The effect of CYP2D6 and CYP2C9 gene polymorphisms on the efficacy and safety of the combination of tramadol and ketorolac used for postoperative pain management in patients after video laparoscopic cholecystectomy

Abstract

Objectives One of the key components of ERAS is adequate pain control in the postoperative period. There are no rational schemes for postoperative pain relief. At the same time, adequate postoperative pain relief promotes early activation and early rehabilitation of patients and shortens the duration of the postoperative stay, and does not cause postoperative complications associated with analgesia (weakness, intestinal paresis, nausea and vomiting). The aims of the present study are to assess the possible association of CYP2D6 and CYP2C9 polymorphisms with the efficacy and safety of tramadol and ketorolac in postoperative pain. Methods A total of 107 patients were genotyped for CYP2D6 and CYP2C9 polymorphisms. All patients underwent laparoscopic cholecystectomy. Postoperative pain relief was carried out with ketorolac and tramadol. Postoperative pain syndrome was assessed using a visual analogue scale and McGill pain questionnaire. The profile of side effects was assessed by the dynamics of red blood counts as a possible trigger for the development of gastrointestinal bleeding according to the method of global assessment of triggers. Results Pain was statistically significantly lower in CYP2C9*2 carriers, according to visual analogue scale (VAS): after 12 h – by 1.5 (p=0.002); after 24 h – by 1.1 (p=0.012); after 36 h – by 1.05 (p=0.004); after 48 h – by 0.7 (p=0.026). In CYP2C9*3 carriers the results were not statistically significant. In carriers of CYP2D6*4 pain syndromes were higher at all-time intervals, but statistically reliable results were obtained only after 2 h – by 1.01 (p=0.054) and after 24 h – by 0.8 (p=0.035). The profile of adverse reactions for NSAIDs was evaluated by the dynamics of hemoglobin and erythrocyte indices. A more pronounced decrease in the relative difference in hemoglobin levels was noted in CYP2C9*2 and CYP2C9*3 polymorphism carriers – by 1.7 (p=0.00268) and-by 2.2 (p=0.000143), respectively. Conclusions CYP2D6 and CYP2C9 can predict analgesic effectiveness of tramadol and ketorolac. CYP2C9 can predict the risk of gastrointestinal bleeding, including those hidden to ketorolac.

CYP2D6 gene polymorphisms and the quality of postoperative analgesia with tramadol after vascular surgery

“…Интенсивность послеоперационной боли у всех пациентов была умеренной, в единичных случаях несколько превышая принятые критерии адекватности аналгезии (30 мм в покое и 40 мм при активизации пациента) [18,19]. Однако, при межгрупповом сравнении интенсивности боли в покое у пациентов с выявленными полиморфизмами гена CYP2D6 она была выше на протяжении первых послеоперационных суток (рис.…”

“…Это ведёт к снижению качества послеоперационного обезболивания, в частности, при гинекологических операциях, что мы продемонстрировали ранее [17]. На снижение качества послеоперационной анальгезии кеторолаком и трамадолом влияли полиморфизмы генов CYP2D6 и CYP2C9 после операций малой травматичности -лапароскопической холецистэктомии [18].У более возрастных пациентов в сосудистой хирургии подобные исследования отсутствуют, хотя значимость адекватной послеоперационной аналгезии подчеркивается её потенциальной ролью в профилактике кардиальных осложнений.…”

Patients’ Pharmacogenetic Characteristics and the Risk of Adverse Reactions to Non-steroidal Anti-inflammatory Drugs: Case Reports

“…Отметим, что основным путем биотрансформации кеторолака является конъюгация с глюкуроновой кислотой, дополнительным -P-гидроксилирование [16]. CYP2C9 не является ферментом метаболизма кеторолака, тем не менее существуют отдельные исследования о связи эффективности и безопасности кеторолака с носительством полиморфизмов CYP2C9 [17].…”