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ANALGESIA

Transdermal Nicotine for Analgesia After Radical Retropubic Prostatectomy

Ashraf S. Habib, MBBCh, MSc, FRCA^*, William D. White, MPH^*, Magdi A. El Gasim, MD^*, Gamal Saleh, MD^*, Thomas J. Polascik, MD, Judd W. Moul, MD, and Tong J. Gan, MB, FRCA^*

From the *Department of Anesthesiology, Division of Urologic Surgery and Duke Prostate Center, Department of Surgery, Duke University Medical System, Durham, North Carolina.

Address correspondence and reprint requests to Ashraf S. Habib, MBBCh, MSc, FRCA, Duke University Medical System, Box 3094, Durham, North Carolina. Address e-mail to habib001{at}mc.duke.edu.

Abstract

BACKGROUND: Previous animal and human studies suggested that nicotine might have an antinociceptive effect. We hypothesized that the preoperative application of a 7 mg nicotine patch would result in reduced postoperative analgesic requirements in patients undergoing radical retropubic prostatectomy (RRP) under general anesthesia.

METHODS: Nonsmokers undergoing RRP under general anesthesia were enrolled in this prospective, double-blind, placebo-controlled study. Patients were randomly assigned to receive a patch of 7 mg nicotine or placebo applied behind the ear 30–60 min before induction of anesthesia. The anesthetic technique was standardized. Postoperative analgesia was provided with a standardized morphine patient-controlled analgesia and 6 hourly ketorolac 15 mg IV. Data were collected in the postanesthesia care unit and at 6, 12, and 24 h after surgery.

RESULTS: Ninety patients were included in the analysis: 44 in the nicotine group and 46 in the placebo group. The groups did not differ significantly with respect to age, height, weight, ASA class, length of surgery, or amounts of intraoperative fentanyl received. The nicotine group showed significantly lower cumulative morphine consumption at 24 h (mean ± sd): 33.3 ± 30.8 mg vs 44.7 ± 26.4 mg (P = 0.0059, time x treatment P = 0.0031). However, the repeated measures tests found no difference in amount of pain reported on coughing or at rest, either as treatment effects or in interaction with time. In post hoc comparisons, there was no significant difference in amount of pain reported on coughing or at rest at any of the times assessed. There were also no significant differences between the groups in the incidence of postoperative nausea and vomiting or the need for rescue antiemetics. However, the maximum nausea verbal rating scale score was higher in the nicotine than in the placebo group (median, 25th to 75th percentiles = 4, 0–6 vs 0, 0–6, P = 0.0158). There was a significant negative correlation between the 24 h plasma nicotine levels and postoperative morphine consumption in the postanesthesia care unit (P = 0.049), as well as at 6, 12, and 24 h (P = 0.002).

CONCLUSION: The preoperative application of a 7 mg nicotine patch resulted in a significant reduction in opioid consumption in patients undergoing RRP under general anesthesia. Despite this reduction in opioid use, there was no reduction in pain scores or postoperative nausea and vomiting with the use of transdermal nicotine.

Despite the increased focus on pain management over the last several years and the development of formal standards and guidelines for the management of acute pain, a significant number of patients continue to experience unacceptable levels of pain after surgery. In a survey of 250 adults who had undergone surgical procedures in the United States, approximately 80% of patients experienced moderate to extreme acute pain after surgery.1 Systemic administration of opioid analgesics such as morphine remains one of the most commonly used methods for postoperative pain relief. However, some patients are so distressed by the adverse effects of opioids that they may prefer to experience pain rather than opioid adverse effects.2 To reduce the dose requirements and therefore the side effects of opioids, adjunct medications should be used in an effort to achieve multimodal analgesia and more optimal pain management.3

Nicotine, a potent stimulant found in cigarette smoke, was found to have analgesic properties. The antinociceptive effects of nicotine have been consistently observed in animal studies.4–7 A number of volunteer studies also reported that nicotine had pain-inhibitory effects.8–10 The effect of nicotine on postoperative analgesia was investigated in one study in 20 women undergoing uterine surgery. The administration of a single dose of 3 mg nicotine by nasal spray produced beneficial analgesic effects for up to 24 h with no associated hemodynamic disturbances or other side effects.11

We hypothesized that the preoperative application of a nicotine patch releasing 7 mg over 24 h would result in reduced postoperative analgesic requirements in patients undergoing radical retropubic prostatectomy (RRP) under general anesthesia. The primary objective of this study was therefore to assess the 24 h morphine-sparing effect of the preoperative administration of a 7 mg nicotine patch in this patient population.

METHODS

After IRB approval, and written informed patient consent, 96 male nonsmokers, 18–75-yr-old, scheduled to undergo RRP under general anesthesia were enrolled in this double-blind, randomized, placebo-controlled trial. Nonsmokers were defined as those individuals who had never smoked regularly or who had successfully quit smoking for a minimum of 5 yr.8 Exclusion criteria included smokers, patients with chronic pain conditions or taking regular analgesics, patients with uncontrolled hypertension, ischemic heart disease, peripheral vascular disease, arrhythmias, diabetes, asthma, hyperthyroidism, or pheochromocytoma because increases in arterial blood pressure, heart rate, and plasma glucose can follow the effects of nicotine-induced catecholamine release.

The anesthetic technique was standardized; patients were premedicated with midazolam IV (up to 2 mg) and fentanyl IV (up to 100 µg). Anesthesia was induced with propofol (1–2.5 mg/kg), and a muscle relaxant of the anesthesiologist's choice was used to facilitate tracheal intubation. Maintenance of anesthesia was with isoflurane (0.5%–2.5%), 50% nitrous oxide in oxygen, and fentanyl (up to 5 µg · kg^–1 · h^–1). All patients received postoperative nausea and vomiting (PONV) prophylaxis using ondansetron 4 mg given within 30 min of the end of surgery. Neuromuscular blockade was reversed with neostigmine 70 µg/kg and glycopyrrolate 10 µg/kg. Postoperative analgesia was provided using a patient-controlled analgesia (PCA) with morphine using standard weight-based settings and with IV ketorolac 15 mg every 6 h. Rescue analgesia was provided in the postanesthesia care unit (PACU) using boluses of morphine if required. If the pain score was >5/10, twice the PCA dose could be administered no closer than 10 min apart for a maximum of three doses. If the pain score remained >5/10 for over 1 h, the PCA dose was increased by a factor of 1.25.

Patients were randomized in equal numbers to receive either a nicotine patch releasing 7 mg/24 h or an identical placebo patch. The patch was applied behind the patient's ear 30–60 min preoperatively and left in place for 24 h. Data were collected by study personnel unaware of the patients' randomization every 30 min for 2 h in the PACU, and at 6, 12, and 24 h postoperatively. The primary outcome measure was the amount of morphine consumption at 24 h. Other data collected included intraoperative fentanyl consumption, heart rate and rhythm, arterial blood pressure, respiratory rate, oxygen saturation, pain scores at rest and after coughing (11 point verbal rating scale (VRS), 0 = no pain, 10 = worst possible pain), sedation scores (modified Ramsay score),12 itching score (11 point VRS, 0 = no itching, 10 = worst possible itching), and nausea score (11 point VRS, 0 = no nausea, 10 = worst possible nausea). The duration of PACU and hospital stays, time to first flatus, the incidence and frequency of vomiting, and the need for rescue treatment for PONV and itching were recorded. At 24 h, the patients were asked to rate pain control (11 point VRS, 0 = worst control, 10 = excellent control), satisfaction with postoperative pain control (5 points scale: very satisfied, somewhat satisfied, neither satisfied nor dissatisfied, somewhat dissatisfied, and very dissatisfied), and quality of sleep (continuous or intermittent, if pain interfered with their night sleep, and if they had any nightmares).

At 4 and 24 h, blood samples were taken for measuring the plasma nicotine concentration. Concentrations of nicotine were determined by gas chromatography with nitrogen-phosphorus detection.13 This method has been modified for simultaneous extraction of nicotine and cotinine, and determination using capillary gas chromatography and has been previously validated.14 The internal standards, 5-methylnicotine and 1-methyl-5-(2-pyridyl)-pyrrolidin-2-one ("ortho-cotinine"), were obtained from the Division of Clinical Pharmacology of the Department of Medicine, University of California, San Francisco.

For sample size determination, data from a previous study in patients undergoing RRP showed a mean (sd) morphine consumption of 30 (15) mg.15 A sample size of 48 patients in each group was calculated to have 90% power to detect a difference in mean 24-h morphine consumption when the group means are 30 and 20 mg, respectively, assuming that the common sd is 15 mg, and setting a significance level of = 0.05.

Treatment groups were compared on demographics, pain VRS scores at rest and on coughing, and plasma nicotine levels with t-tests or rank-sum tests. For the analysis of nausea, the highest nausea score at any time and the sum of nausea scores over time for each patient were calculated. The non-normally distributed nausea scores and total cumulative morphine use at 24 h were compared with rank-sum tests. Categorical outcomes, including the incidence of PONV and the need for rescue antiemetics, were compared with exact ² tests. Plasma nicotine levels were correlated with morphine consumption and maximum nausea scores using Spearman rank correlation. The effect of treatment on cumulative morphine consumption over time was tested using repeated-measures ANOVA (SAS® Mixed Procedure). The model tested differences between groups overall, as well as differences in the slopes of morphine use over time (the time x treatment interaction). A nonlinear time fit was tested with a quadratic term in the model. The model also adjusted for patient's weight and the postoperative pain VRS scores, which varied over time. An autoregressive correlation structure was specified for the model to account for the correlation of repeated measures. The effect of treatment on postoperative pain was tested in a similar repeated-measures model, which adjusted for morphine consumption. Bonferroni adjustment was applied to post hoc group comparisons at specific times. Overall, P value <0.05 was considered significant.

RESULTS

Ninety-six patients were enrolled in the study. Six were subsequently excluded: the patch fell off intraoperatively in two patients, and a PCA was not prescribed for four patients. Ninety patients were therefore included in the analysis: 44 in the nicotine group and 46 in the placebo group. There was no difference between the groups with respect to age, weight, height, ASA status, history of PONV or motion sickness, duration of surgery, and the amount of fentanyl used intraoperatively (Table 1).

Unadjusted morphine consumption, pain scores, and other postoperative data are presented in Table 2. Morphine use over time is also presented in Figure 1. In the repeated measures tests, observed morphine consumption (mean ± sd) was significantly lower in the nicotine group compared with the placebo group at 24 h: 33.3 ± 30.8 mg vs 44.7 ± 26.4 mg (P = 0.0059, time x treatment P = 0.0031). There was no significant difference in the amount of morphine consumed in the PACU, and 6 h postoperatively. There were also no significant differences in pain scores reported on coughing or at rest, either as treatment effects or in interaction with time. In post hoc comparisons, there was no significant difference in pain scores on coughing or at rest at any of the times assessed. The incidence of PONV or pruritus, number of vomiting episodes, or the need for rescue treatment for PONV or pruritus were not different between the groups. The median (interquartile range) nausea scores in both groups at all times were 0 (0–0). However, the maximum nausea VRS score was higher in the nicotine group than in the placebo group (median, 25th to 75th percentiles = 4, 0–6 vs 0, 0–4, P = 0.0172). Also, the sum of the nausea VRS scores was higher in the nicotine group compared with the placebo group (median, 25th to 75th percentiles = 4, 0–7.5 vs 0, 0–4, P = 0.0197). There were no significant differences between the groups in postoperative heart rate, arterial blood pressure, respiratory rate, or oxygen saturation. There were also no significant differences between the two groups in the quality of sleep, the interference of pain with sleep, the occurrence of nightmares, or inpatient satisfaction with pain control.

View larger version (17K): [in this window] [in a new window]   Figure 1. Total cumulative morphine consumption over time (P = 0.008).

Plasma nicotine levels were significantly higher in the nicotine group compared with the placebo group at 4 and 24 h (P < 0.0001). There was a significant negative correlation between serum nicotine levels at 4 h and the cumulative 24 h morphine consumption (P = 0.018). There was also a significant negative correlation between the 24 h serum nicotine levels and morphine consumption in the PACU (P = 0.049), 6, 12, and 24 h (P = 0.002 at all three time points). There was also a significant positive correlation between maximum nausea scores and the plasma nicotine levels at 4 h (P = 0.007) and 24 h (P = 0.003).

DISCUSSION

In this study, the preoperative application of a 7 mg nicotine patch resulted in a significant reduction in 24 h morphine consumption in patients undergoing RRP under general anesthesia. There was a significant negative correlation between the 24 h serum nicotine levels and morphine consumption in the PACU, as well as at 6, 12, and 24 h after surgery.

A number of animal studies suggested an analgesic effect of nicotine.4–7 In humans, increased tolerance, threshold, or both to painful stimulation have been reported with smoking. This analgesic effect has been reported in smokers smoking high-nicotine-yield cigarettes compared with abstinent smokers (e.g., smoking deprived or "sham smoking").9,10,16,17

The findings from several other human studies suggest an inherent pain-inhibitory action of nicotine. For instance, compared with a placebo snuff, tobacco snuff was found to increase pain tolerance in a group of ex-smokers in one study.18 Dose-dependent increases of pain tolerance, pain threshold, or both have been reported in smokers as a function of nicotine content9,17,19 and nasal spray concentration.20 Gender differences in response to the analgesic effect of nicotine have been reported in both animal and human studies.21 In one study, a transdermal nicotine patch delivered 7 mg/24 h to nonsmokers and 21 mg/24 h to smokers. Nicotine increased the pain threshold and tolerance ratings of men but had no effect on the pain ratings of women. Among men, there was no effect of smoking history, suggesting that the changes in pain perception reflect a direct pain-inhibitory effect of nicotine rather than a relief from acute nicotine withdrawal.8

The effect of nicotine on postoperative analgesia was only investigated in one study in 20 women undergoing uterine surgery. At the completion of surgery, patients were given a single dose of either nicotine nasal spray 3 mg or saline. Throughout the first hour after surgery, the patients treated with nicotine reported less pain and used half the morphine compared with control patients. At 24 h, patients who received nicotine still had less pain than control patients. The beneficial analgesic effect of nicotine was not associated with any hemodynamic or other side effects.11

Nicotine-induced analgesia is thought to be partly mediated by neuronal nicotinic acetylcholine receptors that are distributed throughout the nervous system.22–24 Nicotine analgesia is weak in the "knockout" mice lacking 4 or β2 nAChR subunits,25 and nAChR antagonists, such as mecalmylamine, reduced nicotine- induced analgesia.25,26 Stimulation of the 4 β2 nAChR located on noradrenergic terminals may produce analgesia by stimulating spinal norepinephrine release.27 Activation of the 7 nicotinic receptor located in the central nervous system has also been shown to elicit antinociceptive effects in some acute pain models.28 It has also been suggested that the pressor actions of nicotine on the cardiovascular system might mediate its analgesic effects.8 However, there was no difference between the groups in postoperative arterial blood pressure or heart rates in this study. These findings agree with the previous study in which a nicotine spray was used in surgical patients.11

We chose to administer nicotine using a transdermal patch, since this method of delivery ensures continuous delivery of the drug over a 24-h period. We also included a surgical procedure performed in men since some previous studies suggested that the pain-inhibitory effects of nicotine are more pronounced in men.8,29 We used a 7 mg transdermal dose of nicotine, since this dose was tolerated by nonsmokers without producing nausea or other adverse effects.8 A meta-analysis involving patients participating in randomized trials of nicotine replacement therapy suggested that acute nicotine exposure can cause nausea in some settings, and sleep disturbances.30 Despite the use of prophylactic ondansetron in all patients in this study, the maximum nausea scores were higher in patients in the nicotine group. Also, while the incidence of PONV was higher in the nicotine group, the differences were not statistically significant. However, this study was not powered to evaluate differences in the incidence of PONV. The quality of sleep and the occurrence of nightmares were not different in this study in the nicotine group compared with the placebo group.

Although the morphine consumption was significantly less in patients who received the nicotine patch, there was no difference in pain scores. This was probably due to the use of PCA for postoperative analgesia when the patients titrate their analgesia to a similar comfort level. There was also no improvement in other outcomes including opioid-related side effects, time to first flatus, as well as duration of PACU and hospital stays. This could have been due to the addition of the nicotine patch to a regimen incorporating regular ketorolac. Previous studies have documented up to a 40% opioid-sparing effect with the use of nonsteroidal antiinflammatory drugs,31 together with a reduction in opioid-related side effects.32 It is possible that the nicotine-induced decrease in postoperative opioid consumption could have resulted in a reduction in opioid-related side effects if no other opioid-sparing drug (ketorolac) was used. This needs to be investigated in future studies.

There was a significant negative correlation between the 24 h serum nicotine levels and morphine consumption in the PACU, as well as at 6, 12, and 24 h after surgery. The findings suggest a dose–response effect of nicotine and morphine consumption, with higher serum concentrations of nicotine correlating with lower morphine consumption. Interestingly, we also found a significant negative correlation between serum nicotine levels at 4 h and the cumulative 24 h morphine consumption (P = 0.018). We are uncertain about the implication of this observed relationship although it may be that early serum nicotine levels could have a predictive value in the amount of opioid use in the late postoperative period.

This study has some limitations. We used only one concentration of the nicotine patch; therefore, we were unable to establish if there is a dose–response relationship for the analgesic effect of nicotine. Furthermore, our patient population only included nonsmoking men. The results might not be, therefore, extrapolated to women or to smokers.

In conclusion, the preoperative application of a 7 mg nicotine patch resulted in a significant reduction in postoperative opioid consumption in nonsmoking men undergoing RRP in this study. Its use was generally well tolerated, but the maximum nausea scores were higher in patients who received nicotine. Further studies are required to determine the optimum dose and route of administration of nicotine in the perioperative period. The use of nicotine in smokers for postoperative analgesia also needs to be investigated.

Footnotes

Accepted for publication February 1, 2008.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Habib, A. S. Articles by Gan, T. J. Search for Related Content PubMed PubMed Citation Articles by Habib, A. S. Articles by Gan, T. J. Related Collections Pain Medicine Clinical Pharmacology Pain Pharmacology