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Background and aim Chronic musculoskeletal pain, e.g. whiplash associated disorders (WAD), fibromyalgia and myalgia, causes significant burden on both the individual and on society as a whole. In a previous study, the authors concluded that there is a likely connection between chronic benign paroxysmal positional vertigo (BPPV)/canalithiasis and headache, neck pain, generalized pain, fatigue, cognitive dysfunctions as well as tinnitus. The balance dysfunction in BPPV/canalithiasis is dynamic and not static. This leads to a perpetual postural mismatch. The vicious cycle of a disturbed equilibrium control system may be the driving force behind the vicious cycle of pain. The aim of this study is to investigate if otolith-repositioning manoeuvres in patients with chronic BPPV/canalithiasis can be beneficial. Methods During a period of about two years a prospective observational study on patients with chronic musculoskeletal pain referred for physiotherapy was performed. Those with a Dizziness Handicap Inventory (DHI) inquiry score above 20 underwent further investigations to diagnose chronic BPPV/canalithiasis. Diagnostic criteria: (A) The diagnosis of BPPV/canalithiasis was confirmed with the following: (1) specific history of vertigo or dizziness provoked by acceleration/deceleration, AND (2) nystagmus and symptoms during at least one of the test positions; (B) the disorder had persisted for at least one year. Specific otolith repositioning manoeuvre for each semi-circular canal (SCC) was performed. Symptom questionnaire (“yes” or “no” answers during a personal interview) and a follow-up questionnaire were used. Results The responders of the follow-up questionnaire constituted the study group. Thirty-nine patients responded (i.e. 87%) (31 females, 8 males) with a median age of 44 years (17–65). The median duration of the disease was5 years. Seventy-nine percent had ahistory ofhead or neck trauma. The DHI median score was 48 points (score >60 indicates a risk of fall). The video-oculography confirmed BPPV/canalithiasis in more than one semi-circular canal in all patients. In the present study the frequency of affected anterior semi-circular canal (SSC) was at a minimum of 26% and could be as high as 65%. Ninety-five percent suffered from headache, 92% from neck pain, 54% had generalized pain, and 56% had temporo-mandibular joint region pain. Fatigue (97%), aggravation by physical exertion (87%), decreased ability to concentrate (85%) aswellas visual disturbances (85%) were the most frequently reported symptoms, and 49% suffered from tinnitus. The median number of otolith repositioning manoeuvres done was six (2–29). Median time span between finishing otolith repositioning manoeuvres and answering the questionnaire was 7 months. Effects of treatment and conclusion The present study has shown that repositioning of otoliths in the SCCs in nearly all patients with chronic BPPV/canalithiasis ameliorated pain and other symptoms. The correlation between vertigo/dizziness and the majority of symptoms was significant. Therefore, there is strong evidence to suggest that there is a connection between chronic BPPV/canalithiasis and chronic pain as well as the above-mentioned symptoms. Implications Patients with unexplained pain conditions should be evaluated withthe Dizziness Handicap Inventory-questionnaire, which can identify treatable balance disorders.

Aabstract Background and aim Migraine often includes co-existing tension-type headache (TTH) and neck pain (NP). Multiple headache questionnaires assessing headache impact have beendescribed previously; however, none of the existing questionnaires have been designed to cover migraine with co-existing TTH and NP. Therefore a new questionnaire was developed to measure these co-morbidities. The aim was to determine face and content validity of the newly developed questionnaire, “Impact of Migraine, Tension-Type Headache and Neck Pain” (impact M-TTH-NP) and to determine face and content validity of the International Physical Activity Questionnaire (IPAQ short form), Migraine-Specific Quality of Life Questionnaire (MSQ v. 2.1), WHO-Five Well-Being Index (WHO-5), Major Depression Inventory (MDI) and Neck Disability Index (NDI) not yet validated in this target population. Material and methods The new multi-dimensional questionnaire “Impact M-TTH-NP” cover pain, triggers, psychosocial, socioeconomic and work related aspects, based on a four-week recall period. The items are rated on an 11-point numeric rating scale with the end points 0 = no impact and 10 = most imaginable impact. Face validity was assessed by migraine patients with co-existing TTH and NP. They were recruited between September 2012 and March 2013 from a tertiary referral headache centre. Nine women with a mean age of 38 years participated in group interviews. The questionnaires were reviewed for relevance and meaningfulness. Content validity was assessed by 13 headache experts. They had worked with headache diseases for an average of 9 (range, 2–38) years. Experts were recruited between August 2012 and October 2012. Nine medical doctors, two physical therapists, one headache nurse and one psychologist (eight women and five men, mean age of 42 years) participated. The experts rated each item of the questionnaires using a four-point Likert scale with the end points 1 = not relevant and 4 = highly relevant. The quantitative measurement of content validity was calculated by the item-level content validity index (I-CVI) and the scale-level content validity average method (S-CVI/Ave). The average deviation (AD) index was used as a measure of interrater agreement. Results Impact M-TTH-NP showed acceptable face validity. Of 78 items twelve were revised and one was added based on group interviews and expert review. Seventy-two items (92%) obtained I-CVI≥0.78 (range 0.78–1.00) indicating excellent content validity, 71 items (91%) obtained acceptable AD index. Nine items did not meet either the limit for excellent I-CVI and/or acceptable AD index. The overall S-CVI/Ave was 0.92 indicating an excellent content validity. In addition, four of the five additional questionnaires showed acceptable face validity (MSQ, WHO-5, MDI and NDI) and three showed excellent content validity (WHO-5, MDI and NDI) for patients suffering from migraine and co-existing TTH and NP. Conclusions and implications The impact M-TTH-NP questionnaire showed acceptable face validity and excellent content validity and may be useful when evaluating treatment effect in this target group. The new impact M-TTH-NP questionnaire in combination with the additional questionnaires that together assess pain, triggers, psychosocial and socioeconomic aspects may provide a deeper understanding of the complexity of migraine with co-existing TTH and NP

Objectives Pain is one of the most common reasons for patients to seek acute medical care. The management of pain is often inadequate both in the prehospital setting and in the emergency department. Our aim was to evaluate the attitudes towards pain management among prehospital personnel in two Scandinavian metropolitan areas. Methods A questionnaire with 36 items was distributed to prehospital personnel working in Helsinki, Finland ( n =70) and to prehospital personnel working in Stockholm, Sweden ( n =634). Each item was weighted on a five-level Likert scale. Factor loading of the questionnaire was made using maximum likelihood analysis and varimax rotation. Six scales were constructed (Hesitation, Encouragement, Side effects, Evaluation, Perceptions, Pain metre). A Student’s t-test, ANOVA, and Pearson Correlation were used for analysis of significance. Results : The response rate among the Finnish prehospital personnel was 66/70 (94.2%) while among the Swedish personnel it was 127/634 (20.0%). The prehospital personnel from Sweden showed significantly more Hesitation to administer pain relief compared to the Finnish personnel (mean 2.01 SD 0.539 vs. 1.67 SD 0.530, p < 0.001). Those who had received pain education at their workplace showed significantly less Hesitation than those who had not participated in education. There was a significant negative correlation ( p < 0.01) between Hesitation and Side effects. There was also astatistically significant( p < 0.01) correlation between Perceptions and Hesitation, indicating that a stoic attitude towards pain was associated with indifference to possible Side effects of pain medication ( p < 0.05). Conclusions The results show that there was a significant correlation between the extent of education and the prehospital personnel’s attitudes to pain management. Gender and age among the prehospital personnel also affected the attitudes to pain management. The main discrepancy between the Swedish and Finnish personnel was that the participants from Stockholm showed statistically significantly more hesitation about administering pain medication compared to the participants from Helsinki. Implications The results of the study highlight the need for continuous medical education (CME) for prehospital personnel. CME and discussions among prehospital personnel may help to make a change in the personnel’s attitudes towards pain and pain management in the prehospital context.

Graphical Abstract Abstract Background and objectives Aloperine (ALO) is an alkaloid compound and presents in several medicinal plants. This study was undertaken to investigate the anti-nociceptive and anti-inflammatory activities of ALO on various chemical- and thermal-induced hypersensitivity models in mice. Methods The anti-nociceptive effect of ALO was evaluated using acetic acid-induced writhing test, hot plate test, tail flick test, formalin test, ear swelling test, locomotor activity test, rota-rod test and carrageenan-induced paw edema test in mice. Inflammatory cytokines including interleukin-10 (IL-10), tumor necrosis factor α (TNF-α), interleukin-1 beta (IL-1β) and prostaglandin E 2 (PGE 2 ) expression were examined in ALO- and vehicle-treated mice. Results The results showed that ALO significantly attenuated acetic acid-induced writhing numbers in mice in a dose-dependent manner. ALO showed no effect on prolonging latency in the hot plate test and the tail-flick test. ALO showed analgesic activity in the inflammatory phase of formalin-induced pain. Its anti-inflammatory effect was also confirmed in the ear-swelling test. In the carrageenan-induced paw edema model, ALO significantly and dose-dependently reduced the carrageenan-induced paw edema, decreased the contents of TNF-α IL-1β and PGE 2 , but increased the IL-10 production. On the other hand, ALO showed no influence on the rota-rod performance time or on spontaneous locomotor activity. Conclusion It is concluded that ALO has both anti-inflammatory and analgesic effects, especially in the field of inflammation pain. Implications Our findings support the hypothesis that ALO ameliorates inflammatory pain induced by chemical and thermal stimuli and provides a scientific basis for the resource development and clinical use of aloperine.

Background Both peripheral nerve injury and neuroma pain are the result of changes in sodium channel expression. Lidocaine selectively inhibits the spontaneous ectopic activity by binding to sodium channels. Subanesthetics concentrations of lidocaine are able to produce a differential block of the ectopic discharges, but not propagation of impulses, suppressing differentially the associated neuropathic pain symptoms. The aim of this study was to investigate the differences between the analgesic effects of lidocaine 0.5% and a control group of lidocaine 0.1% on several neuroma related pain modalities. Methods Sixteen patients with neuropathic pain due to painful neuromas caused by nerve injury participated in this randomized, double-blind experiment. The patterns of sensory changes were compared before and after injection of 1ml lidocaine 0.5% and 0.1% close to the neuroma, the sessions being 1–2 weeks apart. Spontaneous and evoked pains were assessed using a visual analogue scale (VAS), quantitative and qualitative sensory testing. The primary end-point measure was defined as the change in pain score measured from baseline until 60min after injection. Assessments of spontaneous pain and evoked pain were done post injection at 15s, 30s, 1min, and at 5-min intervals for the first 30-min post injection and then every 10-min to 1 hr post injection. The assessments of pain were performed between the limbs in the following order: spontaneous pain, then assessment of dynamic mechanical allodynia and then hyperalgesia. Results Lidocaine dose-dependently reduced spontaneous and evoked pain scores by more than 80% with maximum effects between 1 and 5min for evoked pain and between 3 and 15min for spontaneous pain. While evoked pain normalized rapidly reaching about 50% of the control level 20min after the injection, spontaneous pain levels continue to be lower in comparison with baseline values for more than 60min. When comparing the time course of analgesia between spontaneous and evoked pain, lidocaine-induced a greater reduction of evoked pain, but with shorter duration than spontaneous pain. The differences between evoked pain and spontaneous pain were statistically significant in both groups (lidocaine 0.5% group; p = 0.02 and lidocaine 0.1% group; p = 0.01). Reproducibility was high for all assessed variables. Surprisingly, both lidocaine concentrations produced a sensory loss within the area with hyperalgesia and allodynia: hypoesthesia occurred earlier and lasted longer with lidocaine 0.5% (between 30s and 5min) in comparison with lidocaine 0.1% ( p = 0.018). Conclusion Differential analgesic effects of subanesthetic concentrations of local lidocaineon evoked and spontaneous pain in human neuroma suggest that different mechanisms underlie these two key clinical symptoms. Spontaneous pain and evoked pain need an ongoing peripheral drive and any possible CNS amplification change is temporally closely related to this peripheral input. Implications Painful neuroma represents a clinical model of peripheral neuropathic pain that could lead to a significant step forward in the understanding of pain pathophysiology providing the opportunity to study spontaneous and evoked pain and the underlying mechanisms of neuropathic pain. The proposed model of neuropathic pain allows testing new substances by administration of analgesics directly where the pain is generated.

Aims Increasing evidence indicates that extracellular high mobility group box-1 protein (HMGB1) is involved in the pathogenesis of inflammatory and autoimmune disease. Data from our laboratory demonstrates that HMGB1 contributes to nociceptive behavior in a model of rheumatoid arthritis-induced pain. HMGB1 binds to multiple receptors, including toll like receptor (TLR) 2, TLR4 and receptor for advanced glycation end products (RAGE). When the cysteine in position C106 is in the reduced thiol form and C23 and C45 are engaged in a disulfide bridge (disulfide HMGB1), the molecule functions as a cytokine-inducing TLR4 ligand. In contrast, when these three cysteines are all reduced (all-thiol HMGB1), HMGB1 exclusively potentiates chemotactic activity via CXCR4. It is currently not well understood which receptor and which redox form of HMGB1 that mediates pain hypersensitivity and is therefore the aim of this study. Methods All animal work was carried out in accordance with protocol approved by the local ethics committee for animal experiments in Sweden. Balb/c, C57B/l6 (WT), Tlr2 –/– , Tlr4 –/– and Rage –/– male mice were used for this study. Disulfide (ds) and all thiol (at) form of HMGB1 were injected intrathecally (1 μg) and mechanical hypersensitivity assessed by von Frey filaments. Lumbar spinal cords were collected after i.t. injection of atHMGB1 and ds HMGB1 and mRNA levels for cytokine and glia markers assessed by quantitative PCR. Results In Balb/c and C57Bl/6 WT mice, i.t injection of dsHMGB1, but not atHMGB1, led to a significant reduction in mechanical thresholds. dsHMGB1 induced mechanical hypersensitivity 6 h after i.t. injection, which lasted for 5 days, compared to i.t. injection of saline. When dsHMGB1 was injected i.t. to Tlr4 deficient mice it did not induce mechanical hypersensitivity. In contrast Tlr2 and Rage deficient mice were still susceptible to dsHMGB1-induced mechanical hypersensitivity. Analysis of mRNA for cytokines and glial cell-associated factors in lumbar spinal cords revealed increased levels of Tnf, Ccl2, Cxcl1, Cxcl2, Gfap and Cd11b in mice injected with dsHMGB1, but not atHMGB1, with exception for Il1β and Cxcr3 that was induced also by atHMGB1 . Intrathecal injection of dsHMGB1 to Tlr4 –/– deficient mice, did not increase mRNA levels for Tnf, Il1β, Ccl2, Gfap and Cd11b . Conclusions We found the i.t. injection of the disulfide, but not the all-thiol, form of HMGB1 to induce pronouncedand long-lasting mechanical hypersensitivity, glial reactivity and cytokine induction in a TLR4-, but not TLR2- or RAGE-dependent manner. Thus our data indicates that, the redox state of HMGB1 is key for determining its nociceptive property and receptor usage and thus also the functional consequences of HMGB1 release. Agents interfering with extracellular HMGB1 may be considered in the development of new pain relieving therapeutics.

Aims Women show higher frequency of most painful disorders. This is usually explained that endogenous pain modulation pathways, which affect incoming nociceptive signals, act differently in women and men, but psycho-social factors are likelytoinfluence as well. Ghanaian women suffer different disabilities that may lead to severe pain. The hard climatic conditions and the hard physical toil in work exert untold injuries. How do women in Ghana cope with painful disorders, and do they show certain behavioural pattern during diagnosis and treatments? Methods The study used in-depth interviews with health care providers to accomplish its aim. The “snowball effect” was added by which those interviewed aided us to find other prospective interviewee. In qualitative methodology, such an approach can be adopted to enable the researcher acquire relevant data with help from respondents.Practitioners were askedtoreflectontheir experiences from meeting women with severe pain as their patients. Seven practitioners, four female and three male, were interviewed. Results By talking spontaneously about pain, women cope with painful disorders. This ensures easy diagnoses and treatments. The majority of women report their severe pain disabilities freely as against a smaller group who behave differently.The other group has explored other practitioners and have been unsuccessful. They are afraid to reveal their situations openly. Others test the skills of the practitioners whether they could perform efficient diagnoses. This strengthens patients’ faith and ability to be cured. In behavioural terms, inability to report severe pain stem from comorbid depressive symptoms (timidity-shyness, over-worried/confusion, distraction), lack of trust-expectant faith, thought of practitioner’s omniscient power, threat of practitioner’s knowledge (patient’s wrongs and evil thoughts), religious affiliation-constraints, etc. Women cope and show more positive attitudes than men; they expect practitioners to be in careful control. Conclusions Ghanaian women deal with their severe pains in meaningful manner by talking spontaneously about them. They show their willingness to be helped during diagnosis. Only few patients are not spontaneous, and are due to the condition of the mind and uncertainty with previous treatment encounters.

Aims Sex hormones play an important role in pain in many chronic pain conditions. Relationship between chronic pain and sperm quality has not been investigated thoroughly and may provide an insight to better understanding, management and treatment of cases where chronic pain and male sub-fertility co-exist. Methods Neat (fresh semen) and processed sperm from 15 males with orthopedic chronic pain (CP) were assessed and compared with 15 healthy age matched controls. Sperm analysis was performed using the SCA computer-aided sperm analyzer. Results There was no significant difference in any parameters of the neat semen between the pain and control group. However the percentage of non-progressive motile spermatozoa (type B) was significantly higher in the pain group (27.96) compared to the control group (15.96). Straight line trajectories including linearity, straightness, wobble and beat cross frequency were also significantly higher in the processed sample of the CP group. Conclusions This study demonstrated that chronic pain does not affect the sperm morphology, total concentration and motility based on conventional analysis but has significant influence at the level of sperm motion kinetics which could prove to be clinically valuable, prognostic indicators of successful fertilization. Maturation of sperm motility occurs during their transit through the epididymis and vas deferens regulated by androgens. As male gonadal hormones haveaninhibitory, adaptive effectonthe behavioral and neuronal responses to repeated nociceptive stimulation, it can be speculated that the observed difference in sperm kinematic parameters could be related to the alterations in serum sex hormone levels emanating from the chronic pain. Further studies are required to explain the possible mechanism of actionof chronic pain on male fertility.

Aims Arthritis is the leading cause of chronic pain in European adults (painineurope.com). Arthritis-induced chronic pain is a major clinical problem that is frequently inadequately treated by current analgesics and results in significant reduction in the patient’s quality of life. Outcome measures used in pain research to assess injury-induced pain-like behaviours in preclinical models are often dependent on the assessment of withdrawal reflexes, typically evoked by mechanical or thermal stimuli.Advances inpre-dictive validity may be improved by assessing the global impact of pain and the reinstatement of innate behaviours suppressed by injury. Burrowing, an indicator of the global “wellbeing” of the animal can be objectively measured. We aimed to assess the impact of several preclinical modelsof arthritis onburrowing behaviour in mice. Methods The collagen antibody-induced arthritis (CAIA) pre-clinical model of rheumatoid arthritis, the complete Freund’s adjuvant (CFA), monosodium iodoacetate (MIA) and partial medial menisectomy (MMT) preclinical models of osteoarthritis were assessed in female and/or male C57/Black6J adult mice, comparing to control (salineorsham-operated) and naïve animals. Mechanical hypersensitivity using von Frey filaments and spontaneous burrowing behaviour were assessed over60days (CAIA), 14days (CFA), 28 days (MIA) and up to 200 days (MMT). Results We show the development of mechanical hypersen-sitivity in all preclinical models of arthritis, whereas spontaneous burrowing behaviour was altered differently between the preclin-ical models. A deficit in burrowing behaviour was observed in the preclinical models of osteoarthritis and a gain in burrowing behaviour noted in the preclinical model of rheumatoid arthritis, with no effect seen in the CFA model. Conclusions Burrowing behaviour appears more sensitive to detecting variation in preclinical models of arthritis when compared to mechanical hypersensitivity. Burrowing behaviour can detect both gain and deficits in the behaviour, which differs between preclinical models of rheumatoid and osteoarthritis.

Aims This study aimed to gain methodological knowledge about quantification of mechanical nociceptive thresholds in pigs stimulated on the hind legs. Methods Thirty-two castrated male pigs were used, weighing 50–60kg, 16 weeks of age and housed in standard pens (4.40m×4.40m) with ad libitum access to water and feed. Mechanical nociceptive testing (4 stimulations/pig) was done by an electronic von Frey anesthesiometer (IITC Life Science Inc., CA) with a rigid, hollow plastic tip (cut-off: 1000 gf) and an area of 0.3 mm 2 . Stimulations targeted caudal aspects of the metatarsus while the pigs were restrained in a cage measuring 35cm×40cm (length×width). During the last 3d before nociceptive testing, half of the pigs were habituated to the experimental set-up twice daily. Results Across the three days, the habituation procedure led to a reduction in time required to approach and release the pigs from the home pen ( P <0.05) and to increased acceptance of the confinement ( P <0.01). The habituated animals had a lower mechanical nociceptive threshold (median: 495gf (302–675) vs 745gf (479–1000); P <0.05), and a decreased occurrence of censored observations (0 vs 25%; P <0.05) compared to animals tested without habituation. Conclusions The present experiment focussed on methodological aspects of hand-held tests of mechanical nociceptive thresholds in pigs. The results show that the pigs responded to a 3-day habituation regime by increased ease of handling and tolerance of being confined in a test cage. In addition, habituation to the test environment and handling led to reduced mechanical nociceptive thresholds as well as a lowered proportion of censored observations. The current results reiterate the value of habituation in research involving animal behaviour. Further characterization of the methodology is needed to allow its application in the evaluation of clinical conditions in pigs.

Aims To identify and describe the most common category of patients in a newly established mono-disciplinary pain clinic, in order to plan, test, evaluate and implement targeted health promotion interventions. Methods The study was a register-based retrospective cohort study comprising data from the hospital registration system GS!open. Including chronic non-malignant pain patients in the period January 1st 2013 to December 31st 2014; analysing only patients who underwent a treatment trajectory by the mono-disciplinary pain clinic. Results The study population consisted of 300 men and 509 women, mean age 53.6 year. By descriptive statistics the three major patient groups was identified: (1) Long lasting/chronic non-malignant pain – comprising 52% of the cohort, representing 37% male, mean age 54.9 year, mainly labeled nonspecific back pain; (2) Other chronic pain– representing 15% of the cohort, comprising 45% male, mean age 56.0 year; (3) Reflex dystrophy – comprising 8% of the cohort, with 30% male, mean age 43.6 year. The clinic had 4.161 outpatient consultations in the period with an increase of 13.9% from 2013 to 2014; average consultation rate per individual was 5.2 for women both years; for men the average was 5.1 in 2013 and 4.9 in 2014. In addition, the pain clinic patients were referred from: hospital (89.3%); hospital waiting trajectory (1.7%); general practitioner (7.3%) and practitioner specialist (1.7%). Conclusions This register-based study revealed that patients with nonspecific back pain were the most frequent patient category treated in the mono-disciplinary pain clinic. This finding suggests that targeted health promotion intervention may advantageously be organized with focus on the large group of patients with chronic nonspecific back pain.

Aims Treatment of the most complex chronic pain patients, often not accepted in regular pain management programs, remains a challenge.To beable todesign interventions for these patients we must know what characterize them. The aim of this study was to characterize a subgroup of pain patients, treated in our in-patient rehabilitation programme, organized at the University Hospital in Uppsala, the only tertiary treatment for pain patients in Sweden. Methods The study was approved by the Regional Ethical Review Board in Uppsala (Dnr 2010/182). Seventy-two patients, consecutive new referrals seen at the rehabilitation program in 2008–2010 were enrolled and examined with a 41-item questionnaire of symptoms other than pain. The 41 symptoms were listed on an ordinal scale from 0–10, with 0–no problems and 10–severe problem. The mean pain intensity within the preceding 24-h was assessed using an 11-point NRS, numeric rating scale from 0–no problems to 10–severe problems. Information about drug-consumption was obtained from the medical record. The opioid medication was translated to morphine-equivalents dos using EAPC (European Association for Palliative Care) conversion table. Results Seventy-two patients were enrolled and screened, 39% men and 61% woman. Median age 45 years (range 20–70). Seventy-four percent of patients were treated with opioids, 15 patients with more than one opioid. They all reported high pain intensity, the four patients with doses over 150 mg MEq reported pain 5–8. There was no correlation between the dose of opioids and pain intensity. The patients reported 22 symptoms (median) other than pain. The number of symptoms reported using this scaleina normal population is three–four. The most common symptoms reported were lethargy, tiredness, concentration difficulties and headache reported by over 80%. Sleeping disorders and tiredness were considered as the two most problematic symptom to deal with. We found no correlation between the degree of pain and presence and severity of symptoms reported. Number of symptoms reported diminished when the dose of opioids increased. Conclusions The pain patient considered too complex for regular pain-management programs are characterized by reporting many symptoms other than pain. High pain intensity or high opioid-dose does not correlate to presence or severity of other symptoms, and high dose of opioids does not have a connection to low pain intensity. Many of the symptoms commonly reported – lethargy, tiredness, concentration difficulties and headache are real obstacles for successful rehabilitation, and have to be dealt with to achieve successful results.

Aims Lumbar radicular pain following intervertebral disc herniation may be caused by a local inflammatory response induced by nucleus pulposus (NP) cells. Here in an animal model mimicking the clinical situation following disc herniation we investigated the effect of NP on the spinal nociceptive signaling and local gene expression. Methods In anaesthetized Lewis rats, extracellular single unit recordings of spinal nociceptive activity and qPCR were used to explore the effect of NP application onto the dorsal nerve roots (L3-L5). All animal experiments were approved by the Norwegian Animal Research Authority and were performed in conformity with the laws and regulations controlling experiments and procedures on live animals in Norway. Results A clear increase in C-fiber response was observed following NP conditioning. In the NP tissue, the gene expression of interleuking-1 β (IL-1β), colony stimulating factor 1 (Csf1), fractakine (CX3CL1) and the fractalkine receptor CX3CR1 was increased. Minocycline, an inhibitor of microglial activation, inhibited the increase in neuronal activity, and attenuated the increase in gene expression in NP tissue. Interestingly, gene expression analysis demonstrated an increase in the expression of TNF, CX3CL1 and CX3CR1 in the dorsal roots ganglion (DRG). An increase in the expression of IL-1 β and TNF in cultured DRG cells was also induced in vitro. Conclusions The present study suggests that hyperexcitability in the pain pathways after disc herniation may involve upregulation of CX3CL1 signaling in NP - but also in the DRG.

Aims To investigate patients’ perception of chronic pain related patient-provider communication in relation to socio-demographic and pain-related variables. Methods Apostal questionnaire measuring socio-demographic variables, pain characteristics, health-related quality of life (HRQoL), pain-related health care utilization and perceived patient provider communication, was sent to a sample of 4500 individuals randomly drawn from the national population of Iceland. Relationships between patient perceived patient-provider communication and perceived outcome, satisfaction with care as well as sociodemographic and pain-related variables were tested by using bivariate and multivariate statistical analysis. Results The prevalence of chronic pain (≥3months) among respondents was 47.5%. Among participants reporting chronic pain, 53.2% had consulted a health care provider for pain during the previous six months. Patients’ perception of providers’ behaviour and control in the communication was mostly related to pain impact on daily life and physical components of HRQoL as well as to patients’ satisfaction with health care providers. The more pain interfered with daily life and impaired patients’ physical health, the more they felt that the provider did not spend time to listen to their concerns and discuss symptoms and treatment options. Patients’ perception of own activity and control in the patient-provider communication and participation in care was related to socio-demographic variables but not with pain related variables. Conclusions To be understood as an individual and having their concerns legitimized by the health care provider is crucial for patients when consulting health care for chronic pain. The more pain interferes with daily life and impairs HRQoL, the more important this is. Patients’ perception of own control in patient-provider communication and participation in care is more related to socio-demographics than pain related variables.

Aims To investigate predictors for health-care utilization for chronic pain and whether there are gender differences in variables predicting chronic pain-related health care utilization. Methods A postal questionnaire measuring socio-demographic variables, pain characteristics, health related quality of life (HRQoL) and pain related health care utilization, was sent to a sample of 4500 individuals randomly drawn from the national population of Iceland. The relationships between socio-demographic and pain related variables and pain related health care utilization among participants reporting chronic pain (≥3 months) were tested by using bivariate and multivariate statistical analysis. Results The prevalence of chronic pain among respondents was 47.5%. Among participants reporting chronic pain, 53.2% had consulted a health care provider for pain during the previous six months.Predictors for pain related health care utilization were pain interference with daily life and pain pattern (daily pain) as well as physical components of HRQoL. Even though health care utilization was not related to gender, there were gender differences in pain-related predictors for health care utilization. Interference with daily life and pain pattern were the strongest predictors among women, but interference with life and the physical components of HRQoL were the strongest predictors for men. Pain related health care utilization was not related to socio-demographic variables. Conclusions Pain related variables are better predictors of chronic pain related health care utilization than socio-demographics. Even though gender does not predict chronic pain-related health care utilization, there are gender differences in the relationships between pain-related variables and health care utilization. These gender differences warrant further exploration.

Aims Neuropathic pain is a complex and painful condition, which is difficult to treat and causes a lot of suffering. The substance P (SP) system is well known to be involved in nociceptive signaling and it has previously been shown that the cerebrospinal fluid (CSF) level of SP is decreased in neuropathic pain. In this study we analyzed CSF from chronic neuropathic pain patients for the levels of SP 1–7 , an N-terminal fragment of SP with the ability to alleviate thermal as well as mechanical hypersensitivity in different animal models of chronic neuropathic pain, e.g. [1,2]. Methods CSF was collected from 11 neuropathic pain patients, treated with SCS, who had refrained from using their spinal cord stimulator for 48h. Control CSF was collected from 11 patients without any known neurological disorder, who underwent minor surgery under spinal anesthesia. The CSF samples were analyzed for the levels of SP 1–7 using radioimmunoassay. Results The results revealed a decrease in the level of SP 1–7 compared to controls. We believe that the lower level ofSP 1–7 most likely is a consequence of reduced amount of its precursor SP in the neuropathic pain patients. Conclusions Our results indicate that the SP system is changed in patients with neuropathic pain and that SP-related peptides, including SP 1–7 , might serve as biological markers for the patho-physiology of chronic neuropathic pain.

Aims The introduction of skin biopsies to examine small nerve fiber morphology together with functional measures such as quantitative sensory testing (QST) has led to an improvement in diagnosing patients with small fiber neuropathy (SFN). Quantification of intraepidermal nerve fiber density (IENFD) is an important measure in SFN. However, the relationship between structure and function is not straightforward and the morphological and functional fiber characteristics are still unclear. This study aimed to combine structural and functional measurements to improve the diagnosis of distal symmetric polyneuropathy and small fiber involvement. Additionally, we investigated whether patients and healthy controls have differential patterns of correlations between structural and functional nerve measurements. Methods 17 patients with painful distal symmetric polyneu-ropathy (DSP) and 19 controls underwent comprehensive small fiber assessments that included quantitative sensory testing, response to topical capsaicin and analysis of skin biopsy samples (IENFD, epidermal and dermal nerve fiber length densities (eNFLD, dNFLD) and swellings). Results DSP patients had reduced sensitivity to cold and heat, diminished capsaicin response, and lower IENFD, eNFLD and dNFLD (all p < 0.0003).The correlation between structural and functional parameters was better in controls than in DSP. A diagnostic approach of combined IENFD and eNFLD utilization, increased DSP diagnostic sensitivity from 82.0% to 100% and specificity from 84.0% to 89.5%. Conclusions A correlation is found between functional and structural small fiber parameters for DSP and controls, and an approach to improve diagnostic accuracy in DSP is suggested.

Aims In PET studies of patients suffering from chronic pain following whip lash trauma, d-deprenyl was shown to bind to painful sites in the neck [1]. High uptake points towards an existence of an inflammation-specific binding site. Thus, the aim of this study was to identify the binding site for d-deprenyl employing radioligand receptor binding and high-throughput analysis of its activity towards 165 G-protein coupled receptors and 84 enzyme targets commonly used in drug discovery and development. Methods D -Deprenyl activity towards GPCR targets was assessed by DiscoverX in CHO-K1 EDG1 β-arrest in EFC cell line utilizing the PathHunter™ technique. Enzyme inhibition by D-deprenyl was identified in the EnzymeProfiling™ screening panel provided by Eurofins Cerep Panlabs. [H 3 ] D -deprenyl binding studies with specific GPCR agonists and enzyme inhibitors at newly identified targets were also performed. Results Our investigation revealed that a 10μM concentration of d-deprenyl inhibited MAO-B and MAO-A activity by 99% and 55%, respectively. In addition, a 70% inhibition of angiotens in converting enzyme (ACE) activity in rabbit lung preparations was found. Furthermore, binding studies in rat mitochondrial membrane homogenates confirmed a submicromolar [H 3 ] D -deprenyl competition with a selective MAO-B inhibitor seligiline, but not with the selective MAO-A inhibitor pirlindole mesylate. No evident hits among GPCR targets were identified. However, attention was drawn towards the histamine HRH1 and HRH3 receptors to which d-deprenyl showed a 20% and 42% antagonistic activity. Conclusions MAO-B might be a candidate target for D -deprenyl, as many other studies documented higher d-deprenyl uptake in activated astrocytes, non-secreting pituitary adenomas and brown adipose tissue, where MAO-B is over expressed. Moreover, ACE inhibition was shown to hamper down-regulation of transcription factors preventing ROS-mediated cartilage damage.

Aims The aim of this study was to uncover possible proteins involved in the mechanism for neuropathic spinal cord stimulation (SCS) pain relief in humans. Methods Using two different proteomic protocols we compared the protein concentration in cerebrospinal fluid (CSF) from 14 SCS responsive neuropathic pain patients using a shotgun proteomic approach. The comparison was made between samples from the same individual taken when the stimulator had been off for 48 h, and after the stimulator had been used as normal for three weeks. Mass spectrometry raw files from both experimental setups were analysed using MS Quant and DeCyder softwares and proteins were identified using MASCOT search against Swissprot database. After median normalization moderate paired t -test statistics were used in R limma package to find up-and down regulated proteins. Results In total, 255 and 216 proteins could be identified by the dimethyl and label free methods respectively and relatively quantified. Of these several were significantly up- and down regulated. Conclusions These novel proteins add to the SCS mechanism in patients with neuropathic pain. These results strengthen the evidence for SCS as altering extracellular matrix components and affecting central nervous system plasticity.

Aims Sleep restriction (SR) increases pain sensitivity. The aim of this study was to compare the effects of night work on pain sensitivity with experimental SR. Methods In study I 22 healthy volunteers (14 females) and in study II 24 nurses (17 females) received pain stimuli in the laboratory twice; after 2 nights with habitual sleep (study I and II) and after 2 nights of experimental 50% SR (study I) or after 2 nights of work (study II). Order of sleep conditions was randomized. Heat pain at intensity 6/10 (pain-6), the pressure pain threshold (PPT), and subjective sleepiness with Karolinska sleepiness scale (KSS) were assessed. A linear mixed model (LMM) with random intercept and random slope was used. Difference scores were compared between study I and II by independent t-tests (PPT and pain-6) and the Mann–Whitney U test (KSS). Results Baseline subjective sleepiness (KSS), PPT or pain-6 ratings did not differ between study I and II ( p > 0.47). KSS and heat pain ratings increased after both sleep conditions ( p < 0.001), but did not differ between study I and II ( p > 0.15). PPT was lower after experimental SR ( p = 0.007), but unchanged after night work ( p = 0.63), but did not differ between study I and II ( p = 0.16). Conclusions Both experimental and night work-induced SR leads to comparable increased subjective sleepiness and higher pain ratings to heat pain stimuli. PPT was lower after experimental SR, but was not affected by night work-induced SR.

Aims Lumbar radicular pain after disc herniation may be associated release of pro-inflammatory cytokines from nucleus pulposus (NP) tissue. In the present study we examined the role of interferon-γ (IFN-γ) and cluster of differentiation 68 (CD68) in the acute phase of this process. Methods First, in an animal model mimicking the clinical situation after disc herniation, the role of IFN-γ on the dorsal horn single cell activity and gene expression close to the nerve roots was studied. Second, in patients with severe lumbar radicular pain due to disc herniation, we examined how two single nucleotide polymorphisms (SNPs; rs2069705 and rs2069718) important for the IFN-γ expression influenced the pain and disability measured by visual analogue scale (VAS) and Oswestry Disability Index (ODI). Results The animal data demonstrated a significant increase in the nociceptive activity at the spinal level after local application of NP and IFN-γ onto the nerve-roots. A positive correlation between IFN-γ and CD68 in the NP tissue was also observed. Moreover, the data of the patients revealed that carriers of the IFN-γ SNPs; rs2069705 A allele and rs2069718 G allele had an increased disability score i.e. ODI. Conclusions The present data suggest that IFN-γ through activation of tissue-specific macrophages close to the nerve roots may be important for acute inflammatory pain and disability following lumbar disc herniation.

Background Adverse experiences in early life, such as exposure to stress, can have long term detrimental effects on the future physiology and behaviour of the animal. Typically animals exposed to such experiences are more anxious and more reactive to stress in later life. Tail biting is a major problem in modern pig production, both in terms of animal welfare and productivity. Tail docking in early postnatal life is common practice to reduce risk of this problem, but causes pain and may alter pain sensitivity. Aims To investigate whether a significant painful experience in early life (tail docking) alters the expression of genes in the amygdala that are linked to an anxiety-prone phenotype. Methods Eight female piglets (Landrace/Large White × synthetic sireline) were used. Four piglets were tail docked (amputation of approx. 2/3 of the tail) on post-natal day 3 using hot-iron cautery and four sham-docked piglets served as intact controls. On post-natal day 10, pigs were sedated and then euthanized by barbiturate overdose. Brains were removed, the amygdala grossly dissected and frozen on dry ice. 20 μm sections were cut and subsequently processed using in situ hybridisation with radiolabelled probes complementary to corticotropin-releasing hormone receptor-1 ( Crhr1 ) and CRH receptor-2 ( Crhr2 ) mRNA. Results Crhrl mRNA expression was significantly greater in the amygdala of tail-docked piglets compared with the sham-docked animals. There was no significant difference detected in Crhr2 expression in the amygdala between the groups. Conclusion Increased expression of Crhrl in the amygdala is associated with an anxiety-prone phenotype in rats and pigs, thus it is likely that tail docking in early life leads to enhanced anxiety which may have a negative impact on pig welfare. Ongoing experiments will determine whether these central changes in gene expression are long-lasting. [Support: BBSRC/DEFRA, part of ANIWHA ERA-NET initiative].

Aims The lysophosphatidic acid (LPA) is an important mediator involved in neuropathic and bone cancer pain models. We are investigating if LPA is involved in arthritis-induced pain in the collagen antibody-induced arthritis (CAIA) mice model. Methods Arthritis was induced in male CBA mice by injection of 1.5 mg collagen type II antibody cocktail. Mechanical and thermal sensitivity and the degree of arthritis were assessed with von Frey filaments, Hargreaves box (heat), acetone test (cold) and visual scoring, respectively. LPA antibody and control IgG (10mg/kg), or saline was injected s.c. twice a week from day 12 through day 47. qPCR and immunohistochemical studies were undertaken in dorsal root ganglia (DRGs) to explore the expression of pain-related ion channels. Results Administration of LPA antibody treatment reversed CAIA-induced mechanical and thermal hypersensitivity ( p < 0.05) while had no effect on the early clinical signs of arthritis ( p > 0.05). mRNA levels for the LPA synthesizing enzyme autotaxin were elevated in the CAIA group. On day 48, expression of the voltage-gated calcium channel Cavα2δ1 and the ATP-gated P2X3 receptor were significantly increased in the CAIA DRGs, which were completely prevented by LPA antibody treatment. Of note, based on in vitro experiment, LPA stimulation upregulated Cavα2δ1 and P2X3 expression in primary adult mouse DRG cultures. Conclusions Blocking the action of systemic LPA reverses arthritis-induced hypersensitivity, potentially through regulation of Cavα2δ1 and P2X3 expression in peripheral neurons. Thus, our data point to that LPA may serve as a target for providing pain relief in arthritis.

Aims To compare musculoskeletal pain intensity and duration of construction workers as a function of type of work. Methods 239 male construction workers in active employment filled out a (baseline) questionnaire for a prospective study of jobs with assumed heavy work load. Reports of pain presented here was collected from the men in four work categories; project leaders/foremen ( N = 62, age 45 y, SD ± 13), carpenters ( N = 60, 41 y ± 13), concrete workers ( N = 35, 42 y ± 12) and miscellaneous other manual workers (e.g. brick layers, henchmen, N = 28, 45 y ± 13). The participants were asked to report pain intensity in different body regions during the last four weeks (0: none, 1: mild, 2: moderate and 3: severe) and the duration of this pain (1: 1–5, 2: 6–10, 3: 11–14 and 4: 15–28 days). A severity index was constructed by multiplying the two recordings, intensity and duration (range 0–12). Two dichotomized variables were defined; for the intensity with a cut point ≥2 (in %) and for the index with a cut point ≥6 (in %). Five % trimmed mean is used due to skewed data. Results Low back pain was the most frequently reported pain symptom for all categories of workers (mean for all: mean intensity: 0.74, intensity ≥2: 23%, mean severity index: 1.64, index ≥6: 13% ), expect carpenters that reported knee pain most frequent ( mean intensity: 0.78, intensity ≥2: 26%, mean severity index: 2.08, index ≥6: 22% ). The miscellaneous worker group reported the highest level of neck pain ( mean intensity: 0.84, intensity ≥2: 25%, mean severity index: 2.03, index ≥6: 20% ). Due to different time distribution of pain symptoms between individuals the use of pain duration gave additional information. Conclusions Most construction workers reported low levels of pain. The measurement of both intensity and duration allows computation of a proxy for pain severity.

Aims To test the effectiveness of the Pain Resource Nurse (PRN) education program in a university hospital. Methods This was a randomized controlled trial. Two nurses from each of the 23 participating surgical and medical units were selected to participate in the PRN program. The program consisted of a three day course in pain management with a structured follow up. After a baseline measurement, the units were randomized to either receive the intervention or to serve as a wait-list control. The control group received the intervention following a second data collection 10 months from baseline. Data regarding knowledge and attitudes regarding pain were collected from nurses, but patient data were collected with the American Pain Society Patient Outcome Questionnaire and from medical records. Patients had to be ≥18 years, hospitalized for ≥24 h, alert and able to participate. Results Participating patients were 308 at T1 (73% response rate (RR)) and 329 at T2 (79% RR). Participating nurses were 224 (48% RR) at T1 and 176 (38% RR) at T2. No difference was found between the intervention and control groups regarding knowledge and attitudes of nurses, or in any of the patient outcome variables. The only significant effect of the intervention was improvement in documented standardized pain assessment, which increased from 12% at T1 to 24% at T2 on the intervention units, compared to a decrease from 12% at T1 to 9% at T2 on the control units, p < 0.05. Conclusions Patient outcomes remained unchanged after the intervention, as were nurses’ knowledge and attitudes. The intervention was, however, successful in changing pain assessment practices. Multifarious efforts to change nursing practice resulted in modest changes. Further studies are needed to advance pain management practices in clinical settings.