US 20100227876A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0227876 A1 Rech (43) Pub. Date: Sep. 9, 2010 (54) METHODS OF REDUCING SIDE EFFECTS Publication Classi?cation OF ANALGESICS (51) Int CL A61K 31/485 (2006.01) A61K 31/40 (2006.01) (75) Inventor: Richard H. Rech, Okemos, MI A61K 31/445 (2006-01) (Us) A61K 31/439 (2006.01) (52) US. Cl. ........................ .. 514/282; 514/409; 514/329 (57) ABSTRACT Correspondence Address: The invention provides for compositions and methods of MARSHALL, GERSTEIN & BORUN LLP reducing pain in a subject by administering a combination of 233 SOUTH WACKER DRIVE, 6300 WILLIS mu-opioid receptor agonist, kappal-opioid receptor agonist TOWER and a nonselective opioid receptor antagonist in amounts CHICAGO, IL 60606-6357 (US) effective to reduce pain and ameliorate an adverse side effect of treatment combining opioid-receptor agonists. The inven tion also provides for methods of enhancing an analgesic effect of treatment With an opioid-receptor agonist in a sub (73) Assignee: RECHFENSEN LLP, RidgeWood, ject suffering from pain While reducing an adverse side effect NJ (US) of the treatment. The invention also provides for methods of reducing the hyperalgesic effect of treatment With an opioid receptor agonist in a subject suffering from pain While reduc ing an adverse side effect of the treatment. The invention (21) Appl. No.: 12/399,629 further provides for methods of promoting the additive anal gesia of pain treatment With an opioid-receptor agonist in a subject in need While reducing an adverse side effect of the (22) Filed: Mar. 6, 2009 treatment. Patent Application Publication Sep. 9, 2010 Sheet 1 0f 4 US 2010/0227876 A1 Figure l 1 I I I I I I I I 80 ~ * 80 ‘ 60 — ~ 60 — LL! 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E E 40 20 0 0 15 30 0 15 30 Time (minutes) Time (minutes) Patent Application Publication Sep. 9, 2010 Sheet 4 0f 4 US 2010/0227876 A1 Figure 4 A 100 * [:1 Fentanyi .012 89‘ T IZZZ Spiradoiine 0.3 60 m Combination Lu _ n. *@ 5 4o— T I @ __ T T 20 y # T T 0 / y 1 r /i Saline ?-FNA nor-BNI B 100 E: Fentanyl.012 80“ I22 Spiradoiine 0.3 m Combination LU n- *9: E 40*“ T T 2o— T T T 0 - FLiF/i iii -» Saline B-FNA nor-BNi US 2010/0227876 A1 Sep. 9, 2010 METHODS OF REDUCING SIDE EFFECTS (1996), Briggs et al. Pharmacol. Biochem. Behav. 60: 467-72 OF ANALGESICS (1998). Briggs et al., Pharmacol. Biochem. Behav. 60: 467-72 (1998) also demonstrated selective antagonism of mu-opioid FIELD OF INVENTION receptor antinociception by beta-funaltrexamine ([3-FNA) [0001] The invention provides for compositions of opioid and selective antagonism of kappa-opioid receptor antinoci receptor agonists and opioid-receptor antagonists and meth ception by nor-binaltorphamine (n-BNI) in the CWTF model. ods for reducing pain in subjects. [0006] Additive or enhanced pain relief, With reduced side effects produced by combining agonists, Were also observed BACKGROUND by Verborgh et al., Acla. Anaesthesiol. Scand. 41: 895-902 (1997).; Sutters et al., Brain Res. 530: 290-4 (1990); and Ross [0002] In attempts to develop analgesics devoid of mu et al., Pain. 84: 421-8 (2000), among others. Bie et al., J. opioid receptor type tolerance, dependence, opioid-induced Neurosci. 23: 7262-8 (2003), on the other hand, reported hyperalgesia (OIH), and addiction lability, kappa-opioid potent antagonism of mu-opioid receptor agonist analgesia receptor agonists Were developed (Walker et al., Psychophar by kappa-opioid receptor agonists With acute dosing targeted macology. 155: 362-71 (2001); Wadenberg, CNS Drug Rev. at the brainstem nucleus raphe magnus. But they also shoWed 9(2):187-98, 2003)). PentaZocine, the ?rst kappa-opioid receptor agonist marketed (a mixed agonist, With mu-opioid that kappa-opioid receptor agonists reversed the hyperalgesia receptor activity) had little effect on respiratory function, induced by chronic mu-opioid receptor agonist activation. limited analgesic ef?cacy and loW dependence/addiction Thus, the interactions of these agonists differed on the basis of liability. But as a partical mixed agonist pentaZocine also had acute and chronic treatment. They also appear to differ on the modest e?icacy at kappa1-and kappa2-receptors. Unpleasant basis of single-site application versus diffuse application, as side effects of anxiety, dysphoria, and psychotomimetic With systemic administrations or mixed administrations of actions hindered patient acceptance. mu-opioid receptor agonists microinj ected into brain sites [0003] Henck et al. (Pharmacol Biochem Behav. 18(1):41 and kappa agonists applied to spinal sites by intrathecal injec 5.1983)) studied a congener, cyclaZocine, reporting a behav tion (MiaskoWski et al., Brain Res. 608: 87-94 (1993). ioral spectrum in rats similar to the hallucinogens lysergic [0007] The Work of Yaksh (Acla. Anaesthesiol. Scand. 41: acid diethylamide (LSD), 1-(2,5-Dimethoxy-4-methylphe 94-111 (1997)) relates in large part to concepts of visceral nyl)-2-aminopropane (DOM), mescaline, and dimethyl pain and opioid actions on visceral receptors. Yaksh used tryptamine (DMT), and these actions are mediated via brain microinjections of drugs into supra-spinal (brain) and spinal 5-HT-2 agonist activity. Additional kappa-opioid receptor sites to test effects on chemical, mechanical, or high-level agonists Were shortly introduced: butorphanol (mixed partial thermal nociceptive stimuli. These antinociceptive insults agonist at kappa1-, kappa2-, and mu-opioid receptors) and preferentially activate visceral pain. Yaksh and colleagues nalbuphine (kappa1-, kappa2-receptor agonist and mu-opioid formulated theories of complex pain pathWays and drug receptor antagonist), With pentaZocine-like side effects. Nev actions still extant today. This Work proposes that ascending ertheless, butorphanol has had more success for pain relief in and descending neuronal circuits connect to brain stem hubs human and veterinary medicine than pentaZocine, perhaps (periaqueductal gray (PAG), mu-opioid receptors; rostral relating to the more de?nitive mixed agonist ef?cacies. ventral medulla, mu/delta-opioid receptors; substantia nigra, [0004] A host of research studies have demonstrated mu-opioid receptors) and to the spinal and dorsal-horn junc prominent antinociceptive effects of kappa-opioid receptor tions (mu-/delta-/kappa-opioid receptors). Yaksh described agonists over the last three decades, particularly for the ary these pathWays and junctions as integrating and modulating lacetamide class (U-50,488H, enadoline, spiradoline, U-69, nociceptive and antinociceptive impulses and greatly eluci 593). Using the colorectal distension assay (CRD, a model of dated the concepts of mechanisms of pain perception and visceral pain) in dogs, SaWyer et al. (Amer. Vet. Res. J. 52: analgesic drug actions. 1826-30 (1 991)) reported enhanced antinociception by butor [0008] Use of combinations of mu- and kappa-opioid phanol When combined With oxymorphone or ketamine. Ket receptor agonists has been proposed to improve therapy of amine attenuates acute mu-opioid tolerance by antagonizing chronic clinical pain (Smith, Pain Physician. 11: 201-14 NMDA activity and thus inhibits emergence of endogenous (2008)). This hypothesis portended separate antinociceptive excitatory opioid receptor systems, decreasing their activa drug actions on junctions in parallel- or serially-connected tion of pain-facilitatory systems (Fundytus, CNS Drugs. 15: neuronal chains in pain-related central nervous regions as 29-85 (2001)). Briggs et al. (Vet. Surg. 27: 466-72 (1998)) affecting synergistic analgesic interactions. Chronic visceral combined oxymorphone and butorphanol in cats tested in pain, more often prevalent in severe clinical cases than is CRD to enhance antinociception and reduce side effects, as somatic and cutaneous pain, is also more dif?cult to manage had been noted in dogs by Houghton et al., Proc.