Naively one might have expected an early division between phosphate monoesterases and diesterases of the alkaline phosphatase (AP) superfamily. On the contrary, prior results and our structural and biochemical analyses of phosphate monoesterase PafA, from Chryseobacterium meningosepticum, indicate similarities to a superfamily phosphate diesterase [Xanthomonas citri nucleotide pyrophosphatase/phosphodiesterase (NPP)] and distinct differences from the three metal ion AP superfamily monoesterase, from Escherichia coli AP (EcAP). We carried out a series of experiments to map out and learn from the differences and similarities between these enzymes. First, we asked why there would be independent instances of monoesterases in the AP superfamily? PafA has a much weaker product inhibition and slightly higher activity relative to EcAP, suggesting that different metabolic evolutionary pressures favored distinct active-site architectures. Next, we addressed the preferential phosphate monoester and diester catalysis of PafA and NPP, respectively. We asked whether the >80% sequence differences throughout these scaffolds provide functional specialization for each enzyme’s cognate reaction. In contrast to expectations from this model, PafA and NPP mutants with the common subset of active-site groups embedded in each native scaffold had the same monoesterase:diesterase specificities; thus, the >107-fold difference in native specificities appears to arise from distinct interactions at a single phosphoryl substituent. We also uncovered striking mechanistic similarities between the PafA and EcAP monoesterases, including evidence for ground-state destabilization and functional active-site networks that involve different active-site groups but may play analogous catalytic roles. Discovering common network functions may reveal active-site architectural connections that are critical for function, and identifying regions of functional modularity may facilitate the design of new enzymes from existing promiscuous templates. More generally, comparative enzymology and analysis of catalytic promiscuity can provide mechanistic and evolutionary insights.

ImportancePostoperative opioid prescriptions are associated with delayed recovery, perioperative complications, opioid use disorder, and diversion of overprescribed opioids, which places the community at risk of opioid misuse or addiction.ObjectiveTo assess a protocol for eliminating postdischarge opioid prescriptions after major urologic cancer surgery.Design, Setting, and ParticipantsThis cohort study of the no opioid prescriptions at discharge after surgery (NOPIOIDS) protocol was conducted between May 2017 and June 2021 at a tertiary referral center. Patients undergoing open or minimally invasive radical cystectomy, radical or partial nephrectomy, and radical prostatectomy were sorted into the control group (usual opioids), the lead-in group (reduced opioids), and the NOPIOIDS group (no opioid prescriptions).InterventionsThe NOPIOIDS group received a preadmission educational handout, postdischarge instructions for using nonopioid analgesics, and no routine opioid prescriptions. The lead-in group received a postdischarge instruction sheet and reduced opioid prescriptions at prescribers’ discretion. The control group received opioid prescriptions at prescribers’ discretion.Main Outcomes and MeasuresPrimary outcome measures included rate and dose of opioid prescriptions at discharge and for 30 days postdischarge. Additional outcome measures included patient-reported pain and satisfaction level, unplanned health care utilization, and postoperative complications.ResultsOf 647 opioid-naive patients (mean [SD] age, 63.6 [10.0] years; 478 [73.9%] male; 586 [90.6%] White), the rate of opioid prescriptions at discharge for the control, the lead-in, and the NOPIOIDS groups was 80.9% (157 of 194), 57.9% (55 of 95), and 2.2% (8 of 358) (Kruskal-Wallis test of medians: P < .001), and the overall median (IQR) tablets prescribed was 14 (10-20), 4 (0-5.3), and 0 (0-0) per patient in the control, lead-in, and NOPIOIDS groups, respectively (Kruskal-Wallis test of medians: P < .001). In the NOPIOIDS group, median and mean opioid dose was 0 tablets for all procedure types, with the exception of kidney procedures (mean [SD], 0.5 [1.7] tablets). Patient-reported pain surveys were received from 358 patients (72.6%) in the NOPIOIDS group, demonstrating low pain scores (mean [SD], 2.5 [0.86]) and high satisfaction scores (mean [SD], 86.6 [3.8]). There was no increase in postoperative complications in the group with no opioid prescriptions.Conclusions and RelevanceThis perioperative protocol, with emphasis on nonopioid alternatives and patient instructions, may be safe and effective in nearly eliminating the need for opioid prescriptions after major abdominopelvic cancer surgery without adversely affecting pain control, complications, or recovery.

Purpose: Opioid prescriptions after surgery are major contributors to the opioid abuse epidemic. Several measures designed to limit opioid prescriptions at discharge have been evaluated. We conducted a comprehensive review and metaanalysis of the effectiveness of various types of interventions in reducing opioid prescriptions after urological surgery. Materials and Methods: A systematic review including MEDLINEÒ, Web of ScienceÔ and Cochrane databases was conducted to identify studies on opioid prescriptions and urological surgery. Twenty-two studies met the inclusion criteria, of which 19 were used for quantitative analysis for reduction in opioid prescriptions. Additional outcomes included opioid consumption and satisfaction with analgesia. Results: Of the 8,318 patients, 53% were in the pre-and 47% in the postintervention cohort. Overall mean reduction/patient in prescribed opioids was À67.59 (95% CI 54.23 to 80.94) morphine milligram equivalents (MME). Direct interventions, implemented by providers within their local department or hospital, were more effective in reducing prescribed opioids compared to indirect, or systemic, interventions, at À76.68 MME (95% CI 60.04 to À93.31) vs À46.72 MME (95% CI 24.20 to À69.23; p[0.04). Opioid consumption significantly decreased post-intervention with a mean reduction of -18.31 MME (95% CI 7.89 to 28.72). Patient satisfaction with analgesia remained unchanged between the pre-and post-intervention groups. Conclusions: Successful reduction in opioid prescriptions, without compromising pain control, can be achieved through a variety of interventions. Direct interventions appear to have a greater impact than indirect interventions in reducing opioid prescriptions. Despite the reduction, unused, excess prescription opioids were still noted, which provides an opportunity for further control on opioid prescriptions.

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