PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Trends Pharmacol Sci. Author manuscript; available in PMC 2013 November 1.
Published in final edited form as:
PMCID: PMC3482290
NIHMSID: NIHMS405621

CURRENT CHALLENGES IN TRANSLATIONAL PAIN RESEARCH

Abstract

The current gap between basic science research and new analgesic development presents a serious challenge for the future of pain medicine. This challenge is particularly difficult in the search for better treatment for comorbid chronic pain conditions because i) animal “pain” models do not simulate multi-dimensional clinical pain conditions; ii) animal behavioral testing does not assess subjective pain experience; iii) preclinical data provide little assurance regarding the direction of new analgesic development; and iv) clinical trials routinely use over-sanitized study populations and fail to capture the multidisciplinary consequences of comorbid chronic pain. Therefore, a paradigm shift in translational pain research is necessary to transform the current strategy from focusing on molecular switches of nociception to studying pain as a system-based integral response that includes psychosocial comorbidities. Several key issues of translational pain research are discussed in this article.

Clinical pain

Despite the subjective and comorbid nature of clinical pain, pain is traditionally regarded as a sensory modality and a branch of sensory physiology. Over nearly five decades, basic science research has largely focused on understanding generation, transmission, and modulation of nociceptive signals. This effort has been substantially intensified over the past three decades owing to an explosion of neuroscience research with state-of-the-art techniques, generating a long list of tantalizing cellular and molecular targets for potential analgesic development [1, 2] (Table 1). However, few of these new targets have been successfully brought to clinical use [2] and many pharmaceutical companies have recently moved out of analgesic research and development. In the wake of this reality, some in the field question the validity of pain research using animal “pain” models, and others insist on continuing the current strategy that emphasizes the molecular and genetic mechanisms of nociception. As a physician-scientist in the field of pain medicine, I believe that a paradigm shift is needed in pain research that moves away from searching for molecular switches of nociception and toward studying pain as a system-based integral response that includes psychosocial comorbidities such as anxiety and depression. In this regard, translational pain research can play a unique role by developing innovative experimental paradigms and integrating multi-faceted research findings at the system level. In this article, I will discuss several issues related to translational pain research and offer some thoughts on future directions.

Table 1
A partial list of potential targets for new drug development

Nociception versus clinical pain: a physician’s perspective

Nociception is the neural processes encoding noxious stimuli that could create tissue damage, whereas clinical pain is what patient complains of the perceived actual or potential nociception. Currently, acute pain due to surgery or trauma can typically be treated with time-honored conventional analgesics including opioids and non-steroidal anti-inflammatory drugs (NSAIDs) because these drugs blunt nociceptive input. Coincidently, the majority of new analgesics developed over the past five decades fall into these two categories [1, 2]. Other recent additions to the armamentarium of pain medicine include anti-migraine triptans, COX-2 inhibitors, mixed opioid agonist and norepinephrine reuptake inhibitors, and drugs approved for other medical conditions such as depression and epilepsy but increasingly being used for pain management [1, 2].

However, conventional analgesics are often less effective in alleviating chronic pain [3], and numerous examples of mismatches can be found between nociception and clinical pain (Figure 1). For instance, clinical pain can result from seemingly trivial tissue damage (e.g., complex regional pain syndrome) and outlast the duration of original injury. Clinical pain is also highly individualized in its intensity and quality depending on affective, autonomic and motor responses. Clinical pain, particularly chronic pain, does not correlate linearly with nociception and can be influenced by psychosocial comorbidities such as depression, anxiety, and catastrophizing in up to 50% of pain patients [4, 5]. This critical distinction between nociception and clinical pain, as well as pain-related psychosocial comorbidities, has been largely unaddressed in basic science research. Instead, the focus has been placed on understanding nociception, increasingly widening the gap between pain research and new analgesic development.

Figure 1
Nociception versus clinical pain

Challenges in pain research: a researcher’s perspective

Given the distinction between nociception and clinical pain, the current strategy focusing on the cellular and molecular mechanisms of nociception would be understandably deficient due to a number of limitations in both bench and clinical studies. These limitations may explain some of the fundamental reasons as to why pain research has seen only tepid success in new analgesic development.

Limitations in bench studies

Three crucial limitations in bench studies are animal “pain” models, behavioral testing, and experimental paradigms. These are explored in detail below.

Most animal models of pain simulate a pathological condition such as complete freund’s adjuvant-induced hindpaw inflammation or sciatic nerve injury, whereas others mimic a disease entity such as bone cancer [1, 69]. Although rodents have anatomy and physiology that resembles those of human beings and can be used to study nociception, the goal of pain research is to understand pain and nociception is only part of this process. In this regard, animal models do not reproduce multiple dimensions of clinical pain including cognitive and affective changes. This deficiency may explain why we have had reasonable success in understanding physiological pain and acute pain in which nociception is the major driving force. By comparison, treatment of chronic pain continues to be a challenge because clinical comorbidities such as depression and anxiety, rather than nociception itself, are likely to be much more influential. Unfortunately, most currently available animal models do not account for such conditions.

Significant mismatches are present between nociceptive behavioral testing in rodents and pain assessment in human beings [1, 6, 10, 11]. First, the most commonly used behavioral tests in animal studies involve an evoked withdrawal response to thermal or mechanical stimulation, whereas clinical pain is self-reported by patients often as spontaneous pain in the absence of overt stimulation. Second, the modality of sensory testing in animal studies does not reflect common clinical situations. For instance, thermal hyperalgesia is the most frequently used behavioral testing in animal studies but it is hardly a characteristic feature of clinical pain. Third, the duration of animal studies is often brief (days and weeks), which does not adequately reproduce the impact of prolonged nociception on clinical pain.

Current experimental paradigms lay a heavy emphasis on the cellular and molecular mechanisms of nociception including synaptic plasticity without paying much attention to the role of system integration in pain and related comorbidities [1, 1216]. This issue is further compounded by a disproportionate focus on primary order neurons and spinal cord mechanisms, and a bias towards exploring often redundant signal transduction pathways under a broad concept of neuroplasticity. Many sensational breakthroughs in the pain research field really are repetitions of known signal transduction pathways that have already been delineated in other specialties such as immunology, cell biology, and oncology but are reinvented in pain research using animal models of tissue injury. For example, many overlapping signal transduction pathways (e.g., protein kinase C, mitogen-activated protein kinases and their related intracellular pathways) are known to be involved in many biological functions and non-specific to nociception [1, 12, 16], although they have been shown to be sufficient and necessary in demonstrating animal nociceptive behaviors. This situation has left the field seriously puzzled as to which of these signal transduction pathways really is sufficient and necessary to serve as a target for new analgesic development.

Limitations in clinical studies

To date, few drug development targets identified in animal studies have been successfully brought to clinical use, such as neurokinin-1 (NK-1) receptor antagonists, TRPV1 antagonists, or NMDA receptor antagonists [2]. Some of these targets lack clinical efficacy (e.g., NK-1 receptor antagonists), whereas others cause significant side effects (e.g., hyperthermia by TRPV1 antagonists) [2]. Given the complexity of human pain experiences that can be influenced by genetic and psychosocial factors, three major issues are likely to have a significant impact on clinical pain studies: (i) mismatches between preclinical and clinical pain conditions and over-sanitation of human study subjects; ii) a dearth of meaningful clinical pain assessment tools; and iii) lack of understanding of pharmacokinetic, pharmacodynamics, and pharmacogenomic profiles and their interactions.

Several obstacles in clinical pain research increase the uncertainty of new analgesic development [1, 1719]. First, mismatches are very common between animal “pain” models and actual clinical pain conditions, making it difficult to test those hypotheses coming out of preclinical studies. For example, although NMDA receptor antagonists are shown to be anti-hyperalgesic in animal studies of neuropathic pain, many human studies showed no effect of NMDA receptor antagonists (e.g., dextromethorphan, ketamine) because these studies used post-operative, non-neuropathic pain condition as a clinical pain model [1]. Second, over-sanitation of study subjects, in order to comply with scientific, ethical, and regulatory stipulations, makes many clinical studies far removed from the clinical reality. For example, strict inclusion and exclusion criteria are often used to enhance the power of clinical studies, such as age limit (e.g., 18–65 years old), a narrow range of pain scores (4 – 6 out of 10), and exclusion of comorbid conditions and concurrent use of other medications. This issue particularly affects studies of chronic pain because of its long duration and more complex clinical conditions. Third, many clinical studies are designed to test over-simplistic and sometimes misinformed hypotheses (e.g., pre-emptive analgesia in patients with uncomplicated, acute post-operative pain) due to the lack of appreciation over the limitations in animal studies and technical difficulties in recruiting study subjects (e.g., for a 3-month longitudinal study that requires subjects to be off their usual medications and thus facing significant pain). In addition, clinical pain studies often focus on “spontaneous pain” rather than evoked pain symptoms such as allodynia (painful response to innocuous stimulation) and hyperalgesia (exacerbated painful response to noxious stimulation).

Visual analog or numerical pain scales used in human subjects are tools of a self-reporting system [20], which is clearly different from reflexive tests commonly used in animal studies. By the nature of self-reporting, this system does not have an anchoring value, varies among individuals, and could not be objectively verified [21]. Pain scales are typically influenced by clinical comorbidities such as mood swing, depression, stress, and anxiety; age, gender, genetic, and cultural differences; and placebo responders versus non-responders. Although clinical pain studies often include secondary measures to account for some of these factors [21], this complexity of clinical pain makes the margin of success exceedingly small in clinical trials of potential analgesics.

Differences in pharmacokinetic and pharmacodynamic profiles between rodents and human beings are frequent challenges in the design and interpretation of clinical studies [2224]. These include the half-life of a drug, as well as its bioavailability, elimination, dosing regimen, receptor affinity, and side effect profile. Some compounds such as ziconotide (a peptide N-type calcium channel blocker) have very limited clinical utility because it can only be delivered intrathecally in its current formulation. In addition, animal studies typically test one compound at a time, whereas drug-drug interactions are an unavoidable reality in clinical practice. For example, in one study of more than 900,000 patients undergoing a urine drug test, 29% of the samples showed evidence of a non-prescribed drug in their systems, including 11% with evidence of illicit drug use [25]. Despite these confounding issues, few clinical studies are designed to simultaneously assess pharmacokinetic and pharmacodynamics profiles as well as their influence on the efficacy and side effects of pain medications [24].

A paradigm shift through translational pain research

Given the substantial gap between basic science research and new analgesic development, a major paradigm shift is needed in pain research. Although studying nociception is a fundamental aspect of pain research, we need to recognize that multiple dimensions of clinical pain cannot be addressed by understanding nociception only. In this regard, translational pain research must engage a new roadmap by integrating various areas of basic science and clinical studies. In particular, I suggest focusing on six key attributes of translational pain research.

Produce a new variety of animal models

It should be made unequivocally clear that animal models of tissue injury produce conditions of nociception, a gateway to pain research, but they are not a reliable surrogate of clinical pain. This deficiency in animal models may be mended by assimilating other features of clinical pain in these same models. In recent studies, tissue injury has been combined with behavioral phenotypes indicative of comorbid conditions such as depression, anxiety, or substance abuse in rodents. For example, in one model, rodents with genetically predisposed or induced depression and anxiety are exposed to tissue injury (e.g., sciatic nerve ligation) and both nociceptive and depressive/anxiety-like behaviors are then concurrently examined in the same rodents [2628]. This new variety of animal models will be particularly useful to study chronic pain, as well as the transition from acute to chronic pain, by adding a new dimension of clinical pain into an otherwise single dimensional (nociception) animal model. In addition, animal models need to account for gender and individual differences in clinical pain conditions [2933]. Both male and female rodents may be included to compare the similarities and differences in their nociceptive response. Rather than relying on group analysis based on mean and standard deviation, rodents exposed to the same condition of tissue injury may be differentiated based on their onset, degree, duration, and recovery of nociceptive behaviors.

Transform the conceptual framework

A major setback in pain research is the lack of progress in new analgesic development [1, 2]. This situation is, at least in part, due to the current conceptual framework that appears to be biased towards studying redundant and parallel signal transduction pathways without a less concerted effort on the system-based data integration. For example, the transition from acute to chronic pain may reflect a shift from a mainly nociception-driven process to a progressively system-based response. Accordingly, a shift in the conceptual framework may be required by focusing on exploring the underlying mechanisms of disease entities that cause pain and uncommon mechanisms of pathological pain [3436] and finding common pathways at the system (brain) level that regulate motor, autonomic, affective, and sensory dimensions of clinical pain [37]. We cannot conquer pain by simply dividing its mechanism into hundreds of single molecules. Pain is a system-based experience and must be studied and integrated at the system level.

Develop meaningful assessment tools

Several new tools have recently been introduced into basic science pain research, including measurement of operant performance (assessment of painful response based on performance of certain tasks), facial and behavioral profiling (correlation between facial features/exploratory behaviors and the degree of nociception), and conditioned place preference or aversion (towards or away from an environment of nociception in response to a treatment) [3843]. Although the validity of these tools needs further verification, they could potentially provide new measures complementary to conventional reflex-based behavioral tests. Another approach is that the reflex-based behavioral testing can be combined with behavioral phenotypes indicative of depression, anxiety, drug addiction, and cognitive changes to present a broader picture of “pain” behaviors in rodents [2628]. For clinical pain, developing tools for “objective” pain assessment may be aided by biomarkers and neuroimaging techniques [44, 45]. Whether this approach is plausible remains to be seen and its success may largely depend on the progress in neuroscience and innovative technologies. In addition, clinical pain scales need to take into account the impact of pain medication itself on pain perception and pain mechanisms such as opioid-induced hyperalgesia [46] and medication-induced rebound headache [47].

Identify and distinguish biomarkers and genotypes of nociception and pain

Biomarkers are now considered such a crucial aspect of drug development that regulatory authorities in the EU and USA have come together to provide guidance on how to qualify and quantify novel biomarkers [48]. However, biomarkers of pain have been difficult to obtain. A fundamental misperception in the field of pain research is to consider biomarkers of nociception as the equivalent of biomarkers of pain. The former is a predictable outcome of tissue injury (e.g., release of cytokines) that produces nociception, similar to the clinical scenario of cardiac infarction that causes release of troponin. But identifying biomarkers of pain is a quite different proposition, perhaps an unrealistic one, as nociception does not predict the severity and duration of clinical pain. Recent studies have indicated a role for brain imaging in assessing clinical pain and predicting the pain chronicity [4951]. An innovative approach would be to combine biomarkers of nociception with brain imaging techniques such as PET and functional MRI to integrate both cellular and system responses. Genetic association studies including genome-wide association studies (GWAS) and epigenetic regulation have recently been integrated into pain research [5259]. Although GWAS have identified dozens of candidate genes associated with experimental or clinical pain, many of these findings have been difficult to replicate, and results appear mainly clustered around 10 genes [59]. Thus far, genetic studies have failed to identify any one gene that explains a clinically significant amount of variance in susceptibility to or experience of chronic pain. Studying epigenetic regulation provides a useful tool to investigate the pattern of expression for a pool of genes related to a common clinical pain phenotype. However, a cautionary note to this line of research is whether this effort will simply embrace the same strategy of studying redundant and non-specific signal transduction pathways but at the genetic level.

Advance clinical pain research

An important task is to reform the current paradigm of clinical pain research that is often compromised by over-sanitation of study subjects and dependence on group statistics. Several new elements of clinical pain research include N-of-one study design, population-based data collection, post-marketing patient survey, and use of human models of experimentally evoked pain [6062] (Table 2). The goal is to identify a true clinical profile comprised of individual responses and use such a profile to formulate individualized medicine. The success of new analgesic development may also require a significant reform of the current drug approval process stipulated by the US FDA, which often leads to the widespread off-label use of new analgesics once they are approved for a narrow therapeutic indication. For example, in addition to pain score, a broader spectrum of clinical outcomes including functionality and improvement in pain-related comorbid conditions may be used to constitute a composite score to examine the effectiveness of new analgesics for chronic pain management. In addition, new candidate drugs with indications for specific pain symptoms such as allodynia and hyperalgesia may be processed differently for approval as compared to conventional analgesics, because allodynia and hyperalgesia are evoked pain symptoms that are often episodic and fluctuate over time in the clinical setting.

Table 2
New tools of clinical pain research [6062]

Select new targets for drug development

A recent preclinical study suggests that the comorbidity between pain and depression may be concurrently treated by inhibiting brain indoleamine 2,3, dioxygenase, a rate-limiting enzyme in tryptophan metabolism [27]. This raises the possibility that clinical pain and related comorbidities may be effectively treated by targeting their underlying causes instead of symptomatic management using multi-drug therapy such as the combination of analgesics with antidepressants [3]. It also appears that new candidate drugs that could diminish nociceptive signals at the peripheral site, such as chemokine inhibitors and topical agents (Table 1), would be more attractive than those that target redundant intracellular pathways implicated in the central mechanisms of nociceptive processing.

Concluding remarks

Significant progress has been made in pain research over the past five decades. As a result, much has been known regarding the mechanisms of nociception (generation, transmission, and modulation) at the peripheral and spinal cord level. This has led to the significant improvement in clinical management of acute and post-operative pain. What remains challenging is chronic pain that is often disproportionate to the degree and duration of nociception and is heavily influenced by psychosocial factors. I believe that the most pressing issue in pain research is to develop and validate a new variety of animal models that are capable of integrating persistent nociception with pain-related comorbidities, thereby facilitating a paradigm shift from focusing on molecular switches of nociception to studying chronic pain as a system-based integral response. In this regard, translational pain research will play a pivotal role in advancing pain research and pain medicine. The framework of translational pain research should not be limited to a process commonly referred as “from bench to bedside”. The success of translational pain research can improve new analgesic development and facilitate the transition from research to clinical application.

Acknowledgement

This work was supported by NIH grants RO1 DA22576, RO1 DE18214, and P20 DA26002.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflict of Interest

I declare no conflict of interest.

References

1. Mao J. Translational pain research: achievements and challenges. J. Pain. 2009;10:1101–1111.
2. Kissin I. The development of new analgesics over the past 50 years: a lack of real breakthrough drugs. Anesth. Analg. 2010;110:780–789. [PubMed]
3. Mao J, et al. Combination drug therapy for chronic pain: a call for more clinical studies. J. Pain. 2011;12:157–166. [PMC free article] [PubMed]
4. Elman I, et al. The missing p in psychiatric training; why it is important to teach pain to psychiatrists. Arch Gen Psychiatry. 2011;68:12–20. [PMC free article] [PubMed]
5. Rainville J, et al. Fear-avoidance beliefs and pain avoidance in low back pain – translating research into clinical practice. Spine J. 2011;11:895–903. [PubMed]
6. Barrot M. Tests and models of nociception and pain in rodents. Neuroscience. 2012;211:39–50. [PubMed]
7. Mogil JS. Animal models of pain: progress and challenges. Nat. Rev. Neurosci. 2009;10:283–294. [PubMed]
8. Taneja A. Translation of drug effects from experimental models of neuropathic pain and analgesia to humans. Drug Discov. Today. 2012 (in press). [PubMed]
9. Bulmer DC, Grundy D. Achieving translation in models of visceral pain. Curr. Opin. Pharmacol. 2011;11:575–581. [PubMed]
10. Maag R, Baron R. Neuropathic pain: translational research and impact for patient care. Curr. Pain Headache Rep. 2006;10:191–198. [PubMed]
11. Backonja MM. Quantitative sensory testing in measurement of neuropathic pain phenomena and other sensory abnormalities. Clin. J. Pain. 2009;25:641–647. [PubMed]
12. Zhuo M. Targeting neuronal adenylyl cyclase for the treatment of chronic pain. Drug Discov. Today. 2012;17:573–582. [PubMed]
13. Namer B, Handwerker HO. Translational nociceptor research as guide to human pain perception and pathophysiology. Exp. Brain Res. 2009;196:163–172. [PubMed]
14. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152:S2–S15. [PMC free article] [PubMed]
15. Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat. Med. 2010;16:1267–1276. [PMC free article] [PubMed]
16. Ji RR, Jr, et al. Emerging roles of resolvins in the resolution of inflammation and pain. Trends Neurosci. 2011;34:599–609. [PMC free article] [PubMed]
17. Dworkin RH, et al. Considerations for extrapolating evidence of acute and chronic pain analgesic efficacy. Pain. 2011;152:1705–1708. [PubMed]
18. Dworkin RH, et al. Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations. Pain. 2012;153:1148–1158. [PubMed]
19. Dworkin RH, et al. Evidence-based clinical trial design for chronic pain pharmacotherapy: a blueprint for ACTION. Pain. 2011;152:S107–S115. [PubMed]
20. Edwards RR, Fillingim RB. Self-reported pain sensitivity: lack of correlation with pain threshold and tolerance. Eur. J. Pain. 2007;11(Suppl 5):594–598. [PMC free article] [PubMed]
21. Farrar JT. Advances in clinical research methodology for pain clinical trials. Nat. Med. 2010;16:1284–1293. [PubMed]
22. Kruger L, Light AR, editors. Translational Pain Research: from mouse to man. CRC Press; 2010. [PubMed]
23. Mao J, editor. Translational Pain Research. vol 2. Nova Sciences Publisher; 2006.
24. Sabia M, et al. Advances in translational neuropathic research: example of enatioselective pharmacokinetic-pharmaodynamic modeling of ketamine-induced pain relief in complex regional pain syndrome. Curr. Pain Headache Rep. 2011;15:207–214. [PubMed]
25. Couto JE, et al. High rates of inappropriate drug use in the chronic pain population. Popul. Health Manag. 2009;12:185–190. [PubMed]
26. Zeng Q, et al. Exacerbated mechanical allodynia in rats with depression-like behavior. Brain Res. 2008;1200:27–38. [PMC free article] [PubMed]
27. Kim H, et al. Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression. J. Clin. Invest. 2012 [PMC free article] [PubMed]
28. Seminowicz DA, et al. MRI structural brain changes associated with sensory and emotional function in a rat model of long-term neuropathic pain. Neuroimage. 2009;47:1007–1014. [PubMed]
29. Toomey M. Gender differences in pain: does X = Y? AANA J. 2008;76(Suppl 5):355–359. [PubMed]
30. Campbell CM. Ethnic differences in diffuse noxious inhibitory controls. J. Pain. 2008;9(Suppl 8):759–766. [PMC free article] [PubMed]
31. Coghill RC. Neural correlates of interindividual differences in the subjective experience of pain. Proc. Natl. Acad. Sci. U. S. A. 2003;100(Suppl 14):8538–8542. [PubMed]
32. Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science. 2000;288(Suppl 5472):1769–1772. [PubMed]
33. Greenspan JD. Consensus Working Group of the Sex, Gender, and Pain SIG of the IASP: Studying sex and gender differences in pain and analgesia: a consensus report. Pain. 2007;132(Suppl 1):S26–S45. [PMC free article] [PubMed]
34. Bennett GJ, et al. Terminal arbor degeneration--a novel lesion produced by the antineoplastic agent paclitaxel. Eur. J. Neurosci. 2011;33:1667–1676. [PMC free article] [PubMed]
35. Farrari L, et al. Role of Drp1, a key mitochondrial fission protein, in neuropathic pain. J. Neurosci. 2011;31:11404–11410. [PMC free article] [PubMed]
36. Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat. Rev. Neurosci. 2009;10:230–236. [PMC free article] [PubMed]
37. Sharif-Naeini R, Basbaum AI. Targeting pain where it resides … in the brain. Sci. Transi. Med. 2011;3:65ps1. [PubMed]
38. Johnston IN, et al. Post-conditioning experience with acute or chronic inflammatory pain reduces contextual fear conditioning in the rat. Behav. Brain Res. 2012;226:361–368. [PubMed]
39. He Y, et al. Negative reinforcement reveals non-evoked ongoing pain in mice with tissue or nerve injury. J. Pain. 2012;13:598–607. [PMC free article] [PubMed]
40. King T, et al. Unmasking the tonic-aversive state in neuropathic pain. Nat. Neurosci. 2009;12:1364–1366. [PMC free article] [PubMed]
41. Jandford DJ, et al. Coding of facial expressions of pain in the laboratory mouse. Nat. Methods. 2010;7:447–449. [PubMed]
42. Morgan D, et al. Evaluation of prescription opioids using operant-based pain measures in rats. Exp. Clin. Psychopharmacol. 2008;16:367–375. [PubMed]
43. Nolan TA, et al. Adaptation of a novel operant orofacial testing system to characterize both mechanical and thermal pain. Behav. Brain Res. 2011;217:447–480. [PMC free article] [PubMed]
44. Borsook D, et al. Neuroimaging revolutionizes therapeutic approaches to chronic pain. Mol. Pain. 2007;3:25. [PMC free article] [PubMed]
45. Chizh BA, et al. Identifying biological markers of activity in human nociceptive pathways to facilitate analgesic drug development. Pain. 2008;140(Suppl 2):249–253. [PubMed]
46. Mao J. Opioid-induced abnormal pain sensitivity: Implications in clinical opioid therapy. Pain. 2002;100:213–217. [PubMed]
47. De Felice M, et al. Triptan-induced latent sensitization: a possible basis for medication overuse headache. Ann. Neurol. 2010;67:325–337. [PubMed]
48. Goodsaid F, Papaluca M. Evolution of biomarker qualification at the health authorities. Nat. Biotechnology. 2010;28:441–443. [PubMed]
49. Baliki MN, et al. Brain morphological signatures for chronic pain. PLos One. 2011;6:e26010. [PMC free article] [PubMed]
50. Basliki MN, et al. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat. Neurosci. 2012 [PMC free article] [PubMed]
51. Stohler CS, Zubieta JK. Pain imaging in the emerging era of molecular medicine. Methods Mol. Biol. 2010;617:517–537. [PMC free article] [PubMed]
52. Wang D, et al. Genomic methods for clinical and translational pain research. Methods Mol. Biol. 2012;851:9–46. [PMC free article] [PubMed]
53. Young EE, et al. Genetic basis of pain variability: recent advances. J Med. Genet. 2012;49:1–9. [PMC free article] [PubMed]
54. Sorge RE, et al. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat. Med. 2012;18:595–599. [PMC free article] [PubMed]
55. Costigan M, et al. Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain. 2010;133:2519–2527. [PMC free article] [PubMed]
56. Smith SB, et al. Potential genetic risk factors for chronic TMD: genetic associations from the OPPERA case control study. J. Pain. 2011;12:T92–T101. [PMC free article] [PubMed]
57. Zhang Z, et al. Epigenetic suppression of GAD65 expression mediates persistent pain. Nat. Med. 2011;17:1448–1455. [PMC free article] [PubMed]
58. Basbaum AI, et al. Cellular and molecular mechanisms of pain. Cell. 2009;139:267–284. [PMC free article] [PubMed]
59. Mogil JS. Pain genetics: past, present and future. Trends Genet. 2012;28:258–266. [PubMed]
60. Arendt-Nielsen L, et al. Human experimental pain models in drug development: translational pain research. Curr. Opin. Investing. Drugs. 2007;8:41–53. [PubMed]
61. Quessay SN. Two-stage enriched enrollment pain trials: A brief review of designs and opportunities for broader application. Pain. 2010;148:8–13. [PubMed]
62. Gilron I, Jensen MP. Clinical trial methodology of pain treatment studies: selection and measurement of self-report primary outcomes for efficacy. Reg Aneth. Pain Med. 2011;36:374–381. [PubMed]
63. Webster L, et al. Effect of duration of postherpetic neuralgia on efficacy analyses in a multicenter, randomized, controlled study of NGX-4010, an 8% capsaicin patch evaluated for the treatment of postherpetic neuralgi. BMC Neurol. 2010;10:92. [PMC free article] [PubMed]
64. Othman AA, et al. Pharmacokinetics of the TRPV1 Antagonist ABT-102 in Healthy Human Volunteers: Population Analysis of Data From 3 Phase 1 Trials J. Clinical Pharmacology. J. Clin. Pharmacol. 2012;52:1028–1041. [PubMed]
65. Moran MM, et al. Transient receptor potential channels as therapeutic targets. Nat. Rev. Drug Disc. 2011;10:601–620. [PubMed]
66. McGivern PG. Ziconotide: a review of its pharmacology and use in the treatment of pain. Neuropsychiatr. Dis. Treat. 2007;3:69–85. [PMC free article] [PubMed]
67. Mantegazza M, et al. Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol. 2010;9:413–424. [PubMed]
68. Donnelly-Roberts D, et al. Painful Purinergic Receptors. J. Phamacol. Exp. Ther. 2008;324:409–415. [PubMed]
69. Katz N, et al. Efficacy and safety of tanezumab in the treatment of chronic low back pain. Pain. 2011;152:248–258. [PubMed]
70. Zylka MJ. Pain-relieving prospects for adenosine receptors and ectonucleotidases. Trends Molecular. Med. 2010;17:188–196. [PMC free article] [PubMed]
71. Collins S, et al. NMDA Receptor Antagonists for the Treatment of Neuropathic Pain. Pain Med. 2010;11:1726–1742. [PubMed]
72. Napier IA, et al. Glutamate transporter dysfunction associated with nerve injury-induced pain in mice. J. Neurophysiol. 2012;107:649–657. [PubMed]
73. Rowbotham MC, et al. A randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain. Pain. 2009;146:245–252. [PubMed]
74. Song JG, et al. Adenosine Triphosphate–Sensitive Potassium Channel Blockers Attenuate the Antiallodynic Effect of R-PIA in Neuropathic Rats. Anesth & Analg. 2011;112:1494–1499. [PubMed]
75. Es-Salah-Lamoureux Z, et al. Research into the therapeutic roles of two-pore-domain potassium channels. Trends Pharmacol. Sci. 2010;31:587–595. [PubMed]
76. White FA, et al. Chemokines: Integrators of pain and inflammation. Nat. Rev. Drug Disc. 2005;4:834–844. [PMC free article] [PubMed]