Anesthesia and Postoperative Pain

Intranasal Nicotine for Postoperative Pain Treatment: A Comparison of Its Effects in the Context of Isoflurane-induced Anesthesia Versus Propofol Anesthesia

The purpose of this study is to compare post-operative pain after anesthesia with either isoflurane or propofol. Each group will be further randomized to recieve intranasal nicotine or placebo inorder to detect potetial pronociceptive action of isoflurane. The study is a randomized, prospective, double-blinded controlled trial. Eighty adult women undergoing uterine surgery will be recruited for this study. Enrollment in this study is limited to women, because our animal studies suggest that females have a greater hyperalgesic response to volatile anesthetics than do males. The patient will be given one of two standard anesthetics for their surgery: isoflurane or propofol. We are interested in these two anesthetics because we seek to see if there exists a difference in their effects on a patient's perception of pain, as has been shown to be the case in animal studies but has not yet been studied in humans. The primary outcome variable will be postoperative pain, as measured by a numerical analog pain score (VAS) at 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, and 1440 minutes postoperatively. Secondary outcome measures will include morphine utilization via PCA and hemodynamics variables including heart rate, systolic BP, and diastolic BP, all of which will be measured at the same time points as the VAS score.

A. Study Proposal and Rational The purpose of this study is to determine whether intranasal nicotine can decrease the negative side effects of the general anesthetic isoflurane. Isoflurane and other volatile anesthetics are potent antagonists of central nicotinic receptors (Flood, RamirezLatorre et al. 1997; Violet, Downie et al. 1997). Nicotinic receptors are inhibited by isoflurane at the low concentrations that are present on emergence from anesthesia. Evidence from animal experiments suggests that inhibition of nicotinic receptors may cause increased sensitivity to pain and amnesia that occurs at low anesthetic concentrations. These anesthetic concentrations are frequently present on emergence from anesthesia (Zhang, Eger et al. 2000; Flood, Sonner et al. 2002). In these experiments, treatment with nicotine prevented the hyperalgesic state caused by isoflurane (Flood, Sonner et al. 2002). Intranasal nicotine treatment has been used in smokers as an aid to smoking cessation. As nicotine acts as an agonist at sympathetic ganglia, it can cause increases in heart rate and blood pressure. At the dose to be used in this protocol (3mg intranasally) there was an average increase of 7 mM of mercury in systolic blood pressure and no change in diastolic blood pressure or heart rate in nonsmoking volunteers (Fishbein, O'Brien et al. 2000). B. Study Design and Statistical Analysis The study is a randomized prospective controlled trial. Women scheduled to undergo total abdominal hysterectomy or myomectomy will be randomly allocated intranasal nicotine or intranasal saline before emergence from a standard general anesthetic. The patient will be randomized to one of two standard anesthetics regimens that are described below. Both patient and investigator will be blinded to treatment. Nicotine or saline will be placed in a single use nasal spray bottle by the research pharmacy and identified by number. Randomization will be accomplished with a random number table. Patients will be enrolled sequentially. We wish to detect a 50% change in pain sensitivity and in our other studies, VAS scores and PCA utilization varied by approximately 40% (pooled variance). In order to achieve 80% power and p<0.05, 40 women per group will be enrolled (total of 80 women). This study will include only female patients as animal studies suggest that females have a greater hyperalgesic response to isoflurane than males. Patients treated with nicotine will be compared to those treated with placebo for VAS score, PCA utilization and memory at 1 and 24 hours. C. Study Procedure The study subjects will be given one of two standardized anesthetics by an anesthesiologist at NYPH not involved with the study. The anesthesiologist will be familiarized with the study protocol prior to the surgery. The anesthetic protocols chosen are typical for this type of surgery, but is standardized to decrease variability in postoperative condition. After placing an intravenous catheter and standard anesthetic monitors, the patient will be pre oxygenated. Fentanyl will be administered at 12 micrograms/kg and a continuous infusion of 12 micrograms/kg/hr will be begun. Vecuronium 1 mg will be used to reduce fasciculation from succinylcholine. Anesthesia will be induced with propofol 2 mg/kg and intubation facilitated with succinylcholine 12 mg/kg. Anesthesia will be maintained with either isoflurane or propofol titrated by the anesthesiologist. All patients will be have a BIS monitor (a measure of processed EEG) titrated between 45-60 to assure adequacy and equivalence of anesthesia. Hypotension will be treated with ephedrine or phenylephrine as deemed necessary by the anesthesiologist. Hypertension will be treated with hydralazine or labatelol in doses determined by the anesthesiologist. If other hemodynamic or anesthetic drugs are deemed necessary by the anesthesiologist, the patient will be removed from the protocol. After closure of the abdominal fascia (typically, approximately 5 minutes before anticipated completion of the surgery) the general anesthetic and fentanyl drip will be titrated to off. Muscle relaxant will be reversed with neostigmine 0.1 mg/kg and glycopyrolate 0.01 mg/kg. At this time the study drug (nicotine 3 mg or saline) will be administered intranasally 3 mg (half to each nostril). The patient will be extubated by the anesthesiologist when she meets normal criteria (as determined by the anesthesiologist). Five minutes after extubation, the patient will be asked for a VAS score by the study coordinator. Pain will be treated with fentanyl by the anesthesiologist, 1 mg/kg every 5 minutes until VAS score is less than 3. PCA will then be begun with morphine 1 mg with a lockout of 6 minutes and a maximal 1 hour dose of 10 mg. A rescue dose of 3 mg morphine will be available to be administered by the nurse through the PCA every 5 minutes for a maximum of 12 mg in 4 hours. If pain is inadequately treated there will be an option to increase the patient demand dose to 1.5 mg morphine and the 1 hour maximum to 15 mg. This is a typical PCA protocol for this surgery. PACU monitoring will be standard except that the patient's pain intensity will be monitored every 5 minutes in the first hour, once at the second hour and once at the twenty four hour period postoperatively by the study coordinator who will ask for a VAS score. PCA utilization will be determined from the amount of narcotic used from the PCA machine. The study will last during the patient's first postoperative day. We expect to enroll on average 2 patients per week and expect our protocol to take approximately two years to complete. D. Study Drugs Nicotine has been used commonly on an outpatient basis for smoking cessation. We have chosen the intranasal route because of the kinetics of its action. Intranasal nicotine has its peak effect in five minutes and is dissipated in about 1 hour. In human studies, the hyperalgesic effect after a volatile anesthetic lasted about 1 hour. As nicotine acts as an agonist at sympathetic ganglia, it can cause increases in heart rate and blood pressure. At the dose to be used in this protocol (3mg intranasally) there was an average increase of 7 mM of mercury in systolic blood pressure and no change in diastolic blood pressure or heart rate in nonsmoking volunteers (Fishbein, O'Brien et al. 2000). Our preliminary data do not show any significant increase in blood pressure or heart rate in patients who recieved nicotine. We have chosen to study a dose of 3 mg because that dose had minimal hemodynamic effects and resulted in an arterial peak concentration of 100 microM and a steady state venous concentration of 30 microM nicotine (Guthrie, Zubieta et al. 1999). As nicotine crosses the blood brain barrier, these concentrations would be expected to result in significant activation of nicotinic receptors in the brain and spinal cord.

- Score on a pain rating scale (numerical analog score) at 5, 10, 15, 20, 25, 30, 35, 40, 45, 60, 120, and 1440 minutes post-op

- Heart rate and blood pressure at 5, 10, 15, 20, 25, 30, 35, 40, 45, 60, 120, and 1440 minutes post-op

Inclusion Criteria: greater than or equal to 18 years of age female sex present to New York Presbyterian Hospital for open pelvic surgery Exclusion Criteria: smoking uncontrolled hypertension myocardial disease history of stroke

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Guthrie SK, Zubieta JK, Ohl L, Ni L, Koeppe RA, Minoshima S, Domino EF. Arterial/venous plasma nicotine concentrations following nicotine nasal spray. Eur J Clin Pharmacol. 1999 Nov;55(9):639-43. doi: 10.1007/s002280050686.

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Zhang Y, Eger EI 2nd, Dutton RC, Sonner JM. Inhaled anesthetics have hyperalgesic effects at 0.1 minimum alveolar anesthetic concentration. Anesth Analg. 2000 Aug;91(2):462-6. doi: 10.1097/00000539-200008000-00044.

Flood P, Daniel D. Intranasal nicotine for postoperative pain treatment. Anesthesiology. 2004 Dec;101(6):1417-21. doi: 10.1097/00000542-200412000-00023.