Emerging Strategies for the Treatment of Neuropathic Pain

Campbell JN, Basbaum Al, Dray A, Dubner R, Dworkin RH, Sang CN, eds, Emerging Strategies for the Treatment of Neuropathic Pain. Seattle: IASP Press, 2006. ISBN 0-93109261-2; 2514 pages; US$80; IASP member price US$64

This book is the result of a five-day meeting in Scottsdale, Arizona, in April 2005, with the purpose of developing new ways to treat neuropathic pain (NP). It is divided into four parts: peripheral nervous system targets, central nervous system targets, disease-specific targets, and measurement and new technologies. It is the intent that the book represents the state of the art and a blueprint for the future.

Part 1 (chapters 1 to 4) contains chapters on peripheral targets, generators and receptors, and discusses the role of sensitization of primary afferents in NP. Some examples of consensus are for the term dynamic mechanical allodynia, the meanings of the term 'mechanisms', ectopic activity, central sensitization, the induction of central sensitization by C fibers, dynamic mechanical allodynia being signalled by A-beta fibers, and that physiological central sensitization does not usually outlast peripheral provoking stimuli for more than one day. Research questions are whether injured A-beta fibers can induce central sensitization, the role of mechano-insensitive afferents, under what circumstances peripheral NP becomes independent of the periphery input, how quickly it develops and whether C-fiber activity is essential for the induction/maintenance of neuropathic pain. Targeted monotherapy versus polypharmacy and the future of genetics are important issues raised here. An important question is whether focusing aggressively on the periphery can arrest central changes and prevent chrontcity. There is a stimulating review of current systemic drug actions pointing out that many effective agents act as membrane stabilizers on ion channels suppressing ectopia. Plasma membrane receptors are exhaustively detailed. The section comes up somewhat short on topical agents admittedly of very limited effect currently and excludes reference to the several trials of opibids in neuropathic pain. Finally, peripheral sensitization is emphasized as an important mechanism and therapeutic target for the prevention of sensitization.

Part II (chapters 5 to 10) is entitled Central Nervous System Targets. The relevant topics chosen in the first chapter of this section are central sensitization, plasticity, neuronal-glial interaction, competition in the brain, descending modulation, pain experience, animal models, genomics and proteomics and therapeutics. Important research questions are identified, with particular regard to central sensitization. Chapter 6 discusses descending modulatory circuitry and begins with a superb review of research into the descending inhibition of pain. The chapter then proceeds to a thorough discussion of descending inhibitory and facilitatory modulation, the effects of injury and clinical implications. Chapter 7 concerns Opioids and Neuropathic Pain. It reviews the controversies about chronic opioid therapy in neuropathic pain and clinical research. A plea is made for more long-term studies and evaluation of how well the design of preclinical investigations have provided guidance to clinical investigations. Chapter 8 discusses the role of Neuroimmune Activation in Chronic Neuropathic Pain and Possible Future Therapies. It addresses approaches to treating NP involving the immune system and highlights the role of cytokines and neuroimmune activation and treatment strategies. Chapter 9 is entitled Signaling Pathways in Pain Neuroplasticity in the Spinal Darsd Horn. This chapter begins with a nice summary of the physiology and pathophysiology of the dorsal horn, emphasizing plasticity and the emerging role of microglia and pain hypersensitivity following nerve injury. It nicely discriminates 'wind-up' versus classical 'central sensitization' and goes on to discuss persistent enhancement of excitatory synaptic neurotransmission and suppression of inhibition. Chapter 10 deals with Ascending and Descending Facilitatory Circuits in Neuropathic Pain States. It reviews sensitization of the dorsal horn by primary afferents and the current evidence that initial discharges cause central sensitization but that neuroplastic changes in the central nervous system maintain central sensitization. It then goes on to discuss primary afferent input and spinal sensitization in some detail and then ascending pathways of possible importance. Of interest is the discussion of descending pain facilitatory pathways that maintain central sensitization and the involvement of serotonin. We have long thought about descending pain inhibitory systems, but we now need to think from a therapeutic point of view about this facilitatory system. The chapter finishes with a nice synthesis which suggests points at which pharmacological manipulation may be considered.

Part III (Chapters 11 to 16): Chapter 11 will be of interest not only to basic researchers, but also to clinical scientists doing controlled trials. It is entitled Disease Specific Targets and highlights three general issues of importance to clinical research. The section on novel diagnostic approaches includes good discussions of quantitative sensory testing, skin biopsy, biomarkers, microneurography, imaging techniques, autopsies and drug challenges. The clinical trials section includes a discussion of innovations in trial design and addresses the issue of mechanism-based versus disease-based approaches, trials of concomitant analgesics and the need for long-term studies. The section on disease-specific targets discusses in detail the benefits of using models such as diabetic neuropadiy, postherpetic neuralgia and others. The chapter concludes with recommending natural history studies, early treatment studies, interdisciplinary interactions, the need for long duration studies, especially of opioids, the need for head to head trials and the importance of registration, timely publication and the publication of negative trials. Chapter 12 is entitled The Role of Growth. Factors in Painful Length-Dependent Axonal Neuropathies. I have seldom read a better or more succinct account of the types of painful neuropathy than in the beginning of this chapter. It discusses at length two basic patterns that may account for pain in neuropathies. Although the chapter would have benefited from a summary section at the end, the table in part compensates for that. Chapter 13 discusses Pain Related to Inflammatory, Infectious and Toxic Neuropathies - Mechanisms and Perspective on Treatment. This chapter is a comprehensive discussion of the different types of HIV-associated neuropathies, the mechanisms of pain in antiretroviral toxic neuropathy and also of chemotherapy-induced neuropathies, such as cisplatin, taxanes and vincristine. Although the purpose of the chapter focuses on pathophysiological mechanisms, there have been some recent randomized controlled trials showing that tricyclic antidepressants do not relieve HIV-associated neuropathy but there is no discussion of these or any other published literature. Chapter 14 is entitled The Depression Pain Complex: Overlap Between the Two Problems and Implications for Neuropathic Pain. Three of the authors work for Lilly Pharmaceutical Company, which may explain the emphasis on duloxetine in the chapter, but it is a reasonable account of the relationship between pain and depression, epidemiological data on both, the contribution of serotonin and norepinephrine and although it is a good review of clinical studies, it does not include early research and the research in postherpetic neuralgia. It does not mention the dearth of comparative trials which are the best way of determining whether new drugs such as duloxetine and venlafaxine are any better than the older tricyclics, as we are led to believe by advertising. One of the conclusions could have been the crying need for comparative trials. Chapter 15 is entitled Dissecting Molecular Causes of the Components of Chronic Neuropathic Pain Syndrome. This chapter looks at the potential links among pain, mood, sleep and substance abuse disorders, molecular epidemiology of chronic neuropathic pain, genetics, quantitative sensory testing, measurement of neurotransmitters, brain imaging and environmental influences. It concludes that to better understand and treat the 'disease' of NP, we must use large prospective studies to determine causal relationships among pain, mood and substance abuse disorder. It concludes that preliminary evidence suggests that the risk of chronic pain in humans, as well as animals, may be partially determined by common genetic variants but cautions that because of the expense of large cohort studies researchers may need to piggyback their questions into other studies funded by more established researchers. It also concludes that advances may be more rapid if there is a focus on more common neuropathic conditions and suggests the need for briefer measures of variables, such as sleep, mood and substance abuse. There follows an Appendix which will be of great use to those interested in genetics and pain. Chapter 16 deals with tailoring pharmacotherapy to diagnostic subgroups in NP. This is a succinct chapter that reviews current treatment options and provides a table of drugs that are approved in the United States. This might give the impression that treatment is limited to these drugs, but many patients are treated offlabel with drugs such as tricyclic antidepressants and opioids, There are concise tables of investigational compounds for NP with approval for other diseases to stimulate investigators. There is a third table indicating newer approaches to the treatment of NP in terms of potential targets. Chapter 17 is entitled Measurements and New Technologies. The consensus is that new developments are held back because of limitations in these areas. Although numerous targets have been identified, validation has been difficult and as a result molecules are inappropriately rejected based on animal testing while other molecules that appear useful in animals are not effective in the clinic. The chapter addresses the issue of what NP is and the role of uninjured primary afferents, injured afférents and dorsal horn changes. It specifically addresses whether we should be targeting the disease or the pain and then addresses measurement and pain models and psychophysics. With animal models it addresses the issue of whether drug studies in animals predict efficacy in humans, whether withdrawal reflexes are a valid measure of pain in animals and the role of operant tests. There is a brief discussion of the chronicity of NP and opioid sensitivity and the placebo effect and of a variety of technologies such as functional brain imaging, DNA, gene screens and proteomics. The summary of the chapter is that there are no shortages of new technologies or new targets for pain treatment, but there is a pressing need for the development of new behavioural screening tests and reiterates that many molecules are inappropriately discarded or inappropriately studied and proceed to later phase testing and that 80% of centrally acting drug candidates ultimately fail. The conclusion is that if we discover new treatments it will be important to combine progress in basic science with better screening techniques in early phase human trials. Chapter 18 deals with brain imaging as a surrogate measure of pain in humans and animals. The chapter concludes that brain imaging in both humans and animals has great potential and can be used as a tool to examine the site of actions of new pharmaceutical agents and to provide an overview of brain areas affected by analgesic manipulation. Some caveats are expressed with regard to the possibility of false-negative imaging and the chapter concludes that the technology is advancing at a great rate in terms of spatial and temporal resolution and sensitivity. Chapter 19 is entitled Microarray Studies in Pain and gives an overview with relevance to pain, describing them as powerful tools for the molecular analysis of tissues with the potential ability to assay the expression of every gene in a biological sample. Chapter 20 is entitled Psychophysical Models of Neuropathic Pain. This chapter focuses on the potential of human surrogate models of NP and explores the role of these models in translational research on mechanism based treatment. It concludes by stating that human surrogate models of pain are already very useful for the investigation of pharmacological mechanisms of action and therapeutic efficacy because they are based on the same assessment techniques used in clinical studies. Chapter 21 deals with psychophysical tests that characterize pain mechanisms and discusses their utility in aiding diagnosis, understanding mechanisms and matching treatment to mechanisms. Chapter 22 is about biomarkers in pain. The authors point out that correct usage depends on the principle of close association of a molecule or a pattern of expression of several molecules with the disease. The chapter is divided into sections on proteomic patterns and biomarkers in experimental pain, rheumatoid arthritis, osteoarthritis and NP syndromes. The authors state that it is too early to judge the results of these pilot studies, but based on experience in other fields, the authors are confident clinical pain studies will increasingly turn to this powerful technique for insight into pain mechanisms and better pain management. The final chapter is entitled Animal Studies of Pain: Lessons for Drug Development. The chapter give a thorough examination of the pros and cons of reflex measures and operant testing paradigms. The authors propose operant testing as an alternative to reflex testing.

In conclusion, this book is a valuable resource for both the basic and clinical scientist. It will probably be of more value to the former, but any clinician who wants to be current with the state of the art and to gain insight into future trends in basic and clinical research in NP will find a wealth of information here. The book is good value, as is usual for IASP publications.