It is important to manage postthoracotomy pain, to avoid respiratory complications.1 Postoperative pain–related complications include airway closure, atelectasis, and hypoxemia.2,3
Multimodal analgesia is a strategy that uses different analgesics with different modes of action, thus avoiding the risks of single-agent therapy as opioids. Although regional anesthesia is a major component of multimodal analgesia, it carries risks associated with their techniques, such as failure, dural puncture, and spinal cord damage secondary to abscess or hematoma.4,5
Although opioids are considered the gold standard for postoperative pain management, they can cause respiratory depression, postoperative nausea and vomiting (PONV) and, rarely, paradoxical hyperalgesia that also may delay postoperative discharge. Therefore, analgesic adjuvants are commonly added to decrease both opioid consumption and their related side effects.6–9
Both magnesium sulfate and pregabalin are potential agents in controlling acute postthoracotomy pain. Magnesium sulfate is an NMDA receptor blocker,10 whereas pregabalin binds potently to the alpha-2-delta protein in the brain,11 reducing depolarization-induced calcium influx at nerve terminals, with a consequential reduction in the release of several excitatory neurotransmitters, including glutamate, noradrenaline, substance P, and calcitonin gene–related peptide.12–14
Pregabalin is rapidly and extensively absorbed after oral dosing in the fasted state, with maximal plasma concentrations occurring ∼1 hour after single or multiple doses. The oral bioavailability of pregabalin is high at ≥90%.15
PATIENTS AND METHODS
After approval from the Ethics Committee (IRB number: 2010014053.3) and registration with clinicaltrial.gov number (NCT02678117), 120 patients with American Society of Anesthesiologists (ASA) physical status II scheduled for thoracic surgeries for lung or pleural cancer were included in a randomized double-blinded study. A written informed consent was taken from all patients.
Patients were excluded from this study if they met one of the following criteria: (1) refused to participate in the study, (2) known sensitivity or contraindication to drugs used in the study, (3) history of psychological disorders (eg, patients on antidepressants or antipsychotic medications), (4) on regular opioid medications for chronic pain (ie, pain >3 mo), and (5) with documented impairment of hepatic and/or kidney functions.
This study was randomized by a sealed opaque envelope, placebo controlled, and double blinded in which the patients and the residents who recorded the study data were not informed about the administered medications. Patients were allocated into 4 groups. Group MP received pregabalin 300 mg orally and IV magnesium sulfate 50 mg/kg mixed with 200 mL NS; group P received 300 mg pregabalin orally and IV 200 mL NS; group M received IV magnesium sulfate 50 mg/kg mixed with 200 mL NS and a placebo capsule, and group C received a placebo capsule and IV 200 mL NS. All medications were given 1 hour before surgery, and the infusions were given over 30 minutes.
The dose of pregabalin administered in this study was based on Bornemann-Cimenti et al16 wherein 300 mg oral pregabalin was administered to decrease postoperative pain in transperitoneal nephrectomy.
The dose of magnesium sulfate administered in this study was based on the study by Kiran et al17 wherein 50 mg/kg magnesium sulfate was infused, along with 250 mL normal saline (NS) over 30 minutes, before inguinal surgery.
The aim of the present study was to investigate the effects of the preoperative combination of oral pregabalin and intravenous (IV) magnesium sulfate as analgesic adjuvants in postthoracotomy pain.
Magnesium sulfate was presented as 1 g ampoules. The pregabalin capsules were evacuated, cleared, and filled with starch, under sterile conditions in the Clinical Pharmacy Department, to make placebo capsules.
A posterolateral thoracotomy incision was made in all patients by the same surgical team. All patients were under general anesthesia using standard ASA monitoring. Induction of anesthesia was carried out using propofol (2 to 3 mg/kg), fentanyl (2 µg/kg), and rocuronium (0.6 mg/kg).
A left double-lumen tube was inserted, and anesthesia was maintained by sevoflurane 1% to 2%. If there was a rise of ≥20% in the baseline mean arterial blood pressure or heart rate, fentanyl (0.5 µg/kg) was given. At the end of the surgery, reversal of residual muscle relaxation was carried out using sugammadex (2 mg/kg). After extubation and full recovery, all patients were transferred to the intermediate care unit.
Postoperatively, the patients received morphine sulfate using a patient-controlled analgesia (PCA) (the disposable silicon PCA device was prepared using 300 mL total volume NS containing 60 mg morphine, 60 mg ketorolac, and 8 mg ondansetron).18
The PCA was started with a basal rate of 5 mL/h and a bolus dose of 1 mL with a lockout period of 15 minutes from the immediate postoperative period.
Total morphine consumption in the first 24 hours of the postoperative period was recorded. The pain intensity was evaluated by the patient using 0 to 10 on a horizontal VAS at rest (wherein 0 indicates no pain and 10 indicates the worst imaginable pain), which was explained to all patients before administration of anesthesia. The VAS scores were assessed at 0, 4, 8, 12, and 24 hours. PONV was recorded as no PONV, PONV not requiring treatment, and PONV requiring treatment in the first 24 hours of the postoperative period. Patients with PONV requiring treatment received 1 mg granisetron IV.
Ramsay Sedation Scale19 was recorded at 0, 4, 8, 12, and 24 hours postoperatively:
This study included 120 cases divided into 4 groups. This sample size was calculated to provide 80% power to discriminate a 50% reduction in mean VAS score for pain between pregabalin and magnesium sulfate monotherapy and combined therapy and was guided by previous studies with pregabalin20 and magnesium sulfate.21
Data were analyzed using SPSS 21.0 for Windows (SPSS, Chicago, IL). Analysis of variance was used to compare the 4 groups for quantitative parametric data, and, if there was a significant difference among the groups, a post hoc Tukey’s test was performed. Kruskal-Wallis test was used for quantitative nonparametric data with Mann-Whitney test as post hoc test. Chi-square test was used for comparison of qualitative data. Continuous parametric data were presented as mean±SD, nonparametric data as median (IQR), and categorical data were presented as number of patients. P-values of <0.05 were considered significant.
A total of 120 patients completed the study and were randomized (30 patients for each group), and their data were included in the final analysis.
Results of the current study did not show any significant difference in the patients’ demographic data (age, body mass index, ASA physical status) and the duration of surgery, as shown in Table 1.
There was a statistically significant difference between the 4 groups in 24-hour total morphine consumption, P-value <0.001. There was a significantly lower morphine consumption in group MP, in comparison with group P (P-value<0.008), group M (P-value <0.001), and group C (P-value <0.001), as shown in Table 2. Although the median of the VAS records was ≤4 in the 4 groups, the IQR was less in group MP than in groups M and C at 0, 4, 12, and 24 hours. At 4 and 12 hours, it was less in group MP in comparison with group P, as shown in Figure 1.
Postoperative heart rate and mean arterial blood pressure showed no statistical significance between the 4 groups. According to postoperative oxygen saturation, it was noted that the oxygen saturation was higher in groups MP, P, and M compared with group C at 4, 8, and 12 hours.
As seen in Table 3, the median Ramsay sedation score in group MP was 3 all through the postoperative period, whereas, in groups P and M, the median was 3 at 0, 4, and 8 hours, and the median was 2 at 12 and 24 hours postoperatively.
In group C, although the median Ramsay sedation score was 2, the IQR at 0 and 24 hours was 1–2, which means that some patients were agitated.
There was a statistically significant difference between the 4 groups as regards PONV P<0.05. Groups MP and P had the fewest number of patients who required antiemetic medications when compared with groups M and C, as shown in Table 4.
The present study showed that the combined preoperative use of magnesium sulfate and pregabalin causes a significant decrease in the morphine consumption in the first 24 hours postoperatively, when compared with the other groups.
According to the VAS measurements for pain at rest, there was a noticeable decrease in postoperative VAS score at 0 and 4 hours when the combination of both drugs was used. There was no statistically significant difference in the VAS scores at 8, 12, and 24 hours between the 4 groups, and most patients had VAS scores in a clinically acceptable range, as all patients were provided with postoperative PCA.
In addition, the use of pregabalin and/or magnesium sulfate showed a significant decrease in PONV. This may be a direct result of the decrease in morphine requirements. Those patients who developed PONV responded to 1 mg granisetron IV.
Jo et al22 evaluated the use of combined magnesium sulfate and pregabalin as an approach of multimodal analgesia versus a control group in arthroscopic rotator cuff repair. Their study revealed that the use of combined pregabalin and magnesium sulfate showed a sufficient duration of pain reduction (lasting up to 48 h)—with less rescue morphine consumption—compared with the control group. This finding is in line with the results of our study.
There are no more studies that evaluated the use of combined pregabalin and magnesium sulfate in postoperative pain, but there are many studies for each drug alone as an adjuvant medication in postoperative pain.
Mishriky et al23 published a systematic review and meta-analysis including 55 studies to assess the impact of the individual dose and frequency of pregabalin administration on analgesic efficacy wherein all doses and administration regimens were combined. They concluded that pregabalin was associated with a significant reduction in pain scores at rest and during movement, and decreased opioid consumption at 24 hours when compared with the patients who received the placebo. Patients receiving pregabalin had less postoperative nausea, vomiting, and pruritus, when compared with the patients who received the placebo. In contrast, sedation, dizziness, and visual disturbances were more common with pregabalin.
Choubsaz et al24 studied 168 patients undergoing laparoscopic cholecystectomy, wherein they were divided into 2 groups: one group received 75 mg pregabalin orally preoperatively and the other was a control group. They found that at both 4 and 6 hours following surgery, the patients in the control group were 2.9 times more likely to have severe pain; hence, they determined that their study may encourage the use of low-dose pregabalin to achieve short-term postoperative analgesia.
Gianesello et al25 studied 60 patients scheduled for elective decompressive spine surgery, wherein, 1 hour before surgery, the patients received either 300 mg oral pregabalin or a placebo, and 150 mg pregabalin or a placebo was given twice daily for 48 hours postoperatively. Patients received IV morphine for the postoperative pain, and they assumed that perioperative pregabalin administration reduces early postsurgical pain at rest, and during movement, with reduced opioid consumption.
Kiran et al17 studied 100 patients undergoing inguinal hernia, wherein they were divided into 2 groups. Fifty patients received 50 mg/kg magnesium sulfate 30 minutes preoperatively, and the other group was a control group. The results showed that magnesium sulfate decreased postoperative pain and rescue analgesia requirements, but these results were inconsistent with our results. Our study showed that there was no major difference between the magnesium sulfate and control groups, which may be due to the severity of postthoracotomy pain.
Ozcan et al26 investigated the effect of magnesium sulfate on pain management for postthoracotomy patients, including 24 patients undergoing thoracotomy divided into 2 groups. One group received magnesium sulfate (30-mg/kg bolus), followed by a 10 mg/kg/h infusion for 48 hours, and the other was a control group. Similar to our study, this study showed that there were no significant differences between the magnesium and control groups, with respect to the pain and sedation scores. However, in contrast to our study, postoperative morphine consumption was found to be higher in the control group compared with the magnesium group at 4, 8, and 48 hours. This may be explained by the different study designs, wherein we used a single bolus dose, whereas they administered infusions following the initial bolus dose.
In the systematic review published by Mishriky et al,23 they addressed the postoperative sedation risk. They found that in the groups that received pregabalin, greater levels of sedation were exhibited at 2 hours, but not at 24 hours. There was a noteworthy increase in the risk of sedation with both single and multiple doses of pregabalin (300 mg), whereas there was an increase in the risk of severe sedation with multiple doses of 300 mg of pregabalin. The wide confidence intervals shown with other pregabalin regimens indicate that the data are not conclusive with regard to the lower 2 doses of pregabalin.
As regards the study by Kiran et al,17 the patients who were given magnesium sulfate were found to be more sedated in the immediate postoperative period, when compared with the control group—although, they were easily aroused. This was anticipated, due to the depressant effect magnesium has on the CNS.
These findings with regard to the patients’ sedation status were consistent with our own conclusions, as these 2 drugs are known to have sedative effects, especially when used in combination wherein higher levels of sedation are produced. This is a drawback when using these drugs in thoracotomies. The patients’ awareness and activity are essential for respiratory exercise, physiotherapy, and coughing in order to expand their lungs and clear any secretions; hence, the patients must be properly observed postoperatively.
The combined preoperative single dose of pregabalin and magnesium sulfate is an effective method for attenuating postoperative pain and total morphine consumption in patients undergoing thoracotomy.
In the studies by Sommer et al27 and Beatriz et al,28 they showed that the prevalence of moderate to severe postoperative pain after 24 hours was 30% and 22%, respectively. Furthermore, thoracotomy pain seems to have a continuous dynamic character, most likely due to patient breathing.
In retrospect, we should have followed-up the pain 2 to 3 days after the procedure, to adequately assess the delayed effect of these drugs properly, and the pain should have also been assessed when there was coughing, or when the patient took a deep breath. In addition, we should have also studied the effect of lower doses of pregabalin on postoperative morphine consumption and sedation levels.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
pregabalin; magnesium sulfate; postthoracotomy pain; analgesic adjuvants