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

Summary This systematic review includes epidemiological studies of neuropathic pain within the general population. There is a wide range of incidence and prevalence rates. ABSTRACT 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%.


Introduction
Neuropathic pain is widely recognised as one of the most difficult pain syndromes to manage, and outcomes often are unsatisfactory. This is partly because the contribution of neuropathy to pain presenting in primary care may be unrecognized [2,10] and there is evidence of suboptimal drug use in the treatment of neuropathic pain [12,36,37]. Epidemiological research in this area can be problematic, and the reasons for this are multifactorial: the lack of agreed, valid case definitions that truly reflect the condition(s) under consideration and that are feasible to apply in population-based studies; heterogeneous studies of variable quality, using different means of case ascertainment; and inclusion or exclusion of cases in which pain is not a primary presenting complaint [10]. Existing estimates of the general population prevalence therefore vary widely, and it is likely that more people experience neuropathic symptoms than have been diagnosed with a neuropathic pain-related condition [11].
Population-based estimates of neuropathic pain prevalence are important in order to determine resource requirements (clinical, financial, educational) for primary care, where most people with chronic pain are treated and managed, and to inform the targeting of treatment and prevention strategies [17]. As validated screening tools to identify neuropathic pain have been developed [3,34], these have enabled questionnaire-based epidemiological studies, and there is a growing body of literature exploring the epidemiology of neuropathic pain symptoms and conditions in the community. We conducted a systematic search and structured literature review of the epidemiology of neuropathic pain in the general population and aimed to provide, where possible, estimates of incidence and prevalence.

Study selection
A comprehensive search strategy was developed to identify all articles reporting population-based studies of the epidemiology of neuropathic pain (see Supplementary Materials). Electronic databases MEDLINE, EMBASE, ISI Web of Science, and CINAHL were searched from January 1966 to December 2012 for English-language articles that fulfilled the inclusion/exclusion criteria. We included studies in which (1) the main focus was on neuropathic pain, either as part of a specific clinical condition or as a global clinical entity; (2) the core emphasis was on incidence and/or prevalence of neuropathic pain; and (3) the study sample was reasonably representative of the general population (thus including studies conducted in primary care/general practice populations where these approximated to general population samples). Article titles were reviewed to determine those that obviously did not meet the inclusion criteria and those that were required assessment in greater depth.
Excluded articles were those in which data were specifically obtained from pain or other specialist clinics, those that focused on specific population subgroups (eg, age, gender, occupation, ethnicity), and review articles (although reference lists of these were hand-searched for additional relevant studies). A grey literature search was performed after completion of the main search, seeking articles from conference proceedings and meetings on the ISI Web of Science database.

Data extraction
The database searches were conducted by S.A. and R.A.K. Titles were reviewed for possible inclusion, then abstracts examined, before the full-text version of the remaining articles were obtained. All authors were involved in various stages throughout this process and in the final selection and data extraction of included articles (Table 1). We extracted data on study characteristics (country, study design, and method of data retrieval); the sample size and number of patients with neuropathic pain in the sample population; case ascertainment instrument or tool used to identify the neuropathic pain condition; and the specific condition or disease associated with neuropathic pain.

Quality assessment
All articles that fully met the inclusion criteria were critically appraised using the STROBE checklist (STrengthening the Reporting of OBservational studies in Epidemiology) [40]. This is a structured, standardised checklist consisting of 22 items, each relating to the different sections in an article (ie, title, abstract, introduction, methods, results, discussion, and funding) with the main purpose being to improve the transparency of reporting in epidemiological observational research [40].
Quality factors based on key items of the STROBE quality checklist instrument were combined to form a modified checklist consisting of a total of 30 items with a simple point system. Each article was then given a total score out of 30. The quality scores calculated for each article gave comparisons of the relative quality of included studies, a higher score indicating higher quality. A relatively low score did not necessarily imply poor-quality research, as the score was a guide to the quality of reporting according to a specific (STROBE) checklist.

Analysis
We aimed to compare the prevalence and incidence rates of specific neuropathic pain diagnoses, and/or of neuropathic pain as a global clinical entity. . 1 shows the results of the article selection process.

Characteristics of studies
We identified 3826 articles from the electronic searches after removal of duplicates (Fig. 1). These articles were then reviewed by title, abstract, and full-text review and either included or excluded based on the selection criteria. Of these, 21 articles fulfilled the inclusion criteria and underwent quality assessment and data extraction and were included in the final review.
A wide variety of study designs was identified by the systematic review. There are 3 main ways in which the studies seemed to differ: first, in the method of data retrieval; secondly, in the case ascertainment tool used; and finally, in the presentation of the prevalence/incidence rates found. In order to make sense of the data, and to present results appropriately, it is important to take these factors into account.

Data presentation of the prevalence/incidence rates
Some studies focused on identifying rates of neuropathic pain that was a characteristic of chronic pain, whereas other studies reported rates of a clinical condition or disease associated with neuropathic pain. Due to the heterogeneity of included studies as noted earlier, the prevalence or incidence rates cannot be simply combined for meta-analysis. For this reason, we have categorised the incidence and prevalence rates into chronic pain with neuropathic characteristics or of neuropathic origin and neuropathic pain associated with a specific disease or condition.

Method of data retrieval
Data retrieval was either by electronic database searching or use of research questionnaires. Of the final 21 articles identified ( Fig. 1), 14 studies were conducted using a database or primary care medical records, 6 studies were conducted by questionnaire or survey, and 1 study used a combination of both methods (Table 1).

Case ascertainment of neuropathic pain
A number of different ways of identifying cases were found. Generally, studies based on research questionnaires used validated case ascertainment tools such as the Douleur Neuropathique en 4 questions (DN4) [5] or the Self complete Leeds Assessment of Neuropathic Symptoms & Signs (S-LANSS) [1], whereas studies that extracted data from databases relied on coding systems, such as the Oxford Medical Information System (OXMIS) classification [19] or the International Classification of Primary Care (ICPC) coding system [41] to identify cases.
As shown in Table 1, most studies included either incidence or prevalence rates, and 1 provided both [26]. Four studies did not provide specific incidence or prevalence rates [6,7,9,30]. However, these studies did provide sufficient information from which a prevalence or incidence rate could be calculated.

3.2.
Results for studies on chronic pain with neuropathic characteristics or pain of predominantly neuropathic origin

Incidence
Dieleman et al. [10] (2008) was the only study included. Reported incidence rates for a number of conditions associated with neuropathic pain were obtained, with an overall incidence rate in the general/study population of neuropathic pain of 8.   Tables 3 and 4.
These studies were almost all database retrieval studies. A wide variety of case identification methods was used, often involving a number of different steps to verify the cases identified. For example, researchers in the study by Koopman et al. [24] used a 2-step process of case ascertainment: first, the researchers used the International Association for the Study of Pain (IASP) case definition criteria to search the database for different facial pain conditions associated with neuropathic pain and classed as either probable, possible, or no neuropathic pain; all probable cases were reviewed by a second medical doctor and discrepancies were arbitrated by a pain specialist. Secondly, additional information from the patients' medical records was sought to verify all possible cases.

PHN
Prevalence rates of PHN were reported in 2 included studies [9,26]. They ranged from 0.09% per annum and 0.7 per 1000 ( Table 4). The study by Di Luzio Paparatti et al. [9] contained missing data. They reported that 408 of the 95,508 patients in their population had herpes zoster (HZ); however, only 322 of those were screened for complications. Of those screened, 21.4% had PHN. For the purposes of this analysis, we assumed that the rate for those screened was the same as for those not screened. The prevalence therefore was calculated by the equation [(408 ⁄ 21.4)/98,508]. The incidence rates of PHN were reported in 9 studies [6,10,18,19,21,24,26,30,32]. Note that some articles calculated incidence rates in percent of population per year [ [26]. For this reason, direct comparisons could not be made among all studies. For those that were comparable, rates ranged from 3.9/ 100,000 person-years to 42.0/100,000 person-years ( Table 3).
The study by Opstelten et al. [30] (2002) was calculated from the data provided over a 5-year period, and the number in the total

PDPN
The population prevalence of PDPN was calculated at 0.8%, representing 26.4% of those with type 2 diabetes who responded positively to screening questions and attended clinical assessment (Table 4). Incidence rates of PDPN were reported in 3 studies [10,18,19]. Rates ranged from 15.3/100,000 person-years to 72.3/ 100,000 person-years (Table 3). PHN, TN, and PDPN had the highest incidence rates, compared to GN and PLP.

Discussion
This is the first comprehensive systematic literature review of epidemiological studies of neuropathic pain in the general population. Rather than a traditional systematic review of randomised controlled trials, this review is based on observational studies within the general population using recently standardised methodology [31,40]. The heterogeneity between the identified studies precluded meta-analysis and calculation of combined estimates of prevalence and/or incidence rates of neuropathic pain. Nevertheless, we are able to draw comparisons between different studies and conditions and to consider these in the context of the relative quality, strengths and weaknesses, and study designs and reporting.

Main findings
Overall, the prevalence of neuropathic pain as a feature of chronic pain (or pain of predominantly neuropathic origin) was examined by 8 studies and ranged from 1% to 17.9% (Table 2). In studies that used questionnaire-based case ascertainment tools such as DN4 and S-LANSS, the range of prevalence estimates was wide (3.3-17.9%). However, including only studies that administered case ascertainment tools precisely as they were designed and validated, the range of prevalence rates was much narrower (6.9-10%) [4,8,35,42].
Gustorff et al. [15] utilised the LANSS (Part A) along with additional pain questions and some specific exclusion criteria, limiting their analysis to people with a known underlying neuropathic pain diagnosis (people with exclusive joint pain or reported rheumatism, migraine, fibromyalgia, visceral pain, and/or satisfying response to over-the-counter analgesic medication were excluded from further interview, as well as people suffering from an undifferentiated cause as the main cause of their pain); this explains their estimate of the lowest prevalence of neuropathic pain at 3.3%.
In contrast, Toth et al. [8] included all respondents who reported ''daily or near daily pain'' from telephone surveys of the general population in a Canadian province (finding a prevalence of 38%). Respondents then completed the DN4, with a resultant highest prevalence estimate of neuropathic pain at 17.9%. This is likely an overestimate due to the screening question used to identify the presence of pain or selection bias in the underlying population. Other studies, utilising data obtained from computerised medical records, found a much lower overall prevalence of around 1% [13,14]. This lower rate likely reflects differences in case ascertainment, and in particular that electronic records can only identify patients who have presented to primary care and had a diagnosis recorded by the attending physician.
When we examined studies of specific neuropathic pain conditions, most of them reported incidence rates per person-years, which is a useful parameter for comparing rates, although less clinically useful as a direct indicator of the number of cases likely to arise in a specific population during a specific period. Koopman et al. [24] consistently reported lower incidence rates of PHN, TN, and GN (Table 3) than the other studies, and this is mostly likely due to differences in case ascertainment. This can be illustrated by comparing this study with that reported by Dieleman et al. [10]. Both of these studies were conducted in consecutive years and both used the IPCI database in the Netherlands, yet they found very different incidence rates. For example, looking at TN, Koopman et al. reported an incidence rate of 12.6/100,000 person-years, whereas Dieleman et al. reported a rate of 28.9/100,000 personyears. Koopman et al. accessed additional information when identifying the cases, and the authors were able to identify and then to exclude misclassified cases (false-positive cases) from the analysis. As a result, the authors suggest their estimate of the incidence of TN was less likely to be exaggerated due to misclassification.

Other findings
It was surprising that some articles did not provide a working definition for neuropathic pain as a starting point. The articles that did include a definition cited the IASP (Merskey and Bogduk) definition [27]: chronic pain that is ''initiated or caused by a primary lesion or dysfunction in the nervous system.'' This definition has since been superseded as pain ''arising as a direct consequence of a lesion or disease affecting the somatosensory system'' [20,25].
Although case ascertainment tools were used by a number of studies, these were neither designed to nor did they claim to make a diagnosis of definite neuropathic pain; rather they were validated in identifying pain with neuropathic characteristics [5]. Some studies were clear in their acknowledgment of this in describing the cases [4,35,38,42], but other studies did not distinguish between neuropathic features and neuropathic pain [8,15].
In studies based on reviews of medical records, the identification of cases relies on accurate diagnoses of neuropathic pain (conditions) by the physician, who then must enter details accurately, using an accurate coding system and an accurate method of retrieving these codes. Rates calculated from medical records also may be affected by severity of pain or disease, as patients with more severe cases are more likely to seek medical attention [37]. Factors that may affect incidence and prevalence rate estimates (in general) are summarised in Table 5.
Although there are published guidelines on the assessment of neuropathic pain [17], the lack of an agreed-upon specific diagnostic tool has resulted in a proposed grading system of definite, probable, and possible neuropathic pain [20]. This is based on a combination of plausible distribution and history of pain, other positive confirmatory tests, and clinical investigation(s) by a pain specialist or neurologist [39]. For large epidemiological studies, the grading of probable or definite neuropathic pain is not practicable to achieve, and at best the case definitions included in this review may approximate possible neuropathic pain. Existing Special Interest Group on Neuropathic Pain (NeuPSIG) guidelines on neuropathic pain assessment advise that existing screening tools require further validation before they can be completely useful for epidemiological studies in general population samples [16]. Further research should look to explore how the findings of these questionnaire-based screening instruments/case ascertainment tools relate to specialist clinical examinations in a general population sample.
Neuropathic pain is associated with a number of clinical conditions and diseases, but only a small number of them were examined in the articles identified for inclusion in this review. Particular aetiologies such as PHN were more commonly studied, whereas others such as spinal cord injury [33] were not studied in a general population context. Published studies of the epidemiology of these less common subgroups tended to be conducted in small samples, in specialist settings, or in secondary care, providing an indication of their likelihood in these subgroups, but not of the overall population burden or risk.

Strengths and weaknesses
The strengths of this review are in its strict systematic approach and consistency in application of the criteria throughout. A thorough search strategy was developed. The studies included were all of medium to high quality.
Although a number of the screening tools that identify pain with neuropathic characteristics have been translated and validated for use in other languages [29], a limitation in this review was the exclusion of non-English-language articles, as translation was beyond the available resources.
Unlike other systematic reviews [28,31], there is no recognised quality checklist pertaining to observational studies within the general population. Hence a quality checklist was developed from a well-used standard tool specifically for epidemiological studies [40]. Although it is not a standard instrument for systematic reviews, it does provide a reasonable indicator of quality and validity, allowing rejection of articles or studies of low quality and comparison between studies.

Implications for research and clinical practice
As the use of screening tools within the published literature increases, it may be possible to restrict a future review to a specified case ascertainment tool, eg, DN4 or S-LANSS. The studies included would therefore have greater consistency, would have similar features in common, and would be more comparable when analysing the results. Now that there is an agreed-upon definition of neuropathic pain, it is important to acknowledge its limitations and the application of this within large epidemiological studies. There is also a good argument that neuropathic pain should be considered as a Medical Subject Headings (MeSH) term in databases.

Conclusions
A comprehensive literature search and systematic review was performed on the epidemiology of neuropathic pain in the general population. A range of incidence and prevalence rates has been identified. The lack of consensus on a definition, diagnostic criteria, and appropriate and consistent use of the screening tools are reflected by the varying methods and results of the studies included in this review. Future epidemiological studies into neuropathic pain within the community should take note of these factors, using a standardised approach for identifying pain with possible neuropathic features.

Conflict of interest
B.S. and N.T. have previously received an unrestricted educational grant from Pfizer UK Ltd. for research on neuropathic pain. B.S. has received occasional lecture and consultancy fees, on behalf of his institution, from Pfizer and Napp. The authors otherwise assert no personal pecuniary or other conflict of interest in the writing of this article. No writing assistance or external funding was obtained for this study. Table 5 Summary of the factors influencing reported incidence and prevalence rates of neuropathic pain.
Definitions of neuropathic pain or pain with neuropathic characteristics Definitions of clinical conditions/diseases associated with neuropathic pain Case ascertainment methods Case ascertainment tools (eg, screening tools vs cases coded from electronic databases) Severity of neuropathic pain Accuracy of recording and coding in medical records