Alterations in Temporal Summation of Pain and Conditioned Pain Modulation Across an Episode of Experimental Exercise-Induced Low Back Pain

Persistent pain conditions, including low back pain (LBP), are often accompanied by alterations in pronociceptive and antinociceptive mechanisms, as quantified by temporal summation of pain (TSP) and conditioned pain modulation (CPM). It remains unclear whether altered pain sensitivity, CPM, and/or TSP are a consequence of pain presence or determine the degree of pain development. Pressure pain sensitivity, TSP, and CPM were assessed across an episode of exercise-induced LBP maintained for several days. Thirty healthy individuals participated in 3 experimental sessions: before (day 0), 2 days after fatiguing back muscle exercise with exercise-induced LBP present (day 2), and after pain resolution (day 7). Both handheld and cuff pressure–pain thresholds, along with TSP (10-cuff pain stimuli at .5 Hz) and CPM (cuff pain detection threshold prior versus during painful pressure conditioning) were assessed, alongside questionnaires pertaining to pain, disability, mood, sleep, menstruation, physical activity, and catastrophizing. The exercise-induced LBP model produced mild pain and disability, and reductions in pressure pain thresholds over both the lumbar and distant testing sites (p < .007). No pain-related changes were observed for TSP (p > .44) or CPM (p > .17). The baseline TSP was associated with the peak pain intensity of the exercise-induced LBP (p < .003).Perspective: Pressure–pain sensitivity was impacted by the presence of exercise-induced LBP, whereas TSP seemed to be more stable and was instead associated with the intensity of pain developed. No significant pain-related changes or associations were observed for CPM, suggesting this measure may have less usefulness in mild musculoskeletal pain conditions.     

One night of total sleep deprivation promotes a state of generalized hyperalgesia: A surrogate pain model to study the relationship of insomnia and pain

Sleep disturbances are highly prevalent in chronic pain patients. Understanding their relationship has become an important research topic since poor sleep and pain are assumed to closely interact. To date, human experimental studies exploring the impact of sleep disruption/deprivation on pain perception have yielded conflicting results. This inconsistency may be due to the large heterogeneity of study populations and study protocols previously used. In addition, none of the previous studies investigated the entire spectrum of nociceptive modalities. To address these shortcomings, a standardized comprehensive quantitative sensory protocol was used in order to compare the somatosensory profile of 14 healthy subjects (6 female, 8 male, 23.5 ± 4.1 year; mean ± SD) after a night of total sleep deprivation (TSD) and a night of habitual sleep in a cross-over design. One night of TSD significantly increased the level of sleepiness (P < 0.001) and resulted in higher scores of the State Anxiety Inventory (P < 0.01). In addition to previously reported hyperalgesia to heat (P < 0.05) and blunt pressure (P < 0.05), study participants developed hyperalgesia to cold (P < 0.01) and increased mechanical pain sensitivity to pinprick stimuli (P < 0.05) but no changes in temporal summation. Paradoxical heat sensations or dynamic mechanical allodynia were absent. TSD selectively modulated nociception, since detection thresholds of non-nociceptive modalities remained unchanged. Our findings show that a single night of TSD is able to induce generalized hyperalgesia and to increase State Anxiety scores. In the future, TSD may serve as a translational pain model to elucidate the pathomechanisms underlying the hyperalgesic effect of sleep disturbances.     

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

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

Sessions of Prolonged Continuous Theta Burst Stimulation or High-frequency 10 Hz Stimulation to Left Dorsolateral Prefrontal Cortex for 3 Days Decreased Pain Sensitivity by Modulation of the Efficacy of Conditioned Pain Modulation

The 10 Hz repetitive transcranial magnetic stimulation (10 Hz-rTMS) to the left dorsolateral prefrontal cortex produces analgesia, probably by activating the pain modulation system. A newer rTMS paradigm, called theta burst stimulation (TBS), has been developed. Unlike 10 Hz-rTMS, prolonged continuous TBS (pcTBS) mimics endogenous theta rhythms, which can improve induction of synaptic long-term potentiation. Therefore, this study investigated whether pcTBS to the left dorsolateral prefrontal cortex reduced pain sensitivity more efficiently compared with 10 Hz-rTMS, the analgesic effects lasted beyond the stimulation period, and the reduced pain sensitivity was associated with increased efficacy of conditioned pain modulation (CPM) and/or intracortical excitability. Sixteen subjects participated in a randomized cross-over study with pcTBS and 10 Hz-rTMS. Pain thresholds to heat (HPT), cold, pressure (PPT), intracortical excitability assessment, and CPM with mechanical and heat supra-pain threshold test stimuli and the cold pressor test as conditioning were collected before (Baseline), 3 (Day3) and 4 days (Day4) after 3-day session of rTMS. HPTs and PPTs increased with 10 Hz-rTMS and pcTBS at Day3 and Day4 compared with Baseline (P = .007). Based on pooled data from pcTBS and 10 Hz-rTMS, the increased PPTs correlated with increased efficacy of CPM at Day3 (P = .008), while no correlations were found at Day4 or with the intracortical excitability.PerspectivePreliminary results of this comparative study did not show stronger pain sensitivity reduction by pcTBS compared with 10 Hz-rTMS to the L-DPFC. Both protocols maintained increased pain thresholds up to 24-hours after the last session, which were partially associated with modulation of CPM efficacy but not with the intracortical excitability changes.     

Investigation of pain sensitivity following 3 nights of disrupted sleep in healthy individuals

Background

Poor quality sleep is a common complaint among people with chronic pain. The co-occurrence of poor sleep quality and chronic pain often comes with increased pain intensity, more disability and a higher cost of healthcare. Poor sleep has been suggested to affect measures of peripheral and central pain mechanisms. To date, sleep provocations are the only models proven to affect measures of central pain mechanisms in healthy subjects. However, there are limited studies investigating the effect of several nights of sleep disruption on measures of central pain mechanisms.

Methods

The current study implemented three nights of sleep disruption with three planned awakenings per night in 30 healthy subjects sleeping at home. Pain testing was conducted at the same time of day at baseline and follow-up for each subject. Pressure pain thresholds were assessed bilaterally on the infraspinatus and gastrocnemius muscles. Using handheld pressure algometry, suprathreshold pressure pain sensitivity and area were also investigated on the dominant infraspinatus muscle. Cuff-pressure pain detection and tolerance thresholds, temporal summation of pain and conditioned pain modulation were investigated using cuff-pressure algometry.

Results

Temporal summation of pain was significantly facilitated (p = 0.022), suprathreshold pain areas (p = 0.005) and intensities (p < 0.05) were significantly increased, and all pressure pain thresholds were decreased (p < 0.005) after sleep disruption compared to baseline.

Conclusions

The current study found that three consecutive nights of sleep disruption at home induced pressure hyperalgesia and increased measures of pain facilitation in healthy subjects, which is consistent with previous findings.

Significance

Poor quality of sleep is often experienced by patients with chronic pain, with the most common complaint being nightly awakenings. This exploratory study is the first to investigate changes in measures of central and peripheral pain sensitivity in healthy subjects after sleep disruptions for three consecutive nights without any restrictions on total sleep time. The findings suggest that disruptions to sleep continuity in healthy individuals can induce increased sensitivity to measures of central and peripheral pain sensitization.     

Conditioned Pain Modulation and Pressure Pain Sensitivity in the Adult Danish General Population: The DanFunD Study

Increased pressure pain sensitivity and impaired descending pain control have been associated with chronic pain, but knowledge on the variability in the adult general population is lacking. Pressure pain thresholds (PPTs) and descending pain control assessed using conditioned pain modulation (CPM) were recorded in a randomly selected sample (n = 2,199, 53% female) of the Danish adult general population aged 18 to 70 years. PPTs were recorded over the tibialis anterior muscle and the upper trapezius muscle. CPM was defined as the difference between PPT assessments before and during conditioning with cold pressor pain (hand) for 2 minutes. Conditioning pain intensity was assessed using a visual analog scale and questionnaire data were collected. Female sex (P < .001) and younger age (P ≤ .02) was associated with lower PPTs at both body sites. For the trapezius muscle, high perceived stress was associated with lower PPTs (P < .02), whereas an interaction was found between body mass index and sex. CPM potency was lower in female compared with male participants (P ≤ .003), whereas no association with age was found. Higher level of education (P ≤ .05), premature withdrawal from the cold pressor test (P ≤ .02), and high visual analog scale score (P ≤ .02) were associated with a larger CPM response.

Immediate effects of dry needling on pain sensitivity and pain modulation in patients with chronic idiopathic neck pain: a single-blinded randomized clinical trial

BackgroundDry needling is frequently used for the treatment of neck pain but knowledge about its neurophysiological central effects is scarce.ObjectivesTo compare the immediate effects of a single session of dry needling (DN) and sham needling (SN) on local and distant pressure pain thresholds and conditioned pain modulation in patients with chronic idiopathic neck pain.MethodParticipants with chronic idiopathic neck pain were randomly allocated to a DN or SN group. The primary outcome measure was the pressure pain threshold (PPT) at one peripheral location: quadriceps muscle (Q). Secondary outcome measures were local PPTs at the treated (most painful) (tUT) and non-treated upper trapezius muscle (ntUT), absolute and relative conditioned pain modulation (CPM) effects and pain during hot water immersion. Patients were assessed at baseline and immediately post intervention. Linear mixed models were used to examine interaction effects as well as between- and within-group differences.ResultsFifty-four participants were included for statistical analysis. Linear mixed model analyses showed no significant “group X time” interaction effects for any of the outcome measures. The relative CPM effect at the Q was significantly higher post-intervention, compared to baseline within the DN group (mean difference= 13.52%; 95% CI: 0.46, 26.59).ConclusionThe present study shows no superior effect of DN, compared to SN, in the immediate effect on local and distant PPTs and CPM in patients with chronic idiopathic neck pain.     

Schlafentzug und Schmerz

It has now been established that sleep deprivation or fragmentation causes hyperalgesia which cannot be explained by a general change in somatosensory perception. However, it has not yet been clarified which of the sleep stages are most relevant for this effect. The seemingly paradoxical effects of sleep deprivation on pain-evoked brain potentials on the one hand and the subjective pain report on the other hand suggest complex changes in gating mechanisms. As the effects on pain and affect can be dissociated a common mechanism of action seems unlikely. Data from animal studies suggest that hyperalgesia due to sleep deprivation might be particularly strong under preexisting neuropathic conditions. Together with results from animal research the finding that endogenous pain modulation (CPM) is impaired by sleep deprivation suggests that the serotoninergic system mediates the effect of sleep deprivation on pain perception. However, other neurotransmitters and neuromodulators still have to be considered. The clinically relevant question arises why sleep deprivation induces hyperalgesia more easily in certain individuals than in others and why this effect then has a longer duration?     

Widespread sensitization in patients with chronic pain after revision total knee arthroplasty

Pain and sensitization are major issues in patients with osteoarthritis both before and after total knee arthroplasty (TKA) and revision TKA (re-TKA). The aim of this study was to assess sensitization in patients with and without chronic pain after re-TKAs. Twenty patients with chronic knee pain and 20 patients without pain after re-TKA participated. Spreading of pain was evaluated as the number of pain sites using a region-divided body chart. The pressure pain threshold (PPT) and pressure pain tolerance (PTT) were assessed by cuff algometry at the lower leg. Temporal summation of pain was assessed by recordings of the pain intensity on a visual analog scale (VAS) during repeated cuff pressure stimulations. Conditioning pain modulation (CPM) was recorded by experimental tonic arm pain by cuff pressure stimulation and assessment of PPTs on the knee, leg, and forearm using handheld pressure algometry. Participants with pain after re-TKA compared to participants without pain demonstrated: (1) significantly more pain sites (P = .004), (2) decreased cuff PPTs and PTTs at the lower leg (P < .001), (3) facilitated temporal summation (P < .001), and (4) impaired CPM (P < .001). Additionally, significant correlations between knee pain intensity and cuff PPTs, temporal summation, and CPM and between total duration of knee pain and temporal summation were found (P < .05). This study demonstrated widespread sensitization in patients with pain after re-TKA and highlighted the importance of ongoing nociceptive input for the chronification process. This has important implications for future revisions, and precautions should be taken if patients have widespread sensitization.     

Punishing the Self: Post-Traumatic Guilt Mediates the Link Between Trauma and Deficient Pain Modulation

Trauma survivors may suffer from post-traumatic stress disorder (PTSD), elevated post-traumatic guilt (PG), and alterations in the pain system. However, the association between PG and alterations in pain perception and modulation among trauma survivors has not been established, nor has the possible underlying role of PG. This longitudinal study investigated: 1) the unique contribution of PG in predicting pain perception and modulation, while controlling for PTSD symptoms; and 2) the mediating role of PG in explaining pain perception and modulation among torture survivors, above and beyond PTSD symptoms. Participants were 59 torture survivors and 44 age-matched controls. PG and PTSD symptoms were assessed in 2003 (T1). Heat-pain threshold, heat-pain tolerance, temporal summation of pain (TSP), and conditioned pain modulation (CPM) were measured 5 years later (T2). Torture survivors had elevated PG and PTSD symptoms, enhanced TSP, and reduced CPM, compared to controls. While PTSD predicted reduced pain tolerance and CPM, PG predicted increased pain tolerance. Moreover, PG mediated the associations between torture and (increased) pain threshold, pain tolerance, and TSP. It appears that PTSD and PG induce opposite effects on the pain modulation capacity of torture survivors, a dichotomy that may explain paradoxical pain responses among trauma survivors, as discussed.PerspectiveThis longitudinal study sheds light on the possible mechanisms underlying variations in pain perception and modulation among trauma survivors. PTSD and PG each mediated opposing pain modulation profiles, suggesting that individual responses to trauma, rather than the trauma itself, influence pain responses.     

Similarities between exercise-induced hypoalgesia and conditioned pain modulation in humans

Pain inhibitory mechanisms are often assessed by paradigms of exercise-induced hypoalgesia (EIH) and conditioned pain modulation (CPM). In this study it was hypothesized that the spatial and temporal manifestations of EIH and CPM were comparable. The participants were 80 healthy subjects (40 females), between 18 and 65 years of age in this randomized, repeated-measures cross-over trial that involved data collection on 2 different days. CPM was assessed by 2 different cold pressor tests (hand and foot). EIH was assessed by 2 intensities of aerobic bicycling exercises and 2 intensities of isometric muscle contraction exercises (arm and leg). Pressure pain thresholds (PPTs) were recorded before, during, after, and 15 minutes after conditioning/exercise at sites local to and remote from the extremity used for cold pressor stimulation and exercise. PPTs increased at local as well as at remote sites during both cold pressor tests and after all of the exercise conditions except low-intensity bicycling. EIH after bicycling was higher in women than in men. CPM and the EIH responses after isometric exercises were comparable in men and women and were not affected by age. The EIH response was larger in the exercising body part compared with nonexercising body parts for all exercise conditions. High-intensity exercise produced greater EIH responses than did low-intensity exercise. The change in PPTs during cold pressor tests and the change in PPTs after exercises were not correlated. The CPM response was not dominated by local manifestations, and the effect was seen only during the stimulation, whereas exercise had larger local manifestations, and the effects were also found after exercise.     

Effect of Estrogen Depletion on Pain Sensitivity in Aromatase Inhibitor–Treated Women With Early-Stage Breast Cancer

Aromatase inhibitors (AIs), which are used to treat breast cancer, inhibit estrogen production in postmenopausal women. AI-associated musculoskeletal symptoms occur in approximately half of treated women and lead to treatment discontinuation in 20 to 30%. The etiology may be due in part to estrogen deprivation. In premenopausal women, lower estrogen levels have been associated with increased pain as well as with impairment of descending pain inhibitory pathways, which may be a risk factor for developing chronic pain. We prospectively tested whether AI-induced estrogen deprivation alters pain sensitivity, thereby increasing the risk of developing AI-associated musculoskeletal symptoms. Fifty postmenopausal breast cancer patients underwent pressure pain testing and conditioned pain modulation (CPM) assessment prior to AI initiation and after 3 and 6 months. At baseline, 26 of 40 (65%) assessed patients demonstrated impaired CPM, which was greater in those who had previously received chemotherapy (P = .006). No statistically significant change in pressure pain threshold or CPM was identified following estrogen deprivation. In addition, there was no association with either measure of pain sensitivity and change in patient-reported pain with AI therapy. AI-associated musculoskeletal symptoms are not likely due to decreased pain threshold or impaired CPM prior to treatment initiation, or to effects of estrogen depletion on pain sensitivity.PerspectiveThis article presents our findings of the effect of estrogen deprivation on objective measures of pain sensitivity. In postmenopausal women, medication-induced estrogen depletion did not result in an identifiable change in pressure pain threshold or CPM. Impaired CPM may be associated with chemotherapy.     

Modulation of central pain mechanisms using high-definition transcranial direct current stimulation: A double-blind,sham-controlled study

Background

The use of high-definition transcranial direct current stimulation (HD-tDCS) has shown analgesic effects in some chronic pain patients, but limited anti-nociceptive effects in healthy asymptomatic subjects.

Methods

This double-blinded sham-controlled study assessed the effects of HD-tDCS applied on three consecutive days on central pain mechanisms in healthy participants with (N = 40) and without (N = 40) prolonged experimental pain induced by intramuscular injection of nerve growth factor into the right hand on Day 1. Participants were randomly assigned to Sham-tDCS (N = 20 with pain, N = 20 without) or Active-tDCS (N = 20 with pain, N = 20 without) targeting simultaneously the primary motor cortex and dorsolateral prefrontal cortex for 20 min with 2 mA stimulation intensity. Central pain mechanisms were assessed by cuff algometry on the legs measuring pressure pain sensitivity, temporal summation of pain (TSP) and conditioned pain modulation (CPM), at baseline and after HD-tDCS on Day 2 and Day 3. Based on subject's assessment of received HD-tDCS (sham or active), they were effectively blinded.

Results

Compared with Sham-tDCS, Active-tDCS did not significantly reduce the average NGF-induced pain intensity. Tonic pain-induced temporal summation at Day 2 and Day 3 was significantly lower in the NGF-pain group under Active-tDCS compared to the pain group with Sham-tDCS (p ≤ 0.05). No significant differences were found in the cuff pressure pain detection/tolerance thresholds or CPM effect across the 3 days of HD-tDCS in any of the four groups.

Conclusion

HD-tDCS reduced the facilitation of TSP caused by tonic pain suggesting that efficacy of HD-tDCS might depend on the presence of sensitized central pain mechanisms.     

Exposure to an Immersive Virtual Reality Environment can Modulate Perceptual Correlates of Endogenous Analgesia and Central Sensitization in Healthy Volunteers

Virtual reality (VR) has been shown to produce analgesic effects during different experimental and clinical pain states. Despite this, the top-down mechanisms are still poorly understood. In this study, we examined the influence of both a real and sham (ie, the same images in 2D) immersive arctic VR environment on conditioned pain modulation (CPM) and in a human surrogate model of central sensitization in 38 healthy volunteers. CPM and acute heat pain thresholds were assessed before and during VR/sham exposure in the absence of any sensitization. In a follow-on study, we used the cutaneous high frequency stimulation model of central sensitization and measured changes in mechanical pain sensitivity in an area of heterotopic sensitization before and during VR/sham exposure. There was an increase in CPM efficiency during the VR condition compared to baseline (P < .01). In the sham condition, there was a decrease in CPM efficiency compared to baseline (P < .01) and the real VR condition (P < .001). Neither real nor sham VR had any effect on pain ratings reported during the conditioning period or on heat pain threshold. There was also an attenuation of mechanical pain sensitivity during the VR condition indicating a lower sensitivity compared to sham (P < .05). We conclude that exposure to an immersive VR environment has no effect over acute pain thresholds but can modulate dynamic CPM responses and mechanical hypersensitivity in healthy volunteers.PerspectiveThis study has demonstrated that exposure to an immersive virtual reality environment can modulate perceptual correlates of endogenous pain modulation and secondary hyperalgesia in a human surrogate pain model. These results suggest that virtual reality could provide a novel mechanism-driven analgesic strategy in patients with altered central pain processing.     

Individual Variation in Pain Sensitivity and Conditioned Pain Modulation in Acute Low Back Pain: Effect of Stimulus Type,Sleep, and Psychological and Lifestyle Factors

Generalized hyperalgesia and impaired pain modulation are reported in chronic low back pain (LBP). Few studies have tested whether these features are present in the acute phase. This study aimed to test for differences in pain presentation in early-acute LBP and evaluate the potential contribution of other factors to variation in sensitivity. Individuals within 2 weeks of onset of acute LBP (n?=?126) and pain-free controls (n?=?74) completed questionnaires related to their pain, disability, behavior, and psychological status before undergoing conditioned pain modulation (CPM) and pain threshold (heat, cold, and pressure) testing at the back and forearm/thumb. LBP participants were more sensitive to heat and cold at both sites and pressure at the back than controls, without differences in CPM. Only those with high-pain (numeric rating scale ≥4) were more sensitive to heat at the forearm and pressure at the back. Four subgroups with distinct features were identified: “high sensitivity,” “low CPM efficacy,” “high sensitivity/low CPM efficacy,” and “low sensitivity/high CPM efficacy.” Various factors such as sleep and alcohol were associated with each pain measure. Results provide evidence for generalized hyperalgesia in many, but not all, individuals during acute LBP, with variation accounted for by several factors. Specific pain phenotypes provide candidate features to test in longitudinal studies of LBP outcome.

Should Exercises be Painful or not? Effects on Clinical and Experimental Pain in Individuals with Shoulder Pain

Exercise can reduce pain, however the effect of painful versus non-painful exercises is uncertain. The primary aim of this randomized crossover study was to compare the effect of painful versus nonpainful isometric shoulder exercises on pain intensity after exercise in individuals with rotator cuff-related shoulder pain. Secondary exploratory aims were to describe the effects on pressure pain thresholds (PPTs), conditioned pain modulation (CPM) and muscle strength. On separate days, 35 individuals performed painful isometric shoulder exercises (external rotation; 20% above pain threshold), nonpainful isometric shoulder exercises (external rotation; 20% below pain threshold), and a rest condition, in randomised order. Shoulder pain intensity, PPTs, CPM, and external rotation strength were assessed before, immediately after and 45 minutes after conditions. No significant differences were observed between painful and nonpainful exercises. Visual analogue scale scores increased immediately after both painful and non-painful exercises compared with rest (P = .047, partial ƞ² = .07), but were similar to preexercise levels after 45 minutes. No changes in PPTs, CPM, or muscle strength after exercises compared with rest were observed. Painful and non-painful isometric exercises caused a moderate but short-lasting increase in shoulder pain in individuals with RCRSP. Isometric exercises had no effect on pain sensitivity and shoulder muscle strength or CPM.PerspectiveThis study evaluated for the first time in individuals with rotator cuff-related shoulder pain the effects of painful versus non-painful isometric exercises on different pain-related outcome measures. Both painful and non-painful isometric exercises caused a moderate but relatively short-lasting increase in shoulder pain in individuals with rotator cuff-related shoulder pain.Trial registration number: (ClinicalTrials.gov) NCT03675399     

Adaptability to pain is associated with potency of local pain inhibition,but not conditioned pain modulation: A healthy human study

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.     

Activation of the prostaglandin system in response to sleep loss in healthy humans: Potential mediator of increased spontaneous pain

Insufficient duration of sleep is a highly prevalent behavioral pattern in society that has been shown to cause an increase in spontaneous pain and sensitivity to noxious stimuli. Prostaglandins (PGs), in particular PGE2, are key mediators of inflammation and pain, and we investigated whether PGE2 is a potential mediator in sleep-loss-induced changes in nociceptive processing. Twenty-four participants (7 females, age 35.1 ± 7.1 years) stayed for 7 days in the Clinical Research Center. After two baseline days, participants were randomly assigned to either 3 days of 88 h of sleep deprivation (TSD, N = 15) or 8 h of sleep per night (N = 9), followed by a night of recovery sleep. Participants rated the intensity of various pain-related symptoms every 2 h across waking periods on computerized visual analog scales. PGE2 was measured in 24-h-urine collections during baseline and third sleep deprivation day. Spontaneous pain, including headache, muscle pain, stomach pain, generalized body pain, and physical discomfort significantly increased by 5–14 units on a 100-unit scale during TSD, compared to the sleep condition. Urinary PGE2 metabolite significantly increased by about 30% in TSD over sleep condition. TSD-induced increase in spontaneous pain, in particular headache and muscle pain, was significantly correlated with increase in PGE2 metabolite. Activation of the PGE2 system appears to be a potential mediator of increased spontaneous pain in response to insufficient sleep.     

Pain referral and regional deep tissue hyperalgesia in experimental human hip pain models

Hip disorder patients typically present with extensive pain referral and hyperalgesia. To better understand underlying mechanisms, an experimental hip pain model was established in which pain referrals and hyperalgesia could be studied under standardized conditions. In 16 healthy subjects, pain was induced by hypertonic saline injection into the gluteus medius tendon (GMT), adductor longus tendon (ALT), or gluteus medius muscle (GMM). Isotonic saline was injected contralaterally as control. Pain intensity was assessed on a visual analogue scale (VAS), and subjects mapped the pain distribution. Before, during, and after injections, passive hip joint pain provocation tests were completed, together with quantitative sensory testing as follows: pressure pain thresholds (PPTs), cuff algometry pain thresholds (cuff PPTs), cutaneous pin-prick sensitivity, and thermal pain thresholds. Hypertonic saline injected into the GMT resulted in higher VAS scores than hypertonic injections into the ALT and GMM (P < .05). Referred pain areas spread to larger parts of the leg after GMT and GMM injections compared with more regionalized pain pattern after ALT injections (P < .05). PPTs at the injection site were decreased after hypertonic saline injections into GMT and GMM compared with baseline, ALT injections, and isotonic saline. Cuff PPTs from the thigh were decreased after hypertonic saline injections into the ALT compared with baseline, GMT injections, and isotonic saline (P < .05). More subjects had positive joint pain provocation tests after hypertonic compared with isotonic saline injections (P < .05), indicating that this provocation test also assessed hyperalgesia in extra-articular soft tissues. The experimental models may open for better understanding of pain mechanisms associated with painful hip disorders.     

Experimental human muscle pain and muscular hyperalgesia induced by combinations of serotonin and bradykinin.

In the present study, we assessed the muscle pain and possible development of muscular hyperalgesia to mechanical stimuli after two subsequent intramuscular infusions of serotonin (5-HT) and bradykinin (BKN). The pain intensity after the infusions was continuously scored on a visual analogue scale (VAS). The subjects drew the distribution of the pain areas on a map. Pressure pain thresholds (PPTs) and suprapressure pain thresholds (SPPTs) stimulations as 150% of the pre-infusion PPTs were assessed with a pressure algometer at the injection site (10 cm below the patella), at the ankle, and at the contralateral leg and ankle. Skin sensibility was assessed with a Von Frey hair at the same sites. This was done before and after an infusion into the tibialis anterior (TA) muscle on the right leg in ten volunteers. The first infusion in each combination was either serotonin (20 nmol) or isotonic saline (NaCl 0.9%). The second infusion was bradykinin (5 or 10 nmol) or isotonic saline. The two infusions were given over 20 s and separated by 3 min. The isotonic saline followed by BKN did not induce muscle pain or muscular hyperalgesia. However, the combination of 5-HT and BKN (10 nmol) produced: (1) significantly higher VAS scores (P < 0.05) compared with all other combinations; (2) significantly longer pain offset (P < 0.05) compared with the combinations of isotonic saline and BKN; (3) significantly lower PPTs at 5, 20, and 40 min post-infusion (P < 0.05) compared with baseline PPT and PPTs after all other combinations. Cutaneous sensibility to mechanical stimuli and SPPTs were not affected by any of the combinations. The combinations of serotonin and bradykinin produce experimental muscle pain and muscular hyperalgesia to mechanical stimuli. Pre-treatment with serotonin may enhance the effect of bradykinin in the generation of muscle pain and muscular hyperalgesia in humans.