The Impact of Perioperative Use of a Statin–Magnesium Combination on Opioid Consumption in Patients Who Underwent Cardiac Surgery: A Retrospective Study with Propensity-Score Matching

The management of pain after cardiac surgery is crucial because inadequately controlled pain may become chronic, thereby delaying rehabilitation, prolonging treatment duration, and detrimentally affecting the patient's quality of life. Effective treatment of pain in patients undergoing cardiac surgery should be multidimensional. The most frequently recommended type of analgesia is multimodal (combined pharmacotherapy), involving the simultaneous use of a few analgesic agents with different mechanisms of action, but with common properties.1, 2 Statins reduce the synthesis and increase the clearance of cholesterol, while decreasing triglyceride levels. Preclinical studies have shown that the anti-inflammatory effects of statins are associated with reductions in C-reactive protein (CRP) and proinflammatory cytokine levels.3, 4 To date, there have been very few clinical studies on the effects of statins on pain in the perioperative period.5 A few studies have reported that perioperative statin use is not effective for reducing postoperative pain and opioid consumption.6, 7

Magnesium, which is a cofactor of all enzymes in phosphate-transfer reactions that utilize adenosine triphosphates as substrates, is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that blocks ion channels in a voltage-dependent manner.8 Systemic administration of perioperative magnesium reduces postoperative pain and opioid consumption and is considered a strategy to mitigate postoperative pain in surgical patients.1, 8, 9

Both statins and magnesium are associated with NMDA receptors and have anti-inflammatory effects. Peripheral NMDA receptors are known to be involved in inflammation-induced pain.1, 8, 10 The effects of the combination of these two agents with similar properties but different mechanisms of action on pain outcomes are still unknown.

We hypothesized that because both statins and magnesium are associated with NMDA receptors and have anti-inflammatory effects, their combined therapy could reduce opioid consumption postoperatively. The aim of our study was to investigate the impact of the perioperative use of a statin–magnesium combination on opioid consumption, as the primary outcome, in patients who underwent cardiac surgery.

Six hundred patients underwent cardiac surgery at this hospital from January 1, 2013 through December 30, 2018. Of these, 58 patients were excluded because of incomplete medical records, previous cardiac surgery, antiarrhythmic medication before surgery, and re-operation because of bleeding. Thus, 542 patients were included in this study. Propensity-score matching for baseline and clinical characteristics identified 228 paired patients in the two groups (n=114 per group).

The proportions of patients with diabetes mellitus, hypertension, smoking, peripheral arterial occlusive disease, and preoperative cerebrovascular accident were significantly higher in the magnesium-only group than in the statin–magnesium group before matching; however, these differences between the groups were not statistically significant after matching. The statin–magnesium combination treatment significantly increased the creatinine level at 1-day postoperatively after matching. The combination therapy also reduced the peak CRP level and the CRP level from the first to the third day postoperatively, before and after matching. Age, sex, body mass index, type of commonly prescribed statins, type and duration of cardiac surgery, mechanical ventilation, intensive care unit stay, creatinine level before surgery, and preoperative CRP levels were not significantly different between the two groups both before and after matching. Creatinine at 1 day after surgery was not significant between two groups before matching but creatinine was significantly increased in statin–magnesium group compared with magnesium only group (p=0.017) (Table 1).

TABLE 1
Patients' demographic data

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The statin–magnesium group consumed significantly lower volumes of PCA containing fentanyl (in milliliters) over a 72-h period postoperatively than did the magnesium-only group, both before matching (p=0.010) and after matching (p=0.017). The VAS pain scores during movement in the first 24 h postoperatively were significantly lower in the statin–magnesium group than in the magnesium-only group, before matching. However, the VAS pain scores at 24, 48, and 72 h were not significantly different between the groups after matching (Table 2).

TABLE 2
Pain intensity and opioid consumption in patients who underwent cardiac surgery

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Patients with statin treatment ≥1 yr consumed significantly lower PCA volumes than did those with statin treatment <1 year, both before (p=0.047) and after matching (p=0.047). The VAS pain scores over a 72-h period in patients with statin treatment ≥1 year were significantly lower (p<0.05) than those in patients with statin treatment <1 year, before matching. However, the duration of statin treatment had a weaker effect on reducing the VAS pain scores over the 72-h period after matching (Table 3). There was a statistically significantly negative, although weak, association of statin-treatment duration with opioid consumption over 72 h postoperatively (r=−0.154, p=0.047), VAS score at rest (r=−0.167, p=0.031), and VAS score with movement (r=−0.167, p=0.031) in the first 24 h postoperatively. Additionally, the VAS score at rest (r=−0.173, p=0.025) and VAS score with movement (r=−0.185, p=0.017) in the first 48 h postoperatively, and the VAS score at rest (r=−0.169, p=0.029) and VAS score with movement in the first 72 h postoperatively (r=−0.132, p=0.09), were statistically significantly negatively, but weakly, correlated (Table 4).

TABLE 3
Pain intensity and opioid consumption according to the duration of statin treatment in patients who underwent cardiac surgery

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TABLE 4
Association of statin-treatment duration with pain intensity and opioid consumption

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The incidence of postoperative atrial fibrillation was not significant, regardless of the subtype of cardiac surgery before matching. After matching, the incidence of postoperative atrial fibrillation in the statin–magnesium group was significantly reduced compared with that in the magnesium-only group, but was reduced only in patients who underwent CABG surgery (Table 5).

TABLE 5
Postoperative atrial fibrillation in patients according to type of cardiac surgery

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The present study showed that the statin–magnesium group consumed significantly lower volumes of PCA containing fentanyl over a 72-h period postoperatively than did the magnesium-only group, both before and after propensity-score matching. Before matching, the VAS pain scores with movement in the first 24 h postoperatively in patients who received the statin–magnesium combination was significantly lower than those in patients who received magnesium alone. After matching, the VAS pain scores at 24, 48, and 72 h were not significantly different between the two groups. The finding that the VAS pains scores at these time-points did not differ significantly between the groups might be attributable to the increased use of opioids by the magnesium-only group to reduce pain levels.

Preclinical and clinical studies have shown conflicting results regarding the effect of statins on pain outcomes.3, 4, 6, 7 Animal studies have also suggested the beneficial effects of statins on pain,3, 4 whereas clinical studies have indicated that statin treatment is not effective with respect to pain outcomes.6, 7 At our hospital, magnesium has been administered as a standard of care for preventing postoperative atrial fibrillation. Some studies recommended magnesium administration as a strategy to mitigate postoperative pain in surgical patients.8, 9 In the present study, the statin–magnesium combination significantly reduced pain compared with magnesium alone. Although statins and magnesium each have their own specific properties, both are associated with NMDA receptors and have an anti-inflammatory effect.1, 8, 10 Due to these common properties, the statin–magnesium combination shows a synergic effect compared with magnesium alone and may affect opioid consumption. Available clinical studies have reported the relationship between perioperative statin use and postoperative pain and opioid consumption.6, 7 However, this study addresses the synergistic effect of a perioperative statin–magnesium combination on opioid consumption and pain intensity.

Since the results of studies on the effect of prolonged use of statins on pain and nociception are contradictory, the use of statins as analgesic adjuvants is not yet supported by evidence.6, 7 In the present study, statin treatment ≥1 yr resulted in significantly greater reduction in opioid consumption than did statin treatment <1 yr. However, correlation analysis showed a weakly negative relationship between the duration of statin treatment and opioid consumption or pain intensity. This result indicates that the effect of statin-treatment duration on opioid consumption and pain intensity remains controversial in terms of clinical implications.

Some studies have reported that there is an excess risk of acute kidney injury (AKI) within 2 years after statin initiation in high-potency statin users compared to lower-potency statin users, but only among patients without chronic kidney disease at baseline.11, 12 However, other studies did not find a significant association between statin treatment and the risk of AKI or an excess risk of AKI with high-potency versus moderate-/low-potency regimens.13, 14 The creatinine level after surgery in the present study did not differ significantly between the two groups, but the statin-magnesium group was higher than magnesium group after propensity-score matching. The most frequently reported risk factors for AKI after cardiac surgery include advanced age, female sex, New York Heart Association function class IV, reduced left ventricular ejection fraction or congestive heart failure, diabetes mellitus, poor glycemic control, peripheral vascular disease and chronic obstructive pulmonary disease, type of surgery, duration of CPB, blood transfusion, and hemolysis.15

According to the type of cardiac surgery in the present study, the incidence of postoperative atrial fibrillation in the statin–magnesium group was significantly lower in patients who underwent coronary artery bypass surgery than in those who underwent valve surgery or combined surgery. Some studies have reported that the beneficial effect of statins on postoperative atrial fibrillation was found only in patients who underwent CABG, but not in those who underwent valve surgery. Valvular diseases are mostly related to the aging process, due to calcification of the valves, but not to inflammatory responses or lipid deposition.16

This study had some limitations. First, this retrospective study had a small sample size, which limits the generalization of the results.17 Studies with very large sample sizes may be needed to identify rare or controversial outcomes. Second, retrospective studies are known to have an inherent risk of bias if some key points are not addressed. Although we attempted to reduce this risk through propensity-score matching, some unmeasured or confounding factors may have influenced the results of the present study. Third, the observed effect of the statin–magnesium combination on opioid consumption and pain intensity in the present study might be difficult to apply to the effect of statin use only on pain outcomes. Finally, data on perioperative factors that could potentially affect the outcomes, such as total dose of opioids and anxiolytics, method of sedation, and postoperative nausea and vomiting, were not available for analysis.

In conclusion, the results of the present study demonstrate that the perioperative use of the statin–magnesium combination seems to reduce opioid consumption significantly postoperatively, which might be due to the synergistic reaction between statin and magnesium; however, it was unable to reduce pain intensity.