Intrathecal neostigmine causes analgesia [1-4] in a dose-dependent pattern [1,2]. Unfortunately, the incidence of side effects is also dose-dependent, with bradycardia  or nausea and vomiting  the most troublesome in volunteers. We have shown that intrathecal neostigmine provided dose-dependent analgesia for vaginoplasty surgery similar in duration to that provided by spinal morphine . However, intrathecal neostigmine was highly effective for vaginal postoperative somatic pain, but failed to relieve discomfort from urinary catheterization and vaginal probing, causing an uncomfortable sensation of the need to evacuate . These observations showed that not all types of pain or sensations were equally relieved by the same intrathecal dose. To further elucidate the analgesic profile of neostigmine and overcome untoward side effects, the present study was designed to qualitatively evaluate profound somatic and visceral pain in selected patients undergoing both sensations at the same surgical time, in a randomized, prospective, blind trial. Because patients have described the remaining pain during a preliminary study as being typically colic diffuse pain, we hypothesized that the association of a peripheral anticholinergic that would not cross the blood-brain barrier would improve the analgesic effect of intrathecal neostigmine for visceral pain, avoiding any problems arising from the association of opioids and neostigmine.
The study protocol was approved by the Ethical Committee of the University of Sao Paulo's Teaching Hospital, Ribeirao Preto. After giving written, informed consent, 27 female ASA physical status I and II patients scheduled for both tubal ligation and vaginoplasty to be performed at the same surgical time were randomized into one of three groups Table 1 and prospectively studied in a double-blind manner. The anesthesiologist had ready access to the information in case of an emergency. Patients were excluded if they were being treated with any analgesic at the time of the surgery or if they had a past history of epilepsy. Both surgeries in each patient were performed through the vagina, which allowed for a clear differentiation between somatic pain (vaginoplasty) and visceral pain (tubal ligation). All perioperative conditions were similar in the three groups. The patients were visited on the day before surgery, when they were introduced to the concept of the visual analog scale (VAS), which consisted of a 10-cm line with 0 equaling "no pain" and 10 being the "worst possible pain"; the concept of visceral pain, felt as a dull, aching, ill-defined or colic pain; and the concept of somatic pain, felt as a burning, well localized pain.
All patients were premedicated with intravenous (IV) midazolam 0.05 mg/kg in the reception room. In the operating room, preservative-free neostigmine 100 micro gram after dilution with saline or just saline to a 2-mL final volume was administered at the L3-L4 interspace with the patient in a sitting position. Anesthesia was then induced with thiopental (5-7 mg/kg) IV and tracheal intubation facilitated by IV atracurium (0.5 mg/kg). Controlled ventilation was maintained using N2 O 66%/O (2) 34% in enflurane in a semiclosed valvular system. Enflurane was administered at a constant fresh gas flow and adjusted to keep arterial blood pressure and heart rate within 15% of baseline values. Routine intraoperative monitoring consisted of noninvasive blood pressure and heart rate measured at 5-min intervals, continuous heart rate by surface electrocardiogram, continuous oxyhemoglobin saturation, and capnography. The pupils were also systematically examined every 5 min for the first hour and every 10 min thereafter using a pupillometer (Bausch & Lomb, Inc., Rochester, NY). Twenty to 30 minutes before the end of the surgical procedure, N-butyl-scopolamine (20 mg) or saline was administered as a 2-mL IV injection Table 1. Neuromuscular blockade was not pharmacologically reversed. The time at which patients arrived in the recovery room was recorded as time zero. Patients were then assessed at 30-min intervals and asked to clearly describe their pain, point to the painful site, and assess it using a 10-cm VAS for up to 6 h or until patients requested rescue analgesia. The rescue analgesia, which consisted of a bolus of 2 mg of morphine, was administered by a blinded investigator participating in the pain assessment when patients requested pain relief and the VAS score was 3 or more. IV morphine was administered upon request to a maximum of 12 mg/h at 10-min intervals until patients felt comfortable or pain free. VAS results were compared at the time of the request for morphine (VAS score of 3 or more) in the recovery room. Side effects, if present, were recorded. Time to first analgesia request was also recorded. All patients stayed in the recovery room for at least 6 h, or until complete anesthetic recovery, where any adverse effects were noted and treated, if necessary. Statistical analyses were performed using analysis of variance, paired Student's t-test, and two-way Student's t-test assuming unequal variances, when indicated.
All patients underwent vaginoplasty and tubal ligation through the vagina. All surgical procedures were performed by the same surgeon. The three groups did not differ statistically in ASA physical status, age, weight, height, surgical time, and anesthetic time Table 2.
There was little evidence of neostigmine producing intraoperative analgesia, as indicated by similar delivered enflurane concentrations (milliliters per minute) (control group [CG]: 0.202 +/- 0.034; neostigmine group [NG]: 0.177 +/- 0.076; neostigmine-N-butyl-scopolamine group [NSG]: 0.205 +/- 0.056; P = 0.282), adjusted according to cardiovascular variables, measured as mean arterial blood pressure and heart rate at fixed intervals, within the surgical time range (93-135 min). Figure 1 displays the mean arterial blood pressure at the first 30 min after the spinal puncture. The mean arterial pressure was stable and statistically the same for all groups during all procedures. Although the cardiovascular variables were in the normal range, the pupils were slightly mydriadic between 20 and 40 min after the spinal puncture in the NG and the NSG compared to those in the CG, which were characteristically myotic during all the anesthetic procedures (P > 0.05). No other adverse effects were observed during the intraoperative period.
Postoperatively, patients from the CG complained of both visceral pain (diffuse, ill-localized abdominal colic pain; VAS 4.88 +/- 0.93) and somatic pain (burning, aching pain well-localized at the vaginal site; VAS 4.44 +/- 0.88) (P < 0.0001) at the first 30-min assessment, and all patients requested morphine (5.33 +/- 1 mg) at that time Table 3. Patients from the NG complained of only visceral pain from the first 30-min assessment, however, and had statistically lower VAS scores compared with the CG at the time of the request for an analgesic (VAS 3.88 +/- 0.78 vs 4.88 +/- 0.93, respectively; P sub (two tail) = 0.026). At the 3-h assessment, all patients from the NG requested rescue IV morphine (one patient at the first half hour postoperatively, five others at 1.5 h, one at 2 h, and the remaining two at 3 h). The NG requested less morphine than the CG (4 +/- 1.41 mg vs 5.33 +/- 1 mg, respectively; P sub (two tail) = 0.037). Patients from the NSG did not complain of somatic or visceral pain when assessed at 30-min intervals for up to 6 h and did not request IV morphine during this assessment period.
Four patients from the NG and two from the NSG spontaneously complained of some discomfort from urinary catheterization, which was routinely used in the surgeries. No adverse effects were observed postoperatively during the 6-h assessment period.
We have shown that 100 micro gram intrathecal neostigmine was more effective as an analgesic for somatic pain than for visceral pain in the group of patients studied. Although visceral and somatic pain are difficult to separate, we were confident that the patients could readily and convincingly discriminate between them. Spinal neostigmine apparently activates descending pain inhibitory systems that rely on a spinal cholinergic interneuron, probably exacerbating a cholinergic tonus that is already activated during the acute postoperative period , and seems to be extremely efficient for alleviating vaginal somatic pain. The analgesic effects of parenteral N-butyl-scopolamine have not been reported, and its sedative effect in large doses would have interfered with pain evaluation. However, the dose given (20 mg IV) would not interfere with pain evaluation, especially because is not a large dose. A dose as large as 30 mg has been used routinely in our service in adults, with minimal sedative effects. N-butyl scopolamine administered at the end of the surgical procedure must have acted peripherally as an effective complement for visceral pain. All patients from the NSG were pain free, reflecting an association between central cholinergic effects and peripheral anticholinergic effects in the treatment of visceral postoperative pain. N-butyl scopolamine would act peripherally to block sympathetic and parasympathetic ganglions and also as an antispasmodic. Acute visceral pain after the cutting of a viscus is often intense, vaguely localized, referred to distant regions of the body, and accompanied by powerful motor and autonomic reactions, including spasms of the abdominal musculature and increased sympathetic outflow . Therefore, the analgesic effect observed would reflect either the block of sympathetic ganglion through nicotinic receptors or a direct antispasmodic effect on the viscera through muscarinic receptors. However, further animal research with specific antagonists is necessary to clarify the role of N-butyl scopolamine as a complement in visceral analgesia.
In this study, no adverse effects were observed, which is in agreement with our previous study where we used a very similar anesthetic technique . We did not intend to reverse the neuromuscular block, avoiding administration of atropine and any possible effect on neostigmine analgesic action. The block of the parasympathetic ganglion would theoretically diminish the incidence of nausea and vomiting. In fact, we did not observe any nausea or vomiting in our patients, but this cannot be attributed to the parasympathetic block in this specific study.
In our study, N2 O was used throughout the operation, and it, too, has analgesic qualities . However, it was used in the three groups and did not confer a long-lasting analgesic benefit to the CG. Enflurane may have contributed to the analgesic effects of the study drugs, as it has been shown to lower the K (m) of choline acetyltransferase at 3 minimum alveolar anesthetic concentration in rat brain, without altering maximum velocity . Acetylcholine turnover under enflurane anesthesia is reduced in cortical but not subcortical structures in the brain . Intraoperatively, there was little evidence of neostigmine producing analgesia, as indicated by similar delivered enflurane concentrations, adjusted according to cardiovascular variables in each group. However, the absence of an intraoperative analgesic effect could in fact reflect a later onset of action of intrathecal neostigmine, which would not be observed in the surgical time range (93-135 min).
The small sample size (n = 9) was a reflection of the surgical technique chosen. We emphasized selecting ideal patients, rather than large numbers, to perform both the tubal ligation and vaginoplasty through the vagina. We felt that such a study, involving both somatic and visceral pain in the same patient with an anesthesia technique previously shown to be efficient for vaginal somatic pain , would be more informative and would improve our knowledge about the analgesic profile of intrathecal neostigmine. A deficiency in the experimental design was the lack of a group receiving only IV N-butyl-scopolamine, which certainly would have enriched the understanding of the real role of this peripheral anticholinergic on postoperative pain.
In conclusion, 100 micro gram intrathecal neostigmine was shown to be more effective in the treatment of vaginal somatic pain, compared with tubal ligation visceral pain, in patients undergoing a standard anesthetic and surgical technique. The addition of a peripheral anticholinergic substantially improved the intrathecal neostigmine analgesic effect on visceral pain.
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