Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Translation regulation by autophagy and nutrient stress

Protein translation is necessary for cell function, but it is an incredibly energy demanding process, and is therefore tightly regulated by the metabolic state of the cell. There are a plethora of translation control mechanisms that are only recently being elucidated. My thesis research has investigated how perturbing the metabolic state of the cell, both subtly via autophagy inhibition and with a sledge-hammer of acute amino acid starvation, impacts translation rates on both a global and mRNA by mRNA basis. Overall, I found that these stresses do not repress translation as expected, indicating the identification of novel mechanisms of protein translation regulation.The majority of my thesis focused on the role of autophagy in regulating protein translation. Autophagy, a cellular sorting, degradation and recycling system, is crucial for the survival of cells under stress and has been demonstrated to play a role in the progression of many human diseases, including cancer and neurodegeneration. By promoting protein degradation, autophagy is proposed to maintain amino acid pools to sustain protein synthesis during metabolic stress. I utilized ribosome profiling to delineate the effects of acute genetic ablation of autophagy on protein translational control. Instead of shaping overall global rates of cap dependent translation, autophagy supports the translation of specific mRNAs, most notably targets involved in cell cycle control and DNA damage repair, by modulating the availability of RNA binding proteins to interact with mRNAs. Specifically, by enabling the protein translation of the DNA damage repair protein BRCA2, autophagy is functionally required to attenuate DNA damage as well as promote cell survival in response to PARP inhibition. This helps to explain the reported increased DNA damage in autophagy deficient cells, and is an important consideration for autophagy inhibitors as adjuvant chemotherapies, which are being tested now. I have also uncovered a novel mechanism of protein translation regulation following acute amino acid starvation. Although mTORC1 signaling indicates repressed translation, 35S-methionine incorporation rates more than double following amino acid withdrawal. This increase in translation rates can be prevented by addition of leucine, although the molecular mechanisms controlling this novel process remain to be identified