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Pain: Current Understanding, Emerging Therapies, and Novel Approaches to Drug Discovery

2003 Edition, May 13, 2003

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Active, Most Current

EN
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ISBN: 978-0-8247-8865-0
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Product Details:

  • Revision: 2003 Edition, May 13, 2003
  • Published Date: May 13, 2003
  • Status: Active, Most Current
  • Document Language: English
  • Published By: CRC Press (CRC)
  • Page Count: 1006
  • ANSI Approved: No
  • DoD Adopted: No

Description / Abstract:

Preface

When we first drafted the outline of this book, we had a number of objectives and questions in mind:

1. What is the latest thinking in terms of pathological mechanisms (e.g., peripheral and central sensitization) underlying acute and chronic pain? Do these specific pathologies correlate with a particular symptom, irrespective of patient population? If so, will a novel molecule, which reverses or attenuates a particular symptom and thereby a particular mechanism, do so irrespective of patient population? What is the role of the immune system or peripheral nervous system in maintaining chronic pain? If we dampen or attenuate these peripheral changes, will they also reverse central pathological changes resulting in chronic pain?

2. Are technologies now available that we can apply both in preclinical animal disease models and in human volunteer models or patient groups? What nonpharmacological treatments are currently available, and how effective are they? How do we best classify pain in order to facilitate our understanding and development of novel pharmacological treatments (temporally- acute, chronic; disease association-cancer, diabetic neuropathy; etiology-nerve injury, tissue injury; site-headache, chronic back, visceral-abdominal, pelvic)? How do we best assess pain in clinical trials, e.g., evoked (mechanical, chemical, or thermal), postsurgical, hyperalgesic or allodynic, ongoing, or on movement? How do we demonstrate superiority over gold standards, without necessarily knowing how good gold standards are in specific patient populations (e.g., responder rate, ceiling of efficacy, dose-response, onset of action of tricyclic antidepressants or anticonvulsants in different types of neuropathic pain)? Are there imaging techniques (PET, fMR!, etc.) that can help with the diagnosis of specific pain states or serve as surrogate markers of efficacy in clinical trials of novel therapeutics? Of course, the challenge is made even greater by the demands in the pharmaceutical industry to demonstrate' 'superiority" or "differentiation" quickly and cheaply by doing proof-of-concept or proof-of-efficacy studies in small patient groups.

3. Why has it been so difficult to demonstrate proof-of-efficacy in humans with molecules targeting novel mechanisms? The classic example in the industry has been NKI receptor antagonists. Pharmaceutical companies have worked with many of the world's pain experts at leading academic institutions to identify and evaluate such molecules in specific patient groups. They were unanimously unsuccessful in demonstrating a lack of efficacy. Why was this? Are animal models not predictive of efficacy in the clinic? Could there be significant differences in target receptor affinity or function in rodents vs. humans, or differences in convergent pain pathways, or other factors that must be considered? Is it naive to assume that molecules targeting single molecular targets will have significant efficacy in patient groups where the presenting symptoms are a result of multiple pathologies? How can we better understand the complex heterogeneity of pain in the clinic and design predictive preclinical assays to facilitate prioritization of new chemical entities for clinical evaluation? How can we exploit novel target validation strategies? What is the role of genetics in this heterogeneity?

4. Many approaches are being pursued in this hungry quest for treating intractable pain. Many of these are reviewed in Part 4, "New and Emerging Therapies." A key issue in using many novel targets is not simply demonstrating clinical efficacy in the right patient group but also showing that such targets/molecules have an adequate "safety window" or "therapeutic index." It is, of course, a well-recognized possibility that many molecules are not able to achieve adequate therapeutic exposure in the appropriate compartment, prior to running into safety issues. Since patients generally prefer oral dosing regimes, once or twice a day, the result may be to expose the whole body compartment to a high concentration of a drug when all that is required is a lower therapeutic concentration in a specific region of the peripheral or central nervous system-a beautiful analogy likens this to pouring gas on the roof of a car and hoping that some of it reaches the tank. This dilemma has led to the quest for more tightly targeted formulations of drugs (e.g., topical, spinal) or other interventional techniques to control pain at its site of origin.

5. What analgesics are currently available or in development, and for what indications? How can we develop novel drug combinations? How do we "hunt" for new drugs, and from where are the next generation of pharmaceutical agents likely to emerge?

We have therefore deliberately structured this book in four broad sections devoted to basic aspects, clinical aspects, novel approaches to drug discovery, and new and emerging therapies.

The book offers a comprehensive review of many of the preceding aspects and challenges. It is designed to be a reference source for academic, clinical, and pharmaceutical researchers and to foster interaction among these various groups of professionals. We anticipate that it will appeal to both new and established researchers in this exciting and incredibly attractive field of research. We hope that such cross-functional/cross-disciplinary collaborations will result in major advances in our understanding of pain mechanisms and innovative approaches to drug discovery.

Some of the most pressing issues that remain for all of us to ponder include preclinical target validation, how we demonstrate proof of concept in humans, and how we develop combination treatments for pain (i.e., molecules with multiple activities or multiple molecules each with discrete molecular targets). For the latter, there are clear technical and regulatory challenges that extend beyond the scope of this book.

The book has taken longer to prepare than initially anticipated, due largely to the number of contributors and the breadth of the task. For that we apologize to the authors who submitted their chapters early in the process and offer in the Further Readings section recent references relevant to the respective chapters, which may guide the reader to additional thoughts and discovery.

There have doubtless been fantastic advances in pain therapeutics over the past few years. For example, gabapentin is providing significant therapeutic benefit for many neuropathic patient groups. Similarly, COX-2 inhibitors represent a major advance over existing NSAIDs for specific patient populations. We remain convinced that, with major advances in understanding the basic pathophysiology of pain and how it can be manipulated at the anatomical, physiological, immunological, pharmaceutical, and psychological levels, the most exciting discoveries remain before us.

We are all immensely optimistic that in the next decade we will continue to build on these advances, and hopefully deliver rationally designed, novel therapies to patients so that they may lead more manageable, less debilitating lives.