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Background and aims Previous systematic reviews have reported manifestations of pain sensitisation as a feature of painful knee disorders, in particular osteoarthritis, with moderate evidence for pain sensitisation in patellofemoral pain (PFP). However, despite past studies recruiting female mostly adolescent PFP patients, it is unclear if sex or age plays a role. Investigation is required to determine if altered pain processing is a key feature of PFP and if a subgroup of patients is at an increased risk to help provide targeted management. The primary aim of this systematic review was to examine evidence investigating pain processing in PFP. Secondary aims were to evaluate the relationship between pain processing and (1) sex, (2) age and (3) symptom duration. Methods The protocol was prospectively registered with PROSPERO (CRD42019129851). PubMed, CINAHL, Web of Science and EMBASE were systematically searched from inception to April 2019 for studies investigating pain processing in PFP patients compared to controls using quantitative sensory testing. Each included paper was assessed for methodological quality using a modified version of Downs and Black. Means and standard deviations were extracted to calculate standardised mean differences (SMD) and 95% confidence intervals (95% CI). Where possible meta-analysis and meta-regression were performed using a random effects model. Results Eleven studies were identified, two medium and nine high quality. Meta-analysis indicates moderate evidence for decreased pressure pain thresholds (SMD −0.68, 95% CI −0.93 to −0.43), increased tactile detection thresholds (SMD 1.35, 95% CI 0.49–2.22) and increased warmth detection thresholds (SMD 0.61, 95% CI 0.30–0.92) in PFP patients compared to controls. Secondary analysis indicates moderate evidence for decreased pressure pain thresholds in female compared to male patients (SMD −0.75, 95% CI −1.34 to −0.16). Meta-regression indicates a moderate correlation between decreasing local and distal pressure pain thresholds and decreasing patient age (local R 2  = 0.556, p  = 0.0211; distal R 2  = 0.491, p  = 0.0354) but no correlation with symptom duration ( p  > 0.05). Conclusions Evidence from this systematic review with meta-analysis and meta-regression appears to suggest the presence of altered pain processing and sensitisation in patients with PFP with increased sensitivity indicated in female patients and younger patients. Implications With evidence of altered pain processing and sensitisation in PFP, it may be beneficial for clinicians to consider management approaches that aim specifically at adressing neuropathic pain, for example neuroscience education, to improve patients outcomes. With female patients and younger patients indicated as experiencing greater degree of sensitivity, this may be a good demographic to start screening for sensitisation, in order to better identify and treat those most affected.

As professional health care personnel we are well educated in anatomy, physiology, clinical medicine and so forth. Our patients present with various symptoms and signs that we use this knowledge to diagnose and treat. But sometimes the patient case contradicts our knowledge. Since the patient is the terrain and our knowledge is the map, these patient cases are anomalies that give us the opportunity to update our maps. One such anomaly is how time restricted amnesia can improve or even eradicate an underlying chronic pain condition and eliminate the patient’s dependence on daily opioid consumption. In this short communication I will use amnesia as a starting point to briefly review chronic pain from a learning and memory perspective. I will introduce, for many readers, new concepts like degeneracy and criticality, and together with more familiar concepts like habits and brain network activity, we will end with overarching principles for how chronic pain treatment in general can be crafted and individualized almost independently of the chronic pain condition at hand. This introductory article is followed by a review series that elaborates on the fundamental biological principles for chronic pain, treatment options, and testing the theory with real world data.

Background Acute pain is a warning mechanism that exists to prevent tissue damage, however pain can outlast its protective purpose and persist beyond injury, becoming chronic. Chronic Pain is maladaptive and needs addressing as available medicines are only partially effective and cause severe side effects. There are profound differences between acute and chronic pain. Dramatic changes occur in both peripheral and central pathways resulting in the pain system being sensitised, thereby leading to exaggerated responses to noxious stimuli (hyperalgesia) and responses to non-noxious stimuli (allodynia). Critical role for immune system cells in chronic pain Preclinical models of neuropathic pain provide evidence for a critical mechanistic role for immune cells in the chronicity of pain. Importantly, human imaging studies are consistent with preclinical findings, with glial activation evident in the brain of patients experiencing chronic pain. Indeed, immune cells are no longer considered to be passive bystanders in the nervous system; a consensus is emerging that, through their communication with neurons, they can both propagate and maintain disease states, including neuropathic pain. The focus of this review is on the plastic changes that occur under neuropathic pain conditions at the site of nerve injury, the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. At these sites both endothelial damage and increased neuronal activity result in recruitment of monocytes/macrophages (peripherally) and activation of microglia (centrally), which release mediators that lead to sensitisation of neurons thereby enabling positive feedback that sustains chronic pain. Immune system reactions to peripheral nerve injuries At the site of peripheral nerve injury following chemotherapy treatment for cancer for example, the occurrence of endothelial activation results in recruitment of CX3C chemokine receptor 1 (CX 3 CR 1 )-expressing monocytes/macrophages, which sensitise nociceptive neurons through the release of reactive oxygen species (ROS) that activate transient receptor potential ankyrin 1 (TRPA1) channels to evoke a pain response. In the DRG, neuro-immune cross talk following peripheral nerve injury is accomplished through the release of extracellular vesicles by neurons, which are engulfed by nearby macrophages. These vesicles deliver several determinants including microRNAs (miRs), with the potential to afford long-term alterations in macrophages that impact pain mechanisms. On one hand the delivery of neuron-derived miR-21 to macrophages for example, polarises these cells towards a pro-inflammatory/pro-nociceptive phenotype; on the other hand, silencing miR-21 expression in sensory neurons prevents both development of neuropathic allodynia and recruitment of macrophages in the DRG. Immune system mechanisms in the central nervous system In the dorsal horn of the spinal cord, growing evidence over the last two decades has delineated signalling pathways that mediate neuron-microglia communication such as P 2 X 4 /BDNF/GABA A , P 2 X 7 /Cathepsin S/Fractalkine/CX 3 CR 1 , and CSF-1/CSF-1R/DAP12 pathway-dependent mechanisms. Conclusions and implications Definition of the modalities by which neuron and immune cells communicate at different locations of the pain pathway under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction and provides opportunities for novel approaches for the treatment of chronic pain.

Background and aims Cervicogenic headache (CEH) is a debilitating condition and analgesics have limited effect. Percutaneous cryoneurolysis is thus still in use although the clinical evidence is lacking. We present a randomized, controlled study to assess the clinical efficacy of cryoneurolysis compared with a corticosteroid combined with a local anaesthetic. Methods In a university-based outpatient pain clinic we performed a randomized, double blinded, comparative study with an 18-week follow-up. After positive diagnostic test blocks 52 eligible patients were randomly allocated in a ratio of 3:2, 31 participants to occipital cryoneurolysis and 21 participants to injections of 1 mL methylprednisolone 40 mg/mL (Depo-Medrol ® ) combined with 1 mL bupivacaine 5 mg/mL. Results We observed a significant pain reduction of more than 50% in both treatment groups, slightly improved neck function and reduced number of opioid consumers. After 6–7-weeks, however, pain intensity increased gradually, but did not reach baseline within 18 weeks. Although cryoneurolysis provided a more prolonged effect, the group differences did not reach statistical significance. Health related quality of life and psychological distress improved minimally. A large number reported minor and transient side effects, but we found no significant group differences. After 18 weeks, 29% rated the headache as much improved, and 12 (24%) somewhat improved, but a large proportion (78%) reported need for further intervention/treatment. Conclusions Cryoneurolysis provided substantial, but temporary pain relief, and the effect was not significantly different from injections of a corticosteroid combined with a local anaesthetic. Participants were selected by a single test block, and the neurolytic procedure was guided by anatomical landmarks and nerve stimulation. A stricter patient selection and an ultrasound-guided technique might have improved the results. Cryoneurolysis provides temporary pain relief not significantly superior to corticosteroid injection, and the results question the value of occipital cryoneurolysis for a chronic pain condition like CEH. Implications Occipital cryoneurolysis may be considered when non-invasive treatments appear insufficient, but only for patients who have responded substantially to test blocks. A risk of local scar and neuroma formation by repeated cryoneurolysis, leading to neuropathic pain has been discussed by other researchers.

Background and aims Pain catastrophizing has consistently been related to a variety of negative outcomes within chronic pain conditions, but competing models exist explaining the role of catastrophizing. According to the fear-avoidance model (FAM), catastrophizing is primarily related to the appraisal of pain (i.e. “intrapersonal”), whereas the communal coping model (CCM) suggests that catastrophizing is a strategy to elicit support (i.e. “interpersonal”). In order to examine the interpersonal nature of catastrophizing, this cross-sectional study examined interpersonal problems as a predictor of pain catastrophizing in a sample of patients ( n  = 97) with chronic pain. Methods Self-report data was taken from patients entering a multidisciplinary, inpatient rehabilitation program. The four quadrants of the Inventory of Interpersonal Problems circumplex model (Hostile-Dominant, Hostile-Submissive, Friendly-Submissive, Friendly-Dominant) were used as predictors of pain catastrophizing in a series of separate, hierarchical regression analyses. Results After controlling for relevant confounding variables such as demographics (gender, age), pain severity, psychiatric symptoms (anxiety/depression, fatigue, insomnia), adverse life experiences and perceived social support, higher levels of Hostile-Dominant interpersonal problems predicted higher levels of pain catastrophizing ( p  ≤ 0.01, d  = 0.56). Conclusions The results add support to the notion that pain catastrophizing may serve a communicative functioning, as predicted by the CCM, with cold, dominant and controlling behaviors as a maladaptive interpersonal strategy to elicit support. It may thus be useful to consider the broader interpersonal context of the individual, and not only the patient’s appraisal of pain, when conceptualizing the role of pain catastrophizing in patients with chronic pain. Implications Future psychosocial research and treatment of chronic pain could be informed by including interpersonal theory as a useful theoretical framework, which may help shed more light on how interpersonal problems relates to pain catastrophizing.

Background and aims Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal – dominant hereditary neuropathy caused by a deficiency in the peripheral protein PMP-22, due to deletion on chromosome 17p11,2 or in some rare cases point mutations in the PMP-22 gene. The clinical picture is characterized by recurrent mononeuropathies in nerves which frequently may be exposed to pressure, such as the median, ulnar, radial and peroneal nerves or also a more general neuropathy. Although pain is reported to be an unusual clinical symptom, there have been reports of pain in a surprisingly high proportion of these patients. Since pain may be explained by mechanisms in afferent small unmyelinated C- nerve fibers, an assessment of the function of small nerve fibers has been requested. The purpose of the present study was to investigate the presence of pain and the possible affection of afferent small nerve-fibers, A-δ and C-fibers, by quantitative sensory testing (QST)-assessment of thermal thresholds, as well as quantitative sudomotor axon reflex (QSART), a quantitative, validated assessment of efferent postganglionic sumodotor function. QST values were compared to values of age- and sex matched healthy subjects. Methods The 19 patients were investigated clinically, with an emphasis on pain characteristics, with nerve conduction studies (NCS) of major nerves in upper- and lower extremity, small fiber testing (QST, measurement of thermal thresholds) and with QSART. Results A total of 10 patients reported numbness in some extremity, suggesting entrapment of individual nerves as well as a general neuropathy, as verified by NCS in nine patients. A total of 15 patients had findings compatible with a general polyneuropathy. A total of eight patients reported pain, seven patients with pain in the feet, described as burning, aching, shooting and six with severe pathological QST values, mainly cold detection, but also four patients with elevated thresholds to warmth. Four of the patients had signs of a severe sensory neuropathy on NCS, with no sural findings. One patient had only pain in the arms, with only minor changes on NCS and with normal QST-values. Cold detection thresholds (CD) were significantly elevated (reduced sensibility) on the dorsum of the foot (mean of two feet), in patients [26.0 °C (19.7–28.0)] as compared with healthy subjects [28.6 °C (27.4–29.6) p  = 0.000]. There were also significantly elevated warmth detection thresholds (WD) in feet in patients 39.5 °C (36.4–42.9) compared to healthy subjects [37.7 °C (36.1–39.4) p  = 0.048]. However, there were no significant differences in QST values between patients with and without pain. Conclusions Of a total of 19 patients with verified HNPP, eight patients (42.1%) suffered from neuropathic pain, mainly in both feet. Implications Due to the high percentage of pain in HNPP, it is important not to disregard this diagnosis in a patient presenting with pain. Since there are no significant differences in QST values in patients with and without pain, routine QST studies in HNPP do not seem necessary.

Background and aims Recovery in patients hospitalised with severe sciatica is unpredictable. Prognostic tools to aid clinicians in the early identification of patients at risk of developing chronic sciatic pain are warranted. Conditioned pain modulation (CPM) is a psychophysical measure of the endogenous pain modulatory pathways. Several studies have suggested CPM as a potentially important predictive biomarker for the development of chronic pain. The aim of the study was to determine whether CPM effect in patients still suffering from leg pain 6 weeks after hospital discharge for severe sciatica is associated with persistent leg pain at 12 months. A potential association would suggest that measuring CPM effect could be a valuable prognostic tool in the hospital management of sciatica. Methods A prospective cohort study in which CPM effect was measured 6 weeks after hospital discharge following an acute admission with sciatica as the main complaint. The impact of CPM effect on the outcome was analysed using logistic regression. The outcome measured was self-reported leg pain score of ≥1 in the past week on a 0–10 numeric rating scale (NRS) at 12 months post discharge. Results A total of 111 patients completed the entire study, 51 of whom received non-randomised surgical treatment. Crude and confounder adjusted analyses showed no significant association between CPM effect and leg-pain measured at 12 months, crude Odds Ratio 0.87, 95% CI 0.7–1.1, p  = 0.23. Conclusions Our results suggest that CPM assessment has limited prognostic value for the long-term outcome in severe sciatica when measured 6 weeks after hospital discharge. Implications The present study adds important knowledge concerning the limited clinical use of late CPM testing in sciatica patients. The heterogeneity in patients, the wide range of treatments received and a generally favourable outcome are factors that may affect CPM’s clinical value as a prognostic factor for severe sciatica.

Background and aims Persons with chronic widespread pain (CWP) have poor medical outcomes and increased mortality. But there are no universally accepted criteria for CWP or of methods to assess it. The most common criteria come from the 1990 American College of Rheumatology (ACR) fibromyalgia (FM) criteria, but that method (WP1990) can identify CWP with as few as three pain sites, and in subjects with wide differences in illness severity. Recently, to correct WP1990 deficiencies, the 2016 fibromyalgia criteria provided a modified CWP definition (WP2016) by dividing the body into five regions of three pain sites each and requiring a minimum of four regions of pain. Although solving the geographic problem of pain distribution, the problem of just how many pain sites (pain diffuseness) are required remained a problem, as WP2016 required as few as four painful sites. To better characterize CWP, we compared four CWP definitions with respect to symmetry, extent of pain sites and association with clinical severity variables. Methods We characterized pain in 40,960 subjects, including pain at 19 individual sites and five pain regions, and calculated the widespread pain index (WPI) and polysymptomatic distress scales (PDS) from epidemiology, primary care and rheumatology databases. We developed and evaluated a new definition for CWP, (WP2019), defined as pain in four or five regions and a pain site score of at least seven of 15 sites. We also tested a definition based on the number of painful sites (WPI ≥ 7). Results In rheumatology patients, WP1990 and WPI ≥ 7 classified patients with <4 regions as WSP. CWP was noted in 51.3% by WP1990, 41.7% by WP2016, 37.6% of WPI ≥ 7 and 33.9% by WP2019. 2016 FM criteria was satisfied in WP1990 (51.1%), WP2016 (63.3%), WPI ≥ 7 (69.0%) and WP2019 (76.6%). WP2019 positive patients had more severe clinical symptoms compared with WP1990, WP2016 and WPI ≥ 7, and similar to but less than FM 2016 positive patients. In stepwise fashion, scores for functional disability, visual analog scale fatigue and pain, WPI, polysymptomatic distress score and Patient Health Questionnaire 15 (PHQ-15) worsened from WP1990 through WP2016, WPI ≥ 7 and WP2019. Conclusions WP2019 combines the high WPI scores of WPI ≥ 7 and the symmetry of WP2016, and is associated with the most abnormal clinical scores. The WP1990 does not appear to be an effective measure. We suggest that CWP can be better defined by combining 4-region pain and a total pain site score ≥7 (WP2019). This definition provides a simple, unambiguous measure that is suitable for clinical and research use as a standalone diagnosis that is integrated with fibromyalgia definitions. Implications Definitions of CWP in research and clinic care are arbitrary and have varied, and different definitions of CWP identify different sets of patients, making a universal interpretation of CWP uncertain. In addition, CWP is a mandatory component of some fibromyalgia criteria. Our study provides quantitative data on the differences between CWP definitions and their criteria, allowing better understanding of research results and a guide to the use of CWP in clinical care.

Background and aims Previous studies have described the phenomenon of oligo-analgesia in Emergency Department patients with traumatic injuries, despite the high prevalence of pain among these patients. Besides aspects related to health care staff, patient related factors might also play a role in suboptimal pain treatment, however evidence is scarce. Therefore, the objective of the current study was to evaluate patient related factors in adult patients refusing offered analgesics during an Emergency Department presentation with extremity injuries. Methods This was a case control study in the Emergency Department of a level 1 Trauma Centre. Cases were defined as adult patients with an extremity injury who declined analgesia, when offered. They were matched to controls from the same population, who accepted analgesics, in a 1:2 ratio using gender as matching variable. Primary outcome was difference in NRS pain score. Secondary outcomes were the relationship between categorical severity of pain scores and refusal of analgesics, exploration of independent predictors of analgesia refusal utilizing multivariate logistic regression and the evaluation of eight beliefs among patients who refuse analgesics. Results Between August 1st and 31st 2016, a total of 253 patients were eligible for inclusion of whom 55 declined analgesic treatment. They were included as cases and matched to 110 controls. Difference in median NRS pain score was significant between the groups: 5.0 (IQR 3.0–8.0) vs. 8.0 (IQR 6.0–9.0), respectively ( p  < 0.01). Nearly 20% of patients with severe pain declined analgesics, compared to 41% with moderate and 69% with mild pain ( p  < 0.01). The NRS pain score was the only independent predictor of refusal of analgesic treatment with a mean Odds Ratio of 0.67 (95%-CI 0.54–0.83). Most common patients’ beliefs were that pain medication should be used in extreme pain only, fear of decreasing the doctor’s ability to judge the injury and fear of addiction to analgesics. Conclusions Pain severity is the single independent predictor of refusal of analgesia, however the following patient beliefs are important as well: pain medication should be used in extreme pain only; fear of decreasing the doctor’s ability to judge the injury and the fear of becoming addicted to pain medication. Implications In case patients refuse offered analgesics, the health care provider should actively address patient beliefs that might exist and lead to suboptimal pain treatment.

Background and aims Aside from the long term side effects of a nerve injury in the upper extremity with devastating consequences there is often the problem of chronic neuropathic pain. The studies concerning the prevalence of persistent pain of neuropathic origin after peripheral nerve injuries are sparse. The prevalence and risk factors associated with chronic neuropathic pain after nerve injuries in the upper extremity were assessed. Methods A standardized data collection template was employed prospectively and retrospectively for all patients with traumatic nerve injuries accepted at the Hand Surgery Department, Uppsala, Sweden between 2010 and 2018. The template included demographic data, pain diagnosis, type of injured nerve, level of injury, date of the lesion and repair, type of procedure, reoperation, time since the procedure, S-LANSS questionnaire (Self report-Leeds Assessment of Neuropathic Symptoms and Signs), RAND-36 (Item short form health survey), QuickDASH (Disability of Shoulder, Arm and Hand) and additional questionnaires concerned medication, pain intensity were sent to 1,051 patients with nerve injuries. Partial proportional odds models were used to investigate the association between persistent pain and potential predictors. Results More than half of the patients undergoing a surgical procedure developed persistent pain. Prevalence of neuropathic pain was 73% of the patients with pain (S-LANSS ≥ 12 or more). Multivariate analysis indicated that injury of a major nerve OR 1.6 ( p  = 0.013), years from surgery OR 0.91 ( p  = 0.01), younger age OR 0.7 ( p  < 0.001), were the main factors for predicting pain after surgery. The type of the nerve injured was the strongest predictor for chronic pain with major nerves associated with more pain ( p  = 0.019). Conclusions A high prevalence of chronic pain and neuropathic pain with a negative impact on quality of life and disability were found in patients after traumatic nerve injury. Major nerve injury, younger age and less time from surgery were predictors for chronic pain.

Background and aims In the Western world, it has become clear that we are facing a crisis of overuse, abuse and improperly prescribed use of opioids. As part of the ongoing discussion on opioid use, the use and prescription of tramadol have been addressed in recent years. A significant portion of this discussion should adequately address the risk factors for the use of weak opioid products such as tramadol. The risk factors which characterise the long-term tramadol use are still incompletely understood. Thus, we aimed to describe the characteristics of Danish patients using tramadol in more detail, under different scenarios and determinants of subsequent usage patterns. Methods We conducted a nationwide cohort study to identify individuals purchasing tramadol from 01/01/2004 to 31/12/2015 who are age 16 +  years old by using data from The Danish National Databases; these databases consist of unique information for all citizens in Denmark. Logistic regression analyses were used to assess the potential risk factors for repeated tramadol use. Results The final cancer-free cohort consisted of N = 941,839 tramadol users: 54.4% women, with a mean age of 53.2 years. The number of chronic noncancer pain (CNCP) was 430,641 individuals, and 56% of the total third who repeated the use of tramadol with two +  purchased prescriptions were CNCP patients. The increased risk of repeated use for CNCP was, among others, associated with: male sex (HR 1.21), age 69–110 (HR 1.72), back/spine pain men (HR 1.47), women (HR 1.46), spondylopathies (HR 1.24), male osteoporosis (HR 1.22), multimorbid ulcer/skin (HR 1.28), region of municipality Northern Jutland (HR 1.74), Central Jutland (HR 1.75), number of co-medication 4–9 (HR 1.33), dementia (HR 1.27). Factors associated with decreased risk: co-medication ischemic heart disease (HR 0.85), diagnosis headache (HR 0.70), household income highest tertile (HR 0.81), unknown (HR 0.70), single women (HR 0.96). Conclusions This study proved a widespread prescribed use of tramadol in Denmark, and, as know from the literature, weak opioid use may lead to long-term use of high potent opioids, this usage is inappropriate, in general, but especially for the treatment of CNCP. Implications When striving to reduce the overuse of opioids, focus on the extensive use of tramadol may be essential. The current study indicates an excessive and not appropriately prescribed use of tramadol among Danish CNCP patients. In addition to being inappropriate, such use may also have an impact on the growing problem of an illicit Internet market for this drug. Thus, the situation must be taken seriously. The current study confirms the recent clinical guideline and the National Recommendations in Denmark, which emphasises the risks of problematic use of tramadol. The research may also be relevant in other comparable countries. Caution must especially be taken with CNCP patients with comorbidities like diabetes, lung disease, dementia, and osteoporosis.

It has been suggested that alterations in inflammation molecules maintain chronic pain although little is known about how these factors influence homeostatic and inflammatory events in common chronic pain conditions. Nonpharmacological interventions might be associated with alterations in inflammation markers in blood. This study of patients with chronic pain investigates whether an interdisciplinary multimodal rehabilitation program (IMMRP) was associated with significant alterations in the plasma pattern of 68 cytokines/chemokines 1 year after rehabilitation and whether such changes were associated with clinical changes. Blood samples and self-reports of pain, psychological distress, and physical activity of 25 complex chronic pain patients were collected pre-IMMRP and at 12-month follow-up. Analyses of inflammatory proteins (cytokines/chemokines/growth factors) were performed directly in plasma using the multiplex immunoassay technology Meso Scale Discovery. This explorative pilot study found that 12 substances, mainly pro-inflammatory, decreased after IMMRP. In two other relatively small IMMRP studies, four of these proinflammatory markers were also associated with decreases. The pattern of cytokines/chemokines pre-IMMRP was associated with changes in psychological distress but not with pain or physical activity. The present study cannot impute cause and effect. These results together with the results of the two previous IMMRP studies suggest that there is a need for larger and more strictly controlled studies of IMMRP with respect to inflammatory markers in blood. Such studies need to consider responders/non-responders, additional therapies, involved pain mechanisms and diagnoses. This and the two other studies open up for developing biologically measurable outcomes from plasma. Such biomarkers will be an important tool for further development of IMMRP and possibly other treatments for patients w ith chronic pain.

Background and aims Preclinical studies have reported that activation of peripheral γ-aminobutyric acid A (GABA A ) receptors may result in analgesia. The current study was conducted in young healthy men ( n  = 30) and women ( n  = 28) to determine whether injections of GABA into the masseter muscle reduce pain in a sex-related manner. Methods The effect of injection of GABA alone, or in combination with the non-inflammatory algogen glutamate, was assessed in two separate studies. Lorazepam, a positive allosteric modulator of the GABA A -receptor, was co-injected with GABA in both studies to explore the role of this receptor in muscle pain responses of healthy human volunteers. Masticatory muscle mechanical pain intensity was recorded on an electronic visual analogue scale (VAS) while muscle pain sensitivity was assessed by determining the pressure pain threshold (PPT), tolerance and maximal jaw opening (MJO) of the subjects prior to, and again after the various intramuscular injections. Results Intramuscular injection of GABA alone was reported to be significantly more painful, in a concentration related manner, than saline control injections, and this pain was further increased by co-injection of lorazepam with GABA. Co-injection of GABA with glutamate was found to significantly increase glutamate-evoked masseter muscle pain in men, but not in women. There was no effect of injections of either GABA alone, or GABA with glutamate, on PPT, tolerance or maximum jaw opening. Conclusions Injection of GABA into the human masseter muscle appears to excite nociceptors to produce muscle pain without a longer term effect on mechanical pain sensitivity in the muscle. The findings suggest that GABA-mediated pain in humans is produced through peripheral GABA A receptor activation. The mechanism underlying the sex-related difference in the effect of GABA on glutamate-evoked muscle pain was speculated to be due to a methodological artifact. Implications This study was designed to detect analgesic rather than algesic effects of peripherally administered GABA, and as a result, the concentration of glutamate chosen for injection was close to the maximal pain response for healthy women, based on previously determined pain-concentration response relationships for glutamate. This may explain the finding of greater pain in men than women, when GABA and glutamate were co-injected. Overall, the findings suggest that activation of peripheral GABA A receptors in human masticatory muscle produces pain, possibly due to depolarization of the masticatory muscle afferent fibers.

Background and aims Pain-related fear and its subsequent generalization is key to the development and maintenance of chronic pain disability. Research has shown that pain-related fear acquired through classical conditioning generalizes following a gradient, that is, novel movements that are proprioceptively similar to the original pain-associated movement elicit more fear. Studies suggest that classical conditioning can also modulate pain and conditioned fear seems to mediate this effect. However, it remains uninvestigated whether this is also the case for generalized fear. Methods In a voluntary joystick movement paradigm, one movement (conditioned stimulus; CS+) was followed by pain (pain-US), and another was not (CS−). Generalization to five novel movements (generalization stimuli; GSs) with varying levels of similarity to the CSs was tested when paired with an at-pain-threshold intensity stimulus (threshold-USs). We collected self-reported fear and pain, as well as eyeblink startle responses as an additional index of conditioned fear. Results Results showed a fear generalization gradient in the ratings, but not in the startle measures. The data did not support the idea that fear generalization mediates spreading of pain. Conclusions Despite the lack of effects in the current study, this is a promising novel approach to investigate pain modulation in the context of chronic pain. Implications This study replicates the finding that pain-related fear spreads selectively towards movements that are proprioceptively more similar to the original pain-eliciting movement. Although results did not support the idea that such generalized fear mediates spreading of pain, the study provides a promising approach to investigate pain modulation by pain-associated movements.

Background and aims People with shoulder pain often present with abnormal shoulder muscle function. It is not known whether shoulder pain causes or is the result of muscle dysfunction. If pain leads to muscle dysfunction, therapeutic interventions that produce shoulder pain may be contraindicated. Experimentally induced nociception can be used to investigate a causal relationship between shoulder pain and muscle dysfunction. However, the validity of current experimental shoulder pain protocols has not been established. The aim of this study was to determine whether current experimental shoulder pain protocols validly replicate the clinical experience of shoulder pain with respect to pain distribution, quality and behaviour. Methods Nine pain free participants received two injections of hypertonic saline, one into the subacromial space and one into supraspinatus, in random order, at least 1 week apart. Investigators blind to the injection site assessed pain distribution, pain response to clinical tests which provoke shoulder pain and pain quality assessed using the McGill Pain Questionnaire. Results Following hypertonic saline injection into both the subacromial space and supraspinatus: pain was most commonly reported in the deltoid region and did not extend beyond the elbow; the most common response to clinical tests which provoke shoulder pain was a decrease in pain; and the highest rating of pain quality was in the sensory domain with very few responses in the affective domain. Conclusions Experimental shoulder pain induced by injection of hypertonic saline into either the subacromial space or supraspinatus produced a pain distribution similar to that observed in clinical shoulder pain, but neither experimental pain protocol could reproduce the increases in pain intensity following shoulder provocation tests or the emotional distress commonly observed in people with clinical shoulder pain. Implications Pain induced by local shoulder nociception produced by hypertonic saline injection into shoulder structures has significant limitations as a model of clinical shoulder pain. While it is perhaps unsurprising that short duration, chemically-induced experimental pain does not replicate the quality of the clinical experience of shoulder pain, the validity of experimental shoulder pain models which produce the opposite response to provocation testing to clinical shoulder pain must be questioned.

Background and aims Using a computer algorithm to quantify pain drawings could be useful, especially when large numbers of drawings need to be assessed. Whilst informal visual assessment of pain drawings can give clinicians a quick impression of the extent of pain and its location, formal quantification of pain drawings by computer for research purposes is not necessarily trivial. The current study compared seven different approaches to quantification in a large sample of clinical spinal pain drawings. Methods A large number (n = 55,720) of pain drawings were extracted from the SpineData database, a clinical registry of spinal pain patients in the Region of Southern Denmark. Drawings were analyzed both as pixel (raster) and vector based images, with different approaches based on the raw pain drawing, simple encircling polygons, convex-hull encircling polygons and discrete anatomical regions. Data were analyzed using principal component analysis, correlation and linear regression, as well as informal visual inspection of outlier pain drawings. Results Eighty-one percent of the variance could be explained by the first principal component, which we interpreted as the true score variance, i.e. the variance attributable to differences in pain area between individuals. The second principal component explained 10% of the variance and was loaded differentially by polygon-based methods and non-polygon-based methods. Correlations between the different approaches ranged from 0.66 to 1.00. Some approaches correlated so strongly as to be interchangeable, others tended to bias area estimates significantly. Visual inspection of outlier pain drawing indicated that when the different approaches to quantification yielded different results, characteristic patterns could be identified in the style and patterns of those pain drawings. Conclusions The different approaches reflected the same underlying construct (pain area), but could not be relied upon to produce the same area estimates and were affected by the interaction between drawing style and quantification approach. To some extend, the “correct” choice of quantification method is specific to and dictated by the style of each pain drawing. A differentiated approach is required in which the results of quantification and the drawing style are considered in combination. We provide suggestions for such differentiated approaches taking into account the nature of the drawing data (raster vs. vector) and the method of analysis (partly vs completely automated). Implications The chosen method of quantifying pain drawings in combination with the drawing style of the individual patient, can impact the resulting area estimate to a significant degree. These issues should be considered before undertaking computerized area estimation of pain drawings.

Background and aims Neck pain can impair perception of cervical movement, but how this is affected by attention is unknown. In this study, the effects of experimental neck pain on head repositioning accuracy during standardized head movements were investigated. Methods Experimental neck pain was induced by injecting hypertonic saline into the right splenius capitis muscle in 28 healthy participants (12 women). Isotonic saline was used as control. Participants were blindfolded while performing standardized head movements from neutral (start) to either right-rotation, left-rotation, flexion or extension, then back to neutral (end). Movements were triplicated for each direction, separated by 5-s, and performed with or without a cognitive task at baseline, immediately after the injection, and 5-min after pain disappeared. Repositioning accuracy was assessed by 3-dimensional recordings of head movement and defined as the difference between start and end position. Participants were grouped into most/least accurate based on a median split of head repositioning accuracy for each movement direction at baseline without the cognitive task. Results The most accurate group got less accurate following hypertonic injection during right-rotation without a cognitive task, compared with the least accurate group and the isotonic condition ( p  < 0.01). No group difference was found when testing head repositioning accuracy while the participants where distracted by the cognitive task. Conclusions Experimental neck pain alters head repositioning accuracy in healthy participants, but only in those who are most accurate at baseline. Interestingly, this impairment was no longer present when a cognitive task was added to the head repositioning accuracy test. Implications The results adds to our understanding of what factor may influence the head repositioning accuracy test when used in clinical practice and thereby how the results should be interpreted.

Background and aims While social interactions like verbal support and physical touch have repeatedly been shown to reduce experimental pain, analgesic effects of passive social support, i.e. the sole physical presence of a supportive other, remain unclear. Moreover, little is known about individual factors influencing the extent of pain attenuation during social support. This study investigated analgesic effects of passive support by a romantic partner and the role of partner empathy therein. Methods In 48 heterosexual couples, sensitivity to pressure pain was assessed; each participant was tested alone and in the passive presence of his/her partner. Dispositional empathy was quantified by a questionnaire. Results In the presence, as compared to absence, of their partners men and women exhibited higher pain threshold and tolerance, as well as lower sensory and affective pain ratings on constant pressure stimuli. Partner empathy was positively associated with pain tolerance and inversely associated with sensory pain experience. Conclusions The results confirm the analgesic effects of social support, which may even occur without verbal or physical contact. Partner empathy may buffer affective distress during pain exposure, thereby reducing pain sensitivity and promoting pain coping. These processes may occur solely due to a partner’s physical presence and do not necessarily require direct empathetic feedback.

The abducens nerve palsy is most likely caused by microvascular issue. Spontaneous recovery of vasculopathic abducens nerve palsies was common at 3–6 months. But recovery time was longer when many risk factors were present. Several patients had residual esotropia or abduction deficit. Cervical sympathetic block has an established use in treating patients with disorders related to cranial circulatory insufficiency. It causes a significant increase in cerebral blood flow. We report a case of a 67-year-old man with acute horizontal diplopia and right periocular pain. He had been diagnosed with right abducens nerve palsy caused by microvascular ischemia. We performed ultrasound-guided superior cervical sympathetic ganglion blocks. After 4 weeks, the symptoms had been completely resolved. We introduce ultrasound-guided superior cervical sympathetic ganglion blocks for management of abducens nerve palsy caused by microvascular ischemia, which could be an effective novel method to promote recovery from diplopia.