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A major problem in pain medicine is the lack of knowledge about which treatment suits a specific patient. We tested the ability of quantitative sensory testing to predict the analgesic effect of pregabalin and placebo in patients with chronic pancreatitis. Sixty-four patients with painful chronic pancreatitis received pregabalin (150-300 mg BID) or matching placebo for three consecutive weeks. Analgesic effect was documented in a pain diary based on a visual analogue scale. Responders were defined as patients with a reduction in clinical pain score of 30% or more after three weeks of study treatment compared to baseline recordings. Prior to study medication, pain thresholds to electric skin and pressure stimulation were measured in dermatomes T10 (pancreatic area) and C5 (control area). To eliminate inter-subject differences in absolute pain thresholds an index of sensitivity between stimulation areas was determined (ratio of pain detection thresholds in pancreatic versus control area, ePDT ratio). Pain modulation was recorded by a conditioned pain modulation paradigm. A support vector machine was used to screen sensory parameters for their predictive power of pregabalin efficacy. The pregabalin responders group was hypersensitive to electric tetanic stimulation of the pancreatic area (ePDT ratio 1.2 (0.9-1.3)) compared to non-responders group (ePDT ratio: 1.6 (1.5-2.0)) (P = 0.001). The electrical pain detection ratio was predictive for pregabalin effect with a classification accuracy of 83.9% (P = 0.007). The corresponding sensitivity was 87.5% and specificity was 80.0%. No other parameters were predictive of pregabalin or placebo efficacy. The present study provides first evidence that quantitative sensory testing predicts the analgesic effect of pregabalin in patients with painful chronic pancreatitis. The method can be used to tailor pain medication based on patient's individual sensory profile and thus comprises a significant step towards personalized pain medicine.

RationaleMinocycline, a tetracycline antibiotic, inhibits activation of microglia. In preclinical studies, minocycline prevented development of opioid tolerance and opioid-induced hyperalgesia (OIH). The goal of this study was to determine if minocycline changes pain threshold and tolerance in individuals with opioid use disorder who are maintained on agonist treatment.MethodsIn this double-blind, randomized human laboratory study, 20 participants were randomized to either minocycline (200 mg/day) or placebo treatment for 15 days. The study had three test sessions (days 1, 8, and 15 of treatment) and one follow-up visit 1 week after the end of treatment. In each test session, participants were assessed on several subjective and cognitive measures, followed by assessment of pain sensitivity using the Cold Pressor Test (CPT). Daily surveys and cognitive measures using Ecological Momentary Assessment (EMA) were also collected four times a day on days 8 through 14 of treatment, and proinflammatory serum cytokines were assessed before and on the last day of treatment.ResultsMinocycline treatment did not change pain threshold or tolerance on the CPT. Similarly, minocycline did not change severity of pain, opioid craving, withdrawal, or serum cytokines. Minocycline treatment increased accuracy on a Go/No-Go task.ConclusionsWhile these findings do not support minocycline’s effects on OIH, minocycline may have a potential use as a cognitive enhancer for individuals with opioid use disorder, a finding that warrants further systematic studies.

The use of quantitative sensory testing (QST) has become more widespread, with increasing focus on describing somatosensory profiles and pain mechanisms. However, the reliability of thermal QST has yet to be established. We systematically searched the literature using key medical databases. Independent reviewers evaluated reliability data using the Quality Appraisal for Reliability Studies checklist. Of the 21 studies we included in this review, we deemed 5 to have high methodological quality. Narrative analysis revealed that estimates of reliability varied considerably, but overall, the reliability of cold and warm detection thresholds ranged from poor to excellent, while heat and cold pain thresholds ranged from fair to excellent. The methodological quality of research investigating the reliability of thermal QST warrants improvement, particularly in terms of appropriate blinding. The results from this review showed considerable variability in the reliability of each thermal QST parameter.

Declines in sensory functioning with aging are evident for many of the senses. In the present study, thresholds were determined for somatosensory (warming and cooling temperature, pain, touch, and two-point discrimination) and taste stimuli in 178 healthy individuals aged 20-89 yrs. Somatosensory stimuli were applied to the upper lip (glabrous skin) and the chin (hairy skin). The sample was divided into two groups, based on a bimodal split “< 45 yrs” and “≥ 65 yrs”. In all instances, there were elevations in thresholds for the older individuals. Further, males were less sensitive than females for cool at the chin site, for touch, and for sour taste. We conclude that there are elevations in sensory thresholds with age for multimodal somatosensory and gustatory senses.

Purpose This study aimed to establish a new threshold parameter called the physical working capacity at pain intensity threshold (PWC PIT ) using a pain intensity scale and mathematical methods similar to those used to develop the physical working capacity at oxygen consumption threshold (PWC VO2 ) and physical working capacity at heart rate threshold (PWC HRT ). The study had two objectives: (i) to examine the relationship between PWC PIT and traditional PWC measures and (ii) to explore the physiological mechanisms underlying the relationship between pain perception and capacity thresholds. Methods Fourteen male volunteers (age 21 ± 2 years, height 176 ± 6 cm, weight 76 ± 9 kg, VO 2peak 37.8 ± 7.8 ml/kg/min −1 ) underwent an incremental exhaustion test and four 8-min randomly ordered work bouts on different days at 70–100% peak power output (119–320 W) to establish their PWC PIT , PWC HRT and PWC VO2 . One-way repeated-measures ANOVA with Bonferroni post hoc tests and a zero-order correlation matrix were used to analyze these thresholds. Results PWC PIT significantly correlated with PWC HRT ( r  = 0.88, P  < 0.001), PWC VO2 ( r  = 0.84, P  < 0.001), and gas exchange threshold (GET) ( r  = 0.7, P  = 0.006). Conclusion The model for estimating PWC HRT and PWC VO2 can be applied to determine the PWC PIT . By examining how PWC PIT aligns with, differs from, or complements existing PWC threshold measures, researchers may provide a more comprehensive understanding of the factors that govern endurance performance.

Females demonstrate heightened central sensitization (CS), a risk factor for chronic pain characterized by enhanced responsivity of central nervous system nociceptors to normal or subthreshold input. Sleep disruption increases pain sensitivity, but sex has rarely been evaluated as a moderator and few experiments have measured CS. We evaluated whether two nights of sleep disruption alter CS measures of secondary hyperalgesia and mechanical temporal summation in a sex-dependent manner. We also evaluated differences in measures of pain sensitivity. Seventy-nine healthy adults (female n = 46) participated in a randomized crossover experiment comparing two consecutive nights of eight pseudorandomly distributed forced awakenings (FA [-200 min sleep time]) against two nights of undisturbed sleep (US). We conducted sensory testing the mornings following Night 2; the heat-capsaicin pain model was used to induce secondary hyperalgesia. FA reduced total sleep time (REM and NREM Stage 3) more profoundly in males. We observed divergent, sex-dependent effects of FA on secondary hyperalgesia and temporal summation. FA significantly increased secondary hyperalgesia in males and significantly increased temporal summation in females. Sex differences were not attributable to differential sleep loss in males. FA also significantly reduced heat-pain threshold and cold pressor pain tolerance, independently of sex. Sleep disruption enhances different pain facilitatory measures of CS in males and females suggesting that sleep disturbance may increase risk for chronic pain in males and females via distinct pathways. Findings have implications for understanding sex differences in chronic pain and investigating sleep in chronic pain prevention efforts.

The aim of this study was the assessment of progressive low-dose sodium bicarbonate (NaHCO 3 ) supplementation on the anaerobic indices in two bouts of Wingate tests (WT) separated by wrestling-specific performance test and assessing the gender differences in response. Fifty-one (18 F) wrestlers completed a randomized trial of either a NaHCO 3 (up to 100 mg·kg −1 ) or a placebo for 10 days. Before and after treatment, athletes completed an exercise protocol that comprised, in sequence, the first WT 1 , dummy throw test (DT), and second WT 2 . The number of completed throws increased significantly in males from 19.3 ± 2.6 NaHCO 3pre to 21.7 ± 2.9 NaHCO 3post . ΔWT 2 -WT 1 improved particularly in the midsection of 30-s WT on NaHCO 3 . However, no significant differences were found in peak power (PP), power drop (PD) and average power (AP) (analyzed separately for each WT), and ΔWT 2 -WT 1 in PP and PD. Interaction with gender was significant for AP, PP and PD, every second of WT 1 and WT 2 , as well as DT test. In conclusion, our study suggests that the response to NaHCO 3 may be gender-specific and progressive low-dose NaHCO 3 supplementation allows the advantageous strengthening of wrestling-specific performance in males. It can also lead to maintenance of high anaerobic power mainly in the midsection of the 30-s Wingate test.

PurposeAcute physical activity leads to exercise-induced hypoalgesia (EIH). The aim of this study was to investigate the effects of four different exercise intensities on EIH.Methods25 male (age: 24.7 ± 3.0) subjects underwent four different exercise sessions on a bicycle ergometer for 30 min each at 60, 80, 100, and 110% of the individual anaerobic threshold on separate days in a randomized crossover design. Before, as well as 5- and 45-min post-exercise, pain sensitivity was measured employing pain pressure thresholds (PPT) at the elbow, knee, and ankle joints as well as the sternum and forehead. Besides, conditioned pain modulation (CPM) was conducted using thermal test- and conditioned stimuli before, 5-, and 45-min post-exercise.ResultsA main time effect was observed regarding PPT at all landmarks except for the forehead with higher values observed 5 and 45 min post-exercise compared to the pre-values. Yet, no interaction effects occurred. CPM did not change in response to any of the intensities used.ConclusionEIH occurs 5 and 45 min after exercise regardless of the intensity used at the joints and sternum which might be explained by local pain-inhibiting pathways and probably to a limited degree by central mechanisms, as no hypoalgesia was observed at the forehead and no changes in CPM occurred.

Inhibition of Notch signalling with a gamma-secretase inhibitor (GSI) induces mammalian hair cell regeneration and partial hearing restoration. In this proof-of-concept Phase I/IIa multiple-ascending dose open-label trial (ISRCTN59733689), adults with mild-moderate sensorineural hearing loss received 3 intratympanic injections of GSI LY3056480, in 1 ear over 2 weeks. Phase I primary outcome was safety and tolerability. Phase lla primary outcome was change from baseline to 12 weeks in average pure-tone air conduction threshold across 2,4,8 kHz. Secondary outcomes included this outcome at 6 weeks and change from baseline to 6 and 12 weeks in pure-tone thresholds at individual frequencies, speech reception thresholds (SRTs), Distortion Product Otoacoustic Emissions (DPOAE) amplitudes, Signal to Noise Ratios (SNRs) and distribution of categories normal, present-abnormal, absent and Hearing Handicap Inventory for Adults/Elderly (HHIA/E). In Phase I ( N  = 15, 1 site) there were no severe nor serious adverse events. In Phase IIa ( N  = 44, 3 sites) the average pure-tone threshold across 2,4,8 kHz did not change from baseline to 6 and 12 weeks (estimated change −0.87 dB; 95% CI −2.37 to 0.63; P  = 0.252 and −0.46 dB; 95% CI −1.94 to 1.03; P  = 0.545, respectively), nor did the means of secondary measures. DPOAE amplitudes, SNRs and distribution of categories did not change from baseline to 6 and 12 weeks, nor did SRTs and HHIA/E scores. Intratympanic delivery of LY3056480 is safe and well-tolerated; the trial’s primary endpoint was not met. Pharmacological inhibition of gamma-secretase induced partial recovery of hearing in animal models. Here, the authors present the safety and efficacy results and key learnings of the First in Human Phase I/IIa study of a gamma-secretase inhibitor in patients with acquired Hearing Loss.

Decrease of olfactory function in Parkinson's disease (PD) is a well-investigated fact. Studies indicate that pharmacological treatment of PD fails to restore olfactory function in PD patients. The aim of this investigation was whether patients with PD would benefit from \"training\" with odors in terms of an improvement of their general olfactory function. It has been hypothesized that olfactory training should produce both an improved sensitivity towards the odors used in the training process and an overall increase of olfactory function. We recruited 70 subjects with PD and olfactory loss into this single-center, prospective, controlled non-blinded study. Thirty-five patients were assigned to the olfactory training group and 35 subjects to the control group (no training). Olfactory training was performed over a period of 12 weeks while patients exposed themselves twice daily to four odors (phenyl ethyl alcohol: rose, eucalyptol: eucalyptus, citronellal: lemon, and eugenol: cloves). Olfactory testing was performed before and after training using the \"Sniffin' Sticks\" (thresholds for phenyl ethyl alcohol, tests for odor discrimination, and odor identification) in addition to threshold tests for the odors used in the training process. Compared to baseline, trained PD patients experienced a significant increase in their olfactory function, which was observed for the Sniffin' Sticks test score and for thresholds for the odors used in the training process. Olfactory function was unchanged in PD patients who did not perform olfactory training. The present results indicate that olfactory training may increase olfactory sensitivity in PD patients.