• 1
    Katz WA, Barkin RL. Dilemmas in chronic/persistent pain management. Am J Ther 2008; 15: 256264.
  • 2
    Koes BW, Scholten RJ, Mens JM, Bouter LM. Efficacy of non-steroidal anti-inflammatory drugs for low back pain: a systematic review of randomised clinical trials. Ann Rheum Dis 1997; 56: 214223.
  • 3
    Langman MJ, Jensen DM, Watson DJ, Harper SE, Zhao PL, Quan H, Bolognese JA, Simon TJ. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999; 282: 19291933.
  • 4
    Swegle JM, Logemann C. Management of common opioid-induced adverse effects. Am Fam Physician 2006; 74: 13471354.
  • 5
    Morley-Forster PK, Clark AJ, Speechley M, Moulin DE. Attitudes toward opioid use for chronic pain: a Canadian physician survey. Pain Res Manag 2003; 8: 189194.
  • 6
    National Institute on Drug Abuse. Research Report Series. Prescription drugs: abuse and addiction [online]. Updated 2005. Available at (last accessed 15 July 2010).
  • 7
    Wolfert MZ, Gilson AM, Dahl JL, Cleary JF. Opioid analgesics for pain control: Wisconsin physicians’ knowledge, beliefs, attitudes, and prescribing practices. Pain Med 2010; 11: 425434.
  • 8
    Paulozzi LJ, Budnitz DS, Xi Y. Increasing deaths from opioid analgesics in the United States. Pharmacoepidemiol Drug Saf 2006; 15: 618627.
  • 9
    Jara-Oseguera A, Simon SA, Rosenbaum T. TRPV1: on the road to pain relief. Curr Mol Pharmacol 2008; 1: 255269.
  • 10
    Szallasi A, Cortright DN, Blum CA, Eid SR. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 2007; 6: 357372.
  • 11
    Gomtsyan A, Bayburt EK, Schmidt RG, Surowy CS, Honore P, Marsh KC, Hannick SM, McDonald HA, Wetter JM, Sullivan JP, Jarvis MF, Faltynek CR, Lee CH. Identification of (R)-1-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)urea (ABT-102) as a potent TRPV1 antagonist for pain management. J Med Chem 2008; 51: 392395.
  • 12
    Surowy CS, Neelands TR, Bianchi BR, McGaraughty S, El Kouhen R, Han P, Chu KL, McDonald HA, Vos M, Niforatos W, Bayburt EK, Gomtsyan A, Lee CH, Honore P, Sullivan JP, Jarvis MF, Faltynek CR. (R)-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea (ABT-102) blocks polymodal activation of transient receptor potential vanilloid 1 receptors in vitro and heat-evoked firing of spinal dorsal horn neurons in vivo. J Pharmacol Exp Ther 2008; 326: 879888.
  • 13
    Honore P, Chandran P, Hernandez G, Gauvin DM, Mikusa JP, Zhong C, Joshi SK, Ghilardi JR, Sevcik MA, Fryer RM, Segreti JA, Banfor PN, Marsh K, Neelands T, Bayburt E, Daanen JF, Gomtsyan A, Lee CH, Kort ME, Reilly RM, Surowy CS, Kym PR, Mantyh PW, Sullivan JP, Jarvis MF, Faltynek CR. Repeated dosing of ABT-102, a potent and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic activity in rodents, but attenuates antagonist-induced hyperthermia. Pain 2009; 142: 2735.
  • 14
    Bromm B, Jahnke MT, Treede RD. Responses of human cutaneous afferents to CO2 laser stimuli causing pain. Exp Brain Res 1984; 55: 158166.
  • 15
    Schaffler K, Wauschkuhn CH, Brunnauer H, Rehn D. Evaluation of the local anaesthetic activity of dimetindene maleate by means of laser algesimetry in healthy volunteers. Arzneimittelforschung 1992; 42: 13321335.
  • 16
    Schaffler K, Wauschkuhn CH, Gierend M. Analgesic potency of a new anticonvulsant drug versus acetylsalicylic acid via laser somatosensory evoked potentials. Randomized placebo-controlled double-blind (5-way) crossover study. Arzneimittelforschung 1991; 41: 427435.
  • 17
    Chizh BA, Priestley T, Rowbotham M, Schaffler K. Predicting therapeutic efficacy - experimental pain in human subjects. Brain Res Rev 2009; 60: 243254.
  • 18
    Alexander SPH, Mathie A, Peters JA. Guide to Receptors and Channels (GRAC), 5th edition. Br J Pharmacol 2011; 164: (Suppl. 1): S1S324.
  • 19
    Othman AA, Nothaft W, Awni WM, Dutta S. Pharmacokinetics of the TRPV1 antagonist ABT-102 in healthy human volunteers: population analysis of data from 3 phase 1 trials. J Clin Pharmacol 2011; 52: 10281041.
  • 20
    Rowbotham MC, Nothaft W, Duan WR, Wang Y, Faltynek C, McGaraughty S, Chu KL, Svensson P. Oral and cutaneous thermosensory profile of selective TRPV1 inhibition by ABT-102 in a randomized healthy volunteer trial. Pain 2011; 152: 11921200.
  • 21
    Jones B, Kenward M. Design and Analysis of Cross-over Trials. London: Chapman & Hall/CRC, 2003.
  • 22
    Abbott Nutrition. Ensure plus ingredients [online]. Updated 2011. Available at (last accessed 9 December 2011).
  • 23
    Othman AA, Cheskin H, Locke C, Nothaft W, Dutta S. A phase 1 study to evaluate the bioavailability and food effect of twosolid-dispersion formulations of the TRPV1 antagonist ABT-102, relative to the oral solution formulation, in healthy human volunteers. Clin Pharmacol Drug Dev 2012; 1: 2431.
  • 24
    Xu RN, Vaca P, Rieser MJ, El-Shourbagy TA. Highly sensitive LC-MS-MS analysis of a pharmaceutical compound in human plasma using monolithic phase-based on-line extraction. J Chromatogr Sci 2009; 47: 473477.
  • 25
    International Federation of Pharmaceutical Manufacturers and Associations. 2007 Medical Dictionary for Regulatory Activities, Version 10.1. In. VAR1/8A/MSSO ed. 12011 Sunset Hills Rd., Reston VA 20190-3285, USA: MedDRA Maintenance and Support Services Organization.
  • 26
    Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000; 288: 306313.
  • 27
    Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, Harries MH, Latcham J, Clapham C, Atkinson K, Hughes SA, Rance K, Grau E, Harper AJ, Pugh PL, Rogers DC, Bingham S, Randall A, Sheardown SA. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 2000; 405: 183187.
  • 28
    Liao S, Hill J, Nayak R. Pharmacokinetics of tramadol following single and multiple doses in man. Pharm Res 1992; 9: 308
  • 29
    Agrawal ng, Porras AG, Matthews CZ, Rose MJ, Woolf EJ, Musser BJ, Dynder AL, Mazina KE, Lasseter KC, Hunt TL, Schwartz JI, McCrea JB, Gottesdiener KM. Single- and multiple-dose pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, in man. J Clin Pharmacol 2003; 43: 268276.
  • 30
    Carmon A, Dotan Y, Sarne Y. Correlation of subjective pain experience with cerebral evoked responses to noxious thermal stimulations. Exp Brain Res 1978; 33: 445453.
  • 31
    Carmon A, Friedman Y, Coger R, Kenton B. Single trial analysis of evoked potentials to noxious thermal stimulation in man. Pain 1980; 8: 2132.
  • 32
    Hoffmann RT, Schmelz M. Time course of UVA- and UVB-induced inflammation and hyperalgesia in human skin. Eur J Pain 1999; 3: 131139.
  • 33
    Bickel A, Dorfs S, Schmelz M, Forster C, Uhl W, Handwerker HO. Effects of antihyperalgesic drugs on experimentally induced hyperalgesia in man. Pain 1998; 76: 317325.
  • 34
    Lee YM, Kim YK, Chung JH. Increased expression of TRPV1 channel in intrinsically aged and photoaged human skin in vivo. Exp Dermatol 2009; 18: 431436.
  • 35
    Schaffler K. Proof of efficacy and dose-dependency of NSAID and opiate analgesics in Laser evoked potential paradigm - using capsaicin and UV skin model. Spring Pain Conference; 2008 April 26-May 3, 2008; Grand Cayman Island, British West Indies.
  • 36
    Crutchlow M, Dong Y, Schulz V, Hoydonck PV, Laethem T, Maes A, Larson P, Eid S, Kane S, Hans G, Murphy G, Chodakewitz J, Greenspan J, Blanchard R. Pharmacologic inhibition of TRPV1 impairs sensation of potentially injurious heat in healthy subjects. 110th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics; March 18-21, 2009; National Harbor, MD; Abstract LB-II-A-3.
  • 37
    Sugiura T, Tominaga M, Katsuya H, Mizumura K. Bradykinin lowers the threshold temperature for heat activation of vanilloid receptor 1. J Neurophysiol 2002; 88: 544548.
  • 38
    Reeh PW, Petho G. Nociceptor excitation by thermal sensitization–a hypothesis. Prog Brain Res 2000; 129: 3950.
  • 39
    Kichko TI, Reeh PW. TRPV1 controls acid- and heat-induced calcitonin gene-related peptide release and sensitization by bradykinin in the isolated mouse trachea. Eur J Neurosci 2009; 29: 18961904.
  • 40
    Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, Schacht AL. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat Rev Drug Discov 2010; 9: 203214.