Psychometric Validation of the Neuropathic Pain Symptom Inventory for Its Use in Spanish

Transcription

1 134 Journal of Pain and Symptom Management Vol. 42 No. 1 July 2011 Brief Methodological Report Psychometric Validation of the Neuropathic Pain Symptom Inventory for Its Use in Spanish Jesus Villoria, MD, BStat, Manuel Rodrıguez, MD, PhD, Marıa J. Berro, MD, Andres Stern, MD, and Isabel Sanchez-Magro, MD PhD Department of Design and Medical Writing (J.V.), Medicxact, S.L., Alpedrete; Pain Clinic (M.R.), Carlos Haya University Hospital, Malaga; Pain Clinic (M.J.B.), Cruces Hospital, Baracaldo; and Medical Department (A.S., I.S.-M.), Gr unenthal Pharma, Madrid, Spain Abstract Context. Clinical instruments are required for the assessment of neuropathic pain (NP). Objectives. The primary aim of this study was to perform a complete psychometric validation of the Neuropathic Pain Symptom Inventory (NPSI) in Spanish patients. Methods. A linguistically validated version in Spanish of the NPSI and other clinical instruments for NP were administered on two occasions separated by at least one month to 548 patients suffering from chronic NP. The authors evaluated the responsiveness, the construct validity, and the internal structure of the NPSI by means of, respectively, receiver operating characteristic (ROC) curves analysis and calculation of reliable change indices, a multitrait-multimethod (MTMM) design, and primary component analysis. Internal consistency and test-retest reliability were evaluated, respectively, by calculating several Cronbach s alpha coefficients and intraclass correlation coefficients of some scores selected appropriately. Results. The areas under the ROC curves were greater than The MTMM design found convergent-discriminant correlations correctly aligned for all NPSI subscores in the first assessment, and for all but paresthesia/dysesthesia subscores in the second assessment. The five components of the NPSI described by its authors were confirmed on one occasion, but the electric shocks and stabbing items did not associate consistently, as in the original version, the first time the NPSI was administered. All reliability coefficients were above Conclusion. The Spanish NPSI has good concurrent and construct validity and is reliable for a wide range of patients with NP. One exception to the original structure was found affecting one item, presumably relating to a cultural feature. J Pain Symptom Manage 2011;42:134e146. Ó 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Address correspondence to: Jesus Villoria, MD, BStat, Department of Design and Medical Writing, Medicxact, S.L., Primavera 94, E Alpedrete, Spain. villoriajesus@medicxact.es Ó 2011 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. Accepted for publication: September 15, /$ - see front matter doi: /j.jpainsymman

2 Vol. 42 No. 1 July 2011 Validation of the NPSI in Spanish 135 Key Words Neuropathic pain, pain clinics, reproducibility of results, observational research Introduction Pain provoked by injury or a primary dysfunction of the nervous system represents a stubborn clinical problem because it is usually chronic, presents heterogeneous and variable clinical manifestations, lacks the original biological meaning of somatic pain, and is frequently refractory to therapies because of its complex pathophysiology. 1,2 Neuropathic pain (NP) syndromes entail painful symptoms and both positive and negative sensory signs. 3 Pain may have several qualities, including deep aching, superficial burning, stinging or prickling pain, or others. Pain also may be spontaneous and continuous or, less frequently, paroxysmal. The positive signs corresponding to evoked pain may include mechanical hypersensitivity (dynamic mechanical allodynia and/or static punctate hyperalgesia) and some forms of thermal hypersensitivity. Negative signs are much more variable than positive signs and consist of sensory reduction or loss in presence or absence of positive signs. 3 The clinical instruments intended for the assessment of NP should conveniently address all these features of related symptoms and signs. Because classifying or treating NP on the basis of anatomy or the underlying disease is of limited help to suffering patients, an alternative and rational approach to therapy would rely on the identification of the mechanisms presumably responsible for the clinical manifestations to select adequate treatments that target the involved mechanisms. 4 However, the correspondence between clinical manifestations and the pathophysiologic mechanism of NP is particularly challenging because various mechanisms can act simultaneously in the same patient and each of them may be responsible for different manifestations. 5 Additionally, both clinical manifestations and pathophysiologic mechanisms usually change with time. 2,6 As a consequence, a more clinically focused approach to determine how symptoms and signs translate into mechanisms seems to be more realistic than proceeding the opposite way. 6 For this purpose, it is of the utmost importance to develop and validate clinical instruments for an adequate, valid, reliable, and universal recognition of symptoms and signs to classify patients on the basis of their clinical manifestations on one hand and measure the effects of therapeutic interventions accurately on the other. 2,7 The next step, mechanisms recognition, would serve to refine therapeutic interventions and improve outcomes. The Neuropathic Pain Symptom Inventory (NPSI) is a self-administered instrument that assesses the different qualities and types of symptoms that can occur in NP syndromes. The objective of its authors was to produce a clinical instrument easy to administer that provided valid information about the differential nature, intensity, and response of painful symptoms of patients with NP syndromes. 7 The NPSI was originally developed in the French and English languages and, although a linguistically validated version of the NPSI was available for use in Spain, 8 it had not undergone any formal psychometric validation to date. The linguistic validation of the Spanish version had previously been done under the auspices of the Mapi Research Institute, and its original developers handled personally a translated copy for the present research. Spain, with a population over 44 million, a life expectancy about 80 years, 9 and more than 100 pain units widely distributed across the national territory, 10 offers good research opportunities in the field of NP. Expanding the target population to which the NPSI can be applied will aid to homogenize clinical assessment and reporting of results. The authors designed and performed a two-step epidemiological survey in patients attending these pain units with the aim of achieving a comprehensive psychometric validation of the NPSI version intended for Spain, including measures of reliability, internal consistency, internal structure, responsiveness, and construct validity. The present article reports the results of such validation. Methods Design and Patients A clinical survey was conceived to provide nonlongitudinal data from two different time

3 136 Villoria et al. Vol. 42 No. 1 July 2011 points (hereafter referred to as assessments ) with the primary purpose of performing a complete psychometric validation of the Spanish version of the NPSI in patients from Spain. The first assessment took place when a patient was referred to or consulted with a pain clinic specialist for NP of moderate or severe intensity. The second assessment occurred between 30 and 60 days later to leave enough time to establish the clinical response of pain to the therapeutic regimen prescribed by the pain clinic specialist. A complete set of analyses concerning different psychometric aspects was planned. Although the authors did not perform a formal calculation of the size of the sample beforehand, some strategies were used to minimize the probability of Type I error (see the Data Analysis section below). Sampling was done in conglomerates (the pain clinics) that were not randomly selected, because participation was decided as a function of the availability and willingness of faculties to collaborate, but involved almost two-thirds of the units currently operative in Spain. The target population comprised patients suffering from any chronic NP condition within Spain. The source population of the study was a subset of the target population comprising patients who additionally received treatment in a pain clinic. A threshold severity in the first assessment, to ensure that enough individual variation was present for the analyses of sensitivity to change, was required to participate. No other restrictions were imposed in the benefit of sample representativity. Thus, patients aged 18 years or more who suffered from pure or mixed NP from any etiology and mechanism (peripheral or central), who consulted at any of the pain clinics during the study period showing a condition that was present from at least three months before recruitment, and who scored the NPSI at or above 40 points were included. Although the original validation of the NPSI was restricted to patients with pure NP, 7 we chose to also include patients with mixed pain conditions to check its psychometric properties in a more realistic clinical environment because mixed pain origins (somatic and neuropathic) are commonly seen. The study was performed in accordance with the internationally accepted rules for Good Clinical Practice as set forth in the updated guidelines issued by the International Conference of Harmonization and in the Declaration of Helsinki. The study protocol was approved by an accredited Ethics Committee before study start. All patients provided, in advance, written informed consent to participate. Assessments and Procedures The initial assessment took place when a patient was recruited into the study. The investigators collected complete information about the NP condition, including the time since the onset of painful symptoms, the type (pure neuropathic or mixed), the presumed mechanism and etiology, the presumed pathophysiology, the anatomical distribution, the cardinal symptoms at each area, and the interference with daily activities scored on a 1e10 numerical scale. Closed listings of possible etiologies and pathophysiologic mechanisms based on the proposal by Dworkin et al. 11 were presented to investigators to ease data collection. The NPSI, the Neuropathic Pain Scale (NPS), and the Neuropathic Pain Questionnaire-Short Form (NPQ-SF) also were administered at this time. Additionally, investigators were asked to select one pain or one group of pain index symptoms of each patient that could be grouped into a defined anatomical distribution. They were asked to base their judgment while doing this on identifying the most bothersome or debilitating symptoms for the patient and match that recorded by patients themselves while completing the NPQ-SF. Although the information specified above and the identification of index symptoms were not necessary for the primary objective of the study, it will be of great value for eventual further analyses of differential item functioning and to advance our knowledge about how symptom clusters across disease categories are linked to specific mechanisms. The second assessment was performed during a routine follow-up visit to the pain clinic and included the scores of the NPSI, the NPS, and the NPQ-SF, which were administered again at this time. This permitted the repetition of all analyses to avoid issues that might affect the evaluation of reliability, internal structure, and construct validity related to the NPSI range restriction in the first assessment posed by the selection criteria.

4 Vol. 42 No. 1 July 2011 Validation of the NPSI in Spanish 137 To complete the database, information also was gathered about the pharmacologic treatment prescribed for pain at both assessments. Investigators were asked to record the active ingredients, the daily doses, and the routes of administration of all analgesic and coadjuvant medications prescribed for the NP condition. Instruments Although there was a number of clinical instruments available to measure pain symptoms a decade ago, only the NPS was specifically designed for NP. 12 Although the NPS structure combines appraisal with descriptive items and, thus, does not provide a clear and comprehensive description of the entire spectrum of NP symptoms, the authors found this instrument to be the most suitable for contrasting the NPSI results for the analyses of construct validity. Both the NPS 12 and the NPSI 7 have 10 items that are rated with 11-point numerical rating scales ranging from 0 to 10. A global score, which ranges between 0 and 100, can be obtained in both instruments by summing these items. Although the item ratings can be summed, both instruments do not fit entirely within the set of summative Likert-type scales because there is not a single defined latent variable related to the global score, consistent with the notion that NP is a heterogeneous clinical entity that includes several independent dimensions. In this vein, the NPSI in particular has been shown to have a sharp internal structure with separate factors that correspond to defined clinical presentations of NP symptoms. Such factors might not only represent distinct clinically relevant dimensions but also meaningful pathophysiologic concepts; hence, the reproduction of the internal structure across different versions is important. The development of the NPQ is framed within the research efforts directed toward the nosologic conceptualization of NP. The primary aim of the developmental process was to identify which of the frequently used descriptors of NP symptoms are best to discriminate between NP and non-np. 13 Derived from the NPQ, an abbreviated form, the NPQ-SF, contains the minimum number of items sufficient to predict the diagnosis. The selection was made by stepwise discriminant analysis, allowing the reduction to three items. 14 The canonical discriminant function resulting from this analysis was used in the present study as one of the criteria against which the responsiveness of the Spanish version of the NPSI was tested. According to its authors, a discriminant function score at or above zero predicts NP. 14 Data Analysis All the analyses made for this study used observed data. Patients were excluded from the different analytic procedures if the required data were missing (Table 1). The analyses of internal consistency and structure included all Table 1 Patients with Data Available for the Analyses Responders Nonresponders Nonevaluable Total Patients recruited NPSI available First assessment a Second assessment b Both assessments NPSI and NPS available First assessment c Second assessment 196 d 103 d e Both assessments 190 f 97 f,g The analyses of responsiveness according to the discriminant criterion used the data from 339 patients who had the NPSI and the NPQ-SF available at the second assessment and scored the NPSI at or above 40 at the first assessment. a Included in the analyses of reliability (internal consistency) and validity (internal structure) for the first assessment. b Included in the analyses of reliability (internal consistency) and validity (internal structure) for the second assessment. c Included in the analyses of validity (construct) for the first assessment. d Included in the analyses of validity (responsiveness according to the clinical criterion). These 299 patients had the NPSI available also at the first assessment. e Included in the analyses of validity (construct) for the second assessment. f Included in the analyses of validity (responsiveness as per the reliable change index). g Included in the analyses of reliability (test-retest).

5 138 Villoria et al. Vol. 42 No. 1 July 2011 patients who completed the NPSI in any of the assessments, and the analyses of construct validity used a subgroup of these, comprising patients who in addition completed all the numerical rating items of the NPS. As mentioned, all these analyses were done in duplicate, one for each study assessment. The analyses of responsiveness and test-retest reliability required data from both assessments, as well as the definition of a subset of patients to serve as controls. Additionally, the analyses of responsiveness required that the initial pain severity should be above a prespecified threshold and respected the time window between study assessments, as well as that patients completed the instruments concerned in both assessments; thus, patients who scored the NPSI below 40 at the first assessment, not receiving the second assessment within 30 to 60 days after the first assessment, or with incomplete data to assess the response criteria were considered as nonevaluable for the purpose of sensitivity analyses. The investigators used two criteria to define the aforementioned control subset, and the analyses of responsiveness were done in duplicate. One was the discriminant criterion, which used the score of the discriminant function of the NPQ-SF to separate patients with and without a relevant neuropathic component at the second assessment. The latter formed the control subset. These analyses required that patients complete the NPSI and the NPQ-SF at the second assessment. The other was a clinical criterion, based on the reduction of the NPS score from the first to the second assessment, defined as a 30% reduction of the total score and/or an absolute two-point reduction in the first item. Patients who met this clinical criterion were classified as responders; those who did not as nonresponders. Again, the latter group served as the control subset for another round of responsiveness analyses, which required that patients complete the NPS at both assessments and the NPSI at the second assessment. All the data collected were described: continuous quantitative variables as measures of central tendency and dispersion and categorical variables as numbers and frequencies. The analysis of responsiveness was done by describing the accuracy of the NPSI to classify patients according to the clinical and discriminant criteria by calculating receiver operating characteristic (ROC) curves. Optimal cutoff values for the total NPSI score were established by maximizing the function proposed by Zweig and Campbell, 15 considering an equal weight for false positive and false negative results. Also, the reliable change index for the total NPSI score as described by Jacobson and Truax 16 was calculated for responders and nonresponders and compared with the respective mean changes within these subsets. The internal NPSI structure was checked by primary component analysis (PCA) to factorize the matrix of correlations and using rotated orthogonal extraction with the varimax method, with Kaiser normalization to obtain the component aggregates. Construct validity was assessed in terms of convergent and discriminant validity by means of a multitraitmultimethod (MTMM) design. 17 For this purpose, the NPSI and the NPS were considered as the methods in the MTMM design, whereas the five factors described by the authors of the NPSI were considered the traits, for which analogous items were searched in the NPS. The five factors of the NPSI, namely, 1) evoked pain (Items 8e10); 2) deep spontaneous ongoing pain (Items 2 and 3); 3) superficial spontaneous ongoing pain (Item 1); 4) paroxysmal pain (Items 5 and 6); and 5) abnormal sensations (paresthesia/dysesthesia, Items 11 and 12) were corresponded with 1) Items 6 (sensitive) and 10B (surface), 2) Items 10A (deep) and 4 (dull), 3) Items 3 (hot) and 7 (itchy), 4) Item 2 (sharp), and 5) Item 5 (cold), respectively, of the NPS. Thus, there are in total 45 pairwise combinations, of which five are convergent and 40 are discriminant. Because the range of each of the component scores varies (as does the number of items in each), Spearman correlation coefficients were calculated to assess the magnitude within each of these combinations. Last, for the analyses of reliability, Cronbach s alpha coefficients were calculated for the total and the subscale scores of the NPSI at both assessments. Also, an analysis of test-retest reliability was done within the subset of nonresponder patients. For that purpose, the intraclass correlation coefficients of absolute agreement for the total and subscale scores of the NPSI between both assessments were calculated, for a single measure and for the average of both measures, according to the proposal made by McGraw and Wong. 18 Confidence intervals of the areas under the ROC curves and the associated P-values of the

6 Vol. 42 No. 1 July 2011 Validation of the NPSI in Spanish 139 null hypotheses that these areas were equal to 0.5 were calculated using the asymptotic method proposed by Bamber. 19 The null hypothesis related to construct validity was tested by using the binomial probability of getting the observed number of incorrectly aligned correlations (i.e., a discriminant correlation exceeding a convergent correlation) when there is no difference between them (i.e., the probability of an incorrect alignment is 50%). The calculation of P-values associated to the null hypotheses related to concurrent (responsiveness) and construct validity were the unique statistical inferences made in this investigation. A single-step Bonferroni conservative method was used to interpret them to control the global probability of Type I error. Data reduction in the PCA is based on descriptions of variances and no inferences are required. The analyses of reliability were also descriptive. The analyses were repeated within the subset of patients with a pure NP condition to check NPSI robustness and clinical applicability, and as a sensitivity measure by mimicking the original validation process more accurately. Results Sample Description Data from a total of 548 patients from 54 pain clinics were received. Per site, the recruitment varied from three to 20 patients (median 10). Although in some cases incomplete, data from the first assessment were received from the whole sample of 548 patients. Forty-one patients (7.4%) missed the second assessment. Because of noncompliance with the initial pain severity or with the time window between assessments, missing data, or both reasons, 249 and 209 patients in total were considered as nonevaluable for the analyses of responsiveness according to the clinical and discriminant criterion, respectively; therefore, these analyses were done in 299 and 339 patients. The reliable change index could be calculated for 287 patients, 190 of the subset of responders and 97 of the subset of nonresponders (Table 1). For the analyses of internal consistency and structure, all patients who completed the NPSI were considered. These were 510 in the first and 460 in the second assessment (Table 1). For the analyses of construct validity, all patients who completed the NPSI and all the numerical rating items of the NPS were considered. These were 464 in the first and 427 in the second assessment (Table 1). The socioeconomic features match the profile of the population suffering from chronic pain in Spain: aged individuals, mostly women, with low academic degrees and living in an urban area (Table 2). The most common pathologies recorded in the medical history were hypertension, diabetes mellitus, and depression. Just 44 of 548 patients (8.0%) had a malignant neoplasm, prostate carcinoma being the most common (12 patients, 2.2%), followed by breast cancer (10 patients, 1.8%). Painful symptoms were present from approximately two years before enrollment, and the patients spent on average one year from the onset of symptoms until the diagnosis of a neuropathic pain syndrome (Table 3). The type of pain was mixed (nociceptive and neuropathic) in 59.0% of patients and pure neuropathic in 41.0%. The most common Table 2 Patient Sociodemographic and Clinical Characteristics Characteristics Age in years [(N, mean (SD)] 515, 58.8 (14.4) Gender [females, n/n (%)] 339/545 (62.2) Body mass index in kg/m 2 513, 27.4 (4.7) [N, mean (SD)] Marital status [married, n/n (%)] 389/539 (72.2) Vocational status Retired [n/n (%)] 161/545 (29.5) Housekeeper [n/n (%)] 147/545 (27.0) Active [n/n (%)] 118/545 (21.7) Receiving social disability 110/545 (20.2) benefit [n/n (%)] Other [n/n (%)] 9/545 (1.7) Education Primary [n/n (%)] 365/520 (70.2) Secondary [n/n (%)] 103/520 (19.8) Superior [n/n (%)] 52/520 (10.0) Area of residence Urban [n/n (%)] 359/542 (66.2) Semiurban [n/n (%)] 99/542 (18.3) Rural [n/n (%)] 84/542 (15.5) Medical history (present in at least 5% of patients) Hypertension [n/n (%)] 144/548 (26.3) Diebates mellitus [n/n (%)] 78/548 (14.2) Depression [n/n (%)] 73/548 (13.3) Osteoarthritis [n/n (%)] 55/548 (10.0) Hiatus hernia [n/n (%)] 31/548 (5.7) Appendectomy [n/n (%)] 31/548 (5.7) Sciatica [n/n (%)] 30/548 (5.5) N ¼ number of patients with data available; n ¼ absolute frequency; SD ¼ standard deviation.

7 140 Villoria et al. Vol. 42 No. 1 July 2011 Table 3 Chronic NP Characteristics Characteristics Time since onset of symptoms in months 505, 24.0 (52.0) [N, median (IQR)] Time since the diagnosis in months 481, 14.0 (35.0) [N, median (IQR)] Type of pain Mixed [n/n (%)] 301/510 (59.0) Pure neuropathic [n/n (%)] 209/510 (41.0) Site of mechanism Peripheral [n/n (%)] 420/542 (77.5) Peripheral and central [n/n (%)] 84/542 (15.5) Central [n/n (%)] 38/542 (7.0) Presumed peripheral mechanisms (>5%) a Radiculopathy [n/n (%)] 235/542 (43.4) Others (specified, each <5%) 89/542 (16.4) [n/n (%)] Others (unspecified) [n/n (%)] 71/542 (13.1) Entrapment neuropathies [n/n (%)] 66/542 (12.2) Iatrogenic neuralgia [n/n (%)] 50/542 (9.2) Postherpetic neuralgia [n/n (%)] 46/542 (8.5) Post-traumatic neuralgia [n/n (%)] 38/542 (7.0) Diabetic neuropathy [n/n (%)] 30/542 (5.5) Complex regional pain syndrome 28/542 (5.2) [n/n (%)] Presumed central mechanisms (>5%) a Compressive myelopathy [n/n (%)] 73/542 (13.5) Others (specified, each <5%) 56/542 (10.3) [n/n (%)] Others (unspecified) [n/n (%)] 42/542 (7.7) Number or pain anatomical locations One [n/n (%)] 432/548 (78.8) Two [n/n (%)] 91/548 (16.6) Three [n/n (%)] 20/548 (3.7) Fourþ [n/n (%)] 5/548 (0.9) Location of most bothersome pain symptoms b Lumbar [n/n (%)] 291/548 (53.1) Sacral [n/n (%)] 246/548 (44.9) Thoracic [n/n (%)] 160/548 (29.2) Cervical [n/n (%)] 106/548 (19.3) Clinical presentation of most bothersome pain symptoms b Spontaneous pain [n/n (%)] 535/548 (97.6) Stimulus-evoked pain [n/n (%)] 360/548 (65.7) Sensory reduction/loss [n/n (%)] 226/548 (41.2) Abnormal sensations [n/n (%)] 422/548 (77.0) N ¼ number of patients with data available; n ¼ absolute frequency; IQR ¼ interquartile range. a Patients might have more than one presumed pain mechanism. b Patients might have more than one clinical presentation. nociceptive pain among the patients with mixed pain was musculoskeletal pain, affecting 245 of 301 patients in whom at least one nociceptive component was reported (81.4%). Most patients (504 of 542, 93.0%) had at least one presumed peripheral site of origin of the pain syndrome (Table 3); among these, radiculopathies were the most frequent. At least one presumed central site of origin was reported in 122 of 542 patients (22.5%), compression of spinal medulla being the most frequent. Lumbar and sacral dermatomes were the body areas most commonly affected by painful symptoms. In nearly all patients, the symptoms were spontaneous; more than three-fourths had abnormal sensations (paresthesia, dysesthesia, etc.), and more than two-thirds had stimulus-evoked pain (hyperalgesia, allodynia, etc.) (Table 3). At the time of enrollment, the median (interquartile range [IQR]) total NPSI score was 56 (44e69) and most patients (77.8%) had a positive score in the discriminant function of the NPQ-SF, which predicts NP. The latter proportion was lower (61.6%) among patients considered as nonevaluable in the analyses of responsiveness. In the second assessment, the median (IQR) total NPSI score was 45 (30e61). Psychometric Validity The NPSI was accurate to detect responses of pain as defined by either the clinical or the discriminant criteria. The areas under the respective ROC curves were and (Fig. 1). The P-values associated to the Fig. 1. ROC curves of the accuracy of the NPSI to discern between patients with and without response (NPSI vs. NPS, clinical criterion) and between patients with or without NP (NPSI vs. NPQ-SF, discriminant criterion). NPSI ¼ Neuropathic Pain Symptom Inventory; NPQ-SF ¼ Neuropathic Pain Questionnaire-short version; AUC ¼ area under the curve; ROC ¼ receiver operating characteristic.

8 Vol. 42 No. 1 July 2011 Validation of the NPSI in Spanish 141 null hypotheses that these areas were equal to 0.5 were lower than in both cases. The optimal cutoff values of the total NPSI score were 56 (clinical criterion; sensitivity: 68.0%, specificity: 87.2%) and 38 (discriminant criterion; sensitivity: 85.0%, specificity: 75.2%) points. The absolute mean changes of the total NPSI score were 25.5 for responders and 4.5 for nonresponders. The respective calculated reliable change indices were and , indicating that the NPSI is responsive to the effects of treatments prescribed at the pain clinics. In the MTMM design of the data gathered at the first assessment, there were no misaligned correlations (a discriminant correlation exceeding a convergent correlation) within the evoked, paroxysmal, and superficial spontaneous pain subscores, and there was just one in each of the profound spontaneous pain and abnormal sensations subscores (Table 4). The calculated binomial probability of the null hypothesis that this alignment occurred at random (0.006) allows us to reject it in favor of correct alignment. In the data gathered at the second assessment, however, the abnormal sensations subscore did not show the expected pattern of convergent and discriminant validity because there were nine misaligned correlations (Table 4). Under the null hypothesis, the binomial probability of observing nine of 12 misaligned correlations under the null hypothesis is 0.054, marginally significant for rejecting in favor of incorrect alignment. In both assessments, the correlations between total score and all subscores of the NPSI and the NPS were greater than the pairwise correlations between subscores (Table 4). The PCA identified five factors with eigenvalues greater than one at both assessments, as in the original version of the NPSI. The five-factor solutions accounted for 77.9% and Table 4 MTMM Correlation Matrix (Spearman s Correlation Coefficients) Between the NPSI and NPS Scores NPSI NPS First assessment (n ¼ 464) Total Ev Deep Par Sens Sup Total Ev a Deep b Par c Sens d NPSI Ev Deep Par Sens Sup NPS Total Ev a Deep b Par c Sens d Sup e Second assessment (n ¼ 427) Total Ev Deep Par Sens Sup Total Ev a Deep b Par c Sens d NPSI Ev Deep Par Sens Sup NPS Total Ev a Deep b Par c Sens d Sup e MTMM ¼ multitrait-multimethod; Ev ¼ evoked pain subscore; Deep ¼ deep spontaneous ongoing pain subscore; Par ¼ paroxysmal pain subscore; Sens ¼ abnormal sensations subscore; Sup ¼ superficial spontaneous ongoing pain subscore. Bold italic values correspond to the convergent (monotrait-heteromethod) correlations. Figures in italic type are the divergent (heterotrait-monomethod or heterotrait-heteromethod) correlations. Figures in normal type are the correlations between total scores and subscale scores. The values represented in bold italic should exceed all the values in italic type within their corresponding rows and columns. a Items 6 (sensitive) and 10B (surface). b Items 10A (deep) and 4 (dull). c Item 2 (sharp). d Item 5 (cold). e Items 3 (hot) and Item 7 (itchy).

9 142 Villoria et al. Vol. 42 No. 1 July % of the total variance of the data gathered at first and second assessments, respectively. Item aggregation reproduced the structure of the original version, with the exception that Item 5 was aggregated with Item 1 instead of Item 6 at the first assessment (Table 5). Item aggregation in the data gathered at second assessment reproduced exactly the original structure. In both cases, all the items had high loadings on only one factor. Psychometric Reliability The Cronbach s alpha coefficients calculated for the analyses of internal consistency were above 0.80 for total NPSI score and above 0.70 for all NPSI subscores, with the exception of the paroxysmal pain subscore at the first assessment (Table 6). The intraclass correlation coefficients of absolute agreement between both assessments within the subset of nonresponders were above 0.6 for a single measure (taken at either assessment) and above 0.7 for the average of both measurements (Table 6). Results Within the Subset of Patients with Pure NP Detailed results are not included in this report, but they are available on request. In brief, responsiveness and reliability analyses yielded very good and comparable results to those obtained in the whole sample. Misaligned correlations affecting the abnormal sensations subscore also were observed when the data from the second assessment were used. The exception affecting the aggregation of Item 5 in the first assessment also was seen within this subset. The only relevant difference with respect to the results in the whole sample is that Items 10 and 11 showed, in the second assessment, relevant loads on the factors related to abnormal sensations and paroxysmal pain, respectively, in addition to the factors in which they aggregate in the original version. Notwithstanding, the original solution, with five factors Table 5 Five-Factor Solution of the Primary Component Analysis of the 10 Items of the NPSI at Both Study Assessments Rotated Matrix Components NPSI Item Communality First assessment (n ¼ 510) a Item 1 (burning) Item 2 (squeezing) Item 3 (pressure) Item 5 (electric shocks) b Item 6 (stabbing) Item 8 (evoked-brushing) Item 9 (evoked-pressure) Item 10 (contact-cold) Item 11 (pins and needles) Item 12 (tingling) Eigenvalues eee Second assessment (n ¼ 460) c Item 1 (burning) Item 2 (squeezing) Item 3 (pressure) Item 5 (electric shocks) Item 6 (stabbing) Item 8 (evoked-brushing) Item 9 (evoked-pressure) Item 10 (contact-cold) Item 11 (pins and needles) Item 12 (tingling) Eigenvalues eee a This solution explains 77.9% of total variance. b This item is aggregated with Item 6 in the original version. c This solution explains 86.9% of total variance.

10 Vol. 42 No. 1 July 2011 Validation of the NPSI in Spanish 143 Table 6 Cronbach s Alpha and ICCs of the Total Score and the Five Subscores of the NPSI at Each Assessment (Alpha) or Between Assessments (ICC) First assessment (n ¼ 510) Alpha Total Ev Deep Par Sens Sup e Second assessment (n ¼ 460) Alpha Total Ev Deep Par Sens Sup e Between assessments, nonresponders (n ¼ 97) ICC (A,1) ICC (A,2) Total Ev Deep Par Sens Sup Ev ¼ evoked pain subscore; Deep ¼ deep spontaneous ongoing pain subscore; Par ¼ paroxysmal pain subscore; Sens ¼ abnormal sensations subscore; Sup ¼ superficial spontaneous ongoing pain subscore; ICC (A,1) ¼ intraclass correlation coefficient of absolute agreement between both assessments for a single measure (from either assessment); ICC (A,2) ¼ idem for the average of two measures (one from each assessment). having eigenvalues greater than one, was evident within this subset as well. Discussion Key Findings The objective of this research was to perform a complete evaluation of the psychometric validity and reliability of the Spanish version of the NPSI in patients from Spain. The authors performed analyses of internal consistency and test-retest reliability, as well as of internal structure, responsiveness, and construct validity. The results of the reliability analyses were very satisfactory, as were the results of responsiveness. The analyses of construct validity were also satisfactory, with the exception of the incorrect alignment of the abnormal sensations component of the NPSI in one of the assessments, but this finding is more likely related to the absence of a comparable construct in the NPS than to an intrinsic defect of the Spanish NPSI (see below). The internal structure of the original instrument was reproduced by means of PCA using the data from the second assessment. In the first assessment, however, the electric shocks item was aggregated with the burning item instead of the stabbing item as in the original. Speculatively, this fact may relate to a cultural feature rather than to a linguistic issue (see below). The P-values associated to the null hypotheses relating to the analyses of responsiveness (<0.001 in both analyses) and construct validity in the first assessment (0.006) were small. All these three null hypotheses can be rejected in the target population at the 5% significance level ( þ ¼ 0.008). Construct Validity and Misalignments The underlying construct used by the authors of the NPSI was that of a fourdimensional model of NP with spontaneous pain (ongoing and paroxysmal), evoked pain and abnormal sensations. 7 Conceptual frameworks and pathophysiologic knowledge support this model, 11,20 but clinical testing with the NPSI is required to obtain empirical evidence on its validity and, most important, if these dimensions serve to define stable and specific clusters of symptoms, syndromal definitions or, further, correspondence with the mechanisms presumably responsible for the pain. Although no formal verification of the internal structure of the NPS is available, the demonstration of construct validity of the NPSI versus the NPS is an appealing finding. Some of the NPSI items are not included in the NPS and vice versa. The authors of the NPSI pointed out that the comparison of the responses to these two instruments in the same patients would be of interest. Such comparison has been done in the present research to show that, with the exception of abnormal sensations, NPS items can be approximately mapped to NPSI components, giving considerable support to the four-dimensional model proposed initially. The unstable correspondence of the abnormal sensations component of the NPSI more probably relates to the failure of the NPS to address this dimension than to the absence of a latent trait supplying a stable source of variability in the measurement process (i.e., patients can show abnormal sensations regardless of other symptoms). Further, the

11 144 Villoria et al. Vol. 42 No. 1 July 2011 dichotomy of spontaneous ongoing pain into deep and superficial components (to give the final five-factor structure of the NPSI) also is supported by this research, because Item 1 (whether or not aggregated with Item 5) was consistently separated from Items 2 and 3. At this point, it is worth noting that the correlations of total score with the subscores were in the range of moderate to high, whereas the correlations among subscores were more modest in both the NPSI and the NPS. This supports the summative scoring structure of both instruments and suggests that the construct that they measure (NP as a multidimensional experience) is a good predictor of the scores given by patients to the items of the scales. Interestingly, these relationships were somewhat sharper for the NPSI than for the NPS (Table 4). Further efforts should now be directed toward the clarification of correspondence of these dimensions with the known mechanisms that cause NP, such as hyperactivity and hyperexcitability of primary nociceptors, 3 hyperexcitability of spinal cord pain-signaling neurons, aberrant connections in the dorsal horn, or activation of descending painfacilitatory systems, 21 to mention but a few; and then, to determine if different patterns of symptoms are reliable informants for therapeutic decisions. Internal Structure and Differential Functioning In the first assessment, an exception to the original NPSI internal structure was found because the aggregation of the electric shocks item was greater with the burning item than with the stabbing item. This is more likely related to a cultural feature than to a linguistic issue in the Spanish translation, presumably caused by Spanish patients identification of electric shocks with heat sensation or with contact with a burning object. In consequence, although this reflects that the responses by Spanish patients regarding paroxysmal pain have a different structure of variation (differential item functioning), it is not probable that it is caused by the inclusion of irrelevant sources of variation that place respondents in Spain in a biased position regarding the population in which the NPSI was developed. This reasoning is supported by the fact that the factorial load of Item 5 also was high in the fifth component (0.431, see Table 5), suggesting that the electric shock sensation was not understood by all the patients homogeneously. Notwithstanding, with the data from the second assessment, the PCA yielded very close results to the five-factor solution published by the NPSI authors, which is a proof of content validity. Importantly, pain intensity in the primary sample used for the NPSI development was closer to the intensity observed in the second than in the first assessment of the present study because a threshold severity in the first assessment was required to participate, and the sample by the NPSI authors included the full range of pain intensities. 7 Mixed Pain Syndromes and Clinical Applicability of the NPSI The results obtained within the subset of patients with pure NP, matching that of the whole sample in whichdreflecting routine practicedmore than half of the patients had mixed pain origins, constitutes a proof of robustness of the NPSI, and has clear implications. On one hand, this circumstance provides support for a wide clinical use of the instrument, extending to patients with mixed pain conditions. On the other, it suggests that the multidimensional construct of NP also is applicable to the clinical manifestations of NP in patients who additionally feature a somatic component; further research should develop this notion and establish its conceptual implications. Limitations Patients in this study were recruited within Spain. This limits the target population to the respondents living in this country. As a consequence, it is uncertain whether the psychometric properties described apply to other Spanish-speaking countries. The PCA performed showed that the five-factor internal structure is feasible and reproducible, but in the absence of a widely accepted consensus on the dimensions of NP and their correspondence with clinical clusters of symptoms, the exploratory character of PCA recommends to consider this structure with caution. The NPQ-SF was not included among the selection criteria in this study because it was not feasible for the clinical investigators to calculate the canonical discriminant function score on the fly at their desks. Up to one-fifth of the

12 Vol. 42 No. 1 July 2011 Validation of the NPSI in Spanish 145 sample was found afterward to have a negative score at enrollment, which suggests that the presence of a clinically relevant neuropathic component is unlikely. It is uncertain the extent to which this circumstance may have affected the analyses. Last, the psychometric properties of the NPSI in the first assessment were evaluated with only part of its range of scores because the selection criteria included a threshold score. Therefore, the results of the analyses of reliability, internal structure and, particularly, construct validity from this assessment should be considered with caution. This does not concern, however, the second assessment because the considerable proportion of responders permitted that the full range of NPSI scores was available for the analysis. Conclusion The Spanish version of the NPSI is suitable for use in everyday clinical practice and in clinical studies in patients from Spain. It has been demonstrated to have good psychometric properties for the evaluation of the different dimensions of NP syndromes, as does the original version. The results reported should encourage the inclusion of patients from Spain and, more generally, Spanish-speaking patients from other countries in future studies aimed to evaluate the association between the NPSI items or subscores and specific underlying pathophysiologic constructs of NP, as well as the selective or preferential effects of different pharmacological agents on the dimensions of NP syndromes. Disclosures and Acknowledgments This research was funded by Gr unenthal Pharma, S.A. Jesus Villoria has received horonaria for designing and performing the statistical analyses described in the article. Andres Stern and Isabel Sanchez-Magro are full-time employees of Gr unenthal Pharma, S.A. Manuel Rodrıguez and Marıa J. Berro have received fees as clinical investigators from Gr unenthal Pharma, S.A. The authors thank the investigators and institutions that participated in this investigation. References 1. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999;83:389e Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004;140:441e Gold MS, Chessell I, Devor M, et al. Peripheral nervous system targets: rapporteur report. In: Campbell JN, Basbaum AI, Dray A, et al, eds. Emerging strategies for the treatment of neuropathic pain. Seattle, WA: IASP Press, 2006: 3e Woolf CJ, Bennett GJ, Doherty M, et al. Towards a mechanism-based classification of pain? Pain 1998;77:227e Carter GT, Galer BS. Advances in the management of neuropathic pain. Phys Med Rehabil Clin N Am 2001;12:447e Jensen TS, Baron R. Translation of symptoms and signs into mechanisms in neuropathic pain. Pain 2003;102:1e8. 7. Bouhassira D, Attal N, Fermanian J, et al. Development and validation of the Neuropathic Pain Symptom Inventory. Pain 2004;108:248e Crawford B, Bouhassira D, Wong A, Dukes E. Conceptual adequacy of the neuropathic pain symptom inventory in six countries. Health Qual Life Outcomes 2008;6: Spanish National Statistics Institute. Life expectancy at birth. National total. Available from IDB&idtab¼7. Accessed May Spanish Pain Society. Catalog of accredited pain units. Available from diectorio.php. Accessed May Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60:1524e Galer BS, Jensen MP. Development and preliminary validation of a pain measure specific to neuropathic pain: the Neuropathic Pain Scale. Neurology 1997;48:332e Krause SJ, Backonja MM. Development of a neuropathic pain questionnaire. Clin J Pain 2003;19: 306e Backonja MM, Krause SJ. Neuropathic pain questionnaireeshort form. Clin J Pain 2003;19: 315e Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 1993;39: 561e577. [Published erratum appears in Clin Chem 1993;39(8):1589].

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