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Published in:

01-01-2014 | Review Article

Drug Repositioning: Playing Dirty to Kill Pain

Authors: Leandro Francisco Silva Bastos, Márcio Matos Coelho

Published in: CNS Drugs | Issue 1/2014

Abstract

The number of approved new molecular entity drugs has been decreasing as the pharmaceutical company investment in research and development is increasing. As we face this painful crisis, called an innovation gap, there is increasing awareness that development of new uses of existing drugs may be a powerful tool to help overcome this obstacle because it takes too long, costs too much and can be risky to release drugs developed de novo. Consequently, drug repositioning is emerging in different therapeutic areas, including the pain research area. Worldwide, pain is the main reason for seeking healthcare, and pain relief represents an unmet global clinical need. Therefore, development of analgesics with better efficacy, safety and cost effectiveness is of paramount importance. Despite the remarkable advancement in research on cellular and molecular mechanisms underlying pain pathophysiology over the past three decades, target-based therapeutic opportunities have not been pursued to the same extent. Phenotypic screening remains a more powerful tool for drug development than target-based screening so far. It sounds somewhat heretical, but some multi-action drugs, rather than very selective ones, have been developed intentionally. In the present review, we first critically discuss the utility of drug repositioning for analgesic drug development and then show examples of ‘old’ drugs that have been successfully repositioned or that are under investigation for their analgesic actions. We conclude that drug repositioning should be more strongly encouraged to help build a bridge between basic research and pain relief worldwide.

Raju TN. The Nobel chronicles. 1988: James Whyte Black, (b 1924), Gertrude Elion (1918–99), and George H Hitchings (1905–98). Lancet. 2000;355(9208):1022.PubMed

Mullard A. 2011 FDA drug approvals. Nat Rev Drug Discov. 2012;11(2):91–4.PubMed

Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004;3(8):673–83.PubMed

Innovation or stagnation: challenge and opportunity on the critical path to new medical products. U.S. Department of Health and Human Services, The U.S. Food and Drug Administration; 2004. p. 38.

Cavalla D. Therapeutic switching: a new strategic approach to enhance R&D productivity. IDrugs. 2005;8(11):914–8.PubMed

Reaume AG. Drug repurposing through nonhypothesis driven phenotypic screening. Drug Discov Today Ther Strateg. 2012;8(3–4):85–8.

Tobinick EL. The value of drug repositioning in the current pharmaceutical market. Drug News Perspect. 2009;22(2):119–25.PubMed

Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 2004;3(8):711–5.PubMed

Melnikova I. Pain market. Nat Rev Drug Discov. 2010;9(8):589–90.PubMed

10.

Nightingale S. The neuropathic pain market. Nat Rev Drug Discov. 2012;11(2):101–2.PubMed

11.

Bouhassira D, Lanteri-Minet M, Attal N, Laurent B, Touboul C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain. 2008;136(3):380–7.PubMed

12.

Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin: results from a general population survey. J Pain. 2006;7(4):281–9.PubMed

13.

Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–53.PubMed

14.

Kotz J. Phenotypic screening, take two. SciBX: Science-Business Exchange; 2012. p. 1–3.

15.

Swinney DC, Anthony J. How were new medicines discovered? Nat Rev Drug Discov. 2011;10(7):507–19.PubMed

16.

Imming P, Sinning C, Meyer A. Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006;5(10):821–34.PubMed

17.

Zambrowicz BP, Sands AT. Knockouts model the 100 best-selling drugs—will they model the next 100? Nat Rev Drug Discov. 2003;2(1):38–51.PubMed

18.

Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444(7121):894–8.PubMed

19.

Nassar MA, Levato A, Stirling LC, Wood JN. Neuropathic pain develops normally in mice lacking both Na(v)1.7 and Na(v)1.8. Mol Pain. 2005;1:24.PubMedCentralPubMed

20.

Ruilope LM, Dukat A, Bohm M, Lacourciere Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet. 2010;375(9722):1255–66.PubMed

21.

Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380(9851):1387–95.PubMed

22.

Frantz S. Drug discovery: playing dirty. Nature. 2005;437(7061):942–3.PubMed

23.

Mogil JS, Davis KD, Derbyshire SW. The necessity of animal models in pain research. Pain. 2010;151(1):12–7.PubMed

24.

Rice AS, Cimino-Brown D, Eisenach JC, Kontinen VK, Lacroix-Fralish ML, Machin I, et al. Animal models and the prediction of efficacy in clinical trials of analgesic drugs: a critical appraisal and call for uniform reporting standards. Pain. 2008;139(2):243–7.PubMed

25.

McCarberg BH, Billington R. Consequences of neuropathic pain: quality-of-life issues and associated costs. Am J Manag Care. 2006;12(9 Suppl):S263–8.PubMed

26.

Cobos EJ, Ghasemlou N, Araldi D, Segal D, Duong K, Woolf CJ. Inflammation-induced decrease in voluntary wheel running in mice: a nonreflexive test for evaluating inflammatory pain and analgesia. Pain. 2012;153(4):876–84.PubMedCentralPubMed

27.

Langford DJ, Bailey AL, Chanda ML, Clarke SE, Drummond TE, Echols S, et al. Coding of facial expressions of pain in the laboratory mouse. Nat Methods. 2010;7(6):447–9.PubMed

28.

King T, Vera-Portocarrero L, Gutierrez T, Vanderah TW, Dussor G, Lai J, et al. Unmasking the tonic-aversive state in neuropathic pain. Nat Neurosci. 2009;12(11):1364–6.PubMedCentralPubMed

29.

Mogil JS. Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon. Nat Rev Neurosci. 2012;13(12):859–66.PubMed

30.

Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL 3rd. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain. 2009;10(5):447–85.PubMedCentralPubMed

31.

Mogil JS. Animal models of pain: progress and challenges. Nat Rev Neurosci. 2009;10(4):283–94.PubMed

32.

Greenspan JD, Craft RM, LeResche L, Arendt-Nielsen L, Berkley KJ, Fillingim RB, et al. Studying sex and gender differences in pain and analgesia: a consensus report. Pain. 2007;132(Suppl 1):S26–45.PubMedCentralPubMed

33.

Rezende RM, Paiva-Lima P, Dos Reis WG, Camelo VM, Bakhle YS, de Francischi JN. Celecoxib induces tolerance in a model of peripheral inflammatory pain in rats. Neuropharmacology. 2010;59(6):551–7.PubMed

34.

Challapalli V, Tremont-Lukats IW, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev. 2005(4):CD003345.

35.

Tremont-Lukats IW, Challapalli V, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetics to relieve neuropathic pain: a systematic review and meta-analysis. Anesth Analg. 2005;101(6):1738–49.PubMed

36.

Chong C, Schug SA, Page-Sharp M, Jenkins B, Ilett KF. Development of a sublingual/oral formulation of ketamine for use in neuropathic pain: preliminary findings from a three-way randomized, crossover study. Clin Drug Investig. 2009;29(5):317–24.PubMed

37.

Alviar MJ, Hale T, Dungca M. Pharmacologic interventions for treating phantom limb pain. Cochrane Database Syst Rev. 2011(12):CD006380.

38.

Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database Syst Rev. 2013;7:CD008307.

39.

Dahmani S, Michelet D, Abback PS, Wood C, Brasher C, Nivoche Y, et al. Ketamine for perioperative pain management in children: a meta-analysis of published studies. Paediatr Anaesth. 2011;21(6):636–52.PubMed

40.

Zhou HY, Chen SR, Pan HL. Targeting N-methyl-d-aspartate receptors for treatment of neuropathic pain. Expert Rev Clin Pharmacol. 2011;4(3):379–88.PubMedCentralPubMed

41.

Christensen K, Rogers E, Green GA, Hamilton DA, Mermelstein F, Liao E, et al. Safety and efficacy of intranasal ketamine for acute postoperative pain. Acute Pain. 2007;9(4):183–92.

42.

Carr DB, Goudas LC, Denman WT, Brookoff D, Staats PS, Brennen L, et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study. Pain. 2004;108(1–2):17–27.PubMed

43.

Suzumura A, Ito A, Yoshikawa M, Sawada M. Ibudilast suppresses TNFalpha production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS. Brain Res. 1999;837(1–2):203–12.PubMed

44.

Mizuno T, Kurotani T, Komatsu Y, Kawanokuchi J, Kato H, Mitsuma N, et al. Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia. Neuropharmacology. 2004;46(3):404–11.PubMed

45.

Ledeboer A, Liu T, Shumilla JA, Mahoney JH, Vijay S, Gross MI, et al. The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain. Neuron Glia Biol. 2006;2(4):279–91.PubMed

46.

Hama AT, Broadhead A, Lorrain DS, Sagen J. The antinociceptive effect of the asthma drug ibudilast in rat models of peripheral and central neuropathic pain. J Neurotrauma. 2012;29(3):600–10.PubMed

47.

Hutchinson MR, Lewis SS, Coats BD, Skyba DA, Crysdale NY, Berkelhammer DL, et al. Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast). Brain Behav Immun. 2009;23(2):240–50.PubMedCentralPubMed

48.

Lilius TO, Rauhala PV, Kambur O, Kalso EA. Modulation of morphine-induced antinociception in acute and chronic opioid treatment by ibudilast. Anesthesiology. 2009;111(6):1356–64.PubMed

49.

Rolan P, Hutchinson M, Johnson K. Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease. Expert Opin Pharmacother. 2009;10(17):2897–904.PubMed

50.

Choucair-Jaafar N, Yalcin I, Rodeau JL, Waltisperger E, Freund-Mercier MJ, Barrot M. Beta2-adrenoceptor agonists alleviate neuropathic allodynia in mice after chronic treatment. Br J Pharmacol. 2009;158(7):1683–94.PubMed

51.

Yalcin I, Tessier LH, Petit-Demouliere N, Waltisperger E, Hein L, Freund-Mercier MJ, et al. Chronic treatment with agonists of beta(2)-adrenergic receptors in neuropathic pain. Exp Neurol. 2010;221(1):115–21.PubMed

52.

Cok OY, Eker HE, Yalcin I, Barrot M, Aribogan A. Is there a place for beta-mimetics in clinical management of neuropathic pain? Salbutamol therapy in six cases. Anesthesiology. 2010;112(5):1276–9.PubMed

53.

WHO Model List of Essential Medicines. 18th ed. Geneva, Switzerland: World Health Organization; 2013. p. 41.

54.

Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005;433(7021):73–7.PubMed

55.

Chandrasekar PH, Rolston KV, Smith BR, LeFrock JL. Diffusion of ceftriaxone into the cerebrospinal fluid of adults. J Antimicrob Chemother. 1984;14(4):427–30.PubMed

56.

Lin Y, Tian G, Roman K, Handy C, Travers JB, Lin CL, et al. Increased glial glutamate transporter EAAT2 expression reduces visceral nociceptive response in mice. Am J Physiol Gastrointest Liver Physiol. 2009;296(1):G129–34.PubMed

57.

Lin Y, Roman K, Foust KD, Kaspar BK, Bailey MT, Stephens RL. Glutamate transporter GLT-1 upregulation attenuates visceral nociception and hyperalgesia via spinal mechanisms not related to anti-inflammatory or probiotic effects. Pain Res Treat. 2011;2011:507029.PubMedCentralPubMed

58.

Hu Y, Li W, Lu L, Cai J, Xian X, Zhang M, et al. An anti-nociceptive role for ceftriaxone in chronic neuropathic pain in rats. Pain. 2010;148(2):284–301.PubMed

59.

Ramos KM, Lewis MT, Morgan KN, Crysdale NY, Kroll JL, Taylor FR, et al. Spinal upregulation of glutamate transporter GLT-1 by ceftriaxone: therapeutic efficacy in a range of experimental nervous system disorders. Neuroscience. 2010;169(4):1888–900.PubMedCentralPubMed

60.

Chen Z, He Y, Wang ZJ. The beta-lactam antibiotic, ceftriaxone, inhibits the development of opioid-induced hyperalgesia in mice. Neurosci Lett. 2012;509(2):69–71.PubMed

61.

Bastos LFS, de Oliveira ACP, Watkins LR, Moraes MFD, Coelho MM. Tetracyclines and pain. Naunyn Schmiedebergs Arch Pharmacol. 2012;385(3):225–41.PubMed

62.

Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA. 1998;95(26):15769–74.PubMed

63.

Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA. 1999;96(23):13496–500.PubMed

64.

Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009;10(1):23–36.PubMedCentralPubMed

65.

Raghavendra V, Tanga F, DeLeo JA. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther. 2003;306(2):624–30.PubMed

66.

Ledeboer A, Sloane EM, Milligan ED, Frank MG, Mahony JH, Maier SF, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain. 2005;115(1–2):71–83.PubMed

67.

Bastos LFS, Merlo LA, Rocha LTS, Coelho MM. Characterization of the antinociceptive and anti-inflammatory activities of doxycycline and minocycline in different experimental models. Eur J Pharmacol. 2007;576(1–3):171–9.PubMed

68.

Nakamae T, Ochi M, Olmarker K. Pharmacological inhibition of tumor necrosis factor may reduce pain behavior changes induced by experimental disc puncture in the rat: an experimental study in rats. Spine. 2011;36(4):E232–6.PubMed

69.

Mika J, Wawrzczak-Bargiela A, Osikowicz M, Makuch W, Przewlocka B. Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice. Brain Behav Immun. 2009;23(1):75–84.PubMed

70.

Bastos LF, Prazeres JD, Godin AM, Menezes RR, Soares DG, Ferreira WC, et al. Sex-independent suppression of experimental inflammatory pain by minocycline in two mouse strains. Neurosci Lett. 2013;11(553):110–4.

71.

Aronson AL. Pharmacotherapeutics of the Newer Tetracyclines. J Am Vet Med Assoc. 1980;176(10):1061–8.PubMed

72.

Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, et al. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci USA. 1996;93(24):14014–9.PubMed

73.

Kim SS, Kong PJ, Kim BS, Sheen DH, Nam SY, Chun W. Inhibitory action of minocycline on lipopolysaccharide-induced release of nitric oxide and prostaglandin E₂ in BV2 microglial cells. Arch Pharm Res. 2004;27(3):314–8.PubMed

74.

Alano CC, Kauppinen TM, Valls AV, Swanson RA. Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci USA. 2006;103(25):9685–90.PubMed

75.

Nikodemova M, Duncan ID, Watters JJ. Minocycline exerts inhibitory effects on multiple mitogen-activated protein kinases and IkappaBalpha degradation in a stimulus-specific manner in microglia. J Neurochem. 2006;96(2):314–23.PubMed

76.

Nikodemova M, Watters JJ, Jackson SJ, Yang SK, Duncan ID. Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC)alpha/betaII. J Biol Chem. 2007;282(20):15208–16.PubMed

77.

Mika J, Rojewska E, Makuch W, Przewlocka B. Minocycline reduces the injury-induced expression of prodynorphin and pronociceptin in the dorsal root ganglion in a rat model of neuropathic pain. Neuroscience. 2010;165(4):1420–8.PubMed

78.

Bastos LFS, de Oliveira ACP, Schlachetzki JCM, Fiebich BL. Minocycline reduces prostaglandin E synthase expression and 8-isoprostane formation in LPS-activated primary rat microglia. Immunopharm Immunotoxicol. 2011;33(3):576–80.

79.

Bastos LFS, Godin AM, Zhang Y, Jarussophon S, Ferreira BC, Machado RR, et al. A minocycline derivative reduces nerve injury-induced allodynia, LPS-induced prostaglandin E2 microglial production and signaling via Toll-like receptors 2 and 4. Neurosci Lett. 2013;24(543):157–62.

80.

Patel RN, Attur MG, Dave MN, Patel IV, Stuchin SA, Abramson SB, et al. A novel mechanism of action of chemically modified tetracyclines: inhibition of COX-2-mediated prostaglandin E2 production. J Immunol. 1999;163(6):3459–67.PubMed

81.

Bastos LFS, Angusti A, Vilaca MC, Merlo LA, Nascimento EB, Rocha LTS, et al. A novel non-antibacterial, non-chelating hydroxypyrazoline derivative of minocycline inhibits nociception and oedema in mice. Br J Pharmacol. 2008;155(5):714–21.PubMed

82.

Goulden V, Glass D, Cunliffe WJ. Safety of long-term high-dose minocycline in the treatment of acne. Br J Dermatol. 1996;134(4):693–5.PubMed

83.

Martinez V, Szekely B, Lemarie J, Martin F, Gentili M, Ben Ammar S, et al. The efficacy of a glial inhibitor, minocycline, for preventing persistent pain after lumbar discectomy: a randomized, double-blind, controlled study. Pain. 2013;154:1197–203.PubMed

84.

da Costa BR, Nuesch E, Reichenbach S, Juni P, Rutjes AW. Doxycycline for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2012;11:CD007323.

85.

Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(5):625–39.

86.

Wang X, Grace PM, Pham MN, Cheng K, Strand KA, Smith C, et al. Rifampin inhibits Toll-like receptor 4 signaling by targeting myeloid differentiation protein 2 and attenuates neuropathic pain. FASEB J. 2013;27(7):2713–22.PubMed

87.

Caruso I, Montrone F, Fumagalli M, Patrono C, Santandrea S, Gandini MC. Rheumatoid knee synovitis successfully treated with intra-articular rifamycin SV. Ann Rheum Dis. 1982;41(3):232–6.PubMed

88.

Waszkielewicz AM, Gunia A, Sloczynska K, Marona H. Evaluation of anticonvulsants for possible use in neuropathic pain. Curr Med Chem. 2011;18(28):4344–58.PubMed

89.

McNamara JO. Pharmacotherapy of the epilepsies. In: Brunton LL, Chabner B, Knollman BC, Goodman LS, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. New York: McGraw-Hill; 2011. p. 583–607.

90.

Hearn L, Derry S, Moore RA. Lacosamide for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2012;2:CD009318.

91.

Wiffen PJ, Derry S, Moore RA. Lamotrigine for acute and chronic pain. Cochrane Database Syst Rev. 2011(2):CD006044.

92.

Wiffen PJ, Derry S, Lunn MP, Moore RA. Topiramate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2013;8:CD008314.

93.

O’Donnell JM, Shelton RC. Drug therapy of depression and anxiety disorders. In: Brunton LL, Chabner B, Knollman BrC, Goodman LS, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill; 2011. p. 397–416.

94.

Kadiroglu AK, Sit D, Kayabasi H, Tuzcu AK, Tasdemir N, Yilmaz ME. The effect of venlafaxine HCl on painful peripheral diabetic neuropathy in patients with type 2 diabetes mellitus. J Diabetes Complications. 2008;22(4):241–5.PubMed

95.

Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004;110(3):697–706.PubMed

96.

Smitherman TA, Walters AB, Maizels M, Penzien DB. The use of antidepressants for headache prophylaxis. CNS Neurosci Ther. 2011;17(5):462–9.PubMed

97.

Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2012;12:CD008242.

98.

Richards BL, Whittle SL, Buchbinder R. Antidepressants for pain management in rheumatoid arthritis. Cochrane Database Syst Rev. 2011(11):CD008920.

99.

Hauser W, Wolfe F, Tolle T, Uceyler N, Sommer C. The role of antidepressants in the management of fibromyalgia syndrome: a systematic review and meta-analysis. CNS Drugs. 2012;26(4):297–307.PubMed

100.

Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet. 2009;374(9697):1252–61.PubMed

101.

Oliveira AC, Bertollo CM, Rocha LT, Nascimento EB Jr, Costa KA, Coelho MM. Antinociceptive and antiedematogenic activities of fenofibrate, an agonist of PPAR alpha, and pioglitazone, an agonist of PPAR gamma. Eur J Pharmacol. 2007;561(1–3):194–201.PubMed

102.

Churi SB, Abdel-Aleem OS, Tumber KK, Scuderi-Porter H, Taylor BK. Intrathecal rosiglitazone acts at peroxisome proliferator-activated receptor-gamma to rapidly inhibit neuropathic pain in rats. J Pain. 2008;9(7):639–49.PubMedCentralPubMed

103.

Jia H, Zhu S, Ji Q, Hui K, Duan M, Xu J, et al. Repeated administration of pioglitazone attenuates development of hyperalgesia in a rat model of neuropathic pain. Exp Clin Psychopharmacol. 2010;18(4):359–65.PubMed

104.

Takahashi Y, Hasegawa-Moriyama M, Sakurai T, Inada E. The macrophage-mediated effects of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuate tactile allodynia in the early phase of neuropathic pain development. Anesth Analg. 2011;113(2):398–404.PubMed

105.

Morgenweck J, Abdel-Aleem OS, McNamara KC, Donahue RR, Badr MZ, Taylor BK. Activation of peroxisome proliferator-activated receptor gamma in brain inhibits inflammatory pain, dorsal horn expression of Fos, and local edema. Neuropharmacology. 2010;58(2):337–45.PubMedCentralPubMed

106.

Watkins LR, Hutchinson MR, Rice KC, Maier SF. The “toll” of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Trends Pharmacol Sci. 2009;30(11):581–91.PubMedCentralPubMed

107.

Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, et al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of Toll-like receptor 4 (TLR4). Eur J Neurosci. 2008;28(1):20–9.PubMedCentralPubMed

108.

Hutchinson MR, Northcutt AL, Hiranita T, Wang X, Lewis SS, Thomas J, et al. Opioid activation of Toll-like receptor 4 contributes to drug reinforcement. J Neurosci. 2012;32(33):11187–200.PubMedCentralPubMed

109.

Lewis SS, Loram LC, Hutchinson MR, Li CM, Zhang Y, Maier SF, et al. (+)-naloxone, an opioid-inactive Toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats. J Pain. 2012;13(5):498–506.PubMedCentralPubMed

110.

Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009;10(4):663–72.PubMedCentralPubMed

111.

Shin EJ, Nah SY, Chae JS, Bing G, Shin SW, Yen TP, et al. Dextromethorphan attenuates trimethyltin-induced neurotoxicity via sigma1 receptor activation in rats. Neurochem Int. 2007;50(6):791–9.PubMed

112.

Shin EJ, Nah SY, Kim WK, Ko KH, Jhoo WK, Lim YK, et al. The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan. Br J Pharmacol. 2005;144(7):908–18.PubMed

113.

Gambito ED, Gonzalez-Suarez CB, Oquinena TI, Agbayani RB. Evidence on the effectiveness of topical nitroglycerin in the treatment of tendinopathies: a systematic review and meta-analysis. Arch Phys Med Rehabil. 2010;91(8):1291–305.PubMed

114.

McCleane G. The analgesic efficacy of topical capsaicin is enhanced by glyceryl trinitrate in painful osteoarthritis: a randomized, double blind, placebo controlled study. Eur J Pain. 2000;4(4):355–60.PubMed

115.

McCleane GJ, McLaughlin M. The addition of GTN to capsaicin cream reduces the discomfort associated with application of capsaicin alone. A volunteer study. Pain. 1998;78(2):149–51.PubMed

116.

Walsh KE, Berman JR, Berman LA, Vierregger K. Safety and efficacy of topical nitroglycerin for treatment of vulvar pain in women with vulvodynia: a pilot study. J Gend Specif Med. 2002;5(4):21–7.PubMed

117.

Fletcher S, Wright M, Wilkinson A, Farr M, Sellars L. Locally applied transdermal nitrate patches for the treatment of ischaemic rest pain. Int J Clin Pract. 1997;51(5):324–5.PubMed

118.

Dutra MM, Godin AM, Cesar IC, Nascimento EB Jr, Menezes RR, Ferreira WC, et al. Activity of nicorandil, a nicotinamide derivative with a nitrate group, in the experimental model of pain induced by formaldehyde in mice. Pharmacol Biochem Behav. 2013;106C:85–90.

119.

Datta S, Waghray T, Torres M, Glusman S. Amiodarone decreases heat, cold, and mechanical hyperalgesia in a rat model of neuropathic pain. Anesth Analg. 2004;98(1):178–84.PubMed

120.

Akada Y, Ogawa S, Amano K, Fukudome Y, Yamasaki F, Itoh M, et al. Potent analgesic effects of a putative sodium channel blocker M58373 on formalin-induced and neuropathic pain in rats. Eur J Pharmacol. 2006;536(3):248–55.PubMed

121.

McGowan E, Hoyt SB, Li X, Lyons KA, Abbadie C. A peripherally acting Na(v)1.7 sodium channel blocker reverses hyperalgesia and allodynia on rat models of inflammatory and neuropathic pain. Anesth Analg. 2009;109(3):951–8.PubMed

122.

Carroll IR, Kaplan KM, Mackey SC. Mexiletine therapy for chronic pain: survival analysis identifies factors predicting clinical success. J Pain Symptom Manage. 2008;35(3):321–6.PubMedCentralPubMed

123.

Giovannoni MP, Ghelardini C, Vergelli C, Dal Piaz V. Alpha2-agonists as analgesic agents. Med Res Rev. 2009;29(2):339–68.PubMed

124.

Blaudszun G, Lysakowski C, Elia N, Tramer MR. Effect of perioperative systemic alpha2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials. Anesthesiology. 2012;116(6):1312–22.PubMed

125.

Engelman E, Marsala C. Efficacy of adding clonidine to intrathecal morphine in acute postoperative pain: meta-analysis. Br J Anaesth. 2013;110(1):21–7.PubMed

126.

Schnabel A, Reichl SU, Poepping DM, Kranke P, Pogatzki-Zahn EM, Zahn PK. Efficacy and safety of intraoperative dexmedetomidine for acute postoperative pain in children: a meta-analysis of randomized controlled trials. Paediatr Anaesth. 2013;23(2):170–9.PubMed

127.

Nakamura M, Ferreira SH. A peripheral sympathetic component in inflammatory hyperalgesia. Eur J Pharmacol. 1987;135(2):145–53.PubMed

128.

Davidson EM, Doursout MF, Szmuk P, Chelly JE. Antinociceptive and cardiovascular properties of esmolol following formalin injection in rats. Can J Anaesth. 2001;48(1):59–64.PubMed

129.

Favaro-Moreira NC, Parada CA, Tambeli CH. Blockade of beta(1)-, beta(2)- and beta(3)-adrenoceptors in the temporomandibular joint induces antinociception especially in female rats. Eur J Pain. 2012;16(9):1302–10.PubMed

130.

Chen YW, Chu CC, Chen YC, Hung CH, Wang JJ. Propranolol elicits cutaneous analgesia against skin nociceptive stimuli in rats. Neurosci Lett. 2012;524(2):129–32.PubMed

131.

Dorazil-Dudzik M, Mika J, Schafer MK, Li Y, Obara I, Wordliczek J, et al. The effects of local pentoxifylline and propentofylline treatment on formalin-induced pain and tumor necrosis factor-alpha messenger RNA levels in the inflamed tissue of the rat paw. Anesth Analg. 2004;98(6):1566–73.PubMed

132.

Vale ML, Benevides VM, Sachs D, Brito GA, da Rocha FA, Poole S, et al. Antihyperalgesic effect of pentoxifylline on experimental inflammatory pain. Br J Pharmacol. 2004;143(7):833–44.PubMed

133.

Liu J, Feng X, Yu M, Xie W, Zhao X, Li W, et al. Pentoxifylline attenuates the development of hyperalgesia in a rat model of neuropathic pain. Neurosci Lett. 2007;412(3):268–72.PubMed

134.

Liu J, Li W, Zhu J, Zhang J, Feng X, Guan R, et al. The effect of pentoxifylline on existing hypersensitivity in a rat model of neuropathy. Anesth Analg. 2008;106(2):650–3.PubMed

135.

Mika J. Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacol Rep. 2008;60(3):297–307.PubMed

136.

Izadpanah F, Mojtahedzadeh M. Kazem Aghamir SM, Atharikia D, Dashti S, Abbasi A. Effect of intravenous pentoxifylline in inflammatory response in patients undergoing nephrolithotomy. J Endourol. 2009;23(2):323–8.PubMed

137.

Asomoza-Espinosa R, Alonso-Lopez R, Mixcoatl-Zecuatl T, Aguirre-Banuelos P, Torres-Lopez JE, Granados-Soto V. Sildenafil increases diclofenac antinociception in the formalin test. Eur J Pharmacol. 2001;418(3):195–200.PubMed

138.

Mixcoatl-Zecuatl T, Aguirre-Banuelos P, Granados-Soto V. Sildenafil produces antinociception and increases morphine antinociception in the formalin test. Eur J Pharmacol. 2000;400(1):81–7.PubMed

139.

Ambriz-Tututi M, Velazquez-Zamora DA, Urquiza-Marin H, Granados-Soto V. Analysis of the mechanism underlying the peripheral antinociceptive action of sildenafil in the formalin test. Eur J Pharmacol. 2005;512(2–3):121–7.PubMed

140.

Lee HG, Kim WM, Choi JI, Yoon MH. Roles of adenosine receptor subtypes on the antinociceptive effect of sildenafil in rat spinal cord. Neurosci Lett. 2010;480(3):182–5.PubMed

141.

Rocha FA, Silva FS Jr, Leite AC, Leite AK, Girao VC, Castro RR, et al. Tadalafil analgesia in experimental arthritis involves suppression of intra-articular TNF release. Br J Pharmacol. 2011;164(2b):828–35.PubMed

142.

Araiza-Saldana CI, Rocha-Gonzalez HI, Ambriz-Tututi M, Castaneda-Corral G, Caram-Salas NL, Hong E, et al. Sildenafil and glyceryl trinitrate reduce tactile allodynia in streptozotocin-injected rats. Eur J Pharmacol. 2010;631(1–3):17–23.PubMed

143.

Wang L, Chopp M, Szalad A, Liu Z, Bolz M, Alvarez FM, et al. Phosphodiesterase-5 is a therapeutic target for peripheral neuropathy in diabetic mice. Neuroscience. 2011;13(193):399–410.

144.

Bender G, Florian JA Jr, Bramwell S, Field MJ, Tan KK, Marshall S, et al. Pharmacokinetic-pharmacodynamic analysis of the static allodynia response to pregabalin and sildenafil in a rat model of neuropathic pain. J Pharmacol Exp Ther. 2010;334(2):599–608.PubMed

145.

Groeneweg G, Huygen FJ, Niehof SP, Wesseldijk F, Bussmann JB, Schasfoort FC, et al. Effect of tadalafil on blood flow, pain, and function in chronic cold complex regional pain syndrome: a randomized controlled trial. BMC Musculoskelet Disord. 2008;9:143.PubMedCentralPubMed

146.

Grace PM, Rolan PE, Hutchinson MR. Peripheral immune contributions to the maintenance of central glial activation underlying neuropathic pain. Brain Behav Immun. 2011;25(7):1322–32.PubMed

147.

Geranton SM, Jimenez-Diaz L, Torsney C, Tochiki KK, Stuart SA, Leith JL, et al. A rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states. J Neurosci. 2009;29(47):15017–27.PubMedCentralPubMed

148.

Price TJ, Rashid MH, Millecamps M, Sanoja R, Entrena JM, Cervero F. Decreased nociceptive sensitization in mice lacking the fragile X mental retardation protein: role of mGluR1/5 and mTOR. J Neurosci. 2007;27(51):13958–67.PubMedCentralPubMed

149.

Xu Q, Fitzsimmons B, Steinauer J, O’Neill A, Newton AC, Hua XY, et al. Spinal phosphinositide 3-kinase-Akt-mammalian target of rapamycin signaling cascades in inflammation-induced hyperalgesia. J Neurosci. 2011;31(6):2113–24.PubMedCentralPubMed

150.

Norsted Gregory E, Codeluppi S, Gregory JA, Steinauer J, Svensson CI. Mammalian target of rapamycin in spinal cord neurons mediates hypersensitivity induced by peripheral inflammation. Neuroscience. 2010;169(3):1392–402.PubMed

151.

Asante CO, Wallace VC, Dickenson AH. Mammalian target of rapamycin signaling in the spinal cord is required for neuronal plasticity and behavioral hypersensitivity associated with neuropathy in the rat. J Pain. 2010;11(12):1356–67.PubMed

152.

Orhan CE, Onal A, Ulker S. Antihyperalgesic and antiallodynic effect of sirolimus in neuropathic pain and the role of cytokines in this effect. Neurosci Lett. 2010;481(1):17–20.PubMed

153.

Orhan CE, Onal A, Uyanikgil Y, Ulker S. Antihyperalgesic and antiallodynic effect of sirolimus in rat model of adjuvant arthritis. Eur J Pharmacol. 2013;705(1–3):35–41.PubMed

154.

Shih MH, Kao SC, Wang W, Yaster M, Tao YX. Spinal cord NMDA receptor-mediated activation of mammalian target of rapamycin is required for the development and maintenance of bone cancer-induced pain hypersensitivities in rats. J Pain. 2012;13(4):338–49.PubMedCentralPubMed

155.

George A, Marziniak M, Schafers M, Toyka KV, Sommer C. Thalidomide treatment in chronic constrictive neuropathy decreases endoneurial tumor necrosis factor-alpha, increases interleukin-10 and has long-term effects on spinal cord dorsal horn met-enkephalin. Pain. 2000;88(3):267–75.PubMed

156.

Gu X, Zheng Y, Ren B, Zhang R, Mei F, Zhang J, et al. Intraperitoneal injection of thalidomide attenuates bone cancer pain and decreases spinal tumor necrosis factor-alpha expression in a mouse model. Mol Pain. 2010;6:64.PubMedCentralPubMed

157.

Ribeiro RA, Vale ML, Ferreira SH, Cunha FQ. Analgesic effect of thalidomide on inflammatory pain. Eur J Pharmacol. 2000;391(1–2):97–103.PubMed

158.

Barsante MM, Roffe E, Yokoro CM, Tafuri WL, Souza DG, Pinho V, et al. Anti-inflammatory and analgesic effects of atorvastatin in a rat model of adjuvant-induced arthritis. Eur J Pharmacol. 2005;516(3):282–9.PubMed

159.

Wahane VD, Kumar VL. Atorvastatin ameliorates inflammatory hyperalgesia in rat model of monoarticular arthritis. Pharmacol Res. 2010;61(4):329–33.PubMed

160.

Garcia GG, Miranda HF, Noriega V, Sierralta F, Olavarria L, Zepeda RJ, et al. Antinociception induced by atorvastatin in different pain models. Pharmacol Biochem Behav. 2011;100(1):125–9.PubMed

161.

Miranda HF, Noriega V, Olavarria L, Zepeda RJ, Sierralta F, Prieto JC. Antinociception and anti-inflammation induced by simvastatin in algesiometric assays in mice. Basic Clin Pharmacol Toxicol. 2011;109(6):438–42.PubMed

162.

Shi XQ, Lim TK, Lee S, Zhao YQ, Zhang J. Statins alleviate experimental nerve injury-induced neuropathic pain. Pain. 2011;152(5):1033–43.PubMed

163.

Carlson LA. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J Intern Med. 2005;258(2):94–114.PubMed

164.

Godin AM, Ferreira WC, Rocha LT, Ferreira RG, Paiva AL, Merlo LA, et al. Nicotinic acid induces antinociceptive and anti-inflammatory effects in different experimental models. Pharmacol Biochem Behav. 2012;101(3):493–8.PubMed

165.

Lanska DJ. Chapter 30: historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins. Handb Clin Neurol. 2010;95:445–76.PubMed

166.

Stracke H, Lindemann A, Federlin K. A benfotiamine–vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes. 1996;104(4):311–6.PubMed

167.

Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1346–53.PubMed

168.

Franca DS, Souza AL, Almeida KR, Dolabella SS, Martinelli C, Coelho MM. B vitamins induce an antinociceptive effect in the acetic acid and formaldehyde models of nociception in mice. Eur J Pharmacol. 2001;421(3):157–64.PubMed

169.

Godin AM, Ferreira WC, Rocha LT, Seniuk JG, Paiva AL, Merlo LA, et al. Antinociceptive and anti-inflammatory activities of nicotinamide and its isomers in different experimental models. Pharmacol Biochem Behav. 2011;99(4):782–8.PubMed

170.

Cuzzocrea S, Zingarelli B, Caputi AP. Peroxynitrate-mediated DNA strand breakage activates poly(ADP-ribose) synthetase and causes cellular energy depletion in a nonseptic shock model induced by zymosan in the rat. Shock. 1998;9(5):336–40.PubMed

171.

Wang ZB, Gan Q, Rupert RL, Zeng YM, Song XJ. Thiamine, pyridoxine, cyanocobalamin and their combination inhibit thermal, but not mechanical hyperalgesia in rats with primary sensory neuron injury. Pain. 2005;114(1–2):266–77.PubMed

172.

Song XS, Huang ZJ, Song XJ. Thiamine suppresses thermal hyperalgesia, inhibits hyperexcitability, and lessens alterations of sodium currents in injured, dorsal root ganglion neurons in rats. Anesthesiology. 2009;110(2):387–400.PubMed

173.

Jolivalt CG, Mizisin LM, Nelson A, Cunha JM, Ramos KM, Bonke D, et al. B vitamins alleviate indices of neuropathic pain in diabetic rats. Eur J Pharmacol. 2009;612(1–3):41–7.PubMed

174.

Granados-Soto V, Teran-Rosales F, Rocha-Gonzalez HI, Reyes-Garcia G, Medina-Santillan R, Rodriguez-Silverio J, et al. Riboflavin reduces hyperalgesia and inflammation but not tactile allodynia in the rat. Eur J Pharmacol. 2004;492(1):35–40.PubMed

175.

Bertollo CM, Oliveira AC, Rocha LT, Costa KA, Nascimento EB Jr, Coelho MM. Characterization of the antinociceptive and anti-inflammatory activities of riboflavin in different experimental models. Eur J Pharmacol. 2006;547(1–3):184–91.PubMed

176.

Brand C, Snaddon J, Bailey M, Cicuttini F. Vitamin E is ineffective for symptomatic relief of knee osteoarthritis: a six month double blind, randomised, placebo controlled study. Ann Rheum Dis. 2001;60(10):946–9.PubMed

177.

Edmonds SE, Winyard PG, Guo R, Kidd B, Merry P, Langrish-Smith A, et al. Putative analgesic activity of repeated oral doses of vitamin E in the treatment of rheumatoid arthritis. Results of a prospective placebo controlled double blind trial. Ann Rheum Dis. 1997;56(11):649–55.PubMed

178.

Lu R, Kallenborn-Gerhardt W, Geisslinger G, Schmidtko A. Additive antinociceptive effects of a combination of vitamin C and vitamin E after peripheral nerve injury. PLoS ONE. 2011;6(12):e29240.PubMedCentralPubMed

Title: Drug Repositioning: Playing Dirty to Kill Pain
Authors: Leandro Francisco Silva Bastos
Márcio Matos Coelho
Publication date: 01-01-2014
Publisher: Springer International Publishing
Published in: CNS Drugs / Issue 1/2014
Print ISSN: 1172-7047
Electronic ISSN: 1179-1934
DOI: https://doi.org/10.1007/s40263-013-0128-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Drug Repositioning: Playing Dirty to Kill Pain

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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