Seventy to 80% of the 23 million Americans who undergo surgical procedures each year experience moderate to severe pain, despite treatment with all of the analgesic medications that are available.1–3 We expect and accept pain after surgery, in part, because the treatment can be worse than the problem. For some patients, there may be no dose of an opioid that adequately relieves pain without causing respiratory depression, and intolerable nausea, itching, and constipation. However, inadequate treatment of pain results in unnecessary suffering, prolonged hospitalization, and increased health care costs.4 Anesthesia might be considered a benign temporary state that is short lived and has little consequence to the patient after awakening. However, propofol as part of an IV anesthetic technique is clearly preferable to volatile anesthetic techniques for the prevention of postoperative nausea and vomiting (PONV).5–7 In a subset of these studies, postoperative pain was a secondary outcome variable. Although not designed for this indication, many of these studies show a trend to reduced postoperative pain when propofol-based anesthesia is compared with a regimen, including a volatile anesthetic drug.5,7–10
Volatile anesthetics, including isoflurane, have a biphasic effect on pain sensitivity in animal models. Several volatile anesthetics increase sensitivity to pain at the low concentrations present on emergence from anesthesia but relieve pain at higher, near anesthetic concentrations.11,12 One hypothesis suggests that the hyperalgesic action of volatile anesthetics is due to the inhibition of nicotinic acetylcholine receptors in the brain and spinal cord.12–14 In a previous small clinical study, women anesthetized with isoflurane and treated with nicotine nasal spray had less pain than those treated with placebo. In contrast, the IV-administered general anesthetic drug, propofol, has little effect on pain response in animal models15 and may have analgesic properties at sedative doses.16,17 We hypothesize that patients anesthetized with volatile anesthetics have more pain than those anesthetized with propofol. We further posit that the difference is due to a hyperalgesic state induced by isoflurane inhibition of nicotinic receptors. Thus, the hyperalgesia might be reversed by nicotine. We studied 80 women having uterine surgery, who were randomized to be anesthetized with isoflurane and fentanyl or propofol and fentanyl, with or without intranasal nicotine treatment.
PATIENTS AND METHODS
Eighty patients who planned open uterine surgery through a low transverse incision at New York Presbyterian Hospital were enrolled in this double-blind, randomized trial. The trial was approved by IRB #1 at the hospital and registered with the Protocol Registration System. All patients were provided with preoperative written information in English or Spanish. Study enrollment was between July 2003 and July 2005.
Patients who were older than 18 yr were asked to participate in the trial with the approval of their gynecologist. All patients had open hysterectomy or myomectomy. Exclusion criteria were a history of tobacco use within the preceding year, uncontrolled hypertension or other cardiovascular disease, respiratory disease, chronic pain, narcotic use, pregnancy and/or current breast feeding.
After agreeing to study enrollment and providing written informed consent, subjects were randomly assigned to receive one of two standard anesthetic regimens. The clinical anesthesiologist was familiarized with both anesthetic protocols by the research coordinator and then provided with a sealed envelope containing the general anesthetic protocol assignment. Neither the patient nor the study coordinator was aware of the assignment. Subjects in both anesthetic arms were further randomly assigned to receive a nasal spray containing either nicotine 3 mg or saline placebo at the conclusion of surgery. The nasal spray was provided in a sealed container and the clinical anesthesiologist was instructed to open and administer the study drug only at the conclusion of the surgery.
The subjects were then familiarized with the numerical analog score (NAS) for pain and the postoperative routine. The subjects were instructed that if 0 represented no pain and 10 represented the worst imaginable pain they should give the number that represented their current pain. Nausea and vomiting were recorded as present of absent at each data collection point and were compared as cumulative presence or absence. Sedation was measured with a 5-point sedation scale in use in our recovery room, where 4—reflexes not present, 3—reflexes present, does not respond to verbal command, 2—eyes open to verbal command or response to name, 1—lightly asleep, eyes open intermittently, and 0—fully awake, conversant.
Isoflurane subjects received 0–2 mg midazolam and 1–2 μg/kg fentanyl before induction of general anesthesia. Anesthesia was induced with propofol 2 mg/kg and tracheal intubation was facilitated with succinylcholine 1–2 mg/kg. Anesthesia was maintained with isoflurane and fentanyl 1–2 μg · kg−1 · h−1. Isoflurane was titrated by the anesthesiologist to clinical effect and a bispectral index (BIS) value of approximately 50.
Propofol subjects received 0–2 mg midazolam and 1–2 μg/kg fentanyl before induction of general anesthesia. Anesthesia was induced with propofol 2 mg/kg, and tracheal intubation was facilitated with succinylcholine 1–2 mg/kg. Anesthesia was maintained with an infusion of IV propofol and fentanyl 1–2 μg · kg−1 · h−1, titrated by the anesthesiologist to clinical effect, and a BIS value of approximately 50. Propofol was changed to clinical effect by the anesthesiologist. Nitrous oxide was not used in either group. BIS values were not recorded in either group.
Because there is good evidence for increased PONV after an isoflurane anesthetic, and because the detection of PONV was not a primary goal in this study, all subjects were treated prophylactically for nausea with dolasetron 12.5 mg IV. Muscle relaxation was achieved with vecuronium and reversed with neostigmine and glycopyrolate when the surgeon had closed the abdominal fascia. The study drug nasal spray was administered at this time. The subjects’ head was elevated to 45 degrees by the anesthesiologist, and the study drug was administered as 3 sprays to each nostril (3 mg nicotine or placebo). The patient’s trachea was extubated by the anesthesiologist upon meeting normal clinical criteria. A patient-controlled analgesia (PCA) machine containing morphine was connected to the patient’s IV before emergence from anesthesia. Upon pressing the PCA button, the patient received 1 mg morphine with a lockout interval of 6 min. The maximum hourly dose was 10 mg. In addition, the patient had access to a 3 mg morphine bolus to be administered by the nurse if the NAS was more than 5 and the patient was not judged by the nurse to have depressed respiration, cardiac function, or level of consciousness. There was an option to increase the morphine dose to 1.5 mg with a maximum hourly dose of 15 mg for unrelieved pain. No nonsteroidal antiinflammatory medications were used. This protocol is based on that used in our previous study.18
The primary outcome variable was NAS. We determined our sample size using data from our previous study where the placebo group had an average NAS of 7 with a standard deviation of 2. To have 80% power to detect a difference of at least 2 NAS points, we studied 20 patients in each group. Secondary outcome variables were morphine use, arterial blood pressure, heart rate, sedation, and incidence of PONV.
NAS, morphine use, and hemodynamic variables were compared with an ANOVA for repeated measures. Subgroup analysis was corrected with the Tukey–Kramer multiple comparison test. Demographic characteristics and incidence values were compared with a χ2 distribution. Data are expressed as means ± sd or median ± interquartile range as appropriate.
We enrolled 80 women during the study period. All subjects finished the protocol and there were no adverse events. The subjects were similar in age, weight, duration of surgery, and dose of opioid that was received during surgery (Table 1).
Patients who were anesthetized with propofol reported less pain than those anesthetized with isoflurane during the first 24 h after surgery (Fig. 1A, P < 0.01; ANOVA). They also self-administered less morphine (Fig. 1B, 32.2 ± 14.8 vs 49.2 ± 18.4 mg in 24 h; P < 0.05; ANOVA). Treatment with nicotine nasal spray had no effect on pain reported (Figs. 2A and B; P > 0.05, P > 0.05; ANOVA) or morphine consumed (Figs. 2C and D; P > 0.05, P > 0.05; ANOVA) in either group.
Although there were no adverse cardiovascular events, patients anesthetized with isoflurane had slower heart rates when treated with nicotine postoperatively, whereas patients anesthetized with propofol had more rapid heart rates when treated with nicotine particularly during the first 25 min when nicotine would be measurable in the plasma (Figs. 3A and B; P < 0.01, P < 0.01; ANOVA).19–22 The mean heart rates with 95% confidence intervals were (isoflurane-placebo 78 [76–80], isoflurane-nicotine 72 [70–74], propofol-placebo 68 [65–71], propofol-nicotine 72 [70–76]; F = 17.8). Nicotine treatment did not affect mean arterial blood pressure in patients treated with either anesthetic (Figs. 3C and D; P > 0.05; ANOVA). The mean arterial blood pressure with 95% confidence intervals were (isoflurane-placebo 85 [83–86], isoflurane- nicotine 86 [84–88], propofol-placebo 82 [81–84], propofol-nicotine 81 [80–83]).
The incidence of PONV was relatively low in this study where all patients were treated prophylactically with dolasetron (Table 2). No patient treated with nicotine vomited, although there was no statistical difference between groups (P > 0.05, χ2). There was no difference in sedation score between groups at 1 h after surgery (Table 2).
Patients anesthetized with propofol and fentanyl reported less pain than those anesthetized with isoflurane and fentanyl over the 24-h period. Our study was not designed to differentiate whether isoflurane negatively modulates postoperative pain, as suggested in animal experiments, or whether propofol, in combination with opioids is protective against pain. There is evidence in the literature supporting both possibilities. Although no randomized clinical trials have been conducted, as early as 1960, Dundee and Moore showed that individual patients and volunteers have a hyperalgesic period after a volatile anesthetic.23
Propofol might have pain-relieving action, particularly when combined with opioid analgesics. Such an interaction occurs between opioids other drugs that enhance γ-aminobutyric acid type A receptors such as benzodiazepines.24–26 Although systemic propofol has mixed effects on pain when used alone, there is evidence for depression of nociceptive transmission in neurons27 and a reduction of continuing nociceptive barrage.28
Treatment with nasal nicotine had no effect on pain report in this trial. This finding is in contrast to our positive findings in a previous study in which all patients were anesthetized with isoflurane and patients were treated with the same dose of nicotine nasal spray.18 Immediately after anesthesia in the isoflurane group, there is a trend suggesting less pain in the nicotine group that would occur during the time course that we would expect, given the short half-life of nicotine. This difference is not statistically significant; the 95% confidence bounds for the size of the effect are −3.85 to 1.1. There is a great degree of variability with this data point, likely because the volatile anesthetic and fentanyl are having their offset at this time. The etiology of the difference between the isoflurane group in this study and our previous study is not clear. With the results of our previous study, we and our reviewers were disturbed by the intensity of reported pain and apparent lack of treatment with bolus morphine in that trial. We attributed the failure of the nurse to administer a bolus when the reported NAS was more than 5 to be due to perceived narcotic side effects. The study coordinator for this trial was instructed to remind the clinical nurse of the need to administer a morphine bolus according to the PCA protocol. NAS scores in the isoflurane-placebo group in this trial were lower than in the previous study, but the cumulative amount of morphine administered was not different. A second difference between the two protocols is that a BIS monitor was used in this study and not in the previous study. Studies have shown that BIS monitoring can reduce the use of volatile anesthetics.29 It is thus possible that the patients in this trial had lighter anesthesia than in our previous trial when no BIS monitoring was used. Propofol has no effect on nicotinic receptors at clinically used doses13 and would not be expected to affect pain sensitivity on this basis. As expected, there was no effect of nicotine in the women who were anesthetized with propofol.
We have demonstrated a postoperative pain benefit to anesthesia with propofol. The technique of total IV anesthesia with propofol and opioid that we used in the propofol arm has become popular, particularly in Europe and Australia where devices are available to simplify and optimize the delivery of these drugs. Additional benefits include the absence of a requirement for a vaporizer to administer volatile drugs and a decreased incidence in PONV. A significant reduction in postoperative pain and reduced morphine use may translate to earlier mobilization, decreased narcotic side effects and earlier hospital discharge. If these results are borne out in future trials, we suggest that the choice of anesthetic might be a variable in the management of postoperative pain.
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