Paradoxical heat sensation as a manifestation of thermal hypesthesia: a study of 1090 patients with lesions of the somatosensory system.

ABSTRACT: 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.

The association of self-reported symptoms of central sensitization and sleep disturbances in neuropathic pain.

Introduction: Patients with neuropathic pain (NP) report a higher impairment of quality of life and sleep than patients with chronic pain without neuropathic characteristics. These include somatosensory peculiarities like allodynia, a surrogate marker for central sensitization. Objectives: This study aimed to investigate the relation between symptoms of central sensitization and sleep disturbances in patients with NP. Methods: Within this cross-sectional study, data sets of 3339 patients with chronic NP syndromes (painful diabetic polyneuropathy, n = 543; postherpetic neuralgia, n = 1480) or complex regional pain syndromes (CRPS, n = 1316) were analyzed. Neuropathic pain symptoms were assessed with the painDETECT questionnaire (PD-Q), depression with the Patient Health Questionnaire-9, and sleep impairment with items of the Medical Outcomes Study Sleep Scale in 4 subscales. The association of demographic/clinical data, somatosensory phenotype, depression, and pain intensity with sleep impairment was assessed by unadjusted Spearman correlation analyses and multivariable regression analyses. Results: Sleep impairment was observed in all pain aetiologies although with some significant differences in the single sleep items. The intensity of the individual PD-Q items differed to some extent between the 3 pain entities, whereas the PD-Q sum score was similar. Thermal hyperalgesia and burning assessed by the PD-Q were significantly associated with sleep disturbance, adequacy, and quantity but not with sleep somnolence. Only depression and self-reported allodynia had a significant relation to all 4 sleep elements. Conclusion: Beside depression, allodynia as a surrogate marker hints to a possible impact of central sensitization on the sleep disruption of patients with NP.

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.

BACKGROUND AND PURPOSE: In these guidelines, we aimed to develop evidence-based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain (NeP). METHODS: We systematically reviewed studies providing information on the sensitivity and specificity of screening questionnaires, and quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy. We also analysed how functional neuroimaging, peripheral nerve blocks, and genetic testing might provide useful information in diagnosing NeP. RESULTS: Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I-DN4 (self-administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, and S-LANSS (self-administered LANSS) and PainDETECT weak recommendations for their use in the diagnostic pathway for patients with possible NeP. We devised a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials in the NeP diagnosis. Trigeminal reflex testing received a strong recommendation in diagnosing secondary trigeminal neuralgia. Although many studies support the usefulness of corneal confocal microscopy in diagnosing peripheral neuropathy, no study specifically investigated the diagnostic accuracy of this technique in patients with NeP. Functional neuroimaging and peripheral nerve blocks are helpful in disclosing pathophysiology and/or predicting outcomes, but current literature does not support their use for diagnosing NeP. Genetic testing may be considered at specialist centres, in selected cases. CONCLUSIONS: These recommendations provide evidence-based clinical practice guidelines for NeP diagnosis. Due to the poor-to-moderate quality of evidence identified by this review, future large-scale, well-designed, multicentre studies assessing the accuracy of diagnostic tests for NeP are needed.

Diagnosis, management and impact of painful diabetic peripheral neuropathy: A patient survey in four European countries.

AIMS: The aim of this study was to assess patient perspectives and experiences of the impact of neuropathic pain, painful diabetic neuropathy (pDPN) diagnosis and treatment, and the patient-healthcare professional (HCP) relationship. METHODS: We conducted a quantitative online survey in Germany, the Netherlands, Spain, and the UK among adults with diabetes who responded "yes" to at least four of ten questions of in the Douleur Neuropathique en 4 Questions (DN4) questionnaire. RESULTS: Of 3626 respondents, 576 met the eligibility criteria. Daily pain was rated as moderate or severe by 79 % of respondents. Most participants reported a negative impact of their pain on sleep (74 %), mood (71 %), exercise (69 %), concentration (64 %) and daily activities (62 %), and 75 % of those in employment had missed work because of their pain in the past year. Overall, 22 % of respondents avoided discussing pain with their HCP, 50 % had not received formal pDPN diagnosis, and 56 % had not used prescribed pain medications. Although two-thirds (67 %) of respondents reported feeling satisfied or very satisfied with treatment, 82 % of these patients still experienced daily moderate or severe pain. CONCLUSIONS: Neuropathic pain in people with diabetes affects daily life and remains underdiagnosed and undertreated in clinical practice.

Chronic Pain and the Endocannabinoid System: Smart Lipids - A Novel Therapeutic Option?

The development of a high-end cannabinoid-based therapy is the result of intense translational research, aiming to convert recent discoveries in the laboratory into better treatments for patients. Novel compounds and new regimes for drug treatment are emerging. Given that previously unreported signaling mechanisms for cannabinoids have been uncovered, clinical studies detailing their high therapeutic potential are mandatory. The advent of novel genomic, optogenetic, and viral tracing and imaging techniques will help to further detail therapeutically relevant functional and structural features. An evolutionarily highly conserved group of neuromodulatory lipids, their receptors, and anabolic and catabolic enzymes are involved in a remarkable variety of physiological and pathological processes and has been termed the endocannabinoid system (ECS). A large body of data has emerged in recent years, pointing to a crucial role of this system in the regulation of the behavioral domains of acquired fear, anxiety, and stress-coping. Besides neurons, also glia cells and components of the immune system can differentially fine-tune patterns of neuronal activity. Dysregulation of ECS signaling can lead to a lowering of stress resilience and increased incidence of psychiatric disorders. Chronic pain may be understood as a disease process evoked by fear-conditioned nociceptive input and appears as the dark side of neuronal plasticity. By taking a toll on every part of your life, this abnormal persistent memory of an aversive state can be more damaging than its initial experience. All strategies for the treatment of chronic pain conditions must consider stress-related comorbid conditions since cognitive factors such as beliefs, expectations, and prior experience (memory of pain) are key modulators of the perception of pain. The anxiolytic and anti-stress effects of medical cannabinoids can substantially modulate the efficacy and tolerability of therapeutic interventions and will help to pave the way to a successful multimodal therapy. Why some individuals are more susceptible to the effects of stress remains to be uncovered. The development of personalized prevention or treatment strategies for anxiety and depression related to chronic pain must also consider gender differences. An emotional basis of chronic pain opens a new horizon of opportunities for developing treatment strategies beyond the repeated sole use of acutely acting analgesics. A phase I trial to determine the pharmacokinetics, psychotropic effects, and safety profile of a novel nanoparticle-based cannabinoid spray for oromucosal delivery highlights a remarkable innovation in galenic technology and urges clinical studies further detailing the huge therapeutic potential of medical cannabis (Lorenzl et al.; this issue).

[Tapentadol versus classical WHO-III opioids for chronic back pain. Health services research study based on representative data from health insurance funds]. / Tapentadol versus klassische WHO-III-Opioide bei chronischen Rückenschmerzen : Versorgungsforschungsstudie auf Basis repräsentativer Krankenkassendaten.

BACKGROUND/OBJECTIVE: In clinical trials, tapentadol prolonged release (PR) showed a more favourable gastrointestinal tolerability profile compared to other strong opioids in the treatment of pain. The present analysis compared tapentadol PR and classical WHO-III PR opioids in routine clinical practice. METHOD: Retrospective cohort study (matched pair approach) using anonymised health insurance data of patients with chronic low back pain who were prescribed strong opioids following pretreatment with WHO-I/II analgesics. Data were analysed from the date of first prescription in 2015 over a maximum period of two years. The primary analysis parameter was the prescription of laxatives. RESULTS: Data of 227 patients per cohort could be included in the analysis. Significantly fewer tapentadol PR than WHO-III PR patients were prescribed laxatives (20.3% vs. 37%; p < 0.0001). In addition, laxative dosages were significantly lower in the tapentadol PR cohort (26.4 vs. 82.5 defined daily doses; p < 0.0001). A significant difference in laxative prescription was also observed under long-term treatment (tapentadol PR patients 27.7% vs. WHO-III PR patients 50%; p = 0.0029). CONCLUSION: Routine clinical practice indirectly confirmed the more favourable gastrointestinal tolerability of tapentadol PR in the treatment of chronic pain which had previously been demonstrated in clinical trials and non-interventional studies.

Longitudinal resting-state electroencephalography in patients with chronic pain undergoing interdisciplinary multimodal pain therapy.

ABSTRACT: Chronic pain is a major healthcare issue posing a large burden on individuals and society. Converging lines of evidence indicate that chronic pain is associated with substantial changes of brain structure and function. However, it remains unclear which neuronal measures relate to changes of clinical parameters over time and could thus monitor chronic pain and treatment responses. We therefore performed a longitudinal study in which we assessed clinical characteristics and resting-state electroencephalography data of 41 patients with chronic pain before and 6 months after interdisciplinary multimodal pain therapy. We specifically assessed electroencephalography measures that have previously been shown to differ between patients with chronic pain and healthy people. These included the dominant peak frequency; the amplitudes of neuronal oscillations at theta, alpha, beta, and gamma frequencies; as well as graph theory-based measures of brain network organization. The results show that pain intensity, pain-related disability, and depression were significantly improved after interdisciplinary multimodal pain therapy. Bayesian hypothesis testing indicated that these clinical changes were not related to changes of the dominant peak frequency or amplitudes of oscillations at any frequency band. Clinical changes were, however, associated with an increase in global network efficiency at theta frequencies. Thus, changes in chronic pain might be reflected by global network changes in the theta band. These longitudinal insights further the understanding of the brain mechanisms of chronic pain. Beyond, they might help to identify biomarkers for the monitoring of chronic pain.

Association of sensory phenotype with quality of life, functionality, and emotional well-being in patients suffering from neuropathic pain.

ABSTRACT: Neuropathic pain highly affects quality of life, well-being, and function. It has recently been shown based on cluster analysis studies that most patients with neuropathic pain may be categorized into 1 of 3 sensory phenotypes: sensory loss, mechanical hyperalgesia, and thermal hyperalgesia. If these phenotypes reflect underlying pathophysiological mechanisms, they may be more relevant for patient management than underlying neurological diagnosis or pain intensity. The aim of this study was thus to examine the impact of these sensory phenotypes on mental health, functionality, and quality of life. Data of 433 patients from the IMI/EuroPain network database were analyzed, and results of HADS-D/A, Pain Catastrophizing Scale, Euro Quality of Life 5D/-VAS, Brief Pain Inventory, and Graded Chronic Pain Scale between the sensory phenotypes were compared using multiple regression analysis. There was no difference in chronic pain grade, pain intensity, depression, or anxiety scores between phenotypes. Pain interference (Brief Pain Inventory) was higher (P = 0.002); self-reported health state lower (Euro Quality of Life 5D VAS, P = 0.02); and problems regarding mobility (P = 0.008), usual activities (P = 0.004), and self-care (P = 0.039) more prominent (EQ5-D) in the sensory loss compared with the thermal hyperalgesia phenotype. Patients with sensory loss also showed higher pain catastrophizing scores (P = 0.006 and 0.022, respectively) compared with the 2 other groups. Sensory phenotype is associated with the impact of neuropathic pain conditions on well-being, daily functionality, and quality of life but is less associated with pain intensity. These results suggest that the somatosensory phenotype should be considered for personalized pain management.

Cannabis-Based Medicines and Medical Cannabis for Chronic Neuropathic Pain.

Neuropathic pain represents a broad category of pain syndromes that include a wide variety of peripheral and central disorders. The overall prevalence of neuropathic pain in the general population is reported to be between 7 and 10%. Management of neuropathic pain presents an unmet clinical need, with less than 50% of patients achieving substantial pain relief with medications currently recommended such as pregabalin, gabapentin, duloxetine and various tricyclic antidepressants. It has been suggested that cannabis-based medicines (CbMs) and medical cannabis (MC) may be a treatment option for those with chronic neuropathic pain. CbMs/MC are available in different forms: licensed medications or medical products (plant-derived and/or synthetic products such as tetrahydrocannabinol or cannabidiol); magistral preparations of cannabis plant derivatives with defined molecular content such as dronabinol (tetrahydrocannabinol); and herbal cannabis with a defined content of tetrahydrocannabinol and/or cannabidiol, together with other active ingredients (phytocannabinoids other than cannabidiol/tetrahydrocannabinol, terpenes and flavonoids). The availability of different types of CbMs/MC varies between countries worldwide. Systematic reviews of available randomised controlled trials have stated low-quality evidence for CbMs and MC for chronic neuropathic pain. Depending on the studies included in the various quantitative syntheses, authors have reached divergent conclusions on the efficacy of CbMs/MC for chronic neuropathic pain (from not effective to a clinically meaningful benefit). Clinically relevant side effects of CbMs/MC, especially for central nervous system and psychiatric disorders, have been reported by some systematic reviews. Recommendations for the use of CbMs/MC for chronic neuropathic pain by various medical associations also differ, from negative recommendations, no recommendation possible, recommended as third-line therapy, or recommended as an alternative in selected cases failing standard therapies within a multimodal concept. After reading this paper, readers are invited to formulate their own conclusions regarding the potential benefits and harms of CbMs/MC for the treatment of chronic neuropathic pain.

Cannabis-Based Medicines and Medical Cannabis in the Treatment of Nociplastic Pain.

Nociplastic pain is defined as pain due to sensitization of the nervous system, without a sufficient underlying anatomical abnormality to explain the severity of pain. Nociplastic pain may be manifest in various organ systems, is often perceived as being more widespread rather than localized and is commonly associated with central nervous system symptoms of fatigue, difficulties with cognition and sleep, and other somatic symptoms; all features that contribute to considerable suffering. Exemplified by fibromyalgia, nociplastic conditions also include chronic visceral pain, chronic headaches and facial pain, and chronic musculoskeletal pain. It has been theorized that dysfunction of the endocannabinoid system may contribute to persistent pain in these conditions. As traditional treatments for chronic pain in general and nociplastic pain in particular are imperfect, there is a need to identify other treatment options. Cannabis-based medicines and medical cannabis (MC) may hold promise and have been actively promoted by the media and advocacy. The medical community must be knowledgeable of the current evidence in this regard to be able to competently advise patients. This review will briefly explain the understanding of nociplastic pain, examine the evidence for the effect of cannabinoids in these conditions, and provide simplified guidance for healthcare providers who may consider prescribing cannabinoids for these conditions.

Contralateral Sensory and Pain Perception Changes in Patients With Unilateral Neuropathy.

OBJECTIVE: To test whether contralateral sensory abnormalities in the clinically unaffected area of patients with unilateral neuropathic pain are due to the neuropathy or pain mechanisms. METHODS: We analyzed the contralateral clinically unaffected side of patients with unilateral painful or painless neuropathy (peripheral nerve injury [PNI], postherpetic neuropathy [PHN], radiculopathy) by standardized quantitative sensory testing following a validated protocol. Primary outcome was the independent contribution of the following variables on the contralateral sensory function using generalized linear regression models: pain intensity, disease duration, etiology, body area, and sensory patterns in the most painful area. RESULTS: Among 424 patients (PNI n = 256, PHN n = 78, radiculopathy n = 90), contralateral sensory abnormalities were frequent in both painful (n = 383) and painless (n = 41) unilateral neuropathy, demonstrating sensory loss for thermal and mechanical nonpainful stimuli and both sensory loss and gain for painful test stimuli. Analysis by etiology revealed contralateral pinprick hyperalgesia in PHN and PNI. Analysis by ipsilateral sensory phenotype demonstrated mirror-image pinprick hyperalgesia in both mechanical and thermal hyperalgesia phenotypes. Pain intensity, etiology, and affected body region predicted changes in only single contralateral somatosensory parameters. Disease duration had no impact on the contralateral sensory function. CONCLUSION: Mechanisms of sensory loss seem to spread to the contralateral side in both painful and painless neuropathies. Contralateral spread of pinprick hyperalgesia was restricted to the 2 ipsilateral phenotypes that suggest sensitization; this suggest a contribution of descending net facilitation from supraspinal areas, which was reported in rodent models of neuropathic pain but not yet in human patients.

Dynamics of brain function in patients with chronic pain assessed by microstate analysis of resting-state electroencephalography.

ABSTRACT: Chronic pain is a highly prevalent and severely disabling disease that is associated with substantial changes of brain function. Such changes have mostly been observed when analyzing static measures of resting-state brain activity. However, brain activity varies over time, and it is increasingly recognized that the temporal dynamics of brain activity provide behaviorally relevant information in different neuropsychiatric disorders. Here, we therefore investigated whether the temporal dynamics of brain function are altered in chronic pain. To this end, we applied microstate analysis to eyes-open and eyes-closed resting-state electroencephalography data of 101 patients suffering from chronic pain and 88 age- and sex-matched healthy controls. Microstate analysis describes electroencephalography activity as a sequence of a limited number of topographies termed microstates that remain stable for tens of milliseconds. Our results revealed that sequences of 5 microstates, labelled with the letters A to E, consistently described resting-state brain activity in both groups in the eyes-closed condition. Bayesian analysis of the temporal characteristics of microstates revealed that microstate D has a less predominant role in patients than in controls. As microstate D has previously been related to attentional networks and functions, these abnormalities might relate to dysfunctional attentional processes in chronic pain. Subgroup analyses replicated microstate D changes in patients with chronic back pain, while patients with chronic widespread pain did not show microstates alterations. Together, these findings add to the understanding of the pathophysiology of chronic pain and point to changes of brain dynamics specific to certain types of chronic pain.

European* clinical practice recommendations on opioids for chronic noncancer pain - Part 1: Role of opioids in the management of chronic noncancer pain.

BACKGROUND: Opioid use for chronic non-cancer pain (CNCP) is complex. In the absence of pan-European guidance on this issue, a position paper was commissioned by the European Pain Federation (EFIC). METHODS: The clinical practice recommendations were developed by eight scientific societies and one patient self-help organization under the coordination of EFIC. A systematic literature search in MEDLINE (up until January 2020) was performed. Two categories of guidance are given: Evidence-based recommendations (supported by evidence from systematic reviews of randomized controlled trials or of observational studies) and Good Clinical Practice (GCP) statements (supported either by indirect evidence or by case-series, case-control studies and clinical experience). The GRADE system was applied to move from evidence to recommendations. The recommendations and GCP statements were developed by a multiprofessional task force (including nursing, service users, physicians, physiotherapy and psychology) and formal multistep procedures to reach a set of consensus recommendations. The clinical practice recommendations were reviewed by five external reviewers from North America and Europe and were also posted for public comment. RESULTS: The key clinical practice recommendations suggest: (a) first optimizing established non-pharmacological treatments and non-opioid analgesics and (b) considering opioid treatment if established non-pharmacological treatments or non-opioid analgesics are not effective and/or not tolerated and/or contraindicated. Evidence- and clinical consensus-based potential indications and contraindications for opioid treatment are presented. Eighteen GCP recommendations give guidance regarding clinical evaluation, as well as opioid treatment assessment, monitoring, continuation and discontinuation. CONCLUSIONS: Opioids remain a treatment option for some selected patients with CNCP under careful surveillance. SIGNIFICANCE: In chronic pain, opioids are neither a universal cure nor a universally dangerous weapon. They should only be used for some selected chronic noncancer pain syndromes if established non-pharmacological and pharmacological treatment options have failed in supervised pain patients as part of a comprehensive, multi-modal, multi-disciplinary approach to treatment. In this context alone, opioid therapy can be a useful tool in achieving and maintaining an optimal level of pain control in some patients.

European clinical practice recommendations on opioids for chronic noncancer pain - Part 2: Special situations.

BACKGROUND: Opioid use for chronic non-cancer pain (CNCP) is under debate. In the absence of pan-European guidance on this issue, a position paper was commissioned by the European Pain Federation (EFIC). METHODS: The clinical practice recommendations were developed by eight scientific societies and one patient self-help organization under the coordination of EFIC. A systematic literature search in MEDLINE (up until January 2020) was performed. Two categories of guidance are given: Evidence-based recommendations (supported by evidence from systematic reviews of randomized controlled trials or of observational studies) and Good Clinical Practice (GCP) statements (supported either by indirect evidence or by case-series, case-control studies and clinical experience). The GRADE system was applied to move from evidence to recommendations. The recommendations and GCP statements were developed by a multiprofessional task force (including nursing, service users, physicians, physiotherapy and psychology) and formal multistep procedures to reach a set of consensus recommendations. The clinical practice recommendations were reviewed by five external reviewers from North America and Europe and were also posted for public comment. RESULTS: The European Clinical Practice Recommendations give guidance for combination with other medications, the management of frequent (e.g. nausea, constipation) and rare (e.g. hyperalgesia) side effects, for special clinical populations (e.g. children and adolescents, pregnancy) and for special situations (e.g. liver cirrhosis). CONCLUSION: If a trial with opioids for chronic noncancer pain is conducted, detailed knowledge and experience are needed to adapt the opioid treatment to a special patient group and/or clinical situation and to manage side effects effectively. SIGNIFICANCE: If a trial with opioids for chronic noncancer pain is conducted, detailed knowledge and experience are needed to adapt the opioid treatment to a special patient group and/or clinical situation and to manage side effects effectively. A collaboration of medical specialties and of all health care professionals is needed for some special populations and clinical situations.

Is opioid therapy for chronic non-cancer pain associated with a greater risk of all-cause mortality compared to non-opioid analgesics? A systematic review of propensity score matched observational studies.

BACKGROUND: The many risks associated with opioid therapy for chronic non-cancer pain (CNCP) have led to questions about use. This is particularly relevant for risk of increased mortality. However, underlying medical conditions of those using opioids may influence mortality findings due to confounding by indication. Similarly, non-opioid analgesics are also associated with an increased risk of mortality, too. METHODS: We have conducted a systematic review of propensity score matched observational studies comparing mortality associated with opioid use compared to non-opioid analgesics. Clinicaltrials.gov, Google Scholar, MEDLINE and Scopus were searched from inception to July 2020. Propensity score matched observational studies comparing opioids to non-opioid analgesics in real-world settings were analysed. Primary outcome was pooled adjusted hazard ratio (aHR) of all-cause death. Effects were summarized by a random effects model. RESULTS: Four studies with seven study arms and 120,186 patients were analysed. Pooled aHR for all-cause death was 1.69 (95% confidence interval [CI] 1.47, 1.95). When mortality risk was confined to out-of-hospital deaths, the pooled aHR was 2.12 (95% CI 1.46, 3.09). The most frequent cause of death was cardiovascular death. Before matching, patients with opioids were older and had more somatic diseases than patients with non-opioids. Despite extensive propensity score matchings and sensitivity analyses, all studies could not fully exclude confounding by indication. CONCLUSIONS: Possibly, opioids are associated with an increased all-cause mortality risk compared to non-opioid analgesics. When considering treatment options for patients with CNCP, the possible risk of increased all-cause mortality with opioids should be discussed. SIGNIFICANCE: An increased all-cause mortality associated with opioid use compared to non-opioid analgesics for CNCP was identified by a systematic review of four propensity score matched cohort studies in real-world settings. The number needed to harm for an additional excess death per 10,000 person-years was 116. Despite extensive propensity score matchings and sensitivity analyses, all studies could not fully exclude confounding by indication. The potential risk of increased all-cause mortality with opioids should be discussed with patients when considering opioid treatment.

Pregabalin for neuropathic pain in primary care settings: recommendations for dosing and titration.

Pregabalin is one of the first-line treatments approved for the management of neuropathic pain (NeP). While many patients benefit from treatment with pregabalin, they are often treated with suboptimal doses, possibly due to unfamiliarity around prescribing the drug and/or side effects that can occur with up-titration. This narrative review discusses key aspects of initiating, titrating, and managing patients prescribed pregabalin therapy, and addresses concerns around driving and the potential for abuse, as well as when to seek specialist opinion. To ensure that patients derive maximum therapeutic benefit from the drug, we suggest a 'low and slow' dosing approach to limit common side effects and optimize tolerability alongside patients' expectations. When requiring titration to higher doses, we recommend initiating 'asymmetric dosing,' with the larger dose in the evening. Fully engaging patients in order for them to understand the expected timeline for efficacy and side effects (including their resolution), can also help determine the optimal titration tempo for each individual patient. The 'low and slow' approach also recognizes that patients with NeP are heterogeneous in terms of their optimal therapeutic dose of pregabalin. Hence, it is recommended that general practitioners closely monitor patients and up-titrate according to pain relief and side effects to limit suboptimal dosing or premature discontinuation.

Safety and efficacy of an equimolar mixture of oxygen and nitrous oxide: a randomized controlled trial in patients with peripheral neuropathic pain.

ABSTRACT: Nitrous oxide (N2O) is an odorless and colorless gas routinely used as an adjuvant of anesthesia and for short-duration analgesia in various clinical settings mostly in the form of an N2O/O2 50%-50% equimolar mixture (EMONO). Experimental studies have suggested that EMONO could also induce long-lasting analgesic effects related to the blockade of N-methyl-D-aspartate receptors. We designed the first international multicenter proof of concept randomized, placebo-controlled study to assess the efficacy and safety of a 1-hour administration of EMONO or placebo (medical air) on 3 consecutive days up to 1 month after the last administration in patients with chronic peripheral neuropathic pain. A total of 240 patients were recruited in 22 centers in France and Germany and randomly assigned to 1 study group (120 per group). Average pain intensity (primary outcome), neuropathic pain characteristics (Neuropathic Pain Symptom Inventory), Patient Global Impression of Change, anxiety, depression, and quality of life were systematically assessed before and after treatment. The changes in average pain intensity between baseline and 7 days after the last administration were not significantly different between the 2 groups. However, evoked pain intensity (predefined secondary endpoint) and Patient Global Impression of Change (exploratory endpoint) were significantly improved in the EMONO group, and these effects were maintained up to 4 weeks after the last treatment administration. Mostly transient side effects were reported during the treatment administration. These encouraging results provide a basis for further investigation of the long-term analgesic effects of EMONO in patients with neuropathic pain.

No pain, still gain (of function): the relation between sensory profiles and the presence or absence of self-reported pain in a large multicenter cohort of patients with neuropathy.

ABSTRACT: The pathophysiology of pain in neuropathy is complex and may be linked to sensory phenotypes. Quantitative sensory testing, a standardized method to evaluate sensory profiles in response to defined stimuli, assesses functional integrity of small and large nerve fiber afferents and central somatosensory pathways. It has revealed detailed insights into mechanisms of neuropathy, yet it remains unclear if pain directly affects sensory profiles. The main objective of this study was to investigate sensory profiles in patients with various neuropathic conditions, including polyneuropathy, mononeuropathy, and lesions to the central nervous system, in relation to self-reported presence or absence of pain and pain sensitivity using the Pain Sensitivity Questionnaire. A total of 443 patients (332 painful and 111 painless) and 112 healthy participants were investigated. Overall, loss of sensation was equally prevalent in patients with and without spontaneous pain. Pain thresholds were equally lowered in both patient groups, demonstrating that hyperalgesia and allodynia are just as present in patients not reporting any pain. Remarkably, this was similar for dynamic mechanical allodynia. Hypoalgesia was more pronounced in painful polyneuropathy, whereas hyperalgesia was more frequent in painful mononeuropathy (compared with painless conditions). Self-reported pain sensitivity was significantly higher in painful than in painless neuropathic conditions. Our results reveal the presence of hyperalgesia and allodynia in patients with central and peripheral lesions of the somatosensory system not reporting spontaneous pain. This shows that symptoms and signs of hypersensitivity may not necessarily coincide and that painful and painless neuropathic conditions may mechanistically blend into one another.