Đánh giá độc tính tiền lâm sàng của AAV cho đau: bằng chứng từ các nghiên cứu AAV ở người và từ dược lý của thuốc giảm đau

Institute of Medicine: Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press; 2011. Van den Beuken-van Everdingen MHJ, de Rijke JM, Kessels AG, Schouten HC, van Kleef M, Patijn J: High prevalence of pain in patients with cancer in a large population-based study in The Netherlands. Pain 2007, 132: 312–320. Green CR, Hart-Johnson T, Loeffler DR: Cancer-related chronic pain: examining quality of life in diverse cancer survivors. Cancer 2011, 117: 1994–2003. Fink DJ, Wechuck J, Mata M, Glorioso JC, Goss J, Krisky D, Wolfe D: Gene therapy for pain: results of a phase I clinical trial. Ann Neurol 2011, 70: 207–212. Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J: Gene therapy clinical trials worldwide to 2012 - an update. J Gene Med 2013, 15: 65–77. Gaudet D, Méthot J, Déry S, Brisson D, Essiembre C, Tremblay G, Tremblay K, de Wal J, Twisk J, van den Bulk N, Sier-Ferreira V, van Deventer S: Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene Ther 2013, 20: 361–369. De la Calle JL, Paino CL: A procedure for direct lumbar puncture in rats. Brain Res Bull 2002, 59: 245–250. Storkson RV, Kjorsvik A, Tjolsen A, Hole K: Lumbar catheterization of the spinal subarachnoid space in the rat. J Neurosci Methods 1996, 65: 167–172. Malkmus SA, Yaksh TL: Intrathecal catheterization and drug delivery in the rat. Methods Mol Med 2004, 99: 109–121. Mestre C, Pelissier T, Fialip J, Wilcox G, Eschalier A: A method to perform direct transcutaneous intrathecal injection in rats. J Pharmacol Toxicol Methods 1994, 32: 197–200. Rijsdijk M, van Wijck AJ, Kalkman CJ, Meulenhoff PC, Grafe MR, Steinauer J, Yaksh TL: Safety assessment and pharmacokinetics of intrathecal methylprednisolone acetate in dogs. Anesthesiology 2012, 116: 170–181. Yaksh TL, Rathbun ML, Dragani JC, Malkmus S, Bourdeau AR, Richter P, Powell H, Myers RR, Lebel CP: Kinetic and safety studies on intrathecally infused recombinant-methionyl human brain-derived neurotrophic factor in dogs. Fundam Appl Toxicol 1997, 38: 89–100. Pleticha J, Maus TP, Jeng-Singh C, Marsh MP, Al-Saiegh F, Christner JA, Lee KH, Beutler AS: Pig lumbar spine anatomy and imaging-guided lateral lumbar puncture: A new large animal model for intrathecal drug delivery. J Neurosci Methods 2013, 216: 10–15. Evans RW: Complications of lumbar puncture. Neurol Clin 1998, 16: 83–105. Sapunar D, Kostic S, Banozic A, Puljak L: Dorsal root ganglion - a potential new therapeutic target for neuropathic pain. J Pain Res 2012, 5: 31–38. Yu H, Fischer G, Ferhatovic L, Fan F, Light AR, Weihrauch D, Sapunar D, Nakai H, Park F, Hogan QH: Intraganglionic AAV6 Results in Efficient and Long-Term Gene Transfer to Peripheral Sensory Nervous System in Adult Rats. PLoS One 2013, 8: e61266. Puljak L, Kojundzic SL, Hogan QH, Sapunar D: Targeted delivery of pharmacological agents into rat dorsal root ganglion. J Neurosci Methods 2009, 177: 397–402. Towne C, Pertin M, Beggah AT, Aebischer P, Decosterd I: Recombinant adeno-associated virus serotype 6 (rAAV2/6)-mediated gene transfer to nociceptive neurons through different routes of delivery. Mol Pain 2009, 5: 52. Xu Y, Gu Y, Wu P, Li G-W, Huang L-YM: Efficiencies of transgene expression in nociceptive neurons through different routes of delivery of adeno-associated viral vectors. Hum Gene Ther 2003, 14: 897–906. Pleticha J, Maus TP, Christner JA, Marsh MP, Lee KH, Hooten WM, Beutler AS: Minimally invasive convection enhanced delivery of biologics into dorsal root ganglia: validation in the pig model and prospective modeling in humans: technical note. J Neurosurg 2014, 4: 1–8. Gofeld M, Brown MN, Bollag L, Hanlon JG, Theodore BR: Magnetic positioning system and ultrasound guidance for lumbar zygapophysial radiofrequency neurotomy: a cadaver study. Reg Anesth Pain Med 2014, 39: 61–66. Gonçalves MA: Adeno-associated virus: from defective virus to effective vector. Virol J 2005, 2: 43. Paulk NK, Wursthorn K, Wang Z, Finegold MJ, Kay MA, Grompe M: Adeno-associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo. Hepatology 2010, 51: 1200–1208. Miller DG, Wang P-R, Petek LM, Hirata RK, Sands MS, Russell DW: Gene targeting in vivo by adeno-associated virus vectors. Nat Biotechnol 2006, 24: 1022–1026. Donsante A, Miller DG, Li Y, Vogler C, Brunt EM, Russell DW, Sands MS: AAV vector integration sites in mouse hepatocellular carcinoma. Science 2007, 317: 477. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, Rasko J, Ozelo MC, Hoots K, Blatt P, Konkle B, Dake M, Kaye R, Razavi M, Zajko A, Zehnder J, Rustagi PK, Nakai H, Chew A, Leonard D, Wright JF, Lessard RR, Sommer JM, Tigges M, Sabatino D, Luk A, Jiang H, Mingozzi F, Couto L, Ertl HC, et al.: Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006, 12: 342–347. Hewitt FC, Li C, Gray SJ, Cockrell S, Washburn M, Samulski RJ: Reducing the risk of adeno-associated virus (AAV) vector mobilization with AAV type 5 vectors. J Virol 2009, 83: 3919–3929. Frank KM, Hogarth DK, Miller JL, Mandal S, Mease PJ, Samulski RJ, Weisgerber GA, Hart J: Investigation of the cause of death in a gene-therapy trial. N Engl J Med 2009, 361: 161–169. Evans CH, Ghivizzani SC, Robbins PD: Arthritis gene therapy’s first death. Arthritis Res Ther 2008, 10: 110. Cunningham J, Pivirotto P, Bringas J, Suzuki B, Vijay S, Sanftner L, Kitamura M, Chan C, Bankiewicz KS: Biodistribution of adeno-associated virus type-2 in nonhuman primates after convection-enhanced delivery to brain. Mol Ther 2008, 16: 1267–1275. Herzog CD, Brown L, Gammon D, Kruegel B, Lin R, Wilson A, Bolton A, Printz M, Gasmi M, Bishop KM, Kordower JH, Bartus RT: Expression, bioactivity, and safety 1 year after adeno-associated viral vector type 2-mediated delivery of neurturin to the monkey nigrostriatal system support cere-120 for Parkinson’s disease. Neurosurgery 2009, 64: 602–612. discussion 612–3 Hadaczek P, Forsayeth J, Mirek H, Munson K, Bringas J, Pivirotto P, McBride JL, Davidson BL, Bankiewicz KS: Transduction of nonhuman primate brain with adeno-associated virus serotype 1: vector trafficking and immune response. Hum Gene Ther 2009, 20: 225–237. Sondhi D, Johnson L, Purpura K, Monette S, Souweidane MM, Kaplitt MG, Kosofsky B, Yohay K, Ballon D, Dyke J, Kaminksy SM, Hackett NR, Crystal RG: Long-term expression and safety of administration of AAVrh.10hCLN2 to the brain of rats and nonhuman primates for the treatment of late infantile neuronal ceroid lipofuscinosis. Hum Gene Ther Meth 2012, 23: 324–335. Haurigot V, Marcó S, Ribera A, Garcia M, Ruzo A, Villacampa P, Ayuso E, Añor S, Andaluz A, Pineda M, García-Fructuoso G, Molas M, Maggioni L, Muñoz S, Motas S, Ruberte J, Mingozzi F, Pumarola M, Bosch F: Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy. J Clin Invest 2013, 123: 3254–3271. Gray SJ, Nagabhushan Kalburgi S, McCown TJ, Jude Samulski R: Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates. Gene Ther 2012, 2013: 1–10. Tardieu M, Zerah M, Husson B, de Bournonville S, Deiva K, Adamsbaum C, Vincent F, Hocquemiller M, Broissand C, Furlan V, Ballabio A, Fraldi A, Crystal R, Baugnon T, Roujeau T, Heard J-M, Danos O: Intracerebral administration of AAV rh.10 carrying human SGSH and SUMF1 cDNAs in children with MPSIIIA disease: results of a phase I/II trial. Hum Gene Ther 2014, 25: 506–516. Hwu W-L, Muramatsu S, Tseng S-H, Tzen K-Y, Lee N-C, Chien Y-H, Snyder RO, Byrne BJ, Tai C-H, Wu R-M: Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med 2012, 4: 134ra61. Marks WJ, Bartus RT, Siffert J, Davis CS, Lozano A, Boulis N, Vitek J, Stacy M, Turner D, Verhagen L, Bakay R, Watts R, Guthrie B, Jankovic J, Simpson R, Tagliati M, Alterman R, Stern M, Baltuch G, Starr PA, Larson PS, Ostrem JL, Nutt J, Kieburtz K, Kordower JH, Olanow CW: Gene delivery of AAV2-neurturin for Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol 2010, 9: 1164–1172. Christine CW, Starr PA, Larson PS, Eberling JL, Jagust WJ, Hawkins RA, VanBrocklin HF, Wright JF, Bankiewicz KS, Aminoff MJ: Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 2009, 73: 1662–1669. Worgall S, Sondhi D, Hackett NR, Kosofsky B, Kekatpure MV, Neyzi N, Dyke JP, Ballon D, Heier L, Greenwald BM, Christos P, Mazumdar M, Souweidane MM, Kaplitt MG, Crystal RG: Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum Gene Ther 2008, 19: 463–474. Kaplitt MG, Feigin A, Tang C, Fitzsimons HL, Mattis P, Lawlor PA, Bland RJ, Young D, Strybing K, Eidelberg D, During MJ: Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: an open label, phase I trial. Lancet 2007, 369: 2097–2105. McPhee SWJ, Janson CG, Li C, Samulski RJ, Camp AS, Francis J, Shera D, Lioutermann L, Feely M, Freese A, Leone P: Immune responses to AAV in a phase I study for Canavan disease. J Gene Med 2006, 8: 577–588. Gray SJ, Matagne V, Bachaboina L, Yadav S, Ojeda SR, Samulski RJ: Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates. Mol Ther 2011, 19: 1058–1069. Samaranch L, Salegio EA, San Sebastian W, Kells AP, Foust KD, Bringas JR, Lamarre C, Forsayeth J, Kaspar BK, Bankiewicz KS: Adeno-Associated Virus Serotype 9 Transduction in the Central Nervous System of Nonhuman Primates. Hum Gene Ther 2012,389(April):382–389. Mingozzi F, High KA: Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood 2013, 122: 23–36. Nguyen DH, Hurtado-Ziola N, Gagneux P, Varki A: Loss of Siglec expression on T lymphocytes during human evolution. Proc Natl Acad Sci U S A 2006, 103: 7765–7770. Li H, Lasaro MO, Jia B, Lin SW, Haut LH, High KA, Ertl HCJ: Capsid-specific T-cell Responses to Natural Infections With Adeno-associated Viruses in Humans Differ From Those of Nonhuman Primates. Mol Ther 2011, 19: 2021–2030. Vandenberghe LH, Wang L, Somanathan S, Zhi Y, Figueredo J, Calcedo R, Sanmiguel J, Desai RA, Chen CS, Johnston J, Grant RL, Gao G, Wilson JM: Heparin binding directs activation of T cells against adeno-associated virus serotype 2 capsid. Nat Med 2006, 12: 967–971. Nathwani AC, Tuddenham EGD, Rangarajan S, Rosales C, McIntosh J, Linch DC, Chowdary P, Riddell A, Pie AJ, Harrington C, O’Beirne J, Smith K, Pasi J, Glader B, Rustagi P, Ng CYC, Kay MA, Zhou J, Spence Y, Morton CL, Allay J, Coleman J, Sleep S, Cunningham JM, Srivastava D, Basner-Tschakarjan E, Mingozzi F, High KA, Gray JT, Reiss UM, et al.: Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 2011, 365: 2357–2365. Ellinwood NM, Ausseil J, Desmaris N, Bigou S, Liu S, Jens JK, Snella EM, Mohammed EE, Thomson CB, Raoul S, Joussemet B, Roux F, Chérel Y, Lajat Y, Piraud M, Benchaouir R, Hermening S, Petry H, Froissart R, Tardieu M, Ciron C, Moullier P, Parkes J, Kline KL, Maire I, Vanier M-T, Heard J-M, Colle M-A: Safe, efficient, and reproducible gene therapy of the brain in the dog models of Sanfilippo and Hurler syndromes. Mol Ther 2011, 19: 251–259. Herzog CD, Dass B, Gasmi M, Bakay R, Stansell JE, Tuszynski M, Bankiewicz K, Chen E-Y, Chu Y, Bishop K, Kordower JH, Bartus RT: Transgene expression, bioactivity, and safety of CERE-120 (AAV2-neurturin) following delivery to the monkey striatum. Mol Ther 2008, 16: 1737–1744. Hackett NR, Redmond DE, Sondhi D, Giannaris EL, Vassallo E, Stratton J, Qiu J, Kaminsky SM, Lesser ML, Fisch GS, Rouselle SD, Crystal RG: Safety of direct administration of AAV2(CU)hCLN2, a candidate treatment for the central nervous system manifestations of late infantile neuronal ceroid lipofuscinosis, to the brain of rats and nonhuman primates. Hum Gene Ther 2005, 16: 1484–1503. Bartus RT, Baumann TL, Siffert J, Herzog CD, Alterman R, Boulis N, Turner DA, Stacy M, Lang AE, Lozano AM, Olanow CW: Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. Neurology 2013, 80: 1698–1701. Rafii MS, Baumann TL, Bakay RA, Ostrove JM, Siffert J, Fleisher AS, Herzog CD, Barba D, Pay M, Salmon DP, Chu Y, Kordower JH, Bishop K, Keator D, Potkin S, Bartus RT: A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer’s disease. Alzheimers Dement 2014,10(5):571–581. Leone P, Shera D, McPhee SWJ, Francis JS, Kolodny EH, Bilaniuk LT, Wang D-J, Assadi M, Goldfarb O, Goldman HW, Freese A, Young D, During MJ, Samulski RJ, Janson CG: Long-term follow-up after gene therapy for canavan disease. Sci Transl Med 2012, 4: 165ra163. Mittermeyer G, Christine CW, Rosenbluth KH, Baker SL, Starr P, Larson P, Kaplan PL, Forsayeth J, Aminoff MJ, Bankiewicz KS: Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson’s disease. Hum Gene Ther 2012, 23: 377–381. Samaranch L, Sebastian WS, Kells AP, Salegio EA, Heller G, Bringas JR, Pivirotto P, Dearmond S, Forsayeth J, Bankiewicz KS: AAV9-mediated Expression of a Non-self Protein in Nonhuman Primate Central Nervous System Triggers Widespread Neuroinflammation Driven by Antigen-presenting Cell Transduction. Mol Ther 2013, 22: 329–337. Sames L, Bonnemann C, Gray SJ, Samulski RJ, Dastgir J: Giant Axonal Neuropathy Gene Therapy. National Institutes of Health: Recombinant Advisory Committee; 2013. Jacques SJ, Ahmed Z, Forbes A, Douglas MR, Vigenswara V, Berry M, Logan A: AAV8(gfp) preferentially targets large diameter dorsal root ganglion neurones after both intra-dorsal root ganglion and intrathecal injection. Mol Cell Neurosci 2012, 49: 464–474. Vulchanova L, Schuster DJ, Belur LR, Riedl MS, Podetz-Pedersen KM, Kitto KF, Wilcox GL, McIvor RS, Fairbanks CA: Differential adeno-associated virus mediated gene transfer to sensory neurons following intrathecal delivery by direct lumbar puncture. Mol Pain 2010, 6: 31. Storek B, Reinhardt M, Wang C, Janssen WGM, Harder NM, Banck MS, Morrison JH, Beutler AS: Sensory neuron targeting by self-complementary AAV8 via lumbar puncture for chronic pain. Proc Natl Acad Sci U S A 2008, 105: 1055–1060. Bucher T, Colle M-A, Wakeling E, Dubreil L, Fyfe J, Briot-Nivard D, Maquigneau M, Raoul S, Cherel Y, Astord S, Duque S, Marais T, Voit T, Moullier P, Barkats M, Joussemet B: scAAV9 intracisternal delivery results in efficient gene transfer to the central nervous system of a feline model of motor neuron disease. Hum Gene Ther 2013, 24: 670–682. Federici T, Taub JS, Baum GR, Gray SJ, Grieger JC, Matthews KA, Handy CR, Passini MA, Samulski RJ, Boulis NM: Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs. Gene Ther 2011, 19: 852–589. Janson C, McPhee S, Bilaniuk L, Haselgrove J, Testaiuti M, Freese A, Wang D-J, Shera D, Hurh P, Rupin J, Saslow E, Goldfarb O, Goldberg M, Larijani G, Sharrar W, Liouterman L, Camp A, Kolodny E, Samulski J, Leone P: Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum Gene Ther 2002, 13: 1391–1412. Marks WJ, Ostrem JL, Verhagen L, Starr PA, Larson PS, Bakay RA, Taylor R, Cahn-Weiner DA, Stoessl AJ, Olanow CW, Bartus RT: Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson’s disease: an open-label, phase I trial. Lancet Neurol 2008, 7: 400–408. Eberling JL, Jagust WJ, Christine CW, Starr P, Larson P, Bankiewicz KS, Aminoff MJ: Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology 2008, 70: 1980–1983. Muramatsu S, Fujimoto K, Kato S, Mizukami H, Asari S, Ikeguchi K, Kawakami T, Urabe M, Kume A, Sato T, Watanabe E, Ozawa K, Nakano I: A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson’s disease. Mol Ther 2010, 18: 1731–1735. Crystal RG: Direct CNS Administration of a Replication Deficient Adeno-associated Virus Gene Transfer Serotype rh.10 Expressing the Human CLN2 cDNA to Children with Late Infantile Neuronal Ceroid Lipofuscinosis. Bethesda, MD: Recombinant DNA Advisory Committee, National Institutes of Health; 2009. McCarty DM: Self-complementary AAV vectors; advances and applications. Mol Ther 2008, 16: 1648–1656. Asokan A, Schaffer DV, Samulski RJ: The AAV vector toolkit: poised at the clinical crossroads. Mol Ther 2012, 20: 699–708. Bowles DE, McPhee SWJ, Li C, Gray SJ, Samulski JJ, Camp AS, Li J, Wang B, Monahan PE, Rabinowitz JE, Grieger JC, Govindasamy L, Agbandje-McKenna M, Xiao X, Samulski RJ: Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol Ther 2012, 20: 443–455. Milligan ED, Sloane EM, Langer SJ, Cruz PE, Chacur M, Spataro L, Wieseler-Frank J, Hammack SE, Maier SF, Flotte TR, Forsayeth JR, Leinwand LA, Chavez R, Watkins LR: Controlling neuropathic pain by adeno-associated virus driven production of the anti-inflammatory cytokine, interleukin-10. Mol Pain 2005, 1: 9. Lau D, Harte SE, Morrow TJ, Wang S, Mata M, Fink DJ: Herpes simplex virus vector-mediated expression of interleukin-10 reduces below-level central neuropathic pain after spinal cord injury. Neurorehabil Neural Repair 2012, 26: 889–897. Milligan ED, Sloane EM, Langer SJ, Hughes TS, Jekich BM, Frank MG, Mahoney JH, Levkoff LH, Maier SF, Cruz PE, Flotte TR, Johnson KW, Mahoney MM, Chavez RA, Leinwand LA, Watkins LR: Repeated intrathecal injections of plasmid DNA encoding interleukin-10 produce prolonged reversal of neuropathic pain. Pain 2006, 126: 294–308. Beutler AS, Banck MS, Bach FW, Gage FH, Porreca F, Bilsky EJ, Yaksh TL: Retrovirus-mediated expression of an artificial beta-endorphin precursor in primary fibroblasts. J Neurochem 1995, 64: 475–481. Koulousakis A, Kuchta J, Bayarassou A, Sturm V: Intrathecal opioids for intractable pain syndromes. Acta Neurochir Suppl 2007,97(Pt 1):43–48. Finegold AA, Mannes AJ, Iadarola MJ: A paracrine paradigm for in vivo gene therapy in the central nervous system: treatment of chronic pain. Hum Gene Ther 1999, 10: 1251–1257. Milligan ED, Langer SJ, Sloane EM, He L, Wieseler-Frank J, O’Connor K, Martin D, Forsayeth JR, Maier SF, Johnson K, Chavez RA, Leinwand LA, Watkins LR: Controlling pathological pain by adenovirally driven spinal production of the anti-inflammatory cytokine, interleukin-10. Eur J Neurosci 2005, 21: 2136–2148. Soderquist RG, Milligan ED, Harrison JA, Chavez RA, Johnson KW, Watkins LR, Mahoney MJ: PEGylation of interleukin-10 for the mitigation of enhanced pain states. J Biomed Mater Res A 2010, 93: 1169–1179. Mason MRJ, Ehlert EME, Eggers R, Pool CW, Hermening S, Huseinovic A, Timmermans E, Blits B, Verhaagen J: Comparison of AAV serotypes for gene delivery to dorsal root ganglion neurons. Mol Ther 2010, 18: 715–724. Fischer G, Kostic S, Nakai H, Park F, Sapunar D, Yu H, Hogan Q: Direct injection into the dorsal root ganglion: technical, behavioral, and histological observations. J Neurosci Methods 2011, 199: 43–55. Storek B, Harder NM, Banck MS, Wang C, McCarty DM, Janssen WG, Morrison JH, Walsh CE, Beutler AS: Intrathecal long-term gene expression by self-complementary adeno-associated virus type 1 suitable for chronic pain studies in rats. Mol Pain 2006, 2: 4. Goss JR, Mata M, Goins WF, Wu HH, Glorioso JC, Fink DJ: Antinociceptive effect of a genomic herpes simplex virus-based vector expressing human proenkephalin in rat dorsal root ganglion. Gene Ther 2001, 8: 551–556. Chaney MA: Side effects of intrathecal and epidural opioids. Can J Anaesth 1995, 42: 891–903. Noble M, Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C, Schoelles KM: Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev 2010, ᅟ: CD006605. King S, Forbes K, Hanks GW, Ferro CJ, Chambers EJ: A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment: a European Palliative Care Research Collaborative opioid guidelines project. Palliat Med 2011, 25: 525–552. Baldini A, Von Korff M, Lin EHB: A review of potential adverse effects of long-term opioid therapy: a practitioner’s guide. Prim Care Companion CNS Disord 2012, 14: 1–12. Bell TJ, Panchal SJ, Miaskowski C, Bolge SC, Milanova T, Williamson R: The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European Patient Survey (PROBE 1). Pain Med 2009, 10: 35–42. Vuong C, Van Uum SHM, O’Dell LE, Lutfy K, Friedman TC: The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev 2010, 31: 98–132. Carman WJ, Su S, Cook SF, Wurzelmann JI, McAfee A: Coronary heart disease outcomes among chronic opioid and cyclooxygenase-2 users compared with a general population cohort. Pharmacoepidemiol Drug Saf 2011, 20: 754–762. Al-Hashimi M, Scott SWM, Thompson JP, Lambert DG: Opioids and immune modulation: more questions than answers. Br J Anaesth 2013, 111: 80–88. Foley KM, Kourides IA, Inturrisi CE, Kaiko RF, Zaroulis CG, Posner JB, Houde RW, Li CH: beta-Endorphin: analgesic and hormonal effects in humans. Proc Natl Acad Sci U S A 1979, 76: 5377–5381. Matsuki A, Kudo T, Ishihara H, Jin T, Taneichi T, Oyama T, Guillemin R, Ling N: Plasma beta-endorphin levels during obstetrical analgesia with synthetic beta-endorphin. Agressologie 1986, 27: 133–137. Oyama T, Fukushi S, Jin T: Epidural beta-endorphin in treatment of pain. Can Anaesth Soc J 1982, 29: 24–26. Oyama T, Jin T, Yamaya R, Ling N, Guillemin R: Profound analgesic effects of beta-endorphin in man. Lancet 1980, 1: 122–124. Oyama T, Matsuki A, Taneichi T, Ling N, Guillemin R: beta-Endorphin in obstetric analgesia. Am J Obstet Gynecol 1980, 137: 613–616. Wen HL, Mehal ZD, Ong BH, Ho WK, Wen DY: Intrathecal administration of beta-endorphin and dynorphin-(1–13) for the treatment of intractable pain. Life Sci 1985, 37: 1213–1220. Milligan ED, Penzkover KR, Soderquist RG, Mahoney MJ: Spinal interleukin-10 therapy to treat peripheral neuropathic pain. Neuromodulation 2012, 15: 520–526. Chacur M, Milligan ED, Sloan EM, Wieseler-Frank J, Barrientos RM, Martin D, Poole S, Lomonte B, Gutiérrez JM, Maier SF, Cury Y, Watkins LR: Snake venom phospholipase A2s (Asp49 and Lys49) induce mechanical allodynia upon peri-sciatic administration: involvement of spinal cord glia, proinflammatory cytokines and nitric oxide. Pain 2004, 108: 180–191. Laughlin TM, Bethea JR, Yezierski RP, Wilcox GL: Cytokine involvement in dynorphin-induced allodynia. Pain 2000, 84: 159–167. Plunkett JA, Yu CG, Easton JM, Bethea JR, Yezierski RP: Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat. Exp Neurol 2001, 168: 144–154. Yu C-G, Fairbanks CA, Wilcox GL, Yezierski RP: Effects of agmatine, interleukin-10, and cyclosporin on spontaneous pain behavior after excitotoxic spinal cord injury in rats. J Pain 2003, 4: 129–140. Mani R, Paulus H, Breedveld F: RHuIL-10 in subjects with active rheumatoid arthritis: a phase I and cytokine response study [abstract]. Arthritis Rheum 1997, 40: 224. Schreiber S, Fedorak RN, Nielsen OH, Wild G, Williams CN, Nikolaus S, Jacyna M, Lashner BA, Gangl A, Rutgeerts P, Isaacs K, van Deventer SJ, Koningsberger JC, Cohard M, LeBeaut A, Hanauer SB: Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn’s disease. Crohn's Disease IL-10 Cooperative Study Group. Gastroenterology 2000, 119: 1461–1472. Kimball AB, Kawamura T, Tejura K, Boss C, Hancox AR, Vogel JC, Steinberg SM, Turner ML, Blauvelt A: Clinical and immunologic assessment of patients with psoriasis in a randomized, double-blind, placebo-controlled trial using recombinant human interleukin 10. Arch Dermatol 2002, 138: 1341–1346. Friedrich M, Döcke W-D, Klein A, Philipp S, Volk H-D, Sterry W, Asadullah K: Immunomodulation by interleukin-10 therapy decreases the incidence of relapse and prolongs the relapse-free interval in Psoriasis. J Invest Dermatol 2002, 118: 672–677. National Institute of Allergy and Infectious Diseases: Phase I Trial of Recombinant Human Interleukin-10 (SCH 52000) in Patients With Wegener’s Granulomatosis. In Clinical Trials.gov [Internet]. Bethesda (MD): National Library of Medicine (US); 2008. [cited 2014 Apr 11]. Available from: http://clinicaltrials.gov/ct2/show/NCT00001761?term=NCT00001761&rank=1 Huhn RD, Radwanski E, O’Connell SM, Sturgill MG, Clarke L, Cody RP, Affrime MB, Cutler DL: Pharmacokinetics and immunomodulatory properties of intravenously administered recombinant human interleukin-10 in healthy volunteers. Blood 1996, 87: 699–705. Rosenblum IY, Johnson RC, Schmahai TJ: Preclinical safety evaluation of recombinant human interleukin-10. Regul Toxicol Pharmacol 2002, 35: 56–71.