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We explored the ongoing question of whether placebo analgesia alters afferent nociceptive processing in a novel paradigm designed to minimize the role of response bias in placebo measurement. First, healthy adult participants received a standard heat placebo induction and conditioning procedure using a topical "analgesic" cream applied to one arm. During a subsequent placebo testing procedure, participants rated stimuli on the placebo-treated arm and untreated arm, using a task that minimized subjects' ability to guess the expected response, thus reducing experimenter demand. Retrospectively participants reported moderate analgesia effectiveness (mean=5.3/10), but for individual temperature ratings, only 2 subjects exhibited a perceptual placebo response >5 points. Next, these subjects completed a novel, exploratory task designed to measure changes in inter-arm in discriminative accuracy that would be expected from changes in afferent nociception. Both placebo responders (but no non-responders) showed reduced discriminative ability when the hotter stimulus occurred on the placebo arm, an effect consistent with alterations in nociceptive afferent flow and unlikely to be caused by response bias.
Learn More >Non-restorative sleep is a key diagnostic feature of the musculoskeletal pain disorder fibromyalgia, and is robustly associated with poor physical functioning, including activity interference. However, the mechanisms through which non-restorative sleep elicits activity interference among individuals with fibromyalgia at the within-person level remain unclear. The present study tested the following three-path mediation model, using data gathered from a 21-day electronic daily diary in 220 individuals with fibromyalgia: previous night non-restorative sleep → morning pain catastrophizing → afternoon pain severity → end-of-day activity interference. Results of multilevel structural equation modeling supported the three-path mediation model. Previous night's non-restorative sleep and morning pain catastrophizing were also directly related to end-of-day activity interference. Previous night non-restorative sleep did not significantly predict afternoon pain severity while controlling for the effect of morning pain catastrophizing. Greater non-restorative sleep during the previous night and a higher level of morning pain catastrophizing appear to serve as risk factors for experiencing greater daily pain and activity interference later in the day. These findings point to the potential utility of targeted interventions that improve both sleep quality and pain catastrophizing to help individuals with chronic pain engage in important daily activities despite experiencing pain.
Learn More >Quantitative sensory testing (QST) is used to systematically interrogate normal responding and alterations of nervous system function, including pain related central sensitization (CS). However, up to now QST of CS in human subjects has been mostly focused on temporal summation of second pain (TSSP), has been difficult to perform, and has been associated with low reliability. In contrast, slow ramp & hold (RH) procedures are simpler tests of temporal summation and easier to perform. We examined the usefulness of RH procedures as reliable generators of CS using two validated QST procedures: decay of pain aftersensations and wind-down. Twenty-seven pain-free subjects (74% female) were enrolled into the study. Trains of sensitivity adjusted TSSP or RH heat stimuli were applied to the hands of participants to achieve moderate temporal pain summation [50 NRS (0-100)]. Fifteen second aftersensations and 30s wind-down related to TSSP or RH were used for CS comparisons. Reliability of all test procedures was tested over 24 h. Use of sensitivity adjusted TSSP and RH heat stimuli resulted in average pain ratings of 48.2 and 49.6 NRS, respectively. Aftersensations or wind-down decay were not significantly different after either TSSP or RH, (all p > .05), indicating that each procedure achieved similar levels of short-term CS. Sensitivity adjusted RH stimuli were well tolerated and resulted in reliable pain increases of 50 NRS. The magnitude of short-term CS, determined by aftersensations and wind-down was similar after sensitivity-adjusted TSSP and RH stimuli (p > .05), suggesting that pain facilitation of healthy participants and likely chronic pain patients can not only be tested with TSSP but also with RH procedures. Perspective: This article examines the ability of RH procedures to generate similar central sensitivity augmentation than TSSP. The results suggest that RH is similarly well suited as TSSP to explore central pain mechanisms in healthy subjects and most likely also in chronic pain patients.
Learn More >Compared to acute postsurgical pain, studies regarding the role of ketamine in persistent postsurgical pain (PPSP) are limited.
Learn More >The use of long-term opioid therapy for chronic pain remains common, yet data on long-term outcomes, especially after dose escalation, are sparse. This study examined potential benefits and harms associated with prescription opioid dose escalation. Participants from two institutions were enrolled in a two-year prospective cohort study. All participants (n=517) had a musculoskeletal pain diagnosis and were receiving a stable dose of long-term opioid therapy at baseline. Participants completed self-report measures of pain, disability, depression, and potential adverse effects at baseline and every six months for two years. We reviewed electronic health record data weekly to identify episodes of prescription opioid dose escalation; participants who had increases in their dose were seen for additional research visits within one month of dose escalation. Over two years, 19.5% of participants had prescription opioid dose increases. After controlling for covariates, there were no significant changes on any variable following dose escalation. Of those with a dose increase, 3% experienced a clinically meaningful improvement in pain following dose escalation. Participants in the entire sample had small improvements in pain intensity, depressive symptoms, medication-related side effects, and lower risk for prescription opioid misuse during the study period. Sexual functioning worsened over time. There were no significant changes in the full sample on pain disability, sleep functioning, or experiencing a fall. In summary, patients prescribed stable doses of long-term opioid therapy may demonstrate small changes in key pain-related outcomes over time, but prescription opioid dose escalation status is unrelated to clinical outcomes.
Learn More >Traumatic injury is a major source of chronic pain, particularly for individuals with traumatic fracture of the fibula and/or tibia (lower extremity fracture) [LEFx]. Although several factors (e.g., older age, being female sex, high pain intensity at time of initial injury) have been identified as risk factors for chronic pain associated with LEFx. Comprehensive biopsychosical models to predict the odds of transitioning from acute to chronic pain after LEFx are needed to better understand the underlying processes, predict risk for chronic pain, and develop personalized therapies for individuals at higher risk for developing chronic pain.
Learn More >To identify and validate an fMRI-based neural marker for migraine without aura (MwoA) and to examine its association with treatment response.
Learn More >Lasmiditan (LY573144/COL-144) is a high-affinity, centrally penetrant, selective 5-HT receptor agonist currently under investigation for acute treatment of migraine. Although lasmiditan is not known to induce vasoconstriction, it remains important to understand its effect on cardiovascular parameters because it is likely to be coadministered with β-adrenergic receptor antagonists used for migraine prophylaxis, such as propranolol. This phase 1, single-center, open-label, fixed-sequence study evaluated the cardiovascular and pharmacokinetic effects of 200 mg lasmiditan in 44 healthy subjects receiving repeated oral doses of twice-daily 80 mg propranolol under fasting conditions. Coadministration caused statistically significant decreases in mean hourly heart rate relative to propranolol alone, but the maximum magnitude of this effect was -6.5 bpm and recovered to predose levels by 3 to 4 hours before stabilizing. Additionally, short-lived (≤2.5 hours) statistically significant increases in systolic blood pressure (8.3 mm Hg) and diastolic blood pressure (6.4 mm Hg) were observed following coadministration. Consistent with the largely nonoverlapping metabolic pathways of lasmiditan and propranolol, exposure to either drug was not affected by coadministration. Overall, compared with administration of either drug alone, coadministration was generally well tolerated.
Learn More >Offset analgesia (OA), a large reduction in pain after a brief increase in intensity of an otherwise stable painful stimulus, has been established by a large body of research. But the opposite effect, onset hyperalgesia (OH), a disproportional hyperalgesic response after a briefly decreased intensity of a painful stimulus, has only been investigated in one previous study.
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