Publications
391 results found
Vollert J, Kumar A, Coady EC, et al., 2024, Pain after combat injury in male UK military personnel deployed to Afghanistan., Br J Anaesth
BACKGROUND: Chronic pain after injury poses a serious health burden. As a result of advances in medical technology, ever more military personnel survive severe combat injuries, but long-term pain outcomes are unknown. We aimed to assess rates of pain in a representative sample of UK military personnel with and without combat injuries. METHODS: We used data from the ADVANCE cohort study (ISRCTN57285353). Individuals deployed as UK armed forces to Afghanistan were recruited to include those with physical combat injuries, and a frequency-matched uninjured comparison group. Participants completed self-reported questionnaires, including 'overall' pain intensity and self-assessment of post-traumatic stress disorder, anxiety, and depression. RESULTS: A total of 579 participants with combat injury, including 161 with amputations, and 565 uninjured participants were included in the analysis (median 8 yr since injury/deployment). Frequency of moderate or severe pain was 18% (n=202), and was higher in the injured group (n=140, 24%) compared with the uninjured group (n=62, 11%, relative risk: 1.1, 95% confidence interval [CI]: 1.0-1.2, P<0.001), and lower in the amputation injury subgroup (n=31, 19%) compared with the non-amputation injury subgroup (n=109, 26%, relative risk: 0.9, 95% CI: 0.9-1.0, P=0.034). Presence of at least moderate pain was associated with higher rates of post-traumatic stress (RR: 3.7, 95% CI: 2.7-5.0), anxiety (RR: 3.2, 95% CI: 2.4-4.3), and depression (RR: 3.4, 95% CI: 2.7-4.5) after accounting for injury. CONCLUSION: Combat injury, but not amputation, was associated with a higher frequency of moderate to severe pain intensity in this cohort, and pain was associated with adverse mental health outcomes.
Vollert J, Fardo F, Attal N, et al., 2024, Paradoxical heat sensation as a manifestation of thermal hypesthesia: a study of 1090 patients with lesions of the somatosensory system., Pain, Vol: 165, Pages: 216-224
Paradoxical heat sensation (PHS) is the perception of warmth when the skin is cooled. Paradoxical heat sensation rarely occurs in healthy individuals but more frequently in patients suffering from lesions or disease of the peripheral or central nervous system. To further understand mechanisms and epidemiology of PHS, we evaluated the occurrence of PHS in relation to disease aetiology, pain levels, quantitative sensory testing parameters, and Neuropathic Pain Symptom Inventory (NPSI) items in patients with nervous system lesions. Data of 1090 patients, including NPSI scores from 404 patients, were included in the analysis. We tested 11 quantitative sensory testing parameters for thermal and mechanical detection and pain thresholds, and 10 NPSI items in a multivariate generalised linear model with PHS, aetiology, and pain (yes or no) as fixed effects. In total, 30% of the neuropathic patients reported PHS in contrast to 2% of healthy individuals. The frequency of PHS was not linked to the presence or intensity of pain. Paradoxical heat sensation was more frequent in patients living with polyneuropathy compared with central or unilateral peripheral nerve lesions. Patients who reported PHS demonstrated significantly lower sensitivity to thermal perception, with lower sensitivity to normally painful heat and cold stimuli. Neuropathic Pain Symptom Inventory scores were lower for burning and electric shock-like pain quality for patients with PHS. Our findings suggest that PHS is associated with loss of small thermosensory fibre function normally involved in cold and warm perception. Clinically, presence of PHS could help screening for loss of small fibre function as it is straightforward to measure or self-reported by patients.
Bäckryd E, Themistocleous A, Stensson N, et al., 2024, Serum levels of endocannabinoids and related lipids in painful vs painless diabetic neuropathy: results from the Pain in Neuropathy Study., Pain, Vol: 165, Pages: 225-232
N-arachidonoylethanolamine (also known as anandamide) and 2-arachidonoylglycerol are activators of the cannabinoid receptors. The endocannabinoid system also includes structurally and functionally related lipid mediators that do not target cannabinoid receptors, such as oleoylethanolamide, palmitoylethanolamide, and stearoylethanolamide. These bioactive lipids are involved in various physiological processes, including regulation of pain. The primary aim of the study was to analyze associations between serum levels of these lipids and pain in participants in the Pain in Neuropathy Study, an observational, cross-sectional, multicentre, research project in which diabetic patients with painless or painful neuropathy underwent deep phenotyping. Our hypothesis was that painful neuropathy would be associated with higher levels of the 5 lipids compared with painless neuropathy. Secondary aims were to analyze other patient-reported outcome measures and clinical data in relationship to lipid levels. The lipid mediators were analyzed in serum samples using liquid chromatography tandem mass spectrometry (LC-MS/MS). Serum levels of anandamide were significantly higher in the painful group, but the effect size was small (Cohen d = 0.31). Using cluster analysis of lipid data, patients were dichotomized into a "high-level" endocannabinoid group and a "low-level" group. In the high-level group, 61% of patients had painful neuropathy, compared with 45% in the low-level group ( P = 0.039). This work is of a correlative nature only, and the relevance of these findings to the search for analgesics targeting the endocannabinoid system needs to be determined in future studies.
Haroutounian S, Holzer KJ, Kerns RD, et al., 2023, Patient engagement in designing, conducting, and disseminating clinical pain research: IMMPACT recommended considerations., Pain
In the traditional clinical research model, patients are typically involved only as participants. However, there has been a shift in recent years highlighting the value and contributions that patients bring as members of the research team, across the clinical research lifecycle. It is becoming increasingly evident that to develop research that is both meaningful to people who have the targeted condition and is feasible, there are important benefits of involving patients in the planning, conduct, and dissemination of research from its earliest stages. In fact, research funders and regulatory agencies are now explicitly encouraging, and sometimes requiring, that patients are engaged as partners in research. Although this approach has become commonplace in some fields of clinical research, it remains the exception in clinical pain research. As such, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials convened a meeting with patient partners and international representatives from academia, patient advocacy groups, government regulatory agencies, research funding organizations, academic journals, and the biopharmaceutical industry to develop consensus recommendations for advancing patient engagement in all stages of clinical pain research in an effective and purposeful manner. This article summarizes the results of this meeting and offers considerations for meaningful and authentic engagement of patient partners in clinical pain research, including recommendations for representation, timing, continuous engagement, measurement, reporting, and research dissemination.
Kemp H, Kumar A, Soliman N, et al., 2023, A systematic review of the prevalence of post amputation and chronic neuropathic pain associated with combat injury in military personnel, Pain, ISSN: 0304-3959
Combat trauma can lead to widespread tissue damage and limb loss. This may result in chronic neuropathic and post amputation pain, including phantom limb pain (PLP) and residual limb pain (RLP). The military population is distinct with respect to demographic, injury, and social characteristics compared with other amputation and trauma cohorts. We undertook a systematic review of studies of military personnel, with a history of combat injury, that reported a prevalence of any type of postamputation pain or chronic neuropathic pain, identified from Embase and MEDLINE databases.Using the inverse variance method with a random-effects model, we undertook a meta-analysis to determine an overall prevalence and performed exploratory analyses to identify the effect of the type of pain, conflict, and time since injury on prevalence. Pain definitions and types of pain measurement tools used in studies were recorded. Thirty-one studies (14,738 participants) were included. The pooled prevalence of PLP, RLP, and chronic neuropathic pain were 57% (95% CI: 46-68), 61% (95% CI: 50-71), and 26% (95% CI: 10-54), respectively. Between-study heterogeneity was high (I2: 94%-98%). Characterisation of duration, frequency, and impact of pain was limited. Factors reported by included studies as being associated with PLP included the presence of RLP and psychological comorbidity. The prevalence of postamputation pain and chronic neuropathic pain after combat trauma is high. We highlight inconsistency of case definitions and terminology for pain and the need for consensus in future research of traumatic injury.
Petersen KKS, Rice ASC, Arendt-Nielsen L, 2023, The use of cannabidiol (CBD) as an analgesic component, The Lancet Regional Health - Europe, Vol: 35
Dixon Smith S, Aldington D, Hay G, et al., 2023, “I did not expect the doctor to treat a ghost”: a systematic review of published reports regarding chronic postamputation pain in British First World War veterans, PAIN Reports, Vol: 8, ISSN: 2471-2531
Limb trauma remains the most prevalent survivable major combat injury. In the First World War, over 700,000 British soldiers received limb wounds and over 41,000 underwent an amputation, creating one of the largest amputee cohorts in history. Postamputation pain affects up to 85% of military amputees, suggesting that up to 33,000 British First World War veterans potentially reported postamputation pain.This qualitative systematic review explores the professional medical conversation around clinical management of chronic postamputation pain in this patient cohort, its development over the 20th century, and how this information was disseminated amongst medical professionals.We searched The Lancet and British Medical Journal archives (1914-1985) for reports referring to postamputation pain, its prevalence, mechanisms, descriptors or clinical management. Participants were First World War veterans with a limb amputation, excluding civilians and veterans of all other conflicts. The search identified 9809 potentially relevant texts, of which 101 met the inclusion criteria.Reports emerged as early as 1914 and the discussion continued over the next four decades. Unexpected findings included early advocacy of multidisciplinary pain management, concerns over addiction and the impact of chronic pain on mental health emerging decades earlier than previously thought. Chronic postamputation pain is still a significant issue for military rehabilitation. Similarities between injury patterns in the First World War and recent Iraq and Afghanistan conflicts mean these historical aspects remain relevant to today’s military personnel, clinicians, researchers and policymakers.
Shepherd AJ, Rice AS, Smith MT, 2023, Angiotensin II type 2 receptor signalling as a pain target: Bench, bedside and back-translation., Curr Opin Pharmacol, Vol: 73
Translating promising preclinical pain relief data for novel molecules from drug discovery to positive clinical trial outcomes is challenging. The angiotensin II type 2 (AT2) receptor is a clinically-validated target based upon positive proof-of-concept clinical trial data in patients with post-herpetic neuralgia. This trial was conducted because AT2 receptor antagonists evoked pain relief in rodent models of neuropathic pain. EMA401 was selected as the drug candidate based upon its suitable preclinical toxicity and safety profile and good pharmacokinetics. Herein, we provide an overview of the discovery, preclinical and clinical development of EMA401, for the alleviation of peripheral neuropathic pain.
Bedwell GJ, Chikezie PC, Siboza FT, et al., 2023, A Systematic Review and Meta-analysis of Non-pharmacological Methods to Manipulate Experimentally Induced Secondary Hypersensitivity, JOURNAL OF PAIN, Vol: 24, Pages: 1759-1797, ISSN: 1526-5900
Langford DJ, Baron R, Edwards RR, et al., 2023, What should be the entry pain intensity criteria for chronic pain clinical trials? An IMMPACT update, PAIN, Vol: 164, Pages: 1927-1930, ISSN: 0304-3959
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- Citations: 1
Kemp HI, Kennedy DL, Vollert J, et al., 2023, Chronic pain and cognitive impairment: a cross-sectional study in people living with HIV, AIDS Care: psychological and socio-medical aspects of AIDS-HIV, Vol: 35, Pages: 1201-1214, ISSN: 0954-0121
Cognitive impairment and chronic pain are amongst the most prevalent neurological sequelae of HIV infection, yet little is understood about the potential bidirectional relationship between the two conditions. Cognitive dysfunction can occur in chronic pain populations whilst those with cognitive impairment can display modified responses to experimentally induced painful stimuli. To date, this has not been explored in HIV cohorts.This study aimed to identify any contribution of chronic pain to cognitive impairment in HIV and to determine differences in pain characteristics between those with and without cognitive dysfunction.This was an observational cohort study involving people living with HIV (n = 148) in the United Kingdom. Participants underwent validated questionnaire-based measurement of pain severity, interference and symptom quality as well as conditioned pain modulation and quantitative sensory testing. All participants completed a computer-based cognitive function assessment.Fifty-seven participants met the criteria for cognitive impairment and 73 for chronic pain. The cognitive impairment group had a higher prevalence of chronic pain (p = 0.004) and reported more neuropathic symptoms (p = 0.001). Those with chronic pain performed less well in emotional recognition and verbal learning domains. The interaction identified between chronic pain and cognitive dysfunction warrants further exploration to identify causal links or shared pathology.
Merlin JS, Hamm M, Cameron FDA, et al., 2023, The Global Task Force for Chronic Pain in People with HIV (PWH): Developing a research agenda in an emerging field, AIDS Care: psychological and socio-medical aspects of AIDS-HIV, Vol: 35, Pages: 1215-1223, ISSN: 0954-0121
Chronic pain is a common comorbidity in people with HIV (PWH), with prevalence estimates of 25-85%. Research in this area is growing, but significant gaps remain. A Global Task Force of HIV experts was organized to brainstorm a scientific agenda and identify measurement domains critical to advancing research in this field. Experts were identified through literature searches and snowball sampling. Two online questionnaires were developed by Task Force members. Questionnaire 1 asked participants to identify knowledge gaps in the field of HIV and chronic pain and identify measurement domains in studies of chronic pain in PWH. Responses were ranked in order of importance in Questionnaire 2, which was followed by a group discussion. 29 experts completed Questionnaire 1, 25 completed Questionnaire 2, and 21 participated in the group. Many important clinical and research priorities emerged, including the need to examine etiologies of chronic pain in PWH. Pain-related measurement domains were discussed, with a primary focus on domains that could be assessed in a standardized manner across various cohorts that include PWH in different countries. We collaboratively identified clinical and research priorities, as well as gaps in standardization of measurement domains, that can be used to move the field forward.
Truini A, Aleksovska K, Anderson CC, et al., 2023, Joint European Academy of Neurology-European Pain Federation-Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment, EUROPEAN JOURNAL OF NEUROLOGY, Vol: 30, Pages: 2177-2196, ISSN: 1351-5101
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- Citations: 2
Arendt-Nielsen L, Pedersen KK-S, Dreyer L, et al., 2023, Methodology considerations for 'Safety and effectiveness of cannabinoids to Danish patients with treatment-refractory chronic pain' by Horsted et al., EUROPEAN JOURNAL OF PAIN, Vol: 27, Pages: 661-663, ISSN: 1090-3801
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- Citations: 1
Hohenschurz-Schmidt DJ, Cherkin D, Rice ASC, et al., 2023, Research objectives and general considerations for pragmatic clinical trials of pain treatments: IMMPACT statement, PAIN, Vol: 164, Pages: 1457-1472, ISSN: 0304-3959
Hohenschurz-Schmidt D, Vase L, Scott W, et al., 2023, Recommendations for the development, implementation, and reporting of control interventions in efficacy and mechanistic trials of physical, psychological, and self-management therapies: the CoPPS Statement, BMJ: British Medical Journal, Vol: 381, Pages: 1-16, ISSN: 0959-535X
Control interventions (often called “sham,” “placebo,” or “attention controls”) are essential for studying the efficacy or mechanism of physical, psychological, and self-management interventions in clinical trials. This article presents core recommendations for designing, conducting, and reporting control interventions to establish a quality standard in non-pharmacological intervention research. A framework of additional considerations supports researchers’ decision making in this context. We also provide a reporting checklist for control interventions to enhance research transparency, usefulness, and rigour.
Themistocleous AC, Baskozos G, Blesneac I, et al., 2023, Investigating genotype-phenotype relationship of extreme neuropathic pain disorders in a UK national cohort, BRAIN COMMUNICATIONS, Vol: 5
Hohenschurz-Schmidt D, Draper-Rodi DJ, Vase PL, et al., 2023, Blinding and sham control methods in trials of physical, psychological, and self-management interventions for pain (article II): a meta-analysis relating methods to trial results, Pain, Vol: 164, Pages: 509-533, ISSN: 0304-3959
Sham interventions in randomised clinical trials (RCTs) of physical, psychological, and self-management (PPS) therapies for pain are highly variable in design and thought to contribute to poor internal validity. It has, however, not been formally tested whether the extent to which sham controls resemble the treatment under investigation consistently affects trial outcomes, such as effect sizes, differential attrition, participant expectancy, and blinding effectiveness.Placebo or sham-controlled RCTs of PPS interventions of clinical pain populations were searched in twelve databases. The similarity of control interventions to the experimental treatment was rated across 25 features. Meta-regression analyses assessed putative links between employed control interventions, observed effect sizes in pain-related outcomes, attrition, and blinding success.The sample included 198 unique control interventions, dominated by manual therapy and chronic musculoskeletal pain research. Meta-analyses indicated small to moderate benefit of active treatments over control interventions, across subgroups of manual therapies, exercise, and rehabilitation, and psychological intervention trials. Multiple meta-regression modelling demonstrated that similarity between sham control and tested interventions predicted variability in pain-related outcomes, attrition, and blinding effectiveness. Influential were differences relating to the extent of intervention exposure, participant experience, and treatment environments.The results support the supposed link between blinding methods and effect sizes, based on a large and systematically sourced overview of methods. Challenges to effective blinding are, however, complex, and often difficult to discern from trial reports. Nonetheless, these insights have the potential to change trial design, conduct, and reporting and will inform guideline development.
Vollert J, Kleykamp BA, Farrar JT, et al., 2023, Real-world data and evidence in pain research: a qualitative systematic review of methods in current practice, PAIN Reports, Vol: 8, Pages: 1-8, ISSN: 2471-2531
The use of routinely collected health data (real-world data, RWD) to generate real-world evidence (RWE) for research purposes is a growing field. Computerized search methods, large electronic databases, and the development of novel statistical methods allow for valid analysis of data outside its primary clinical purpose. Here, we systematically reviewed the methodology used for RWE studies in pain research. We searched 3 databases (PubMed, EMBASE, and Web of Science) for studies using retrospective data sources comparing multiple groups or treatments. The protocol was registered under the DOI:10.17605/OSF.IO/KGVRM. A total of 65 studies were included. Of those, only 4 compared pharmacological interventions, whereas 49 investigated differences in surgical procedures, with the remaining studying alternative or psychological interventions or epidemiological factors. Most 39 studies reported significant results in their primary comparison, and an additional 12 reported comparable effectiveness. Fifty-eight studies used propensity scores to account for group differences, 38 of them using 1:1 case:control matching. Only 17 of 65 studies provided sensitivity analyses to show robustness of their findings, and only 4 studies provided links to publicly accessible protocols. RWE is a relevant construct that can provide evidence complementary to randomized controlled trials (RCTs), especially in scenarios where RCTs are difficult to conduct. The high proportion of studies reporting significant differences between groups or comparable effectiveness could imply a relevant degree of publication bias. RWD provides a potentially important resource to expand high-quality evidence beyond clinical trials, but rigorous quality standards need to be set to maximize the validity of RWE studies.
Edwards RR, Schreiber KL, Dworkin RH, et al., 2023, Optimizing and Accelerating the Development of Precision Pain Treatments for Chronic Pain: IMMPACT Review and Recommendations, JOURNAL OF PAIN, Vol: 24, Pages: 204-225, ISSN: 1526-5900
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- Citations: 7
Kosek E, Clauw D, Nijs J, et al., 2023, Elevated 18:0 lysophosphatidylcholine contributes to the development of pain in tissue injury Reply, PAIN, Vol: 164, Pages: E116-E117, ISSN: 0304-3959
Kemp HI, Vollert J, Davies NWS, et al., 2023, A Comparison of Self-reported Pain Measures Between Sensory Phenotypes in HIV-associated Sensory Neuropathy, JOURNAL OF PAIN, Vol: 24, Pages: 112-127, ISSN: 1526-5900
Zhang XY, Diaz-delCastillo M, Kong L, et al., 2023, A systematic review and meta-analysis of thigmotactic behaviour in the open field test in rodent models associated with persistent pain., PLoS One, Vol: 18
Thigmotaxis is an innate predator avoidance behaviour of rodents. To gain insight into how injury and disease models, and analgesic drug treatments affect thigmotaxis, we performed a systematic review and meta-analysis of studies that assessed thigmotaxis in the open field test. Systematic searches were conducted of 3 databases in October 2020, March and August 2022. Study design characteristics and experimental data were extracted and analysed using a random-effects meta-analysis. We also assessed the correlation between thigmotaxis and stimulus-evoked limb withdrawal. This review included the meta-analysis of 165 studies We report thigmotaxis was increased in injury and disease models associated with persistent pain and this increase was attenuated by analgesic drug treatments in both rat and mouse experiments. Its usefulness, however, may be limited in certain injury and disease models because our analysis suggested that thigmotaxis may be associated with the locomotor function. We also conducted subgroup analyses and meta-regression, but our findings on sources of heterogeneity are inconclusive because analyses were limited by insufficient available data. It was difficult to assess internal validity because reporting of methodological quality measures was poor, therefore, the studies have an unclear risk of bias. The correlation between time in the centre (type of a thigmotactic metric) and types of stimulus-evoked limb withdrawal was inconsistent. Therefore, stimulus-evoked and ethologically relevant behavioural paradigms should be viewed as two separate entities as they are conceptually and methodologically different from each other.
Eisenach JC, Rice ASC, 2022, Improving Preclinical Development of Novel Interventions to Treat Pain: Insanity Is Doing the Same Thing Over and Over and Expecting Different Results, ANESTHESIA AND ANALGESIA, Vol: 135, Pages: 1128-1136, ISSN: 0003-2999
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- Citations: 4
Zhang XY, Barakat A, Diaz-delCastillo M, et al., 2022, A systematic review and meta-analysis of studies in which burrowing behaviour was assessed in rodent models of disease associated persistent pain, Pain, Vol: 163, Pages: 2076-2102, ISSN: 0304-3959
Burrowing behaviour is employed to assess pain-associated behaviour in laboratory rodents. To gain insight in how models of disease associated persistent pain and analgesics affect burrowing behaviour, we performed a systematic review and meta-analysis of studies that assessed burrowing behaviour. A systematic search in March 2020 and update in September 2020 was conducted in 4 databases. Study design characteristics and experimental data were extracted, followed by a random-effects meta-analysis. We explored the association between burrowing and monofilament-induced limb withdrawal. Dose response relationship was investigated for some analgesics. Forty-five studies were included in the meta-analysis, in which 16 model types and 14 drug classes were used. Most experiments used rat (79%) and male (72%) animals. Somatic inflammation and trauma induced neuropathy models were associated with reduced burrowing behaviour. Analgesics (NSAID and gabapentinoids) attenuated burrowing deficits in these models. Reporting of measures to reduce risk of bias was unclear except for randomisation which was high. There was not a correlation (R2 = 0.1421) between burrowing and monofilament-induced limb withdrawal. Opioids, gabapentin and naproxen showed reduced burrowing behaviour at high doses, while ibuprofen and celecoxib showed opposite trend. The findings indicate that burrowing could be used to assess pain-associated behaviour. We support the use of a portfolio of composite measures including spontaneous and stimulus-evoked tests. The information collected here could help in designing experiments involving burrowing assessment in models of disease associated pain.
Vollert J, Macleod M, Dirnagl U, et al., 2022, The EQIPD framework for rigor in the design, conduct, analysis and documentation of animal experiments, NATURE METHODS, Vol: 19, Pages: 1334-1337, ISSN: 1548-7091
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- Citations: 14
Finnerup NB, Nikolajsen L, Rice ASC, 2022, Transition from acute to chronic pain: a misleading concept?, PAIN, Vol: 163, Pages: E985-E988, ISSN: 0304-3959
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- Citations: 5
Finnerup NB, Nikolajsen L, Rice ASC, 2022, Long-term opioid therapy unsettles us both coming and going (vol 163, pg 807, 2022), PAIN, Vol: 163, Pages: E1040-E1040, ISSN: 0304-3959
Eccleston C, Fisher E, Liikkanen S, et al., 2022, A prospective, double-blind, pilot, randomized, controlled trial of an "embodied" virtual reality intervention for adults with low back pain, PAIN, Vol: 163, Pages: 1700-1715, ISSN: 0304-3959
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- Citations: 4
Onwumere J, Stubbs B, Stirling M, et al., 2022, Pain management in people with severe mental illness: an agenda for progress, PAIN, Vol: 163, Pages: 1653-1660, ISSN: 0304-3959
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- Citations: 2
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