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.

Assessing Corneal Confocal Microscopy and Other Small Fiber Measures in Diabetic Polyneuropathy.

BACKGROUND AND OBJECTIVES: Damage to small nerve fibers is common in diabetic polyneuropathy (DPN), and the diagnosis of DPN relies on subjective symptoms and signs in a combination with objective confirmatory tests, typically electrophysiology or intraepidermal nerve fiber density (IENFD) from skin biopsy. Corneal confocal microscopy (CCM) has been introduced as a tool to detect DPN. However, it is unclear if CCM can reliably be used to diagnose DPN and how the technique compares with other commonly used measures of small fiber damage, such as IENFD, cold detection threshold (CDT), and warm detection threshold (WDT). Therefore, we assessed and compared the use of CCM, IENFD, CDT, and WDT in the diagnosis of DPN in patients with type 2 diabetes. METHODS: In this cohort study, the participants underwent detailed neurologic examination, electrophysiology, quantification of IENFD, CCM, and quantitative sensory testing. Definition of DPN was made in accordance with the Toronto criteria for diabetic neuropathy (without relying on IENFD and thermal thresholds). RESULTS: A total of 214 patients with at least probable DPN, 63 patients without DPN, and 97 controls without diabetes were included. Patients with DPN had lower CCM measures (corneal nerve fiber length [CNFL], nerve fiber density, and branch density), IENFD, CDT, and WDT compared with patients without DPN (p ≤ 0.001, <0.001, 0.002, p < 0.001, p = 0.003, and <0.005, respectively), whereas there was no difference between controls and patients with diabetes without DPN. All 3 CCM measures showed a very low diagnostic sensitivity with CNFL showing the highest (14.4% [95% CI 9.8-18.4]) and a specificity of 95.7% (88.0-99.1). In comparison, the sensitivity of abnormal CDT and/or WDT was 30.5% (24.4-37.0) with a specificity of 84.9% (74.6-92.2). The sensitivity of abnormal IENFD was highest among all measures with a value of 51.1% (43.7-58.5) and a specificity of 90% (79.5-96.2). CCM measures did not correlate with IENFD, CDT/WDT, or neuropathy severity in the group of patients with DPN. DISCUSSION: CCM measures showed the lowest sensitivity compared with other small fiber measures in the diagnosis of DPN. This indicates that CCM is not a sensitive method to detect DPN in recently diagnosed type 2 diabetes. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CCM measures aid in the detection of DPN in recently diagnosed type 2 diabetics but with a low sensitivity when compared with other small fiber measures.

Efficacy, safety, and tolerability of antidepressants for pain in adults: overview of systematic reviews.

OBJECTIVE: To provide a comprehensive overview of the efficacy, safety, and tolerability of antidepressants for pain according to condition. DESIGN: Overview of systematic reviews. DATA SOURCES: PubMed, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials from inception to 20 June 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Systematic reviews comparing any antidepressant with placebo for any pain condition in adults. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data. The main outcome measure was pain; for headache disorders it was frequency of headaches. Continuous pain outcomes were converted into a scale of 0 (no pain) to 100 (worst pain) and were presented as mean differences (95% confidence intervals). Dichotomous outcomes were presented as risk ratios (95% confidence intervals). Data were extracted from the time point closest to the end of treatment. When end of treatment was too variable across trials in a review, data were extracted from the outcome or time point with the largest number of trials and participants. Secondary outcomes were safety and tolerability (withdrawals because of adverse events). Findings were classified from each comparison as efficacious, not efficacious, or inconclusive. Certainty of evidence was assessed with the grading of recommendations assessment, development, and evaluation framework. RESULTS: 26 reviews (156 unique trials and >25 000 participants) were included. These reviews reported on the efficacy of eight antidepressant classes covering 22 pain conditions (42 distinct comparisons). No review provided high certainty evidence on the efficacy of antidepressants for pain for any condition. 11 comparisons (nine conditions) were found where antidepressants were efficacious, four with moderate certainty evidence: serotonin-norepinephrine reuptake inhibitors (SNRIs) for back pain (mean difference -5.3, 95% confidence interval -7.3 to -3.3), postoperative pain (-7.3, -12.9 to -1.7), neuropathic pain (-6.8, -8.7 to -4.8), and fibromyalgia (risk ratio 1.4, 95% confidence interval 1.3 to 1.6). For the other 31 comparisons, antidepressants were either not efficacious (five comparisons) or the evidence was inconclusive (26 comparisons). CONCLUSIONS: Evidence of efficacy of antidepressants was found in 11 of the 42 comparisons included in this overview of systematic reviews-seven of the 11 comparisons investigated the efficacy of SNRIs. For the other 31 comparisons, antidepressants were either inefficacious or evidence on efficacy was inconclusive. The findings suggest that a more nuanced approach is needed when prescribing antidepressants for pain conditions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022311073.

Neuropathy and pain after breast cancer treatment: a prospective observational study.

OBJECTIVES: Neurological complications including pain are common after treatment for breast cancer. This prospective study investigated the symptoms, intensity and interference of chemotherapy-induced peripheral neuro-pathy. (CIPN) in the feet and hands compared to surgery- and radiation-induced neuropathy in the breast and upper arm. METHODS: Consecutive patients referred to surgery for breast cancer were included in a prospective study and completed a questionnaire at baseline and a follow-up questionnaire and interview after one year. CIPN was assessed with the CIPN20 questionnaire and the Michigan Neuropathy Screening Instrument questionnaire (MNSIq). Pain intensity was rated on a numeric rating scale (NRS, 0-10). RESULTS: In total 144 patients were included, of which 73 received chemotherapy. At one-year follow-up, symptoms of polyneuropathy were more common in patients treated with chemotherapy. Tingling or numbness in the feet in those treated/not treated with chemotherapy was reported by 44 (62%) and 15 (21%), respectively. Pain was present in 22 (30%) and 10 (14%), respectively. Pain in the area of surgery was reported by 66 (46%). Although less common, pain in the feet in those treated with chemotherapy was rated as more intense and with more daily life interference than pain in the surgical area (NRS 5.5 (SD 1.9) vs. 3.1 (SD 1.9). CONCLUSIONS: Neurological complications including pain following surgery and chemotherapy represent a burden to breast cancer survivors. In those who had received chemotherapy, pain in the feet was less common than pain in the surgical area, but pain in the feet was more intense and had a higher interference with daily life. Our study emphasizes the need for either baseline data or a control population for improved estimation of the presence and severity of CIPN and pain from questionnaires.

Functional and structural markers of peripheral microvascular autonomic neuropathy.

INTRODUCTION/AIMS: Autonomic dysfunction is a common complication of small-fiber neuropathy (SFN). In this study we aimed to assess the applicability of autonomic microvascular indices as a potential marker for SFN assessment. METHODS: Fifteen patients with confirmed SFN (idiopathic neuropathy [n = 10], chemotherapy-induced peripheral neuropathy [n = 2], impaired glucose tolerance [n = 1], hereditary transthyretin amyloidosis (hATTR) [n = 1], pulmonary sarcoidosis [n = 1]) and 15 matched control subjects underwent assessment of vascular skin responses assessed through laser Doppler flowmetry and evaluation of microvascular vessel and nerve density in skin biopsies. All participants underwent peripheral autonomic evaluation by quantitative sudomotor axon reflex testing (QSART). RESULTS: We found no significant differences in vascular skin responses, or in any microvascular skin biopsy markers, when comparing SFN with control subjects. We found no correlation between vascular skin responses and skin biopsy indices. We saw no significant difference in any microvascular indices when comparing subjects with and without impaired sudomotor function. DISCUSSION: Our findings suggest markers of peripheral microvascular innervation and function are not associated with the diagnosis of SFN. Furthermore, we saw no association between microvascular markers and sudomotor function, suggesting that these are independent and unrelated components of the autonomic nervous system.

Axonal Excitability Does Not Differ between Painful and Painless Diabetic or Chemotherapy-Induced Distal Symmetrical Polyneuropathy in a Multicenter Observational Study.

OBJECTIVE: Axonal excitability reflects ion channel function, and it is proposed that this may be a biomarker in painful (vs painless) polyneuropathy. Our objective was to investigate the relationship between axonal excitability parameters and chronic neuropathic pain in deeply phenotyped cohorts with diabetic or chemotherapy-induced distal symmetrical polyneuropathy. METHODS: Two hundred thirty-nine participants with diabetic polyneuropathy were recruited from sites in the UK and Denmark, and 39 participants who developed chemotherapy-induced polyneuropathy were recruited from Denmark. Participants were separated into those with probable or definite neuropathic pain and those without neuropathic pain. Axonal excitability of large myelinated fibers was measured with the threshold tracking technique. The stimulus site was the median nerve, and the recording sites were the index finger (sensory studies) and abductor pollicis brevis muscle (motor studies). RESULTS: Participants with painless and painful polyneuropathy were well matched across clinical variables. Sensory and motor axonal excitability measures, including recovery cycle, threshold electrotonus, strength-duration time constant, and current-threshold relationship, did not show differences between participants with painful and painless diabetic polyneuropathy, and there were only minor changes for chemotherapy-induced polyneuropathy. INTERPRETATION: Axonal excitability did not significantly differ between painful and painless diabetic or chemotherapy-induced polyneuropathy in a multicenter observational study. Threshold tracking assesses the excitability of myelinated axons; the majority of nociceptors are unmyelinated, and although there is some overlap of the "channelome" between these axonal populations, our results suggest that alternative measures such as microneurography are required to understand the relationship between sensory neuron excitability and neuropathic pain. ANN NEUROL 2022;91:506-520.

Risk factors for persistent pain after breast and thoracic surgeries: a systematic literature review and meta-analysis.

ABSTRACT: Persistent postsurgical pain (PPSP) is common after breast and thoracic surgeries. Understanding which risk factors consistently contribute to PPSP will allow clinicians to apply preventive strategies, as they emerge, to high-risk patients. The objective of this work was to systematically review and meta-analyze the literature on risk factors of PPSP after breast and thoracic surgeries. A systematic literature search using Ovid Medline, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Embase, PsycINFO, and Scopus databases was conducted. Study screening with inclusion and exclusion criteria, data extraction, and risk of bias assessment was performed independently by 2 authors. The data for each surgical group were analyzed separately and meta-analyzed where possible. The literature search yielded 5584 articles, and data from 126 breast surgery and 143 thoracic surgery articles were considered for meta-analysis. In breast surgery, younger age, higher body mass index, anxiety, depression, diabetes, smoking, preoperative pain, moderate to severe acute postoperative pain, reoperation, radiotherapy, and axillary lymph node dissection were the main factors associated with higher risk of PPSP. In thoracic surgery, younger age, female sex, hypertension, preoperative pain, moderate to severe acute postoperative pain, surgical approach, major procedure, and wound complications were associated with PPSP. This systematic review demonstrated certain consistent risk factors of PPSP after breast and thoracic surgeries, as well as identified research gaps. Understanding the factors that increase susceptibility to PPSP can help selectively allocate resources to optimize perioperative care in high-risk patients and help develop targeted, risk-stratified interventions for PPSP prevention.

Classification of pain in children with cerebral palsy.

Pain in patients with cerebral palsy (CP) is a major health issue strongly associated with reduced quality of life. In this study, we provide an overview of pain conditions in children with CP using the International Classification of Diseases, 11th Revision (ICD-11), which has been updated with a classification of chronic pain. Common causes of pain in children with CP, including hip displacement, muscle spasms, and procedures, are discussed; less studied pain types including headaches, neuropathic pain, visceral pain, and acute versus chronic pain are also highlighted. The addition of chronic pain to the ICD-11 is an important step forward in optimizing both the registration and assessment of pain conditions. However, a tool designed specifically for the different types of pain in patients with CP is imperative. In this paper, we propose a Cerebral Palsy Pain Classification that is aligned with the underlying mechanisms of pain and the ICD-11 pain classification.

Axonal swellings are related to type 2 diabetes, but not to distal diabetic sensorimotor polyneuropathy.

AIMS/HYPOTHESIS: Distal diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes with many patients showing a reduction of intraepidermal nerve fibre density (IENFD) from skin biopsy, a validated and sensitive diagnostic tool for the assessment of DSP. Axonal swelling ratio is a morphological quantification altered in DSP. It is, however, unclear if axonal swellings are related to diabetes or DSP. The aim of this study was to investigate how axonal swellings in cutaneous nerve fibres are related to type 2 diabetes mellitus, DSP and neuropathic pain in a well-defined cohort of patients diagnosed with type 2 diabetes. METHODS: A total of 249 participants, from the Pain in Neuropathy Study (UK) and the International Diabetic Neuropathy Consortium (Denmark), underwent a structured neurological examination, nerve conduction studies, quantitative sensory testing and skin biopsy. The study included four groups: healthy control study participants without diabetes (n = 45); participants with type 2 diabetes without DSP (DSP-; n = 31); and participants with evidence of DSP (DSP+; n = 173); the last were further separated into painless DSP+ (n = 74) and painful DSP+ (n = 99). Axonal swellings were defined as enlargements on epidermal-penetrating fibres exceeding 1.5 µm in diameter. Axonal swelling ratio is calculated by dividing the number of axonal swellings by the number of intraepidermal nerve fibres. RESULTS: Median (IQR) IENFD (fibres/mm) was: 6.7 (5.2-9.2) for healthy control participants; 6.2 (4.4-7.3) for DSP-; 1.3 (0.5-2.2) for painless DSP+; and 0.84 (0.4-1.6) for painful DSP+. Swelling ratios were calculated for all participants and those with IENFD > 1.0 fibre/mm. When only those participants with IENFD > 1.0 fibre/mm were included, the axonal swelling ratio was higher in participants with type 2 diabetes when compared with healthy control participants (p < 0.001); however, there was no difference between DSP- and painless DSP+ participants, or between painless DSP+ and painful DSP+ participants. The axonal swelling ratio correlated weakly with HbA1c (r = 0.16, p = 0.04), but did not correlate with the Toronto Clinical Scoring System (surrogate measure of DSP severity), BMI or type 2 diabetes duration. CONCLUSIONS/INTERPRETATION: In individuals with type 2 diabetes where IENFD is >1.0 fibre/mm, axonal swelling ratio is related to type 2 diabetes but is not related to DSP or painful DSP. Axonal swellings may be an early marker of sensory nerve injury in type 2 diabetes.

Oxaliplatin- and docetaxel-induced polyneuropathy: clinical and neurophysiological characteristics.

The aim of this study was to evaluate the presence and characterization of chemotherapy-induced neuropathy (CIPN) and neuropathic pain 5 years after adjuvant chemotherapy with docetaxel or oxaliplatin. Patients from an ongoing prospective study, who had received adjuvant chemotherapy with docetaxel or oxaliplatin in 2011 to 2012 were invited to participate. The patients underwent a thorough examination with interview, neurological examination, questionnaires, assessment tools, nerve conduction studies (NCS), quantitative sensory testing, MScan motor unit number estimation (MUNE), and corneal confocal microscopy (CCM). Patients were divided into no, possible, probable, and confirmed CIPN. Out of the 132 eligible patients, 63 agreed to participate: 28 had received docetaxel and 35 had received oxaliplatin. Forty-one percent had confirmed CIPN, 34% possible or probable CIPN, and 22% did not have CIPN. The CIPN was characterized mainly by sensory nerve fiber loss, with a more pronounced large fiber than small fiber loss but also some motor fiber loss identified on NCS and MUNE. In general, patients had mild neuropathy with relatively low scores on assessment tools and no association with mood and quality of life. CCM was not useful as a diagnostic tool. Of the patients with probable or confirmed CIPN, 30% experienced pain, which was most often mild, but still interfered moderately with daily life in 20% to 25% and was associated with lower quality of life. In conclusion CIPN was confirmed in 41% 5 years after chemotherapy. The neuropathy was generally mild, but in patients with neuropathic pain it was associated with lower quality of life.

Long-term symptoms of polyneuropathy in breast and colorectal cancer patients treated with and without adjuvant chemotherapy.

BACKGROUND: The aim of this study was to assess chemotherapy-induced polyneuropathy (CIPN) 5 years after adjuvant chemotherapy in patients with breast and colorectal cancer. The association of CIPN with quality of life, anxiety, and depression was analyzed. METHODS: Of a set of 100 patients with breast cancer and of 74 with colorectal cancer who had undergone surgery and adjuvant chemotherapy in 2011-2012, 80 and 52 patients alive, respectively, were included together with two reference groups of 249 breast cancer patients and 83 colorectal cancer patients who had undergone surgery only. All patients were sent a questionnaire on alcohol consumption, smoking habits, comorbidity, medicine consumption, and oxaliplatin-specific questions, as well as the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), the Douleur Neuropathique 4 Questions (DN4q), the EQ-5D, and the Hospital Anxiety and Depression Scale. Possible polyneuropathy was defined as the presence of numbness and/or tingling in the feet, secondly as a score of ≥4 on the MNSIq. Possible painful polyneuropathy was defined as pain in both feet and a score ≥3 on the DN4q. RESULTS: The prevalence of possible polyneuropathy defined by numbness and/or tingling in the feet was 38.8% (28.1-50.3) after adjuvant docetaxel and 57.7% (43.2-71.3) after adjuvant oxaliplatin, with no significant difference from a previous 1-year follow-up (P >.35). Fewer had possible polyneuropathy as defined by the MNSIq. Patients with possible polyneuropathy after adjuvant chemotherapy reported significantly lower quality of life than patients treated with surgery only. CONCLUSION: Symptoms of polyneuropathy following adjuvant docetaxel and oxaliplatin persist 5 years after treatment and affect quality of life negatively.

Metabolic Factors, Lifestyle Habits, and Possible Polyneuropathy in Early Type 2 Diabetes: A Nationwide Study of 5,249 Patients in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Cohort.

OBJECTIVE: To investigate the association of metabolic and lifestyle factors with possible diabetic polyneuropathy (DPN) and neuropathic pain in patients with early type 2 diabetes. RESEARCH DESIGN AND METHODS: We thoroughly characterized 6,726 patients with recently diagnosed diabetes. After a median of 2.8 years, we sent a detailed questionnaire on neuropathy, including the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), to identify possible DPN (score ≥4) and the Douleur Neuropathique en 4 Questions (DN4) questionnaire for possible associated neuropathic pain (MNSIq ≥4 + pain in both feet + DN4 score ≥3). RESULTS: Among 5,249 patients with data on both DPN and pain, 17.9% (n = 938) had possible DPN, including 7.4% (n = 386) with possible neuropathic pain. In regression analyses, central obesity (waist circumference, waist-to-hip ratio, and waist-to-height ratio) was markedly associated with DPN. Other important metabolic factors associated with DPN included hypertriglyceridemia ≥1.7 mmol/L, adjusted prevalence ratio (aPR) 1.36 (95% CI 1.17; 1.59); decreased HDL cholesterol <1.0/1.2 mmol/L (male/female), aPR 1.35 (95% CI 1.12; 1.62); hs-CRP ≥3.0 mg/L, aPR 1.66 (95% CI 1.42; 1.94); C-peptide ≥1,550 pmol/L, aPR 1.72 (95% CI 1.43; 2.07); HbA1c ≥78 mmol/mol, aPR 1.42 (95% CI 1.06; 1.88); and antihypertensive drug use, aPR 1.34 (95% CI 1.16; 1.55). Smoking, aPR 1.50 (95% CI 1.24; 1.81), and lack of physical activity (0 vs. ≥3 days/week), aPR 1.61 (95% CI 1.39; 1.85), were also associated with DPN. Smoking, high alcohol intake, and failure to increase activity after diabetes diagnosis associated with neuropathic pain. CONCLUSIONS: Possible DPN was associated with metabolic syndrome factors, insulin resistance, inflammation, and modifiable lifestyle habits in early type 2 diabetes.

Cold aggravates abnormal excitability of motor axons in oxaliplatin-treated patients.

INTRODUCTION: Cold allodynia is often seen in the acute phase of oxaliplatin treatment, but the underlying pathophysiology remains unclear. METHODS: Patients scheduled for adjuvant oxaliplatin for colorectal cancer were examined with quantitative sensory testing and nerve excitability tests at baseline and after the second or third oxaliplatin cycle at different skin temperatures. RESULTS: Seven patients were eligible for examination. All patients felt evoked pain and tingling when touching something cold after oxaliplatin infusion. Oxaliplatin decreased motor nerve superexcitability (P < .001), increased relative refractory period (P = .011), and caused neuromyotonia-like after-activity. Cooling exacerbated these changes and prolonged the accommodation half-time. DISCUSSION: The findings suggest that a combined effect of oxaliplatin and cooling facilitates nerve excitability changes and neuromyotonia-like after-activity in peripheral nerve axons. A possible mechanism is the slowing in gating of voltage-dependent fast sodium and slow potassium channels, which results in symptoms of cold allodynia.

Chronic pain after bilateral thoracotomy in lung transplant patients.

Background and aims The relative contribution of patient-related factors and intraoperative nerve damage for the development of chronic pain after surgery is unclear. This study aimed to examine chronic pain after bilateral thoracotomy. We hypothesized, that individual patient-related risk factors would be important resulting in an intraindividual uniformity of pain and hyperphenomena between the two sides of the thorax. Methods Twenty patients who had undergone lung transplantation via bilateral thoracotomy 6-12 months previously were included from the Danish Lung Transplant program, Rigshospitalet, Denmark, from October 2016 to August 2017. All patients answered questionnaires about pain in and around the scar, completed the Neuropathic Pain Symptom Inventory, and underwent bedside examination for hyperphenomena (brush- and cold-evoked allodynia, pinprick hyperalgesia) and pinprick hypoalgesia. Results Nine patients reported spontaneous pain bilaterally, five patients had pain on one side only, and six patients had no pain. Hyperphenomena were present on both sides of the thorax in 13 patients, on one side in four patients, and three patients had no hyperphenomena. The intraindividual uniformity of pain (p=0.029) and hyperphenomena (p=0.011) between the two sides of the thorax suggests that patient-related factors play an important role in the development of chronic pain. Conclusions The results of the present study provide support for the hypothesis of an individual predisposition for the development of chronic pain after thoracotomy. Implications Patient-related risk factors contribute to the development of chronic pain after thoracotomy. This result most likely can be transferred to chronic pain after other surgical procedures and therefore help us understand risk factors for chronic pain after surgery.

Chronic pain as a symptom or a disease: the IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11).

Chronic pain is a major source of suffering. It interferes with daily functioning and often is accompanied by distress. Yet, in the International Classification of Diseases, chronic pain diagnoses are not represented systematically. The lack of appropriate codes renders accurate epidemiological investigations difficult and impedes health policy decisions regarding chronic pain such as adequate financing of access to multimodal pain management. In cooperation with the WHO, an IASP Working Group has developed a classification system that is applicable in a wide range of contexts, including pain medicine, primary care, and low-resource environments. Chronic pain is defined as pain that persists or recurs for more than 3 months. In chronic pain syndromes, pain can be the sole or a leading complaint and requires special treatment and care. In conditions such as fibromyalgia or nonspecific low-back pain, chronic pain may be conceived as a disease in its own right; in our proposal, we call this subgroup "chronic primary pain." In 6 other subgroups, pain is secondary to an underlying disease: chronic cancer-related pain, chronic neuropathic pain, chronic secondary visceral pain, chronic posttraumatic and postsurgical pain, chronic secondary headache and orofacial pain, and chronic secondary musculoskeletal pain. These conditions are summarized as "chronic secondary pain" where pain may at least initially be conceived as a symptom. Implementation of these codes in the upcoming 11th edition of International Classification of Diseases will lead to improved classification and diagnostic coding, thereby advancing the recognition of chronic pain as a health condition in its own right.

Risk-Factor Trajectories Preceding Diabetic Polyneuropathy: ADDITION-Denmark.

OBJECTIVE: To study cardiometabolic risk-factor trajectories (in terms of levels and changes over time) preceding diabetic polyneuropathy (DPN) 13 years after a screen-detected diagnosis of type 2 diabetes. RESEARCH DESIGN AND METHODS: We clinically diagnosed DPN in a nested case-control study of 452 people in the Danish arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION). By linear regression models, we estimated preceding risk-factor trajectories during 13 years. Risk of DPN was estimated by multivariate logistic regression models of each individual's risk-factor trajectory intercept and slope adjusting for sex, age, diabetes duration, height, and trial randomization group. RESULTS: Higher baseline levels of HbA1c (odds ratio [OR] 1.76 [95% CI 1.37; 2.27] and OR 1.68 [95% CI 1.33; 2.12] per 1% and 10 mmol/mol, respectively) and steeper increases in HbA1c over time (OR 1.66 [95% CI 1.21; 2.28] and OR 1.59 [95% CI 1.19; 2.12] per 1% and 10 mmol/mol increase during 10 years, respectively) were associated with DPN. Higher baseline levels of weight, waist circumference, and BMI were associated with DPN (OR 1.20 [95% CI 1.10; 1.31] per 5 kg, OR 1.27 [95% CI 1.13; 1.43] per 5 cm, and OR 1.24 [95% CI 1.12; 1.38] per 2 kg/m2, respectively). CONCLUSIONS: Both higher levels and slopes of HbA1c trajectories were associated with DPN after 13 years. Our findings indicate that the rate of HbA1c increase affects the development of DPN over and above the effect of the HbA1c level. Furthermore, this study supports obesity as a risk factor for DPN.

Risk Factors for Incident Diabetic Polyneuropathy in a Cohort With Screen-Detected Type 2 Diabetes Followed for 13 Years: ADDITION-Denmark.

OBJECTIVE: To study incident diabetic polyneuropathy (DPN) prospectively during the first 13 years after a screening-based diagnosis of type 2 diabetes and determine the associated risk factors for the development of DPN. RESEARCH DESIGN AND METHODS: We assessed DPN longitudinally in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION) using the Michigan Neuropathy Screening Instrument questionnaire (MNSIQ), defining DPN with scores ≥4. Risk factors present at the diabetes diagnosis associated with the risk of incident DPN were estimated using Cox proportional hazard models adjusted for trial randomization group, sex, and age. RESULTS: Of the total cohort of 1,533 people, 1,445 completed the MNSIQ at baseline and 189 (13.1%) had DPN at baseline. The remaining 1,256 without DPN entered this study (median age 60.8 years [interquartile range 55.6; 65.6], 59% of whom were men). The cumulative incidence of DPN was 10% during 13 years of diabetes. Age (hazard ratio [HR] 1.03 [95% CI 1.00; 1.07]) (unit = 1 year), weight (HR 1.09 [95% CI 1.03; 1.16]) (unit = 5 kg), waist circumference (HR 1.14 [95% CI 1.05; 1.24]) (unit = 5 cm), BMI (HR 1.14 [95% CI 1.06; 1.23]) (unit = 2 kg/m2), log2 methylglyoxal (HR 1.45 [95% CI 1.12; 1.89]) (unit = doubling), HDL cholesterol (HR 0.82 [95% CI 0.69; 0.99]) (unit = 0.25 mmol/L), and LDL cholesterol (HR 0.92 [95% CI 0.86; 0.98]) (unit = 0.25 mmol/L) at baseline were significantly associated with the risk of incident DPN. CONCLUSIONS: This study provides further epidemiological evidence for obesity as a risk factor for DPN. Moreover, low HDL cholesterol levels and higher levels of methylglyoxal, a marker of dicarbonyl stress, are identified as risk factors for the development of DPN.

Axonal excitability changes and acute symptoms of oxaliplatin treatment: In vivo evidence for slowed sodium channel inactivation.

OBJECTIVE: Neurotoxicity is the most frequent dose-limiting side effect of the anti-cancer agent oxaliplatin, but the mechanisms are not well understood. This study used nerve excitability testing to investigate the pathophysiology of the acute neurotoxicity. METHODS: Questionnaires, quantitative sensory tests, nerve conduction studies and nerve excitability testing were undertaken in 12 patients with high-risk colorectal cancer treated with adjuvant oxaliplatin and in 16 sex- and age-matched healthy controls. Examinations were performed twice for patients: once within 3 days after oxaliplatin treatment (post-infusion examination) and once shortly before the following treatment (recovery examination). RESULTS: The most frequent post-infusion symptoms were tingling paresthesias and cold allodynia. The most prominent nerve excitability change was decreased superexcitability of motor axons which correlated with the average intensity of abnormal sensations (Spearman Rho = 0.80, p < .01). The motor nerve excitability changes were well modeled by a slowing of sodium channel inactivation, and were proportional to dose/m2 with a half-life of about 10d. CONCLUSIONS: Oxaliplatin induces reversible slowing of sodium channel inactivation in motor axons, and these changes are closely related to the reversible cold allodynia. However, further studies are required due to small sample size in this study. SIGNIFICANCE: Nerve excitability data provide an index of sodium channel dysfunction: an objective biomarker of acute oxaliplatin neurotoxicity.

DOLORisk: study protocol for a multi-centre observational study to understand the risk factors and determinants of neuropathic pain.

Background: Neuropathic pain is an increasingly prevalent condition and has a major impact on health and quality of life. However, the risk factors for the development and maintenance of neuropathic pain are poorly understood. Clinical, genetic and psychosocial factors all contribute to chronic pain, but their interactions have not been studied in large cohorts. The DOLORisk study aims to study these factors. Protocol: Multicentre cross-sectional and longitudinal cohorts covering the main causes leading to neuropathic pain (e.g. diabetes, surgery, chemotherapy, traumatic injury), as well as rare conditions, follow a common protocol for phenotyping of the participants. This core protocol correlates answers given by the participants on a set of questionnaires with the results of their genetic analyses. A smaller number of participants undergo deeper phenotyping procedures, including neurological examination, nerve conduction studies, threshold tracking, quantitative sensory testing, conditioned pain modulation and electroencephalography. Ethics and dissemination: All studies have been approved by their regional ethics committees as required by national law. Results are disseminated through the DOLORisk website, scientific meetings, open-access publications, and in partnership with patient organisations. Strengths and limitations: Large cohorts covering many possible triggers for neuropathic painMulti-disciplinary approach to study the interaction of clinical, psychosocial and genetic risk factorsHigh comparability of the data across centres thanks to harmonised protocolsOne limitation is that the length of the questionnaires might reduce the response rate and quality of responses of participants.

The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes.

Small fibre neuropathies are a heterogeneous group of disorders affecting thinly myelinated Aδ-fibres and unmyelinated C-fibres. Although multiple causes of small nerve fibre degeneration have been reported, including via genetic mutations, the cause of small fibre neuropathy remains unknown in up to 50% of cases. The typical clinical presentation of small fibre neuropathy is that of a symmetrical, length-dependent polyneuropathy associated with sensory or autonomic symptoms. More rarely, the clinical presentation is characterised by non-length-dependent, focal, or multifocal symptoms. The diagnostic tests to identify small fibre neuropathy include skin biopsy, quantitative sensory, and autonomic testing. Additional tests, such as those measuring small fibre-related evoked potentials and corneal confocal microscopy, might contribute to a better understanding of these neuropathies. Biochemical markers can also help in screening patients for the presence of small fibre neuropathy and to assess disease progression.