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Chronic pain is a highly prevalent and costly issue that often emerges during childhood or adolescence and persists into adulthood. Adverse childhood experiences (ACEs) increase risk for several adverse health conditions, including chronic pain. Recent evidence suggests that parental trauma (ACEs, post-traumatic stress disorder (PTSD) symptoms) confers risk of poor health outcomes in their children. Intergenerational relationships between parental trauma and child chronic pain may be mediated by epigenetic mechanisms. A clinical sample of youth with chronic pain and their parents completed psychometrically sound questionnaires assessing ACEs, PTSD symptoms, and chronic pain, and provided a saliva sample. These were used to investigate the intergenerational relationships between four epigenetic biomarkers (COMT, DRD2, GR, and SERT), trauma, and chronic pain. The results indicated that the significant biomarkers were dependent upon the gender of the child, wherein parental ACEs significantly correlated with changes in DRD2 expression in female children and altered COMT expression in the parents of male children. Additionally, the nature of the ACE (maltreatment vs. household dysfunction) was associated with the specific epigenetic changes. There may be different pathways through which parental ACEs confer risk for poor outcomes for males and females, highlighting the importance of child gender in future investigations.
Learn More >: The opioid overdose epidemic has led health care providers to increased vigilance for opioid-related risks in the treatment of chronic non-cancer pain (CNCP). Media have conveyed stigmatizing representations of opioid analgesics. This study aimed to understand how the opioid overdose epidemic has impacted health care experiences among people living with CNCP in two Canadian provinces (British Columbia, Quebec). This qualitative study proceeded through 22 semi-structured interviews conducted in 2019. Participants were recruited from a cross-sectional survey examining the effects of the opioid overdose epidemic on individuals with CNCP. We collected in-depth narratives that we analyzed using a thematic framework. The sample included 12 women and 10 men aged 20 to 70 years, with 11 from each province. Several participants described increased difficulty in accessing medical services for pain since the onset of the opioid overdose epidemic. They reported that some physicians urged them to taper opioids regardless of their pain severity and functional limitations. Some participants reported facing discrimination and care denials as they were labeled "drug-seeking," especially in hospital. Depending on their educational resources, they were unequally able to counter providers' stigmatizing behaviors. However, participants described empathetic relationships with providers with whom they had a long-term relationship. Some participants drew distinctions between themselves and the stigmatized status of "addict" in ways that reinforced stigma toward people who are dependent on opioids. Health policies and provider education programs aimed at reducing opioid-related stigma are needed to counter detrimental consequences of the opioid overdose epidemic for people living with CNCP.
Learn More >Preclinical studies have demonstrated the analgesic potential of cannabidiol (CBD). Those suggesting an effect on pain-processing receptors have brought CBD back into focus. This study assessed the effect of CBD on acute pain, hyperalgesia, and allodynia compared with placebo. Twenty healthy volunteers were included in this randomized, placebo-controlled, double-blinded, crossover study assessing pain intensities (using numeric rating scale), secondary hyperalgesia (von Frey filament), and allodynia (dry cotton swab) in a well-established acute pain model with intradermal electrical stimulation. The authors compared the effect of 800-mg orally administered CBD on pain compared with placebo. They further examined the effect on hyperalgesia and allodynia. Cannabidiol whole blood levels were also measured. Pain ratings (mean ± SD) did not differ significantly after CBD application compared with placebo (5.2 ± 0.7 vs 5.3 ± 0.7, P-value 0.928), neither did the areas of hyperalgesia and allodynia differ significantly after CBD application compared with placebo (hyperalgesia 23.9 ± 19.2 cm2 vs 27.4 ± 17.0 cm2, P-value 0.597; allodynia 16.6 ± 13.1 cm2 vs 17.3 ± 14.1 cm2, P-value 0.884). The CBD whole blood level (median, first to third quartile) was 2.0 µg/L (1.5-5.1) 60 minutes and 5.0 µg/L (4.0-10.4) 130 minutes after CBD application. Although the oral application of 800-mg CBD failed to show a significant effect, it is important to focus future research on different dosing, routes of administration, and CBD as a part of multimodal treatment strategies before negating its effects on acute pain.
Learn More >Excess pain after visceral provocation has been suggested as a marker for chronic pelvic pain risk in women. However, few noninvasive tests have been validated that could be performed readily on youth in early risk windows. Therefore, we evaluated the validity and reliability of a noninvasive bladder pain test in 124 healthy premenarchal females (median age 11, [interquartile range 11-12]), as previously studied in adult women. We explored whether psychosocial, sensory factors, and quantitative sensory test results were associated with provoked bladder pain and assessed the relation of bladder pain with abdominal pain history. Compared with findings in young adult females (age 21 [20-28]), results were similar except that adolescents had more pain at first sensation to void (P = 0.005) and lower maximum tolerance volume (P < 0.001). Anxiety, depression, somatic symptoms, and pain catastrophizing predicted provoked bladder pain (P's < 0.05). Bladder pain inversely correlated with pressure pain thresholds (r = -0.25, P < 0.05), but not with cold pressor pain or conditioned pain modulation effectiveness. Bladder pain was also associated with frequency of abdominal pain symptoms (r = 0.25, P = 0.039). We found strong retest reliability for bladder pain at standard levels of sensory urgency in 21 adolescents who attended repeat visits at 6 to 12 months (intraclass correlations = 0.88-0.90). Noninvasive bladder pain testing seems reproducible in adolescent females and may predict abdominal pain symptomatology. Confirmation of our findings and further investigation of the bladder test across menarche will help establish how visceral sensitivity contributes to the early trajectory of pelvic pain risk.
Learn More >Nalfurafine has been used clinically in Japan for treatment of itch in kidney dialysis patients and in patients with chronic liver diseases. A one-year post-marketing study showed nalfurafine to be safe and efficacious without producing side effects of typical KOR agonists such as anhedonia and psychotomimesis. In this chapter, we summarize in vitro characterization and in vivo preclinical studies on nalfurafine. In vitro, nalfurafine is a highly potent and moderately selective KOR full agonist; however, whether it is a biased KOR agonist is a matter of debate. In animals, nalfurafine produced anti-pruritic effects in a dose range lower than that caused side effects, including conditioned place aversion (CPA), hypolocomotion, motor incoordination, consistent with the human data. In addition, nalfurafine showed antinociceptive effects in several pain models at doses that did not cause the side effects mentioned above. It appears to be effective against inflammatory pain and mechanical pain, but less so against thermal pain, particularly high-intensity thermal pain. U50,488H and nalfurafine differentially modulated several signaling pathways in a brain region-specific manners. Notably, U50,488H, but not nalfurafine, activated the mTOR pathway, which contributed to U50,488H-induced CPA. Because of its lack of side effects associated with typical KOR agonists, nalfurafine has been investigated as a combination therapy with an MOR ligand for pain treatment and for its effects on opioid use disorder and alcohol use disorder, and results indicate potential usefulness for these indications. Thus, although in vitro data regarding uniqueness of nalfurafine in terms of signaling at the KOR are somewhat equivocal, in vivo results support the assertion that nalfurafine is an atypical KOR agonist with a significantly improved side-effect profile relative to typical KOR agonists.
Learn More >Osteoarthritis (OA) is a chronic condition often associated with pain, affecting approximately fourteen percent of the population, and increasing in prevalence. A globally aging population have made treating OA-associated pain as well as maintaining mobility and activity a public health priority. OA affects all mammals, and the use of spontaneous animal models is one promising approach for improving translational pain research and the development of effective treatment strategies. Accelerometers are a common tool for collecting high-frequency activity data on animals to study the effects of treatment on pain related activity patterns. There has recently been increasing interest in their use to understand treatment effects in human pain conditions. However, activity patterns vary widely across subjects; furthermore, the effects of treatment may manifest in higher or lower activity counts or in subtler ways like changes in the frequency of certain types of activities. We use a zero inflated Poisson hidden semi-Markov model to characterize activity patterns and subsequently derive estimators of the treatment effect in terms of changes in activity levels or frequency of activity type. We demonstrate the application of our model, and its advance over traditional analysis methods, using data from a naturally occurring feline OA-associated pain model.
Learn More >The main objective of this pilot clinical trial was to evaluate outcome measures for the assessment of the nonsteroidal anti-inflammatory drug (NSAID) robenacoxib in cats with degenerative joint disease-associated pain (DJD-pain). Otherwise healthy cats (n = 109) with DJD-pain entered a parallel group, randomized, blinded clinical trial. Cats received placebo (P) or robenacoxib (R) for two consecutive 3-week periods. Treatment groups were PP, RR, and RP. Actimetry and owner-assessment data were collected. Data were analyzed using mixed-effects and generalized mixed-effects linear models. Activity data showed high within-cat and between-cat variability, and 82.4% of the values were zero. Compared to placebo, mean total activity was higher (5.7%) in robenacoxib-treated cats (p = 0.24); for the 80th percentile of activity, more robenacoxib-treated cats had a > 10% increase in activity after 3 (p = 0.046) and 6 weeks (p = 0.026). Robenacoxib treatment significantly decreased owner-assessed disability, (p = 0.01; 49% reduction in disability; effect size ~ 0.3), and improved temperament (p = 0.0039) and happiness (p = 0.021) after 6 weeks. More robenacoxib-treated cats were successes at 6 weeks (p = 0.018; NNT: 3.8). Adverse effect frequencies were similar across groups. Results identified suitable endpoints for confirmatory studies, while also indicating efficacy of robenacoxib in cats with DJD-pain.
Learn More >Headache and facial pain are among the most common, disabling and costly diseases in Europe, which demands for high quality health care on all levels within the health system. The role of the Danish Headache Society is to educate and advocate for the needs of patients with headache and facial pain. Therefore, the Danish Headache Society has launched a third version of the guideline for the diagnosis, organization and treatment of the most common types of headaches and facial pain in Denmark. The second edition was published in Danish in 2010 and has been a great success, but as new knowledge and treatments have emerged it was timely to revise the guideline. The recommendations for the primary headaches and facial pain are largely in accordance with the European guidelines produced by the European Academy of Neurology. The guideline should be used a practical tool for use in daily clinical practice for primary care physicians, neurologists with a common interest in headache, as well as other health-care professionals treating headache patients. The guideline first describes how to examine and diagnose the headache patient and how headache treatment is organized in Denmark. This description is followed by sections on the characteristics, diagnosis and treatment of each of the most common primary and secondary headache disorders and trigeminal neuralgia. The guideline includes many tables to facilitate a quick overview. Finally, the particular challenges regarding migraine and female hormones as well as headache in children are addressed.
Learn More >Pain that lingers beyond the early weeks after the acute postoperative period is an important risk factor for chronic postsurgical pain. This study examined the hypothesis that patients' expectations about their postsurgical pain would be independently associated with lingering postsurgical pain.
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