Highlights
- •No biomarkers to evaluate pain have been qualified for pain treatment trials.
- •Sensory testing, skin biopsy, and brain imaging have potential as pain biomarkers.
- •Further standardization and evidence of validity and reliability are needed.
Abstract
Valid and reliable biomarkers can play an important role in clinical trials as indicators
of biological or pathogenic processes or as a signal of treatment response. Currently,
there are no biomarkers for pain qualified by the U.S. Food and Drug Administration
or the European Medicines Agency for use in clinical trials. This article summarizes
an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting
in which 3 potential biomarkers were discussed for use in the development of analgesic
treatments: 1) sensory testing, 2) skin punch biopsy, and 3) brain imaging. The empirical
evidence supporting the use of these tests is described within the context of the
4 categories of biomarkers: 1) diagnostic, 2) prognostic, 3) predictive, and 4) pharmacodynamic.
Although sensory testing, skin punch biopsy, and brain imaging are promising tools
for pain in clinical trials, additional evidence is needed to further support and
standardize these tests for use as biomarkers in pain clinical trials.
Perspective
The applicability of sensory testing, skin biopsy, and brain imaging as diagnostic,
prognostic, predictive, and pharmacodynamic biomarkers for use in analgesic treatment
trials is considered. Evidence in support of their use and outlining problems is presented,
as well as a call for further standardization and demonstrations of validity and reliability.
Key words
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References
- Excessive peptidergic sensory innervation of cutaneous arteriole-venule shunts (AVS) in the palmar glabrous skin of fibromyalgia patients: Implications for widespread deep tissue pain and fatigue.Pain Med. 2013; 14: 895-915
- Pain and the brain: Specificity and plasticity of the brain in clinical chronic pain.Pain. 2011; 152: S49-S64
- A mechanism-based pain sensitivity index to characterize knee osteoarthritis patients with different disease stages and pain levels.Eur J Pain. 2015; 19: 1406-1417
- Association between experimental pain biomarkers and serologic markers in patients with different degrees of painful knee osteoarthritis.Arthritis Rheumatol. 2014; 66: 3317-3326
- Translational pain biomarkers in the early development of new neurotherapeutics for pain management.Expert Rev Neurother. 2014; 14: 241-254
- Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera.J Pain. 2009; 10: 556-572
- Functional connectivity is associated with altered brain chemistry in women with endometriosis-associated chronic pelvic pain.J Pain. 2016; 17: 1-13
- Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): A randomised, double-blind, placebo-controlled trial.Lancet Neurol. 2016; 15: 555-565
- Systemic lidocaine in pain due to peripheral nerve injury and predictors of response.Neurology. 2004; 62: 218-225
- Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus.Pain. 2013; 154: 1807-1819
- Corticostriatal functional connectivity predicts transition to chronic back pain.Nat Neurosci. 2012; 15: 1117-1119
- Brain morphological signatures for chronic pain.PLoS One. 2011; 6: e26010
- Complex regional pain syndrome is associated with structural abnormalities in pain-related regions of the human brain.J Pain. 2014; 15: 197-203
- Neuropathic pain: Diagnosis, pathophysiological mechanisms, and treatment.Lancet Neurol. 2010; 9: 807-819
- Peripheral neuropathic pain: A mechanism-related organizing principle based on sensory profiles.Pain. 2017; 158: 261-272
- Analogous responses in the nucleus accumbens and cingulate cortex to pain onset (aversion) and offset (relief) in rats and humans.J Neurophysiol. 2013; 110: 1221-1226
- Intrinsic brain networks normalize with treatment in pediatric complex regional pain syndrome.Neuroimage Clin. 2014; 6: 347-369
- Parallel buprenorphine phMRI responses in conscious rodents and healthy human subjects.J Pharmacol Exp Ther. 2013; 345: 41-51
- Mechanism-based therapy for neuropathic pain-a concept in danger?.Pain. 2015; 156: 2113-2114
- Neuroimaging as a tool to investigate how cognitive factors influence analgesic drug outcomes.Neurosci Lett. 2012; 520: 149-155
- The effect of treatment expectation on drug efficacy: Imaging the analgesic benefit of the opioid remifentanil.Sci Transl Med. 2011; 3: 70ra14
- Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework.Clin Pharmacol Ther. 2001; 69: 89-95
- Quantitative sensory testing profiles in chronic back pain are distinct from those in fibromyalgia.Clin J Pain. 2011; 27: 682-690
- Use of functional imaging across clinical phases in CNS drug development.Transl Psychiatry. 2013; 3: e282
- Effects of pregabalin on central sensitization in patients with chronic pancreatitis in a randomized, controlled trial.PLoS One. 2012; 7: e42096
- Pregabalin and placebo responders show different effects on central pain processing in chronic pancreatitis patients.J Pain Res. 2015; 8: 375-386
- Mechanosensitivity before and after hysterectomy: A prospective study on the prediction of acute and chronic postoperative pain.Br J Anaesth. 2011; 107: 940-947
- Decoding the perception of pain from fMRI using multivariate pattern analysis.Neuroimage. 2012; 63: 1162-1170
- Longitudinal assessment of oxaliplatin-induced neuropathy.Neurology. 2011; 77: 980-986
- Defeating migraine pain with triptans: A race against the development of cutaneous allodynia.Ann Neurol. 2004; 55: 19-26
- Dynamic pain phenotypes are associated with spinal cord stimulation-induced reduction in pain: A repeated measures observational pilot study.Pain Med. 2015; 16: 1349-1360
- Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy.Pain. 2012; 153: 1815-1823
- Evidence of abnormal epidermal nerve fiber density in fibromyalgia. Clinical and immunologic implications.Arthritis Rheumatol. 2014; 66: 1945-1954
- Partial recovery of abnormal insula and dorsolateral prefrontal connectivity to cognitive networks in chronic low back pain after treatment.Hum Brain Mapp. 2015; 36: 2075-2092
- Sudomotor innervation in transthyretin amyloid neuropathy: Pathology and functional correlates.Ann Neurol. 2015; 78: 272-283
- Increased axonal regeneration and swellings in intraepidermal nerve fibers characterize painful phenotypes of diabetic neuropathy.J Pain. 2013; 14: 941-947
- Altered quantitative sensory testing outcome in subjects with opioid therapy.Pain. 2009; 143: 65-70
- Pharmacological MRI in awake rats reveals neural activity in area postrema and nucleus tractus solitarius: Relevance as a potential biomarker for detecting drug-induced emesis.Neuroimage. 2006; 33: 1152-1160
- Awake rat pharmacological magnetic resonance imaging as a translational pharmacodynamic biomarker: Metabotropic glutamate 2/3 agonist modulation of ketamine-induced blood oxygenation level dependence signals.J Pharmacol Exp Ther. 2011; 336: 709-715
- Coordinate-based (ALE) meta-analysis of brain activation in patients with fibromyalgia.Hum Brain Mapp. 2016; 37: 1749-1758
- Pain relief with lidocaine 5% patch in localized peripheral neuropathic pain in relation to pain phenotype: A randomised, double-blind, and placebo-controlled, phenotype panel study.Pain. 2015; 156: 2234-2244
- The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: A randomised, double-blind, placebo-controlled phenotype-stratified study.Pain. 2014; 155: 2263-2273
- Pain vulnerability: A neurobiological perspective.Nat Neurosci. 2014; 17: 192-200
- Reversal of insular and microstructural nerve abnormalities following effective surgical treatment for trigeminal neuralgia.Pain. 2015; 156: 1112-1123
- The diagnostic criteria for small fibre neuropathy: From symptoms to neuropathology.Brain. 2008; 131: 1912-1925
- Learning to identify CNS drug action and efficacy using multistudy fMRI data.Sci Transl Med. 2015; 7: 274ra16
- Patterns of quantitative sensation testing of hypoesthesia and hyperalgesia are predictive of diabetic polyneuropathy: A study of three cohorts. Nerve growth factor study group.Diabetes Care. 2000; 23: 510-517
- Denervation of skin in neuropathies: The sequence of axonal and Schwann cell changes in skin biopsies.Brain. 2007; 130: 2703-2714
- Variability in conditioned pain modulation predicts response to NSAID treatment in patients with knee osteoarthritis.BMC Musculoskelet Disord. 2016; 17: 284
- Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations.Pain. 2016; 157: 1851-1871
- Basal heat pain thresholds predict opioid analgesia in patients with postherpetic neuralgia.Anesthesiology. 2006; 104: 1243-1248
- Identifying specific profiles in patients with different degrees of painful knee osteoarthritis based on serological biochemical and mechanistic pain biomarkers: A diagnostic approach based on cluster analysis.Pain. 2015; 156: 96-107
- Rapid treatment-induced brain changes in pediatric CRPS.Brain Struct Funct. 2016; 221: 1095-1111
European Medicines Agency. Guideline on the Clinical Development of Medicinal Products Intended for the Treatment of Pain. 2nd draft. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/12/WC500199242.pdf. Accessed February 22, 2016.
European Medicines Agency: Qualification of Novel Methodologies for Drug Development: Guidance to Applicants. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004201.pdf. Accessed January 27, 2016.
- Psychophysiological responses to visceral and somatic pain in functional chest pain identify clinically relevant pain clusters.Neurogastroenterol Motil. 2014; 26: 139-148
- Brain white matter abnormalities in female interstitial cystitis/bladder pain syndrome: A MAPP Network neuroimaging study.J Urol. 2015; 194: 118-126
- The Semmes Weinstein monofilament examination is a significant predictor of the risk of foot ulceration and amputation in patients with diabetes mellitus.J Vasc Surg. 2011; 53: 220-226.e1-5
- Postherpetic neuralgia: Irritable nociceptors and deafferentation.Neurobiol Dis. 1998; 5: 209-227
- The ACTTION-American Pain Society Pain Taxonomy (AAPT): An evidence-based and multidimensional approach to classifying chronic pain conditions.J Pain. 2014; 15: 241-249
- Assessment of chronic pain: Domains, methods, and mechanisms.J Pain. 2016; 17: T10-T20
- Reduced insular gamma-aminobutyric acid in fibromyalgia.Arthritis Rheum. 2012; 64: 579-583
- Sensory profiles of patients with neuropathic pain based on the neuropathic pain symptoms and signs.Pain. 2014; 155: 367-376
- Randomized clinical trials with biomarkers: Design issues.J Natl Cancer Inst. 2010; 102: 152-160
- Pain sensitivity profiles in patients with advanced knee osteoarthritis.Pain. 2016; 157: 1988-1999
- Test-retest and interobserver reliability of quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain (DFNS): A multi-centre study.Pain. 2011; 152: 548-556
- Chronic widespread back pain is distinct from chronic local back pain: Evidence from quantitative sensory testing, pain drawings, and psychometrics.Clin J Pain. 2016; 32: 568-579
- The utility of skin biopsy for prediction of progression in suspected small fiber neuropathy.Neurology. 2006; 66: 256-258
- Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers.Neuropsychopharmacology. 2003; 28: 2000-2009
- Thermal pain in complex regional pain syndrome type I.Pain Physician. 2014; 17: 71-79
- Thalamic atrophy associated with painful osteoarthritis of the hip is reversible after arthroplasty: A longitudinal voxel-based morphometric study.Arthritis Rheum. 2010; 62: 2930-2940
- Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients.Arthritis Rheum. 2009; 61: 1226-1234
- Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients.Anesthesiology. 2013; 119: 1453-1464
- Elevated insular glutamate in fibromyalgia is associated with experimental pain.Arthritis Rheum. 2009; 60: 3146-3152
- Traditional Chinese acupuncture and placebo (sham) acupuncture are differentiated by their effects on mu-opioid receptors (MORs).Neuroimage. 2009; 47: 1077-1085
- Pressure pain sensitivity and insular combined glutamate and glutamine (Glx) are associated with subsequent clinical response to sham but not traditional acupuncture in patients who have chronic pain.Med Acupunct. 2013; 25: 154-160
- Pharmacologic attenuation of cross-modal sensory augmentation within the chronic pain insula.Pain. 2016; 157: 1933-1945
- Brain networks predicting placebo analgesia in a clinical trial for chronic back pain.Pain. 2012; 153: 2393-2402
- Abnormal cross-network functional connectivity in chronic pain and its association with clinical symptoms.Brain Struct Funct. 2016; 221: 4203-4219
- Epidermal nerve fiber density, axonal swellings and QST as predictors of HIV distal sensory neuropathy.Muscle Nerve. 2004; 29: 420-427
- Is skin biopsy a predictor of transition to symptomatic HIV neuropathy? A longitudinal study.Neurology. 2006; 66: 857-861
- Skin biopsy and quantitative sensory testing do not predict response to lidocaine patch in painful neuropathies.Muscle Nerve. 2006; 33: 42-48
- Small-fiber sensory neuropathies: Clinical course and neuropathology of idiopathic cases.Ann Neurol. 1998; 44: 47-59
- Intraepidermal nerve fiber density in patients with painful sensory neuropathy.Neurology. 1997; 48: 708-711
- Gabapentin-induced pharmacodynamic effects in the spinal nerve ligation model of neuropathic pain.Eur J Pain. 2014; 18: 223-237
- Brain white matter changes associated with urological chronic pelvic pain syndrome: Multisite neuroimaging from a MAPP case-control study.Pain. 2016; 157: 2782-2791
- Altered brain structure and function correlate with disease severity and pain catastrophizing in migraine patients.eNeuro. 2014; 1: e20.14
- Quantitative sensory testing in fibromyalgia patients and in healthy subjects: identification of subgroups.Clin J Pain. 2001; 17: 316-322
- Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans.Proc Natl Acad Sci U S A. 2005; 102: 18195-18200
- Serum levels of proinflammatory cytokines in painful knee osteoarthritis and sensitization.Int J Inflam. 2015; 2015: 329792
- Pharmacologic magnetic resonance imaging (phMRI): Imaging drug action in the brain.Neuroimage. 2012; 62: 1072-1085
- A cross-sectional study of pain sensitivity, disease-activity assessment, mental health, and fibromyalgia status in rheumatoid arthritis.Arthritis Res Ther. 2015; 17: 11
- Increased brain gray matter in the primary somatosensory cortex is associated with increased pain and mood disturbance in patients with interstitial cystitis/painful bladder syndrome.J Urol. 2015; 193: 131-137
- Structural and functional differences between neuropathy with and without pain?.Exp Neurol. 2011; 231: 199-206
- Structural and functional characterization of nerve fibres in polyneuropathy and healthy subjects.Scand J Pain. 2016; 10: 28-35
- Epidermal nerve fiber length density estimation using global spatial sampling in healthy subjects and neuropathy patients.J Neuropathol Exp Neurol. 2013; 72: 186-193
- Altered structure and function in the hippocampus and medial prefrontal cortex in patients with burning mouth syndrome.Pain. 2014; 155: 1472-1480
- Longitudinal assessment of small fiber neuropathy: Evidence of a non-length-dependent distal axonopathy.JAMA Neurol. 2016; 73: 684-690
- Alterations in resting state oscillations and connectivity in sensory and motor networks in women with interstitial cystitis/painful bladder syndrome.J Urol. 2014; 192: 947-955
- The somatosensory link in fibromyalgia: Functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction.Arthritis Rheumatol. 2015; 67: 1395-1405
- The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy.J Diabetes Complications. 2012; 26: 424-429
- Bilateral sensory abnormalities in patients with unilateral neuropathic pain; a quantitative sensory testing (QST) study.PLoS One. 2012; 7: e37524
- Reduction of intraepidermal nerve fiber density (IENFD) in the skin biopsies of patients with fibromyalgia: A controlled study.J Neurol Sci. 2014; 347: 143-147
- Thermal thresholds predict painfulness of diabetic neuropathies.Diabetes Care. 2004; 27: 2386-2391
- Somatic and vicarious pain are represented by dissociable multivariate brain patterns.Elife. 2016; 5: e15166
- Characterization and diagnostic evaluation of chronic polyneuropathies induced by oxaliplatin and docetaxel comparing skin biopsy to quantitative sensory testing and nerve conduction studies.Eur J Neurol. 2014; 21: 623-629
- Accelerated brain gray matter loss in fibromyalgia patients: Premature aging of the brain?.J Neurosci. 2007; 27: 4004-4007
- Altered resting state neuromotor connectivity in men with chronic prostatitis/chronic pelvic pain syndrome: A MAPP: Research Network neuroimaging study.Neuroimage Clin. 2015; 8: 493-502
- Clarification of developing and established clinical allodynia and pain-free outcomes.Headache. 2007; 47: 247-252
- Intraepidermal nerve fiber density at the distal leg: A worldwide normative reference study.J Peripher Nerv Syst. 2010; 15: 202-207
- Skin biopsy as a diagnostic tool in peripheral neuropathy.Nat Clin Pract Neurol. 2007; 3: 546-557
- Neuropathological alterations in diabetic truncal neuropathy: Evaluation by skin biopsy.J Neurol Neurosurg Psychiatry. 1998; 65: 762-766
- Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies.Neurology. 2003; 61: 631-636
- Imaging pain: A potent means for investigating pain mechanisms in patients.Br J Anaesth. 2013; 111: 64-72
- Identifying brain activity specifically related to the maintenance and perceptual consequence of central sensitization in humans.J Neurosci. 2008; 28: 11642-11649
- Neurophysiological markers of small fibre neuropathy in TTR-FAP mutation carriers.J Neurol. 2013; 260: 1497-1503
- Transient and persistent pain induced connectivity alterations in pediatric complex regional pain syndrome.PLoS One. 2013; 8: e57205
- Remifentanil administration reveals biphasic phMRI temporal responses in rat consistent with dynamic receptor regulation.Neuroimage. 2007; 34: 1042-1053
- Multiphasic modification of intrinsic functional connectivity of the rat brain during increasing levels of propofol.Neuroimage. 2013; 83: 581-592
- Hierarchical alteration of brain structural and functional networks in female migraine sufferers.PLoS One. 2012; 7: e51250
- Default mode network connectivity encodes clinical pain: An arterial spin labeling study.Pain. 2013; 154: 24-33
- Altered functional magnetic resonance imaging responses to nonpainful sensory stimulation in fibromyalgia patients.Arthritis Rheumatol. 2014; 66: 3200-3209
- Towards a neurophysiological signature for fibromyalgia.Pain. 2017; 158: 34-47
- Concomitant persistent pain in classical trigeminal neuralgia–evidence for different subtypes.Headache. 2014; 54: 1173-1183
- Reference data for quantitative sensory testing (QST): Refined stratification for age and a novel method for statistical comparison of group data.Pain. 2010; 151: 598-605
- 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: 439-450
- Presence of hyperalgesia predicts analgesic efficacy of topically applied capsaicin 8% in patients with peripheral neuropathic pain.Eur J Pain. 2016; 20: 116-129
- Chronic pain: The role of learning and brain plasticity.Restor Neurol Neurosci. 2014; 32: 129-139
- Risk factors predictive of chronic postsurgical neuropathic pain: The value of the iliac crest bone harvest model.Pain. 2012; 153: 1478-1483
- Towards physiologically based treatment of patients with neuropathic pain.Pain. 1990; 42: 131-137
- Is mechanism-based pain treatment attainable? Clinical trial issues.J Pain. 2000; 1: 2-9
- Epidermal nerve fiber density: Normative reference range and diagnostic efficiency.Arch Neurol. 1998; 55: 1513-1520
- Cutaneous innervation in sensory neuropathies: Evaluation by skin biopsy.Neurology. 1995; 45: 1848-1855
- Divergent sensory phenotypes in nonspecific arm pain: Comparisons with cervical radiculopathy.Arch Phys Med Rehabil. 2015; 96: 269-275
- Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia.Arthritis Rheum. 2012; 64: 2398-2403
- Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.Arthritis Rheum. 2010; 62: 2545-2555
- Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy.Br J Anaesth. 2014; 113: 148-156
- Epidermal reinnervation concomitant with symptomatic improvement in a sensory neuropathy.Muscle Nerve. 2003; 27: 507-509
- The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy.Muscle Nerve. 2001; 24: 1229-1231
- Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia.Pain. 2013; 154: 2310-2316
- Quantitative sensory testing predicts pregabalin efficacy in painful chronic pancreatitis.PLoS One. 2013; 8: e57963
- Cornea nerve fiber quantification and construction of phenotypes in patients with fibromyalgia.Sci Rep. 2016; 6: 23573
- Peripheral neuropathic changes in pachyonychia congenita.Pain. 2016; 157: 2843-2853
- Presurgical assessment of temporal summation of pain predicts the development of chronic postoperative pain 12 months after total knee replacement.Pain. 2015; 156: 55-61
- Capsaicin evoked pain and allodynia in post-herpetic neuralgia.Pain. 2000; 88: 125-133
- Sensitization and serological biomarkers in knee osteoarthritis patients with different degrees of synovitis.Clin J Pain. 2016; 32: 841-848
- Quantitative sensory testing of neuropathic pain patients: potential mechanistic and therapeutic implications.Curr Pain Headache Rep. 2012; 16: 199-206
- Somatosensory profiles in subgroups of patients with myogenic temporomandibular disorders and fibromyalgia syndrome.Pain. 2009; 147: 72-83
- Sensory, psychological, and metabolic dysfunction in HIV-associated peripheral neuropathy: A cross-sectional deep profiling study.Pain. 2014; 155: 1846-1860
- Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy.Neurology. 2002; 58: 115-119
- Somatosensory abnormalities for painful and innocuous stimuli at the back and at a site distinct from the region of pain in chronic back pain patients.PLoS One. 2013; 8: e58885
- Surrogate markers of small fiber damage in human diabetic neuropathy.Diabetes. 2007; 56: 2148-2154
- Somatosensory nociceptive characteristics differentiate subgroups in people with chronic low back pain: A cluster analysis.Pain. 2015; 156: 1874-1884
- Predictors of postoperative movement and resting pain following total knee replacement.Pain. 2012; 153: 2192-2203
- Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain.Ann Neurol. 2008; 64: 274-283
- Brain gray matter decrease in chronic pain is the consequence and not the cause of pain.J Neurosci. 2009; 29: 13746-13750
- An investigation to dissociate the analgesic and anesthetic properties of ketamine using functional magnetic resonance imaging.Anesthesiology. 2004; 100: 292-301
- Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values.Pain. 2006; 123: 231-243
- Post-herpetic neuralgia: The relation of pain complaint, sensory disturbance, and skin temperature.Pain. 1989; 39: 129-144
- Cutaneous innervation density in the allodynic form of postherpetic neuralgia.Neurobiol Dis. 1996; 3: 205-214
- Skin innervation at different depths correlates with small fibre function but not with pain in neuropathic pain patients.Eur J Pain. 2012; 16: 1414-1425
- Resting state connectivity correlates with drug and placebo response in fibromyalgia patients.Neuroimage Clin. 2014; 6: 252-261
- An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients.Neuroimage. 2006; 32: 256-265
- Investigation into the neural correlates of emotional augmentation of clinical pain.Neuroimage. 2008; 40: 759-766
- Increased gray matter density in young women with chronic vulvar pain.Pain. 2008; 140: 411-419
- Predicted costs and outcomes from reduced vibration detection in people with diabetes in the U.S..Diabetes Care. 2003; 26: 2305-2310
- Contralateral hyperalgesia and allodynia following intradermal capsaicin injection in man.Rheumatology (Oxford). 2008; 47: 1417-1421
- Linking altered central pain processing and genetic polymorphism to drug efficacy in chronic low back pain.BMC Pharmacol Toxicol. 2015; 16: 23
- Pregabalin for painful HIV neuropathy: A randomized, double-blind, placebo-controlled trial.Neurology. 2010; 74: 413-420
- Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy.Diabetes Care. 2001; 24: 1448-1453
- Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy.Neurology. 2001; 57: 1701-1704
- Lifestyle intervention for pre-diabetic neuropathy.Diabetes Care. 2006; 29: 1294-1299
- The relationship among pain, sensory loss, and small nerve fibers in diabetes.Diabetes Care. 2006; 29: 883-887
- Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions.Expert Rev Neurother. 2012; 12: 577-585
- Slow temporal summation of pain for assessment of central pain sensitivity and clinical pain of fibromyalgia patients.PLoS One. 2014; 9: e89086
- The spectrum of neuropathy in diabetes and impaired glucose tolerance.Neurology. 2003; 60: 108-111
- Quantitative sensory testing in painful osteoarthritis: A systematic review and meta-analysis.Osteoarthritis Cartilage. 2012; 20: 1075-1085
- Contribution of QSART to the diagnosis of small fiber neuropathy.Muscle Nerve. 2013; 48: 883-888
- The Pain in Neuropathy Study (PiNS): A cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy.Pain. 2016; 157: 1132-1145
- Monitoring the 3-year efficacy of enzyme replacement therapy in fabry disease by repeated skin biopsies.J Invest Dermatol. 2004; 122: 900-908
- Can neuroimaging studies identify pain endophenotypes in humans?.Nat Rev Neurol. 2011; 7: 173-181
- “Seeing” how our drugs work brings translational added value.Anesthesiology. 2013; 119: 1247-1248
- The plasticity of cutaneous hyperalgesia during sympathetic ganglion blockade in patients with neuropathic pain.Brain. 1992; 115: 607-621
- Does the epidermal nerve fibre density measured by skin biopsy in patients with peripheral neuropathies correlate with neuropathic pain?.Pain. 2014; 155: 828-832
- Small fibers in Fabry disease: Baseline and follow-up data under enzyme replacement therapy.J Peripher Nerv Syst. 2011; 16: 304-314
- Small fibre pathology in patients with fibromyalgia syndrome.Brain. 2013; 136: 1857-1867
United States Food and Drug Administration: Guidance for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Available at: http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf. Accessed January 27, 2016.
United States Food and Drug Administration. Guidance for Industry and FDA Staff. Qualification Process for Drug Development Tools. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdf. Accessed January 27, 2016.
United States Food and Drug Administration. Guidance for Industry. Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm332181.pdf. Accessed May 31, 2016.
- Modulation of CNS pain circuitry by intravenous and sublingual doses of buprenorphine.Neuroimage. 2012; 59: 3762-3773
- Imaging drugs with and without clinical analgesic efficacy.Neuropsychopharmacology. 2011; 36: 2659-2673
- Pharmacological modulation of brain activity in a preclinical model of osteoarthritis.Neuroimage. 2013; 64: 341-355
- Alterations in brain structure and functional connectivity in prescription opioid-dependent patients.Brain. 2010; 133: 2098-2114
- Sensitivity testing in irritable bowel syndrome with rectal capsaicin stimulations: Role of TRPV1 upregulation and sensitization in visceral hypersensitivity?.Am J Gastroenterol. 2014; 109: 99-109
- Predicting individual differences in placebo analgesia: Contributions of brain activity during anticipation and pain experience.J Neurosci. 2011; 31: 439-452
- An fMRI-based neurologic signature of physical pain.N Engl J Med. 2013; 368: 1388-1397
- Quantitative sensory testing before and after regional guanethidine block in patients with neuralgia in the hand.Pain. 1991; 46: 23-30
- Concordance between epidermal nerve fiber density and sensory examination in patients with symptoms of idiopathic small fiber neuropathy.J Neurol Sci. 2007; 255: 23-26
- Prechemotherapy touch sensation deficits predict oxaliplatin-induced neuropathy in patients with colorectal cancer.Oncology. 2016; 90: 127-135
- Functional trade-offs in white matter axonal scaling.J Neurosci. 2008; 28: 4047-4056
- Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects.Proc Natl Acad Sci U S A. 2012; 109: 17705-17710
- Disambiguating pharmacodynamic efficacy from behavior with neuroimaging: Implications for analgesic drug development.Anesthesiology. 2016; 124: 159-168
- Neural correlates of chronic low back pain measured by arterial spin labeling.Anesthesiology. 2011; 115: 364-374
- Postherpetic neuralgia: Topical lidocaine is effective in nociceptor-deprived skin.J Neurol. 2005; 252: 677-686
- Pharmacogenetics and personalized medicine in pain management.Clin Lab Med. 2016; 36: 493-506
- Morphological features of nerves in skin biopsies.J Neurol Sci. 2006; 242: 15-21
- The anxiolytic effects of midazolam during anticipation to pain revealed using fMRI.Magn Reson Imaging. 2007; 25: 801-810
- Combining fMRI with a pharmacokinetic model to determine which brain areas activated by painful stimulation are specifically modulated by remifentanil.Neuroimage. 2002; 16: 999-1014
- Using fMRI to quantify the time dependence of remifentanil analgesia in the human brain.Neuropsychopharmacology. 2004; 29: 626-635
- Distinct brain systems mediate the effects of nociceptive input and self-regulation on pain.PLoS Biol. 2015; 13: e1002036
- Towards a mechanism-based classification of pain?.Pain. 1998; 77: 227-229
- Mechanism-based pain diagnosis: Issues for analgesic drug development.Anesthesiology. 2001; 95: 241-249
- The association between pre-operative pain sensitisation and chronic pain after knee replacement: An exploratory study.Osteoarthritis Cartilage. 2013; 21: 1253-1256
- Recommendations on practice of conditioned pain modulation (CPM) testing.Eur J Pain. 2015; 19: 805-806
- Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy.Pain. 2012; 153: 1193-1198
- Prescription opioid analgesics rapidly change the human brain.Pain. 2011; 152: 1803-1810
- Thermal hypersensitivity in a subset of irritable bowel syndrome patients.World J Gastroenterol. 2009; 15: 3254-3260
- Correlates of epidermal nerve fiber densities in HIV-associated distal sensory polyneuropathy.Neurology. 2007; 68: 2113-2119
- Buprenorphine-induced changes in mu-opioid receptor availability in male heroin-dependent volunteers: A preliminary study.Neuropsychopharmacology. 2000; 23: 326-334
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Published online: February 28, 2017
Footnotes
The views expressed in this article are those of the authors, none of whom have financial conflicts of interest specifically related to the issues discussed in this article. At the time of the meeting on which this article is based, several authors were employed by pharmaceutical companies and others had received consulting fees or honoraria from one or more pharmaceutical or device companies. Authors of this article who were not employed by industry or government at the time of the meeting received travel stipends, hotel accommodations, and meals during the meeting provided by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration (FDA), which has received research contracts, grants, or other revenue from the FDA, multiple pharmaceutical and device companies, and other sources. Preparation of background literature reviews and the article was supported by ACTTION. No funding from any outside source was received for the meeting, nor the literature reviews and article preparation. No official endorsement by the FDA, U.S. National Institutes of Health, or the pharmaceutical and device companies that have provided unrestricted grants to support the activities of ACTTION should be inferred.
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© 2017 by the American Pain Society
