Modulation of muscle pain is not somatotopically restricted : an experimental model using concurrent hypertonic-normal saline infusions in humans

We have previously shown that during muscle pain induced by infusion of hypertonic saline (HS), concurrent application of vibration and gentle brushing to overlying and adjacent skin regions increases the overall pain. In the current study, we focused on muscle-muscle interactions and tested whether HS-induced muscle pain can be modulated by innocuous/sub-perceptual stimulation of adjacent, contralateral, and remote muscles. Psychophysical observations were made in 23 healthy participants. HS (5%) was infused into a forearm muscle (flexor carpi ulnaris) to produce a stable baseline pain. In separate experiments, in each of the three test locations (n = 10 per site)—ipsilateral hand (abductor digiti minimi), contralateral forearm (flexor carpi ulnaris), and contralateral leg (tibialis anterior)—50 μl of 0.9% normal saline (NS) was infused (in triplicate) before, during, and upon cessation of HS-induced muscle pain in the forearm. In the absence of background pain, the infusion of NS was imperceptible to all participants. In the presence of HS-induced pain in the forearm, the concurrent infusion of NS into the ipsilateral hand, contralateral forearm, and contralateral leg increased the overall pain by 16, 12, and 15%, respectively. These effects were significant, reproducible, and time-locked to NS infusions. Further, the NS-evoked increase in pain was almost always ascribed to the forearm where HS was infused with no discernible percept attributed to the sites of NS infusion. Based on these observations, we conclude that intramuscular infusion of HS results in muscle hyperalgesia to sub-perceptual stimulation of muscle afferents in a somatotopically unrestricted manner, indicating the involvement of a central (likely supra-spinal) mechanism

Psychophysical Investigations into the Role of Low-Threshold C Fibres in Non-Painful Affective Processing and Pain Modulation

We recently showed that C low-threshold mechanoreceptors (CLTMRs) contribute to touch-evoked pain (allodynia) during experimental muscle pain. Conversely, in absence of ongoing pain, the activation of CLTMRs has been shown to correlate with a diffuse sensation of pleasant touch. In this study, we evaluated (1) the primary afferent fibre types contributing to positive (pleasant) and negative (unpleasant) affective touch and (2) the effects of tactile stimuli on tonic muscle pain by varying affective attributes and frequency parameters. Psychophysical observations were made in 10 healthy participants. Two types of test stimuli were applied: stroking stimulus using velvet or sandpaper at speeds of 0.1, 1.0 and 10.0 cm/s; focal vibrotactile stimulus at low (20 Hz) or high (200 Hz) frequency. These stimuli were applied in the normal condition (i.e. no experimental pain) and following the induction of muscle pain by infusing hypertonic saline (5%) into the tibialis anterior muscle. These observations were repeated following the conduction block of myelinated fibres by compression of sciatic nerve. In absence of muscle pain, all participants reliably linked velvet-stroking to pleasantness and sandpaper-stroking to unpleasantness (no pain). Likewise, low-frequency vibration was linked to pleasantness and high-frequency vibration to unpleasantness. During muscle pain, the application of previously pleasant stimuli resulted in overall pain relief, whereas the application of previously unpleasant stimuli resulted in overall pain intensification. These effects were significant, reproducible and persisted following the blockade of myelinated fibres. Taken together, these findings suggest the role of low-threshold C fibres in affective and pain processing. Furthermore, these observations suggest that temporal coding need not be limited to discriminative aspects of tactile processing, but may contribute to affective attributes, which in turn predispose individual responses towards excitatory or inhibitory modulation of pain

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Low-threshold unmyelinated mechanoreceptors : a novel substrate of allodynia in human skin

A thesis presented to the University of Western Sydney, School of Medicine, in fulfilment of the requirements for the degree of Doctor of Philosoph

Colloid versus crystalloid soaked gelfoam with morphine for postoperative pain relief after lumbar laminectomy

Background: Epidural opiate analgesia carried by gelfoam in the epidural space is to improve the quality of perioperative pain relief. The aim of this study was to compare the analgesic efficacy of gelfoam soaked in morphine with crystalloids versus colloid versus direct application of morphine in epidural space in patients undergoing lumbar laminectomy under general anesthesia. Methods: This study was a prospective, randomized, double-blinded trial. 75 male and female patients aged from 18 to 65 years  from ASA class I or II scheduled for Lumbar laminectomy surgery were randomly divided into three equal groups: group A: (control group): 5 ml of 1 mg/ml morphine was directly instilled over intact epidural space, group B (crystalloid group): apiece of gelfoam 5 cm × 1 cm soaked in 5 mg morphine diluted with 5 ml crystalloid (0.9% sodium chloride) placed in intact epidural space; and group C (colloid group): apiece of gelfoam 5 cm × 1 cm soaked in 5 mg morphine diluted with 5 ml hydroxyethyl starch 6% (HES 6%) placed in intact epidural space by the neurosurgeon. Total analgesics, time to first analgesic request, visual analogue scale (VAS), hemodynamics, respiratory rates and adverse effects were recorded. Results: As regards Patient’s characteristics, age, gender, weight, ASA class and operative time were comparable in all studied groups, and groupsB and C showed less amount of analgesia, long time to analgesic request, and less main VAS. No statistically significant differences are in hemodynamics, and the incidences of side effects showed no statistically significant differences among the three groups of study. Conclusion: Epidural use of gelfoam soaked by morphine in HES 6% is an effective method for post operative analgesia after lumbar laminectomy

An investigation into the peripheral substrates involved in the tactile modulation of cutaneous pain with emphasis on the C-tactile fibres

We recently demonstrated the emergence of touch-evoked pain (allodynia) during innocuous tactile stimulation of the skin overlying a painful muscle. This effect appeared to depend on a class of low-threshold unmyelinated mechanoafferents, termed C-tactile fibres (CT). In this study, we investigated the peripheral neurocircuitry of allodynia when pain originates in the skin. Psychophysical observations were carried out in 28 healthy subjects. Cutaneous pain was induced by infusing hypertonic saline (HS: 5 %) into the hairy skin overlying tibialis anterior muscle. An innocuous tactile stimulus (sinusoidal vibration: 200 Hz-200 μm) was concurrently applied to the hairy skin ~90 mm distal to the HS-infusion site. The contribution of different fibre classes to allodynia was determined by employing conduction blocks of myelinated (sciatic nerve compression) and unmyelinated (intradermal anaesthesia, Xylocaine 0.25 %) fibres. In absence of background nociceptive input, vibration was reported as non-painful. During cutaneous pain, vibration evoked a significant and reproducible increase in the overall pain intensity (allodynia). The blockade of myelinated fibres abolished the vibration sense, but the vibration-evoked allodynia persisted. Conversely, the blockade of unmyelinated cutaneous fibres abolished the allodynia (while the myelinated fibres were conducting or not). On the basis of these findings, in addition to our earlier work, we conclude that the allodynic effect of CT-fibre activation is not limited to nociceptive input arising from the muscle, but can be equally realized when pain originates in the skin. These results denote a broader role of CTs in pain modulation

Why does a cooled object feel heavier? Psychophysical investigations into the Webers Phenomenon

Background: It has long been known that a concomitantly cooled stimulus is perceived as heavier than the same object at a neutral temperature-termed Webers Phenomenon (WP). In the current study, we re-examined this phenomenon using well-controlled force and temperature stimuli to explore the complex interplay between thermal and tactile systems, and the peripheral substrates contributing to these interactions. A feedback-controlled apparatus was constructed using a mechanical stimulator attached to a 5- x 5-mm thermode. Force combinations of 0.5 and 1 N (superimposed on 1-N step) were applied to the ulnar territory of dorsal hand. One of the forces had a thermal component, being cooled from 32 to 28 degrees C at a rate of 2 degrees C/s with a 3-s static phase. The other stimulus was thermally neutral (32 degrees C). Participants were asked to report whether the first or the second stimulus was perceived heavier. These observations were obtained in the all-fibre-intact condition and following the preferential block of myelinated fibres by compression of ulnar nerve. Results: In normal condition, when the same forces were applied, all subjects displayed a clear preference for the cooled tactile stimulus as being heavier than the tactile-only stimulus. The frequency of this effect was augmented by an additional similar to 17% when cooling was applied concurrently with the second stimulus. Following compression block, the mean incidence of WP was significantly reduced regardless of whether cooling was applied concurrently with the first or the second stimulus. However, while the effect was abolished in case of former (elicited in amp;lt; 50% of trials), the compression block had little effect in four out of nine participants in case of latter who reported WP in at least 80% of trials (despite abolition of vibration and cold sensations). Conclusions: WP was found to be a robust tactile-thermal interaction in the all-fibre-intact condition. The emergence of inter-individual differences during myelinated block suggests that subjects may adopt strategies, unbeknownst to them, that focus on the dominant input (myelinated fibres, hence WP abolished by block) or the sum of convergent inputs (myelinated and C fibres, hence WP preserved during block) in order to determine differences in perceived heaviness.Funding Agencies|Western Sydney University Early Career Research Grant [P00021752]; School of Medicine, Western Sydney University</p

C-tactile fibers contribute to cutaneous allodynia after eccentric exercise

We recently showed that during acute muscle pain, C-tactile (CT) fibers mediate allodynia in healthy human subjects. In this study, we pursued the following questions: Do CTs contribute to allodynia observed in delayed onset muscle soreness (DOMS)? Is CT-mediated allodynia reproducible in a clinical pain state? In 30 healthy subjects, DOMS was induced in anterior compartment muscles of the leg by repeated eccentric contractions. DOMS was confirmed by mapping the emergence of tender points (decreased pressure pain thresholds). Furthermore, we measured pressure pain thresholds in a clinical subject who presented with activity-triggered heel pain but no resting pain. Cutaneous vibration (sinusoidal; 200 Hz–200 μm)—an otherwise innocuous stimulus—was applied to anterolateral leg before exercise, during DOMS, and following recovery from DOMS. The peripheral origin of allodynia was determined by employing conduction blocks of unmyelinated (intradermal anesthesia) and myelinated (nerve compression) fibers. In DOMS state, there was no resting pain, but vibration reproducibly evoked pain (allodynia). The blockade of cutaneous C fibers abolished this effect, whereas it persisted during blockade of myelinated fibers. In the clinical subject, without exposure to eccentric exercise, vibration (and brushing) produced a cognate expression of CT-mediated allodynia. These observations attest to a broader role of CTs in pain processing

A novel class of unmyelinated (C) tactile afferents in human glabrous skin

Introduction: We recently showed that unmyelinated (C) tactile afferents in human hairy skin can contribute to the cross-over between neutral touch (vibration) and painful touch, i.e. allodynia. In the hairy skin, allodynia persisted following the blockade of myelinated afferents, whereas blockade of unmyelinated cutaneous afferents abolished allodynia. Although there is no evidence for the existence of a similar class of fibers in the glabrous skin, the ‘qualia’ of affective stimuli are comparable in hairy and glabrous skin. Methods: Detailed psychophysical observations were made in 30 healthy subjects. Sustained muscle pain was induced by infusing hypertonic saline (HS: 5%) into flexor carpi ulnaris muscle. Sinusoidal vibration (200Hz-200µm) was applied to the glabrous skin of little finger. Pain ratings were recorded using a Visual Analog Scale (VAS). Each experiment examined the impact of cutaneous vibration on muscle pain before, during and after myelinated-compression of ulnar nerve and/ or anesthesia of unmyelinated cutaneous afferents (Xylocaine 0.25%) about the vibration site. McGill pain questionnaire was used to document the quality of vibration-evoked allodynia relative to HS-pain. Results: Prior to the induction of muscle pain, all subjects reported vibration as non-painful (VAS=0). During muscle pain (VAS 4-6), vibration evoked a significant and reproducible increase in pain (allodynia) that was comparable in quality to the background HS-pain. Allodynia persisted following the blockade of myelinated afferents (compression block). In contrast, blockade of unmyelinated afferents (low-dose intradermal anesthesia) abolished allodynia. Allodynia was preserved in the adjacent non-anesthetized skin of little finger. Once the HS-induced pain disappeared, all subjects described vibration as non-painful. Conclusions: This is the first study we know that has reported a class of unmyelinated (C) tactile afferents in glabrous skin. This class of fibers may subserve an affective touch system, akin to the C-tactile fibers in hairy skin, which has immense implications for understanding sensory-perceptual abnormalities in clinical-pain states and neurological disorders

Minocycline reduces experimental muscle hyperalgesia induced by repeated nerve growth factor injections in humans: A placebo-controlled double-blind drug-crossover study

Background Hyperalgesia is a heightened pain response to a noxious stimulus and is a hallmark of many common neuropathic and chronic pain conditions. In a double-blind placebo-controlled drug-crossover trial, the effects of concomitant and delayed minocycline treatment on the initiation and resolution of muscle hyperalgesia were tested. Methods An initial cohort (n = 10) received repeated injections (5 mu g: days 0, 2 and 4) of nerve growth factor (NGF) in the flexor carpi ulnaris muscle of the forearm and pressure pain thresholds were collected at day 0 (control), day 7 (peak) and day 14 (recovery). A second cohort (n = 18) underwent an identical procedure, however, half received a placebo between days 0 and 7 before switching to minocycline from days 7 to 14 (P1/M2), while the remaining subjects received minocycline (day 0: 200mg then 100mg b.i.d. for 7 days) before switching to placebo (M1/P2). Results The initial cohort exhibited a diffuse muscular pain hypersensitivity with a decrease in pressure pain thresholds at day 7 before a partial return to normalcy at day 14. The P1/M2 treatment group exhibited an identical peak in hypersensitivity at day 7, however, after switching to minocycline in week 2 showed a significant reduction in muscle hyperalgesia compared with the initial cohort at day 14. The M1/P2 treatment group had significantly less (similar to 43%) hyperalgesia at day 7 compared with the other groups. Conclusions The study indicates that the administration of minocycline can reduce experimentally induced muscle pain regardless of the time of administration. Significance In a double-blind placebo-controlled drug-crossover study, the common antibiotic minocycline was found to reduce the muscle hyperalgesia induced by intramuscular injection of nerve growth factor. The results of the study showed that both concomitant (pre-emptive) and delayed administration of minocycline can ameliorate the onset and facilitate the resolution of experimentally induced muscle hyperalgesia.Funding Agencies|Western Sydney University School of Medicine under the Research Training Program (RTP)</p