Evidence of opioid-induced hyperalgesia in clinical populations after chronic opioid exposure: a systematic review and meta-analysis.

BACKGROUND: Opioid-induced hyperalgesia (OIH) is well documented in preclinical studies, but findings of clinical studies are less consistent. The objective was to undertake a systematic review and meta-analysis of studies examining evidence for OIH in humans after opioid exposure. METHODS: Systematic electronic searches utilised six research databases (Embase, Medline, PubMed, CINAHL Plus, Web of Science, and OpenGrey). Manual 'grey' literature searches were also undertaken. The Population, Interventions, Comparators, Outcomes, and Study design (PICOS) framework was used to develop search strategies, and findings are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. Data synthesis and subgroup analyses were undertaken using a random effects model (DerSimonian-Laird method). RESULTS: A total of 6167 articles were identified. After abstract and full-text reviews, 26 articles (involving 2706 participants) were included in the review. There was evidence of OIH, assessed by pain tolerance, in response to noxious thermal (hot and cold) stimuli, but not electrical stimuli. There was no evidence of OIH when assessing pain detection thresholds. OIH was more evident in patients with opioid use disorder than in patients with pain, and in patient groups treated with N-methyl-d-aspartate receptor antagonists (primarily evidenced in methadone-maintained populations). CONCLUSIONS: OIH was evident in patients after chronic opioid exposure, but findings were dependent upon pain modality and assessment measures. Further studies should consider evaluating both pain threshold and pain tolerance across a range of modalities to ensure assessment validity. Significant subgroup findings suggest that potential confounders of pain judgements, such as illicit substance use, affective characteristics, or coping styles, should be rigorously controlled in future studies.

Incidence of iatrogenic opioid dependence or abuse in patients with pain who were exposed to opioid analgesic therapy: a systematic review and meta-analysis.

BACKGROUND: The prevalence and incidence of chronic conditions, such as pain and opioid dependence, have implications for policy development, resource allocation, and healthcare delivery. The primary objective of the current review was to estimate the incidence of iatrogenic opioid dependence or abuse after treatment with opioid analgesics. METHODS: Systematic electronic searches utilised six research databases (Embase, Medline, PubMed, Cinahl Plus, Web of Science, OpenGrey). A 'grey' literature search and a reference search of included articles were also undertaken. The PICOS framework was used to develop search strategies and the findings are reported in accordance with the PRISMA Statement. RESULTS: After eligibility reviews of 6164 articles, 12 studies (involving 310 408 participants) were retained for inclusion in the meta-analyses. A random effects model (DerSimonian-Laird method) generated a pooled incidence of opioid dependence or abuse of 4.7%. There was little within-study risk of bias and no significant publication bias; however, substantial heterogeneity was found among study effects (99.78%). Sensitivity analyses indicated that the diagnostic criteria selected for identifying opioid dependence or abuse (Diagnostic Statistical Manual (DSM-IV) vs International Classification of Diseases (ICD-9)) accounted for 20% and duration of exposure to opioid analgesics accounted for 18% of variance in study effects. Longer-term opioid analgesic exposure, and prescription of strong rather than weak opioids, were associated with a significantly lower incidence of opioid dependence or abuse. CONCLUSIONS: The incidence of iatrogenic opioid dependence or abuse was 4.7% of those prescribed opioids for pain. Further research is required to confirm the potential for our findings to inform prevention of this serious adverse event.

Association of opioid prescribing practices with chronic pain and benzodiazepine co-prescription: a primary care data linkage study.

BACKGROUND: Opioid prescribing is increasing worldwide with associated increases in misuse and other harms. We studied variations in national opioid prescription rates, indicators of prescribing quality, co-prescribing of benzodiazepines and relationship with pain severity in Scotland. METHODS: Electronic linkages of opioid prescribing in Scotland were determined from: (i) national data from Information Services Division, NHS Scotland (2003-2012); and (ii) individual data from Generation Scotland: Scottish Family Health Study. Descriptive analyses were conducted on national data, multilevel modelling to examine factors associated with variations in prescribing rates. χ2 tests examined associations between individual pain severity and opioid prescriptions. RESULTS: The number of strong opioid prescriptions more than doubled from 474 385 in 2003 to 1 036 446 in 2012, and weak opioid prescribing increased from 3 261 547 to 4 852 583. In Scotland, 938 674 individuals were prescribed an opioid in 2012 (18% of the population). Patients in the most deprived areas were 3.5 times more likely to receive a strong opioid than patients in the least deprived. There was significant variation in prescribing rates between geographical areas, with much of this explained by deprivation. Of women aged 25-40 yr prescribed a strong opioid, 40% were also prescribed a benzodiazepine. There was significant association between pain severity and receipt of opioid prescription. Over 50% of people reporting severe pain were not prescribed an opioid analgesic. CONCLUSIONS: We found opioid prescribing in primary care to be common and increasing in Scotland, particularly for severe pain. Co-prescribing of opioids and benzodiazepines was common.

Renal Allograft Histology at 10 Years After Transplantation in the Tacrolimus Era: Evidence of Pervasive Chronic Injury.

Improving long-term renal allograft survival remains an important unmet need. To assess the extent of histologic injury at 10 years after transplantation in functioning grafts, we studied 575 consecutive adult solitary renal transplants performed between 2002 and 2005: 77% from living donors and 81% maintained on tacrolimus-based immunosuppression. Ten-year graft survival was 59% and death-censored graft survival was 74%. Surveillance allograft biopsies were assessed at implantation, 5 years, and 10 years from 145 patients who reached 10 years. At implantation, 5% of biopsies had major histologic abnormalities (chronic transplant glomerulopathy score > 0, other chronic Banff scores ≥ 2, global glomerulosclerosis > 20%, or mesangial sclerosis ≥ 2). This increased to 54% at 5 years and 82% at 10 years. Major lesions at 10 years included the following: arteriolar hyalinosis (66%), mesangial sclerosis (67%), and global glomerulosclerosis > 20% (43%), with 48% of grafts having more than one major lesion. Transplant glomerulopathy and moderate-to-severe interstitial fibrosis were uncommon (12% each). Major lesions were associated with increased proteinuria and decreased graft function. In patients with diabetes at baseline, 52% had diabetic nephropathy/mesangial sclerosis at 10 years. We conclude that almost all renal allografts sustain major histologic injury by 10 years after transplantation. Much damage appears nonimmunologic, suggesting that new approaches are needed to decrease late injury.

Comparison Between Total IgG, C1q, and C3d Single Antigen Bead Assays in Detecting Class I Complement-Binding Anti-HLA Antibodies.

BACKGROUND: Complement-binding donor-specific antibodies (DSAs) are associated with antibody-mediated rejection and allograft loss. Novel single antigen bead (SAB) assays-that is, complement component 1q (C1q) and complement component 3d (C3d) assays-have been developed to specifically detect complement-binding DSA, but it remains unclear whether these assays have an improved ability to detect complement-binding DSA as compared with using the total IgG SAB assay with a high mean fluorescence intensity (MFI) cutoff. The aim of this study was to compare the ability of the total IgG, C1q, and C3d SAB assays in detecting complement-binding anti-HLA antibodies. METHODS: Twenty sera known to have complement-binding anti-HLA antibodies (serologic class I HLA typing by complement-dependent cytotoxicity method) were tested with 3 different SAB assays: total IgG (undiluted and 1:8 dilution), C1q, and C3d. Serologic anti-HLA specificities were compared with those obtained by IgG, C1q, and C3d SAB assays. RESULTS: IgG SAB was more sensitive in detecting complement-binding antibodies (sensitivity 24 of 24 = 1, odds ratio infinity). Pearson correlation showed the association between (1) C1q and IgG SAB assays (cutoff C1q SAB 1000 MFI, cutoff IgG SAB 5000 MFI: r = 0.347, P < .0001) and (2) C3d and IgG SAB assays (cutoff 500 MFI C3d SAB, 5000 MFI for IgG SAB: r = -0.173, P = .279). CONCLUSIONS: For class I anti-HLA antibodies, IgG SAB (cutoff MFI > 5000) was more sensitive in detecting complement-binding antibodies when compared with C1q and C3d SAB assays.

Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112 117).

Alcohol consumption has been linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well-known genetic variants in alcohol metabolizing genes, for example, ALDH2 and ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112 117 individuals in the UK Biobank (UKB) sample of white British individuals. We report significant genome-wide associations at 14 loci. These include single-nucleotide polymorphisms (SNPs) in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and two loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, CADM2 and FAM69C. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (DRD2, PDE4B). GCTA analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13% (se=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation (rG) between male and female alcohol consumption was 0.90 (s.e.=0.09, P-value=7.16 × 10-23). Using LD score regression, genetic overlap was found between alcohol consumption and years of schooling (rG=0.18, s.e.=0.03), high-density lipoprotein cholesterol (rG=0.28, s.e.=0.05), smoking (rG=0.40, s.e.=0.06) and various anthropometric traits (for example, overweight, rG=-0.19, s.e.=0.05). This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.

Do regional brain volumes and major depressive disorder share genetic architecture? A study of Generation Scotland (n=19 762), UK Biobank (n=24 048) and the English Longitudinal Study of Ageing (n=5766).

Major depressive disorder (MDD) is a heritable and highly debilitating condition. It is commonly associated with subcortical volumetric abnormalities, the most replicated of these being reduced hippocampal volume. Using the most recent published data from Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium's genome-wide association study of regional brain volume, we sought to test whether there is shared genetic architecture between seven subcortical brain volumes and intracranial volume (ICV) and MDD. We explored this using linkage disequilibrium score regression, polygenic risk scoring (PRS) techniques, Mendelian randomisation (MR) analysis and BUHMBOX. Utilising summary statistics from ENIGMA and Psychiatric Genomics Consortium, we demonstrated that hippocampal volume was positively genetically correlated with MDD (rG=0.46, P=0.02), although this did not survive multiple comparison testing. None of the other six brain regions studied were genetically correlated and amygdala volume heritability was too low for analysis. Using PRS analysis, no regional volumetric PRS demonstrated a significant association with MDD or recurrent MDD. MR analysis in hippocampal volume and MDD identified no causal association, however, BUHMBOX analysis identified genetic subgrouping in GS:SFHS MDD cases only (P=0.00281). In this study, we provide some evidence that hippocampal volume and MDD may share genetic architecture in a subgroup of individuals, albeit the genetic correlation did not survive multiple testing correction and genetic subgroup heterogeneity was not replicated. In contrast, we found no evidence to support a shared genetic architecture between MDD and other regional subcortical volumes or ICV.

Assessing the presence of shared genetic architecture between Alzheimer's disease and major depressive disorder using genome-wide association data.

Major depressive disorder (MDD) and Alzheimer's disease (AD) are both common in older age and frequently co-occur. Numerous phenotypic studies based on clinical diagnoses suggest that a history of depression increases risk of subsequent AD, although the basis of this relationship is uncertain. Both illnesses are polygenic, and shared genetic risk factors could explain some of the observed association. We used genotype data to test whether MDD and AD have an overlapping polygenic architecture in two large population-based cohorts, Generation Scotland's Scottish Family Health Study (GS:SFHS; N=19 889) and UK Biobank (N=25 118), and whether age of depression onset influences any relationship. Using two complementary techniques, we found no evidence that the disorders are influenced by common genetic variants. Using linkage disequilibrium score regression with genome-wide association study (GWAS) summary statistics from the International Genomics of Alzheimer's Project, we report no significant genetic correlation between AD and MDD (rG=-0.103, P=0.59). Polygenic risk scores (PRS) generated using summary data from International Genomics of Alzheimer's Project (IGAP) and the Psychiatric Genomics Consortium were used to assess potential pleiotropy between the disorders. PRS for MDD were nominally associated with participant-recalled AD family history in GS:SFHS, although this association did not survive multiple comparison testing. AD PRS were not associated with depression status or late-onset depression, and a survival analysis showed no association between age of depression onset and genetic risk for AD. This study found no evidence to support a common polygenic structure for AD and MDD, suggesting that the comorbidity of these disorders is not explained by common genetic variants.

Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci.

Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population.

Cognitive impairment is common among individuals diagnosed with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). It has been suggested that some aspects of intelligence are preserved or even superior in people with ASD compared with controls, but consistent evidence is lacking. Few studies have examined the genetic overlap between cognitive ability and ASD/ADHD. The aim of this study was to examine the polygenic overlap between ASD/ADHD and cognitive ability in individuals from the general population. Polygenic risk for ADHD and ASD was calculated from genome-wide association studies of ASD and ADHD conducted by the Psychiatric Genetics Consortium. Risk scores were created in three independent cohorts: Generation Scotland Scottish Family Health Study (GS:SFHS) (n=9863), the Lothian Birth Cohorts 1936 and 1921 (n=1522), and the Brisbane Adolescent Twin Sample (BATS) (n=921). We report that polygenic risk for ASD is positively correlated with general cognitive ability (beta=0.07, P=6 × 10(-7), r(2)=0.003), logical memory and verbal intelligence in GS:SFHS. This was replicated in BATS as a positive association with full-scale intelligent quotient (IQ) (beta=0.07, P=0.03, r(2)=0.005). We did not find consistent evidence that polygenic risk for ADHD was associated with cognitive function; however, a negative correlation with IQ at age 11 years (beta=-0.08, Z=-3.3, P=0.001) was observed in the Lothian Birth Cohorts. These findings are in individuals from the general population, suggesting that the relationship between genetic risk for ASD and intelligence is partly independent of clinical state. These data suggest that common genetic variation relevant for ASD influences general cognitive ability.

GWAS for executive function and processing speed suggests involvement of the CADM2 gene.

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Major depressive disorder and current psychological distress moderate the effect of polygenic risk for obesity on body mass index.

Major depressive disorder (MDD) and obesity are frequently co-morbid and this correlation is partly due to genetic factors. Although specific genetic risk variants are associated with body mass index (BMI) and with larger effect sizes in depressed individuals, the genetic overlap and interaction with depression has not been addressed using whole-genome data. Polygenic profile scores for MDD and BMI were created in 13,921 members of Generation Scotland: the Scottish Family Health Study and tested for their association with BMI, MDD, neuroticism and scores on the General Health Questionnaire (GHQ) (current psychological distress). The association between BMI polygenic profile scores and BMI was tested fitting GHQ, neuroticism or MDD status as an interaction term to test for a moderating effect of mood disorder. BMI polygenic profile scores were not associated with lifetime MDD status or neuroticism although a significant positive association with GHQ scores was found (P = 0.0001, ß = 0.034, r(2) = 0.001). Polygenic risk for MDD was not associated with BMI. A significant interaction between BMI polygenic profile scores and MDD (P = 0.0003, ß = 0.064), GHQ (P = 0.0005, ß = 0.027) and neuroticism (P = 0.003, ß = 0.023) was found when BMI was the dependent variable. The effect of BMI-increasing alleles was greater in those with MDD, high neuroticism or current psychological distress. MDD, neuroticism and current psychological distress amplify the effect of BMI polygenic profile scores on BMI. Depressed individuals with a greater polygenic load for obesity are at greater risk of becoming obese than control individuals.

Changes in opioid and other analgesic use 1995-2010: repeated cross-sectional analysis of dispensed prescribing for a large geographical population in Scotland.

BACKGROUND: Despite recent concerns about increasing rates of analgesic prescribing, detailed epidemiological studies are lacking. We identified and described changes in the pattern of community-dispensed prescriptions to the Tayside population, Scotland, between 31st March 1995 (n = 301,020) and 31st March 2010 (n = 311,881). METHODS: Repeated cross-sectional analysis of patient-level population data on dispensed analgesics, stratified by sociodemographic variables; logistic regression to identify factors associated with strong opioid dispensing in 2010. RESULTS: The proportion of people currently dispensed any analgesic increased in 2010 (17.9%) compared with 1995 (15.7%). This increase was not equal across drug classes, with paracetamol, opioids and gabapentin/pregabalin showing an increase, but others showing a decrease. Weak opioids were less commonly dispensed in 2010 (8.2% vs. 8.4%) but dispensing of strong opioids increased 18-fold (3.6% vs. 0.2%), including a five-fold increase of morphine, fentanyl or oxycodone (0.75% vs. 0.15%). People receiving more non-analgesic drugs (odds ratio 20.7 if dispensed >14 non-analgesic medications vs. those dispensed <4) and those living in more deprived areas (OR 1.63 most deprived vs. most affluent) were more likely to receive a strong opioid in 2010. CONCLUSIONS: Analgesic use rose modestly between 1995 and 2010, but with larger changes within individual classes, only partly reflecting evidence-based guidance. Dispensing of strong opioids increased dramatically, largely driven by tramadol, although other strong opioids tripled. Polypharmacy and socio-economic deprivation were strongly associated with strong opioid use. Research is needed to establish the causes, benefits and harms of the increase in analgesic, and especially strong opioid use.

A genome-wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain.

BACKGROUND: Neuropathic pain, caused by a lesion or a disease affecting the somatosensory system, is one of the most common complications in diabetic patients. The purpose of this study is to identify genetic factors contributing to this type of pain in a general diabetic population. METHOD: We accessed the Genetics of Diabetes Audit and Research Tayside (GoDARTS) datasets that contain prescription information and monofilament test results for 9439 diabetic patients, among which 6927 diabetic individuals were genotyped by Affymetrix SNP6.0 or Illumina OmniExpress chips. Cases of neuropathic pain were defined as diabetic patients with a prescription history of at least one of five drugs specifically indicated for the treatment of neuropathic pain and in whom monofilament test result was positive for sensory neuropathy in at least one foot. Controls were individuals who did not have a record of receiving any opioid analgesics. Imputation of non-genotyped SNPs was performed by IMPUTE2, with reference files from 1000 Genomes Phase I datasets. RESULTS: After data cleaning and relevant exclusions, imputed genotypes of 572 diabetic neuropathic pain cases and 2491 diabetic controls were used in the Fisher's exact test. We identified a cluster in the Chr8p21.3, next to GFRA2 with a lowest p-value of 1.77 × 10(-7) at rs17428041. The narrow-sense heritability of this phenotype was 11.00%. CONCLUSION: This genome-wide association study on diabetic neuropathic pain suggests new evidence for the involvement of variants near GFRA2 with the disorder, which needs to be verified in an independent cohort and at the molecular level.

Does a history of depression actually mediate smoking-related pain? Findings from a cross-sectional general population-based study.

BACKGROUND: Smokers report more pain and worse functioning. The evidence from pain clinics suggests that depression affects this relationship: The association between smoking and chronic pain is weakened when controlling for depression. This study explored the relationship between smoking, pain and depression in a large general population-based cohort (Generation Scotland: Scottish Family Health Study). METHODS: Chronic pain measures (intensity, disability), self-reported smoking status and a history of major depressive disorder (MDD) were analysed. A multivariate analysis of covariance determined whether smoking status was associated with both pain measures and a history of depressive illness. Using a statistical mediation model any mediating effect of depression on the relationship between smoking and chronic pain was sought. RESULTS: Of all 24,024 participants, 30% (n = 7162) reported any chronic pain. Within this chronic pain group, 16% (n = 1158) had a history of MDD; 7108 had valid smoking data: 20% (n = 1408) were current smokers, 33% (n = 2351) former and 47% (n = 3349) never smokers. Current smokers demonstrated higher pain intensity and pain-related disability scores compared with former and non-smokers (p < 0.001 for all analyses). From the mediation model, the effect on pain intensity decreased (p < 0.001), indicating that the relationship between smoking and a history of depression contributes significantly to the effect of smoking on pain intensity. When applied to smoking-related pain disability, there was no mediation effect. CONCLUSIONS: In contrast to smokers treated in pain clinics, a history of MDD mediated the relationship between smoking and pain intensity, but not pain-related disability in smokers in the community.

Neuropathic pain in the general population: a systematic review of epidemiological studies.

Most patients with neuropathic pain symptoms present and are managed in primary care, with only a minority being referred for specialist clinical assessment and diagnoses. Previous reviews have focused mainly on specific neuropathic pain conditions based in specialist settings. This is the first systematic review of epidemiological studies of neuropathic pain in the general population. Electronic databases were searched from January 1966 to December 2012, and studies were included where the main focus was on neuropathic pain prevalence and/or incidence, either as part of a specific neuropathic pain-related condition or as a global entity in the general population. We excluded studies in which data were extracted from pain or other specialist clinics or focusing on specific population subgroups. Twenty-one articles were identified and underwent quality assessment and data extraction. Included studies differed in 3 main ways: method of data retrieval, case ascertainment tool used, and presentation of prevalence/incidence rates. This heterogeneity precluded any meta-analysis. We categorised comparable incidence and prevalence rates into 2 main subgroups: (1) chronic pain with neuropathic characteristics (range 3-17%), and (2) neuropathic pain associated with a specific condition, including postherpetic neuralgia (3.9-42.0/100,000 person-years [PY]), trigeminal neuralgia (12.6-28.9/100,000 PY), painful diabetic peripheral neuropathy (15.3-72.3/100,000 PY), glossopharyngeal neuralgia (0.2-0.4/100,000 PY). These differences highlight the importance of a standardised approach for identifying neuropathic pain in future epidemiological studies. A best estimate of population prevalence of pain with neuropathic characteristics is likely to lie between 6.9% and 10%.

Chronic pain epidemiology and its clinical relevance.

Chronic pain affects ∼20% of the European population and is commoner in women, older people, and with relative deprivation. Its management in the community remains generally unsatisfactory, partly because of lack of evidence for effective interventions. Epidemiological study of chronic pain, through an understanding of its distribution and determinants, can inform the development, targeting, and evaluation of interventions in the general population. This paper reviews current knowledge of risk markers associated with chronic pain and considers how these might inform management and prevention. Risk factors include socio-demographic, clinical, psychological, and biological factors. These are relevant to our understanding of chronic pain mechanisms and the nature of, and responses to, current and future treatments.