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Background Chronic pain conditions as well as Restless Legs Syndrome (RLS) are known to be associated with subjectively and objectively disturbed sleep. RLS has been recently described as highly prevalent in multisite pain and the role of sleep as a modifying factor in this RLS phenotype is unknown. This study aimed to investigate if perceived sleep deficit and other sleep related parameters predict RLS in subjects with multisite pain. Current knowledge/study rationale We have recently demonstrated a strong association between Restless Legs Syndrome (RLS) and number of pain locations. In the current analysis we hypothesized that impaired sleep predicts RLS in subjects with multisite pain. Method Questionnaire-based data from 2727 randomly selected women aged 18-64 years were used to analyze RLS symptoms, self-reported sleep quality, and the degree of daytime sleepiness (Epworth Sleepiness Scale (ESS)) in relation to type, degree and localization of body pain. Potential confounders including anthropometrics, pain localization, co-morbidities, and medication were adjusted for in the Generalized Linear Models (GLM). Results Perceived sleep deficit ≥90 min (OR 2.4 (1.5-3.8), p < 0.001) and frequent nocturnal awakenings (OR 2.3 (1.4-3.6), p <0.001) were the strongest sleep related predictors for RLS in subjects with multisite pain. Additional factors include prolonged sleep latency (≥30 min, OR 1.8 (1.1-2.8), p = 0.01) and daytime symptoms like elevated daytime sleepiness (ESS score ≥9, OR 1.8 (1.2-2.7), p = 0.005). Accordingly, RLS diagnosis was associated with impaired sleep quality (TST (Total Sleep Time) -8.2 min, sleep latency +8.0 min, and number of awakenings from sleep +0.4, p <0.01). ESS score increased with RLS diagnosis (+0.74, p <0.01) and number of pain locations (0.5, 1.7, and 1.8 for 1, 3, and 5 pain areas, p <0.001). In addition, confounders like pain severity, the history of psychiatric disease, and current smoking were associated with impaired sleep quality in this group of females. Conclusions Perceived sleep deficit and sleep fragmentation are the strongest sleep related predictors of RLS in multisite pain. Potential implication of our results are that clinical management programmes of RLS in subjects with multisite pain need to consider both sleep quality and sleep quantity for individually tailored treatment regimes. Study impact RLS, pain, and sleep disorders are highly interrelated. Our study strongly suggests that clinical management of RLS in patients with multisite pain needs to consider sleep quality as an independent risk factor.

Objectives Painful diagnostic and therapeutic procedures are common in the health care setting. Eliminating, or at least, minimizing the pain associated with various procedures should be a priority. Although there are many benefits of providing local/topical anesthesia prior to performing painful procedures, ranging from greater patient/family satisfaction to increased procedural success rates; local/topical anesthetics are frequently not used. Reasons include the need for a needlestick to administer local anesthetics such as lidocaine and the long onset for topical anesthetics. Vapocoolants eliminate the risks associated with needlesticks, avoids the tissue distortion with intradermal local anesthetics, eliminates needlestick pain, have a quick almost instantaneous onset, are easy to apply, require no skills or devices to apply, are convenient, and inexpensive. The aims of this study were to ascertain if peripheral intravenous (PIV) cannulation pain would be significantly decreased by using a vapocoolant (V) versus sterile water placebo (S) spray, as determined by a reduction of at least >1.8 points on numerical rating scale (NRS) after vapocoolant versus placebo spray, the side effects and incidence of side effects from a vapocoolant spray; and whether there were any long term visible skin abnormalities associated with the use of a vapocoolant spray. Materials and methods Prospective, randomized, double-blind controlled trial of 300 adults (ages 18-80) requiring PIV placement in a hospital ED, randomized to S ( N = 150)or V ( N = 150) prior to PIV. Efficacy outcome was the difference in PIV pain: NRS from 0 (none) to worst (10). Safety outcomes included a skin checklist for local adverse effects (i.e., redness, blanching, edema, ecchymosis, itching, changes in skin pigmentation), vital sign (VS) changes, and before/after photographs of the PIV site. Results Patient demographics (age, gender, race), comorbidity, medications, and vital signs; and PIV procedure variables (e.g., IV needle size, location, number of IV attempts, type and experience of healthcare provider performing the IV) were not significantly different for the two groups. Median (interquartile range) PIV pain was 4 (2,7) (S) and 2 (0,4) (V) ( P < 0.001). Skin checklist revealed minimal erythema: S 0% ( N = 0/150), V: 2.7% (4/150), which resolved within 5min, and no blanching, skin pigmentation changes, itching, edema, or ecchymosis. Photographs at 5-10 min revealed no visible skin changes in any patient (N=300), vapocoolant ( N = 150) or placebo groups ( N = 150). Complaints ( N = 26) were coolness/cold feeling S 8.7% ( N = 13), V 7.3% ( N = 11), coolness/numbness S 0% ( N =0), V 0.7% ( N =1), and burning S 0.7% ( N =1), V 0 (0%). Patient acceptance of the vapocoolant spray was high: 82% (123/150) of the patients stated they would use the spray in the future, while only 40.7% (61/150) of the placebo group stated they would use the placebo spray in the future. Conclusions and Implications Vapocoolant spray significantly decreased peripheral intravenous cannulation pain in adults versus placebo spray and was well tolerated with minor adverse effects that resolved quickly. There were no significant differences in vital signs and no visible skin changes documented by photographs taken within 5-10 min postspray/PIV.

Long standing non-malignant pain leads to a variety of limitations which can be assessed by means of the self-assessment questionnaire Functional Barometer. It is designed to assess the extent and limitations in function, activity and decreased quality-of-life and is adapted to the International Classification of Functioning and Health. Aim To investigate the outcome and differences in age, gender and origin of pain in patients with longstanding non-malignant pain regarding the subjective experience of functional-, activity- and quality-of-life limitations. Method 300 patients with a median duration of pain of 49 months referred to a Pain Management Centre filled out the Functional Barometer questionnaire, adapted to the International Classification of Functioning and Health. Results 66% patients were women and 34% were men. Seventy-five percent were in working age, 18-64 years. The duration before being referred to a pain specialist was over 4 years and 65% reported pain from more than three origins. Significant differences in functioning, activity and quality-of-life were found in comparing gender, age and origin of pain. Men more often reported physiological limitations while women more often reported psychological limitations of functioning, activity and quality-of-life. The most important were that men more often had difficulties in walking and climbing stairs, while women reported problems with concentration, stress and psychological demands, family relations and contact with friends. Conclusion The significant differences regarding functioning, activity and quality-of-life between women and men as age and origin of pain must be taken into account when tailoring individual treatment and rehabilitation programmes.

Graphical Abstract Abstract Background It has been reported that in 13-32% of patients with chronic low back pain, the pain may originate in the sacroiliac (SI) joints. When treatment of these patients with analgesics and physiotherapy has failed, a surgical solution may be discussed. Results of such surgery are often based on small series, retrospective analyses or studies using a minimal invasive technique, frequently sponsored by manufacturers. Purpose To report the clinical outcome concerning pain, function and quality of life following anterior arthrodesis in patients presumed to have SI joint pain using validated questionnaires pre- and post-operatively. An additional aim was to describe the symptoms of the patients included and the preoperative investigations performed. Material and methods Over a 6 year period we treated 55 patients, all women, with a mean age of 45 years (range 28-65) and a mean pelvic pain duration of 9.1 years (range 2-30). The pain started in connection with minor trauma in seven patients, pregnancy in 20 and unspecified in 28. All patients had undergone long periods of treatment including physiotherapy, manipulation, needling, pelvic belt, massage and chiropractic without success, and 15 had been operated for various spinal diagnoses without improvement. The patients underwent thorough neurological investigation, plain X-ray and MRI of the spine and plain X-ray of the pelvis. They were investigated by seven clinical tests aimed at indicating pain from the SI joints. In addition, all patients underwent a percutaneous mechanical provocation test and extra-articular local anaesthetic blocks against the posterior part of the SI joints. Before surgery all patients answered the generic Short-Form-36 (SF-36) questionnaire, the disease specific Balanced Inventory for Spinal Disorders (BIS) questionnaire and rated their level of pelvic and leg pain (VAS, 0-100). At follow-up at a mean of 2 years 49 patients completed the same questionnaires (89%). Results At follow-up 26 patients reported a lower level of pelvic pain than before surgery, 16 the same level and six a higher level. Applying Svensson’s method RP pelvic pain = 0.3976, with 95% CI (0.2211, 0.5740) revealed a statistically significant systematic improvement in pelvic pain. At follow-up 28 patients reported a higher quality of life and 26 reported sleeping better than pre-operatively. In most patients the character of the pelvic pain was dull and aching, often accompanied by a stabbing component in connection with sudden movements. Referred pain down the leg/s even to the feet and toes was noted by half of the patients and 29 experienced frequency of micturition. Conclusions It is apparent that in some patients the SI joints may cause long-term pain that can be treated by arthrodesis. We speculate that continued pain despite a healed arthrodesis may be due to persistent pain from adjacent ligaments. The next step should be a prospective randomized study comparing posterior fusion and ligament resection with non-surgical treatment. Implications Anterior arthrodesis can apparently relieve pain in some patients with presumed SI joint pain. The problem is how to identify these patients within the low back pain group.

Background and aims There has been a growth in the proportion of emerging adults vulnerable to pain-related sequelae of chronic health conditions (CHCs). Given the paucity of research during this important developmental period, this study investigated the association between CHCs and chronic disruptive pain among emerging adults and the extent to which psychiatric disorders moderate this association. Methods Data come from the 2012 Canadian Community Health Survey - Mental Health (CCHS-MH). This cross-sectional survey included 5987 participants that were 15-30 years of age and self-reported their CHCs ( n = 2460,41%) and the extent to which pain impacted daily functioning using items from the Health Utilities Index Mark 3 (HUI 3). Group comparisons between respondents with CHCs and healthy controls were made using chi-square tests. Odds ratios (OR) and 95% confidence intervals (CI) were computed from ordinal logistic regression models adjusting for sociodemographic covariates. Product-term interactions between CHCs and psychiatric disorders were included in the models to explore moderating effects. All analyses were weighted to maintain representativeness of the study sample to the Canadian population. Results The mean age of participants was 23.5 (SE 0.1) years and 48% were female. Compared to healthy controls, a greater proportion of participants with CHCs reported having chronic pain (20.3% vs. 4.5%, p < 0.001). Among those with chronic pain, respondents with CHCs reported a greater number of activities prevented because of chronic disruptive pain (χ 2 = 222.28, p < 0.001). Similarly, in logistic regression models, participants with CHCs had greater odds of reporting chronic disruptive pain (OR = 4.94, 95% CI = 4.08-5.99). Alcohol ( β = –0.66; p = 0.025) and drug abuse/dependence disorders ( β = –1.24; p = 0.012) were found to moderate the association between CHCs and chronic disruptive pain. Specifically, the probability of chronic disruptive pain was higher for emerging adults without CHCs and with alcohol or drug disorders; however, among participants with CHCs, probability was higher for those without these disorders. Conclusions There is a robust association between CHCs and chronic disruptive pain. The moderating effects suggest that alcohol or drug disorders are especially harmful for emerging adults without CHCs and contribute to higher levels of chronic disruptive pain; however, among those with CHCs, alcohol and illicit drugs may be used as a numbing agent to blunt chronic disruptive pain. Implications Findings from this study have implications for the integration and coordination of services to design strategies aimed at managing chronic disruptive pain and preventing pain-related disabilities later in life. Within the health system, healthcare providers should engage in dialogues about mental health and substance use regularly with emerging adults, be proactive in screening for psychiatric disorders, and continue to monitor the impact of pain on daily functioning. Given the age range of emerging adults, there is tremendous opportunity for clinicians to work cooperatively with colleagues in the education system to support emerging adults with and without CHCs. Overall, clinicians, researchers, educators, and those in social services should continue to be mindful of the complex interrelationships between physical and mental health and chronic disruptive pain and work cooperatively to optimize health outcomes and prevent pain-related disabilities among emerging adults.

Background and aims The use of intrathecal morphine therapy has been increasing. Intrathecal morphine therapy is deemed the last resort for patients with intractable chronic non-cancer pain (CNCP) who failed other treatments including surgery and pharmaceutical interventions. However, effective treatments for patients with CNCP who “failed” this last resort because of severe side effects and lack of optimal pain control remain unclear. Methods and results Here we report two successfully managed patients (Ms. S and Mr. T) who had intractable pain and significant complications years after the start of intrathecal morphine therapy. The two patients had intrathecal morphine pump implantation due to chronic consistent pain and multiple failed surgical operations in the spine. Years after morphine pump implantation, both patients had significant chronic pain and compromised function for activities of daily living. Additionally, Ms. S also had four episodes of small bowel obstruction while Mr. T was diagnosed with end stage severe “dementia”. The successful management of these two patients included the simultaneous multidisciplinary approach for pain management, opioids tapering and discontinuation. Conclusion The case study indicates that for patients who fail to respond to intrathecal morphine pump therapy due to side effects and lack of optimal pain control, the simultaneous multidisciplinary pain management approach and opioids tapering seem appropriate.

Background and aims Trait behavioral inhibition represents a tendency to react with negative emotions - primarily worry - to cues which signal potential threats. This tendency has been hypothesized by a two-factor model of chronic pain to have direct effects on psychological and physical function in individuals with chronic pain, as well as to influence the associations between pain-related maladaptive cognitions and function. Our aim was to test these hypothesized associations in a sample of individuals who were being screened for possible interdisciplinary chronic pain treatment. Methods Eighty-eight patients referred to an interdisciplinary chronic pain management program were administered measures of average pain intensity, trait behavioral inhibition, kinesiophobia, pain catastrophizing, depressive symptoms, and pain interference. We then performed two linear regression analyses to evaluate the direct effects of trait behavioral inhibition on depressive symptoms and pain interference and the extent to which behavioral inhibition moderated the associations between kinesiophobia and pain catastrophizing, and the criterion variables. Results In partial support of the study hypotheses, the results showed significant (and independent) direct effects of trait behavioral inhibition on depressive symptoms, and behavioral inhibition moderated the association between kinesiophobia and depression, such that there were stronger associations between kinesiophobia and depressive symptoms in those with higher dispositional sensitivity to fear-inducing stimuli. However, neither direct nor moderating effects of behavioral inhibition emerged in the prediction of pain interference. Conclusions If replicated in additional studies, the findings would indicate that chronic pain treatments which target both reductions in maladaptive cognitions (to decrease the direct negative effects of these on depressive symptoms) and the individual’s tendency to respond to pain with worry (as a way to buffer the potential effects of maladaptive cognitions on depressive symptoms) might be more effective than treatments that targeted only one of these factors. Implications Additional research is needed to further evaluate the direct and moderating effects of pain-related behavioral inhibition on function, as well as the extent to which treatments which target behavioral inhibition responses provide benefits to individuals with chronic pain.

Background and aim Chronic pain conditions can be diagnosed and treated in both somatic and psychiatric settings. It is still a discussed and unanswered question whether the two groups of patients differ. The purpose of this short article is to inform further reflections concerning the classifications of somatoform pain and complex pain. Method Sociodemographic and questionnaire data concerning anxiety and depression, perceived injustice, well-being, and levels of psycho-physiological functioning were compared for patients diagnosed with complex pain (somatic diagnosis) at a pain clinic and somatoform pain (psychiatric diagnosis) at a Liaison-psychiatric clinic. Results Very little differences were found between patients with complex pain (N = 162) and somatoform conditions (N = 89). Both patient groups were seriously impaired both physically and mentally. Conclusion These comparisons lend support to the viewpoint of non-segregation of somatoform and complex pain. Implications Pain treatment might be better-managed in common multidisciplinary centers with specialists in both pain treatment and psychiatric aid.

Background and Aims Chronic pain is a debilitating condition that requires prompt access to care for effective treatment. Wait times for care often exceed benchmark recommendations, with potential consequences to patient health outcomes. The goal of this paper is to gain the perspectives of patients attending a chronic pain clinic regarding the acceptability of current wait times and the impact of their experiences of waiting for chronic pain care. Methods The study took place in a chronic pain clinic at an academic-affiliated teaching hospital in Ottawa, Canada, which housed seven clinicians at the time of the study. New patients attending the chronic pain clinic between July 14, 2014 and August 5, 2015 were eligible to participate based on the availability of the research and clerical staff who administered the survey on a variety of days over the course of the study. Patients completed a self-administered 29-item survey. The survey took approximately five to ten minutes to complete. Questions pertained to patients’ socioeconomic factors, chronicity and burden of pain symptoms, and satisfaction with current wait times. Actual wait times were self-reported. Survey results were entered into an Excel spreadsheet, exported to SPSS, and coded numerically to facilitate descriptive analyses using comparative graphs and tables. Open-text responses were reviewed by the authors. Results Sixty-six patients completed the survey. While 83% of patients stated that their ideal wait time was less than three months, 32% reported receiving an appointment within this period, and 31% reported waiting a year or more. Only 37% of patients felt the wait time for their appointment was appropriate. During their wait,41% of patients reported receiving written information about chronic pain and 47% were referred to a local chronic pain management group. 94% reported interference with social/recreational activities and normal activities of daily living, 31% had to miss work or school due to the frequency of ongoing symptoms, and 22% reported being unable to attend work or school altogether. Furthermore, 37% of patients reported visiting the emergency room within the previous year and 65% worried about having a serious undiagnosed disease. Conclusions Our study found that wait times for chronic pain care, even those triaged as urgent cases, far exceeded what patients considered ideal. Only a third of patients received care within three months of making their appointment, while nearly another third waited over a year. During the waiting period, nearly all patients experienced some impact on their day-to-day activities and work or school attendance, half were unemployed, and nearly a quarter reported a complete inability to attend work or school because of pain. Implications Wait times for chronic pain care exceed timelines deemed acceptable by patients, causing anxiety and reducing function. The patient perspective must be considered in initiatives attempting to improve access to care for this population with specific needs and goals. Innovative solutions, such as electronic consultation and shared care models, hold promise.

Background Personality traits may influence development and adjustment to ongoing pain. Over the past 120 years, there has been considerable research into the relationship between pain and personality. This paper presents new evidence for common personality traits found amongst chronic pain sufferers. In particular, it evaluates evidence for Cloninger’s biopsychosocial model of personality in distinguishing typical personality features of chronic pain sufferers. It evaluates this evidence in the context of the past 120 years of research including psychodynamic formulations, MMPI studies, personality disorder investigations, and the influence of neuroticism on chronic pain. Methods A literature search was conducted using PubMed, Medline, PsyclNFO, SCOPUS and Cochrane library. Search terms included chronic pain, pain, personality, neuroticism, harm avoidance, self-directedness, attachment, Temperament and Character Inventory (TCI-R), MMPI, MMPI-2, NEO-PI, EPI, Millon Clinical Multiaxial Inventory, Millon Behavioral Health Inventory, Millon Behavioral Medicine Diagnostic, the Personality Assessment Inventory, the Locus of Control Construct and different combinations of these terms. Conclusions Recent descriptive studies using Cloninger’s Temperament and Character Inventory (TCI-R) suggest that higher harm avoidance and lower self-directedness may be the most distinguishing personality features of chronic pain sufferers. High harm avoidance refers to a tendency to be fearful, pessimistic, sensitive to criticism, and requiring high levels of re-assurance. Low self-directedness often manifests as difficulty with defining and setting meaningful goals, low motivation, and problems with adaptive coping. Evidence for this personality profile is found across a wide variety of chronic pain conditions including fibromyalgia, headache and migraine, temporomandibular disorder, trigeminal neuropathy, musculo-skeletal disorders and heterogeneous pain groups. Limitations are also discussed. For example, high harm avoidance is also found in those suffering anxiety and depression. While many studies control for such factors, some do not and thus future research should address such confounds carefully. The evidence is also evaluated within the context of past research into the existence of ‘a pain personality’. Psychodynamic formulations are found to be deficient in objective scientific methods. MMPI studies lack sufficient evidence to support ‘a pain personality’ and may be confounded by somatic items in the instrument. More recent neuroticism studies suggest a relationship between neuroticism and pain, particularly for adjustment to chronic pain. Personality disorders are more prevalent in chronic pain populations than non-pain samples. Clinical implications Because harm avoidance reflects a tendency to developed conditioned fear responses, we suggest that higher harm avoidance may create more vulnerability to developing a fear-avoidance response to chronic pain. Furthermore, lower self-directedness may contribute to keeping a sufferer within this vicious cycle of fear, avoidance and suffering. Moreover, we suggest that harm avoidance and self-directedness are broader and more complex constructs than current clinical targets of CBT such as fear-avoidance and self-efficacy. Thus, assessing such personality traits may help to address the complexity of chronic pain presentations. For example, it may help to identify and treat sufferers more resistant to treatment, more prone to comorbidity and more vulnerable to entering the vicious cycle of chronic pain, suffering and disability.

Background and aims Psychometric inventories and scales intended to measure cognitive, emotional and behavioural concomitants of pain are typically constructed by deducting items from theoretically derived concepts related to pain states, e.g. social support, perceived control, depressiveness, and catas- trophizing. The aim of this study was to design a clinically useful, generic pain distress inventory - The Multi-Facet Pain Survey (MFPS) - inductively derived from psychological and social complaints reported by a study group of individuals with severe chronic nonmalignant pain. Methods Extensive clinical interviews with hospitalized chronic pain patients were made by clinical psychologists. The purpose was to highlight the patients’ pain histories and their beliefs and feelings about the pain, and to determine factors possibly influencing their rehabilitation potential. The types of distress reported were sorted into categories with a procedure similar to content analysis. Distress reports were converted to statements, forming items in a questionnaire, the Multi-Facet Pain Survey. Results Our analyses supported a distress structure including 15 categories, or “facets”, comprising in all 190 types of psychosocial distress. Ten of the facets denote beliefs about the present condition and aspects of distress experienced in daily life (e.g. cognitive problems); three facets reflect the illness history, and two the patient’s views on future prospects. To improve the clinical utility, we shortened the scale into a 53 items inventory. A factor analysis of these 53 items revealed four clinically meaningful factors: (1) stress-related exhaustion; (2) impact of pain on daily life; (3) self-inefficacy in regard to future prospects; and (4) negative experiences of health care. While the second factor represents distress directly related to the pain, the first factor reflects long-term exhaustion effects of the pain condition similar to those seen in individuals exposed to long periods of stress. Items loading in the third factor reflect a pessimistic outlook on the future. The content validity of the scale was explored by predicting and testing correlations between the 15 MFPS facets, and the Symptom Checklist (SCL-90) and the West Haven Yale Multidimensional Pain Inventory (MPI). Some of the MFPS facets showed little or no agreement with any of the subscales of the comparison measures. The homogeneity was satisfactory both for facets and factors. Conclusions The Multi-Facet Pain Survey (MFPS) facets cover a broad array of experienced psychosocial distress in patients with severe, longstanding pain. Some facets of psychosocial impact of longstanding pain states shown in the qualitatively derived distress facets, or by the latent factors found in the factor analysis, may complement our understanding of the long-term impact of pain. Consequently, MFPS may improve the assessment of psychological and social complaints and complications in patients with chronic pain. Implications The MFPS will hopefully be an assessment tool supporting the psychological contribu-tion to a biopsychosocial evaluation of patients with severe, longstanding pain. By exposing a broadrange of suffering, MFPS may contribute to alternative treatment options and a better prognosis of future rehabilitation.

Background and aims Validating and invalidating responses play an important role in communication with pain patients, for example regarding emotion regulation and adherence to treatment. However, it is unclear how patients’ perceptions of validation and invalidation relate to patient characteristics and treatment outcome. The aim of this study was to investigate the occurrence of subgroups based on pain patients’ perceptions of validation and invalidation from their physicians. The stability of these perceptions and differences between subgroups regarding pain, pain interference, negative affectivity and treatment outcome were also explored. Methods A total of 108 pain patients answered questionnaires regarding perceived validation and invalidation, pain severity, pain interference, and negative affectivity before and after pain rehabilitation treatment. Two cluster analyses using perceived validation and invalidation were performed, one on pre-scores and one on post-scores. The stability of patient perceptions from pre- to post-treatment was investigated, and clusters were compared on pain severity, pain interference, and negative affectivity. Finally, the connection between perceived validation and invalidation and treatment outcome was explored. Results Three clusters emerged both before and after treatment: (1) low validation and heightened invalidation, (2) moderate validation and invalidation, and (3) high validation and low invalidation. Perceptions of validation and invalidation were generally stable over time, although there were individuals whose perceptions changed. When compared to the other two clusters, the low validation/heightened invalidation cluster displayed significantly higher levels of pain interference and negative affectivity post-treatment but not pre-treatment. The whole sample significantly improved on pain interference and depression, but treatment outcome was independent of cluster. Unexpectedly, differences between clusters on pain interference and negative affectivity were only found post-treatment. This appeared to be due to the pre- and post-heightened invalidation clusters not containing the same individuals. Therefore, additional analyses were conducted to investigate the individuals who changed clusters. Results showed that patients scoring high on negative affectivity ended up in the heightened invalidation cluster post-treatment. Conclusions Taken together, most patients felt understood when communicating with their rehabilitation physician. However, a smaller group of patients experienced the opposite: low levels of validation and heightened levels of invalidation. This group stood out as more problematic, reporting greater pain interference and negative affectivity when compared to the other groups after treatment. Patient perceptions were typically stable over time, but some individuals changed cluster, and these movements seemed to be related to negative affectivity and pain interference. These results do not support a connection between perceived validation and invalidation from physicians (meeting the patients pre- and post-treatment) and treatment outcome. Overall, our results suggest that there is a connection between negative affectivity and pain interference in the patients, and perceived validation and invalidation from the physicians. Implications In clinical practice, it is important to pay attention to comorbid psychological problems and level of pain interference, since these factors may negatively influence effective communication. A focus on decreasing invalidating responses and/or increasing validating responses might be particularly important for patients with high levels of psychological problems and pain interference.

Background and aims Recent studies reveal high prevalence rates of patients receiving long-term opioids. However, well designed studies assessing effectiveness with longer than 3 months follow-up are sparse. The present study investigated the outcomes of long-term opioid therapy compared to nonopioid treatment in CNCP patients with respect to measures of pain, functional disability, psychological wellbeing, and quality of life (QoL). Methods Three hundred and thirty three consecutive patients at our pain clinic were included and divided into patients with continuous opioid treatment for at least 3 months (51%) and patients receiving nonopioid analgesics (49%). Further, outcome of different doses of opioid (<120 mg vs. >120 mg morphine equivalents) and differences between high and low potency opioids were examined. Results The opioid and nonopioid groups did not differ with regard to pain intensity or satisfaction with analgesic. Patients with continuous opioids treatment reported higher neuropathic like pain, longer duration of pain disorder, lower functional level, wellbeing, and physical QoL in comparison to patients receiving nonopioid analgesics. Higher opioid doses were associated with male gender, intake of high potency opioids and depression but there were no differences with regard to pain relief or improvement of functional level between high and low doses. Similarly, patients on high potency opioids reported more psychological impairment than patients on low potency opioids but no advantage with regard to pain relief. Overall, remaining level of pain, functional disability and poor QoL were quite high irrespective of the analgesic used or opioid dosing. Conclusions In the long-term no clear advantage of opioid vs. non-opioid analgesics could be revealed. In terms of remaining pain intensity, functional disability and quality of life, treatment with pain medication proved insufficient. Additionally, with higher doses of opioids the benefit to risk relationship becomes worse and patients on high potency opioids reported more psychological impairment than patients on low potency opioids but no advantage with regard to pain relief. Implications Our results raise questions about the long-term effectiveness of analgesic treatment regimens irrespective of analgesics type employed and call for more multidisciplinary treatment strategies.

Background and aims The prevalence of pain in cancer patients are relatively high and indicate inadequate pain management strategies. Therefore, it is necessary to develop new methods and to improve implementation of guidelines to assess and treat pain. The vast improvement in information technology facilitated development of a computerized symptom assessment and decision support system (CCDS) - the Combat system - which was implemented in an outpatient cancer clinic to evaluate improvement in pain management. Methods We conducted a controlled before-and-after study between patient cohorts in two consecutive study periods: before ( n = 80) and after ( n = 134) implementation of the Combat system. Patients in the first cohort completed questionnaires with the paper-and-pencil method and this data was not shown to physicians. Patients in the latter cohort completed an electronic questionnaire by using an iPad and the data were automatically transferred and presented to physicians at point of care. Additionally, the system provided computerized decision support at point of care for the physician based on the electronic questionnaires completed by the patients, an electronic CRF completed by physicians and clinical guidelines. Results The Combat system did not improve pain intensity and there were no significant alterations in the prescribed dose of opiates compared to the cohort of patients managed without the Combat system. Conclusion The Combat system did not improve pain management. This may be explained by several factors, however, we consider lack of proper implementation of the CCDS in the clinic to be the most important factor. As a result, we did not manage to change the behaviour of the physicians in the clinic. Implications There is a need to conduct larger prospective studies to evaluate the efficacy of modern information technology to improve pain management in cancer patients. Before introducing new information technology in the clinics, it is important to have a well thought out implementation strategy. The trial is registered at Clinialtrials.gov, number NCT01795157.

Introduction Quantitative sensory tests (QST) can be used for profiling anti-nociceptive effects of analgesics. However, anti-nociceptive effects detected by QST are not necessarily associated with analgesic effects in pain patients. As part of a large investigation on low back pain, this paper describes the immediate analgesic and anti-nociceptive effects of oxycodone in chronic low-back pain and ranks different QST according to their ability to reflect this effect. The results are expected to support the selection of QST for future studies on potential novel opioid agonists in human pain. Methods In this randomized, placebo-controlled and double-blinded cross-over study, 50 patients with chronic low-back pain received a single oral dose of oxycodone 15 mg or active placebo, and underwent multiple QST testing. The intensity of low-back pain was recorded during 2 h. The areas under the ROC curves and 95% confidence intervals were determined, whereby responder status (≤30% pain reduction) was set as reference variable and changes in QST from baseline were set as classifiers. Results Significant analgesic effect on low-back pain as well as anti-nociceptive effects for almost all QST parameters were observed. The QST with the highest area under the curve were heat pain detection threshold (0.65,95%-CI 0.46 to 0.83), single-stimulus electrical pain threshold (0.64,95%-CI 0.47 to 0.80) and pressure pain detection threshold (0.63,95%-CI 0.48 to 0.79). Conclusions The results suggest that anti-nociceptive effects assessed by QST fairly reflect clinical efficacy of oxycodone on low-back pain. Pressure pain detection threshold, heat pain detection threshold and single-stimulus electrical pain threshold may be more suitable to sort out potential non-responders rather than identifying potential responders to opioid medication. Future pre-clinical human research may consider these results when investigating the analgesic effect of opioid agonists by means of QST.

Background Increasing recall of instructions and advice in a pain consultation is important, since it is a prerequisite for adherence to treatment recommendations. However, interference due to pain-related distress may result in poor recall. Whereas there are some indications that recall can be increased by empathic communication that reduces interference, this interesting possibility remains largely untested experimentally. The current experiment aimed at studying effects of empathic communication, and more specifically validation, on recall during a pain test and possible mediators and moderators of this effect. Method Participants received either validating ( N = 25) or invalidating responses ( N = 25) from the experimenter during a pain provoking task, followed by self-report measures of interference (affect, situational pain catastrophizing) and recall (accurate and false memories of words). Results As expected, the validated group exhibited higher accurate recall and less false memories following the pain test as compared to the invalidated group. This was partly due to the effect of interference being counteracted by moderating the relationship between pain catastrophizing and recall. Conclusion These novel results suggest that validating communication can counteract interference due to pain catastrophizing on recall, at least in a controlled experimental setting. Implications Good communication by health professionals is of utmost importance for adherence to pain management. The current results expand our knowledge on the effects of pain communication by establishing and explaining a clear link between empathic communication and recall, highlighting the role of pain catastrophizing.

Background and aims The nociceptive system appears to have evolved a range of protective characteristics that are of great interest in understanding both acute and chronic pain. Spatial summation is one important characteristic, whereby increasing area of a stimulus, or distance between multiple stimuli, results in more intense pain—not only greater area of pain. One of the mysteries of chronic pain is why spinal pain is so prevalent relative to pain at other sites. Since pathological tissue models have failed to fully explain spinal pain, we theorized that body region specific differences in sensory processing—such as a greater propensity for spatial summation—may help to explain its vulnerability. We aimed to examine this by comparing the properties of summation at different body parts: the dorsal forearm, neck, and back. Methods Spatial summation of pain was investigated using noxious intra-dermal electrical stimuli in healthy pain-free adults (14 males, 6 females), and the perceived pain intensity was rated on a 0-100 pain scale. Area-based stimulation was investigated by doubling the stimulation area with the addition of a second electrode placed adjacent to the first. Distance-based summation was investigated by randomly varying the separation distance between paired noxious electrical stimuli at separations of 0,10,15, and 20 cm. Results This study demonstrated that the properties of area- and distance-based summation are uniform across the neck, back, and forearm in healthy adults. Spatial summation of pain was also found to be greatest at 15- and 20-cm paired separations for all body regions tested, confirming that noxious information can be integrated over an extensive anatomical area. Conclusion Data from this investigation refutes the thesis that spatial summation of pain may be a contributing factor for the reported difference in chronicity rates between spinal and peripheral sites. It remains, however, a potentially important mechanism by which noxious inputs from multi-level pathology might integrate and contribute to pain. Implications While data from this project suggest that there are no regional differences in the properties of spatial summation of noxious stimuli, regional differences in other characteristics of the nociceptive system may yet provide insight into why some spinal pain is so highly prevalent; nociceptive distance-based summation may be highly relevant where two or more conditions co-exist in close proximity.

Background/Aims Transient receptor potential vanilloid type 1 (TRPV1) receptor antagonists have been evaluated in clinical studies for their analgesic effects. Mavatrep, a potent, selective, competitive TRPV1 receptor antagonist has demonstrated pharmacodynamic effects consistent with target engagement at the TRPV1 receptor in a previous single-dose clinical study. The current study was conducted to evaluate the analgesic effects of a single dose of mavatrep. Methods In this randomized, placebo- and active-controlled, 3-way crossover, phase 1b study, patients with painful knee osteoarthritis were treated with a single-dose of 50 mg mavatrep, 500 mg naproxen twice-daily, and placebo. Patients were randomized to 1 of 6 treatment sequences. Each treatment sequence included three treatment periods of 7 days duration with a 7 day washout between each treatment period. The primary efficacy evaluation was pain reduction measured by the 4-h postdose sum of pain intensity difference (SPID) based on the 11-point (0-10) Numerical Rating Scale (NRS) for pain after stair-climbing (PASC). The secondary efficacy evaluations included 11-point (0-10) NRS pain scores entered into the Actiwatch between clinic visits, the Western Ontario and McMaster Universities Arthritis Index subscales (WOMAC) questionnaire, and use of rescue medication. Safety and tolerability of single oral dose mavatrep were also assessed. Results Of 33 patients randomized, 32 completed the study. A statistically significantly ( p <0.1) greater reduction in PASC was observed for mavatrep versus placebo (4-h SPID least square mean [LSM] [SE] difference: 1.5 [0.53]; p = 0.005 and 2-h LSM [SE] difference of PID: 0.7 [0.30]; p = 0.029). The mean average daily current pain NRS scores were lower in the mavatrep and naproxen treatment arm than in the placebo arm (mavatrep: 7 day mean [SD], 3.72 [1.851]; naproxen: 7 day mean [SD], 3.49 [1.544]; placebo: 7 day mean [SD], 4.9 [1.413]). Mavatrep showed statistically significant improvements as compared with placebo on the WOMAC subscales (pain on days 2 [ p = 0.049] and 7 [ p = 0.041], stiffness on day 7 [ p = 0.075]), and function on day 7 [ p = 0.077]). The same pattern of improvement was evident for naproxen versus placebo. The mean (SD) number of rescue medication tablets taken during the 7-day treatment period was 4.2 (6.49) for mavatrep treatment, 2.8 (5.42) for naproxen, and 6.3 (8.25) for placebo treatment. All patients that received mavatrep reported at least 1 treatment emergent adverse event (TEAE). Feeling cold (79%), thermohypoesthesia (61%), dysgeusia (58%), paraesthesia (36%), and feeling hot (15%) were the most common TEAEs in the mavatrep group. Total 9% patients receiving mavatrep experienced minor thermal burns. No deaths or serious AEs or discontinuations due to AEs occurred. Conclusion Overall, mavatrep was associated with a significant reduction in pain, stiffness, and physical function when compared with placebo in patients with knee osteoarthritis. Mavatrep’s safety profile was consistent with its mechanism of action as a TRPV1 antagonist. Implications Further studies are required to evaluate whether lower multiple doses of mavatrep can produce analgesic efficacy while minimizing adverse events, as well as the potential for improved patient counselling techniques to reduce the minor thermal burns related to decreased heat perception. Trial Registration 2009-010961-21 (EudraCT Number).

Background and purpose The purpose of this case report is to describe a multimodal pain therapeutic concept including the adjunct use of pregabalin in a 4.5 year-old child after forefoot amputation. Phantom limb pain and sensation is a complex pain syndrome that is difficult to treat and prevent. 70–75% of all children develop such a pain syndrome after amputation. We describe here a paediatric patient who underwent forefoot amputation following traumatic foot injury and received multimodal pain therapy including pregabalin. The current experiment aimed at studying effects of empathic communication, and more specifically validation, on recall during a pain test and possible mediators and moderators of this effect. Methods A 4.5 year-old otherwise healthy girl suffered severe injuries of the right foot and lower leg during a motor vehicle accident. Due to development of severe necrosis, forefoot amputation had to be performed during the hospital stay. Results Initial pain therapy included paracetamol, ibuprofen, metamizol, morphine and fentanyl. With mounting pain and anxiety, regional anaesthesia of the distal sciatic nerve was administered in combination with a ketamine and morphine patient controlled analgesia pump (PCA). The peripheral blockade of the distal sciatic nerve was placed with the guidance of ultrasound and nerve stimulator. The PCA concept included a continuous basal rate combined with a bolus function. Although the regional anaesthesia was well positioned and functioning, there was inadequate pain control. The pain was described by the patient as short, highly intense and sharp sensations with intensity on the visual analogue scale (VAS) of 10 (out of 10). Furthermore, she suffered from anxiety episodes and sleep disturbance. The medical team decided to treat with pregabalin to resolve these issues while awaiting amputation (Lisfranc line). She received psychological counselling as adjunct treatment. This multimodal concept enabled an early and efficient pain reduction pre- and post-amputation and allowed for the possibility of a hospital discharge without any opioid pain medication. Conclusion The multimodal pain therapy including pregabalin was well tolerated, safe and highly effective in this case of traumatic limb injury and subsequent amputation. The use of pregabalin allowed significant pain and anxiety reduction for the patient. Implications Pregabalinis frequentlyused in adult patients for severe complex pain syndromes. There are only few reports of such adjunct medication (pregabalin) in paediatric pain syndromes. These reports focus mainly on the paediatric oncologic population. The case reported here encourages physicians to consider adjunct medications when treating complex pain, which are well established in the adult population. The benefits of such therapy in complex pain and anxiety can be extended to the paediatric population in select cases. Of course, one must always take into account that many routine medications used in children are well established but are off-label use. The authors are well aware of this problem and have conducted a critical literature review prior to pregabalin administration, including the search for randomized trials examining safety and tolerability. The parents or legal guardians of a minor must be thoroughly informed and consent to such a constellation of medical treatment.

Background and purpose The Fear-Avoidance Model of Chronic Pain proposed by Vlaeyen and Linton states individuals enter a cycle of chronic pain due to predisposing psychological factors, such as negative affectivity, negative appraisal or anxiety sensitivity. They do not, however, address the closely related concept of anxious rumination. Although Vlaeyen and Linton suggest cognitive-behavioral treatment methods for chronic pain patients who exhibit pain-related fear, they do not consider mindfulness treatments. This cross-sectional study investigated the relationship between chronic musculoskeletal pain (CMP), ruminative anxiety and mindfulness to determine if (1) ruminative anxiety is a risk factor for developing chronic pain and (2) mindfulness is a potential treatment for breaking the cycle of chronic pain. Methods Middle-aged adults ages 35-50 years ( N = 201) with self-reported CMP were recruited online. Participants completed standardized questionnaires assessing elements of chronic pain, anxiety, and mindfulness. Results Ruminative anxiety was positively correlated with pain catastrophizing, pain-related fear and avoidance, pain interference, and pain severity but negatively correlated with mindfulness. High ruminative anxiety level predicted significantly higher elements of chronic pain and significantly lower level of mindfulness. Mindfulness significantly predicted variance ( R 2 ) in chronic pain and anxiety outcomes. Pain severity, ruminative anxiety, pain catastrophizing, pain-related fear and avoidance, and mindfulness significantly predicted 70.0% of the variance in pain interference, with pain severity, ruminative anxiety and mindfulness being unique predictors. Conclusions The present study provides insight into the strength and direction of the relationships between ruminative anxiety, mindfulness and chronic pain in a CMP population, demonstrating the unique associations between specific mindfulness factors and chronic pain elements. Implications It is possible that ruminative anxiety and mindfulness should be added into the Fear-Avoidance Model of Chronic Pain, with ruminative anxiety as a psychological vulnerability and mindfulness as an effective treatment strategy that breaks the cycle of chronic pain. This updated Fear-Avoidance Model should be explored further to determine the specific mechanism of mindfulness on chronic pain and anxiety and which of the five facets of mindfulness are most important to clinical improvements. This could help clinicians develop individualized mindfulness treatment plans for chronic pain patients.

Background and aims Opioid use disorder (OUD) refers to a maladaptive pattern of opioid use leading to clinically significant impairment or distress. OUD causes, and vice versa, misuses and abuse of opioid medications. Clinicians face daily challenges to treat patients with prescription opioid use disorder. An evidence-based management for people who are already addicted to opioids has been identified as the national priority in the US; however, options are limited in clinical practices. In this study, we aimed to explore the success rate and important adjuvant medications in the medication assisted treatment with temporary use of methadone for opioid discontinuation in patients with prescription OUD. Methods This is a retrospective chart review performed at a private physician office for physical medicine and rehabilitation. We reviewed all medical records dated between December 1st, 2011 and August 30th, 2016. The initial evaluation of the included patients ( N =140) was completed between December 1st, 2011 and December 31st, 2014. They all have concumittant prescription OUD and chronic non-cancer pain. The patients (87 female and 53 male) were 46.7 ± 12.7 years old, and had a history of opioid use of 7.7 ±6.1 years. All patients received the comprehensive opioid taper treatments (including interventional pain management techniques, psychotherapy, acupuncture, physical modalities and exercises, and adjuvant medications) on top of the medication assisted treatment using methadone (transient use). Opioid tapering was considered successful when no opioid medication was used in the last patient visit. Results The 140 patients had pain of 9.6 ± 8.4 years with 8/10 intensity before treatment which decreased after treatment in all comparisons ( p < 0.001 for all). Opioids were successfully tapered off in 39 (27.9%) patients after 6.6 ±6.7 visits over 8.8 ±7.2 months; these patients maintained opioid abstinence over 14.3 ± 13.0 months with regular office visits. Among the 101 patients with unsuccessful opioid tapering, 13 patients only visited the outpatient clinic once. Significant differences were found between patients with and without successful opioid tapering in treatment duration, number of clinic visits, the use of mirtazepine, bupropion, topiramate, and trigger point injections with the univariate analyses. The use of mirtazepine (OR, 3.75; 95% CI, 1.48–9.49), topiramate (OR, 5.61; 95% CI, 1.91–16.48), or bupropion (OR, 2.5; 95% CI, 1.08–5.81) was significantly associated with successful opioid tapering. The associations remain significant for mirtazepine and topiramate (not bupropion) in different adjusted models. Conclusions With comprehensive treatments, 27.9% of patients had successful opioid tapering with opioid abstinence for over a year. The use of mirtazepine, topiramate, or likely bupropion was associated with successful opioid tapering in the medication assisted treatment with temporary use of methadone. Opioid tapering may be a practical option and should be considered for managing prescription OUD. Implications For patients with OUD, indefinite opioid maintenance treatment may not be necessary. Considering the ethical values of autonomy, nonmaleficence, and beneficence, clinicians should provide patients with OUD the option of opioid tapering.

Background and aims Patients suffering from chronic nonmalignant pain constitute a heterogeneous population in terms of clinical presentation and treatment results. Few data are available about what distinguishes different groups in this huge population of patients with chronic persistent pain (CPP). A subgroup that is poorly studied, consists of the most severely impaired chronic pain patients. At the Uppsala University Hospital Pain Clinic, there is a specialized department accepting the most complex patients for rehabilitation. In the endeavour to improve and evaluate treatment for this subgroup, a better understanding of the complex nature of the illness is essential. This prospective study aimed to describe the characteristics of this subgroup of patients with CPP. Methods Seventy-two consecutive patients enrolled in the Uppsala programme were evaluated. We collected data on demographics, type of pain and experienced symptoms other than pain using a checklist of 41 possible symptoms. Psychiatric comorbidity was assessed by a psychiatrist using a structured clinical interview. Quality of life (QoL), pain rating and medication/drug/alcohol usage were measured by validated questionnaires: SF-36, NRS, DUDIT and AUDIT. Concerning physical functioning and sick leave, a comparison was made with data from the Swedish Quality Register Registry for pain rehabilitation (SQRP). Results The cohort consisted of 61% women and the average age was 45 (range 20-70) years. For this cohort, 74% reported being on sick leave or disability-pension. In the SQRP 59% were on sick leave at the time they entered the rehabilitation programmes [1]. On average, the study-population reported 22 symptoms other than pain, to be at a high rate of severity. Patients treated in conventional pain-rehabilitation programmes reported a mean of 10 symptoms in average. Symptoms reported with the highest frequency (>80%), were lethargy, tiredness, headache and difficulties concentrating. Seventy- six percent were diagnosed with a psychiatric disorder. Sixty-nine fulfilled the criteria for depression or depression/anxiety disorder despite that most (65%) were treated with psychotropic medication. Alcohol/drug abuse was minimal. Seventy-one percent were on opioids but the doses were moderate (<100 mg) MEq. The pain rating was ≥7 (out of a maximum of 10) for 60% of the patients. Conclusion This study describes what makes the subgroup of pain patients most affected by their pain special according to associated factors and comorbidity We found that they were distinguished by a high degree of psychiatric comorbidity, low physical functioning and extreme levels of symptom preoccupation/hypervigilance. Many severe symptoms additional to pain (e.g. depression/anxiety, tiredness, disturbed sleep, lack of concentration, constipation) were reported. The group seems hypervigilant, overwhelmed with a multitude of different symptoms on a high severity level. Implications When treating this complex group, the expressions of the illness can act as obstacles to achieve successful treatment outcomes. The study provides evidence based information, for a better understanding of the needs concerning these pain patients. Our result indicates that parallel assessment and treatment of psychiatric comorbidities and sleep disorders combined with traditional rehabilitation, i.e. physical activation and cognitive reorganization are imperative for improved outcomes.

Background As pain is often a comorbid condition, many patients use opioid analgesics in combination with several other drugs. This implies a generally increased risk of drug interactions, which along with inherent pharmacogenetic variability and other factors may cause differences in therapeutic response of opioids. Aim To provide an overview of interactions and pharmacogenetic variability of relevance for individual differences in effect and tolerability of opioid analgesics, which physicians and other healthcare professionals should be aware of in clinical practice. Methods The article was based on unsystematic searches in PubMed to identify literature highlighting the clinical impact of drug interactions and pharmacogenetics as sources of variable response of opioid analgesics. Results Cytochrome P450 (CYP)-mediated metabolism is an important process for both clinically relevant interactions and pharmacogenetic variability of several opioids. Concomitant use of CYP inhibitors (e.g. paroxetine, fluoxetine and bupropion) or inducers (e.g. carbamazepine, phenobarbital and phenytoin) could counteract the clinical effect or trigger side effects of analgesics in the same manner as genetically determined differences in CYP2D6-mediated metabolism of many opioids. Moreover, combination treatment with drugs that inhibit or induce P-glycoprotein (ABCB1), a blood-brain barrier efflux transporter, may alter the amount (‘dose’) of opioids distributed to the brain. At the pharmacodynamic level, it is crucial to be aware of the potential risk of interaction causing serotonergic syndrome when combining opioids and serotonergic drugs, in particular antidepressants inhibiting serotonin reuptake (SSRIs and SNRIs). Regarding pharmacogenetics at the receptor level of pain treatment, the knowledge is currently scarce, but an allelic variant of the μ1 opioid receptor (OPRM1) gene has been associated with higher dosage requirement to achieve analgesia. Conclusions and implications Drug interactions and pharmacogenetic differences may lead to therapeutic failure or serious side effects of opioid analgesics. Many interactions involve combinations with antidepressants and antiepileptics, which are highly relevant drugs in patients suffering from pain. To prevent unfavourable drug interactions it is important that clinicians pay close attention and use electronic drug interaction checkers when treatments are initiated or discontinued. For the management of issues related to pharmacogenetic differences, blood-based CYP genotyping is available as routine test at many laboratories, and provide a valuable tool for proper choice of drugs and doses for treatment of pain and other diseases.

Background and aims Cholinergic agents cause antinociception by mimicking the release of acetylcholine (ACh) from spinal cholinergic nerves. PhKv is a peptide isolated from the venom of the armed spider Phoneutria nigriventer . It has an antiarrythmogenic activity that involves the enhanced release of acetylcholine. The aim of this study was to investigate whether PhKv had an antinociceptive action in mice. Methods Male albino Swiss mice (25–35 g) were used in this study. The PhKv toxin was purified from a PhTx3 fraction of the Phoneutria nigriventer spider’s venom. Because of its peptide nature, PhKv is not orally available and it was delivered directly into the central nervous system by an intrathecal (i.t.) route. PhKV on the thermal and mechanical sensitivity was evaluated using plantar test apparatus and the up-and-down method. The analgesic effects of PhKv were studied in neuropathic pain (CCI) and in the peripheral capsicin test. In order to test whether PhKv interfered with the cholinergic system, the mice were pre-treated with atropine (5mg/kg, i.p.) or mecamylamine (0.001 mg/kg, i.p.) and the PhKv toxin (30 pmol/site i.t.) or neostigmine (100 pmol/site) were applied 15 min before the intraplantar capsaicin (1 nmol/paw) administrations. To investigate PhKv action on the AChE activities, was performed in vitro and ex vivo assay for AChE. For the in vitro experiments, mice spinal cord supernatants of tissue homogenates (1 mg/ml) were used as source of AChE activity. The AChE assay was monitored at 37 °C for 10 min in a FlexStation 3 Multi-Mode Microplate Reader (Molecular Devices) at 405 nm. Results PhKv (30 and 100pmol/site, i.t.) had no effect on the thermal or mechanical sensitivity thresholds. However, in a chronic constriction injury model of pain, PhKv (10pmol/site, i.t.) caused a robust reduction in mechanical withdrawal with an antinociceptive effect that lasted 4 h. A pretreatment in mice with PhKv (30pmol/site, i.t.) or neostigmine (100pmol/site, i.t.) 15min before an intraplantar injection of capsaicin (1 nmol/paw) caused a maximal antinociceptive effect of 69.5 ± 4.9% and 85 ± 2.5%, respectively. A pretreatment in mice with atropine; 5 mg/kg, i.p. or mecamylamine 0.001 mg/kg, i.p. inhibited a neostigimine and PhKv-induced antinociception, suggesting a cholinergic mechanism. Spinal acetylcholinesterase was inhibited by PhKv with ED 50 of 7.6 (4.6–12.6 pmol/site, i.t.). PhKv also inhibited the in vitro AChE activity of spinal cord homogenates with an EC 50 of 20.8 (11.6–37.3 nM), shifting the Km value from 0.06 mM to 18.5 mM, characterizing a competitive inhibition of AChE activity by PhKv. Conclusions Our findings provide, to our knowledge, the first evidence that PhKv caused inhibition of AChE, it increased the ACh content at the neuronal synapses, leading to an activation of the cholinergic system and an antinociceptive response. Implications Studies regarding the nociceptive mechanisms and the identification of potential targets for the treatment of pain have become top priorities. PhKv, by its action of stimulating the cholinergic receptors muscarinic and nicotinic system, reduces pain it may be an alternative for controlling the pain processes.

Background and aims Chronic abdominal pain may occasionally be due to terminal endings of intercostal nerves (ACNES, abdominal cutaneous nerve entrapment syndrome) that are entrapped in the abdominal wall. Spontaneous neuropathic flank pain may also be caused by involvement of branches of these intercostal nerves. Aim is to describe a series of patients with flank pain due to nerve entrapment and to increase awareness for an unknown condition coined Lateral Cutaneous Nerve Entrapment Syndrome (LACNES). Methods Patients possibly having LACNES (constant area of flank tenderness, small point of maximal pain with neuropathic characteristics, locoregional altered skin sensation) presenting between January 2007 and May 2016 received a diagnostic 5–10 mL 1% lidocaine injection. Pain levels were recorded using a numerical rating scale (0, no pain to 10, worst possible). A >50% pain reduction was defined as success. Long term effect of injections and alternative therapies were determined using a satisfaction scale (1, very satisfied, no pain - 5, pain worse). Results 30 patients (21 women, median age 52, range 13-78) were diagnosed with LACNES. Pain following one injection dropped from 6.9 ± 1.4 to 2.4 ±1.9 (mean, p < 0.001) leading to an 83% immediate success rate. Repeated injection therapy was successful in 16 (pain free n = 7, pain acceptable, n = 9; median 42 months follow-up). The remaining 14 patients received (minimally invasive) surgery ( n = 5) or other treatments (medication, manual therapy or pulsed radiofrequency, n = 9). Overall treatment satisfaction (scale 1 or 2) was attained in 79%. Conclusions and implications LACNES should be considered in patients with chronic flank pain. Injection therapy is long term effective in more than half of the population.

Background and aims Context insensitivity has been put forward as a potential mechanism explaining the high co-occurrence of pain and emotional distress. In the pain literature, the concept has only been introduced at a theoretical level and an assessment tool for exploring its impact is lacking. In an interpersonal setting, a core aspect of context sensitivity and insensitivity concerns when to disclose and when to avoid expressing pain and related distress. Both context insensitive disclosure and context insensitive avoidance may hamper interpersonal support and fuel the problem. This exploratory study describes an attempt to develop a self-report instrument to assess tendencies to disclose vs. avoid expressions of pain and related distress, as well as self-perceived adjustment of disclosure vs. avoidance to the context. Methods Apool of items was systematically developed to assess different aspects of context insensitivity, including disclosure vs. avoidance of expression. 105 participants with persistent pain were recruited at pain rehabilitation clinics (80% of the sample) and in a university setting (20% of the sample). The participants responded to the pool of items as well as to a number of validated self-report instruments covering pain, pain-related disability, pain catastrophizing, emotion regulation tendencies, self-compassion and pain acceptance. The analyses explored the factorial structure of the initial instrument, as well as the criterion and construct validity. Results The analyses confirmed a stable underlying structure of the initial scale, with four distinct factors explaining 64.4% of the total variance. However, the criterion and construct validity could only be confirmed for one of the factors, which contained items reflecting context insensitive avoidance of expression. Consequently, only this factor, demonstrating very good internal consistency, was kept in the final version of the instrument which was named context insensitive avoidance (CIA). Conclusions We found support for the final version of our instrument, capturing one prominent aspect of context insensitivity. Avoidance of expression was related to higher ratings of pain, disability, catas- trophizing and suppression as well as to lower levels of self-compassion. We encourage further studies to explore the impact of context insensitive avoidance for regulating pain and associated negative emotions. Yet, more research is needed that goes beyond self-report and includes other aspects of context. It is urgent to develop systematic ways for assessing context insensitivity, as it will enhance our understanding of regulatory strategies as potential transdiagnostic mechanisms in pain and emotion. Implications This tool for assessing contextually insensitive avoidance of expression could potentially be used both clinically and in future research to advance our understanding of comorbid problems with pain and emotional distress. Further research is needed to develop methods for assessing other aspects of context insensitivity to fully understand its impact in patients suffering from pain.

Background and aims Pain is one of the most common reasons for patients to seek primary health care. Pain relief is likely to be achieved for patients suffering from acute pain, but for individuals with chronic pain it is more likely that the condition will persist. These patients have the option of being referred to specialised pain clinics. However, the complexity surrounding chronic pain patients is not well studied in these settings. This study aimed to describe patients with chronic pain referred to a pain clinic by using the information submitted during their first visit and one year later and also to identify associations between baseline characteristics and improvements in health-related quality of life in the follow-up. Methods This was a longitudinal observational study of a sample consisting of 318 patients referred to a pain clinic. One group of patients containing 271 individuals (median age 48, 64% females) was assessed and received conventional pain treatment (CPT group) and a second group of 47 patients (median age 53, 64% females) was assessed by a pain specialist and referred back to their physician with a treatment recommendation (assessment only, AO group). Patient-reported outcome measures in health-related quality of life (EQ-5D), pain intensity (VAS), mental health (HADS), insomnia (ISI), pain-related disability (PDI), kinesiophobia (TSK) and sense of coherence (SOC) were collected at the first visit and one year later. Results At baseline, the CPT group reported a low EQ-5D Index (median (md) 0.157) and EQVAS (md 40) as well as considerable high, current pain intensity VAS (md 58), HADS anxiety (md 8), ISI (md 17), PDI (md 36) and TSK (md 39). The AO group showed similar problems (no significant differences compared to the CPT group), except for ISI, where the AO group reported less severe problems. At the one-year follow-up, the CPT group had a statistically significant improvement in EQ-5D, VAS, ISI, PDI and TSK. In the AO group no significant changes were observed. In the CPT group there was an association between a high ISI level at baseline and an improved EQ-5D Index in the follow-up. Conclusions The study describes rarely explored groups of patients with chronic pain at a pain clinic. Severe pain problems were present in both groups at their first visit. A statistically significant improvement could be seen in the group that was conventionally treated while this was not the case among those subjects who were assessed and referred. The results imply, that relatively limited treatment strategies were helpful for the patients’ health-related quality of life. Despite these improvements, the patients were not fully recovered, pointing to the chronicity of pain conditions and the need of support for many patients. Implications Increased knowledge about assessment, selection and treatment at pain clinics is important to improve the quality of the work performed at these clinics. Despite limited resources, further efforts should be made to collect comparable, valid data on a regular base from pain clinics in order to develop recommendation models.

Graphical Abstract Abstract Background and aims Neuropathic pain is a significant medical problem needing more effective treatments with fewer side effects. Overactive glutamatergic transmission via N -methyl-D-aspartate receptors (NMDARs) are known to play a role in central sensitization and neuropathic pain. Although ketamine, a NMDAR channel-blocking antagonist, is often used for neuropathic pain, its side-effect profile and abusive potential has prompted the search for a safer effective oral analgesic. A novel oral prodrug, AV-101 (L-4 chlorokynurenine), which, in the brain, is converted into one of the most potent and selective GlyB site antagonists of the NMDAR, has been demonstrated to be active in animal models of neuropathic pain. The two Phase 1 studies reported herein were designed to assess the safety and pharmacokinetics of AV-101, over a wide dose range, after daily dosing for 14-days. As secondary endpoints, AV-101 was evaluated in the capsaicin-induced pain model. Methods The Phase 1A study was a single-site, randomized, double-blind, placebo-controlled, single oral ascending dose (30–1800 mg) study involving 36 normal healthy volunteers. The Phase 1B study was a single-site randomized, double-blind, placebo-controlled, study of multiple ascending doses (360, 1080, and 1440mg/day) of AV-101 involving 50 normal healthy volunteers, to whom AV-101 or placebo were administered orally daily for 14 consecutive days. Subjects underwent PK blood analyses, laboratory assessments, physical examination, 12-lead ECG, ophthalmological examination, and various neurocognitive assessments. The effect of AV-101 was evaluated in the intradermally capsaicin-induced pain model (ClinicalTrials.gov Identifier: NCT01483846). Results Two Phase 1, with an aggregate of 86 subjects, demonstrated that up to 14 days of oral AV-101, up to 1440mg per day, was safe and very well tolerated with AEs quantitively and qualitatively like those observed with placebo. Mean half-life values of AV-101 were consistent across doses, ranging with an average of 1.73 h, with the highest C max (64.4 μg/mL) and AU C 0- t (196 μgh/mL) values for AV-101 occurring in the 1440-mg dose group. In the capsaicin induce-pain model, there was no significant change in the area under the pain time curve (AUPC) for the spontaneous pain assessment between the treatment and the placebo groups on Day 1 or 14 (the primary endpoint). In contrast, there were consistent reductions at 60–180 min on Day 1 after dosing for allodynia, mechanical hyperalgesia, heat hyperalgesia, and spontaneous pain, and on Day 14 after dosing for heat hyperalgesia. Conclusions Although, AV-101 did not reach statistical significance in reducing pain, there were consistent reductions, for allodynia pain and mechanical and heat hyperalgesia. Given the excellent safety profile and PK characteristics demonstrated by this study, future clinical trials of AV-101 in neuropathic pain are justified. Implications This article presents the safety and PK of AV-101, a novel oral prodrug producing a potent and selective GlyB site antagonist of the NMDA receptor. These data indicate that AV-101 has excellent safety and PK characteristics providing support for advancing AV-101 into Phase 2 studies in neuropathic pain, and even provides data suggesting that AV-101 may have a role in treating depression.

Introduction Chronic pain is a major health problem, considered as a disease in its own right. The prevalence of chronic pain is estimated to be between 2% and 40% in adult populations. In Niger, there are no data on chronic pain. Aims This study was designed to provide the demographic, clinical and etiological profile of chronic pain in patients from Niger in order to create a database on chronic pain in Niger. Patients and methods Our study is prospectively conducted at the department of external consultation of the Hôpital National de Niamey over a period of 10 months from 31 May 2016 to 30 January 2017 collecting all cases of chronic pain. The demographic, clinical and etiological characteristics of all patients were collected and analyzed. Results During the period of the study, 1927 patients consulted at the department of external consultation of the Hôpital National de Niamey, among which 411 patients had chronic pain (21.33% [95% CI: 19.53% and 23.13%]). The average age was 48.28 years (±12.84) with 51.6% of patients aged over 50 years. The male sex was predominant (61.8%). The most common sites of chronic pain were legs (25.5%), back (14.4%), neck (13.6%), knees (13.4%) and feet (13.1%). Osteoarthritis was the most common cause of chronic pain (35.5%), followed by herniated disc (22.2%), spondylodiscitis (14.6%) and migraine (4.1%). Significantly patients aged 50-59 years suffered from neck and legs pain ( p value < 0.001). Significantly chronic headaches and rheumatoid arthritis were more common in women while osteoarthritis, herniated disc and spondylodiscite were more common in men ( p value = 0.001). Significantly osteoarthritis and herniated disc were more common in patients older than 40 years ( p value < 0.001). Conclusion Our study provides demographic, clinical and etiological data of chronic pain in patients from Niger, and shows that chronic pain is a common reason for consultation in Niger concerning 1 in 5 patients with a high prevalence among men and patients aged over 40 years.

Background and aims No published studies have looked at the dosing and use of rapid onset fentanyl preparations in children. The primary aim of this study was to assess whether there is a correlation between effective dose of rapid onset fentanyl and background oral morphine equivalent analgesia in children less than 18 years old. Secondary objectives included establishing whether there is a correlation between effective dose of rapid onset fentanyl and age and weight. Reported side effects were also reviewed. Methods This study is a retrospective case note review of all children less than 18 years old who received rapid onset fentanyl products in a tertiary paediatric oncology centre in England between 2010 and 2015. Correlations were analysed using Spearman’s correlation coefficient as data was non-parametric. Results Data on 26 children (5-17 yrs; 13-100 kg) was analysed. The most common diagnosis in children being given rapid onset fentanyl products was a solid tumour (84.6%). Eleven children used sublingual tablets, 17 used lozenges and one used a fentanyl nasal spray (three patients used two different preparations). The only significant correlation found was between dose of fentanyl lozenge and weight ( r s = 0.81, p < 0.001). Very few side effects were reported with the most frequent being nausea (8%) and sleepiness (8%). Conclusions Fentanyl lozenges seem to be safe and well tolerated in children as young as five years old, weighing as little as 13 kg. Results suggest that children should always be started on the lowest available dose of chosen preparation and that this dose should be titrated according to response. This study demonstrates that there is no correlation between background opioid dose and effective dose of rapid onset fentanyl in children. This mirrors findings of similar studies in adults. There was a strong correlation between effective dose of fentanyl lozenge and weight. This may be in part due to clinicians being more inclined to increase fentanyl lozenge doses as the child is in control of when they have had enough medication. In contrast, buccal tablets are absorbed quickly and the child always receives the full dose, making clinicians more reluctant to titrate the dose. Implications This article presents initial evidence for feasibility and tolerability of fentanyl lozenges in children as young as five years old, who are on relatively low doses of background opioids. This could be of interest to clinicians who are looking for alternatives to oral opioids to manage breakthrough pain in children with cancer.

Background and purpose Acid has long been thought to play an important role in the pain process. Animal study showed that repeated acid stimulation induced central sensitization. The purpose of the study is to investigate muscle pain and hyperalgesia evoked byintramuscular infusion of saline at different pH levels, and to compare the effect of a single versus repeated acid infusions. Methods Twenty healthy subjects received infusions of buffered saline (pH 5.0, 6.0, and 7.4) into the brachioradialis muscle in a randomized order. Twelve of the subjects received repeated infusions. The subjects rated the pain intensity on visual analogue scale (VAS). Thermal pain sensitivity, and pressure pain threshold (PPT) were assessed in both arm before, during, immediately after, one hour after, and one day after the infusion. A McGill Pain Questionnaire and pain mapping were completed after each infusion. Results The pH 5 solution caused significantly higher pain and larger areas than pH 6.0 or 7.4. The local PPTs were significantly decreased (hyperalgesia) during and immediately after infusion of all three solutions. No significant differences were detected between the first and second infusion. Conclusions The intensity of acid-induced muscle pain is pH-dependent. All three solutions induced pressure hyperalgesia at the infusion site. Repeated infusions did not induce increased pain or prolonged hyperalgesia as compared with a single injection. Human intramuscular acidic saline infusion could not produce chronic pain model. Implications The acid-induced pain model may reflect the early stage responses to tissue injury of clinical conditions. Repeated intramuscular acidic saline injection model of prolonged hyperalgesia in rodents could not be translated into a human for modelling chronic musculoskeletal pain.

Background and aims Research suggests swearing can moderate pain perception. The present study assessed whether changes in pain perception due to swearing reflect a “scripting” effect by comparing swearing as a response to pain in native English and Japanese speakers. Cognitive psychology denotes a ‘script’ to be a sequence of learnt behaviours expected for given situations. Japanese participants were included as they rarely, if ever, swear as a response to pain and therefore do not possess an available script for swearing in the context of pain. It was hypothesised that Japanese participants would demonstrate less tolerance and more sensitivity to pain than English participants, and – due to a lack of an available script of swearing in response to pain – that Japanese participants would not experience swearword mediated hypoalgesia. Methods Fifty-six native English (mean age = 23 years) and 39 Japanese (mean age = 21) speakers completed a cold-pressor task whilst repeating either a swear on control word. A 2 (culture; Japanese, British) × 2 (word; swear; non-swear) design explored whether Japanese participants showed the same increase in pain tolerance and experienced similar levels of perceived pain when a swearing intervention was used as British participants. Pain tolerance was assessed by the number of seconds participants could endure of cold-pressor exposure and self-report pain measurements. Levels of perceived pain were assessed using a 120-mm horizontal visual analogue scale anchored by descriptors in the participant’s native language of “no pain” (left) and “terrible pain” (right). The participant was asked to mark a 10 mm vertical line to indicate overall pain intensity. The score was measured from the zero anchor to the participant’s mark. Results Japanese participants reported higher levels of pain ( p < 0.005) and displayed lower pain tolerance than British participants ( p <0.05). Pain tolerance increased in swearers regardless of cultural background ( p < 0.001) and no interaction was found between word group and culture ( p = 0.96), thereby suggesting that swearing had no differential effect related to the cultural group of the participant. Conclusions The results replicate previous findings that swearing increases pain tolerance and that individuals from an Asian ethnic background experience greater levels of perceived pain than those from a Caucasian ethnic background. However, these results do not support the idea of pain perception modification due to a “scripting” effect. This is evidenced as swearword mediated hypoalgesia occurs irrespective of participant cultural background. Rather, it is suggested that modulation of pain perception may occur through activation of descending inhibitory neural pain mechanisms. Implications As swearing can increase pain tolerance in both Japanese and British people, it may be suggested that swearword mediated hypoalgesia is a universal phenomenon that transcends socio-cultural learnt behaviours. Furthermore, swearing could be encouraged as an intervention to help people cope with acute painful stimuli.

Objectives Little is known about the affected cognitive problems in chronic low back pain patients. For this patient cohort research mostly focused on memory of pain, rather than cognitive difficulties related to pain. Chronic pain may be associated with specific (yet undefined) cognitive deficits that affect everyday behaviour. We set out to compare the cognitive function of patients with chronic low back pain (cLBP) in the course of multidisciplinary pain treatments before and after therapy. Methods Thirty-three patients with cLBP and 25 healthy controls between 20 and 70 years were recruited into the study. The inclusion criteria for patients were: (1) a history of at least 12 weeks of chronic myofascial low back pain without radicular pain sensation before enrolment; (2) grade II and higher chronicity according to von Korff; (3) no opioid medication. The patients recruited had a mean pain duration of 7.13 ± 7.16 years and reported a mean pain intensity of 6.62 ± 2.04 (visual analogue score, VAS). Their mean back function according to the Funktionsfragebogen Hannover (FFbH, a questionnaire comparable with the Health Assessment Questionnaire) was 52.39 ± 20.23%. At three time points (before therapy, 3 weeks and 6 months after therapy) the study subjects were assessed prospectively with a battery of visual memory tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). These included choice reaction time (CRT), pattern recognition memory (PRM) and spatial span (SSP). In parallel, the Trail-Making Test (TMT-A, TMT-B) and the Wechsler Adult Intelligence Scale (WAIS-III) were used to evaluate intelligence and cognitive flexibility. Results At the beginning of MDPT (T1), it took patients with cLBP significantly longer than HC to complete TMT-A (38.29 ± 19.99 s vs 30.25 ± 14.19 s, p = 0.047) and TMT-B (72.10 ± 26.98 s vs 55.99 ± 22.14 s, p = 0.034). There were no significant differences between patients and HC in CRT, PRM and SSP. Three weeks (T2) and 6 months (T3) after MDPT, TMT-A reaction time of patients significantly improved by 6.5 s and 8.1 ms (38.3 ±19.9 s vs 31.8 ±12.3 s, p = 0.02 and 31.8 ± 12.3 s vs 30.2 ± 8.9 s, p = 0.021, respectively). The patients’ working memory was also better 6 months after MDPT (48.8 ± 11.1% at T1, 51.2 ±11.9% at T2, 57.1 ±10.9% at T3, p = 0.008). Significant correlations among pain, depression/anxiety, medication and neuropsychological tests were found. Conclusions These findings show that patients with cLBP have slowed speeds of information processing and working memory, but no alteration in attention and recognition memory. There are clearly interactions of cognitive function with pain, depression, anxiety, and medication. MDPT may improve the impaired cognitive function of patients with cLBP. Implication Health professionals should contemplate the results from this study when planning therapy strategies especially when prescribing pain medications such opioids to patients with chronic low back pain.

Pain is the hallmark of sickle cell anemia (SCA), presenting as recurrent acute events or chronic pain. Central sensitization, or enhanced excitability of the central nervous system, alters pain processing and contributes to the maintenance of chronic pain. Individuals with SCA demonstrate enhanced sensitivity to painful stimuli however central mechanisms of pain have not been fully explored. We hypothesized that adults with SCA would show evidence of central sensitization as observed in other diseases of chronic pain. Methods We conducted a prospective study of static and dynamic quantitative sensory tests in 30 adults with SCA and 30 matched controls. Results Static thermal testing using cold stimuli showed lower pain thresholds ( p = 0.04) and tolerance ( p = 0.04) in sickle cell subjects, but not for heat. However, SCA subjects reported higher pain ratings with random heat pulses ( p < 0.0001) and change in scores with temporal summation at the heat pain threshold ( p = 0.002). Similarly, with the use of pressure pain stimuli, sickle cell subjects reported higher pain ratings ( p = 0.04), but not higher pressure pain tolerance/thresholds or allodynia to light tactile stimuli. Temporal summation pain score changes using 2 pinprick probes (256 and 512 mN) were significantly greater ( p = 0.004 and p = 0.008) with sickle cell, and delayed recovery was associated with lower fetal hemoglobin ( p = 0.002 and 0.003). Conclusions Exaggerated temporal summation responses provide evidence of central sensitization in SCA. Implications The association with fetal hemoglobin suggests this known SCA modifier may have a therapeutic role in modulating central sensitization.

Background Neuropathic pain is a challenging condition often refractory to existing therapies. An increasing number of studies have indicated that the immune system plays a crucial role in the mediation of neuropathic pain. Exploration of the various functions of individual cytokines in neuropathic pain will provide greater insight into the mechanisms of neuropathic pain and suggest potential opportunities to expand the repertoire of treatment options. Methods A literature review was performed to assess the role of pro-inflammatory and antiinflammatory cytokines in the development of neuropathic pain. Both direct and indirect therapeutic approaches that target various cytokines for pain were reviewed. The current understanding based on preclinical and clinical studies is summarized. Results and conclusions In both human and animal studies, neuropathic pain has been associated with a pro-inflammatory state. Analgesic therapies involving direct manipulation of various cytokines and indirect methods to alter the balance of the immune system have been explored, although there have been few large-scale clinical trials evaluating the efficacy of immune modulators in the treatment of neuropathic pain. TNF-α is perhaps the widely studied pro-inflammatory cytokine in the context of neuropathic pain, but other pro-inflammatory (IL-1β, IL-6, and IL-17) and anti-inflammatory (IL-4, IL-10, TGF-β) signaling molecules are garnering increased interest. With better appreciation and understanding of the interaction between the immune system and neuropathic pain, novel therapies may be developed to target this condition.

Background and purpose Low back pain (LBP) is a lifelong problem for many. In acute episodes, or as a persistent condition, LBP is fluctuating in nature, with pain and other features of the condition varying in intensity and duration over time. Symptom flares (also known as flare ups) contribute to this variation and can have a great impact on the lives of those who have LBP. An important goal of treatments for, and research on, LBP is arguably to decrease symptom flare in both frequency and severity. However, this goal is problematic with little research, and no consensus, on how to define LBP flare. In particular, patients’ understandings of LBP flare have received limited attention in the literature. To appropriately address this issue, we sought to understand how flares are conceptualized by individuals with LBP. Methods We used an inductive, predominantly qualitative methodology, conducting an online survey with 130 individuals who self-reported experiencing LBP. The survey investigated participants’ views on LBP flare including its meaning, features and symptoms, and whether ‘flare’ and ‘pain increase’ were synonymous. Qualitative analysis of responses involved thematic and content analysis with descriptive statistics used for the quantitative component. Results Our data analysis found that participants identified many aspects of a flare to be important. Qualitative analyses highlighted a number of themes including that LBP flare was conceptualized as: (1) on increase in pain and other uncomfortable sensations such as paraesthesia or muscle tension, (2) an increase in the area, quality and/or duration of symptoms, (3) a reduction in physical, cognitive and/or social functioning, and (4) negative psychological and/or emotional factors. Flare was also discussed as a change that was difficult to settle. When participants considered whether ‘flare’ and ‘pain increase’ were synonymous, responses were evenly divided between ‘no’ (47%) and ‘yes’ (46%) with remaining participants ‘unsure’. Conclusions The key finding was that many people with LBP do not consider their condition to be flared simply on the basis of a pain increase. In general, other features were required to also change. Results highlighted that a narrow focus on pain is unlikely to differentiate minor pain events from a flare. these findings are important as they contrast with most commonly used definitions of a flare that focus predominantly on pain increase. Implications Our findings have implications for understanding the trajectory of LBP over time. Understandings derived from perspectives of individuals with LBP highlight that defining flare in LBP is complex. In order to provide person-centred care, individual context and experiences should be taken into account. Therefore, understandings of LBP flare require consideration of factors beyond simply an increase in pain. A comprehensive, person-centred understanding of flare that includes a number of features beyond simply an increase in pain intensity is likely to be useful to better identify flares in research settings, assisting endeavours to understand and reduce LBP. Similarly, in clinical settings a nuanced conceptualisation of flare is likely to help health professionals communicate understandings of flare when working with individuals to manage their LBP.

Background and aims Chronic vulvovaginal pain is strikingly common and has a serious impact on women’s lives. Nevertheless, there are few longitudinal studies focusing on mechanisms involved in the pain development. One area of interest is how women cope with sexual activities and how this affects their pain. In this study, avoidance and endurance coping behaviors were explored as possible mediators of the relation between catastrophizing and pain, cross-sectionally and longitudinally. Methods 251 women (18-35 years old) with vulvovaginal pain were recruited in university settings and filled out questionnaires about their pain, catastrophizing and coping behaviors at two occasions, with five months in between. Multiple mediation models were tested, exploring avoidance and endurance as mediators of the relation between catastrophizing and pain. Results The results showed that avoidance was an influential mediator of the link between catastro¬phizing and pain. Using multiple mediation models we found that although the indirect effects of both avoidance and endurance were significant cross-sectionally, only avoidance was a significant mediator in the combined model exploring associations over time. Conclusions This study indicates that the strategies women with vulvovaginal pain use for coping with sexual activities are important for the course of pain. Avoidance and, to a lesser degree, endurance strate¬gies were identified as important mediators of the effects of catastrophizing on pain. When exploring the links over time, only avoidance emerged as a significant mediator. Implications In this longitudinal study, catastrophizing was linked to vulvovaginal pain, via avoidance and endurance of sexual activities. Hence, targeting catastrophizing early on in treatment, as well as addressing coping, may be important in clinical interventions.

Background and aims Based on a transdiagnostic approach, this study assesses the impact of cognitive and emotional processes (difficulties in emotional regulation, impulsiveness, rumination and somatosensory amplification) on the psychological risk factors of chronic low-back pain. Methods The study was carried out with 256 patients with chronic low-back pain. All the variables were assessed through a booklet of 10 validated questionnaires. Multiple regression analysis and moderation analysis were performed. Results Predictors included in multiple regression models explain 3%-42% (adjusted R 2 ) of the variance in psychological risk factors. Moreover, analyses reveal a significant moderator effect of somatosensory amplification on the link between fear-avoidance beliefs linked to work and pain intensity ( F (3;250) = 12.33; p = .00), of somatosensory amplification and brooding on the link between depression and functional repercussions (FR) on everyday life ( F (3;252) = 13.36; p = .000; F (1;252) = 12.42; p = .00), of the reflection dimension of rumination on the link between the helplessness dimension of catastrophizing and FRs on sociability ( F (3;252) = 37.02; p = .00). There is also a moderation analysis with a significant trend concerning the lack of emotional awareness and the difficulties in controlling impulsive behaviours. Conclusions Our results indicate an important role of some dimensions of difficulties in emotional regulation, somatosensory amplification and rumination in the increase in negative affects and dysfunctional beliefs, and in the links between those psychological risk factors and pain/disability. Implications This study identifies some cognitive and emotional dysregulations substantially involved in work-related chronic pain. This contribute to put in place psychotherapeutic protocols to tackle these deficits and dysregulations in a relevant way.

Background and aims Obesity is a significant health concern in the Western world and the presence of comorbid conditions suggests an interaction. The overlapping distributions of chronic pain populations and obesity suggests that an interaction may exist. Poor quality diet (high carbohydrates, saturated fats, omega-6 polyunsaturated fatty acids) can lead to increased adiposity which can activate immune cells independent of the activating effect of the diet components themselves. This dual action can contribute to chronic inflammation that may alter susceptibility to chronic pain and prolong recovery from injury. However, traditional examinations of diet focus on high-fat diets that often contain a single source of fat, that is not reflective of an American diet. Thus, we examined the impact of a novel human-relevant (high-carbohydrate) American diet on measures of pain and inflammation in rats, as well as the effect on recovery and immune cell activation. Methods We developed a novel, human-relevant Standard American Diet (SAD) to better model the kilocalorie levels and nutrient sources in an American population. Male and female rats were fed the SAD over the course of 20 weeks prior to persistent inflammatory pain induction with Complete Freund’s Adjuvant (CFA). Mechanical and thermal sensitivity were measured weekly. Spontaneous pain, open field locomotion and blood glucose levels were measured during diet consumption. Body composition was assessed at 20 weeks. Following full recovery from CFA-induced hypersensitivity, blood was analyzed for inflammatory mediators and spinal cords were immunohistochemically processed for microglial markers. Results Chronic consumption of the SAD increased fat mass, decreased lean mass and reduce bone mineral density. SAD-fed rats had increased leptin levels and pro-inflammatory cytokines in peripheral blood serum. Following CFA administration, mechanical sensitivity was assessed and recovery was delayed significantly in SAD-fed animals. Sex differences in the impact of the SAD were also observed. The SAD increased body weight and common T-cell related inflammatory mediators in female, but not male, animals. In males, the SAD had a greater effect on bone mineral density and body composition. Long-term consumption of the SAD resulted in elevated microglial staining in the dorsal horn of the spinal cord, but no sex differences were observed. Conclusions We demonstrate the negative effects of an American diet on physiology, behavior and recovery from injury. SAD consumption elevated pro-inflammatory mediators and increased microglial activation in the spinal cord. While there were sex differences in weight gain and inflammation, both sexes showed prolonged recovery from injury. Implications These data suggest that poor quality diet may increase susceptibility to chronic pain due to persistent peripheral and central immune system activation. Furthermore, consumption of a diet that is high in carbohydrates and omega-6 polyunsaturated fatty acid is likely to lead to protracted recovery following trauma or surgical procedures. These data suggest that recovery of a number of patients eating a poor quality diet may be expedited with a change in diet to one that is healthier.

Background and aims Post thoracotomy pain syndrome (PTPS) remains a common complication of thoracic surgery with significant impact on patients’ quality of life. Management usually involves a mul¬tidisciplinary approach that includes oral and topical analgesics, performing appropriate interventional techniques, and coordinating additional care such as physiotherapy, psychotherapy and rehabilitation. A variety of interventional procedures have been described to treat PTPS that is inadequately managed with systemic or topical analgesics. Most of these procedures are technically complex and are associated with risks and complications due to the proximity of the targets to neuraxial structures and pleura. The ultrasound-guided erector spinae plane (ESP) block is a novel technique for thoracic analgesia that promises to be a relatively simple and safe alternative to more complex and invasive techniques of neural blockade. We have explored the application of the ESP block in the management of PTPS and report our preliminary experience to illustrate its therapeutic potential. Methods The ESP block was performed in a pain clinic setting in a cohort of 7 patients with PTPS following thoracic surgery with lobectomy or pneumonectomy for lung cancer. The blocks were performed with ultrasound guidance by injecting 20–30mL of ropivacaine, with or without steroid, into a fascial plane between the deep surface of erector spinae muscle and the transverse processes of the thoracic vertebrae. This paraspinal tissue plane is distant from the pleura and the neuraxis, thus minimizing the risk of complications associated with injury to these structures. The patients were followed up by telephone one week after each block and reviewed in the clinic 4–6 weeks later to evaluate the analgesic response as well as the need for further injections and modification to the overall analgesic plan. Results All the patients had excellent immediate pain relief following each ESP block, and 4 out of the 7 patients experienced prolonged analgesic benefit lasting 2 weeks or more. The ESP blocks were combined with optimization of multimodal analgesia, resulting in significant improvement in the pain experience in all patients. No complications related to the blocks were seen. Conclusion The results observed in this case series indicate that the ESP block may be a valuable therapeutic option in the management of PTPS. Its immediate analgesic efficacy provides patients with temporary symptomatic relief while other aspects of chronic pain management are optimized, and it may also often confer prolonged analgesia. Implications The relative simplicity and safety of the ESP block offer advantages over other interventional procedures for thoracic pain; there are few contraindications, the risk of serious complications (apart from local anesthetic systemic toxicity) is minimal, and it can be performed in an outpatient clinicsetting. This, combined with the immediate and profound analgesia that follows the block, makes it an attractive option in the management of intractable chronic thoracic pain. The ESP block may also be applied to management of acute pain management following thoracotomy or thoracic trauma (e.g. rib fractures), with similar analgesic benefits expected. Further studies to validate our observations are warranted.

Background and aims Dysfunction of GABAergic inhibitory controls contributes to the development of neuropathic pain. We examined our hypotheses that (1) chronic constriction injury (CCI)-induced neuropathic pain is associated with increased spinal GABAergic neuron apoptosis, and (2) hyperbaric oxygen therapy (HBO) alleviates CCI-induced neuropathic pain by inhibiting GABAergic neuron apoptosis. Methods Male rats were randomized into 3 groups: CCI, CCI+HBO and the control group (SHAM). Mechanical allodynia was tested daily following CCI procedure. HBO rats were treated at 2.4 atmospheres absolute (ATA) for 60 min once per day. The rats were euthanized and the spinal cord harvested on day 8 and 14 post-CCI. Detection of GABAergic cells and apoptosis was performed. The percentages of double positive stained cells (NeuN/GABA), cleaved caspase-3 or Cytochrome C in total GABAergic cells or in total NeuN positive cells were calculated. Results HBO significantly alleviated mechanical allodynia. CCI-induced neuropathic pain was associated with significantly increased spinal apoptotic GABA-positive neurons. HBO considerably decreased these spinal apoptotic cells. Cytochrome-C-positive neurons and cleaved caspase-3-positive neurons were also significantly higher in CCI rats. HBO significantly decreased these positive cells. Caspase-3 mRNA was also significantly higher in CCI rats. HBO reduced mRNA expression of caspase-3. Conclusions CCI-induced neuropathic pain was associated with increased apoptotic GABAergic neurons induced by activation of key proteins of mitochondrial apoptotic pathways in the dorsal horn of the spinal cord. HBO alleviated CCI-induced neuropathic pain and reduced GABAergic neuron apoptosis. The beneficial effect of HBO may be via its inhibitory role in CCI-induced GABAergic neuron apoptosis by suppressing mitochondrial apoptotic pathways in the spinal cord. Implications Increased apoptotic GABAergic neurons induced by activation of key proteins of mitochondrial apoptotic pathways in the dorsal horn of the spinal cord is critical in CCI-induced neuropathic pain. The inhibitory role of HBO in GABAergic neuron apoptosis suppresses ongoing neuropathic pain.

Background Numerous publications describe chronic pain following surgery in both adults and children. However, data in the paediatric population are still sparse and both prevalence of chronic pain after surgery and risk factors of this complication still undetermined. Methods We prospectively evaluated the prevalence of chronic pain and its neuropathic pain component at 1 year following correction of idiopathic scoliosis in children less than 18 years of age. Pain was defined as the presence of pain (numerical rating scale – NRS ≥4), the presence of signs of neurologic damage within the area of surgery and the presence of the neuropathic symptoms as a DN4 (Douleur Neuropathique 4) questionnaire ≥4. Factors investigated as potentially associated with the presence of a persistent neuropathic pain were: age, weight, the presence of continuous preoperative pain over the 3 months before surgery, surgical characteristics, pain scores during the first five postoperative days, and DN4 at day 3. Statistical analysis employed univariate analysis and a multivariate logistic regression model. Results Thirty six patients were included in the study. Nineteen (52.8%) had pain at one year after surgery. Among them 17 (48.2%) had neuropathic pain. Logistic regression found continuous pain over the 3 months preceding surgery and day 1 morphine consumption ≥0.5 mg kg -1 as independent predictors of persistent chronic pain with a neuropathic component. The overall model accuracy was 80.6 and the area under the curve of the model was 0.89 (95% confidence interval 0.78–0.99). Conclusions The present study found a high proportion of paediatric patients developing chronic persistent pain after surgical correction of scoliosis diformity. It allows identifying two factors associated with the occurrence of persistent chronic pain with a neuropathic component: the presence of persistent preoperative pain during the 3 months preceeding surgery and postoperative opioid consumption at day 1 –;0.5 mg kg -1 Implication Patients scheduled for spine surgery and presenting with preoperative pain should be considered at risk of chronic pain after surgery and managed accordingly by the chronic and/or acute pain team. Postoperative opioid consumption should be lowered as possible by using multimodal analgesia and regional analgesia such as postoperative epidural analgesia.

Background and aims Hospitalization as a result of acute exacerbation of complex chronic pain is a largely hidden problem, as patients are often admitted to hospital under a variety of specialities, and there is frequently no overarching inpatient chronic pain service dedicated to their management. Our institution had established an inpatient acute pain service overseen by pain physicians and staffed by specialist nurses that was intended to focus on the management of perioperative pain. We soon observed an increasing number of nurse-to-nurse referrals of non-surgical inpatients admitted with chronic pain. Some of these patients had seemingly intractable and highly complex pain problems, and consequently we initiated twice-weekly attending physician-led inpatient pain rounds to coordinate their management. From these referrals, we identified a cohort of 20 patients who were frequently hospitalized for long periods with exacerbations of chronic pain. We sought to establish whether the introduction of the physician-led inpatient pain ward round reduced the number and duration of hospitalizations, and costs of treatment. Methods We undertook a retrospective, observational, intervention cohort study. We recorded acute Emergency Department (ED) attendances, hospital admissions, and duration and costs of hospitalization of the cohort of 20 patients in the year before and year after introduction of the inpatient pain service. Results The patients’ mean age was 38.2 years (±standard deviation 13.8 years, range 18-68 years); 13 were women (65.0%). The mode number of ED attendances was 4 (range 2–15) pre-intervention, and 3 (range 0–9) afterwards ( p = 0.116). The mode bed occupancy was 32 days (range 9–170 days) pre-intervention and 19 days (range 0–115 days) afterwards ( p = 0.215). The total cost of treating the cohort over the 2-year study period was £733,010 (US$1.12m), comprising £429,479 (US$656,291) of bed costs and £303,531 (US$463,828) of investigation costs. The intervention did not achieve significant improvements in the total costs, bed costs or investigation costs. Conclusions Despite our attending physician-led intervention, the frequency, duration and very substantial costs of hospitalization of the cohort were not significantly reduced, suggesting that other strategies need to be identified to help these complex and vulnerable patients. Implications Frequent hospitalization with acute exacerbation of chronic pain is a largely hidden problem that has very substantial implications for patients, their carers and healthcare providers. Chronic pain services tend to focus on outpatient management. Breaking the cycle of frequent and recurrent hospitalization using multidisciplinary chronic pain management techniques has the potential to improvepatients’ quality of life and reduce hospital costs. Nonetheless, the complexity of these patients’chronic pain problems should not be underestimated and in some cases are very challenging totreat.

Objective To report a novel wireless neuromodulation system for treatment of refractory craniofacial pain. Background Previous studies utilizing peripheral nerve stimulation (PNS) of the occipital and trigeminal nerves reported positive outcomes for alleviating neuropathic pain localized to the craniofacial and occipital areas. However several technological limitations and cosmetic concerns inhibited a more widespread acceptance and use of neuromodulation. Also, a relatively high incidence of adverse events like electrode erosions, dislocation, wire fracture and/or infection at the surgical site mandates a change in our approach to neuromodulation technology and implant techniques in the craniofacial region. Methods We report a novel approach for the management of craniofacial pain with a wirelessly powered, minimally invasive PNS system. The system is percutaneously implanted and placed subcutaneously adjacent to affected facial nerves via visual guidance by the clinician. In this feasibility study, pilot evidence was gathered in a cohort of ten subjects suffering from a combination of chronic headaches, facial pain for at least 15 days per month and for at least 4 h/day. Results At four weeks post-implant follow up, all patients reported sustained pain relief of the primary pain area. Electrode location and total number of electrodes used per subject varied across the cohort. The average pain reduction using the visual analog scale was >82%. The procedure had no adverse events or side effects. Conclusions Percutaneous placement of a wireless neurostimulation device directly adjacent to affected craniofacial nerve (s) is a minimally invasive and reversible method of pain control in patients with craniofacial pain refractory to conventional medical managements. Preliminary results are encouraging and further larger scale studies are required for improved applications.

Background and aims Pain and protective behaviour are dependent on implicit evaluations of danger to the body. However, current assessment of perceived danger relies on self-report, on information of which the person is aware and willing to disclose. To overcome this limitation, attempts have been made to investigate implicit evaluation of movement-related threatening images in people with persistent low back pain (PLBP) and pain-related fear. Lack of specificity of the sample and stimuli limited those explorations. This study investigated implicit evaluations and physiological responses to images of tasks commonly reported as threatening by people with PLBP: bending and lifting. We hypothesized that people who differ in self-reported fear of bending with a flexed lumbar spine ( fear of bending ) would also differ in implicit evaluations and physiological responses. Methods This study used a convenience sample of 44 people (54% female) with PLBP, who differed in selfreported fear of bending . Participants completed a picture-viewing paradigm with pleasant, neutral and unpleasant images, and images of people bending and lifting with a flexed lumbar spine (‘round-back’) to assess physiological responses (eye-blink startle modulation, skin conductance). They also completed an implicit association test (IAT) and an affective priming task (APT). Both assessed implicit associations between (i) images of people bending/lifting with a flexed lumbar spine posture (‘round-back’ posture) or bending/lifting with a straight lumbar spine posture (‘straight-back’ posture), and (ii) perceived threat (safe vs. dangerous). Results An implicit association between ‘danger’ and ‘round-back’ bending/lifting was evident in all participants (IAT (0.5, CI [0.3; 0.6]; p <0.001) and APT (24.2, CI [4.2; 44.3]; p = 0.019)), and unrelated to self-reported fear of bending (IAT ( r = -0.24, 95% CI [-0.5, 0.04], p = 0.117) and APT ( r = -0.00, 95% CI [-0.3, 0.3], p = 0.985)). Levels of self-reported fear of bending were not associated with eye-blink startle ( F (3,114) = 0.7, p = 0.548) or skin conductance responses ( F (3,126) = 0.4, p = 0.780) to pictures of bending/lifting. Conclusions Contrary to our expectation, self-reported fear of bending was not related to physiological startle response or implicit measures. People with PLBP as a group (irrespective of fear levels) showed an implicit association between images of a round-back bending/lifting posture and danger, but did not display elevated physiological responses to these images. These results provide insight to the understanding of the relationship between pain and fear of movement. Implications The potential clinical implications of our findings are twofold. First, these results indicate that self-report measures do not always reflect implicit associations between particular movements and threat. Implicit association tasks may help overcome this limitation. Second, a lack of the predicted physiological and behavioural responses may reflect that the visualization of a threatening task by people in pain does not elicit the same physiological defensive responses measured in people with fear of specific objects. It may be necessary to expose the person to the actual movement to elicit threat-responses. Together, these results are consistent with current views of the role of ‘fear’ in the fear-avoidance model, in which a fear response may only be elicited when the threat is unavoidable.

Background and purpose Many psychological factors are known to influence pain perception. Among them, intolerance of uncertainty (IU) may play a key modulating role in situations where uncertainty prevails, especially uncertainty regarding the timing of painful events. The objective of this study was to explore the impact of individual differences in IUon pain perception during predictable and unpredictable stimulation timings. We hypothesized that people with high IU, as opposed to those with low IU, would perceive more pain when the timing of painful stimulations cannot be predicted, as compared to when they can. Methods Twenty (20) healthy adults, aged between 18 and 35 years old, were recruited. Painful sensations were provoked using transcutaneous electrical stimulations of the right sural nerve. By measuring IU (Intolerance of Uncertainty Scale) and subjective pain (verbal numerical rating scale), it was possible to test the relationship between IU and pain perception, by simulating predictable and unpredictable painful experiences. This was done through cued shock interval (CSI) blocks, with either variable timing or fixed timings (long or short time frame). Self-administered questionnaires were also used to measure pain hypervigilance, pain catastrophizing, state anxiety, and trait anxiety. Results Pearson correlations confirmed the presence of an association ( r = 0.63) between IU and the change in pain intensity provoked by unpredictable stimulation timings. Importantly, this association was significant only for stimulations provided at long CSIs, indicating that higher IU scores predicted higher pain intensity scores when stimulation timings became unpredictable, and when the cued delay was long. No association was found between pain scores and other psychological variables. Conclusions Our results show that IU moderately correlates to the change in pain intensity provoked by unpredictable stimulation timings. High IU scores were associated with a worsening of the subjective pain experience, especially during long delays in an unpredictable situation. These observations suggest that IU could be considered as a psychological variable that is able to influence pain perception in certain situations. Implications Assessing and addressing IU could be an added value in pain-related therapy, especially in chronic pain.

Background and aims Pain acceptance, measured by the chronic pain acceptance questionnaire (CPAQ), is related to exercise adherence for those with arthritis. The CPAQ measure has 20 items comprising two subscales - pain willingness and activities engagement about pursuing “valued daily activities” despite pain. However, exercise is not specified as a valued activity and respondents may be considering other activities raising generalizability and strength of prediction concerns. Methods Accordingly, a modified CPAQ solely for exercise (CPAQ-E) was developed to heighten salience to pursuit of exercise in the face of pain. An exercising sample with arthritis ( N =98) completed the CPAQ-E at baseline and exercise 2 weeks later. Exploratory factor analysis of the CPAQ-E was performed using Mplus. Regression was used to predict exercise. Results Analysis revealed a two-factor, 14 item model with good psychometric properties reflecting pain willingness and activities engagement subscales ( χ 2 = 85.695, df=64, p <.037; RMSEA = .055; CFI = .967; TLI = .954). Both subscales and the total score positively predicted future weekly exercise bouts (range ps from < .05 to <.001). Activities engagement predicted future weekly exercise volume ( p < .05). Conclusions This study offers preliminary support for the factorial and predictive validity of the CPAQ-E among exercising individuals with arthritis. Implications This measure could help researchers increase the specificity and sensitivity of pain acceptance responses to exercising among individuals with arthritis. A more sensitive measure might help clinicians interpret patient responses to exercise for pain self-management.

Background and aims To improve care and management of patients with chronic pain it is important to understand patients’ experiences of treatment, and of the people and the environment involved. As chronic pain patients often have long relationships with medical clinics and pain management centres, the team and team interactions with the patients could impact the treatment outcome. The aim of this study was to elicit as honest as possible an account of chronic pain patients’ experiences associated with their care and feed this information back to the clinical team as motivation for improvement. Methods The research was conducted at a large hospital-based pain management centre. One hundred consecutive patients aged 18 years and above, who had visited the centre at least once before, were invited to participate. Seventy patients agreed and were asked to write a letter, as if to a friend, describing the centre. On completion of the study, all letters were transcribed into NVivo software and a thematic analysis performed. Results Six key themes were identified: (i) staff attitude and behaviour; (ii) interactions with the physician; (iii) importance of a dedicated pain management centre; (iv) personalized care; (v) benefits beyond pain control; (vi) recommending the pain management centre. Conclusion The findings suggest that the main reasons that patients recommended the centre were: (i) support and validation provided by the staff; (ii) provision of detailed information about the treatment choices available; (iii) personalized management plan and strategies to improve overall quality of life alongside pain control. None of the letters criticized the care provided, but eight of seventy reported long waiting times for the first appointment as a problem. Implications Patient views are central to improving care. However, satisfaction questionnaires or checklists can be intimidating, and restrictive in their content, not allowing patients to offer spontaneous feedback. We used a novel approach of writing a letter to a friend, which encouraged reporting of uncensored views. The results of the study have encouraged the clinical team to pursue their patient management strategies and work to reduce the waiting time for a first appointment.

Background Long-term low back pain is associated with multiple challenges to a person’s identity and social position. Despite efforts to understand the challenges of low back pain, recovery remains a major problem both personally and socially. This indicate a need for a different approach. Although personal stories have been used to extend knowledge of issues that relate to low back pain, they also make i possible to learn about how people understand themselves and their lives. As such, analysis of narrative: may provide further insights into people’s coping processes and novel insights about how best to support them. Objective The aim of the study was to analyse personal recovery narratives to gain an insight into how people understand themselves and cope with long-term low back pain 2-4 years after a bio-psycho-social counselling intervention. Study design Using a Ricoeurian phenomenological-hermeneutic perspective, qualitative in-depth interviews were undertaken and interpreted to explore people’s narratives of long-term recovery after an intervention. Methods We interviewed 25 informants 2-4 years after participating in a counselling intervention for low back pain where they were advised to exercise regularly; they were part of the intervention group in a randomised clinical trial. The sample included both informants who had benefited from the intervention and some who had not. Analysis was informed by Ricoeur’s interpretation theory. Findings The informants’ stories revealed two main narratives regarding themselves and their lives: (1) getting on with life without pain, (2) life with continual pain and variations of the emplotment. The first included Recovering from low back pain and returning to prior lifestyle if possible, Keeping low back pain in check by strict regimes , or Developing strategies when low back pain recurs . The second related to Finding a way to a functioning everyday life with continual pain while narratives of being stuck with low back pain and finding no way out highlight the significance of being able to configure a narrative that can support an understanding of the pain and how to deal with it to have a functioning life. Furthermore, the health professional has a significant role to play in the configuration of narratives. Conclusions The challenge for people with low back pain was to find ways of getting on with life, and this included their ability to configure an understandable narrative that opened up for a future, implying new understandings of the self and how life could be lived. When healthcare professionals offered personal and realistic suggestions to the informants’ configuration of narratives of life with low back pain, they supported a positive change in the informants’ ways of coping with their situation. Implications Health professionals can play an important role in low back pain sufferers’ configuration of meaningful narratives that help in coping with pain and learning about the relationship between pain and everyday life.

Background and purpose Previous research has highlighted the importance of cognitive appraisal processes in determining the nature and effectiveness of coping with chronic pain. Two of the key variables implicated in appraisal of pain are catastrophizing and perceived injustice, which exacerbate the severity of pain-related distress and increase the risk of long-term disability through maladaptive behavioural responses. However, to date, the influences of these phenomena have not been examined concurrently, nor have they been related specifically to quality of life measures, such as life satisfaction. Methods Using data froman online survey of330 individuals with chronic pain, structural path modelling techniques were used to examine the independent effects of pain catastrophizing, perceived injustice, and average pain intensity on life satisfaction. Two potential mediators of these relationships were examined: depressive symptoms and pain-related interference. Results Results indicated that depressive symptoms fully mediated the relationship between pain catastrophizing and life satisfaction, and pain interference fully mediated the relationship between pain intensity and life satisfaction. Both depressive symptoms and pain interference were found to significantly mediate the relationship between perceived injustice and life satisfaction, but perceived injustice continued to demonstrate a significant and negative relationship with life satisfaction, above and beyond the other study variables. Conclusions The current findings highlight the distinct affective and behavioural mediators of pain and maladaptive cognitive appraisal processes in chronic pain, and highlight their importance in both perceptions of pain-related interference and longer-term quality of life.

Background and aims Some 100 million adults in the United States suffer from chronic pain. While research to date has focused primarily on pain interference with physical and psychological function and its effects on employment, few studies have examined the impact of pain interference on social functioning and its effects on employment. The aims of our study were to (1) evaluate the association between pain interference with ability to work and actual employment status among working age adults with chronic pain; and (2) evaluate pain interference with four types of functioning - cognitive, physical, psychological, and social - as possible mediators of pain interference with the ability to work. Methods Data were collected via a self-selected sample of individuals visiting the American Chronic Pain Association (ACPA) website. The final dataset included 966 respondents. We examined the association between pain interference with the ability to work and employment in a population with chronic pain. We then analyzed pain interference with four types of functioning, physical, psychological, cognitive, and social, for their impact on the ability to work. Results Pain interference with ability to work was significantly inversely associated with employment status, i.e., the less that pain interfered with one’s ability to work, the greater the likelihood of being employed. Moreover, pain interference with ability to work was a stronger predictor of employment status than an individual’s rating of their pain intensity. Pain interference with social functioning partially mediated the effects of pain interference with cognitive and physical functioning and fully mediated the effects of pain intensity and pain interference with psychological functioning on pain interference with the ability to work. Results suggest that pain interference with social function may be a significant contributor to pain interference with ability to work in working age adults with chronic pain.? Conclusions In the development of effective solutions to address the economic and societal burden of chronic pain, this paper highlights the role of social function as an important, yet frequently overlooked, contributor to chronic pain’s effect on the ability to work. Our findings underscore the importance of an integrated biopsychosocial approach to managing chronic pain, especially when addressing ability to work. From a clinical standpoint, assessing and managing pain intensity is necessary but not sufficient in addressing the far-reaching negative consequences of chronic pain. Implications The development of interventions that improve social function may improve the ability to work in adults with chronic pain. Likewise, sick leave should be prescribed restrictivelyin the management of chronic pain since it may further interfere with social functioning. Perspective This study highlights the importance of the assessment of pain interference with social function as a part of a comprehensive biopsychosocial approach to the evaluation and management of patients with chronic pain. Interventions that improve social function may improve the ability to work in this population. In addition, sick leave should be prescribed restrictively in the management of chronic pain since it by itself interferes with social functioning.

Background and aims Chronic scrotal pain is a common yet poorly understood urologic disease. Current treatment paradigms are sub-optimal and include anti-inflammatory drugs and opioids as well as invasive surgical management such as microdenervation of the spermatic cord. In this study, the efficacy of external vibratory stimulation (EVS) was evaluated as an alternative treatment option for idiopathic scrotal pain. Materials and methods Ten consecutive patients presenting to an academic urology clinic between December 2016 and April 2017 with scrotal pain were prospectively enrolled. After a comprehensive history and physical exam, patients were presented with and oriented to a spherical vibratory device that they were instructed to use topically each day for four weeks. Average and maximum pain severity, frequency, and bother scores were tracked at 2-week intervals using a visual analog scale (0-10) via survey. Descriptive statistics facilitated interpretation of individual changes in pain. Results Nine men, with a median age of 46 years, completed at least 2 weeks of the study intervention. 78% (7/9) of men achieved some improvement in daily scrotal pain levels. Overall, average pain decreased from 4.9 to 2.7 ( p = 0.009) while maximum pain severity decreased from 6.3 to 4.0 ( p = 0.013). The frequency of pain also decreased for 55.6% (5/9) of men. No severe side effects were noted by any of the participants though several patients reported mild paresthesia only during application of the device. The majority of men expressed interest in continuing treatment after conclusion of the study. Conclusion External vibratory stimulation has been suggested as a promising non-invasive tool to alleviate chronic pain. As a proof-of-concept, we implemented EVS to treat men with idiopathic orchialgia. The majority of patients noted benefit in both severity and frequency of pain. Given its low risk profile, EVS deserves further evaluation and inclusion in treatment guidelines as a promising experimental therapy for a disease with few conservative treatment options available to providers. Implications In this longitudinal study, external vibratory stimulation was found to decrease chronic scrotal pain without any adverse effects. The use of this non-invasive, non-pharmaceutical therapy to treat chronic scrotal pain has the potential to decrease physician and patient dependence on surgical procedures and opioid prescriptions. Future randomized, double blind clinical trials with a placebo arm are required to corroborate these findings and establish the true efficacy of EVS.

Background and aims Pain is common in older adults but may be undertreated in part due to concerns about medication toxicity. Analgesics may affect cognition. In this retrospective cohort study, we used the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to examine the interaction of cognitive status and medications, especially non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesized NSAID use would be associated with cognition and that this could be mediated through changes in brain structure. Methods In this post hoc analysis of the ADNI database, subjects were selected by searching the “concurrent medications log” for analgesic medications. Subjects were included if the analgesic was listed on the medication log prior to enrollment in ADNI and throughout the study. Subjects taking analgesics, particularly NSAIDs, at each study visit were compared to control subjects taking no analgesics. Using descriptive statistics as well as univariate, multivariate and repeated measure ANOVA, we explored the relationship between NSAID use and scores for executive function and memory related cognitive activities. We further took advantage of the extensive magnetic resonance imaging (MRI) data available in ADNI to test whether cognitive change was associated with brain structure. The multitude of imaging variables was compressed into a small number of features (five eigenvectors (EV)) using principal component analysis. Results There were 87 NSAID users, 373 controls, and 71 taking other analgesics. NSAID use was associated with higher executive function scores for cognitively normal (NL) subjects as well as subjects with mild cognitive impairment (MCI). NSAID use was also associated with higher memory scores, but for NL females only. We analysed MRI data using principal component analysis to generate a set of five EVs. Examining NL and MCI subjects, one EV had significantly larger values in subjects taking NSAIDs versus control. This EV was one of two EVs which significantly correlated with composite executive function and memory scores as well as cognitive diagnosis. Conclusions NSAID use was associated with higher executive function, and memory scores in certain subjects and larger cortical volumes in particular regions. Limitations of the study include secondary analysis of existing data and the possibility of confounding. Implications These results suggest it is important to consider the secondary effects of medications when choosing a treatment regimen. Further prospective studies are needed to examine the role of analgesics on cognition and whether NSAIDs act through cortical dimension changes and how they are related to gender and cognitive diagnosis.

Graphical Abstract Abstract Background and aims Positron emission tomography (PET) with the radioligand [ 11 C]-D-deprenyl has shown increased signal at location of pain in patients with rheumatoid arthritis and chronic whiplash injury. The binding site of [ 11 C]-D-deprenyl in peripheral tissues is suggested to be mitochondrial monoamine oxidase in cells engaged in post-traumatic inflammation and tissue repair processes. The association between [ 11 C]-D-deprenyl uptake and the transition from acute to chronic pain remain unknown. Further imaging studies of musculoskeletal pain at the molecular level would benefit from establishing a clinical model in a common and well-defined injury in otherwise healthy and drug-naive subjects. The aim of this study was to investigate if [ 11 C]-D-deprenyl uptake would be acutely elevated in unilateral ankle sprain and if tracer uptake would be reduced as a function of healing, and correlated with pain localizations and pain experience. Methods Eight otherwise healthy patients with unilateral ankle sprain were recruited at the emergency department. All underwent [ 11 C]-D-deprenyl PET/CT in the acute phase, at one month and 6-14 months after injury. Results Acute [ 11 C]-D-deprenyl uptake at the injury site was a factor of 10.7 (range 2.9-37.3) higher than the intact ankle. During healing, [ 11 C]-D-deprenyl uptake decreased, but did not normalize until after 11 months. Patients experiencing persistent pain had prolonged [ 11 C]-D-deprenyl uptake in painful locations. Conclusions and implications The data provide further support that [ 11 C]-D-deprenyl PET can visualize, quantify and follow processes in peripheral tissue that may relate to soft tissue injuries, inflammation and associated nociceptive signaling. Such an objective correlate would represent a progress in pain research, as well as in clinical pain diagnostics and management.

Background Fear of pain is highly correlated with pain report and physiological measures of arousal when pain is inflicted. The Fear of Pain Questionnaire III (FPQ-III) and The Fear of Pain Questionnaire Short Form (FPQ-SF) are self-report inventories developed for assessment of fear of pain (FOP). A previous study assessed the fit of the FPQ-III and the FPQ-SF in a Norwegian non-clinical sample and proved poor fit of both models. This inspired the idea of testing the possibility of a Norwegian FOP-model. Aims and methods A Norwegian FOP-model was examined by Exploratory Factor Analysis (EFA) in a sample of 1112 healthy volunteers. Then, the model fit of the FPQ-III, FPQ-SF and the Norwegian FOP-model (FPQ-NOR) were compared by Confirmatory Factor Analysis ( CFA). Sex neutrality was explored by examining model fit, validity and reliability of the 3 models amongst male and female subgroups. Results The EFA suggested either a 4-, a 5- or a 6-factor Norwegian FOP model. The eigenvalue criterion supported the suggested 6-factor model, which also explained most of the variance and was most interpretable. A CFA confirmed that the 6-factor model was better than the two 4- and 5-factor models. Furthermore, the CFA used to test the fit of the FPQ-NOR, the FPQ-III and the FPQ-SF showed that the FPQ-NOR had the best fit of the 3 models, both in the whole sample and in sex sub-groups. Conclusions A 6-factor model for explaining and measuring FOP in Norwegian samples was identified and termed the FPQ-NOR. This new model constituted six factors and 27 items, conceptualized as Minor, Severe, Injection, Fracture, Dental, and Cut Pain. The FPQ-NOR had the best fit overall and in male- and female subgroups, probably due to cross-cultural differences in FOP. Implications This study highlights the importance on exploratory analysis of FOP-instruments when applied to different countries or cultures. As the FPQ-III is widely used in both research and clinical settings, it is important to ensure that the models construct validity is high. Country specific validation of FOP in both clinical and non-clinical samples is recommended.

Graphical Abstract Abstract Background and purpose (aims) Psychoneuroimmunology is both a theoretical and practical field of medicine in which human biology and psychology are considered an interconnected unity. Through such a framework it is possible to elucidate complex syndromes in gastrointestinal related pain, particularly chronic non-malignant. The aim is to provide insight into pathophysiological mechanisms and suggest treatment modalities according to a comprehensive paradigm. The article also presents novel findings that may guide clinicians to recognize new targets or scientists to find new research topics. Methods A literature search of ‘PubMed’ and ‘Google Scholar’ databases was performed. Search terms included: ‘Visceral pain’, ‘Psychoneuroimmunology’, ‘Psychoneuroimmunology and pain’, ‘Pain in GI system’, ‘GI related pain’, ‘Pain and microbiota’, ‘Enteric nervous system’, ‘Enteric nervous system and inflammation’, ‘CNS and pain’, ‘Inflammation and pain in GI tract’, ‘Neurogastroenterology’, ‘Neuroendocrinology’, ‘Immune system in GI pain’. After searching and reading sources deemed recent and relevant, a narrative review was written with a tendency to discriminate the peripheral, intermediate, and central pathophysiological mechanisms or treatment targets. Results Recent evidence point out the importance of considering the brain-gut axis as the main connector of the central and peripheral phenomena encountered in patients suffering from chronic non-malignant gastrointestinal related pain. This axis is also a prime clinical target with multiple components to be addressed in order for therapy to be more effective. Patients suffering from inflammatory bowel disease or functional gastrointestinal disorders represent groups that could benefit most from the proposed approach. Conclusions (based on our findings) Rather than proceeding with established allopathic single-target central or peripheral treatments, by non-invasively modulating the brain-gut axis components such as the psychological and neuroendocrinological status, microbiota, enteric nervous system, or immune cells (e.g. glial or mast cells), a favourable clinical outcome in various chronic gastrointestinal related pain syndromes may be achieved. Clinical tools are readily available in forms of psychotherapy, prebiotics, probiotics, nutritional advice, and off-label drugs. An example of the latter is low-dose naltrexone, a compound which opens the perspective of targeting glial cells to reduce neuroinflammation and ultimately pain. Implications (our opinion on what our findings mean) Current findings from basic science provide sound mechanistic evidence and once entering clinical practice should yield more effective outcomes for patients. In addition to well-established pharmacotherapy comprised notably of anti-inflammatories, antibiotics, and proton-pump inhibitors, valid treatment strategies may contain other options. These disease modulating add-ons include probiotics, prebiotics, food supplements with anti-inflammatory properties, various forms of psychotherapy, and low-dose naltrexone as a glial modulator that attenuates neuroinflammation. Clearly, a broader and still under exploited set of evidence-based tools is available for clinical use.

Graphical Abstract Abstract Acetaminophen is thought to be the safest analgesic and antipyretic medicine for pregnant women, and it is widely used all over the world. However, prenatal acetaminophen was reported to be associated with asthma, lower performance intelligence quotient (IQ), shorter male infant anogenital distance (predicting poor male reproductive potential), autism spectrum disorder, neurodevelopmental problems (gross motor development, communication), attention-deficit/hyperactivity disorder, poorer attention and executive function, and behavioral problems in childhood. Each article has poor power to show risks of acetaminophen, however, the integration of the articles that showed adverse effects of acetaminophen may have power to show them. Acetaminophen use in childhood was associated with autism spectrum disorder, asthma symptoms, wheezing, and allergic disease. Acetaminophen is the safest medicine as analgesics for nociceptive pain and antipyretics in childhood and pregnancy. There is no alternative medication of acetaminophen. Acetaminophen should not be withheld from children or pregnant women for fears it might develop adverse effects. Acetaminophen should be used at the lowest effective dosage and for the shortest time. When we know the possible, rare but serious complications, we should use acetaminophen in pregnancy only when needed and no safer option for pain or fever relief is available. Health care providers should help inform the general lay public about this difficult dilemma.