| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
 
|
|
|
||
|
|
Anesth Analg 2004;98:159-165 © 2004 International Anesthesia Research Society
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
We conducted this double-blinded, randomized study to assess the analgesic effect of repeated administrations of paracetamol, administered as propacetamol, an injectable prodrug formulation of paracetamol, and to compare this with the analgesic effects of morphine. Patients experiencing moderate to severe pain after elective surgical removal of bone-impacted third-molar teeth under general anesthesia were randomly assigned to receive IV propacetamol 2 g (n = 31), IM morphine 10 mg (n = 30), or placebo (n = 34). Five hours later, the treatments were readministered at half of the previous dosages. Standard measures of analgesia were collected repeatedly for 10 h. Propacetamol and morphine were significantly more effective than placebo in all primary measures of analgesia over 5 h after the first administration and globally over 10 h (first and second administrations). After the first dose, 21 of the 34 patients in the placebo group required rescue medication, compared with 6 of the 31 in the propacetamol group (P < 0.0009) and 4 of the 30 in the morphine group (P < 0.0001). No statistically or clinically significant differences were found between propacetamol and morphine for any sum or peak measures of analgesia. No serious adverse events were reported; adverse events were significantly less frequent in the propacetamol group than in the morphine group (P < 0.027). Propacetamol administered IV in repeated doses (2 g followed by 1 g) has a significant analgesic effect that is indistinguishable from that of morphine administered IM (10 mg followed by 5 mg) after dental surgery, with better tolerability.
IMPLICATIONS: After moderately painful surgical procedures, IV paracetamol, administered as propacetamol, may be an asset in the control of acute postoperative pain.
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Paracetamol (acetaminophen) is an effective and safe analgesic used worldwide to relieve mild to moderate pain in conditions such as headache, toothache, dysmenorrhea, and arthritis (1). Oral or rectal formulations are used perioperatively as a component of a balanced analgesia regimen (2–4). However, paracetamol is poorly soluble and unstable in aqueous solution and therefore cannot be administered parenterally.
Propacetamol is a water-soluble prodrug of paracetamol that can be administered parenterally when greater efficacy or a fast onset of analgesia is desirable, for example, in the postoperative period after general anesthesia. In the blood, propacetamol is readily cleaved by esterases into paracetamol and the promoiety diethylglycine (5); propacetamol 2 g of propacetamol yields 1 g of paracetamol.
Propacetamol is available in several European countries, where it is mostly used in the short-term management of acute postoperative pain. IV infusion of propacetamol 2 g was significantly more effective than paracetamol 1 g taken orally in patients with moderate to severe postoperative pain after hallux valgus surgery (6). Used in conjunction with opioids administered by patient-controlled analgesia, propacetamol had an opioid-sparing effect (7–9).
Opioids and nonsteroidal antiinflammatory drugs (NSAIDs) are the main analgesics often used to manage perioperative pain. In this study, the analgesic activity of propacetamol was directly compared with that of morphine, the archetypal injectable analgesic for use in moderate to severe pain. Morphine is also the "gold standard" against which the analgesic activity of more recent injectable drugs is gauged.
The aim of this study was to assess, relative to a placebo, the analgesic effect of two consecutive doses of IV propacetamol (2 g followed by 1 g) administered 5 h apart to control postoperative pain after the surgical removal of one or more bone-impacted third molars and to compare this analgesic effect with that of two consecutive doses of IM morphine (10 mg followed by 5 mg).
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This double-blinded, single-center, randomized, placebo-controlled, parallel-group study was conducted in accordance with the ethical principles of the current amendment of the Declaration of Helsinki over 22 months at the University Hospital of Leuven (Belgium) after the hospital’s Ethics Committee approved. Patients of either sex, aged 15–70 years, and who were in ASA risk classes I or II and presented for elective surgical removal of one or more bone-impacted third molars under general anesthesia were enrolled in the study. Patients undergoing surgery under general anesthesia were selected because they stayed overnight in the ward, were generally unable to take oral medications, and were thus more suitable for a 10-h investigation of parenteral drug administration. Exclusion criteria were clinically significant respiratory, liver, or kidney disease; increased intracranial pressure; history of alcohol or drug abuse; and hypersensitivity to morphine, propacetamol, or paracetamol. Drugs likely to distort the assessment of analgesia (e.g., caffeine, antihistamine, sedatives, and anxiolytics) were withheld from the patients the night before surgery. All NSAIDs and analgesic drugs were withdrawn 6 h before the administration of the study drugs.
All patients gave written, informed consent before enrollment. Patients received training from the study observer on the use of the pain verbal rating scales (VRS) and visual analog scale (VAS). After premedication with lorazepam 2.5 mg, general anesthesia was induced with propofol (2 mg/kg) and alfentanil (10 µg/kg). Muscle relaxation was achieved with vecuronium. Anesthesia was maintained with oxygen (40%) and nitrous oxide (60%) and supplemented with isoflurane as required. Patients were randomized when they experienced moderate to severe pain (VRS) within 3 h after regaining consciousness; they were randomly allocated to receive propacetamol 2 g IV, morphine 10 mg IM, or placebo.
Because the study drugs differed in their appearance, preparation, and administration, a double-dummy placebo technique was used: propacetamol 2 g or placebo, diluted into 150 mL in NaCl 0.9% infusion fluid, was infused IV over 15 min in one forearm vein, and morphine 10 mg or placebo was simultaneously administered by deep intragluteal injection in the upper outer quadrant of the buttock. To comply with the recommended instructions for use in Belgium, the second administration of propacetamol was reduced to 1 g (half-dose); accordingly, the second dose of morphine was 5 mg. The second administrations were given 5 h after the first one. The reduced doses made it possible to establish a study design featuring internal control of the up-side sensitivity of the trial (the dose effect). If patients experienced insufficient pain relief (PR) at any time later than 30 minutes after the first administration of the study drug, rescue analgesia was provided as morphine 2 mg IV; the dose was repeated if necessary until the patient obtained satisfactory relief.
Before each administration of the study drugs and 0.25, 0.5, 0.75, 1, 2, 3, 4, and 5 h afterward, patients were interviewed by the study observer to obtain a self-assessment of their pain intensity (PI) with a four-point VRS (0, none; 1, light; 2, moderate; and 3, severe) and a 100-mm VAS (0, no pain; 100, worst possible pain). PR was also assessed with a five-point VRS (0, none; 1, a little; 2, moderate; 3, a lot; and 4, complete). Patients were wakened if they were asleep at a scheduled interview time. Patients requesting rescue medication were asked to assess their PI (VAS and VRS) and PR at the time of the request. Ten hours after receiving the drug, patients were asked to provide a global assessment of the treatment by using a five-point VRS (1, poor; 2, fair; 3, good; 4, very good; and 5, excellent).
Standard summary measures of analgesia were derived from the data obtained at the scheduled interviews. PI difference (PID) is the difference between the PI score at an observation point and the baseline PI. The sum of the PID (SPID) is the sum of the hourly PID scores weighted by the time interval between observations and represents an estimate of the area under the time-effect curve. Similarly, the total PR score (TOTPAR) is the sum of the hourly PR scores weighted by the time interval between observations and is an estimate of the area under the curve of PR over time. SPID and TOTPAR were computed over the 5-h period (SPID5h and TOTPAR5h) and over the total 10-h period after the initial dose of the study drug (SPID10h and TOTPAR10h). Peak values for PID and PR were defined for each patient as the first maximum value during the first 5-h postinjection period. TOTPAR5h and TOTPAR10h were the primary criteria for evaluating analgesic efficacy after single and repeated doses, respectively. Secondary efficacy variables were SPID5h and SPID10h, peak values of PID and PR and their times of occurrence after the initial dose, and the proportion of patients requiring rescue medication and the time to the request. In the efficacy analysis, the PI and PR scores that were recorded when a patient requested rescue medication or dropped out of the study were carried forward until the end of the 10-h study period (last observation carried forward). Vital signs (heart rate, blood pressure, respiratory rate, and level of consciousness) were measured before drug administrations and at each scheduled interview during the first hour and 5 h after administrations. Percutaneous oxygen saturation was monitored by pulse oximeter (Nellcor, Pleasanton, CA). Adverse events were recorded throughout the course of the study.
All statistical analyses were performed in the intention-to-treat population by using SAS (Version 6.04; SAS Institute, Cary, NC). The study was empowered to distinguish, with 80% power and at a significance level of 0.05, an average difference of TOTPAR10h of ±3.50 between the propacetamol and morphine groups—i.e., an average score difference of 0.35 for PR over the 10 h. The primary efficacy variable TOTPAR and other summed variables were analyzed with one-way analysis of variance; when analysis of variance was significant at the 0.05 level, the treatment groups were compared by using multiple means Waller-Duncan ratios and nonparametric methods. PID and PR scores were compared between morphine and propacetamol groups at each scheduled interview by using the Student’s t-test and the nonparametric Wilcoxon’s ranked sum test. The independence of sampling distributions, of peak PR and peak PID, was analyzed with the Cochran-Mantel-Haenszel 
2 test; the number of patients receiving rescue medication in each treatment group and the global assessment of the treatment were analyzed with Fisher’s exact test and the Cochran-Mantel-Haenszel 2 test. The number of patients with at least one adverse event and the number of adverse events in each treatment group were analyzed and compared by using the likelihood ratio 2 test.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Ninety-nine patients were included in the study. Four patients (one in the propacetamol group and three in the morphine group) were excluded for major protocol deviations before any efficacy data had been collected. All 95 patients for whom efficacy data were obtained were included in the efficacy analysis. The demographic and selected background characteristics of the three groups were similar at baseline (Table 1), with one minor exception: the morphine group included a larger proportion of ASA II patients than the placebo group (P < 0.01); the difference with the propacetamol group was not significant.
|
Single and repeated IM injections of morphine were significantly superior to placebo in alleviating postoperative pain in this patient population, as indicated by all summary measures of analgesia—TOTPAR (P < 0.0003) and SPID (VAS and VRS; P < 0.0044 and 0.004, respectively)—over 5 and 10 h (Table 2). The study was thus a valid analgesic assay. Similarly, single and repeated infusions of propacetamol provided analgesia that was significantly superior to placebo throughout the 5- and 10-h periods. No significant differences in the TOTPAR and SPID (VAS and VRS) values were observed between propacetamol and morphine after the first administration (2 g versus 10 mg) or after both administrations (2 g + 1 g versus 10 mg + 5 mg). The number of patients requiring rescue medication was significantly larger in the placebo group than in the morphine group (P < 0.0001 after the first 5-h period and during the 10-h period) and in the propacetamol group (P < 0.0009 and P < 0.0023 for the two periods, respectively). The difference in the numbers of patients requiring rescue medication in the morphine and propacetamol groups was not statistically significant (P = 0.731).
|
The average PR and PID (VAS and VRS) curves over the 10-h period were similar (Figs. 1 and 2). In the active treatment groups, the average increases in PR and PID measures were steeper and larger than in the placebo group. After 60 min, the placebo response declined, whereas analgesia in the active treatment groups reached a plateau. From 1 h after administration onward, all hourly PR and PID measures in both active treatment groups became, and remained, significantly superior to placebo up to the 10th hour. The response to propacetamol 2 g was slightly faster and greater than the response to morphine during the early postinjection period: the PID (VAS and VRS) and PR scores became significantly superior to placebo 30 min after infusion. For morphine, this response was not achieved before 30–60 min. The second administration of the drugs, at half their initial doses, produced a significant reinforcement of the analgesic activity, with an additive response, in both active treatment groups. There was no significant difference between the two active treatments over the 10-h period. Overall, the PR scores in the propacetamol group were better than those in the morphine group; the reverse was consistently observed for PID on both of the scales used. Peak PR was significantly higher in the two active treatment groups than in the placebo group, with no significant differences between the two active treatments (Table 3). The peak PID (VAS and VRS) was significantly weaker in patients in the placebo group compared with those in the active treatment groups; there was no difference between propacetamol and morphine. The small differences observed in the global rating for satisfaction with the treatment, obtained when patients completed the 10-h period, were not statistically significant (Table 2).
|
|
|
The three treatment groups had similar baseline heart rates, blood pressures, and respiratory rates. Minor changes in the three groups after drug administration were neither statistically significant nor clinically relevant. Transcutaneous oxygen saturation values and changes in these over time after drug administration were similar in all three groups. No serious adverse events were reported. The number of patients who experienced at least one adverse event and the total number of adverse events (Table 4) were significantly larger in the morphine treatment group (P < 0.027). The most common adverse event likely to be related to propacetamol was pain at the infusion site or along the vein used for infusion. The most common adverse events likely to be related to morphine were somnolence and nausea or vomiting. These events were mild in intensity and resolved spontaneously.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The main objective of this study was to gauge the analgesic efficacy of propacetamol against that of standard doses of morphine and to assess its analgesic profile after single and repeated administrations relative to placebo. Postoperative pain after surgical removal of bone-impacted third molars was selected as a model for several reasons. After the initial work by Cooper and Beaver (10) and Seymour et al. (11), this pain model has been widely used by investigators and regulators (e.g., the Food and Drug Administration) as a tool to assess and compare the analgesic effects of different drugs. The model is robust and reliable; it has sufficient sensitivity to consistently distinguish between the analgesic effects of different drugs or between different doses of the same drug (12). Short-term repeated-dose studies have also been conducted successfully with this model (13,14). Morphine is the archetypal analgesic and is the standard injectable opioid of reference for the management of moderate to severe pain. Dental pain appears to be preferentially sensitive to NSAIDs, and reliance on NSAIDs has been recommended as preferable in the management of dental pain (15–17). Few studies have used parenteral morphine as a comparator in this model: morphine 6 mg IV, in combination with fluoxetine, was reported to produce a modest and short analgesic effect (18). In addition, IM injection of morphine was the routine practice of PR in Belgium at the time this study was performed. Unfortunately, this practice still has a major effect all over Europe, as was revealed in recent publications (19,20).
Norholt et al. (21) compared several doses of IM bromfenac with two doses of IM morphine (10 and 20 mg). A clear dose-effect relationship was demonstrated for morphine: after 10 mg, many of the patients achieved complete relief with a mean duration of analgesia of 2.5 hours, whereas the 20-mg dose was more effective, but with a worse safety profile.
Propacetamol and morphine have similar pharmacokinetics and a similar recommended dosing interval of approximately four to six hours, so that the design of the repeated-dose administration and the overall comparison of effects are straightforward. Official instructions for the use of propacetamol in Belgium at the time of the study recommended a dose of 1 g after an initial 2-g loading dose. For the repeated-dose regimen, the dose of morphine was reduced accordingly to 5 mg, to maintain parallelism and to incorporate an internal dose-effect control into the study design, which also allowed the testing of the study assay’s up-side sensitivity. However, as the baseline PI and PR before the second administration were not necessarily comparable between the treatment groups, no attempt was made to analyze the analgesic effect of the second administration separately.
This study demonstrated the analgesic efficacy of a single dose of propacetamol 2 g IV or morphine 10 mg IM in controlling acute postoperative pain after dental surgery. The patient population was able to distinguish unambiguously between the analgesic drugs and the placebo: all primary and most secondary efficacy variables indicated that propacetamol and morphine were significantly superior to placebo during the first 5 hours after the initial administration. The results of the study also established that a regimen of two IV administrations of propacetamol 2 g followed by 1 g 5 hours later provided sustained analgesic efficacy that was significantly superior to placebo over the 10-hour period after the initial administration and was comparable to that of morphine 10 mg IM followed by 5 mg 5 hours later, by using the standard methods of assessing analgesic efficacy after single-dose administration.
The lack of significant differences between the analgesic effects of propacetamol and morphine could be real or could be related to the methodology of the study: the study may not have had adequate power to identify real differences between propacetamol and morphine in this model, or it might have lacked the appropriate assay up-side sensitivity, related to the moderate level of pain. However, the study was powered to distinguish hourly average differences over a 10-hour period that were smaller than those usually regarded as clinically significant (10 mm for PI [VAS] and 0.5 for PR and PID [VRS], that is, for 80% power in this study, 0.35 for PR [VSR], 8 mm for PID [VAS], and 0.3 for PID [VRS]). The mean actual differences between propacetamol and morphine observed in our study remained less than these values. Also, the additive response achieved by the second administration of the study drugs at half-dose provides evidence that the study up-side sensitivity was adequate. In addition, the percentage theoretical maximum TOTPAR (%TMT) was calculated according to Cooper and Beaver’s procedure (22): the TOTPAR5h for propacetamol reached 64.3% of TMT. The corresponding figures were 56.7% for morphine and 36.5% for placebo. Although the %TMT response of placebo is somewhat high in this study compared with the data reported by Cooper and Beaver (22), it leaves a sufficient upper margin above the propacetamol %TMT response for a more powerful drug to achieve a larger %TMT. Moreover, the difference of 25%–30% of TMT between placebo and morphine 10 mg observed in this study is similar to the difference reported by Norholt et al. (21) in the same pain model.
Postoperative pain after impacted third molar surgery is a sensitive and reliable pain model for assessing analgesics but, admittedly, is not a standard therapeutic indication for the use of parenteral morphine. Therefore, the lack of differences between morphine and propacetamol in this study must be interpreted with some caution. It should be taken as an indication that single and repeated doses of propacetamol can be used effectively as an alternative to morphine for the management of postoperative pain after mild to moderately painful surgery, with the added benefit of better tolerability. Similar conclusions were also drawn by others (23). After more painful surgery, propacetamol, an injectable form of paracetamol, may be a valuable adjunct to opioids in the management of postoperative pain.
|
Acknowledgments |
|---|
Supported by a grant from Laboratories Upsa/Bristol-Myers Squibb.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Prescott LF. Paracetamol (acetaminophen): a critical bibliographic review. Washington, DC: Taylor and Francis, 1996.
- Rawal N, Berggren L. Organisation of acute pain services: a low-cost model. Pain 1994; 57: 117–23.[Web of Science][Medline]
- Breivik H, Hogstrom H, Niemi G, et al. Safe and effective postoperative pain relief: introduction and continuous quality-improvement of comprehensive postoperative pain management programs. Baillieres Clin Anaesthesiol 1995; 9: 423–60.[Web of Science]
- Schug SA, Sidebotham DA, McGuinnety M, et al. Acetaminophen as an adjunct to morphine by patient-controlled analgesia in the management of acute postoperative pain. Anesth Analg 1998; 87: 368–72.
[Abstract/Free Full Text] - Depré M, Van Hecken A, Verbesselt H, et al. Tolerance and pharmacokinetics of propacetamol, a paracetamol formulation for intravenous use. Fundam Clin Pharmacol 1992; 6: 259–62.[Web of Science][Medline]
- Jarde O, Boccard E. Parenteral versus oral route increases paracetamol efficacy. Clin Drug Invest 1997; 6: 474–81.
- Delbos A, Boccard E. The morphine-sparing effect of propacetamol in orthopedic postoperative pain. J Pain Symptom Manage 1995; 10: 279–86.[Web of Science][Medline]
- Peduto VA, Ballabio M, Stefanini S. Efficacy of propacetamol in the treatment of postoperative pain: morphine-sparing effect in orthopedic surgery (Italian Collaborative Group on Propacetamol). Acta Anaesthesiol Scand 1998; 42: 293–8.[Web of Science][Medline]
- Hernandez-Palazon J, Tortosa JA, Martinez-Lage J, Perez-Flores D. Intravenous administration of propacetamol reduces morphine consumption after spinal fusion surgery. Anesth Analg 2001; 92: 1473–6.
[Abstract/Free Full Text] - Cooper SA, Beaver WT. A model to evaluate mild analgesics in oral surgery outpatients. Clin Pharmacol Ther 1976; 20: 241–50.[Web of Science][Medline]
- Seymour A, Hawkesford JE, Weldon M, Brewster D. An evaluation of different ibuprofen preparations in the control of postoperative pain after third molar surgery. Br J Clin Pharmacol 1980; 31: 83–7.
- Forbes JA. Oral surgery. In: Max ME, Portenoy RK, Laska EM, eds. Advances in pain research and therapy. Vol 18: The design of analgesic clinical trials. New York: Raven Press, 1991: 347–74.
- Hersh EV, Cooper S, Betts N, et al. Single dose and multidose analgesic study of ibuprofen and meclofenamate sodium after third molar surgery. Oral Surg 1993; 76: 680–7.
- McQuay HJ, Carroll D, Guest PG, et al. A multiple dose comparison of ibuprofen and dihydrocodeine after third molar surgery. Br J Oral Maxillofac Surg 1993; 31: 95–100.[Web of Science][Medline]
- Dionne RA. New approaches to preventing and treating postoperative pain. J Am Dent Assoc 1992; 123: 26–34.[Web of Science][Medline]
- Haas DA. Current concepts in the use of analgesics in dentistry. Oral Health 1993; 83: 7–11.[Medline]
- Ahmad N, Grad HA, Haas DA, et al. The efficacy of nonopioid analgesics for postoperative dental pain: a meta-analysis. Anesth Prog 1997; 44: 119–26.[Medline]
- Gordon NC, Heller PH, Gear RW, Levine JD. Interactions between fluoxetine and opiate analgesia for postoperative dental pain. Pain 1994; 58: 85–8.[Web of Science][Medline]
- Stamer UM, Mpasios N, Stuber F, Maier C. A survey of acute pain services in Germany and a discussion of international survey data. Reg Anesth Pain Med 2002; 27: 125–31.[Web of Science][Medline]
- Dolin SJ, Cashman JN, Bland JM. Effectiveness of acute postoperative pain management. I. Evidence from published data. Br J Anaesth 2002; 89: 409–23.
[Abstract/Free Full Text] - Norholt SE, Sindet-Petersen S, Larsen U, et al. Pain control after dental surgery: a double-blind, randomised trial of lornoxicam versus morphine. Pain 1996; 67: 335–43.[Web of Science][Medline]
- Cooper SA. Commentary: single-dose analgesic studies—the up side and down side of assay sensitivity. In: Max MB, Portenoy RK, Laska EM, eds. Advances in pain research and therapy. Vol 18: The design of analgesic clinical trials. New York: Raven Press, 1991: 117–24.
- Vuilleumiez PA, Buclih T, Biollaz J. Comparaison du propacetamol et de la morphine dans l’analgésie postopératoire. Schweiz Med Wochenschr 1998; 128: 259–63.[Web of Science][Medline]
This article has been cited by other articles:
|
|
 |
|
  I. Power Recent advances in postoperative pain therapy Br. J. Anaesth., July 1, 2005; 95(1): 43 - 51. [Full Text] [PDF]
|
|
|
|
|
|
P. L. Moller, S. Sindet-Pedersen, C. T. Petersen, G. I. Juhl, A. Dillenschneider, and L. A. Skoglund Onset of acetaminophen analgesia: comparison of oral and intravenous routes after third molar surgery Br. J. Anaesth., May 1, 2005; 94(5): 642 - 648. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
