Introduction

In March 2016, the Centers for Disease Control and Prevention released the Guideline for Prescribing Opioids for Chronic Pain, intended for primary care clinicians. One recommendation advised against concurrent prescription of opioids and benzodiazepines. Although existing research suggests a reduction in co-prescribing of these drug classes by clinicians after guideline release, there are limited data assessing its possible effect on patient medical outcomes, such as overdoses.

Methods

This retrospective observational study analyzed opioid and benzodiazepine exposures, alone or in combination, reported to the California Poison Control System from January 2012 to June 2021. Interrupted time series analyses identified the difference in monthly call volume between pre- and post-guideline release. For exposures resulting in serious medical outcomes, additional analyses assessed trends and identified associated variables.

Results

There was no significant change in concomitant opioid and benzodiazepine exposures reported to California Poison Control System between pre- and post-guideline release. Compared to pre-guideline release, exposures to a single opioid or to a single benzodiazepine significantly decreased by 1.07 (95% CI: -1.62, -0.51) and 1.82 (95% CI: -2.33, -1.31) calls per month, respectively, after the guideline release. For exposure calls associated with serious medical outcomes, there was a significant increase of 0.11 (95% CI: 0.04, 0.18) and 0.2 (95% CI: 0.05, 0.34) calls per month for concomitant opioid and benzodiazepine and single opioid exposures, respectively, following guideline release.

Discussion

The guideline release appeared to have a variable association with exposures to single opioid, single benzodiazepines, and concomitant opioid and benzodiazepine cases reported to California Poison Control System. Although exposures to opioids or benzodiazepines alone significantly decreased after guideline release, there was no significant change in concomitant exposures. Additionally, for exposures associated with serious medical outcomes, concomitant exposures, and single opioid exposures significantly increased following guideline release.

Conclusion

Our results suggest that the guideline was not associated with a corresponding decrease in the number of concomitant poisoning exposures reported to California Poison Control System. Additional interventions may be needed to reduce concomitant exposures to opioids and benzodiazepines.

Apocarotenoids are important signaling molecules generated from carotenoids through the action of carotenoid cleavage dioxygenases (CCDs). These enzymes have a remarkable ability to cleave carotenoids at specific alkene bonds while leaving chemically similar sites within the polyene intact. Although several bacterial and eukaryotic CCDs have been characterized, the long-standing goal of experimentally visualizing a CCD-carotenoid complex at high resolution to explain this exquisite regioselectivity remains unfulfilled. CCD genes are also present in some archaeal genomes, but the encoded enzymes remain uninvestigated. Here, we address this knowledge gap through analysis of a metazoan-like archaeal CCD from Candidatus Nitrosotalea devanaterra (NdCCD). NdCCD was active toward β-apocarotenoids but did not cleave bicyclic carotenoids. It exhibited an unusual regiospecificity, cleaving apocarotenoids solely at the C14'-C13' alkene bond to produce β-apo-14'-carotenals. The structure of NdCCD revealed a tapered active site cavity markedly different from the broad active site observed for the retinal-forming Synechocystis apocarotenoid oxygenase (SynACO) but similar to the vertebrate retinoid isomerase RPE65. The structure of NdCCD in complex with its apocarotenoid product demonstrated that the site of cleavage is defined by interactions along the substrate binding cleft as well as selective stabilization of reaction intermediates at the scissile alkene. These data on the molecular basis of CCD catalysis shed light on the origins of the varied catalytic activities found in metazoan CCDs, opening the possibility of modifying their activity through rational chemical or genetic approaches.

Visual arrestin (Arr1) terminates rhodopsin signaling by blocking its interaction with transducin. To do this, Arr1 translocates from the inner to the outer segment of photoreceptors upon light stimulation. Mounting evidence indicates that inositol phosphates (InsPs) affect Arr1 activity, but the Arr1-InsP molecular interaction remains poorly defined. We report the structure of bovine Arr1 in a ligand-free state featuring a near-complete model of the previously unresolved C-tail, which plays a crucial role in regulating Arr1 activity. InsPs bind to the N-domain basic patch thus displacing the C-tail, suggesting that they prime Arr1 for interaction with rhodopsin and help direct Arr1 translocation. These structures exhibit intact polar cores, suggesting that C-tail removal by InsP binding is insufficient to activate Arr1. These results show how Arr1 activity can be controlled by endogenous InsPs in molecular detail.