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PAIN: NON-MALIGNANT DISEASES: Edited by Anthony H. Dickenson and Kirsty Bannister

Bedside testing for precision pain medicine

Reimer, Marena,∗; Sachau, Julianea,∗; Forstenpointner, Juliaa,b; Baron, Ralfa

Author Information
Current Opinion in Supportive and Palliative Care: June 2021 - Volume 15 - Issue 2 - p 116-124
doi: 10.1097/SPC.0000000000000556
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Abstract

INTRODUCTION

Persistent neuropathic pain is a therapeutic challenge. As variable as the clinical presentation, so is the therapeutic response of these patients. Despite encouraging results from preclinical studies in animals, recent trials with new analgesic drugs showed repeatedly negative results. Explanations may include the limited translatability between animals and humans as well as the neglect of multifaceted contributing factors in chronic pain (e.g. pathophysiology, genetic, psychosocial).

To date, no direct biomarkers of pain mechanisms are available. Hence, patterns of surrogate parameters, closely linked to pain generation, like sleep, pain characteristics or psychosocial measures can be considered [1]. Recent studies suggest that sensory phenotyping is a promising stratification tool, which might have implications for a tailored mechanism-based treatment [2]. Quantitative Sensory Testing (QST) precisely analyses the function of the somatosensory nervous system [3] and is suitable to generate a patient's sensory profile. In addition, patient-reported outcome measures (PROMs) can be used to easily cover different pain-related symptoms. 

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SENSORY PHENOTYPING WITH LABORATORY QUANTITATIVE SENSORY TESTING

A standardized laboratory QST (lab-QST) protocol was introduced by the German Research Network on Neuropathic Pain (DFNS) in 2006 [3]. Sensory stimuli are applied to the skin or deep somatic structures to elicit a painful or nonpainful sensation, that can be quantified on a rating scale. QST uses a standardized battery of mechanical and thermal stimuli (graded v. Frey hairs, pinprick stimuli, pressure algometer, thermal testing, etc.).

Retrospective studies (for review, see Baron et al.[4]) and a prospectively designed trial have already shown promising results for QST being a potential predictive biomarker for treatment response [5].

A hypothesis-free hierarchical cluster analysis revealed three subgroups of patients in a large cohort of more than 900 neuropathic pain patients [6]. Cluster 1 presented loss of small and large nerve fiber function as well as paradoxical heat sensations ('sensory loss’, 42%). Cluster 2 was characterized by thermal hyperalgesia and mild allodynia with preserved small nerve fiber function (’thermal hyperalgesia’, 33%). Cluster 3 showed a combination of loss of small fiber function and mechanical hyperalgesia (’mechanical hyperalgesia’, 24%). These clusters provide insights into possible mechanisms of pain generation and are the basis of a mechanism-based pain therapy. The European Medicine Agency (EMA) acknowledged sensory phenotyping as stratification approach in exploratory trials [7].

Despite achievements in trials, the expense for equipment and long duration of testing procedures proves as disadvantages. Thus, the development of an inexpensive easy-to-use bedside test may foster the integration of sensory phenotyping into clinical routine and clinical trials.

SENSORY BEDSIDE TOOLS

Several bedside tools have been developed in the past for the assessment of single pain modalities. Selected tools are described in the following section, others are part of recently developed bedside testing protocols (see below).

In 1976, one of the first bedside devices, a thermal roller for assessment in large skin areas, was developed by Lindblom [8].

The TipTherm is a small pocket-sized device, feasible for quick punctual thermal sensory testing. A metal area serves as cold and a plastic area as warm stimulus.

NerveCheck is a portable device (Phi Med Europe S.L.) to perform vibration and thermal testing, with good reproducibility and comparability to established QST parameters [9]. For vibration, different stimulus strengths are applied and perception or absence of the stimuli has to be indicated. The thermal testing via a thermode (5 cm × 2.5 cm) either includes a threshold-based assessment (ramp [1 °C/s)]) for heat pain or the application of predefined temperatures for cold (void, 22.4, 17.8, 9.8 °C) and for warm detection (void, 37, 39.4, 44.7 °C).

SENSORY BEDSIDE TESTING PROTOCOLS

Selected, recently published bedside-test protocols are presented in Table 1. Two approaches [10,11▪▪] were designed based on the DFNS lab-QST battery as gold standard. Some additional bedside batteries refer to other established lab-QST.

Table 1 - Bedside testing protocols
Laboratory QST The clinical sensory QSTZhu et al. [10] The Boston bedside sensory QSTKoulouris et al.[12▪▪] The Kiel bedside sensory QSTReimer et al.[11▪▪] The North American bedside sensory QSTWasan et al.[13▪▪]
CDT Metal coin, room temperature; same/decreased/increased (1) 22 °C metal, room temperature, CT 3 s; yes/no; Int 0–10(2) 08 °C metal (fridge), CT 3 s; yes/no; Int 0–10 Tuning fork at room temperature (20--22 °C), CT 3 s;more, less, different, same
WDT Metal coin, warmed up in the pocket;same/decreased/increased (1) 37 °C metal (heated with milk heater), CT 3 s;yes/no; Int 0–10(2) 45 °C metal (heated with milk heater), CT 3 s;yes/no; Int 0–10 Custom heat probe 38 °C, CT 2 s;more, less, different, same
TSL
PHS 22° and 08° metal, yes/no
CPT Ice cubes, placed in plastic bags, CT 10 s;same/decreased/increased; NRS (1) Cold allodynia: metal rod, previously immersed in ice water for 3 s; CT 10 s, Temp 18 °C; NRS(2) Cold hyperalgesia: metal rod previously submerged in ice water; CT 10 s, Temp 6°C; NRS (1) 22 °C metal, room temperature, CT 3 s; yes/no; NRS(2) 08 °C metal (fridge), CT 3 s; yes/no; NRS Tuning fork immersed in ice water for more than 5 min, CT 3 s;more, less, different, same
HPT Glass filled with hot tap water; CT 10 s, 40°C;same/decreased/increased; NRS (1) Warmth allodynia: metal rod previously dipped in a mixture of boiling and tap water; CT 10 s, Temp 35°C; NRS(2) Heat hyperalgesia: metal rod immersed in a mixture of boiling and tap water; CT 10 s, Temp 43 °C; NRS (1) 37°C metal (heated with milk heater), CT 3 s;yes/no; NRS(2) 45 °C metal (heated with milk heater), CT 3 s;yes/no; NRS Custom heat probe 47 °C, CT 1 s;more, less, different, same
MDT (1) Light stroke with cotton wool(2) Sensitivity to von Frey filament;same/decreased/increased Series of nylon von Frey filaments (2.83, 3.61, 4.31, 4.56, 5.07, 6.65 mN), CT 1.5 s;Threshold mN (1) Q-tip 5 cm stroke; Int 0–20 (10 ≙ control area)(2) 0.4 mm CMS hair; yes/no(3) 64 mN von Frey hairyes/no Light stroke with brush; applied five timesmore, less, different, same
MPS Neurotip (sharp tip), applied twice, CT 1.5 s; NRS CMS 0.7 mm hair; yes/no, NRS
MPT (1) Toothpick(2) von Frey filament 256 mN;same/decreased/increased Neurotip (sharp tip), applied twice, CT 1.5 s; NRS CMS 0.7 mm hair; yes/no, NRS Neuropen with Neurotipmore, less, different, same
WUR Toothpick, single stimulus, followed by 10 stimuli; NRS (0–100) Von Frey filament 6.65 mN, repeated tapping (2 Hz) for 60 s; NRS CMS 0.7 mm hair, single stimulus, followed by 10 stimuli; NRS (0–100)
DMA Brush; absent/present Foam brush, strokes in ‘X’ shape, repeated twice, rate 3–5 s, length 5–10 cm; NRS Brush, Q-tip, cotton wisp, applied 4× each in ‘X’ shape, length of strokes 5 cm; NRS Light stroke with brush;more, less, different, same
PPT (1) Eraser on pencil (7 mm diameter)(2) Examiner's thumb; CT 10 s, pressure had indent soft tissue and lead to skin blanching;same/decreased/increased, NRS Static mechanical allodynia:Plastic end of Von Frey Filament, CT 10 s; NRS Bedside algometer10 mg syringe sealed with a plug and felt (contact area)(1) compression up to 4 ml mark, NRS(2) slow compression until pressure pain threshold (in ml) Wagner algometer (1 cm2 rubber tip);threshold kg/cm2
VDT Tuning fork 128 Hz;same/decreased/increased Tuning fork 128 Hz; 8-point scale Tuning fork 128 Hz;same/decreased/increased
Cuff pressure algometer (CPA) Static mechanical allodynia:Plastic end of Von Frey Filament, CT 10 s; NRS
Response to noxious cold pressor task Cold hyperalgesia: metal rod previously submerged in ice water; CT 10 s, Temp 6 °C; NRS
Equipment Metal coins (50 UK pence, 50 AUS cents) at room temperature or placed in the pocket of the investigator for 30 minice cubes in a plastic bag1 glass filled with 40 °C hot tap water1 cotton wool2 von Frey filament (16 mN, 256 mN)1 tuning fork c 128 Hz/C 64 Hz, 8/8 scale1 toothpick1 eraser mounted on a pencil (7 mm diameter)1 brush (Somedic, Sweden) 6 von Frey filaments (2.83 mN, 3.61 mN, 4.31 mN, 4.56 mN, 5.07 mN, 6.65 mN)1 foam brush1 Neurotip, Hopkins Medical Products1 stainless steel rod 3/8-inch-diameter, custom size 0’61 bowl for ice water1 electric water kettle Four metal cubes 2,7 × 2,7 cm (8, 22, 37, 45 °C) (fridge for cooling, milk warmer for warming)Three von Frey hairs (0.4 mm CMS, 0.7 mm CMS, 64 mN Fruhstorfer)1 syringe (10 ml)1 soft make-up brush1 Q-Tip1 cotton swab (15 cm)1 tuning fork, c 128 Hz, 8/8 scale Soft brush (flat tip 15 mm × 5 mm (width × depth)1 pinprick 40 g1 Wagner algometer (1 cm2 rubber tip)1 128 Hz tuning fork1 Heat probe1 Bowl for ice water
In the protocols listed, two different approaches were used to generate parameters. 1) Patients were asked how they perceived the stimulus. According to the particular protocol, these parameters are marked in the table as ‘same/reduced/increased,’ ‘yes/no’ (did you perceive the stimulus?), or ‘more, less, different, same.’ 2) The intensity of the stimulus or perceived pain was assessed. These parameters are labeled as ‘Int 0-10’ (for non-painful stimuli) or ‘NRS.’CDT, cold detection threshold; CPT, cold pain threshold; CT, contact time; DMA, dynamical mechanical allodynia; HPT, heat pain threshold; MDT, mechanical detection threshold; MPS, mechanical pain sensitivity; MPT, mechanical pain threshold; PPT, pressure pain threshold; TSL, thermal sensory limen; VDT, vibration detection threshold; WDT, warm detection threshold; WUR, wind-up ratio.

The Boston battery shows valid parameters with inexpensive handheld equipment (Boston bedside sensory QST) [12▪▪]. Neuropathic pain patients (n = 51) attended two visits (2 weeks interval) and underwent both bedside QST and lab-QST in a control and test area. The following lab-QST was obtained: PPT (somedic algometer), WUR (128, 256 mN), PPT [Cuff pressure algometer (CPA)], HPT and CPT (Medoc Q-Sence), response to noxious cold pressor task (submersion of the dominant hand in a 4 °C water bath). Pain ratings (NRS, numeric rating scale) were evaluated for all bedside parameters. All parameters showed good correlations to lab-QST and revealed good variability and test--retest correlations.

The Neuropathic Pain Research Consortium was formed in North America to develop a reliable bedside test (North American bedside test) [13▪▪]. The test modalities were based on literature review and testing procedures previously reported. There was no direct comparison to a gold standard lab-QST. The test battery was performed twice (2 weeks interval) by two trained independent investigators, in 32 patients with postherpetic neuralgia in a symptom free control area and test area. The bedside protocol proved to be reliable across examiners and over time (test-retest 60–87%, inter examiner agreement 63–87%).

In a multicentre project, Zhu et al. compared 13 clinical sensory bedside tests to the DFNS QST [10]. In total, 142 patients and 31 healthy, gender-matched and age-matched volunteers as controls for the calculation of z scores, were tested. The participants indicated, whether the stimuli were perceived in- or decreased as compared with the symptom-free control area. For ‘gain of function’ parameters, the pain intensity was recorded on an NRS. Several bedside parameters were significantly correlated with the respective lab-QST parameters. Bedside parameters for CPT, HPT and PPT had good discriminative power to identify gain of function (AUC, respectively 0.87, 0.77, 0.78). This bedside test is characterized by very easy-to-use tests, like ice cubes stored in plastic, tooth prick and coins, kept at room temperature and the examiner's pocket. However, in comparison to other bedside protocols (e.g. Koulouris et al.[12▪▪] and Reimer at al. [11▪▪]), this battery is less easy to standardize.

The Kiel bedside test was evaluated in 73 patients and 20 healthy controls [11▪▪]. In total, 13 simple bedside-QST stimuli were compared with the DFNS QST. To address the impact of training, 50 patients were tested by a well trained and a nonexperienced investigator. In addition, short-term and long-term test-retest reliability was investigated. New in comparison to other bedside tests, nonpainful intensities of stimuli were rated on an 11-point NRS, for example, the intensity of the perception to 08° metal. Bedside-QST parameters with best agreement to lab-QST were pain intensity to 08° metal (CDT), Q-tip perception intensity (MDT), pressure pain threshold (syringe; PPT) and DMA by Q-Tip. Additionally, five parameters were identified, which sufficiently stratified patients according to the above-mentioned sensory clusters. The selected bedside-QST parameters (08° metal, Q-tip perception intensity, WUR, vibration threshold and pain intensity to pinprick) showed the following agreements with the lab-QST-based cluster allocation: excellent for ‘sensory loss’ (AUC = 0.91), good for ‘thermal hyperalgesia’ (AUC = 0.83) and fair for ‘mechanical hyperalgesia’. Furthermore, a test for intact fibers was defined including pinprick pain intensity (CMS 0.7 mm) and cold intensity (08° metal).

CONDITIONED PAIN MODULATION

Conditioned pain modulation (CPM) protocols dynamically assess the descending pain control system. An altered CPM effect, that is, impaired endogenous pain control, was suggested in different chronic pain entities. CPM can be used to stratify patients into ‘nonresponders’ and ‘responders’ (for review, see Smith et al. 2017 [14]). Recently, an easy-to-use bedside CPM protocol, which uses a pressure algometer as test stimulus and a clamp attached to the earlobe as conditioning stimulus was introduced [15].

SENSORY PHENOTYPING WITH PATIENT-REPORTED OUTCOMES MEASURES

An easy option to evaluate symptoms and therapeutic responses in patients is the use of validated questionnaires (PROMs) [16].

Two types of (neuropathic) pain PROMs can be distinguished: screening and assessment questionnaires [17]. Screening questionnaires are valuable in complex pain disorders with unclear neuropathic or nociceptive pain. They are used to identify neuropathic pain components via a patient's self-evaluation and the calculation of a score, indicating presence or absence of neuropathic features. This is important as therapeutic management of neuropathic pain differs from nociceptive pain treatment. Assessment questionnaires are used to measure and quantify different neuropathic symptoms to monitor treatment response.

Different screening and assessment questionnaires were validated for neuropathic pain and recommended by the EMA to assess chronic pain in trials [7] (Table 2). Data from retrospective analyses showed that screening and assessment questionnaires can stratify patients to distinct groups and thus suggest a predictive value.

Table 2 - Validated neuropathic pain screening and assessment questionnaires
Patient-reported outcome measure Author Description Cut-off/scoring
Screening questionnaires
 PainDetect Questionnaire (PD-Q) Freynhagen et al.[18] 7 descriptors (0–5 categorical scale)one item radiating pain (yes/no)two spatiotemporal items (yes/no) ≥19/38: NeP likely12–18: uncertain<12: unlikely
 Doleur Neuropathique 4 Questions (DN4)(interview, self-report) Bouhassira et al.[19,20] 7 descriptors (yes/no) ≥4/10: NeP likely
 Self-Administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) Bennett et al.[21] 7 descriptors (yes/no) ≥12/24: NeP likely
 Neuropathic Pain Questionnaire (NPQ) Krause and Backonja [22] 12 descriptors (0–100 VAS) ≥0: NeP likely
 ID Pain Portenoy [23] 6 descriptors (yes/no) ≥3/5: NeP likely0 or −1: NeP unlikely
Assessment questionnaires
 Neuropathic Pain Symptom Inventory (NPSI) Bouhassira et al.[33] 10 descriptors (0–10 NRS)2 temporal items (categorical scale) 5 dimensions: burning pain, deep pain, paroxysmal pain, evoked pain, paresthesia/dysesthesia Higher scores: more severe neuropathic symptoms
 Neuropathic Pain Scale (NPS) Galer and Jensen [25] 10 descriptors (0–10 NRS)1 temporal item (categorical scale)
 Pain Quality Assessment Scale (PQAS) Jensen et al.[26] 10 descriptors of the NPS plus 10 additional descriptors for nociceptive pain (0–10 NRS)
 painPREDICT questionnaire Tölle et al.[27] 16 descriptors2 items pain intensityone item course of painone item pain location
NRS, numeric rating scale.

PAINDETECT QUESTIONNAIRE

The PainDetect Questionnaire (PD-Q) is a validated screening questionnaire to identify neuropathic symptoms in chronic pain disorders [18]. Additionally, the PD-Q indicates feasibility as an assessment questionnaire for longitudinal neuropathic pain evaluation [28,29] (for review, see Freynhagen et al.[30]). The PD-Q consists of seven descriptors indicative for neuropathic pain, which are rated on a categorical scale (0 = never to 5 = very strongly). Additionally, patients indicate their pain course and radiation. The total PD-Q sore indicates if neuropathic pain is likely (≥19 points), uncertain (13--18 points) or unlikely (≤13 points).

A cluster analysis in 2100 patients with painful diabetic neuropathy and postherpetic neuralgia has revealed five subgroups of patients with characteristic PD-Q symptom combinations that can be tentatively assigned to different pathomechanisms [31]. Subgroup 5 is characterized by burning and prickling pain in combination with numbness, likely to indicate deafferentation, whereas subgroup 1 presents burning pain and some allodynia reflecting an irritable nociceptor subgroup with surrogates of central sensitization. Consequently, it is likely that the efficacy of a drug differs between these subgroups.

Retrospective analyses of clinical studies underpin the potential predictive value of the PD-Q. A higher PD-Q baseline score was shown to predict a better response to tapentadol regarding functionality and quality of life in patients with low back pain [24]. Given the dual mechanism of action of tapentadol (μ-opioid receptor agonism and noradrenaline reuptake inhibition), this result is plausible [32].

NEUROPATHIC PAIN SYMPTOM INVENTORY

The NPSI measures and evaluates symptoms indicative for neuropathic pain [33]. It constitutes 10 descriptors and two temporal items (duration of spontaneous pain, number of pain paroxysms). The total score includes 10 descriptors with higher scores indicating more severe neuropathic symptoms. Additionally, sub-scores for five dimensions can be calculated: burning pain, deep pain, paroxysmal pain, evoked pain, paresthesia and dysesthesia.

A secondary analysis of the multicenter COMBO-DN study [34] showed that neuropathic symptoms are affected differentially by pregabalin and duloxetine supporting the idea of a mechanism-based therapy [35].

Moreover, three subgroups were identified, indicating different pain intensity and NPSI symptoms; however, without significant differences in treatment response between groups [35]. A post hoc hierarchical cluster analysis of four randomized placebo-controlled studies with pregabalin also revealed three NPSI clusters [36].

Recently, the three NPSI clusters were confirmed in 628 neuropathic pain patients [37▪▪]: the ‘pinpointed pain’ cluster was characterized by paresthesia/dysesthesia, the ‘evoked-pain’ cluster by pain provoked by cold, pressure and electric shocks and the ‘deep-pain’ cluster by pressure and squeezing (Fig. 1). On the basis of these findings, a stratification algorithm was invented to allocate each patient to one of these clusters. In a third step, a post hoc analysis of pooled data from two placebo-controlled botulinum toxin A studies was conducted [38,39]. Interestingly, a significant treatment effect was observed for both clusters with moderate-to-high scores for evoked pain symptoms (’deep pain’ and the ‘evoked pain’ cluster). In contrast, there was no significant decrease in pain intensity for the ‘pinpointed-pain’ cluster, which was characterized by below-average evoked pain. These results (although retrospectively) suggest that stratification based on a simple questionnaire can be used to predict treatment response.

FIGURE 1
FIGURE 1:
Description of the three clusters of patients with distinct sensory profiles (i.e. combinations of symptoms assessed with the 10 neuropathic pain descriptors included in the NPSI). Reproduced with permission from Bouhassira et al. [37▪▪]. Dashed lines represent confidence intervals (95% CI). (a) Cluster 1, ‘pinpointed pain’, was characterized by above average scores for items relating to paresthesia/dysesthesia (i.e. tingling and pins and needles) and below average scores for evoked pain (brush allodynia and pressure allodynia). (b) Cluster 2, ‘evoked pain’, was characterized by above average pain provoked by brushing, provoked by cold or pressure and electric shocks and below average deep pain and paresthesia/dysesthesia. (c) Cluster 3, ‘deep pain’, was characterized by above average pressure and squeezing pain and below average paresthesia/dysesthesia. NPSI, Neuropathic Pain Symptom Inventory.

PAINPREDICT QUESTIONNAIRE

In 2019, painPREDICT questionnaire was developed with the ultimate aim to predict treatment response [27]. It constitutes 20 items including questions about the pain intensity, course and location and 16 sensory symptoms characteristic for neuropathic and nociceptive pain. A cluster analysis in 840 neuropathic pain patients revealed three subgroups: irritable nociceptor (predominant evoked pain), deafferentation pain (numbness and high levels of burning and tingling) and pain attacks with nociceptive component (pain attacks and nociceptive-like symptoms).

NONPAIN PATIENT-REPORTED OUTCOME MEASURES

The most frequently used primary outcome in neuropathic pain trials is ‘pain intensity’. However, other outcome parameters like physical and emotional functioning may be even more important depending on the patient's individual perception [40]. Thus, stratification of patients based on pain questionnaires alone is not sufficient to predict treatment response.

Post hoc prediction models of treatment efficacy were performed incorporating different outcome parameters. A retrospective analysis of a study comparing the efficacy of tapentadol versus tapentadol plus pregabalin in chronic low back pain identified predictive parameter combinations for response to median doses of tapentadol [41]: low baseline pain intensity, good sleep quality and high PD-score.

One important limitation of sensory testing and PROMs is their psychophysiological nature, that is, the testing is dependent on the patient's compliance. Although variability can be reduced by using standardized protocols and validated questionnaires, more objective testing procedures like skin biopsies, brain imaging and genetic testing should be used to cover other pathophysiological pain aspects. The relationship between these different stratification approaches should be addressed in future studies.

IMPLICATIONS FOR THE FUTURE

The description of the three lab-QST clusters [6] laid the foundation for a mechanism-based principle, which is further supported by results from questionnaire-based stratification studies.

In order to implement sensory bedside testing into clinical trials, further steps should be accomplished. First, cut-off values for interval-scaled bedside parameters (e.g. pain or intensity ratings) should be defined. This might be based on the collection of normative data, or on a comparison to an established lab-QST. In order to assign patients to specific subgroups, corresponding parameter combinations must be labelled. One approach could be to define a specific protocol, which aims to represent certain pathophysiological mechanisms, such as ‘intact small fibers’ with a combination of parameters for preserved thermal and mechanical perception. Another approach, analogous to the lab-QST study [6], is to calculate new hypothesis-free cluster algorithms. Alternatively, assignment to predefined clusters can be performed as suggested by the Kiel bedside test [11▪▪].

CONCLUSION

Both bedside sensory testing and questionnaires are simple tools for patient's stratification and can be easily applied in large clinical trials and clinical practice. PROMs and sensory testing are not interchangeable but complementary. Although sensory testing can be used to investigate sensory signs, PROMs are used to measure symptoms. An advantage of questionnaires is the recording of spontaneous pain, whereas sensory testing only assesses evoked pain. Sensory testing, in turn, provides an individual sensory profile for each patient, indicating gain and loss of nerve fiber function. In contrast, questionnaires focus mainly on gain of function whereas sensory loss is represented less sufficiently [42]. The lack of association between signs and symptoms [43] clearly underlines that sensory testing and PROMs examine different pain aspects. This may also explain the partly negative results of post hoc, purely QST-based analyses [44,45].

Acknowledgements

We would like to thank Mundipharma Research Limited for the financial support of the study ‘Sensory assessment in analgesic clinical trials: comparison between patient-reported-outcomes, bed-side testing and quantitative sensory testing’.

Financial support and sponsorship

This work ('Sensory assessment in analgesic clinical trials: comparison between patient-reported-outcomes, bed-side testing and quantitative sensory testing’) was supported by Mundipharma Research Limited.

Conflicts of interest

M.R. has received research support/grants from Mundipharma Research Limited.

J.S. has received research support/grants from Mundipharma Research Limited. J.S. reports consultant fees from Pfizer Pharma GmbH, speaker fees from Grünenthal GmbH, travel support from Alnylam Pharmaceuticals Inc. and Pfizer outside the submitted work.

J.F. has received research support/grants from Mundipharma Research Limited. J.F. reports grants from the German Research Foundation (DFG,FO 1311/1-1), personal fees and nonfinancial support from Grünenthal GmbH, Sanofi, Genzyme GmbH, personal fees from Bayer an nonfinancial support from Novartis outside the submitted work. R.B. reports grant and research support from EU Projects: Europain (115007), DOLORisk (633491), IMI Paincare (777500), German Federal Ministry of Education and Research (BMBF): Verbundprojekt: Frühdetektion von Schmerzchronifizierung (NoChro) (13GW0338C), German Research Network on Neuropathic Pain (01EM0903), Pfizer Pharma GmbH, Genzyme GmbH, Grünenthal GmbH, Mundipharma Research GmbH und Co. KG., Novartis Pharma GmbH, Alnylam Pharmaceuticals Inc., Zambon GmbH, Sanofi-Aventis Deutschland GmbH, speaker fees from Pfizer Pharma GmbH, Genzyme GmbH, Grünenthal GmbH, Mundipharma, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai Co.Ltd., Lilly GmbH, Boehringer Ingel-heim Pharma GmbH & Co. KG, Astellas Pharma GmbH, Desitin Arzneimittel GmbH, Teva GmbH, Bayer-Schering, MSD GmbH, Seqirus Australia Pty. Ltd, Novartis Pharma GmbH, TAD Pharma GmbH, Grünenthal SA Portugal, Sanofi-Aventis Deutschland GmbH, Agentur Brigitte Süss, Grünenthal Pharma AG Schweiz, Grü-nenthal B.V. Niederlande, Evapharma, Takeda Pharmaceuticals International AG Schweiz, Ology Medical Education Netherlands and consultant fees from Pfizer Pharma GmbH, Genzyme GmbH, Grünenthal GmbH, Mundipharma Research GmbH und Co. KG, Allergan, Sanofi Pasteur, Medtronic, Eisai, Lilly GmbH, Boehrin-ger Ingelheim Pharma GmbH&Co.KG, Astellas Pharma GmbH, Novartis Pharma GmbH, Bristol-Myers Squibb, Biogenidec, AstraZeneca GmbH, Merck, Abbvie, Daiichi Sankyo, Glenmark Pharmaceuticals S.A., Seqirus Australia Pty. Ltd, Teva Phar-maceuticals Europe Niederlande, Teva GmbH, Genentech, Mundipharma Internatio-nal Ltd. UK, Astellas Pharma Ltd. UK, Galapagos NV, Kyowa Kirin GmbH, Vertex Pharmaceuticals Inc., Biotest AG, Celgene GmbH, Desitin Arzneimittel GmbH, Regeneron Pharmaceuticals Inc. USA, Theranexus DSV CEA Frankreich, Abbott Pro-ducts Operations AG Schweiz, Bayer AG, Grünenthal Pharma AG Schweiz, Mundipharma Research Ltd. UK, Akcea Therapeutics Germany GmbH, Asahi Kasei Pharma Corporation, AbbVie Deutschland GmbH & Co. KG, Air Liquide Sante Inter-national Frankreich, Alnylam Germany GmbH, Lateral Pharma Pty Ltd, Hexal AG, An-gelini, Janssen, SIMR Biotech Pty Ltd Australien, Confo Therapeutics N. V. Belgium.

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                Maren Reimer and Juliane Sachau contributed equally to the writing of this article.

                Keywords:

                bedside sensory testing; patient-reported outcome measures; predictors; stratification

                Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.