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Evidence and gap maps (EGM) can be used to identify gaps within specific research areas and help guide future research agendas and directions. Currently, there are no EGMs within the broad domain of chronic musculoskeletal (MSK) pain in adults. The aim of this study was to create a contemporary EGM of interventions and outcomes used for research investigating chronic MSK pain. This EGM was based on systematic reviews of interventions published in scientific journals within the last 20 years. Embase, PubMed, the Cochrane Library, and PsycINFO were used to retrieve studies for inclusion. The quality of the included reviews was assessed using AMSTAR-II. Interventions were categorised as either physical, psychological, pharmacological, education/advice, interdisciplinary, or other. Outcomes were categorised using the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations. Of 4299 systematic reviews, 457 were included. Of these, 50% were rated critically low quality, 25% low quality, 10% moderate quality and 15% were rated high quality. Physical interventions (e.g., exercise therapy) and education were the most common interventions reported in 80% and 20% of the studies, respectively. Pain (97%) and physical functioning (87%) were the most reported outcomes in the systematic reviews. Few systematic reviews used interdisciplinary interventions (3%) and economic-related outcomes (2%). This contemporary EGM revealed a low proportion of high-quality evidence within chronic musculoskeletal (MSK) pain. This EGM clearly outlines the lack of high-quality research and the need for increased focus on interventions encompassing the entire biopsychosocial perspective.

This multicenter cohort study investigated the prevalence of musculoskeletal post-COVID pain during the first year after the infection with mosaic plots and an exponential bar plot model and its associated risk factors. Patients hospitalized because of COVID-19 in 5 hospitals of Madrid (Spain) were scheduled for a telephone interview at 2 follow-up periods after hospitalization for collecting data about musculoskeletal post-COVID pain. Hospitalization and clinical data were collected from hospital medical records. From 2000 patients initially recruited, 1593 (44.6% women, age: 61 +/- 15 years) were assessed at T0 (hospital admission), T1 (mean: 8.0 +/- 1.5 months after discharge), and T2 (mean: 13.2 +/- 1.5 months after discharge). The prevalence of musculoskeletal pain (myalgia) was 30.3% (n = 483) at T0, increased to 43.4% (n = 692) at T1, and decreased to 37.8% (n = 603) at T2. The trajectory curve revealed a decreasing prevalence trend of musculoskeletal post-COVID pain the following years after hospitalization. According to the presence of pre-existing pain symptoms, the prevalence of new-onset post-COVID pain was 75.9%. Female sex (odds ratio [OR] 1.593, 95% confidence interval [CI] 1.148-2.211), history of musculoskeletal pain (OR 1.591, 95% CI 1.211-2.07), the presence of myalgia (OR 1.371, 95% CI 1.032-1.821) or headache (OR 2.278, 95% CI 1.622-3.199) at hospitalization, the days of hospitalization (OR 1.013, 95% CI 1.000-1.025), and the presence of post-COVID pain at T1 (OR 11.02, 95% CI 8.493-14.305) were factors associated with musculoskeletal post-COVID pain 1 year after hospitalization. In conclusion, musculoskeletal post-COVID pain remains highly prevalent 1 year after hospitalization. Female sex, previous history of pain symptoms, pain symptoms at onset, and days at hospital were factors associated with musculoskeletal post-COVID pain 1 year after hospitalization.

The aim of this review or meta-analysis is to synthesize the prevalence of post-coronavirus disease (COVID) pain symptoms of musculoskeletal origin in hospitalized or nonhospitalized patients recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers were searched up to May 1, 2021. Studies or preprints reporting data on post-COVID pain symptoms such as myalgias, arthralgias, or chest pain after SARS-CoV-2 infection and collected by personal, telephonic, or electronical interview were included. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. Random-effects models were used for meta-analytical pooled prevalence of each post-COVID musculoskeletal pain symptom. Data synthesis was categorized at onset or hospital admission and at 30, 60, and 90, and ≥180 days after. From a total of 12,123 studies identified, 27 peer-reviewed studies and 6 preprints were included. The sample included 14,639 hospitalized and 11,070 nonhospitalized COVID-19 patients. The methodological quality of almost 70% studies was fair. The overall prevalence of post-COVID myalgia, joint pain, and chest pain ranged from 5.65% to 18.15%, 4.6% to 12.1%, and 7.8% to 23.6%, respectively, at different follow-up periods during the first year postinfection. Time trend analysis showed a decrease prevalence of musculoskeletal post-COVID pain from the symptom's onset to 30 days after, an increase 60 days after, but with a second decrease ≥180 days after. This meta-analysis has shown that almost 10% of individuals infected by SARS-CoV-2 will suffer from musculoskeletal post-COVID pain symptomatology at some time during the first year after the infection.

This study investigated the association between COVID-related myalgia experienced by patients at hospital admission and the presence of post-COVID symptoms. A case-control study including patients hospitalised due to COVID-19 between February 20 and May 31, 2020, was conducted. Patients reporting myalgia and patients without myalgia at hospital admission were scheduled for a telephone interview 7 months after hospital discharge. Hospitalisation and clinical data were collected from medical records. A list of post-COVID symptoms with attention to musculoskeletal pain was evaluated. Anxiety and depressive symptoms, and sleep quality were likewise assessed. From a total of 1200 hospitalised patients with COVID-19, 369 with and 369 without myalgia at hospital admission were assessed 7.2 months (SD 0.6) after hospital discharge. A greater proportion (P = 0.03) of patients with myalgia at hospital admission (20%) showed ≥3 post-COVID symptoms when compared with individuals without myalgia (13%). A higher proportion of patients presenting myalgia (odds Rratio 1.41, 95% confidence interval 1.04-1.90) exhibited musculoskeletal post-COVID pain when compared to those without myalgia. The prevalence of musculoskeletal post-COVID pain in the total sample was 38%. Fifty percent of individuals with preexisting musculoskeletal pain experienced a worsening of their symptoms after COVID-19. No differences in fatigue, dyspnoea, anxiety/depressive levels, or sleep quality were observed between myalgia and nonmyalgia groups. The presence of myalgia at hospital admission was associated with preexisting history of musculoskeletal pain (OR 1.62, 95% confidence interval 1.10-2.40). In conclusion, myalgia at the acute phase was associated with musculoskeletal pain as long-term post-COVID sequelae. In addition, half of the patients with preexisting pain conditions experienced a persistent exacerbation of their previous syndromes.

Itch and pain share numerous mechanistic similarities. Patients with chronic itch conditions (for instance atopic dermatitis or neuropathic itch) often experience symptoms such as mechanical alloknesis and hyperknesis. These dysesthesias are analogous to the pain-associated phenomena allodynia and hyperalgesia, which are often observed, for example, in neuropathic pain conditions. Mechanical itch dysesthesias represent abnormal sensory states (caused by neuroplastic changes), wherein considerable itch is evoked, for instance by light cutaneous stimuli such as from clothing (alloknesis), or where increased itch is perceived in response to normally itch-evoking stimuli (hyperknesis). These itch sensitization phenomena have been explored in experimental human studies, observed in chronic itch patients, and in animal models of itch. Limited attention has been paid to these sensory phenomena in clinical studies, and it is unknown how they respond to antipruritics. Psychophysical quantitative sensory testing can quantify the presence, severity, and spatial extent of itch dysesthesias in chronic itch patients, providing a proxy measurement of itch sensitization. This review outlines current assessment techniques, knowledge on the mechanisms of mechanical alloknesis and hyperknesis, and presents the diverse results derived from clinical studies exploring the presence of itch dysesthesias in chronic itch patients. A key role of quantitative sensory testing and neuronal sensitization in patients with chronic pain is accepted and used in clinical assessments. However, the precise mechanisms and potential clinical implications of itch sensitization in chronic itch patients remain to be evaluated.

Topical high-concentration L-menthol is the only established human experimental pain model to study mechanisms underlying cold hyperalgesia. We aimed at investigating the combinatorial effect of cold stimuli and topical L-menthol on cold pain and secondary mechanical hyperalgesia. Analogue to the heat-capsaicin model on skin sensitization, we proposed that cold/menthol enhances or prolong L-menthol-evoked sensitization. Topical 40% L-menthol or vehicle was applied (20 minutes) on the volar forearms of 20 healthy females and males (age, 28.7 ± 0.6 years). Cold stimulation of 5°C for 5 minutes was then applied to the treated area 3 times with 40-minute intervals. Cold detection threshold and pain, mechanical hyperalgesia (pinprick), static and dynamic mechanical allodynia (von Frey and brush), skin blood flow (laser speckle), and temperature (thermocamera) were assessed. Cold detection threshold and cold pain threshold (CPT) increased after L-menthol and remained high after the cold rekindling cycles (P < 0.001). L-menthol evoked secondary hyperalgesia to pinprick (P < 0.001) particularly in females (P < 0.05) and also induced secondary allodynia to von Frey and brush (P < 0.001). Application of cold stimuli kept these areas enlarged with a higher response in females to brush after the third cold cycle (P < 0.05). Skin blood flow increased after L-menthol (P < 0.001) and stayed stable after cold cycles. Repeated application of cold on skin treated by L-menthol facilitated and prolonged L-menthol-induced cold pain and hyperalgesia. This model may prove beneficial for testing analgesic compounds when a sufficient duration of time is needed to see drug effects on CPT or mechanical hypersensitivity.

Offset analgesia could be activated with a feedback-controlled near-infrared laser system. Larger and delayed response to temperature decrease than to temperature increase was observed., Physical stimuli are subject to pronounced temporal filtering during afferent processing such that changes occurring at certain rates are amplified and others are diminished. Temporal filtering of nociceptive information remains poorly understood. However, the phenomenon of offset analgesia, where a disproportional drop in perceived pain intensity is caused by a slight drop in noxious heat stimulation, indicates potent temporal filtering in the pain pathways. To develop a better understanding of how dynamic changes in a physical stimulus are constructed into an experience of pain, a transfer function between the skin temperature and the perceived pain intensity was modeled. Ten seconds of temperature-controlled near-infrared (970 nm) laser stimulations above the pain threshold with a 1°C increment, decrement, or constant temperature were applied to the dorsum of the hand of healthy human volunteers. The skin temperature was assessed by an infrared camera. Offset analgesia was evoked by laser heat stimulation. The estimated transfer functions showed shorter latencies when the temperature was increased by 1°C (0.53 seconds [0.52-0.54 seconds]) than when decreased by 1°C (1.15 seconds [1.12-1.18 seconds]) and smaller gains (increase: 0.89 [0.82-0.97]; decrease: 2.61 [1.91-3.31]). The maximal gain was observed at rates around 0.06 Hz. These results show that temperature changes occurring around 0.06 Hz are best perceived and that a temperature decrease is associated with a larger but slower change in pain perception than a comparable temperature increase. These psychophysical findings confirm the existence of differential mechanisms involved in temporal filtering of dynamic increases and decreases in noxious stimulus intensity.

Chronic or episodic severe itch is recurrent in atopic dermatitis (AD). Nonhistaminergic itch pathways are suggested to dominate in AD itch, contributing to an "itch-scratch-itch cycle" that prolongs and worsens itch, pain, and skin lesions. We hypothesized that nonhistaminergic neuronal sensitization contributes to itch in AD. Hence, we compared sensitivity with thermal, mechanical, and chemical pruritic stimuli in patients with AD and controls. The study comprised 25 patients with AD with chronic itch and 25 healthy controls. Questionnaires on itch characteristics were administered, and sensory tests were conducted intralesionally, extralesionally, and in homologous areas of controls. Thermal and mechanical quantitative sensory testing (QST) as well as histamine and cowhage provocations were performed. Subsequently, hyperknesis and vasomotor reactivity were assessed. Average itch and associated pain among patients with AD were 60.7 ± 4.3 and 39.7 ± 5.2 (VAS0-100), respectively. Patients experienced significantly higher itch from cowhage both intralesionally and extralesionally compared with controls, whereas histamine-evoked itch intensity was not significantly different between groups. No group differences were found for thermal quantitative sensory testings or pain evoked by itch provocations. Patients had decreased mechanical detection thresholds intralesionally and increased mechanical pain sensitivity intralesionally and extralesionally. Lastly, patients exhibited intralesional and extralesional hyperknesis before chemical itch provocations and augmented hyperknesis after itch provocations. Increased itch in response to cowhage (but not histamine) suggests nonhistaminergic pathway-specific itch sensitization in AD, whereas increased susceptibility to mechanically evoked itch and pain, particularly intralesionally suggests sensitization of mechanosensitive circuitry not normally associated with itch. Drugs targeting the nonhistaminergic (PAR2/TRPA1) itch pathway and itch sensitization are promising for treating AD itch.

This study investigated the relationship between pain sensitivity, adaptability, and potency of endogenous pain inhibition, including conditioned pain modulation (CPM) and local pain inhibition. Forty-one healthy volunteers (20 male, 21 female) received conditioning stimulation (CS) over 2 sessions in a random order: tonic heat pain (46°C) on the right leg for 7 minutes and cold pressor pain (1°C to 4°C) on the left hand for 5 minutes. Participants rated the intensity of pain continuously using a 0 to 10 electronic visual analogue scale. The primary outcome measures were pressure pain thresholds (PPT) measured at the heterotopic and homotopic location to the CS sites before, during, and 20 minutes after CS. Two groups of participants, pain adaptive and pain nonadaptive, were identified based on their response to pain in the cold pressor test. Pain-adaptive participants showed a pain reduction between peak pain and pain at end of the test by at least 2 of 10 (n = 16); whereas the pain-nonadaptive participants reported unchanged peak pain during 5-minute CS (n = 25). Heterotopic PPTs during the CS did not differ between the 2 groups. However, increased homotopic PPTs measured 20 minutes after CS correlated with the amount of pain reduction during CS. These results suggest that individual sensitivity and adaptability to pain does not correlate with the potency of CPM. Adaptability to pain is associated with longer-lasting local pain inhibition.

Widespread hyperalgesia has been found in patients with painful hip osteoarthritis (OA) which can be normalized after total hip arthroplasty (THA) if patients have no residual postoperative pain. This study characterized the preoperative somatosensory profiles and provided possible interpretation of underlying pain mechanisms that might influence the development of postoperative pain. Forty hip OA patients with unilateral pain were assessed before and 6 weeks post-THA and compared with 40 asymptomatic control subjects. Hip pain intensity at rest and while walking was assessed on a visual analogue scale (VAS). Bilateral cuff algometry from the thighs was used to assess the cuff pressure pain thresholds, pressure values at VAS scores equal with 6 cm (PVAS6), cuff pressure tolerance, and temporal summation of pain (TSP) quantified by an increase in VAS scores to repeated phasic cuff stimulations. Correlations between hip pain VAS post-THA and preoperative quantitative sensory testing results were analyzed. Post-THA hip pain VAS scores decreased (P0.05) compared with pre-THA. The cuff pressure pain threshold, PVAS6, and cuff pressure tolerance were significantly lower bilaterally in both patients with pre-THA and post-THA compared with controls (P0.05). Temporal summation of pain was facilitated bilaterally in patients with pre-THA compared with controls and normalized after THA in postoperative pain-free patients (P0.05). Postoperative hip pain VAS scores correlated with preoperative ipsilateral TSP (r = 0.44, P0.05). Bilateral pressure pain hypersensitivity and facilitated TSP were demonstrated in patients with preoperative hip OA. Although persistent postoperative pain is known as multifactorial, greater preoperative TSP was associated with greater pain and less reduction in pain after THA.

Pain in myofascial temporomandibular disorder (TMD) can affect both the masseter and temporalis muscles. Glutamate injection into the masseter muscle evokes pain that is greater in men than in women and this pain is attenuated by co-injection of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine (10 mmol/L) in men. Animal studies suggested that pain induced by peripheral NMDA receptor activation could differ between the temporalis and masseter muscles and between men and women. The study aims were to investigate differences in glutamate-evoked pain between these muscles and the effectiveness of ketamine to attenuate glutamate-evoked pain in both genders. Pain and mechanical sensitivity were induced in 2 sessions of an experiment in 14 women and 16 men by repeated injections of glutamate (0.5 mol/L) with and without ketamine (20 mmol/L) into the masseter and temporalis muscles. Two injections were applied into the same masseter muscle and 2 injections into the same anterior temporalis muscle at each session. Visual analogue scale (VAS) pain intensities and pain drawing areas were assessed. Glutamate-evoked pain and pain drawing area were significantly greater from the temporalis muscle than from the masseter muscle (P.02) in both genders. Women reported significantly greater glutamate-evoked masseter muscle pain than men (P.03). Co-injection of ketamine, at higher dose than previously used, was equally effective in attenuating glutamate-evoked pain from both muscles in both genders (P.01). The current findings indicate that the characteristics of pain generated by intramuscular injection of glutamate vary for different masticatory muscles and may be partially generated through activation of peripheral NMDA receptors.

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 2mg, and tropisetron 5mg 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.

Widespread central hypersensitivity is present in chronic pain and contributes to pain and disability. According to animal studies, expansion of receptive fields of spinal cord neurons is involved in central hypersensitivity. We recently developed a method to quantify nociceptive receptive fields in humans using spinal withdrawal reflexes. Here we hypothesized that patients with chronic pelvic pain display enlarged reflex receptive fields. Secondary endpoints were subjective pain thresholds and nociceptive withdrawal reflex thresholds after single and repeated (temporal summation) electrical stimulation. 20 patients and 25 pain-free subjects were tested. Electrical stimuli were applied to 10 sites on the foot sole for evoking reflexes in the tibialis anterior muscle. The reflex receptive field was defined as the area of the foot (fraction of the foot sole) from which a muscle contraction was evoked. For the secondary endpoints, the stimuli were applied to the cutaneous innervation area of the sural nerve. Medians (25-75 percentiles) of fraction of the foot sole in patients and controls were 0.48 (0.38-0.54) and 0.33 (0.27-0.39), respectively (P=0.008). Pain and reflex thresholds after sural nerve stimulation were significantly lower in patients than in controls (P

Udgivelsesdato: 2009-Jan The present human study aimed at investigating the effect of subcutaneous administration of Botulinum toxin type A (BoNT/A) on capsaicin-induced trigeminal pain, neurogenic inflammation and experimentally induced cutaneous pain modalities. Fourteen healthy males (26.3+/-2.6 years) were included in this double-blind and placebo-controlled trial. The subjects received subcutaneous BoNT/A (22.5U) and isotonic saline in the mirror sides of their forehead. Pain and neurogenic inflammation was induced by four intradermal injections of capsaicin (100mug/muL) (before, and days 1, 3 and 7 after treatments). The capsaicin-induced pain intensity, pain area, the area of secondary hyperalgesia, the area of visible flare and vasomotor reactions were recorded together with cutaneous heat, electrical and pressure pain thresholds. BoNT/A reduced the capsaicin-induced trigeminal pain intensity compared to saline (F=37.9, P0.05). Findings from the present study suggest that BoNT/A appears to preferentially target Cfibers and probably TRPV1-receptors, block neurotransmitter release and subsequently reduce pain, neurogenic inflammation and cutaneous heat pain threshold.

To determine if short-term (15 min) training in a novel tongue-task is associated with rapid neuroplasticity of the tongue primary motor area (MI) in the human cerebral cortex, and if intra-oral tonic pain affects the tongue MI neuroplasticity and tongue-task training performance. Nine healthy volunteers (7 men, 2 women, mean age 24 ± 1.1 years) participated in two cross-over training sessions in which the application to the tongue of the algesic chemical capsaicin (1%) or vehicle cream was randomized. Prior to and again immediately after 15 min of training in a tongue-protrusion task, transcranial magnetic stimulation (TMS) was applied to the MI in each session and motor evoked potentials (MEPs) were recorded in the tongue musculature and the first dorsal interosseous (FDI) muscle (as control). Neuroplasticity of the tongue MI, as reflected in a significantly enhanced TMS–MEP stimulus–response curve and reduced MEP threshold, was observed after the vehicle session but not after the capsaicin session. Subjects’ overall mean performance scores were significantly higher in the vehicle session than in the capsaicin session. MI neuroplasticity may rapidly occur in association with successful performance in novel tongue-task training, but intra-oral tonic pain interferes with these effects. These findings suggest that nociceptive input modulates MI neuroplasticity associated with novel motor training and may impair the ability to learn a new motor task.

There is evidence that elevated tissue concentrations of glutamate may contribute to pain and sensitivity in certain musculoskeletal pain conditions. In the present study, the food additive monosodium glutamate (MSG) was injected intravenously into rats to determine whether it could significantly elevate interstitial concentrations of glutamate in the masseter muscle and whether MSG administration could excite and/or sensitize slowly conducting masseter afferent fibers through N-methyl-D-aspartate (NMDA) receptor activation. The interstitial concentration of glutamate after systemic injection of isotonic phosphate-buffered saline (control) or MSG (10 and 50mg/kg) was measured with a glutamate-selective biosensor. The pre-injection baseline interstitial concentration of glutamate in the rat masseter muscle was 24+/-11 microM. Peak interstitial concentration after injection of 50mg/kg MSG was 63+/-18 microM and remained elevated above baseline for approximately 18 min. In vivo single unit recording experiments were undertaken to assess the effect of MSG (50mg/kg) on masseter afferent fibers. Injection of MSG evoked a brief discharge in one afferent fiber, and significantly decreased ( approximately 25%) the average afferent mechanical threshold (n=10) during the first 5 min after injection of MSG. Intravenous injection of ketamine (1mg/kg), 5 min prior to MSG, prevented the MSG-induced decreases in the mechanical threshold of masseter afferent fibers. The present results indicate that a 2- to 3-fold elevation in interstitial glutamate levels in the masseter muscle is sufficient to excite and induce afferent mechanical sensitization through NMDA receptor activation. These findings suggest that modest elevations of interstitial glutamate concentration could alter musculoskeletal pain sensitivity in humans.

In September 2006, members of the Sex, Gender and Pain Special Interest Group of the International Association for the Study of Pain met to discuss the following: (1) what is known about sex and gender differences in pain and analgesia; (2) what are the "best practice" guidelines for pain research with respect to sex and gender; and (3) what are the crucial questions to address in the near future? The resulting consensus presented herein includes input from basic science, clinical and psychosocial pain researchers, as well as from recognized experts in sexual differentiation and reproductive endocrinology. We intend this document to serve as a utilitarian and thought-provoking guide for future research on sex and gender differences in pain and analgesia, both for those currently working in this field as well as those still wondering, "Do I really need to study females?"

Biochemical and pain biomarkers can be applied to patients with painful osteoarthritis profiles and may provide more details compared with conventional clinical tools. The aim of this study was to identify an optimal combination of biochemical and pain biomarkers for classification of patients with different degrees of knee pain and joint damage. Such profiling may provide new diagnostic and therapeutic options. A total of 216 patients with different degrees of knee pain (maximal pain during the last 24 hours rated on a visual analog scale [VAS]) (VAS 0-100) and 64 controls (VAS 0-9) were recruited. Patients were separated into 3 groups: VAS 10 to 39 (N = 81), VAS 40 to 69 (N = 70), and VAS 70 to 100 (N = 65). Pressure pain thresholds, temporal summation to pressure stimuli, and conditioning pain modulation were measured from the peripatellar and extrasegmental sites. Biochemical markers indicative for autoinflammation and immunity (VICM, CRP, and CRPM), synovial inflammation (CIIIM), cartilage loss (CIIM), and bone degradation (CIM) were analyzed. WOMAC, Lequesne, and pain catastrophizing scores were collected. Principal component analysis was applied to select the optimal variable subset, and cluster analysis was applied to this subset to create distinctly different knee pain profiles. Four distinct knee pain profiles were identified: profile A (N = 27), profile B (N = 59), profile C (N = 85), and profile D (N = 41). Each knee pain profile had a unique combination of biochemical markers, pain biomarkers, physical impairments, and psychological factors that may provide the basis for mechanism-based diagnosis, individualized treatment, and selection of patients for clinical trials evaluating analgesic compounds. These results introduce a new profiling for knee OA and should be regarded as preliminary.

The present study aimed to investigate if (1) subcutaneous injection of glutamate induces pain, sensitization and vasomotor responses in humans and (2) if sex differences exist in these responses. Thirty healthy volunteers (men-15 and women-15) were included. Each subject received four subcutaneous injections (0.1ml; glutamate 100, 10, 1mM and isotonic saline 0.9%) into the forehead skin in two sessions separated by one week. Assessments of pain intensity (VAS), quality, distribution; area of pinprick hyperalgesia; pressure pain threshold (PPT) at the injection site; surface skin temperature and local blood flow were performed at predetermined time points. The highest concentration of glutamate evoked the highest pain intensity, the longest duration of pain and the largest pain area under the VAS-time curve (P

Visceral pain can be difficult to treat with classical μ-opioid agonists and it has been suggested to use opioids with distinct pharmacological profiles. In animal experiments, oxycodone has shown different effects compared to morphine, and clinical observations have shown that oxycodone may occasionally be superior to, e.g., morphine in the treatment of visceral pain. In the current study, we randomised 24 healthy subjects to treatment with either morphine (30 mg), oxycodone (15 mg) or placebo in a crossover study. The experimental pain model involved multi-modal (mechanical, thermal and electrical) pain tests in the skin, muscles and viscera. The pain tests were carried out at baseline and 30, 60 and 90 min after oral administration of the drugs. The model showed effect of the two opioids compared to placebo on all stimulus modalities in all three types of tissues (all P values

Experimental data on age-related changes in pain perception have so far been contradictory. It has appeared that the type of pain induction method is critical in this context, with sensitivity to heat pain being decreased whereas sensitivity to pressure pain may be even enhanced in the elderly. Furthermore, it has been shown that temporal summation of heat pain is more pronounced in the elderly but it has remained unclear whether age differences in temporal summation are also evident when using other pain induction methods. No studies on age-related changes in spatial summation of pain have so far been conducted. The aim of the present study was to provide a comprehensive survey on age-related changes in pain perception, i.e. in somatosensory thresholds (warmth, cold, vibration), pain thresholds (heat, pressure) and spatial and temporal summation of heat and pressure pain. We investigated 20 young (mean age 27.1 years) and 20 elderly (mean age 71.6 years) subjects. Our results confirmed and extended previous findings by showing that somatosensory thresholds for non-noxious stimuli increase with age whereas pressure pain thresholds decrease and heat pain thresholds show no age-related changes. Apart from an enhanced temporal summation of heat pain, pain summation was not found to be critically affected by age. The results of the present study provide evidence for stimulus-specific changes in pain perception in the elderly, with deep tissue (muscle) nociception being affected differently by age than superficial tissue (skin) nociception. Summation mechanisms contribute only moderately to age changes in pain perception.

Little is known about sex differences in the temporal pattern of descending inhibitory mechanisms, such as descending noxious inhibitory control (DNIC). Sex differences in temporal characteristics of DNIC were investigated by measuring pressure pain thresholds (PPTs) over time in the trapezius muscles (local pain areas) and the posterolateral neck muscles (referred pain areas) following repeated bilateral injection of hypertonic versus isotonic saline into both trapezius muscles. Ten females and 11 males received two consecutive bilateral injections, with 15 min interval, of either 5.8% hypertonic saline (0.5 ml in each side for each bilateral injection) or isotonic saline as a control in a randomized manner. Following hypertonic saline injection, the maximal pain intensities of the first and second bilateral injections were significantly higher in females than in males. The PPTs in the trapezius muscles were significantly lower in females than in males. Significantly higher PPTs (hypoalgesia) in men than in women were shown 15 min after the first bilateral injection, and 7.5 and 15 min after the second bilateral injection in the referred pain areas. Importantly, the second bilateral injection failed to further increase the PPTs for both sexes. These results showed that there were sex differences in temporal characteristics of descending inhibition with long-lasting hypoalgesia in men than in women. Repeated noxious muscular stimuli may inhibit further build-up of DNIC, which may reflect a mechanism of plasticity of the descending inhibitory systems following recurrent nociceptive barrage for both sexes.

The present study examined the effect of peripheral administration of the excitatory amino acid (EAA) glutamate on the intensity of perceived pain and pressure pain thresholds (PPTs) in healthy young women (n=17) and men (n=18). Two injections separated by 25 min of 0.2 ml, 1.0M glutamate into the masseter muscle produced significantly higher scores of pain on 0-10 cm visual analogue scales (VAS) in women than in men (analysis of variance, ANOVA: P0.001). There was no significant difference between the VAS scores for the first and the second injections in either men or women. The PPTs determined in the masseter muscle were significantly reduced following the first injection and further significantly reduced after the second injection (ANOVA: P0.001). Furthermore, the PPTs were reduced to a similar extent in both women and men (maximum 44-56%), suggesting that gender did not influence the process of sensitization. There were no significant difference in VAS scores or PPTs between women taking oral contraceptives (n=9) and those who did not (n=8) (ANOVAs: P=0.709, P=0.153). It is concluded that the VAS scores produced by intramuscular administration of 1.0M glutamate may reflect a gender-dependent activation of nociceptive pathways which, in part, may be mediated through peripheral EAA receptors. The reduction of PPTs in the masseter muscle following administration of glutamate in a concentration of 1.0M may reflect allodynia to mechanical stimuli. This process of sensitization was not gender-dependent. The present results suggest that injection of 1.0M glutamate into the masseter muscle may provide a useful experimental method to test sensitization and efficacy of peripheral EAA receptor antagonists in human subjects.

Pain originating from the female reproductive organs is a substantial clinical problem to treat. Experimental models may be a tool for the study of visceral pain mechanisms and hence provide information to aid in formulating new treatment strategies. The aim was to develop and evaluate the performance and safety of a model for nociceptive stimulation of the uterine cervix by balloon dilatation using impedance planimetry. Three consecutive (repeated) dilatations at 1 ml/min, an isovolumetric and a fast dilatation at 2 ml/min were performed. Pilot studies were conducted in vitro on hysterectomy specimens, followed by application of the model in 14 healthy females. Subjects indicated the quality of perception and pain during dilatations by verbal reports and the McGill Pain Questionnaire (MPQ), and the intensity by a continuous electronic visual analog scale. The pain location was marked on an anatomical map. The balloon cross-sectional area (CSA) was measured simultaneously. The experimental procedure was atraumatic. Pain was evoked in all subjects, with referral to the hypogastric and low back regions. The word descriptors on the MPQ and the areas of referred sensations were similar to that seen clinically in abortion, labor and menstrual pain. The pain intensity correlated with balloon CSA (r=0.9, P

Hypertonic saline effectively excites muscle nociceptors. Muscle hyperalgesia was assessed in osteoarthritis (OA) by intramuscular infusion of 0.5 ml hypertonic saline (6%) into the tibialis anterior muscle in humans. Patients (n=14) with OA in the lower extremities were compared with an equal number of age- and sex-matched healthy controls. Ten of the 14 OA patients had pain in the knee joint as the most common presenting complaint. Visual analogue scale (VAS) pain intensity and assessment of pain areas were recorded before infusion and immediately, 2, 5, 10 and 20 min after infusion, and then every 10 min, until the pain vanished. The mean pain offset time in OA patients (11.3+/-7.9 min) was larger as compared with the control subjects (6.04+/-2.1 min) (P=0.025). OA patients had increased pain intensity VAS after the infusion in the right leg compared with controls (P0.05). Referred and radiating pain areas at 2 min post-infusion increased in OA patients and not in controls as compared with the local pain areas (P0.05). It is concluded that muscle hyperalgesia and extended pain areas might be due to central sensitization caused by painful osteoarthritis.

Chronic pain, lymphoedema, post-irradiation neuropathy and other symptoms are reported in as many as 75% of women following breast cancer treatment. This study examined pain and sensory abnormalities in women following breast cancer surgery. Sensory tests were carried out on operated and contralateral sides in 15 women with spontaneous pain and sensory abnormalities and 11 pain-free women. Testing included the VAS score of spontaneous pain, detection and pain threshold to thermal and mechanical stimuli, temporal summation to repetitive heat and pinprick stimuli, and assessment of skin blood flow during repetitive brush and pinprick stimulation. Sensory threshold to pinprick and thermal stimuli was significantly higher on the operated side in both groups while pressure pain threshold was significantly lower in pain patients on the operated side compared to the contralateral side. No side to side difference was seen in pressure pain threshold in the pain-free group. Evoked pain intensity to repetitive stimuli at 0.2 and 2.0 Hz was significantly higher on the operated side in pain patients compared to the control area while no such difference was seen in pain-free patients. Cutaneous blood flow measured by laser Doppler (flux) was significantly higher when the skin was tapped at 2.0 Hz on the operated side compared to contralaterally in pain patients, while no side to side difference was seen in pain-free patients. Pinprick-evoked pain was correlated to spontaneous pain but not to flux. Spontaneous pain was not correlated to flux. Sensitization seems to be a feature in breast cancer-operated women with pain, but not in pain-free women.

The whiplash syndrome has immense socio-economic impact. Despite extensive studies over the past years, the mechanisms involved in maintaining the pain in chronic whiplash patients are poorly understood. The aim of the present experimental study was to examine the muscular sensibility in areas within and outside the region involved in the whiplash trauma. Eleven chronic whiplash patients and 11 sex and age matched control subjects were included in the study. Before the experiment, the whiplash patients had pain in the neck and shoulder region with radiating pain to the arm. Five patients reported pain that was more widespread. The somatosensory sensibility in the areas over the infraspinatus, brachioradial, and anterior tibial muscles was assessed by pressure stimulation, pin-prick stimulation, and cotton swap stimulation. Infusion of hypertonic saline (5.85%, 0.5 ml) into the infraspinatus and anterior tibial muscles was performed to assess the muscular sensibility and referred pain pattern. The saline-induced muscle pain intensity was assessed on a continuous visual analogue scale (VAS). The distribution of pain was drawn on an anatomical map. The pressure pain thresholds were significantly lower in patients (P

The mechanisms underlying local and referred muscle pain are poorly understood. The aim of this experiment was to determine to which degree referred pain is dependent on peripheral or central mechanisms. This was studied by blocking sensory input from the referred pain area. Intramuscular electrical stimulation in the right anterior tibial muscle induced local muscle pain and referred pain in 12 subjects. Nerve blocks were applied on the lower limb between the local and the referred pain area for 60 min. Three different studies were performed: (1) no nerve block (2) compression block, and (3) compression block combined with intravenous regional anaesthesia. The referred pain intensity was assessed every 5 min. To monitor the blockade of myelinated and unmyelinated nerve fibres, touch, pinprick, position sense and heat and heat-pain detection thresholds were assessed on the dorsal side of the foot every 5 min. A significant reduction in referred pain intensity (40.5%) compared with the control experiment was found after 40 min with the compression ischemia nerve block until release of the tourniquet. In the combined nerve block experiment, a significant reduction of referred pain intensity (38.5%) was seen after 20 min and until the release of the tourniquet. There was no significant difference in the referred pain intensity between the two types of blocks. The present findings suggest that both peripheral and central mechanisms play a role in referred pain and that the myelinated fibres mediate the peripheral component.

The aim of the present study was to test (1) whether muscle pain is influenced by temporal and spatial summation, and (2) whether sequential noxious muscle stimuli applied at hourly interstimulus-intervals could produce an increased sensation of pain due to central hyperexcitability. In the study eleven healthy men were exposed to computer-controlled intramuscular infusion of saline (5%) given over 20 s in m. tibialis anterior (m. TA). The intensities of local and referred pain were assessed by recordings on visual analogue scales (VAS), and the areas of local pain (around the injection site) and referred pain (outside the local pain area) were localised by the subject. Three experiments were performed. Experiment 1: Each subject participated in three tests separated by one week: (a) bolus (0.4 ml saline) infusion at one site; (b) four sequential infusions (0.1 ml saline) given at 90-s interstimulus-intervals at one site; and (c) four sequential infusions (0.1 ml saline) given at 360-s interstimulus-intervals at one site. Experiment 2: This was performed as experiment 1, but the infusions were given at spatially separated sites. Experiment 3. Hypertonic saline (0.1 ml) was injected one, four and 24 h after the sequential infusions (90-s interstimulus-intervals) given at spatially separated sites. The highest VAS peak and the largest local and referred pain areas were found after the bolus infusions. Compared to the first infusion, significant increases were found in the VAS peak, the size of the local pain area, and the size of the referred pain area (non-significant) after the four sequential infusions given at 90-s interstimulus-intervals (temporal summation). Four spatially separated infusions given simultaneously produced a higher VAS peak, a larger local pain area, and a larger referred pain area (non-significant) compared to one infusion (spatial summation). The infusion given 4 h after the sequential infusions tended to produce an increase in the referred pain area and in the pain intensity. In all three experiments significant correlations were found between the VAS peak and the size of the local (R = 0.64, P0.0001, n = 231) and referred (R = 0.47, P0.0001, n = 231) pain areas. Based on the above results it can be concluded that experimental muscle pain is influenced by temporal and spatial summation.

Previous animal and human studies have indicated that nociceptive thresholds are decreased by acute hyperglycemia. The results of these studies may be challenged due to methodological problems. We therefore conducted a double-blind, controlled, cross-over study on the effect of acute hyperglycemia on nociceptive and non-nociceptive thresholds in 10 type 1 (insulin-dependent) diabetic patients (diabetes < 5 years) without symptoms or clinical signs of peripheral neuropathy. During an overnight fast, blood glucose concentration was normalized by refract insulin injections. Then, blood glucose was kept at 6 mmol/1 for 3 h by an intravenous infusion of glucose and insulin. On one study day, blood glucose was kept at 6 mmol/1 for a further 3 h and on another day, blood glucose was elevated to 12 mmol/1 during 0.5 h by additional glucose infusion and kept at that level for 2.5 h. Sensory testing was carried out twice during the initial 3 h with euglycemia and 3 times during the following period with either hyper- or euglycemia. The test procedure included determination of pain detection and pain tolerance thresholds to heat (wrists) and pressure (fingers) as well as detection thresholds to warmth/cooling (wrist), vibration (finger), and mechanical (wrist) stimulation. The changes in neither nociceptive nor non-nociceptive thresholds showed any statistically significant differences between the 2 study days. The pressure pain detection and tolerance thresholds showed, however, minor decreases at each of the test days, probably due to cutaneous sensitization caused by the repeated measurements. Compared to baseline, the pressure pain thresholds decreased significantly on the day with hyperglycemia. None of the other thresholds showed such changes. It cannot be excluded that more pronounced or longer term hyperglycemia can cause changes in sensibility. We conclude that acute hyperglycemia (12 mmol/1) does not cause major changes in nociceptive or non-nociceptive thresholds in the upper extremity, however, pressure pain thresholds was reduced significantly with hyper glycemia.

To characterize the sensory effects of epidural lidocaine, 2 groups each of 10 human subjects received 25 ml of 2% lidocaine at the L1-L2/L2-L3 interspace (high lumbar group) or at the L3-L4/L4-L5 interspace (low lumbar group). Twelve quantitative sensory tests in the L5 and S1 dermatomes and leg extension strength were determined every 30 min for 3 h. Sensory and motor blockade were more pronounced in the low than in the high lumbar group. Sensory functions were blocked in the following order by epidural lidocaine: warm > cold > electrical stimuli. Perception of brief localized noxious stimuli was attenuated more than perception of noxious stimuli of longer duration and involving larger stimulus areas. It is suggested that both peripheral mechanisms (differential conduction blockade of afferent fibres) and central mechanisms (temporal and spatial summation) play a role in the sensory effects of epidural lidocaine.

High-energy light from an argon laser was applied to human oral mucosa in order to investigate regional pain sensitivity. Significant regional differences in sensory and pain thresholds were observed between the test sites on the hard and soft palatal mucosa, the buccal mucosa, the tongue, the lower lip, and the skin on the hand. Pain thresholds were lowest on the tip of the tongue and highest on the hard palate. Sensory and pain thresholds were influenced by different stimulus parameters: pulse duration and laser beam diameter. Blackening of the mucosa in regions with high optical reflectance, such as the hard palate, increased light absorption and, hence, reduced both thresholds significantly. Reflectance spectrophotometric measurements indicated that the hard palatal mucosa reflected argon laser light about 1.5 times more than the tip of the tongue. The different threshold values could, in part, be ascribed to different reflectance and absorption properties of the mucosal areas but also indicated substantial regional variation in pain sensitivity of the human oral mucosa. Measurement of laser thresholds is an appropriate and standardized method for investigating sensory differences in human oral mucosa and may be used to study various pain conditions e.g., burning mouth syndrome.

The exteroceptive capabilities of the nociceptive system have long been thought to be considerably more limited than those of the tactile system. However, most investigations of spatio-temporal aspects of the nociceptive system have largely focused on intensity coding as consequence of spatial or temporal summation. Graphesthesia, the identification of numbers "written" on the skin, and assessment of the two-point discrimination thresholds were used to compare the exteroceptive capabilities of the tactile and nociceptive systems. Numbers were "written" on the forearm and the abdomen by tactile stimulation and by painful non-contact infrared laser heat stimulation. Subjects performed both graphesthesia tasks better than chance. The tactile graphesthesia tasks were performed with 89% (82-97%) correct responses on the forearm and 86% (79-94%) correct responses on the abdomen. Tactile graphesthesia tasks were significantly better than painful heat graphesthesia tasks that were performed with 31% (23-40%) and 44% (37-51%) correct responses on the forearm and abdomen, respectively. These findings demonstrate that the central nervous system is capable of assembling complex spatio-temporal patterns of nociceptive information from the body surface into unified mental objects with sufficient accuracy to enable behavioral discrimination.

The generalized hypersensitivity associated with fibromyalgia syndrome (FMS) may in part be driven by peripheral nociceptive sources. The aim of the study was to investigate whether local and referred pain from active myofascial trigger points (MTrPs) contributes to fibromyalgia pain. FMS patients and healthy controls (n = 22 each, age- and gender-matched) were recruited. The surface area over the upper trapezius muscle on each side was divided into 13 sub-areas (points) of 1 cm in diameter for each point. Pressure pain threshold (PPT) and the local and referred pain pattern induced by manual palpation at 13 points bilaterally in the upper trapezius were recorded. Results showed that PPT levels at all measured points were significantly lower in FMS than controls. Multiple active MTrPs (7.4 ± 2.2) were identified bilaterally in the muscle in FMS patients, but no active MTrPs were found in controls. The mid-fiber region of the muscle had the lowest PPT level with the largest number of active MTrPs in FMS and with the largest number of latent MTrPs in controls. The local and referred pain pattern induced from active MTrPs bilaterally in the upper trapezius muscle were similar to the ongoing pain pattern in the neck and shoulder region in FMS. In conclusion, active MTrPs bilaterally in the upper trapezius muscle contribute to the neck and shoulder pain in FMS. Active MTrPs may serve as one of the sources of noxious input leading to the sensitization of spinal and supraspinal pain pathways in FMS.

The roles of central protein kinases A and C (PKA and PKC) in various pain states have intensively been investigated during the past decade. The aim of the present study was to investigate the peripheral involvement of PKA and PKC in persistent nociceptive response, evoked pain behaviors, and inflammation induced by subcutaneous (s.c.) injection of bee venom (BV, 0.2mg/50 microl) in rats. The effects of intraplantar injection of H-89 (a PKA inhibitor, 5-100 microg/50 microl) and chelerythrine chloride (a PKC inhibitor, 5-100 microg/50 microl) on BV-elicited persistent nociception (nociceptive flinching reflex), mechanical hyperalgesia, and inflammation were systematically investigated. Pre-treatment with H-89 dose-dependently inhibited only BV-induced mechanical hyperalgesia, but not the persistent nociception and inflammation. In contrast, pre-treatment with chelerythrine chloride dose-dependently inhibited BV-induced sustained nociception and inflammation, but not the mechanical hyperalgesia. Topical pre-treatment of the sciatic nerve with 1% capsaicin significantly blocked the inhibitory effects of the PKC inhibitor on BV-induced inflammation, but not the persistent flinching response. These results indicate that peripheral PKA and PKC involvements in BV-induced pain behaviors differ, and capsaicin-sensitive afferents appear to participate in the pro-inflammatory role of PKC in the BV pain model. Findings from the present study also suggest that targeting specific peripheral protein kinases might prove effective in the treatment of persistent pain and inflammation.

Migraine is much more common in women (18%) than in men (6%). Menstrual migraine in female migraineurs also varies from 7 to 19%. The main goals of the present study were (1) to investigate gender specific differences in an experimental capsaicin model of trigeminal sensitization (a proposed mechanism of migraine) and (2) to explore the influence of menstrual cycle phases. Twenty-eight healthy female and male volunteers were studied. Capsaicin (100 microg/0.1 ml) was injected intradermally to the forehead. Pain intensity and distribution together with the visual flare and allodynic area (central sensitization) were assessed for females (during their menstrual and luteal phases) and for males. Pain area significantly changed across the menstrual cycle with 19.2+/-2.0 cm x min at menstrual and 16.4+/-0.9 cm x min at luteal phase (P

Human experimental visceral pain models using chemical stimulation are needed for the study of visceral hyperexcitability. Our aim was to stimulate the human gut with chemical activators (capsaicin, glycerol) and measure quantitatively the induced hyperexcitability to painful mechanical gut distension. Ten otherwise healthy subjects with an ileostoma participated. Increasing volumes of capsaicin 50 μg/ml (0.25, 0.5, 0.75, 1.0, 1.5, 2.0, and 3 ml), glycerol (2.5, 5, and 10 ml) or saline (2.5, 5, and 10 ml) intermingled with sham stimuli were randomly applied to the ileum via the stomal opening at three occasions separated by a week. After each application, pain intensity, qualities, and referred pain area were assessed together with the pain threshold to distension of the proximal gut. ‘Boring’ and ‘hot’ pain were evoked in all subjects by low doses (median 0.5 ml) of capsaicin. The median pain onset, peak pain, and pain duration were 55, 85, and 420 s, respectively. Referred somatic pain developed around the stomal opening with a correlation between the pain area and pain intensity. After application of capsaicin, significant hyperalgesia was found to distension of the gut (a 28% reduction pressure in pain threshold). No significant manifestations were found after application of glycerol and saline. Application of capsaicin to the human ileum induces pain and mechanical hyperalgesia. Specific activation of nociceptors in the gut mucosa provides new possibilities to study clinical relevant visceral pain mechanisms.

We assessed the trigeminal nociceptive pathways in patients with painful temporomandibular disorders (TMD) and control subjects using a CO(2)-laser stimulator which provides a predominant activation of the nociceptive system. Fifteen patients with unilateral pain were examined in accordance with the Research Diagnostic Criteria for TMD and 30 gender- and age-matched individuals were included as a control group. Laser-evoked potentials (LEPs) and laser silent periods (LSPs) after stimulation of the perioral region (V2/V3) on the painful and non-painful sides were recorded in all subjects. LEPs were evoked by low-intensity pulses (1.5 x perception threshold (PTh)) and recorded from scalp electrodes at the vertex. LSPs were evoked by high-intensity pulses (4 x PTh) and recorded bilaterally from masseter muscles with surface electromyogram (EMG) electrodes. Subjects also assessed the stimulus intensity on a 0-10 rating scale. LEPs had normal latency but smaller amplitude in TMD patients compared to the control group (P

This study assessed spatial and temporal aspects of pressure pain during increasing and constant compressions using a cuff algometer and during adaptive compressions using a closed-loop feedback system for maintaining stable pain. Experimental setup consisted of a pneumatic tourniquet cuff, a computer-controlled air compressor, and a 10-cm electronic visual analogue scale (VAS). The first experiment assessed spatial summation for cuff pain by recording the pressure-pain stimulus-response (SR) function during increasing compressions with single and double cuffs. The second experiment assessed temporal profile of cuff pain during constant compression for 10 min beginning at pain intensities of 2, 4, and 6 cm on the VAS. The third experiment assessed temporal pressure profile when pain was maintained for 10 min by a close-loop system within target zones of +/-0.5 cm VAS at pain intensities of 2, 4, and 6 cm on the VAS.Doubling the tissue volume under the cuff shifted the SR function to the left, demonstrating spatial summation. The constant cuff pressure evoked typical biphasic response consisting of an overshoot in pain intensity, followed by decreasing pain, or adaptation. The pain intensity was significantly correlated to the time of constant stimulation, showing time-dependency of pain encoding. Both overshoot magnitude and adaptation rate were dependent on the starting pain intensity. The pain decrease rate was lowest for a pain intensity of 2 cm on the VAS. The overshoot magnitude was lowest for a pain intensity of 6 cm on the VAS. Both the overshoot and the adaptation were maximal for a pain intensity of 4 cm on the VAS. The oscillating pressure generated by closed-loop system led to constant rather than adapting pain at intensities of 2, 4, and 6 cm on the VAS. The cuff algometer is highly configurable tool for assessment of pain sensitivity by pressure-pain and time-pain functions. The presented models are useful additions to a researcher's armamentarium for further pharmacological and clinical studies on deep tissue pain and related mechanisms.

Udgivelsesdato: JUN

Temporal summation of pain occurs when repeated stimuli become increasingly painful in spite of unchanged stimulus intensity. Summation can be quantified as the difference in pain between the first and the last stimulus in a train of stimuli. The aim of the study was to compare temporal summation of pain in normal skin with summation of pain in skin with primary and secondary hyperalgesia evoked by a heat injury. A heat injury was produced on the crus of 12 volunteers with a 50 x 25 mm thermode (47 degrees C, 7 min). Measurements were made before, and 0, 1, 2, and 4 h after the heat injury, in three areas: primary and secondary mechanical hyperalgesia induced by the heat injury, and in a mirror image of the injury on the opposite leg. Temporal summation of pain was induced by repeated electrical stimuli (five stimuli at 2 Hz) and assessed by visual analog scale (VAS). Primary hyperalgesia was evaluated by von Frey hairs and electrical stimuli, and the areas of secondary hyperalgesia with a rigid von Frey hair (314 mN). Significant primary (P0.000001) and secondary (P0.00006) mechanical hyperalgesia were evoked by the heat injury. The pain threshold to single electrical stimuli was reduced within the injury (P0.03), but not outside. The pain responses to single and repeated electrical stimuli were not significantly altered by the injury. Temporal summation of pain occurred in 418 stimulus trains out of 576 (73%), but no significant changes in summation developed in skin with primary or secondary mechanical hyperalgesia compared with normal skin (baseline measurements). Temporal summation at high stimulus intensities was more pronounced than at lower intensities (P0.0002). We found no correlation between either temporal summation and area of secondary hyperalgesia, or temporal summation and pain intensity during the induction of heat injury. We conclude that the development of primary and secondary mechanical hyperalgesia after heat injury in man was not associated with changes in temporal summation of painful electrical stimuli.

Chronic low back pain (CLBP) is a major clinical problem with a substantial socio-economical impact. Today, diagnosis and therapy are insufficient, and knowledge concerning interaction between musculoskeletal pain and motor performance is lacking. Most studies in this field have been performed under static conditions which may not represent CLBP patients' daily-life routines. A standardized way to study the sensory-motor interaction under controlled motor performances is to induce experimental muscle pain by i.m. injection of hypertonic saline. The aim of the present controlled study was to analyze and compare electromyographic (EMG) activity of and coordination between lumbar muscles (8 paraspinal recordings) during gait in 10 patients with CLBP and in 10 volunteers exposed to experimental back muscle pain induced by bolus injection of 5% hypertonic saline. When the results are compared to sex- and age-matched controls, the CLBP patients showed significantly increased EMG activity in the swing phase; a phase where the lumbar muscles are normally silent. These changes correlated significantly to the intensity of the back pain. Similar EMG patterns were found in the experimental study together with a reduced peak EMG activity in the period during double stance where the back muscles are normally active. Generally, these changes were localized ipsilaterally to the site of pain induction. The clinical and experimental findings indicate that musculoskeletal pain modulates motor performance during gait probably via reflex pathways. Initially, these EMG changes may be interpreted as a functional adaptation to muscle pain, but the consequences of chronic altered muscle performance are not known. New possibilities to monitor and investigate altered motor performance may help to develop more rational therapies for CLBP patients.

Using two different stimulators, we have induced activity in A delta and C afferents in order to investigate a possible summation of nociceptive activity from these two fiber types. We used nociceptive electrical stimulation to evoke activity in A delta fibers. High-intensity light from a xenon lamp, focused into a liquid light guide which was positioned on a spot painted black under the sole of the foot, resulted in a characteristic delayed burning sensation, indicating selective C-fiber activation. By varying the delay between radiant heat and electrical stimuli (0-3000 msec), sensations evoked by these stimuli were brought to coincide. When we elicited the electrical stimulation during on-going burning pain, corresponding to a delay of approximately 1 sec between the stimulations, we found a significantly higher nociceptive withdrawal reflex in tibialis anterior (P0.01) and a higher overall pain rating (P0.05). The existence of a summation mechanism at the spinal cord is the most likely explanation for our findings. Furthermore, the results demonstrate that the nociceptive reflex may be modulated by on-going C-fiber activity.