of back pain
US7528175B2 (en) 2004-10-08 2009-05-05 Inverseon, Inc. Method of treating airway diseases with beta-adrenergic inverse agonists
US20060205753A1 (en) * 2005-01-20 2006-09-14 Israel Robert J Use of methylnaltrexone and related compounds to treat post-operative gastrointestinal dysfunction
US9662325B2 (en) 2005-03-07 2017-05-30 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US20060258696A1 (en) * 2005-03-07 2006-11-16 Jonathan Moss Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US9717725B2 (en) 2005-03-07 2017-08-01 The University Of Chicago Use of opioid antagonists
US8524731B2 (en) 2005-03-07 2013-09-03 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US8518962B2 (en) 2005-03-07 2013-08-27 The University Of Chicago Use of opioid antagonists
US9662390B2 (en) 2005-03-07 2017-05-30 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US9675602B2 (en) 2005-03-07 2017-06-13 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US20080274119A1 (en) * 2005-03-07 2008-11-06 The University Of Chicago Use of Opioid Antagonists to Attenuate Endothelial Cell Proliferation and Migration
US8003794B2 (en) 2005-05-25 2011-08-23 Progenics Pharmaceuticals, Inc. (S)-N-methylnaltrexone
US8343992B2 (en) 2005-05-25 2013-01-01 Progenics Pharmaceuticals, Inc. Synthesis of R-N-methylnaltrexone
US20100311781A1 (en) * 2005-05-25 2010-12-09 Progenics Pharmaceuticals, Inc. Synthesis of r-n-methylnaltrexone
US20100105911A1 (en) * 2005-05-25 2010-04-29 Boyd Thomas A (S)-N-methylnal trexone
US7674904B2 (en) 2005-05-25 2010-03-09 Progenics Pharmaceuticals, Inc. Synthesis of R-N-methylnaltrexone
US9597327B2 (en) 2005-05-25 2017-03-21 Progenics Pharmaceuticals, Inc. Synthesis of (R)-N-methylnaltrexone
US7563899B2 (en) 2005-05-25 2009-07-21 Progenics Pharmaceuticals, Inc. (S)-N-methylnaltrexone
US8916581B2 (en) 2005-05-25 2014-12-23 Progenics Pharmaceuticals, Inc. (S)-N-methylnaltrexone
US20070265293A1 (en) * 2005-05-25 2007-11-15 Boyd Thomas A (S)-N-methylnaltrexone
US20070099946A1 (en) * 2005-05-25 2007-05-03 Doshan Harold D Synthesis of R-N-methylnaltrexone
US20080194611A1 (en) * 2005-06-03 2008-08-14 Alverdy John C Modulation of Cell Barrier Dysfunction
US20070212414A1 (en) * 2006-03-08 2007-09-13 Penwest Pharmaceuticals Co. Ethanol-resistant sustained release formulations
WO2008027442A3 (en) * 2006-08-30 2008-10-16 Theraquest Biosciences Llc Abuse deterrent oral pharmaceutical formulations of opioid agonists and method of use
WO2008027442A2 (en) * 2006-08-30 2008-03-06 Theraquest Biosciences, Llc Abuse deterrent oral pharmaceutical formulations of opioid agonists and method of use
US20080064743A1 (en) * 2006-09-08 2008-03-13 Wyeth Dry powder compound formulations and uses thereof
US20080261991A1 (en) * 2007-02-12 2008-10-23 Dmi Biosciences, Inc. Reducing Side Effects of Tramadol
US20080262094A1 (en) * 2007-02-12 2008-10-23 Dmi Biosciences, Inc. Treatment of Comorbid Premature Ejaculation and Erectile Dysfunction
US8546418B2 (en) 2007-03-29 2013-10-01 Progenics Pharmaceuticals, Inc. Peripheral opioid receptor antagonists and uses thereof
US9102680B2 (en) 2007-03-29 2015-08-11 Wyeth Llc Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof
US8772310B2 (en) 2007-03-29 2014-07-08 Wyeth Llc Peripheral opioid receptor antagonists and uses thereof
US9879024B2 (en) 2007-03-29 2018-01-30 Progenics Pharmaceuticals., Inc. Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof
US20100099699A1 (en) * 2007-03-29 2010-04-22 Wyeth Peripheral opioid receptor antagonists and uses thereof
US8853232B2 (en) 2007-03-29 2014-10-07 Wyeth Llc Peripheral opioid receptor antagonists and uses thereof
US20110190331A1 (en) * 2007-03-29 2011-08-04 Avey Alfred A Peripheral opioid receptor antagonists and uses thereof
US8338446B2 (en) 2007-03-29 2012-12-25 Wyeth Llc Peripheral opioid receptor antagonists and uses thereof
US20090124650A1 (en) * 2007-06-21 2009-05-14 Endo Pharmaceuticals, Inc. Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instructions on Effects of Alcohol
US8916706B2 (en) 2008-02-06 2014-12-23 Progenics Pharmaceuticals, Inc. Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone
US20110100099A1 (en) * 2008-02-06 2011-05-05 Progenics Pharmaceuticals, Inc. Preparation and use of (r),(r)-2,2'-bis-methylnaltrexone
US8471022B2 (en) 2008-02-06 2013-06-25 Progenics Pharmaceuticals, Inc. Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone
US9526723B2 (en) 2008-03-21 2016-12-27 The University Of Chicago Treatment with opioid antagonists and mTOR inhibitors
US8685995B2 (en) 2008-03-21 2014-04-01 The University Of Chicago Treatment with opioid antagonists and mTOR inhibitors
US10383869B2 (en) 2008-03-21 2019-08-20 The University Of Chicago Treatment with opioid antagonists and mTOR inhibitors
US20110021551A1 (en) * 2008-03-21 2011-01-27 Jonathan Moss TREATMENT WITH OPIOID ANTAGONISTS AND mTOR INHIBITORS
US9724343B2 (en) 2008-09-30 2017-08-08 Wyeth, Llc Peripheral opioid receptor antagonists and uses thereof
US8247425B2 (en) 2008-09-30 2012-08-21 Wyeth Peripheral opioid receptor antagonists and uses thereof
US8455644B2 (en) 2008-09-30 2013-06-04 Wyeth Peripheral opioid receptor antagonists and uses thereof
US8822490B2 (en) 2008-09-30 2014-09-02 Wyeth Llc Peripheral opioid receptor antagonists and uses thereof
US9492445B2 (en) 2008-09-30 2016-11-15 Wyeth, Llc Peripheral opioid receptor antagonists and uses thereof
US8420663B2 (en) 2008-09-30 2013-04-16 Wyeth Peripheral opioid receptor antagonists and uses thereof
US20100120813A1 (en) * 2008-09-30 2010-05-13 Wyeth Peripheral opioid receptor antagonists and uses thereof
US9180125B2 (en) 2008-09-30 2015-11-10 Wyeth, Llc Peripheral opioid receptor antagonists and uses thereof
US8883831B2 (en) 2008-11-05 2014-11-11 Pharmorx Therapeutics, Inc. Compositions and methods for minimizing or reversing agonist-induced desensitization
US20100168119A1 (en) * 2008-11-05 2010-07-01 Pharmorx, Inc. Compositions and methods for minimizing or reducing agonist-induced desensitization
US9278094B2 (en) 2013-01-30 2016-03-08 Pharmorx Therapeutics, Inc. Treatments for depression and other diseases with a low dose agent

Similar Documents

Publication Publication Date Title
USRE36547E (en) Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists
US5512578A (en) Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists
US5472943A (en) Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists
US6096756A (en) Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
US5580876A (en) Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
US20010006967A1 (en) Method of simultaneously enhancing analgesic potency and attenuating adverse side effects caused by tramadol and other bimodally-acting opioid agonists
US5633259A (en) Method for identification of low/non-addictive opioid analgesics and the use of said analgesics for treatment of opioid addiction
US5585348A (en) Use of excitatory opioid receptor antagonists to prevent growth factor-induced hyperalgesia
Crain et al. Acute thermal hyperalgesia elicited by low-dose morphine in normal mice is blocked by ultra-low-dose naltrexone, unmasking potent opioid analgesia
Comer et al. Convulsive effects of systemic administration of the delta opioid agonist BW373U86 in mice.
Crain et al. After chronic opioid exposure sensory neurons become supersensitive to the excitatory effects of opioid agonists and antagonists as occurs after acute elevation of GM1 ganglioside
Shen et al. Antagonists at excitatory opioid receptors on sensory neurons in culture increase potency and specificity of opiate analgesics and attenuate development of tolerance/dependence
Ramarao et al. Effect of κ-opioid receptor agonists on morphine analgesia in morphine-naive and morphine-tolerant rats
Kamei et al. Paradoxical analgesia produced by naloxone in diabetic mice is attributable to supersensitivity of δ-opioid receptors
Shen et al. Biphalin, an enkephalin analog with unexpectedly high antinociceptive potency and low dependence liability in vivo, selectively antagonizes excitatory opioid receptor functions of sensory neurons in culture
Crain et al. Chronic morphine-treated sensory ganglion neurons remain supersensitive to the excitatory effects of naloxone for months after return to normal culture medium: an in vitro model of ‘protracted opioid dependence’
Crain et al. Etorphine elicits unique inhibitory-agonist and excitatory-antagonist actions at opioid receptors on sensory neurons: New rationale for improved clinical analgesia and treatment of opiate addiction
AU782665B2 (en) Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists
AU782475B2 (en) Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists
AU4739999A (en) Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists
AU2005229765A1 (en) Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists
Crain et al. Etorphine elicits anomalous excitatory opioid effects on sensory neurons treated with GM1 ganglioside or pertussis toxin in contrast to its potent inhibitory effects on naive or chronic morphine-treated cells
Ferri et al. ACTH1− 24 counteracts the prolactin-releasing effect of an opioid

Legal Events

Date Code Title Description
RR Request for reexamination filed

Effective date: 20021202

FPAY Fee payment

Year of fee payment: 8

B1 Reexamination certificate first reexamination

Free format text: THE PATENTABILITY OF CLAIMS 1-15, 19, 20 AND 26-32 IS CONFIRMED. CLAIMS 16-18 AND 21-25 ARE CANCELLED. NEW CLAIMS 33-97 ARE ADDED AND DETERMINED TO BE PATENTABLE.

FPAY Fee payment

Year of fee payment: 12

CC Certificate of correction
AS Assignment

Owner name: COM AFFILIATION, INC., NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIVERSITY;REEL/FRAME:036851/0595

Effective date: 20150909

AS Assignment

Owner name: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC., NEW YOR

Free format text: CHANGE OF NAME;ASSIGNOR:COM AFFILIATION, INC.;REEL/FRAME:036887/0298

Effective date: 20150909

AS Assignment

Owner name: ALBERT EINSTEIN COLLEGE OF MEDICINE, NEW YORK

Free format text: MERGER AND CHANGE OF NAME;ASSIGNORS:ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.;ALBERT EINSTEIN COLLEGE OF MEDICINE;REEL/FRAME:048438/0275

Effective date: 20190101