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PAIN MEDICINE

Multimodal Analgesia to Prevent Propofol-Induced Pain: Pretreatment with Remifentanil and Lidocaine Versus Remifentanil or Lidocaine Alone

From the Department of Anesthesiology, American University of Beirut Medical Center, Beirut, Lebanon.

Address correspondence to Marie T. Aouad, Associate Professor, Department of Anesthesiology, American University of Beirut Medical Center, P. O. Box 11 0236, Beirut, Lebanon. Address e-mail to mm01{at}aub.edu.lb.

	Abstract

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BACKGROUND: Propofol is well-known for its pain on injection. Premixture with lidocaine or pretreatment with remifentanil reduces injection pain. A multimodal approach might offer additional mitigation of propofol injection pain.

METHODS: In a randomized, prospective, double-blind study of 156 patients, we compared the incidence and severity of propofol pain among three groups. Patients in the lidocaine group (n = 54) received 2% lidocaine premixed with propofol (40 mg lidocaine in 180 mg propofol). Patients in the remifentanil group (n = 50), received pretreatment with remifentanil 2 µg · kg^–1 IV over 30 s. Patients in the combination group (n = 52) received both lidocaine and remifentanil.

RESULTS: A significant decrease in the overall incidence of propofol pain at induction was achieved in the combination group (9.6%) compared with that in the remifentanil group (36%) and the lidocaine group (35%) (P = 0.003). The incidence of severe and moderate pain was also significantly different in the combination group (0%), compared with that in the remifentanil (18%) and lidocaine groups (12.9%) (P < 0.02). Similar, statistically significant differences among the three groups were achieved concerning recalled pain in the postanesthesia care unit.

CONCLUSIONS: The combination of two different analgesic modalities, remifentanil and lidocaine completely abolishes moderate and severe pain associated with propofol injection, and significantly reduces the incidence of mild pain when compared with each drug used alone.

	Introduction

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Propofol is the most frequently used IV anesthetic drug. However, the widely used long-chain triglycerides (LCT) formulation ("Diprivan") is associated with pain on injection in up to 70% of patients (1). This pain can be severe enough to produce profound patient discomfort and is ranked seventh among 33 clinical problems (2). Many drugs, such as alfentanil, fentanyl, lidocaine, thiopental, or metoclopramide, have been used to alleviate pain after IV injection of propofol with variable efficacy (1).

In our daily practice, we noticed that very few patients reported injection pain when remifentanil was given immediately before injection of propofol, even in the absence of lidocaine. The effect of remifentanil on the pain after injection of propofol has been investigated (3–7). However, the doses used in previous clinical studies were lower than those used for induction of anesthesia (3–5), and did not completely eliminate pain on propofol injection. Our hypothesis was that a combination of pretreatment with remifentanil and premixing with lidocaine may decrease the incidence and severity of propofol injection pain compared with each drug used alone.

In this study, we compared the incidence and severity of propofol pain on injection among three groups: premixing of 2% lidocaine 40 mg with 180 mg propofol, pretreatment with remifentanil 2 µg · kg^–1 IV, and the combination of both lidocaine and remifentanil.

	METHODS

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After approval was obtained from the IRB, and written consent from patients, 156 patients scheduled for general anesthesia were enrolled in this prospective, randomized, double-blind study. Exclusion criteria were indication for rapid sequence induction of anesthesia, known allergy to any of the study drugs, ASA physical status 4, hemodynamic instability, psychiatric disorders, severe neurological deficits, and patients receiving opioids as long-term treatment.

All patients were premedicated with diazepam 5 mg orally 30–60 min before induction of anesthesia. Upon arrival to the operating room, an 18-G cannula was inserted in the dorsum of the hand of each patient and an infusion of lactated Ringer’s solution was started. A syringe pump (Medfusion 3010 a Medex Health Care company, Duluth, GA) containing the study drug (remifentanil 100 µg/mL or saline) was connected via a 3-way stop cock located at the proximal end of the cannula. Another 3-way stop cock was attached to the first one to allow the injection of propofol and all other drugs used for induction of anesthesia. Propofol 1% (Fresenius Kabi. Austria), 18 mL was premixed with 2 mL of lidocaine 2% or with 2 mL of saline, depending on the group to which the patient was assigned, to achieve a total volume of 20 mL. Those mixtures were freshly prepared immediately before induction of anesthesia. Propofol 0.1 mL · kg^–1 premixed with lidocaine or saline was defined as the study dose of propofol during which pain would be assessed.

The patients were randomly assigned according to a computer-generated random table to one of three groups. Patients in the lidocaine group (n = 54) received 0.02 mL · kg^–1 of saline via a syringe pump over 30 s, followed by 0.1 mL · kg^–1 of propofol premixed with 2% lidocaine over 5 s. Patients in the remifentanil group (n = 50) received remifentanil (Ultiva®, Glaxo Wellcome, Greenford. UK) 2 µg · kg^–1 (0.02 mL · kg^–1) via a syringe pump over 30 s followed by the administration of 0.1 mL · kg^–1 of propofol premixed with saline over 5 s. Patients in the combination group (n = 52) received remifentanil 2 µg · kg^–1 (0.02 mL · kg^–1) via a syringe pump over 30 s, followed by the administration of 0.1 mL · kg^–1 of propofol premixed with 2% lidocaine over 5 s.

After the above treatment, additional propofol was given to a total dose of 1.5–2 mg · kg^–1 in all patients. During the completion of propofol administration, the syringes on the syringe pump were replaced. Patients in the remifentanil and combination groups received 0.02 mL · kg^–1 of saline over 30 s. Patients in the lidocaine group received remifentanil 2 µg · kg^–1 over 30 s. Rocuronium 0.6 mg · kg^–1 was then injected to facilitate tracheal intubation. Anesthesia was maintained with remifentanil and isoflurane. All the syringes used were prepared by the resident and their identity was concealed. The syringes were numbered according to their sequence of use as per patients’ randomization. In all groups, the carrier fluid was stopped during the administration of the pretreatment drug and the study dose of propofol.

The incidence and severity of pain were assessed during the injection of the study dose of propofol by an anesthesiologist who was blinded to the group to which the patient was assigned, using an observer’s pain scale where pain was graded 1 = absent, if the patient denied its occurrence, 2 = mild, if only reported after questioning the patient, 3 = moderate, if spontaneous verbal expression of pain without grimacing or withdrawal of arm occurred, 4 = severe, if spontaneous strong vocal response with facial grimacing or withdrawal of arm occurred during the injection of propofol (3). In addition, during the injection of the study dose of propofol, the anesthesiologist repeatedly asked patients to grade their pain for up to 20 s before the completion of the propofol dose using a numeric rating scale from 0 to 10 where 0 is no pain and 10 the worst imaginable pain. In the postanesthesia care unit, patients were asked if they recalled pain during the injection of propofol. If yes, the patients were asked to rate their pain using the same 0–10 numeric rating scale, as well as using a verbal rating scale with 1 = no pain, 2 = mild pain, 3 = moderate pain, and 4 = severe pain. Patients were instructed about both the numeric rating scale, and the verbal rating scale before premedication with diazepam.

Continuous data are reported as means ± sd and are analyzed using ANOVA and Bonferroni post hoc test. Categorical data are reported as numbers and percentages and are analyzed using ² or Fisher’s exact test as appropriate. Nonparametric data are reported as medians and ranges and are analyzed using Mann–Whitney U-test. P < 0.05 was considered statistically significant. Considering from previous studies that the incidence of propofol pain after pretreatment with either lidocaine or remifentanil is in the range of 35% (3), 50 subjects per group would be required to decrease this incidence to 10% (power 80% and = 0.05).

	RESULTS

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One-hundred-fifty-six patients completed the study; 54 patients in the lidocaine group, 50 patients in the remifentanil group, and 52 patients in the combination group. Groups were similar with respect to patients’ characteristics and type of surgery (Table 1).

All patients were fully awake during the 20 s time interval during which pain was repeatedly assessed before the injection of the completion dose of propofol. A significant decrease in the overall incidence of propofol pain at induction was achieved in the combination group (9.6%) compared with that in the lidocaine group (35%) (P = 0.003) and the remifentanil group (36%) (P = 0.003). The severity of pain was significantly less in the combination group compared with that in the lidocaine and remifentanil groups, as evidenced by lower values of the numeric rating scale (P < 0.001) and a 0% incidence of severe and moderate pain in the combination group when compared with 12.9% in the lidocaine group (P = 0.013) and 18% in the remifentanil group (P = 0.001) (Table 2, Fig. 1). Similar results were achieved concerning recalled pain. The incidence of overall pain was less frequent in the combination group (3.8%) compared with the lidocaine group (25.9%) (P = 0.002) and the remifentanil group (26%) (P = 0.002). Similarly, the numeric rating scale score was lower in the combination group compared with that in the lidocaine and remifentanil groups (P = 0.001). There was a 0% incidence of moderate and severe pain in the combination group, compared with 11% in the lidocaine group (P = 0.027) and 16% in the remifentanil group (P = 0.002) (Table 2, Fig. 1). All these values were comparable between the lidocaine and remifentanil groups.

View larger version (15K): [in this window] [in a new window]   Figure 1. Distribution of the pain scores among the patients in the groups. A—-Observer’s Pain Scale (OPS) at induction; B—-Verbal Rating Scale (VRS) of recalled pain.

No statistical significance was found among the three groups in the ratio of patients who recalled pain to those who experienced pain (Table 2). Thirteen patients from the three groups were unable to recall the pain they reported at induction; this pain was rated mild in 12 patients and moderate in one patient.

	DISCUSSION

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Our results showed that either premixing propofol with 2% lidocaine 40 mg or pretreatment with remifentanil 2 µg · kg^–1 yields a similar incidence of propofol-induced pain (35% and 36% respectively). However, combining remifentanil pretreatment with premixing propofol with lidocaine significantly reduced the incidence of pain to 9.6%, one of the lowest incidences of propofol-induced pain reported using different drugs or propofol formulations (1,8). This low incidence of pain was observed despite injection of propofol into the veins on the dorsum of the hand typically associated with a frequent incidence of pain on injection (1).

Propofol-induced pain on injection is related to the amount of free propofol present in the aqueous phase (9). The contact of free propofol with free nerve endings of vessels activates the plasma kallikrein-kinin system, which locally liberates pain mediators (9).

Mixing lidocaine with propofol reduces injection pain (10–12). Lidocaine seems to act via two mechanisms, by blocking pain transmission via the free nerve endings of vessels, and by decreasing the pH of the solution, which leads to a lower concentration of free propofol, as suggested by Eriksson et al. (13). This concept has been recently challenged by Yamakage et al. (14), who showed that premixing lidocaine and propofol does not decrease free propofol concentration, suggesting that lidocaine acts mainly through inhibition of pain transmission.

An alternative method of giving lidocaine involves applying a tourniquet proximal to the IV catheter site, and injecting 40 mg 30–120 s before the injection of propofol (1). Although this has superb efficacy, it is awkward to perform routinely. One study showed better results with lidocaine added to propofol when compared to pretreatment with lidocaine (15). However, mixing lidocaine with propofol is not recommended because such mixtures may be unstable if kept for more than 30 min and are not recommended by the manufacturer (16). In the present report, we used freshly prepared mixtures, which seem to avoid this drawback.

Remifentanil is a short-acting phenylpiperidine derivative with µ-opioid receptor agonist effects (17). Similar to other opioids, the site of action of remifentanil may be either central or peripheral. Opioid receptors are found centrally in the dorsal root in the central terminals of primary afferent nerves, and also in peripheral sensory nerve fibers and their terminals (18). Opioids may also exert a local anesthetic effect (19). Our speculation is that the pain-reducing action of remifentanil in our study was mainly peripheral because no running fluid was used with no possible quick washout of remifentanil. Moreover, propofol was injected immediately after the infusion of remifentanil. Therefore, the onset was too fast to be explained by a central mechanism of opioid action.

Pretreatment with remifentanil is effective in reducing propofol-induced pain (3–7), similar to findings for fentanyl and alfentanil (16,20). Roehm et al. (3) reduced propofol-induced pain by 50% using remifentanil at a dose of 0.25 µg · kg · min^–1. Iyilikci et al. (4) achieved adequate reduction of pain with remifentanil doses of 10 and 20 µg, with a better efficacy of the 20 µg dose. Basaranoglu et al. (7) showed a better efficacy of remifentanil 1 µg · kg^–1 · min^–1 versus 0.25 µg · kg · min^–1. We administered 2 µg · kg^–1, the dose routinely used in our department to blunt the hemodynamic response to laryngoscopy.

In our study, the ratio of patients having memory of pain in the postanesthesia care unit to those complaining of pain during injection was similar in the three groups. Previously reported incidences of recall range between 0% and 100% (15,16). The lower incidence of recalled pain in our patients may have been related to the premedication with diazepam, which may have caused amnesia.

The new formulations of propofol containing a mixture of LCT and medium-chain triglycerides cause less pain during injection than propofol LCT that was used in our study, because it contains a lower concentration of free propofol (8,21). However, the incidence of pain with propofol LCT/medium-chain triglycerides remains higher than that achieved by the combination of propofol LCT and lidocaine (8,22).

In conclusion, premixing propofol with 2% lidocaine 40 mg and pretreatment with remifentanil 2 µg · kg^–1 yielded similar incidences of propofol pain on injection of 35%. However, the combination of both analgesic modalities significantly reduced the incidence of mild pain on injection to 9.6%, and completely abolished moderate and severe pain.

	Footnotes

 
Accepted for publication February 13, 2007.

This study was supported by Departmental funds.

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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 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 (4) Citing Articles via Google Scholar Google Scholar Articles by Aouad, M. T. Articles by Baraka, A. S. Search for Related Content PubMed Articles by Aouad, M. T. Articles by Baraka, A. S. Related Collections Pain Medicine Pain Pharmacology