\llllllllllllllllllilllllllllllllllllllllllllllllllllllllllllllllllllllllll US005512578A United States Patent [19] [11] Patent Number: 5,512,578 Crain et al. [45] Date of Patent: Apr. 30, 1996

[54] METHOD OF SIMULTANEOUSLY 5,352,680 10/1994 Portoghese et al...... 514/282 ENHANCING ANALGESIC POTENCY AND FOREIGN PATENT DOCUIVIENTS ATTENUATING DEPENDENCE LIABILITY CAUSED BY EXOGENOUS AND 9406426 3/1994 WIPO ...... 514/285 ENDOGENOUS OPIOD AGONISTS Primary Examiner—James H. Reamer [75] Inventors: Stanley M. Crain, Leonia, N.J.; Ke-Fei Attorney, Agent, or Firm-Amster, Rothstein & Ebenstein Shen, Flushing, NY. [57] ABSTRACT [73] Assignee: Albert Einstein College of Medicine This invention relates to a method of selectively enhancing of Yeshiva University, a Division of the analgesic potency of morphine and other clinically used Yeshiva University, Bronx, NY. bimodally-acting opioid agonists and simultaneously attenu ating development of physical dependence, tolerance and [21] Appl. No.: 276,966 other undesirable side effects caused by the chronic admin istration of said bimodally-acting opioid agonists compris [22] Filed: Jul. 19, 1994 ing the co-administration of a bimodally-acting opioid ago nist which activates both inhibitory and excitatory opioid Related U.S. Application Data receptor-mediated functions of neurons in the nociceptive (pain) pathways of the nervous system and an opioid recep» [63] Continuation-in-part of Ser. No. 97,460, Jul. 27, 1993, which is a continuation-in-part of Ser. No. 947,690, Sep. 19, tor antagonist which selectively inactivates excitatory opioid 1992, abandoned. receptor-mediated side eifects. This invention also relates to a method of using excitatory opioid receptor antagonists [51] Int. Cl.6 ...... A61K 31/14 alone to block the undesirable excitatory side eifects of [52] U.S. Cl...... 514/282; 514/811; 514/812 endogenous bimodally-acting opioid agonists which may be [58] Field of Search ...... 514/282, 811, markedly elevated during chronic pain. This invention fur 514/812 ther relates to a method of long-term treatment of previously detoxi?ed opiate, cocaine and alcohol addicts utilizing said References Cited excitatory opioid receptor antagonists, either alone or in U.S. PATENT DOCUMENTS combination with low-dose methadone, to prevent pro tracted physical dependence, and to compositions compris 4,760,069 7/1988 Rezeszotarski et al...... 514/285 ing an excitatory opioid receptor antagonist of the invention 4,889,860 12/1989 Rezeszotarski et al...... 514/279 and a bimodally-acting opioid agonist. 5,075,341 12/1991 Mendelson et al...... 514/279

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5,512,578 1 2 METHOD OF SIMULTANEOUSLY BACKGROUND OF THE INVENTION ENHANCING ANALGESIC POTENCY AND Morphine or other bimodally-acting opioid agonists are ATTENUATIN G DEPENDENCE LIABILITY administered to relieve severe pain due to the fact that they CAUSED BY EXOGENOUS AND have analgesic eifects mediated by their activation of inhibi ENDOGENOUS OPIOD AGONISTS tory 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. 77~8l (1990)). STATEMENT OF GOVERNMENT INTEREST However, bimodally-acting opioid agonists also activate This invention was made with government support under opioid excitatory receptors on nociceptive neurons, which NIDA research grant number DA 02031. As such, the attenuates the analgesic potency of the opioids and results in government has certain rights in the invention. 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, CROSS-REFEREN CE TO RELATED hyperalgesia and other undesirable (excitatory) side effects. APPLICATIONS As a result, a long-standing need has existed to develop a method of both enhancing the analgesic (inhibitory) effects This application is a Continuation-In-Part of application of bimodally-acting opioid agonists and limiting the unde Ser. No. 08/097,460 ?led Jul. 27, 1993, entitled METHOD sirable (excitatory) side effects caused by such opioid ago OF SIMULTANEOUSLY ENHANCING ANALGESIC nists. POTENCY AND ATTENUATING DEPENDENCE The grandparent Patent Application for the instant inven LIABILITY CAUSED BY MORPHINE AND OTHER tion, Ser. No. 07/947,690, relates to a speci?c group of OPIOID AGONISTS, currently pending, which is a Con opioid agonists for use as low/non-addictive analgesics and tinuation-In-Part of application Ser. No. 07/947,690 ?led for the treatment of opioid addiction. In the grandparent Sep. 19, 1992, entitled A METHOD OF IDENTIFICATION Application, it is stated that this group of opioid agonists OF NON-ADDICT‘IVE OPIOID AN ALGESICS AND THE 25 bind to and activate inhibitory but not excitatory opioid USE OF SAID ANALGESICS FOR TREATMENT OF receptors. In contrast, morphine and most other opioid OPIOID ADDICTION, now abandoned. alkaloids and peptides elicit bimodal eifects by binding to and activating both excitatory and inhibitory opioid recep FIELD OF THE INVENTION tors. To date, no method has been discovered or developed This invention relates to a method of enhancing the whereby two opioid compounds are co-administered, one of analgesic (inhibitory) e?‘ects of bimodally-acting opioid which binds to and acts as a selective agonist at inhibitory agonists, including morphine, codeine and other clinically opioid receptors to cause analgesia and the other of which used opioid analgesics, while at the same time attenuating binds to and acts as a selective antagonist at excitatory anti-analgesic e?‘ects, physical dependence, tolerance, 35 opioid receptors so as to attenuate undesirable side eifects hyperexcitability, hyperalgesia, and other undesirable (exci caused by the administration of bimodally-acting opioid tatory) side eifects typically caused by chronic use of agonists while simultaneously enhancing the analgesic bimodally-acting (excitatory and inhibitory) opioid agonists. eifects of said bimodally-acting opioid agonists. As used herein, the term “opioid” refers to compounds It is therefore an object of this invention to provide a which bind to speci?c opioid receptors and have agonist 40 method of enhancing the analgesic potency of morphine and (activation) or antagonist (inactivation) effects at these other bimodally-acting opioid agonists by blocking their receptors, such as opioid alkaloids, including the agonist anti-analgesic side effects. morphine and the antagonist naloxone, and opioid peptides, It is a further object of this invention to provide a method including enkephalins, dynorphins and endorphins. As used of attenuating physical dependence, tolerance, hyperexcit herein, the term “opiate” refers to drugs derived from opium 45 ability, hyperalgesia and other undesirable side e?ects or related analogs. caused by the chronic administration of bimodally-acting In the instant invention, a very low dose of a selective opioid agonists. excitatory opioid receptor antagonist is combined with a It is another object of this invention to provide a method reduced dose of a bimodally-acting opioid agonist so as to for maintenance treatment of previously detoxi?ed opiate, enhance the degree of analgesia (inhibitory eiTects) and cocaine and alcohol addicts utilizing ultra-low doses of an attenuate undesired side e?ects (excitatory effects). Opioid excitatory opioid receptor antagonists, either alone or in analgesia results from activation (by opioid agonists) of combination with long-term administration of low doses of inhibitory opioid receptors on neurons in the nociceptive methadone. (pain) pathways of the peripheral and central nervous sys tems. The undesirable side eifects, including anti-analgesic 55 It is yet another object of this invention to provide a actions, hyperexcitability and hyperalgesia, the development composition which enhances the analgesic effects of bimo of physical dependence, and some types of tolerance result dally-acting opioid agonists while simultaneously attenuat from sustained activation (by bimodally-acting opioid ago ing undesirable side effects caused by said opioid agonists, nists) of excitatory opioid receptors on neurons in the including physical dependence, tolerance, hyperexcitability nociceptive (pain) pathways of the peripheral and central and hyperalgesia. nervous systems. In addition, in the instant invention, long It is still a further object of this invention to provide a terrn administration of ultra-low doses of the excitatory composition which is useful for treatment of opiate, cocaine opioid receptor antagonists of the invention, either alone or and alcohol addicts. in combination with low doses of conventional bimodally SUMMARY OF THE INVENTION acting opioid agonists, provides effective maintenance treat 65 ment of previously detoxi?ed opiate, alcohol and cocaine This invention is directed to a method of selectively addicts. enhancing the analgesic potency of morphine and other 5,512,578 3 4 conventional bimodally-acting opioid agonists and simulta the presently preferred, albeit illustrative, embodiments of neously attenuating undesirable side effects, including the present invention when taken in conjunction with the physical dependence, caused by the chronic administration accompanying drawings wherein: of said opioid agonists. Morphine and other bimodally FIG. 1 represents the structural formulae of the bimod acting (inhibitory/excitatory) opioid agonists bind to and ally-acting opioid agonist morphine and the preferred exci activate both inhibitory and excitatory opioid receptors on tatory opioid receptor antagonists of the invention, naltrex nociceptive neurons which mediate pain. Activation of one and naloxone. Na'ltrexone is the N-cyclopropylmethyl inhibitory receptors by said agonists causes analgesia. Acti» congener of naloxone; vation of excitatory receptors by said agonists results in anti-analgesic effects, hyperexcitability, hyperalgesia, as FIG. 2 represents the direct inhibitory effect of etorphine well as development of physical dependence and tolerance on the action potential duration (APD) of nociceptive types of sensory neurons and the blocking effect of etorphine on and other undesirable side effects. A series of antagonists the excitatory response (APD prolongation) elicited by which bind to excitatory opioid receptors (e.g., diprenor morphine. Acute application of low (pM-nM) concentrations phine, naltrexone and naloxone) selectively block excitatory of etorphine to naive dorsal root ganglion (DRG) neurons opioid receptor functions of nociceptive types of DRG 15 elicits dose-dependent, naloxone-reversible inhibitory short neurons at 1,000 to 10,000-fold lower concentrations than ening of the APD. In contrast, morphine and other bimod are required to block inhibitory opioid receptor functions in ally-acting opioid agonists elicit excitatory APD prolonga these neurons. The co-administration of a bimodally-acting tion at these low concentrations which can be selectively opioid agonist together with an ultra-low dose of an opioid blocked by dihydroetorphine elicit only potency. This enhanced analgesic potency permits the use of inhibitory dose-dependent shortening of the APD of DRG lower doses of morphine or other conventional opioid anal 25 neurons at all concentrations tested (fM-pM). In contrast, gesics. . dynorphin A (as well as morphine and other bimodally The preferred excitatory opioid receptor antagonists of the acting opioids) elicits dose-dependent excitatory APD pro longation at low concentrations (fM-nM) and requires much invention include naltrexone and naloxone, in addition to higher concentrations (about 0.1-1 M) to shorten the APD, etorphine, dihydroetorphine, and diprenorphine which are thereby resulting in-a bell-shaped dose-response curve; disclosed in parent US patent application Ser. No. 08/097, 30 460 and similarly acting opioid alkaloids and opioid pep FIGS. 4A and 4B represent the selective blocking of tides. Prior hereto, clinical uses of naloxone and naltrexone excitatory APD-prolonging effects elicited by morphine in have been formulated to be administered at much higher DRG neurons by co-administration of a low (pM) concen doses (eg. 50 mg), which block inhibitory opioid receptor tration of diprenorphine, thereby unmasking potent dose functions mediating analgesia in addition to blocking exci 35 dependent inhibitory APD shortening by low concentrations tatory opioid receptors. These high doses of antagonist are of morphine (comparable to the inhibitory potency of etor required as an antidote for acute opiate agonist overdose phine). In contrast, co-treatment with a higher (nM) con (e. g., respiratory depression). However, in the instant inven centration of DPN blocks both inhibitory as well as excita tion, long-term oral administration of ultra-low doses of tory opioid e?'ects; naltrexone (for example about 1 pg) alone or in combination FIG. 5 represents similar selective blocking of excitatory with low doses of methadone (e.g. mg) prevents protracted APD-prolonging effects elicited by morphine in DRG neu physical dependence which underlies resumption of drug rons when co-administered with a low (pM) concentration of abuse in previously detoxi?ed opiate, cocaine and alcohol naltrexone, thereby unmasking potent inhibitory APD short addicts. This is in contrast to clinical use of naltrexone prior ening by low concentrations of morphine. In contrast, a hereto, wherein large (50 mg) tablets (Trexan) are admin 45 higher (pM) concentration of naltrexone blocks both inhibi istered, which produce dysphoria and other aversive side tory as well as excitatory opioid effects; and effects, and long-term treatment with high doses of metha FIG. 6 represents the assay procedure used to demonstrate done which results in physical dependence on methadone. that selective antagonists at excitatory opioid receptors The opioid agonists of the invention include morphine or prevent development of tolerance/dependence during other bimodally-acting (inhibitory/excitatory) opioid alka 50 chronic co-treatment of DRG neurons with morphine. loids or opioid peptides that are in clinical use as analgesics, including codeine, fentanyl analogs, pentazocine, buprenor DETAILED DESCRIPTION OF THE phine, methadone and endorphins. INVENTION Further, in chronic pain patients, the excitatory opioid This invention is directed to a method of selectively receptor antagonists of the invention are administered alone enhancing the analgesic effect caused by the administration in ultra-low doses to enhance the analgesic potency and of a bimodally-acting opioid agonist and simultaneously decrease the dependence liability of endogenous (as opposed attenuating undesirable side effects caused by the chronic to exogenous) opioid peptides, including enkephalins, administration of said bimodally-acting opioid agonists. dynorphins and endorphins, so as to facilitate physiologic mechanisms which normally regulate opioid responsivity This is performed by simultaneously inactivating excitatory opioid receptor-mediated functions of neurons in the noci and nociceptive systems. ceptive (pain) pathways and activating inhibitory opioid BRIEF DESCRIPTION OF THE DRAWINGS receptor-mediated mediated functions of nociceptive neu rons. Low doses of a bimodally-acting opioid agonist and an The above brief description, as well as further objects and 65 excitatory opioid receptor antagonist are co~administered. features of the present invention, will be more fully under The bimodally-acting opioid agonist binds to inhibitory stood by reference to the following detailed description of receptors on nociceptive neurons so as to activate inhibitory 5,512,578 5 6 opioid receptor-mediated functions, including analgesia, and cine buprenorphine, fentanyl analogs, endorphins, and other concomitantly activates excitatory opioid receptors on noci opioid alkaloids and opioid peptides. Typically, the opioid ceptive neurons. The excitatory opioid receptor antagonist agonists of the invention are mu, delta, kappa or epsilon binds to excitatory receptors on said neurons and thereby opioid receptor agonists, and are capable of binding to inactivates excitatory opioid receptor-mediated functions, inhibitory opioid receptors on neurons in the pain pathway. including anti-analgesic effects, physical dependence and When these bimodally-acting agonists bind to inhibitory tolerance to the opioid agonist, hyperexcitability and hype opioid receptors, they thereby activate inhibitory opioid ralgesia. receptor-mediated functions, including analgesia. Alternatively, the excitatory opioid receptor antagonists As discussed below, the inventors have discovered by of the invention can be used to pretreat patients prior to studies of nociceptive DRG neurons that certain compounds administering bimodally-acting exogenous opioids thereto, (the excitatory opioid receptor antagonists of the invention), or used alone to enhance the analgesic potency and decrease when used for pretreatment or when co-administered with the dependence liability of endogenous opioid peptides bimodally-acting opioid agonists, are capable at very low including enkephalins, dynorphins and endorphins, which dosages of enhancing the analgesic effects of the bimodally are markedly unregulated in chronic pain patients. 15 acting opioid agonists at least 100-1000 fold by inactivating In addition, this invention is directed to the use of said excitatory anti-analgesic side effects of said agonists. In excitatory opioid receptor antagonists and opioid agonists addition, the excitatory opioid receptor antagonists of the for maintenance treatment of previously detoxi?ed opiate invention prevent development of opioid tolerance and addicts. Because addiction to cocaine and alcohol are also dependence which are mediated by sustained activation of mediated by speci?c opioid-sensitive brain cell networks excitatory opioid receptor functions. (see Gardner, et al. Substance Abuse 2 ed. pp. 70-99 In addition, the excitatory opioid receptor antagonists of (1992)), and because addiction to cocaine and alcohol are the invention can be administered either alone or in con mediated by speci?c opioid-sensitive brain cell networks, junction with low, sub-analgesic doses of inhibitory opioid the method of the invention for treating opiate addicts can receptor agonists for long-term maintenance treatment of also be used for the treatment of cocaine or alcohol addicts. 25 previously detoxi?ed opiate, cocaine and alcohol addicts to Further, this invention is directed to a composition compris prevent protracted physical dependence (see Goldberg, et al. ing an excitatory opioid receptor antagonist and a bimod (1969) and Crain, et al. (1992)), which underlies resumption ally-acting opioid agonist. of drug abuse. The inventors have discovered that certain compounds act The long-term treatment of detoxi?ed addicts with selec as excitatory opioid receptor antagonists, that is, they bind to tive antagonists blocks sustained activation of excitatory and inactivate excitatory opioid receptors on neurons in the opioid receptor functions by endogenous opioid peptides. nociceptive pathways. The excitatory opioid receptor These peptides are present in the brain at concentrations that antagonists of the invention are preferably selected from the are W611 above the markedly reduced threshold required to group consisting of naloxone, naltrexone, diprenorphine, activate chronic morphine-sensitized excitatory opioid etorphine and dihydroetorphine. One of the excitatory receptors, thereby blocking the cellular mechanism pro opioid receptor antagonists of the invention, naltrexone, can posed to underlie protracted physical dependence. Further, be administered orally at very low doses. For example, the excitatory opioid receptor antagonists can be adminis naltrexone can be administered at a level as low as 1 pg and tered alone to chronic pain patients to enhance the analgesic will have selective antagonist action at excitatory, but not potency and decrease the dependence liability of endog inhibitory, opioid receptors. All previous clinical use of enous opioid peptides, including enkephalins, dynorphins naltrexone, as well as naloxone, has been at much higher and endorphins which normally regulate nociceptive (pain) (>mg) doses which results in antagonist actions at both sensitivity and which are elevated during chronic pain. inhibitory as well as excitatory opioid receptors. In addition, Ordinarily, most conventional bimodally-acting opioid since the antagonists enhance the analgesic potency of the 45 agonists are administered clinically in milligram dosages. agonists, the agonists become effective when administered By co-administering bimodally-acting opioid agonists with at markedly reduced doses which would otherwise be sub the excitatory opioid receptor antagonists of the invention, it analgesic. is possible to achieve an analgesic effect with 10-100 times The alkaloid opioid receptor antagonists of the invention lower doses of the bimodally-acting opioid agonist than inactivate mu, delta, kappa and other subtypes of excitatory when said opioid agonist is administered alone. This is opioid receptors. Etorphine and dihydroetorphine have very because the excitatory opioid receptor antagonists of the similar chemical structures and are potent analgesics which invention enhance the analgesic effects of the bimodally selectively activate inhibitory but not excitatory opioid acting opioid agonists by attenuating the anti-analgesic receptors (see Shen and Crain, Brain Res, Vol. 636, pp. excitatory side effects of said opioid agonists. Hence, bimo 286—297 (1994)). Naltrexone, naloxone (see FIG. 1) and 55 dally-acting opioid agonists which are administered with the diprenorphine have slightly different chemical structures excitatory opioid receptor antagonists of the invention are than etorphine and dihydroetorphine, which results in their administered in an amount 10-100 times less than the acting as general opioid receptor antagonists at all types of amount of that bimodally-acting opioid agonist which has inhibitory and excitatory opioid receptors (see Shen and typically been administered for analgesia. Crain, Brain Res., Vol. 491, pp. 227-242 (1989) and Brain According to the present invention, the dose of excitatory Res., Vol. 636, (1994)). Nevertheless, at very low (pM) opioid receptor antagonist to be administered is 100-1000 concentrations, these compounds are all capable of selec times less than the dose of bimodally-acting opioid agonist tively binding to and acting as antagonists at excitatory, but to be administered, for example, about 1 rnicrogram of said not inhibitory, opioid receptors on nociceptive DRG neu antagonist together with 100-1000 micrograms of said ago rons. 65 nist. These estimates of dosages are based on studies of The bimodally-acting opioid agonists of this invention nociceptive DRG neurons in culture. The excitatory opioid preferably include morphine, codeine, methadone, pentazo receptor antagonists, as well as the inhibitory opioid ago 5,512,578 7 8 nists, can be administered orally, sublingually, intramuscu elfects of these opioid agonists, as well as the opioid larly, subcutaneously or intravenously. Naltrexone is par antagonist, naloxone (see Crainand Shen, Brain Res., Vol. ticularly useful since it can be administered orally at 1 pg 575, pp. 13-24 (1992) and Shen and Crain, Brain Res., Vol. doses, has long-lasting action and has been safely used in 597, pp. 74-83 (1992)). It has been suggested that the latter treatment of opiate addiction at 50 mg doses several times electrophysiologic effects and related biochemical adapta per week for several years (see Greenstein et al., Subst. tions are cellular manifestations of physical dependence that Abuse, 2d ed. (1992) and Gonzales et al., Drugs, Vol. 35, pp. may underlie some aspects of opiate addiction (see Shen and 192-213 (1988). - Crain, Brain Res., Vol. 597, pp. 74-83 (1992) and Terwill iger et al., Brain Res., Vol. 548, pp. 100-110 (1991)). The co-administration of the opioid agonists and excita tory opioid receptor antagonists of the invention simulta In contrast to bimodally-acting opioids, it has been dis covered by the inventors that the opioid alkaloids etorphine neously activates inhibitory functions of nociceptive neu (see Bentley and Hardy, Proc. Chem. Soc, pp. 220 (1963) rons mediating pain and inactivates excitatory functions of and Blane et al., Brit. J. Pharmacol. Chemother., Vol. 30, pp. the same or other nociceptive neurons. In order to demon 11-22 (1967)) and dihydroetorphine (see Bentley and strate this, electrophysiologic studies on the e?ects of opio Hardy, J. Amer. Chem. Soc., Vol. 89, pp. 3281-3286 (1967)) ids on nociceptive types of mouse sensory DRG neurons in uniquely elicit dose-dependent, naloxone-reversible inhibi tissue cultures were performed. It is shown below that this tory effects on sensory neurons in DRG-spinal cord explants, bimodal modulation is mediated by activating putative exci even at concentrations as low as 1 pM, and show no tatory opioid receptors in addition to previously character excitatory eiTects at lower concentrations (see Shen and ized inhibitory opioid receptors on sensory neurons. Crain, Brain Res.,, Vol. 636, pp. 286-297 (1994)). In addi- - It is shown that at low pM-nM concentrations, nearly all 20 tion, these potent inhibitory opioid receptor agonists also bimodally-acting opioids, including morphine, enkephalins, display unexpected antagonist effects at excitatory opioid dynorphins, endorphins and speci?c mu, delta and kappa receptors on DRG neurons. Acute pretreatment of DRG opioid agonists, elicit naloxone-reversible dose-dependent neurons with etorphine or dihydroetorphine, at low concen excitatory effects manifested by prolongation of the cal trations (dynorphin A pertussis toxin-sensitive inhibitory G proteins: Gi to the release in spinal cord in mice (see Fujimoto et al., Neurop adenylate cyclase/cyclic AMP system and Go to ionic con 40 harmacoL, Vol. 29, pp. 609-617, (1990)). ductances that shorten the APD (resembling, for example, The inventors have discovered that at ultra-low (pM) ‘alphaZ-adrenergic receptors). Shortening by opioids of the concentrations, naloxone and naltrexone act as selective action potential of primary sensory neurons has generally antagonists at excitatory opioid receptors on DRG neurons, been considered to be a useful model of their inhibition of thereby unmasking potent inhibitory effects of bimodally calcium in?ux and transmitter release at presynaptic tenni 45 acting opioid agonists. At nM concentrations, naloxone nals in the dorsal spinal cord, thereby accounting for opioid blocks both inhibitory APD shortening in DRG neurons by induced analgesia in vivo. (See North, Trends Neurosci., M opioid agonists as well as excitatory APD prolongation Vol. 9, pp. 114-117 (1986) and Crain and Shen, Trends by pM-nM opioids. Systematic tests with lower concentra Pharmacol. Sci., Vol. 11, pp. 77-81 (1990)). tions of naloxone have revealed that pM naloxone acts Similarly, the delayed repolarization associated with the 50 selectively as an antagonist at excitatory opioid receptors. In observed opioid-induced prolongation of action potential DRG neurons where fM-nM morphine elicited dose-depen has been interpreted as evidence of excitatory effects of dent excitatory APD prolongation, subsequent tests on the opioids on nociceptive types of sensory neurons (see Shen same neurons in the presence of 1 pM naloxone showed a and Crain, J. Neurosci., (1994, in press)) that may result in complete block of opioid excitatory effects, and in some of enhanced calcium in?ux and transmitter release at presyn 55 the cells inhibitory APD shortening was evoked at these low aptic terminals. This could account for some types of (iM-nM) morphine concentrations. Similar unmasking of hyperalgesia and hyperexcitatory states elicited by opioids potent inhibitory e?ects of low concentrations of morphine in vivo (see Grain and Shen, Trends Pharmacol. Sci., Vol. was obtained in another series of DRG neurons tested with 11, pp. 77-81 (1990); Shen and Crain, Brain Res., Vol. 491, fM-nM morphine in the presence of pM naltrexone, pp. 227-242 (1989); and Shen and Crain, J. Neurosci. 60 whereas higher concentrations of naltrexone (nM-uM) (1994). blocked both inhibitory as well as excitatory opioid effects Chronic treatment of DRG neurons with typical bimod (see FIG. 5). ally-acting (excitatory/inhibitory) opioids (e.g., 1 pM The selective antagonist action of ultra-low dose naloxone D-ala’z-D-leu5 enkephalin (DADLE) or morphine for 1 at excitatory opioid receptors is consonant with in vivo data week) results in tolerance to the usual inhibitory APD 65 where 0.1 fg of naloxone (i.t.) enhanced a type of behavioral shortening effects of high concentrations of these opioids (tail-?ick) analgesia in mice shown to be mediated by an and supersensitivity to the excitatory APD-prolonging endogenous dynorphin A-(1-17) anti-analgesic system, 5,512,578 9 10 whereas 100 fg of naloxone (i.t.) was required to signi? African J. Science Vol. 83, pp. 560-563 (1987); (2) cantly reduce analgesia mediated by direct it. injection of buprenorphine analgesia in humans and animals (see Ped morphine or k opioid agonists (see Fujimoto et al., J. Pharm. erson et al., Brit. J. Anaesth, Vol.57, pp. 1045-1046 (1985); Exp. Ther., Vol. 251, pp. 1045-1052 (1989)). Schmidt et al., Anesthesia, Vol. 40, pp. 583-586 (1985); and Co-administration of low (pM) concentrations of etor Bergman et al., Arch. Int. Pharmacodyn., Vol. 291, pp. phine during chronic treatment of DRG neurons with M 229-237 (1988)); and (3) pentazocine analgesia in humans levels of morphine is e?ective in preventing development of (see Levine et al., J Clin, Invest, Vol. 82, pp. 1574-1577 the opioid excitatory supersensitivity and tolerance that (1988). generally occurs after sustained exposure to bimodally 10 acting opioids. Acute application of l fM dynorphin EXAMPLE 1 A(l-13) or 10 nM naloxone to DRG neurons chronically exposed to 3 11M morphine together with 1 pM etorphine (for The effects of etorphine and dihydroetorphine on nocice greater than 1 week) did not evoke the usual excitatory APD ptive types of DRG neurons in culture are described in prolongation observed in chronic morphine-treated cells, Example 1. Etorphine and dihydroetorphine are the ?rst even when tested up to 6 hours after return to BSS. Fur compounds determined by the inventors by electrophysi~ thermore, there was little or no evidence of tolerance to the ologic analyses on DRG neurons to have speci?c antagonist inhibitory APD-shortening effects of M morphine. action on excitatory opioid receptor functions when applied If etorphine was acting simply as an agonist at inhibitory at ultra-low (pM) concentrations. This is in contrast to their opioid receptors, it might be predicted that the addition of 1 well-known agonist action at inhibitory opioid receptors pM etorphine together with a 106-fold higher concentration when applied at higher concentrations. of morphine would have a negligible effect on chronic Etorphine and Dihydroetorphine Act as Potent Selective morphine-treated DRG neurons or would augment develop Antagonists at Excitatory Opioid Receptors on DRG Neu ment of cellular signs of dependence. However, the results rons Thereby Enhancing Inhibitory Effects of Bimodally obtained are accounted for by the potent antagonist action of Acting Opioid Agonists 25 etorphine at excitatory opioid receptors during chronic mor Methods (Used in This and Following Examples): The phine treatment, thereby preventing development of opioid experiments described herein were carried out on dorsal root excitatory supersensitivity and tolerance, just as occurs ganglion (DRG) neurons in organotypic explants of spinal during chronic opioid treatment of DRG neurons in the cord with attached DRGs from l3-day-old fetal mice after 3 presence of cholera toxin-B sub-unit (see Shen et al., Brain to 5 weeks of maturation in culture. The DRG-cord explants 30 Res, Vol. 575, pp. 13-24 (1992)), which selectively inter were grown on collagen-coated coverslips in Maximow feres with GM1 ganglioside regulation of excitatory opioid depression-slide chambers. The culture medium consisted of receptor functions (see Shen et al., Brain Res., Vol. 531, pp. 65% Eagle’s minimal essential medium, 25% fetal bovine 1-7 (1990) and Shen et al., Brain Res, Vol. 559, pp. serum, 10% chick embryo extract, 2 mM glutamine and 130-138 (1991)). 0.6% glucose. During the ?rst week in vitro the medium was 35 Similarly, co-adrninistration of ultra-low (pM) concentra supplemented with nerve growth factor (NGF-7S) at a tions of naloxone or naltrexone during chronic treatment of concentration of about 0.5 ug/ml, to enhance survival and DRG neurons with M levels of morphine was e?’ective in growth of the fetal mouse DRG neurons. preventing development of the opioid excitatory supersen In order to perform electrophysiologic procedures, the sitivity and tolerance that generally occurs after sustained culture coverslip was transferred to a recording chamber exposure to bimodally-acting opioids. Acute application of containing about 1 ml of Hanks’ balanced salt solution M dynorphin A-(l-l3) or fM morphine, as well as 1 nM (BSS). The bath solution was supplemented with 4 mM Ca2+ naloxone to DRG neurons chronically exposed to 1 pM and 5 mM Ba2+ (i.e., Ca,Ba/BSS) to provide a prominent morphine together with 1 pM naloxone or naltrexone (for baseline response for pharmacological tests. Intracellular 1-10 weeks) did not evoke the usual excitatory APD pro 45 recordings were obtained from DRG perikarya selected at longation observed in chronic morphine~treated cells (see random within the ganglion. The micropipettes were ?lled Crain et al., (1992) and Shen et al., (1992)) tested after with 3M KCl (having a resistance of about 60-100 mego washout with BSS. Furthermore, there was no evidence of hms) and were connected via a chloridized silver wire to a tolerance to the usual inhibitory eifects of M opioids. neutralized input capacity preampli?er (Axoclamp 2A) for Chronic co-treatment of nociceptive types of DRG neu current-clamp recording. After impalement of a DRG neu rons with morphine together with ultra-low (pM) concen ron, brief (2 msec) depolarizing current pulses were applied trations of naltrexone or naloxone can therefore prevent the via the recording electrode to evoke action potentials at a cellular manifestations of tolerance and dependence that frequency of 0.1 Hz. Recordings of the action potentials generally occur in chronic morphine-treated DRG neurons. were stored on a ?oppy disc using the P-clamp program This data for naltrexone and naloxone on chronic morphine 55 (Axon Instruments) in a microcomputer (IBM AT-compat treated nociceptive DRG neurons provides evidence that the ible). formulation of opioid analgesic preparations comprising Drugs were applied by bath perfusion with a manually ultra-low doses of these excitatory opioid receptor antago operated, push-pull syringe system at a rate of 2-3 ml/min. nists and morphine (or codeine) will result in enhanced Perfusion of test agents was begun after the action potential analgesic potency and low dependence liability. 60 and the resting potential of the neuron reached a stable The unmasking by pM naloxone or naltrexone of potent condition during >4 minute pretest periods in control Ca, inhibitory (APD-shortening) effects of low pM-nM concen Ba/BSS. Opioid-mediated changes in the APD were con trations of morphine in DRG neurons accounts for the sidered signi?cant if the APD alteration was >10% of the paradoxical enhancement by low-dose naloxone of: (l) control value for the same cell and was maintained for the morphine analgesia in humans (see Gillman et al., Intern. J. 65 entire test period of 5 minutes. The APD was measured as Neurosci., Vol. 48, pp. 321-324 (1989); Gillman et al., J. the time between the peak of the APD and the in?ection Nuerol. Sciences, Vol.‘ 49, pp. 41-49 (1981); and South point on the repolarizing phase. The following drugs were 5,512,578 11 12 used in this and the following Examples: etorphine, cation of 1 pM etorphine does not alter the APD. FIG. 2C diprenorphine and morphine (gifts from Dr. Eric Simon); record 5 shows that APD is no longer prolonged by 3 nM dihydroetorphine (gift from Dr. B.-Y. Qin, China and United morphine when co-perfused with 1 pM etorphine and Biomedical, Inc.); naloxone (Endo Labs); naltrexone, instead is markedly shortened to a degree which would DADLE, dynorphin and other opioid peptides (Sigma). require a much higher morphine concentration in the absence of etorphine. Similar results were obtained by Opioid alkaloids and peptides were generally prepared as pretreatment with 1 pM diprenorphine (see FIG. 4), with 1 1 mM solutions in H20 and then carefully diluted with BSS pM naltrexone (FIG. 5) or 1 pM naloxone. Records in this to the desired concentrations, systematically discarding and subsequent Figures are from DRG neurons in organo pipette tips after each successive 1-10 or 1-100 dilution step typic DRG-spinal cord explants maintained for 3-4 weeks in to ensure accuracy of extremely low (fM-pM) concentra culture. tions. FIG. 3 shows dose-response curves demonstrating that Results: Intracellular recordings were made from small etorphine (Et) ([1) and dihydroetorphine (DHE) (0) elicit and medium-size DRG neuron perikarya (about 10-30 pm in only inhibitory dose-dependent shortening of the APD of diameter) which generate relatively long APDs (greater than DRG neurons at all concentrations tested (fM-pM). In 3 msec in Ca/Ba BSS) and which show characteristic contrast, dynorphinA (l-l3) (Dyn) (X) (as well as morphine responsiveness to opioid agonists and other properties of and other bimodally-acting opioids) elicits dose-dependent primary afferent nociceptive neurons as occur in vivo. Acute excitatory APD prolongation at low concentrations application of selective inhibitory opioid receptor agonists, (fM-nM) and generally requires much higher concentrations e.g., etorphine, to these DRG neurons shortens the APD in (about 0.1-1 M) to shorten the APD, thereby resulting in a 80-90% of the cells tested, whereas low concentrations of 20 bell-shaped dose-response curve. Data were obtained from bimodally-acting (excitatory/inhibitory) opioids, e.g., mor 11 neurons for the etorphine tests, 13 for the DHE tests and phine, dynorphin, enkephalins, prolong the APD in these 35 for the dynorphin tests; 5, 8 and 9 neurons were tested (as same cells. Relatively small numbers of large DRG neurons in FIG. 2) with all four concentrations of etorphine, DHE (about 30-50 pm in diameter) survive in DRG-cord explants and dynorphin, respectively (from fM to M). For sequential (about 10-20%) and show much shorter APDs (about 1-2 25 dose-response data on the same neuron, the lowest concen msec in Ca/Ba BSS), with no clear-cut in?ection or “hump” trations (e.g., l M) were applied ?rst. on the falling phase of the spike. The APD of these large Dihydroetorphine was even more effective (n=38; FIG. DRG neurons is not altered by exogenous opioids. 3). Naloxone (10 nM) prevented the etorphine- and dihy The opioid responsiveness of DRG neurons was analyzed 30 droetorphine-induced APD shortening which was previously by measuring the opioid-induced alterations in the APD of elicited in the same cells (n=12; FIG. 2B). These potent DRG perikarya. A total of 64 DRG neurons (from 23 inhibitory effects of etorphine and dihydroetorphine on DRG DRG-cord explants) were studied for sensitivity to progres neurons at low concentrations are in sharp contrast to the sive increases in the concentration of etorphine (n=30) or excitatory APD-prolonging effects observed in similar tests dihydroetorphine (n=38). Etorphine rapidly and dose-depen with morphine and a wide variety of mu, delta and kappa dently shortened the APD in progressively larger fractions of opioids. None of the DRG neurons tested with different DRG cells at concentrations from 1 fM (30% of cells; n:26) concentrations of etorphine or dihydroetorphine showed to 1 M (80% of cells; n=l6) (see FIGS. 2 and 3). prominent APD prolongation. FIG. 2 shows that acute application of low (pM-nM) The absence of excitatory APD-prolonging effects of concentrations of etorphine to naive DRG neurons elicits 40 etorphine and dihydroetorphine on DRG neurons could be dose-dependent, naloxone-reversible inhibitory shortening due to low binding a?inity of these opioid agonists to of the action potential duration (APD). In contrast, dynor excitatory opioid receptors. Alternatively, these opioids phin (and many other bimodally-acting opioid agonists, e. g., might bind strongly to excitatory receptors, but fail to morphine, DADLE) elicit excitatory APD prolongation at activate them, thereby functioning as antagonists. In order to these low concentrations (see FIG. 3), which can be selec 45 distinguish between these two modes of action, DRG neu tively blocked by < pM levels of etorphine, as well as by rons were pretreated with etorphine at low concentrations diprenorphine or naltrexone (see FIGS. 4 and 5). FIG. 2A (fM-pM) that evoked little or no alteration of the APD. record 1 shows the action potential (AP) generated by a Subsequent addition of nM concentrations of morphine, DRG neuron in balanced salt solution containing 5 mM Ca2+ DAGO, DADLE or dynorphin to etorphine-treated cells no and 5 mM Ba“ (BSS). AP response in this record (and in all 50 longer evoked the usual APD prolongation observed in the records below) is evoked by a brief (2 msec) intracellular same cells prior to exposure to etorphine (n=l1; see FIG. depolarizing current pulse. FIG. 2A records 2-5 show that 2C). This etorphine-induced blockade of opioid excitatory APD is not altered by bath perfusion with 1 fM etorphine effects on DRG neurons was often effective for periods up (Et) but is progressively shortened in 1 pM, 1 nM and 1 uM to 0.5-2 hours after washout (n=4). concentrations (5 minute test periods). FIG. 2A record 6 55 These results demonstrate that etorphine, which has been shows that APD returns to control value after transfer to BSS considered to be a “universal" agonist at mu, delta and kappa (9 minute test). FIG. 2B records 1 and 2 show that APD of opioid receptors (see Magnan et al., Naunyn-Schmiede another DRG neuron is shortened by application of l'nM berg’sArch. PharmacoL, Vol. 319, pp. 197-205 (1982)), has etorphine (2 minute test). FIG. 2B record 3 shows that APD potent antagonist actions at mu, delta and kappa excitatory returns to control value after transfer to 10 nM naloxone 60 opioid receptors on DRG neurons, in addition to its well (NLX). FIG. 2B records 4 and 5 show that APD is no longer known agonist effects at inhibitory opioid receptors. Pre shortened by 1 nM or even 1 uM etorphine when co treatment with dihydroetorphine (fM-pM) showed similar perfused with 10 nM naloxone (5 minute test periods). antagonist action at excitatory opioid receptor mediating nM FIG. 2C records 1 and 2 show that APD of another DRG opioid-induced APD prolongation (n=2). Furthermore, after neuron is prolonged by application of 3 nM morphine. FIG. selective blockade of opioid excitatory APD-prolonging 2C record 3 shows that APD returns to control value by 5 effects by pretreating DRG neurons with low concentrations . minutes after washout. FIG. 2C record 4 shows that appli of etorphine (fM-pM), which showed little or no alteration 5,512,578 13 14 of the APD, fM-nM levels of bimodally-acting opioids now tration of naltrexone (NTX), thereby unmasking potent showed potent inhibitory APD-shortening effects (5 out of 9 dose-dependent inhibitory APD shortening by low concen cells) (see FIG. 2C and FIG. 4). This is presumably due to trations or morphine (X). In contrast, pretreatment with a unmasking of inhibitory opioid receptor-mediated functions higher (pM) concentration of NTX blocks both inhibitory as in these cells after selective blockade of their excitatory well as excitatory effects of morphine ([1) (similar blockade opioid receptor functions by etorphine. occurs with 1 nM NTX). These dose-response curves are based on data from 18 neurons, all of which showed only EXAMPLE 2 excitatory APD prolongation responses when tested prior to Diprenorphine, Naloxone and Naltrexone, at Low Con introduction of NTX. The inhibitory potency of morphine in centrations, Show Potent Selective Antagonist Action at the presence of pM NTX becomes comparable to that of Excitatory Opioid Receptors etorphine and dihydroetorphine (see FIG. 3). Drug tests: Mouse DRG-cord explants, grown for >3 EXAMPLE 3 weeks as described in Example I, were tested with the Chronic Co-treatment of DRG Neurons with Morphine opioid antagonists, diprenorphine, naltrexone and naloxone. and Ultra-low-dose Naloxone or Naltrexone Prevents Electrophysiological recordings were made as in Example 1. Development of Opioid Excitatory Supersensitivity Results: The opioid receptor antagonists naloxone and (“Dependence”) and Tolerance diprenorphine were previously shown to block, at nM con Co-administration of ultra-low (pM) concentrations of centrations, both inhibitory APD shortening of DRG neu naloxone or naltrexone during chronic treatment of DRG rons by M opioid agonists as well as excitatory APD neurons with M levels of morphine was effective in pre prolongation by nM opioids. Tests at lower concentrations venting development of opioid excitatory supersensitivity have revealed that pM diprenorphine, as well as pM nalox and tolerance which generally occurs after sustained expo one or naltrexone, act selectively as antagonists at mu, delta sure to bimodally-acting opioids. Acute application of M and kappa excitatory opioid receptors, comparable to the dynorphinA~(l-13) or fM morphine (n=21), as well as 1 nM antagonist effects of pM etorphine and dihydroetorphine. In 25 naloxone (n=ll), to DRG neurons chronically exposed to 1 the presence of pM diprenorphine, morphine (n:7) and pM morphine together with 1 pM naloxone or naloxone or DAGO (n=7) no longer elicited APD prolongation at low naltrexone (for 1-10 weeks) did not evoke the usual exci (pM-nM) concentrations (see FIG. 4A). Instead, they tatory APD prolongation observed in chronic morphine showed progressive dose-dependent APD shortening treated cells tested after washout with BSS (see FIG. 6). throughout the entire range of concentrations from M to M Furthermore, there was no evidence of tolerance to the usual (see FIG. 4B), comparable to the dose-response curves for inhibitory effects of M opioids (n=6) (FIG. 6). etorphine and dihydroetorphine (see FIG. 3 and FIG. 2C). This unmasking of inhibitory opioid receptor-mediated These results are consonant with previous data that block APD-shortening effects by pM diprenorphine occurred even ade of sustained opioid excitatory effects by cholera toxin-B sub~unit during chronic morphine treatment of DRG neurons in the presence of l06-fold higher concentrations of mor 35 phine (see FIG. 4A, records 11 vs. 5). prevents development of tolerance and dependence. (See Shen and Crain, Brain Res., Vol. 597, pp. 74—83 (1992)). FIG. 4 shows that excitatory APD-prolonging effects This toxin sub-unit selectively interferes with GMl ganglio elicited by morphine in DRG neurons are selectively side regulation of excitatory opioid receptor functions (see blocked by co-administration of a low (pM) concentration of Shen and Crain, Brain Res., Vol. 531, pp. l-7 (1990) and diprenorphine, thereby unmasking potent dose-dependent Shen et al., Brain Res., Vol. 559, pp. l30—l38 (1991)). inhibitory APD shortening by low concentrations of mor phine. FIG. 4A records 1-4 show that APD of a DRG neuron Similarly, in the presence of pM etorphine, chronic uM is progressively prolonged by sequential bath perfusions morphine-treated DRG neurons did not develop signs of with 3 M, 3 pM and 3 nM morphine (Mor). FIG. 4A record tolerance or dependence. FIG. 6 outlines the assay procedure used for testing the effectiveness of these and other antago 5 shows that APD of this cell is only slightly shortened after 45 increasing morphine concentration to 3 uM. FIG. 4A records nists at excitatory opioid receptors in preventing develop 6 and 7 show that after transfer to BSS, the APD is slightly ment of tolerance/ dependence during chronic co-treatment shortened during pretreatment for 17 minutes with 1 pM of DRG neurons with morphine. diprenorphine (DPN). FIG. 4A records 8—11 show that after Excitatory Opioid Receptor Antagonists Enhance Anal the APD reached a stable value in DPN, sequential appli gesic Potency and Reduce Dependence Liability and Other cations of 3 M, 3 pM, 3 nM and 3 pM Mor progressively Side Eifects of Morphine or Other Conventional Opioid shorten the APD, in contrast to the marked APD prolonga Analgesics When Administered in Combination tion evoked by these same concentrations of Mor in the Electrophysiological studies on DRG neurons in culture absence of DPN (see also FIG. 2C). FIG. 4B dose-response indicated that pretreatment with low fM-pM concentrations curves demonstrate similar unmasking’by 1 pM DPN of 55 of naltrexone, naloxone, diprenorphine, etorphine or dihy potent dose-dependent inhibitory APD shortening by mor droetorphine is remarkably e?ective in blocking excitatory phine (III) in a group of DRG neurons (n=7), all of which APD-prolonging effects of morphine or other bimodally showed only excitatory APD prolongation responses when acting opioid agonists by selective antagonist actions at mu, tested prior to introduction of DPN (X). Note that the delta and kappa excitatory opioid receptors on these cells. In inhibitory potency of morphine in the presence of pM DPN 60 the presence of these selective excitatory opioid receptor becomes comparable to that of etorphine and dihydroetor antagonists, morphine and other clinically used bimodally phine (see FIG. 3). In contrast, pretreatment with a higher acting opioid agonists showed markedly increased potency (nM) concentration of DPN blocks both inhibitory as well as in evoking the inhibitory effects on the action potential of excitatory e?ects of morphine (O). sensory neurons which are generally considered to underlie FIG. 5 shows that excitatory APD~prolonging effects 65 opioid analgesic action in vivo. elicited by morphine in DRG neurons (O) are also selec These bimodally~acting opioid agonists became eifective tively blocked by co-administration of a low (pM) concen in shortening, instead of prolonging, the APD at pM-nM 5,512,578 15 16 (i.e., 10'12—l0_9M) concentrations, whereas 0.1~l pM (i.e., that these embodiments are merely illustrative of various 10_7—10_6M) levels were generally required to shorten the aspects of the invention. Thus, it is to be understood that APD (FIGS. 4B and 5). Selective blockade of the excitatory numerous modi?cations may be made in the illustrative side effects of these bimodally-acting opioid agonists elimi embodiments and other arrangements may be devised with nates the attenuation of their inhibitory effectiveness that out departing from the spirit and scope of the invention. would otherwise occur. Hence, according to this invention, We claim: the combined use of a relatively low dose of one of these 1. A method for selectively enhancing the analgesic selective excitatory opioid receptor antagonists, together potency of a bimodally-acting opioid agonist and simulta with morphine or other bimodally-acting mu, delta or kappa neously attenuating anti-analgesia, hyperalgesia, hyperex opioid agonists, will markedly enhance the analgesic 10 citability, physical dependence and/or tolerance e?ects asso potency of said opioid agonist, and render said opioid ciated with the administration of said bimodally-acting agonist comparable in potency to etorphine or dihydroetor opioid agonist, comprising administering to a subject an phine, which, when used alone at higher doses, are >l000 analgesic or sub-analgesic amount of said bimodally-acting times more potent than morphine in eliciting analgesia. opioid agonist and an amount of an excitatory opioid recep Co-administration of one of these excitatory opioid recep 15 tor antagonist eifective to enhance the analgesic potency of tor antagonists at low (pM) concentration (10"2M) during said bimodally-acting opioid agonist and attenuate the anti chronic treatment of sensory neurons with 10"6M morphine analgesia, hyperalgesia, hyperexcitability, physical depen or other bimodally-acting opioid agonists (>1 week in dence and/or tolerance effects of said bimodally-acting culture) prevented development of the opioid excitatory opioid agonist. supersensitivity, including naloxone-precipitated APD-pro 20 2. The method of claim 1 wherein the excitatory opioid longation, as well as the tolerance to opioid inhibitory eifec'ts receptor antagonist is selected from the group consisting of that generally occurs after chronic opioid exposure. This naltrexone, naloxone, etorphine, diprenorphine, dihydroet experimental paradigm was previously utilized by the inven orphine, and similarly acting opioid alkaloids and opioid tors on sensory neurons in culture to demonstrate that peptides. co-administration of l0_7M cholera toxin-B sub-unit, which 25 3. The method of claim 1 wherein the bimodally-acting . binds selectively to GMl ganglioside and thereby blocks opioid agonist is selected from the group consisting of excitatory GMl-regulated opioid receptor-mediated eifects, morphine, codeine, fentanyl analogs, pentazocine, buprenor but not opioid inhibitory eifects (see Shen and Grain, Brain phine, methadone, enkephalins, dynorphins, endorphins and Res., Vol. 531, pp. 1-7 (1990)), during chronic opioid similarly acting opioid alkaloids and opioid peptides. treatment prevents development of these plastic changes in 30 4. The method of claim 1 wherein the amount of the neuronal sensitivity that are considered to be cellular mani~ excitatory opioid receptor antagonist administered is at least festations related to opioid dependence/addiction and toler 100-1000 fold less than the amount of the bimodally-acting ance in vivo (see Shen and Crain, Brain Res., Vol. 597, pp. opioid agonist administered. 74-83 (1992)). 5. The method of claim 2 wherein the excitatory opioid Hence, according to this invention, the sustained use of a 35 receptor antagonist is naltrexone. relatively low clinical dose of one of these selective exci 6. The method of claim 3 wherein the bimodally-acting tatory opioid receptor antagonists, e.g., about 1 microgram opioid agonist is morphine. of naltrexone, naloxone, etorphine, dihydroetorphine or 7. The method of claim 3 wherein the bimodally-acting diprenorphine, in combination with 100-1000 micrograms opioid agonist is codeine. of morphine or other conventional bimodally-acting opioid 8. The method of claim 1 wherein the mode of adminis analgesics will result in analgesia comparable to that elicited tration is selected from the group consisting of oral, sublin by said analgesics when administered alone in >10 milli gual, intramuscular, subcutaneous and intravenous. gram doses and will attenuate or even prevent development 9. The method of claim 1 wherein the opioid receptor of tolerance, physical dependence and other undesirable antagonist is naltrexone, and is administered orally. excitatory side eifects generally associated with said anal 10. A method for treating a detoxi?ed opiate, cocaine or gesics. Furthermore, administration of pg doses of these alcohol addict so as to prevent protracted dependence excitatory opioid receptor antagonists alone will enhance the thereon comprising administering to the detoxi?ed addict analgesic effects of endogenous opioid peptides and thereby over a long term an amount of an excitatory opioid receptor decrease chronic pain. antagonist which does not block but instead enhances the 50 analgesic effect of morphine and other bimodally~acting Treatment of Detoxi?ed Opiate Addicts opioid agonists. Long-term maintenance treatment of previously detoxi 11. The method of claim 10 wherein the antagonist is ?ed opiate, cocaine and alcohol addicts to prevent protracted administered in combination with a sub-analgesic amount of dependence is carried out by long-term oral administration a long-lasting bimodally-acting opioid agonist. of ultra-low doses (about 1 pg) of naltrexone. Ultra-low dose 55 12. The method of claim 11 wherein the opioid agonist is naltrexone selectively blocks resumption of the sustained methadone. activation of excitatory opioid receptor ftmctions that are 13. The method of claim 10 wherein the excitatory opioid required for the development of protracted opioid depen receptor antagonist is selected from the group consisting of dence as well as opioid-mediated cocaine and alcohol naloxone, naltrexone, etorphine, dihydroetorphine, ' dependence without inducing dysphoria or other adverse 60 diprenorphine, and similarly acting opioid alkaloids and side effects caused by high-dose naltrexone blockade of opioid peptides. inhibitory opioid receptor functions. Alternatively, ultra-low 14. The method of claim 13 wherein the excitatory opioid dose (about 1 pg) naltrexone can be administered long-term receptor antagonist is naltrexone. in combination with low-dose methadone to provide effec 15. The method of claim 11 wherein the bimodally-acting tive treatment for addiction. 65 opioid agonist is methadone and the excitatory opioid recep Although the invention herein has been described with tor antagonist is naltrexone. reference to particular embodiments, it is to be understood 16. A composition comprising an analgesic or sub-anal 5,512,578 17 18 gesic amount of a bimodally-acting opioid agonist and an acting opioid agonist is morphine and the excitatory opioid amount of an excitatory opioid receptor antagonist eiTective receptor antagonist is naltrexone. to enhance the analgesic potency of said bimodally-acting 26. A method for treating pain in a subject comprising opioid agonist and attenuate the anti-analgesia, hyperalge administering to said subject an analgesic or sub-analgesic sia, hyperexcitability, physical dependence and/or tolerance amount of a bimodally-acting opioid agonist and an amount e?‘ects of said bimodally-acting opioid agonist. of an excitatory opioid receptor antagonist eifective to 17. The composition of claim 16 wherein the excitatory enhance the analgesic potency of said bimodally-acting opioid receptor antagonist is selected from the group con opioid agonist and attenuate the anti~analgesia, hyperalge sisting of naltrexone, naloxone, etorphine, diprenorphine, sia, hyperexcitability, physical dependence and/or tolerance dihydroetorphine, and similarly acting opioid alkaloids and eifects of said bimodally-acting opioid agonist. 27. The method of claim 26 wherein the bimodally-acting opioid peptides. opioid agonist is selected from the group consisting of 18. The composition of claim 16 wherein the bimodally morphine, codeine, fentanyl analogs, pentazocine, metha acting opioid agonist is selected from the group consisting of done, buprenorphine, enkephalins, dynorphins, endorphins morphine, codeine, fentanyl analogs, pentazocine, metha and similarly acting opioid alkaloids and opioid peptides. done, buprenorphine, enkephalins, dynorphins, endorphins 28. The method of claim 26 wherein the excitatory opioid and similarly acting opioid alkaloids and opioid peptides. receptor antagonist is selected from the group consisting of 19. The method of claim 1 wherein the bimodally-acting naltrexone, naloxone, etorphine, diprenorphine and dihydro opioid agonist is morphine and the excitatory opioid recep etorphine, and similarly acting opioid alkaloids and opioid tor antagonist is naltrexone. peptides. 20. The method of claim 3 wherein the bimodally-acting 20 29. The method of claim 26 wherein amount of the opioid agonist is methadone. excitatory opioid receptor antagonist administered is at least 21. The composition of claim 16 wherein the amount of 100-1000 fold less than the amount of the bimodally-acting the excitatory opioid receptor antagonist is at least 100-1000 opioid agonist administered. fold less than the amount of the bimodally-acting opioid 30. The method of claim 26 wherein the excitatory opioid agonist. 25 receptor antagonist is naltrexone. 22. The composition of claim 17 wherein the excitatory 31. The method of claim 26 wherein the bimodally-acting opioid receptor antagonist is naltrexone. opioid receptor agonist is morphine. 23. The composition of claim 18 wherein the bimodally 32. The method of claim 26 wherein the bimodally-acting acting opioid agonist is morphine. opioid agonist is morphine and the excitatory opioid recep 24. The composition of claim 18 wherein the bimodally 30 tor antagonist is naltrexone. acting opioid agonist is methadone. 25. The composition of claim 16 wherein the bimodally *****