Influence of cytochrome P450 2D6*10/*10 genotype on the risk for tramadol associated adverse effects: a retrospective cohort study

Background: Tramadol is primarily metabolized by the highly polymorphic CYP2D6 enzyme, leading to a large spectrum of adverse events and clinical response. Ample evidence pointed a reduced CYPD26 activity score in individuals harboring the CYP2D6*10/*10 genotype, nevertheless, there is scarce studies on the impact of CYP2D6*10/*10 genetic polymorphism on long-term tramadol’s adverse effects.Aim: To test the correlation between CYP2D6*10/*10 expression and the risk for tramadol-associated adverse effects.Method: Using a database of Leumit Healthcare Services in Israel, we retrospectively assessed the occurrence of adverse events in patients who were prescribed tramadol. A binary logistic regression model was applied to model the relationship between CYP2D6*10/*10 genotype and the occurrence of adverse effects.Results: Data from four hundred ninety-three patients were included in this study. Only 25 (5.1%) patients were heterozygous for the CYP2D6*10 variant, while 56 patients (11%) were tested positive to the CYP2D6*10/*10 genotype. Compared to carriers of other variants, patients with the CYP2D6*10/*10 variant exhibited a higher occurrence of adverse events (odds ratio [OR] = 6.14, 95% confidence interval 3.18–11.83); the odds ratio for central nervous system adverse events and gastrointestinal adverse events were 5.13 (95% CI 2.84–9.28), and 3.25 (95% CI 1.78–5.93), respectively.Conclusion: Among the different CYP2D6 genotypes, CYP2D6*10/*10 genotype carries the higher risk of tramadol related adverse events. Appreciating the frequency of this specific allele it seems prudent to pharmacogenetically screen patients considered for long term tramadol treatment for better tolerability and efficacy outcomes

The Risk for Prostate Cancer With Calcium Channel Blockers: A Systematic Review, Meta-Analysis, and Meta-Regression

Background For decades, conflicting results were published regarding the increased risk of Prostate cancer (PCa) among calcium channel blocker (CCB) users. Objective We aimed to evaluate the association between PCa and CCB exposure and assess moderating factors. Methods We performed a systematic literature search in PubMed, Embase, and Cochrane databases for observational and randomized studies published until November 2020 with no language limitations, including data on the risk for PCa in CCB users compared with non-CCB users. We applied a random-effects model meta-analysis to pool results. In addition, we investigated potential moderating factors, such as CCB type, study type, participants’ age, and duration of exposure, using meta-regression methods. Results In our primary analysis, we included 18 studies. A statistically significant 5% increase in the risk for PCa was observed among CCB users (risk ratio [RR] = 1.05; 95% confidence interval [CI]: 1.01-1.10), with no significant association between the duration of exposure to CCBs and the risk for PCa (RR = 1.08; 95% CI: 0.98-1.19 for exposure for &lt; 5years and RR = 1.01; 95% CI: 0.9-1.14 for exposure ≥ 5 years). The association remained statistically significant for the subgroup of dihydropyridines (RR = 1.13; 95% CI: 1.05-1.22). In addition, the association was not influenced by participants’ age. Conclusion and Relevance CCBs are an important modality in treating hypertension. The 5% increased risk observed in the current meta-analysis could be influenced by residual confounding factors and should not affect hypertension treatment guidelines until more studies provide additional clinical information. </jats:sec

Calcium Channel Blocker Use and the Risk for Breast Cancer: A Population-Based Nested Case-Control Study

We investigated whether long-term exposure to calcium channel blockers (CCBs) is associated with an increased risk of breast cancer (BCa). We designed a nested case&ndash;control study based on data from the Clalit electronic database, the largest Israeli Health Services organization. All newly diagnosed breast cancer (BCa) cases were selected from a cohort of patients with hypertension. Ten controls were matched for each BCa case. The odds ratios (ORs) of BCa among CCBs users were calculated using multivariate conditional logistic regression analyses. A total of 4875 patients with newly diagnosed BCa were identified from the cohort with a median follow-up of 5.15 years. The exposure to CCBs was not associated with an increased risk of BCa (OR = 0.98; 95% CI, 0.92&ndash;1.04). Additionally, there was no association between long-term exposure to CCBs (above eight years) and increased BCa risk (OR = 0.91; 95% CI, 0.67&ndash;1.21). Higher cumulative doses of CCBs were not associated with an elevated risk of BCa (OR = 0.997; 95% CI, 0.962&ndash;1.034, calculated per 1000 DDD). Based on this large population-based study, long-term exposure to CCBs was not associated with an increased risk of BCa. Considering that CCBs are widely used medications, our results provide important safety information on a population level, especially for patients with an increased risk of BCa