Optimizing chronic pain management through patient engagement with quality of life measures: a randomized controlled trial.

CONTEXT: Health-related quality of life (HRQOL) represents a new approach for guiding chronic pain management because it is patient-centered and more likely to be understood and accepted by patients. OBJECTIVES: To assess the value and utility of an eHealth intervention for patients with chronic low back pain (CLBP) that was primarily based on HRQOL measures and to measure the clinical outcomes associated with its use. METHODS: A randomized controlled trial was conducted within the Pain Registry for Epidemiological, Clinical, and Interventional Studies and Innovation (PRECISION Pain Research Registry) using participants screened from November 2019 through February 2021. A total of 331 registry participants within the 48 contiguous states and the District of Columbia met the eligibility criteria, which included having CLBP and HRQOL deficits. Almost three-fourths of the participants were enrolled after onset of the COVID-19 pandemic. The participants were randomized to an eHealth intervention for HRQOL or wait list control. The primary outcome measures involved HRQOL based on the Patient-Reported Outcomes Measurement Information System (PROMIS), including the SPADE cluster (Sleep disturbance, Pain interference with activities, Anxiety, Depression, and low Energy/fatigue) and each of its five component scales. Secondary outcome measures involved low back pain intensity and back-related functioning. Changes over time for each outcome measure reported by participants in each treatment group were compared utilizing the student's t-test for statistical significance and Cohen's d statistic for clinical importance. Outcomes were reported as between-group differences in change scores and the d statistic, with positive values favoring the experimental treatment group. RESULTS: There were no significant differences between the experimental and control treatment groups for changes over time in any primary outcome measure. The d statistic (95% confidence interval) for the difference between the experimental and control treatment groups on the SPADE cluster was 0.04 (-0.18-0.25). The corresponding d statistics for the SPADE scales ranged from -0.06 (-0.27 to 0.16) for anxiety to 0.11 (-0.10 to 0.33) for sleep disturbance. There were also no significant or clinically important differences between the experimental and control treatment groups on the secondary outcome measures. Additionally, in subgroup analyses involving participants treated by osteopathic vs allopathic physicians, no significant interaction effects were observed. CONCLUSIONS: The eHealth intervention studied herein did not achieve statistically significant or clinically important improvements in any of the primary or secondary outcome measures. However, the validity and generalizability of the findings may have been limited by the unforeseen onset and impact of the COVID-19 pandemic shortly after beginning the trial.

Estrogen modulation of the pronociceptive effects of serotonin on female rat trigeminal sensory neurons is timing dependent and dosage dependent and requires estrogen receptor alpha.

ABSTRACT: The role of the major estrogen estradiol (E2) on orofacial pain conditions remains controversial with studies reporting both a pronociceptive and antinociceptive role of E2. E2 modulation of peripheral serotonergic activity may be one mechanism underlying the female prevalence of orofacial pain disorders. We recently reported that female rats in proestrus and estrus exhibit greater serotonin (5HT)-evoked orofacial nocifensive behaviors compared with diestrus and male rats. Further coexpression of 5HT 2A receptor mRNA in nociceptive trigeminal sensory neurons that express transient receptor potential vanilloid 1 ion channels contributes to pain sensitization. E2 may exacerbate orofacial pain through 5HT-sensitive trigeminal nociceptors, but whether low or high E2 contributes to orofacial pain and by what mechanism remains unclear. We hypothesized that steady-state exposure to a proestrus level of E2 exacerbates 5HT-evoked orofacial nocifensive behaviors in female rats, explored the transcriptome of E2-treated female rats, and determined which E2 receptor contributes to sensitization of female trigeminal sensory neurons. We report that a diestrus level of E2 is protective against 5HT-evoked orofacial pain behaviors, which increase with increasing E2 concentrations, and that E2 differentially alters several pain genes in the trigeminal ganglia. Furthermore, E2 receptors coexpressed with 5HT 2A and transient receptor potential vanilloid 1 and enhanced capsaicin-evoked signaling in the trigeminal ganglia through estrogen receptor α. Overall, our data indicate that low, but not high, physiological levels of E2 protect against orofacial pain, and we provide evidence that estrogen receptor α receptor activation, but not others, contributes to sensitization of nociceptive signaling in trigeminal sensory neurons.

Estrogen exacerbates the nociceptive effects of peripheral serotonin on rat trigeminal sensory neurons.

Orofacial pain disorders involving trigeminal sensory neurons disproportionately affect women and can be modulated by hormones, especially estrogen (E2). Proinflammatory mediators, like serotonin (5HT), can act on sensory neurons expressing the transient receptor potential vanilloid 1 (TRPV1) ion channel, resulting in peripheral sensitization. We previously reported peripheral 5HT evokes greater pain behaviors in the hindpaw of female rats during proestrus and estrus, stages when E2 fluctuates. It is unknown if this interaction is comparable in the trigeminal system. We hypothesized that E2 exacerbates 5HT-evoked nocifensive pain behaviors and pain signaling in female trigeminal sensory neurons. We report 5HT-evoked nocifensive behaviors are significantly higher during estrus and proestrus, which is attenuated by blocking the 5HT2A receptor. The comparable dose of 5HT was not nociceptive in males unless capsaicin was also administered. When administered with capsaicin, a lower dose of 5HT evoked trigeminal pain behaviors in females during proestrus. Further, basal 5HT content in the vibrissal pad was higher in cycling females compared to males. Ex vivo, E2 enhanced 5HT-potentiated CGRP release from trigeminal neurons, which was not significantly reduced by blocking the 5HT2A receptor. Our data indicates that estrogen fluctuation influences the pronociceptive effects of 5HT on trigeminal sensory neurons.