Neuropathic pain phenotyping as a predictor of treatment response in painful diabetic neuropathy: Data from the randomized,double-blind,COMBO-DN study

Sensory profiles are heterogeneous in neuropathic pain disorders, and subgroups of patients respond differently to treatment. To further explore this, patients in the COMBO-DN study were prospectively assessed by the Neuropathic Pain Symptom Inventory (NPSI) at baseline, after initial 8-week therapy with either duloxetine or pregabalin, and after subsequent 8-week combination/high-dose therapy. Exploratory post hoc cluster analyses were performed to identify and characterize potential subgroups through their scores in the NPSI items. In patients not responding to initial 60 mg/d duloxetine, adding 300 mg/d pregabalin for combination treatment was particularly effective regarding the dimensions pressing pain and evoked pain, whereas maximizing the duloxetine dose to 120 mg/d appeared more beneficial regarding paresthesia/dysesthesia. In contrast, adding 60 mg/d duloxetine to 300 mg/d pregabalin in case of nonresponse to initial pregabalin led to numerically higher decreases in all NPSI dimensions/items compared to maximizing the pregabalin dose to 600 mg/d. Cluster analysis revealed 3 patient clusters (defined by baseline scores for the 10 NPSI sensory items) with different pain profiles, not only in terms of overall pain severity, but also across NPSI items. Mean Brief Pain Inventory average pain improved in all clusters during combination/high-dose therapy. However, in patients with severe pain, the treatment effect showed a trend in favor of high-dose monotherapy, whereas combination therapy appeared to be more beneficial in patients with moderate and mild pain (not significant). These complementary exploratory analyses further endorse the idea that sensory phenotyping might lead to a more stratified treatment and potentially to personalized pain therapy.     

Symptom profiles differ in patients with neuropathic versus non-neuropathic pain.

The distinction between neuropathic and non-neuropathic pain reflects partially distinct mechanisms and patterns of treatment response. It was therefore hypothesized that patients with neuropathic and non-neuropathic pain have different profiles of symptoms and signs. To test this hypothesis, pain intensity, unpleasantness, quality, and spatial characteristics were examined in 618 patients with 1 of 3 peripheral neuropathic pain conditions (painful diabetic peripheral neuropathy, painful idiopathic sensory polyneuropathy, or postherpetic neuralgia), osteoarthritis pain, or low back pain. These assessments were conducted before treatment had begun in clinical trials of lidocaine patch 5% administered alone or with stable dosages of other analgesics. Patients with osteoarthritis pain and low back pain did not differ in their profile of pain quality and spatial characteristics and were combined to form a group of patients with non-neuropathic pain. In univariate analyses, patients with peripheral neuropathic pain reported significantly more intense hot, cold, sensitive, itchy, and surface pain and significantly less intense dull and deep pain than patients with non-neuropathic pain. In a multivariate analysis, the overall pattern of pain quality and spatial characteristics differed significantly between patients with neuropathic and non-neuropathic pain. In addition, specific pain quality and spatial characteristics improved the discrimination of patients with neuropathic and non-neuropathic pain in a logistic regression model that adjusted for demographic covariates and overall pain intensity and unpleasantness. PERSPECTIVE: The results indicate that the distinction between neuropathic and non-neuropathic pain is reflected in different profiles of pain quality and spatial characteristics and suggest that the assessment of patterns of pain symptoms might contribute to the identification of distinct pathophysiologic mechanisms and the development of mechanism-based treatment approaches.     

Neurophysiologic and quantitative sensory testing in the diagnosis of trigeminal neuropathy and neuropathic pain

This study investigated the utility of neurophysiologic examination and thermal quantitative sensory testing (QST) in the diagnosis of trigeminal neuropathy and neuropathic pain. Fifty-eight patients (14 men), 34 with sensory deficit within the inferior alveolar nerve (IAN) and 24 within the lingual nerve (LN) distribution, were included. Twenty-six patients (45%) reported neuropathic pain. Patients underwent blink reflex (BR) test and thermal QST; sensory neurography was done to the IAN patients. Results of clinical sensory testing were available from the charts of 48 patients revealing abnormal findings in 77% of the IAN and in 94% of the LN patients. The BR test was abnormal in 41%, neurography in 96%, and QST in 91% of the IAN patients. In the LN group, BR was abnormal in 33%, and QST in 100% of the patients tested. Neurophysiologic tests and QST verified the subjective sensory alteration in all but 2 IAN patients, both with old injuries, and 4 LN patients who did not undergo QST. When abnormal, thermal QST showed elevation of warm and cold detection thresholds (hypo/anesthesia), hypoalgesia was less marked, and heat allodynia was only occasionally present. Contralateral thermal hypoesthesia after unilateral injury was found in 14 patients. It was associated with the occurrence of neuropathic pain (P=0.016). Axonal Abeta afferent damage was less severe in the IAN patients with pain than in those without pain (P=0.012). Neurophysiologic tests and thermal QST provide sensitive tools for accurate diagnosis of trigeminal neuropathy and study of pathophysiological features characteristic to human neuropathic pain.     

A pain model with a neuropathic somatosensory lesion: Morton neuroma

A randomized, double-blind, three-period cross-over study was performed to characterize the sensory phenotype and pain demographics in patients with Morton neuroma (n = 27) and to explore the effects of local administration (2 mL) of placebo and lidocaine (1 and 10 mg/mL) around the neuroma. Using the pain quality assessment scale (PQAS), the highest rating was seen for unpleasant pain and intensity of deep pain and the lowest for sensitive skin. Ongoing pain was reported in 32% of patients. Patients reported mild to moderate average pain, and that pain had interfered with sleep only marginally. Quantitative sensory testing (QST) measurements in the innervation territory showed hypophenomena or hyperphenomena in all patients, indicating that all had neuropathy. There was no particular QST modality that appeared to be specifically affected. Even the high-dose lidocaine resulted in limited effects on nerve-impulse conduction as judged by the effect on QST variables. However, both doses of lidocaine significantly reduced pain after step-ups, compared to placebo, indicating that lidocaine in this setting affected predominantly impulse generation and not impulse conduction. Following placebo treatment, pain after step-ups was similar in patients with and without hyperalgesia, indicating that the presence of hyperalgesia does not affect the pain intensity evoked by step-ups or walking.     

Transcranial Direct Current Stimulation and Visual Illusion Effect According to Sensory Phenotypes in Patients With Spinal Cord Injury and Neuropathic Pain

Treatment of neuropathic pain (NP) in patients with spinal cord injury (SCI) remains a major challenge. The aim of the present study is to investigate if the effect of transcranial direct current stimulation combined with visual illusion, following a previously published protocol, has differential effects on pain-related sensory symptoms according to sensory phenotypes profiles. One hundred and thirty SCI patients with NP participated in this open-label trial. Sixty-five patients were given a daily 20-minutes combined treatment of transcranial direct current stimulation and visual illusion for 2 weeks. Sixty-five patients served as a control group. Clinical assessment was performed before and 2 weeks later, by using Neuropathic Pain Symptom Inventory (NPSI), Brief Pain Inventory, and Patient Health Questionnaire-9. There was significant improvement in the combined treatment group according to NPSI, Brief Pain Inventory, and Patient Health Questionnaire-9, but no changes in the control group. Following a cluster analysis of NPSI items at baseline assessment, 5 subgroups of patients with different pain-related characteristics were identified among the treated group, although differences between clusters were not significant. There was also improvement in mood, sleep quality, and enjoyment of life in the treated group. Despite a reduction of NP with the combined treatment, the analysis of sensory phenotype pain profiles does not provide a predictive value regarding the analgesic results of this combined neuromodulatory treatment.PerspectiveIn this article we confirm the analgesic effect of a combined neuromodulatory therapy, transcranial direct current stimulation associated with visual illusion in patients with NP after an SCI. We have identified 5 clusters of NP with distinct sensory phenotypes, but there was not any specific sensory phenotype cluster that significantly responded to the combined therapy better than the other.     

Sensory,psychological, and metabolic dysfunction in HIV-associated peripheral neuropathy: A cross-sectional deep profiling study

HIV-associated sensory neuropathy (HIV-SN) is a frequent complication of HIV infection and a major source of morbidity. A cross-sectional deep profiling study examining HIV-SN was conducted in people living with HIV in a high resource setting using a battery of measures which included the following: parameters of pain and sensory symptoms (7 day pain diary, Neuropathic Pain Symptom Inventory [NPSI] and Brief Pain Inventory [BPI]), sensory innervation (structured neurological examination, quantitative sensory testing [QST] and intraepidermal nerve fibre density [IENFD]), psychological state (Pain Anxiety Symptoms Scale-20 [PASS-20], Depression Anxiety and Positive Outlook Scale [DAPOS], and Pain Catastrophizing Scale [PCS], insomnia (Insomnia Severity Index [ISI]), and quality of life (Short Form (36) Health Survey [SF-36]). The diagnostic utility of the Brief Peripheral Neuropathy Screen (BPNS), Utah Early Neuropathy Scale (UENS), and Toronto Clinical Scoring System (TCSS) were evaluated. Thirty-six healthy volunteers and 66 HIV infected participants were recruited. A novel triumvirate case definition for HIV-SN was used that required 2 out of 3 of the following: 2 or more abnormal QST findings, reduced IENFD, and signs of a peripheral neuropathy on a structured neurological examination. Of those with HIV, 42% fulfilled the case definition for HIV-SN (n = 28), of whom 75% (n = 21) reported pain. The most frequent QST abnormalities in HIV-SN were loss of function in mechanical and vibration detection. Structured clinical examination was superior to QST or IENFD in HIV-SN diagnosis. HIV-SN participants had higher plasma triglyceride, concentrations depression, anxiety and catastrophizing scores, and prevalence of insomnia than HIV participants without HIV-SN.     

A cross-sectional cohort survey in 2100 patients with painful diabetic neuropathy and postherpetic neuralgia: Differences in demographic data and sensory symptoms

Patients with neuropathic pain syndromes are heterogeneous. They present with a variety of sensory symptoms and pain qualities. The knowledge of these data and etiology-specific differences is important to optimize clinical trial design and to develop more effective drugs. This investigation uses epidemiological and clinical data on the symptomatology of 2100 patients with painful diabetic neuropathy (DPN) and postherpetic neuralgia (PHN) from a cross-sectional survey (painDETECT) to (1) describe characteristic epidemiological differences, (2) analyse typical patterns of sensory symptoms in both cohorts and (3) determine whether questionnaires can capture these characteristics. PHN patients suffer more often from clinically relevant sensory disturbances although the average pain intensity is only marginally higher. This difference is particularly obvious with dynamic mechanical allodynia which is present in half of the PHN patients and in 18% of the DPN patients. Thermal hyperalgesia occurs twice as often in PHN. Numbness is described more often in DPN. Age has no influence on sensory symptoms in both entities. A hierarchical cluster analysis revealed five distinct subgroups of patients showing a characteristic sensory profile, a typical constellation and combination of neuropathic symptoms. All subgroups occur in relevant numbers in both entities but the frequencies differ between PHN and DPN. Since sensory symptoms likely translate into pain-generating mechanisms enrichment for potential treatment responders might be possible in clinical trials by assessing the sensory profiles. Patient-Reported Outcomes can be used to obtain a precise sensory characterization of each patient.     

A Comparison of Self-reported Pain Measures Between Sensory Phenotypes in HIV-associated Sensory Neuropathy

Painful HIV-associated neuropathy (HIV-SN) is a prevalent co-morbidity of HIV infection. Sensory phenotyping, using quantitative sensory testing (QST) could allow for improved stratification to guide personalized treatment. However, previous methods of QST interpretation have demonstrated limited association with self-reported pain measures. This study sought to identify differences in self-reported pain measures between composite QST-derived sensory phenotypes, and to examine any differences in participants reporting multi-site, multi-etiology chronic pain. In this cross-sectional observational study of participants with HIV (n = 133), individuals were allocated to neuropathy and neuropathic pain groups through clinical assessment and nerve conduction testing. They completed symptom-based questionnaires and underwent standardized QST. Participants were assigned, by pre-determined algorithm, to a QST-derived sensory phenotype. Symptoms were compared between sensory phenotypes. Symptom characteristics and Neuropathic Pain Symptom Inventory scores differed between QST-derived sensory phenotypes: ‘sensory loss’ was associated with more paroxysmal and paraesthetic symptoms compared to ‘thermal hyperalgesia’ and ‘healthy’ phenotypes (P = .023–0.001). Those with painful HIV-SN and additional chronic pain diagnoses were more frequently allocated to the ‘mechanical hyperalgesia’ phenotype compared to those with painful HIV-SN alone (P = .006). This study describes heterogeneous sensory phenotypes in people living with HIV. Differences in self-reported pain outcomes between sensory phenotypes has the potential to guide future stratified trials and eventually more targeted therapy.PerspectiveThis article presents quantitative sensory testing derived phenotypes, thought to reflect differing pathophysiological pain mechanisms and relates them to self-reported pain measures in people with HIV infection. This could help clinicians stratify patients to individualize analgesic interventions more effectively.     

Neuropathies périphériques douloureuses explorées par électrophysiologie conventionnelle et potentiels évoqués laser

Diffuse peripheral neuropathy (polyneuropathy) can be suspected in case of distal, symmetric pain affecting the lower limbs. Burning feet is usually considered a sign of small-fiber neuropathy, but this statement is probably wrong. In fact, patients with painful feet are heterogeneous, presenting both large and small fiber sensory neuropathies. Various neurophysiological methods can be applied to characterize painful neuropathies. Neurophysiological testing includes: 1) conventional electroneuromyographic assessment, comprising nerve conduction studies and needle electromyography; 2) H-reflex recording to assess proprioceptive fibers; 3) sympathetic skin reflex (SSR) recording to assess autonomic fibers; 4) quantitative sensory testing (QST) to mechanical or thermal stimuli; 5) somatosensory evoked potentials to electrical (SSEP) or laser (LEP) stimulation. An electrophysiological battery, comprising thermal QST, SSR and LEP recordings, can be used to assess small nerve fibers. An electrophysiological battery, comprising mechanical QST, H-reflex and SSEP recordings, can be used to assess large nerve fibers. The comparative analysis of results provided by these two batteries of investigation could help determine pain mechanisms involved in painful neuropathies. However, conventional electroneuromyographic assessment remains the first-line test in all cases. In the present text, the various neurophysiological methods for the evaluation of peripheral neuropathy are presented with particular emphasis on the value of LEP recordings in the diagnosis of small-fiber neuropathies.     

Quantitative assessment of neuropathic pain

Quantitative sensory testing (QST) refers to a group of protocols that allows for quantitative measures of somesthetic function. Several protocols evaluate perceptual threshold, whereas others evaluate perception of stimuli above threshold. Each protocol has its own advantages and disadvantages, but one must always weigh a trade-off between accuracy (with longer protocols) and expediency (with shorter protocols). In assessing patients with neuropathic pain, one is interested in both positive and negative sensory symptoms. QST studies, using either neuropathic pain patients or healthy volunteers who have been rendered temporarily hyperalgesic, have demonstrated that pain abnormalities can be modality specific. The fact that various pain abnormalities can exist independently of each other suggests that (at least partially) different neuropathologic processes are responsible for each one. Current research suggests that both peripheral sensitization and central sensitization play a role in these abnormal pain conditions, and identification of precise neuropathologic mechanisms is under active investigation.     

Zusammenhang von Quantitativer Sensorischer Testung und Fragebögen zu neuropathischen Schmerzen am Beispiel chronischer Ischämieschmerzen bei PAVK

Background

A neuropathic component to chronic ischemic pain in peripheral arterial disease (PAD) has recently been shown using quantitative sensory testing (QST) and pain questionnaires. The aim of this study was to examine correlations between QST and pain questionnaires in patients with chronic ischemic pain.

Methods

A total of 10 patients with severe PAD (Fontaine stages III and IV) without diabetes mellitus answered a questionnaire and were examined with QST. The questionnaire consisted of several validated instruments which were used to examine the intensity of pain, quality of pain and neuropathic pain (VAS, SF-MPQ, S-LANSS, NPSI).

Results

The results of the QST confirmed previously published data. Several terms of the SF-MPQ showed a correlation with parameters of the QST, such as Allodynia (QST) which correlated with the term tender (SF-MPQ) (Spearman’s correlation coefficient 0.911; p≤0.001) and the NPSI subscore evoked pain correlated with the QST parameter wind-up ratio (0.683; p=0.042).

Conclusion

The results suggest that there might be correlations between psychophysical tests (QST) and pain questionnaires. Subjective perceptions of pain might be represented by a certain pattern in the QST. These connections could contribute to further clarify the pathophysiologic mechanisms leading to the perception of pain.     

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes

Neuropathic pain is accompanied by both positive and negative sensory signs. To explore the spectrum of sensory abnormalities, 1236 patients with a clinical diagnosis of neuropathic pain were assessed by quantitative sensory testing (QST) following the protocol of DFNS (German Research Network on Neuropathic Pain), using both thermal and mechanical nociceptive as well as non-nociceptive stimuli.     

Brain imaging of neuropathic pain

Many studies have focused on defining the network of brain structures involved in normal physiological pain. The different dimensions of pain perception (i.e., sensory discriminative, affective/emotional, cognitive/evaluative) have been shown to depend on different areas of the brain. In contrast, much less is known about the neural basis of pathological chronic pain. In particular, it is unclear whether such pain results from changes to the physiological "pain matrix". We review here studies on changes in brain activity associated with neuropathic pain syndromes-a specific category of chronic pain associated with peripheral or central neurological lesions. Patients may report combinations of spontaneous pain and allodynia/hyperalgesia-abnormal pain evoked by stimuli that normally induce no/little sensation of pain. Modern neuroimaging methods (positron emission tomography (PET) and functional MRI (fMRI)) have been used to determine whether different neuropathic pain symptoms involve similar brain structures and whether these structures are related to the physiological "pain matrix". PET studies have suggested that spontaneous neuropathic pain is associated principally with changes in thalamic activity and the medial pain system, which is preferentially involved in the emotional dimension of pain. Both PET and fMRI have been used to investigate the basis of allodynia. The results obtained have been very variable, probably reflecting the heterogeneity of patients in terms of etiology, lesion topography, symptoms and stimulation procedures. Overall, these studies indicated that acute physiological pain and neuropathic pain have distinct although overlapping brain activation pattern, but that there is no unique "pain matrix" or "allodynia network".     

Dimensions of catastrophic thinking associated with pain experience and disability in patients with neuropathic pain conditions

The objective of the present study was to examine the relative contributions of different dimensions of catastrophic thinking (i.e. rumination, magnification, helplessness) to the pain experience and disability associated with neuropathic pain. Eighty patients with diabetic neuropathy, post-herpetic neuralgia, post-surgical or post-traumatic neuropathic pain who had volunteered for participation in a clinical trial formed the basis of the present analyses. Spontaneous pain was assessed with the sensory and affective subscales of the McGill Pain Questionnaire. Pinprick hyperalgesia and dynamic tactile allodynia were used as measures of evoked pain. Consistent with previous research, individuals who scored higher on a measure of catastrophic thinking (Pain Catastrophizing Scale; PCS) also rated their pain as more intense, and rated themselves to be more disabled due to their pain. Follow up analyses revealed that the PCS was significantly correlated with the affective subscale of the MPQ but not with the sensory subscale. The helplessness subscale of the PCS was the only dimension of catastrophizing to contribute significant unique variance to the prediction of pain. The PCS was not significantly correlated with measures of evoked pain. Catastrophizing predicted pain-related disability over and above the variance accounted for by pain severity. The findings are discussed in terms of mechanisms linking catastrophic thinking to pain experience. Treatment implications are addressed.     

Neuropathic pain: Are there distinct subtypes depending on the aetiology or anatomical lesion?

Neuropathic pain can be caused by a variety of nerve lesions and it is unsettled whether it should be categorised into distinct clinical subtypes depending on aetiology or type of nerve lesion or individualised as a specific group, based on common symptomatology across aetiologies. In this study, we used a multivariate statistical method (multiple correspondence analyses) to investigate associations between neuropathic positive symptoms (assessed with a specific questionnaire, the Neuropathic Pain Symptom Inventory [NPSI]) and aetiologies, types of nerve lesion and pain localisations. We also examined the internal structure of the NPSI and its relevance to evaluation of symptoms of evoked pains by exploring their relationships with clinician-based quantified measures of allodynia and hyperalgesia. This study included 482 consecutive patients (53% men; mean age: 58 ± 15 years) with pain associated with peripheral or central lesions. Factor analysis showed that neuropathic symptoms of the NPSI can be categorised into five dimensions. Spearman correlation coefficients indicated that self-reported pain evoked by brush, pressure and cold stimuli strongly correlated to allodynia/hyperalgesia to brush, von Frey hairs and cold stimuli (p < 0.0001, n = 90). Multiple correspondence analyses indicated few associations between symptoms (or dimensions) and aetiologies, types of lesions, or pain localisations. Exceptions included idiopathic trigeminal neuralgia and postherpetic neuralgia. We found that there are more similarities than differences in the neuropathic positive symptoms associated with a large variety of peripheral and central lesions, providing rationale for subgrouping aetiologically diverse neuropathic patients into a specific multidimensional category for therapeutic management.     

Identification of neuropathic pain in patients with neck/upper limb pain: Application of a grading system and screening tools

The Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain has proposed a grading system for the presence of neuropathic pain (NeP) using the following categories: no NeP, possible, probable, or definite NeP. To further evaluate this system, we investigated patients with neck/upper limb pain with a suspected nerve lesion, to explore: (i) the clinical application of this grading system; (ii) the suitability of 2 NeP questionnaires (Leeds Assessment of Neuropathic Symptoms and Signs pain scale [LANSS] and the painDETECT questionnaire [PD-Q]) in identifying NeP in this patient cohort; and (iii) the level of agreement in identifying NeP between the NeuPSIG classification system and 2 NeP questionnaires. Patients (n = 152; age 52 ± 12 years; 53% male) completed the PD-Q and LANSS questionnaire and underwent a comprehensive clinical examination. The NeuPSIG grading system proved feasible for application in this patient cohort, although it required considerable time and expertise. Both questionnaires failed to identify a large number of patients with clinically classified definite NeP (LANSS sensitivity 22%, specificity 88%; PD-Q sensitivity 64%, specificity 62%). These lowered sensitivity scores contrast with those from the original PD-Q and LANSS validation studies and may reflect differences in the clinical characteristics of the study populations. The diagnostic accuracy of LANSS and PD-Q for the identification of NeP in patients with neck/upper limb pain appears limited.     

Pain in chemotherapy-induced neuropathy – More than neuropathic?

Chemotherapy-induced neuropathy (CIN) is an adverse effect of chemotherapy. Pain in CIN might comprise neuropathic and nonneuropathic (ie, musculoskeletal) pain components, which might be characterized by pain patterns, electrophysiology, and somatosensory profiling. Included were 146 patients (100 female, 46 male; aged 56 ± 0.8 years) with CIN arising from different chemotherapy regimens. Patients were characterized clinically through nerve conduction studies (NCS) and quantitative sensory testing (QST). Questionnaires for pain (McGill) and anxiety/depression (Hospital Anxiety and Depression Scale) were supplied. Patients were followed-up after 17 days. Large- (61%) and mixed- (35%) fibre neuropathies were more frequent than small-fibre neuropathy (1.4%). The 5 major chemotherapeutic regimens impacted differently on large- but not on small-fibre function and did not predict painfulness. Chronic pain associated with CIN was reported in 41.7%. Painless and painful CIN did not differ in QST profiles or electrophysiological findings, but different somatosensory patterns were found in CIN subgroups (pain at rest [RestP], n = 25; movement-associated pain [MovP], n = 15; both pain characteristics [MovP+RestP], n = 21; or no pain [NonP], n = 85): small-fibre function (cold-detection threshold, CDT: z score: −1.46 ± 0.21, P < 0.01) was most impaired in RestP; mechanical hyperalgesia was exclusively found in MovP (z score: +0.81 ± 0.30, P < 0.05). “Anxiety” discriminated between painful and painless CIN; “CDT” and “anxiety” discriminated between patients with ongoing (RestP) and movement-associated pain (MovP) or pain components (MovP+RestP). The detrimental effect of chemotherapy on large fibres failed to differentiate painful from painless CIN. Patients stratified for musculoskeletal or neuropathic pain, however, differed in psychological and somatosensory parameters. This stratification might allow for the application of a more specific therapy.     

Characterization of persistent postoperative pain by quantitative sensory testing

Postoperative pain remains inadequately treated, and it has been estimated that 5–10% undergoing surgery will develop moderate to severe persistent pain leading to chronic physical disability and psychosocial distress.Quantitative sensory testing (QST) is a graded, standardized activation of the sensory system either by mechanical, thermal or electrical stimuli, with assessment of the evoked psychophysical response. QST has been used in prospective assessments of how and why some individuals develop persistent postoperative pain.This comprehensive review describes, first, QST as a predictive research tool in studies investigating the correlation between responses to preoperatively applied experimental pain stimuli and clinical postoperative pain. Second, the use of QST as a valuable prognostic, sequential assessment tool in surgical procedure specific research is presented. Third, the implications of these findings for use of QST in future research are discussed. More rational design of predictive studies in PPP, based on surgical procedure specific approaches, is needed in order to improve our understanding of prevention and management of this debilitating postsurgical condition.