We demonstrate a facile approach for the synthesis of gem-disubstituted cyclooctanoids, a motif found in several biologically active compounds. Appropriately substituted 1-alkenyl-5-pentyn-1-ols bearing gem-dialkyl substituents at either the C2, C3, or C4 position serve as useful precursors to a number of cyclooct-4-enone derivatives via a tandem, microwave-assisted oxyanionic 6-exo-dig cyclization/Claisen rearrangement reaction. gem-Dialkyl activation is necessary for these reactions to occur, as unactivated 1-alkenyl-5-pentyn-1-ols fail to undergo 6-exo-dig cyclization under the conditions employed. Further application of the methodology to the corresponding gem-dialkoxy system was also explored to facilitate access to more complex carbocycles.
This study investigated the tolerability and preliminary efficacy of duloxetine as an alternative nonopioid therapeutic option for the prevention of persistent musculoskeletal pain (MSP) among adults presenting to the emergency department with acute MSP after trauma or injury. In this randomized, double-blind, placebo-controlled study, eligible participants (n 5 78) were randomized to 2 weeks of a daily dose of one of the following: placebo (n 5 27), 30 mg duloxetine (n 5 24), or 60 mg duloxetine (n 5 27). Tolerability, the primary outcome, was measured by dropout rate and adverse effects. Secondary outcomes assessed drug efficacy as measured by (1) the proportion of participants with moderate to severe pain (numerical rating scale $ 4) at 6 weeks (pain persistence); and (2) average pain by group over the six-week study period. We also explored treatment effects by type of trauma (motor vehicle collision [MVC] vs non-MVC). In both intervention groups, duloxetine was well tolerated and there were no serious adverse events. There was a statistically significant difference in pain over time for the 60 mg vs placebo group (P 5 0.03) but not for the 30 mg vs placebo group (P 5 0.51). In both types of analyses, the size of the effect of duloxetine was larger in MVC vs non-MVC injury. Consistent with the role of stress systems in the development of chronic pain after traumatic stress, our data indicate duloxetine may be a treatment option for reducing the transition from acute to persistent MSP. Larger randomized controlled trials are needed to confirm these promising results.
Study Objectives: The primary aim was to examine the tolerability of duloxetine as a preventative treatment for emergency department (ED) patients who present with acute musculoskeletal pain after trauma or an injury. Tolerability was measured by drop-out rate and adverse effects. Secondary outcomes assessed drug effectiveness as measured by: (1) the proportion of participants with moderate to severe pain (numerical rating scale (NRS) > 4) at six weeks (pain persistence); (2) average pain by group over the six-week study period.Methods: Eligible participants were 18-69 years of age and had acute moderate to severe axial musculoskeletal pain. Exclusion criteria included: fracture, history of coronary artery disease, uncontrolled hypertension, antidepressant use, and chronic pain. Participants who consented were randomized to two weeks of a daily dose of one of the following: placebo (n¼27), 30 mg duloxetine (n¼24), and 60 mg duloxetine (n¼27). Follow-up assessments were completed at days 3, 7, 10, 14, 17, and 21. An in-person assessment was completed at day 42. Descriptive data were examined. We conducted a mixedeffects model to examine pain over time by group and mechanism (traumatic vs. atraumatic).Results: Participants (n¼78 at baseline) were recruited from two EDs in the Northeastern USA. 29/78 (37%) presented after a traumatic stress exposure (motor vehicle collision, MVC), 49/78 (63%) were atraumatic (eg, lifting). Dropout rates were 11.1%, 12.5%, and 25.9% in the placebo, 30mg, and 60mg groups, accordingly. There were no serious adverse events. Six weeks after enrollment, moderate to severe persistent pain was present in 52%, 50%, and 36% of participants in the placebo, 30mg, and 60mg groups, respectively. Among enrollees experiencing MVC, these proportions were 71%, 67%, and 25%, respectively. Mean MVC-related pain scores at six weeks were 5.3 (2.6), 4.2 (2.5), and 3.0 (2.5), respectively, and the proportion of those who remained very anxious getting in a car six weeks after MVC were 57%, 33%, and 13%, respectively. A piecewise trend with a break at 14 days provided the best fit for pain intensity scores amongst the entire sample. After controlling for age, sex, and race there was a significant difference in pain over time for 60mg vs placebo group (B¼-.07, p¼.03) across the whole sample, but not the 30mg vs placebo group (B¼-.02, p¼.51).Conclusions: Although patients receiving 60mg duloxetine had higher drop-out rates than placebo, these drop-out rates were similar to those reported for duloxetine in other pain trials, and no serious adverse events were observed. Among all participants, 60mg duloxetine was associated with a reduction in pain intensity at 6 weeks compared to placebo. Duloxetine may be a promising treatment option for reducing the transition from acute to persistent axial pain. Point estimates suggested that duloxetine may be particularly efficacious among individuals with acute pain after traumatic stress exposure/MVC and may also reduce psychological sequelae in such patients. These data ...
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