Anesthesia and Postoperative Pain

June 12, 2024 updated by: Columbia University

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 receive intranasal nicotine or placebo in order to detect potential 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 the 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. The investigators 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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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. 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. In these experiments, treatment with nicotine prevented the hyperalgesic state caused by isoflurane.

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.

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.

The study wishes to detect a 50% change in pain sensitivity and in our other studies, Visual Analog Pain Scale (VAS) scores and patient-controlled analgesia (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 New York Presbyterian Hospital (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.

Post-anesthesia care unit (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.

D. Study Drugs

Nicotine has been used commonly on an outpatient basis for smoking cessation. The investigators 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. The preliminary data do not show any significant increase in blood pressure or heart rate in patients who received nicotine.

The investigators 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. 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.

Study Type

Interventional

Enrollment (Actual)

23

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • New York, New York, United States, 10032
        • New York Presbyterian Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 1
Propofol anesthetic with and without nicotine
Drug: Nicotine (drug)
nicotine nasal spray (3mg) before surgery
Experimental: 2
isoflurane anesthetic with and without nicotine
Drug: Nicotine (drug)
nicotine nasal spray (3mg) before surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Score on a Pain Rating Scale (Numerical Analog Score)
Time Frame: Up to 24 hours
Pain was reported on the Numerical Rating Scale for pain (NRS) with 0=no pain and 10=worst pain. Pain was assessed at 5, 10, 15, 20, 25, 30, 35, 40, 45, 60, 120, and 1440 minutes post-op, and the average of all time-points is reported.
Up to 24 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cumulative Morphine Usage
Time Frame: Up to 24 hours
The amount of morphine used by each patient at the following time points will be summed: 5, 10, 15, 20, 25, 30, 35, 40, 45, 60, 120, and 1440 minutes post-operative. A patient-controlled analgesia pump was programmed to deliver a dose of 1 mg morphine when the button is pressed with a lockout interval of 6 min and a maximal dose during 1 h of 10 mg. The pump is also programmed to allow a rescue dose of 3mg morphine to be administered by a nurse every 5 min with additional 12 mg morphine maximally by this route every 4 hours. A patient could receive 24 mg of morphine as a maximal dose in the first hour.
Up to 24 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Columbia University

Investigators

  • Principal Investigator: Pamela D Flood, M.D., Columbia University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 1, 2003

Primary Completion (Actual)

July 1, 2005

Study Completion (Actual)

March 1, 2006

Study Registration Dates

First Submitted

October 3, 2005

First Submitted That Met QC Criteria

October 3, 2005

First Posted (Estimated)

October 5, 2005

Study Record Updates

Last Update Posted (Actual)

July 12, 2024

Last Update Submitted That Met QC Criteria

June 12, 2024

Last Verified

June 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AAAA6698

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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