Lopes, Guilherme S

Objectives Sex as a biological variable affects response to opioids. However, few reports describe the prevalence of specific adverse reactions to commonly prescribed opioids in men and women separately. A large cohort was used to investigate sex differences in type and occurrence of adverse reactions associated with use of codeine, tramadol, oxycodone and hydrocodone. Design Retrospective cohort study. Setting Participants in the Right Drug, Right Dose, Right Time (RIGHT) Study. Participants The medical records of 8457 participants in the RIGHT Study who received an opioid prescription between 1 January 2004 and 31 December 2017 were reviewed 61% women, 94% white, median age (Q1–Q3)=58 (47–66). Primary and secondary outcome measures Adverse reactions including gastrointestinal, skin, psychiatric and nervous system issues were collected from the allergy section of each patient’s medical record. Sex differences in the risk of adverse reactions due to prescribed opioids were modelled using logistic regression adjusted for age, body mass index, race and ethnicity. Results From 8457 participants (of which 449 (5.3%) reported adverse reactions), more women (6.5%) than men (3.4%) reported adverse reactions to at least one opioid (OR (95% CI)=2.3 (1.8 to 2.8), p<0.001). Women were more likely to report adverse reactions to tramadol (OR (95% CI)=2.8 (1.8 to 4.4), p<0.001) and oxycodone (OR (95% CI)=2.2 (1.7 to 2.9), p<0.001). Women were more likely to report gastrointestinal (OR (95% CI)=3.1 (2.3 to 4.3), p<0.001), skin (OR (95% CI)=2.1 (1.4 to 3.3), p=0.001) and nervous system issues (OR (95% CI)=2.3 (1.3 to 4.2), p=0.004). Conclusions These findings support the importance of sex as a biological variable to be factored into pain management studies.

Background Current adverse event reporting practices do not document longitudinal characteristics of adverse effects, and alternative methods are not easily interpretable and have not been employed by clinical trials. Introducing time parameters in the evaluation of safety that are comprehensive yet easily interpretable could allow for a better understanding of treatment quality. In this study, we developed and applied a novel adverse event reporting method based on longitudinal adverse event changes to aid describing, summarizing, and presenting adverse event profile. We termed it the “Adverse Event Load, Onset, and Maximum Grade” method. Methods We developed two adverse event summary metrics to complement the traditional maximum grade report. Onset time indicates the time period in which the maximum grade for a specific adverse event occurred and was defined as “early” (i.e. maximum grade happened for the first time before 6 weeks) or “late” (i.e. after the 6 th week). Adverse event load indicates the overall severity of a specific adverse event over the entire treatment. Higher adverse event load indicates a worse overall experience. These metrics can be calculated for adverse events with different maximum grades, in treatments with planned changes (e.g. dosage changes), using data sets with different number of adverse event data points between treatments (e.g. treatments with longer cycle lengths may have less adverse event data points) and on data sets with different adverse event data availability (e.g. cycle basis and patient-outcome reports). We tested the utility of this method using individual patient data from two major backbone therapies (“Irinotecan” and “Oxaliplatin”) from the N9741 trial available in the Fondation ARCAD database ( fondationarcad.org ). We investigated profiles of diarrhea, neutropenia/leukopenia, and nausea/vomiting. Results Our method provided additional information compared to traditional adverse event reports. For example, for nausea/vomiting, while patients in Irinotecan had a higher risk of experiencing maximum grade 3–4 (15.6% vs 7.6%, respectively; p < 0.001), patients in both groups experienced similar severity over time (adverse effect load = 0.102 and 0.096, respectively; p = 0.26), suggesting that patients in Oxaliplatin experienced a lower-grade but more persistent nausea/vomiting. For neutropenia/leukopenia, more patients in Irinotecan experienced their maximum grade for the first time early in the treatment compared to patients in Oxaliplatin (67.9% vs 41.7%; p < 0.001), regardless of maximum grade. Longitudinal information can help compare treatments or guide clinicians on choosing appropriate interventions for low-grade but persistent adverse event or early adverse event onset. Conclusion We developed an adverse event reporting method that provides clinically relevant information about treatment toxicity by incorporating two longitudinal adverse event metrics to the traditional maximum grade approach. Future research should establish clinical benchmarks for metrics included in this adverse event reporting method.