ORIGINAL ARTICLE
Validation of the Greek Version of the DN4 Diagnostic Questionnaire for Neuropathic Pain Panagiota Sykioti, MD, MRCPsych*; Panagiotis Zis, MD, MRCPsych, MSc, PhD†; Athina Vadalouca, MD, PhD, FIPP*; Ioanna Siafaka, MD, PhD*; Eriphili Argyra, MD, PhD*; Didier Bouhassira, MD, PhD‡; Evmorfia Stavropoulou, MD*; Nikolaos Karandreas, MD, PhD§ *1st Anaesthesiology Clinic, Pain Relief and Palliative Care Unit, Aretaieion University Hospital, University of Athens, Athens; †Department of Neurology, Evangelismos General Hospital, Athens, Greece; ‡Inserm U987, Ambroise Pare Hospital, Boulogne-Billancourt and UVSQ University, Versailles, France; §1st Department of Neurology, Aeginition Hospital, University of Athens, Athens, Greece
& Abstract Background: The Douleur Neuropathique 4 questionnaire (DN4) was developed by the French Neuropathic Pain Group and is a simple and objective tool, primarily designed to screen for neuropathic pain. The aim of our study is to validate the DN4 in the Greek language. Methods: The study was set up as a prospective observational study. Two pain specialists independently examined patients and diagnosed them with neuropathic, nociceptive, or mixed pain, according to the International Association for the Study of Pain (IASP) definitions. A third and a fourth physician administered the DN4 questionnaire to the patients. Results: Out of the 237 patients who met our inclusion criteria and had identical diagnoses regarding the type of pain, 123 were diagnosed with neuropathic, 59 with nociceptive, and 55 with mixed pain. Among patients with identical diagnoses of neuropathic or nociceptive pain, using
Address correspondence and reprint requests to: Panagiotis Zis, MD, MRCPsych, MSc, PhD, Department of Neurology, Evangelismos General Hospital, 45-47 Ipsilantou Str, 10676, Athens, Greece. E-mail: [email protected]. Submitted: November 11, 2013; Revision accepted: March 19, 2014 DOI. 10.1111/papr.12221
© 2014 World Institute of Pain, 1530-7085/14/$15.00 Pain Practice, Volume , Issue , 2014 –
a receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.92. A cutoff point of equal or greater than 4 resulted in a sensitivity of 93% and a specificity of 78%. Among patients suffering from pain with neuropathic element (neuropathic or mixed pain) or pain with no neuropathic element (nociceptive pain), using a ROC curve analysis, the AUC was 0.89. A cutoff point of equal or greater than 4 resulted in a sensitivity of 89% and a specificity of 78%. Conclusion: The Greek version of DN4 is a valid tool for discriminating between neuropathic and nociceptive pain conditions in daily practice. & Key Words: pain, neuropathic, DN4, Douleur Neuropathique 4, validation, Greek
INTRODUCTION We can ignore even pleasure, but pain insists upon being attended to. God whispers to us in our pleasures, speaks in our conscience, but shouts in our pains: it is his megaphone to rouse a deaf world. 1 Pain is a universal experience and the human body’s most valuable alerting system. According to International Association for the Study of Pain (IASP), pain is defined as an unpleasant sensory and emotional
2
SYKIOTI ET AL.
experience associated with actual or potential tissue damage, or described in terms of such damage. It is recognized that pain is always subjective and each person forms its understanding of the word through his experiences related to injury in early life.2 The need for a systematic classification of pain has long been recognized and IASP suggests 5 axes for the description of pain, according to anatomical location, body system involved, temporal characteristics, intensity, time of onset, and etiology.2,3 A broad categorization of pain, as nociceptive and/or neuropathic, is useful in clinical practice. Nociceptive pain is the pain that arises from actual or threatened damage to nonneural tissue and is due to the activation of nociceptors, while neuropathic pain (NP) is defined as the pain caused by a lesion or disease of the somatosensory nervous system.4 Neuropathic pain is a clinical diagnosis based on medical history, neurological examination, and further investigations such as neurophysiological testing and neuroimaging.5 In order to aid clinicians to diagnose NP, several questionnaires are being used. These include the McGill Pain Questionnaire (MPQ),6 the Leeds assessment of neuropathic symptoms, and signs (LANSS) Pain Scale,7 the ID Pain,8 the Neuropathic Pain Questionnaire (NPQ),9 the painDETECT,10 the Standardized Evaluation of Pain (StEP),11 and the Douleur Neuropathique 4 (DN4) Questionnaire.12 Recent studies that compare DN4 with other questionnaires suggest that tools are highly discriminative but DN4 has a better predictive ability.13–15 The DN4 questionnaire, developed and validated by Bouhassira et al. in 2005,12 is a clinician administered screening tool consisting of 10 items divided in 4 categories. The first 2 categories include 7 items that are completed during the interview with the patient, when the last 2 (which include the remaining 3 items) are completed during the clinical examination. More specifically, the first category includes 3 items that are related to pain characteristics (burning, painful cold, and electric shock). The second category includes 4 items that concern symptoms which might accompany the experienced pain (tingling, pins and needles, numbness, and itching). The third category includes 2 items that are related to signs on physical examination (tactile hypoaesthesia and pinprick hypoaesthesia). The fourth category, also assessed during the clinical examination, has only 1 item regarding allodynia. Since its development, the DN4 has been translated in over 50 languages and clear guidelines for the linguistic
validation for use in international studies have been developed.5,16 To our knowledge, DN4 has already been psychometrically validated in 8 languages including French,12 Arabic,17 Portuguese,18 Spanish,19 Turkish,20 Farsi,21 Dutch,3 and Italian.15 The aim of our study is to evaluate the diagnostic value of the Greek version of the DN4 questionnaire.
METHODS Participants All consecutive patients with pain complaints who were examined in the Pain Relief Clinic of our hospital were invited to participate to the study. To be enrolled, the patients had to meet the following inclusion criteria: (1) age equal to or greater than 18 years; (2) duration of pain of equal to or greater than 3 months; (3) intensity of pain being moderate or severe (scoring 5 or higher on a 0 to 10 visual analog scale); (4) being first-time visitors and not previously diagnosed by the investigators; (5) being a native Greek speaker; and (6) be willing to provide a written informed consent to undergo the experimental procedures. Exclusion criteria were suffering from headache, having gross cognitive deficits or intellectual disability, and severe psychiatric comorbidity (ie, severe depression, psychotic disorders). Study Design The study was designed as a prospective observational study. During the first visit 2, pain specialists independently examined the patients and diagnosed them with neuropathic, nociceptive, or mixed pain according to the IASP definitions.2 A third physician collected the demographic data of the patients and independently administered the DN4 questionnaire to them. Details about the linguistic validation and the forward and backward translation in the Greek language by the MAPI Research Group have been published elsewhere.16 We aimed for a sample size of 200 patients. To investigate the inter-rater reliability, the DN4 questionnaire was administered for a second time in a subsample of 100 patients by a fourth investigator. Moreover, to investigate the test–retest reliability, the third physician administered the DN4 questionnaire for a second time in a subsample of 34 patients, 48 hours after the first time. The local scientific committee approved the study and all participants provided informed consent.
Validation of the Greek DN4 Questionnaire 3
Statistical Analyses A database was developed using the Statistical Package for Social Science (version 16.0 for Mac; SPSS). Frequencies and descriptive statistics were examined for each variable. Statistical comparisons were performed between the neuropathic, nociceptive, and mixed pain subgroups concerning demographics and pain characteristics. Dichotomous variables were compared with the chi-square test and continuous variables using one-way analysis of variance. Bonferroni’s correction for multiple comparisons was applied as appropriate. Only patients who were diagnosed with neuropathic, nociceptive, or mixed pain by both physicians were included in our analysis. For the internal consistency, Cronbach’s a coefficient was calculated within each of the 4 domains and for the whole questionnaire. The inter-rater reliability was evaluated using Kappa coefficients. Strength of agreement is seen as poor for values of j < 0.20, fair 0.21 to 0.40, moderate 0.41 to 0.60, good 0.61 to 0.80, and very good > 0.80.22 Furthermore, intraclass coefficients (ICC) and their 95% confidence intervals (CI) were calculated to evaluate the test–retest reliability of the questionnaire. To identify the discriminatory properties of the DN4, we performed 2 subanalyses. Firstly, similar to the methodology followed by van Seventer et al.,3 we limited the analysis to patients who were diagnosed with neuropathic or nociceptive pain by both physicians, as the least doubt exists regarding the type of pain in these patients and therefore providing the most appropriate groups to analyze the discriminatory properties of DN4. In the second subanalysis, we included patients with mixed pain together with the patients with purely NP in a new group: patients suffering from pain with a neuropathic element. We proceeded to this analysis, as this is a more clinically real scenario.23 Therefore, obtaining a cut-off score after analyzing all 3 categories of pain would be of more clinical use even in nonspecialists who are treating patients presenting with pain.23 Receiver operator characteristics (ROC) analysis was calculated to assess the utility of the DN4 total score in order to distinguish the diagnosis of NP defined by the gold standard diagnosis of the first 2 physicians. Area under the curve (AUC) and its 95% confidence intervals (CI) for the ROC curve were calculated. The AUC is a measure of the diagnostic power of the test, independent of cut-off points. An AUC < 0.60 is considered “nega-
tive”, 0.61 to 0.80 as “doubtful”, 0.81 to 0.90 as “good”, and > 0.91 as “very good”.22 The Youden Index was calculated as the sum of sensitivity, plus specificity, minus 1 for all possible cutoff points to identify the most relevant cutoff values. A value of P < 0.05 was considered to be statistically significant.
RESULTS Study Population Between January 2011 and January 2014, 351 first-time visitors, not previously diagnosed by the investigators, were examined at the Pain Relief Clinic of our hospital and were eligible candidates to participate to the study. However, 114 patients were excluded from the study. Fifty-one patients were suffering from pain of less than 3 months duration, 29 patients were not diagnosed with identical types of pain by the first and the second pain specialists, 14 patients had scored less than 5 in the visual analog scale (VAS), 8 were not native Greek Speakers, 4 were less than 18 years old, and 8 did not consent to participate. In total, the final study population included 237 individuals who fulfilled the abovementioned inclusion criteria. Demographic and Pain Characteristics From the final study population, 123 patients were diagnosed with NP, 59 patients with nociceptive, and 55 patients with mixed pain. Demographic and clinical characteristics of each subgroup are shown in Table 1. There were no differences regarding the demographic characteristics between the 3 groups. Patients diagnosed with mixed pain had a statistically significant longer duration of pain compared to patients with neuropathic or nociceptive pain. Patients with nociceptive pain experienced a statistically significant lower intensity of pain compared to patients with neuropathic or mixed pain. The most common etiology of pain among patients with NP was postherpetic neuralgia (53.3%), when among patients with nociceptive and mixed pain was cancer (35.0% and 40.0% respectively). The mean DN4 score differed significantly between all 3 subgroups (P < 0.001). Similarly to Madani et al.,21 a not too strong, but still statistically significant, direct correlation was observed between total DN4 score and intensity of pain measured with VAS (Pearson r = 0.193, P = 0.021).
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Table 1. Demographic and Clinical Characteristics of Study Total Population and Subgroups
Demographic characteristics Male sex (%) Age, in years (SD) Body mass index, in kg/m2 (SD) Pain characteristics Duration of pain, in years (SD) Intensity of pain, mean (SD) Acceptable pain intensity, mean (SD) Etiology (%) Postherpetic neuralgia Cancer Low back pain-nonspecific Arthrosis FBSS Radiculopathy Trigeminal neuralgia Post-traumatic Spinal stenosis Polyneuropathy Soft tissue Other DN4 score, mean (SD)
Total (n = 237)
Neuropathic (n = 123)
Nociceptive (n = 59)
Mixed (n = 55)
88 (37.1) 66.2 (14.9) 26.7 (5.5)
54 (43.9) 67.0 (14.5) 27.5 (4.9)
17 (28.8) 66.1 (15.8) 25.7 (5.9)
17 (30.9) 64.6 (14.6) 26.6 (5.7)
0.079 0.657 0.274
3.8 (6.1) 8.2 (1.4) 4.3 (1.3)
2.3 (3.6) 8.6 (1.4) 4.5 (1.2)
4.0 (5.6) 7.6 (1.5) 3.9 (1.7)
5.9 (8.6) 8.2 (1.2) 4.3 (1.1)
0.013 0.003 0.183
65 (27.4) 46 (19.4) 19 (8.0) 17 (7.2) 15 (6.3) 13 (5.5) 11 (4.6) 11 (4.6) 9 (3.8) 8 (3.4) 6 (2.5) 17 (7.2) 5.0 (2.3)
65 3 4 0 8 5 11 6 7 8 0 6 6.2
0 21 9 11 0 1 0 5 1 0 5 6 2.5
0 22 6 6 7 7 0 0 1 0 1 5 5.0
Internal Consistency, Inter-rater Reliability, and Test–retest Reliability of the Greek DN4 Table 2 summarizes the indexes of the Greek version of the DN4 Questionnaire, regarding the internal consistency, the inter-rater reliability and the test–retest reliability. Regarding the internal consistency, the highest Cronbach’s a coefficient of 0.725 was achieved in third question on physical examination. The Cronbach’s a coefficient of the whole questionnaire was 0.650. Although there was a strong correlation between total DN4 score of 2 raters (r = 0.818, P < 0.001), the inter-rater agreement was also assessed for each item, all achieving a significant level of agreement (P < 0.001). The weakest agreement was seen in the third item of the first question (electric shocks) and the highest Kappa-Cohen coefficient was found in the fourth item of the second question (itching). Retest results showed that the DN4 questionnaire has good test–retest stability, with intraclass correlation coefficient for the total score being 0.956. Validity of DN4 Among patients with identical diagnoses of neuropathic or nociceptive pain, using a ROC curve analysis, the AUC was 0.919 (95% CI, 0.877 to 0.961; SE, 0.022; P < 0.001). To detect NP, at a cutoff score of equal to or greater than 4, the DN4 showed a sensitivity of 93%, a
(53.3) (2.5) (3.3) (0.0) (6.6) (4.1) (9.0) (4.9) (5.7) (6.6) (0.0) (4.9) (1.7)
(0.0) (35.0) (15.0) (18.3) (0.0) (1.7) (0.0) (8.3) (1.7) (0.0) (8.3) (10.0) (1.7)
(0.0) (40.0) (10.9) (10.9) (12.7) (12.7) (0.0) (0.0) (1.8) (0.0) (1.8) (10.0) (2.0)
P
< 0.001
< 0.001
Table 2. Internal Consistency, Inter-rater Reliability and Test–retest Reliability of the Greek Version of DN4 Questionnaire
Question 1 Burning Painful cold Electric shocks Question 2 Tingling Pins and needles Numbness Itching Question 3 Hypoaesthesia to touch Hypoaesthesia to pinprick Question 4 Brushing Total
Internal Consistency Cronbach’s a coefficient
Inter-rater Reliability j-Cohen coefficient
Test–Retest Reliability Intraclass coefficient (95% CI)
0.447
0.928 0.820 0.812
0.857 (0.733 to 0.936) 0.875 (0.765 to 0.936) 0.825 (0.678 to 0.909)
0.480
0.915 0.869 0.877 0.933
0.857 (0.733 to 0.886 (0.628 to 0.837 (0.697 to 0.940 (0.884 to
0.725
0.820
0.879 (0.771 to 0.937)
0.880
0.849 (0.719 to 0.922)
0.920 0.818
0.866 (0.748 to 0.931) 0.956 (0.913 to 0.978)
0.650
0.926) 0.892) 0.915) 0.970)
specificity of 78%, a positive predictive value (PPV) of 90%, and a negative predictive value (NPV) of 84% (Table 3). Among patients with all types of pain (including mixed), using a ROC curve analysis, the area AUC was 0.887 (95% CI, 0.840 to 0.934; SE, 0.024; P < 0.001). To detect neuropathic element of pain, at a cutoff score of equal to or greater than 4, the DN4 showed a sensitivity of 89%, a specificity of 78%, a PPV of 92%, and a NPV of 70% (Table 4).
Validation of the Greek DN4 Questionnaire 5
Table 3. Receiver Operating Characteristic and Diagnostic Efficiency of the Greek Version of the DN4 for the Diagnosis of Neuropathic Pain Cut-off Score ≥ ≥ ≥ ≥ ≥
2 3 4 5 6
Youden Index
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
0.31 0.49 0.71 0.66 0.62
100 96.7 92.7 81.3 67.5
30.5 52.5 78.0 84.7 94.9
75.0 81.0 89.8 91.7 96.5
100 88.6 83.6 68.5 58.3
PPV, positive predictive value; NPV, negative predictive value.
Table 4. Receiver Operating Characteristic and Diagnostic Efficiency of the Greek Version of the DN4 for the Diagnosis of Neuropathic Element of Pain Cut-off Score ≥ ≥ ≥ ≥ ≥
2 3 4 5 6
Youden Index
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
0.29 0.46 0.67 0.60 0.55
98.3 93.3 88.8 75.3 59.6
30.5 52.5 78.0 84.7 94.9
81.0 85.6 92.4 93.7 97.2
85.7 72.1 69.7 53.2 43.8
PPV, positive predictive value; NPV, negative predictive value.
DISCUSSION The accurate diagnosis of NP has major therapeutic and research implications. As NP has distinctive mechanisms from nociceptive pain (NOP), the accurate diagnosis would adjust treatment directives accordingly. In our study, we analyzed the psychometric properties of the Greek version of the DN4 questionnaire. DN4 questionnaire is an easy to administer and rate short questionnaire, combining descriptive adjectives of the pain with bedside tests. Its transcultural validity has been long established in previous studies in different languages,3, 15, 17–21 along with its original version in French.12 The Greek translation of the tool has been linguistically validated with a state of the art methodology, as described by Van Sevender et al.16 The Greek version of the DN4 has showed excellent psychometric properties. We confirmed its high discriminative ability in patients with clear NP or NOP with an AUC score of 0.919, a sensitivity of 93%, and a specificity of 78% at the cut-off value of 4/10. These findings are comparable with studies in other languages, where sensitivity has been reported ranging from 75% in the Dutch version 3 to 100% in the Portuguese version,18 and specificity from 72% in the Persian version 21 to 96% in the Turkish version.20 The cut-off value has been established to 4/10 in most languages
with the exemption of the Dutch version, in which the cut-off was 5/10.3 The Arabic version has established a cut-off point of 3/10; however, this was regarding the 7-item version of DN4, which includes only the first 2 categories (interview only) of the original DN4.17 This disparity highlights the importance of analyzing the psychometric properties of the screening questionnaires to different languages on top of the linguistic validations. In our study population, we managed to include patients of both sexes, of most age groups (age range was 18 to 90 years), with a moderate to severe pain (VAS ≥ 5), and a wide range of diagnosis, representative of the population likely to seek help from a primary care physician. Another advantage of our study was that by performing 2 sets of analyses for our group of patients, we also managed to establish its discriminatory power for patients with a neuropathic element of pain. In these patients, Greek DN4 showed a sensitivity of 89% and a specificity of 78% at the same cut-off value of 4/10. This finding is consistent with other studies12,19 showing that DN4 has a good potential as a discriminatory tool of the neuropathic element of pain. Our results should be interpreted with some caution, however, given the limitations of our design. Despite the fact that our population included patients with a wide range of diagnosis, it did not include patients with central NP, such as poststroke and multiple sclerosis patients. Moreover, the fact that we only included patients suffering from pain of moderate or severe intensity (scoring 5 or higher on VAS) may restrain the use of the Greek version of the DN4 in patients with less severe pain. The total Greek speaking population, including Cyprus, Greece and Diaspora communities, exceeds 13 million people.24 Having a screening tool for NP with excellent discriminatory properties even for complex cases of mixed pain syndromes will affect everyday clinical practice and will influence treatment strategies. Because it is the first screening tool for NP to be validated in Greek, it will assist in research and create a better understanding of epidemiologic data of NP in this population.
REFERENCES 1. Lewis CS. The Problem of Pain. New York, NY: Macmillan; 1944. 2. International Association for the Study of Pain, Subcommittee on Taxonomy. Classification of chronic pain.
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Descriptions of chronic pain syndromes and definitions of pain terms. Pain Suppl. 1986;3:S1–S226. 3. van Seventer R, Vos C, Giezeman M, et al. Validation of the Dutch version of the DN4 diagnostic questionnaire for neuropathic pain. Pain Pract. 2013;13:390–398. 4. Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology. 2008;70:1630–1635. 5. Cruccu G, Sommer C, Anand P, et al. EFNS guidelines on neuropathic pain assessment: revised 2009. Eur J Neurol. 2010;17:1010–1018. 6. Melzack R. The McGill pain questionnaire: major properties and scoring methods. Pain. 1975;1:277–299. 7. Bennett MI. The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs. Pain. 2001;92:147– 157. 8. Portenoy R. Development and testing of a neuropathic pain screening questionnaire: ID pain. Curr Med Res Opin. 2006;22:1555–1565. 9. Krause SJ, Backonja MM. Development of a neuropathic pain questionnaire. Clin J Pain. 2003;19:306–314. 10. Freynhagen R, Baron R, Gockel U, Tolle T. painDETECT: a new screening questionnaire to detect neuropathic components in patients with back pain. Curr Med Res Opin. 2006;22:1911–1920. 11. Scholz J, Mannion RJ, Hord DE, et al. A novel tool for the assessment of pain: validation in low back pain. PLoS Med. 2009;6:e1000047. 12. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain. 2005;114:29–36. 13. Hallstr€ om H, Norrbrink C. Screening tools for neuropathic pain: can they be of use in individuals with spinal cord injury? Pain. 2011;152:772–779. 14. Hamdan A, Luna JD, Del Pozo E, Galvez R. Diagnostic accuracy of two questionnaires for the detection of neuropathic pain in the Spanish population. Eur J Pain. 2014;18:101–109.
15. Padua L, Briani C, Truini A. Consistence and discrepancy of neuropathic pain screening tools DN4 and ID-Pain. Neurol Sci. 2013;34:373–377. 16. Van Seventer R, Vos C, Meerding W. Linguistic validation of the DN4 for use in international studies. Eur J Pain. 2010;14:58–63. 17. Harifi G, Ouilki I, El Bouchti I, et al. Validity and reliability of the Arabic adapted version of the DN4 questionnaire (Douleur Neuropathique 4 Questions) for differential diagnosis of pain syndromes with a neuropathic or somatic component. Pain Pract. 2011;11:139–147. 18. Santos JG, Brito JO, de Andrade DC. Translation to Portuguese and validation of the Douleur Neuropathique 4 questionnaire. J Pain. 2010 May;11:484–490. 19. Perez C, Galvez R, Huelbes S, et al. Validity and reliability of the Spanish version of the DN4 (Douleur Neuropathique 4 questions) questionnaire for differential diagnosis of pain syndromes associated to a neuropathic or somatic component. Health Qual Life Outcomes. 2007;4:66. 20. Unal-Cevik I, Sarioglu-Ay S, Evcik D. A comparison of the DN4 and LANSS questionnaires in the assessment of neuropathic pain: validity and reliability of the Turkish version of DN4. J Pain. 2010;11:1129–1135. 21. Madani SP, Fateh HR, Forogh B, et al. Validity and reliability of the Persian (Farsi) version of the DN4 (Douleur Neuropathique 4 Questions) questionnaire for differential diagnosis of neuropathic from non-neuropathic pains. Pain Pract. 2013; doi: 10.1111/papr.12088. [Epub ahead of print]. 22. Altman DG. Practical Statistics for Medical Research. Washington: Chapman & Hall; 1999. 23. Sykioti P, Zis P, Vadalouca A, van Seventer R, Huygen F. Estimating the diagnostic value of DN4 versions. Pain Pract. 2014;14:95. 24. Zis P, Yfanti P, Siatouni A, Tavernarakis A, Gatzonis S. Validation of the Greek version of the neurological disorders depression inventory for epilepsy (NDDI-E). Epilepsy Behav. 2013;29:513–515.
Validation of the Greek Version of the DN4 Diagnostic Questionnaire for Neuropathic Pain Panagiota Sykioti, MD, MRCPsych*; Panagiotis Zis, MD, MRCPsych, MSc, PhD†; Athina Vadalouca, MD, PhD, FIPP*; Ioanna Siafaka, MD, PhD*; Eriphili Argyra, MD, PhD*; Didier Bouhassira, MD, PhD‡; Evmorfia Stavropoulou, MD*; Nikolaos Karandreas, MD, PhD§ *1st Anaesthesiology Clinic, Pain Relief and Palliative Care Unit, Aretaieion University Hospital, University of Athens, Athens; †Department of Neurology, Evangelismos General Hospital, Athens, Greece; ‡Inserm U987, Ambroise Pare Hospital, Boulogne-Billancourt and UVSQ University, Versailles, France; §1st Department of Neurology, Aeginition Hospital, University of Athens, Athens, Greece
& Abstract Background: The Douleur Neuropathique 4 questionnaire (DN4) was developed by the French Neuropathic Pain Group and is a simple and objective tool, primarily designed to screen for neuropathic pain. The aim of our study is to validate the DN4 in the Greek language. Methods: The study was set up as a prospective observational study. Two pain specialists independently examined patients and diagnosed them with neuropathic, nociceptive, or mixed pain, according to the International Association for the Study of Pain (IASP) definitions. A third and a fourth physician administered the DN4 questionnaire to the patients. Results: Out of the 237 patients who met our inclusion criteria and had identical diagnoses regarding the type of pain, 123 were diagnosed with neuropathic, 59 with nociceptive, and 55 with mixed pain. Among patients with identical diagnoses of neuropathic or nociceptive pain, using
Address correspondence and reprint requests to: Panagiotis Zis, MD, MRCPsych, MSc, PhD, Department of Neurology, Evangelismos General Hospital, 45-47 Ipsilantou Str, 10676, Athens, Greece. E-mail: [email protected]. Submitted: November 11, 2013; Revision accepted: March 19, 2014 DOI. 10.1111/papr.12221
© 2014 World Institute of Pain, 1530-7085/14/$15.00 Pain Practice, Volume , Issue , 2014 –
a receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.92. A cutoff point of equal or greater than 4 resulted in a sensitivity of 93% and a specificity of 78%. Among patients suffering from pain with neuropathic element (neuropathic or mixed pain) or pain with no neuropathic element (nociceptive pain), using a ROC curve analysis, the AUC was 0.89. A cutoff point of equal or greater than 4 resulted in a sensitivity of 89% and a specificity of 78%. Conclusion: The Greek version of DN4 is a valid tool for discriminating between neuropathic and nociceptive pain conditions in daily practice. & Key Words: pain, neuropathic, DN4, Douleur Neuropathique 4, validation, Greek
INTRODUCTION We can ignore even pleasure, but pain insists upon being attended to. God whispers to us in our pleasures, speaks in our conscience, but shouts in our pains: it is his megaphone to rouse a deaf world. 1 Pain is a universal experience and the human body’s most valuable alerting system. According to International Association for the Study of Pain (IASP), pain is defined as an unpleasant sensory and emotional
2
SYKIOTI ET AL.
experience associated with actual or potential tissue damage, or described in terms of such damage. It is recognized that pain is always subjective and each person forms its understanding of the word through his experiences related to injury in early life.2 The need for a systematic classification of pain has long been recognized and IASP suggests 5 axes for the description of pain, according to anatomical location, body system involved, temporal characteristics, intensity, time of onset, and etiology.2,3 A broad categorization of pain, as nociceptive and/or neuropathic, is useful in clinical practice. Nociceptive pain is the pain that arises from actual or threatened damage to nonneural tissue and is due to the activation of nociceptors, while neuropathic pain (NP) is defined as the pain caused by a lesion or disease of the somatosensory nervous system.4 Neuropathic pain is a clinical diagnosis based on medical history, neurological examination, and further investigations such as neurophysiological testing and neuroimaging.5 In order to aid clinicians to diagnose NP, several questionnaires are being used. These include the McGill Pain Questionnaire (MPQ),6 the Leeds assessment of neuropathic symptoms, and signs (LANSS) Pain Scale,7 the ID Pain,8 the Neuropathic Pain Questionnaire (NPQ),9 the painDETECT,10 the Standardized Evaluation of Pain (StEP),11 and the Douleur Neuropathique 4 (DN4) Questionnaire.12 Recent studies that compare DN4 with other questionnaires suggest that tools are highly discriminative but DN4 has a better predictive ability.13–15 The DN4 questionnaire, developed and validated by Bouhassira et al. in 2005,12 is a clinician administered screening tool consisting of 10 items divided in 4 categories. The first 2 categories include 7 items that are completed during the interview with the patient, when the last 2 (which include the remaining 3 items) are completed during the clinical examination. More specifically, the first category includes 3 items that are related to pain characteristics (burning, painful cold, and electric shock). The second category includes 4 items that concern symptoms which might accompany the experienced pain (tingling, pins and needles, numbness, and itching). The third category includes 2 items that are related to signs on physical examination (tactile hypoaesthesia and pinprick hypoaesthesia). The fourth category, also assessed during the clinical examination, has only 1 item regarding allodynia. Since its development, the DN4 has been translated in over 50 languages and clear guidelines for the linguistic
validation for use in international studies have been developed.5,16 To our knowledge, DN4 has already been psychometrically validated in 8 languages including French,12 Arabic,17 Portuguese,18 Spanish,19 Turkish,20 Farsi,21 Dutch,3 and Italian.15 The aim of our study is to evaluate the diagnostic value of the Greek version of the DN4 questionnaire.
METHODS Participants All consecutive patients with pain complaints who were examined in the Pain Relief Clinic of our hospital were invited to participate to the study. To be enrolled, the patients had to meet the following inclusion criteria: (1) age equal to or greater than 18 years; (2) duration of pain of equal to or greater than 3 months; (3) intensity of pain being moderate or severe (scoring 5 or higher on a 0 to 10 visual analog scale); (4) being first-time visitors and not previously diagnosed by the investigators; (5) being a native Greek speaker; and (6) be willing to provide a written informed consent to undergo the experimental procedures. Exclusion criteria were suffering from headache, having gross cognitive deficits or intellectual disability, and severe psychiatric comorbidity (ie, severe depression, psychotic disorders). Study Design The study was designed as a prospective observational study. During the first visit 2, pain specialists independently examined the patients and diagnosed them with neuropathic, nociceptive, or mixed pain according to the IASP definitions.2 A third physician collected the demographic data of the patients and independently administered the DN4 questionnaire to them. Details about the linguistic validation and the forward and backward translation in the Greek language by the MAPI Research Group have been published elsewhere.16 We aimed for a sample size of 200 patients. To investigate the inter-rater reliability, the DN4 questionnaire was administered for a second time in a subsample of 100 patients by a fourth investigator. Moreover, to investigate the test–retest reliability, the third physician administered the DN4 questionnaire for a second time in a subsample of 34 patients, 48 hours after the first time. The local scientific committee approved the study and all participants provided informed consent.
Validation of the Greek DN4 Questionnaire 3
Statistical Analyses A database was developed using the Statistical Package for Social Science (version 16.0 for Mac; SPSS). Frequencies and descriptive statistics were examined for each variable. Statistical comparisons were performed between the neuropathic, nociceptive, and mixed pain subgroups concerning demographics and pain characteristics. Dichotomous variables were compared with the chi-square test and continuous variables using one-way analysis of variance. Bonferroni’s correction for multiple comparisons was applied as appropriate. Only patients who were diagnosed with neuropathic, nociceptive, or mixed pain by both physicians were included in our analysis. For the internal consistency, Cronbach’s a coefficient was calculated within each of the 4 domains and for the whole questionnaire. The inter-rater reliability was evaluated using Kappa coefficients. Strength of agreement is seen as poor for values of j < 0.20, fair 0.21 to 0.40, moderate 0.41 to 0.60, good 0.61 to 0.80, and very good > 0.80.22 Furthermore, intraclass coefficients (ICC) and their 95% confidence intervals (CI) were calculated to evaluate the test–retest reliability of the questionnaire. To identify the discriminatory properties of the DN4, we performed 2 subanalyses. Firstly, similar to the methodology followed by van Seventer et al.,3 we limited the analysis to patients who were diagnosed with neuropathic or nociceptive pain by both physicians, as the least doubt exists regarding the type of pain in these patients and therefore providing the most appropriate groups to analyze the discriminatory properties of DN4. In the second subanalysis, we included patients with mixed pain together with the patients with purely NP in a new group: patients suffering from pain with a neuropathic element. We proceeded to this analysis, as this is a more clinically real scenario.23 Therefore, obtaining a cut-off score after analyzing all 3 categories of pain would be of more clinical use even in nonspecialists who are treating patients presenting with pain.23 Receiver operator characteristics (ROC) analysis was calculated to assess the utility of the DN4 total score in order to distinguish the diagnosis of NP defined by the gold standard diagnosis of the first 2 physicians. Area under the curve (AUC) and its 95% confidence intervals (CI) for the ROC curve were calculated. The AUC is a measure of the diagnostic power of the test, independent of cut-off points. An AUC < 0.60 is considered “nega-
tive”, 0.61 to 0.80 as “doubtful”, 0.81 to 0.90 as “good”, and > 0.91 as “very good”.22 The Youden Index was calculated as the sum of sensitivity, plus specificity, minus 1 for all possible cutoff points to identify the most relevant cutoff values. A value of P < 0.05 was considered to be statistically significant.
RESULTS Study Population Between January 2011 and January 2014, 351 first-time visitors, not previously diagnosed by the investigators, were examined at the Pain Relief Clinic of our hospital and were eligible candidates to participate to the study. However, 114 patients were excluded from the study. Fifty-one patients were suffering from pain of less than 3 months duration, 29 patients were not diagnosed with identical types of pain by the first and the second pain specialists, 14 patients had scored less than 5 in the visual analog scale (VAS), 8 were not native Greek Speakers, 4 were less than 18 years old, and 8 did not consent to participate. In total, the final study population included 237 individuals who fulfilled the abovementioned inclusion criteria. Demographic and Pain Characteristics From the final study population, 123 patients were diagnosed with NP, 59 patients with nociceptive, and 55 patients with mixed pain. Demographic and clinical characteristics of each subgroup are shown in Table 1. There were no differences regarding the demographic characteristics between the 3 groups. Patients diagnosed with mixed pain had a statistically significant longer duration of pain compared to patients with neuropathic or nociceptive pain. Patients with nociceptive pain experienced a statistically significant lower intensity of pain compared to patients with neuropathic or mixed pain. The most common etiology of pain among patients with NP was postherpetic neuralgia (53.3%), when among patients with nociceptive and mixed pain was cancer (35.0% and 40.0% respectively). The mean DN4 score differed significantly between all 3 subgroups (P < 0.001). Similarly to Madani et al.,21 a not too strong, but still statistically significant, direct correlation was observed between total DN4 score and intensity of pain measured with VAS (Pearson r = 0.193, P = 0.021).
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Table 1. Demographic and Clinical Characteristics of Study Total Population and Subgroups
Demographic characteristics Male sex (%) Age, in years (SD) Body mass index, in kg/m2 (SD) Pain characteristics Duration of pain, in years (SD) Intensity of pain, mean (SD) Acceptable pain intensity, mean (SD) Etiology (%) Postherpetic neuralgia Cancer Low back pain-nonspecific Arthrosis FBSS Radiculopathy Trigeminal neuralgia Post-traumatic Spinal stenosis Polyneuropathy Soft tissue Other DN4 score, mean (SD)
Total (n = 237)
Neuropathic (n = 123)
Nociceptive (n = 59)
Mixed (n = 55)
88 (37.1) 66.2 (14.9) 26.7 (5.5)
54 (43.9) 67.0 (14.5) 27.5 (4.9)
17 (28.8) 66.1 (15.8) 25.7 (5.9)
17 (30.9) 64.6 (14.6) 26.6 (5.7)
0.079 0.657 0.274
3.8 (6.1) 8.2 (1.4) 4.3 (1.3)
2.3 (3.6) 8.6 (1.4) 4.5 (1.2)
4.0 (5.6) 7.6 (1.5) 3.9 (1.7)
5.9 (8.6) 8.2 (1.2) 4.3 (1.1)
0.013 0.003 0.183
65 (27.4) 46 (19.4) 19 (8.0) 17 (7.2) 15 (6.3) 13 (5.5) 11 (4.6) 11 (4.6) 9 (3.8) 8 (3.4) 6 (2.5) 17 (7.2) 5.0 (2.3)
65 3 4 0 8 5 11 6 7 8 0 6 6.2
0 21 9 11 0 1 0 5 1 0 5 6 2.5
0 22 6 6 7 7 0 0 1 0 1 5 5.0
Internal Consistency, Inter-rater Reliability, and Test–retest Reliability of the Greek DN4 Table 2 summarizes the indexes of the Greek version of the DN4 Questionnaire, regarding the internal consistency, the inter-rater reliability and the test–retest reliability. Regarding the internal consistency, the highest Cronbach’s a coefficient of 0.725 was achieved in third question on physical examination. The Cronbach’s a coefficient of the whole questionnaire was 0.650. Although there was a strong correlation between total DN4 score of 2 raters (r = 0.818, P < 0.001), the inter-rater agreement was also assessed for each item, all achieving a significant level of agreement (P < 0.001). The weakest agreement was seen in the third item of the first question (electric shocks) and the highest Kappa-Cohen coefficient was found in the fourth item of the second question (itching). Retest results showed that the DN4 questionnaire has good test–retest stability, with intraclass correlation coefficient for the total score being 0.956. Validity of DN4 Among patients with identical diagnoses of neuropathic or nociceptive pain, using a ROC curve analysis, the AUC was 0.919 (95% CI, 0.877 to 0.961; SE, 0.022; P < 0.001). To detect NP, at a cutoff score of equal to or greater than 4, the DN4 showed a sensitivity of 93%, a
(53.3) (2.5) (3.3) (0.0) (6.6) (4.1) (9.0) (4.9) (5.7) (6.6) (0.0) (4.9) (1.7)
(0.0) (35.0) (15.0) (18.3) (0.0) (1.7) (0.0) (8.3) (1.7) (0.0) (8.3) (10.0) (1.7)
(0.0) (40.0) (10.9) (10.9) (12.7) (12.7) (0.0) (0.0) (1.8) (0.0) (1.8) (10.0) (2.0)
P
< 0.001
< 0.001
Table 2. Internal Consistency, Inter-rater Reliability and Test–retest Reliability of the Greek Version of DN4 Questionnaire
Question 1 Burning Painful cold Electric shocks Question 2 Tingling Pins and needles Numbness Itching Question 3 Hypoaesthesia to touch Hypoaesthesia to pinprick Question 4 Brushing Total
Internal Consistency Cronbach’s a coefficient
Inter-rater Reliability j-Cohen coefficient
Test–Retest Reliability Intraclass coefficient (95% CI)
0.447
0.928 0.820 0.812
0.857 (0.733 to 0.936) 0.875 (0.765 to 0.936) 0.825 (0.678 to 0.909)
0.480
0.915 0.869 0.877 0.933
0.857 (0.733 to 0.886 (0.628 to 0.837 (0.697 to 0.940 (0.884 to
0.725
0.820
0.879 (0.771 to 0.937)
0.880
0.849 (0.719 to 0.922)
0.920 0.818
0.866 (0.748 to 0.931) 0.956 (0.913 to 0.978)
0.650
0.926) 0.892) 0.915) 0.970)
specificity of 78%, a positive predictive value (PPV) of 90%, and a negative predictive value (NPV) of 84% (Table 3). Among patients with all types of pain (including mixed), using a ROC curve analysis, the area AUC was 0.887 (95% CI, 0.840 to 0.934; SE, 0.024; P < 0.001). To detect neuropathic element of pain, at a cutoff score of equal to or greater than 4, the DN4 showed a sensitivity of 89%, a specificity of 78%, a PPV of 92%, and a NPV of 70% (Table 4).
Validation of the Greek DN4 Questionnaire 5
Table 3. Receiver Operating Characteristic and Diagnostic Efficiency of the Greek Version of the DN4 for the Diagnosis of Neuropathic Pain Cut-off Score ≥ ≥ ≥ ≥ ≥
2 3 4 5 6
Youden Index
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
0.31 0.49 0.71 0.66 0.62
100 96.7 92.7 81.3 67.5
30.5 52.5 78.0 84.7 94.9
75.0 81.0 89.8 91.7 96.5
100 88.6 83.6 68.5 58.3
PPV, positive predictive value; NPV, negative predictive value.
Table 4. Receiver Operating Characteristic and Diagnostic Efficiency of the Greek Version of the DN4 for the Diagnosis of Neuropathic Element of Pain Cut-off Score ≥ ≥ ≥ ≥ ≥
2 3 4 5 6
Youden Index
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
0.29 0.46 0.67 0.60 0.55
98.3 93.3 88.8 75.3 59.6
30.5 52.5 78.0 84.7 94.9
81.0 85.6 92.4 93.7 97.2
85.7 72.1 69.7 53.2 43.8
PPV, positive predictive value; NPV, negative predictive value.
DISCUSSION The accurate diagnosis of NP has major therapeutic and research implications. As NP has distinctive mechanisms from nociceptive pain (NOP), the accurate diagnosis would adjust treatment directives accordingly. In our study, we analyzed the psychometric properties of the Greek version of the DN4 questionnaire. DN4 questionnaire is an easy to administer and rate short questionnaire, combining descriptive adjectives of the pain with bedside tests. Its transcultural validity has been long established in previous studies in different languages,3, 15, 17–21 along with its original version in French.12 The Greek translation of the tool has been linguistically validated with a state of the art methodology, as described by Van Sevender et al.16 The Greek version of the DN4 has showed excellent psychometric properties. We confirmed its high discriminative ability in patients with clear NP or NOP with an AUC score of 0.919, a sensitivity of 93%, and a specificity of 78% at the cut-off value of 4/10. These findings are comparable with studies in other languages, where sensitivity has been reported ranging from 75% in the Dutch version 3 to 100% in the Portuguese version,18 and specificity from 72% in the Persian version 21 to 96% in the Turkish version.20 The cut-off value has been established to 4/10 in most languages
with the exemption of the Dutch version, in which the cut-off was 5/10.3 The Arabic version has established a cut-off point of 3/10; however, this was regarding the 7-item version of DN4, which includes only the first 2 categories (interview only) of the original DN4.17 This disparity highlights the importance of analyzing the psychometric properties of the screening questionnaires to different languages on top of the linguistic validations. In our study population, we managed to include patients of both sexes, of most age groups (age range was 18 to 90 years), with a moderate to severe pain (VAS ≥ 5), and a wide range of diagnosis, representative of the population likely to seek help from a primary care physician. Another advantage of our study was that by performing 2 sets of analyses for our group of patients, we also managed to establish its discriminatory power for patients with a neuropathic element of pain. In these patients, Greek DN4 showed a sensitivity of 89% and a specificity of 78% at the same cut-off value of 4/10. This finding is consistent with other studies12,19 showing that DN4 has a good potential as a discriminatory tool of the neuropathic element of pain. Our results should be interpreted with some caution, however, given the limitations of our design. Despite the fact that our population included patients with a wide range of diagnosis, it did not include patients with central NP, such as poststroke and multiple sclerosis patients. Moreover, the fact that we only included patients suffering from pain of moderate or severe intensity (scoring 5 or higher on VAS) may restrain the use of the Greek version of the DN4 in patients with less severe pain. The total Greek speaking population, including Cyprus, Greece and Diaspora communities, exceeds 13 million people.24 Having a screening tool for NP with excellent discriminatory properties even for complex cases of mixed pain syndromes will affect everyday clinical practice and will influence treatment strategies. Because it is the first screening tool for NP to be validated in Greek, it will assist in research and create a better understanding of epidemiologic data of NP in this population.
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