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Can self-reported pain characteristics and bedside test be used for the assessment of pain mechanisms? An analysis of results of neuropathic pain questionnaires and quantitative sensory testing

Gierthmühlen, Jannea,*; Schneider, Ulrikea; Seemann, Martinaa; Freitag-Wolf, Sandrab; Maihöfner, Christianc; Enax-Krumova, Elena K.d,e; Azad, Shahnaz-C.f; Üçeyler, Nurcang; Birklein, Frankh; Maier, Christophd; Tölle, Thomasi; Treede, Rolf-Detlefj; Baron, Ralfa

doi: 10.1097/j.pain.0000000000001601
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Hyperalgesia and allodynia are frequent in neuropathic pain. Some pain questionnaires such as the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) and the Neuropathic Pain Scale (NPS) include self-assessment or bedside testing of hyperalgesia/allodynia. The aim of this study was to determine to what extent LANSS and NPS data are congruent with findings on quantitative sensory testing (QST). Self-reported presence of dynamic mechanical allodynia (DMA) and descriptors of hot, cold, or deep ongoing pain (the NPS and LANSS) as well as bedside findings of mechanical allodynia (LANSS) were compared with signs of DMA and thermal hyperalgesia on QST in 617 patients with neuropathic pain. Self-reported abnormal skin sensitivity (LANSS) showed a moderate concordance with DMA during bedside test (67.9%, κ = 0.391) or QST (52.8%, κ = 0.165). Receiver operating curve analysis for self-reported DMA yielded similar area-under-the-curve values for the LANSS (0.65, confidence interval: 0.59%-0.97%) and NPS (0.71, confidence interval: 0.66%-0.75%) with high sensitivity but low specificity. Self-reported deep pain intensity was higher in patients with blunt pressure hyperalgesia, but not in patients with DMA or thermal hyperalgesia. No correlations were observed between self-reported hot or cold pain quality and thermal hyperalgesia on QST. Self-reported abnormal skin sensitivity has a high sensitivity to identify patients with DMA, but its low specificity indicates that many patients mean something other than DMA when reporting this symptom. Self-reported deep pain is related to deep-tissue hypersensitivity, but thermal qualities of ongoing pain are not related to thermal hyperalgesia. Questionnaires mostly evaluate the ongoing pain experience, whereas QST mirrors sensory functions. Therefore, both methods are complementary for pain assessment.

Self-reported symptoms show only little or moderate association with findings on quantitative sensory testing. Both methods should be used complementary for pain assessment and optimizing treatment.

aDivision of Neurological Pain Research and Therapy, Department of Neurology, University Hospital of Schleswig-Holstein, Campus Kiel, Germany

bInstitut of Medical Informatics and Statistics, University of Kiel, University Hospital of Schleswig-Holstein, Campus Kiel, Germany

cDepartment of Neurology, General Hospital Fürth, Fürth, Germany

Departments of dPain Management and

eNeurology, BG University Hospital Bergmannsheil gGmbH, Ruhr-University Bochum, Bochum, Germany

fDepartment of Anesthesiology, University Hospital Munich, Campus Groβhadern, Munich, Germany

gDepartment of Neurology, University of Würzburg, Würzburg, Germany

hDepartment of Neurology, University Medical Centre Mainz, Mainz, Germany

iDepartment of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

jChair of Neurophysiology, Center of Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany

Corresponding author. Address: Division of Neurological Pain Research and Therapy, Department of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 3, Haus 41, 24105 Kiel, Germany. Tel.: +49 431 500 23911. E-mail address: j.gierthmuehlen@neurologie.uni-kiel.de (J. Gierthmühlen).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received December 13, 2018

Received in revised form February 22, 2019

Accepted March 06, 2019

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1. Introduction

Mechanical hyperalgesia/allodynia and thermal hyperalgesia are common sensory signs in patients with different etiologies of neuropathic pain16,21,23,24,35,56 as well as surrogate animal and human models of neuropathic pain.6,11,15,27,32,47 The German Research Network on Neuropathic Pain (DFNS) has developed a standardized quantitative sensory testing (QST) battery that investigates small and large afferent nerve fiber functions or central pathways to assess signs of sensory gain and loss.45 These so called “evoked pain” patterns reflect altered nociceptive signal processing.53 However, it is currently unclear how they relate to the “ongoing pain” that the patients report when seeking treatment.46 Some studies have recently shown that QST-based sensory profiles do not correlate with the presence or absence of ongoing pain in patients with similar neurological diseases.10,42 Nevertheless, QST has entered the clinical diagnostic routine and has relevance in neuropathic pain diagnosis,50 treatment, and research.3,12,22,35,30 Furthermore, with regard to an individualized mechanism-based treatment,9,19,54 QST can help stratification of analgesics used.13,14,36

Besides clinical examination, several pain questionnaires have been established to support the diagnosis and assess the severity of neuropathic pain such as the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS7) and the Neuropathic Pain Scale (NPS18), respectively. Compared with QST, both questionnaires are easy to apply and can be used by nonspecialists.22 Although the NPS assesses only self-reported items on the characteristics of ongoing pain,18 the LANSS also includes bedside tests for presence of mechanical hyperalgesia/allodynia (evoked pain), but neither for thermal hyperalgesia, nor for sensory loss.7 Although QST assesses sensory signs, these questionnaires assess characteristic symptoms of neuropathic pain. Results of both questionnaires have not been linked to findings on a comprehensive standardized QST in a large cohort of patients so far.

The most common phenotypes in neuropathic pain are dominated by mechanical hyperalgesia, thermal hyperalgesia, and sensory loss.52–54 Thus, the aim of this study was to investigate whether self-report of characteristics of ongoing pain or self-report and bedside assessment of skin hypersensitivity by LANSS or NPS are congruent with findings of mechanical and thermal hyperalgesia/allodynia assessed by QST, ie, can predict each other, and might thus be able to depict underlying mechanisms and substitute QST in the clinical setting.

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2. Methods

2.1. Patients

Of the 1236 patients with neuropathic pain of various etiologies in the DFNS database35 that had undergone thorough QST testing, 617 completed both the LANSS and NPS questionnaires (274 males, 343 females, 56 ± 14.4 years, range 10-84 years). The sample consisted of 204 patients with polyneuropathy (PNP), n = 40 with postherpetic neuralgia (PHN), n = 99 with peripheral nerve injury (PNI, signs and symptoms within the innervation territory of the injured nerve according to clinical examination and/or sensory neurography), n = 187 with complex regional pain syndrome (CRPS), n = 9 with trigeminal neuralgia (TGN), n = 32 with central pain, and n = 46 with other neuropathic pain syndromes including radiculopathy (n = 10), phantom limb, or stump pain (n = 7), and localized neuropathic pain after surgery or trauma (n = 23). Only patients without comorbidities that could otherwise influence QST or pain assessment through questionnaires such as any additional neurological or pain diseases, vascular diseases, skin lesions or dermatological disorders in the areas to be tested, impaired vigilance, dementia, and/or cognitive impairment or inadequate knowledge of the German language were included in the analysis. Diagnosis, inclusion into the database, and examination of the patients were made in the different centers of the DFNS exclusively by physicians specialized in diagnosis and treatment of neuropathic pain as according to the clinical criteria as described in Ref. 35. All patients provided written, informed consent in accordance with the Declaration of Helsinki, and the study was approved by all local ethics committees.

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2.2. Assessment of clinical symptoms

2.2.1. Medical history

Before QST, information about disease duration and current pain intensity (on an 11-point numerical rating scale (NRS), range 0 to 10, “0” indicating “no pain,” and “10” indicating “maximum imaginable pain”) was taken, and patients completed the questionnaires mentioned below. Except the results of the bedside test on LANSS, the investigator did not know the results of self-reported symptoms until completing the QST.

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2.2.2. Leeds Assessment of Neuropathic Symptoms and Signs

The LANSS contains questions on the presence or absence of 5 typical symptoms of neuropathic pain and 2 bedside examination items.7 It can be used as a screening tool to identify patients with pain of predominantly neuropathic origin.8,22 The LANSS has been tested and validated in several settings26,41,55 with a sensitivity of 82% to 91% and a specificity of 80% to 94%, compared to clinical diagnosis using a previous and less precise definition of neuropathic pain that is now obsolete.8 For symptom self-assessment of dynamic mechanical allodynia (DMA), the question: “Does your pain make the affected skin abnormally sensitive to touch? Getting unpleasant sensations when lightly stroking the skin, or getting pain when wearing tight clothes might describe the abnormal sensitivity” was used. Results were compared with bedside test of the LANSS for presence of mechanical allodynia (examining the response to lightly stroking cotton wool on the painful area compared with the nonpainful area) and measurements of DMA on QST. Because the LANSS bedside test for presence of an altered pinprick threshold does not differentiate between mechanical hypoalgesia or hyperalgesia, this bedside test could not be compared with findings of mechanical hypoalgesia/hyperalgesia on QST.

With regard to mechanisms of neuropathic pain, ongoing burning pain is suggested to be a consequence of spontaneous discharges of peripheral afferent nerve fibers in the context of peripheral sensitization.5 A reduction of heat pain thresholds (HPTs) is also regarded as a marker of peripheral sensitization.51 Therefore, the question “Does your pain feel as if the skin temperature in the painful area has changed abnormally? Words like hot and burning describe these sensations” was used as a marker for presence of peripheral sensitization (characterized by burning pain) for comparison with HPTs on QST.

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2.2.3. Neuropathic Pain Scale

The NPS18 includes 10 pain quality items rated on a 0 to 10 Likert scale and one temporal assessment of pain. In contrast to the LANSS, the NPS has not been developed as a screening tool, but measures presence and intensity of typical neuropathic pain symptoms; therefore, there is no validated cutoff value for this questionnaire. It contains only self-assessment items but no bedside testing.18 The NPS has been validated specifically for neuropathic pain.4,18,38,44

To investigate a possible association between the subjective sensation of certain pain characteristics on NPS and signs on QST, the following questions were chosen:

  • (1) Please use the scale below to tell us how hot your pain feels. Words used to describe very hot pain include “burning” and “on fire”—for comparison with heat paint threshold (HPT) on QST.
  • (2) Please use the scale below to tell us how cold your pain feels. Words used to describe very cold pain include “like ice” and “freezing”—for comparison with cold pain threshold (CPT) on QST.
  • (3) “How intense is your deep pain?” for comparison with pressure pain threshold (PPT) on QST (as PPT is the only QST parameter that investigates deep somatic pain).
  • (4) Please use the scale below to tell us how sensitive your skin is to light touch or clothing. Words used to describe sensitive skin include “like sunburned skin” and “raw skin”—for comparison with dynamic mechanical allodynia (DMA) on QST.
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2.3. Quantitative sensory testing

All patients were examined with the whole test battery of QST according to the protocol of the German Research Network on Neuropathic pain (DFNS) in the painful body area and the corresponding contralateral side on hands, feet, or face, respectively. Detailed instructions for the assessment of the whole QST battery of the DFNS have been described previously.45 Distribution of QST values, frequencies of pathological values, and sensory phenotypes including combinations of gain and loss of function across different etiologies of neuropathic pain compared with healthy controls have been described in detail by Maier et al.35 Thus, in this study, we only analysed parameters investigating mechanical and thermal hyperalgesia/allodynia. These included the investigation of PPT, HPT, and CPT as well as an investigation of DMA.40 Pressure pain threshold was investigated with a pressure gauge device (probe area of 1 cm2; FDN200, Wagner Instruments, Greenwich, CT) placed on the thenar, abductor hallucis muscle, or masseter muscle, respectively, and determined by 3 series of ascending stimulus intensities with a slowly increasing stimulus ramp (50 kPa/second). The final threshold was the arithmetic mean of the 3 consecutive measurements. Dynamic mechanical allodynia was assessed using 3 different stimuli: a cotton wisp, a cotton wool tip fixed to an elastic strip, and a soft brush. Each of the 3 stimuli were applied 5 times in a randomized order, and subjects were asked to rate their pain on a 0/100 NRS. Dynamic mechanical allodynia was quantified as the geometric mean of all numerical ratings across the 3 different types of light touch stimulators.

For all thermal tests, a Thermode (TSA 2001-II; Medoc Ltd, Ramat Yishai, Israel) with an area of 9.0 cm2 was used. Initial temperature was 32°C, and cutoff temperatures were 0 and 50°C. All thresholds were measured by a continuously increasing or decreasing temperature (1°C/second) until the patient pressed a stop button. Each threshold was measured 3 times, and the mean was calculated as HPT or CPT, respectively.

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2.4. Statistical analysis

Statistical comparison of individual QST measurements was made to a reference database of healthy controls.34,45 Common z-values were calculated as recently described45 and both, z-values of the 95% confidence interval (absolute abnormal value) and side-to-side differences of the 95% confidence interval of the side-to-side differences in healthy controls (abnormal side-to-side difference, in the cases of unilateral diseases, when the QST parameter values in the affected area and the corresponding unaffected control area were both within the normal range) were considered as abnormal.34 Because the patients' statements on pain questionnaires refer to the painful (= affected) area tested with QST, only QST results evaluating the affected side were analysed. Thus, contralateral QST values were only used to calculate abnormal side-to-side differences. Presence of blunt pressure, cold, and heat hyperalgesia, respectively, was defined as abnormal PPT, CPT, and HPT on QST, whereas presence of DMA was defined as presence of DMA on QST. Coefficients (Spearman correlation, eta, kappa) were calculated and tested (χ2 test) to assess the associations between QST parameters and results of questionnaires. To have dichotomized values from NPS for the calculation of sensitivity and specificity of NPS for the detection of heat/cold or pressure pain hyperalgesia on QST, all values rated ≥1 on NPS were regarded as presence of self-reported heat/cold or pressure pain hyperalgesia. Values ≥1 were chosen because NPS has no official cutoff for abnormal values.

Group differences between patients with/without hyperalgesia/allodynia were analyzed using unpaired t test. Where appropriate, sensitivity and specificity of each of the above-mentioned items of the questionnaires (symptoms) for presence of clinical signs on QST were calculated. LANSS and NPS were compared with each other using correlation coefficients as well as comparisons of the eta-coefficient and AUC values on ROC analysis. If not otherwise mentioned, values are presented as mean ± SD. P < 0.05 was considered significant.

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3. Results

3.1. Patients

Mean duration of pain was 28.1 ± 28.4 months. Current pain intensity was rated 6.1 ± 2.4.

As mentioned above, the studied patient cohort represents a subset of those that Maier et al.35 had already been described; distribution of frequencies of abnormal values among the different entities for the different mechanical and thermal pain sensitivity parameters on QST is similar as in the larger sample (Table 1).

Table 1

Table 1

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3.2. Questionnaires

Results of questionnaires are shown in Table 2. Although all the included patients were diagnosed with neuropathic pain based on clinical criteria, according to the LANSS score, only about 2/3 of the patients fulfilled the cutoff for a neuropathic pain diagnosis. According to the self-reported items, 61% of patients reported skin hypersensitivity, but bedside testing could identify DMA only in 35%. Bedside test for pinprick threshold yielded findings interpreted as abnormal in 78%, but sensory loss and gain are not differentiated on LANSS. Hot and burning pain was reported by 69% of patients; however, this item also asks for presence of “altered skin temperature.”

Table 2

Table 2

Pain intensity (6.1 ± 2.4/10 NRS) and deep pain intensity (6.1 ± 2.6/10 NRS) were rated equally high with pain intensities spanning from mild, moderate to severe pain. Skin hypersensitivity (4.4 ± 3.3/10 NRS) and burning quality (4.7 ± 3.2/10 NRS) were rated lower and freezing even lower (2.4 ± 3.1/10 NRS), but also with pain intensities spanning from mild and moderate to severe pain.

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3.3. Dynamic mechanical allodynia

Dynamic mechanical allodynia was found in 125 patients (20.3%) and those patients provided significantly higher self-reports on skin hypersensitivity on both the LANSS and NPS and also had DMA on bedside test at a higher percentage (77%) than patients without DMA in QST (17%, Table 3). One hundred two (81.6%) of the patients with DMA on QST were detected by the LANSS bedside test and of these, 94 (92.1%) reported abnormal skin sensitivity on the LANSS.

Table 3

Table 3

However, only 197/376 (52.4%) of the patients who reported abnormal skin sensitivity to touch on the LANSS showed DMA on bedside test and of these, only 94 (47.7%) had DMA measured on QST (Fig. 1).

Figure 1

Figure 1

Patients with DMA on QST rated higher values for the question on abnormal skin sensitivity on NPS compared to those without DMA on QST (Fig. 2). Due to the low frequency of DMA on QST, there was only a small correlation between ratings for DMA on QST and NPS ratings (R = 0.22, P < 0.001) with a huge range for the NPS ratings between 0 and 10 (Figs. 2A and B).

Figure 2

Figure 2

Patients who reported abnormal skin sensitivity to touch on the LANSS had higher pain ratings for skin hypersensitivity on the NPS than those without (5.8 ± 2.9 vs 2.1 ± 2.6, P < 0.0001) and the eta coefficient showed a high association (η = 0.57; Fig. 3). Further on, patients with DMA on bedside test of the LANSS had higher ratings for skin hypersensitivity on the NPS than those without (6.1 ± 2.9 vs 3.4 ± 3.2, P < 0.001), but association was only moderate (η = 0.4). 350/617 (56.7%) reported hypersensitivity of the skin on both the LANSS and NPS. Concordance rate of the 2 questionnaires regarding self-reported hypersensitivity of the skin (for dichotomized NPS) was 73.9% (κ = 0.403).

Figure 3

Figure 3

ROC analysis for self-reported hypersensitivity of the skin yielded similar AUC values for the LANSS (0.65, confidence interval [CI]: 0.59%-0.97%) and NPS (0.71, CI: 0.66%-0.75%). Although self-reported hypersensitivity of the skin in both the LANSS and NPS had a high sensitivity to identify patients with DMA (as confirmed by QST), almost half of the patients apparently indicated something different from DMA when stating that their skin was hypersensitive.

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3.4. Blunt pressure hyperalgesia

Patients with hyperalgesia to blunt pressure reported higher deep pain intensity than patients without it (P < 0.05; Table 3), whereas there was no difference in deep pain intensity between patients with or without DMA as confirmed by QST.

Both groups of patients, that is, those with and without blunt pressure hyperalgesia on QST, rated values between 0 and 10 for intensity of deep pain on the NPS, and frequencies of rated values did not differ between both groups (Fig. 4A). Although variance of rated pain values was large on both groups, patients with presence of blunt pressure hyperalgesia on QST rated significantly higher values on the NPS for intensity of deep pain compared to those without blunt pressure hyperalgesia (Fig. 4B). Correlation between pain ratings for intensity of deep pain on the NPS with PPT z-values was only marginal (R = 0.08, P < 0.05). 594/617 (96.3%) patients reported presence of deep pain; of these, 244 (39.5%) patients had blunt pressure hyperalgesia on QST (Fig. 4C).

Figure 4

Figure 4

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3.5. Cold hyperalgesia

Patients with cold hyperalgesia reported higher cold pain intensity in the NPS than patients without it (P < 0.05; Table 4), whereas there was no difference in cold pain intensity between patients with or without heat hyperalgesia. Of note, patients with cold hyperalgesia in QST also reported skin hypersensitivity in the LANSS (P < 0.01) and NPS (P < 0.05; Table 4). Possibly, the self-report of skin hypersensitivity reflected cold rather than touch in some of them.

Table 4

Table 4

In contrast to all other pain self-rated symptoms, frequencies of rated values on the NPS differed between both patients with and without cold hyperalgesia on QST, that is, most of the patients without cold hyperalgesia rated “0” for cold pain on the NPS and patients with presence of cold hyperalgesia on QST rated higher values on the NPS for intensity of cold pain compared to those without cold hyperalgesia (Fig. 5A). However, both groups of patients, that is, those with and without cold hyperalgesia on QST, rated values between 0 and 10 for intensity of cold pain on the NPS (P < 0.05, Fig. 5B). No correlation was found between the self-reported intensity of cold pain on the NRS and Z-values for CPT on QST (R = 0.05, P = 0.235). 295/585 patients (50.4%) reported presence of cold pain; of these, only 61 (20.6%) patients had cold hyperalgesia diagnosed on QST (Fig. 5C).

Figure 5

Figure 5

Although the reported abnormal skin temperature on the LANSS refers to burning pain, we also analyzed the association with presence of cold hyperalgesia on QST. Patients who reported abnormal skin temperature on the LANSS had higher pain ratings for cold pain on the NPS than those without (2.6 ± 3.2 vs 1.8 ± 2.8, P < 0.001, η = 0.093). 216/586 (36.8%) reported abnormal skin temperature (LANSS) or intensity of cold pain (NPS), and concordance rate was 54.2% (κ = 0.085).

ROC analysis for self-reported abnormal skin temperature/cold pain yielded similar AUC values for the LANSS (0.51, CI: 0.45%-0.57%) and NPS (0.56, CI: 0.5%-0.62%).

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3.6. Heat hyperalgesia

Patients with heat hyperalgesia on QST reported hot/burning sensations on the LANSS and hot or cold pain on the NPS no different than patients without it (Table 4).

Both groups of patients, ie, those with and without heat hyperalgesia on QST, rated values between 0 and 10 for intensity of heat pain on the NPS. Frequencies of rated values did not differ between both groups (Fig. 6A), and rated values on the NPS for intensity of heat pain were similar in both groups (Fig. 6B). No correlation was observed between self-reported intensity of heat pain on the NPS and Z-values for HPT on QST (R = 0.06, P = 0.15). 492/592 patients (83.1%) reported presence of hot burning pain; of these, 114/492 (23.1%) patients had heat hyperalgesia on QST (Fig. 6C).

Figure 6

Figure 6

Patients who reported abnormal skin temperature on the LANSS had higher pain ratings for hot pain on the NPS than those without (5.6 ± 2.8 vs 2.7 ± 2.8, P < 0.0001, η = 0.46). 379/587 (64.5%) reported abnormal skin temperature (LANSS) or intensity of hot pain (NPS), and concordance rate was 76.1% (κ = 0.354).

ROC analysis for self-reported abnormal skin temperature/hot pain yielded similar AUC values for the LANSS (0.54, CI: 0.49%-0.6%) and NPS (0.55, CI: 0.5%-0.61%).

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3.7. Concordance and diagnostic accuracy

Table 5 summarizes concordance rates between QST and the 2 questionnaires.

Table 5

Table 5

As to DMA, self-reports in both the LANSS (84%) and NPS (96%) had a high sensitivity to identify patients with DMA as confirmed by QST, but their specificity was low, because not even half of the patients with self-reported hypersensitivity of the skin exhibit DMA on QST (Table 5).

Similar results, but with slightly lower sensitivity and specificity rates as well as much lower concordance rates, were observed between self-reported abnormal skin temperature (LANSS) or intensity of hot pain (NPS) to heat hyperalgesia on QST (Table 5).

The questions on intensity of deep or cold pain on NPS were even less sensitive in the detection of blunt pressure resp. cold hyperalgesia on QST (Table 5).

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4. Discussion

Quantitative sensory testing is currently the gold standard for quantification of somatosensory abnormalities,3,5,12,22,30,35 which is one step in the diagnosis of neuropathic pain. However, QST is time consuming, and a special training is necessary for performance and analysis. Thus, the question to what extent questionnaires based on self-report of clinical symptoms can predict QST results is of relevance for the clinical routine and pharmacological trials, in particular in terms of a mechanism-based treatment decision.9,19 The results of this study show, however, that self-reported pain symptoms in questionnaires used either as a screening tool (as on LANSS which screens for symptoms of neuropathic pain) or for the quantification of neuropathic pain symptoms (as with NPS that quantifies symptoms of neuropathic pain) show only a small to moderate concordance with corresponding signs assessed on QST. Self-reported pain descriptions showed a moderate to high sensitivity, but low specificity for corresponding QST parameters, suggesting that they can be used as good screening tools for a subsequent assessment of certain pain descriptors, but not for the diagnosis of neuropathic pain. Although it seems partly possible to draw conclusions from QST to findings of self-reported symptoms on questionnaires, the other way round which is clinically much more relevant is not or only partly (in terms of DMA) possible. Furthermore, because patients with any kind of hyperalgesia, ie, thermal or mechanical, rated higher values for most of the items on questionnaires compared to those without, questions do not seem to specifically address one single sign or mechanism, respectively.

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4.1. Background

There is only little and partly contradictory data available evaluating the association between self-reported symptoms and clinically observed signs. Although some studies reported a good association between several self-reported symptoms on the Neuropathic Pain Symptom Inventory and QST in neuropathic pain patients1 (not DFNS protocol, but described in Attal et al.2) or between painDETECT questionnaire (PDQ) and QST in joint pain,48 others have observed only small associations or only between certain self-reported symptoms and clinical signs,20 and the observed associations additionally differed in the different studies.31,33,39,49 The discrepancy between the different studies can not only be explained by the use of various questionnaires using different descriptions for pain symptoms, but may also depend on the clinical examination used as well as the investigated diseases.49

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4.2. Ongoing vs evoked pain

Another important issue is that questionnaires assess subjective descriptors of the patients' pain, which often refer to ongoing (spontaneous) pain, whereas QST usually measures stimulus-evoked pain. This might be a limitation for the comparability of self-reported pain questionnaires and QST; however, some of the questions on the different questionnaires can also refer to evoked pain, eg, the question whether pain makes the affected skin abnormally sensitive to touch. Furthermore, it has to be kept in mind that many items of the questionnaires are pain quality descriptors such as “hot” and “burning pain,” but are not self-reports of thermal hyperalgesia. Thus, questionnaires often do not define whether they refer to ongoing or evoked pain sensations because they use open questions that can refer to both kinds of pain (“Please use the scale below to tell us how hot your pain feels. Words used to describe very hot pain include “burning” and “on fire”). In these cases, some patients might rate pain intensity referring to ongoing pain, and others might also include pain in response to temperature changes etc. referring to evoked pain. However, from a mechanism-based approach both, ongoing burning pain and reduced HPT are suggested to be a consequence of spontaneous discharges of peripheral afferent nerve fibers in the context of peripheral sensitization.5 Thus, one might argue that reduced HPT on QST could also refer to ongoing pain.

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4.3. Differences of comprehension

Differences between the comprehension of the patient and the examiner might also explain deficient association between self-reported pain symptoms and signs on QST. For example, the questions in the different questionnaires have been developed by researchers that aim to investigate presence of certain symptoms, eg, DMA, when asking for presence of skin sensitivity. However, when a patient with trigeminal neuralgia will be asked this question, he or she would surely answer yes or give high intensity rating because touching the skin of the affected trigeminal nerve is often a trigger for pain attacks. However, this is not a DMA as classically defined. During QST, according to the DFNS protocol, the patient instructions are standardized and it is clearly defined what the patient is asked for and responds to Refs. 34,45. Thus, different definitions could account especially for the observed discrepancies between the LANSS bedside examination and QST because categorization of abnormal/normal for DMA on QST and presence of an altered response to lightly stroking cotton wool on the LANSS bedside test (aiming also to detect mechanical allodynia) is defined different: Although the investigator asks patients to judge any “sharp,” “pricking,” “stinging,” or “burning” sensation during testing of DMA on QST,40 the LANSS bedside test asks for presence of “unpleasant sensations” in the painful area.7 Thus, from the perspective of a researcher, patients need exact instructions about what we want to measure to obtain reliable results of somatosensory abnormalities.

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4.4. Methodical issues

It also has to be kept in mind that QST assesses only a defined area at a certain time point–usually the area of maximum pain–whereas pain questionnaires ask for presence of certain pain characteristics without a clear definition of the body area or time frame that they are responding to. For some entities such as CRPS, signs and symptoms are dynamic19,21 and this can influence results. Another important point is that contralateral abnormalities, which have been frequently reported in unilateral pain disorders,25,28,43 need to be taken into account. Taking the contralateral side as a reference comparison, the LANSS bedside test might be less sensitive to detect sensory abnormalities because it asks for an abnormal response present in the painful area only, whereas on QST, painful area and corresponding contralateral area are analysed separately (and can thus be abnormal independent of each other). In addition, a fundamental difference between bedside test and QST is that bedside tests use human judgement for detecting abnormalities, whereas QST according to DFNS uses criteria similar to any blood test. Differences between the way the stimulus is applied, eg, on the LANSS bedside test and QST, might represent a further methodical issue. Furthermore, differences between the physical properties of the stimulus might also account for discrepancies on testing.

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4.5. Gain and loss

Although questionnaires and bedside testing aim to investigate the presence of typical subjective pain characteristics, QST aims to quantify somatosensory abnormalities in terms of gain and loss using standardized and calibrated stimuli. Questionnaires focus mainly on presence of hyperalgesia, ie, presence of sensory gain and might therefore in general be more useful in detection of a pronociceptive phenotype rather than deafferentiation. Thus, questionnaires cannot be used for diagnosing neuropathic pain, especially when taking the current definition of neuropathic pain (pain caused by lesion or disease of the somatosensory system) into account that also considers sensory loss to a greater extent than the former definitions that were more focused on sensory gain.17 The LANSS and NPS have been developed before the new definition of neuropathic pain had been established, which explains their focus on sensory gain. It is unclear whether the LANSS and NPS are also sensitive for nociplastic pain where altered nociception without evidence of disease or lesion of the somatosensory system causes pain, thus also focussing on sensory gain.29

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4.6. Bedside test vs quantitative sensory testing

The bedside test is faster, simpler, and less expensive compared with QST. In cases where a clear quantification of somatosensory abnormalities is not needed, it can be easily used and brings sufficient information. However, it has to be kept in mind that self-reported symptoms do not necessarily correlate with findings on the bedside test as demonstrated for mechanical hyperalgesia/allodynia on the LANSS in this study.

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5. Conclusion

In conclusion, results of tools for assessment of symptoms and signs of neuropathic pain (the LANSS and NPS) are not entirely congruent with findings of mechanical and thermal hyperalgesia/allodynia on QST. Questionnaires mostly evaluate the quality of ongoing clinical pain experience rather than cutaneous sensory functions that are mirrored by QST. Thus, they can neither replace QST, nor can they solely be used for diagnosis of neuropathic pain, mechanism-based treatment decisions, or prediction of treatment response. Notably, self-reported skin hypersensitivity seems to reflect both, touch and cold, but not heat hypersensitivity. Moreover, self-reported deep pain intensity and hyperalgesia to blunt pressure were also associated, although they seem to reflect different dimensions of pain experience (ongoing vs evoked).

These results are in line with recent findings and recommendations that screening tools to identify patients with possible neuropathic pain fail to identify about 10% to 20% of patients with clinically diagnosed neuropathic pain and have limited measurement properties, indicating that these questionnaires should not replace a thorough clinical assessment.22,37 Nevertheless, it might be useful to combine these examinations to get both, a self-report of pain characteristics that impair the patients' daily life by questionnaires as well as measurement by QST focusing on underlying mechanisms, thus improving pain management.

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Conflict of interest statement

The authors have no conflict of interest to declare.

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Acknowledgements

This work was supported by the Bundesministerium für Bildung und Forschung (BMBF, Grants 01EM0501-01EM0512, 01EM0901-01EM0904) for the German Research Network on Neuropathic Pain (DFNS)). None of the sponsors was involved in design and conduct of the study, in collection, management, analysis, interpretation, and preparation of the data, review, or approval of the manuscript.

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Keywords:

Neuropathic pain; Questionnaires; QST; NPS; LANSS; PRO

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