Grey matter brain alterations in temporomandibular disorder tested in a population cohort and three clinical samples

Using voxel based morphometry (VBM) two samples with chronic temperomandibular pain were compared to controls investigating the brains grey matter volume (GMV). Only the clinical sample showed a decease in anterior cingulate GMV. Contradicting results on GMV loss in temperomandibular pain might be based on small samples in prior studies.

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Imprecise visual feedback about hand location increases a classically conditioned pain expectancy effect

Chronic musculoskeletal pain is a major health problem with a one-year prevalence of 25% to 36% in the general population35. Costs related to persistent pain in the United States of America are between $560 and $635 billion annually18. Many persistent pain states are not associated with ongoing tissue pathology, an originally perplexing observation that is now explained by functional changes in the nociceptive system and brain79-81. Broadly speaking, these functional changes may be considered learning; stimulus-response profiles change such that stimuli that are not normally painful come to evoke pain, a situation termed allodynia, and normally painful stimuli come to evoke more pain, a situation termed hyperalgesia79.

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Effect of topical analgesia on desensitization following 8% topical capsaicin application

The transient receptor potential V1 (TRPV1) is a non-selective cation channel activated by heat and capsaicin, the pungent ingredient contained in hot chili peppers.35 TRPV1 is expressed in the majority of polymodal nociceptors (thinly myelinated Aδ and unmyelinated C-fibers)3,7,50 involved in the transduction of nociceptive and pruritic signals and in the pathophysiology of neuropathic pain.1 Initially, the activation of TRPV1 by capsaicin induces an influx of Ca2+ and Na+ ions resulting in depolarization and thereby generating an action potential.

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Effectiveness of a structured group intervention based on pain neuroscience education for patients with fibromyalgia in primary care: a multicenter randomized open‐label controlled trial

Abstract

Background

There has been increased interest in pain neuroscience education (PNE) as a therapeutic approach for the management of fibromyalgia (FM).

Methods

A multicenter randomized, open‐label, controlled trial was conducted to assess the effectiveness of a structured group intervention based on PNE in patients with FM. A total of 139 patients were included in the study and randomized to the intervention group (7 group sessions of education in neurobiology of pain) or to the control group (treatment as usual only). The primary outcome was the improvement of functional status and pain measured with the Fibromyalgia Impact Questionnaire (FIQ), and secondary outcomes were the reduction of the impact of pain and other symptoms (catastrophizing, anxiety, and depression) and number of patients reaching no worse than moderate functional impairment (FIQ score < 39). Differences between groups were calculated by linear mixed‐effects (intention‐to‐treat approach) and mediational models through path analyses.

Results

At 1 year, improvements in FIQ scores were higher in the intervention group with moderate or high effect size, and decreases of ≥ 20% in 69.1% of patients (20.9 % in the control group) and of ≥ 50% in 39.7% (4.5% in the control group). Also, 52.9% of patients had a FIQ < 39 points (13.4% in the control group).

Conclusions

In this sample of patients with FM, the improvement in quality of life and control of symptoms obtained by adding a PNE intervention showed promising results, equaling or surpassing previously reported outcomes.

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Non-steroidal anti-inflammatory drugs (NSAIDs) for musculoskeletal pain

What you need to knowOral non-steroidal anti-inflammatory drugs (NSAIDs) can reduce musculoskeletal pain but increase the risk of gastrointestinal (perforation, ulcers, bleeding), cardiovascular...

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[Clinical Picture] Widespread soft tissue calcification in systemic sclerosis, polymyositis, and polyarthritis

A 55-year-old woman was admitted to our department with gradual onset of pain in her hands, hips, and knees, which had progressively limited her mobility over the past 6 years. She also reported feeling tired and feverish.

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Inhibition of ferroptosis‐like cell death attenuates neuropathic pain reactions induced by peripheral nerve injury in rats

Abstract

Background

Relationships between iron dependent ferroptosis and nerve system diseases have been recently revealed. However, the role of ferroptosis in neuropathic pain (NeP) remains to be elucidated. Thus, we aimed to investigate whether ferroptosis in spinal cord contributes to NeP induced by a chronic constriction injury (CCI) of the sciatic nerve.

Method

Forty Sprague Dawley rats received CCI or sham surgery, and were randomly assigned to the following four groups: sham group; CCI+LIP group; CCI+Veh group; and CCI group. Liproxstatin‐1 or corn oil were separately injected intraperitoneally for three consecutive days after surgery in the CCI+LIP or CCI+Veh group. The mechanical and thermal hypersensitivities were tested after surgery. Biochemical and morphological changes related to ferroptosis in the spinal cord were also assessed. These included iron content, glutathione peroxidase 4 (GPX4) and anti‐acyl‐CoA synthetase long‐chain family member 4 (ACSL4) expression, lipid peroxidation assays, as well as mitochondrial morphology.

Result

CCI‐induced NeP was followed by iron accumulation, increased lipid peroxidation, and dysregulation of ACSL4 and GPX4. Moreover, transmission electron microscopy confirmed the presence of aberrant morphological changes on mitochondrial, such as mitochondria shrinkage and membrane rupture. Furthermore, the administration of liproxstatin‐1 on CCI rats attenuated hypersensitivities, lowered the iron level, decreased spinal lipid peroxidation, restored the dysregulations in GPX4 and ACSL4 levels, and protected against CCI induced morphological changes in mitochondria.

Conclusion

Our findings indicated the involvement of ferroptosis in CCI induced NeP, and point to ferroptosis inhibitors such as liproxstatin‐1 as potential therapies for hypersensitivity induced by peripheral nerve injury.

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Inhibition of ferroptosis‐like cell death attenuates neuropathic pain reactions induced by peripheral nerve injury in rats

Abstract

Background

Relationships between iron dependent ferroptosis and nerve system diseases have been recently revealed. However, the role of ferroptosis in neuropathic pain (NeP) remains to be elucidated. Thus, we aimed to investigate whether ferroptosis in spinal cord contributes to NeP induced by a chronic constriction injury (CCI) of the sciatic nerve.

Method

Forty Sprague Dawley rats received CCI or sham surgery, and were randomly assigned to the following four groups: sham group; CCI+LIP group; CCI+Veh group; and CCI group. Liproxstatin‐1 or corn oil were separately injected intraperitoneally for three consecutive days after surgery in the CCI+LIP or CCI+Veh group. The mechanical and thermal hypersensitivities were tested after surgery. Biochemical and morphological changes related to ferroptosis in the spinal cord were also assessed. These included iron content, glutathione peroxidase 4 (GPX4) and anti‐acyl‐CoA synthetase long‐chain family member 4 (ACSL4) expression, lipid peroxidation assays, as well as mitochondrial morphology.

Result

CCI‐induced NeP was followed by iron accumulation, increased lipid peroxidation, and dysregulation of ACSL4 and GPX4. Moreover, transmission electron microscopy confirmed the presence of aberrant morphological changes on mitochondrial, such as mitochondria shrinkage and membrane rupture. Furthermore, the administration of liproxstatin‐1 on CCI rats attenuated hypersensitivities, lowered the iron level, decreased spinal lipid peroxidation, restored the dysregulations in GPX4 and ACSL4 levels, and protected against CCI induced morphological changes in mitochondria.

Conclusion

Our findings indicated the involvement of ferroptosis in CCI induced NeP, and point to ferroptosis inhibitors such as liproxstatin‐1 as potential therapies for hypersensitivity induced by peripheral nerve injury.

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Inhibition of ferroptosis‐like cell death attenuates neuropathic pain reactions induced by peripheral nerve injury in rats

Abstract

Background

Relationships between iron dependent ferroptosis and nerve system diseases have been recently revealed. However, the role of ferroptosis in neuropathic pain (NeP) remains to be elucidated. Thus, we aimed to investigate whether ferroptosis in spinal cord contributes to NeP induced by a chronic constriction injury (CCI) of the sciatic nerve.

Method

Forty Sprague Dawley rats received CCI or sham surgery, and were randomly assigned to the following four groups: sham group; CCI+LIP group; CCI+Veh group; and CCI group. Liproxstatin‐1 or corn oil were separately injected intraperitoneally for three consecutive days after surgery in the CCI+LIP or CCI+Veh group. The mechanical and thermal hypersensitivities were tested after surgery. Biochemical and morphological changes related to ferroptosis in the spinal cord were also assessed. These included iron content, glutathione peroxidase 4 (GPX4) and anti‐acyl‐CoA synthetase long‐chain family member 4 (ACSL4) expression, lipid peroxidation assays, as well as mitochondrial morphology.

Result

CCI‐induced NeP was followed by iron accumulation, increased lipid peroxidation, and dysregulation of ACSL4 and GPX4. Moreover, transmission electron microscopy confirmed the presence of aberrant morphological changes on mitochondrial, such as mitochondria shrinkage and membrane rupture. Furthermore, the administration of liproxstatin‐1 on CCI rats attenuated hypersensitivities, lowered the iron level, decreased spinal lipid peroxidation, restored the dysregulations in GPX4 and ACSL4 levels, and protected against CCI induced morphological changes in mitochondria.

Conclusion

Our findings indicated the involvement of ferroptosis in CCI induced NeP, and point to ferroptosis inhibitors such as liproxstatin‐1 as potential therapies for hypersensitivity induced by peripheral nerve injury.

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Inhibition of ferroptosis‐like cell death attenuates neuropathic pain reactions induced by peripheral nerve injury in rats

Abstract

Background

Relationships between iron dependent ferroptosis and nerve system diseases have been recently revealed. However, the role of ferroptosis in neuropathic pain (NeP) remains to be elucidated. Thus, we aimed to investigate whether ferroptosis in spinal cord contributes to NeP induced by a chronic constriction injury (CCI) of the sciatic nerve.

Method

Forty Sprague Dawley rats received CCI or sham surgery, and were randomly assigned to the following four groups: sham group; CCI+LIP group; CCI+Veh group; and CCI group. Liproxstatin‐1 or corn oil were separately injected intraperitoneally for three consecutive days after surgery in the CCI+LIP or CCI+Veh group. The mechanical and thermal hypersensitivities were tested after surgery. Biochemical and morphological changes related to ferroptosis in the spinal cord were also assessed. These included iron content, glutathione peroxidase 4 (GPX4) and anti‐acyl‐CoA synthetase long‐chain family member 4 (ACSL4) expression, lipid peroxidation assays, as well as mitochondrial morphology.

Result

CCI‐induced NeP was followed by iron accumulation, increased lipid peroxidation, and dysregulation of ACSL4 and GPX4. Moreover, transmission electron microscopy confirmed the presence of aberrant morphological changes on mitochondrial, such as mitochondria shrinkage and membrane rupture. Furthermore, the administration of liproxstatin‐1 on CCI rats attenuated hypersensitivities, lowered the iron level, decreased spinal lipid peroxidation, restored the dysregulations in GPX4 and ACSL4 levels, and protected against CCI induced morphological changes in mitochondria.

Conclusion

Our findings indicated the involvement of ferroptosis in CCI induced NeP, and point to ferroptosis inhibitors such as liproxstatin‐1 as potential therapies for hypersensitivity induced by peripheral nerve injury.

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Cognition in the Chronic Pain Experience: Preclinical Insights

Publication date: Available online 25 January 2021

Source: Trends in Cognitive Sciences

Author(s): Caroline E. Phelps, Edita Navratilova, Frank Porreca

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Diagnosis and referral of adults with suspected bony metastases

What you need to knowRed flag symptoms for cancer related bone pain include severe progressive pain that is worse on movement or at night, inability to bear weight, signs of hypercalcaemia, and pain...

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Modelling at‐level allodynia after mid‐thoracic contusion in the rat

Abstract

Background

The rat mid‐thoracic contusion model has been used to study at‐level tactile allodynia, a common type of pain that develops after spinal cord injury (SCI). An important advantage of this model is that not all animals develop hypersensitivity. Therefore, it can be used to examine mechanisms that are strictly related to the development of pain‐like behaviour separately from mechanisms related to the injury itself. However, how to separate animals that develop hypersensitivity from those that do not is unclear.

Methods

The aims of the current study were to identify where hypersensitivity and spasticity develop and use this information to identify metrics to separate animals that develop hypersensitivity from those that do not to study differences in their behaviour. To accomplish these aims, a grid was used to localize hypersensitivity on the dorsal trunk relative to thoracic dermatomes and supraspinal responses to tactile stimulation were tallied. These supraspinal responses were used to develop a hypersensitivity score to separate animals that develop hypersensitivity, or pain‐like response to nonpainful stimuli.

Results

Similar to humans, the development of hypersensitivity could occur with the development of spasticity or hyperreflexia. Moreover, the time course and prevalence of hypersensitivity phenotypes (at‐, above‐, or below level) produced by this model were similar to that observed in humans with SCI.

Conclusion

However, the amount of spared spinal matter in the cord did not explain the development of hypersensitivity, as previously reported. This approach can be used to study the mechanisms underlying the development of hypersensitivity separately from mechanisms related to injury alone.

Significance

To model at‐level tactile allodynia, rat hypersensitivity was assessed by carefully observing supraspinal responses that are indicative of pain‐like behaviours after mid‐thoracic SCI. By quantifying these supraspinal responses, a hypersensitivity score was developed that models allodynia and was used to separate animals that develop at‐level hypersensitivity from those that did not. Hypersensitivity that included supraspinal responses was localized to thoracic dermatomes T4‐T11 and could be identified by considering only audible vocalisation and avoidance behaviours. Like human allodynia, at‐level hypersensitivity often occurred without hypersensitivity at other levels, was distinguishable from spasticity and hyperreflexia, and developed early after SCI, suggesting that this model could be used to study mechanisms underlying at‐level allodynia.

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Prefrontal White Matter Abnormalities Associated With Pain Catastrophizing in Patients With Complex Regional Pain Syndrome

Publication date: February 2021

Source: Archives of Physical Medicine and Rehabilitation, Volume 102, Issue 2

Author(s): Jooyeon Jamie Im, Jungyoon Kim, Hyeonseok Jeong, Jin Kyoung Oh, Suji Lee, In Kyoon Lyoo, Yong-An Chung, Sujung Yoon

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Paracetamol, traumatic injury, . . . and other stories

Pain after traumaParacetamol is as good as a non-steroidal anti-inflammatory drug for post-traumatic pain and no advantage is gained in combining both treatments, according to a trial from an...

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Mindful self‐compassion program for chronic pain patients: A randomized controlled trial

Abstract

Background

Although evidence‐based psychological treatments for chronic pain have been demonstrated to be effective for a variety of outcomes, modest effects observed in recent reviews indicate scope for improvement. Self‐compassion promotes a proactive attitude towards self‐care and actively seeking relief from suffering. Consequently, more compassionate people experience better physical, psychological, and interpersonal wellbeing.

Methods

We conducted a single‐blind, randomized, controlled trial to examine the effects of a Mindful Self‐Compassion program (MSC) on relevant clinical outcomes in patients with chronic pain. Patients were randomly assigned to one of the two intervention arms: MSC or Cognitive‐Behavioral Therapy (CBT). The protocols of both intervention arms were standardized and consisted of a 150‐minute session once every 8 weeks formatted to groups of no more than 20 participants. The primary outcome was self‐compassion, measured with the self‐compassion scale (SCS). The secondary outcomes were other pain‐related scores, quality‐of‐life measures, and anxiety and depression scores.

Results

Sixty‐two and sixty‐one patients were assigned to the MSC and CBT group, respectively. The MSC intervention was more effective than CBT for self‐compassion (ATE = 0.126, p < 0.05). The secondary outcomes, pain acceptance (ATE = 5.214, p < 0.01), pain interference (ATE = ‐0.393, p < 0.05), catastrophizing (ATE = ‐2.139, p < 0.10), and anxiety (ATE = ‐0.902, p < 0.05), were also favored in the experimental arm (MSC). No serious adverse events were observed.

Conclusions

MSC is an appropriate therapeutic approach for chronic pain patients and may result in greater benefits on self‐compassion and emotional well‐being than CBT.

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A Systematic Review and Meta‐analysis of Radiofrequency Procedures on Innervation to the Shoulder Joint for relieving Chronic Pain

ABSTRACT

Background and Objective

Studies have reported relief of chronic shoulder pain with non‐ablative pulsed neuromodulatory [pRF] or ablative radiofrequency [aRF] procedures on innervation of the shoulder joint but interpretation of these reports is hampered by inconsistent indications, anatomic targets, and follow‐up. This systematic review was conducted to synthesize the existing literature on procedures employing pRF or aRF for treating chronic shoulder pain.

Databases and Data Treatment

MEDLINE and other medical literature databases were reviewed up to December 31, 2019 for publications on pRF or aRF procedures on shoulder joint innervation to relieve chronic pain. Data on analgesic and functional outcomes measured at any time point following the interventions were extracted. Existing knowledge on innervation of the shoulder joint with relevance to RF procedures was also synthesized.

Results

Forty‐two publications, seven randomized controlled trials [RCTs] and 35 observational studies, case series or reports were identified. Thirty‐six of these publications were on pRF procedure and 29 of these reported procedures exclusively targeting the suprascapular nerve. A meta‐analysis of the seven RCTs evaluating pRF indicated no analgesic benefit or functional improvement with this treatment over conventional medical management. Case series and reports on aRF indicate a potential for analgesic benefit but the quality of this evidence was low.

Conclusions

RF treatments targeting the sensory innervation of the shoulder joint affected by degenerative conditions have the potential to reduce pain but the current evidence does not suggest analgesic or functional benefit (GRADE certainty of evidence ‐ low). Studies of high methodological quality are required to further investigate the role of these interventions.

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Factors associated with seeking medical care for low back pain in a twin adult sample

ABSTRACT

Background

Previous studies have only investigated how symptom presentation and socio‐demographic factors influence care‐seeking for low back pain (LBP). However, the influence of health and lifestyle factors remains unclear, and the potential confounding effects of aggregated familial factors (including genetics and the early shared environment) has not been considered extensively.

Methods

A cross‐sectional analysis was performed on 1605 twins enrolled in the Murcia Twin Registry (Spain). The outcome was seeking medical care for LBP and various self‐reported demographic, health, and lifestyle factors were considered predictors. All variables except sleep quality and diabetes were collected in 2013, which were cross‐referenced from 2009/2010. A multivariate logistic regression model was performed on the total sample, followed by a co‐twin case‐control analysis.

Results

The only significant factor found to increase the odds of seeking medical care for LBP without being affected by familial factors was poor sleep quality (total sample OR=1.58, 95%CI 1.24‐2.01; case‐control OR=1.75, 95%CI 1.14‐2.69). The factors that were associated with reduced odds of seeking medical care for LBP and not confounded by familial factors were male sex (case‐control OR=0.55, 95%CI 0.33‐0.93), alcohol intake (case‐control OR=0.90, 95%CI 0.82‐0.99) and a history of diabetes (case‐control OR=0.50, 95%CI 0.25‐0.97). No other factors significantly influenced medical care‐seeking for LBP.

Conclusions

People reporting poor sleep quality are more likely to seek medical care for LBP in the long term, with this relationship being independent from aggregated familial factors. Conversely, males, people reporting higher alcohol intake, and people with a history of diabetes are less likely to seek medical care for LBP.

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Desire to receive more pain treatment – a relevant patient-reported outcome measure to assess quality of post-operative pain management? Results from 79,996 patients enrolled in the pain registry QUIPS from 2016 to 2019.

Pain after surgery is still a major issue in healthcare.3, 16 Although there are efforts to objectify it.7 pain is still routinely assessed by asking patients to rate their subjective pain intensity on various scales, e.g., the numeric rating scale, the visual analog scale, different faces pain scales, and others.20 Often, pain treatment is then based on or at least influenced by these ratings.

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Internet‐delivered acceptance and commitment therapy as microlearning for chronic pain: A randomized controlled trial with 1‐year follow‐up

Abstract

Background

Studies of Internet‐delivered acceptance and commitment therapy (ACT) for chronic pain have shown small to moderate positive effects for pain interference and pain acceptance. Effects on pain intensity, depression, anxiety and quality of life (QoL) have been less favourable, and improvements for values and sleep are lacking. In this randomized controlled trial iACT – a novel format of Internet‐ACT using daily microlearning exercises – was examined for efficacy compared to a waitlist condition.

Methods

Adult participants (mean age 49.5 years, pain duration 18.1 years) with diverse chronic pain conditions were recruited via self‐referral, and randomized to iACT (n = 57) or waitlist (n = 56). The primary outcome was pain interference. The secondary outcomes were QoL, depression, anxiety, insomnia and pain intensity. The process variables included psychological inflexibility and values. Post‐assessments were completed by 88% (n = 100) of participants. Twelve‐month follow‐up assessments were completed by 65% (iACT only, n = 37). Treatment efficacy was analysed using linear mixed models and an intention‐to‐treat‐approach.

Results

Significant improvements in favour of iACT were seen for pain interference, depression, anxiety, pain intensity and insomnia, as well as process variables psychological inflexibility and values. Between‐group effect sizes were large for pain interference (d = 0.99) and pain intensity (d = 1.2), moderate for anxiety and depressive symptoms and small for QoL and insomnia. For the process variables, the between‐group effect size was large for psychological inflexibility (d = 1.0) and moderate for values. All improvements were maintained at 1‐year follow‐up.

Conclusions

Internet‐ACT as microlearning may improve a broad range of outcomes in chronic pain.

Significance

The study evaluates a novel behavioral treatment with positive results on pain interference, mood as well as pain intensity for longtime chronic pain sufferers. The innovative format of a digital ACT intervention delivered in short and experiential daily learnings may be a promising way forward.

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Pain after a motor vehicle crash: The role of socio‐demographics, crash characteristics, and peri‐traumatic stress symptoms

Abstract

Background

The vast majority of individuals who come to the emergency department (ED) for care after a motor vehicle collision (MVC) are diagnosed with musculoskeletal strain only and are discharged to home. A significant subset of this population will still develop persistent pain and posttraumatic psychological sequelae may play an important role in pain persistence.

Methods

We conducted a multisite longitudinal cohort study of adverse post‐traumatic neuropsychiatric sequelae (APNS) among patients seeking emergency department (ED) treatment in the aftermath of a traumatic life experience. We report on a sub‐group of patients (n=666) presenting after an MVC, the most common type of trauma and we examine associations of socio‐demographic and MVC characteristics, and persistent pain eight weeks after MVC. We also examine the degree to which these associations are related to peritraumatic psychological symptoms and 2‐week acute stress reactions using an applied approach.

Results

Eight‐week prevalence of persistent moderate or severe pain was high (67.4%) and positively associated with patient sex (female), older age, low socioeconomic status (education and income), and pain severity in the ED. Peritraumatic stress symptoms (distress and dissociation) appear to exert some influence on both acute pain and the transition from acute to persistent pain

Discussion and Conclusions

The early aftermath of an MVC may be an important time period for intervening to prevent and reduce persistent pain. Substantial variation in mediating pathways across predictors also suggests potential diverse and complex underlying biological and psychological pathogenic processes are at work in the early weeks following trauma.

Significance

The first several days after trauma may dictate recovery trajectories. Persistent pain, pain lasting beyond the expected time of recovery, is associated with pain early in the recovery period, but also mediated through other pathways. Future work is needed to understand the complex neurobiological processes in involved in the development of persistent and acute post‐traumatic pain.

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P2X7‐induced nociception in the temporomandibular joint of rats depends on inflammatory mechanisms and C‐fibers sensitization

Abstract

Background

P2X7 receptors are responsible for triggering inflammatory responses contributing to processes of pain in articular tissues. This study aimed to investigate whether the activation of the P2X7 receptor located in the temporomandibular joint (TMJ) tissues induces nociception through an inflammatory mechanisms and/or the activation of C‐fibers (small‐diameter primary afferents) of rats’ TMJ.

Methods

The TMJ hypernociception induced by the activation of P2X7 receptor was assessed by measuring the behavioral nociceptive responses. After behavioral experiments, the animals were terminally anaesthetized and periarticular tissues were removed and homogenate for enzyme‐linked immunosorbent assay, leukocyte infiltration and Western blotting analysis.

Results

The non‐selective P2X7 receptor agonist BzATP induced a dose‐dependent TMJ nociception, which was blocked by the selective P2X7 receptor antagonist A‐438079. The co‐administration of the selective β2‐adrenoceptor antagonist (ICI‐118,551) and the pre‐treatment with cyclooxygenase inhibitor indomethacin or with the nonspecific selectin inhibitor Fucoidan significantly reduced BzATP‐induced TMJ nociception. BzATP also induced an increase of pro‐inflammatory cytokines TNFα, IL‐1β, and CINC‐1 levels, as well as leukocyte recruitment in TMJ tissue, effects that were reduced by A‐438079. Moreover, BzATP‐induced TMJ nociception was inhibited in rats neonatal‐treated with Capsaicin (depleting C‐fibers). Finally, BzATP‐induced an increase of TRPV1 expression in TMJ tissue.

Conclusions

These findings suggest that P2X7 receptor activation in TMJ of rats induces nociceptive responses mediated by sympathomimetic amines, prostaglandins, leukocyte migration, and increased levels of pro‐inflammatory cytokines. Furthermore, the P2X7 receptor activation induces nociceptive responses dependent on the activation of the primary afferent nociceptors of rats’ TMJ.

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A Systematic Review and Meta-Analysis of the Association between Perceived Injustice and Depression

The past decade has witnessed a dramatic increase in research concerning the identification, development and validation of a psychosocial construct referred to as perceived injustice. While contributions to injustice from an organisational and psychological perspective date back to the 1960’s with the development of Equity Theory1 and include various interpretations and definitions of procedural, distributive, informational and interpersonal injustice in workplace settings,14,22 efforts to consider injustice from a clinical health perspective have been comparatively recent.

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Serotonin plays a key role in the development of opioid-induced hyperalgesia in mice

Opioids are essential for the management of perioperative pain as well as palliative treatment of cancer pain. However, chronic administering of opioids may cause a reduction in the analgesic effect (tolerance), and lead to paradoxical hyperalgesia (opioid-induced hyperalgesia (OIH)) and subsequent physical dependency.2,24,47 More specifically, OIH is often associated with a requirement for increased, and often long-term, administering of opioids, which worsen tolerance, resulting in physical and mental dependence.

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A better touch: C-tactile fibres related activity is associated to pain reduction during temporal summation of second pain

This study extends previous findings on the analgesic potential of affective touch, documenting a clear pain reduction during temporal summation of second pain (TSSP). Since TSSP is thought to reflect central sensitization, the psychophysiological mechanisms of affective touch could be exploited for new chronic pain treatments.

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Exposure to an immersive virtual reality environment modulate perceptual correlates of endogenous analgesia and central sensitisation in healthy volunteers

Exposure to immersive 360° virtual reality (VR) environments has been shown to produce analgesic effects during acute medical procedures as well as in human surrogate pain models and chronic pain states 12, 21, 30, 31. Growing evidence suggests that cognitive and attentional factors are known to have an influence on spinal cord representations of central sensitisation as well as endogenous analgesic circuitry implicated in the descending control of pain 10, 45. However, there is a lack of research into whether the pain-relieving effects of an immersive VR experience are due to top-down influences on perceptual correlates of descending pain modulation.

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Polymorphisms of the μ‐opioid receptor gene influence cerebral pain processing in fibromyalgia

Abstract

Background

Dysregulation of the μ‐opioid receptor has been reported in fibromyalgia (FM) and was linked to pain severity. Here, we investigated the effect of the functional genetic polymorphism of the μ‐opioid receptor gene (OPRM1) (rs1799971) on symptom severity, pain sensitivity and cerebral pain processing in FM subjects and healthy controls (HC).

Methods

Symptom severity and pressure pain sensitivity was assessed in FM subjects (n = 70) and HC (n = 35). Cerebral pain‐related activation was assessed by functional magnetic resonance imaging during individually calibrated painful pressure stimuli.

Results

Fibromyalgia subjects were more pain sensitive but no significant differences in pain sensitivity or pain ratings were observed between OPRM1 genotypes. A significant difference was found in cerebral pain processing, with carriers of at least one G‐allele showing increased activation in posterior cingulate cortex (PCC) extending to precentral gyrus, compared to AA homozygotes. This effect was significant in FM subjects but not in healthy participants, however, between‐group comparisons did not yield significant results. Seed‐based functional connectivity analysis was performed with the seed based on differences in PCC/precentral gyrus activation between OPRM1 genotypes during evoked pain across groups. G‐allele carriers displayed decreased functional connectivity between PCC/precentral gyrus and prefrontal cortex.

Conclusions

G‐allele carriers showed increased activation in PCC/precentral gyrus but decreased functional connectivity with the frontal control network during pressure stimulation, suggesting different pain modulatory processes between OPRM1 genotypes involving altered fronto‐parietal network involvement. Furthermore, our results suggest that the overall effects of the OPRM1 G‐allele may be driven by FM subjects.

Significance

We show that the functional polymorphism of the μ‐opioid receptor gene OPRM1 was associated with alterations in the fronto‐parietal network as well as with increased activation of posterior cingulum during evoked pain in FM. Thus, the OPRM1 polymorphism affects cerebral processing in brain regions implicated in salience, attention, and the default mode network. This finding is discussed in the light of pain and the opioid system, providing further evidence for a functional role of OPRM1 in cerebral pain processing.

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The impact of paradigm and stringent analysis parameters on measuring a net conditioned pain modulation effect: A test, retest, control study

Abstract

Background

Reporting in conditioned pain modulation (CPM) studies is not standardised. Here, two CPM protocols were performed in populations of healthy human subjects in order to investigate the influence of the CPM paradigm and stringent analyses parameters on the identification of a net CPM effect.

Methods

A standard thermal or mechanical CPM protocol was carried out on 25 and 17 subjects, respectively. The standard error of measurement (SEM) of the CPM effect was calculated in order to determine a change in pain thresholds greater than that due to measurement error or ‘real’ change in test scores. In addition, each individual underwent a minimum of two control CPM sessions, which were paired with the CPM test sessions. To quantify a net CPM effect, the intrasession difference between baseline and conditioning was subtracted from the difference calculated at the same time points during the control session.

Results

For both protocols, excellent reliability for intrasession repeats of the test stimulus at baseline was demonstrated for thermal and mechanical stimulation (ICC > 0.9). Test‐retest subject responses (in terms of experimental Session 1 versus. Session 2) showed excellent reliability for mechanical (ICC > 0.8), compared to thermal stimulation, which ranged from poor to moderate (ICC < 0.4‐>0.75). However, calculating the net CPM effect using control session data demonstrated poor‐fair reliability for both protocols (ICC < 0.4–0.59).

Conclusion

Calculating the net CPM effect should be optimised and standardised for comparison of CPM data collected from global research groups. Recommendation is made for the performance of a multicentre, test‐retest study.

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‘Drawing a line in the sand’: Physician diagnostic uncertainty in paediatric chronic pain

Abstract

Background

Diagnostic uncertainty is the subjective perception of an inability to provide an accurate explanation of the patient's health problem or that a label is missing or incorrect. While recently explored in youth with chronic pain and families, this is the first study to investigate diagnostic uncertainty from the perspectives of physicians.

Methods

Individual, semi‐structured interviews were conducted with 16 paediatricians who assess and/or treat youth who experience complex chronic pain. Interviews explored paediatricians’ perceptions, beliefs and confidence regarding the assessment and management of chronic pain in youth and how they manage uncertainty regarding the diagnosis. Interviews were analysed using inductive reflexive thematic analysis.

Results

Analyses generated one prominent theme: ‘drawing a line in the sand’. Within this theme, physicians discussed uncertainty as inherent to their role treating youth with chronic pain. The metaphor of ‘drawing a line in the sand’ was used to describe a process of identifying a point at which physicians no longer sought a new diagnosis for the child's pain or continued diagnostic investigations. This line was influenced by numerous factors, which are highlighted through four subthemes: physician training, experience and mentorship; individual patient and family factors; perceived reassurance of diagnostic investigations; and the broader social context and implications.

Conclusions

How physicians manage diagnostic uncertainty must be understood, as it is likely to critically impact how a diagnosis of chronic pain is communicated, the diagnostic investigations undertaken, the wait time to receiving a diagnosis, and ultimately youths’ pain experiences.

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Interpretation of cluster structures in pain‐related phenotype data using explainable artificial intelligence (XAI)

Abstract

Background

In pain research and clinics, it is common practice to subgroup subjects according to shared pain characteristics. This is often achieved by computer‐aided clustering. In response to a recent EU recommendation that computer‐aided decision making should be transparent, we propose an approach that uses machine learning to provide (1) an understandable interpretation of a cluster structure to (2) enable a transparent decision process about why a person concerned is placed in a particular cluster.

Methods

Comprehensibility was achieved by transforming the interpretation problem into a classification problem: A sub‐symbolic algorithm was used to estimate the importance of each pain measure for cluster assignment, followed by an item categorization technique to select the relevant variables. Subsequently, a symbolic algorithm as explainable artificial intelligence (XAI) provided understandable rules of cluster assignment. The approach was tested using 100‐fold cross‐validation.

Results

The importance of the variables of the data set (6 pain‐related characteristics of 82 healthy subjects) changed with the clustering scenarios. The highest median accuracy was achieved by sub‐symbolic classifiers. A generalized post‐hoc interpretation of clustering strategies of the model led to a loss of median accuracy. XAI models were able to interpret the cluster structure almost as correctly, but with a slight loss of accuracy.

Conclusions

Assessing the variables importance in clustering is important for understanding any cluster structure. XAI models are able to provide a human‐understandable interpretation of the cluster structure. Model selection must be adapted individually to the clustering problem. The advantage of comprehensibility comes at an expense of accuracy.

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How do patients with Alzheimer's disease imagine their pain?

Abstract

Introduction

Pain is underdiagnosed and undertreated in patients with Alzheimer's disease (AD). Pain management is of major importance in this population to limit behavioural and functional consequences. Our study aimed to assess the capacity of AD patients to represent pain using a questionnaire exploring daily painful situations and to determine the most appropriate pain scale assessment.

Methods

Twenty‐eight patients with mild AD, 21 with moderate AD and 28 matched controls underwent the Situation Pain Questionnaire (SP‐Q) and assessed imaginary pain with four pain scales. Two scores were compared between the three groups: the P(A) discrimination score and the response bias β score. P(A) reflects the degree of discrimination between high‐pain and low‐pain events, whereas the β score means the degree to which situations are considered as painful.

Results

Our results showed that AD patients hardly discriminated the high‐ from low‐pain events. Compared to controls, the mean P(A) score was significantly lower for Mild AD (p < 0.03) and Moderate AD (p < 0.004). In addition, the β score indicated that the response bias is higher for AD patients (p < 0.01) in that they overestimated the level of pain.

Conclusion

The present results suggest that patients with Mild and Moderate AD are able to recognize and assess an imagined painful situation even though their pain tolerance is lower than that of controls. The pain scales used should be chosen according to the cognitive, sensorial and personal profiles of the patients.

Significance

The present research is significant because it examines how patients with Alzheimer’s disease understand and assess painful situations. Cognitive impairments can modify this ability. Pain is a sensory and subjective experience and to define its feeling can help us in our clinical practice.

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Some like it hot: Preference for temperature and pungency consumption is associated with sensitivity to noxious heat

Abstract

Background

Individuals vary in their temperature and pungency preferences; whereas some individuals prefer to bath in, or consume food and beverages at very high temperatures, others prefer lukewarm temperatures. Similarly, pungent food may be preferred by some, but not by others. The aim was to investigate, for the first time whether temperature and pungency preferences are associated with variations in thermal sensitivity or ethnic origin related to pungency consumption.

Methods

115 healthy volunteers participated. The thresholds for warm (WST) and heat‐pain (HPT) sensations were measured over the tongue and dorsal hand, and the participants’ preferred drinking and bath temperatures were measured. In addition, data on the participants’ ethnic background as well as temperature and pungency preferences and household habits regarding eating, drinking and bathing were collected.

Results

The reported drinking and bathing preferences correlated significantly with the measured drinking and bath temperatures, respectively, validating subjects’ reports. Tongue and hand HPT, but not WST, correlated with both the reported and the measured drinking and bathing preferences, as well as with pungency preferences. Neither ethnic origin nor gender affected HPT or temperature preferences; however, males preferred a greater level of spiciness than females.

Conclusions

The association of the reported and measured preferences with noxious heat sensitivity in both relevant and irrelevant body regions, and lack of an ethnicity effect may suggest that these qualities are innate. The association of HPT and spiciness preferences correspond with the mutual activation of the tongue vanilloid receptors by noxious heat and capsaicin.

Significance

People vary with regard to their temperature and spiciness preferences for reasons yet unknown. The study revealed that these preferences correlate with one another and were associated with the sensitivity to noxious heat but not with age, gender and cultural background, which suggests that they may be innate.

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Identifying participants with knee osteoarthritis likely to benefit from physical therapy education and exercise: A hypothesis‐generating study

Abstract

Background

The purpose of this investigation was to undertake a hypothesis‐generating study to identify candidate variables that characterize people with knee osteoarthritis who are most likely to experience a positive response to exercise.

Methods

One hundred and fifty participants with knee osteoarthritis participated in this observational, longitudinal study. All participants received a standard exercise intervention that consisted of 20‐min sessions two to three times a week for three months. The classification and regression tree methodology (CART) was used to develop prediction of positive clinical outcome. Positive pain and disability outcomes (dependent variables) were defined as an improvement in pain intensity by >50% or an improvement of five or more on the Oxford knee score, respectively. The predictor variables considered included age, sex, body mass index, knee osteoarthritis severity (Kellgren/Lawrence grade), pain duration, use of medication, range of knee motion, pain catastrophizing, self‐efficacy and knee self‐perception.

Results

Fifty‐five participants (36.6%) were classified as responders for pain intensity and 36.6% were classified as responders for disability. The CART model identified impairments in knee self‐perception and knee osteoarthritis severity as the discriminators for pain intensity reduction following exercise. No variables predicted reduction of disability level following exercise.

Conclusions

Such findings suggest that both body perception and osteoarthritis severity may play a role in treatment outcome with exercise. It also raises the possibility that those with higher levels of disrupted body perception may need additional treatment targeted at restoring body perception prior to undertaking exercise.

Significance

Regardless age, sex, body mass index, pain duration, use of medication, knee range of motion, pain catastrophizing and self‐efficacy, participants with knee osteoarthritis who report low levels of body perception disruption (a FreKAQ score ≦ 17) and minimal structural changes (KL grade I) demonstrate significantly better outcomes from exercise therapy than other participants.

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Digital manikins to self‐report pain on a smartphone: A systematic review of mobile apps

Abstract

Background

Chronic pain is the leading cause of disability. Improving our understanding of pain occurrence and treatment effectiveness requires robust methods to measure pain at scale. Smartphone‐based pain manikins are human‐shaped figures to self‐report location‐specific aspects of pain on people's personal mobile devices.

Methods

We searched the main app stores to explore the current state of smartphone‐based pain manikins and to formulate recommendations to guide their development in the future.

Results

The search yielded 3,938 apps. Twenty‐eight incorporated a pain manikin and were included in the analysis. For all apps, it was unclear whether they had been tested and had end‐user involvement in the development. Pain intensity and quality could be recorded in 28 and 13 apps, respectively, but this was location specific in only 11 and 4. Most manikins had two or more views (n = 21) and enabled users to shade or select body areas to record pain location (n = 17). Seven apps allowed personalising the manikin appearance. Twelve apps calculated at least one metric to summarise manikin reports quantitatively. Twenty‐two apps had an archive of historical manikin reports; only eight offered feedback summarising manikin reports over time.

Conclusions

Several publically available apps incorporated a manikin for pain reporting, but only few enabled recording of location‐specific pain aspects, calculating manikin‐derived quantitative scores, or generating summary feedback. For smartphone‐based manikins to become adopted more widely, future developments should harness manikins’ digital nature and include robust validation studies. Involving end users in the development may increase manikins’ acceptability as a tool to self‐report pain.

Significance

This review identified and characterised 28 smartphone apps that included a pain manikin (i.e. pain drawings) as a novel approach to measure pain in large populations. Only few enabled recording of location‐specific pain aspects, calculating quantitative scores based on manikin reports, or generating manikin feedback. For smartphone‐based manikins to become adopted more widely, future studies should harness the digital nature of manikins, and establish the measurement properties of manikins. Furthermore, we believe that involving end users in the development process will increase acceptability of manikins as a tool for self‐reporting pain.

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Dexmedetomidine versus clonidine adjuvants to levobupivacaine for ultrasound‐guided transversus abdominis plane block in paediatric laparoscopic orchiopexy: Randomized, double‐blind study

Abstract

Background

Laparoscopic surgeries are associated with less postoperative pain and adverse events compared to open procedures. But, it still reduces the quality of life in children. Transversus abdominis plane (TAP) block is used to reduce pain. We hypothesized that dexmedetomidine or clonidine could improve the analgesic profile of levobupivacaine to the same extent during TAP block in children.

Methods

Ninety children were randomly allocated in a randomized double‐blind trial to receive bilateral TAP block with levobupivacaine plus normal saline (group B, n = 30), or dexmedetomidine (group D, n = 30) or clonidine (group C, n = 30). Primary outcome was the modified Children's Hospital of Eastern Ontario Pain Scale score. Secondary outcomes included time to initial analgesic request, number of analgesic claims, total analgesic consumption, parents' satisfaction, sedation score and complications.

Results

Children of group D showed reduced pain scores compared to other groups. They represented the longest period of analgesia (565.00 ± 71.5 min) with p < 0.001, and fewer patients required two doses of analgesia during the first postoperative day. The cumulative amount of backup analgesia was significantly different between these groups (p = 0.026). Higher parents’ satisfaction scores were recorded in groups D and C compared to group B. Sedation among the study groups revealed significant differences (p = 0.035), but no severe complications were recorded.

Conclusions

Adding dexmedetomidine to levobupivacaine can extend the time of analgesia and reduce the use of postoperative backup analgesics with minimal sedation effects when used in TAP block in paediatrics undergoing laparoscopic orchiopexy. Clonidine can be used as an alternative adjuvant to local anaesthetics with good postoperative analgesic profiles.

Significance

Clonidine can alternate dexmedetomidine during TAP block with local anesthetics for pediatrics laparoscopies. Both can lead to better postoperative analgesic profiles. Clonidine may be preferred, especially in our developing regions, because of its easy availability and lower cost than that of dexmedetomidine.

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Herpes Zoster Duplex Unilateralis as a manifestation of severe lymphopenia in COVID19

European Journal of Pain, Volume 25, Issue 2, Page 508-509, February 2021.

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Pain catastrophizing as a treatment process variable in cognitive behavioural therapy for adults with chronic pain

Abstract

Background

Interdisciplinary cognitive behavioural therapy (CBT) for chronic pain is effective at improving function, mood and pain interference among individuals with disabling chronic pain. Traditionally, CBT assumes that cognitive change is an active therapeutic ingredient in the determination of treatment outcome. Pain catastrophizing, a cognitive response style that views the experience of pain as uncontrollable, permanent and destructive, has been identified as an important maladaptive cognition which contributes to difficulties with the management of chronic pain. Consequently, pain catastrophizing is commonly targeted in CBT for chronic pain.

Objectives

To examine change trajectories in pain catastrophizing during treatment and assess the relevance of these trajectories to outcomes at posttreatment.

Methods

Participants included individuals with chronic pain (N = 463) who completed a 3‐week program of interdisciplinary CBT. Pain catastrophizing was assessed weekly over the 3 weeks of treatment and latent growth curve modelling was used to identify trajectories of change.

Results

Findings indicated the presence of two classes of linear change, one with a significant negative slope in pain catastrophizing (i.e. improved class) and the other with a non‐significant slope (i.e. unchanged class). Next, latent growth mixture modelling examined treatment outcome in relation to class membership. These results indicated that individuals in the ‘improved’ PCS class had significantly greater improvement in pain interference and mood, as well as physical and mental quality of life compared to the ‘unchanged’ class.

Conclusions

Implications for our findings, in relation to the CBT model, are discussed.

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Which passengers are on your bus? A taxonomy of the barriers adolescents with chronic pain face in achieving functional recovery

Abstract

Background

Despite evidence that intensive interdisciplinary pain treatment (IIPT) is effective in facilitating functional recovery in adolescents with chronic pain, engagement with IIPT is suboptimal among adolescents. A key aspect of IIPT is to support functional recovery via (re)engagement with age‐appropriate daily activities. The aim of this study was to gain a comprehensive insight into adolescents’ perceptions of the barriers they need to overcome to engage with age‐appropriate activities in order to achieve functional recovery.

Methods

Forty‐one adolescents who were starting an IIPT programme completed the ‘passenger‐on‐the‐bus metaphor’, an exercise in which they identify and describe their perceived barriers (i.e. ‘passengers’ on their bus) that prevent them from engaging with age‐appropriate activities. The responses were analysed using inductive thematic analyses to generate a taxonomy of perceived barriers to functional recovery.

Results

We generated a taxonomy of seven different barriers that participants described facing on their road to functional recovery: physical constraints, being ‘fed up’, low self‐confidence and self‐esteem, perfectionism, avoidance of engagement with pain, feelings (such as sadness, anger, guilt, anxiety) and social barriers (received from a range of sources such as parents, friends, school and wider society).

Conclusion

The findings reveal a variety of barriers that were perceived to hinder functional recovery through reduced engagement with age‐appropriate activities and thereby hamper progress within IIPT. The Passenger on the bus metaphor can be used to identify similar barriers faced by adolescents in an individualized treatment approach, thereby making it possible for clinicians to target their IIPT more precisely.

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Time course of DNA methylation in pain conditions: From experimental models to humans

Abstract

Background and Objective

Throughout the last decade, research has uncovered associations between pain and epigenetic alterations caused by environmental factors. Specifically, studies have demonstrated correlations between pain conditions and altered DNA methylation patterns. Thus, DNA methylation has been revealed as a possible modulator or contributor to pain conditions, providing a potential therapeutic target for treatment by DNA methylation modification. To develop such treatments, it is necessary to clarify a wide number of aspects on how DNA methylation affects pain perception; first and foremost, the temporal dynamics. The objective of the present review is to provide an overview of current knowledge on temporal dynamics of DNA methylation in response to pain, and to investigate if a timeframe can be established based on the data of currently published studies.

Databases and data treatment

PubMed, MEDLINE, Google Scholar and Embase were searched comprehensively for studies of DNA methylation in neuropathic, inflammatory and alternative animal pain models, and in chronic pain patients including Complex Regional Pain Syndrome, chronic postsurgical pain, chronic widespread pain, fibromyalgia and Crohn's disease.

Results

We identified 34 articles highlighting variations in temporal dynamics of DNA methylation across species and between different types of pain. These studies represent a starting point to uncover new insights in the DNA methylation time course in pain.

Conclusions

No timeframe can currently be made for the DNA methylation response to pain in any of the reviewed conditions, highlighting an important focus area for future research.

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Medical cannabis treatment for chronic pain: Outcomes and prediction of response

Abstract

Background

Although studied in a few randomized controlled trials, the efficacy of medical cannabis (MC) for chronic pain remains controversial. Using an alternative approach, this multicentre, questionnaire‐based prospective cohort was aimed to assess the long‐term effects of MC on chronic pain of various aetiologies and to identify predictors for MC treatment success.

Methods

Patients with chronic pain, licensed to use MC in Israel, reported weekly average pain intensity (primary outcome) and related symptoms before and at 1, 3, 6, 9 and 12 months following MC treatment initiation. A general linear model was used to assess outcomes and identify predictors for treatment success (≥30% reduction in pain intensity).

Results

A total of 1,045 patients completed the baseline questionnaires and initiated MC treatment, and 551 completed the 12‐month follow‐up. At 1 year, average pain intensity declined from baseline by 20% [−1.97 points (95%CI = −2.13 to −1.81; p < 0.001)]. All other parameters improved by 10%–30% (p < 0.001). A significant decrease of 42% [reduction of 27 mg; (95%CI = −34.89 to 18.56, p < 0.001)] from baseline in morphine equivalent daily dosage of opioids was also observed. Reported adverse effects were common but mostly non‐serious. Presence of normal to long sleep duration, lower body mass index and lower depression score predicted relatively higher treatment success, whereas presence of neuropathic pain predicted the opposite.

Conclusions

This prospective study provides further evidence for the effects of MC on chronic pain and related symptoms, demonstrating an overall mild‐to‐modest long‐term improvement of the tested measures and identifying possible predictors for treatment success.

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Differential effects of visually induced analgesia and attention depending on the pain stimulation site

Abstract

Background

The term ‘visually induced analgesia’ describes a reduced pain perception induced by watching the painful body part as opposed to watching a neutral object. In chronic back pain patients, experimental pain, movement‐induced pain and habitual pain can be reduced with visual feedback. Visual feedback can also enhance the effects of both massage treatment and manual therapy. The impact of somatosensory attentional processes remains unclear.

Methods

In the current study, participants received painful electrical stimuli to their thumb and back while being presented with either a real‐time video of their thumb or back (factor feedback). In addition, using an oddball paradigm, they had to count the number of deviant stimuli, applied to either their back or thumb (factor attention) and rate the pain intensity.

Results

We found a significant main effect for attention with decreased pain ratings during attention. There was no main effect for visual feedback and no significant interaction between visual feedback and attention. Post‐hoc tests revealed that the lowest pain intensity ratings were achieved during visual feedback of the back/ thumb and counting at the back/ thumb.

Conclusion

These data suggest that the modulation of perceived acute pain by visually induced analgesia may be influenced by a simultaneous somatosensory attention task.

Significance

Somatosensory attention reduced experimental pain intensity in the thumb and back in the presence of both congruent and incongruent visual feedback. We found no significant visual feedback effect on the complex interplay between visual feedback and somatosensory attention.

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Metabolomics in chronic pain research

Abstract

Background and Objective

Metabolomics deals with the identification and quantification of small molecules (metabolites) in biological samples. As metabolite levels can reflect normal or altered metabolic pathways, their measurement provides information to improve the understanding, diagnosis and management of diseases. Despite its immense potential, metabolomics applications to pain research have been sparse. This paper describes current metabolomics techniques, reviews published human metabolomics pain research and compares successful metabolomics research in other areas of medicine with the goal of highlighting opportunities offered by metabolomics to advance pain medicine.

Databases and Data Treatment

Non‐systematic review.

Results

Our search identified 19 studies that adopted a metabolomics approach in: fibromyalgia (7), chronic widespread pain (4), other musculoskeletal pain conditions (5), neuropathic pain (1), complex regional pain syndrome (1) and pelvic pain (1). The studies used either mass spectrometry or nuclear magnetic resonance. Most are characterized by small sample sizes. Some consistency has been found for alterations in glutamate and testosterone metabolism, and metabolic imbalances caused by the gut microbiome.

Conclusions

Metabolomics research in chronic pain is in its infancy. Most studies are at the pilot stage. Metabolomics research has been successful in other areas of medicine. These achievements should motivate investigators to expand metabolomics research to improve the understanding of the basic mechanisms of human pain, as well as provide tools to diagnose, predict and monitor chronic pain conditions. Metabolomics research can lead to the identification of biomarkers to support the development and testing of treatments, thereby facilitating personalized pain medicine.

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Nerve growth factor sensitizes nociceptors to C‐fibre selective supra‐threshold electrical stimuli in human skin

Abstract

Background

Intradermal injection of 1 µg nerve growth factor (NGF) causes sustained nociceptor sensitization. Slowly depolarizing electrical current preferentially activates C‐nociceptors.

Methods

We explored the differential contribution of A‐delta and C‐nociceptors in NGF‐sensitized skin using slowly depolarizing transcutaneous electrical current stimuli, CO2 laser heat, mechanical impact, and A‐fibre compression block. In 14 healthy volunteers, pain rating was recorded on a numeric scale at days 1–14 after NGF treatment. Ratings during A‐fibre conduction block were investigated at days 3 and 7 post‐NGF.

Results

Pain ratings to electrical, CO2 heat and mechanical impact stimuli were enhanced (>30%, p < .0005, ANOVA) at NGF‐injection sites. Axon reflex erythema evoked by electrical stimulation was also larger at NGF‐injection sites (p < .02, ANOVA). Diminution of pain during continuous (1 min) sinusoidal current stimulation at 4 Hz was less pronounced after NGF (p < .05, ANOVA). Pain ratings to electrical sinusoidal and mechanical impact stimuli during A‐fibre conduction block were significantly elevated at the NGF sites compared to NaCl‐treated skin (p < .05, ANOVA).

Conclusions

NGF‐induced sensitization of human skin to electrical and mechanical stimuli is primarily driven by C‐nociceptors with little contribution from A‐delta fibres. Less‐pronounced accommodation during ongoing sinusoidal stimulation suggests that NGF could facilitate axonal spike generation and conduction in primary afferent nociceptors in humans. Further studies using this sinusoidal electrical stimulation profile to investigate patients with chronic inflammatory pain may allow localized assessment of skin C‐nociceptors and their putative excitability changes under pathologic conditions.

Significance

The application of novel slowly depolarizing electrical stimuli demonstrated a predominant C‐nociceptor sensitization in NGF‐treated skin. Increased pain ratings, larger axon reflex erythema and less accommodation of C‐fibres to ongoing sinusoidal stimulation all indicated an enhanced nociceptor discharge after NGF. A‐fibre conduction block had little effect on electrical and mechanical hyperalgesia skin in NGF‐treated compared to NaCl‐treated skin. This electrical stimulus profile may be applicable for patients with chronic inflammatory pain, allowing localized assessment of skin C‐nociceptors and their putative excitability changes under pathologic conditions.

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Evidence‐based treatment recommendations for neck and low back pain across Europe: A systematic review of guidelines

Abstract

Background and objective

This systematic review synthesized evidence from European neck and low back pain (NLBP) clinical practice guidelines (CPGs) to identify recommended treatment options for use across Europe.

Databases and Data Treatment

Comprehensive searches of thirteen databases were conducted, from 1st January 2013 to 4th May 2020 to identify up‐to‐date evidence‐based European CPGs for primary care management of NLBP, issued by professional bodies/organizations. Data extracted included; aim and target population, methods for development and implementation and treatment recommendations. The AGREE II checklist was used to critically appraise guidelines. Criteria were devised to summarize and synthesize the direction and strength of recommendations across guidelines.

Results

Seventeen CPGs (11 low back; 5 neck; 1 both) from eight European countries were identified, of which seven were high quality. For neck pain, there were consistent weak or moderate strength recommendations for: reassurance, advice and education, manual therapy, referral for exercise therapy/programme, oral analgesics and topical medications, plus psychological therapies or multidisciplinary treatment for specific subgroups. Notable recommendation differences between back and neck pain included, i) analgesics for neck pain (not for back pain); ii) options for back pain‐specific subgroups—work‐based interventions, return to work advice/programmes and surgical interventions (but not for neck pain) and iii) a greater strength of recommendations (generally moderate or strong) for back pain than those for neck pain.

Conclusions

This review of European CPGs identified a range of mainly non‐pharmacological recommended treatment options for NLBP that have broad consensus for use across Europe.

Significance

Consensus regarding evidence‐based treatment recommendations for patients with neck and low back pain (NLBP) from recent European clinical practice guidelines identifies a wide range of predominantly non‐pharmacological treatment options. This includes options potentially applicable to all patients with NLBP and those applicable to only specific patient subgroups. Future work within our Back‐UP research team will transfer these evidence‐based treatment options to an accessible clinician decision support tool for first contact clinicians.

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Issue Information

European Journal of Pain, Volume 25, Issue 2, Page 273-274, February 2021.

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Comparison of two different protocol for the treatment of Chronic Low Back Pain (Extracorporeal Shock Wave Therapy with oral medication and exercise program versus sham with oral medication and exercise program): A Randomized Controlled Trial

Publication date: Available online 14 January 2021

Source: Archives of Physical Medicine and Rehabilitation

Author(s): Mitra Ramezani, Parisa Taheri, Saeed khosrawi

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Effectiveness of Botulinum Toxin A in Treatment of Hemiplegic Shoulder Pain: A Systematic Review and Meta-Analysis

Publication date: Available online 14 January 2021

Source: Archives of Physical Medicine and Rehabilitation

Author(s): Hui-Min Xie, Ting-Ting Guo, Xuan Sun, Han-Xiao Ge, Xue-Dan Chen, Ke-Jia Zhao, Li-Ning Zhang

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Local immune response to food antigens drives meal-induced abdominal pain

Nature, Published online: 13 January 2021; doi:10.1038/s41586-020-03118-2

In mice, oral tolerance to food antigens can break down after enteric infection, and this leads to food-induced pain resembling irritable bowel syndrome in humans.

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STING controls nociception via type I interferon signalling in sensory neurons

Nature, Published online: 13 January 2021; doi:10.1038/s41586-020-03151-1

Studies using mouse and non-human primate models identify the innate immune regulator STING—acting via type I interferons—as a key regulator of nociception, suggesting new targets for the treatment of chronic pain.

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Food for thought about the immune drivers of gut pain

Nature, Published online: 13 January 2021; doi:10.1038/d41586-020-03661-y

Debilitating gut pain is common, but the underlying cause is often unclear. It emerges that gut infection triggers localized immune responses that cause normally innocuous foods to be perceived as harmful, leading to persistent pain.

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Cauda equina syndrome

What you need to knowSciatica is pain or numbness that is usually referred below the knee (in contrast to non-radicular pain referred to the upper posterior thigh). Although bilateral sciatica is the...

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Is Europe facing an opioid epidemic: what does European Monitoring Data tell us?

Abstract

This paper addresses the question of whether Europe is facing an opioid epidemic and utilises data from the European monitoring system on opioid use, harms and availability, to help assess the situation. Data sources covering the last decade on overdose deaths, drug treatment entrants and drug‐related emergencies suggest that the health burden associated with opioid use is mostly related to the consumption of heroin ‐ and to a lesser extent diverted opioid substitution treatment medications ‐ and that it is primarily affecting an ageing cohort of vulnerable users, with little evidence of an increase in initiation. While opioid‐related deaths are currently at much lower levels than in the US, they still represent a large preventable health burden with differences across EU countries. There is also increasing concern related to the high availability of heroin, illicitly produced synthetic opioids and diverted opioid pain medications on the European drugs market. Trends in the latter categories are poorly monitored and we may miss signs of emerging problems. Moreover, the economic recession following the COVID‐19 pandemic has a potential to lead to resurgence in opioid use and harms.

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Facial expressions of pain in daily clinical practice to assess postoperative pain in children: Reliability and validity of the Facial Action Summary Score

Abstract

Background

Behavioral pain scales are recommended to assess postoperative pain for children who are too young to use self‐report tools. Their main limitation is underestimation of pain in the days following an intervention. Although relevant, facial expression is not used in daily clinical practice. This prospective study aimed to assess the validity and reliability of the Facial Action Summary Score (FASS), a five‐item scale, to assess postoperative pain until hospital discharge in children <7 years.

Methods

Assessments of pain and anxiety of 123 children using FASS and validated scales were used to study the psychometric validity of the FASS in clinical practice.

Results

The content validity was previously investigated in a development study. The internal validity of the FASS was high with excellent reliability (intraclass coefficient = 0.94) and a high Cronbach α (0.89). Convergent validity with pain scales (FLACC [Face, Legs, Activity, Cry, Consoling] and FPS‐R [Faces Pain Scale – Revised]) was high (r > 0.8). Sensitivity to change was verified by a significant decrease in the score after rescue analgesia. For a threshold of 2/5, the FASS shows excellent specificity (97%) and sensitivity (82%). The low number of false negatives is the main strength of this tool.

Conclusions

This work highlights the interest in using facial expression in daily clinical practice to manage postoperative pain. The FASS is easy to use with excellent psychometric properties and is particularly sensitive to measure pain in the days following surgery.

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Real‐world effectiveness and tolerability of carbamazepine and oxcarbazepine in 354 patients with trigeminal neuralgia

Abstract

Background

It is widely agreed that carbamazepine and oxcarbazepine are highly effective in the long‐term treatment of trigeminal neuralgia. However, the tolerability of these drugs across the different aetiologies of trigeminal neuralgia is still undetermined.

Methods

In this retrospective, real‐world study, we assessed the effectiveness and tolerability of carbamazepine and oxcarbazepine in a large cohort of patients with classical (254 patients), secondary (60 patients) and idiopathic (40 patients) trigeminal neuralgia. We analysed data using a propensity score analysis to account for selection bias; frequencies of side effects associated to carbamazepine and oxcarbazepine were calculated by adjusting data with the inverse probability of treatment weighting.

Results

The initial proportion of responders was 88.3% with carbamazepine, and 90.9% with oxcarbazepine. The number of refractory patients was significantly higher in idiopathic (15%) and secondary forms (27%) than in classical trigeminal neuralgia (6%), (p<0.05). In 53 patients treated with carbamazepine (29.6%) and in 22 treated with oxcarbazepine (12.6%), major side effects caused treatment interruption or dosage reduction to an unsatisfactory level. Side effects occurred more frequently in patients treated with carbamazepine (43.6%) than with oxcarbazepine (30.3%, p<0.0001). The frequency of treatment discontinuation was higher in patients with secondary and idiopathic forms than in those with classical trigeminal neuralgia (p<0.05).

Conclusions

Our real‐world study show that carbamazepine and oxcarbazepine are effective in most patients with trigeminal neuralgia; nevertheless, side effects are still a major issue, particularly in patients with secondary and idiopathic trigeminal neuralgia.

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A role for protease activated receptor type 3 (PAR3) in nociception demonstrated through development of a novel peptide agonist

Protease activated receptor 3 (PAR3) belongs to the PAR family of G-protein coupled receptors (GPCRs), a group of receptors expressed in many cell types and implicated in a variety of inflammatory pathologies 11, 26, 28, 56. Like the other PARs, PAR3 does not have an endogenously present ligand but rather is activated through extracellular cleavage of the N-terminal end via proteases. After proteolytic cleavage, the newly available tethered ligand can bind to the receptor, initiating multiple downstream signaling cascades 51.

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[Comment] Offline: The cosmopolitan state

Britain feels broken. Broken by COVID-19. Broken by Brexit. Broken by the lies that have been dripped into British political debates these past 5 years. Those scientists and doctors who voted to remain in the European Union—perhaps based on a belief in the public value of research and clinical networks that have been painstakingly built over half a century between the UK and its European neighbours—were accused of Project Fear. But now that the UK has finally left the EU, with the thinnest of thin deals, one can look back and say that the arguments to leave were themselves based on nothing but fear—fear of European expansion, fear of the costs of EU membership, fear of immigration, fear of the Euro, and fear of the European Court of Justice.

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[Clinical Picture] Leg weakness and paraesthesia provide a clue to sudden death due to aortic dissection

An 86-year-old man was seen at home by an ambulance crew after a fall associated with sudden severe lower back pain and weakness in his legs. The paramedics reported that they found the patient alert and haemodynamically stable; his legs appeared pale—although the colour returned during the journey to the hospital—and he had weak pedal pulses.

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Brain maps show how empathetic mice feel each other's pain

Nature, Published online: 07 January 2021; doi:10.1038/d41586-021-00016-z

A mouse sharing a companion's fear has different neural patterns to one sharing another animal’s pain.

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Age differences in cognitive‐affective processes in adults with chronic pain

Abstract

Background

Chronic pain is associated with significant physical and psychological impairments across the adult lifespan. However, there is a relative gap in knowledge on individual differences that predict pain‐related functioning. The current study highlights one important source of individual variation: age.

Methods

Using cross‐sectional data from a large treatment‐seeking cohort of 2,905 adults (M age = 46.6 [13.1]; 71.8 % female) presenting to a tertiary pain center in the United Kingdom (UK), we sought to determine age differences in cognitive‐affective processes (catastrophizing, acceptance, self‐efficacy), including their differential patterns and effects on disability and depression.

Results

Older adults (ages 65‐ 75) were found to experience higher pain acceptance and pain self‐efficacy compared to both middle‐aged (ages 40‐64) and young adult (ages 18‐39) age groups. Older adults also experienced lower levels of catastrophizing compared to middle‐age adults. Testing age as a moderator, we found that the relationships of pain self‐efficacy and acceptance with depression as well as the relationship between pain self‐efficacy and disability were comparatively weakest among older adults and strongest among young adults. Similarly, the relationship between pain catastrophizing and depression was relatively stronger for young and middle‐aged adults compared to older adults.

Conclusions

Age‐related differences in psychological mechanisms that influence pain‐related functioning present unique challenges and opportunities for scientists and clinicians to improve our understanding and treatment of pain across the lifespan. Additional work is needed to refine our knowledge of age‐related differences in cognitive‐affective, biopsychosocial dimensions of chronic pain and to develop and test the efficacy of age‐tailored interventions.

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A widening gap between boys and girls in musculoskeletal complaints, while growing up from age 11 to age 20 ‐ The PIAMA Birth Cohort Study

Abstract

Introduction

The adolescent years represent a key period for the development of musculoskeletal complaints (MSC) and the differences between boys and girls. We evaluated the prevalence and course of MSC and factors associated with MSC while growing up from age 11 to age 20.

Methods

Questionnaire‐based data at age 11 (n=2638), age 14 (n=2517), age 17 (n=2094) and at age 20 (n=2206) from the ongoing Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort were analyzed. MSC refers to pain of lower back, upper‐ and/or lower extremities. Multivariable logistic regression analysis was used to evaluate a number of factors in relation to persistent pain (pain reported at three out of four measurements).

Results

Prevalence of MSC increased from 14.2% at age 11 to 22.1% at age 20 for boys, and from 17.4% at age 11 to 37.9% at age 20 for girls. Persistent pain was found among 5.1% of the boys and 16.5% of the girls. Being bullied, sleeping problems and tiredness during the day were significantly associated with persistent pain, in both boys and girls, while the latter two were more prevalent among girls. Self‐reported (sports‐)accidents, and among girls also early onset of puberty, were also significantly associated with persistent pain, but lifestyle factors, such as physical activity and smoking, were not.

Conclusion

Prevalence of MSC increases during adolescence, with a widening gap between boys and girls. The factors associated with MSC are similar in boys and girls, though the prevalence of some of these differ by sex.

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A Systematic Review into the Influence of Temperature on Fibromyalgia Pain: Meteorological Studies and Quantitative Sensory Testing

Fibromyalgia syndrome (FMS) is a chronic widespread pain condition of uncertain aetiology and may be viewed as pain state with central amplification13, 14, 74. However, there is also mounting evidence of peripheral abnormalities including small fibre polyneuropathy with abnormal nociceptor function25, 33, 51, 73, abnormal thermoregulatory peripheral innervations1, and even peripherally binding pain-sensitising IgG autoantibodies31. FMS is characterised by widespread pain and a constellation of other symptoms, most markedly fatigue, sleep disturbance and cognitive problems14, 90.

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Central endothelin-1 confers analgesia by triggering spinal neuronal histone deacetylase 5 (HDAC5) nuclear exclusion in peripheral neuropathic pain in mice

The rationale of spinal administration of endothelin-1(ET-1) mediated anti-nociceptive effect has not been elucidated. ET-1 is reported to promote nuclear effluxion of histone deacetylase 5 (HDAC5) in myocytes, and spinal HDAC5 is implicated in modulation of pain processing. In this study, we aimed to investigate whether central ET-1 plays an anti-nociceptive role by facilitating spinal HDAC5 nuclear shuttling under neuropathic pain. Here, we demonstrate that upregulating spinal ET-1 attenuated the nociception induced by partial sciatic nerve ligation (pSNL) surgery and this analgesic effect mediated by ET-1 was attenuated by intrathecal injection of endothelin A receptor (ETAR) selective inhibitor (BQ123) or by blocking the exportation of nuclear HDAC5 by adeno-associated viruses targeting neuronal HDAC5 (AVV-HDAC5 S259/498A Mutant).

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Primary sensorimotor cortex is modified by a 6 week graded motor imagery training in chronic CRPS patients: a randomized trial

Complex regional pain syndrome (CRPS) shows severe painful symptoms of the affected body part (for a concise description of symptoms and pathophysiology see 6) and has an incidence rate of approximately 26 per 100,000 person years33. Because of its high rate of chronification, powerful treatment options are needed. Longitudinal intervention studies with neurophysiological and imaging control can help to understand treatment gain and underlying brain changes.

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Characteristics of pain in patients with pituitary adenomas: a cross‐sectional study

Abstract

Background

This study determines the prevalence and particularities of headache and pain with neuropathic characteristics (NC) in a large French group of patients with pituitary adenoma (PA).

Methods

Analysis of validated self‐administered questionnaires, radiological characteristics, and treatment strategies of PA was performed.

Results

Of the 221 sent questionnaires, 146 could be used for statistical analysis, 50% of which were completed by women. Among responders, 58.9% had pain: 30.1% migraine, 15.7% pain with NC, and 13.1% other types of pain. Migraine was more common in patients with PA than in the general population (30.1% vs 21.3%, p=0.010) and attacks received appropriate treatment for less than 20% of these patients. Furthermore, the prevalence of chronic migraine was much higher than in the general population (6.8% vs 2.2%, p=0.003). Neuropathic pain was also more frequent in PA patients than in the general population (15.8% vs 6.9%, p<0.001). Neuropathic pain was most often located in the extremities and was frequently described as an “electric shock”, “numbness”, or “pins‐and‐needles”. Multivariate analyses linked migraine to younger age, anxiety, pain with NC, and a visible tumor on MRI, regardless of its invasiveness or secretory nature.

Conclusions

Migraine headaches and neuropathic pain are more frequent and disabling in PA patients than in the general population. Both types of pain are comorbid in PA patients and are poorly treated. Migraine is associated with the presence of a tumor. Thus, biological mechanisms of this relationship need to be characterized to design optimal treatments for these individuals.

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Impaired Exercise‐induced Hypoalgesia in Individuals Reporting an Increase in Low Back Pain During Acute Exercise

Abstract

Objectives

Exercise therapy is recommended for low back pain (LBP) although the immediate effects on pain are highly variable. In 96 individuals with LBP this cross‐sectional study explored 1) the magnitude of exercise‐induced hypoalgesia (EIH), and 2) measures of pain sensitivity and clinical pain manifestations in individuals reporting a clinical relevant increase in back pain during physical activity compared with individuals reporting low or no increase in back pain during physical activity.

Methods

Cuff algometry was performed at baseline on the leg to assess pressure pain threshold (cPPT), tolerance (cPTT), and temporal summation of pain (cTSP). Manual PPTs were assessed on the back and leg before and after a six minute walk test (6MWT). Back pain was scored on a numerical rating scale (NRS) after each minute of walking. The EIH‐effect was estimated as the increase in PPTs after the walk exercise.

Results

Twenty‐seven individuals reported an increase of ≥2/10 in pain NRS scores during walking and compared with the individuals with <2/10 NRS scores: cPPT and EIH‐effects were lower whereas cTSP, pain intensity and disability were increased (P<0.03). Baseline NRS scores, EIH and pain thresholds were associated with the likelihood of an increase of ≥2/10 in back pain intensity during walking (P<0.05).

Conclusions

Pain flares in response to physical activity in individuals with LBP seem to be linked with baseline pain sensitivity and pain intensity, and impair the beneficial exercise‐induced hypoalgesia. Such information may better inform when individuals with LBP will have a beneficial effect of physical activity.

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