Pain medicine training: FPM essentials

Abstract
Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.

Abstract
One popular description of current society is that it is a depressed society and medical evidence about depression's prevalence may well make such an estimation plausible. However, such normative-critical assessments surrounding depression have to date usually operated with a one-sided understanding of depression. This understanding widely neglects the various ways depression manifests as well as its comorbidities. This becomes evident at the latest when considering one of depression's most prominent and well-known comorbidities: chronic pain. Against this background, we aim in this article to substantiate our leading claim that the phenomenal interconnection between depression and chronic pain must be acknowledged in the global diagnosis of a depressive society. Thus, we argue here for a complementation of the dominant interpretation of a depressed society. This would support the overcoming of oversimplified images and estimations about depression in current society and further, help to recognize chronic pain properly on the larger scale of assessments that address society as a whole.

Abstract
Despite the increasing use of a variety of different analgesic strategies, opioids continue as the mainstay for management of moderate to severe acute pain. However concerns remain about their potential adverse effects on ventilation. The most commonly used term, respiratory depression, only describes part of that risk. Opioid-induced ventilatory impairment (OIVI) is a more complete term encompassing opioid-induced central respiratory depression (decreased respiratory drive), decreased level of consciousness (sedation) and upper airway obstruction, all of which, alone or in combination, may result in decreased alveolar ventilation and increased arterial carbon dioxide levels. Concerns about OIVI are warranted, as deaths related to opioid administration in the acute pain setting continue to be reported. Risks are often said to be higher in patients with obstructive sleep apnoea. However, the tendency to use the term 'obstructive sleep apnoea' to encompass the much broader spectrum of sleep- and obesity-related hypoventilation syndromes and the related misuse of terminology in papers relating to obstructive sleep apnoea and sleep-disordered breathing remain significant problems in discussions of opioid-related effects. Opioids given for management of acute pain must be titrated to effect for each patient. However strategies aiming for better pain scores alone, without highlighting the need for appropriate monitoring of OIVI, can and will lead to an increase in adverse events. Therefore, all patients must be monitored appropriately for OIVI (at the very least using sedation scores as a '6th vital sign') so that it can be detected at an early stage and appropriate interventions triggered.

Objective: To summarize and to analyze the available literature on the efficacy of intra-articular injections of corticosteroids for low back pain.

Design: Publications, in English, French, and German, were obtained that reported the proportions of patients who obtained complete relief of pain following intra-articular steroids, and that provided any form of follow-up. These publications were analyzed to determine the rationale, indications, and outcomes of the treatment.

Results: The only rationale for intra-articular steroids appears to be the expectation that they should work. The most commonly used indication has been back pain, for which no specific diagnosis has been made. When the results of observational studies are pooled, they paint a picture of impressive immediate responses, but a rapid decay of outcomes by three and six months. Initial responses, however, are dissonant with the literature from controlled studies of the prevalence of lumbar zygapophysial joint pain. Moreover, controlled trials have shown that there is no attributable effect to the injection of steroids.

Conclusion: The apparent efficacy of lumbar intra-articular steroids is no greater than that of a sham injection. There is no justification for the continued use of this intervention. Better outcomes can be achieved with deliberate placebo therapy.

This study constituted the first step in the psychometric development of a self-report screening instrument for risk of opioid medication misuse among chronic pain patients. A 26-item instrument, the Pain Medication Questionnaire (PMQ), was constructed based on suspected behavioral correlates of opioid medication misuse, which heretofore have received limited empirical investigation. The PMQ was administered to 184 patients at an interdisciplinary pain treatment center. Reliability coefficients for the PMQ were found to be of moderate but acceptable strength. Construct and concurrent validity were examined through correlation of PMQ scores to measures of substance abuse, physical and psychological functioning, and physicians' risk assessments. To explore high and low cutoff points for misuse risk, subgroups were formed according to the upper and lower thirds of PMQ scores and compared on validity measures. Higher PMQ scores were associated with history of substance abuse, higher levels of psychosocial distress, and poorer functioning. Future psychometric analyses will consider predictive validity and examine shortened versions of the instrument.

In the last ten years, gabapentin and pregabalin have been becoming dispensed broadly and sold on black markets, thereby, exposing millions to potential side-effects. Meanwhile, several pharmacovigilance-databases have warned for potential abuse liabilities and overdose fatalities in association with both gabapentinoids. To evaluate their addiction risk in more detail, we conducted a systematic review on PubMed/Scopus and included 106 studies. We did not find convincing evidence of a vigorous addictive power of gabapentinoids which is primarily suggested from their limited rewarding properties, marginal notes on relapses, and the very few cases with gabapentinoid-related behavioral dependence symptoms (ICD-10) in patients without a prior abuse history (N=4). In support, there was no publication about people who sought treatment for the use of gabapentinoids. Pregabalin appeared to be somewhat more addictive than gabapentin regarding the magnitude of behavioral dependence symptoms, transitions from prescription to self-administration, and the durability of the self-administrations. The principal population at risk for addiction of gabapentinoids consists of patients with other current or past substance use disorders (SUD), mostly opioid and multi-drug users, who preferred pregabalin. Pure overdoses of gabapentinoids appeared to be relative safe but can become lethal (pregabalin > gabapentin) in mixture with other psychoactive drugs, especially opioids again and sedatives. Based upon these results, we compared the addiction risks of gabapentin and pregabalin with those of traditional psychoactive substances and recommend that in patients with a history of SUD, gabapentinoids should be avoided or if indispensable, administered with caution by using a strict therapeutic and prescription monitoring.

Abstract
Patients with acute lumbar disc prolapse with sciatica who are not considered candidates for surgery are usually treated with physiotherapy and non-steroidal anti-inflammatory agents. Moreover, the treatment with benzodiazepines is common practice in the absence of class I or II level of evidence. Here we assessed the role of benzodiazepines in the conservative management of acute lumbar disc prolapse. Using a placebo-controlled, double-blinded design, 60 patients were randomized to receive placebo or diazepam in addition to mechanical physiotherapy and analgesics for the first 7 days of conservative treatment of clinically and radiologically confirmed lumbar disc prolapse. The primary objective was to evaluate if physiotherapy plus analgesics, but without benzodiazepines, is equivalent to the same therapy plus benzodiazepines. The primary endpoint was centralization of referred pain at day 7. Twenty-six female and 34 male patients were enrolled. The median age was 42 years (range 22-68 years). Analysis of the primary endpoint demonstrated equivalence between placebo and diazepam (median 60% vs. 50% reduction of distance of referred pain at day 7) within the predefined equivalence tolerance of 20% at a significance level of p<0.05. Regarding the secondary endpoints, the median duration of the stay in hospital was shorter in the placebo arm (8 vs. 10 days, p=0.008), and the probability of pain reduction on a visual analog scale by more than 50% was twice as high in placebo patients (p<0.0015). Benzodiazepines should not be used routinely in patients treated with mechanical physiotherapy for lumbar disc prolapse.

Abstract
Background and aims: Pregabalin is a gamma-aminobutyric acid (GABA) analogue, used to treat neuropathic pain and epilepsy. Pregabalin was registered in Australia in 2005, and subsidized publically in 2013. We aimed to describe Australian patterns of pregabalin use and intentional poisoning, and identify people potentially at high risk of misuse.

Design and setting: Population-based retrospective cohort study of dispensings in the 10% sample of Australian Pharmaceutical Benefits Scheme (July 2012-February 2017); intentional poisoning calls to New South Wales Poisons Information Centre (NSWPIC) (2004-2016); intentional poisonings in two Australian toxicology service databases; and poisoning fatalities in NSW coronial records (2005-2016).

Participants: A total of 122 572 people dispensed pregabalin, people with intentional pregabalin overdoses managed by NSWPIC and the toxicology services and pregabalin-associated deaths referred to the NSW coroner.

Measurements: Trends in dispensing, poisoning, death; demographics and patient characteristics, proportion of users at high risk of misuse (latent class analysis, LCA) and characteristics of high-risk users.

Findings: Pregabalin dispensing increased by 73 424 per year [95% confidence interval (CI) = 61726-85 121 P < 0.001] between 2013 and 2016. NSWPIC received 1158 reports of intentional pregabalin poisonings, with a 53.8% increase per year, 2005-2016 (95% CI = 44.0-64.2%, P < 0.001). We identified 88 pregabalin-associated deaths, 57.8% yearly increase (95% CI = 30.0-91.6%, P < 0.001). Patients overdosing on pregabalin commonly co-ingested opioids, benzodiazepines and illicit drugs, and had high rates of psychiatric and substance use comorbidities; 14.7% of pregabalin users were classed by the LCA as at high risk of misuse, and were more likely to be younger, male, co-prescribed benzodiazepines or opioids, have more individual prescribers and higher pregabalin strengths dispensed.

Conclusions: There has been a dramatic increase in pregabalin use, poisonings and deaths in Australia since it became subsidized publicly in 2013. One in seven Australians dispensed pregabalin appears to be at high risk of misuse.

Abstract
The International Classification of Diseases (ICD) and the Diagnostic and Statistical Manual (DSM) are routinely used in diagnosing illicit substance use disorders, but for people taking prescribed opioids they remain controversial. In pain medicine, the concept of "Addiction" is preferred with reduced emphasis on tolerance and withdrawal. This article examines the prevalence and characteristics of pharmaceutical opioid dependence/disorder according to ICD, DSM, and the pain medicine concept of "Addiction," among chronic noncancer pain (CNCP) patients prescribed opioids. In the current study, we used data from a national sample of 1134 people prescribed opioids for CNCP. Past 12-month "Addiction" (based on Pain Medicine definition), DSM, and ICD dependence definitions were assessed using the Composite International Diagnostic Interview. Twenty-four percent of the cohort met the criteria for "Addiction," 18% for DSM-5 use disorder and 19% for ICD-11 dependence. There was "substantial" concordance between "Addiction" and both DSM-5 use disorder and ICD-11 dependence, although concordance was much greater with ICD-11 dependence (kappa = 0.63 and 0.79, respectively). Participants meeting the criteria for "Addiction" only were older, less likely to engage in nonadherent behaviours, self-reported fewer problems or concerns with their medication, and had lower rates of psychological distress than those who also met the DSM-5 and ICD-11 criteria. The definition of "Addiction" captures a larger group of patients than other classification systems and includes people with fewer "risk" behaviours. Despite removal of tolerance and withdrawal for prescribed opioid use for DSM-5, we found that "Addiction" was more closely related to an ICD-11 diagnosis of pharmaceutical opioid dependence.

Optimal methods to predict risk of aberrant drug-related behaviors before initiation of opioids for chronic noncancer pain and to identify aberrant behaviors after therapy is initiated are uncertain. We systematically reviewed published literature identified through searches of Ovid MEDLINE and the Cochrane databases through July 2008. Diagnostic test characteristics and accompanying confidence intervals were calculated with data extracted from the studies. Four prospective studies evaluated diagnostic accuracy of risk prediction instruments. Two higher-quality derivation studies found that high scores on the Screener and Opioid Assessment for Patients with Pain (SOAPP) Version 1 and the Revised SOAPP (SOAPP-R) instruments weakly increased the likelihood for future aberrant drug-related behaviors (positive likelihood ratios [PLR], 2.90 [95% CI, 1.91 to 4.39] and 2.50 [95% CI, 1.93 to 3.24], respectively). Low scores on the SOAPP Version 1 moderately decreased the likelihood for aberrant drug-related behaviors (negative likelihood ratio [NLR], 0.13 [95% CI, 0.05 to 0.34]) and low scores on the SOAPP-R weakly decreased the likelihood (NLR, 0.29 [95% CI, 0.18 to 0.46]), but estimates are too imprecise to determine if there is a difference between these instruments. One lower-quality study found that categorization as high risk using the Opioid Risk Tool strongly increased the likelihood for future aberrant drug-related behaviors (PLR, 14.3 [95% CI, 5.35 to 38.4]) and classification as low risk strongly decreased the likelihood (PLR, 0.08 [95% CI, 0.01 to 0.62]). Nine studies evaluated monitoring instruments for identification of aberrant drug-related behaviors in patients on opioid therapy. One higher-quality derivation study found higher scores on the Current Opioid Misuse Measure (COMM) weakly increased the likelihood of current aberrant drug-related behaviors (PLR, 2.77 [95% CI, 2.06 to 3.72]) and lower scores weakly decreased the likelihood (NLR, 0.35 [95% CI, 0.24 to 0.52]). In 8 studies of other monitoring instruments, diagnostic accuracy was poor, results were difficult to interpret due to methodological shortcomings, or standard diagnostic test characteristics were not reported. Definitions for aberrant drug-related behaviors were not standardized across studies and did not account for seriousness of identified behaviors. No reliable evidence exists on accuracy of urine drug screening, pill counts, or prescription drug monitoring programs; or clinical outcomes associated with different assessment or monitoring strategies.

Perspective: Evidence on prediction and identification of aberrant drug-related behaviors is limited. Although several screening instruments may be useful, evidence is sparse and primarily based on derivation studies, and methodological shortcomings exist in all studies. Research that performs external validation, uses standardized definitions for clinically relevant aberrant drug-related behaviors, and evaluates clinical outcomes associated with different assessment and monitoring strategies is needed.

Abstract
We summarise the evidence for medicinal uses of opioids, harms related to the extramedical use of, and dependence on, these drugs, and a wide range of interventions used to address these harms. The Global Burden of Diseases, Injuries, and Risk Factors Study estimated that in 2017, 40·5 million people were dependent on opioids (95% uncertainty interval 34·3-47·9 million) and 109 500 people (105 800-113 600) died from opioid overdose. Opioid agonist treatment (OAT) can be highly effective in reducing illicit opioid use and improving multiple health and social outcomes-eg, by reducing overall mortality and key causes of death, including overdose, suicide, HIV, hepatitis C virus, and other injuries. Mathematical modelling suggests that scaling up the use of OAT and retaining people in treatment, including in prison, could avert a median of 7·7% of deaths in Kentucky, 10·7% in Kiev, and 25·9% in Tehran over 20 years (compared with no OAT), with the greater effects in Tehran and Kiev being due to reductions in HIV mortality, given the higher prevalence of HIV among people who inject drugs in those settings. Other interventions have varied evidence for effectiveness and patient acceptability, and typically affect a narrower set of outcomes than OAT does. Other effective interventions focus on preventing harm related to opioids. Despite strong evidence for the effectiveness of a range of interventions to improve the health and wellbeing of people who are dependent on opioids, coverage is low, even in high-income countries. Treatment quality might be less than desirable, and considerable harm might be caused to individuals, society, and the economy by the criminalisation of extramedical opioid use and dependence. Alternative policy frameworks are recommended that adopt an approach based on human rights and public health, do not make drug use a criminal behaviour, and seek to reduce drug-related harm at the population level.

Abstract
Each year, over 50 million Americans suffer from persistent pain, including debilitating headaches, joint pain, and severe back pain. Although morphine is amongst the most effective analgesics available for the management of severe pain, prolonged morphine treatment results in decreased analgesic efficacy (i.e., tolerance). Despite significant headway in the field, the mechanisms underlying the development of morphine tolerance are not well understood. The midbrain ventrolateral periaqueductal gray (vlPAG) is a primary neural substrate for the analgesic effects of morphine, as well as for the development of morphine tolerance. A growing body of literature indicates that activated glia (i.e., microglia and astrocytes) facilitate pain transmission and oppose morphine analgesia, making these cells important potential targets in the treatment of chronic pain. Morphine affects glia by binding to the innate immune receptor toll-like receptor 4 (TLR4), leading to the release of proinflammatory cytokines and opposition of morphine analgesia. Despite the established role of the vlPAG as an integral locus for the development of morphine tolerance, most studies have examined the role of glia activation within the spinal cord. Additionally, the role of TLR4 in the development of tolerance has not been elucidated. This review attempts to summarize what is known regarding the role of vlPAG glia and TLR4 in the development of morphine tolerance. These data, together, provide information about the mechanism by which central nervous system glia regulate morphine tolerance, and identify a potential therapeutic target for the enhancement of analgesic efficacy in the clinical treatment of chronic pain.

Moderate-to-severe pain represents a heavy burden in patients' quality of life, and ultimately in the society and in healthcare costs. The aim of this review was to summarize data on tramadol and tapentadol adverse effects, toxicity, potential advantages and limitations according to the context of clinical use. We compared data on the pharmacological and toxicological profiles of tramadol and tapentadol, after an extensive literature search in the US National Library of Medicine (PubMed). Tramadol is a prodrug that acts through noradrenaline and serotonin reuptake inhibition, with a weak opioid component added by its metabolite O-desmethyltramadol. Tapentadol does not require metabolic activation and acts mainly through noradrenaline reuptake inhibition and has a strong opioid activity. Such features confer tapentadol potential advantages, namely lower serotonergic, dependence and abuse potential, more linear pharmacokinetics, greater gastrointestinal tolerability and applicability in the treatment of chronic and neuropathic pain. Although more studies are needed to provide clear guidance on the opioid of choice, tapentadol shows some advantages, as it does not require CYP450 system activation and has minimal serotonergic effects. In addition, it leads to less side effects and lower abuse liability. However, in vivo and in vitro studies have shown that tramadol and tapentadol cause similar toxicological damage. In this context, it is important to underline that the choice of opioid should be individually balanced and a tailored decision, based on previous experience and on the patient's profile, type of pain and context of treatment.

Significance: This review underlines the need for a careful prescription of tramadol and tapentadol. Although both are widely prescribed synthetic opioid analgesics, their toxic effects and potential dependence are not completely understood yet. In particular, concerning tapentadol, further research is needed to better assess its toxic effects.

Background: Prescription drug monitoring programs (PDMPs) are a key component of the president's Prescription Drug Abuse Prevention Plan to prevent opioid overdoses in the United States.

Purpose: To examine whether PDMP implementation is associated with changes in nonfatal and fatal overdoses; identify features of programs differentially associated with those outcomes; and investigate any potential unintended consequences of the programs.

Data sources: Eligible publications from MEDLINE, Current Contents Connect (Clarivate Analytics), Science Citation Index (Clarivate Analytics), Social Sciences Citation Index (Clarivate Analytics), and ProQuest Dissertations indexed through 27 December 2017 and additional studies from reference lists.

Study selection: Observational studies (published in English) from U.S. states that examined an association between PDMP implementation and nonfatal or fatal overdoses.

Data extraction: 2 investigators independently extracted data from and rated the risk of bias (ROB) of studies by using established criteria. Consensus determinations involving all investigators were used to grade strength of evidence for each intervention.

Data synthesis: Of 2661 records, 17 articles met the inclusion criteria. These articles examined PDMP implementation only (n = 8), program features only (n = 2), PDMP implementation and program features (n = 5), PDMP implementation with mandated provider review combined with pain clinic laws (n = 1), and PDMP robustness (n = 1). Evidence from 3 studies was insufficient to draw conclusions regarding an association between PDMP implementation and nonfatal overdoses. Low-strength evidence from 10 studies suggested a reduction in fatal overdoses with PDMP implementation. Program features associated with a decrease in overdose deaths included mandatory provider review, provider authorization to access PDMP data, frequency of reports, and monitoring of nonscheduled drugs. Three of 6 studies found an increase in heroin overdoses after PDMP implementation.

Limitation: Few studies, high ROB, and heterogeneous analytic methods and outcome measurement.

Conclusion: Evidence that PDMP implementation either increases or decreases nonfatal or fatal overdoses is largely insufficient, as is evidence regarding positive associations between specific administrative features and successful programs. Some evidence showed unintended consequences. Research is needed to identify a set of "best practices" and complementary initiatives to address these consequences.

Primary funding source: National Institute on Drug Abuse and Bureau of Justice Assistance.

Aims: A number of screening instruments are routinely used in Emergency Department (ED) situations to identify alcohol-use disorders (AUD). We wished to study the psychometric features, particularly concerning optimal thresholds scores (TSs), of four assessment scales frequently used to screen for abuse and/or dependence, the cut-down annoyed guilty eye-opener (CAGE), Rapid Alcohol Problem Screen 4 (RAPS4), RAPS4-quantity-frequency and AUD Identification Test (AUDIT) questionnaires, particularly in the sub-group of people admitted for acute alcohol intoxication (AAI).

Methods: All included patients [AAI admitted to ED (blood alcohol level ≥0.8 g/l)] were assessed by the four scales, and with a gold standard (alcohol dependence/abuse section of the Mini International Neuropsychiatric Interview), to determine AUD status. To investigate the TSs of the scales, we used Youden's index, efficiency, receiver operating characteristic (ROC) curve techniques and quality ROC curve technique for optimized TS (indices of quality).

Results: A total of 164 persons (122 males, 42 females) were included in the study. Nineteen (11.60%) were identified as alcohol abusers alone and 128 (78.1%) as alcohol dependents (DSM-IV). Results suggest a statistically significant difference between men and women (P < 0.05) in performance of the screening tests RAPS4 (≥1) and CAGE (≥2) for detecting abuse. Also, in this population, we show an increase in TSs of RAPS4 (≥2) and CAGE (≥3) for detecting dependence compared with those typically accepted in non-intoxicated individuals. The AUDIT test demonstrates good performance for detecting alcohol abuse and/or alcohol-dependent patients (≥7 for women and ≥12 for men) and for distinguishing alcohol dependence (≥11 for women and ≥14 for men) from other conditions.

Conclusion: Our study underscores for the first time the need to adapt, taking into account gender, the thresholds of tests typically used for detection of abuse and dependence in this population.

Abstract
Introduction: Many psychopharmacologic agents are used as primary or adjuncts in pain management. Atypical antipsychotics (AAs) have also been used as adjuncts in pain management regimens in a variety of manners; however, their efficacy in this capacity is unclear.

Methods: A systematic review of all studies examining AA use for pain was conducted. Three literature databases were utilized to search for word combinations of "pain" and a variety of commonly prescribed AAs ie, (olanzapine, quetiapine, risperidone, aripiprazole, ziprasidone, clozapine, paliperidone, iloperidone, lurasidone). Articles chosen for review included retrospective analyses, randomized control trials, and case series/reports. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram illustrates the study selection process.

Results: Olanzapine, quetiapine, risperidone, aripiprazole, and ziprasidone are the only AAs with published studies in pain management. Among these, olanzapine and quetiapine have the most studies (11 and 6, respectively). Olanzapine shows preliminary and consistent efficacy in fibromyalgia and headache/migraine, although only 1 study was a randomized controlled trial with level I evidence of efficacy. Other AAs eg, (quetiapine) fail to demonstrate efficacy in pain syndromes and/or lack robust study designs.

Conclusions: Few studies have been conducted to evaluate the analgesic effects of AAs. The collective findings of multiple studies evaluating olanzapine in pain syndromes suggest a high, yet preliminary level of evidence of efficacy, warranting prospective studies in various pain syndrome contexts. Pharmacological mechanisms of AA action are elaborated, and the findings of this review are discussed. Risk and benefits of using AAs in chronic pain are described, and investigational implications and future directions are explored.

Abstract
Background: Early identification of problems is essential in minimising the unintended consequences of opioid therapy. This study aimed to develop a brief scale that identifies and quantifies recent aberrant behaviour among diverse patient populations receiving long-term opioid treatment.

Method: 40 scale items were generated via literature review and expert panel (N=19) and tested in surveys of: (i) N=41 key experts, and (ii) N=426 patients prescribed opioids >3 months (222 pain patients and 204 opioid substitution therapy (OST) patients). We employed item and scale psychometrics (exploratory factor analyses, confirmatory factor analyses and item-response theory statistics) to refine items to a brief scale.

Results: Following removal of problematic items (poor retest-reliability or wording, semantic redundancy, differential item functioning, collinearity or rarity) iterative factor analytic procedures identified a 10-item unifactorial scale with good model fit in the total sample (N=426; CFI=0.981, TLI=0.975, RMSEA=0.057), and among pain (CFI=0.969, TLI=0.960, RMSEA=0.062) and OST subgroups (CFI=0.989, TFI=0.986, RMSEA=0.051). The 10 items provided good discrimination between groups, demonstrated acceptable test-retest reliability (ICC 0.80, 95% CI 0.60-0.89; Cronbach's alpha=0.89), were moderately correlated with related constructs, including opioid dependence (SDS), depression and stress (DASS subscales) and Social Relationships and Environment domains of the WHO-QoL, and had strong face validity among advising clinicians.

Conclusions: The Opioid-Related Behaviours In Treatment (ORBIT) scale is brief, reliable and validated for use in diverse patient groups receiving opioids. The ORBIT has potential applications as a checklist to prompt clinical discussions and as a tool to quantify aberrant behaviour and assess change over time.

Abstract
Aims: This paper (i) reviews the language used to describe and manage those patient practices that fall outside standard medical models of opioid treatment (for pain and opioid dependence), and (ii) proposes a consistent terminology that can be applied across multiple healthcare settings.

Method: Peer-reviewed and grey literature documenting empirical studies of (non-)adherence with opioid treatment, proposed definitions or other potentially important aspects of terminology were included in this review.

Results: There are international inconsistencies in the terminology used to describe the unintended consequences of opioid treatment, and the terms used often lack specificity. The terms 'hazardous use', 'extramedical use', 'opioid dependence', 'diversion', 'non-adherence' and 'aberrant behaviours' are defined. We advocate for consistent application of these terms in the context of opioid treatment, and propose that care is taken to describe individual practices and intentions.

Conclusions: The increasing global attention on the use and diversion of pharmaceutical opioids warrants a discussion of current terms and definitions. Exaggerated concerns regarding 'addiction potential' may result in restrictions in the supply of opioids and the under-treatment of legitimate medical conditions. Researchers, clinicians, policy-makers and patients need to ensure greater care is given to terminology, including detailed descriptions of patient practices, the context in which they occur and severity of associated harm.

Abstract
We have previously observed that the non-opioid morphine metabolite, morphine-3-glucuronide, enhances pain via a toll-like receptor 4 (TLR4) dependent mechanism. The present studies were undertaken to determine whether TLR4-dependent pain enhancement generalizes to other classes of glucuronide metabolites. In silico modeling predicted that glucuronic acid alone and ethyl glucuronide, a minor but long-lasting ethanol metabolite, would dock to the same MD-2 portion of the TLR4 receptor complex previously characterized as the docking site for morphine-3-glucuronide. Glucuronic acid, ethyl glucuronide and ethanol all caused an increase in TLR4-dependent reporter protein expression in a cell line transfected with TLR4 and associated co-signaling molecules. Glucuronic acid-, ethyl glucuronide-, and ethanol-induced increases in TLR4 signaling were blocked by the TLR4 antagonists LPS-RS and (+)-naloxone. Glucuronic acid and ethyl glucuronide both caused allodynia following intrathecal injection in rats, which was blocked by intrathecal co-administration of the TLR4 antagonist LPS-RS. The finding that ethyl glucuronide can cause TLR4-dependent pain could have implications for human conditions such as hangover headache and alcohol withdrawal hyperalgesia, as well as suggesting that other classes of glucuronide metabolites could have similar effects.

Abstract
Objectives: This study evaluated the prevalence and correlates of aberrant drug-taking behaviours in two populations: patients with HIV-related pain and a history of substance abuse (n = 73) and patients with cancer pain and no history of substance abuse (n = 100).

Methods: All patients completed a Drug-Taking Behaviors Interview, the Brief Symptom Inventory (BSI), Brief Pain Inventory (BPI), Memorial Symptom Assessment Scale (MSAS), and the Marlowe Crowne Social Desirability Scale (MCSDS). The Pain Management Index was calculated to assess the adequacy of opioid prescribing.

Results: The cancer sample comprised 38 men and 62 women, and the AIDS sample comprised 63 men and 10 women. Patients with AIDS-related pain had higher global distress on the MSAS (F1, 170 = 20.05, P < 0.001), greater pain-related interference in their daily functioning on the BPI (F1, 161 = 22.87, P < 0.001), and a lower percentage of relief from their current medications (F1, 156 = 76.14, P < 0.001). AIDS patients also reported more than twice as many examples of aberrant drug-related behaviors per patient (mean = 6.14, SD = 4.60) as the cancer patients (mean = 1.42, SD = 1.91).

Conclusion: These data suggest that AIDS patients with histories of substance abuse receiving opioid therapy are more symptomatic, have more distress, experience more interference from residual pain, and engage in more problematic drug-related behaviors than patients with no history of drug abuse receiving opioids for cancer pain. Treatment of substance abusers with pain requires skills that complement best practices in opioid prescribing. Better approaches to the long-term treatment of these populations are needed.

Physician burnout is a universal dilemma that is seen in healthcare professionals, particularly physicians, and is characterized by emotional exhaustion, depersonalization, and a feeling of low personal accomplishment. In this review, we discuss the contributing factors leading to physician burnout and its consequences for the physician's health, patient outcomes, and the healthcare system. Physicians face daily challenges in providing care to their patients, and burnout may be from increased stress levels in overworked physicians. Additionally, the healthcare system mandates physicians to keep a meticulous record of their physician-patient encounters along with clerical responsibilities. Physicians are not well-trained in managing clerical duties, and this might shift their focus from solely caring for their patients. This can be addressed by the systematic application of evidence-based interventions, including but not limited to group interventions, mindfulness training, assertiveness training, facilitated discussion groups, and promoting a healthy work environment.

Keywords: Injecting drug use; Opioid; Overdose; Post-marketing surveillance; Prescription drug diversion; Tapentadol.

Abstract
Objectives: Driving under the influence of prescription and over-the-counter medication is a growing public health concern. A systematic review of the literature was performed to investigate which specific medications were associated with increased risk of motor vehicle collision (MVC).

Methods: The a priori inclusion criteria were: (1) studies published from English-language sources on or after January 1, 1960, (2) licensed drivers 15 years of age and older, (3) peer-reviewed publications, master's theses, doctoral dissertations, and conference papers, (4) studies limited to randomized control trials, cohort studies, case-control studies, or case-control type studies (5) outcome measure reported for at least one specific medication, (6) outcome measure reported as the odds or risk of a motor vehicle collision. Fourteen databases were examined along with hand-searching. Independent, dual selection of studies and data abstraction was performed.

Results: Fifty-three medications were investigated by 27 studies included in the review. Fifteen (28.3%) were associated with an increased risk of MVC. These included Buprenorphine, Codeine, Dihydrocodeine, Methadone, Tramadol, Levocitirizine, Diazepam, Flunitrazepam, Flurazepam, Lorazepam, Temazepam, Triazolam, Carisoprodol, Zolpidem, and Zopiclone.

Conclusions: Several medications were associated with an increased risk of MVC and decreased driving ability. The associations between specific medication use and the increased risk of MVC and/or affected driving ability are complex. Future research opportunities are plentiful and worthy of such investigation.

Abstract
Several over-the-counter (OTC) drugs are known to be misused. Among them are opioids such as codeine, dihydrocodeine, and loperamide. This work elucidates their pharmacology, interactions, safety profiles, and how pharmacology is being manipulated to misuse these common medications, with the aim to expand on the subject outlined by the authors focusing on abuse prevention and prevalence rates. The reviewed literature was identified in several online databases through searches conducted with phrases created by combining the international non-proprietary names of the drugs with terms related to drug misuse. The results show that OTC opioids are misused as an alternative for illicit narcotics, or prescription-only opioids. The potency of codeine and loperamide is strongly dependent on the individual enzymatic activity of CYP2D6 and CYP3A4, as well as P-glycoprotein function. Codeine can also be utilized as a substrate for clandestine syntheses of more potent drugs of abuse, namely desomorphine ("Krokodil"), and morphine. The dangerous methods used to prepare these substances can result in poisoning from toxic chemicals and impurities originating from the synthesis procedure. OTC opioids are generally safe when consumed in accordance with medical guidelines. However, the intake of supratherapeutic amounts of these substances may reveal surprising traits of common medications.

Abstract
Chronic pelvic pain affects both men and women; there are probably common mechanisms that involve the central nervous system. In many cases, the symptoms may be localised to a single end organ. However, the involvement of the central nervous system may result in a complex regional pain syndrome affecting the whole pelvis and as a consequence, multiple-organ symptomatology. The initial trigger may be relatively benign but a predisposed individual may develop a range of significant sensory and efferent functional abnormalities. Stimuli not normally reaching threshold may be perceived and normal sensations may be magnified to become dysphoric or painful. Problems of emptying viscera and maintaining continence may occur. Significant musculoskeletal disability may arise as well as abnormalities of the autonomic nervous system. There is an association with systemic disorders. Also, psychological, behavioural, sexual and social problems arise. In the chronic pelvic pain syndromes, treatment of the end organ has a limited role, and multidisciplinary as well as interdisciplinary management is essential.

Abstract
Objective: To describe the relationship between viscero-somatic pain syndromes and myofascial pain syndromes [MPS]. Findings: Myofascial pain syndromes can be primary conditions or secondary. When they are secondary, they occur as a manifestation of another disorder. A regional pain referral from a visceral disorder can induce secondary MPS. Visceral disorders induce central sensitization with hypersensitivity and expansion in the number and size of receptive fields. Central sensitization is topographically organized in the spinal cord, being segmentally predominant at the level of the affected viscera. The associated MPS tend to be regional, but are related to the segmental innervation of the affected viscera. Regional MPS in turn can mimic visceral disease, or be the diagnostic sign of visceral disease. Cardiac disease, gastrointestinal disorders, hepatic and biliary disorders, irritable bowel syndrome and interstitial cystitis are some of the conditions in which MPS can occur secondarily or mimic.
Conclusion: Myofascial pain syndromes can occur as a result of visceral disorders, but can also mimic visceral disease. Visceral disease must be considered in the differential diagnosis of regional MPS.

Abdominal and Pelvic Pain integrates basic science and clinical phenotypes into a multidisciplinary continuum of care, encouraging improved national and international standards of management. More than 45 contributors provide clear discussions of management strategies; multidisciplinary teamwork; somatic and psychological aspects of pain; pharmacotherapy, physiotherapy, psychology, and neuromodulation; and much more.

Purpose of review: Visceral pain represents a major clinical problem, yet far less is known about its mechanisms compared with somatic pains, for example, from cutaneous and muscular structures.

Recent findings: In this review, we describe the neuroanatomical bases of visceral pain signalling in the peripheral and central nervous system, comparing to somatic pains and also the channels and receptors involved in these events. We include an overview of potential new targets in the context of mechanisms of visceral pain and hypersensitivity.

Summary: This review should inform on the recognition of what occurs in patients with visceral pain, why comorbidities are common and how analgesic treatments work.

Abstract
Background: Migraine is one of the most frequent disabling neurological conditions with a major impact on the patients' quality of life.

Objectives: To give evidence-based or expert recommendations for the different drug treatment procedures in the particular migraine syndromes based on a literature search and the consensus of an expert panel.

Methods: All available medical reference systems were screened for the range of clinical studies on migraine with and without aura and on migraine-like syndromes. The findings in these studies were evaluated according to the recommendations of the European Federation of Neurological Societies (EFNS) resulting in level A, B, or C recommendations and good practice points.

Recommendations: For the acute treatment of migraine attacks, oral non-steroidal antiinflammatory drug (NSAID) and triptans are recommended. The administration should follow the concept of stratified treatment. Before intake of NSAID and triptans, oral metoclopramide or domperidone is recommended. In very severe attacks, intravenous acetylsalicylic acid or subcutaneous sumatriptan are drugs of first choice. Status migrainosus can be treated by cortoicosteroids, although this is not universally held to be helpful, or dihydroergotamine. For the prophylaxis of migraine, betablockers (propranolol and metoprolol) flunarizine, valproic acid, and topiramate are drugs of first choice. Drugs of second choice for migraine prophylaxis include amitriptyline, naproxen, petasites, and bisoprolol.

Aims: The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) Axis I diagnostic algorithms were demonstrated to be reliable but below target sensitivity of > 0.70 and specificity of > 0.95. Empirical data supported Axis I algorithm revisions that were valid. Axis II instruments were shown to be both reliable and valid. An international consensus workshop was convened to obtain recommendations and finalization of new Axis I diagnostic algorithms and new Axis II instruments. Methods: A comprehensive search of published TMD diagnostic literature was followed by review and consensus via a formal structured process by a panel of experts for revision of the RDC/TMD. The panel’s recommendations for revision of the diagnostic algorithms were assessed for validity using available data. Results: The recommended Diagnostic Criteria for TMD (DC/TMD) Axis I protocol includes both a valid screener for pain diagnoses and valid criteria (sensitivity > 0.80, specificity > 0.95) for the most common pain-related TMDs and for one intra-articular disorder. Diagnostic criteria for other common intra-articular disorders lacked adequate validity for clinical diagnoses but can be used for screening purposes. The Axis II protocol retains selected RDC/TMD screening instruments augmented with new instruments to better assess the interactions between pain and psychosocial functioning. A comprehensive classification system is also presented. Conclusion: The recommended evidence-based DC/TMD protocol is appropriate for use in both the clinical and research settings. Simple Axis I and II screening tests augmented by validated Axis I and Axis II instruments allow for identification of simple to complex TMD patients.

Abstract
Spontaneous intracranial hypotension typically results from spontaneous cerebrospinal fluid (CSF) leak, often at spine level and only rarely from skull base. Once considered rare, it is now diagnosed far more commonly than before and is recognized as an important cause of headaches. CSF leak leads to loss of CSF volume. Considering that the skull is a rigid noncollapsible container, loss of CSF volume is typically compensated by subdural fluid collections and by increase in intracranial venous blood which, in turn, causes pachymeningeal thickening, enlarged pituitary, and engorgement of cerebral venous sinuses on magnetic resonance imaging (MRI). Another consequence of CSF hypovolemia is sinking of the brain, with descent of the cerebellar tonsils and brainstem as well as crowding of the posterior fossa noted on head MRI. The clinical consequences of these changes include headaches that are often but not always orthostatic, nausea, occasional emesis, neck and interscapular pain, cochleovestibular manifestations, cranial nerve palsies, and several other manifestations attributed to pressure upon or stretching of the cranial nerves or brain or brainstem structures. CSF lymphocytic pleocytosis or increase in CSF protein concentration is not uncommon. CSF opening pressure is often low but can be within normal limits. Stigmata of disorders of connective tissue matrix are seen in some of the patients. An epidural blood patch, once or more, targeted or distant, at one site or bilevel, has emerged as the treatment of choice for those who have failed the conservative measures. Epidural injection of fibrin glue of both blood and fibrin glue can be considered in selected cases. Surgery to stop the leak is considered when the exact site of the leak has been determined by neurodiagnostic studies and when less invasive measures have failed. Subdural hematomas sometimes complicate the CSF leaks; a rebound intracranial hypertension after successful treatment of a leak is not rare. Cerebral venous sinus thrombosis as a complication is fortunately less common, and superficial siderosis and bibrachial amyotrophy are rare. Short-term recurrences are not uncommon, and long-term recurrences are not rare.

Abstract
Although pain after craniotomy is a clinically significant problem that has a continuously expanding literature, it is still a source of concern and controversy. Postcraniotomy headache (PCH) has been neglected for years. It is assessed regularly by only a few neurosurgical centers, and its frequency and severity tend to be underestimated by medical staff; hence, PCH is often undertreated and poorly managed. Various patient and surgical factors have an impact on the severity and incidence of PCH; thus, effective analgesic protocols are hard to define, which could explain the absence of available therapeutic guidelines. According to recent studies, certain surgical measures and the use of local anesthetics are promising in the prevention of PCH. NSAIDs seem to have inadequate analgesic effects, whereas opioids have a wide range of drawbacks; nevertheless, both types of medicaments are regarded as cornerstones of a balanced and adequate multimodal therapy. The purpose of this review is to collect the currently available knowledge about the incidence, assessment, pathophysiological mechanism, and predictors of acute and chronic PCH. Therefore, a broad search of the literature has been carried out to collect evidence of potential prevention and treatment strategies.

Abstract
Complex regional pain syndrome (CRPS) is a neuropathic pain disorder with significant autonomic features. Few treatments have proven effective, in part, because of a historically poor understanding of the mechanisms underlying the disorder. CRPS research largely conducted during the past decade has substantially increased knowledge regarding its pathophysiologic mechanisms, indicating that they are multifactorial. Both peripheral and central nervous system mechanisms are involved. These include peripheral and central sensitization, inflammation, altered sympathetic and catecholaminergic function, altered somatosensory representation in the brain, genetic factors, and psychophysiologic interactions. Relative contributions of the mechanisms underlying CRPS may differ across patients and even within a patient over time, particularly in the transition from "warm CRPS" (acute) to "cold CRPS" (chronic). Enhanced knowledge regarding the pathophysiology of CRPS increases the possibility of eventually achieving the goal of mechanism-based CRPS diagnosis and treatment.

Abstract
Numerous studies have shown that pain-related fear is one of the strongest predictors of pain disability in patients with chronic musculoskeletal pain, and there is evidence that the reduction of pain-related fear through an exposure treatment can be associated with restoration of functional abilities in patients with complex regional pain syndrome type I (CRPS-I). These findings suggest that pain-related fear may be associated with functional limitations in neuropathic pain as well. The aim of the current study was to test whether the debilitating role of pain-related fear generalizes to patients with CRPS-I. The results of 2 studies are presented. Study I includes a sample of patients with early CRPS-I referred to an outpatient pain clinic. In Study II, patients with chronic CRPS who are members of a patients' association were invited to participate. The results show that in early CRPS-I, pain severity but not fear of movement/(re)injury as measured with the Tampa Scale for Kinesiophobia was related to functional limitations. In patients with chronic CRPS-I, however, perceived harmfulness of activities as measured with the pictorial assessment method significantly predicted functional limitations beyond and above the contribution of pain severity. Not fear of movement/(re)injury in general, but the perceived harmfulness of activities appears a key factor that might be addressed more systematically in the clinical assessment of patients with CRPS-I. These results support the idea that pain-related fear might be a promising concept in the understanding of pain disability in patients with neuropathic pain.

Perspective: This is the first study showing that perceived harmfulness of activities contribute to the functional limitations in CRPS-I. The current findings may help clinicians customizing cognitive-behavioral treatments for patients with chronic neuropathic pain.

Abstract
There have been some modest recent advancements in the research of Complex Regional Pain Syndrome, yet the amount and quality of the work in this complicated multifactorial disease remains low (with some notable exceptions; e.g., the recent work on the dorsal root ganglion stimulation). The semi-systematic (though in some cases narrative) approach to review is necessary so that we might treat our patients while waiting for "better research." This semi-systematic review was conducted by experts in the field, (deliberately) some of whom are promising young researchers supplemented by the experience of "elder statesman" researchers, who all mention the system they have used to examine the literature. What we found is generally low- to medium-quality research with small numbers of subjects; however, there are some recent exceptions to this. The primary reason for this paucity of research is the fact that this is a rare disease, and it is very difficult to acquire a sufficient sample size for statistical significance using traditional statistical approaches. Several larger trials have failed, probably due to using the broad general diagnostic criteria (the "Budapest" criteria) in a multifactorial/multi-mechanism disease. Responsive subsets can often be identified in these larger trials, but not sufficient to achieve statistically significant results in the general diagnostic grouping. This being the case the authors have necessarily included data from less compelling protocols, including trials such as case series and even in some instances case reports/empirical information. In the humanitarian spirit of treating our often desperate patients with this rare syndrome, without great evidence, we must take what data we can find (as in this work) and tailor a treatment regime for each patient.

Abstract
Complex regional pain syndrome (CRPS) is a disabling pain condition poorly understood by medical professionals. Because CRPS is particularly enigmatic, and has significant impact on patient function, researchers have examined psychological processes present among patients with this diagnosis. This systematic review examines psychosocial factors associated with CRPS, both predictors and sequelae. Our conclusions are that CRPS is associated with negative outcomes, both psychological (e.g., increased depression and anxiety) and psychosocial (e.g., reduced quality of life, impaired occupational function) in nature. However, research does not reveal support for specific personality or psychopathology predictors of the condition.

Abstract
A complex regional pain syndrome (CRPS)--multiple system dysfunction, severe and often chronic pain, and disability--can be triggered by a minor injury, a fact that has fascinated scientists and perplexed clinicians for decades. However, substantial advances across several medical disciplines have recently improved our understanding of CRPS. Compelling evidence implicates biological pathways that underlie aberrant inflammation, vasomotor dysfunction, and maladaptive neuroplasticity in the clinical features of CRPS. Collectively, the evidence points to CRPS being a multifactorial disorder that is associated with an aberrant host response to tissue injury. Variation in susceptibility to perturbed regulation of any of the underlying biological pathways probably accounts for the clinical heterogeneity of CRPS.

Abstract
Complex regional pain syndrome (CRPS) is a devastating condition often seen after foot and ankle injury and surgery. Prevention of this pathology is attractive not only to patients but also to surgeons, because the treatment of this condition can be difficult. We evaluated the effectiveness of vitamin C in preventing occurrence of CRPS in extremity trauma and surgery by systematically reviewing relevant studies. The databases used for this review included: Ovid EMBASE, Ovid MEDLINE, CINAHL, and the Cochrane Database. We searched for comparative studies that evaluated the efficacy of more than 500 mg of daily vitamin C. After screening for inclusion and exclusion criteria, we identified 4 studies that were relevant to our study question. Only 1 of these 4 studies was on foot and ankle surgery; the rest concerned the upper extremities. All 4 studies were in favor of this intervention with minimal heterogeneity (Tau(2) = 0.00). Our quantitative synthesis showed a relative risk of 0.22 (95% confidence interval = 0.12, 0.39) when daily vitamin C of at least 500 mg was initiated immediately after the extremity surgery or injury and continued for 45 to 50 days. A routine, daily administration of vitamin C may be beneficial in foot and ankle surgery or injury to avoid CRPS. Further foot and ankle specific and dose-response studies are warranted.

Abstract
Objective: To address how health professionals may inadvertently contribute to the stigmatization of patients with chronic pain.

Setting: Formulation and implementation of the Australian National Pain Strategy.

Design: Review of current concepts of stereotyping and stigma, consideration of their relationship to empathy, and how they might impinge upon the clinical encounter.

Findings: The extinction of empathy, which we refer to as "negative empathy," can overwhelm health professionals, allowing the entry of negative community stereotypes of chronic pain sufferers and add to their stigmatization. Prevailing dualistic frames of reference encourage this process.

Conclusion: Greater awareness by health professionals of their own potential, often inadvertent, contribution to the stigmatization of their patients with chronic pain may serve as a basis for an expanded model of clinical engagement.

Abstract
Objective: The study aimed to seek a unifying biological basis for the phenomena encompassed in fibromyalgia syndrome (chronic widespread pain and associated morbidities).

Setting: While much progress has been made in the last decade in understanding chronic widespread pain, its pathogenesis remains stubbornly obscure and its treatment difficult. Two themes are gaining currency in the field: that chronic widespread pain is the result of central sensitization of nociception, and that chronic pain is somehow related to activation of a global stress response.

Design: In this article we merge these two ideas within the perspective of evolutionary biology to generate a hypothesis about the critical molecular pathway involved in chronic stress response activation, namely substance P and its preferred receptor, neurokinin-1 (NK-1R), which has many empirically testable implications.

Conclusion: Drawing on diverse findings in neurobiology, immunology, physiology, and comparative biology, we suggest that the form of central sensitization that leads to the profound phenomenological features of chronic widespread pain is part of a whole-organism stress response, which is evolutionarily conserved, following a general pattern found in the simplest living systems.

Abstract
Objective: To identify whether the biopsychosocial framework of illness has overcome the limitations of the biomedical model of disease when applied in the practice of pain medicine.

Design: Critical review of the literature concerning the application of biopsychosocial models to the praxis of pain medicine and the concepts of living systems.

Results: The biopsychosocial model of illness, formulated by Engel in 1977, has generated the International Association for the Study of Pain (IASP) definition of pain, two major conceptual frameworks in pain medicine, and three putative explanatory models for pain. However, in the absence of a theory that seeks to understand the lived experience of pain as an emergent and unpredictable phenomenon, these progeny of the biopsychosocial model have been caught in circular argument and have been unable to overcome biomedical reductionism or the perpetuation of body-mind dualism. In particular, the implication that pain can be a "thing" separate and distinct from the body bears little relationship to the lived experience of pain. Such marginalizing results when an observer attempts to reduce the experience of the pain of another person.

Conclusions: The self-referentiality of living systems (through their qualities of autopoiesis, noncentrality and negentropy) sees pain "emerge" in unpredictable ways that defy any lineal reduction of the lived experience to any particular "thing." Pain therefore constitutes an aporia, a space and presence that defies us access to its secrets. We suggest a project in which pain may be apprehended in the clinical encounter, through the engagement of two autonomous self-referential beings in the intersubjective or so-called third space, from which new therapeutic possibilities can arise.

Abstract
We review the concept and importance of functional somatic symptoms and syndromes such as irritable bowel syndrome and chronic fatigue syndrome. On the basis of a literature review, we conclude that a substantial overlap exists between the individual syndromes and that the similarities between them outweigh the differences. Similarities are apparent in case definition, reported symptoms, and in non-symptom association such as patients' sex, outlook, and response to treatment. We conclude that the existing definitions of these syndromes in terms of specific symptoms is of limited value; instead we believe a dimensional classification is likely to be more productive.