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ANALGESIA

Transdermal Nicotine Patch Failed to Improve Postoperative Pain Management

Alparslan Turan, MD^*, Paul F. White, PhD, MD, Onur Koyuncu, MD, Beyhan Karamanliolu, MD^*, Gaye Kaya, MD^*, and Christian C. Apfel, MD, PhD^||

From the *Department of Anesthesiology, Trakya University, Turkey, and Department of Anesthesiology and Perioperative Medicine, and the Outcomes Research Institute, University of Louisville, Louisville, Kentucky; Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; and Departments of Anesthesiology, ||Anesthesiology and Perioperative Care, Perioperative Clinical Research Care, University of California at San Francisco, San Francisco, California.

Address correspondence and reprint requests to Dr. Alparslan Turan, Department of Anesthesiology and Perioperative Medicine, 530 S. Jackson St., University Hospital, Louisville, KY 40202. Address e-mail to alparslanturan{at}yahoo.com.

Abstract

BACKGROUND: A single 3 mg intranasal dose of nicotine has been reported to have analgesic properties. We designed placebo-controlled study to test the hypothesis that transdermal nicotine (TDN) administered over a 3-day period would decrease postoperative pain and opioid analgesic usage and improve the recovery process after lower abdominal surgery.

METHODS: Ninety-seven patients undergoing abdominal hysterectomy procedures were randomly assigned to one of two treatment groups: (1) control group received inert (sham) patches 1 h before and for 2 days after surgery, or the (2) nicotine group received TDN 30 (21 mg nicotine) patches 1 h before induction of anesthesia and for two additional days after surgery. The anesthetic technique was identical in both groups, and the postoperative assessments included verbal rating scales for pain and sedation, IV patient-controlled analgesia morphine usage, quality of recovery assessment, recovery of bowel function, resumption of normal activities, and patient satisfaction with their pain management. Follow-up evaluations were performed at 1 and 3 mo after the operation to assess late recovery events.

RESULTS: Postoperative patient-controlled analgesia morphine usage and pain scores while supine or sitting up, intraoperative fentanyl use, oral analgesic consumption, return of bowel sounds, and passage of flatus did not differ between the two groups. Although ambulation and hospitalization times, as well as quality of recovery scores, did not differ, resumption of oral intake was delayed in the nicotine group. Discharge eligibility scores were higher in the nicotine group at 48 and 72 h compared with the control group, but the time to return to work was 19 days in both treatment groups.

CONCLUSIONS: Perioperative administration of a high-dose TDN patch did not improve postoperative pain control or decrease the analgesic requirement after pelvic gynecological surgery. Despite delayed resumption of oral intake, more patients in the nicotine group were ready for discharge at 48 and 72 h after surgery. However, times to resuming activities of daily living were similar in both groups.

Postoperative pain is an important factor influencing early recovery after surgery. Despite the widespread use of opioid analgesics in the postoperative period, Dolin et al.1 determined that the overall incidence of moderate-to-severe pain was 30% (and the overall incidence of severe pain was 11%). There is evidence to suggest that more extensive use of non-opioid analgesics will lead to improvements in postoperative pain control with fewer opioid-related side effects.2

Nicotine, the primary psychoactive component of cigarette smoke, produces its pharmacological effects by stimulating central nicotinic (acetylcholine) receptors.3 These receptors may play a role in modulating pain transmission within the central nervous system (CNS).4 Nicotine activa of cholinergic pathways has been reported to produce antinociceptive effects in a variety of different pain models,5,6 and there is increasing evidence to suggest that the antinociceptive effect of nicotine occur via activation of acetylcholine nicotinic receptors in a variety of loci within the CNS.6 Although neuronal nicotinic agonists have been alleged to produce analgesia in a variety of different pain states, Block et al.7 reported that only 60% of the animals they studied demonstrated an analgesic response to nicotine in their antinociceptive model.

Although nicotine is widely acknowledged to possess analgesic properties, there are surprisingly few well-controlled clinical studies in the literature evaluating its analgesic effects. In 2004, Flood and Daniel8 reported that nicotine (3 mg) produced an opioid-sparing effect and decreased pain scores when administered intranasally at the end of pelvic surgery. However, there have been no confirmatory studies published in the anesthesia or pain literature.

Therefore, we tested the hypothesis that transdermal nicotine (TDN) would decrease postoperative pain and opioid analgesic usage, thereby improving the early recovery process after pelvic gynecological surgery. The secondary objectives of this study were to examine the effect of TDN on recovery of bowel function, resumption of normal activities of daily living, overall quality of recovery, and patient satisfaction with their pain management.

METHODS

After obtaining the approval of the Institutional Ethics Committee at Trakya University in Edirne, Turkey, and written informed consent, 97 patients undergoing elective total abdominal hysterectomy and salpingo-oophorectomy performed via a low transverse incision were enrolled in this study. Patients were eligible for enrollment if they were at least 18-yr-old, within 50% of their ideal body weight, had no clinically significant cardiovascular or CNS disease, and could operate a patient-controlled analgesia (PCA) device. Exclusion criteria were known allergy to any of the study medications, contraindications to the use of PCA morphine or any anesthetic drugs, renal insufficiency, peptic ulcer disease, hypertension, preexisting pain syndromes, and a history of cardiovascular disease or drug abuse. A detailed smoking history was obtained from each patient participating in the study. None of the patients was allowed to smoke during the 72 h study period.

The patients were prospectively assigned to one of two treatment groups using a computer-generated random numbers table. The control group (n = 48) received inert (placebo) patches, and the nicotine group (n = 49) received 30 TDN patches containing 52.5 mg of nicotine, with release of 21 mg of nicotine in 24 h (Novartis, Munich, Germany). The first patch was applied 60 min before induction of anesthesia, and the same type of patch was reapplied at 09:00 on the second and third postoperative days. All patches were identical in appearance, and were placed on the patient's upper arm and covered with a sterile gauze and tape by an anesthesiology resident not involved in the data collection process.

All patients were premedicated with midazolam, 0.07 mg/kg IM, 45 min before the surgical procedure. Upon arrival in the operating room, an IV infusion of crystalloid solution was started. Mean arterial blood pressure (MAP), heart rate (HR), and peripheral oxygen saturation (Cato PM 8040, Dräger, Lübeck, Germany) were recorded upon arrival in the operating room (baseline), before induction, and every 10 min throughout the operation. Anesthesia was induced with propofol (2 mg/kg IV) and atracurium (0.5 mg/kg IV), and maintained with sevoflurane, 1.5%–2% inspired, at a fresh gas flow rate of 2 L/min in combination with nitrous oxide 50% in oxygen. Fentanyl, 2 µg/kg IV, was administered 3–5 min before the surgical incision. Surgery was performed via a Pfannenstiel incision. Patients' lungs were mechanically ventilated to maintain an end-expiratory CO₂ value between 34 and 36 mm Hg. At the end of surgery, morphine 4 mg IV, was administered immediately before discontinuing sevoflurane and nitrous oxide. At the start of skin closure, residual neuromuscular blockade was reversed with neostigmine, 2–3 mg IV, and atropine, 0.3–0.5 mg IV.

After tracheal extubation, patients were transferred to the postanesthesia care unit (PACU). Assessment of postoperative pain was performed using an 11-point verbal rating scale (VRS), with 0 = no pain and 10 = "worst pain imaginable." After arrival in the PACU, patients were connected to a PCA device and postoperative analgesia was provided with PCA morphine, using 2 mg IV bolus injections with a lockout interval of 10 min and a 4 h limit of 40 mg. The incremental bolus dose was increased to 3 mg if pain relief was inadequate after 1 h of PCA use. Sedation was assessed using an 11-point VRS, with 0 = no sleepiness or drowsiness and 10 = almost asleep and/or extremely drowsy. An anesthesiology resident blinded to group allocation performed assessments for pain, sedation, opioid usage, and side effects at 1, 4, 8, 12, 16, 20, 24, 30, 36, 42, 48, 60, and 72 h intervals after arrival in the PACU. After 72 h, analgesia was provided with acetaminophen, 500 mg po, in combination with codeine, 30 mg po every 6–8 h, on demand. Postoperative side effects (e.g., nausea, vomiting [or retching], constipation, respiratory depression, dizziness, somnolence, peripheral edema, diarrhea, headache, and pruritus) were recorded at 24, 48, and 72 h after surgery. Assessment of postoperative pain was made both while resting in bed (supine) and with activity (e.g., sitting up [seated]). If the patient experienced sustained nausea or vomiting, ondansetron (4 mg IV) was administered as a "rescue" antiemetic.

The time to initial return of bowel function (i.e., time after surgery when bowel sounds returned and the patient passed flatus), as well as the duration of hospitalization were recorded. A research assistant also evaluated the times to resumption of oral dietary intake and ambulation without assistance. At 24-h intervals after the operation, patients were assessed as to their readiness for discharge from the hospital using the following discharge criteria: (1) normal defecation and no urinary retention; (2) ability to mobilize and get dressed without assistance; (3) pain adequately controlled with oral analgesics; and (4) no surgical complications requiring continuing care. Patient satisfaction with postoperative pain control was assessed using a 100-point VRS, with 1 = highly dissatisfied and 100 = completely satisfied. All patients were asked to assess their quality of recovery using a standardized quality of life (SF-12) assessment questionnaire before surgery, at discharge and at 72 h after surgery. Follow-up telephone evaluations were also performed at 1 and 3 mo after surgery to assess the time to return to work and any residual pain.

A sample size of 26 patients per group was calculated to detect a difference of 20% or more in PCA morphine consumption (usage) with a power of 80% and a significance level of 0.05 for a two-sided test (based on the assumption that the control group would self-administer 36 mg of morphine with a standard deviation of 8 mg). Data on VRS scores, morphine consumption, MAP, and HR were summarized over time for each patient by computing the area under the curve (AUC) out to 72 h. Median AUC values for each group were compared using nonparametric Mann–Whitney tests. Mann–Whitney tests were also used for comparing times and scores shown in Table 1 and patient satisfaction scores in Table 2. Side effect rates were compared using Fisher's exact tests. All analyses were done with SAS Version 9.1 software. A P value <0.05 was considered to be statistically significance.

RESULTS

From February 1, 2005, to May 1, 2006, 162 patients were screened for study eligibility (49 patients failed to meet the inclusion criteria and 16 patients refused to sign the consent form). Of the 97 consenting patients, 85 patients completed the entire study and were included in the final analyses (Fig. 1). The two groups were comparable with respect to age, body weight, duration of surgery, active smoking status, and intraoperative opioid analgesic dosages (Table 3).

View larger version (35K): [in this window] [in a new window]   Figure 1. The flow of patients from the preoperative evaluation period through the follow-up assessments at 1 and 3 mo after surgery in the control and nicotine groups.

Oral analgesic consumption, return of bowel sounds, and passage of flatus did not differ between the control and nicotine groups (Table 1). Resumption of oral intake occurred significantly later in the nicotine group (33 ± 9 vs 29 ± 8 h, P = 0.04). However, times to ambulation, the duration of hospitalization, and quality of recovery scores did not differ between the two groups (Table 1). The VRS pain scores in both groups while supine and sitting up were not different at any of the measurement intervals (Figs. 2a and b). The AUCs for the pain VRS scores while supine (P = 0.11) and sitting up (P = 0.16) were also similar in the two groups. Although these data were not reported, the sedation VRS scores did not differ at any of the measured time intervals. Finally, morphine consumption was not different in the two groups throughout the initial 72 h study period (Fig. 3).

View larger version (19K): [in this window] [in a new window]   Figure 2. Postoperative verbal rating scale (VRS) pain scores with patients in: (a) the supine position and (b) in the sitting (seated) position in bed. The nicotine group (n = 42) had three nicotine patches applied at 24 h intervals, each delivering 21 mg of nicotine over 24 h. The control group (n = 43) had placebo patches placed at identical time intervals. The patients rated their pain using an 11-point VRS, with 0 = to no pain and 10 = worst imaginable pain. Data are presented as the group means + sd. No significant differences were observed between treatment groups.

View larger version (20K): [in this window] [in a new window]   Figure 3. The cumulative morphine consumption in the control and nicotine groups during the initial 72 h postoperative period. The nicotine group (n = 42) had a nicotine patch applied for the duration of the study that delivered 21 mg nicotine over 24 h. The control group (n = 43) had three placebo patches applied at 24 h intervals. Data are presented as the group means + sd. No significant differences were found between groups.

In a subset analysis of the smokers (versus nonsmokers) in the two study groups, no differences were found in their pain scores or opioid analgesic requirement in the postoperative period (Table 4). The MAP and HR values, as well as the AUC for MAP (P = 0.77) or HR (P = 0.81), did not differ between the two groups at any of the specified time intervals (Fig. 4). Discharge eligibility scores in the nicotine group were higher at 48 and 72 h compared with the control group (Table 1). However, there were no differences in patient satisfaction with their postoperative pain management at 48 or 72 h (Table 2). The most common side effects during the postoperative period were nausea and vomiting, and the incidences did not differ between the two groups (Table 2).

View larger version (20K): [in this window] [in a new window]   Figure 4. Postoperative heart rate (HR) in the control and nicotine groups The nicotine group (n = 42) had three nicotine patches applied for the duration of the study that delivered 21 mg nicotine over 24 h. The placebo group (n = 43) had placebo patches applied at identical time intervals. Data are presented as the group means + sd. No significant differences were found between groups.

Finally, the follow-up evaluations performed at 1 and 3 mo after the operation failed to demonstrate any differences in long-term outcomes (e.g., return to work, persistent [chronic] pain) (Table 1).

DISCUSSION

In contrast to the earlier study by Flood and Daniel,8 this randomized, double-blind, placebo-controlled trial failed to detect any beneficial analgesic effect from perioperative administration of TDN. Although patients in the nicotine group required more time to resume oral intake (P = 0.04), they had higher discharge eligibility scores at 48 and 72 h after surgery. The well known appetite-suppressant effect of nicotine may have contributed to the delayed resumption of normal dietary intake.9,10 Flood and Daniel8 studied the opioid-sparing effects of a single 3 mg dose of nicotine administered as a nasal spray at the end of surgery. However, these investigators did not evaluate recovery of gastrointestinal function, patient satisfaction, and other clinically important outcome variables (e.g., return to work).

Our negative results raise the question of whether or not the TDN patch delivery system we used delivered an effective blood concentrations of nicotine during the 72 h study period. Although the distribution half-life of intranasal nicotine is only 2 to 3 h,11 the TDN patch system, which was used in our study, delivers 21 mg nicotine over 24 h, and has a higher maximum (peak) concentration than other nicotine patch delivery systems.12 In addition, the minimum plasma concentration achieved with this patch, 5.76 ng/mL, should be higher than the maximum concentration achieved with the nasal spray, 4.7 ng/mL.11,12 The plasma nicotine concentration is also more constant with the TDN patch than after intranasal administration. Therefore, failure to achieve an adequate nicotine serum concentration after TDN nicotine appears to be an unlikely explanation for the differing outcomes in these two studies involving similar surgical populations. It is possible that chronic exposure to nicotine throughout the perioperative period produced acute down-regulation of the nicotine receptor system, leading to the development of tolerance to the centrally mediated analgesic effects of the drug.

Nicotine appears to possess a variable antinociceptive effect in animal pain models,7 which is mediated via activation of nicotinic acetylcholine receptors at ligand-gated ion channels.13 The spinal cholinergic system is also alleged to play an important role in the analgesic action of IV morphine. Morphine activates a descending inhibitory system, leading to increased release of endogenous acetylcholine in the spinal cord, thereby producing analgesia through activation of spinal muscarinic and nicotinic receptors.5 Endogenous opioid peptides14 and µ-opioid receptor activation15 have also been reported to mediate the antinociceptive properties of nicotine. Campbell et al.16 reported that the combination of alcohol and nicotine can result in a synergistic antinociceptive response that is at least partially mediated by the opioid system.

The effect of smoking on pain thresholds and perception in humans is complex, and experimental studies have produced inconsistent findings. Smoking increases both the tolerance and threshold to painful stimuli.17 Interestingly, Jamner et al.18 found that a nicotine patch increased pain thresholds in men but not in women. On the other hand, Girdler et al.19 reported that female smokers have decreased pain sensitivity to ischemic pain, whereas male smokers have decreased pain sensitivity to cold pressor pain. Smoking status did not appear to influence pain perception for either gender in response to thermal heat pain. Damaj20 found evidence of greater analgesic efficacy when nicotine was administered to male (versus female) mice. However, nicotine has been reported to produce differing antinociceptive profiles depending on the pain model being investigated.7,21

In a subset analysis of the smokers (versus nonsmokers) in our study, we found no differences in their pain scores or opioid analgesic requirement during the postoperative period. Unfortunately, our study was not adequately powered to assess the effect of the prior exposure to nicotine in cigarette smoke. However, the smoking history of the study patients was identical in both treatment groups. Furthermore, none of the study patients was allowed to smoke in the hospital during the perioperative period in which the study was conducted.

A preliminary report by Cheng using a TDN patch for treating chronic pelvic pain in nonsmokers demonstrated only a modest improvement in pain scores.22 Another preliminary study using a TDN patch containing 7 mg of nicotine reported a decrease in morphine consumption only during the first 4 h after surgery.23 However, both of these preliminary studies contained an inadequate number of patients to draw any definitive conclusions. Furthermore, neither study evaluated clinically important outcome variables.

The TDN patch can produce acute tolerance (or tachyphylaxis), as a result of receptor-mediated desensitization.24 Neuronal adaptations underlying nicotine tolerance begin upon initial exposure and persist after repeated exposures.25 It has also been suggested that µ-opioid receptor down regulation may also play an important role in the development of tolerance to nicotine's antinociceptive effects.26 The patients in our study were continuously exposed to nicotine from 60 min before surgery until 72 h after the operation. It would appear that tolerance to nicotine's central antinociceptive effects may develop very rapidly. Therefore, future studies are needed to examine the effects of a TDN patch when it is administered only in the postoperative (versus perioperative) period.

Nicotine can also cause acute increase of HR and MAP as a result of both CNS and peripheral sympathetic nervous system stimulation.27 Nicotine can also produce vasoconstriction of the coronary arteries, thereby decreasing coronary blood flow in response to an increase in oxygen demand.27,28 In the current study, we were unable to detect any significant differences in perioperative HR or MAP with TDN (versus placebo) treatments. The hemodynamic effects of TDN may also be modified as a result of tachyphylaxis after continuous exposure during the 72 h perioperative period. These findings were also consistent with the conclusions of a large meta-analysis.29

Important, potentially confounding factors which were avoided in the present study included differences between the two treatment groups with respect to gender, surgical site, type of operation, active smoking status, intraoperative anesthetic and analgesic regimens, medical complications, and diurnal variation in the surgery and recovery periods. A limitation of the current study design may be the arbitrarily chosen dose of the study medication (nicotine 21 mg/d). In the absence of any dose–response data on the antinociceptive effect of nicotine, we chose to use the maximum available TDN patch strength to insure that an adequate effect-site concentration of the active drug was achieved in the early postoperative period. There is little reason to expect that a lower dosage TDN patch would lead to different results. Another limitation of our study design was that we enrolled only female patients undergoing pelvic gynecological surgery. Further studies are clearly needed in other surgical populations (e.g., male patients undergoing orthopedic procedures).

It would also be interesting to measure nicotine levels and pain scores after applying the TDN patch (versus bolus injections) to more closely examine nicotine's pharmacokinetic and dynamic relationships. These data suggest that there may be important differences between a single intranasal bolus dose and continuous transdermal administration of nicotine. Future studies are needed to examine the effects of a TDN patch when it is administered only in the postoperative (versus perioperative) period, as well as the effects of a single versus multiple bolus doses. However, tolerance to the analgesic effects of nicotine could still develop even if the patch was only administered in the postoperative period. Finally, it will be important to carefully examine the effects of nicotine on clinically relevant patient outcomes in other surgical populations.30

In summary, perioperative administration of nicotine via a transdermal patch did not improve postoperative pain control or decrease opioid consumption after pelvic gynecological surgery. However, significantly more patients in the nicotine (versus control) group were judged to be ready for discharge at 48 and 72 h after surgery.

Footnotes

Accepted for publication January 22, 2008.

Dr. Paul F. White, Section Editor for Special Projects, was recused from all editorial decisions related to the manuscript.

Supported by institutional and departmental sources at Trakya University in Trakya, Turkey (Dr. A.T.), the McDermott Distinguished Chair endowment fund, Departmental Start-up Fund, Department of Anesthesia, UCSF and a nonprofit private foundation, the White Mountain Institute (Dr. P.F.W., President).

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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 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 Turan, A. Articles by Apfel, C. C. Search for Related Content PubMed PubMed Citation Articles by Turan, A. Articles by Apfel, C. C. Related Collections Pain Medicine Clinical Pharmacology Pain Pharmacology