Nicotine has an analgesic effect.1,2 Its analgesic properties likely function through both central and peripheral nicotine acetylcholine receptors.3–5 Nicotine acts also by interactions with the endogenous opioid pathways. Although nicotine seems to have antinociceptive effects,6–9 several studies suggest that smokers show higher pain intensity and incidence of chronic pain.10–13 Acute pain is also likely to be significant in smokers during the perioperative period14,15 and postoperative analgesic use is higher in these patients.16–21 In addition, ceasing smoking before surgery to prevent postoperative pulmonary complications can make the patients anxious, which leads to more opioid use in smokers during perioperative period.17 It has been proposed that tolerance to nicotine-induced analgesia develops during its chronic administration and subsequent abstinence from nicotine can increase nociception.22 Increasing use of opioids can cause side effects such as nausea, vomiting, and pruritus. Insufficient pain control and these side effects can lead to increased recovery time, wound dehiscence, extended hospital stay, and chronic pain.17,22–25 Consequently, it is important to recognize increments of postoperative opioid consumption in smokers as they can affect surgical outcomes. However, some studies conclude that smoking was not associated with postoperative development of severe pain or with increment of postoperative opioid use.26,27 Therefore, to evaluate whether postoperative opioid requirement is higher in smokers, we retrospectively analyzed the opioid requirements of smokers who had undergone laparoscopic distal gastrectomy with gastroduodenostomy for early stomach cancer and compared with nonsmokers. Primary end-points were the difference of postoperative opioid consumption between smokers and nonsmokers. Secondary end-points were the occurrence of side effects according to smoking status.
This study was approved by our institutional review board and registered at the University of Ulsan, Seoul, Republic of Korea (2015-0112, 2/2/2015, Musong Lee). We searched information technology of service management (ITSM) of our institution using the terms “early malignant neoplasm of stomach,” “distal gastrectomy,” and “gastroduodenostomy.” Cases were included in the study only if they met the following conditions: total intravenous (IV) anesthesia and postoperative intravenous patient-controlled analgesia (IV PCA) with oxycodone from October 2013 to September 2014. Total 549 patients were found after searching ITSM. From these records, we further excluded patients who underwent distal gastrectomy with gastroduodenostomy and cholecystectomy simultaneously, or who underwent distal gastrectomy with δ-shaped anastomosis or with anastomosis to jejunum. Patients undergoing distal gastrectomy with gastoduodenostomy as a palliative measure were also excluded. The remaining patients without history of drug abuse, chemotherapy, radiotherapy had no preoperative pain and no preoperative opioid use. Heavy alcoholics were excluded.
After exclusion, we extracted 250 records of patients who received elective laparoscopic distal gastrectomy with gastroduodenostomy due to early stomach cancer. The 14 patients who stopped IV PCA caused by nausea, vomiting, dizziness, and postoperative bleeding before postoperative day 2 were excluded after data review. Data from the remaining 236 patients were analyzed (Fig. 1). In the literature, smokers are generally categorized according to the following definitions28: (1) Nonsmokers who have never smoked a cigarette or who have smoked <100 cigarettes in their whole lifetime. (2) Ex-smokers who have smoked at least 100 cigarettes in their lifetime, but do not currently smoke. (3) Current smokers who have smoked >100 cigarettes in their lifetime and currently smoke. Current smoker and ex-smokers were included in smokers group.
Methods of Anesthesia and Analgesia
The oxygen saturation, blood pressure, heart rate, electrocardiography, temperature, and bispectral index were measured in all patients. Total IV anesthesia was used for induction and maintenance of anesthesia. Propofol and remifentanil were administrated via target-controlled infusion (TCI). The Marsh model was used for propofol TCI and the Schnider model was applied for remifentanil TCI. B.Braun Perfusor Space (B.Braun Medical Inc., Bethlehem, PA) was used for TCI. The plasma concentration of propofol and remifentanil were adjusted to meet the target bispectral index value of 40 to 60 and proper vital signs. Analgesic single bolus doses of fentanyl (1 μg/kg) or oxycodone (1 mg/kg) were injected 30 minutes before the end of the surgery. IV ramosetron 0.3 mg was administrated to the patients for preventing postoperative nausea and vomiting (PONV) before starting IV PCA. Additional doses of fentanyl (1 μg/kg) or oxycodone (1 mg/kg) were injected in cases of insufficient analgesia at the postanesthetic care unit.
Only oxycodone was used in the IV PCA device (Accumate 1100, Wooyoungmedical, Seoul/Korea). The PCA device was programmed with the following settings: 1 mL/h basal infusion rate, 1 mL bolus dose, and 15 minutes lockout interval. The maximum dose of oxycodone per hour was 5 mg. Rescue analgesics including fentanyl, oxycodone, and meperidine were used if analgesia was not sufficient (numeric rating scales [NRS]>4) after operation. IV oxycodone was mainly used for postoperative pain control. In case of the patient with renal failure, fentanyl was administrated first. When the patients had shivering, meperidine was injected for pain management. Total amounts of opioid used in postanesthetic care unit and the general ward were also recorded until postoperative day 2. Certified nurses on the acute pain service monitored all the patients 3 times a day and recorded the amount of PCA solution used and any side effects. The side effects of opioid are defined as nausea, vomiting, dizziness, pruritus, urinary retention, respiratory depression, and tendency to fall asleep during IV PCA infusion. All opioids that were administered to patients were converted to IV oxycodone equianalgesic dose according to published conversion factors (IV fentanyl 100 μg=meperidine 100 mg=oxycodone 10 mg).29
The data were analyzed using Statistical Package for the Social Sciences (SPSS Version 21.0, SPSS Inc., Chicago, IL). Demographics and continuous data from the 2 groups of patients were compared using the Student t test and were documented as mean (±SD). Analysis of variance and Kruskal-Wallis test were used for comparing ≥3 groups for statistical significance. Categorical data were compared using a χ2 test or a Fisher exact test. The factors relating to postoperative opioid requirements were analyzed with simple regression analysis. Significant variables were compared with multiple regression analysis to evaluate independent factors. Pearson correlation analysis was conducted to verify associations between amount of smoking and postoperative opioid consumption. P<0.05 were considered to be statistically significant.
Demographic characteristics of the 2 groups are summarized in Table 1. There was no difference in average age and the American Society of Anesthesiologists class and Body Mass Index. There was a significant sex difference between the 2 groups. Male smoking rate was 80.1% and female smoking rate was just 4.2% in the current study group. The mean surgical time and amount of remifentanil was significantly more among smoker than among nonsmokers during intraoperative period.
NRS in smokers was significantly greater than that in nonsmokers on the day of surgery (Fig. 2). Opioid consumption was significantly higher in smokers than in nonsmokers during the postoperative period except on postoperative day 1 (P<0.05, mean difference for each postoperative day 0, 1, 2=2.04, 2.45, 4.01 mg, respectively). Total opioid requirement was also higher in smokers (P=0.003, mean difference=8.49 mg, 95% confidence interval [2.97-14.03]) (Fig. 3). We performed analysis of opioid consumption between smokers and nonsmokers in males only because of significant sex differences between the 2 groups. Male smokers showed more opioid consumption than male nonsmokers on postoperative day 2 (P=0.022, mean difference=5.03 mg), and total opioid requirements in male smokers were also higher (P=0.037, mean difference=9.33 mg, 95% confidence interval [0.58-18.08]) (Fig. 4).
We analyzed pain intensity, opioid consumption, surgical time, and remifentanil amount in intraoperative period between nonsmokers, ex-smokers, and current smokers. Surgical time, remifentanil amount, NRS on the day of surgery, opioid consumption on all postoperative days, and total opioid consumption were significantly higher in current smokers or ex-smokers than in nonsmokers (Table 2). These results were similar between smokers and nonsmokers. Opioid consumption on postoperative day 1 and total opioid consumption in current smokers was more than in ex-smokers (P=0.004, 0.003).
Simple regression analysis showed that age, smoking status, amount of intraoperative remifentanil, and sex were relevant factors for postoperative opioid requirements. The only statistical significant variables (P<0.05) in simple regression analysis were included into the final multiple regression analysis. Multiple regression analysis identified age (β=−0.633, P<0.001), smoking (β=7.831, P=0.006), and amount of intraoperative remifentanil (β=3.261, P=0.041) as the only significant predictors of postoperative opioid requirements (Table 3).
Pearson correlation analysis showed that pack-years and postoperative opioid consumption were not correlated (Fig. 5). All P-values were greater than 0.05 in this Pearson correlation analysis. Subgroup analysis according to the amount of pack-years was performed to clarify the relationship between smoking amount and opioid requirement, then no correlation among 2 variables was confirmed (Table 4).
PONV in the smokers was significantly less than that in nonsmokers on postoperative day 1 (P<0.003). Subgroup analysis in males showed that PONV was less frequent in male smokers on postoperative day 1 (P=0.029) (Table 5). There were no postoperative pulmonary complications in this study.
The major finding of this study is that postoperative opioid requirements are higher in smokers than nonsmokers. Although opioid consumption in the smokers on postoperative day 1 was not significantly different, it was still higher than that in nonsmokers. There was a trend for smokers to use more opioids than nonsmokers within postoperative day 2. Another finding was that smokers showed an increased pain perception on the day of surgery compared with nonsmokers. It was speculated that increment of pain intensity in smokers might lead to an increased postoperative opioid consumption.
There was no meaningful difference in the proportion of males to females in prior studies.17,20 However, the number of males and females in the smoking and nonsmoking groups were significantly different in this study. The smoking rate of males above 19 years was 43.1% and that of females above 19 years was 5.7% in Korea in 2014.30 Male smoking rates was 80.1% and female smoking rate was 4.2% in our study. The overall difference between male and female smoking rates in our study group was similar to that of the Korean population average. We performed subgroup analysis in males because the disproportionate smoking rates between genders could be a confound. The male smokers also showed greater opioid requirements on postoperative day 2 and higher total opioid requirements. There was a similar trend for total opioid use in smokers. We did not analyze postoperative opioid requirement in female smokers, because there were only 4 such patients.
Current smokers required more opioid during postoperative period compared with ex-smokers and nonsmokers. Quantity of opioid use among ex-smokers was similar to that among nonsmokers. Our results were inconsistent with the results of prior studies.15,31 We speculated that smoking cessation could help physiological alteration in opioid consumption induced by smoking normalize.
Variable factors like age, sex, opioid tolerance, and surgical characteristics can influence postoperative opioid requirements.32 Weingarten et al27 reported that although current tobacco smokers used more opioid analgesics in the first 48 hours postsurgery than nonusers of tobacco, after adjusting for age and sex, tobacco use was not independently associated with differences in postoperative opioid use, and only age and sex were independently associated with postoperative opioid use. Accordingly, we performed regression analysis to confirm the influence of smoking on postoperative opioid use in this study. Simple regression analysis conducted to evaluate the factors associated with postoperative opioid requirements shows that age, smoking, amount of intraoperative remifentanil, and sex were relevant factors for postoperative opioid requirements. Significant factors searched in single regression analysis were analyzed with multiple regression analysis to predict the value of variables more precisely. The results showed that the only significant factors for postoperative opioid requirements were age, smoking, and amount of intraoperative remifentanil independently. We confirmed that age was an independent factor associated with postoperative opioid requirements. This is similar to the results identified by Weingarten et al27 and Gagliese et al.33
In our study, there was a positive correlation between smoking and postoperative opioid requirements. There are several studies relating smoking to increments of postoperative opioid requirements in the literature.16–21 These studies support our finding that smoking is an independent factor associated with increments of postoperative opioid requirements. After taking our result and previous studies into consideration, smoking almost seems to be a predictor for postoperative opioid consumption. However, some studies suggest the opposite opinion. Brattwall et al26 demonstrated no influence of nicotine use on postoperative pain in day surgery. However, day surgical procedures such as cosmetic breast augmentation, inguinal hernia repair, and arthroscopic procedures do not induce moderate to severe pain.34 Mild to moderate pain would not require many analgesics, which could mask the effect of smoking on postoperative analgesics use. The distal gastrectomy with gastroduodenostomy in the present study is an upper abdominal surgery, which produces moderate to severe postoperative pain.34 This significant pain could lead to use of more analgesics, which would make the effect of smoking on postoperative analgesics consumption more distinct. Moreover, we evaluated only patients with IV PCA, which reflects analgesic requirements more precisely. Therefore, this study might have more relevant data on postoperative analgesics consumption than other studies. Development of tolerance to nicotine-induced analgesia in smoker might increase perception of pain; abstinence from nicotine could increase nociception and induce anxiety, all of which could lead to more opioid use in smokers during perioperative period.
Another independent factor associated with postoperative opioid requirements was amount of intraoperative remifentanil. Smoking was associated with increased perioperative blood loss. Bleeding can cause increased surgical time and difficulty during operation.35 Surgical time in smokers was increased in this study. Prolonged surgical time might cause the increment of remifentanil use, which could lead to opioid tolerance or opioid-induced hyperalgesia.36,37 These factors might influence on postoperative opioid requirement.
The association between amount of smoking (pack-years) and postoperative opioid requirements was evaluated with Pearson correlation analysis and subgroup analysis. Amount of smoking was not associated with postoperative opioid consumption in our study. There are multiple studies about increments of postoperative analgesics related to smoking in the literature, but there are few studies of association between amount of smoking and postoperative analgesics.16,31 Berge and colleagues reported that heavy smokers have higher postoperative analgesic requirements. But the analgesic used in that study was a tablet containing paracetamol (500 mg) and codeine (30 mg). Heavy cigarette smoking has been associated with an increased demand for paracetamol, due to smoking-induced increased glucuronidation activity. Accordingly, the cause of higher postoperative analgesics requirements might be increments of paracetamol instead of codeine. Woodside showed that opioid requirements did not correlate with pack-years smoked. These studies support our result that amount of smoking is not correlated with postoperative opioid consumption. The effect of pack-years on postoperative opioid requirements could reflect a persistent influence of smoking on pain perception and opioid response. In other words, alterations in neuronal function induced by smoking could be sustained regardless of amount of smoking.
Adequate administration of analgesics is very important for patient’s outcome.17,22,23 Smokers seemed to increase the perception of pain and required more postoperative opioid use regardless of amount of smoking in the present study. Consequently, titration of postoperative opioid administration in smoking patients can provide sufficient analgesia and good surgical outcomes.
We also surveyed the side effect of opioids between the 2 groups. The results show that only PONV was less in smokers than nonsmokers. Other side effects were not significantly different. PONV in male smokers was significantly less on the postoperative day 1 in subgroup analysis. This is in line with other studies that show the antiemetic effect of smoking,38–41 although the mechanism is still not clear. The male smokers had significantly less PONV only on the postoperative day 1 in this study. White et al42 reported that although the antiemetic effect of smoking is still present, it is no longer significant day 1 after surgery. We did not record incidence of PONV on the day of surgery. In our study, the antiemetic effect of smoking was evident only on the postoperative day 1, not day 2. Comparing this with Whitestudy, there was a similar result in that the effect of tobacco was significant early after surgery. Smokers required more opioid postoperatively, but PONV was still less in smokers in our study. Consequently, we believe that smoking might be a strong preventive factor for PONV until postoperative day 1.
There were several limitations in our study. First, significant sex imbalance in the 2 groups was present in our study, especially female. Opioid requirement seems to be affected by sex. Several studies show that postoperative opioid requirements are less in females.27,43 There was a significant sex imbalance in both our groups as smoking rates amongst Koreans vary greatly between sexes. Consequently, female could not be analyzed as an independent factor influencing postoperative opioid consumption in this study. Second, occasionally our patients received heterogenous nonsteroidal anti-inflammatory drugs, which cannot be readily converted into equianalgesic doses of oxycodone. Third, there was no significant difference in the fraction of NSAIDs recipients between the 2 groups. Fourth, it was not a prospective controlled study but retrospective study. Finally, postoperative opioid use was recorded only during immediate postoperative period. Long-term studies may yield varied results between smokers and nonsmokers.
Smokers undergoing distal gastrectomy with gastroduodenostomy required more opioids than nonsmokers within postoperative period. After adjusting for other clinical variables that influence opioid use, age, smoking, and amount of intraoperative remifentanil were still independent factors associated with increments of postoperative opioid consumption. Despite smokers having more postoperative opioid consumption, PONV was significantly less in smokers compared with nonsmokers.
The authors thank the Clinical Nurse Specialist (Myung Hee Kim, Master's Degree in Nursing) in the Department of Pain Management, Operating Room Nursing Team, Asan Medical Center Seoul, Korea; for collecting data in the present study.
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