Cancer Pain: From Molecules to Suffering

Q: What are some of the latest breakthroughs in understanding the mechanisms of cancer pain?
A: In the past few years there have been extraordinary breakthroughs in our understanding of the mechanisms of cancer-related pain. New findings regarding the underlying neurobiology of malignant bone pain by Patrick Mantyh and his collaborators have changed the way we understand and treat pain due to primary or metastatic bone lesions. Several investigators, notably Gary Bennett, Jon Levine, and Patrick Dougherty, are exploring the neuronal changes underlying chemotherapy-induced painful peripheral neuropathy. This important work has highlighted the role of cancer treatment as a serious cause of persistent pain. Furthermore, it is leading to strategies that might one day be employed in the clinic to prevent this type of pain, allowing patients to complete potentially curative therapy and improving their quality of life.

Q: Are opioids still the mainstay of cancer pain treatment?
A: Opioids remain crucial to the management of cancer-related pain; however, there is now greater appreciation for the need to employ multimodal therapies. These include nonopioid drugs (nonsteroidal anti-inflammatory drugs and acetaminophen/paracetamol) and adjunctive agents (e.g., anticonvulsants and antidepressants for neuropathic pain), along with newer therapies that are currently under investigation. Furthermore, the role of disease-modifying therapies remains essential, including radiotherapy, chemotherapy, biological treatments, interventional approaches, and other techniques.

Q: How might current insights into the pharmacology of opioid tolerance be applied to the clinical setting?
A: Much more research is needed to better understand opioid tolerance. Currently, there are no randomized controlled trials in humans that explore the rate of tolerance development with opioid administration. It is difficult to differentiate tolerance from disease progression and changes in absorption or elimination of drugs that may be responsible for the need for increasing doses of an opioid. One excellent example is the recent finding that cachexia results in lower plasma levels of fentanyl when administered transdermally. Additionally, strategies to prevent or reduce opioid tolerance may be found in the future through activation of delta-opioid receptors or other targets. Many drugs that are already available still need to be studied in the clinic. These include the NMDA-receptor antagonists ketamine and memantine.

Q: Do you see new options for cancer pain treatment on the horizon?
A: As the underlying mechanisms of cancer pain are unraveled, new treatments are being designed to target these mechanisms. Examples include anti-nerve growth factor (NGF) monoclonal antibodies, which bind to tyrosine kinase receptor A (TrkA) on sensory neurons, reducing activation of nociceptors after noxious stimulation. Another example is the reduction of osteoclast activity by osteoprotegerin ligand (OPG) to reduce malignant bone pain. Many more compounds are currently in development.

Q: What are some of the difficulties in designing clinical trials in cancer patients?
A: Research design issues in cancer pain are critical. Starting with the laboratory, the models employed in animals must accurately predict the experience of patients with malignancy. Designing clinical trials in cancer-related pain can be complicated by disease progression, by the potentially confounding effect of concomitant cancer therapies, and by the heterogeneity of cancer pain syndromes. Conducting these trials can be like shooting at a moving target. Yet there are strategies that can ensure that cancer pain research is designed to answer the most crucial questions. Collaboration between basic scientists and clinicians is vital. The development of international collaborative groups will help with subject accrual and generalizability of findings. Ethical aspects are also particularly important when studying very ill patients. However, most cancer patients are willing to advance pain research by participating in clinical studies. It is a well-known fact that patients who participate in clinical trials do better than those who do not.

Q: Do curative therapies such as radiation and chemotherapy increase or decrease the cancer patient's risk of pain?
A: Disease-modifying therapies such as radiation therapy and chemotherapy can have a significant pain-relieving effect. Radiotherapy has been shown to be very effective in the alleviation of pain due to bone metastases. However, there is also the potential for chronic pain syndromes to occur as a result of cancer treatment. Chemotherapy-induced painful peripheral neuropathy is increasing in prevalence as more neurotoxic agents have been introduced. Plexopathies from radiation can lead to long-term neuropathic pain syndromes. Graft versus host disease is a complex syndrome resulting from stem cell transplant that can lead to severe pain. More research is needed to understand these complications and strategies to prevent or treat the resultant pain.

Q: What are some of the ways in which cancer pain treatment can be tailored to the individual patient?
A: By taking each cancer patient as an individual regarding the disease, pain characteristics, psychosocial factors, and pharmacogenetics.

Q: How can we overcome some of the obstacles to worldwide accessibility to cancer pain relief?
A: Obstacles to global relief of cancer pain center around access issues. Lack of access to clinicians who are educated about pain assessment and management is a significant barrier in both developed and developing worlds. In the developing world, limited availability of medications, particularly opioids, precludes good cancer pain control. Educational efforts can begin to address some of the knowledge deficits. Organizations such as IASP can work with governments and other regulatory bodies to develop policies that will reduce impediments to opioid availability.

Q: Does the book contain any new insights into psychological issues that may affect patients with cancer?
A: The psychological context of cancer pain will greatly affect the entire experience. The role of anxiety, helplessness, catastrophizing, and other states may have a neural substrate. Extraordinary work is being conducted to teach patients and families coping skills to improve self-efficacy. More work is clearly needed in this area, and strategies for dissemination of these strategies into the clinical setting must be encouraged.

Q: Any final comments?
A: We hope that this research symposium and book will inspire more research in cancer pain that combines basic and clinical sciences and also involves many centers globally.

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Contributing Authors
Foreword
Preface

Part I: Basic Mechanisms of Cancer Pain

1. Mechanisms of Chemotherapy-Induced Neuropathic Pain
   Juan P. Cata, Haijun Zhang, Larry C. Driver, Basem Hamid, Sergio Giralt, Allen W. Burton, and Patrick M. Dougherty
2. Mechanisms of Radiotherapy-Induced Pain Relief
   Yvette M. van der Linden
3. Mechanisms of Malignant Bone Pain
   Patrick Mantyh

Part II: Inflammation, Hyperalgesia, and Cancer Pain

4. Cytokines and Cancer Pain
   Michaela Kress
5. General Inflammatory Reaction and Cachexia in Cancer:Implications for Hyperalgesia
   Marie T. Fallon, Lesley Colvin, and Barry J.A. Laird
6. Opioid-Induced Hyperalgesia and Cancer Pain: Effects on Tumor Growth and Disease Progression
   Tamara King, Frank Porreca, and Todd W. Vanderah

Part III: Opioid Tolerance

7. Mechanisms of Opioid Tolerance
   Charles E. Inturrisi and Ann M. Gregus
8. Opioid Switching: A Technique for Optimizing Pain Relief and Reducing Side Effects in Cancer Pain
   Kris C.P. Vissers, Kees Besse, Yvette M. van der Linden, Maurice Giezeman, and Marieke H.J. van den Beuken-van Everdingen
9. Drugs That Act against Opioid Tolerance
   Eija A. Kalso

Part IV: Clinical Trial Design in Cancer Pain

10. New Drugs for Cancer Pain Relief
    Andy Dray
11. Methodological Issues in Cancer Pain: Pharmacological Trials
    Ulf E. Kongsgaard and Mads U. Werner
12. Methodological Issues in Cancer Pain: Nonpharmacological Trials
    Michael I. Bennett

Part V: Psychology of Cancer Pain: The Basic Research and Clinical Research Agenda

13. Anxiety from an Evolutionary Perspective and the Relationship between Anxiety and Cancer Pain
    Predrag Petrovic
14. Dealing with Cancer Pain: Coping, Pain Catastrophizing, and Related Outcomes
    Tamara J. Somers, Francis J. Keefe, Sejal Kothadia, and Agustina Pandiani
15. Attention Management
    Stephen Morley

Part VI: Interaction, Education, Resources: How to Make a Difference

16. Empathy in Cancer Pain
    Amanda C. de C. Williams and Sue Gessler
17. A Global Perspective on Patient and Family Cancer Pain Education
    Jean C. Yi, Samantha B. Artherholt, and Karen L. Syrjala
18. Teaching Medical Students about Cancer Pain
    Karen Forbes and Jane Gibbins
19. Are Research and Clinical Practice Improving Management of Pain in Cancer Patients? Why Do Patients Still Suffer?
    Augusto Caraceni
20. How to Make a Difference in the Developing World: Organizing Resources
    Olaitan A. Soyannwo

Index

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"The book's strength is its global perspective on cancer pain. ... The book's technical quality is excellent, with graphics that enhance the text by providing visuals for complex information. ... Cancer Pain is an important cancer pain resource for any healthcare professional interested in up-to-date, evidence-based information on cancer pain."
Reviewed by Linda Easton, MN, RN. Oncology Nursing Forum 2011;38(6):741.

"There are many aspects of each chapter that can advance researchers' and clinicians' knowledge of cancer pain. ... Unlike other books on cancer pain, the chapters are succinct, firmly rooted in empirical findings from the research literature, and include practical suggestions for healthcare providers. Each chapter ends with a conclusion that synthesizes its main points. This book will be a valuable reference for researchers and clinicians with expertise in cancer pain, and will also be of considerable value to healthcare professionals and investigators who are new to the field."
Reviewed by Lara K. Dhingra, PhD. Psycho-Oncology 2011:20:792.

"The book guides you logically from the basic science of cancer, through to clinical aspects (treatment and research), and on to improving education for all stakeholders. ... There is good use of figures and tables to summarize the latest research findings in a clear form which the non-scientist can understand. ... I recommend this book to all those wishing an up-to-date review of all aspects of cancer pain."
Reviewed by M. Serpell, Glasgow, UK. British Journal of Anaesthesia 2011;106(5):757-8.

"Although the expressed purpose in writing the volume was to bring together current research related to cancer pain, it contains much information with everyday clinical applicability. ... The IASP text is a must have for anyone who wishes to gain an international perspective on where key research in this area is headed, including in developing countries, and who might wish to join this global effort to alleviate cancer-related pain."
Reviewed by Daniel B. Carr, MD. Anesthesia and Analgesia 2011;113(3):668-9.

"From a practising clinician's perspective, the chapters outlining the mechanisms of chemotherapy induced neuropathic pain, radiotherapy induced pain relief and the mechanisms of malignant bone pain bridge the gap between the basic sciences and the care of the individual patient. This is a very useful addition to the list of International Association for the Study of Pain publications. The editors have achieved their goal of providing a text that will be an excellent resource for researchers and clinicians."
Reviewed by T. Cramond. Anaesthesia and Intensive Care 2011;89(3):519.

"Its style of presenting the clinical problem, underlying pathophysiology, emerging research and the clinical application, as well as offering a final conclusion if you have missed the details of the science, is very helpful. ... The breadth and depth of the key areas covered will make this book an invaluable addition to any library and will help readers to gain understanding of the significant complexities and challenges in cancer pain research. ... [T]his book should be on the shelf of healthcare professionals wanting to better understand cancer pain."
Reviewed by Dr Declan Cawley, Pilgrims Hospices/University of Kent. Hospice Information Bulletin; August 2011.

"The editors of Cancer Pain: From Molecules to Suffering effectively meet their goal of providing an inspiring and comprehensible text on cancer pain for both clinicians and researchers. The editors are to be congratulated for a book that has impeccable consistency and a seamless transition from bench research to bedside application. This book facilitates the understanding of physiology and pharmacology of cancer pain that can readily be translated into better treatment and satisfactory outcome. ... I highly recommend Cancer Pain: From Molecules to Suffering to all trainees in pain management as a supplemental text to standard references on pain management. The first three parts may well be selected as topics for journal clubs or clinical symposia. This book can certainly inspire the entire team of health-care professionals in both oncology and pain management. Medical students and resident physicians in not only primary care but also all other specialties could benefit from studying this book in their early stage of training. In addition, many bench and clinical researchers devoted to advance cancer pain management may also find this book and its future editions to be a valuable resource."
Anesthesiology 2011;115:218–20, reviewed by Eric Shen-Zen Hsu, MD, David Geffen School of Medicine, University of California

"It is not another classical textbook about cancer pain. Instead this book focuses on the most important current scientific and clinical issues of cancer pain. It successfully closes the gap between basic science and clinical practice by linking basic scientific findings with clinical questions. All authors are well-known specialists in their particular fields."
European Journal of Pain 2011;15:333, reviewed by M. Schenk, Center of Palliative Care Medicine and Pain Therapy, Berlin, Germany

"Cancer Pain: From Molecules to Suffering is a wide-ranging update on cancer pain for anyone whose curiosity takes them beyond the basics of cancer pain management. It reveals the progress made in understanding the complexity of cancer pain at the molecular, pharmacological, individual, organizational, and national levels – but also highlights multiple barriers still blocking the way."
Journal of Palliative Care 2011;27:181, reviewed by Romayne Gallagher, MD, University of British Columbia

"When I finished reading [this book], I felt as though I had just attended a spectacular conference where I was not forced to pick and choose among concurrent sessions but had the luxury of listening to all the experts in their respective fields. The breadth of subject matter here is wide and varied, giving the reader a profound appreciation for the multidisciplinary approach demanded by the nature of this complex set of clinical problems. There is cogency between the efforts of bench research and bedside applicability. ... The chapters are bursting with references, acting as a natural launch point for new projects. This is truly the ‘‘Up-To-Date'' of cancer pain, the ultimate resource during the next few years for each topic ... The chapters tasked to expound on the psychology of cancer pain poignantly bring to life the mood disorders commonly found alongside cancer pain but too often neglected. The discussion on attention management was something this reviewer found fascinating, introducing me to concepts that necessitate integration into my role as a clinician-educator. The closing chapters on education and resources assist the reader in gaining a better worldwide perspective while providing tools for effective educational initiatives, from local to national in scope."
Journal of Pain and Symptom Management 2011;41:809-10, reviewed by Stephen J. Bekanich, MD

"This book covers in depth the issues that complicate effective cancer pain management. ... [It] is well written and ... fills the gap between research and clinical practice in an accessible format."
Doody's Book Review Service (Score: 95/100, 4/5 stars), Nov. 2010, reviewed by Tariq M. Malik, MD

"Each of the clearly written chapters is based on a speaker’s presentation and is well referenced, analogous to a review article on the relevant topic. ... Essentially, the book offers readers a wide-ranging review of the issues surrounding cancer pain management and the direction of future research. ... [T]his well written, predominantly scientific review by experts conveys up-to-date information on the subject of cancer pain. The book is not written specifically for anesthesiology or pain medicine practitioners, as there are no sections devoted to the interventional management of chronic cancer pain, which would generate more interest from this peer group. Nonetheless, the book provides interesting background reading and is to be recommended, particularly for those with cancer pain patients in their care."
Reviewed by Christopher Green, MBBCh, The Ottawa Hospital, Ottawa, ON, Canada; Canadian Journal of Anaesthesia, December 7, 2010

"This book ... brings together discussions of the cutting-edge of developments in our understanding of the basic biological, clinical and social aspects of cancer pain; hence the title From Molecules to Suffering. … What do we know about the molecular mechanisms involved with malignant bone pain, chemotherapy-induced neuropathic pain, and cancer pain in general?  What do we know about the mechanism of opioid tolerance, the effectiveness of opioid switching, and other drugs that act against opioid tolerance? ... This book will be of interest to those involved in both basic and clinical research into cancer pain."
Reviewed by Roger Woodruff, December 2010 issue of the International Association of Hospice and Palliative Care (IAHPC) Newsletter

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