Chronic Inflammatory and Neuropathic Pain

Agenda

*Presentation times are subject to change.

Abstracts

Day 1: Thursday, June 2, 2011

Selection of a target represents the first step in the drug discovery process. Choice of a wrong target will guarantee failure. Successful development of novel analgesics is contingent, therefore, on a detailed molecular understanding of the mechanisms of pain. New technologies now enable this process to shift from the standard hypothesis-based candidate approach used so far with very limited success, to an unbiased genome-wide strategy; a change to a discovery science strategy to reveal true novelty. This will include genome-wide association studies in patient cohorts, computational genetics in mice, proteomics, transcription profiling and genetic manipulation in model organisms with iterative validation and replication. While each individual strategy may have limitations, combining them increases confidence. To meet this challenge a cooperative pre-competitive effort is required since no single investigator or company can do this alone.

Session I: Novel Targets and Pre-clinical Discovery

Normal tactile sensation, including acute pain, is perceived through predictable patterns of activity involving a mix of peripheral sensory neuron types whose cutaneous endings are differentially activated by particular physical properties of tactile stimuli. Various neuronal types supply Aβ fibers, Aδ fibers, or C fibers. Subtypes predictably terminate as endings that have a unique combination of morphology, disposition and molecular expression that impart unique albeit overlapping functional properties involving differing proportions and types of mechanical, thermal, and chemical stimuli. The normal variety, proportion and disposition of cutaneous innervation is genetically programmed through complex molecular interactions during development and sustained maintenance. Likewise, a programmed pattern of differential terminations develops in the central nervous system so that a given tactile encounter will produce a predictable pattern of neuronal activity whose correlations provide the basis of normal perception. Under many chronic neuropathic pain conditions, a substantial disruption, reorganization, and instability occurs among the proportions, morphologies, dispositions and molecular expressions. Thus, normal skin stimulation may result in aberrant, volatile patterns of activity that are unpredictable and uninterpretable, and, therefore, unperceived (numbness) or misperceived as threatening (pain). Recent evidence indicates that a differentially stratified distribution of multiple neuronal signaling properties among epidermal keratinocytes also contributes to normal tactile perception, and abnormalities in this stratified organization may also contribute to chronic pain. Strategies to facilitate the ability to re-establish stable, predictable patterns of tactile neural activity, even if they are abnormal, may help alleviate chronic pain.

Most chronic pain states can be temporarily ameliorated by local anaesthesia of the affected tissues. This suggests that in these states, peripheral pain signalling pathways are being tonically activated. The mediators responsible are for the most part unknown but the limited efficacy of NSAIDs suggest the existence of factors other than prostanoids. One factor that has been identified and shown to act as a peripheral pain mediator is the neurotrophin nerve growth factor (NGF). A wealth of pre-clinical data and more recently clinical trial data has shown the efficacy of peripheral anti-NGF strategies in relieving several forms of chronic pain, most notably pain associated with osteoarthritis. This literature will be reviewed along with the potential limitations of this approach. I will also describe a novel approach being pursued in our own laboratory to indentify other peripheral pain mediators. We undertake transcriptional profiling of human biopsy specimens from painful conditions to identify candidate mediators and then test the role of these candidates and their mechanism of action in preclinical models. With this approach we have identified the chemokine CXCL5 as a mediator of some inflammatory pain states.

Chronic pain conditions present a huge burden on modern society. Both inflammatory and neuropathic pain is poorly treated in man; the majority of patients do not benefit from adequate pain relief, and side effects of currently used treatments are common. Discovery and development of novel therapies remains an imperative, but the ability to genuinely test the efficacy of novel therapies is often limited by effects at targets other than intended, particularly with novel small molecule approaches. Approaches which limit these off-target activities may provide a greater ability to genuinely test targets of choice clinically. Here, biologic therapeutics, in particular monoclonal antibodies provide such an opportunity. However, consideration must be given to the discoverability and developability of mAbs against various target classes. An optimal target for mAb intervention is a soluble mediator such as a cytokine (e.g. IL-6) or growth factor (e.g.NGF) but recent advances have also been made in the targeting of ion channel targets with mAbs (e.g. P2X family). As such, the target landscape for analgesic biologics is indeed a broad one, even when considering only peripheral targets. Further development of blood–brain-barrier penetrating platforms will serve to open this landscape still further. In this presentation, the current status of biologic therapies, as well as future opportunities are reviewed.

Voltage-gated sodium channels have long been known to play essential roles in electrogenesis. Over the past fifteen years, it has become clear that multiple genes encode distinct sodium channels (Na_V1.1-Na_V1.9) which share a common overall structural motif but differ in terms of amino acid sequence, pharmacology, and functional characteristics. Three of these sodium channel isoforms (Na_V1.7, Na_V1.8, Na_V1.9) are preferentially expressed within peripheral neurons, including nociceptive DRG neurons, and expression of Na_V1.3 is up-regulated following peripheral nerve axotomy. There is evidence implicating each of these sodium channel isoforms in chronic pain. Interest in Na_V1.7 as a molecular target has been heightened by the demonstration, in human subjects, that gain-of-function mutations in this channel can lead to severe pain (inherited erythromelalgia; paroxysmal extreme pain syndrome), while loss-of-function mutations of this channel produce congenital insensitivity to pain. As a result of its slow recovery from inactivation Na_V1.7 cannot generate the upstroke of high-frequency action potentials within repetitive trains. Na_V1.7 acts as a "threshold channel," activating in a voltage range below the threshold for action potential generation, thereby setting the gain on nociceptors, with Na_V1.8 producing the majority of the inward transmembrane current underlying the rapid depolarizing phase of the action potential. Na_V1.3, Na_V1.7, and Na_V1.8 all accumulate within the blindly ending axon tips within painful neuromas in humans. Identification of these sodium channels as molecular targets may facilitate the development of new, more effective pain therapeutics.

Several reports indicate that L-acetylcarnitine (LAC) can be considered as a therapeutic agent in neuropathic disorders including painful peripheral neuropathies. Our studies aimed at defining the mechanism of LAC analgesia indicated that LAC acts in part by epigenetic regulation of mGlu2 metabotropic glutamate receptor expression. Consistent with this finding, activation of mGlu2 is robustly analgesic in animal models, though the therapeutic utility of mGlu2 agonists for the treatment of pain is limited by the robust development of analgesic tolerance to mGlu2 agonists. Mechanistic studies suggest that LAC exerts this effect via regulation of p65/RelA acetylation. These findings led us to test whether inhibiting deacetylation using HDAC inhibitors might similarly have analgesic effects via upregulation of mGlu2. We find that indeed two separate HDAC inhibitors promote analgesia and upregulation of mGlu2, and that the analgesic effects of HDAC inhibitors are reversed by an mGlu2 antagonist. Importantly, we find no evidence for the development of analgesic tolerance on repeated dosing of HDAC inhibitors. In conclusion, "epigenetic" drugs that increase mGlu2 receptor expression, including L-acetylcarnitine and inhibitors of histone deacetylases, have a unique analgesic profile with no tolerance to the therapeutic effect after repeated dosing.

Work over the past 18 years has challenged classical views of pain & opioid actions. Glia (microglia & astrocytes) in the central nervous system are now recognized as key players in: pain amplification, including pathological pain such as neuropathic pain; compromising the ability of opioids, such as morphine, for suppressing pain; causing chronic morphine to lose effect, contributing to opioid tolerance; driving morphine dependence / withdrawal; driving morphine reward, linked to drug craving & drug abuse; & even driving negative side effects such as respiratory depression. Glial activation arises under conditions of chronic pain from neuron-to-glia signaling. Intriguingly, the glial activation receptor that creates neuroinflammation under conditions of chronic pain is one and the same receptor that is activated by opioids. Atop this, what is both fascinating & fundamentally important for drug development is that opioid effects on glia that create neuroinflammation are via the activation of a non-classical, non-stereoselective opioid receptor distinct from the receptor expressed by neurons that suppresses pain. This implies that the effects of opioids on glia & neurons should be pharmacologically separable so to lead to new drugs for the control of chronic pain & to increase the clinical efficacy of pain therapeutics. Indeed, drugs in development that target this glial activation receptor have shown remarkable efficacy as stand alone treatments for neuropathic pain, by blocking neuron-to-glia signaling, plus blocking unwanted side effects of opioids, as well as other drugs of abuse.

Day 2: Friday, June 3, 2011

Session II: Transitioning from Pre-Clinical to Clinical Studies

An important criticism of preclinical measures of neuropathic pain is that reflexive responses to evoked stimuli may not capture dimensions of pain that are important clinically. Patients often experience pain that is spontaneous or ongoing.Our inability to assess mechanisms of spontaneous pain may be an impediment to clinical translation. We have explored the concept that alleviation of aversiveness elicited by chronic pain states (i.e. pain relief) might be used to reveal the presence of spontaneous or ongoing pain. Standard preclinical pain models (e.g., experimental neuropathic, inflammatory, osteoarthritis, cancer pain) were explored using the principle of negative reinforcement. Aversiveness of pain provides motivation to seek relief and can thus drive behavior. We used conditioned place preference to assess the presence of an aversive state associated with chronic pain. Thus, pairing a context with a manipulation presumed to produce pain relief should produce place preference selectively in animals with spontaneous or ongoing pain. This idea was confirmed in multiple models of pain to reveal that drugs that are not rewarding in the absence of pain become rewarding in the presence of chronic pain. This approach allows investigation of pathways that might differentially contribute to evoked and spontaneous components of pain as well as exploration of circuits underlying the aversive state. Assessment of molecular targets that play a role in these components of pain can be used as a mechanistic basis to inform decisions for development of human therapeutics. Such studies may improve our ability to translate new mechanisms into better therapy for patients.

The Pharma industry is amidst a productivity crisis with ever increasing costs for research and development and decreasing approvals for new medicines. This is evident in the pain field with few new medicines successfully moving through development to the market to help patients. Over the past 10–15 years compounds with novel mechanisms of actions such as pregabalin, duloxetine and most recently tapentadol have made it to the market but still a large proportion of patients remain refractory to the available treatments. The translation of positive preclinical data into clinical efficacy is a key area of focus as many promising compounds / mechanisms fail to reach a positive 'proof of concept' study. A major issue is the lack of understanding of the complex clinical chronic pain condition and the simple numeric rating scales used to assess clinical pain which give limited feedback to preclinical scientists. The concept of 'translational research' hopes to build bridges between preclinical scientists and clinicians and identify biomarkers to assist in the development of novel pain medicines. Biomarkers can range from complex imagining techniques to simple blood borne markers which allow assessment of target engagement, pharmacology and even efficacy in early clinical trails. Closer co-operation between preclinical and clinical scientists through open innovation and pre-competitive consortia will be essential to ensure we are more successful in identifying novel medicines to treat the patients.

There is mounting evidence that neuropathic pain conditions in humans have profound effects on brain anatomy and structure. This presentation will focus on the use of rodent models of neuropathic pain to understand changes in behavior and brain function and anatomy. A majorstrength of brain imaging studies in rodent models of neuropathic pain is the ability to employ longitudinal designs, with comparisons before and at several time-points after injury, in order to follow the onset and progression of changes. We examined brain structural changes and behaviors in rats with the spared nerve injury (SNI) model of peripheral neuropathic pain. We found that in areas related to the sensory aspect of pain, including the anterior cingulate cortex and primary somatosensory cortex, decreased volume correlated with mechanical hypersensitivity, such that the more hypersensitive an animal became, the smaller those sensory regions were. Furthermore, we observed decreased volume of the prefrontal cortex that occurred several months after the injury and corresponded in time with signs of anxiety-like behavior. Findings from our more recent studies support these behavioral changes and also suggest that SNI rats show cognitive deficits several months after injury. The presentation will end with a discussion of recent and ongoing work in a model of spinal cord injury neuropathic pain, in which we examine functional MRI responses to noxious stimulation and at rest. These longitudinal studies will shed light on the changing brain circuits associated with a neuropathic pain model and in relation to affective and cognitive behaviors.

Pain is not a linear readout of incoming sensory information but a highly subjective experience that is determined by sensory and cognitive–affective factors and can even vary in the absence of change in physical input. Given the subjective nature of pain, pain assessment in research and clinical settings commonly relies on self-report measures. However, objective readouts might be desirable where individuals are unable or unwilling to report pain.

In this presentation, I will discuss different approaches to identify an objective measure of pain. Specifically, I will introduce recent advances in the decoding of pain using multivariate analysis techniques that aim at predicting cognitive or perceptual states such as the experience of pain from brain images only.

Abundant human pain models have been developed to understand pain physiology. Models range from assessments in normal skin to models inducing increased sensitivity to pain upon provocation, i.e. evoked pain. Lately also models of ongoing pain have been characterized. Pain has been induced by ischemia, heat, UV irradiation, chemical agents, electricity, etc.

Is there then still a role for such models in drug development? When developing new analgesics for new and unprecedented targets, there may be a place for these models. Models involving well understood mechanisms of action, such as capsaicin injection have been used for candidate drug selection for TRPV1 compounds, as a first step in demonstrating human targets engagement. Lately, models of inflammation, such as UV irradiation has been characterized, linking models to known and new targets. Many new drug targets are identical in animal species and humans, making preclinical testing insufficient in candidate selection. There is a great advantage to be able to test gain confidence in the target mechanism by local testing avoiding systemic exposure, before traditional first time in man safety and tolerability studies.

Chronic pain remains a significant problem that has few effective therapies. Choosing the right patients to receive a targeted therapeutic is critical from both the efficacy and safety perspective. There is a great need to reduce the cost of developing new pharmaceuticals, now approaching 1 billion per drug. A bulk of this cost is attributed to failed drugs. The FDA estimates that a 10% improvement in predicting clinical trial failures could reduce the average cost of drug development by nearly $100 million. An effort to generate more discriminatory biomarkers of efficacy and toxicity should eliminate suboptimal compounds earlier in development. Traditional preclinical animal studies often do not predict human-specific metabolic and toxic effects. Currently, the most commonly used toxicity biomarkers generate safety signals only when substantial organ damage has occurred. Ongoing efforts at finding efficacy and safety biomarkers that can predict or anticipate either desirable or undesirable effects in chronic pain and other indications will be discussed.

Session III: Post-candidate Clinical Development

Chronic pain is a complex disorder, manifesting with persistent pain and many other somatosensory symptoms, disturbance of sleep and mood, and it results in negative impact on work, function and quality of life. Since at the present time there is no known cure for chronic pain, the best modern medicine can offer is multimodal and multidisciplinary pain management. This approach has been accepted and promoted by professional pain societies and organizations as the standard for managing chronic pain. Elements of multimodal approach to pain management include pharmacotherapy, interventional treatments, physical medicine and rehabilitation, psychological counseling and support and the development of appropriate coping skills. Drugs proven in randomized clinical trials to be effective in providing partial pain relief are the basis of pharmacotherapy of pain and these drugs are used alone and most commonly in combination taking advantage of diverse mechanisms of action. Interventional approaches include injections of anatomic sites presumed to be sources of pain, usually with combination of local anesthetics and steroids, and neurostimulation therapy with implanted devices are frequently used as a last resource for pain relief. Physical and rehabilitation medicine treatments include a wide range of physical modalities but the most critical is patients' engagement into active exercise program. Psychological therapies are important for development of strategies to diminish psychological comorbidities and cathastrophization as well as development of coping skills that allow patients to deal with chronic pain more efficiently. To implement multimodal approach to best of its potential, clinicians from all of thedisciplines that are best trained and equipped to administer respective therapies need to work together in coordinated fashion.

A new concept was proposed in which pain is analyzed on the basis of underlying mechanisms rather than on the basis of the etiology. The German Research Network on Neuropathic Pain established a large data-base that includes epidemiological, clinical and history data as well as a standardized quantitative sensory testing (QST). Up to now more than 2000 patients with different neuropathic pain states have been examined. Furthermore, epidemiological and clinical data on the symptomatology of 4200 patients with painful diabetic neuropathy, postherpetic neuralgia and radicular pain from a cross sectional survey (painDETECT) are available.

Neuropathic pain—defined as "pain initiated or caused by a primary lesion or dysfunction in the nervous system"—results from various disorders affecting the brain, spinal cord, or peripheral nerves and is distinct from inflammatory pain both in its clinical manifestations and responses to various available treatments. Due, in part, to limited understanding of the pathophysiology of neuropathic pain, evolution of clinical trials in this area has somewhat lagged behind that of other painful conditions. Following a brief historical perspective, this presentation will review various key elements of neuropathic pain clinical trials including research goals, study treatments, study populations, outcome measures and specific clinical trial designs. Finally, current controversies and knowledge gaps in this field will be discussed with a view to identifying future directions for improvement in neuropathic pain trial design.

The subjective nature of pain and pain measurements have often been sighted as a reason why clinical trials of potential therapies are difficult to conduct and interpret. However, beginning with simple parallel two group short term randomized trials by Ray Houde, Henry Beecher and others in the middle of the last century focused on analgesics, consistent and valid results have been obtained for a variety of analgesics including non-steroidal anti-inflammatories, opioids, and adjuvant analgesics. The underlying principals of random allocation, blinding, and a priori hypotheses based on primary pain outcomes remain the underpinnings necessary to produce valid clinical trial results. Standardization of patient reported pain outcomes including pain intensity, pain interference, and global perception of change have been validated in hundreds of studies. Our expanded conceptual framework for the pain process has provided a greater level of understanding of physiologic components that underlying the pain experience and how they influence the self report of pain and have improved our understanding of the appropriate use of measures and analysis techniques, how to provide clinically useful interpretations of pain studies. Our improved understanding of the physiologic processes that underlie the pain response have also resulted in the development of a number of new pain therapeutics which underscores the need to create standard approaches to pain studies to allow for comparisons across disease states and types of therapies. Improved efficiency of these studies has also become an important focus of current research.

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