Quantitative sensory testing – Quo Vadis?

1 Introduction

The Editorial Comment is a brief introduction to upcoming articles on quantitative sensory testing (QST) in the Scandinavian Journal of Pain. This sensory assessment method has been used comprehensively in pain research, particularly in Northern Europe, during the last four decades. A search on PubMed using the term “quantitative sensory testing” yields 4,700 results, while adding the term “pain” renders 2,800 results, highlighting the method’s strong association with pain research. Over the past 5 years, the annual number of articles featuring QST as a central research methodology has remained stable at around 320. The upcoming articles in this journal aim to provide a comprehensive, up-to-date review of the background, equipment, pitfalls, advantages, and limitations of QST, both from clinical and research perspectives, presented by specialists in anesthesiology, engineering, neurology, and pain management.

• What is QST? QST is a refined variant of the classic neurological bedside sensory examination [1]. The method is a standardized, non-invasive psychophysical testing procedure in which an individual is exposed to graded stimulation modalities (i.e., electrical, mechanical, or thermal). The magnitudes of stimulus-evoked perceptions are quantified by the test individual in accordance with specified terms of detection thresholds, pain thresholds, pain intensities, or pain tolerance [2]. Stimuli are perceived as somatosensory sensations from somatic structures (e.g., skin, fascia, muscles) or viscerosensory sensations from visceral structures (e.g., gastrointestinal tract, genitourinary system). Note that QST is not an objective electrophysiologic measurement method but a subjective (although sometimes referred to as semi-objective) psychophysical assessment method (Figure 1).

Figure 1

Diagnostic set-up in peripheral neuropathies. The left part illustrates the investigative paradigm used in peripheral neuropathic pain, from medical history and clinical examination (in red) to various objective neurophysiological tests (in blue). The right part illustrates the graded approach for diagnoses of possible (1 Ʌ 2), probable (1 Ʌ 2 Ʌ (3 V 4), and definite neuropathic pain (1 Ʌ 2 Ʌ 3 Ʌ 4) [6,7]. Please observe that the medical history and the clinical examination constitute the diagnostic base (left part). QST (in red) can be seen as an extension of the clinical examination, i.e., a psychophysical test delineating a neuroanatomically plausible pain distribution. The confirmatory tests may also include genetics, intraoperative nerve lesion identification, the R1 component in the blink reflex, or the RIII component in the NWR. MR = magnetic resonance; NP = neuropathic pain; US = ultrasound.

The ascending information from the periphery to central appraising structures is physiologically and pathophysiologically modulated at spinal and supraspinal levels [3], which may contribute to the variability of QST variables.

• Why use QST? “The key idea is that the mechanisms that drive [chronic] pain also imprint characteristic patterns in the processing of acutely evoked sensory information” [4]. Neurological minus or plus signs, indicating “loss” or “gain” of function, respectively, can be detected by stimulating preferentially small nerve fibers (Aδ, C)^[1] but, in some cases, also larger fibers (Aβ)^[2] and assessing the response. Note, neurographic studies of “small” nerve fibers are not easily performed, as such studies require forceful electric stimulation due to the high activation threshold of these fibers, usually requiring stimulus strengths of 3–4 times the ones used for sensory neurography and also being markedly painful for the tested individual [8]. In healthy individuals, thermal QST provides basic strategies for temperature sensory system evaluation [9], which can also be used for the assessment of possible pain modulation effects.

• How is QST performed? The test must conform to verified peripheral system function [3], and its strategies depend on both the sensory parameters to be evaluated and the necessary psychophysical test principles for this testing. The basic equipment consists of a computer-driven thermode, pressure algometer, brush, metal roller, and pin-prick device (polyamide filaments or metal pins). More advanced methods may include a vibrameter (Aβ fibers) or a CO₂ laser [10]. UV-B radiation or topical application of mustard oil or capsaicin may sensitize or condition the test area, increasing the sensitivity of the sensory assessments. Presently, QST is approved by the International Federation of Clinical Neurophysiology (IFCN) as one complementary method for the evaluation of small nerve fiber conditions [11].

• When should QST be used? Characteristic response patterns, called sensory phenotypes, may predict the development of chronic pain or project pharmacological outcomes [12] and are key findings in peripheral neuropathy diagnoses (e.g., small fiber neuropathies) [13,14] and in delineating treatment trajectories. In particular, the use of more dynamic QST paradigms, conditioned pain modulation (CPM), and temporal summation of pain seems to be associated with more accurate outcome predictions [12]. However, an increasing appreciation of the plurality in dermatomal sensory representation makes the selection of appropriate QST approaches more complex [15]. Patients with genetically verified and symptomatic hereditary transthyretin-amyloidosis show pathological QST findings prior to electroneurographic changes [16], and pathology is also found in patients with leprosy [17].

2 Objectives

The main objectives of QST are as follows:

• Investigating basic sensory pain mechanisms in animals and humans;

• Assessing and predicting analgesic drug efficacy;

• Assessing loss or gain of function or spatial modulation of specific somatosensory modalities in PPN* and PSP*;

• Predicting disease trajectories of PPN and PSP; and

• Assessing treatment trajectories of PPN and PSP.

* PPN = painful peripheral neuropathy; PSP = persistent postsurgical pain

3 Standardization

Automated assessment methods of touch-pressure, vibration, and thermal cutaneous sensation were described by Dyck and colleagues in 1978 [18]. A technology assessment report published in 2003 by the American Academy of Neurology [19], based on a review of 350 articles, pointed to a diversity among assessment systems used, impeding data replicability and comparisons across studies. The report revealed a lack of evidence regarding the diagnostic efficacy of QST evaluating any particular disorder.

The German Research Network on Neuropathic Pain (DFNS) has established a standardized and extensive QST protocol [20,21],^[3] including tabularized reference data [22]. The provision of such general data, however, is contradictory to the view of the IFCN, which underlines the complexity of both sensory testing and QST [11]. The IFCN strongly advocates for laboratory-specific values. Nevertheless, the DFNS guidelines have been followed during the last two decades by several research groups and have been reported to contribute significantly to the understanding of somatosensory phenotypes and the associated underlying pathophysiology in adults and children [23]. However, findings have not always been consistent. In the early studies, somatosensory phenotypes were compared across individuals with neuropathic pain and healthy volunteers [21], indicating distinct differences, while later findings indicated that differences were smaller or sometimes even absent when comparing individuals with peripheral neuropathies, with or without pain [24,25]. Interestingly, for thermal assessments, the DFNS protocol [26] does not discriminate between test values obtained with different sizes of active thermode areas, introducing systematic measurement errors of 6–28%, depending on the modality reported [27].

4 Reliability and validity

Data reliability (precision) and data validity (accuracy) are essential in research and in scientific communication. Several reliability studies have reported robust repeatability of QST data in healthy subjects [28,29] and in patients [30,31,32]. Concurrent validity has been tested by the nociceptive withdrawal reflex (NWR), where the magnitude of the RIII EMG component has been reported to correlate with pain thresholds and suprathreshold pain intensities [33]. Convergent validity has been evaluated in diabetic polyneuropathy (DPN) by examining the correlation of thermal thresholds across measurements of intra-epithelial nerve fiber densities (IENFDs) [14,24] and corneal confocal microscopy (CCM) [14]. The loss of cutaneous afferent fibers, i.e., deafferentation, seen in DPN would intuitively seem to impact sensory thresholds in an inverse relationship. A decrease in IENFD should result in an increase in sensory thresholds. A linear regression analysis of QST thresholds vs IENFD confirmed and demonstrated correlation coefficients ranging between −0.17 and −0.54, indicating that 3–29% of the variances in QST thresholds were predictable by the regression model. This means that other factors significantly contribute to the variance. Interestingly, IENFD and thermal thresholds demonstrated better sensitivity and specificity in the early diagnosis of DPN than CCM [14].

5 Pain states: neuropathic vs non-neuropathic pain

QST paradigms are centered on neuropathies, particularly peripheral neuropathies, e.g., diabetic polyneuropathy [24], traumatic nerve lesions [25], chemotherapy-induced peripheral neuropathy [13], and amyloid neuropathy [16,34]. In the latter, the thermal QST data were impaired at symptomatic debut but prior to the somatosensory or motor-neurographic deteriorations [16]. Although the etiology of pain in persistent postsurgical pain is debated (is it neuropathic or nociceptive origin?), a number of studies using QST have been published [2,12,35].

The stimulation modalities used are primarily adapted to assess the afferent function of small nerve fibers in the skin and its appendages. However, the nociceptive function of deeper structures residing in the fascia, muscle, bone, or synovia can be tested by algometry using blunt pressure, pinch, or cuff pressure [36].

6 Conditioning

The sensory functions of the testing site can temporarily be changed by the application of a conditioning stimulus acting peripherally or/and centrally. The heat injury model [37], the capsaicin model [38], or the capsaicin-heat model [39] are locally applied methods sensitizing the test area and used in basic and pharmacodynamic research. In the CPM paradigm, the endogenous pain inhibitory system is tested by activating a “counter-irritation” mechanism. The CPM involves a conditioning high-intensity pain stimulus applied to the arm/hand or leg/foot (e.g., cold water submersion, heat, ischemia) and a contralaterally applied test stimulus (e.g., pressure or heat pain) administered before and after the conditioning procedure [40]. An efficient CPM response is characterized by a reduced pain perception of the test stimulus after the conditioning stimulus and is commonly employed to evaluate pain modulation in studies of chronic pain and in basic pain research.

7 Epidemiologic aspects: experimental and observational studies

In parallel with clinical traditions, QST has been extensively used in experimental pain research, which typically (though not always) involves healthy volunteers. Applications include studies of psychophysics and pain scales, elucidation of placebo mechanisms, studies of inhibitory and facilitating pain mechanisms, and pharmaceutical trials, among others. Perhaps most significantly, QST studies have been critical for brain imaging methods, such as functional magnetic resonance imaging or event-related potentials, where stimulus onset must be tightly controlled to enable averaging multiple time-locked responses. Arguably, our current understanding of pain processing in the human brain has largely been shaped by such studies.

In more recent years, QST measures have been incorporated into large-scale population-based epidemiological studies including representative samples drawn from the general population. Examples include the Tromsø Study (Norway), the Rotterdam Study (Netherlands), and Generation XXI (Portugal). These studies have revealed that pain sensitivity varies enormously in the general population, with pain detection thresholds for some individuals exceeding pain tolerance thresholds for others (Figure 2). Such differences, at least for some stimuli, appear to be highly heritable [41]. Increased pain sensitivity (hyperalgesia) has been found to be associated with many of the same outcomes as chronic widespread pain, including cardiovascular disease and increased mortality [42]. As sample sizes increase, it is expected that epidemiological studies of QST will increasingly be leveraged for genome-wide association studies and other OMIC approaches to molecular discovery. This is of considerable importance since molecular findings in animal models have a poor track record of translation to humans [43].

Figure 2

Frequency distribution of heat pain and heat tolerance thresholds in a sample of 930 adolescents aged 15–17 years (unpublished observations from the Fit Futures study including 1,038 adolescents [CSN]).

8 Quo Vadis: new venues

The rapid advancements in biochemical and physiological understanding of membrane channels, particularly their role as therapeutic targets, have been exemplified by the work of the 2021 Nobel Prize laureates, David Julius and Ardem Patapoutian, who made groundbreaking identification of the TRP and PIEZO1/2 receptors as key mediators of temperature and mechanical sensing [44,45,46,47,48,49]. Assessing the function of temperature-sensitive receptor channels is not only essential for pain analysis and treatment but may also have broader physiological implications [47,48,50]. Moreover, rigorous evaluation of stimuli and the corresponding psychophysical sensations could serve as a valuable tool for diagnosing potential channelopathies [51].

9 Conclusion

The authors have presented QST as a reliable and validated, well-established method for examining somatosensory phenotypes in peripheral neuropathies, persistent postsurgical pain, pharmacodynamical trials, and basic pain research. The Editorial Comment is meant to be an introduction to the upcoming in-depth articles discussing the pros and cons of the many techniques available in QST.