Mishriky, Basem M. MD; Habib, Ashraf S. MBBCh, MSc, MHSc, FRCA
High levels of postoperative pain continue to be reported by many patients.1 Systemic administration of opioid analgesics remains one of the most commonly used methods for postoperative pain relief. However, opioid-related side effects can be distressing to patients and may be associated with prolonged hospital stay and increased costs.2 To reduce the dose requirements and the side effects of opioids, adjunct medications are used in an effort to achieve multimodal analgesia and more optimal pain management.2
Nicotine, the main stimulant in cigarette smoke, was found to have antinociceptive effects in animal and volunteer studies.3,4 More recently, the potential analgesic effect of the perioperative administration of nicotine was investigated. Furthermore, since nonsmokers have a higher risk for postoperative nausea and vomiting (PONV),5 the perioperative administration of nicotine was investigated as a possible modality to reduce the incidence of PONV.
We therefore performed this systematic review to assess the impact of perioperative administration of nicotine on postoperative pain and PONV.
We followed the recommendations of the PRISMA statement.6
We searched MEDLINE (1966–2012), the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE (1947–2012), and CINAHL for randomized controlled trials that investigated the effects of nicotine compared with placebo regarding postoperative pain and/or PONV in patients undergoing surgery under general anesthesia. Search engines were explored using the following combination of terms “nicotine AND postoperative pain” and “nicotine AND postoperative nausea and vomiting.” The search was performed without language restriction. The date of the last computer search was July 2012. In addition, the bibliographies of retrieved articles were searched for additional studies. Reviews, abstracts, letters to the editor, and retrospective studies were excluded.
Articles meeting the inclusion criteria were assessed separately by the 2 reviewers using the risk of bias table suggested by the Cochrane Collaboration.7 There was a discrepancy between the 2 reviewers in 2 items, and this was resolved by discussion.
A data collection sheet was created, and the 2 reviewers extracted data independently on: (1) type of surgery, (2) dose, time, and mode of nicotine administered, (3) number and gender of patients included, (4) smoking status, (5) primary outcome of the study, (6) postoperative analgesia regimen, (7) pain scores at rest and during movement, (8) opioid consumption, (9) side effects (nausea, vomiting, need for rescue antiemetics, pruritus, sedation, and time to first flatus), and (10) patient satisfaction. If any of the data were reported in a graph, the authors were contacted to provide the numerical data.
The primary outcomes were pain scores and cumulative opioid consumption at 24 hours. Secondary outcomes were pain scores and opioid consumption at 1, 6, 48, and 72 hours, side effects (postoperative nausea, postoperative vomiting, need for rescue antiemetics, pruritus, and sedation) at 1 and 24 hours, and patient satisfaction.
Verbal/numerical rating scale scores 0 to 10 for pain were used for analysis. If results were not reported at the exact time point specified in this analysis, those recorded close to that time point were used instead. If side effects were reported only beyond 24 hours, those data were grouped with the 24 hours results.
Continuous data were summarized as mean difference with 95% confidence interval (CI). If the 95% CI included a value of 0, we considered that the difference between nicotine and control was not statistically significant. Dichotomous data were summarized as relative risk with 95% CI. If the 95% CI included a value of 1, we considered that the difference between nicotine and control was not statistically significant. We considered a 30% reduction in 24 hours pain scores (visual analog scale reduction of 1.2) and opioid consumption (12.5 mg reduction in morphine equivalents) compared with control to be clinically relevant. Analyses were performed using the R routines metacont and metabin (R package Meta) including a statistical adjustment (Hartnup-Knapp adjustment) for the number of studies, Review Manager (RevMan). Version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011, and Comprehensive Meta-Analysis software (Version 2.0). A random effects model was used. The correlation between mean pain scores at 24 hours and mean opioid use at 24 hours for the 9 studies was calculated with Kendall’s τ. For side effects with statistically significant differences between the groups, number need to harm (NNH) was calculated. We considered heterogeneity to be present if the I2 test was >50%. Forest plots were used to graphically represent and evaluate treatment effects. If postoperative nausea and postoperative vomiting were only reported collectively as PONV, we considered PONV as postoperative nausea. A sensitivity analysis was performed for the primary end points according to the mode of administration of nicotine, smoking status, and gender. Another sensitivity analysis was performed by excluding studies with high risk of bias for any of the risk of bias parameters assessed. We also performed subgroup analyses using the Q-test for the primary end points according to the mode of administration of nicotine (transdermal patch versus nasal spray), gender (women versus men), and smoking status (nonsmokers versus smokers). A random effects meta-regression was performed for pain scores and cumulative opioid consumption at 24 hours for studies investigating transdermal nicotine patch to assess if there was a dose-response relationship. Publication bias for the primary end points was assessed using Egger test.8
The search strategy identified 242 studies (Fig. 1). Nine studies9–17 with 662 patients (347 received nicotine and 315 served as control) met the inclusion criteria and were included in the final analysis. In those studies, there were 480 females and 182 males. We requested additional data from the authors of 6 studies.10,12–14,16,17 The characteristics of the included studies are shown in Table 1. The risk of bias of the included studies is shown in Table 2.
Four studies10,12,15,17 involved gynecologic surgical procedures (310,12,17 abdominal hysterectomy or myomectomy and 115 abdominal or vaginal gynecologic procedures), 214,16 included both abdominal and gynecologic surgeries, 111 included various inpatient surgeries (ear, nose, and throat, lumbar disc, and abdominal surgeries with 54% involving ear, nose, and throat surgeries), 113 included radical retropubic prostatectomy, and 19 included laparoscopic cholecystectomy. Nicotine was administered as a transdermal patch in 6 studies9,11,13,14,16,17 and as a nasal spray in 3.10,12,15 Transdermal nicotine patch was investigated in doses ranging from 5 mg/16 hours to 21 mg/24 hours administered before induction of anesthesia. All studies10,12,15 investigating nicotine nasal spray used a dose of 3 mg administered at the end of surgery. Four studies10,12,15,17 recruited females only, 4 studies9,11,14,16 recruited both males and females, while 1 study13 recruited males only. Seven studies9–15 included nonsmokers, 116 smokers, and 117 both smokers and nonsmokers.
Postoperative analgesia was provided using patient-controlled analgesia with morphine alone in 3 studies10,12,17 and a combination of nonsteroidal anti-inflammatory drugs and opioids in 6 studies.9,11,13–17
Pain Scores at 24 Hours
Pain scores at rest at 24 hours were investigated in 7 studies10,12–17 and during movement in 2 studies.13,17 Figure 2 shows the results of the pooled studies for pain reduction at rest at 24 hours. The Forest plot suggests that the study by Flood and Daniel12 had a much larger treatment effect than the other studies. The I2 value of 86% suggests considerable heterogeneity among the study results, likely due to the outlying study. The pooled analysis shows a reduction in pain score of 0.69 points, 95% CI, = −1.60 to 0.22, P = 0.12. The wide CI suggests that the data are insufficient to reach a conclusion about this outcome. This reduction in mean pain score also does not reach clinical significance.18,19 Excluding the study by Flood and Daniel12 reduced the heterogeneity (I2 = 8%), with no difference in pooled pain scores at rest (mean difference = −0.18, 95% CI, = −0.39 to 0.28). There was no difference between the 2 groups in pain scores during movement, mean difference = 0.10, 95% CI, = −0.39 to 0.59.
Cumulative Opioid Consumption at 24 Hours
Opioid consumption at 24 hours was investigated in 7 studies.10,12–17 Figure 3 shows the pooled results. There was a statistically significant reduction in cumulative opioid consumption with the administration of nicotine, mean difference = −4.85 mg morphine equivalents, 95% CI, = −9.40 to −0.30, P = 0.04. Opioid consumption outcome showed less heterogeneity (I2 = 24%). Although the opioid sparing at 24 hours was appreciable (approximately 5 mg), it should not be considered conclusive because the CI nearly included 0, and the P value was only modestly significant.
Concordance Between Pain Score and Opioid Consumption at 24 Hours
Kendall’s τ was 0.5 (P = 0.038) for the concordance between pain score at 24 hours and opioid use at 24 hours. This statistically significant Kendall’s τ strengthens our confidence in the concurrent validity of the reported measures of pain scores and opioid consumption.
Pain Scores at Other Time Points
Results are presented in Table 3. Pooled results showed no difference between the groups in pain scores at rest at 1 hour and during movement at 48 and 72 hours. Pooled results for pain scores at rest at 6, 48, and 72 hours and during movement at 1 and 6 hours had a wide CI, suggesting that the data are insufficient to reach a conclusion at those time points. Incidence of incisional pain at 3 months was investigated in 1 study,17 with no difference between the nicotine and control groups (7% vs 10%, respectively). The R code for 1 hour pain at rest is provided in the Appendix.
Cumulative Opioid Consumption at Other Time Points
Results are presented in Table 3. Pooled results for cumulative opioid consumption showed no difference between the 2 groups at 1 and 48 hours. At 6 and 72 hours, the wide CI of the pooled results suggests that the data are insufficient to reach a conclusion about opioid consumption at those time points.
Duration of Postanesthesia Care Unit and Hospital Stay
Duration of PACU stay was investigated in 2 studies,13,15 with both studies reporting longer PACU stay with the administration of nicotine. Pooled results, however, had a wide CI (mean difference = 12.7 minutes, 95% CI, = −21.2 to 46.6, I2 = 49%) suggesting that the data are insufficient to reach a conclusion about this outcome. Duration of hospital stay was investigated in 1 study,13 with no difference between the 2 groups.
Side effects are presented in Table 4. The R code for 24 hours nausea is provided in the Appendix. During the first postoperative hour, the administration of nicotine was associated with a significantly higher incidence of postoperative nausea (NNH = 10), and greater need for rescue antiemetics (NNH = 8). The incidence of nausea was also significantly higher with nicotine administration at 24 hours (NNH = 33). For postoperative vomiting, the wide CI of pooled results at both 1 and 24 hours indicates that the data are insufficient to reach conclusion about this outcome. The same applies to need for rescue antiemetics and pruritus at 24 hours. Insomnia at 24 hours was investigated in 1 study,11 with a significantly higher incidence with the use of nicotine (27% for nicotine vs 7% for control, P = 0.01). Time to first nausea and vomiting episodes was investigated in 1 study,11 and although nausea and vomiting occurred earlier in the nicotine group, the difference was not statistically significant. Nausea scores were investigated in 2 studies,13,15 with one13 using an 11-point scale (0–10) and reporting significantly higher maximum nausea scores in the nicotine group, and the other15 using a 4-point scale (0–3) and reporting higher scores in the PACU but not at 24 hours with nicotine. Time to first flatus was investigated in 2 studies,13,17 with no difference between the 2 groups (mean difference = 2.3 hours, 95% CI, = −0.44 to 5.1, I2 = 0%). At 24 hours, intermittent sleep and nightmares, headache, and dizziness were investigated in 1 study with no difference between the 2 groups.9,11,13 At 72 hours, somnolence, dizziness, urinary retention, dry mouth, and constipation were investigated in 1 study,17 with no difference between the 2 groups.
Two studies13,17 investigated patient satisfaction on an 11-point scale (0–10), with no difference between the 2 groups (mean difference = 0.16, 95% CI, = −0.45 to 0.78, I2 = 0%).
When restricting the analysis to studies administering nicotine as a nasal spray,10,12,15 or transdermal patch,13,14,16,17 or those involving only female patients,10,12,15,17 the reduction in cumulative opioid consumption at 24 hours was no longer statistically significant. However, when restricting the analysis to studies involving nonsmokers,10,12–15 opioid consumption was still significantly reduced with nicotine at 24 hours (mean difference = −6.3 mg morphine equivalents, 95% CI, = −12.4 to −0.11, I2 = 37%). When excluding 1 study with high risk of bias,9 nicotine was still associated with a significantly higher risk of postoperative nausea (NNH = 13) at 24 hours (relative risk = 1.15, 95% CI, = 1.05 to 1.25, I2 = 0%) when compared with control.
Comparing the 2 modes of nicotine administration (transdermal patch versus nasal spray), both genders (women versus men) and smoking status (nonsmokers versus s mokers) did not show any difference between the subgroups in the primary outcomes of pain scores and cumulative opioid consumption at 24 hours.
No evidence of dose-response relationship was detected for studies administering nicotine as a transdermal patch (slope = 0.71, 95% CI, = −0.14 to 1.55, P = 0.1 for pain scores at rest, and slope = 0.003, 95% CI, = −0.11 to 0.11, P = 0.96 for cumulative opioid consumption).
No evidence of publication bias was detected for the primary outcomes of pain scores at rest and cumulative opioid consumption at 24 hours (P = 0.24 and P = 0.052, respectively).
This systematic review and meta-analysis suggest that nicotine administration was associated with reduction in opioid consumption of approximately 0 to 9 mg over the first 24 hours. The reduction in pain score at 24 hours was neither clinically nor statistically significant. The reduction in opioid consumption seemed to be limited to nonsmokers. Other time points did not show a benefit in either opioid sparing or improved analgesia. There was an increased incidence of postoperative nausea with nicotine in patients undergoing surgery under general anesthesia.
The antinocicetive effect of nicotine was previously reported in animal and volunteer experimental pain studies.3,4 This effect is thought to be mediated by nicotinic acetylcholine receptors (nAChRs) throughout the nervous system.20 The nAChR is composed of pentameric combination of subunits derived from at least 17 genes
Equation (Uncited)Image Tools
21–23 Nicotine is a nonselective agonist at the α4 and β2 combination subunit,4,24,25 which is the predominant nAChR subunit26 mediating the analgesic effect through increasing the affinity of nAChRs to nicotine.21,27 While this subunit is the main mediator for the antinociceptive action of nicotine, other subunits such as the α7 subunit are thought to be involved.20,21
Continuous exposure to nicotine in smokers causes upregulation of nAChRs specifically the α4 and β2 subunits.20,24,28 Furthermore, it can cause a shift in nAChRs subunits combinations.24,26 Previous studies suggested that smokers experience higher level of postoperative pain compared with nonsmokers.29,30 This may explain why the analgesic action of nicotine may be limited to nonsmokers and why smokers can tolerate higher doses of nicotine without benefiting from its analgesic effect.20,31,32
Previous reports have shown that nicotine increases the incidence and severity of nausea especially in nonsmokers.32–34 However, since nonsmokers are more prone to PONV,5 the perioperative administration of nicotine for PONV prophylaxis was investigated.9,11 Two studies9,11 investigated PONV as a primary outcome with one11 reporting a higher incidence of PONV with nicotine compared with control, while the other9 reported a lower incidence of PONV with nicotine; however, it had a high risk of bias. Pooled results suggested higher risk of postoperative nausea at 1 and 24 hours with nicotine. The 95% CIs of the pooled results for postoperative vomiting were wide preventing any solid conclusions to be drawn.
Although some previous reports have suggested gender differences35–37 regarding nicotine analgesia, others did not.38 There were also conflicting results regarding whether men35,37 or women36 benefit more from nicotine analgesia. Our review did not show a gender effect regarding nicotine administration in the perioperative area. However, our results should be interpreted with caution due to the small number of included studies investigating nicotine analgesia.
This opioid-sparing effect of nicotine seemed to be limited to nonsmokers. While the 20% opioid sparing seen in the pooled results might be considered clinically relevant, this did not translate into enhanced recovery or improved outcomes. Specifically, pain scores were not reduced in nicotine-treated patients, and other outcomes such as recovery of bowel function were not improved. Furthermore, the increased incidence and severity of postoperative nausea limit the clinical usefulness of the perioperative administration of nicotine.
The investigators of the studies included in this meta-analysis administered nicotine as a transdermal patch or nasal spray. Nicotine patch allows less variability in plasma nicotine with a slow steady level delivered through the skin over the duration of the patch, whereas nasal administration leads to rapid absorption through the mucous membranes achieving a peak nicotine concentration within 10 minutes from administering the drug.39–41 Our subgroup analysis did not suggest a difference in efficacy between the 2 modes of administration. There was also no evidence of dose responsiveness regarding the opioid-sparing effect of the nicotine patch.
This review has several limitations. We combined different types of surgery, both genders, both smokers and nonsmokers, and different routes and doses of nicotine in our main analysis. We performed a number of sensitivity analyses, subgroup analyses, and meta-regression to try to assess the impact of those factors on primary outcomes. Results from these analyses however may be biased and need to be interpreted with caution.7 The small number of included trials is another limitation that did not allow us to perform a meta-regression examining all the possible predictors together since it was suggested that 10 studies are needed per predictor.7 This small number also resulted in wide CIs for the pooled results of many of the reported outcomes preventing definitive conclusions to be drawn. Finally, reporting some of the important outcomes was not satisfactory. For instance, PONV reporting was inconsistent among the studies with some studies reporting nausea and vomiting separately and other lumping them together as PONV. The duration of PACU stay was only reported in 2 studies,13,15 and recovery of bowel movements in 2 studies.13,17
Some areas for future research have been identified by this review. Antiemetic prophylaxis was achieved in only 4 of the included studies using a single drug.10,12,13,16 Large adequately powered studies incorporating multimodal PONV prophylactic regimens are warranted to assess if the side effect of PONV could be reduced with more aggressive prophylaxis. Studies investigating other nicotinic receptor agonists are also needed.
In conclusion, this systematic review and meta-analysis suggest that nicotine has an opioid-sparing effect in nonsmokers undergoing surgery under general anesthesia. This benefit is limited by an increased incidence of postoperative nausea and is not associated with improved patient outcomes. Current data do not support a role of nicotine for perioperative analgesia.
APPENDIX: EXAMPLES OF R CODE FOR A CONTINUOUS VARIABLE (1 HOUR PAIN AT REST) AND A DICHOTOMOUS VARIABLE (24 HOUR NAUSEA)
One hour pain at rest
META <- metacont(N1, Mean1, SD1, N2, Mean2, SD2, Names,sm=“MD”,level = 0.95, level.comb = 0.95,comb.fixed=FALSE, comb.random=TRUE,hakn=TRUE,method.tau=“DL”, tau.preset=NULL, TE.tau=NULL,method.bias=“linreg”,title=““, complab=““, outclab=““,label.e=“Nicotine”, label.c=“Placebo”,label.left=“Favors Nicotine”, label.right=“Favors Control”)
Twenty-four hour nausea
META <- metabin(Events1, N1, Events2, N2, Names, method = “Inverse”,sm = “RR”,level = 0.95, level.comb = 0.95,comb.fixed = FALSE, comb.random = TRUE,hakn = TRUE,method.tau = “DL”, tau.preset = NULL, TE.tau = NULL,method.bias = NULL,title = ““, complab = ““, outclab = ““,label.e = “Nicotine”, label.c = “Placebo”,label.left = “Favors Nicotine”, label.right = “Favors Control”)
Name: Basem M. Mishriky, MD.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Attestation: Basem M. Mishriky has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Ashraf S. Habib, MBBCh, MSc, MHSc, FRCA.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Ashraf S. Habib has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
This manuscript was handled by: Steven L. Shafer, MD.
The authors would like to thank Igor Akushevich, PhD, and Vic Hasselblad, PhD, for statistical assistance, and Drs. Flood and Turan for responding to our queries and providing the requested data.
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