Reply to Jensen, O.K. On the Use of Quantitative Sensory Testing to Estimate Central Sensitization in Humans. Comment on "Schuttert et al. The Definition, Assessment, and Prevalence of (Human Assumed) Central Sensitisation in Patients with Chronic Low Back Pain: A Systematic Review. J. Clin. Med. 2021, 10, 5931".

We thank Dr. Jensen for his interest [...].

Positive affect and distraction enhance whereas negative affect impairs pain modulation in patients with recurrent low back pain and matched controls.

ABSTRACT: Pathophysiological causes of low back pain (LBP) remain generally unclear, so focus has shifted to psychosocial features and central pain processing. Effects of attentional and affective manipulation on conditioned pain modulation and tonic pain perception were examined in 30 patients with recurrent LBP in 2 sessions, one with and one without clinical pain, and compared with healthy participants. Phasic cuff pressure on one leg, scored on a Numerical Rating Scale, was used for test stimuli, and contralateral tonic cuff pain rated on an electronic Visual Analogue Scale was the conditioning stimulus (CS). Test stimuli were assessed before and during (1) control with no manipulation or CS, (2) 3 attentional manipulations (Flanker with or without CS or CS-Only), and (3) 3 affective manipulations (positive, neutral, and negative images) with CS. Greater inhibition of test stimuli Numerical Rating Scale scores was observed in CS-only (P = 0.028), combined CS&attention (P = 0.026), and CS&Positive (P = 0.006) than control paradigms, and greater in CS&Positive (P = 0.019) than CS&Negative paradigms. Electronic Visual Analogue Scale scores of CS pain increased throughout all paradigms with CS (P < 0.05), except the CS&Positive paradigm, and greater facilitation was observed in the CS-Only paradigm than all others (P < 0.02), and lower facilitation was additionally observed in the CS&Positive paradigm compared with CS&Attention and CS&Negative paradigms (P < 0.01). Flanker effects and interruptive effects of CS pain on attention were observed consistent with prior findings, and affective manipulation produced less shift in valence among people with recurrent LBP than controls (P < 0.05). Attention and positive affect with CS pain evoked conditioned pain modulation, and all attentional or affective tasks, especially positive affect, reduced facilitation of CS pain.

The Definition, Assessment, and Prevalence of (Human Assumed) Central Sensitisation in Patients with Chronic Low Back Pain: A Systematic Review.

Central sensitisation is assumed to be one of the underlying mechanisms for chronic low back pain. Because central sensitisation is not directly assessable in humans, the term 'human assumed central sensitisation' (HACS) is suggested. The objectives were to investigate what definitions for HACS have been used, to evaluate the methods to assess HACS, to assess the validity of those methods, and to estimate the prevalence of HACS. Database search resulted in 34 included studies. Forty different definition references were used to define HACS. This review uncovered twenty quantitative methods to assess HACS, including four questionnaires and sixteen quantitative sensory testing measures. The prevalence of HACS in patients with chronic low back pain was estimated in three studies. The current systematic review highlights that multiple definitions, assessment methods, and prevalence estimates are stated in the literature regarding HACS in patients with chronic low back pain. Most of the assessment methods of HACS are not validated but have been tested for reliability and repeatability. Given the lack of a gold standard to assess HACS, an initial grading system is proposed to standardize clinical and research assessments of HACS in patients with a chronic low back.

Psychophysical predictors of experimental muscle pain intensity following fatiguing calf exercise.

Musculoskeletal pain affects approximately 20% of the population worldwide and represents one of the leading causes of global disability. As yet, precise mechanisms underlying the development of musculoskeletal pain and transition to chronicity remain unclear, though individual factors such as sleep quality, physical activity, affective state, pain catastrophizing and psychophysical pain sensitivity have all been suggested to be involved. This study aimed to investigate whether factors at baseline could predict musculoskeletal pain intensity to an experimental delayed onset of muscle soreness (DOMS) pain model. Demographics, physical activity, pain catastrophizing, affective state, sleep quality, isometric force production, temporal summation of pain, and psychophysical pain sensitivity using handheld and cuff algometry were assessed at baseline (Day-0) and two days after (Day-2) in 28 healthy participants. DOMS was induced on Day-0 by completing eccentric calf raises on the non-dominant leg to fatigue. On Day-2, participants rated pain on muscle contraction (visual analogue scale, VAS, 0-10cm) and function (Likert scale, 0-6). DOMS resulted in non-dominant calf pain at Day-2 (3.0±2.3cm), with significantly reduced isometric force production (P<0.043) and handheld pressure pain thresholds (P<0.010) at Day-2 compared to Day-0. Linear regression models using backward selection predicted from 39.3% (P<0.003) of VAS to 57.7% (P<0.001) of Likert score variation in DOMS pain intensity and consistently included cuff pressure pain tolerance threshold (P<0.01), temporal summation of pain (P<0.04), and age (P<0.02) as independent predictive factors. The findings indicate that age, psychological and central pain mechanistic factors are consistently associated with pain following acute muscle injury.

Medial Prefrontal Transcranial Direct Current Stimulation Aimed to Improve Affective and Attentional Modulation of Pain in Chronic Low Back Pain Patients.

Chronic low back pain (CLBP) is often without clear underlying pathology. Affective disturbance and dysfunctional pain mechanisms, commonly observed in populations with CLBP, have, therefore, been suggested as potential contributors to CLBP development and maintenance. However, little consensus exists on how these features interact and if they can be targeted using non-invasive brain stimulation. In this pilot trial, 12 participants completed two phases (Active or Sham) of high-definition transcranial direct current stimulation (HD-tDCS) to the medial prefrontal cortex, applied for 20 min on three consecutive days. Clinical pain ratings, questionnaires, and sensitivity to painful cuff pressure were completed at baseline, then 4 trials of conditioned pain modulation (CPM; alone, with distraction using a Flanker task, with positive affect induction, and with negative affect induction using an image slideshow) were performed prior to HD-tDCS on Day 1 and Day 4 (24 h post-HD-tDCS). At baseline, attentional and affective manipulations were effective in inducing the desired state (p < 0.001) but did not significantly change the magnitude of CPM-effect. Active HD-tDCS was unable to significantly alter the magnitude of the shift in valence and arousal due to affective manipulations, nor did it alter the magnitude of CPM under any basal, attentional, or affective manipulation trial significantly on Day 4 compared to sham. The CPM-effect was greater across all manipulations on Day 1 than Day 4 (p < 0.02) but also showed poor reliability across days. Future work is needed to expand upon these findings and better understand how and if HD-tDCS can be used to enhance attentional and affective effects on pain modulation.

Medial Prefrontal High-Definition Transcranial Direct Current Stimulation to Improve Pain Modulation in Chronic Low Back Pain: A Pilot Randomized Double-blinded Placebo-Controlled Crossover Trial.

Chronic low back pain (CLBP) is highly disabling, but often without identifiable source. Focus has been on impaired anti-nociceptive mechanisms contributing to pain maintenance, though methods of targeting this impairment remain limited. This randomised-controlled cross-over pilot trial used active versus sham medial prefrontal cortex (mPFC) high-definition transcranial direct current stimulation (HD-tDCS) for 3-consecutive days to improve descending pain inhibitory function. Twelve CLBP patients were included with an average visual analogue scale (VAS) pain intensity of 3.0 ± 1.5 and pain duration of 5.3 ± 2.6 years. Pressure pain thresholds (PPTs), conditioned pain modulation (CPM), and temporal summation of pain (TSP) assessed by cuff algometry, as well as pain symptomatology (intensity, unpleasantness, quality, disability) and related psychological features (pain catastrophizing, anxiety, affect), were assessed on Day1 before 3 consecutive days of HD-tDCS sessions (each 20 minutes), at 24-hours (Day 4) and 2-weeks (Day 21) following final HD-tDCS. Blinding was successful. No significant differences in psychophysical (PPT, CPM, TSP), symptomatology or psychological outcomes were observed between active and sham HD-tDCS on Day4 and Day21. CPM-effects at Day 1 negatively correlated with change in CPM-effect at Day4 following active HD-tDCS (P = .002). Lack of efficacy was attributed to several factors, not least that patients did not display impaired CPM at baseline. TRIAL REGISTRATION: : ClinicalTrials.gov (NCT03864822). PERSPECTIVE: Medial prefrontal HD-tDCS did not alter pain, psychological nor psychophysical outcomes, though correlational analysis suggested response may depend on baseline pain inhibitory efficacy, with best potential effects in patients with severe impairments in descending pain inhibitory mechanisms. Future work should focus on appropriate patient selection and optimising stimulation targeting.

Alterations in pronociceptive and antinociceptive mechanisms in patients with low back pain: a systematic review with meta-analysis.

Altered pronociceptive and antinociceptive mechanisms are often implicated in painful conditions and have been increasingly studied over the past decade. For some painful conditions, alterations are well-established, but in populations with low back pain (LBP), there remains considerable debate whether these mechanisms are altered. The present systematic review aimed to address this issue by identifying studies assessing conditioned pain modulation (CPM) and/or temporal summation of pain (TSP) in patients with LBP, comparing with either a healthy control group or using a method with reference data available. Qualitative synthesis and quantitative meta-analysis of group differences were performed. For CPM and TSP, 20 and 29 original articles were eligible, with data for meta-analysis obtainable from 18 (1500 patients and 505 controls) and 27 (1507 patients and 1127 controls) studies, respectively. Most studies were of poor-to-fair quality with significant heterogeneity in study size, population, assessment methodology, and outcome. Nonetheless, CPM was impaired in patients with LBP compared with controls (standardized mean difference = -0.44 [-0.64 to -0.23], P < 0.001), and the magnitude of this impairment was related to pain chronicity (acute/recurrent vs chronic, P = 0.003), duration (RS = -0.62, P = 0.006), and severity (RS = -0.54, P = 0.02). Temporal summation of pain was facilitated in patients with LBP compared with controls (standardized mean difference = 0.50 [0.29-0.72], P < 0.001), and the magnitude of this facilitation was weakly related to pain severity (RS= 0.41, P = 0.04) and appeared to be influenced by test modality (P < 0.001). Impaired CPM and facilitated TSP were present in patients with LBP compared with controls, although the magnitude of differences was small which may direct future research on the clinical utility.

Recurrent low back pain patients demonstrate facilitated pronociceptive mechanisms when in pain, and impaired antinociceptive mechanisms with and without pain.

Low back pain (LBP) has been inconsistently associated with enhanced pronociceptive and impaired antinociceptive mechanisms. It remains unknown whether alterations are causal, consequential, or coincidental to pain presence. This study investigated pronociceptive and antinociceptive mechanisms in recurrent LBP (RLBP) patients across painful and pain-free periods, compared with age/sex-matched asymptomatic controls. During a painful episode (day 0) and when pain-free (day 28), 30 RLBP patients were assessed and compared with 30 controls over the same timeframe. Pressure pain thresholds were recorded bilaterally on the arm, back, and leg. Cuff algometry was used to assess cuff pressure pain detection threshold and cuff pain tolerance threshold on the lower legs, as well as temporal summation of pain (10 repeated painful cuff test stimuli on the dominant leg scored on a visual analogue scale) and conditioned pain modulation ([CPM]: cuff pain detection/tolerance threshold on dominant leg, before vs during painful cuff conditioning on the contralateral leg). Recurrent LBP patients displayed reduced pressure pain thresholds at the arm and back on day 0 compared with day 28 (P < 0.047) and with controls on day 0 (P < 0.049). Cuff pain detection threshold was reduced, and ratings of suprathreshold test stimuli were increased in RLBP patients on day 0 compared with day 28 (P < 0.02). Temporal summation of pain magnitude (increase in visual analogue scale scores) was enhanced in RLBP participants on day 0 compared with day 28 (P = 0.027) and with controls on day 0 (P = 0.039). Conditioned pain modulation magnitude (increased threshold during conditioning) was lower overall in RLBP participants than in controls (P = 0.021). Enhanced pronociceptive mechanisms were observed in RLBP patients. When pain-free, measures returned to similar levels as controls, except for CPM, which remained impaired.

Assessment of conditioned pain modulation in healthy participants and patients with chronic pain: manifestations and implications for pain progression.

PURPOSE OF REVIEW: The purpose of this review is to summarize recent findings on conditioned pain modulation (CPM) in humans with a focus on methodology, factors modulating CPM, and the potential for CPM as a clinical marker for pain progression. RECENT FINDINGS: CPM can be evoked by combining different stimulus modalities with good reliability; sequential CPM effects are stable over time with limited carryover effects. Optimism and pain catastrophizing might influence pain inhibition. Further, studies suggest that the CPM effect can be improved by gabapentinoids, transcranial direct current stimulation to cortical structures, and exercise and that long-term opioid use might impair CPM in patients with chronic pain. Clinical evidence suggests that preoperative impaired CPM may predict more severe chronic postoperative pain. The effect of pain duration on CPM impairment has been challenged by recent studies. SUMMARY: As CPM methodology is optimized, studies are revealing factors that can modulate descending pain inhibitory pathways. Understanding underlying mechanisms of CPM will improve the utility of CPM in a clinical setting and potentially lead to personalized treatments for chronic pain patients.