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VOLUME 1 NUMBER 1 2007

Advances in PAIN MANAGEMENT

EDITOR-IN-CHIEF Russell Portenoy, New York, NY, USA

Breakthrough Pain in Cancer Patients Giovambattista Zeppetella

Mechanisms of Neuropathic Pain Nanna Finnerup and Troels Jensen

Pamidronates for Non-Cancer Pain Marco Pappagallo

www.advancesinpainmanagement.com

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Kentucky College of Medicine and Remedica. The University of Kentucky College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The University of Kentucky is an equal This journal is supported by an opportunity university. educational grant from Cephalon R8185_1 Pain Man_Cov01.qxd 11/1/07 17:34 Page 4

ADVANCES IN PAIN MANAGEMENT Advances in Pain Management is supported by an educational grant from Cephalon Reader Survey – Let Us Know What You Think! Please take a few moments to complete this survey. We would value your opinion.

EDITOR-IN-CHIEF ASSOCIATE EDITOR Please photocopy this page, complete the survey below, and fax it back to Remedica on Russell K Portenoy Ricardo A Cruciani +44 (0)20 7759 2951. Or you can visit ADVANCES IN PAIN MANAGEMENT website and complete Chairman and Gerald J and Dorothy R Friedman Chair Vice-Chairman and Director, Research Division, the survey online (registration online is FREE): in Pain Medicine and Palliative Care, Department of Department of Pain Medicine and Palliative Care, Pain Medicine and Palliative Care, Beth Israel Medical Beth Israel Medical Center, New York, NY, USA www.advancesinpainmanagement.com Center, Professor of Neurology and Anesthesiology Albert Einstein College of Medicine, Chief Medical 1. We are aiming to provide practical information for Pain specialists, including anesthesiologists, neurologists, oncologists, Officer Continuum Hospice Care, New York, NY, USA general physicians, and primary care physicians. How would you rate the information presented in this issue?

EDITORS Strongly agree Strongly disagree Lara Dhingra Helena Knotkova a) The technical quality of information included in Research Psychologist, Department of Pain Medicine Research Scientist, Research Division, Department ADVANCES IN PAIN MANAGEMENT was acceptable: 12345 and Palliative Care, Beth Israel Medical Center, of Pain Medicine and Palliative Care, Beth Israel New York, NY, USA Medical Center, New York, NY, USA b) The information was relevant to my practice: 12345

c) The information was presented clearly: 12345 EDITORIAL ADVISORY BOARD d) The leading articles provided new information regarding Miroslav Backonja Howard Heit the understanding and treatment of pain management: 12345 Professor of Neurology, Anesthesiology and Chronic Pain Specialist, Assistant Clinical Professor, Orthopedics & RehabilitationDirector of Research Georgetown University, Washington, DC, USA e) The clinical review section was helpful and and Education of the UW-Pain Treatment and I would like to see analyses in future issues: 12345 Frank Keefe Research Center, Medical School, the University of Professor of Psychiatry and Behavioral Sciences, 2. Did you learn anything through the CME activity Wisconsin, Madison, WI, USA ■ ■ Duke University, Durham, NC, USA ADVANCES IN PAIN MANAGEMENT that will change the way you practice medicine? Yes No Peggy Compton Jianren Mao If so, what? ...... Associate Professor, School of Nursing, Acute Care Associate Professor, Director, MGH Center for Section, University of California Los Angeles, Translational Pain Research, Division of Pain 3. Is there anything you learned from the CME activity ADVANCES IN PAIN MANAGEMENT Los Angeles, CA, USA Medicine, Department of Anesthesia and Critical that prompts you to seek further information that may influence the way you practice medicine in the future? ■ Yes ■ No Robert Dworkin Care, Massachusetts General Hospital, Professor of Anesthesiology, Neurology, Oncology, Harvard Medical School, Boston, MA, USA If so, what? ...... and Psychiatry, Director, Anesthesiology Clinical Judith A Paice Research Center, University of Rochester School 4. Would you like to recommend ADVANCES IN PAIN MANAGEMENT to a colleague? ■ Yes ■ No Director, Cancer Pain Program, Division of of Medicine and Dentistry, Rochester, NY, USA Hematology-Oncology, Northwestern University; My colleague’s email is: ...... Doug Gourlay Feinberg School of Medicine, Chicago, IL, USA Medical Consultant, Pain and Chemical Dependency 5. What specific topics do you think should be covered in future issues? Steven D Passik Division, The Wasser Pain Management Centre, Associate Attending Psychologist, Memorial Sloan Mount Sinai Hospital, The Centre for Addiction ...... Kettering Cancer Center, Associate Professor of and Mental Health, Toronto, ONT, Canada Psychiatry, Weill College of Cornell Medical Center, Name ...... Job title ...... Martin Grabois New York, NY, USA Professor and Chairman, Physical Medicine and Neal Slatkin Institution ...... Rehabilitation, Professor, Anesthesiology, Baylor Director, Department of Supportive Care, Pain and College of Medicine, Professor, Physical Medicine Address ...... Palliative Medicine, Professor, Division of Medicine, and Rehabilitation, University of Texas Health Departments of Supportive Care, Pain and Palliative Country ...... Post/zip code ...... Science Center-Houston, Houston, TX, USA Medicine and Neurology, City of Hope National Medical Center, Duarte, CA, USA Email ...... R8185_1 Pain_1_04 17/1/07 10:08 Page 1

Dear Colleagues, Welcome to the first issue of Advances in Pain Management. Contents

Advances in Pain Management, a new CME accredited Editorial journal, has been founded to identify and highlight the Pain Management in Transition important developments in the assessment and treatment of Russell Portenoy and Ricardo A Cruciani 2 pain. The journal will appear quarterly and will provide access to a critical and clinically relevant review of information regarding pain management, providing up-to-date and clinically important information as it pertains to the appropriate Leading Articles diagnosis, treatment, and management of chronic pain. Breakthrough Pain in Cancer Patients Giovambattista Zeppetella 5 Each issue will include major review articles authored by leading specialists. These manuscripts are peer-reviewed for Mechanisms of Neuropathic Pain quality and CME accredited to provide an ongoing Nanna B Finnerup and Troels S Jensen 12 educational resource. In addition, summaries and analyses of recent papers, chosen for their impact upon the field, are provided for the reader together with highlights from recent Bisphosphonate Therapy for Non-Cancer Pain international conferences. Marco Pappagallo 19 Drs Portenoy and Cruciani (Beth Israel Medical Center, New York, NY, USA) lead us into this first issue with an editorial Clinical Reviews highlighting the challenges facing pain physicians in terms of Novel Therapies 24 the immensity of the problem and the many difficulties in the research and treatment of this condition. Opioids 26 This first issue contains three articles. Dr Zeppetella (St Clare Hospice, Hastingwood, Essex, UK) discusses breakthrough Post-operative Pain 29 pain (BTP) in cancer patients, emphasizing the importance of distinguishing BTP from background pain, and implementing Palliative Care 30 a specific strategy for its management. Involving a number of pharmacological and non-pharmacological treatment modalities, along with thorough patient assessment Neuropathic Pain 31 and reassurance of the individual and carer, can help ease this burden. Miscellaneous 34 In the second article, Drs Finnerup and Jensen (Aarhus University, Aarhus, Denmark) provide an overview of neuropathic pain, discussing its clinical characteristics and the mechanisms involved. After summarising the different mechanisms behind neuropathic pain, they go on to discuss the extent to which available treatment can target specific mechanisms or specific signs and symptoms, thereby improving the standard of care for these patients. Dr Pappagallo (Mount Sinai School of Medicine, New York, NY, USA) reviews the use of bisphosphonates for non-cancer pain. Bisphosphonates have been of vital importance in the treatment of bone pain. This article provides a background to their development, method of analgesia, and their utilization in painful joint and bone syndromes as well as complex regional pain syndrome. This issue concludes with a synopsis and critique of recently published scientific findings from several key areas of pain management. We hope you find Advances in Pain Management an educational and valuable tool. We welcome your feedback regarding the material presented as well as your suggestions for future topics to be covered. On behalf of the Editorial Board, we would like to thank you for reading the first issue of what we believe will be an exciting and useful new journal in this developing field.

The Remedica Medical Education and Publishing Team R8185_1 Pain_1_04 17/1/07 10:08 Page 2

Pain Management in Transition

Russell Portenoy and Ricardo A Cruciani Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, NY, USA Adv Pain Manage 2007;1(1):2–4.

EDITORIAL There are few areas of healthcare broader in scope or more measured but are likely to be huge. Further impact relates to profound in importance than pain management. The array of the problem of poorly controlled acute pain, which prolongs issues in this field extends from the most sophisticated basic hospitalizations and accounts for a substantial number of science to concerns that must be addressed at a public policy visits to emergency departments. Given this epidemiology, level. In basic science, interest has recently drilled down to the pain must be viewed as a major public health issue, as large level of molecular biology, which may illuminate factors that as any other facing developed countries today. predispose to the development of persistent pain after injury or the specific response to targeted therapies. The breadth of the New disciplines issues relevant in clinical investigation and clinical practice Pain research and management are, relatively speaking, is suggested by the apt description of pain as a young disciplines, a status that augments the challenges that “biopsychosocial” phenomenon. The clinical issues cross must be faced in addressing the scientific, clinical, and public epidemiology, the pathophysiology and characteristics of health aspects. In the US, the concept of specialist-level, diverse set of chronic pain disorders, assessments that range multidisciplinary pain management emerged only about 40 from objective changes in neurological functioning to complex years ago and specialized programs to manage acute pain processes involving somatization and coping, and a arrived years later. Support for a specialist physician complicated and evolving science and practice of pain therapy. workforce continues to be in the formative stage. An At yet a higher level, the public health perspectives include independent American Board of Pain Medicine began concerns as varied as disparities in access to care, the financing certifying physicians in pain management in 1992, and the of specialist-level care, the approach to pain-related American Board of Anesthesiology began offering a productivity loss in the workplace, the regulation of controlled “Certificate of Added Qualification in Pain Management” in prescription analgesics, mandated educational policies, and 1993. Although other disciplines in the US (including many others issues. neurology, psychiatry, and physical medicine and rehabilitation) now recognize pain as a subspecialty, there The scope of the problem are only 2500 board-certified physician specialists in pain The number and complexity of the issues surrounding pain management, a number that suggests a total of four board- and its management take on critical importance in light of certified specialists per 100 000 patients with chronic pain the epidemiology of the problem and the impact of rapid [2]. All of these specialists seek advanced training in only change in both pain-related research and practice. Large 105 accredited Fellowship training programs, a number that population-based surveys have demonstrated that chronic is likely to decline in the coming years. These limitations are pain occurs in approximately 10–45% of adults in developed mirrored in the status of pain research. In the US, for countries. Some of these surveys further suggest that pain- example, research continues to be minimally supported at a related functional impairment is clear in at least one-third of federal level. A recent analysis showed that only 1% of the this group [1]. Chronic pain costs Americans upwards of 2003 National Institutes of Health budget was devoted to US$100 billion/year in healthcare costs and lost productivity research primarily focused on pain [3]. related to absenteeism from work. The adverse outcomes associated with poor performance among those who Transitions continue to work despite uncontrolled pain have not been Although a daunting disparity exists between the scope of the problems related to pain and current efforts to Address for correspondence: Russell Portenoy, Department of Pain understand and manage it, there is reason for optimism in Medicine and Palliative Care, Beth Israel Medical Center, First Avenue at the extraordinary progress that has occurred during the past 16th Street, New York, NY 10003, USA. Email: [email protected] few decades. Some of these are summarized below.

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Research excitability and the cortical representation of the affected Despite limited support for research, advances in basic body part change in association with pain and that these neuroscience have burgeoned and begun to elucidate both changes are reversible [6]. This type of information is nociception and pain pathophysiology. Findings are now beginning to yield insights into the mechanisms of brain being translated into new treatments. Studies that described plasticity important in the genesis of pain. pathways involved in pain perception and modulation, and the localization of neurotransmitters that contribute to pain Clinical paradigm signaling, have helped identify new targets for pain therapy. As basic research has explored the pathophysiology of varied Early on, autoradiography allowed mapping of these pain-related disorders, a critical conceptual leap has evolved neurotransmitters and their receptors, both in brain and that promises a fundamental change in the way pain is spinal cord. Subsequent experimentation 20–30 years ago addressed in the clinical setting. The concept of “pain as utilized voltage clamp methods and generated data that illness” is now accepted among specialists and suggests that clarified the effect of opioids on electrical transmission. Later, pain should not be viewed as merely a symptom of disease, with the advent of patch-clamp techniques, these effects but rather, as a disease in its own right. The science supporting were studied at the channel level, and more recently, this notion is clear: In the acute pain setting, uncontrolled pain molecular biological methods have identified numerous is associated with a broad array of adverse physiological and molecules that participate directly (N-methyl-D-aspartate medical outcomes. In the chronic pain setting, disability and [NMDA] receptors, opioid receptors) or indirectly (sodium suffering appears far less determined by pain etiology than channels) in the transmission of pain signals. other characteristics of the pain and the person who is Advances in opioid research are representative of the experiencing it. When persistent, pain itself is the main progress that is being made. The discovery of endogenous impediment to functional restoration. Equally important, there opioid ligands and multiple opioid receptors, which began in are many millions of patients with chronic pain that cannot be the 1970s and extended over two decades, had profound ameliorated by addressing an underlying disease. For these influence in neurobiology and drug development [4]. Further patients, primary pain management is the only avenue toward progress was made with the cloning of the opioid receptors, renewed health. Recognition of pain as illness appears to be beginning with the δ-receptor in the early 1990s [5]. This new growing among non-specialist physicians and others, and this knowledge allowed the sequencing of the proteins, the change in paradigm may lead to significant improvements in description of splice variants of opioid receptors, the programs and resources devoted to this problem. elucidation of the concept of dimerization, and ultimate recognition that there are actually many genetically Pain therapies determined receptor variations that may underlie individual Advances in pain management have provided numerous new differences in opioid responsiveness. The implications of these therapies and more refined use of older ones. Striking change findings are immense. It is possible, for example, that side has occurred, for example, in the use of opioid therapy. effects and analgesia might be mediated by different receptors. Although relatively well accepted in the treatment of acute The synthesis of specific agonists to selected receptors could severe pain for many years, the role of opioid therapy in result in analgesia with fewer side effects. Opioids less likely to chronic pain has defied a simple guideline. In cancer pain, the produce physical dependence could be on the horizon. Tests World Health Organization (WHO) provided an important that could be given to patients before treatment to determine foundation for care when an expert committee proposed an the differential response to available drugs may be coming. “analgesic ladder” approach to cancer pain management All of these advances have occurred in parallel with during the mid-1980s [7]. This approach has had a neurophysiological, biochemical, pharmacological, and most worldwide effect on clinical practice. Equally important, a recently, neuroimaging studies to reveal the nature of the consensus evolved among pain specialists since that time that processes that underlie pain persistence after injury, chronic opioid therapy should also be used in a including inflammation and neuroplasticity. In the realm of subpopulation of patients with persistent non-cancer pain. neuroimaging, the potential for functional magnetic This consensus has been accompanied by ongoing resonance imaging (fMRI), positron emission tomography controversy, however, as clinical practice attempts to apply (PET), and single photon emission computed tomography limited science to important questions related to the long- (SPECT) scanning to reveal cerebral processes involved in the term effectiveness of this treatment, patient selection, perception of noxious events is just beginning to be approach to monitoring, appraisal of risk associated with recognized. Recent studies on brain plasticity in amputees abuse and addiction, strategies for risk management, with phantom limb pain, for example, suggest that the concurrent therapies, and other issues. Pain specialists no

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longer argue about whether opioid therapy is appropriate for transcranial stimulation, may become available and offer novel chronic pain, but instead debate the pragmatic issues related strategies for selected patients with pain. to the best approach to patient selection and care [8]. New pharmacotherapies (and new delivery) systems for Education and policy analgesic drugs have also begun to change practice in a very Although variation across states, regions, and countries is positive way and are likely to have significant impact in the large, there is, overall, a gradual worldwide movement to future. Very active research focused on the creation of drugs mainstream pain management in healthcare, increase access with specific mechanisms is already yielding an expanding to basic analgesic drugs, improve the availability and therapeutic armamentarium for acute and chronic pain, an reliability of specialist-level care, and in some cases, to require armamentarium that is beginning to tap modes of action that that medical education include information about pain. In the have never been applied for analgesic purposes before. US, for example, many states have substantively changed During the past 10 years, evidence that pain that is clinically policies in an effort to eliminate barriers to the legitimate classified as neuropathic can be specifically attenuated by medical use of controlled prescription drugs; others have α δ varied classes of drugs, such as those that modulate the 2 mandated pain education. It is, in many settings, an era of protein of the voltage-gated neuronal calcium channel, or open discussion about the need to balance conflicting forces those that alter synaptic levels of monoamines, has radically – access to controlled prescription drugs for pain versus altered the clinical approach to these problems [9]. The future reduction in drug abuse and diversion; increased availability is likely to bring other drugs that may be selectively analgesic of sophisticated pain management techniques versus fiscal in neuropathic pain, inflammatory pain, bone pain, and constraints on healthcare; more intensive education about visceral pain – all with modes of action that involve the molecular basis of disease versus greater emphasis on neurotransmitters, neuromodulators, receptors, and channels holistic care including symptom control – in a way that will that previously were not routinely targeted for therapy. ultimately yield a class of healthcare professionals and healthcare systems capable of addressing the enormous Technological advances problem of acute and chronic pain. There also has been a revolution in drug delivery systems. Short-acting medications can now be slowly released into Conclusion the bloodstream, providing sustained pain relief after a dose. The problem of pain undertreatment is widely recognized, Both oral and transdermal formulations have been notwithstanding the significant advances in both the science of successfully developed and have become the convention for pain and clinical practice. Access to state-of-the-art care is opioid management of chronic pain. The success of patient- limited even in developed countries, and is lacking in the controlled analgesia during the past several decades has developing world. Remedies are possible, however, and are underscored the value of self-administered, rapidly acting being driven by vibrant research and the translation of research analgesics in the setting of acute severe pain, and new findings into innovative therapies. Basic and clinical research, studies are yielding a group of rapid-onset short-acting education, and societal change can provide an ever-expanding drugs for non-parenteral administration, such as the oral foundation for efforts to improve pain management and so transmucosal formulations, which may provide better address a major source of human suffering. management of acute severe pains, including breakthrough pain [10]. Abuse-deterrent formulations of opioid drugs are References 1. Portenoy RK, Ugarte C, Fuller I et al. Population-based survey of pain in the United States: in development and may help in the management of Differences among Caucasians, African Americans, and Hispanics. J Pain 2004;5:317–28. inappropriate use, or diversion, associated with long-term 2. Breuer B, Pappagallo M, Tai JY et al. US board-certified pain physician practices: uniformity and census data of their location. J Pain 2007 [in press]. opioid therapy of chronic pain. 3. Bradshaw DH, Nakamura Y, Chapman CR. National Institutes of Health grant awards for pain, nausea, and dyspnea research: J Pain 2005;6:277–93. Other advances involve interventional approaches [11]. 4. Lord JA, Waterfield AA, Hughes J et al. Endogenous opioid peptides: multiple agonists and Both spinal cord stimulation and neuraxial infusion have been receptors. Nature 1977;267:495–9. 5. Evans CJ, Keith DE, Morrison H et al. Cloning of a delta opioid receptor by functional subjected to randomized trials and shown to have significant expression. Science 1992;258:1952–5. 6. Flor H, Nikolajsen L, Staehelin Jensen T. Phantom limb pain: a case of maladaptive CNS benefit in some chronic pain populations. Technical advances plasticity? Nat Rev Neurosci 2006;7:873–81. promise to refine these approaches and allow expanded use, 7. World Health Organization: Cancer Pain Relief, 2nd ed, with a guide for opioid availability. Geneva, World Health Organization, 1996. hopefully with better outcomes. In a similar way, the clinical 8. Fine P, Portenoy RK. Opioid analgesia. New York: McGraw Hill, 2004 (http://www.stoppain.org/pcd/content/forpros/opioidbook.asp). development of a broad array of injection therapies, combined 9. Dworkin RH, Backonja M, Rowbotham MC et al. Advances in neuropathic pain: diagnosis, with studies of new methods, such as radiofrequency lesioning, mechanisms, and treatment recommendations. Arch Neurol 2003;60:1524–34. 10. Zeppetella G, Ribeiro MD. Opioids for the management of breakthrough (episodic) pain in have led to the potential for improved application of these cancer patients. Cochrane Database Syst Rev 2006 Jan 25;(1):CD004311. 11. Boswell MV, Shah RV, Everett CR et al. Interventional techniques in the management of interventions. In the future, entirely new technologies, such as chronic spinal pain: evidence-based practice guidelines. Pain Physician 2005;8:1–47.

4 ADVANCES IN PAIN MANAGEMENT Vol 1 No 1 2007 LEADING ARTICLE l 5 (1):5–11. 1 2007; Adv Pain Manage Vol 1 No 1 2007 Vol Incident pain has been reported in 32–94% of patients in 32–94% Incident pain has been reported in 28–45% of Spontaneous pain has been reported in 2–29% of patients End-of-dose pain has been reported [9,10]. It may be predictable when precipitated by volitional when precipitated [9,10]. It may be predictable changes, and dressing factors, such as movement, coughing, by when precipitated or unpredictable activity, increased or bowel spasm. non-volitional factors, such as bladder of a poor predictor Incident pain has been shown to be successful pharmacological therapy [11,12]. patients [1,10]. of a specific It develops in the absence with little trigger and can occur randomly and unpredictably and less severe or no warning. Spontaneous pain is generally pain [6] and its of longer duration than incident makes management difficult. unpredictability [1,10]. occurs just prior to the next scheduled It consistently usually because of an inadequate analgesia, dose of ATC analgesic dose or the interval between administrations being too long. This pain subtype typically has a gradual onset and not lasts longer than incident or spontaneous pain. However, that end-of-dose pain is a true BTP all clinicians agree with subtype, as baseline pain is by definition not controlled medication. the optimum dose of ATC Characteristics of BTP Investigations into the characteristics of BTP have been carried out in patients attending cancer centers, pain clinics, and hospice inpatient and outpatient units, with some studies BTP as an BTP and others reporting specifically addressing no validated tools to currently are incidental finding [7]. There characterized it although most studies have assess BTP, temporal characteristics, severity, to location, according factors, pre- analgesia, precipitating to regular relationship and palliative factors [13]. etiology, pathophysiology, dictability, ANAGEMENT M AIN P DVANCES IN A The prevalence of BTP has been evaluated in a number of BTP The prevalence Address for correspondence: G Zeppetella, St Clare Hospice, G Zeppetella, St Clare for correspondence: Address Hastingwood Road, Hastingwood, Essex CM17 9JX, UK. Email: [email protected] challenge. As pain assessment and management strategies have evolved it has become increasingly clear that patients with have evolved it has become increasingly assessment and management strategies challenge. As pain of pain patterns have been identified; types Two of the day. variations in their pain during the course cancer often report involves a transitory exacerbation of and breakthrough pain (BTP), which is present for most of the day, background pain, which from background pain and strategies should distinguish BTP apparent that successful pain management pain. It is increasingly communication, reassurance achieved by a thorough assessment, good plan for its management. This is best implement a specific appropriate for the stage of the should be and care giver participation. Treatment about pain relief, and encouraging patient and non-pharmacological modalities. disease and may involve a number of pharmacological Definition of breakthrough pain in pain pain (BTP) is a transient increase Breakthrough pain. It is a common and distinct intensity over background in 1990 by component of cancer pain first highlighted has been used to Portenoy and Hagen [1]. The term BTP around-the- through” of pain that “breaks describe reports Portenoy and Hagen analgesia (Fig. 1). clock (ATC) taking opioids who described BTP in cancer patients than in pain to a greater increases transient reported it has since become clear moderate intensity [1]. However, or opioid therapy. that BTP is not specific either to cancer definitions for contains a number of different The literature than others [1–4]. This lack broader of which are some BTP, has led to difficulties of consensus on a formal definition management when comparing studies and recommending that BTP was strategies. An international study suggested in different often defined or characterized differently countries [5]. variations in the terminology Additionally, [6]. include episodic pain, transient pain, and pain flare 19–95% [7]. This wide range can of studies and ranges from and be partly explained by variations in sampling procedures the studies. Several inclusion/exclusion criteria across subtypes of BTP have been described, including incident pain, spontaneous pain, and end-of-dose pain. However, on is no universal agreement there like the definition of BTP, the subtypes, for example some describe incident pain as a subtype of BTP whilst others consider BTP as a subtype of incident pain [8]. Pain is a common feature of cancer. It is one of the most feared consequences of the disease and presents a significant clinica consequences of the disease and It is one of the most feared of cancer. Pain is a common feature Giovambattista Zeppetella Zeppetella Giovambattista Hospice, Essex, UK St Clare Medical Director, Breakthrough Pain in Cancer Patients in Cancer Pain Breakthrough R8185_1 Pain_1_04 17/1/07 10:08 Page 5 Page 10:08 17/1/07 Pain_1_04 R8185_1 R8185_1 Pain_1_04 17/1/07 10:08 Page 6

GIOVAMBATTISTA ZEPPETELLA

Figure 1. Model of breakthrough pain.

Over-medication

Around-the-clock Breakthrough pain medication Pain

Background pain

Time

The current evidence in cancer patients suggests that pain [19,20]. Therefore, the distinction between cancer and BTP can be predictable or unpredictable, typically of fast non-cancer BTP may be arbitrary and a focus on the pain onset (reaching maximum severity within 5 min), of short mechanisms may be more helpful in understanding this duration (subsiding in most within 30 min), and feel similar clinical problem [21]. to background pain although it is usually more severe. Like background pain, the pathophysiology of BTP may be Management of BTP visceral, somatic, neuropathic, or mixed, and the etiology Successful management of BTP is best achieved by a may be directly due to cancer or its treatment, or may be thorough assessment, good communication, reassurance unrelated to the cancer. Patients typically report between about pain relief, and encouraging patient and care giver one to four episodes daily [6] and these can be from participation. Key features to be identified in the multiple sites or causes. Each episode of BTP should be assessment include the severity, pathophysiology, and distinguished from uncontrolled background pain. etiology of the pain. Previous studies have shown that BTP Despite the self-limiting nature of BTP it can place is usually related to the mechanisms that cause background significant physical, psychological, and economic burdens on pain although it is often more severe. Treatment should be both patients and their care givers. Patients with BTP are integrated into the overall care regime; it should be often less satisfied with their analgesic therapy [14,15], they appropriate for the stage of the disease and may involve have decreased functioning because of their pain, and may a number of treatment modalities, both pharmacological also experience social and psychosocial consequences, such and non-pharmacological. as increased levels of anxiety and depression [14]. BTP can be a poor prognostic indicator [11,16] and the site of BTP may Non-pharmacological therapies predict the response to treatment [17]. Furthermore, The non-pharmacological approaches for the management inadequately relieved BTP can place additional burdens on of BTP include stimulatory, rehabilitative, psychological, and the healthcare system, with increases in emergency and complimentary techniques. Each of these options may be medical visits, more hospital admissions, and longer stays helpful in preventing or relieving BTP and can encourage [18]. Understanding this impact on the patient’s quality of life patients to become involved in their management. Patients is important in setting realistic treatment goals. may volunteer that such treatments are successful although Although most studies have focused on BTP in the in most cases non-pharmacological therapies have not been cancer population, recent reports suggest that BTP is proven through appropriately designed clinical trials. Non- prevalent in patients with non-cancer chronic pain, sharing pharmacological treatments can be tried either before or many of the characteristics associated with BTP in cancer alongside pharmacological therapy.

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Figure 2. Adjusting around-the-clock: possibility of over-medication.

Over-medication

Around-the-clock medication

Breakthrough pain Pain

Background pain

Time

Pharmacological therapies patient according to the severity of their pain and not the There is currently no “gold standard” for the disease; adjuvant analgesics may be considered at each step. pharmacological treatment of BTP. It is important to In the absence of dose-limiting adverse effects, an increase individualize management and three principles have been in ATC opioid dose may be considered in an effort to reduce proposed [13]: the frequency or intensity of BTP. Adjusting the dose of ATC medication appears to be most • Implementation of primary therapies. appropriate for end-of-dose pain; the value for other types of • Optimization of scheduled analgesia. BTP remains unclear. One study demonstrated a fall in • Specific analgesia for BTP. incidence of BTP from 70% to 32% within 1 week when both ATC and adjuvant analgesics were increased; some types of Given the heterogeneous nature of BTP a combination of BTP did not respond [17]. In another open study of patients the above may be required. with incident pain titration beyond analgesia and to the point of adverse effects appeared to prevent or limit BTP [23]. Implementing primary therapies However, a study of 137 oncology outpatients with pain from BTP may be precipitated by numerous processes, some of bone metastases suggested that patients using opioids on an which may be amenable to therapy. Examples of primary as-required basis reported similar degrees of pain relief to interventions include management of reversible causes, such those taking opioids ATC, despite the former taking an as cough, constipation, and infection, which might be average lower daily dose of opioid [24]. The challenge related to the disease or its treatment. Other primary presented by short-lasting pain is that when the dose of ATC interventions that modify the pathological process of the is titrated sufficiently to control it the patient may experience disease may result in an improvement in both background adverse effects during pain-free periods (Fig. 2). In these cases pain and BTP analgesia; these include chemotherapy, the ATC dose should be lowered and another management hormone therapy, biological therapy, radiotherapy, and option considered. surgical procedures. Although the mainstay of pharmacological BTP management is opioid therapy, the possible role of non-opioids Optimizing scheduled analgesia and adjuvant analgesics should not be overlooked. The World Health Organization (WHO) analgesic ladder Acetaminophen and nonsteroidal anti-inflammatory drugs provides a simple framework for the pharmacological (NSAIDs) are widely used in the management of mild cancer management of cancer pain [22]. Presented in the form of a pain. There is little evidence supporting acetaminophen used three-step ladder it recommends that both opioid and non- alone and studies examining a possible additive analgesic opioid analgesics should be adequately tailored for each effect adding concurrent opioid therapy have had conflicting

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Figure 3. Ideal rescue medication.

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Ideal rescue medication Around-the-clock medication Pain

Background pain

Time

results [25,26]. In contrast, the evidence suggests NSAIDs are subtype [36]. The ideal rescue medication should be effective in cancer pain, both when used in a single dose and efficacious and patient friendly, with a rapid onset of action, with chronic dosing, although the heterogeneity of study a relatively short duration of action, and minimal adverse designs and outcome measures make analysis difficult [27–30]. effects (Fig. 3). Rescue medication can be used either Adjuvant analgesics are a heterogeneous group of drugs prophylactically for predicable pains or as soon as pain starts that include bisphosphonates, antidepressants, anticonvulsants, for unpredictable pains. Opioids are the most commonly corticosteroids, membrane-stabilizing drugs, tranquilizers, and used rescue medication. antispasmodics [31]. Adjuvant analgesics are usually indicated for a variety of conditions other than pain, but are capable of Oral opioids: The most common method of providing rescue producing an analgesic effect. Studies have suggested a role medication is with normal-release formulations of morphine, for anticonvulsants and antidepressants in the treatment of hydromorphone, or oxycodone. In most cases, oral opioids paroxysmal neuropathic pain [32,33], and for bisphosphonates can take 30–40 min to produce an analgesic effect, which in reducing the frequency or intensity of BTP in bone then lasts for 4 h [37]. Therefore, BTP with a slow onset and metastases [34]. lasting for ≥1 h is likely to respond best to oral opioids Nerve blocks and spinal analgesia can be used to whereas BTP of short duration may not (Fig. 4). Methadone complement oral medication in the control of cancer pain is occasionally used for BTP rescue therapy, typically in [35]. These procedures may be helpful when pain is patients receiving methadone as their ATC opioid. There is controlled at rest, but not on movement or when localized some evidence to suggest that methadone has a faster pain breaks through otherwise well-controlled background onset of action than the other oral opioids [36]; however, pain. A number of procedures may be used, including local its use is complicated by complex pharmacokinetics anesthetic agents, neurolytic agents, and physical agents. and pharmacodynamics. In the case of spinal administration, drugs may be The most effective dose of rescue medication remains administered through either a percutaneous catheter or a unknown. A fixed proportion of the ATC is usually advised, fully implanted system. typically 10–15% of the daily dose, although this is based on anecdotal evidence only [38]. As BTP can vary in Specific analgesia for BTP etiology, intensity, and duration it may be possible that the The management of BTP typically involves the use of effective rescue dose will also vary. Indeed, the results of supplemental analgesia or rescue medication. A number of recent controlled trials with transmucosal fentanyl factors should be taken into account when selecting rescue formulations did not confirm that the most effective dose for medication, including the class of drug, the route of BTP was in fact proportional to the ATC medication dose administration, the dosage, the patient setting, and the BTP (see below).

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Figure 4. Mismatch between breakthrough pain and oral rescue medication.

Over-medication

Current oral breakthrough medication Around-the-clock medication Pain

Background pain

Time

Although the oral route is often preferred for drug However, a major disadvantage with the currently available delivery, the pharmacokinetic and pharmacodynamic profile preparations is the relatively small volume of drug the nose is of many orally delivered opioids does not always closely able to accommodate; more concentrated preparations are mirror the characteristics of BTP. This can result in only currently being tested by this route in clinical trials. partially effective treatment and/or troublesome adverse Sublingual and buccal transmucosal routes offer an easily effects. In an effort to deliver more effective treatment accessible, convenient, non-invasive route of administration, alternative routes of administration have been explored, which does not require technical equipment, expertise, including transmucosal opioid delivery. preparation, and supervision. There have been reports of morphine, fentanyl, alfentanil, sufentanil, and diamorphine Transmucosal opioids: Transmucosal formulations comprise a administered sublingually with variable results [45,51–54]. variety of delivery systems that present the drug to the oral, The buccal route has been a recent focus of drug nasal, bronchial, or rectal mucosa. Rectal administration has development and two preparations are currently available; been used for many years and a number of opioids are oral transmucosal fentanyl citrate (OTFC) and fentanyl available as rectal formulations. These drugs may be useful buccal tablet (FBT), both of which have been specifically when patients are temporarily unable to tolerate oral developed for the management of BTP. medication or the parenteral route becomes compromised OTFC is a fentanyl-impregnated lozenge applied to and by a bleeding disorder or generalized edema. The use of absorbed across the buccal mucosa. The unit can provide rectal drugs for BTP is compromised by dose-to-dose pain relief within minutes and is indicated in cancer-related variability in absorption and effects, as well as limited patient BTP in patients using ATC opioids for background pain. Peak acceptance for long-term use [39,40]. effects occur within 20–30 min after the beginning of Inhaled opioid therapy has been described for post- administration; approximately one-quarter of the total dose operative pain [41–43], although there are few data on is rapidly absorbed from the buccal mucosa and becomes patients with BTP [44]. Standard nebulizer equipment can be immediately available, and approximately one-third of the inefficient and cumbersome and more precise devices are in remainder becomes systemically available, giving a total development, including a formulation of free and liposome- bioavailability of 50% [55]. A number of trials have encapsulated nebulized fentanyl in a patient-controlled confirmed the efficacy, safety, and tolerability of OTFC, analgesia system. including two randomized controlled studies and a long- A number of reports have described the nasal term follow-up study [56–58]. administration of opioids [45–50]. The nasal sprays contained FBT is a sugar-free tablet formulation that provides rapid morphine, fentanyl, alfentanil, or sufentanil and allowed self- penetration of fentanyl through the buccal mucosa by using administration of opioid with a rapid onset of action. effervescence to cause pH shifts that enhance the rate and

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GIOVAMBATTISTA ZEPPETELLA

extent of fentanyl absorption. Compared with OTFC, FBT Disclosures provides a larger proportion of the dose transmucosally Dr Zeppetella has received honoraria, consultancy fees, or research

(48% vs. 22%) and has an earlier Tmax (47 min vs. 91 min) support from the following pharmaceutical companies: Archimedes [59]. The efficacy of this formulation has been shown in a Pharma Ltd, Cephalon UK, Elan Pharma, Grünenthal Ltd, Janssen-Cilag randomized placebo-controlled study with an open-label Ltd, Pfizer, Napp Pharmaceuticals, and Norgine. titration phase that demonstrated an onset of effect more rapid than would be expected from oral therapy [60]. References The results of clinical trials with both OTFC and FBT 1. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain 1990;41:273–81. suggest that the successful rescue dose cannot be predicted 2. Fine PG, Busch MA. Characterization of breakthrough pain by hospice patients and their from the ATC opioid dose [56,57,60]. Therefore, it is caregivers. J Pain Symptom Manage 1998;16:179–83. 3. Mercadante S, Radbruch L, Caraceni A et al. Episodic (breakthrough) pain: consensus recommended that each patient should be titrated to a conference of an expert working group of the European Association for Palliative Care. successful dose that produces adequate analgesia and Cancer 2002;94:832–9. 4. Bennett D, Burton AW, Fishman S et al. Consensus panel recommendations for the minimal adverse effects. assessment and management of breakthrough pain: part 1 assessment. Pharmacol Ther 2005;30:296–301. 5. Caraceni A, Portenoy RK. An international survey of cancer pain characteristics and Parenteral opioids: Intravenous morphine has been shown to syndromes: IASP Task Force on Cancer Pain, International Association for the Study of Pain. Pain 1999;82:263–74. be effective, well tolerated, and safe for the inpatient 6. Colleau SM. The significance of breakthrough pain in cancer. Cancer Pain Release management of BTP [61,62], and hydromorphone has been 1999;12:1–3. 7. Zeppetella G, Ribeiro MDC. Pharmacotherapy of cancer-related episodic pain. Expert Opin delivered subcutaneously using a “pain pen” [63]. In all three Pharmacother 2003;4:493–502. studies the successful dose of rescue medication was a fixed 8. McQuay HJ, Jadad AR. Incident pain. Cancer Surv 1994;21:17–24. ratio of ATC opioid. However, the use of parenteral opioids 9. Banning A, Sjogren P. Henriksen H. Treatment outcome in a multidisciplinary cancer pain clinic. Pain 1991;47:129–34. is not always practical as they are invasive, inconvenient, 10. Swanwick M, Haworth M, Lennard RF. The prevalence of episodic pain in cancer: a survey and uncomfortable, although if pain is severe this route of hospice patients on admission. Palliat Med 2001;15:9–18. 11. Mercadante S, Maddaloni S, Roccella S, Salvaggio L. Predictive factors in advanced cancer appears to be acceptable. pain treated only by analgesics. Pain 1992;50:151–5. 12. Bruera E, Scholler T, Wenk R et al. A prospective multicentre assessment of the Edmonton staging system for cancer pain. J Pain Symptom Manage 1995;10:348–55. Non-opioids: Both non-opioid analgesics and adjuvant 13. Portenoy RK. Treatment of temporal variations in chronic cancer pain. Semin Oncol analgesics are commonly used as rescue medication. 1997;24:S16-7-12. 14. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in However, the slow onset, relatively long duration of action, patients with cancer pain. Pain 1999;81:129–34. and dose-limiting adverse effects of non-opioids often limits 15. Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in cancer patients admitted to a hospice. J Pain Symptom Manage 2000;20:87–92. their utility. A number of reports have described the use of 16. Bruera E, Fainsinger R, MacEachern T et al. The use of methylphenidate in patients with other adjuvant analgesics in the management of BTP, incident cancer pain receiving regular opiates: a preliminary report. Pain 1992;50:75–7. 17. Hwang SS, Chang VT, Kasimis B. Cancer breakthrough pain characteristics and responses including nitrous oxide, ketamine, midazolam, and to treatment at a VA medical center. Pain 2003;101:55–64. cannabinoids [64–68]. The evidence for these treatments is 18. Fortner BV, Okon TA, Portenoy RK. A survey of pain-related hospitalizations, emergency department visits, and physician office visits reported by cancer patients with and without mostly in the form of case reports or small controlled studies history of breakthrough pain. J Pain 2002;3:38–44. and is often conflicting. 19. Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in patients with non-malignant terminal disease admitted to a hospice. Palliat Med 2001;15:243–6. 20. Portenoy RK, Bennett DS, Rauck R et al. Prevalence and characteristics of breakthrough Summary pain in opioid-treated patients with chronic noncancer pain. J Pain 2006;7:583–91. BTP is a heterogeneous pain state that is different for each 21. Svendsen KB, Andersen S, Arnason S et al. Breakthrough pain in malignant and non- malignant diseases: a review of prevalence, characteristics and mechanisms. patient, often unpredictable, typically comes on quickly, lasts Eur J Pain 2005;9:195–206. as long as 1 h, and feels much like background pain except 22. World Health Organization: Cancer Pain Relief (2nd edition). World Health Organization, that it may be more severe. Despite the self-limiting nature Geneva;1996. 23. Mercadante S, Villari P, Ferrera P, Casuccio A. Optimization of opioid therapy for preventing of BTP it can have a significant impact on both patients, and incident pain associated with bone metastases. J Pain Symptom Manage 2004;28:505–10. 24. Miaskowski C, Mack KA, Dodd M et al. Oncology patients with pain from bone care givers quality of life. The successful management of metastases require more than around-the-clock dosing of analgesia to achieve adequate cancer pain depends on a comprehensive assessment that pain control. J Pain 2002;3:12–20. 25. Axelsson B, Borup S. Is there an additive analgesic effect of paracetamol at step 3? A must take into account both background pain and BTP and double-blind randomized controlled study. Palliat Med 2003;17:724–5. may require a combination of pharmacological and non- 26. Stockler M, Vardy J, Pillai A, et al. Acetaminophen (paracetamol) improves pain and well- being in people with advanced cancer already receiving a strong opioid regimen: a pharmacological treatment strategies. Of the available randomized, double-blind, placebo-controlled cross-over trial. J Clin Oncol 2004;22:3389–94. pharmacological options, rescue dosing is commonly 27. McNicol E, Strassels S, Goudas L et al. Nonsteroidal anti-inflammatory drugs, alone or combined with opioids, for cancer pain: a systematic review. J Clin Oncol 2004;22:1975–92. employed and currently the strongest evidence is for the 28. Eisenberg E, Berkey CS, Carr DB et al. Efficacy and safety of nonsteroidal anti- OTFC and FBT; other options are currently being evaluated inflammatory drugs for cancer pain: a meta-analysis. J Clin Oncol 1994;12:2756–65. 29. Alkhenizan A, Librach L, Beyene J. NSAIDs: are they effective in treating cancer pain? in controlled studies. Eur J Pall Care 2004;11:5–8.

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30. Carr DB, Goudas LC, Balk EM et al. Evidence report on the treatment of pain in cancer 50. Jackson K, Ashby M, Keech J. Pilot dose finding study of intranasal sufentanil for patients. J Natl Can Inst Monogr 2004;32:23–31. breakthrough and incident cancer-associated pain. J Pain Symptom Manage 2002;23:450–2. 31. Lussier D, Huskey AG, Portenoy RK. Adjuvant analgesics in cancer pain management. 51. Coluzzi PH. Sublingual morphine: efficacy reviewed. J Pain Symptom Manage Oncologist 2004;9:571–91. 1998;16:184–92. 32. Wiffen P, Collins S, McQuay H et al. Anticonvulsant drugs for acute and chronic pain. 52. Zeppetella G. Sublingual fentanyl citrate for cancer-related breakthrough pain: a pilot Cochrane Database Syst Rev 2005;3:CD001133. study. Palliat Med 2001;15:323–38. 33. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev 53. Gardner-Nix J. Oral transmucosal fentanyl and sufentanil for incident pain. 2005;3:CD005454. J Pain Symptom Manage 2001;22:627–30. 34. Wong R, Wiffen PJ. Bisphosphonates for the relief of pain secondary to bone metastases. 54. McQuay HJ, Moore RA, Bullingham RE. Sublingual morphine, heroin, methadone and Cochrane Database Syst Rev 2002;2:CD002068. buprenorphine: kinetics and efficacy. In: Foley KM, Inturrisi CE (eds). Opioid Aanalgesics in the Management of Clinical Pain, Advances in Pain Research Therapy. Volume 8. 35. Miguel R. Interventional treatment of cancer pain: the fourth step in the World Health Raven Press New York;1986:407–12. Organization analgesic ladder? Cancer Control 2000;7:149–56. 55. Hanks G. Oral transmucosal fentanyl citrate for the management of breakthrough pain. 36. Bennett D, Burton AW, Fishman S et al. Consensus panel recommendations for the Eur J Pall Care 2001;8:6–9. assessment and management of breakthrough pain: part 2 management. Pharmacol Ther 56. Farrar JT, Cleary J, Rauch R et al. Oral transmucosal fentanyl citrate: randomized, double- 2005;30:354–61. blind, placebo-controlled trial for the treatment of breakthrough pain in cancer patients. 37. Fisher K, Stiles C, Hagen NA. Characterization of the early pharmacodynamic profile of J Natl Cancer Inst 1998;90:611–16. oral methadone for cancer-related breakthrough pain: a pilot study. J Pain Symptom 57. Coluzzi PH, Schwartzberg L, Conroy JD et al. Breakthrough cancer pain: a randomized trial Manage 2004;28:619–25. comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate 38. Hanks GW, De Conno F, Cherny N et al. Morphine and alternative opioids in cancer pain: release (MSIR). Pain 2001;91:123–30. Br J Cancer 84 the EAPC recommendations. 2001; :587–93. 58. Payne R, Coluzzi P, Hart L et al. Long-term safety of oral transmucosal fentanyl citrate for 39. Warren DE. Practical use of rectal medications in palliative care. J Pain Symptom Manage breakthrough cancer pain. J Pain Symptom Manage 2001;22:575–83. 1996;11:378–87. 59. Darwish M, Kirby M. Robertson Jr P et al. Relative bioavailability of fentanyl buccal tablet 40. Davis MP, Walsh D, LeGrand SB, et al. Symptom control in cancer patients: the clinical and oral transmucosal fentanyl citrate. J Clin Pharmacol 2007. In press. pharmacology and therapeutic role of suppositories and rectal suspensions. Support Care 60. Portenoy R, Taylor D, Messina J et al. A randomized, placebo-controlled study of fentanyl Cancer 2002;10:117–38. buccal tablet for breakthrough pain in opioid-treated patients with cancer. 41. Worsley MH, MacLeod AD, Brodie MJ et al. Inhaled fentanyl as a method of analgesia. Clin J Pain 2006;22:805–11. Anaesthesia 1990;45:449–51. 61. Mercadante S, Villari P, Ferrera P et al. Safety and effectiveness of intravenous morphine 42. Thipphawong JB, Babul N, Morishige RJ et al. Analgesic efficacy of inhaled morphine in for episodic (breakthrough) pain using a fixed ratio with the oral daily morphine dose. patients after bunionectomy surgery. Anesthesiol 2003;99:693–700. J Pain Symptom Manage 2004;27:352–9. 43. Higgins MJ, Asbury AJ, Brodie MJ. Inhaled nebulised fentanyl for postoperative analgesia. 62. Mercadante S, Villari P, Ferrera P et al. Safety and effectiveness of intravenous morphine Anaesthesia 1991;46:973–6. for episodic breakthrough pain in patients receiving transdermal buprenorphine. J Pain Symptom Manage 2006;32:175–9. 44. Zeppetella G. Nebulized and intranasal fentanyl in the management of cancer-related breakthrough pain. Palliat Med 2000;14:57–8. 63. Enting RH, Mucchiano C, Oldenmenger WH et al. The ‘pain pen’ for breakthrough cancer pain: a promising treatment. J Pain Symptom Manage 2005;29:213–7. 45. Duncan A. The use of fentanyl and alfentanil sprays for episodic pain. Palliat Med 2002;16:550. 64. Parlow JL, Milne B, Tod DA et al. Self-administered nitrous oxide for the management of 46. Dale O, Hjortkjaer R, Kharasch ED. Nasal administration of opioids for pain management incident pain in terminally ill patients: a blinded case series. Palliat Med 2005;19:3–8. in adults. Acta Anaesthesiol Scand 2002;46:759–70. 65. Enting RH, Oldenmenger WH, van der Rijt CC et al. Nitrous oxide is not beneficial for 47. Pavis H, Wilcock A, Edgecombe J et al. Pilot study of nasal morphine-chitosan for the relief breakthrough cancer pain. Palliat Med 2002;16:257–9. of breakthrough pain in patients with cancer. J Pain Symptom Manage 2002;24:598–602. 66. Mercadante S, Arcuri E, Tirelli W et al. The analgesic effect of intravenous ketamine in 48. Fitzgibbon D, Morgan D, Dockter D et al. Initial pharmacokinetic, safety and efficacy cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, evaluation of nasal morphine gluconate for breakthrough pain in cancer patients. double-dose study. 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ADVANCES IN PAIN MANAGEMENT Vol 1 No 1 2007 11 R8185_1 Pain_1_0417/1/0710:08Page12 LEADING ARTICLE DK-8000 AarhusC,Denmark.Email: [email protected] Center, Building1A,AarhusUniversityHospital,Norrebrogade 44, Address forcorrespondence: NannaBFinnerup,DanishPainResearch Aparticularsymptomorsignmaybecaused bydifferent • Asinglemechanismmayberesponsible formany • not straightforward: the translationfrom clinicalmanifestationstomechanismsis our understandingofneuropathic painhascomealongway, essential foramechanism-basedclassification.Eventhough translation from symptomsandsignstomechanismsis The identificationofneuropathic painmechanismsandthe Mechanism-based classification mechanism(s) intheindividualpatient[1–5]. improve treatment bytargeting theunderlyingpain signs ofpainare translatedintomechanismsinaneffort to classification hasbeenproposed where thesymptomsand to thesametreatment. Therefore, amechanism-based and patientswiththesameconditionmayrespond differently pain-relieving effect ofanygiventreatment isunpredictable trials haveidentifiednewpossibledrugtargets. However, the pain hasgrown substantiallyinrecent decadesandpreclinical Our understandingofthemechanismsbehindneuropathic experience chronic paindespitevarioustreatment attempts. neuropathic painischallengingandpatientsoftencontinueto impact onthequalityoflifepatient.Thetreatment of central nervoussystem(CNS),andoftenhasasubstantial injury ordiseaseoftheperipheralnervoussystem(PNS) Neuropathic paincanbeadebilitatingcomplicationtoan target specificmechanismsorsymptomsandsigns. review summarizessomeofthemechanismsinvolvedinneuropathicpainanddiscussestowhatextentavailabletreatment patients differ intheirphenotypicpresentationofpain,whichissuggestedtoreflectdifferent painmechanisms.This maintenance ofneuropathicpain.Despitecommonpainsymptomsinarangeconditions, neuroanatomical, neurochemical,andinflammatorychangesinthenervoussystemcontributetodevelopment system aswellpositivesymptomsincludingspontaneouspainandvarioustypesofevokedpain.Several Neuropathic painischaracterizedbynegativesymptomsassociatedwiththeprimaryinjuryordiseaseaffecting thenervous Department ofNeurology andDanishPainResearch Center, AarhusUniversity, Aarhus,Denmark Nanna BFinnerupandTroels SJensen Mechanisms ofNeuropathic Pain 12 mechanisms indifferent patients. different symptomsandsigns. A VNE IN DVANCES P AIN M ANAGEMENT Adv PainManage Treatments thattarget specificsymptomsandsigns(or • Painisinfluencedbyseveralfactorssuchasexpectation, • Thepainsystemisadynamicandplasticsystem; • Manymechanismsmayoperateinthesamepatient. • the abilitytodemonstratea nervous systemlesionandpain temperature andcolor, andtrophic changesin theskin. hyperactivity withexcessivesweating,changeinskin neuropathic painconditionsthere are signsofsympathetic time ofthestimulation)maybepresent (Fig.1).Insome normally painful)andafter-sensations (painoutlastingthe Hyperalgesia (anincreased response toastimulusthatis shower maycauseintensepainandcanbedisabling. cases evenagentletouch,contactwithclothes,ortaking a patients, allodyniaisthedominatingclinicalfeature. Inthese warmth, pressure, andmovementmayalsobeseen.Insome form ofstimulus-dependentpain.However, allodyniatocold, that doesnotnormallyprovoke pain)isthemostcommon mechanical ortouch-evokedallodynia(painduetoastimulus intervals orbyalessintensebackground pain.Dynamic short-lasting shootingorelectric-likepainswithpain-free squeezing, orcold.Itcouldbedominatedbyparoxysms of and describedintermssuchasburning,aching,pricking, types ofpain[6].Thespontaneousmaybecontinuous that maybeaccompaniedbystimulus-dependent(evoked) of symptoms.Itischaracterizedbyongoingspontaneouspain In theclinicalsetting,neuropathic painpresents with avariety Clinical characteristicsofneuropathicpain clusters ofthese)are neededforclinicalbenefit. mood, socialinteractionsetc.inanunpredictable way. influenced bypastpainexperience. mechanisms maychangeovertimeandbe An essentialpartofthediagnosis ofneuropathic painis Vol 1No2007 2007; 1 (1):12–8. R8185_1 Pain_1_04 17/1/07 10:08 Page 13

MECHANISMS OF NEUROPATHIC PAIN

Table 1. Assessment of positive symptoms and signs during bedside testing or when using quantitative sensory testing [3]. Clinical sign Testing procedure Dynamic mechanical allodynia Stroke the skin with a light tactile stimulus (e.g. a brush or cotton wool) Pinprick hyperalgesia Prick the skin with a pin (e.g. graded monofilaments) Static hyperalgesia Gentle pressure (e.g. a pressure algometer) Temporal summation to Repetitive pinprick stimuli (e.g. 2/s for 30 s) punctuate stimuli (wind up) Cold hyperalgesia or allodynia Stimulate skin with cold metal roller or acetone or measure cold pain threshold and pain evoked by graded thermal stimuli Heat hyperalgesia or allodynia Stimulate skin with warm metal roller or measure heat pain threshold and pain evoked by graded thermal stimuli

Figure 1. Mapping of spontaneous pain, touch-evoked pain, and a medial system projecting via the medial allodynia, and pinprick hyperalgesia in a patient with a distal thalamus or nuclei in the brainstem and midbrain to the thumb amputation. anterior cingulated and prefrontal cortices responsible for the motivational-affective aspects of pain [7,8]. Endogenous pain modulating systems project from the Pin prick peri-aqueductal grey matter to serotonergic and hyperalgesia Allodynia noradrenergic nuclei and endogenous opiate systems. These project in turn to the spinal cord and trigeminal nuclei and modulate the transmission of pain either directly or via interneurons such as γ-aminobutyric acid (GABA) and glycine interneurons [7,9]. Neuropathic pain is a result of an abnormal response to noxious activity in the nociceptive system and a plasticity that may take place at several levels of the neural axis. Animal models of neuropathic pain have revealed a range of Spontaneous pain neuroanatomical, physiological, cellular, and chemical changes that may be involved in the development or maintenance of neuropathic pain [10–12].

perceived in areas of sensory abnormality. As such, Sensitization of primary afferents neurological examination and mapping of sensory abnorm- The sensitization of nociceptors may result in spontaneous alities is essential for the diagnosis of neuropathic pain and nociceptor activity and a lower threshold and higher for characterizing its numerous signs (Table 1). response to suprathreshold stimuli. Microneurographic recordings from C-fibers in patients suffering from Mechanisms of neuropathic pain erythromelalgia and phantom limb pain suggest that Under normal physiological conditions, pain is transmitted spontaneous active and sensitized C-fibers play a role in through small afferent C- and Aδ-nociceptors to the dorsal both ongoing and evoked types of pain [13,14]. horn of the spinal cord. In the dorsal horn, the primary There are multiple mechanisms of nociceptor afferent releases glutamate, calcitonin gene-related peptide, sensitization. After a nerve injury or inflammation of the substance P, and other neurotransmitters. Continuous nerve trunk, pro-inflammatory cytokines, chemokines, and release causes a depolarization of post-synaptic neurons neurotrophic factors released from immune cells may displacing magnesium from the ionotropic N-methyl-D- sensitize the nociceptor by acting on the immune receptors aspartate (NMDA) glutamate receptor, which now can on its surface (Fig. 2) [15]. Wallerian degeneration may become activated. In basic terms, there are two ascending cause recruitment of macrophages and the release of systems that project to the brain – a lateral system projecting chemical substances such as nerve growth factor that can via the lateral part of the thalamus to the somatosensory sensitize spared nociceptors in their vicinity [16]. cortex responsible for the sensory discriminative aspects of Accumulation of tetrodotoxin-resistant sodium channels may

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NANNA B FINNERUP AND TROELS S JENSEN

Figure 2. A. Upregulation of sodium channels in sprouts with spontaneous activity and reduced thresholds of peripheral nociceptors; B. nerve lesions causing deafferentation; C. sprouting of sympathetic nerve fibers around the dorsal root ganglion, upregulation of α-adrenoreceptors; D. neuroimmune inflammation sensitizing peripheral nociceptors are examples of changes in the peripheral afferent that may cause changes in the central nervous system with central sensitization, disinhibition, synaptic reorganization, and descending facilitation, thereby causing higher gains in the pain system.

Na 5-HT NaV Opioid

A

NaV

B

Injury

α

C GABA

NaV mGLU ++ Ca NMDA ++ IL-1 Ca AMPA NGF D GLU NaV TNF-α IL-6

5-HT: serotonin; α: α-adrenoreceptor; AMPA: α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; Ca: calcium; GABA: γ-aminobutyric acid; IL-1/6: interleukin-1/6; mGLU: metabotrophic glutamate; Na: sodium; NaV: sodium voltage-gated channel; NGF: nerve growth factor; NMDA: N-methyl-D-aspartate; TNF-α: tumor necrosis factor-α.

accompany increased excitability as well as spontaneous Spouting of primary afferents neuronal ectopic discharges in sprouts, peripheral nerves, Following peripheral nerve injury, Aβ-fibers have been shown and dorsal root ganglia [17,18]. Neurotransmitter release to sprout into lamina II of the dorsal horn [21], which may be α δ may also be increased by upregulation of the 2 subunit of an underlying mechanism of mechanical allodynia mediated voltage-gated calcium channels [19]. In addition, changes in by large diameter A-fibers (as a consequence of Aβ-fibers gene expression of both injured and uninjured primary gaining access to second-order nociceptive projection afferents with increased expression of brain-derived neurons). However, it has been suggested that phenotypic neurotrophic factor and transient receptor potential channels changes of small neurons bias the interpretation of these have been shown to alter pain behavior in neuropathic pain studies and that such sprouting of afferent fibers may be less models [20]. pronounced than originally assumed [22,23]. In addition,

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intraspinal sprouting of calcitonin gene-related peptides and After nerve injury, reduced expression of the substance P-containing fine primary afferents has been potassium–chloride transporter KCC2 results in a shift in the demonstrated in CNS lesions, and presumably, enhanced transmembrane anion gradient, causing a loss of GABA and input to secondary order nociceptive pathways by intraspinal glycinergic inhibitory tone and even inverting its action into sprouting may contribute to abnormal somatosensory excitation [36]. Downregulation of potassium channels and processing and development of hypersensitivity [24]. reduction in the generation of the M current, a subthreshold potassium current that stabilizes the membrane potential Deafferentation and controls neuronal excitability, has been implicated in Loss of C-fibers may be associated with neuropathic pain enhanced excitability and ectopic activity [37]. and touch-evoked allodynia (Fig. 2) [25]. The mechanism(s) by which this loss of neurons and the resulting imbalance of Central sensitization sensory input may cause pain are not yet clear; however, Central sensitization (enhanced responses of central pain- changes in the CNS due to deafferentation, such as reduced signaling neurons) is manifested by an increased response to inhibition and bursting activity, may play a role. As discussed synaptic inputs, decreased threshold, and expansion of above, regenerative sprouting of Aβ-fibers due to vacant receptive fields [38]. Whether or not central sensitization synaptic sites may be another mechanism. Alternatively, can become independent of peripheral input in neuropathic ectopic activity in the central branches of injured nociceptors pain conditions is important from a treatment perspective. or in intact deep nociceptors may be important. In central If it can become independent, treating the initiating pain states, complete lesion of ascending pathways may be mechanisms at the peripheral level will no longer be associated with ongoing neuropathic pain in deafferentated effective. Activation of NMDA receptors plays a central role areas [26], and lesion of the spinothalamocortical tracts has in central sensitization by increasing influx of calcium ions been suggested as a necessary condition for central pain in and initiating a cascade of intracellular events [39]. Changes patients with stroke and multiple sclerosis [27]. Increased in the expression of sodium channels may also play a role in bursting activity in thalamic neurons may signal the pain central sensitization, since sodium channel expression is following deafferentation [28]. altered in second-order dorsal horn and thalamic neurons after either PNS or CNS lesions [40]. Adrenergic sensitivity Central sensitization is thought to explain how low- In a subset of patients, the sympathetic nervous system may threshold Aβ mechanoreceptors gain access to pain- play a role in the maintenance of pain. In animal models of transmitting systems, causing normally pain-free stimuli to nerve injury, upregulation of α-adrenergic receptors in be perceived as painful [41]. However, other pathways may primary afferents and sprouting of sympathetic fibers be responsible for touch-evoked allodynia. Recent studies forming basket-like structures around cell bodies in dorsal have found that dorsal column lesions abolish touch-evoked root ganglia have been demonstrated [29,30]. The resulting allodynia, suggesting that higher centers are important for adrenergic sensitivity may explain why, for example, the the access of touch stimuli to pain pathways [42,43]. This is injection of norepinephrine in a stump neuroma may induce in accordance with the notion that, in spinal cord injury intense pain [31]. Moreover, it could be a possible patients, touch-evoked allodynia may be present in areas of mechanism for sympathetically maintained pain. complete abolition of spinothalamic function [44].

Disinhibition Glia cell activation Spinal inhibition plays a significant role in controlling Peripheral and central nerve injuries have been shown to nociceptive transmission. The ongoing activity from primary activate spinal cord glia cells. Microglia activation following afferents has been shown to cause degeneration of inhibitory peripheral nerve injury leads to the release of pro- dorsal horn interneurones containing GABA, which may have inflammatory cytokines that act upon neurons, and is likely an additional effect on disinhibition and thereby increase to be an important mechanism of exaggerated pain and sensitivity [32,33]. Moreover, downregulation of GABA and spread of pain to neighboring healthy tissue outside of the opioid receptor levels may contribute to a reduction in tonic nerve injury [15,45]. The role of glia cells in neuropathic pain inhibition [34,35]. Evidence from randomized trials shows is supported by studies on the transplantation of stem cells that opiods are effective in treating neuropathic pain, but the in spinal cord injury patients to improve motor impairment. apparent lower response of neuropathic pain to opioids has If stem cells differentiate into astrocytes, allodynia-like been suggested to be caused by this downregulation of behavior may be seen. This behavior is associated with the opioid receptors [35]. sprouting of nociceptive afferents, an effect that can be

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blocked by directing differentiation of stem cells away from even patients with complete loss of epidermal nerve fiber astrocytes and into oligodendrocytes [46,47]. densities showed a response to the lidocaine patch [53]. In this study, the authors found no clear association between Descending inhibition and facilitation large-fiber sensory function and treatment response to Lesions of descending inhibitory norepinephrine, serotonin support the hypothesis that topical lidocaine acts by (5-HT), dopamine, and opioid pathways in the dorsolateral stabilizing Aβ-fibers. Instead, they suggested an action of funiculus may contribute to enhanced pain sensitivity. lidocaine on intact nociceptors in deeper tissue. Descending pathways can also exert excitatory influences These trials emphasize the challenges researchers are that facilitate nociception, and studies have suggested an facing along the way to a mechanism-based treatment important role for facilitatory 5-HT pathways working via approach, and that a further understanding of the

5-HT3 receptors in maintaining neuropathic pain [48]. mechanism of action of drugs used in neuropathic pain and development of new, more specific drugs are prerequisites Are mechanism-specific treatments available? for the success of such an approach. As discussed above, various peripheral and central mechanisms may cause an increased gain in the central pain Are symptom-specific treatments available? pathways, and any drug that increases inhibition or There is little evidence from human clinical trials that specific decreases excitation (thereby exerting a net neuronal symptoms or signs respond to specific drugs, or that the depressant effect) may relieve pain despite various initiating presence of specific symptoms and signs predicts a positive pain mechanisms (Fig. 2). This may be the case for opioids, outcome to any given treatment. For example, randomized for antidepressants that block the reuptake of controlled trials have shown an effect on touch-evoked norepinephrine or serotonin (thereby augmenting endo- allodynia by a variety of drugs, including sodium channel genous pain-suppressing pathways descending from the blockers, NMDA antagonists, opioids, GABA-A agonists, and brainstem [49]), or for gabapentinoids that bind to serotonin norepinephrine reuptake inhibitors [5]. α δ presynaptic 2 subunits of voltage-dependent calcium Few studies exist that were specifically designed to evaluate channels and cause a reduction in calcium influx and a the efficacy of these drugs on different neuropathic pain reduced release of substances including excitatory amino symptoms and signs. In patients with peripheral neuropathic acids [50]. Even systemic sodium channel blockers may pain, the effect on various types of evoked pain of intravenous inhibit sustained high-frequency repetitive firing in central alfentanil (a μ-opioid agonist), ketamine (an NMDA neurons and thus be effective in pain conditions, in spite of antagonist), and lidocaine (a sodium channel blocker) have the fact that the initiating mechanism does not involve been studied [54–57]. Alfentanil reduced ongoing pain, cold- upregulation of sodium channels in the peripheral nerve and touch-evoked allodynia, and pinprick hyperalgesia [54,55], [40]. For similar reasons, it has been argued that, for the while ketamine reduced touch-evoked allodynia but had an currently available drugs, efficacy in one diagnostic entity inconsistent effect on ongoing pain, pinprick hyperalgesia, and may support the use of such drug for other neuropathic pain cold allodynia [54,55,57]. In one study, lidocaine only reduced conditions despite multiple etiologies [51]. pain evoked by repetitive pinprick [57], while in another, Topical lidocaine has been assumed to act on lidocaine reduced ongoing pain and mechanical allodynia and accumulated sodium channels on sensitized nociceptors, and hyperalgesia but not thermal hyperalgesia [56]. has thus been suggested to be effective in post-herpetic Pharmacological studies such as these are important tools neuralgia patients with “irritable” nociceptors as opposed to in identifying pain mechanisms, but the varying results patients with nociceptor deafferentation [25]. Recent studies among them underscores the complex interactions between have questioned this putative mechanism of action of topical responsiveness of pain symptoms and pain mechanisms – lidocaine. In a randomized trial, patients with complete or statistical power, drug dose, placebo response, psychological considerable nociceptor impairment (examined using factors, genetic polymorphisms etc. quantitative sensory testing and the histamine axon reflex Open-label studies have provided evidence that patients test) responded well to topical lidocaine, and the authors with post-herpetic neuralgia respond to topical lidocaine proposed that lidocaine may target Aβ-fibers, decreasing only if they have touch-evoked allodynia [58]. However, ectopic Aβ-fiber discharges, thereby relieving both evoked more recently, an open-label study found a significant effect and ongoing pain [52]. In an uncontrolled study in patients of topical lidocaine patch 5% in patients with painful with post-herpetic neuralgia, skin biopsy, nerve conduction diabetic polyneuropathy, with comparable efficacy in velocity, and quantitative sensory testing were unable to patients with or without mechanical allodynia [59]. Whether predict the patients who might respond to lidocaine [53]; or not the presence of mechanical allodynia predicts the

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response to treatment in post-herpetic neuralgia or other will show whether we will be able to identify underlying peripheral neuropathic pain conditions needs to be mechanisms in the single pain patient and treat evaluated in randomized controlled trials. these accordingly. Post hoc analyses of randomized trials have suggested that the presence of mechanical allodynia is predictive of the Disclosures response to sodium channel blockers in both peripheral and Dr Finnerup has received research support or honoraria from GSK, and central neuropathic pain [56,60]. In one such analysis, the Neurosearch A/S, UCB Nordic. Dr Jensen has received honoraria, severity of punctuate allodynia at baseline was found to consultancy fees, or research support from Eli Lilly, Grünenthal, Lundbeck, correlate with the effects of lidocaine on spontaneous pain Neurosearch A/S, Pfizer and UCB [56]. However, in a study designed to test this hypothesis, the presence of mechanical and/or thermal allodynia did not References predict response to lidocaine in spinal cord injury pain [61]. 1. Hansson P, Kinnman E. Unmasking of neuropathic pain mechanisms in a clinical perspective. Pain Reviews 1996;3:272–92. Further studies are needed to assess whether specific types 2. Woolf CJ, Bennett GJ, Doherty M et al. Towards a mechanism-based classification of pain? of evoked pain may be a differentiating factor. Pain 1998;77:227–9. 3. Jensen TS, Baron R. Translation of symptoms and signs into mechanisms in neuropathic Further studies are also needed to evaluate which pain. Pain 2003;102:1–8. symptoms and signs may be predictive of a response to 4. Baron R. Mechanisms of disease: neuropathic pain – a clinical perspective. Nat Clin Pract Neurol 2006;2:95–106. treatment. Various neuropathic pain scales have been 5. Finnerup NB, Jensen TS. 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Early onset of spontaneous activity in uninjured procedures such as the histamine test, capsaicin application, C-fiber nociceptors after injury to neighboring nerve fibers. J Neurosci 2001;21:RC140. and skin biopsies have been used to explore the function of 17. Waxman SG, Cummins TR, Dib-Hajj SD et al. Voltage-gated sodium channels and the molecular pathogenesis of pain: a review. J Rehabil Res Dev 2000;37:517–28. the sensory nervous system. The German Research Network 18. Wood JN, Abrahamsen B, Baker MD et al. Ion channel activities implicated in pathological on Neuropathic Pain is an initiative that uses a standardized pain. Novartis Found Symp 2004;261:32–40, discussion 40–54. α δ 19. Li CY, Zhang XL, Matthews EA et al. Calcium channel 2 1 subunit mediates spinal QST protocol to phenotypically characterize patients with hyperexcitability in pain modulation. Pain 2006;125:20–34. various neuropathic pain conditions [66]. It is assumed that 20. Ueda H. 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Eur J Neurosci 2002;16:175–85. treatment of the individual pain patient. 24. Christensen MD, Hulsebosch CE. Chronic central pain after spinal cord injury. J Neurotrauma 1997;14:517–37. 25. Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritable nociceptors and Conclusion deafferentation. Neurobiol Dis 1998;5:209–27. 26. Finnerup NB, Johannesen IL, Fuglsang-Frederiksen A et al. Sensory function in spinal cord Despite the increasing knowledge on pain mechanisms, injury patients with and without central pain. Brain 2003;126:57–70. treatment of neuropathic pain is still unsatisfactory. 27. Boivie J. Central Pain. In: McMahon SB, Koltzenburg M (eds). Textbook of Pain. Philadelphia, PA: Elsevier Churchill Livingstone, 2006:1057–74. Development of pharmacological agents with specific 28. Jensen TS, Lenz FA. Central post-stroke pain: a challenge for the scientist and the clinician targets and of diagnostic methods to identify mechanisms [editorial]. Pain 1995;61:161–4. 29. 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30. McLachlan EM, Janig W, Devor M et al. Peripheral nerve injury triggers noradrenergic 48. Suzuki R, Rahman W, Rygh LJ et al. Spinal-supraspinal serotonergic circuits regulating sprouting within dorsal root ganglia. Nature 1993;363:543–6. neuropathic pain and its treatment with gabapentin. Pain 2005;117:292–303. 31. Lin EE, Horasek S, Agarwal S et al. Local administration of norepinephrine in the stump 49. Sindrup SH, Otto M, Finnerup NB et al. Antidepressants in the treatment of neuropathic evokes dose-dependent pain in amputees. Clin J Pain 2006;22:482–6. pain. Basic Clin Pharmacol Toxicol 2005;96:399–409. 32. Moore KA, Kohno T, Karchewski LA et al. Partial peripheral nerve injury promotes a 50. Sills GJ. The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. 2006;6:108–13. J Neurosci 2002;22:6724–31. 51. Hansson PT, Dickenson AH. 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Leung A, Wallace MS, Ridgeway B et al. Concentration-effect relationship of intravenous levels. Proc Natl Acad Sci USA 1992;89:2571–5. alfentanil and ketamine on peripheral neurosensory thresholds, allodynia and hyperalgesia 35. Kohno T, Ji RR, Ito N et al. Peripheral axonal injury results in reduced μ opioid receptor of neuropathic pain. Pain 2001;91:177–87. pre- and post-synaptic action in the spinal cord. Pain 2005;117:77–87. 55. Jorum E, Warncke T, Stubhaug A. Cold allodynia and hyperalgesia in neuropathic pain: the 36. Coull JA, Boudreau D, Bachand K et al. Trans-synaptic shift in anion gradient in spinal effect of N-methyl-D-aspartate (NMDA) receptor antagonist ketamine – a double-blind, lamina I neurons as a mechanism of neuropathic pain. Nature 2003;424:938–42. cross-over comparison with alfentanil and placebo. Pain 2003;101:229–35. 37. Wua YJ, Dworetzky SI. Recent developments on KCNQ potassium channel openers. 56. Attal N, Rouaud J, Brasseur L et al. 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18 ADVANCES IN PAIN MANAGEMENT Vol 1 No 1 2007 LEADING ARTICLE 19 . (1):19–23 1 ; Vol 1 No 1 2007 Vol The effects of bisphosphonates are mediated through of bisphosphonates are The effects The major disadvantage of the orally utilized bisphospho- Distribution of the bisphosphonates to the liver and generation bisphosphonates, including pamidronate, as well pamidronate, generation bisphosphonates, including bisphosphonates, including zoledronic as third-generation acid and ibandronate. and their cell precursors actions on the osteoclasts and likely on dendritic cells, and cells, such as macrophages, other related osteoclast-mediated bone Bisphosphonates suppress microglia. on osteoclasts, and cause an intracellular effect via resorption of osteoclast inhibition an inhibition of osteoclast recruitment, of the life span of the osteoclast. The and reduction activity, first generation of bisphosphonates, i.e. non-nitrogen- and containing bisphosphonates, such as etidronate cause an intracellular accumulation of a appear to clodronate, analogue compound, while the most recent cytotoxic ATP generation bisphosphonates, i.e. the nitrogen-containing isoprenylation. bisphosphonates, act by inhibiting protein poor absorption in the gastro- nates is their extremely intestinal tract. Less than 1% of the oral dose is absorbed, and to obtain a by food intake. In order absorption is suppressed a relatively anti-osteoclastic effect, effective rapid and more high dose of bisphosphonates must be given by intravenous (IV) infusion, since intramuscular and subcutaneous injections with local tissue damage. associated are is transient. Metabolically active bone acts other organs ANAGEMENT . M Adv Pain Manage 2007 in Fig. AIN P 2 DVANCES IN A myositis ossificans in Fig. 1), bisphosphonates bind 1 1) influence the anti-bone resorptive potency of the various 1) influence the anti-bone resorptive and compounds. Earlier bisphosphonates, such as etidronate by second- replaced been largely have clodronate, Some of the most important drugs that have emerged in the have emerged Some of the most important drugs that Originally, the bisphosphonates. battle against bone pain are designed as synthetic analogues of bisphosphonates were of precipitation a molecule known to inhibit pyrophosphate, and soft tissues and calcium phosphate in plasma, urine, in toothpaste. In the commonly used as an anti-tartar agent by alkaline is rapidly hydrolyzed pyrophosphate body, to the resistant bisphosphonates are phosphatase; however, This is due to the enzymatic action of alkaline phosphatase. of carbon instead of oxygen in the center of the presence was the first (Fig. 1). Etidronate molecule pyrophosphate bisphosphonate used clinically in Over the years, intravenous bisphosphonate therapy has been proven highly valuable in the management of pathological been proven highly valuable in the bisphosphonate therapy has Over the years, intravenous cancer bone pain, and osteoporosis. hypercalcemia of malignancy, with abnormal bone metabolism: conditions associated for bisphosphonates in the have recently helped identify a role experience and a number of studies A growing clinical might not be unique to pain mechanisms non-cancer pain states. Bisphosphonate-responsive management of chronic from complex regional of non-oncological patients suffering a role in maintaining pain in subgroups and may play cancer, Moreover, and other inflammatory arthropathies. disease, ankylosing spondylitis, back pain, Paget’s pain syndrome, chronic and preclinical studies have corroborated the analgesic action of bisphosphonates multiple lines of evidence gleaned from and neuropathic pain. Recently, in numerous animal models of inflammatory have revealed a dose-dependent effect skeleton, an extensive network of nerve fibers in the vicinity and within the immunohistochemical studies have revealed of bone The activation cortical and trabecular bone as well as in the bone marrow. not only in the periosteum but also in and how basis of bone pain. Putative bisphosphonate-responsive pain mechanisms nociceptors is the pathophysiological be more bone nociceptors are hereafter discussed. Bone pain mechanisms might they interfere with the network of putative than previously thought. This review will focus on the bisphosphonates prevalent and clinically more relevant adjuvants in the use of bisphosphonates as analgesics or analgesic off-label mechanisms of analgesia and on the conditions. management of several non-cancer painful was found to block not only abnormal soft tissue Etidronate osteoclastic bone mineralization, but also, surprisingly, and osteolysis. Because of one of the two resorption molecular side chains (R Marco Pappagallo Marco USA NY, New York, Mount Sinai School of Medicine, and Pain Management, Department of Anesthesiology Bisphosphonate Therapy for Non-Cancer Pain Pain for Non-Cancer Therapy Bisphosphonate with a high affinity to the hydroxyapatite crystals of the to the hydroxyapatite with a high affinity bone. Molecular changes in the other side chain (R Address for correspondence: Marco Pappagallo, Director, Pain Medicine Pappagallo, Director, Marco for correspondence: Address of Anesthesiology and Pain and Development, Department Research Management, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, NY 10029, USA. Email: [email protected] Box 1010, New York, R8185_1 Pain_1_04 17/1/07 10:08 Page 19 Page 10:08 17/1/07 Pain_1_04 R8185_1 R8185_1 Pain_1_04 17/1/07 10:08 Page 20

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Figure 1. Chemical structure of bisphosphonates. only with a significant reduction in pathological fractures and

R1 allows bisphosphonate to bind to hydroxyapatite crystals, hypercalcemia, but also with a quick relief of severe bone

R2 modifies bisphosphonate anti-osteoclastic potency. pain [2,3], e.g. “immediately after the first infusion” [4] “within 10–14 days” [5], “within a matter of days” [6], and “within 1 month of infusion” [7]. Approximately 50% or more of the patients treated with R1 R2 intravenous pamidronate at regular intervals, ranging from O C weekly to every 3 months, had relief of cancer-related bone pain [5,8]. O P PO HO P P OH Bone is a common site of metastatic spread for renal cell carcinoma, non-Hodgkin’s lymphoma, as well as for cancer O OOO O O O O of the thyroid, breast, and colon. We are just beginning to understand the pathophysiological mechanism of pain in Pyrophosphate H H cancer patients with bone metastases. The presence of pain Bisphosphonate is not associated with the type of tumor or its location, the number or size of metastases, gender, or age of patients. Moreover, although approximately 80% of patients with quickly as a sponge, absorbing almost the entire IV infusion breast cancer will develop osteolytic or osteoblastic dose. The rest of the dose remains unmetabolized and metastases, about two-thirds of demonstrated sites of bone undergoes urine excretion. The pharmacokinetics of metastases are painless [9]. bisphosphonates is complex. These drugs remain attached to Therefore, while metastasis may be strongly associated bone for weeks to months. The amount of drug released in with cancer-related bone pain, its presence is not a sufficient the plasma and then in the urine is related to the rate of requirement for the development of pain. bone metabolism and turnover, which can result in a Immunohistochemical studies have revealed an extensive protracted terminal elimination half-life of bisphosphonates. network of nerve fibers in the vicinity and within the Bisphosphonates are generally well tolerated and when skeleton, not only in the periosteum but also in cortical and appropriately administrated, are associated with very trabecular bone as well as in the bone marrow [10]. Thinly transient and manageable side effects; however, in the myelinated and unmyelinated peptidergic sensory fibers, as oncology field, there is an emergent concern about a well as sympathetic fibers, occur throughout the bone complication known as osteonecrosis of the jaw [1]. The marrow, mineralized bone, and the periosteum. Although disorder may affect a subgroup of patients with cancer on the periosteum receives the densest innervation, when the chronic bisphosphonate treatment for multiple myeloma or total bone volume is taken into consideration, it is the bone breast, prostate, or lung cancer bone metastases. Tissue marrow that receives the highest number of nerve fibers. biopsies of the affected jaw lesions have revealed findings When malignant cells infiltrate bone spaces, osteoclastic consistent with osteomyelitis. Major risk factors include activity is enhanced. Multiple algogenic factors such as prolonged treatment with potent bisphosphonates (i.e. increased concentration of extracellular protons, local monthly IV administration for more than 1–2 years), poor synthesis of nerve growth factor (NGF), and release of oral hygiene, and a history of a recent dental extraction or proteases and inflammatory substances, such as cytokines dental implant. and prostaglandins (PGs), might act synergistically to This review will focus on the bisphosphonates putative achieve enough critical mass and activate the extensive mechanisms of analgesia and on the off-label use of network of nociceptors and sensory fibers innervating the bisphosphonates as analgesics or analgesic adjuvants in the cortical and trabecular bone as well the bone marrow. The management of several non-cancer painful conditions, activation of bone nociceptors is the pathophysiological including bone and joint pain states and complex regional basis of bone pain. pain syndrome. The majority of sensory afferents in the bone are calcitonin gene-related peptide (CGRP)-, capsaicin receptor Mechanisms of analgesia transient receptor potential vanilloid subtype 1 (TRPV1)-, The idea that IV bisphosphonates might decrease pain arose and the high affinity tyrosine kinase receptor for NGF from observations of patients who were receiving (TrkA)-expressing fibers [11,12]. intravenous clodronate for hypercalcemia due to bone A potential mechanism of bone pain may be the acidic metastases. Bisphosphonate treatment was associated not microenvironment (pH 4.0) produced by the local release of

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protons from activated osteoclasts. A low pH activates the clinical studies revealed prolonged central and peripheral capsaicin receptor TRPV1 involved in primary sensory analgesic properties of the bisphosphonates for non-bone- afferents heat- and proton-transduction mechanisms [13,14]. related pain states [26,27]. Therefore, by inhibiting activity of osteoclasts or even causing Alendronate suppressed the acetic acid-induced writhing their apoptosis [15], bisphosphonates can decrease local response, but had no effect on the formalin-evoked tissue acidosis and act as analgesics for all those pain nociceptive response in the hindpaws of mice [28]. In the conditions where nociception is driven by osteoclasts. sciatic nerve ligature animal model of neuropathic pain, Another potentially relevant pain mechanism for bone bisphosphonates not only reduced the number of activated cancer pain is the activity of NGF on bone nociceptors. NGF macrophages infiltrating the injured nerve and Wallerian was lately found to have a relevant role in bone pain; it nerve fiber degeneration, but also decreased experimental induces hyperalgesia via upregulation of transcription for hyperalgesia [29]. genes encoding receptors, ion channels (e.g. capsaicin Lastly, in animal models of arthritis, some evidence receptor TRPV1), and neuropeptides (e.g. CGRP, suggests that bisphosphonates not only possess an anti- substance P). Pre-clinical evidence indicates that bone pain inflammatory effect via apoptosis of active macrophages, but can successfully be relieved by anti-NGF immunoglobulin G also can prevent arthritis-induced joint degeneration [30,31]. (IgG) therapy [16]. NGF expression is enhanced in bone inflammation, bone cancer, trauma, and fractures. NGF is Bisphosphonates for painful joint produced by many cellular elements, including resident mast and bone syndromes cells, activated macrophages, endothelial cells, and bone The vast majority of patients with chronic axial back pain are marrow stromal cells [17,18]. diagnosed as having chronic back pain of non-specific origin Bisphosphonates may act as analgesics by inhibiting NGF (i.e. without evidence of specific structural diseases or expressing cells and interfering with their NGF synthesis. There etiologies known to cause back pain). This pain is is evidence that tumor cells, endothelial cells, and activated conventionally regarded as pain secondary to spondylitic macrophages when directly exposed to bisphosphonates in disease or degenerative disc disease (i.e. discogenic pain). vitro or in vivo can suffer from bisphosphonate-induced toxic Nevertheless, the exact mechanisms underlying chronic back effects and even undergo apoptosis [19–21]. pain of non-specific origin have remained elusive. The poor Of further interest is the role of neuropeptides such as correlation between back pain and routine imaging studies CGRP and substance P in generating the so-called (X-ray, magnetic resonance imaging) findings is not neurogenic inflammation of bone and periosteum. Within surprising since most mechanical pain is unrelated to gross the bone, unmyelinated peptidergic nerve fibers run anatomical conditions that alter skeletal anatomy, such as intertwined with the blood vessels. Once activated, afferent degenerative disc disease or spondylitic disease. nerve fibers release CGRP and substance P. Neuropeptides Approximately 95% of adult patients with back pain have can activate mast cells (a potent source of NGF) and mechanical pain of non-cancer origin, and a precise endothelial cells to cause vasodilatation and plasma pathoanatomical diagnosis cannot be identified in the vast extravasation. Moreover, the presence of receptors for majority of patients with axial back pain. An open-label trial CGRP and substance P has recently been described on of intravenous pamidronate therapy was recently conducted osteoclasts and osteoblasts. CGRP and substance P appear in patients (n=25) with chronic axial back pain of non-cancer to regulate osteoclast formation, bone formation, and origin unresponsive to nonsteroidal anti-inflammatory drugs resorption [10]. (NSAIDs). None of the patients had a history of osteoporotic Other relevant effects of the bisphosphonates include vertebral fractures or metastatic disease. Improvement in inhibition on the synthesis of matrix metalloproteinases pain was observed in the majority of these patients. Their (MMP-1, MMP-3, MMP-8), as well pro-inflammatory average pain intensity following treatment decreased by 3.6

cytokines, and PGE2 [19,22]. points (on the 0–10 numeric rating scale) from baseline. The Multiple lines of evidence gleaned from pre-clinical investigation revealed no increase in opioid or non-opioid studies corroborate the analgesic action of these drugs. analgesics associated with the bisphosphonate-related pain These studies have revealed a dose-dependent analgesic relief [32]. This experience, although very preliminary, effect in animal models of inflammatory, neuropathic, and suggests that a subgroup of patients with chronic back pain cancer pain [15,23–25]. might suffer from bisphosphonate responsive bone pain. In the tail-flick and writhing tests in rodents, the Within the spine, bone pain mechanisms might be active at analgesic effect of several bisphosphonates administered IV the vertebral endplates, at the facet joint subchondral and/or intracerebroventricularly (ICV) was identified. Pre- surface, and at the periosteum. Moreover, bone pain

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mechanisms might be active independently from co-existing after injection), the hyperperfusion is followed by a spinal disorders, for example, advanced degenerative disk characteristic uptake of the radio-labeled bisphosphonate in disease or osteoporosis. the joints of the affected limb. IV bisphosphonates have also reduced morning stiffness A review of the literature reveals multiple studies of and back pain in patients with ankylosing spondylitis (AS). bisphosphonates for CRPS. To date, four trials of intravenous Two open-label trials suggested that intravenous pamidronate for CRPS have been published. Maillefert et al. in pamidronate might be beneficial in patients with NSAID- 1995 reported on seven of 11 patients with CRPS, who refractory AS [33,34]. experienced clinically significant improvement from These preliminary observations were confirmed by a pamidronate therapy [45]. Cortet et al., in 1997, reported on randomized, double-blind controlled study that evaluated a 10 women and 13 men with CRPS, who showed highly dose–response relationship comparing two groups of AS significant pain reduction and physical functional patients; receiving either 60 mg or 10 mg of IV pamidronate improvement [46]. Kubalek et al., in 2001, treated 29 patients at monthly doses for 6 months [35]. with CRPS [47]. Twenty-five of the patients experienced Bisphosphonates have also been used for rheumatoid excellent pain relief from IV pamidronate at a dose of 60 arthritis with some evidence of benefit, in particular in mg/day for 3 consecutive days. Lastly, in a double-blind, the prevention of bone erosions and in the management of randomized placebo-controlled trial of IV pamidronate pain [36–38]. (n=27), the active treatment group (n=14) reported significant Paget’s disease of bone is a painful, localized disorder of improvement in pain and physical function at 3 months post- bone remodeling, due to abnormally active osteoclasts. infusion [48]. In a controlled trial of clodronate, 32 CRPS Paget’s disease of bone usually occurs in persons over the age patients were randomized to receive either IV clodronate (300 of 40 years and mainly affects the axial skeleton. The etiology mg daily) for 10 consecutive days or placebo [49]. This trial of Paget’s disease remains elusive [39]. Bisphosphonates play demonstrated significant efficacy of the clodronate treatment a relevant therapeutic role in modifying the disease course, over placebo. Adami et al. reported that among 20 patients and improving pain and mobility in the symptomatic Paget’s with CRPS, IV alendronate relieved pain by at least 50% in 13 patients [40–42]. patients, and those who received two infusions performed better than those who received one [50]. Finally, Manicourt et Complex regional pain syndrome al. conducted a randomized controlled trial of oral alendronate Complex regional pain syndrome (CRPS), formerly known as (40 mg daily) for 8 weeks versus placebo in patients (n=40) reflex sympathetic dystrophy (RSD), is a debilitating pain with post-traumatic CRPS of the lower extremities [51]. The syndrome that has been recognized for more than a century. alendronate-treated patients exhibited a significant and In 1993, a Special Consensus Workshop of the International sustained improvement in levels of spontaneous pain, Association for the Study of Pain (IASP) convened to mechanical pressure, and joint mobility. examine and revise the IASP taxonomy and to redefine RSD Several lines of evidence suggest that a subgroup of by international agreement. It was determined that RSD patients with CRPS might have bisphosphonate-responsive should be reclassified in the pain taxonomy as CRPS. Despite bone pain. Therefore, it is conceivable that bisphosphonate- the long history of this disorder, the pathophysiology of responsive pain mechanisms might be involved in CRPS has remained elusive. maintaining some of the symptoms of CRPS. Of interest are the regional skeletal changes observed in several cases of CRPS. Although it has lost diagnostic purposes, Conclusion a three-phase bone scintigraphy is still used in the evaluation Over the years, IV bisphosphonate therapy has proved of this disorder. Bone scintigraphy utilizes a technetium-99 highly valuable in the management of numerous bone- radio-labeled bisphosphonate as an intravenous marker. The related conditions, including hypercalcemia of malignancy, review of pre-IASP diagnostic criteria literature reveals that this cancer bone pain, and osteoporosis. test was reported to have a 50% diagnostic sensitivity and A growing experience and a number of studies have 90% diagnostic specificity, especially in cases of RSD with a recently help to identify a role for bisphosphonates in the duration <6 months and in patients >50 years [43,44].The management of pain states. It appears that bisphosphonate typical RSD bone scan findings consisted of a homogeneous responsive bone pain mechanisms might not be unique to unilateral marker uptake or hyperperfusion within the bone of cancer and might play a role in a subgroup of non- the affected limb during phase 1 (“perfusion phase” 30 s after oncological patients suffering from chronic back pain, AS, the marker injection) and phase 2 (“blood pool phase” 2 min other inflammatory rheumatoid diseases, Paget’s disease of after injection). During phase 3 (“mineralization phase”, 3 h bone, and CRPS.

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Bone pain mechanisms might be more prevalent and 23. Cui JG, Holmin S, Mathiesen T et al. Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy. Pain 2000;88:239–48. clinically more relevant than previously thought. These 24. Walker K, Medhurst SJ, Kidd BL et al. Disease modifying and anti-nociceptive effects of the considerations will hopefully help us to better understand bisphosphonate, zoledronic acid in a model of bone cancer pain. Pain 2002;100:219–29. 25. Kawabata A, Kawao N, Hironaka Y et al. Antiallodynic effect of etidronate, a complex pain mechanisms and pursue new research avenues bisphosphonate, in rats with adjuvant-induced arthritis: involvement of ATP-sensitive K+ for the treatment of some of the most challenging and channels. Neuropharmacology 2006;51:182–90. 26. Bonabello A, Galmozzi MR, Bruzzese T et al. Analgesic effect of bisphosphonates in mice. distressing pain conditions. Pain 2001;91:269–75. 27. Bonabello A, Galmozzi MR, Canaparo R et al. Long-term analgesic effect of clodronate in rodents. Bone 2003;33:567–74. Disclosure 28. Goicoechea C, Porras E, Alfaro MJ et al. Alendronate induces antinociception in mice, not Dr Pappagallo is a member of the scientific advisory boards for related with its effects in bone. Jpn J Pharmacol 1999;79:433–7. 29. Liu T, van Rooijen N, Tracey DJ. Depletion of macrophages reduces axonal degeneration Anesiva and GSK. and hyperalgesia following nerve injury. Pain 2000;86:25–32. 30. Harada H, Nakayama T, Nanaka T et al. Effects of bisphosphonates on joint damage and bone loss in rat adjuvant-induced arthritis. Inflamm Res 2004;53:45–52. References 31. Oelzner P, Kunze A, Henzgen S et al. High-dose clodronate therapy prevents joint 1. Treister N, Woo SB. Images in clinical medicine. Bisphosphonate-associated osteonecrosis destruction in chronic antigen-induced arthritis of the rat but inhibits bone formation at of the jaw. N Engl J Med 2006;355:2348. the axial skeleton. Inflamm Res 2000;49:424–33. 2. Holten-Verzantvoort AT, Bijvoet OL, Cleton FJ et al. Reduced morbidity from skeletal 32. Pappagallo M, Breuer B, Schneider A et al. Treatment of chronic mechanical spinal pain metastases in breast cancer patients during long-term bisphosphonate treatment. with intravenous pamidronate: a review of medical records. Lancet 1987;2:983–5. J Pain Symptom Manage 2003;26:678–83. 3. Paterson AH, Powles TJ, Kanis JA et al. Double-blind controlled trial of oral clodronate in 33. Maksymowych WP, Jhangri GS, Leclercq S et al. An open study of pamidronate in the patients with bone metastases from breast cancer. J Clin Oncol 1993;11:59–65. treatment of refractory ankylosing spondylitis. J Rheumatol 1998;25:714–7. 4. Arzoo K, Sadeghi S, Pullarkat V. Pamidronate for bone pain from osteolytic lesions in 34. Maksymowych WP, Lambert R, Jhangri GS et al. Clinical and radiological amelioration of Langerhans’-cell histiocytosis. N Engl J Med 2001;345:225. refractory peripheral spondyloarthritis by pulse intravenous pamidronate therapy. 5. Fulfaro F, Casuccio A, Ticozzi C et al. The role of bisphosphonates in the treatment of J Rheumatol 2001;28:144–55. painful metastatic bone disease: a review of phase III trials. Pain 1998;78:157–69. 35. Maksymowych WP, Jhangri GS, Fitzgerald AA et al. A six-month randomized, controlled, 6. Adami S, Mian M. Clodronate therapy of metastatic bone disease in patients with prostatic double-blind, dose-response comparison of intravenous pamidronate (60 mg versus carcinoma. Recent Results Cancer Res 1989;116:67–72. 10 mg) in the treatment of nonsteroidal anti-inflammatory drug-refractory ankylosing spondylitis. Arthritis Rheum 2002;46:766–73. 7. Robertson AG, Reed NS, Ralston SH. Effect of oral clodronate on metastatic bone pain: a double-blind, placebo-controlled study. J Clin Oncol 1995;13:2427–30. 36. Rovetta G, Monteforte P. Efficacy of disodium-clodronate in the management of joint pain in rheumatoid arthritis. Six months open study. Minerva Med 2003;94:353–7. 8. Glover D, Lipton A, Keller A et al. Intravenous pamidronate disodium treatment of bone metastases in patients with breast cancer. A dose-seeking study. Cancer 1994;74:2949–55. 37. Jarrett SJ, Conaghan PG, Sloan VS et al. Preliminary evidence for a structural benefit of the new bisphosphonate zoledronic acid in early rheumatoid arthritis. Arthritis Rheum 2006;54:1410–4. 9. Mercadante S. Malignant bone pain: pathophysiology and treatment. Pain 1997;69:1–18. 38. Romas E. Bone loss in inflammatory arthritis: mechanisms and therapeutic approaches with 10. Lerner UH. Neuropeptidergic regulation of bone resorption and bone formation. bisphosphonates. Best Pract Res Clin Rheumatol 2005;19:1065–79. J Musculoskelet Neuronal Interact 2002;2:440–7. 39. Reddy SV. Etiologic factors in Paget’s disease of bone. Cell Mol Life Sci 2006;63:391–8. 11. Mach DB, Rogers SD, Sabino MC et al. Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur. Neuroscience 2002;113:155–66. 40. Walsh JP, Ward LC, Stewart GO et al. A randomized clinical trial comparing oral alendronate and intravenous pamidronate for the treatment of Paget’s disease of bone. 12. Ghilardi JR, Rohrich H, Lindsay TH et al. Selective blockade of the capsaicin receptor Bone 2004;34:747–54. TRPV1 attenuates bone cancer pain. J Neurosci 2005;25:3126–31. 41. Bombassei GJ, Yocono M, Raisz LG. Effects of intravenous pamidronate therapy on Paget’s 13. Caterina MJ, Schumacher MA, Tominaga M et al. The capsaicin receptor: a heat-activated disease of bone. Am J Med Sci 1994;308:226–33. ion channel in the pain pathway. Nature 1997;389:816–24. 42. Vasireddy S, Talwalkar A, Miller H et al. Patterns of pain in Paget’s disease of bone and 14. Reeh PW, Steen KH. Tissue acidosis in nociception and pain. Prog Brain Res 1996;113:143–51. their outcomes on treatment with pamidronate. Clin Rheumatol 2003;22:376–80. 15. Sevcik MA, Luger NM, Mach DB et al. Bone cancer pain: the effects of the 43. Davidoff G, Werner R, Cremer S et al. Predictive value of the three-phase technetium bisphosphonate alendronate on pain, skeletal remodeling, tumor growth and tumor bone scan in diagnosis of reflex sympathetic dystrophy syndrome. Arch Phys Med Rehabil necrosis. Pain 2004;111:169–80. 1989;70:135–7. 16. Sevcik MA, Ghilardi JR, Peters CM et al. Anti-NGF therapy profoundly reduces bone 44. Werner R, Davidoff G, Jackson MD et al. Factors affecting the sensitivity and specificity of cancer pain and the accompanying increase in markers of peripheral and central the three-phase technetium bone scan in the diagnosis of reflex sympathetic dystrophy sensitization. Pain 2005;115:128–41. syndrome in the upper extremity. J Hand Surg [Am] 1989;14:520–3. 17. Halvorson KG, Kubota K, Sevcik MA et al. 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CLINICAL REVIEWS Commentary and Analysis on Recent Key Papers

Clinical reviews were prepared by Lara Dhingra and Helena Knotkova

NOVEL THERAPIES Following a 1-week baseline period, physicians injected placebo or 40 Ipsen units of Dysport into 10 trigger points for Efficacy and safety of a single botulinum type A a 12-week period, and patients completed daily pain diaries. toxin complex treatment (Dysport®) for the relief of The primary outcome was the percentage of patients with upper back myofascial pain syndrome: results from mild or no pain at week 5 (e.g. mean scores from diary data). a randomized double-blind placebo-controlled Secondary outcomes included changes in pain severity multicentre study (intensity and duration), number of pain-free days/weeks, Göbel H, Heinze A, Reichel G et al., on behalf of Dysport sleep duration, trigger point data (number and pain myofascial pain study group. intensity), and length of time to reduced pain. Patient and Pain 2006;125:82–8. physician preference for repeated treatments were recorded. Safety indices included number of adverse events (AEs), vital This randomized, placebo-controlled, double-blind trial signs, and tolerability. evaluated the efficacy and safety of botulinum type A toxin Results indicated that 145 patients were randomized to (BoNT-A) for the treatment of myofascial pain syndrome. the study (placebo group=70, Dysport group=75), with 120 Participants (n=145) received 10 trigger point injections completers in the analyses. At week 5, significantly more weekly for 12 weeks. At week 5, significantly more patients patients in the Dysport group reported mild or no pain who received BoNT-A reported “mild or no pain (51%) (51%) compared with patients in the placebo group (26%). compared with patients who received placebo (26%). Baseline Overall, the number of responders in the Dysport group was changes in pain intensity were significantly better in the higher than in the placebo group, with significant differences BoNT-A group compared with the placebo group at weeks at 5, 6, and 11 weeks. The change from baseline in pain 5–8. Significantly more adverse events (AEs) were reported intensity over time was statistically significant during weeks in the intervention arm (46) versus the control arm (19), 5–8. The Dysport group had significantly more pain-free with 75% of AEs reported as mild-to-moderate in severity. days and more “mild or no pain” days during weeks 5–12. In this sample, BoNT-A significantly alleviated myofascial Mean pain intensity for trigger points was significantly lower pain compared with placebo, and was well-tolerated. in the Dysport group compared with the placebo group at weeks 4–12. Physicians’ and patients’ preferences for Botulinum type A toxin (BoNT-A; Dysport®, Ipsen Ltd., Slough, repeated treatments were higher in the Dysport group. A UK) is a useful treatment for a variety of pain disorders. Prior trend for AEs resolution was observed by weeks 8 and 12. studies show that BoNT-A may be an efficacious therapy for Dysport showed beneficial effects at weeks 4–6 following myofascial pain syndrome. These small studies (6–40 patients) treatment initiation. demonstrate that BoNT-A injections are associated with A major strength of the study is the sample selection, significantly reduced pain compared with placebo and which included a clearly defined patient population. Sound methylprednisolone therapy. This study addressed previous methodological design and a large sample size are additional research gaps by utilizing a larger sample size, using larger strengths. The current study might have benefited from doses of BoNT-A, and tailoring the site of trigger point more details about how the intention-to-treat analyses were injections based on patient preference. conducted, and a rationale for the selection of dosages and The narrow inclusion criteria for the study precluded mild for expected improvement of pain at 5 weeks. Future trials pain intensity, prior treatment with BoNT-A, recent are needed to replicate and extend these promising results. participation in other trials, and use of specific medications Address for reprints: H Gobel, Kiel Pain Centre, Heikendorfer Weg 9-27, up to 4 weeks pre-treatment. 24149 Kiel, Germany. Email: [email protected]

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Fentanyl buccal tablet (FBT) for relief of FBT should be initiated at a low starting dose (100 μg) and breakthrough pain in opioid-treated patients with then titrated to an effective dose. The exploratory covariate chronic low back pain: a randomized, placebo- analyses suggested that age, gender, and functional status controlled study were associated with the response of patients to FBT. The Portenoy RK, Messina J, Xie F et al. reasons that women, patients in some age groups, and Curr Med Res Opin 2007;23:223–33. patients with relatively high (but not the highest) disability may be more likely to respond to FBT than to placebo are This randomized, double-blind placebo-controlled trial not apparent from the data. The results of this controlled evaluated fentanyl buccal tablet (FBT) for breakthrough study show that FBT was efficacious and well tolerated in pain (BTP) in opioid-treated patients with chronic low back the management of opioid-treated patients with BTP pain. The results showed that FBT was efficacious and well associated with chronic low back pain. It is the first such tolerated in the treatment of BTP. This was the first study study in non-cancer-related BTP and provides evidence that of FBT in a population with chronic non-cancer pain. a rapid-onset opioid can provide meaningful pain relief in patients with chronic pain not associated with cancer. There is an emerging consensus that long-term opioid Address for reprints: RK Portenoy, Department of Pain Medicine and therapy may be effective in carefully selected patients with Palliative Care, Beth Israel Medical Center, First Avenue at 16th Street, chronic non-cancer pain. The standard of care for the New York, NY 10003, USA. Email: [email protected] treatment of cancer-related breakthrough pain (BTP) relies on the oral administration of an immediate-release, short- Randomised controlled trial of a short course of acting opioid formulation, taken as required to supplement a traditional acupuncture compared with usual care fixed-schedule opioid regimen. This approach has been for persistent non-specific low back pain empirically extrapolated to the treatment of BTP in selected Thomas KJ, MacPherson H, Thorpe L et al. patients with chronic non-cancer-related pain. The present BMJ 2006;333:623–9. randomized, double-blind placebo-controlled study was undertaken to evaluate the efficacy and tolerability of The aim of this study was to determine whether a short fentanyl buccal tablet (FBT; Fentora, Cephalon, Inc., Frazer, course of traditional acupuncture improves lower back PA, USA), in a population of opioid-treated patients with pain at 12 and 24 months after treatment to a greater chronic low back pain. Participants were patients receiving extent than usual care. The results showed no functional long-term opioid therapy for chronic low back pain at 16 improvement at any time point after the acupuncture. In pain treatment centers in the US. Of the 105 patients terms of pain, there was weak evidence of a beneficial enrolled, 77 entered the double-blind phase. Following effect of acupuncture at 12 months, and stronger open-label titration to identify an effective FBT dose, evidence of a small benefit at 24 months. patients were randomly assigned to one of three double- blind dose sequences (six doses of FBT, three placebo) to Non-specific lower back pain is typically intermittent and treat nine BTP episodes. Pain intensity, measured on an recurrent, and is associated with high health, social, and 11-point scale (0=no pain, 10=worst pain), and other economic costs. The aim of this open-label randomized outcomes were assessed for 2 h after dosing. Results study was to determine whether a short course (10 sessions) showed that 81% of patients with BTP associated with of traditional acupuncture improves long-term outcomes in chronic non-cancer pain identified an effective dose during patients with persistent non-specific lower back pain in the open-label dose-titration phase. In the double-blind primary care. phase, FBT was found to be efficacious compared with The 241 participants were adult patients (aged 18–65 placebo, producing effects as early as 10 min after years) who were assessed by their general practitioner after administration that were sustained throughout the 2-h presenting with lower back pain. Participants were period of observation. Evidence of early treatment effect randomized to receive either 10 sessions of acupuncture or was observed in all secondary efficacy measures. No usual care only. The usual care involved a variety of correlations were found between the effective doses of FBT approaches, including physiotherapy, massage, and exercise. and either the baseline fixed-schedule opioid regimen or The primary outcome measure was the bodily pain quantity of supplemental opioids used prior to the study. dimension of the 36-item short form health survey (SF-36), This observation indicates that selection of a supplemental scored on a scale of 0–100, at 12 months. Secondary dose based on the dose of the fixed-schedule regimen, outcomes were measured at 3, 12, and 24 months using the which is conventional practice, is not appropriate for FBT. disability index, the McGill present pain index, and

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remaining dimensions of the SF-36. At 12 months there Five patients had incomplete data and were not included were no significant differences between the two groups in in the analysis. The authors recorded patients’ pain intensity, any outcome measure. At 24 months, patients receiving opioid dose, number of opioids used, routes of acupuncture reported significantly less pain than the group administration, and opioid-related symptoms from admission receiving usual care only, with an estimated intervention until dose stabilization, and opioid escalation indexes (OEIs) effect of 8.0 points (95% confidence interval 2.8–13.2) after were calculated. The results showed that older patients were adjustment for baseline score and for any clustering of on lower doses of opioids at admission. However, there were intervention patients by acupuncturist. No significant no differences between younger and older patients in terms differences were found for other outcomes (e.g. the of routes of administration, need to switch, OEIs, or other disability index). Thus, from a long-term perspective, a short parameters. Moreover, adverse effects did not significantly course of acupuncture may result in better pain relief than differ between the three age groups. An overall distress conventional treatment, but not functional improvement. score worsened in older patients during acute titration but improved when the dose stabilized. Address for reprints: H MacPherson, Foundation for Traditional Chinese Medicine, York YO24 1ET. Email: [email protected] The results of this study contradict the assumption that older patients who are already receiving opioids are more susceptible than younger patients to opioid effects during OPIOIDS opioid titration. The data indicate that, although the elderly require lower doses of opioids, opioid effects do not vary with age. However, these findings should be interpreted Opioid escalation in patients with cancer with caution because the sample size in this study was pain: the effect of age relatively small. Mercadante S, Ferrera P, Villari P et al. Address for reprints: S Mercadante, Anesthesia and Intensive Care Unit J Pain Symptom Manage 2006;32:413–9. and Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Palermo, Via san Lorenzo 312, 90146 Palermo, Italy. Email: [email protected] This study evaluated differences between younger and older cancer patients in terms of opioid effects during dose refinement. Data were gathered from 100 patients Factors associated with early opioid prescription requiring opioid dose escalation. The authors evaluated among workers with low back injuries pain intensity, opioid dose, number of opioids used, Stover BD, Turner JA, Franklin G et al. routes of administration, and opioid-related symptoms J Pain 2006;7:718–25. from admission until dose stabilization. The results indicated that, although the elderly required lower doses In this prospective cohort study, the authors examined of opioids, opioid effects did not vary with age. factors associated with, and the prescription of opioids for, work-related lower back injuries. The results Patients with cancer pain often require opioid escalation to indicated that, compared with non-Hispanic, white maintain opioid efficacy, and this may cause considerable individuals, Hispanic individuals were less likely to receive concern in the elderly, who are potentially more susceptible to opioid prescriptions. Other characteristics associated with the development of adverse effects as a result of age-related opioid prescription included daily tobacco use, greater changes in pharmacokinetics. Based on this, the authors of pain and physical disability, greater injury severity, pain this prospective cohort study aimed to determine whether radiating below the knee, very high body mass index, there are any differences between younger and older cancer and worse mental health. patients with respect to opioid effects during dose refinement. Consecutive patients (n=100) who were already The prescription of opioids for non-malignant musculoskeletal receiving opioids and were admitted to a palliative care unit pain has substantially increased in recent years. However, for inadequate pain control participated in the study. For there is little empirical evidence to guide decisions on opioid the purpose of the analysis, patients were divided into three prescriptions for musculoskeletal pain. The present study age groups: therefore aimed to investigate potential relationships between early opioid prescription and worker characteristics in 1067 • <65 years (n=58). individuals with work-related back injuries. • 65–74 years (n=27). The authors examined whether any administrative, • ≥75 years (n=10). pharmacy, or worker-reported data were associated with the

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prescription of opioids within 6 weeks of the first medical mechanisms of OIH could optimize new therapeutic visit for workers’ compensation claims for work loss as a strategies. Neurokinin-1 (NK-1) receptor expressing cells result of a back injury. The results indicated that 52% of have been implicated in OIH. Prior studies show that participants who were prescribed an opioid received a ablation blocks opioid-induced thermal and tactile prescription at the first healthcare visit. This contrasts with hypersensitivity, neuropathic pain, and sensitization of spinal current practice guidelines for the treatment of acute lower dorsal horn cells when tissue injury is present. back pain, which recommend nonsteroidal anti- To examine the functional role of NK-1 receptor inflammatory drugs and acetaminophen as first-line expressing cells in conditions without tissue injury, the analgesics [1]. Consistent with findings from another survey authors’ of this study ablated these cells using intrathecal [2], workers who reported daily tobacco use were more than substance P-saporin (SP-SAP). Groups of 6–8 rats received twice as likely as non-smokers to receive an opioid intrathecal SP-SAP or placebo with uninterrupted delivery for prescription. The data also indicated that Hispanic 1 week by osmotic minipumps. To establish thermal individuals were less likely than non-Hispanic, white hyperalgesia, latency responses to noxious thermal stimuli individuals to receive opioid prescriptions. Other factors were recorded. Antinociceptive tolerance was indicated by associated with opioid prescription were greater pain and rightward shifts in morphine dose–response curves. Post physical disability, greater injury severity, pain radiating mortem immunoassays revealed spinal dynorphin content and below the knee, very high body mass index, and worse evaluation of mild tactile stimulation determined mental health. FOS protein expression. Morphine-induced thermal and This study is the first prospective population-based study mechanical hypersensitivity, and antinociceptive tolerance was of acute lower back injury in a workers’ compensation system assessed using injections of saline or ondansetron to determine factors associated with opioid prescription. The (e.g. 5-hydroxytryptamine 3 receptor antagonist). results point to the need to further examine reasons for The ablation of NK-1 receptor expressing cells resulted in ethnic differences in opiate prescription, as well as for higher the prevention of the following effects: prescription rates among daily tobacco users. 1. van Tulder M, Becker A, Bekkering T et al. European guidelines for the management of acute • Morphine-induced thermal and tactile hypersensitivity. nonspecific low back pain in primary care. European commission research directorate General, 2004. Available at: URL: http://www.backpaineurope.org/web/files/WG1_Guidelines.pdf. • Amplified touch-evoked spinal FOS expression. 2. Fanciullo GJ, Ball PA, Girault G et al. An observational study on the prevalence and pattern • Upregulation of spinal dynorphin. of opioid use in 25,479 patients with spine and radicular pain. Spine 2002;27:201–5. • Rightward displacement of the morphine dose–response Address for reprints: BD Stover, Environmental and Occupational Health curves (e.g. antinociceptive tolerance). Sciences, University of Washington, 1914 N. 34th Street, Suite 101, Seattle WA 98103, USA. Email: [email protected] These findings showed that spinal NK-1 receptor Spinal NK-1 receptor expressing neurons mediate expressing cells: opioid-induced hyperalgesia opioid-induced hyperalgesia and antinociceptive tolerance via • Are essential to opiate-induced spinal plasticity, a activation of descending pathways potential underpinning of behavioral hypersensitivity Vera-Portocarrero LP, Zhang ET, King T et al. and central sensitization. Pain 2006; [Epub ahead of print] • Are vital for opiate-induced antinociceptive tolerance. • May be a vehicle for activating the descending The mechanisms of opioid-induced hyperalgesia need facilitatory pathways. illumination. This study examined the function of neurokinin-1 (NK-1) receptor expressing cells in the Furthermore, by blocking OIH, spinal ondansetron spinal dorsal horn on morphine-induced hyperalgesia and demonstrated that serotonin may play a role in descending spinal antinociceptive tolerance in rats. Ablation of NK-1 facilitation from the rostral ventromedial medulla. receptor expressing cells via intrathecal substance P- These effects are consistent with other studies in injury- saporin prevented thermal and tactile hypersensitivity, induced pain that support the role of NK-1 receptor and antinociceptive tolerance. Ablation appears to trigger expressing cells in mechanisms of hyperalgesia and descending pathway activity and relates to spinal antinociceptive tolerance. Ablation of the lamina I projection neuroplasticity, even when tissue damage is absent. neurons that express NK-1 receptors appeared to eradicate the ascending limb of this “spinal-bulbospinal loop”, the Opioid-induced hyperalgesia (OIH) may be an important resultant features of central sensitization, and antinociceptive effect of opioid therapy. Thus, evaluating potential tolerance. These results may lead to the development of an

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explanatory model of OIH and innovative therapeutic between PH– and PH+ subjects with lower back pain. The approaches that do not heighten pain sensitivity. However, impairment of the endogenous opioid analgesic response the relevance of the results and the translation of these data was not detected in the finger pressure pain task. Because of from animal models to clinical studies in humans is unknown. the inconsistency of the response across the two tasks, the This study might have benefited from additional details results should be interpreted with caution. differentiating mechanisms of OIH from opioid tolerance. 1. Violon A, Giurgea D. Familial models of chronic pain. Pain 1984;18:199–203. 2. Katon W, Egan K, Miller D. Chronic pain: Lifetime psychiatric diagnoses and family history. Address for reprints: F Porreca, Department of Pharmacology, University Am J Psych 1985;142:1156–60. of Arizona Health Sciences Center, Tucson, AZ 85724, USA. 3. Messinger HB, Spierings ELH, Vincent AJP et al. Headache and family history. Cephalalgia 1991;11:13–8. Email: [email protected] 4. Schrader H, Obelieniene D, Bovim G et al. Natural evolution of late whiplash syndrome outside the medicolegal context. Lancet 1996;347:1207–11. 5. Reis S, Hermoni D, Borkan JM et al. A new look at low back complaints in primary care: Parental history of chronic pain may be a RAMBAM Israeli Family Practice Research Network study. J Fam Pract 1999;48:299–303. associated with impairments in endogenous 6. Poyhia R, Da Costa D, Fitzcharles MA. Previous pain experience in women with fibromyalgia opioid analgesic systems and inflammatory arthritis and nonpainful controls. J Rheumatol 2001;28:1888–91. Bruehl S, Chung OY. Address for reprints: S Bruehl, Department of Anesthesiology, Vanderbilt Pain 2006;124:287–94. University School of Medicine, Nashville, TN, USA. Email: [email protected]

This double-blind, placebo-controlled crossover study investigated whether a positive parental chronic pain Do opiates affect the clinical evaluation of patients history was associated with impaired endogenous opioid with acute abdominal pain? analgesic responses to acute pain. Subjects with a positive Ranji SR, Goldman LE, Simel DL et al. parental chronic pain history failed to exhibit any JAMA 2006;296:1764–74. endogenous opioid analgesia to acute ischemic pain, while subjects without a positive parental chronic pain This study investigated the effect of opiate analgesics on history elicited effective opioid analgesia. However, there the rational clinical examination and the decision of were no significant differences between these two groups whether to perform surgery in patients with acute of subjects in terms of finger pressure pain responses. abdominal pain. Using a literature survey, the authors analyzed data from placebo-controlled trials on opiate Previous studies have suggested an association between a analgesia. The results indicated that, although opiate family history of chronic pain and an increased risk of both administration may alter the physical examination spontaneous acute pain and chronic pain conditions [1–6]. findings, these changes do not result in a significant The authors of this study tested whether a parental history increase in management errors. of chronic pain (PH+) is associated with the degree of endogenous opioid analgesia elicited in response to two In the US, abdominal pain is the most common reason for laboratory acute pain stimuli. presentation at the emergency department. Historically, the The study sample consisted of 73 patients with chronic provision of opiate analgesia to patients with acute lower back pain (including 43 PH+ subjects) and 46 healthy, abdominal pain has been discouraged. Thus, patients with pain-free controls (including 13 PH+ subjects) received acute abdominal pain may have to wait several hours before opioid blockade and placebo blockade in separate sessions. receiving analgesia, particularly when surgical evaluation is During each session, participants underwent a finger required. Qualitative reviews of the literature have reached pressure pain task and an ischemic forearm pain task. The inconsistent conclusions about the evidence supporting the effects of blockade were determined by subtracting placebo traditional practice of withholding analgesics [1,2]. Thus, the from blockade condition pain responses. The results of aim of the present study was to perform a quantitative placebo blockade revealed that both that both PH+ subjects assessment of the effects of opiate administration to patients and subjects with lower back pain reported greater acute with acute abdominal pain. pain sensitivity than their respective comparison groups The authors performed a focused search in medical (both p<0.05). PH+ subjects had an impaired endogenous databases (MEDLINE, EMBASE) and hand searches of article opioid analgesic response to acute ischemic pain, whereas bibliographies to identify placebo-controlled, randomized PH– subjects elicited effective opioid analgesia (p<0.05); the trials on opiate analgesia reporting changes in the history, observed opioid analgesic impairments were particularly physical examination findings, or diagnostic errors. Nine prominent in PH+ subjects with lower back pain, and there trials in adults and three trials in children were identified and were no significant differences in pain duration or intensity analyzed. The results showed trends toward increased risks

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of altered findings on the abdominal examination due to (PGA) [1]. However, it is possible that adequate pain control opiate administration. Analyzed trials exhibited significant was not achieved when these systems were initiated because heterogeneity, and only two trials distinguished between the entry criteria of this study did not include a minimum pain clinically significant changes (such as loss of peritoneal signs) intensity score. The current study investigated whether the and other, potentially beneficial, changes. However, across predefined level of comfort required before randomization led adult and pediatric trials with adequate analgesia, opiate to higher rates of success according to PGA rating. The administration was associated with non-significant changes authors’ primary aim was to demonstrate that fentanyl ITS is in the risk of management errors. comparable to morphine IV PCA in terms of convenience, The study indicated that opiate analgesics do alter the safety and efficacy as a method of maintaining established physical examination in patients with acute abdominal pain pain control after total hip replacement. but seem to have little impact on the risk of clinical Subjects were randomized to receive ITS (n=395, 40 μg management errors. However, these results should be fentanyl, 10-min infusion/lockout, up to 6 doses/h) or IV PCA interpreted with caution because of the methodological (n=404, 1-mg morphine bolus, 5-min lockout, up to limitations of the study (e.g. heterogeneity of trials or 10 mg/h) after unilateral total-hip replacement. A pain inconsistent data, low number of analyzed trials). intensity score of ≤4 on a verbal numerical rating scale (where 1. Nissman SA, Kaplan LJ, Mann BD. Critically reappraising the literature-driven practice of 0=no pain and 10=worst possible pain) during post-operative analgesia administration for acute abdominal pain in the emergency room prior to surgical evaluation. Am J Surg 2003;185:291–6. screening was required for inclusion into the study. The PGA 2. Thomas SH, Silen W. Effect on diagnostic efficiency of analgesia for undifferentiated success ratings (“good” or “excellent”) and the mean last abdominal pain. Br J Surg 2003;90:5–9. pain intensity scores were similar for the ITS and IV PCA Address for reprints: SR Ranji, Department of Medicine, University of groups in the first 24 h after the operation The two groups California, San Francisco, 533 Parnassus Avenue, Box 0131, San Francisco, CA 94143-0131, USA. Email: [email protected] had a comparable incidence of adverse events; however, a higher proportion of patients in the ITS group withdrew from the study because of inadequate analgesia. This difference in POST-OPERATIVE PAIN the dropout rate warrants further investigation to determine whether it remains in a more naturalistic setting. 1. Viscusi ER, Reynolds L, Chung F et al. Patient-controlled transdermal fentanyl hydrochloride vs intravenous morphine pump for postoperative pain: A randomized Fentanyl iontophoretic transdermal system for controlled trial. JAMA 2004;291:1333–41. acute-pain management after orthopedic surgery: Address for reprints: CT Hartrick, Department of Anesthesiology, a comparative study with morphine intravenous William Beaumont Hospital, 3601 W. 13 Mile Road, Royal Oak, patient-controlled analgesia MI 48073, USA. Email: [email protected] Hattrick CT, Bourne MH, Gargiulo K et al. Reg Anesth Pain Med 2006;31:546–54. Postoperative analgesia after radical retropubic prostatectomy: a double-blind comparison The results of this multicenter, randomized, open-label between low thoracic epidural and patient active-controlled study indicate that the fentanyl HCl controlled intravenous analgesia iontophoretic transdermal system and morphine Gupta A, Fant F, Axelsson K et al. intravenous patient-controlled analgesia are comparable Anesthesiology 2006;105:784–93. methods of pain control for management of acute post- operative pain following unilateral hip replacement. This double-blind randomized study compared low thoracic epidural analgesia and patient-controlled Post-operative pain after total hip replacement is commonly intravenous analgesia for treatment of post-operative pain managed with intravenous patient-controlled analgesia (IV after radical retropubic prostatectomy. Sixty patients PCA). Limitations of IV PCA pumps include the need for IV participated in the study. The study results indicated better access, restricted patient mobility, and the possibility of pain relief and improved expiratory muscle function in the interrupted pain control as a result of device-related events. A group of patients receiving low thoracic epidural analgesia novel patient-controlled system that administers on-demand doses of fentanyl via the transdermal route (ITS) has recently This study was performed with the primary aim of been approved by the US Food and Drug Administration for comparing intravenous patient-controlled analgesia (PCA) the management of acute post-operative pain in adults. A with thoracic epidural analgesia on post-operative pain previous study demonstrated similar rates of success between during the first 48 h after radical retropubic prostatectomy. ITS and IV PCA, as measured by Patient Global Assessment The secondary aims were to assess certain respiratory

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functions, the time to mobilization, home readiness, and World Health Organization for improving the treatment of actual duration of hospital stay. Sixty patients undergoing cancer pain, multidisciplinary pain management has also radical retropubic prostatectomy for prostatic cancer were been widely accepted as a standard of care. Although randomized to receive post-operatively either an infusion of: previously published surveys presented data from large samples of patients [1–3], they were not representative of a • 1 mg/mL ropivacaine, 2 g/mL fentanyl, and 2 g/mL general cancer population at various stages of disease. adrenaline, 10 mL/h during 48 h epidurally, and a Thus, the present survey intended to investigate the pain placebo intravenous PCA pump. management of a wide range of cancer patients generally • An intravenous PCA pump with morphine and 10 mL/h cared for by oncologists and surgeons, rather than only placebo epidurally. those referred to a pain clinic, to reduce possible selection, referral, and observer bias. Pain, the primary outcome variable, was measured using The authors examined the medical records of the numeric rating scale at rest and on coughing. The results 772 patients with advanced cancer. The results revealed showed significantly lower pain scores in the epidural group that 87% of patients suffered from pain at various time compared with the intravenous PCA group. This resulted in periods, while 13% of patients were pain-free throughout improved expiratory muscle function as measured by the their survival; the mean duration of pain was maximum expiratory pressure. However, the authors found approximately 7 months. During the last 6 months of life, that the improvement in pain relief with epidural analgesia the prevalence of pain increased as the survival time did not translate into a reduction in minor or major post- shortened. The survey also identified a list of analgesics operative complications or duration of hospital stay. Quality used to manage pain: of life was poorer in both groups at 1 month compared with preoperative values, but no interaction was seen between • Tramadol was predominantly used in the “weak” group and time during the study period. The benefits of low opioid category. thoracic epidural anesthesia should be weighed against the • Meperidine was briefly used for post-operative pain rare complications seen, the possible higher costs, and the or after invasive interventions increased time taken in patient preparation. • Patient-controlled analgesia and intraspinal analgesia were used in patients with intractable pain. Address for reprints: A Gupta, Division of Anesthesiology and Intensive Care, Örebro University Hospital, SE-701 85 Örebro, Sweden. • Strontium-89 was indicated in patients with multifocal Email: [email protected]. bone pain.

Strong opioids had been used in 85% patients, and 79% PALLIATIVE CARE of patients with pain received non-surgical antineoplastic treatment for pain control. No more than 11% experienced substantial pain in the last 6 months of life. Multidisciplinary management of cancer pain: The authors concluded that a multidisciplinary approach a longitudinal retrospective study on a cohort of to pain management offers effective pain control for end-stage cancer patients most patients with advanced cancer. Although this study Peng WL, Wu GJ, Sun WZ et al. was a retrospective review, which has disadvantages such J Pain Symptom Manage 2006;32:444–52. as incomplete data collection and a lack of control subjects, the survey overcomes the limitations of previous studies, This retrospective survey of 772 patients with advanced and contributes to a better understanding of the current cancer investigated the epidemiology of cancer pain and status of management of cancer pain. 1. Vainio A, Auvinen A, with members of Symptom Prevalence Group. Prevalence of the outcomes associated with pain treatments. The symptoms among patients with advanced cancer: an international collaborative study. cumulative prevalence of pain in the study sample was J Pain Symptom Manage 1996;12:3–10. 2. Grond S, Zech D, Diefenbach C et al. Assessment of cancer pain: a prospective evaluation 87%. Strong opioids had been used in 85% patients, and in 2266 cancer patients referred to a pain service. Pain 1996;64:107–14. 79% of patients with pain received non-surgical 3. Caraceni A, Portenoy RK. An international survey of cancer pain characteristics and syndrome. Pain 1999;82:263–74. antineoplastic treatment for pain control. No more than 11% had substantial pain in the last 6 months of life. Address for reprints: WL Peng, Department of Anesthesiology, Koo Foundation Sun Yat-Sen Cancer Center, 125 LihDer Road, Pain is a very common and potentially debilitating symptom BeiTou District, 112 Taipei, Taiwan, Republic of China. in cancer patients. Besides the guidelines set out by the Email: [email protected]

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A population-based study of the impact of specific this is the first study to provide a comprehensive quantitative symptoms on quality of life in women with breast analysis of the contribution of various symptoms to overall cancer 1 year after diagnosis QOL and its specific dimensions. Arndt V, Stegmaier C, Ziegler H et al. Address for reprints: V Arndt, Division of Clinical Epidemiology and Cancer 2006;107:2496–503. Aging Research, German Cancer Research Center (DKFZ), Bergheimer Strasse 20, D-69115 Heidelberg, Germany. Email: [email protected] This study aimed to identify specific symptoms predicting long-term impairment and overall quality of life (QOL) in 314 women with breast cancer who had completed NEUROPATHIC PAIN primary therapy. Fatigue was the strongest predictor of QOL, accounting for approximately 30–50% of the variability within function scores and overall QOL, while Analgesic action of nicotine on tibial nerve other symptoms, including pain, nausea and/or vomiting, transection (TNT)-induced mechanical allodynia breast symptoms, systemic therapy side effects, and arm through enhancement of the glycinergic inhibitory symptoms, generally accounted for <5% of the system in spinal cord variability of various QOL scales. Abdin J, Morioka N, Morita K et al. Life Sci 2006;80:9–16. Specific symptoms such as pain, fatigue, and sleeping disorders are a particular concern in women with breast It is unclear which subtypes of nicotinic acetylcholine cancer, and these symptoms may have a negative effect on receptors (nAChRs) are involved in the antinociceptive their quality of life (QOL) even after the period of acute effect of nicotine on allodynia induced by nerve injury. treatment. However, little is known about the importance of This study investigated the effects of nicotine at the spinal various breast cancer symptoms to impairment of function, level against mechanical allodynia in an animal model of and few studies have specifically addressed the impact of neuropathic pain. The results indicate that the α4β2 and specific symptoms such as fatigue and arm or breast α7 nAChRs exert the suppressive effect on the nociceptive symptoms on performance of life functions in cancer transduction in neuropathic pain by enhancing activity of survivors. Therefore, in the present study, the authors aimed glycinergic neurons at the spinal level. to quantitatively assess the role specific symptoms or health complaints play in specific impairments to function and in Damage to peripheral nerves triggered by surgery, an overall QOL. infection, or diabetes has been suggested to induce a tactile The study included a population-based, state-wide allodynia, which is a state of pain produced by innocuous cohort of 387 German breast cancer patients. After a stimuli. Although several studies have suggested antinoci- comprehensive baseline interview, patients were followed ceptive actions of nicotine or nicotinic acetylcholine receptor with respect to QOL using mailed questionnaires, namely, (nAChR) agonists [1–4], it is not unclear whether stimulation the European Organisation for Research and Treatment of of nAChRs at the spinal level has an antinociceptive effect Cancer (EORTC) Quality of Life Questionnaire Core 30 on nerve injury-induced allodynia, and it remains to be Items (QLQ-C30) and the EORTC breast cancer-specific established which subtypes of the receptor might be module QLQ-BR23 1 year after diagnosis, and the vital involved in the analgesic action of nicotine. Therefore, in the status of non-respondents was obtained from the municipal present study, the authors aimed to characterize the effects registration offices. Multiple linear regression analysis of nicotine or nicotinic agonists, at the spinal level, on revealed that fatigue was the strongest predictor, accounting mechanical allodynia in an animal model, inducing for approximately 30–50% of the variability within function neuropathic pain by the tibial nerve transection (TNT). scores and overall QOL. In contrast, sociodemographic and In a set of experiments in male Wistar rats, the intrathecal clinical factors did not affect QOL to a significant extent. As injection of nicotine, RJR-2403 (a selective α4β2 nAChR fatigue is relatively common in women with breast cancer, agonist), and choline (a selective α7 nAChR agonist) efforts to reduce fatigue may have a large potential to stimulated an antinociceptive effect on the TNT-induced improve overall QOL in women with breast cancer. The allodynia. Pretreatment with mecamylamine (a nonselective authors suggest that patients may benefit from physician- nicotinic antagonist), or dihydro-β-erythroidine (a selective initiated discussion of causes of and treatments for fatigue, α4β2 nAChR antagonist) almost completely blocked the and that physicians may benefit from education regarding effects of nicotine, and pretreatment with methyllycaconitine available treatment modalities. It is interesting to note that (a selective α7 nAChR antagonist) partially reversed the

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effects. Pretreatment with strychnine (a glycine receptor withdrawal response in the lesioned foot following tactile antagonist) blocked the antinociception induced by nicotine, stimulation with von Frey filaments. RJR-2403, and choline, whereas the γ-aminobutrate (GABA) SCS systems were implanted in the epidural space of rats antagonist bicuculline did not. following protocols in previous studies. Following the These results indicate that the intrathecal administration administration of SCS for 30 minutes, the withdrawal of nicotine has an antinociceptive effect on TNT-induced thresholds were measured at 15 minute intervals. allodynia, which might involve stimulation of the α4β2 and A series of t-tests for dependent samples were conducted, α7 subtypes of nAChR at the spinal level. The authors comparing withdrawal threshold during and after SCS, with concluded that the glycinergic inhibitory system, but not the the withdrawal thresholds prior to the stimulus. GABAergic inhibitory system, might contribute to Results showed that the severity of allodynia was the antinociceptive effect of nicotine on nerve injury- positively correlated with response to SCS. Rats with mild induced allodynia. allodynia had the most superior response, with a full return 1. Gilbert SD, Clark TM, Flores CM. Antihyperalgesic activity of epibatidine in the formalin to baseline, pre-nerve lesion withdrawal threshold levels. In model of facial pain. Pain 2001;89:159–65. 2. Rao TS, Correa LD, Reid RT et al. Evaluation of antinociceptive effects of neuronal contrast, rats with moderate allodynia responded to SCS; nicotinic acetylcholine receptor (NAChR) ligands in the rat tail-flick assay. however, the withdrawal thresholds improved to Neuropharmacology 1996;35:393–405. 3. Wang Y, Su DM, Wang RH et al. Antinociceptive effects of choline against acute and approximately 33% of the baseline function. Finally, rats in inflammatory pain. Neuroscience 2005;132:49–56. the severely allodynic group had no response to SCS. 4. Rashid MH, Ueda H. Neuropathy-specific analgesia action of intrathecal nicotinic agonists and its spinal GABA-mediated mechanism. Brain Res 2002;953:53–62. In this study, rats with mild allodynia had a more rapid and optimal response to SCS compared with rats with severe Address for reprints: T Dohi, Department of Dental Pharmacology, Division of Integrated Medical Science, Hiroshima University Graduate allodynia. The potential clinical significance of allodynia School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima severity on differences in SCS pain relief outcomes in 734-8553, Japan. Email address: [email protected] humans requires additional investigation.

Address for reprints: EAJ Joosten, Pain Management and Research Effect of spinal cord stimulation in an animal model of Center, Department of Anaesthesiology, Maastricht University Hospital, neuropathic pain relates to degree of tactile “allodynia” P. Debyelaan 25, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Smits H, Ultenius C, Deumens R et al. Email: [email protected] Neuroscience 2006;143:541–6. Prevalence of contraindicated medical conditions and This study evaluated the impact of spinal cord stimulation use of precluded medications in patients with painful (SCS) on analgesia according to the severity of neuropathic disorders prescribed amitriptyline mechanical allodynia in a rat model of neuropathic pain. Gore M, Dukes E, Rowbotham D et al. Based on measurement of the withdrawal response to Pain Pract 2006;6:265–72. tactile stimuli, rats with severe allodynia did not respond to SCS, whereas rats with mild allodynia had more Amitriptyline is often prescribed in the management of optimal pain relief. These findings may have potential painful neuropathic disorders (PNDs). However, the clinical implications on predicting patient response to SCS amitriptyline label contains many preclusions as related to allodynia severity. (contraindications, warnings/precautions, drug interactions). This study investigated the frequency of Spinal cord stimulation (SCS) is widely-used for the amitriptyline prescriptions in PND patients and assessed treatment of chronic neuropathic pain. For patients treated whether prescriptions were given to patients with any of with SCS in complex regional pain syndrome (CRPS), mixed the preclusions listed in the product label. Based on data results have been found on the relationship between pain from 13 546 patients, the results indicated that, in a relief and allodynia severity. It is possible that the degree of significant number of cases, the existence of preclusions allodynia severity (mild, moderate, or severe) predicts the did not prevent the prescribing of amitriptyline. magnitude of pain relief from SCS. Following sciatic nerve ligation in 45 rats, the role of Amitriptyline is recommended as first-line therapy for the allodynia severity on pain was examined in 27 rats with management of neuropathic pain, although it is not approved tactile sensitivity due to neuropathic pain. Tactile sensitivity for this indication in the UK. The decision to prescribe this in rats was comparable to tactile allodynia in humans with medication to patients with painful neuropathic disorders nerve damage. Allodynia was classified as “mild” (n=6), (PNDs) must be made following a careful evaluation of the “moderate” (n=14), or “severe” (n=7) based on the preclusions (contraindications, warnings/precautions, drug

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interactions) listed in the label. In cases where the use of studies have shown that nicotinic acetylcholine receptors amitriptyline is not completely contraindicated, but there is a (nAChR) are implicated in peripheral nerve damage. This comorbid presence of a warning or potential for a drug study examined an animal model to expand on prior studies interaction, an intensified level of medical vigilance may be in order to specify a mediator of nAChR site activity. required. The present study aimed to determine the frequency Following chronic constriction injury (CCI) of the sciatic of amitriptyline prescriptions in PND patients and to evaluate nerve in rats, behavioral testing and immunohistochemistry whether prescriptions are given to patients with any revealed the following: of the preclusions. Using the UK General Practice Research Database, the • RgIA, a potent α9α10 antagonist, at the highest authors identified a total of 13 546 patients diagnosed with dose produced analgesia and negated CCI-induced PND who had received at least one prescription for mechanical hypersensitivity. amitriptyline between July 1998 and June 2001. Overall, • Vc1.1 in CCI rats significantly lengthened paw 46.7% of PND patients prescribed amitriptyline had one or withdrawal thresholds due to analgesic effects, and more preclusions for its use, 3.5% had at least one subsequently reduced CCI-induced mechanical contraindication, 22% had one or more warning or hypersensitivity similar to RgIA. precaution, and 33% were taking one or more medication • Following CCI’s effects on amplifying the number of with a potential for drug interactions with amitriptyline. choline acetyltransferase (ChAT)-immunoreactive cells in These results indicate that the prescribing of amitriptyline the ligated sciatic nerve, RgIA modified the peripheral among PND patients with any preclusions is relatively immune response by decreasing the number of ChAT common in UK. According to the authors, a possible immunoreactive cells. explanation for this practice is that the number and efficacy of medications available for management of neuropathic In this study, the administration of RgIA produced pain are limited. Furthermore, amitriptyline is relatively analgesia on nerve injured rats. Furthermore, selective inexpensive and is indicated for the treatment of depression, blockade with RgIA decreased the number of ChAT-positive a known comorbidity among PND patients. Thus, it is cells, macrophages, and lymphocytes. Whereas previous possible that the proven efficacy of amitriptyline in findings have shown that nicotinic agonists result in analgesia, depression as well as in neuropathic pain was the primary this study demonstrated that nAChR antagonism of the impetus for its prescribing in PND patients. The findings of α9α10 receptor subtype produced analgesia. Future studies this study raise concerns about the way in which focusing on α9α10 nAChRs may lead to the development of amitriptyline is being used. novel pharmacological therapies for neuropathic pain.

Address for reprints: M Gore, Avalon Health Solutions, Inc., Address for reprints: JM McIntosh, Psychiatry, University of Utah, 1528 Walnut Street, Suite 1507, Philadelphia, PA 19102, USA. 257 South 1400 East, Salt Lake City, UT 84112, USA. Email: [email protected] Email: [email protected]

Molecular mechanism for analgesia involving Pregabalin in central neuropathic pain associated specific antagonism of α9α10 nicotinic with spinal cord injury: a placebo-controlled trial acetylcholine receptors Siddall PJ, Cousins MJ, Otte A et al. Vincler M, Wittenauer S, Parker R et al. Neurology 2006;67:1792–800. PNAS 2006;103:17880–4. This randomized controlled trial examined the efficacy and Using a rat model, this study proposes a molecular safety of pregabalin (150–600 mg) on central neuropathic mechanism for the pathogenesis of neuropathic pain pain in adults with spinal cord injury. At day 7 of this involving RgIA, a potent antagonist of the α9α10 nicotinic 12-week trial, the lowest dose of 150 mg was associated acetylcholine receptor (nAChR). Findings show that with significant reductions in pain intensity. Efficacy findings blockade of the α9α10 nAChRs produces antinociceptive were consistent for 12 weeks, suggesting that pregabalin effects in peripheral nerve damaged rats, and decreases taken as a monotherapy or supplemental therapy may be the movement of choline acetyltransferase-positive cells, effective for moderate-to-severe neuropathic pain. macrophages, and lymphocytes into the nerve injured site. Central neuropathic pain is a consequence of multiple medical Neuropathic pain is prevalent worldwide; however, the conditions, including 40% of spinal cord injured patients. complex determinants require much investigation. Previous Pregabalin is presently effective in treating seizure disorders,

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anxiety, peripheral neuropathic pain, and pain-related sleep Based on the finding that fibromyalgia syndrome (FMS) is disturbance. To evaluate the efficacy of pregabalin on central more prevalent among women than men, this study neuropathic pain in spinal cord injured patients, a multicenter, investigated whether and how sex hormones may be randomized, placebo-controlled trial was conducted. involved in the pathophysiology of the disorder. The Using flexible dose escalation, patients were randomized authors evaluated levels of sex hormones and pain to pregabalin 150–600 mg twice daily (n=70) or placebo sensitivity during different phases of the menstrual cycle (n=67) over 12 weeks. Pregabalin was given as a in women with FMS and in age-matched healthy controls. monotherapy or supplemental therapy, with continuation of The results suggest that the disproportionate prevalence pre-study medications permitted. Patients were treated with of FMS in women is not likely due to hormonal factors. 150 mg of pregabalin for 1 week, followed by 300 mg at week 2, and escalated to 600 mg at week 3, if needed. Fibromyalgia syndrome (FMS) is a musculoskeletal pain The primary endpoints included mean pain intensity disorder estimated to affect 3–5% of population. One of the (based on the following 7 days of patients’ pain diary data) intriguing characteristics of this disorder is its higher and safety. Secondary endpoints included responder rates, the prevalence in women (4.9%) than in men (1.3%). The Short-Form McGill Pain Questionnaire, sleep interference authors of this study investigated whether FMS is associated (diary data; Medical Outcomes Study Sleep Scale), and with any abnormalities in sex hormone levels during different psychological distress (Hospital Anxiety and Depression Scale). phases of the menstrual cycle, and whether pain sensitivity is Pregabalin was associated with significant reductions in affected by sex hormone levels in female FMS patients or mean pain intensity from baseline to endpoint (6.5 vs. 4.6) healthy controls. The study included 74 women with FMS while placebo was not (6.7 vs. 6.3). At day 7, pain was and 74 age-matched healthy controls who were regularly significantly reduced with pregabalin 150 mg/day, the lowest menstruating and not taking hormone-based contraception. dose, and continued to be lower than placebo for 12 weeks. All participants underwent a 9-day urine test to identify the The average dose of pregabalin was 460 mg between weeks date of ovulation, and then three study visits were scheduled 4–12. The magnitude of improvement did not differ to determine levels of sex hormones at the late-follicular significantly whether pregabalin was supplemental (70% of phase, mid-luteal phase, and peri-menstrual phase of the patients) or administered as a monotherapy. In the pregabalin menstrual cycle. At each visit, pain threshold and tolerance group, 42% reported ≥30% pain reduction and 22% were determined using the ischemic pain test. The results reported ≥50% reduction. Over 33% of patients reported no showed that, compared with healthy controls, women with to mild pain at endpoint (compared with 11% in placebo). FMS had lower pain thresholds and tolerance throughout the Overall, pregabalin was well-tolerated, with somnolence menstrual cycle. Levels of luteal hormone, follicular- the most common adverse event (41.4%) followed by stimulating hormone, estrogen, and testosterone were similar dizziness (24.3%). Attrition due to adverse events was 21%. in the two groups throughout the menstrual cycle. FMS Pregabalin was related to significantly better sleep quality, patients had slightly elevated progesterone levels during the lower sleep disturbance, and lower levels of anxiety, but was mid-luteal phase, but these were within the normal range. unrelated to depression. The phasing of the menstrual cycles in this study appeared to In this study, pregabalin was associated with clinically show normal cycling patterns for both groups, with high significant reductions in central neuropathic pain. Future levels of estradiol and progesterone in the mid-luteal phase, trials are needed to validate these results in patients with low levels of these hormones in the peri-menstrual phase, spinal cord injury and other patient subgroups. and elevated levels of estradiol and low levels of progesterone in the late follicular phase. The results suggest Address for reprints: PJ Siddall, Pain Management and Research Institute, University of Sydney, Royal North Shore Hospital, Sydney, that the disproportionate representation of women among NSW, 2065, Australia. Email: [email protected] FMS patients is not likely due to abnormal levels of sex hormones. The results are consistent with previous studies performing single-phase assessment of sex steroids [1–3]. 1. Akkus S, Delibas N, Tamer MN. Do sex hormones play a role in fibromyalgia? MISCELLANEOUS Rheumatology (Oxford) 2000;39:1161–3. 2. Carette S, Dessureault M, Belanger A. Fibromyalgia and sex hormones. J Rheumatol 1992;19:831. 3. Gur A, Cevik R, Sarac AJ et al. Hypothalamic–pituitary–gonadal axis and cortisol in young Sex hormones and pain in regularly menstruating women with primary fibromyalgia: the potential roles of depression, fatigue, and sleep women with fibromyalgia syndrome disturbance in the occurrence of hypocortisolism. Ann Rheum Dis 2004:63:1504–6. Okifuji A, Turk DC. Address for reprints: A Okifuji, Pain Research Center, Department of Anesthesiology, University of Utah, 615 Arapeen Drive, Suite 200, J Pain 2006;7:851–9. Salt Lake City, UT 84108, USA. Email: [email protected]

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Pain perception and expression: the influence of men. Overall, Indian men and women believed it was less gender, personal self-efficacy, and lifespan socialization appropriate to express pain compared with participants in Miller C, Newton SE. the US. Pain Management Nursing 2006;7:148–52. Implications for nursing include pain assessment techniques that appreciate the potential influence of these Behavioral and psychosocial factors may affect pain person-level variables. Healthcare providers may need to experience more than biomedical factors. This review of increase awareness of possible differences in communication, the empirical literature describes the roles of gender, self- expression, and preferred coping approaches. Tailoring the efficacy, and lifespan socialization on pain experience. delivery of pain education and pain management strategies according to gender may be useful. Pain is not only a function of physical pathology, but 1. Bandura A. Self-efficacy: toward a unifying theory of behavioral change. Psychol Rev 1977;84:191–215. psychosocial and behavioral factors that contribute to the 2. Jackson T, Iezzi T, Gunderson Jet al. Gender differences in pain perception: the mediating pain experience. This literature review describes three role of self-efficacy beliefs. Sex Roles: A Journal of Research 2002;8:8–9. relevant variables that may play important roles on pain Address for reprints: SE Newton, 448 O’Dowd Hall, Oakland University, experience: gender, self-efficacy (SE), and lifespan Rochester, MI 48309, USA. Email: [email protected] socialization. Gender predicts pain perceptions and pain experience. Multiple dose gabapentin attenuates cutaneous A review of the findings shows that women have lower pain pain and central sensitisation but not muscle pain thresholds, greater ability to differentiate pain, and report in healthy volunteers higher pain ratings for noxious stimuli compared with men. Segerdahl M. Women report more sites of pain in endogenous pain Pain 2006;125:158–64. compared with men. A large survey showed that women were more likely to report severe pain and have more This double-blind, placebo-controlled, crossover study frequent episodes of severe pain than men. compared the effect of gabapentin (GBP; 0, 1200, 1800, One potential explanation is that SE mediates the and 2600 mg) on muscle and cutaneous pain in healthy relationship between gender and pain perception. Perceived participants. Single or multiple dosing of GBP relieved SE is the belief in one’s ability to perform specific behaviors pain sensitivity to intracutaneous electrical stimulation, in order to produce a desired outcome due to personal but did not attenuate pain induced by intramuscular experience, modeling of social behavior, and arousal [1]. infusion of hypertonic saline. Jackson et al. showed that physical SE fully mediated the relationship between gender and pain [2]. In this study, Gabapentin (GBP) is well-known to be efficacious in the beliefs about physical capabilities accounted for gender treatment of chronic neuropathic pain. The efficacy of GBP differences in pain. Men reported lower pain sensitivity and as an adjunct to acute post-operative pain therapy has been higher pain tolerance compared with women. Therefore, recently demonstrated. No known studies have evaluated sociocultural influences may shape personal beliefs about the effect of GBP on muscle and cutaneous pain. Muscle one’s capacity to manage pain and express pain-related pain is a major clinical concern, and efficacious treatments distress. More men report discouragement in childhood from for chronic muscle pain are presently limited. expressing pain-specific distress and encouragement to The author of the current study examined the effect of display more stoic responses to pain. single-dose GBP (1200 and 2600 mg) and placebo on In addition, coping style may moderate the relationship continuous intracutaneous electrical stimulation (CESS), and between gender and pain experience. Women may report intramuscular (IM) infusion of hypertonic saline in eight men more psychological distress to elicit interpersonal support, as and eight women volunteers. Participants received the women tend to prefer communal approaches; therefore, SE following treatments in a randomized, crossover design: a for intrapersonal coping with pain may be less salient to single-dose of GBP 1200 mg over 24 h; GBP 600 mg three their preferred style of coping. times daily plus 800 mg (2600 mg in total); and placebo. Developmental data show that infants with acute pain CESS was administered in the forearm and intensified until express no differences in pain behaviors or facial muscle the current produced pain intensity of 5/10 or reached action by gender. Thus, the theory that sociocultural 70mA. CESS has been proposed to induce pain by activating influences shape pain perception and experience appears mechano-insensitive C-fibers. relevant. Cross-cultural findings show that women and men The study of variance analyses for multiple dependent believe it is more appropriate for women to report pain than samples compared placebo and active treatment, and chi

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square analyses compared the frequencies of referred pain • Zone 1 (most cases): Fractures of the sacral ala that are areas post-saline infusion. unrelated to neurological impairments, but may cause Adverse effects were minimal and the drug was well- injury to the lumbosacral nerve roots. tolerated. Following IM infusion of hypertonic saline, single- • Zone 2: Fractures of the sacral foramina that are linked and repeated-dose GBP versus placebo showed no to unilateral lumbosacral radiculopathies. significant difference at baseline and 120 min after final • Zone 3: Fractures throughout the sacrum that are associa- administration. Results of CESS showed pre-treatment with ted with neurological deficits and sphincter dysfunction. GBP 1800 mg necessitated a stronger current to achieve visual analogue scale ratings of 4–5 compared with placebo. The pathophysiology of SIFs is bilateral on onset, occurring As such, GBP significantly decreased sensitivity of skin pain in the sacral ala, with concurrent fractures of the pelvic ring from CESS by 14%. Mechanical pain in the secondary causing breakdown of the osteoporotic sacrum. Approximately hyperalgesia area decreased following pre-treatment. 66% of patients with SIFs lack a history of trauma, therefore These results show promise in establishing the initial use fracture is rarely suspected. of GBP for attenuating cutaneous pain in healthy adults. Post-menopausal osteoporosis is a leading risk factor for SIFs, with corticosteroid-induced osteopenia, pelvic Address for reprints: M Segerdahl, Department for Clinical Science, Intervention and Technology, Division for Anesthesiology, Karolinska irradiation, and secondary osteoporosis also potential factors. Institutet, Karolinska University Hospital, Huddinge, S-141 86 In addition, vitamin D insufficiency and pregnancy-related Stockholm, Sweden. Email: [email protected] osteoporosis are associated with SIFs. Clinical symptoms are gradual in onset and are characterized Sacral insufficiency fractures: by potentially severe pain in the low back and pelvis, causing current concepts of management functional impairment. Physical examination is remarkable for Tsiridis E, Upadhyay N, Giannoudis PV et al. revealing sacral tenderness on lateral compression (sacroiliac joint Osteoporos Int 2006;17:1716–25. tests such as flexion-abduction-external rotation, Gaenslen’s test, and squish test are diagnostically useful) and a slowed gait. Sacral insufficiency fractures (SIFs) are a type of stress The use of radiographic imaging is compromised by a lack fracture causing significant pain and disability in elderly of trauma or visible fractures, curvature of the sacrum, and adults. The incidence of SIFs is expected to rise demineralization. Differential diagnosis is complex given that worldwide as the population ages. However, SIFs are findings often resemble metastatic disease, sacroiliac joint commonly underdiagnosed in elderly patients due to infection, and spinal stenosis. Many SIFs are confused with nonspecific symptoms and radiographic findings. malignancies and osteomyelitis; thus, computed tomography Postmenopausal osteoporosis is the main risk factor for is useful for differential diagnosis. Magnetic resonance SIFs, followed by corticosteroid-induced osteopenia and imaging is the most valid diagnostic method. pelvic irradiation. Treatments include bed rest, Given the link with osteopenia, SIFs may be prevented by analgesia, rehabilitation, and physical therapy, with vitamin D, calcium, and biophosphonates. Teriparatide and some patients requiring hospitalization. This article selective oestrogen receptor modulators are effective for describes the epidemiology, pathophysiology, and treating osteoporosis. Opioids may be indicated, but the differential diagnosis of SIFs, and reviews best practices efficacy of nonsteroidal anti-inflammatory drugs on fractures for prevention and treatment. is unknown. Recent data show that rehabilitation may be more effective in reducing SIF-associated morbidity than bed Rates of sacral insufficiency fractures (SIFs) will increase rest. Ongoing research is evaluating the efficacy of sacroplasty significantly by 2030 due to the growing elderly population for stabilization of the fracture. and improved imaging. Research is needed to examine the This quality review provides a comprehensive analysis of prevalence and financial costs of SIFs. Multiple case studies SIFs and establishes a clear rationale for their significance to (e.g. 3–20 patients) have documented the biomedical and clinicians. However, it could benefit from greater discussion clinical characteristics of SIFs. of areas for additional research, a critique of the empirical SIFs are frequently underdiagnosed as a cause of pain findings, and clearer differentiation of SIFs from other and disability in elderly and high-risk populations. At insufficiency fractures of the pelvic ring. present, there is no standardized classification criteria. Denis 1. Denis F, Davis S, Comfort T. Sacral fractures: an important problem. Clin Orthop Relat Res 1988;227:67–81. et al. have proposed classifying SIFs by site (zone) and sequelae [1]: Address for reprints: PV Giannoudis, Academic Department of Trauma and Orthopedics, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK. Email: [email protected]

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VOLUME 1 NUMBER 1 2007

Advances in PAIN MANAGEMENT

EDITOR-IN-CHIEF Russell Portenoy, New York, NY, USA

Breakthrough Pain in Cancer Patients Giovambattista Zeppetella

Mechanisms of Neuropathic Pain Nanna Finnerup and Troels Jensen

Pamidronates for Non-Cancer Pain Marco Pappagallo

www.advancesinpainmanagement.com

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