bluuebunny/crossref_metadata_2025 huggingface dataset:
Cochlear implant design
Authors: Topsakal Vedat
Published: October 2018

This chapter discusses papers on cochlear implant design including the design of the studies (outcome measures, results, conclusions, and a critique).
Radiological staging of rhinosinusitis
Authors: Bhalla Rajiv
Published: October 2018

This chapter discusses Lund and Mackay’s paper on radiological staging of rhinosinusitis including the design of the study (outcome measures, results, conclusions, and a critique).
Endoscopic sinus surgery
Authors: Field Rebecca
Published: October 2018

This chapter discusses Stammberger’s paper on endoscopic endonasal surgery with nasal polyps including the design of the study (outcome measures, results, conclusions, and a critique).
Surgical outcomes for rhinosinusitis
Authors: Reid Luke
Published: October 2018

This chapter discusses Hopkins, Browne, Slack, Brown, Lund, Copley, and Van der Meulen’s paper on The National Comparative Audit of Surgery for Nasal Polyposis and Rhinosinusitis including the design of the study (outcome measures, results, conclusions, and a critique).
Immunotherapy
Authors: Saleh Hesham , Ahmed Jahangir
Published: October 2018

This chapter discusses Durham and Penagos’s paper on sublingual or subcutaneous immunotherapy for allergic rhinitis including the design of the study (outcome measures, results, conclusions, and a critique).
Hereditary haemorrhagic telangiectasia
Authors: Hopkins Claire
Published: October 2018

This chapter discusses Lund and Howard’s paper on a treatment algorithm in the management of epistaxis in hereditary haemorrhagic telangiectasia including the design of the study (outcome measures, results, conclusions, and a critique).
Facial pain
Authors: Erskine Sally
Published: October 2018

This chapter discusses West and Jones’s paper on facial pain including the design of the study (outcome measures, results, conclusions, and a critique).
Epidemiology of laryngeal cancer
Authors: Erskine Sally
Published: October 2018

This chapter discusses Hoffman, Porter, Karnell, Cooper, Weber, Langer, Ang, Gay, Stewart, and Robinson paper on epidemiology of laryngeal cancer including the design of the study (outcome measures, results, conclusions, and a critique).
Smoking, alcohol, and head and neck cancer
Authors: Roques Tom
Published: October 2018

This chapter discusses Marron et al.’s paper on the cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk including the design of the study (outcome measures, results, conclusions, and a critique).
Human papilloma virus
Authors: Masterson Liam
Published: October 2018

This chapter discusses Ang, Harris, Wheeler, Weber, Rosenthal, Nguyen-Tân, Westra, Chung, Jordan, Lu, Kim, Axelrod, Silverman, Redmond, and Gillison’s paper on the human papilloma virus including the design of the study (outcome measures, results, conclusions, and a critique).
Laser microsurgery for laryngeal cancer
Authors: Paleri Vinidh , Fox Hannah
Published: October 2018

This chapter discusses Steiner’s paper on laser microsurgery for laryngeal cancer including the design of the study (outcome measures, results, conclusions, and a critique).
Oncological management of head and neck cancer II
Authors: Roques Tom
Published: October 2018

This chapter discusses Bernier, Cooper, Pajak, van Glabbeke, Bourhis, Forastiere, Ozsahin, Jacobs, Jassem, Ang, and Lefèbvre’s paper on oncological management of head and neck cancer including the design of the study (outcome measures, results, conclusions, and a critique).
Oncological management of head and neck cancer III
Authors: Roques Tom
Published: October 2018

This chapter discusses Pignon, le Maître, Maillard, and Bourhis’s paper on meta-analysis of chemotherapy in head and neck cancer including the design of the study (outcome measures, results, conclusions, and a critique).
PET-CT as a method of surveillance for head and neck cancer
Authors: Masterson Liam
Published: October 2018

This chapter discusses the PET-NECK Trial Management Group’s paper on PET-CT surveillance versus neck dissection in advanced head and neck cancer including the design of the study (outcome measures, results, conclusions, and a critique).
Quality of life for patients with laryngeal cancer
Authors: Erskine Sally
Published: October 2018

This chapter discusses McNeil, Weichselbaum, and Pauker’s paper on quality of life for patients with laryngeal cancer including the design of the study (outcome measures, results, conclusions, and a critique).
Predicting outcome in thyroid cancer
Authors: England James
Published: October 2018

This chapter discusses Hay, Bergstralh, Goellner, Ebersold, and Grant’s paper on predicting outcome in thyroid cancer including the design of the study (outcome measures, results, conclusions, and a critique).
Pharyngeal pouch surgery
Authors: England James
Published: October 2018

This chapter discusses Collard, Otte, and Kastens’s paper on pharyngeal pouch surgery including the design of the study (outcome measures, results, conclusions, and a critique).
Thyroglossal duct cyst surgery
Authors: England James
Published: October 2018

This chapter discusses Sistrunk’s paper on thyroglossal duct cyst surgery including the design of the study (outcome measures, results, conclusions, and a critique).
The physiology of vocal cord movement
Authors: Cooper Stephanie
Published: October 2018

This chapter discusses Titze’s paper on the physics of small-amplitude oscillation of the vocal folds including the design of the study (outcome measures, results, conclusions, and a critique).
Evaluation of dysphonia
Authors: Cooper Stephanie
Published: October 2018

This chapter discusses Dejonckere, Obbens, de Moor, and Wieneke’s paper on the evaluation of dysphonia including the design of the study (outcome measures, results, conclusions, and a critique).
Laryngopharyngeal reflux disease
Authors: Cooper Stephanie
Published: October 2018

This chapter discusses Koufman’s paper on laryngopharyngeal reflux disease including the design of the study (outcome measures, results, conclusions, and a critique).
Assessing daytime sleepiness
Authors: Vanderveken Olivier
Published: October 2018

This chapter discusses Johns’s paper on assessing daytime sleepiness including the design of the study (outcome measures, results, conclusions, and a critique).
Tonsillitis
Authors: Bath Andy
Published: October 2018

This chapter discusses Paradise, Bluestone, Bachman, Colborn, Bernard, Taylor, et al.’s paper on tonsillitis including the design of the study (outcome measures, results, conclusions, and a critique).
Tonsillectomy
Authors: Little Paul
Published: October 2018

This chapter discusses Lowe and van der Meulen’s paper on tonsillectomy including the design of the study (outcome measures, results, conclusions, and a critique).
Acute otitis media
Authors: Little Paul
Published: October 2018

This chapter discusses Rovers, Glasziou, Appelman, Burke, McCormick, Damoiseaux, Gaboury, Little, and Hoes’s paper on acute otitis media including the design of the study (outcome measures, results, conclusions, and a critique).
Brainstem-evoked response audiometry
Authors: Kennedy Veronica
Published: October 2018

This chapter discusses Schulman-Galambos and Galambos’s paper on brainstem evoked response audiometry in newborn hearing screening including the design of the study (outcome measures, results, conclusions, and a critique).
Grading subglottic stenosis
Authors: Morrison Gavin
Published: October 2018

This chapter discusses Myer, O’Connor, and Cotton’s paper on grading subglottic stenosis including the design of the study (outcome measures, results, conclusions, and a critique).
Cervical lymphadenitis in children
Authors: Bath Andy
Published: October 2018

This chapter discusses Spyridis, Maltezou, Hantzakos, Scondras, and Kafetzis’s paper on mycobacterial cervical lymphadenitis in children including the design of the study (outcome measures, results, conclusions, and a critique).
Skull base flaps
Authors: Bhalla Rajiv
Published: October 2018

This chapter discusses Hadad, Bassagasteguy, Carrau, Mataza, and Kassam’s paper on skull base flaps including the design of the study (outcome measures, results, conclusions, and a critique).
The temporomandibular joint
Authors: Sidebottom Andrew
Published: October 2018

This chapter discusses Wilkes’s paper on the temporomandibular joint including the design of the study (outcome measures, results, conclusions, and a critique).
Drooling
Authors: Sidebottom Andrew
Published: October 2018

This chapter discusses Wilkie’s paper on problem of drooling in cerebral palsy including the design of the study (outcome measures, results, conclusions, and a critique).
Postoperative venous thromboembolism
Authors: Lyall Hamish
Published: October 2018

This chapter discusses Sweetland, Green, Liu, Berrington de Gonzalez, Canonico, Reeves, and Beral’s paper on postoperative venous thromboembolism including the design of the study (outcome measures, results, conclusions, and a critique).
Tranexamic acid
Authors: Lyall Hamish
Published: October 2018

This chapter discusses papers by the CRASH-2 trial collaborators on tranexamic acid including the design of the studies (outcome measures, results, conclusions, and a critique).
Bolam v. Friern Hospital Management Committee
Authors: Webber Peter
Published: October 2018

This chapter discusses the legal case between Bolam v. Friern Hospital Management Committee [1957], including the detail of the case and its implications.
Chappel v. Hart
Authors: Webber Peter
Published: October 2018

This chapter discusses the legal case between Chappel v. Hart [1998], including the details of the case and its implications.
Noise-induced hearing loss
Authors: Dobie Robert
Published: October 2018

This chapter discusses Coles, Lutman, and Buffin’s paper on noise-induced hearing loss including the design of the study (outcome measures, results, conclusions, and a critique).
Introduction
Authors: Phillips John , Erskine Sally
Published: October 2018

This chapter provides the rationale for selecting a ‘landmark paper’, sets out the format for each chapter in the rest of the book, and explains the levels of evidence used throughout the title.
Local anaesthetic substitutes for cocaine
Authors: Wildsmith J. A. W. (Tony)
Published: October 2018

The early twentieth century saw the production of a large number of local anaesthetic drugs as alternatives to cocaine. The paper under consideration describes a study which compared 11 of those drugs with cocaine, using criteria put forward earlier by Braun. The therapeutic ratio, water solubility, chemical stability in solution, potency, systemic toxicity, local tissue toxicity, and compatibility with adrenalin of each drug were assessed and compared in wide-ranging bench and animal studies. Comparisons of potency would also seem to have been performed in man. The overall conclusion was that procaine, which became the standard agent until lidocaine was introduced, was clearly superior. However, the paper is virtually unknown, in spite of describing what would appear to have been the definitive study of the period.
Explaining reflex sympathetic dystrophy
Authors: Brandner Brigitta
Published: October 2018

The medical community had long been aware of a constellation of symptoms involving pain, bone atrophy, and trophic changes that could occur following a trauma; however, this paper was the first to unify and explain the syndrome. James Evans amalgamated other theories of the time and was the first to realize the fundamental role of the autonomic nervous system in explaining the pathophysiology of the condition, which he named ‘reflex sympathetic dystrophy’. Evans uses 57 cases histories to highlight the variety of noxious stimuli that may result in reflex sympathetic dystrophy, and goes onto outline the local anaesthetic blocks and sympathectomies he used to treat them. This is a seminal paper because Evans is the first to use the term ‘reflex sympathetic dystrophy’ and, in doing so, proposes an underlying mechanism for a disease process that, while known, was until then very poorly understood.
The rediscovery of paracetamol
Authors: Mallet Christophe , Eschalier Alain
Published: October 2018

The chapter describes experiments performed by Bernard B. Brodie and Julius Axelrod in an article published in 1948 and entitled ‘The fate of acetanilide in man’. This was an important breakthrough in the history of paracetamol (acetaminophen), which was synthesized in 1878 but only clinically used in 1955. We highlight how this article historically catalysed the rehabilitation (also called ‘the rediscovery’) of this popular over-the-counter painkiller. Demonstrating that paracetamol was the key active metabolite of acetanilide (an antipyretic/analgesic used at that time), and discarding the false idea that paracetamol causes methaemoglobinaemia, Brodie and Axelrod paved the way for this molecule to become nowadays the most sold analgesic worldwide, one which is still the subject of scientific publications.
The pharmacology of placebos
Authors: Benedetti Fabrizio
Published: October 2018

The paper discussed in this chapter was the first to compare some of the pharmacological effects of drugs to the effects induced by placebo treatments. It is one of the first studies to introduce the notion of a pharmacology of placebos, an idea which was quite unusual and innovative in the 1950s. In particular, in this study, many characteristics, which are typical of drug treatments, were investigated regarding placebo treatments. For example, peak effects, cumulative effects, carryover effects, and the relationship between efficacy and severity of disease were analysed in conditions such as post-partum pain. The main results show that placebos may produce effects that are similar to those induced by drugs. This pioneering study paved the way to a true biology of the placebo effect and to the modern emerging concept that placebos and therapeutic rituals use the same receptor and biochemical pathways that are used by drugs.
Three determinants of pain
Authors: Choinière Manon , Pagé M. Gabriella
Published: October 2018

Building on the foundations laid by the gate control theory, Melzack and Casey theorized in 1968 the existence of three separate, yet related determinants of pain: sensory–discriminative, affective–motivational, and cognitive–evaluative. These determinants have roots in separate neurophysiological pathways that modulate the pain experience. The importance of this paper lies in its theoretical contribution to our understanding of pain. Melzack and Casey’s seminal paper, written almost 50 years ago, is not only still contemporary, as evidenced by the internationally agreed upon definition of chronic pain (the IASP taxonomy) but has also contributed to moving from a biomedical understanding of pain to a biopsychosocial model of evaluating and treating pain. This conceptualization of pain continues to influence the way pain is evaluated and is the foundation of the use of non-pharmacological and non-interventional modalities for the treatment of pain (e.g. psychological techniques), and multidisciplinary approaches to pain treatment.
Genetic differences in opiate receptors
Authors: Mogil Jeffrey S.
Published: October 2018

The 1975 manuscript ‘Opioid receptors in mice: Genetic differences’ by Baran and colleagues was the first published paper to forward a hypothesis as to what might underlie mouse strain differences in opioid analgesic response. A strain was identified, CXBK, that exhibited both deficient morphine analgesia and low μ‎-opioid receptor density. Further study of this strain over the next two decades proved very useful, and the phenotype of CXBK mice has now been explained at the molecular level. The Baran et al. paper presaged the modern genetic studies of the μ‎-opioid gene, OPRM1, and was an important early example of the very active modern field of pain genetics.
Ethical pain experimentation in conscious animals
Authors: Troncy Éric , Authier Simon
Published: October 2018

Establishing ethical guidelines for investigations of experimental pain in conscious animals was not only critical with regards to animal rights, but also represented a major challenge for promoting high-quality science and high-value discovery. Thirty-three years later, academia faces an important ‘reproducibility crisis’, reflecting the past decades’ overreliance on reductionist approaches and the poor overall quality of published research. It is time to question the direction we gave collectively to the use of animals in research and, specifically, what we tried to reproduce as clinical conditions. New approaches are possible and are briefly presented in this chapter, keeping in mind that using animals in research is not a right but a duty (adapting the famous quote by Berdiaev): we have a duty of excellence in maintaining the right to use animals for research. Topics discussed include animal models, both experimental and natural; ethics; the 3Rs’ rules, research quality, and research validity.
The back pain revolution
Authors: Price Cathy
Published: October 2018

In 1997 Gordon Waddell and colleagues published a systematic review which explicitly challenged the assumption that back pain should always be treated by rest. Until this time, the belief that back pain was a sign of injury was deeply held, and many surgeries had been performed, often with poor results. The paper, together with the subsequent book The Back Pain Revolution, led to a paradigm shift in the way that back pain was managed: bed rest was no longer actively prescribed; instead, a return to activity was encouraged. This paper is also important because it was one of the first systematic reviews related to pain. However, further systematic reviews on the subject have found only small differences in the success rates of activity-based versus traditional treatments of back pain. Thus, despite the paper being published nearly 20 years ago, there is still a call for further work in this area.
The mechanism of aspirin
Authors: Sirois Pierre , D’Orléans-Juste Pedro
Published: October 2018

Aspirin has been used for the treatment of pain and inflammation for more than a hundred years; however, the medical use of what we now called aspirin dates back to antiquity, since willow-tree extracts containing salicylates were described in the Egyptian pharmacopoeia around 1543 bc. In 1971, Sir John Vane and his collaborators discovered its mechanism of action. This discovery has generated tremendous interest into the beneficial effect of this drug for the treatment of pain, inflammation, many inflammatory diseases, and even cancers. Vane and his collaborators also tested a number of other well-known aspirin-like drugs, or NSAIDs (for non-steroid anti-inflammatory drugs), and found that they all inhibited to a different extent the release of prostaglandins from organs as well as from tissue homogenates.
The effects of morphine on the CNS
Authors: Richebé Philippe , Rivat Cyril
Published: October 2018

The 1973 paper by Jacquet and Lajtha, was a pivotal report in understanding the effects of opioids on nociception, as it investigated the effects of morphine on different brain structures. To do this, the authors used a microinjection technique that allowed them to specifically target subcortical sites. The animals used in this study were rats, and evaluation of the nociceptive threshold was based on the behavioural reaction to electrical shock. Two reactions were evaluated: flinch or jump responses. The main result was that, depending on the dose and the site of injection, morphine produced either an increase in nociceptive threshold (analgesia), or a decrease in the nociceptive threshold (hyperalgesia). The authors also reported severe effects characterized by hyper-reactivity and violent uncontrolled jumping in stereotyped circular leaps when morphine was administered in the periaqueductal grey matter.
Opioids in palliative care
Authors: Hester Joan
Published: October 2018

Before Twycross published the paper discussed in this chapter, the use of opioids in palliative care was more folkloric than evidence based, relying on the wisdom of the ages rather than being observation based: patients with advanced cancer received little or no narcotic (opioid) analgesics because of fears of addiction, of rapid escalation in dose, and of impairment of mental faculties. This paper, published in 1975, was instrumental in questioning some of the myths that had surrounded the dark art of opioid use, and expounding a rational and practical treatise for their use in palliative care. Although it describes an era over 40 years ago, when practice was markedly different from that used today, it also introduced concepts that were ahead of their time, such as the psychosocial aspects of pain.
Spinal opioid analgesia in the rat
Authors: Stevens Craig W.
Published: October 2018

It is hard to imagine a time when the world of science and medicine did not know that morphine or other opioids administered to the spinal cord produced analgesia. However, this was the current state of knowledge in the early 1970s before the studies of Yaksh and Rudy created one of the most important paradigm shifts in the treatment of pain. The landmark paper is a pharmacology paper describing the results of the first comprehensive study of spinal opioid analgesia in the rat. The study produced the first full dose-response curves for morphine, fentanyl, methadone, and meperidine and proved a spinal site of opioid action. Classic pharmacological analysis yielded a competitive interaction at a single site, the as-yet undiscovered opioid receptors. Most importantly, with this paper, Yaksh and colleagues began a lifetime of cutting-edge research that would reveals the complex nature of pain processing and numerous classes of analgesic agents.
The key role of nerve growth factor in inflammatory pain processing
Authors: Farquhar-Smith Paul
Published: October 2018

This paper was one of several that cemented the key role of nerve growth factor (NGF) in sensory neurons in inflammatory pain processing. It used a novel way of biologically ‘removing’ NGF using a sequestration molecule that could then investigate the effect of the absence of NGF in pain paradigms. These data contributed to the robust evidence base indicating the importance of NGF and, although there had been issues in developing usable anti-NGF moieties in human pain conditions, this study could be considered part of the journey that has led to the introduction of antagonists to NGF actions for the treatment of pain in bone.
Mapping of neurotrophin receptors on adult sensory neurons
Authors: Bradbury Elizabeth J. , James Nicholas D.
Published: October 2018

The paper discussed in this chapter describes the first mapping of neurotrophin receptors in adult sensory neurons. Neurotrophins and their receptors were a particularly hot topic at the time, but the primary focus of interest had been in their role in development. In this paper, McMahon and colleagues characterized both mRNA and protein expression of the recently discovered trk receptors on defined populations of adult sensory neurons, correlating trk expression with other primary afferent projection neuron properties such as cell size and neuronal function. Furthermore, by showing clear correlations between the expression of different trk receptors and the physical and functional properties of defined primary afferent projections, the authors provided key evidence suggesting that nerve growth factor and neurotrophin-3 acted on functionally distinct populations of adult sensory neurons. This paper provided the basis for subsequent research on neurotrophin signalling and function in both the healthy and the diseased nervous system.
The cloning and characterization of the cannabinoid type 1 receptor
Authors: Abood Mary E. , Gamage Thomas
Published: October 2018

The cloning and characterization of the first cannabinoid receptor (now known as the cannabinoid type 1 (CB1) receptor) by Matsuda et al. in the landmark paper discussed in this chapter was a seminal discovery in 1990. While the analgesic properties of marijuana had been known for thousands of years, the mechanisms through which marijuana produces analgesia were not understood. The identification and functional characterization of the CB1 receptor led to the discovery of an endogenous cannabinoid system (the endocannabinoid system), which has now been shown to be important not only for acute and chronic pain states, but also for a whole host of physiological and pathophysiological disorders.
Deorphanization of ORL-1/LC132 by reverse pharmacology in two landmark studies
Authors: Bird Mark F. , Lambert David G.
Published: October 2018

Deorphanization of ORL-1/LC132 in 1995 by reverse pharmacology in two simultaneously published landmark studies added a new member to the opioid family of G-protein coupled receptors. Meunier and Reinscheid used cells expressing recombinant ORL-1 (human) or LC132 (rat) and the presumed intracellular inhibition of cyclic AMP formation to ‘fish’ for endogenous peptide ligands in rat whole-brain and pig hypothalamic extracts. Both studies reported the isolation of a 17-amino-acid peptide, which was named nociceptin and orphanin FQ by the two authors, respectively. The behaviour of the isolated peptide was a complete surprise, as a general hyperalgesia was observed when the peptide was administered at supraspinal sites. We now know that this peptide has, in fact, anti-opioid action, particularly in the medulla. The endogenous peptide exerts a multitude of effects both in the nervous system and, unlike classical opioids, has efficacy in neuropathic pain.
The capsaicin receptor
Authors: Nagy Istvan
Published: October 2018

The landmark paper discussed in this chapter is ‘The capsaicin receptor: A heat activated ion channel in the pain pathway’, published by Caterina et al. in 1997. The identification of the molecular basis for the sensitivity of a major proportion of nociceptive primary sensory neurons for capsaicin, the pungent agent in chilli pepper, was undoubtedly one of the most significant pain-related discoveries in the twentieth century, for at least three reasons. First, the mechanism for capsaicin-induced responses could unequivocally be explained. Second, the discovery heralded the starting point for the development of a highly promising, mechanism-based means of analgesia. Third, the discovery also sparked studies which resulted in the discovery of the major cation channel family, the transient receptor potential (TRP) ion channel family, several members of which have also become putative targets for the development of analgesics.
VR1 in inflammatory thermal hyperalgesia
Authors: Nagy Istvan
Published: October 2018

The landmark paper discussed in this chapter, published by Davis et al. in 2000, describes the role of the capsaicin receptor, which is called transient receptor potential cation channel subfamily vanilloid member 1 (TRPV1), in inflammatory thermal hyperalgesia. Capsaicin, the pungent agent found in hot peppers, has been linked to pain for centuries because it induces a burning pain sensation which, after prolonged application of the agent, turns into analgesia. Because of this, capsaicin has been used to relieve pain, most likely since prehistoric times. The elucidation of the role of TRPV1 in nociceptive processing was heralded as the starting point for the development of agents which would revolutionize pain management. Unfortunately, that promise is yet to be realized and apparently we need a more detailed understanding of the role of TRPV1 in physiological and pathological processes in order to fulfil the analgesic potential of drugs acting on this receptor.
A signature of pain in the brain
Authors: Rainville Pierre
Published: October 2018

The discovery of pain biomarkers has profound implications for both pharmacology and neurobiology; in 2013, in the landmark paper discussed in this chapter, Wager et al. presented a neurologic signature of pain based on human brain imaging performed in healthy individuals administered experimental heat-pain stimuli. Using advanced analytic methods based on machine learning and multivariate pattern analysis, Wagner et al. provide very convincing support for the idea that pain is encoded in a distinctive pattern of brain activity in one or several brain areas typically referred to as the ‘pain matrix’, which acts as a saliency detection system for the body. Although the usage of such tool to infer pain in patients poses major challenges and is clearly not indicated in medico-legal contexts, the study provides experimental proof of concept in favour of a pattern theory of pain as well as for a specificity theory of pain.
Cytokines as central to peripheral sensitization and hyperalgesia
Authors: Schutzer-Weissmann John
Published: October 2018

The landmark study discussed in this chapter, published in a letter to Nature in 1988 by Ferreira et al., marked the beginning of a new era of pain research. It demonstrated elegantly and for the first time that cytokines are central to peripheral sensitization and the phenomenon of hyperalgesia. The authors first injected various cytokines into rats’ paws and then tested for hyperalgesic activity using a modified Randall–Sellito rat-paw pressure test. They found that interleukin-1β‎ evoked a dose-dependent hyperalgesic response in the injected paw. The investigators then tried to isolate the peptide domains that were responsible for interleukin-1β‎s hyperalgesic activity and identified two tripeptide sequences which had hyperalgesic activity. Since then, after almost three decades of inquiry into their role in the induction and maintenance of hyperalgesia and other phenomenon such as allodynia, the first human trials of interleukin-1β‎ antagonists for the treatment of pain have begun.
Endogenous opioids mediate stress-induced analgesia
Authors: Sommer Claudia
Published: October 2018

This chapter reviews the landmark paper published in 1990 by Stein et al. and entitled ‘Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation’. Opioids, besides acting centrally as analgesics, may act peripherally upon opioid receptors located on axons and on immune cells. In the publication by Stein et al., it was shown for the first time that endogenous opioid peptides released from immune cells mediate stress-induced analgesia, potentially through opioid receptors on peripheral nerve endings. This finding has led to numerous follow-up studies on endogenous analgesia, including work showing that cannabinoid analgesia is mediated via the peripheral release of opioids, and to the concept of topical opioid analgesia, which may be a good way of using the potent analgesia that opioids can convey, without their CNS-associated side effects.
Control of pain initiation by endogenous cannabinoids
Authors: Hohmann Andrea G.
Published: October 2018

The landmark paper discussed in this chapter, published by Calignano et al. in 1998, focuses on the control of pain initiation by endogenous cannabinoids. In the paper, analgesic lipid mediators are shown to be present in peripheral paw tissue where they control the ability of pain signals to ascend to the central nervous system (CNS). Anandamide acts through a peripheral mechanism to suppress inflammatory pain via cannabinoid type 1 receptors. Palmitoylethanolamine, subsequently identified as an endogenous ligand for peroxisome proliferator-activated receptor-α‎, produces peripheral antinociceptive effects via a mechanism similar to that for the cannabinoid type 2 receptor. These lipids do not serve redundant functions and, in combination, produce synergistic antinociceptive effects. These observations suggested that drug-development efforts targeting peripheral control of pain may elucidate improved pharmacotherapies that lack the unwanted CNS side effects of current treatments.
Peripheral analgesia involves cannabinoid receptors
Authors: Desroches Julie
Published: October 2018

This landmark paper by Agarwal and colleagues was published in 2007, when the exact contribution of the activation of the cannabinoid type 1 receptor (CB1) receptors expressed on the peripheral terminals of nociceptors in pain modulation was still uncertain. At that time, while it was clearly demonstrated that the central nervous system (CNS) was involved in the antinociceptive effects induced by the activation of the CB1 receptor, many strains of mice in which the gene encoding the CB1 receptor was deleted by conditional mutagenesis were used to study the specific role of these receptors in pain. Creating an ingenious model of genetically modified mice with a conditional deletion of the CB1 receptor gene exclusively in the peripheral nociceptors, Agarwal and colleagues were the first to unequivocally demonstrate the major role of this receptor in the control of pain at the peripheral level. In fact, these mutant mice lacking CB1 receptors only in sensory neurons (those expressing the sodium channel Nav1.8) have been designed to highlight that CB1 receptors on nociceptors, and not those within the CNS, constitute an important target for mediating local or systemic (but not intrathecal) cannabinoid analgesia. Overall, they have clarified the anatomical locus of cannabinoid-induced analgesia, highlighted the potential significance of peripheral CB1-mediated cannabinoid analgesia, and revealed important insights into how the peripheral endocannabinoid system works in controlling both inflammatory pain and neuropathic pain.
The challenges of animal models of pain
Authors: Yousuf Muhammad Saad , Kerr Bradley J.
Published: October 2018

The landmark paper discussed in this chapter is ‘Animal models of pain: progress and challenges’, published in the journal Nature Reviews Neuroscience by Jeff Mogil of McGill University in 2009. The most common symptom across various medical conditions and a major reason for seeking physician consultation is pain. It is defined as ‘an unpleasant feeling or emotional experience associated with actual or potential tissue damage’. A large percentage of the research investigating the biological mechanisms of pain is performed on animals. Human studies of pain are limited by lack of practicality, subjectivity, and ethical considerations. This influential review by Mogil discusses the progress and challenges faced in studying pain using various animal models.
Mechanisms of bone cancer pain
Authors: Doré-Savard Louis , Beaudet Nicolas , Sarret Philippe
Published: October 2018

The landmark paper discussed in this chapter focuses on pain arising from malignancy of the bone, which, whether primary or originating from a distant site, is the cause for a majority of cancer pain syndromes. Bone is an innervated organ that can relay nociceptive signals triggered by nerve damage, acidosis, inflammation, and hypoxia. The understanding of the physiopathology of skeletal pain has leaped significantly forwards over the last 15 years. The development of animal models that allowed for the visualization of bone microenvironment modifications by the tumour played an important role in recent advances. One of the most significant discoveries was the contribution of local nerve growth factor (NGF) to nerve remodelling in the bone periosteum presented by Mantyh and colleagues in 2010. NGF remains one the most promising treatment avenues for malignant bone pain, and peripheral innervation has become a therapeutic target in several skeletal pathologies.
The molecular structure of the μ‎-opioid receptor
Authors: Knaggs Roger D.
Published: October 2018

The landmark paper discussed in this chapter describes the crystal structure of the μ‎-opioid receptor (also known as MOP-1). Opioids are some of the oldest known drugs and have been used for over 4,000 years; however, in addition to having beneficial analgesic effects, they are associated with a myriad of side effects that can minimize their use. Although the gene sequences of the opioid receptors were determined in the 1990s it has taken much longer to translate this into visualizing their three-dimensional structure. The μ‎-opioid receptor consists of seven transmembrane α‎-helices that are connected by three extracellular loops and three intracellular loops, with a wide open binding pocket which offers many potential ligand interaction sites, and evidence of dimerization. Understanding the crystal structure of the μ‎-opioid receptor in much more detail aids explanation of the molecular determinants of ligand recognition and selectivity and will be of use in designing novel opioids with improved efficacy and fewer side effects.
The molecular basis for the placebo effect
Authors: Bromley Lesley
Published: October 2018

The landmark paper discussed in this chapter is ‘The neurobiology of placebo analgesia: From endogenous opioids to cholecystokinin’, published by Benedetti and Amanzio in 1997. This major review considered the placebo and nocebo effect in a more scientific framework compared to previous treatise of a nebulous concept whose only role is to act as a comparator for controlled trials. By expounding robust evidence, Benedetti and Amanzio added credence to the placebo effect, with not just psychological but also physiological data, acknowledging it as an effective therapeutic action. Furthermore, the importance of endogenous opioids and cholecystokinin in the mechanism of placebo were put into sharp relief, giving an intuitive basis and scientific validation to this effect.
Early discussions on a mechanistic approach to pain
Authors: Searle Robert D.
Published: October 2018

The landmark paper discussed in this chapter is ‘Towards a mechanism-based classification of pain?’, published by Woolf et al. in 1998. One of the great challenges of managing patients with pain problems has been the idiosyncratic response of patients to therapies designed to improve their symptoms. In part, this has been the consequence of imperfect methods of classifying pain. If it is not possible to robustly categorize patients into common pain groups, how can it be hoped that successful treatments that translate well from the research setting into clinical practice will be developed? In this landmark editorial, Clifford Woolf and his co-authors attempted to address imperfections in historical pain classification systems with a novel approach based on pain mechanisms.
Plasticity
Authors: Magnussen Claire , Ribeiro-da-Silva Alfredo
Published: October 2018

This chapter discusses the landmark paper ‘Neuronal plasticity: increasing the gain in pain’, published by Woolf and Salter in 2000. Excellent review articles not only give a concise overview of a topic but also provide a framework for future research. In 2000, Clifford Woolf and Michael Salter joined forces to write one of the most highly cited review articles in the field of pain research and thus provided a conceptual framework for the plastic changes that occur in nociceptive neurons in response to chronic pain. With over 2,700 citations, this review is one of those rare articles that is still appreciated by pain researchers across domains.
The importance of descending modulatory pain systems
Authors: Collantes Enrique
Published: October 2018

The landmark paper discussed in this chapter is ‘Descending control of pain’, published by M. J. Millan in 2002. The perception of pain is affected by a complex interaction between nociceptors in the dorsal horn of the spinal cord, systems that transfer messages to cerebral structures. The complex interaction between the CNS and the peripheral nervous system in a modifiable and plastic neural system makes the perception of pain unique for each individual. In this regard, the author outlines the neurobiology of pain, providing a detailed description of the descending pathways which modulate the activity of spinal nociceptors which are located in the dorsal horn and which transfer nociceptive messages to cerebellar structures.
Mechanisms of action of acetaminophen for pain treatment
Authors: Beaulieu Pierre
Published: October 2018

The landmark paper discussed in the chapter, published by 2008 by Mallet et al., reports on the mechanisms of action of acetaminophen for pain treatment. Acetaminophen, also known as paracetamol (N-acetyl-para-aminophenol), has analgesic and antipyretic properties and has superior tolerance, compared to non-steroidal anti-inflammatory drugs, making it appropriate for widespread use in patients. However, despite many years of use worldwide and numerous studies, acetaminophen’s mechanism of action is still uncertain. The article by Mallet et al. is a landmark paper because it reconciled many observations made at the time to propose a plausible mechanism of action of acetaminophen in pain treatment.
Making the link from “central sensitization” to clinical pain
Authors: Sandkühler Jürgen
Published: October 2018

The landmark paper discussed in this chapter is ‘Central sensitization: Implications for the diagnosis and treatment of pain’, published by C. J. Woolf in 2011. The phrase ‘central sensitization’ is often used as an umbrella term for all kinds of central nervous system (CNS) mechanisms contributing to pain hypersensitivity. The International Association for the Study of Pain (IASP) defines ‘central sensitization’ as the ‘increased responsiveness of nociceptive neurons in the CNS’. In the CNS, highly distinct mechanisms contribute to pain hypersensitivity depending upon pain aetiology and disease stage. These include modification of synaptic strength, inhibitory tone, and membrane excitability and often involve components of neuroinflammation. It is thus recommended to avoid using the phrase ‘central sensitization’ in the scientific literature all together and replace it with unambiguous technical terms such as ‘CNS mechanisms of pain hypersensitivity’ or with the specific mechanism(s) and CNS location(s) in mind.
Undertreatment of pain with metastatic cancer
Authors: Allsop Matthew J. , Bennett Michael
Published: October 2018

The landmark paper discussed in this chapter is ‘Pain and its treatment in outpatients with metastatic cancer’, published by Cleeland et al. in 1994. Cleeland and colleagues provide one of the first epidemiological studies outlining the prevalence of cancer pain in outpatients with metastatic cancer. The study drew attention to the undertreatment of pain and identified predictors of poor pain management, such as discrepancies between patient and health professional judgements regarding the degree of pain-induced interference. Issues highlighted by Cleeland and colleagues persist, including high prevalence of pain reported in patients with metastatic cancer, a lack of clarity on good practice guidelines for assessing pain in patients with cancer, and substandard quality of palliative and end-of-life services by minority ethnic groups. Pain management in outpatients with cancer remains a complex issue, but innovative strategies are emerging to support the role of the health professional and encouraging self-management in patients.
Faces scales in paediatric pain assessment
Authors: Bliss Alison
Published: October 2018

The landmark paper discussed in this chapter is a systematic review assessing the commonly used faces pain scales employed to aid children in the self-report of their pain intensity. The review provides a critical evaluation of the Faces Pain Scale, the Faces Pain Scale-Revised (FPS-R), the Oucher pain scale, and the Wong–Baker Faces Pain Rating Scale (WBFPRS). The reviewers found that the psychometric properties of the FPS-R supported its superiority for use in research. Although they found that children, and many staff, expressed a preference for the WBFPRS, the reviewers had major concerns about this scale confounding pain intensity with affect. They also noted the paucity of research in younger children, and concluded that future research should not focus on developing more pain scales for paediatric use but on examining the appropriate application of existing scales in a wider range of clinical settings.
Epidural block and phantom limb pain
Authors: Schug Stephan
Published: October 2018

The landmark paper discussed in this chapter, published by Bach et al. in 1988 is a Danish paper that describes a study where patients who were to undergo lower-limb amputation received either preventive, preoperative epidural analgesia for 72 hours before the amputation, or systemic analgesia. At 6 and 12 months post-operatively, all patients in the epidural group were pain free, while 38% and 27%, respectively, in the control group had phantom limb pain. The study has been criticized for a number of points including the pseudorandomization by year of birth, the lack of any blinding, and the small number of patients used in the study (only 25 patients overall).
Paediatric pain epidemiology
Authors: Bliss Alison
Published: October 2018

The landmark paper discussed in this chapter reviewed 51 epidemiological studies looking at the incidence and prevalence of both acute pain and chronic pain in children and adolescents. The paper divided the studies they reviewed into two broad categories: those which examined pain in non-clinical populations, such as school children or general population samples, and those which examined pain in clinical settings, such as inpatients, outpatients from specific clinics, or special populations. In the clinical studies assessed, back pain in athletes and overuse injury syndrome in musicians were also included as studies from special populations. The non-clinical studies included head, stomach/abdominal, and back pain, as well as further studies focusing on oral/dental and limb pain, dysmenorrhoea, and multiple pain problems. The authors concluded that the epidemiology of pain in children and adolescents remained relatively undocumented.
Recognizing the importance of HIV disease and pain
Authors: Kamerman Peter
Published: October 2018

The landmark paper discussed in this chapter is ‘Underestimation and undertreatment of pain in HIV disease: Multicentre study’, published by Larue in 1997. This study provided the first national assessment of pain intensity, prevalence, type, treatment, and risk factors influencing treatment in HIV-infected individuals across a wide range of disease stages. The authors showed that pain was common, was often of clinically significant intensity, got more common and severe with worsening disease stage, produced significant decreases in quality of life, and frequently was undertreated. Importantly, the study highlighted the underestimation of patient pain by doctors, which contributed to the undertreatment of pain.
Fast-acting fentanyl for breakthrough pain
Authors: Davies Andrew N.
Published: October 2018

The landmark paper discussed in this chapter is ‘Oral transmucosal fentanyl citrate: Randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients’, published by Farrar et al. in 1998. It was the first description of a randomized controlled trial of a fast-acting fentanyl formulation for the management of breakthrough pain (i.e. oral transmucosal fentanyl citrate (OTFC)). Indeed, it was the first description of a randomized controlled trial of any of the so-called fast-acting fentanyl/rapid-onset opioid formulations for the management of breakthrough cancer pain. Moreover, the methodology employed in this study formed the basis for the methodology employed in many later studies (of other fast-acting fentanyl formulations).