bluuebunny/crossref_metadata_2025 huggingface dataset:
Otitis media with effusion
Authors: Little Paul
Published: October 2018

This chapter discusses The MRC Multicentre Otitis Media Study Group’s paper on otitis media with effusion including the design of the study (outcome measures, results, conclusions, and a critique).
Laryngeal papillomatosis
Authors: Saunders Mike
Published: October 2018

This chapter discusses Strong, Vaughan, Cooperband, Healy, and Clemente’s paper on recurrent respiratory papillomatosis management with the CO2 laser including the design of the study (outcome measures, results, conclusions, and a critique).
Microvascular free flaps in head and neck surgery
Authors: Haywood Richard
Published: October 2018

This chapter discusses Urken, Weinberg, Buchbinder, Moscoso, Lawson, Catalano, and Biller’s paper on microvascular free flaps in head and neck surgery including the design of the study (outcome measures, results, conclusions, and a critique).
Classification of facial fractures
Authors: Sidebottom Andrew
Published: October 2018

This chapter discusses Le Fort’s paper on the classification of facial fractures including the design of the study (outcome measures, results, conclusions, and a critique).
Steroids for children undergoing tonsillectomy
Authors: Hodgson Phil
Published: October 2018

This chapter discusses Steward, Grisel, and Meinzen-Derr’s paper on steroids for children undergoing tonsillectomy including the design of the study (outcome measures, results, conclusions, and a critique).
Implications of codeine administration after tonsillectomy
Authors: Hodgson Phil
Published: October 2018

This chapter discusses Kelly, Rieder, Van den Anker, Malkin, Ross, Neely, Carleton, Hayden, Madadi, and Koren’s paper on the implications of codeine administration after tonsillectomy including the design of the study (outcome measures, results, conclusions, and a critique).
Managing perioperative anticoagulation
Authors: Lyall Hamish
Published: October 2018

This chapter discusses Douketis, Spyropoulos, Kaatz, Becker, Caprini, Dunn, Garcia, Jacobson, Jaffer, Kong, Schulman, Turpie, Hasselblad, and Ortel’s paper on managing perioperative anticoagulation including the design of the study (outcome measures, results, conclusions, and a critique).
Innovative concepts in pain management
Authors: Thomas Ben M.
Published: October 2018

War, often the catalyst for technological advances, can also provide the substrate for medical advancement. Lieutenant Colonel Henry K. Beecher’s article published in the Annals of Surgery in 1946 is a seminal paper in many respects. This historical paper by Beecher uses heralding methodology to challenge the pre-existing dogma of morphine treatment of pain from battle trauma and to use direct and precise observations to critically appraise the then current management. In doing so, he not only demonstrated early application of the scientific method to a pain problem, but also identified innovative concepts in pain management, concepts whose importance would only later be fully appreciated.
Understanding the responsiveness of C-fibres
Authors: Walczak Jean-Sébastien
Published: October 2018

In the paper discussed in this chapter, Ainsley Iggo used electrophysiology to characterize mechanosensory fibres from the saphenous nerve in cats. Using fine techniques of dissection he recorded from single units and therefore could discriminate between the various types of sensitivity of afferent fibres. This article describes properties of primary afferent neurons in response to precise calibrated mechanical stimuli and focused on mechanical sensitivity of C-fibres. In addition, the manuscript describes the properties of skin-receptor fields. The paper showed that not all C-fibres responded to high-intensity stimuli and that receptive fields were quite small. In addition, it provided a qualitative evaluation of stimuli necessary to activate those fibres. Hence, by isolating fibres that responded only to strong stimulation, this article showed that the peripheral nervous system is equipped with a specific apparatus for detecting nociceptive stimuli; this was a great step forward in understanding the physiology of pain.
A new theory of pain
Authors: Dickenson Tony
Published: October 2018

Of all the seminal papers on pain, the one described in this chapter must be one of the most influential. It has been cited over 11,000 times. This paper proposed the theory that the transmission of pain from peripheral fibres through the spinal cord to the brain was not a passive fixed process but was subject to modulation and alteration. It also suggested that there was interplay between different afferent fibres, spinal excitatory neurons, and inhibitory spinal neuron and that the brain could exert influence on the spinal cord. Most of modern pain science and clinical management is based on this theory, which is now clearly backed up by facts.
Purinergic nerves
Authors: Rousseau Guy
Published: October 2018

It was in 1972 that Burnstock laid the foundation of a new nerve type that he called ‘purinergic nerves’. In this article, he presented experimental data using five criteria to establish that adenosine triphosphate can be considered to be a neurotransmitter, including (1) the release of a purinergic molecule from terminal axons, (2) the structures of purinergic nerves, (3) the electrophysiological properties of purinergic transmission, (4) the pharmacology of adenyl compounds and purinergic transmission, and (5) the distribution and evolution of the purinergic nerves. However, in spite of convincing data, it took more than 20 years for the scientific community to accept this hypothesis. Since then, it has been recognized that the purinergic system is involved in multiple short-term actions such as cell proliferation and pain.
Endogenous opioids in placebo-induced analgesia
Authors: Taylor Véronique A. , Rainville Pierre
Published: October 2018

Placebos achieve scientifically proven pain-relieving effects yet are inactive substances for the treatment of pain. Levine, Gordon, and Fields were the first to demonstrate the role of endogenous opioids in placebo-induced analgesia during dental post-operative pain. Several studies using pharmacological manipulations and/or neuroimaging techniques confirmed their findings that placebo analgesia is reversible by naloxone, and also identified brain pathways involved in opioidergic neurotransmission during placebo analgesia (prefrontal regions rich in opioid receptors such as the anterior cingulate cortex, presumably initiating descending pain modulation through downstream projections to the brainstem). Fifty years of research in pharmacology and neurobiology have contributed to the identification of physical as well as psychological determinants of placebo analgesia. Expectations of pain relief are maintained by conditioned learning and reward-related processes, reflected by interactions between different neurotransmitters (opioids, dopamine, endocannabinoids) in a variety of brain circuits related to executive/cognitive processes as well as affect and reward.
Local anaesthetic creams
Authors: Fassoulaki Argyro
Published: October 2018

Using topical anaesthesia before puncturing veins and arteries or inserting needles in the epidural space is a prerequisite for ameliorating pain elicited by the insertion of needles or catheters. In the eighties, Hanks and White published an article in which they described a number of local anaesthetic creams which were beginning to be used to prevent pain due to needle punctures; in particular, they described an anaesthetic cream called EMLA, which contained a eutectic mixture of lidocaine and prilocaine. The use of this cream was particularly welcome in children. Although, eventually, newer formulations based on new technology were prepared, EMLA remains the gold standard to which the new formulations are compared. EMLA has also been used for relief of neuropathic pain. The article by Hanks and White stands the test of time in describing the EMLA formulation early in its appearance.
Mechanisms of visceral pain in irritable bowel syndrome
Authors: Omran Yasser Al , Aziz Qasim
Published: October 2018

Throughout history, symptoms of nausea, vomiting, constipation, diarrhoea, bloating, and pain have been described in relation to diseases of the gastrointestinal tract. Gastrointestinal disorders that give rise to these symptoms are broadly characterized as one of two types: structural or functional. Although structural diseases can be easily identified, and even cured by means of medical or surgical intervention, functional gastrointestinal disorders (FGIDs) remain a medical enigma. Irritable bowel syndrome (IBS) constitutes one of the 40 or so conditions under the FGIDs umbrella. It is characterized by abdominal pain and altered bowel habits and has an estimated prevalence of 5%–20% in the Western world. Around 40 years ago, little was known about the mechanism behind visceral pain in IBS. Ritchie’s landmark study was one of the first to begin to elucidate some of the mechanisms involved (and therefore provide some insight into putative treatments) in the difficult area of FGIDs.
Endogenous opioids in the CNS
Authors: Dickenson Tony
Published: October 2018

This short and concise paper was the first to unequivocally reveal that there were endogenous opioids in the central nervous system (CNS), identify their peptide nature and sequence, and show that they exerted physiological inhibitory effects. The idea that there were natural opioids fitted with concurrent reports of opiate-binding sites, and this led to the description of multiple receptors with their own families of peptide transmitters. No truly novel opioid drugs have emerged since, and attempts to protect and manipulate the enkephalins for pain control have yet to be successful. This does not detract from this key study, which made us think about pain modulation in a different way, and subsequent work has clearly shown how endogenous opioid signalling is critical in CNS function, perhaps most importantly in endogenous pain control, such as that harnessed by placebo analgesia.
Plasticity in somatic receptive fields after nerve injury
Authors: Humble Stephen R.
Published: October 2018

Devor and Wall, in a pioneering electrophysiological study, examined the change in somatic receptive fields in the dorsal horn of the spinal cord after nerve injury. Rather than the anticipated loss of an area of electrophysiological perception, the system demonstrated ‘plasticity’ whereby novel receptive fields, remote to the corresponding area of damage, were evident. The authors postulated that this neuroplasticity occurred via a hitherto undefined spinal mechanism, which lead to an explosion of interest and research to elucidate the mechanisms of central plasticity. In this truly landmark paper, the idea of the nervous system being an inherently ‘hard-wired’ structure was made redundant and the concept of neuroplasticity was given robust form.
Peripheral neural mechanisms of cutaneous heat hyperalgesia and heat pain
Authors: Klein Amanda H. , Ringkamp Matthias
Published: October 2018

In the landmark paper discussed in this chapter, published in 1982, LaMotte et al. investigated the contribution of different cutaneous nerve fibres to heat pain and heat hyperalgesia in both psychophysical (humans) and electrophysiological studies (human and primates), using identical thermal test and conditioning stimuli; the findings from the two sets of experiments were then correlated. In non-human primates, neuronal activity was recorded from mechanoheat-sensitive A- and C-fibres (AMHs and CMHs, respectively) and warm and cold fibres, whereas, in conscious human volunteers, activity from CMHs was recorded. The authors found that pain is mediated by activity in CMHs and that sensitization of CMHs after a mild burn injury accounts for the increased heat pain after such injury. The combination of psychophysical experiments in human and correlative electrophysiological studies in non-human primates provides an important experimental approach for unravelling the contribution of different classes of afferents to pain.
The first crystal structure of an ionotropic glutamate receptor ligand-binding core
Authors: Ren Ke , Dubner Ronald
Published: October 2018

The known functional ionotropic glutamate receptors (iGluRs) are composed of three major subtypes: AMPA, NMDA, and kainate. In 1998, in the landmark paper discussed in this chapter, Armstrong et al. provided the first crystal structure of an iGluR-subunit ligand-binding core, the S1S2 region of the rat GluA2 ‘flop’ isoform. They solved its structure with X-ray crystallography from selenomethonine crystals. They also identified residues involved in kainate binding, analysed allosteric sites that regulate affinity and specificity of the agonist, and mapped potential subunit–subunit interaction sites. They also proposed that binding of different agonists may result in variable degrees of domain closure. This work has profound impact on the field and it has been importantly cited. Subsequently, numerous high-resolution crystal structures of ligand-binding domains of iGluRs in complex with ligands, both agonists and antagonists, have been solved.
Glia
Authors: Malcangio Marzia
Published: October 2018

The landmark review discussed in this chapter, published in 2003 by Watkins and Maier, showed how glia have a major role in the modulation of pain mechanisms in the spinal cord and act remotely from peripheral nerve injury. This review led the way to a substantial body of literature demonstrating the pivotal role played by both microglia and astrocytes in chronic pain mechanisms. Since 2003 the modalities underlying neuron–microglia communication (e.g. chemokines, proteases, the translocator protein TSPO) have been dissected, and novel pathways of interactions delineated. Concrete molecular targets expressed by spinal microglia in response to a remote injury have been identified and they hold promise for future analgesic therapies for chronic pain.
The milestone effect of DNIC in our understanding of pain
Authors: Marchand Serge
Published: October 2018

While thousands of articles are published each year on pain, only a few have such a major impact on the understanding of pain mechanisms as the landmark paper discussed in this chapter; published by Le Bars and colleagues in 1979, it introduced the concept of diffuse noxious inhibitory control (DNIC; also called diffuse noxious inhibition) mechanisms. Although this work is more than three decades old, it still has a major influence on both the understanding of pain mechanisms and the development of clinical approaches. It is known that apparently similar pain may be caused by different mechanisms: one may be caused by amplified excitatory mechanisms while the other may be related to a deficit of endogenous pain modulation, such as DNIC or conditioned pain modulation (or CPM); these will not respond to the same treatment. The work by Le Bars and colleagues provided a new understanding of mechanisms underlying pain.
The original description of central sensitization
Authors: Black Sheila
Published: October 2018

The landmark study discussed in this chapter is ‘The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin-induced tissue injury’, published by Coderre and Melzack in 1992. Previous studies in this field implicate a contribution of excitatory amino acids (EAAs), specifically l-glutamate and l-aspartate, to injury-induced sensitization of nociceptive responses in the dorsal horn of the spinal cord. Repetitive stimulation of primary afferent fibres demonstrated that l-glutamate and NMDA can produce ‘wind-up’ of neuronal dorsal horn activity, and this is blocked by application of NMDA antagonists. This study uses the formalin test as a behavioural model to investigate the mechanisms underlying central sensitization and the role of EAAs, NMDA, their receptors, and their antagonists in this process.
Nocebo and its importance in clinical practice
Authors: Laycock Helen
Published: October 2018

The landmark paper discussed in this chapter is ‘When words are painful: unravelling the mechanism of the nocebo effect’, published in 2007 by Benedetti et al. This major review considered the placebo and nocebo effect in a more scientific framework compared to the previous nebulous concept of a placebo as an agent whose only role is was to act as a comparator for controlled trials. By expounding robust evidence, Benedetti added credence to the placebo effect with not just psychological but physiological data acknowledging it as an effective therapeutic action. Furthermore the importance of endogenous opioids and cholecystokinin in the mechanism underlying the relief of pain by placebos was put into sharp relief, giving an intuitive basis and scientific validation to this effect.
Proof of concept
Authors: Tidman Victoria
Published: October 2018

The landmark paper discussed in this chapter is ‘Epidural morphine in treatment of pain’, published by Behar et al. in 1979. A small case series in the seventies first highlighted the use of epidural morphine for pain. It consists of only ten patients who were all administered 2 mg of morphine epidurally. Patients suffering from both acute and chronic pain had a significant reduction in the level of pain within 2–3 minutes, and this lasted 6–24 hours. The authors went on to postulate that morphine produced its effect by a direct action on the specific opioid receptors in the substantia gelatinosa. Although morphine is rarely used epidurally, this paper paved the way for the use of epidural opioids in many different pain conditions.
The definition of fibromyalgia
Authors: Shipley Mike
Published: October 2018

The landmark paper discussed in this chapter is ‘Primary fibromyalgia (fibrositis): Clinical study of 50 patients with matched normal controls’, published by Yunus et al. in 1981. Over the years, long-term pain has had a confusing variety of names and, to some extent, that confusion persists. Chronic pain can be defined as pain which persists beyond the time expected for healing. Yunus et al. were the first to define fibromyalgia (fibrositis), as they called it, developing evidence-based diagnostic guidelines by comparing a group of patients with a pain-free matched control group. Based on their work, they also suggested a series of pain management approaches which remain valid today.
The advent of patient-controlled analgesia for post-operative analgesia
Authors: Chapman Suzanne
Published: October 2018

The landmark paper discussed in this chapter is ‘Patient-controlled analgesia: A new concept of postoperative pain relief’, published by Bennett et al. in 1982. This paper presents data from two investigations in which patient-controlled analgesia using morphine was evaluated in patients who had undergone elective gastric bypass surgery for the management of morbid obesity. The paper shows that patient-controlled analgesia achieved adequate analgesia more often than conventional intermittent analgesia did when both administration methods were compared, but with less sedation. In addition, patients who had experienced both methods of analgesia felt that patient-controlled analgesia was superior. The paper also demonstrates that individuals can vary in their analgesic requirements.
Clarifying the concept of breakthrough pain
Authors: Zeppetella Giovambattista
Published: October 2018

The 1990 publication ‘Breakthrough pain: Definition, prevalence and characteristics’ was the first to study to describe breakthrough pain as a discrete pain state. Using the definition that ‘breakthrough pain is a transient increase in the intensity of moderate or severe pain, occurring in the presence of well-established baseline pain’ the authors interviewed 90 cancer pain patients and identified 51 types of breakthrough pain; these varied widely with respect to severity, location, temporal characteristics, relationship to scheduled analgesia, precipitating events, predictability, pathophysiology, aetiology, and palliative factors. As a result of Portenoy and Hagen’s survey, breakthrough pain has been studied as a discrete pain state for almost 30 years, and recognized as an important clinical problem in its own right. An increasing number of published studies exist, with ongoing debate about the breakthrough pain definition, pain assessment, and pain management.
Opioid-induced hyperalgesia
Authors: Bannister Kirsty
Published: October 2018

The landmark paper discussed in this chapter is ‘Opioid-induced hyperalgesia: Abnormal or normal pain?’, published by Simonnet and Rivat in 2003. Morphine remains the analgesic of choice for those patients suffering moderate-to-severe pain, but it is increasingly recognized that worsening pain can be associated with chronic opioid consumption—the so-called phenomenon of opioid-induced hyperalgesia (OIH). This paper combined knowledge from clinical studies and experimental evidence from animal research in order to delve deeper into the workings of OIH and ask whether it represented normal or abnormal pain. The authors, intrigued by evidence indicating that exogenous opioids could activate both inhibitory and facilitatory pain systems, looked to reassess the role of such enhancement in pain sensitivity. As the debate regarding the very existence of OIH rages on, we pain specialists can take comfort in the knowledge that for many before us, over a decade ago, the reality of OIH was never in question.
Endoscopic ultrasound-guided coeliac plexus block
Authors: Bhaskar Arun
Published: October 2018

The landmark paper discussed in this chapter is ‘Endosonography-guided celiac plexus neurolysis’, published by Wiersema and Wiersema in 1996. Pain is one of its most distressing complaints of pancreatic cancer, affecting more than 80% of patients with advanced disease. However, the use of opioids and other drugs is often limited by undesirable side effects, which include somnolence, confusion, lethargy, and decreased cognitive function. Intrathecal drug delivery systems, although effective, are often deemed impractical in pancreatic cancer, due to its poor prognosis and the fact that it is often diagnosed late. Tumour infiltration of the coeliac plexus results in pain in the abdomen and back; thus, this area has often been targeted for analgesia via a neurolytic coeliac plexus block. The paper by Wiersema and Wiersema examines the efficacy of an approach that uses ultrasound to guide needle placement in celiac plexus neurolysis, in a study of 30 patients.
Antineuropathic medication combination therapy
Authors: Serpell Mick G.
Published: October 2018

The landmark paper discussed in this chapter is ‘Morphine, gabapentin, or their combination for neuropathic pain’, published by Gilron et al. in 2005. Although combination drug therapies for neuropathic pain had long been suggested, this seminal paper provided the first evidence for efficacy of combination therapy of mechanistically distinct medications in analgesia, using morphine in combination with gabapentin in post-herpetic neuralgia or diabetic neuropathy. Combination therapy had greater efficacy than gabapentin alone and was equally effective as morphine alone but with a lower dose of morphine; however, this did not seem to translate into reduced side effects. To this day, precious little is known about what are the most effective combinations for neuropathic pain, and the need for large randomized controlled trials in this area is still as pressing it was back in 2005.
Randomized controlled trial evidence for gabapentin in post-herpetic neuralgia
Authors: Gupta Rajesh
Published: October 2018

The landmark paper discussed in this chapter is ‘Gabapentin for the treatment of postherpetic neuralgia: A randomized controlled trial’, published by Rowbotham et al. in 1998. In the study, a 4-week initial period of titration of gabapentin (up to a maximum of 3,600 mg) or matching placebo was given, followed by a further 4-week period at the maximum tolerated dose. The primary efficacy measure was change in average daily pain score from start to finish of the treatment, and secondary measures observed were the average daily sleep score, a short-form McGill Pain Questionnaire, the subject’s global impression of change, the investigator-rated clinical global impression of change, the Short Form 36, a quality-of-life questionnaire, and a Profile of Mood States questionnaire. Subjects receiving gabapentin had significant reduction in daily pain scores as well as improvement in secondary measures of pain, although with an increased incidence of side effects.
Identification of the target of gabapentinoid action in neuropathic pain
Authors: Nurmikko Turo J.
Published: October 2018

The landmark paper discussed in this chapter is ‘Identification of the α‎2-δ‎-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin’, published by Field et al. in 2006. In this seminal paper, Field et al. demonstrated that the anti-allodynic effect of pregabalin is related to its binding to the α‎2δ‎-1 subunit of the voltage-gated calcium channel. In transgenic mice lacking this subunit, pregabalin had no effect on allodynia induced by sciatic nerve ligation, whereas, in wild-type mice, there was a substantial anti-allodynic response. This discovery was well received by the scientific community and was considered to conclusively establish the mechanism of action of pregabalin, which has remarkably similar properties to gabapentin but with increased potency and oral absorption. This exciting result acted as an impetus for further studies on the role of the subunit in the development and maintenance of neuropathic pain.
Recognition of the importance of neuropathic pain epidemiology
Authors: Brown Matthew
Published: October 2018

The landmark paper discussed in this chapter is ‘Prevalence of chronic pain with neuropathic characteristics in the general population’, published by Bouhassira and Lantéri-Minet in 2008. Understanding the extent to which a specific condition affects a population is of great importance, for two main reasons. First, robust epidemiological data influences relevant legislators and policymaking, leading to improvements in the allocation of scarce healthcare resources. Second, epidemiology studies alert clinicians and academics to deficiencies and oversights in current treatment. For decades, chronic pain resided in a twilight world, under-recognized and under-resourced, while patients suffered. Papers such as this pioneering work by Bouhassira and Lantéri-Minet started to turn the tide with respect to chronic pain’s profile in the pathological pecking order. It is important because it demonstrated in unarguable fashion the degree to which chronic neuropathic pain blights the lives of a significant proportion of the population.
Pregabalin in the reduction of chronic pain post knee surgery
Authors: Langford Richard M.
Published: October 2018

The paper discussed in this chapter, published in 2010 by Buvanendran et al. is entitled ‘Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: a prospective, randomized, controlled trial.’ Chronic (or persistent) post-surgical pain is defined as pain that develops after surgical intervention and lasts at least 2 months; other causes being excluded, in particular pain from a condition preceding surgery. The subject of the commentary reviewed in this chapter is a study conducted in 2006–7, regarded as a pivotal step to establish the role of gabapentinoids, and in particular pregabalin, for both perioperative pain management and prevention of chronic post-surgical neuropathic pain, specifically persisting neuropathic pain after total knee arthroplasty.
Disability in chronic low back pain
Authors: Jain Rakesh , Jain Shailesh
Published: October 2018

The landmark paper discussed in this chapter, ‘Pain-related fear is more disabling than pain itself: Evidence on the role of pain-related fear in chronic back pain disability’, published by Crombez et al. in 1999, investigates the issue of disability in chronic low back pain and explores the role of psychological factors in disability. The paper reports on three independent chronic low back pain studies in which behavioural performance and the degree of reported disability were correlated with psychological factors such as catastrophization, negative affect, anxiety, and pain-related fear (e.g. fear of re-injury). In a counterintuitive finding, pain-related fear was more disabling that the pain itself. This paper thus highlighted the need to assess and address the psychological domains of pain; it also validated three questionnaires that are important in the pain field, and established a biopsychosocial approach to understanding, explaining, and treating chronic low back pain.
The understanding of social effects in pain
Authors: Williams Amanda
Published: October 2018

The landmark paper discussed in this chapter is ‘Social modulation of pain as evidence for empathy in mice’, published in 2006 by Langford et al. in Mogil’s lab at McGill University, Montreal. It elegantly demonstrated (1) that mice observed and responded to one another’s pain—effectively, socially mediated hyperalgesia; (2) that this was modulated by the nature of the social relationship, occurring between cagemates but not strangers; (3) that the mechanism in the observing mouse involved central sensitization, not local effects. The interactive behaviour met requirements for empathic responding; neither imitation nor emotional contagion could account for these effects. The findings have implications for lab pain research using rodents, for understanding of empathic responses in animals, and for understanding animal social behaviour more widely.
COMT genotypes in pain responses
Authors: Hamilton Matthew Lloyd
Published: October 2018

The landmark study discussed in this chapter is ‘COMT val158met genotype affects μ‎-opioid neurotransmitter responses to a pain stressor’, published by Zubieta et al. in 2003. Catechol-O-methyl-transferase (COMT) is a key modulator of dopaminergic and noradrenergic neurotransmission. This study focused on a single nucleotide polymorphism of the COMT gene encoding the substitution of valine (val) by methionine (met) at Codon 158 (val158met), resulting in a three- to fourfold reduction in its activity. Individuals with the val/val genotype have the highest activity of COMT, val/met genotypes have intermediate activity, and met/met genotypes have the lowest activity of COMT. Using a mixture of PET imaging of the binding of μ‎-opioid receptors and correlation with clinical outcomes, this groundbreaking study provided evidence that confirmed their hypothesis and established the COMT val158met SNP as one of the first gene modifications with direct ramifications on human pain.
The link between an Nav1.7 mutation and erythromelalgia
Authors: Kerr Bradley J.
Published: October 2018

The landmark paper discussed in this chapter is ‘Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons’, published by Dib-Hajj et al. in 2005. The voltage-dependent sodium channels Nav1.7, Nav1.8, and Nav1.9 have a restricted pattern of expression in sensory neurons in the periphery and are concentrated in small nociceptive neurons of the dorsal root ganglion, the trigeminal ganglion, and the nodose ganglion. In this paper, Dib-Hajj and colleagues studied a family with erythromelalgia (Weir Mitchell disease), an autosomal-dominant, inherited pain disorder in which burning pain in the extremities can be triggered by warming of the skin or moderate exertion. By identifying a novel mutation in SCN9A, which encodes Nav1.7, they established the critical role of this specific ion channel in this patient population. These findings represent an important first step towards developing isoform-specific channel blockers for the treatment of an inherited chronic pain condition.
COMT and morphine use in cancer pain
Authors: Morell-Ducos Fausto
Published: October 2018

The landmark paper discussed in this chapter is ‘Genetic variation in the catechol-O-methyltransferase (COMT) gene and morphine requirements in cancer patients with pain’, published by Rakvåg et al. in 2008. Genetic variation contributes to differences in pain sensitivity and response to analgesics. Catecholamines are involved in the modulation of pain and are metabolized by catchol-O-methyltransferase (COMT). Genetic variability in the COMT gene may therefore contribute to differences in pain sensitivity and response to analgesics. It has been shown that a polymorphism in the COMT gene, Rs4680 (val158met), influences pain sensitivity and efficacy for morphine in cancer pain treatment. This study investigated whether the variability in other regions in the COMT gene also contributes to the inter-individual variability of morphine efficacy by mapping 11 single nucleotide polymorphisms, constructing haplotypes from them, and then comparing genotypes and haplotypes against pharmacological, demographic, and patient symptom measurements in patients receiving morphine for cancer pain.
Left Pan-Hippocampal Low Grade Glioma—2-Stage Transsylvian Transventricular and Paramedian Supracerebellar Transtentorial Approaches: 2-Dimensional Operative Video
Authors: Fernandez-Miranda Juan C
Published: October 2018

The surgical goal for low-grade gliomas (LGGs) is to maximize resection while minimizing morbidity. Pan-hippocampal LGGs extend from the hippocampal head to the hippocampal tail, and involve the parahippocampal gyrus and uncus. Given their anteroposterior extension, they cannot be completely removed with 1 single approach, requiring a 2-stage front-to-back operation.

 In this video, we present the case of a 52-yr-old man with new onset of generalized seizures and a dominant-side, nonenhancing, pan-hippocampal infiltrative lesion compatible with a low-grade glioma. Preoperative high-definition fiber tractography (HDFT) showed the spatial relationship of the tumor with surrounding fiber tracts, such as the arcuate, inferior fronto-occipital, and middle longitudinal fascicles, and optic radiations.

 Surgical resection was planned in 2 separate stages. The first stage consisted of a transsylvian transinferior insular sulcus approach to the extra- and intraventricular aspects of the uncohippocampal region. The entire anterior and middle portions of the tumor were successfully removed with minimal morbidity, including transient naming difficulties and permanent superior quadrantanopia. Postoperative HDFT showed preservation of all fiber tracts, except for a portion of Meyer's loop and the inferior-most aspect of the inferior fronto-occipital fascicle. The second stage was completed 8 wk later and consisted of a paramedian supracerebellar-transtentorial approach on sitting position. The posterior portion of the tumor was entirely removed to achieve a complete macroscopic tumor resection. The final diagnosis was IDH1-positive LGG.

 Pan-hippocampal tumors remain a surgical challenge but accurate knowledge of surgical neuroanatomy and surgical approaches facilitates their safe and effective treatment.

 The patient signed an informed consent including the use of photographic and video material for educational or academic purposes.
Paramedian Supracerebellar Approach in Semi-Sitting Position for Endoscopic Resection of Pineal Cyst: 2-Dimensional Operative Video
Authors: Fernandez-Miranda Juan C
Published: October 2018

In this video, we present the case of a 41-yr-old female with new onset of recurrent syncopal episodes. She underwent extensive evaluations and diagnostic work-up by cardiology and neurology, excluding any other cause than a large pineal cyst that was found on magnetic resonance imaging.

 Surgical indications for pineal cyst resection are very limited as most pineal cyst can be treated conservatively. Recurrent drop-attacks (without loss of consciousness) or syncopal episodes (with brief loss of consciousness) have been associated with pineal cysts secondary to a possible ball valve effect with shift of position causing sudden obstruction of the ventricular system followed by rapid rising of intracranial pressure.

 Several approaches, different positions, and alternative surgical techniques (microscopic vs endoscopic) have been proposed for resection of pineal region lesions. The semi-sitting position provides excellent exposure of the pineal region secondary to gravity-based retraction of the cerebellum, and carries minimal risk of air venous embolism when head elevation is reduced to 30° and lower extremities are elevated. The paramedian supracerebellar approach is less invasive and faster than midline supracerebellar approach, because it requires exposure of just 1 transverse sinus (nondominant for centered lesions) and avoids exposure of the torcula. The endoscopic technique greatly improves the ergonomics of the approach when compared to the microscope based technique, and provides excellent visualization of all the neurovascular structures in the pineal region.

 Surgical resection was successfully performed with no complications and complete cyst resection. Patient was discharged on postoperative day 1 and remains free of syncopal episodes.

 The patient signed informed consent including the use of photographic and video material for educational or academic purposes.
Does Opioid Tapering in Chronic Pain Patients Result in Improved Pain or Same Pain vs Increased Pain at Taper Completion? A Structured Evidence-Based Systematic Review
Authors: Fishbain David A , Pulikal Aditya
Published: October 2018

Objective

To support or refute the hypothesis that opioid tapering in chronic pain patients (CPPs) improves pain or maintains the same pain level by taper completion but does not increase pain.

Methods

Of 364 references, 20 fulfilled inclusion/exclusion criteria. These studies were type 3 and 4 (not controlled) but reported pre/post-taper pain levels. Characteristics of the studies were abstracted into tabular form for numerical analysis. Studies were rated independently by two reviewers for quality. The percentage of studies supporting the above hypothesis was determined.

Results

No studies had a rejection quality score. Combining all studies, 2,109 CPPs were tapered. Eighty percent of the studies reported that by taper completion pain had improved. Of these, 81.25% demonstrated this statistically. In 15% of the studies, pain was the same by taper completion. One study reported that by taper completion, 97% of the CPPs had improved or the same pain, but CPPs had worse pain in 3%. As such, 100% of the studies supported the hypothesis. Applying the Agency for Health Care Policy and Research Levels of Evidence Guidelines to this result produced an A consistency rating.

Conclusions

There is consistent type 3 and 4 study evidence that opioid tapering in CPPs reduces pain or maintains the same level of pain. However, these studies represented lower levels of evidence and were not designed to test the hypothesis, with the evidence being marginal in quality with large amounts of missing data. These results then primarily reveal the need for controlled studies (type 2) to address this hypothesis.
Health inequalities and health equity challenges for victims of modern slavery
Authors: Dando Coral J , Brierley Robin , Saunders Karen , Mackenzie Jay-Marie
Published: October 2018

Background

Modern slavery is a serious organized crime, with severe consequences for the physical and mental health of victims, and so has public health implications. Anecdotally many victims of sex slavery experience difficulties accessing healthcare. Public Health England recently articulated the importance of health engagement to address modern slavery but little is known about the experiences of the survivors.

Methods

We conducted in depth interviews with Albanian female survivors of sex slavery who all displayed significant and complex health needs. Interviews were conducted between July 2017 and January 2018. Thematic analysis identified four primary themes: (i) barriers to access, (ii) negotiating access, (iii) health needs and care received and (iv) overall experience of primary care.

Results

Survivors experienced repeated challenges accessing healthcare, for themselves and their children, and initially could not access GP services. When accompanied by an advocate they reported qualitatively and quantitatively improved experiences resulting in improved permeability. Confusion surrounding eligibility criteria and a lack of understanding of modern slavery emerged as the primary barriers, fueling biased adjudications.

Conclusions

The importance of advocates, enabling rights-based approaches, improving understanding about access to health services for vulnerable groups, and a need for education across health service settings are discussed.
Using a mobile application to detect health needs among children and adolescents who are newly arrived migrants in Europe
Authors: Rath B , Swenshon S , Haase K , Szeles T , Jung C , Jacobi F , Myles P
Published: October 2018

Background

Unprecedented numbers of migrants have arrived in Europe, including children and adolescents. Little is known about their unique health needs. Prospective data collection has been sparse. Mobile applications may help to facilitate global health surveillance.

Methods

A pre-validated survey instrument was converted into a mobile application covering self-reported exposures and disruptions of healthcare before/during migration, communicable and non-communicable diseases. Participation was voluntary, anonymous and confidential.

Results

Data were obtained from 405 migrant children and adolescents in Berlin, Germany, between 7 October 2015 and 15 March 2016 (median age 19 years, range: 1–24; 80.7% males) with the majority from Syria (62.5%), Afghanistan (9.1%) and Iraq (8.2%). In total, 55% were without family, 64% registered asylum-seekers with access to healthcare; 54% had seen a doctor since arrival, with colds or respiratory complaints (37.5 and 13.6%), followed by pain (26.7%) gastrointestinal (12.4%) and skin problems (11.1%). Underlying conditions were reported in 15.6%, predominantly asthma. Overall, 73% reported being up-to date on immunizations, but only 22% held a vaccination record with 46.4% having lost it during migration.

Conclusions

The lack of medical and immunization records among newly arrived migrants provides a challenge to healthcare systems. Mobile applications offer rapid screening tools in times of crisis, helping stakeholders with timely information.
Impact of Disease on Amikacin Pharmacokinetics and Dosing in Children
Authors: Liu Xiaoxi , Smits Anne , Wang Yuhuan , Renard Marleen , Wead Stephanie , Kagan Richard J. , Healy Daniel P. , De Cock Pieter , Allegaert Karel , Sherwin Catherine M.T.
Published: October 2018

Background:

Amikacin is widely used to treat severe Gram-negative bacterial infections. Its peak concentration in plasma is associated with treatment efficacy. Amikacin pharmacokinetics (PK) is influenced by disease conditions, in addition to other patient characteristics. In this retrospective study, we evaluated the impact of clinical characteristics and disease condition on amikacin PK in children with burn injuries and those with cancer.

Methods:

Amikacin PK data from 66 children with burn injuries and 112 children with cancer were analyzed. A population PK model was developed using the nonlinear mixed-effects modeling approach. Models were developed using NONMEM 7.3 (ICON Development Solutions, LLC, Ellicott City, MD). Data processing and visualization was performed using R packages.

Results:

The amikacin PK data were best described by a 2-compartment model. The parameters were estimated with mean values (95% confidence intervals) as follows: central volume of distribution (V1), 5.70 L (4.64–6.76 L); central clearance, 2.12 L/h (1.79–2.46 L/h); peripheral volume of distribution (V2), 4.79 L (2.36–7.22 L); and distribution clearance (Q), 0.71 L/h (0.25–1.16 L/h). The final model identified the disease condition as a significant covariate and indicated 55% (28%–82%) higher central clearance and 17% (1%–34%) higher V1 in burn patients compared with cancer patients. Volume of distribution was significantly influenced by age and body weight. Clearance was significantly influenced by age, body weight, and creatinine clearance. Using the final PK model, we developed a workflow for selecting optimal dosing strategies for 3 representative pediatric patient profiles.

Conclusions:

Disease condition was significant in influencing amikacin PK in children. To reach the same target concentrations (64 mg/L peak concentration) with a daily-dose plan, burn patients need higher doses than cancer patients. Future investigations are needed to explore the impact of other diseases on amikacin disposition in children, and to prospectively validate the proposed dosing strategy.
Pharmacokinetic Characteristics and Limited Sampling Strategies for Therapeutic Drug Monitoring of Colistin in Patients With Multidrug-Resistant Gram-Negative Bacterial Infections
Authors: Kim Eun Jung , Oh Jaeseong , Lee Kyounghoon , Yu Kyung-Sang , Chung Jae-Yong , Hwang Joo-Hee , Nam Eun Young , Kim Hyoung Sook , Kim Moonsuk , Park Jeong Su , Song Kyoung-Ho , Kim Eu Suk , Song Junghan , Kim Hong Bin
Published: October 2018

Background:

Colistin is increasingly used as the last therapeutic option for the treatment of multidrug-resistant, Gram-negative bacterial infections. To ensure safe and efficacious use of colistin, therapeutic drug monitoring (TDM) is needed due to its narrow therapeutic window. This study aimed to evaluate the pharmacokinetic (PK) characteristics of colistin and to guide TDM in colistin-treated patients in Korea.

Methods:

In a prospective study, we analyzed PK characteristics in 15 patients who intravenously received colistin methanesulfonate twice per day. Colistin methanesulfonate doses were adjusted based on renal function of the subjects. The appropriate blood sampling points for TDM were evaluated by analyzing the correlations between the PK parameters and the plasma concentrations at each time point.

Results:

The mean values for the minimum, maximum, and average concentrations (Cmin, Cmax, and Caverage) of colistin at steady state were 2.29, 5.5, and 3.38 mg/L, respectively. The dose-normalized Cmin, Cmax, Caverage, and area under the plasma concentration–time curve from 0 to the last measurable concentration (AUClast) showed negative correlations with the creatinine clearance. The combination of the 0- and 2-hour post-dose plasma concentrations was evaluated as the appropriate sampling point for TDM. Two patients reported nephrotoxic adverse events during colistin administration.

Conclusions:

Our study clarifies the PK characteristics of successful colistin treatment using TDM. Further evaluations in a larger patient population are needed to confirm the clinical usefulness of colistin TDM.
Pathophysiology of Placenta Accreta Spectrum Disorders: A Review of Current Findings
Authors: JAUNIAUX ERIC , BURTON GRAHAM J.
Published: October 2018

Current findings continue to support the concept of a biologically defective decidua rather than a primarily abnormally invasive trophoblast. Prior cesarean sections increase the risk of placenta previa and both adherent and invasive placenta accreta, suggesting that the endometrial/decidual defect following the iatrogenic creation of a uterine myometrium scar has an adverse effect on early implantation. Preferential attachment of the blastocyst to scar tissue facilitates abnormally deep invasion of trophoblastic cells and interactions with the radial and arcuate arteries. Subsequent high velocity maternal arterial inflow into the placenta creates large lacunae, destroying the normal cotyledonary arrangement of the villi.
Surgical Management of Placenta Accreta Spectrum
Authors: EINERSON BRETT D. , BRANCH D. WARE
Published: October 2018

This is a discussion of the standard surgical treatment of placenta accreta spectrum disorders including preoperative considerations, diagnostic imaging, surgical steps for cesarean hysterectomy, and postoperative management.