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ANESTHETIC PHARMACOLOGY

Pain During Injection of Propofol: The Effect of Prior Administration of Butorphanol

Departments of Anesthesia and Biostatistics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

Address correspondence and reprint requests to Anil Agarwal, MD, Type IV/48, SGPGIMS, Lucknow 226 014, India. Address email to aagarwal{at}sgpgi.ac.in

	Abstract

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Propofol causes pain or discomfort on injection in 28%–90% of patients. A number of techniques have been tried for minimizing propofol-induced pain with variable results. We compared the efficacy of butorphanol and lidocaine for prevention of propofol-induced pain. One-hundred-fifty ASA I–II adults, undergoing elective surgery were randomly assigned into 3 groups of 50 each. Group I (NS) received normal saline, Group II (L) received lidocaine 2% (40 mg), and Group III (B) received butorphanol 2 mg. All patients received pretreatment solutions made in 2 mL with normal saline administered over 5 s. One min after pretreatment patients received one-fourth of the total calculated dose of propofol (2.5 mg/kg) over 5 s. Assessment of pain with IV propofol was done by using a four-point scale: 0 = no pain, 1 = mild pain, 2 = moderate pain and 3 = severe pain at the time of propofol injection. In the control Group 39 (78%) patients had pain during propofol injection as compared to 21 (42%) and 10 (20%) in the lidocaine and butorphanol groups, respectively (P < 0.05). Butorphanol was the most effective. We therefore suggest the IV pretreatment with butorphanol 2 mg for attenuation of pain associated with propofol injection.

IMPLICATIONS: Pain associated with IV injection of propofol is seen in 28%–90% patients. Pretreatment with butorphanol 2 mg and lidocaine 40 mg attenuated the incidence and severity of pain associated with propofol injection. Butorphanol was the most effective and can be used routinely to prevent propofol pain.

	Introduction

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Propofol is associated with pain or discomfort on injection in 28%–90% of patients (1). Propofol-induced pain ranked seventh among the 33 low morbidity clinical outcomes by expert anesthesiologists when both clinical importance and frequency were considered (2). Adding lidocaine to propofol with or without tourniquet, injection of propofol into a large vein, cooling or warming propofol, pretreatment with IV injection of lidocaine, ondansetron, metoclopramide, opioid or thiopental, have been tried for minimizing this propofol-induced pain with variable results (3–6). Opioids are central receptor-mediated analgesics. Incidentally, we observed that after IV butorphanol (an agonist-antagonist opioid compound) administration patients did not complain of pain during induction with IV propofol. Therefore, we planned this clinical study. In this randomized, double-blind, placebo-controlled study, we compared the efficacy of pretreatment with butorphanol and lidocaine for prevention of pain associated with propofol injection.

	Methods

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After receiving permission from our institutional ethical committee and written informed consent, this prospective study was conducted in a double-blind randomized fashion. Patients having difficulty in communication or with history of allergy to study drugs were excluded from the study.

Assuming that the incidence of pain after IV propofol is 70% and that this would be reduced to 35% after therapy; with = 0.05 and ß = 0.95 one would need to study 49 patients in each group. We therefore included 50 patients in each group. This study consisted of 150 consecutive patients, ASA physical status I–II adults, aged 18–50 yrs, undergoing elective surgical procedures. With the help of a computer-generated table of random numbers patients were assigned into one of 3 groups of 50 each. All patients received pretreatment solutions 1 min before induction of anesthesia with propofol depending on the group to which they belonged.

Group I (NS): normal saline.

Group II (L): lidocaine 2% (40 mg).

Group III (B): butorphanol 2 mg.

All pretreatment drugs were made in 2 mL and loaded in a 5-mL syringe that was covered by red tape. Patients were premedicated with tab lorazepam 2 mg and ranitidine 150-mg PO the night before surgery and 2 h before induction of anesthesia. After instituting electrocardiogram, noninvasive arterial blood pressure and pulse oximetry monitoring, a dedicated 18-gauge cannula was inserted into the dorsum of the nondominant hand for administration of study drugs. Another cannula was placed in the other hand for infusion of IV fluids.

An independent anesthesiologist prepared pretreatment solutions and the investigator did not know the contents of solutions. Patients then received one-fourth of the total calculated dose of propofol over 5 s. The induction dose of propofol (PROFOL^TM 1% w/v in lipid base; Claris Lifesciences Limited, Ahmedabad, India) was 2.5 mg/kg. All study drugs were maintained at room temperature and were used within 30 min of preparation. A second, independent anesthesiologist, who was unaware of the group to which the patient had been allocated, assessed the level of pain after IV propofol. Fentanyl was administered only after assessment of the pain after propofol injection. Induction of anesthesia was completed with the remaining dose of propofol and tracheal intubation was facilitated with vecuronium. Anesthesia was maintained with 33% O₂ in N₂O, isoflurane and fentanyl.

During the propofol injection, patients were continuously observed for vocal response, facial grimacing, arm withdrawal, or tears suggesting severe pain. If these signs and symptoms were absent then patients were questioned every 5–10 s during induction regarding the presence of pain or discomfort. Pain was graded using a four-point scale: 0 = no pain, 1 = mild pain (pain reported only in response to questioning without any behavioral signs), 2 = moderate pain (pain reported in response to questioning and accompanied by a behavioral sign or pain reported spontaneously without questioning), and 3 = severe pain (i.e., strong vocal response or response accompanied by facial grimacing, arm withdrawal, or tears) (7).

Within 24 h after operation, the injection site was checked for pain, edema, wheal, or flare response by an anesthesiologist who was unaware of which drug was administered. Results were analyzed by comparing two proportions by normal approximation ("Z" test). When the distribution of data was not normal (i.e., the data regarding grading of pain) Fisher’s exact test were applied. The package SPSS 9.0 (SPSS, Chicago, IL) was used for statistical analysis. P 0.05 was considered as significant.

	Results

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All the groups were comparable with respect to demographic characteristics (Table 1). In the control group 39 (78%) patients had pain during propofol injection as compared with 21 (42%) and 10 (20%) in the lidocaine and butorphanol groups, respectively (P < 0.05) (Table 2). Intergroup comparison revealed that the incidence and severity of pain at propofol injection was less in all the study groups when compared with the control group (P < 0.05) (Table 2). Butorphanol decreased the frequency (P < 0.05) but not the severity of propofol pain when compared with lidocaine. The majority of patients in the lidocaine and butorphanol groups had mild pain when compared with the control group (P < 0.05). No complications, such as pain, edema, wheal, or flare response, were observed at the injection site within the first 24 h after the operation.

	Discussion

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Propofol is an excellent IV anesthetic that belongs to the group of phenols, which can irritate the skin, mucous membrane, and venous intima (8). It may activate the kallikrein-kinin system and release bradykinin, thereby producing venous dilation and hyperpermeability, which increases the contact between the aqueous phase of propofol and free nerve endings resulting in pain on injection (3,9). Various methods have been used for attenuating pain during IV injection of propofol, such as using larger veins (10), decreasing speed of injection (11), injecting propofol into a fast running IV fluid (11), diluting it with 5% glucose or 10% intralipid (11), prior injection of lidocaine, alfentanil, fentanyl, or pentothal (11), injecting cold saline at 4°C before propofol, cooling propofol to 4°C (5), or discontinuing fluid during the injection (11) and mixing lidocaine in propofol (12).

We observed that after lidocaine pretreatment 21 patients (42%) had pain with propofol injection, which is comparable with other studies (13,14). Opioids are excellent analgesics, and many opioids, such as fentanyl, morphine, meperidine, and alfentanil, have been used to reduce the pain of propofol injection. Nathanson et al. (1) compared the efficacy of lidocaine with alfentanil for reducing propofol-induced pain by grading pain as mild, moderate, or severe and observed that both alfentanil 1 mg and lidocaine 40 mg were equally effective in attenuating propofol-induced pain. Pang et al. (15) assessed the efficacy of IV pretreatment with fentanyl, morphine, meperidine, or lidocaine in reducing propofol injection pain using a verbal analog scale of 0–10. They observed that only meperidine and lidocaine significantly reduced the propofol injection pain.

Butorphanol tartrate is a synthetic, strong analgesic with both narcotic agonist and antagonistic properties (16). It is an agonist at kappa receptors, is either antagonistic or partial agonist at µ receptors, and is 5–8 times more potent than morphine (17). After IV administration the onset of analgesia occurs rapidly (within 1 minute) with peak effect occurring in about 4–5 minutes (17). The site of action of butorphanol in reducing the pain of propofol injection is not clear, but it could be through opioid receptors (central and or peripheral), local anesthetic action, or both. We administered butorphanol 1 minute before the injection of propofol. Butorphanol could have acted centrally, as the analgesic action of the drug starts within 1 minute (17). However, one cannot exclude the influence, if any, of the sedative effect of butorphanol when assessing pain associated with propofol injection. Further work is suggested for confirming the mechanism of action of butorphanol in preventing propofol-induced pain.

In conclusion, pretreatment with butorphanol 2 mg or 2% lidocaine (40 mg) is effective in attenuating pain associated with propofol injection. Butorphanol pretreatment is most effective in minimizing the incidence and severity of pain associated with propofol injection. Butorphanol is not a restricted drug, like other narcotics, and it provides intraoperative analgesia. Thus butorphanol pretreatment can be chosen as an effective and simple method of attenuating propofol-induced pain. We therefore suggest pretreatment with IV butorphanol 2 mg for attenuation of pain associated with propofol injection.

	References

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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 Web of Science 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 Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Agarwal, A. Articles by Singh, U. Search for Related Content PubMed PubMed Citation Articles by Agarwal, A. Articles by Singh, U. Related Collections Heart Pharmacology