Chronic Inflammatory and Neuropathic Pain

Websites

IMMPACT: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials
Industry, academic and government consensus group meeting twice yearly to discuss standards and methods for clinical study of pain treatments.

ACTTION: Analgesic Clinical Trial Translations, Innovations, Opportunities, and Networks
Public-private partnership responsible for IMMPACT consensus meetings, publications, and other activities as of July 1, 2011.

OMERACT: Outcome Measures in Rheumatoid Arthritis Clinical Trials
Informal international network, working groups and gatherings interested in outcome measurement across the spectrum of rheumatology intervention studies.

American Pain Society
Multidisciplinary group of scientists, clinicians and other professionals working to increase the knowledge of pain and transform public policy and clinical practice to reduce pain-related suffering.

International Association for the Study of Pain
Society of scientists, clinicians, health care providers, and policy makers working to stimulate and support the study of pain and to translate that knowledge into improved pain relief worldwide.

Neurotrophins
August 2005 Molecule of the Month at the RCSB Protein Databank.

Voltage-gated sodium channels
Introduction to sodium channels from the official database of the IUPHAR Committee on Receptor Nomenclature and Drug Classification.

Erythromelalgia
Online Mendelian Inheritance in Man entry.

Congenital Insensitivity to Pain with Anhidrosis
Online Mendelian Inheritance in Man entry.

TRK Receptors
RCSB Protein Databank entry.

Institute of Medicine: Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research
June 2011 report providing a blueprint for action in transforming prevention, care, education, and research on pain in the US.

Journal Articles

Miroslav "Misha" Backonja

Backonja M, Woolf CJ. Future directions in neuropathic pain therapy: closing the translational loop. Oncologist 2010;15 Suppl 2:24-29.

Bril V, England J, Franklin GM, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PM R 2011;3(4):345-352, 352.e1-21.

Haanpää M, Attal N, Backonja M, et al. NeuPSIG guidelines on neuropathic pain assessment. Pain 2011;152(1):14-27.

Hanlon JT, Backonja M, Weiner D, Argoff C. Evolving pharmacological management of persistent pain in older persons. Pain Med. 2009;10(6):959-961.

Hewitt DJ, Ho TW, Galer B, et al. Impact of responder definition on the enriched enrollment randomized withdrawal trial design for establishing proof of concept in neuropathic pain. Pain 2011;152(3):514-521.

Mao J, Gold MS, Backonja MM. Combination drug therapy for chronic pain: a call for more clinical studies. J. Pain 2011;12(2):157-166.

Rosales R, Bashford G, Chaudakshetrin P, et al. Developing neuropathic pain treatment guidelines for Asia Pacific. Pain Pract. 2009;9(4):322-323.

Ralf Baron

Attal N, Bouhassira D, Baron R, et al. Assessing symptom profiles in neuropathic pain clinical trials: can it improve outcome? Eur. J. Pain 2011;15(5):441-443.

Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 2010;9(8):807-819.

Dworkin RH, Turk DC, Peirce-Sandner S, et al. Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations. Pain 2010;149(2):177-193.

Haanpää M, Attal N, Backonja M, et al. NeuPSIG guidelines on neuropathic pain assessment. Pain 2011;152(1):14-27.

Koroschetz J, Rehm SE, Gockel U, et al. Fibromyalgia and neuropathic pain—differences and similarities. A comparison of 3057 patients with diabetic painful neuropathy and fibromyalgia. BMC Neurol. 2011;11:55.

Magerl W, Krumova EK, Baron R, et al. Reference data for quantitative sensory testing (QST): refined stratification for age and a novel method for statistical comparison of group data. Pain 2010;151(3):598-605.

Maier C, Baron R, Tölle TR, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain 2010;150(3):439-450.

John T. Farrar

Cleeland CS, Farrar JT, Hausheer FH. Assessment of cancer-related neuropathy and neuropathic pain. Oncologist 2010;15 Suppl. 2:13-18.

Dworkin RH, Turk DC, McDermott MP, et al. Interpreting the clinical importance of group differences in chronic pain clinical trials: IMMPACT recommendations. Pain 2009;146(3):238-244.

Dworkin RH, Turk DC, Peirce-Sandner S, et al. Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations. Pain 2010;149(2):177-193.

Dworkin RH, Turk DC, Peirce-Sandner S, et al. Placebo and treatment group responses in postherpetic neuralgia vs. painful diabetic peripheral neuropathy clinical trials in the REPORT database. Pain 2010;150(1):12-16.

Dworkin RH, Turk DC, Katz NP, et al. Evidence-based clinical trial design for chronic pain pharmacotherapy: a blueprint for ACTION. Pain 2011;152(3 Suppl):S107-115.

Dworkin RH, Peirce-Sandner S, Turk DC, et al. Outcome measures in placebo-controlled trials of osteoarthritis: responsiveness to treatment effects in the REPORT database. Osteoarthr. Cartil. 2011;19(5):483-492.

Dworkin RH, Turk DC, Basch E, et al. Considerations for extrapolating evidence of acute and chronic pain analgesic efficacy. Pain 2011;152(8):1705-1708.

Farrar JT. Cut-points for the measurement of pain: the choice depends on what you want to study. Pain 2010;149(2):163-164.

Farrar JT. Advances in clinical research methodology for pain clinical trials. Nat. Med. 2010;16(11):1284-1293.

Farrar JT, Pritchett YL, Robinson M, Prakash A, Chappell A. The clinical importance of changes in the 0 to 10 numeric rating scale for worst, least, and average pain intensity: analyses of data from clinical trials of duloxetine in pain disorders. J. Pain 2010;11(2):109-118.

Farrar JT, Polomano RC, Berlin JA, Strom BL. A comparison of change in the 0-10 numeric rating scale to a pain relief scale and global medication performance scale in a short-term clinical trial of breakthrough pain intensity. Anesthesiology 2010;112(6):1464-1472.

Farrar JT, Messina J, Xie F, Portenoy RK. A novel 12-week study, with three randomized, double-blind placebo-controlled periods to evaluate fentanyl buccal tablets for the relief of breakthrough pain in opioid-tolerant patients with noncancer-related chronic pain. Pain Med. 2010;11(9):1313-1327.

Gordon DB, Polomano RC, Pellino TA, et al. Revised American Pain Society Patient Outcome Questionnaire (APS-POQ-R) for quality improvement of pain management in hospitalized adults: preliminary psychometric evaluation. J. Pain 2010;11(11):1172-1186.

Lee JYK, Chen HI, Urban C, et al. Development of and psychometric testing for the Brief Pain Inventory-Facial in patients with facial pain syndromes. J. Neurosurg. 2010;113(3):516-523.

Robert W. Gereau

Chiechio S, Zammataro M, Morales ME, et al. Epigenetic modulation of mGlu2 receptors by histone deacetylase inhibitors in the treatment of inflammatory pain. Mol. Pharmacol. 2009;75(5):1014-1020.

Chiechio S, Copani A, Zammataro M, et al. Transcriptional regulation of type-2 metabotropic glutamate receptors: an epigenetic path to novel treatments for chronic pain. Trends Pharmacol. Sci. 2010;31(4):153-160.

Hu H, Gereau RW. Metabotropic glutamate receptor 5 regulates excitability and Kv4.2-containing K+ channels primarily in excitatory neurons of the spinal dorsal horn. J. Neurophysiol. 2011;105(6):3010-3021.

Kolber BJ, Montana MC, Carrasquillo Y, et al. Activation of metabotropic glutamate receptor 5 in the amygdala modulates pain-like behavior. J. Neurosci. 2010;30(24):8203-8213.

Montana MC, Gereau RW. Metabotropic glutamate teceptors as targets for analgesia: antagonism, activation, and allosteric modulation. Curr. Pharm. Biotechnol. 2011.

Montana MC, Cavallone LF, Stubbert KK, et al. The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine. J. Pharmacol. Exp. Ther. 2009;330(3):834-843.

Qiu C, Lash-Van Wyhe L, Sasaki M, et al. Antinociceptive effects of MSVIII-19, a functional antagonist of the GluK1 kainate receptor. Pain 2011;152(5):1052-1060.

Zammataro M, Chiechio S, Montana MC, et al. mGlu2 metabotropic glutamate receptors restrain inflammatory pain and mediate the analgesic activity of dual mGlu2/mGlu3 receptor agonists. Mol. Pain 2011;7:6.

Ian Gilron

Dworkin RH, Turk DC, Peirce-Sandner S, et al. Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations. Pain 2010;149(2):177-193.

Gilron I. Gabapentin and pregabalin for chronic neuropathic and early postsurgical pain: current evidence and future directions. Curr. Opin. Anaesthesiol. 2007;20(5):456-472.

Gilron I. Optimizing neuropathic pain pharmacotherapy: add on or switch over? Nat. Clin. Pract. Neurol. 2008;4(8):414-415.

Gilron I, Jensen MP. Clinical trial methodology of pain treatment studies: selection and measurement of self-report primary outcomes for efficacy. Reg. Anesth. Pain Med. 2011;36(4):374-381.

Gilron I, Johnson AP. Economics of chronic pain: How can science guide health policy? Can. J. Anaesth. 2010;57(6):530-538.

Gilron I, Orr E, Tu D, Mercer CD, Bond D. A randomized, double-blind, controlled trial of perioperative administration of gabapentin, meloxicam and their combination for spontaneous and movement-evoked pain after ambulatory laparoscopic cholecystectomy. Anesth. Analg. 2009;108(2):623-630.

Gilron I, Bailey JM, Tu D, et al. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet 2009;374(9697):1252-1261.

Gilron I, Wajsbrot D, Therrien F, Lemay J. Pregabalin for peripheral neuropathic pain: a multicenter, enriched enrollment randomized withdrawal placebo-controlled trial. Clin. J. Pain 2011;27(3):185-193.

Moulin DE, Clark AJ, Gilron I, et al. Pharmacological management of chronic neuropathic pain—consensus statement and guidelines from the Canadian Pain Society. Pain Res. Manag. 2007;12(1):13-21.

Srikandarajah S, Gilron I. Systematic review of movement-evoked pain versus pain at rest in postsurgical clinical trials and meta-analyses: A fundamental distinction requiring standardized measurement. Pain 2011;152(8):1734-1739.

Watson CPN, Gilron I, Sawynok J. A qualitative systematic review of head-to-head randomized controlled trials of oral analgesics in neuropathic pain. Pain Res. Manag. 2010;15(3):147-157.

Jane Hughes

Chessell I, Hatcher J, Hughes J. A new utensil in our toolbox: exploring the role of IL-6 in pain using a naturally occurring antagonist. Pain 2010;151(2):235-236.

Hughes JP, Rees S, Kalindjian SB, Philpott KL. Principles of early drug discovery. Br. J. Pharmacol. 2011;162(6):1239-1249.

Hughes J, Hatcher JP, Chessell IP. Biologic drugs for analgesia: redefining the opportunity. Curr. Pharm. Biotechnol. 2011.

Kwan KY, Glazer JM, Corey DP, Rice FL, Stucky CL. TRPA1 modulates mechanotransduction in cutaneous sensory neurons. J. Neurosci. 2009;29(15):4808-4819.

Neely GG, Hess A, Costigan M, et al. A genome-wide Drosophila screen for heat nociception identifies α2δ3 as an evolutionarily conserved pain gene. Cell 2010;143(4):628-638.

Stephen McMahon

Bishop T, Marchand F, Young AR, Lewin GR, McMahon SB. Ultraviolet-B-induced mechanical hyperalgesia: A role for peripheral sensitisation. Pain 2010;150(1):141-152.

Clark AK, Staniland AA, Marchand F, et al. P2X7-dependent release of interleukin-1beta and nociception in the spinal cord following lipopolysaccharide. J. Neurosci. 2010;30(2):573-582.

Dawes JM, Calvo M, Perkins JR, et al. CXCL5 mediates UVB irradiation-induced pain. Sci. Transl. Med. 2011;3(90):90ra60.

D'Mello R, Marchand F, Pezet S, McMahon SB, Dickenson AH. Perturbing PSD-95 interactions with NR2B-subtype receptors attenuates spinal nociceptive plasticity and neuropathic pain. Mol. Ther. 2011.

Heinzmann S, McMahon SB. New molecules for the treatment of pain. Curr. Opin. Support Palliat. Care 2011;5(2):111-115.

Kaan TKY, Yip PK, Grist J, et al. Endogenous purinergic control of bladder activity via presynaptic P2X3 and P2X2/3 receptors in the spinal cord. J. Neurosci. 2010;30(12):4503-4507.

Kaan TKY, Yip PK, Patel S, et al. Systemic blockade of P2X3 and P2X2/3 receptors attenuates bone cancer pain behaviour in rats. Brain 2010;133(9):2549-2564.

Pinto R, Frias B, Allen S, et al. Sequestration of brain derived nerve factor by intravenous delivery of TrkB-Ig2 reduces bladder overactivity and noxious input in animals with chronic cystitis. Neuroscience 2010;166(3):907-916.

Yip PK, Wong L, Sears TA, Yáñez-Muñoz RJ, McMahon SB. Cortical overexpression of neuronal calcium sensor-1 induces functional plasticity in spinal cord following unilateral pyramidal tract injury in rat. PLoS Biol. 2010;8(6):e1000399.

Frank Porreca

Bannister K, Sikandar S, Bauer CS, et al. Pregabalin suppresses spinal neuronal hyperexcitability and visceral hypersensitivity in the absence of peripheral pathophysiology. Anesthesiology 2011;115(1):144-152.

De Felice M, Sanoja R, Wang R, et al. Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain. Pain 2011.

Hanlon KE, Herman DS, Agnes RS, et al. Novel peptide ligands with dual acting pharmacophores designed for the pathophysiology of neuropathic pain. Brain Res. 2011;1395:1-11.

King T, Qu C, Okun A, et al. Contribution of afferent pathways to nerve injury-induced spontaneous pain and evoked hypersensitivity. Pain 2011.

Okun A, DeFelice M, Eyde N, et al. Transient inflammation-induced ongoing pain is driven by TRPV1 sensitive afferents. Mol. Pain 2011;7:4.

Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J. Clin. Invest. 2010;120(11):3779-3787.

Qu C, King T, Okun A, et al. Lesion of the rostral anterior cingulate cortex eliminates the aversiveness of spontaneous neuropathic pain following partial or complete axotomy. Pain 2011;152(7):1641-1648.

Stagg NJ, Mata HP, Ibrahim MM, et al. Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: role of endogenous opioids. Anesthesiology 2011;114(4):940-948.

Vera-Portocarrero LP, Ossipov MH, Lai J, King T, Porreca F. Descending facilitatory pathways from the rostroventromedial medulla mediate naloxone-precipitated withdrawal in morphine-dependent rats. J. Pain 2011;12(6):667-676.

Frank L. Rice

Albrecht PJ, Rice FL. Role of small-fiber afferents in pain mechanisms with implications on diagnosis and treatment. Curr. Pain Headache Rep. 2010;14(3):179-188.

Asiedu MN, Tillu DV, Melemedjian OK, et al. Spinal protein kinase Mζ underlies the maintenance mechanism of persistent nociceptive sensitization. J. Neurosci. 2011;31(18):6646-6653.

Blackbeard J, O'Dea KP, Wallace VCJ, et al. Quantification of the rat spinal microglial response to peripheral nerve injury as revealed by immunohistochemical image analysis and flow cytometry. J. Neurosci. Methods 2007;164(2):207-217.

Bowsher D, Geoffrey Woods C, Nicholas AK, et al. Absence of pain with hyperhidrosis: a new syndrome where vascular afferents may mediate cutaneous sensation. Pain 2009;147(1-3):287-298.

De Felice M, Sanoja R, Wang R, et al. Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain. Pain 2011.

Dussor G, Koerber HR, Oaklander AL, Rice FL, Molliver DC. Nucleotide signaling and cutaneous mechanisms of pain transduction. Brain Res. Rev. 2009;60(1):24-35.

Hough LB, Rice FL. H3 receptors and pain modulation: peripheral, spinal, and brain interactions. J. Pharmacol. Exp. Ther. 2011;336(1):30-37.

Kwan KY, Glazer JM, Corey DP, Rice FL, Stucky CL. TRPA1 modulates mechanotransduction in cutaneous sensory neurons. J. Neurosci. 2009;29(15):4808-4819.

Petersen KL, Rice FL, Farhadi M, Reda H, Rowbotham MC. Natural history of cutaneous innervation following herpes zoster. Pain 2010;150(1):75-82.

Zhao P, Barr TP, Hou Q, et al. Voltage-gated sodium channel expression in rat and human epidermal keratinocytes: evidence for a role in pain. Pain 2008;139(1):90-105.

Märta Segerdahl

Blackbeard J, O'Dea KP, Wallace VCJ, et al. Quantification of the rat spinal microglial response to peripheral nerve injury as revealed by immunohistochemical image analysis and flow cytometry. J. Neurosci. Methods 2007;164(2):207-217.

Dellermalm J, Segerdahl M, Grass S. Caffeine does not attenuate experimentally induced ischemic pain in healthy subjects. Acta. Anaesthesiol. Scand. 2009;53(10):1288-1292.

Schulte H, Sollevi A, Segerdahl M. Dose-dependent effects of morphine on experimentally induced cutaneous pain in healthy volunteers. Pain 2005;116(3):366-374.

Segerdahl M. Multiple dose gabapentin attenuates cutaneous pain and central sensitisation but not muscle pain in healthy volunteers. Pain 2006;125(1-2):158-164.

Segerdahl M. Improving early clinical drug development for neuropathic pain by improving patient selection. Pain 2009;141(1-2):4-5.

Segerdahl M. Pain outcome variables—a never ending story? Pain 2011;152(5):961-962.

Wesnes KA, Annas P, Edgar CJ, et al. Nabilone produces marked impairments to cognitive function and changes in subjective state in healthy volunteers. J. Psychopharmacol. (Oxford) 2010;24(11):1659-1669.

David Seminowicz

Kuchinad A, Schweinhardt P, Seminowicz DA, et al. Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain? J. Neurosci. 2007;27(15):4004-4007.

Legrain V, Damme SV, Eccleston C, et al. A neurocognitive model of attention to pain: behavioral and neuroimaging evidence. Pain 2009;144(3):230-232.

Schweinhardt P, Seminowicz DA, Jaeger E, Duncan GH, Bushnell MC. The anatomy of the mesolimbic reward system: a link between personality and the placebo analgesic response. J. Neurosci. 2009;29(15):4882-4887.

Seminowicz DA, Davis KD. Pain enhances functional connectivity of a brain network evoked by performance of a cognitive task. J. Neurophysiol. 2007;97(5):3651-3659.

Seminowicz DA, Davis KD. A re-examination of pain-cognition interactions: implications for neuroimaging. Pain 2007;130(1-2):8-13.

Seminowicz DA, Laferriere AL, Millecamps M, et al. MRI structural brain changes associated with sensory and emotional function in a rat model of long-term neuropathic pain. Neuroimage 2009;47(3):1007-1014.

Seminowicz DA, Labus JS, Bueller JA, et al. Regional gray matter density changes in brains of patients with irritable bowel syndrome. Gastroenterology 2010;139(1):48-57.e2.

Seminowicz DA, Wideman TH, Naso L, et al. Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function. J. Neurosci. 2011;31(20):7540-7550.

Taylor KS, Seminowicz DA, Davis KD. Two systems of resting state connectivity between the insula and cingulate cortex. Hum. Brain Mapp. 2009;30(9):2731-2745.

Linda R. Watkins

Barrientos RM, Frank MG, Watkins LR, Maier SF. Memory impairments in healthy aging: Role of aging-induced microglial sensitization. Aging Dis. 2010;1(3):212-231.

Benison AM, Chumachenko S, Harrison JA, et al. Caudal granular insular cortex is sufficient and necessary for the long-term maintenance of allodynic behavior in the rat attributable to mononeuropathy. J. Neurosci. 2011;31(17):6317-6328.

Bevan DE, Martinko AJ, Loram LC, et al. Selection, preparation, and evaluation of small-molecule inhibitors of toll-like receptor 4. ACS Med. Chem. Lett. 2010;1(5):194-198.

Buchanan MM, Hutchinson M, Watkins LR, Yin H. Toll-like receptor 4 in CNS pathologies. J. Neurochem. 2010;114(1):13-27.

Frank MG, Watkins LR, Maier SF. Stress- and glucocorticoid-induced priming of neuroinflammatory responses: potential mechanisms of stress-induced vulnerability to drugs of abuse. Brain Behav. Immun. 2011;25 Suppl 1:S21-28.

Hains LE, Loram LC, Weiseler JL, et al. Pain intensity and duration can be enhanced by prior challenge: initial evidence suggestive of a role of microglial priming. J. Pain 2010;11(10):1004-1014.

Hutchinson MR, Lewis SS, Coats BD, et al. Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences. Neuroscience 2010;167(3):880-893.

Hutchinson MR, Loram LC, Zhang Y, et al. Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity. Neuroscience 2010;168(2):551-563.

Hutchinson MR, Shavit Y, Grace PM, et al. Exploring the neuroimmunopharmacology of opioids: an integrative review of mechanisms of central immune signaling and their implications for opioid analgesia. Pharmacol. Rev. 2011;63(3):772-810.

Lewis SS, Hutchinson MR, Rezvani N, et al. Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta. Neuroscience 2010;165(2):569-583.

Liu L, Ghosh N, Slivka PF, et al. An MD2 Hot-Spot-Mimicking Peptide that Suppresses TLR4-Mediated Inflammatory Response in vitro and in vivo. Chembiochem. 2011.

Loram LC, Harrison JA, Chao L, et al. Intrathecal injection of an alpha seven nicotinic acetylcholine receptor agonist attenuates gp120-induced mechanical allodynia and spinal pro-inflammatory cytokine profiles in rats. Brain Behav. Immun. 2010;24(6):959-967.

Loram LC, Taylor FR, Strand KA, et al. Prior exposure to glucocorticoids potentiates lipopolysaccharide induced mechanical allodynia and spinal neuroinflammation. Brain Behav. Immun. 2011.

Muscoli C, Doyle T, Dagostino C, et al. Counter-regulation of opioid analgesia by glial-derived bioactive sphingolipids. J. Neurosci. 2010;30(46):15400-15408.

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):581-591.

Stephen G. Waxman

Ahn H, Black JA, Zhao P, et al. Nav1.7 is the predominant sodium channel in rodent olfactory sensory neurons. Mol. Pain 2011;7:32.

Cheng X, Dib-Hajj SD, Tyrrell L, et al. Mutations at opposite ends of the DIII/S4-S5 linker of sodium channel Na V 1.7 produce distinct pain disorders. Mol. Pain 2010;6:24.

Cheng X, Dib-Hajj SD, Tyrrell L, et al. Deletion mutation of sodium channel NaV1.7 in inherited erythromelalgia: enhanced slow inactivation modulates dorsal root ganglion neuron hyperexcitability. Brain 2011;134(Pt 7):1972-1986.

Choi J, Cheng X, Foster E, et al. Alternative splicing may contribute to time-dependent manifestation of inherited erythromelalgia. Brain 2010;133(Pt 6):1823-1835.

Choi J, Boralevi F, Brissaud O, et al. Paroxysmal extreme pain disorder: a molecular lesion of peripheral neurons. Nat. Rev. Neurol. 2011;7(1):51-55.

Dib-Hajj SD, Waxman SG. Isoform-specific and pan-channel partners regulate trafficking and plasma membrane stability; and alter sodium channel gating properties. Neurosci. Lett. 2010;486(2):84-91.

Faber CG, Hoeijmakers JGJ, Ahn H, et al. Gain of function Na(V) 1.7 mutations in idiopathic small fiber neuropathy. Ann. Neurol. 2011.

Freilich ER, Jones JM, Gaillard WD, et al. Novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy. Arch. Neurol. 2011;68(5):665-671.

Gurkiewicz M, Korngreen A, Waxman SG, Lampert A. Kinetic modeling of Na v 1.7 provides insight into erythromelalgia-associated F1449V mutation. J. Neurophysiol. 2011;105(4):1546-1557.

Persson A, Black JA, Gasser A, et al. Sodium-calcium exchanger and multiple sodium channel isoforms in intra-epidermal nerve terminals. Mol. Pain 2010;6:84.

Persson A, Gasser A, Black JA, Waxman SG. Na(V)1.7 accumulates and co-localizes with phosphorylated ERK1/2 within transected axons in early experimental neuromas. Exp. Neurol. 2011;230(2):273-279.

Waxman SG. Channelopathic pain: a growing but still small list of model disorders. Neuron 2010;66(5):622-624.

Waxman SG. Polymorphisms in ion channel genes: emerging roles in pain. Brain 2010;133(9):2515-2518.

Waxman SG. Neuroscience: Channelopathies have many faces. Nature 2011;472(7342):173-174.

Zhao P, Barr TP, Hou Q, et al. Voltage-gated sodium channel expression in rat and human epidermal keratinocytes: evidence for a role in pain. Pain 2008;139(1):90-105.

Katja Wiech

Ehrsson HH, Wiech K, Weiskopf N, Dolan RJ, Passingham RE. Threatening a rubber hand that you feel is yours elicits a cortical anxiety response. Proc. Natl. Acad. Sci. USA 2007;104(23):9828-9833.

Leknes S, Brooks JCW, Wiech K, Tracey I. Pain relief as an opponent process: a psychophysical investigation. Eur. J. Neurosci. 2008;28(4):794-801.

Moseley GL, Zalucki NM, Wiech K. Tactile discrimination, but not tactile stimulation alone, reduces chronic limb pain. Pain 2008;137(3):600-608.

Ploner M, Lee MC, Wiech K, Bingel U, Tracey I. Prestimulus functional connectivity determines pain perception in humans. Proc. Natl. Acad. Sci. USA 2010;107(1):355-360.

Ploner M, Lee MC, Wiech K, Bingel U, Tracey I. Flexible cerebral connectivity patterns subserve contextual modulations of pain. Cereb. Cortex 2011;21(3):719-726.

Rennefeld C, Wiech K, Schoell ED, Lorenz J, Bingel U. Habituation to pain: further support for a central component. Pain 2010;148(3):503-508.

Wiech K, Tracey I. The influence of negative emotions on pain: behavioral effects and neural mechanisms. Neuroimage 2009;47(3):987-994.

Wiech K, Kalisch R, Weiskopf N, et al. Anterolateral prefrontal cortex mediates the analgesic effect of expected and perceived control over pain. J. Neurosci. 2006;26(44):11501-11509.

Wiech K, Ploner M, Tracey I. Neurocognitive aspects of pain perception. Trends Cogn. Sci. (Regul. Ed.) 2008;12(8):306-313.

Wiech K, Farias M, Kahane G, et al. An fMRI study measuring analgesia enhanced by religion as a belief system. Pain 2008;139(2):467-476.

Wiech K, Lin C, Brodersen KH, et al. Anterior insula integrates information about salience into perceptual decisions about pain. J. Neurosci. 2010;30(48):16324-16331.

Clifford J. Woolf

Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu. Rev. Neurosci. 2009;32:1-32.

Costigan M, Belfer I, Griffin RS, et al. Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain 2010;133(9):2519-2527.

Neely GG, Hess A, Costigan M, et al. A genome-wide Drosophila screen for heat nociception identifies α2δ3 as an evolutionarily conserved pain gene. Cell 2010;143(4):628-638.

Roberson D, Binshtok A, Blasl F, Bean B, Woolf C. Targeting of sodium channel blockers into nociceptors to produce long-duration analgesia: a systematic study and review. Br. J. Pharmacol. 2011.

Woolf CJ. Overcoming obstacles to developing new analgesics. Nat. Med. 2010;16(11):1241-1247.

Woolf CJ. What is this thing called pain? J. Clin. Invest. 2010;120(11):3742-3744.

Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011;152(3 Suppl):S2-15.

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In medicine, chronic pain is defined as pain that lasts for months, as opposed to days for acute pain. Most chronic pain is also neuropathic pain, that is, pain that persists in the absence of a painful stimulus due to pathological changes in the central nervous system. In neuropathic pain, neurological pathways that are intended to alert the body to potentially tissue-damaging events, such as a cut or burn, become chronically activated, leading to lasting pain that no longer serves a useful purpose and that can have a highly deleterious effect on quality of life for affected individuals.

According the Institute of Medicine's recent report, at least 116 million American adults currently suffer from chronic pain, more than are affected by heart disease, cancer, and diabetes combined. The Institute estimates that pain costs the U.S. nearly $635 billion per year in medical treatments and lost productivity.

Much of this pain is inadequately treated, in part because current classes of pain medications lack efficacy, possess significant side effects, or both. New therapies for pain are few and far between: only three have been approved in the past 10 years, despite the considerable efforts of pharmaceutical and biotechnology companies and academic researchers. As in many therapeutic areas, a large proportion of candidate pain therapies fail to make the transition from preclinical to clinical studies, while others fail, very expensively, in large, late-stage trials.

In the keynote lecture Clifford Woolf of Children's Hospital Boston described the use of genome-wide association studies to discover new pain targets. In the subsequent preclinical session Frank Rice of Integrated Tissue Dynamics, LLC, and Albany Medical College presented his work on the basic mechanisms of peripheral plasticity occurring in the development of chronic pain syndromes. New molecular targets for pain that were discussed included neurotrophins and chemokines (Stephen McMahon of King's College London), voltage-dependent sodium channels (Stephen Waxman of the Yale University School of Medicine), histone deacetylases (Robert Gereau of Washington University School of Medicine) and Toll-like receptors on glial cells (Linda R. Watkins of the University of Colorado at Boulder). Jane Hughes of MedImmune provided an overview of the potential for developing biologics, particularly monoclonal antibodies, as novel pain therapeutics.

The difficulties in transitioning preclinical pain candidates to clinical studies have been attributed to several factors, including a lack of correlation between animal models of pain and human pain syndromes and a lack of methods to objectively measure pain and pain relief in human clinical trial subjects. In the session on translational pain research, Frank Porreca of the University of Arizona described the development of an animal model for pain, based on the concept of negative reinforcement. Such a model may more accurately reflect human pain conditions. Mark Field of Grünenthal GmbH in Germany provided an overview of the potential roles of biomarkers, new pain models, and novel technologies in strengthening translational pain research. David Seminowicz of the University of Maryland School of Dentistry and Katja Wiech of the University of Oxford described work using imaging, in rodents and humans respectively, to detect pain more accurately and objectively. These techniques may be particularly useful in individuals who are unable to communicate their pain. Märta Segerdahl of AstraZeneca described how studies of pain in healthy human volunteers could be used to supplement and guide studies in chronic pain patients, and Laura Richman of MedImmune outlined the continuing need for biomarkers to monitor the safety of new pain therapies while they are under clinical investigation.

Clinical trials for new pain medications also suffer from the lack of objective pain measures, and the underlying heterogeneity in the pain patient population can make it difficult to detect efficacy in new pain therapeutics. Clinical researchers shared their findings on the optimal design of clinical trials for pain. The session on drug development included an overview of best practices in clinical pain management by Miroslav Backonja of LifeTree Research and the University of Wisconsin. Ralf Baron of University Hospital, Kiel, Germany described his work on mechanistic classification of pain patients into clinical subtypes that may aid in detecting responses to experimental therapies. Ian Gilron of Queen's University, Ontario and John T. Farrar of the University of Pennsylvania provided extensive reviews of essential aspects of clinical trial design for pain medications, ranging from patient selection to study design to the selection and analysis of outcomes. Lastly, Bob Rappaport of the U.S. FDA provided an update on the FDA's activities that are intended to improve drug discovery in this important therapeutic area.

Until recently, research on new therapies for chronic neuropathic pain has been hampered by insufficient understanding of the basic underlying mechanisms. The preclinical, translational, and clinical approaches reported here are likely to fill in important knowledge gaps in basic and clinical science while advancing the search for more effective, safer medications for this pervasive problem.

Speakers:
Clifford J. Woolf, Children's Hospital Boston
Frank L. Rice, Integrated Tissue Dynamics, LLC and Albany Medical College
Stephen McMahon, King's College London, London, UK
Jane Hughes, MedImmune, Cambridge, UK

Highlights

• New molecular approaches, such as genome-wide association studies, have already begun to identify new targets for pain.
• Chronic pain changes spatial organization, morphology, and molecular expression in peripheral nerve fibers, suggesting new therapeutic approaches.
• Neurotrophins and chemokines represent new targets for pain medications.
• Biologic therapies, particularly monoclonal antibodies, have properties that may make them particularly suitable for development as pain therapeutics.

Genome-wide screens for novel pain targets

The classic approach to developing new therapies is to identify a candidate molecule, such as a gene or protein, or a candidate pathway, and to design molecules that target that candidate. Unfortunately this approach has not worked well for the discovery of new therapeutics for pain in the past 10 to 15 years, largely because our understanding of the mechanisms underlying chronic pain is still developing. The need for new targets for pain therapeutics has led researchers like Clifford Woolf of Children's Hospital in Boston to pursue more comprehensive approaches to target identification, using tools developed for the investigation of whole genomes. In his keynote address, Woolf described work that he and others are pursuing: using genome-wide association studies to identify the genetic determinants of pain syndromes, which can then be used to backtrack to specific pathways and molecules as clinical targets for pain.

The feasibility of a genomic approach to pain targets is supported by multiple lines of evidence, in both animals and humans, that strongly suggest that there is a significant genetic component to pain susceptibility. In mice, for example, classic genetic studies of inbred strains have estimated that the development of neuropathic pain is about 50% attributable to inherited factors. Researchers have long noted that different strains of mice have different susceptibilities to different types of pain. More recently, these differences in susceptibility have been linked to differences at specific genomic loci, which might form the basis for new approaches to pain.

In humans, classic genetic studies, such as twin studies, have found strong evidence for the heritability of spinal pain and of symptom clusters associated with fibromyalgia. There are also a number of rare mutation classes that lead to strong pain phenotypes, such as erythromelalgia, an unusual neurovascular pain disorder, and familial insensitivity to pain, both of which have been traced to mutations in the gene that encodes voltage-gated sodium channels. Single nucleotide polymorphisms (SNPs), which are more common genetic variations that occur in approximately 1 in 100 individuals, have also been associated with chronic pain conditions.

The increasing availability of genomic data and large-scale genomics methods has allowed the pursuit of genome-wide association studies of pain and related sensory phenomena. Woolf and his coworkers performed a genome-wide, neuronal-specific study of thermal nociception using approximately 16,000 transgenic lines of the fruit fly Drosophila, and leading to the identification of 580 associated genes. Mutations in one of these genes, encoding a calcium channel known as α2δ3, were found to reduce sensitivity to pain in both mice and humans. In addition to representing a potential therapeutic target, these findings are shedding light on the central processing of pain signals.

Woolf noted that in addition to identifying new pain susceptibility genes, such studies can be used to identify biomarkers for pain and to develop predictive algorithms for pain treatments. Genomic approaches can be combined with proteomic and classic biochemical methods in an iterative process that will identify new targets and advance our understanding of the molecular underpinnings of chronic pain syndromes.

Plasticity in peripheral fibers and epidermal molecular organization

The skin is a rich target for pain studies as it is the locus of a multitude of pain syndromes, including more than 150 types of peripheral neuropathies and more than 1500 types of dermatopathologies. Normal tactile sensation via the skin depends on a complex mixture of neurons with sensory endings that use combinations of distinct morphologies, precise spatial organization, and varied patterns of molecular expression to detect distinct but overlapping types of stimuli. These nerve endings have predictable responses to stimuli that become disordered in chronic neuropathic pain conditions.

Frank Rice and his coworkers at Integrated Tissue Dynamics and Albany Medical College are studying several peripheral neuropathies. Three types were presented for comparison: postherpetic neuralgia in humans, neuropathies associated with type 2 diabetes in rhesus monkeys, and complex regional pain syndrome (CRPS) type 1 in humans. Rice and colleagues are using anatomical, immunohistochemical, and molecular approaches to study the changes in the distribution and molecular expression of all types of sensory fibers, including those regarded as nociceptive fibers, that occur in each of these disorders. The endings of these fibers, which are known as Aβ, Aδ, and C fibers, become reduced in number and become disorganized. In the skin of monkeys with diabetes, the disorganization shows signs of ongoing instability and remodeling, whereas in CRPS, the disorganization may have a comparative permanence. The pathologies in these pain conditions involve not only sensory endings typically regarded as nociceptors but also those that are normally thought to mediate gentle touch sensation. Importantly, the endings normally involved gentle touch have immunochemical properties that may contribute to pain under pathological conditions.

Axonal tracers expressed from the Mrgprd locus identify a subpopulation of nonpeptidergic, nociceptive neurons that project exclusively to the skin, revealing topographic details of skin sensory circuits. (Image courtesy of Frank Rice)

The group is also investigating the role of keratinocytes, cells that produce the important skin structural element keratin, as mediators of pain. Both nerve fibers and keratinocytes show distinct changes in protein expression under chronic pain conditions in humans and animal models. By carefully tracking the molecular and morphological changes that occur in pain disorders, Rice and his colleagues are building a model of concomitant stratified patterns of sensory endings and keratinocyte chemistry. The normal patterns of sensory endings and keratinocyte chemistry combine to provide a predictable variety of activity from the skin that is perceived as normal tactile sensation. Under pathological conditions, disruptions of these patterns may result in chaotic activity that is perceived as painful. More detailed knowledge of the mechanisms that maintain normal patterns of activity will lead to the identification of new therapeutic approaches to pain syndromes that are characterized by disordered activity.

Peripheral mediators of chronic pain: NGF and beyond

Chronic pain is thought to be a phenomenon of the central nervous system. However, chronic pain can also be alleviated temporarily with the use of local anesthestics, suggesting that ongoing activation of peripheral nerve pathways may also be involved in supporting this phenomenon. Stephen McMahon and his group at King's College London are studying peripheral factors that seem to be involved in mediating chronic pain, including nerve growth factor (NGF) and chemokines.

NGF is a member of the neurotrophin family of growth factors, which activate intracellular signaling through Trk and p75NTR receptors found on neurons. This signaling system plays an important role in nervous system development and is also involved in mediating pain in inflammatory pain states. Several lines of evidence implicate NGF, in particular in nociceptor sensitization and the production of hyperalgesia in human pain states and animal pain models. Mutations in the high affinity receptor for NGF, known as TrkA, have also been found to result in the disorder known as congenital insensitivity to pain with anhidrosis (CIPA).

Increased understanding of the role of NGF in inflammatory pain has led to the development of therapies targeted against it. One such therapy is the monoclonal antibody tanezumab, which binds NGF, preventing it from binding to its receptor and interfering with signaling pathways. Tanezumab is in clinical trials for the treatment of chronic knee and hip pain due to osteoarthritis, cancer pain, interstitial cystitis, chronic low back pain, and diabetic neuropathy. Although promising results were posted for trials in osteoarthritis, some patients developed worsening arthritis and bone necrosis that led them to need joint replacement surgery. Trials in osteoarthritis have been suspended and the future of tanezumab is currently uncertain.

McMahon and his group are studying the roles of other molecules that may also act as peripheral mediators of chronic pain. They have focused on a large family of secreted proteins known as chemotactic cytokines, or chemokines. These proteins are important for immune cell activation and leukocyte chemotaxis, and they can activate sensory neurons as well, by virtue of their effects on specific G-protein coupled receptors.

UVB induced skin inflammation as a human pain model. (Image courtesy of Stephen McMahon)

In humans, overexposure to UVB light results in sunburn, a painful condition characterized by long lasting erythema (redness due to increased vascular activity) as well as mechanical and thermal hyperalgesia. McMahon is using experimentally induced UVB skin inflammation in humans to study molecular changes associated with hyperalgesia in the skin. He has found that UVB overexposure induces transcriptional changes in the expression of multiple chemokines in both human and rat skin, including most notably a chemokine known as CXCL5. Further experiments with this molecule strongly suggest that it acts as a peripheral mediator of UVB-induced inflammatory pain. He and his group are continuing to study this molecule and other potential novel pain mediators that have been revealed by this UVB model.

New targets suitable for biologic approaches

Jane Hughes, of MedImmune, provided an analysis of the potential for monoclonal antibodies, peptides, and other biologics as therapies for pain. Current therapeutic approaches to pain are often limited by side effects. Moreover, in the clinical development pipeline, many compounds are dropped in phase 2 studies because side effects reduce the amount of a drug patients can receive and thereby reduce the chances of detecting efficacy. Side effects are usually the result of off-target activities of drug molecules, so reducing off-target effects might improve the odds that drug candidates will make it through the development pipeline. Biologic therapies tend to be more specific and less susceptible to off-target effects, and thus might fare better than small molecule drugs in this regard.

Monoclonal antibodies in particular are exquisitely selective. There are currently 26 monoclonal antibodies and antibody fragments that have been approved for use in the U.S., most as cancer therapies or for the treatment of immune-related disorders such as rheumatoid arthritis, and another 350 or so are in preclinical or clinical development. The adverse events that are observed with monoclonal antibodies are usually related to their targeted pharmacological mechanisms rather than to their off-target effects, although they can also carry immunological side effects.

Monoclonal antibodies have some potential drawbacks. Their development as drugs is relatively straightforward, but manufacturing large quantities of these molecules for the pharmaceutical marketplace can be technically demanding. Because antibodies and other peptides are vulnerable to digestion in the gut, biologics are also generally limited to parenteral routes of administration, which are less convenient than oral administration. Monoclonal antibodies also tend not to enter the central nervous system, which is likely to be a problem for potential therapies for chronic pain.

As a case study, Hughes discussed the development of MEDI-578, a fully human monoclonal antibody that binds to and selectively sequesters NGF with a very high affinity. This antibody has shown effectiveness against pain hypersensitivity in a number of preclinical animal models. However, its future is uncertain given the current status of tanezumab and the unknown safety profile of antibodies against this target (NGF). Another peripheral, soluble target for monoclonal antibodies is interleukin 6 (IL-6). Anti-IL-6 antibodies have also shown some success in animal models.

Because they generally do not cross cell membranes easily, monoclonal antibody-based therapies have mostly been developed against soluble targets that are accessible in extracellular spaces, such as in the blood. However, membrane-bound channels, receptors, and transporters that have surfaces that are exposed to the extracellular space are also potential targets. Although the development of such antibodies is challenging, monoclonals may provide the selectivity that is often missing from small molecules that target important membrane-bound pain mediators such as sodium channels. An important next step will be to find ways to get monoclonal antibodies into the central nervous system, and researchers have already identified a few strategies that might be able to achieve this goal. Hughes concluded that biologics represent an important new approach to developing pain therapies that is likely to prove fruitful once the technical challenges have been overcome.

Speakers:
Stephen G. Waxman, Yale University School of Medicine
Robert W. Gereau, Washington University School of Medicine
Linda R. Watkins, University of Colorado at Boulder

Highlights

• Multiple lines of evidence suggest that voltage-regulated sodium channels may be effective new targets for pain therapeutics, but care must be taken not to disrupt the channels' other important activities.
• Histone deacetylase inhibitors may provide pain relief by modulating the expression of glutamate receptors.
• Glial cells play important roles in chronic pain and in mediating the activities and side effects of opioid pain medications, representing another potential new target.

Sodium channels as therapeutic targets in pain

Stephen Waxman of Yale University has studied voltage-gated sodium channels extensively, and at this conference he spoke on their potential as targets for pain therapeutics. These channels are the principle conductors of electrical signals in the long axonal processes sent out by neurons to communicate with muscles, neurons, and other types of cells. Nine sodium channel subtypes (named Na_V1.1 through Na_V1.9) have been identified, which have diverse biophysical properties and patterns of expression in different types of neurons. Sodium channel expression is dynamic, changing as a result of injury or pathological conditions. Misexpression of these channels can cause dysregulation of pain signaling, and can result in, for example, the cell membrane hyperexcitability associated with neuropathic pain. Thus some sodium channel subtypes are therapeutic targets.

Waxman reviewed some of the evidence that links sodium channels with chronic pain pathways that has been collected in his and other laboratories in recent years. Sodium channel subtypes Na_V1.7, Na_V1.8, and Na_V1.9 are preferentially expressed in neurons of the dorsal root ganglion, which form part of the neurological pathways that are involved in chronic pain. Another subtype, Na_V1.3, has been shown to be upregulated after axonal injury, where it appears to play an important role in hyperexcitability. Similarly, Na_V1.3, Na_V1.7, and Na_V1.8 all accumulate in injured axon tips in painful neuromas (growths or tumors in nerve tissue) in humans. Na_V1.9 is selectively expressed in nociceptive neurons found in the skin and in other parts of the periphery.

Sodium channels have also been implicated in pain pathways by the identification of mutations that lead to congenital pain disorders in humans. Gain-of-function mutations in the gene that encodes Na_V1.7 can lead to severe pain syndromes, including inherited erythromelalgia and paroxysmal extreme pain syndrome, while loss-of-function mutations in this channel's gene produce congenital insensitivity to pain.

Features of primary erythromelalgia. (Image courtesy of Stephen Waxman)

The ability to express these channels in cultured cells and other model systems has allowed Waxman's group and others to examine in minute detail the unique biophysical and physiological properties of each channel subtype. When the subtypes are expressed together in different combinations, they alter the phenotype of the cell in ways that may be important for pain signal processing. The subtypes are also regulated differently, and this regulation changes depending on the cell background in which they are expressed. These differences in regulation may account for differences in pain sensitivity in individuals carrying SNPs in sodium channel genes.

Model of voltage-gated sodium channel Na_V1.7 showing structural effects of the erythromelalgia-associated mutation F1449V. (Image courtesy of Stephen Waxman)

The complexities of sodium channel expression, function, and regulation are such that it may be some time before this research bears fruit in effective therapies. Further challenges are posed by the fact that all of these channels have additional, physiologically important roles that it might be dangerous to disrupt. Mutations in Na_V1.3, for example, have been found to be associated with a type of pediatric epilepsy, and Na_V1.8 is an important player in cardiac function. These findings suggest that extra caution will be necessary when designing pain therapies against these potentially very useful targets.

Modulation of glutamate receptor expression as a mechanism of analgesia

The compound L-acetylcarnitine has shown efficacy as a therapeutic agent in human neuropathic disorders, including painful peripheral neuropathies such as those caused by HIV infection and diabetes, and in animal models as well. Robert Gereau and his colleagues at Washington University School of Medicine are investigating the analgesic activity of the compound, and their work has led to the discovery of new targets for pain therapeutics.

Preclinical investigation of L-acetylcarnitine's analgesic effects has shown that it acts in part by regulating the expression of a certain class of glutamate receptors known as metabotropic glutamate receptors. There are 8 known types of metabotropic glutamate receptors, and one of them, mGlu2, creates an analgesic effect when it is activated by glutamate. However, the development of therapeutic agonists that would stimulate this receptor's activity has been limited by the emergence of receptor tolerance. Receptor tolerance occurs when repeated stimulation leads to down-regulation of receptor activity, so that a given dose of agonist no longer has the desired effect.

Gereau and his group have determined that L-acetylcarnitine functions as an acetyl donor that promotes acetylation of the NF-κB group of transcription factors, which act in the nucleus to control the expression of specific genes. One of these transcription factors p65 regulates the expression of metabotropic glutamate receptors, increasing their expression when it is acetylated. Gereau has shown that inhibitors of this transcription factor reduce mGlu2 expression and block the ability of L-acetylcarnitine to raise mGlu2 levels, supporting the proposed mechanism.

Proposed mechanism by which histone deactetylase (HDAC) inhibitors might promote increased expression of mGlu2, producing an analgesic effect. (Image courtesy of Robert Gereau)

There are already a number of drugs in development that work by inhibiting histone deactylases (HDACs), which are enzymes that remove acetyl groups from histones and other proteins. Multiple HDAC inhibitors are in clinical trials as potential therapies for cancer, and one, vorinostat, has been approved as a therapy for cutaneous T cell lymphoma. Gereau hypothesized that HDAC inhibitors such as vorinostat might promote acetylation of p65, leading to increased mGlu2 expression. Using animals, he and his group have shown that HDAC inhibitors do in fact promote mGlu2 expression, creating an analgesic effect when given repeatedly. The unique mechanism and novel analgesic profile of these agents makes them promising new candidates for pain therapy.

Neuroinflammation from neuron-to-glial signaling & opioids: implications for drug development

Over the past two decades or so it has become increasingly apparent that non-neuronal glial cells, such as microglia and astrocytes, in the brain and spinal cord are involved in chronic pain syndromes. More recently, it was also found that these cells are involved in CNS responses to opioids, compromising the drugs' analgesic activity, participating in the process of opioid dependence, withdrawal, and reward, and ultimately contributing to drug craving and drug abuse. Linda Watkins and her group at the University of Colorado are studying the roles of these cells and the potential for targeting their activities in novel therapeutic approaches to pain.

She and others have contributed to a body of research which suggests that glial cells are activated under chronic pain conditions by signaling from neurons, which prompts them to release neuroinflammatory substances that further promote chronic pain. Clinically relevant opioids, such as morphine, activate glia as well, also causing them to release substances that increase pain. Watkins and her collaborators have uncovered the underlying molecular mechanisms of these effects and have found that the receptor that mediates glial activation and creates neuroinflammation is the same receptor that is activated by opioids.

This receptor, Toll-like receptor 4, is one of a family of receptors that is involved in innate immune responses to microbial toxins. This receptor is a non-classical, non-stereoselective opioid receptor that is different from the neuronal receptors involved in the mechanism of opioid analgesia, raising the possibility it might be possible to target glial opioid receptors without interfering with the activities of the neuronal ones. Compounds that target this receptor have efficacy by themselves as treatments for neuropathic pain, and also act to block the side effects of opioids and other drugs with abuse potential. These studies contribute another set of novel targets for new pain therapies.

Speakers:
Frank Porreca, University of Arizona
Mark J. Field, Grünenthal GmbH, Aachen, Germany
David A. Seminowicz, University of Maryland School of Dentistry

Highlights

• Animal pain models that involve negative behavioral reinforcement by relief from pain may more effectively model human chronic pain conditions.
• Development of biomarkers and new human models for pain, together with the application of new technologies, is likely to improve the preclinical to clinical translation for new therapies. 
• Imaging methods show great potential as objective measures of pain, and imaging studies will also lead to a better understanding of chronic pain mechanismsin the CNS. 
• Monoclonal antibody therapeutics can lead to rare but severe complications, and there is a strong need for predictive safety biomarkers for pain therapeutics in development.

Pre-clinical measurement and mechanistic assessment of affective dimensions of pain and pain relief

One of the factors that appears to be holding back progress in the search for new analgesics is the lack of animal models for pain that accurately reflect human pain conditions. Most animal models for determining the effectiveness of pain therapies detect analgesic activity as an increase in the threshold at which an animal pulls away from an aversive stimulus, such as a source of heat. Human chronic pain conditions, on the other hand, largely involve spontaneous pain, for which there is no specific external stimulus. Frank Porreca and his group at the University of Arizona are developing new animal models that more closely reflect human pain conditions.

Their approach has been to make use of the concept of negative reinforcement as a way to unmask spontaneous neuropathic pain. Negative reinforcement is an increase in the future frequency or likelihood of a behavior due to the removal of an aversive stimulus. Thus, instead of measuring an animal's response to an aversive stimulus, their model measures the response to alleviation of an aversive stimulus. This technique makes use of a well developed model for drug reward known as conditioned place preference. Using rats with an experimentally induced nerve injury, they have shown that drugs that do not normally reinforce behavior can do so if they provide relief from chronic pain. These drugs are not likely to become drugs of abuse, however, because they do not stimulate reward circuits in brain in the absence of pain.

Brain regions implicated in the transmission and modulation of pain. (Image courtesy of Frank Porreca)

Using this model, combined with animal models of allodynia, hyperalgesia, and post-surgical pain, Porreca and his group have investigated a range of neural pathways that might contribute to spontaneous neuropathic pain. They have identified roles for peripheral nerve fibers that express the TrpV1 receptor and spinal neurons expressing the NK1 receptor. They have also identified specific groups of dopaminergic neurons in the brain that are involved in the rewarding effect of relief from pain. They are investigating the intracellular signaling pathways found in these neurons as potential new targets for pain therapies, including pathways that involve P2X4 receptors, 5-HT3 receptors, and voltage-regulated sodium channels. Therapies developed and tested using these new models may be more likely to find efficacy in human studies.

Translation in pain — from preclinical to clinical efficacy

Mark Field of Grünenthal GmbH discussed another challenging aspect of the search for new pain therapeutics: the need for a better understanding of the underlying mechanisms of chronic pain to enable the translation from preclinical to clinical efficacy. The heterogeneity of human pain conditions most likely reflects heterogeneous underlying mechanisms, and despite recent progress, these mechanisms are still not well understood. Preclinical pain models replicate specific features of chronic pain disorders, such as allodynia and hyperalgesia, but these endpoints do not correspond well to the pain measures typically used to assess patients in the clinic. Human pain is often measured with the use of simple pain rating scales, which describe pain intensity utilising a numeric value (typically between 0 – 10). These measures capture a holistic view on the impact of pain but fail to capture any useful information on the subtype(s) of pain the patient is suffering from (for example, allodynia verus ongoing pain) or the subjective differences in pain sensations (for example, sharp versus dull versus burning pain). In addition, these scales are not objectively quantifiable, they give limited feedback to aid preclinical research and clinically meaningful changes within these scales are difficult to determine.

Multiple sensations and subjective factors underlie qualitative pain scoring. (Image courtesy of Mark Field)

Field highlighted the importance of translational pain research to bridge the gap between preclinical and clinical studies. One important approach is to develop biomarkers that can provide more objective data within the early phase of clinical development and increasing our understanding of specific underlying pain mechanisms. Biomarkers that are based on a mechanistic understanding of pain could be used to evaluate whether a candidate pain therapy hits its intended target, mediates a pharmacological action or has the possibility to affect the underlying disease process prior to the compound entering patients—thereby enabling efficient decision making. Biomarkers can be biochemical or genetic, or they can involve imaging techniques or physiological measures like blood pressure. Newer experimental models, such as the UVB skin exposure model used by Stephan McMahon and others, will also play an important role in the discovery and evaluation of new pain therapeutics.

A number of changes to the research environment could also help. A more open research structure that promotes closer cooperation between university researchers, pharmaceutical and biotechnology companies, and clinical research organizations would facilitate faster research and avoid costly and time-consuming duplication of research. New technologies are available that could help to move research forward while managing the new knowledge gained. For example, new types of diagnostics, new medication delivery systems, more sophisticated ways of monitoring patients, and novel technologies that can promote information sharing among researchers, could all advance pain research efforts. These and other innovations will contribute to a changed model of pharmaceutical R&D that will be crucial to the successful development of new pain therapeutics.

Rodent behavioral testing and rodent brain imaging

Although the sensation of pain begins with the activation of sensory neurons in the skin and other peripheral organs, pain is processed and ultimately experienced in the CNS. This is particularly true of chronic neuropathic pain, which is pathologic because it persists after the painful stimulus has been removed. David Seminowicz and his group at the University of Maryland Dental School are using brain imaging in animals to understand the underlying mechanisms of neuropathic pain in the brain, as a potential guide to the development of novel therapeutic interventions.

Neuropathic pain conditions have been shown to change brain structure and function in humans, but a question that remains unanswered is whether these changes are the cause or an effect of chronic pain. For therapeutic purposes, it would also be informative to find out if these changes can and should be reversed by treating chronic pain. These questions are difficult to address in humans, so Seminowicz and his group are studying them in animals, which are more amenable to manipulation. Their approach has been to perform behavioral studies and brain imaging before the onset of chronic pain, then to induce a chronic pain condition and to follow changes in brain structure and function that occur longitudinally. One advantage of using animals for this work is the ability to control both genetics and environment carefully, but a disadvantage is that rodents cannot report the subjective experience of pain as humans would be able to.

Anatomical changes in the brain related to hypersensitivity in a rodent neuropathic pain model (Image courtesy of David Seminowicz)

Using these methods, Seminowicz has found that brain areas that are related to the sensory aspect of pain, including the anterior cingulate cortex and primary somatosensory cortex, decrease in volume in a manner that is correlated with mechanical hypersensitivity. The more hypersensitive an animal becomes, the smaller their sensory regions become. He and his group have also observed that the volume of the prefrontal cortex decreases several months after injury, corresponding in time with increased signs of anxiety-like behavior. They conclude that chronic pain is the consequence rather than the cause of these changes. Moreover, further studies in their laboratory and by other groups using human subjects suggest that these brain changes are reversible. Seminowicz and colleagues intend to continue to explore how the structure of the brain changes in chronic pain syndromes, how these changes are related to affective and cognitive behaviors, and how chronic pain treatments might be designed to counteract such changes in humans.

Speakers:
Katja Wiech, University of Oxford, Oxford, UK
Laura K. Richman, MedImmune
Märta Segerdahl, AstraZeneca, Södertälje, Sweden

Highlights

• Functional magnetic resonance imaging has the potential to be used as an objective measure of the subjective pain experience. 
• Healthy human volunteer models of pain can augment the findings of clinical trial studies of chronic pain patients, leading to mechanistic insight.
• As a therapeutic class, monoclonal antibodies have specific types of adverse effects that will need to be considered as new pain therapies are developed and tested in humans.

Imaging as an objective measure of pain

Pain is a subjective experience and sometimes occurs and changes in the absence of external stimuli. Katja Wiech and her colleagues at the University of Oxford are investigating the use of brain imaging methods as objective measures of pain. Such measures would be useful in research, to help understand underlying mechanisms and identify new targets, and in pain treatment as well, especially among individuals who are unable or unwilling to report their pain.

The method Wiech is using is Blood Oxygenation Level Dependent (BOLD) MRI imaging, which relies on differences in cerebral blood flow in different areas of the brain to detect and localize brain activity. This method is a standard technique that is used to generate functional MRI images. As an indirect measure of neuronal activity, this method is subject to physiological noise, that is to say, changes in brain metabolism that may have nothing to do with the phenomenon under study. This limitation necessitates careful statistical processing of the data. Other challenges in these studies include the nonlinear relationship between nociceptive input and pain, the high variability in pain responses between individuals, and the involvement in pain of a network of brain regions rather than one or two discrete areas.

Wiech is working on identifying the best methods to analyze brain images to get quantitative measures of human pain, with the ultimate goal of being able to predict the pain experience in a given individual just from looking at the MRI images. Multivariate pattern processing is used to compare images during transitions from pain to no pain and vice versa. She has identified distinct patterns of brain activity that appear to be related to pain perception and to pain-related psychological processing, involving both cognitive-affective and sensory brain regions. Currently these images can be used to predict the experience of pain, although accuracy is relatively low, and predictions only work in the specific individual from whom the data set is derived. Even with these limitations, however, this method might be useful when used longitudinally in individuals with progressive motor disease, such as ALS, that eventually robs them of the ability to express the pain that they are feeling.

Pain models that use human volunteers for early clinical testing

The drawbacks of transitioning from animal models to clinical studies of pain could potentially be avoided with the use of human volunteers. Märta Segerdahl of AstraZeneca discussed the current status of human volunteer studies of pain and pain medications. Human volunteer models could be developed for different types of pain and to investigate both peripheral and central pain mechanisms. An advantage of using healthy volunteers is that it is possible to perform smaller, well controlled trials, without the confounding factors potentially introduced by the heterogeneity of actual pain patients. However, pain studies in healthy individuals will of necessity involve only acute or evoked pain, and it is uncertain how well results derived from these individuals will predict results in patients carrying the neurological changes associated with chronic pain.

Many human volunteer models have already been developed, most involving cutaneous or muscle pain evoked by a wide range of stimuli, including mechanical, thermal, electrical, and chemical sources of pain. Most of these models target peripheral pain mechanisms. Some models have well understood underlying mechanisms, for example, the use of capsaicin injection in different forms to study compounds targeting TrpV1 channels. Capsaicin models induce both central sensitization and areas of secondary hyperalgesia. These models have been validated with known analgesics including opioids, ketamine, and non-steroidal anti-inflammatories. UV skin irradiation is another model that has been validated against known analgesics.

The diversity of human pain models. (Image courtesy of Märta Segerdahl)

These and other volunteer models can be used to increase confidence in target-specific proof of mechanism work for potential drug candidates. Segerdahl emphasized that the choice of a particular model is less important than obtaining the appropriate readout for the experimental question at hand. She noted that such models could also be used in patients with chronic pain to uncover mechanistic differences from healthy individuals and to test the therapeutic efficacy of candidate molecules in a more relevant clinical situation.

Rational biomarker development for predictive sciences and safety monitoring

Safety is an important consideration in the development of new medications. One of the reasons for the high failure rates associated with the transition from preclinical to clinical studies is that animal studies often do not predict human-specific metabolic and toxic effects of drug candidates. In addition, current toxicity markers used in humans only show up when substantial organ damage has already occurred, and these markers are often the same markers that are used to track adverse effects of pre-existing disease conditions, such as hepatitis or diabetes in clinical trial subjects. Laura Richman of MedImmune discussed the current need for predictive safety biomarkers that can detect adverse events. It will be important to have diagnostic or toxicity markers that detect organ damage early while it is still reversible as well as markers that can be used after the cessation of drug treatment to detect delayed and chronic toxicities, such as malignancies, neuropathies, and other potentially irreversible events.

Richman focused her discussion on the safety considerations associated with biologic therapies, particularly monoclonal antibodies, which have unique adverse effect profiles compared to small molecule drugs. As proteins, antibodies are more likely to cause infusion reactions and hypersensitivity, which are immunological reactions to a foreign substance. These reactions are more likely to occur with antibodies that contain non-human sequences. It has been proposed that careful monitoring of cytokine levels may be able to predict these responses or detect them early, before they become serious.

One rare but very serious potential reaction to biologic therapies is the so-called "cytokine storm." This is a potentially fatal immune reaction characterized by the rapid massive release of over 150 different inflammatory mediators, including cytokines, free radicals, coagulation factors, and others. This inflammatory reaction results in symptoms that include fever, severe pain, multi-organ failure, and disseminated intravascular coagulation, which can result in the loss of limbs. This reaction was observed with a drug candidate for rheumatoid arthritis and leukemia, known as TGN1412, in phase 1 testing in healthy volunteers.

Many of the monoclonal antibodies developed to date are highly immunosuppressive, thus increasing rates of common infections, such as tuberculosis, and rare infections such as progressive multifocal leukoencephalopathy (PML). This effect is worsened if the disease being treated is already associated with high infection rates, as in rheumatoid arthritis and chronic obstructive pulmonary disease. PML is a rare but severe infection of the brain that is frequently fatal. It is thought to be caused by a more virulent form of a common virus, which could be tested for before drug administration to exclude patients at high risk of developing this condition.

Richman emphasized that many of the toxicities associated with biologic therapies are unlikely to be detected in animal models, thus creating a strong need for in vitro approaches that can detect risks before therapies are tested in humans. This requirement in turn creates the need to better understand the pharmacodynamic actions and mechanisms of potential new pain therapies.

Speakers:
Miroslav "Misha" Backonja, LifeTree Research and University of Wisconsin–Madison
Ralf Baron, University Hospital, Kiel, Germany

Highlights

• Effective clinical management of pain includes pharmacotherapeutic, physical medicine, and psychological treatments in a multidisciplinary approach.
• Sensory testing and questionnaires can be used to divide chronic pain patients into mechanistic subgroups that are predictive of responses to specific therapies.
• "Sensory phenotypes" might be used to develop individualized therapy even in the absence of detailed knowledge of underlying pain mechanisms.

State of the art in the clinical management of pain

Chronic pain is a complex phenomenon that includes somatosensory symptoms, sleep and mood disturbances, and significant impacts on daily function and quality of life. It also involves multiple body systems, including both peripheral and central nervous system pathways. This complexity necessitates a multimodal, multidisciplinary approach to management. Miroslav Backonja of LifeTree Research and the University of Wisconsin–Madison reviewed the facets of an effective management approach, including pharmacotherapies and other interventions, physical therapy and rehabilitation, and psychological support.

Complexity of diagnosing and treating pain in humans. (Image courtesy of Miroslav Backonja)

Backonja reported that current pharmacotherapies for neuropathic pain provide greater than 30% pain relief in about 30% to 50% of patients. The development and use of pain therapeutics is based on a considerable accumulation of clinical evidence, epidemiological studies, and meta-analyses, the sum of which has led to the development of expert guidelines. Many assessment scales have also been developed. In addition to rating pain intensity, such scales can provide measures of types of pain, psychological aspects of the pain experience, and quality of life. Specific instruments can detect signs of substance misuse and addiction as well.

A number of interventional approaches to pain have also been developed, often entailing injection of local anesthetics and/or steroids at anatomic sites presumed to be the sources of pain. The spine is the most frequent site for such injections. Therapy that involves implanted devices for neurostimulation is a frequent last resort for patients with chronic pain. Efficacy of these more invasive types of therapies is not as well established.

Physical medicine and rehabilitative approaches are also an important aspect of pain management. Patients who pursue an active exercise program show improvements in stability, strength, and flexibility of the musculoskeletal system which can result in reduced pain. Psychological and behavioral medicine can be used to change patients' responses to pain and to improve their coping strategies. Meta-analyses show that these types of interventions have variable and modest benefits in pain management.

Backonja emphasized that since there is no cure for chronic pain, effective clinical management using these tools is the current standard of care. Future needs in pain medicine include better ways to diagnose pain and distinguish among the different types, development of mechanism-based therapies that can be tailored to different types, and identification of combinations of existing and new therapies that will optimize pharmacologic management of chronic pain.

Mechanistic classification of clinical subjects in pain trials: the gate to personalized treatment

Ralf Baron of University Hospital in Kiel, Germany, is investigating the use of "sensory phenotypes" as a means of classifying pain patients into more homogeneous groupings for clinical trials and data analysis. This method is based on the idea that in each pain patient, pathophysiological mechanisms and genotype interact to create a sensory phenotype, composed of an array of specific signs and symptoms. This phenotype might be used to develop individualized therapy even in the absence of detailed knowledge of underlying pain mechanisms, and is likely to be useful for the elucidation of these mechanisms as well.

Baron and his collaborators have identified these sensory phenotypes using a large chronic pain patient database established by the German Research Network on Neuropathic Pain. This database includes epidemiological, clinical, and history data on thousands of patients with different types of neuropathic pain. Baron and his group have performed standardized quantitative sensory testing (QST) on about 2000 of these patients. QST is a profile of 13 different parameters, including responses to cold, heat, and mechanical pressure. This profile provides a standardized assessment of neurotransmission over the different types of afferent fibers. Mean responses to each type of stimulus are calculated, and each patient's profile is determined based on whether and by how much his or her responses deviate from the mean.

The collection and analysis of these data lead to the identification of subgroups of patients who can be grouped together based on the similarities of their sensory phenotypes. Interestingly, these phenotypes cut across the etiologies of pain, suggesting that different underlying mechanisms are at work among patients with the same pain syndromes.

Sensory phenotyping can be used to draw conclusions about underlying mechanisms by comparing the results of QST in human surrogate pain models with the those of in identified patient subgroups. For example, in the capsaicin model, skin to which capsaicin is applied develops highly characteristic thermal and mechanical hyperalgesia that closely resembles the profile of one of the patient subgroups. The presence of similar sensory abnormalities suggests a similarity in the underlying defects, and in this case, it is hypothesized that the TrpV1 receptor is likely to be involved since it is the target of capsaicin. Baron's work has identified SNPs in the TRPV1 gene that are associated with specific sensory profiles in patients.

An important use of sensory phenotyping would be to predict responses to specific therapies, and previous work suggests that this may be possible. In a clinical trial of the calcium channel inhibitor pregabalin for HIV-associated neuropathy, a subgroup of patients who showed severe pinprick hyperalgesia responded to the therapy, while the group as a whole did not show statistically significant improvement. This finding is particularly suggestive since pinprick hyperalgesia is a sign of central sensitization, which is thought to involve calcium channel activity.

QST is too time-consuming to use routinely in clinical trials, so Baron and his group are developing questionnaires that might be able to identify patient subgroups based on profiles of symptoms, such as burning pain, pricking pain, numbness, and others. They tested this method on another group of 2000 patients with painful diabetic neuropathy and postherpetic neuralgia, and again found it possible to identify distinct patient subgroups within the same pain etiology. Comparing these results to those of 2000 patients with radiculopathy, they found the same subgroups except for one that was unique to radiculopathy, suggesting a unique mechanism in some of these patients.

The group used another profiling questionnaire, the Neuropathic Pain Symptom Inventory, to identify differences between patients with diabetic neuropathy, HIV-associated neuropathy, post surgical pain and post trauma pain. This profile identified five patient subgroups, three of which showed responses to pregabalin. Such tools could ultimately be used routinely to test patients, identify their subgroup assignment, and plan therapeutic interventions accordingly.

Speakers:
Ian Gilron, Queen's University, Kingston, Canada
John T. Farrar, University of Pennsylvania
Bob Rappaport, U.S. Food and Drug Administration

Highlights

• Design of clinical trials for pain therapeutics can be optimized by careful attention to patient selection, trial design, outcomes measures, and other factors.
• Current outcomes measures for pain trials are backed by a considerable accumulation of evidence and can be used effectively if employed properly.
• The FDA is pursuing multiple projects intended to improve drug development in the area of chronic pain.

Neuropathic pain clinical trial design

The pursuit of new therapies for neuropathic pain creates a need for clinical trials that meet a number of important overlapping goals for industry, which is interested in product development, and for academia, which is interested in improving clinical practice with regard to pain. Trials are needed to assess the safety and efficacy of new therapies, to provide proof of concept, to compare new therapies with existing therapies, and for multiple other purposes. To provide useful data, these trials must be designed appropriately, with attention paid to the choice and form of study treatments, to the choice of study populations and outcome measures, and to clinical trial designs that are the most conducive to productive research in this clinical area. Ian Gilron of Queen's University in Kingston, Ontario provided a comprehensive overview of design considerations for clinical trials of pain treatments.

There are many considerations beyond which specific treatments to test, including choices of dosage, formulation, and treatment duration. Researchers also must to take into account the need to study the pharmacokinetics and pharmcodynamics of the study medication. In addition, they must decide whether to use a placebo and/or an active comparator, and study interventions must be effectively matched to provide adequate blinding.

Choice of study population is guided by the characteristics of the patient population to which the study results are to be applied. Researchers must consider how they will sample the study population and recruit and retain study participants. Researchers may choose to use a broad, heterogeneous population or a narrower population that is selected based on the proposed mechanism of the investigational therapy. They must also consider who should be excluded due to contraindications, risk of adverse events, or potential difficulties with retention.

Pain is an inherently composite measure made up of sensory, discriminatory, emotional, affective, and other types of components. These characteristics can be measured as separate outcomes or as an aggregate of average pain over a given time period. The qualitative aspects of pain are also important characteristics that can be collected in different ways and that may shed light on the mechanisms of investigational therapies.

Given these considerations, certain clinical trial designs are more appropriate for use in pain studies, including parallel designs that use active comparators to look for superiority or non-inferiority rather than placebo-controlled trials, crossover trials that compare single agents with combinations, and enriched enrollment-randomized withdrawal trials, which are designed to eliminate non-responders and individuals who will experience significant adverse events before the randomized active-control comparison phase of the trial.

A useful trial design for pain medications: enriched enrollment-randomized withdrawal. (Image courtesy of Ian Gilron)

Future needs in randomized clinical trials of pain therapies include better methods of pain measurement, systematic reviews of trial characteristics to promote evidence-based trial design, and continued attempts to design mechanism-based pain interventions. Strengthening the interactions between academic researchers, industry, and regulatory bodies working in this area will also promote overall improvements in clinical trials for pain medications.

The measurement, analysis, and interpretation of pain clinical trial outcomes

The lack of objective pain measures leads to considerable variability in individuals' reporting of their pain and contributes to observer discomfort about the validity of pain measures that are used in clinical studies. Despite the inherent subjectivity of pain self-reporting, researchers in this field have been able to standardize pain reported outcomes well enough to validate a range of analgesics, including non-steroidal anti-inflammatories, opioids, and adjuvant analgesics.

John Farrar of the University of Pennsylvania and his colleagues are working to create an expanded conceptual framework for pain that takes into account how physiological processes, neurobiological processes such as perception and nociception, and mood and memory interact with each other to create the experience of pain. A better understanding of the interactions between these components and their influence on self-reported pain will assist with the design of appropriate measures and choices of effective analytical techniques, which will in turn provide more clinically useful interpretations of the data derived from pain studies.

Pain model reflecting the interplay of environmental, physical, emotional, and other factors. (Image courtesy of John Farrar)

Farrar reviewed a number of scales that have already been designed and validated for assessing pain responses, including measures of pain type or pain intensity, scales that assess levels of pain relief, and measures of supportive outcomes such as health-related quality of life, pain interference with life activities, and other global measures. These scales each have specific advantages and limitations. Researchers must also consider whether to use such measures by themselves or in combination with other measures as outcomes in clinical trials.

Researchers can further optimize clinical trials by avoiding missing data. Farrar described a number of potential strategies, including careful patient population selection, flexible dosing, allowing rescue medications, reducing the length of follow up, and defining outcomes that can be measured in a high proportion of participants. Choosing the most effective methods of data analysis may also improve detection and measurement of clinical responses in a study population.

Farrar concluded that while current tools for detecting the type of pain and determining its etiology are not very accurate or objective, carefully collected and appropriately analyzed self-reported pain data can still be used to accurately measure improvements in pain in randomized clinical trials. A carefully chosen clinical trial design will improve the possibility that useful data will be collected on patient responses for a given clinical scenario.

The role of the FDA in improving the treatment of pain in the United States

In addition to its role in ensuring drug safety and effectiveness, the FDA takes part in activities designed to advance the overall field of drug development, including activities intended to improve the quality of research and clinical practice in pain. Bob Rappaport of the FDA provided an overview of some of these activities.

One important activity in which the FDA participates is a consensus group known as the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), which brings together academic, industry, and government experts once or twice a year to discuss topics related to clinical studies of pain treatments. Topics of discussion include acute and chronic adult pain and pediatric pain. The disciplines represented at these meetings vary but have included anesthesiology, clinical pharmacology, internal medicine, law, neurology, nursing, oncology, outcomes research, psychology, rheumatology, and surgery. The group makes recommendations and performs systematic reviews to assist with clinical trial design. The resulting widely cited publications have led to improvements in the design, consistency, interpretability, and efficiency of analgesic studies.

The FDA is also working to prepare an Analgesic Drugs Development Guidance Document, which will provide industry with guidance on how to study drugs intended for pain relief. This document has been in process for nearly 10 years, but a draft will be published for comments in the near future, after which a final version will be released. The development of this document has been held up by the lack of a clear scientific foundation, but was assisted by the IMMPACT studies and by several workshops on the extrapolation of efficacy between pain disorders, extrapolation between adult and pediatric pain data, and the appropriate design of pediatric studies.

The Food and Drug Administration Amendments Act in 2007 gives the FDA the authority to require manufacturers to implement Risk Evaluation and Mitigation Strategies, or REMS, for medications considered to be at high risk for adverse effects. Because of their high potential for abuse and the burgeoning epidemic of addiction, the FDA has been working with industry on a REMS program for opioid-based pain medications. This strategy will include guidance on the safe use of these medications, together with provisions for provider and patient education in this area.

Finally, the FDA has established ACTTION, a public-private partnership that will conduct critical research to improve the success rates of analgesic trials, to guide the design of future trials, and to assist in the development of safer and more effective analgesic drug products. This partnership will provide funding for innovative research studies that facilitate evidence-based design of clinical trials, together with a large number of ancillary support and data analysis activities. These activities and the ongoing research described at this meeting have great potential for improving the diagnosis and treatment of chronic pain, filling a substantial medical need in the U.S. and around the world.