The nociceptive withdrawal reflex: Normative values of thresholds and reflex receptive fields

Assessments of spinal nociceptive withdrawal reflexes can be used in human research both to evaluate the effect of analgesics and explore pain mechanisms related to sensitization. Before the reflex can be used as a clinical tool, normative values need to be determined in large scale studies. The aim of this study was to determine the reference values of spinal nociceptive reflexes and subjective pain thresholds (to single and repeated stimulation), and of the area of the reflex receptive fields (RRF) in 300 pain‐free volunteers. The influences of gender, age, height, weight, body‐mass index (BMI), body side of testing, depression, anxiety, catastrophizing and parameters of Short‐Form 36 (SF‐36) were analyzed by multiple regressions. The 95% confidence intervals were determined for all the tests as normative values. Age had a statistically and quantitatively significant impact on the subjective pain threshold to single stimuli. The reflex threshold to single stimulus was lower on the dominant compared to the non‐dominant side. Depression had a negative impact on the subjective pain threshold to single stimuli. All the other analyses either did not reveal statistical significance or displayed quantitatively insignificant correlations. In conclusion, normative values of parameters related to the spinal nociceptive reflex were determined. This allows their clinical application for assessing central hyperexcitability in individual patients. The parameters investigated explore different aspects of sensitization processes that are largely independent of demographic characteristics, cognitive and affective factors.     

Reflex receptive fields are enlarged in patients with musculoskeletal low back and neck pain

Pain hypersensitivity has been consistently detected in chronic pain conditions, but the underlying mechanisms are difficult to investigate in humans and thus poorly understood. Patients with endometriosis pain display enlarged reflex receptive fields (RRF), providing a new perspective in the identification of possible mechanisms behind hypersensitivity states in humans. The primary hypothesis of this study was that RRF are enlarged in patients with musculoskeletal pain. Secondary study end points were subjective pain thresholds and nociceptive withdrawal reflex (NWR) thresholds after single and repeated (temporal summation) electrical stimulation. Forty chronic neck pain patients, 40 chronic low back pain patients, and 24 acute low back pain patients were tested. Electrical stimuli were applied to 10 sites on the sole of the foot to quantify the RRF, defined as the area of the foot from where a reflex was evoked. For the secondary end points, electrical stimuli were applied to the cutaneous innervation area of the sural nerve. All patient groups presented enlarged RRF areas compared to pain-free volunteers (P < .001). Moreover, they also displayed lower NWR and pain thresholds to single and repeated electrical stimulation (P < .001). These results demonstrate that musculoskeletal pain conditions are characterized by enlarged RRF, lowered NWR and pain thresholds, and facilitated temporal summation, most likely caused by widespread spinal hyperexcitability. This study contributes to a better understanding of the mechanisms underlying these pain conditions, and it supports the use of the RRF and NWR as objective biomarkers for pain hypersensitivity in clinical and experimental pain research.     

Generalized deep-tissue hyperalgesia in patients with chronic low-back pain.

Some chronic painful conditions including e.g. fibromyalgia, whiplash associated disorders, endometriosis, and irritable bowel syndrome are associated with generalized musculoskeletal hyperalgesia. The aim of the present study was to determine whether generalized deep-tissue hyperalgesia could be demonstrated in a group of patients with chronic low-back pain with intervertebral disc herniation. Twelve patients with MRI confirmed lumbar intervertebral disc herniation and 12 age and sex matched controls were included. Subjects were exposed to quantitative nociceptive stimuli to the infraspinatus and anterior tibialis muscles. Mechanical pressure (thresholds and supra-threshold) and injection of hypertonic saline (pain intensity, duration, distribution) were used. Pain intensity to experimental stimuli was assessed on a visual analogue scale (VAS). Patients demonstrated significantly higher pain intensity (VAS), duration, and larger areas of pain referral following saline injection in both infraspinatus and tibialis anterior. The patients rated significantly higher pain intensity to supra-threshold mechanical pressure stimulation in both muscles. In patients, the pressure pain-threshold was lower in the anterior tibialis muscle compared to controls. In conclusion, generalized deep-tissue hyperalgesia was demonstrated in chronic low-back pain patients with radiating pain and MRI confirmed intervertebral disc herniation, suggesting that this central sensitization should also be addressed in the pain management regimes.     

Dynamic tuning of human withdrawal reflex receptive fields during cognitive attention and distraction tasks

Objectives

The aim of the present study was to investigate supraspinal modulation of human lower limb reflex receptive fields (RRFs) on the plantar side of the foot during cognitive tasks either distracting the subjects or actively directing their attention to the electrical stimuli directed to the sole of the foot.

Methods

Twelve healthy volunteers participated. Nociceptive withdrawal reflexes (NWRs) were recorded in the ankle flexor tibialis anterior. The RRF was acquired by randomized activation of ten stimulation sites on the sole of the foot. The RRF was assessed during baseline, distraction, and attention in randomized order. Distraction was induced by the Stroop test, while attention was induced by requiring the subjects to localize the site of the stimulation and thereby forcing them to focus on the sole of the foot.

Results

The area of the RRF was significantly enlarged during the distraction task compared to baseline (P < 0.05), whereas the RRF area was significantly reduced during the attention task compared to baseline (P < 0.05).

Conclusion

The size of the RRF area was modulated by the cognitive state demonstrating a link between the cognitive activity and the descending control on spinal withdrawal reflex pathways.     

Central hyperexcitability as measured with nociceptive flexor reflex threshold in chronic musculoskeletal pain: a systematic review

Chronic musculoskeletal conditions are increasingly conceived as involving altered central nervous system processing, and impaired nociceptive flexor reflex (NFR) appears to reflect altered central nervous system processing. The primary objective was to synthesize the evidence for impaired NFR in these conditions. The secondary objective was to evaluate the NFR stimuli parameters employed by reviewed studies. Electronic databases: MEDLINE, CINAHL, Embase, PEDro, Google Scholar, and Cochrane library were searched from the mid-1960s to June 2010. Experimental reports were systematically reviewed and meta-analysis (where possible) was performed. NFR thresholds and parameters of NFR stimuli were extracted. Sixteen trials were identified, 11 of which were suitable for inclusion in the meta-analysis. Compared to healthy controls, standardized mean differences in NFR threshold were significantly lower in subjects with primary headache (−0.45; 95% confidence interval [CI] −0.77 to −0.13, P = 0.005), fibromyalgia (−0.63; 95% CI −0.93 to −0.34, P < 0.0001), knee pain (−1.51; 95% CI −2.10 to −0.93, P < 0.00001) and whiplash (−0.73; 95% CI −1.11 to −0.35, P = 0.0002). Employed stimuli parameters vary between studies, with inter-pulse duration (P = 0.044) being identified by multiple regression analysis as independent predictors of the variability in NFR threshold in healthy controls. The results indicate that there is evidence of central hyperexcitability in people with chronic musculoskeletal pain. Our review also suggests that shorter inter-pulse duration tends to yield smaller variability in NFR threshold. However, further research investigating optimal stimulation parameters is still warranted.     

The effect of distraction strategies on pain perception and the nociceptive flexor reflex (RIII reflex)

Distraction from pain reduces pain perception, and imaging studies have suggested that this may at least partially be mediated by activation of descending pain inhibitory systems. Here, we used the nociceptive flexor reflex (RIII reflex) to directly quantify the effects of different distraction strategies on basal spinal nociception and its temporal summation. Twenty-seven healthy subjects participated in 3 distraction tasks (mental imagery, listening to preferred music, spatial discrimination of brush stimuli) and, in a fourth task, concentrated on the painful stimulus. Results show that all 3 distraction tasks reduced pain perception, but only the brush task also reduced the RIII reflex. The concentration-on-pain task increased both pain perception and the RIII reflex. The extent of temporal summation of pain perception and the extent of temporal summation of the RIII reflex were not affected by any of the tasks. These results suggest that some, but not all, forms of pain reduction by distraction rely on descending pain inhibition. In addition, pain reduction by distraction seems to preferentially affect mechanisms of basal nociceptive transmission, not of temporal summation.     

Stretch reflex and pressure pain thresholds in chronic tension-type headache patients and healthy controls

To compare the jaw-stretch reflex and pressure pain thresholds (PPT) in chronic tension-type headache (CTTH) patients and healthy controls, 30 patients (15 male and 15 female) and 30 age- and sex-matched healthy subjects were investigated. Stretch reflexes were recorded in the temporalis and masseter muscles and PPT was determined in the anterior temporalis, splenius capitis and masseter muscles. The results showed that the amplitude of the stretch reflex in CTTH patients was higher compared with control subjects ( P  < 0.045), and higher in women compared with men in the right and left anterior temporalis muscles ( P  < 0.009). There were no differences in the PPT value between CTTH and control subjects ( P  > 0.509), whereas women showed significantly lower PPT measurements ( P  < 0.046). The results demonstrated a facilitation of the stretch reflex pathways in CTTH patients that is unrelated to measures of pericranial sensitivity.     

Effect of intravenous tropisetron on modulation of pain and central hypersensitivity in chronic low back pain patients

The activation of 5-hydroxytryptamine-3 (5-HT-3) receptors in spinal cord can enhance intrinsic spinal mechanisms of central hypersensitivity, possibly leading to exaggerated pain responses. Clinical studies suggest that 5-HT-3 receptor antagonists may have an analgesic effect. This randomized, double-blind, placebo-controlled crossover study tested the hypothesis that the 5-HT-3 receptor antagonist tropisetron attenuates pain and central hypersensitivity in patients with chronic low back pain. Thirty patients with chronic low back pain, 15 of whom were women (aged 53 ± 14 years) and 15 men (aged 48 ± 14 years), were studied. A single intravenous injection of 0.9% saline solution, tropisetron 2 mg, and tropisetron 5 mg was administrated in 3 different sessions, in a double-blind crossover manner. The main outcome was the visual analogue scale (VAS) score of spontaneous low back pain before, and 15, 30, 60, and 90 minutes after drug administration. Secondary outcomes were nociceptive withdrawal reflexes to single and repeated electrical stimulation, area of reflex receptive fields, pressure pain detection and tolerance thresholds, conditioned pain modulation, and area of clinical pain. The data were analyzed by analysis of variance and panel multiple regressions. All 3 treatments reduced VAS scores. However, there was no statistically significant difference between tropisetron and placebo in VAS scores. Compared to placebo, tropisetron produced a statistically significant increase in pain threshold after single electrical stimulation, but no difference in all other secondary outcomes was found. A single-dose intravenous administration of tropisetron in patients with chronic low back pain had no significant specific effect on intensity of pain and most parameters of central hypersensitivity.     

Long‐term facilitation of nociceptive withdrawal reflexes following low‐frequency conditioning electrical stimulation: A new model for central sensitization in humans

Central sensitization is believed to be one of the key mechanisms behind chronic pain conditions, and several models have been developed in order to characterize this phenomenon in humans. One of these models relies on conditioning electrical stimulation to elicit long‐lasting effects on the nociceptive system. The aim of this study was to evaluate these effects using an objective electrophysiological measurement, the nociceptive withdrawal reflex (NWR). Long‐term changes in spinal nociception after high‐ and low‐frequency conditioning electrical stimulation were assessed in 13 healthy volunteers. Perceptual intensity ratings to mechanical stimuli and blood flow variations were assessed in the conditioned area (dorsum of the foot) and surroundings. To evaluate the excitability of the nociceptive system, the NWR was elicited within the same innervation area (superficial peroneal nerve) at graded stimulation intensities and recorded in the hamstrings. Following low‐frequency stimulation, an intensity‐independent long‐lasting facilitation of the NWR was observed, with a significant increase in the reflex size (average of 31 ± 4%, p < 0.001) and in the number of reflexes (average increase of 22 ± 10%, p < 0.01), accompanied by a significant increase in the blood flow (average increase of 40 ± 10%, p < 0.001). These findings suggest that activity‐dependent central sensitization can be elicited using conditioning electrical stimulation with a stimulation frequency that lies within the physiological firing range of primary afferents, and that it can be objectively assessed in humans using the NWR.     

Ranking of parameters of pain hypersensitivity according to their discriminative ability in chronic low back pain

Low back pain is associated with plasticity changes and central hypersensitivity in a subset of patients. We performed a case-control study to explore the discriminative ability of different quantitative sensory tests in distinguishing between 40 cases with chronic low back pain and 300 pain-free controls, and to rank these tests according to the extent of their association with chronic pain. Gender, age, height, weight, body mass index, and psychological measures were recorded as potential confounders. We used 26 quantitative sensory tests, including different modalities of pressure, heat, cold, and electrical stimulation. As measures of discrimination, we estimated receiver operating characteristics (ROC) and likelihood ratios. Six tests seemed useful (in order of their discriminative ability): (1) pressure pain detection threshold at the site of most severe pain (fitted area under the ROC, 0.87), (2) single electrical stimulation pain detection threshold (0.87), (3) single electrical stimulation reflex threshold (0.83), (4) pressure pain tolerance threshold at the site of most severe pain (0.81), (5) pressure pain detection threshold at suprascapular region (0.80), and (6) temporal summation pain threshold (0.80). Pressure and electrical pain modalities seemed most promising and may be used for diagnosis of pain hypersensitivity and potentially for identifying individuals at risk of developing chronic low back pain over time.     

Modulation of the human nociceptive flexion reflex by pleasant and unpleasant odors

The nociceptive withdrawal reflex (NWR), a defensive response that allows withdrawal from a noxious stimulus, is a reliable index of spinal nociception in humans. It has been shown that various kinds of stimuli (emotional, visual, auditory) can modulate the transmission and perception of pain. The aim of the present study was to evaluate, by means of the NWR, the modulatory effect on the spinal circuitry of olfactory stimuli with different emotional valence. The magnitude of the NWR elicited by electrical stimulation of the sural nerve was measured while 18 subjects (9 women, 9 men) smelled pleasant, unpleasant, or neutral odors. The NWR was conditioned by odor probe with interstimulus intervals (ISIs) of 500 ms and 1,500 ms. The magnitude of NWR was significantly greater after the unpleasant odor probe (P <.001) and reduced following the pleasant odor probe (P < .001) at both ISIs. A significant effect of olfactory stimuli on subjective pain ratings were found at both ISIs for pleasant vs unpleasant odors (P < .000), and for both pleasant and unpleasant odors vs neutral and basal conditions (P < .000). No statistical differences in subjective pain ratings at different ISIs were found. Consistent with the notion that NWR magnitude and pain perception can be modulated by stimuli with different emotional valence, these results show that olfactory stimuli, too, can modulate spinal nociception in humans.     

Effects of progressive muscle relaxation training on nociceptive flexion reflex threshold in healthy young adults: a randomized trial

Although prior studies have demonstrated effects of progressive muscle relaxation (PMR) in reducing self-reported pain, no laboratory studies have examined the effects of PMR on objective indicators of descending modulation of nociception. This randomized controlled study utilized the nociceptive flexion reflex (NFR) to evaluate nociceptive responding among 55 college-age men and women (mean age = 19.4 ± 1.2 years). Participants completed laboratory assessments of NFR threshold and questionnaires evaluating pain and stress. Participants were then randomly assigned to either a 25-min PMR condition or a no-treatment control condition. Following the brief intervention, participants completed a second NFR procedure and self-report questionnaires. Results indicated a significant time by condition interaction for NFR, with participants in the PMR condition experiencing a significant increase in NFR threshold while participants in the no-treatment condition experienced no change in NFR. Ratings of pain did not change during the study, but PMR participants reported decreased stress following the PMR intervention. This is the first study with a randomized no-treatment control group demonstrating the effect of a brief PMR protocol on descending inhibition of nociception. Results support the efficacy of PMR in reducing nociceptive response and provide further evidence of the utility of behavioral pain management strategies.     

Physiotherapy management of patients with chronic pelvic pain (CPP): A systematic review

Introduction: Chronic pelvic pain (CPP) is a common pain condition. However, treatment remains challenging. Musculoskeletal findings are frequent; therefore physiotherapy might be helpful. The purpose of this review was to evaluate the current evidence on physiotherapy in patients with CPP (PROSPERO registration number CRD42016037516). Methods: Six databases were searched and additional hand searches were performed. Two reviewers independently conducted the database search and selected studies using a two-step approach. The methodological quality was assessed applying the Critical Review Form – Quantitative Studies. Results: A total of eight studies were included. Trigger point therapy was examined in four studies; two of which were randomized controlled trials. All studies indicate a significant change in pain measurement. The other four studies evaluated the effect of biofeedback, Thiele massage, Mensendieck somatocognitive therapy and aerobic exercises, whereas the last two were tested in controlled trials. All studies showed significant improvements in pain assessment. Conclusions: The evidence currently available is sparse with methodological flaws, making it difficult to recommend a specific physiotherapy option. There is an urgent need for high-quality randomized controlled trials to identify the most effective physiotherapy management strategy for patients with CPP.     

Pathophysiology of non-specific arm pain

Abstract

Background: Non-specific arm pain (NSAP) is a vague clinical entity which may constitute up to 53% of work related upper limb disorders. The pathophysiology of NSAP is poorly understood with hypotheses ranging from disturbance of muscle function and neuropathic arm pain to central sensitization.

Objectives: The purpose of this review was to investigate the current level of evidence to support three main classifications of pain (peripheral neuropathic pain, nociceptive pain and central sensitization) in NSAP.

Major findings: There is evidence in the literature to support each of the three classifications of pain; however, this evidence is weak. No one classification of pain is better supported than another. It is also likely that overlap exists between pain classifications which present in NSAP.

Conclusion: Different pain classifications are likely to exist in NSAP and indeed may co-exist. In the absence of definitive support for one classification over another, clinicians should be encouraged to perform thorough pain assessments in individuals with NSAP in order to optimize clinical decision making.     

Increased wind-up to heat pain in women with a childhood history of functional abdominal pain

Idiopathic or functional abdominal pain (FAP) is common in school-age children and typically reflects a functional gastrointestinal disorder (FGID). FGIDs in adults have been distinguished by enhanced responses of the central nervous system to pain stimuli, known as central sensitization. This study investigated whether adolescents and young adults with a history of pediatric FAP (n = 144), compared with well control subjects (n = 78), showed enhanced central sensitization demonstrated by greater temporal summation (wind-up) to brief, repetitive heat pulses. We also assessed the role of gender and trait anxiety in wind-up to heat pain. Women with a history of FAP showed greater wind-up to heat pain than men with a history of FAP (P < .05) and well control subjects of both genders (P < .05). Results were similar for FAP participants whose abdominal pain was ongoing at follow-up and those whose pain had resolved. Although anxiety was significantly higher in the FAP group compared with control subjects (P < .01) and in women compared with men (P < .05), anxiety did not explain the increased wind-up observed in women with a childhood history of FAP. Results suggest that women with a pediatric history of FAP may have a long-term vulnerability to pain associated with enhanced central nervous system responses to pain stimuli.     

Impaired circadian rhythmicity of nociceptive reflex threshold in cluster headache

BACKGROUND: Alteration of circadian rhythmicity involving several endocrinologic and autonomic parameters has been observed in cluster headache. OBJECTIVES: To explore whether circadian failure of the pain control system may exist in cluster headache. METHODS: The nociceptive flexion reflex threshold was studied in 25 patients with episodic cluster headache (14 active, 11 in remission) and 6 patients with chronic cluster headache, along with 10 normal volunteers throughout a 24-hour period. The reflex response was evoked at the level of the biceps femoris by stimulating the sural nerve at the ankle. Single and population mean cosinor methods were used to detect the circadian rhythmicity. RESULTS: In the patients with episodic cluster headache, a significant reduction in the nociceptive flexion reflex threshold was observed in both the active subgroup and the subgroup in remission (P < .05). In these patients, persistence of a significant 24-hour rhythm during both the active period and remission was observed, but a shift of the phase was observed during clinical activity when compared with the remission period. A lack of circadian nociceptive flexion reflex threshold rhythmicity was found in the patients with chronic cluster headache. CONCLUSIONS: Our findings suggest that in cluster headache there may be impairment of the pain control system that is associated with periodic failure of the mechanisms involved in the organization of biological rhythms.     

Inhibition of the nociceptive R2 blink reflex after supraorbital or index finger stimulation is normal in migraine without aura between attacks

In order to explore possible interictal brainstem dysfunctions in migraine, we have studied the R2 component of the nociceptive specific blink reflex (nBR) after conditioning by supraorbital or index finger stimuli in 14 untreated migraine without aura patients (MO) between attacks and in 15 healthy volunteers. We determined the R2 recovery curve at increasing inter-stimulus intervals between 50 and 600 ms. The nBR was conditioned by a paired supraorbital stimulus and, in another session, by an ipsilateral electrical shock delivered to the index finger. The R2 nBR recovery curves were normal in MO patients for both the supraorbital and peripheral conditioning. These results do not favour persistent interictal sensitization in the spinal trigeminal sensory system. They also suggest that the control exerted by descending brainstem pathways on medullary R2 interneurones is normal in migraine between attacks.     

Basal inflammation and innate immune response in chronic multisite musculoskeletal pain

Dysregulation of the immune system may play a role in chronic pain, although study findings are inconsistent. This cross-sectional study examined whether basal inflammatory markers and the innate immune response are associated with the presence and severity of chronic multisite musculoskeletal pain. Data were used on 1632 subjects of the Netherlands Study of Depression and Anxiety. The Chronic Pain Grade questionnaire was used to determine the presence and severity of chronic multisite musculoskeletal pain. Subjects were categorized in a chronic multisite musculoskeletal pain group (n = 754) and a control group (n = 878). Blood levels of the basal inflammatory markers C-reactive protein, interleukin-6, and tumor necrosis factor-alpha were determined. To obtain a measure of the innate immune response, 13 inflammatory markers were assessed after lipopolysaccharide (LPS) stimulation in a subsample (n = 707). Subjects with chronic multisite musculoskeletal pain showed elevated levels of basal inflammatory markers compared with controls, but statistical significance was lost after adjustment for lifestyle and disease variables. For some LPS-stimulated inflammatory markers, we did find elevated levels in subjects with chronic multisite musculoskeletal pain both before and after adjustment for covariates. Pain severity was not associated with inflammation within chronic pain subjects. An enhanced innate immune response in chronic multisite musculoskeletal pain may be examined as a potential biomarker for the onset or perpetuation of chronic pain.     

Pelvic musculoskeletal dysfunctions in women with and without chronic pelvic pain

Aim

This study aimed to compare the prevalence of pelvic musculoskeletal dysfunctions in women with and without Chronic Pelvic Pain (CPP).