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* From the Departments of Anesthesiology and Critical Care; and
the Department of Emergency Medicine and Surgery, Groupe hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France.
Address correspondence to: Dr. F. Aubrun, Département d’anesthésie-réanimation chirurgicale, CHU Pitié-Salpêtrière, 47 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. Phone: 33 1 42 16 22 59; Fax: 33 1 42 16 22 69: E-mail: frederic.aubrun{at}psl.ap-hop-paris.fr
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Abstract |
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Methods: Postoperative pain was assessed using the visual analogue scale (VAS; 0 to 100) and the threshold required to administer morphine in the PACU was a score of 30. VAS was measured every 15 min up to two hours after the end of iv morphine titration. Patients were divided into two groups, those who required sc morphine before two hours and those who did not. Data are expressed as mean ± SD or odds ratio (OR; 95% confidence interval).
Results: Four hundred and two patients were analyzed. Mean age was 51 ± 19 yr, initial VAS 69 ± 19, and the dose of iv morphine 11.7 ± 6.6 mg. The number of patients requiring sc morphine within two hours was 84 (21%). These patients had more severe initial postoperative pain (73 ± 20 vs 68 ± 19, P < 0.05), and experienced sedation more frequently during morphine titration (45 vs 25%, P < 0.001). Using a multivariate analysis, occurrence of sedation during titration [OR 2.3 (1.4–3.8), P < 0.001] and an initial pain score 
60 [OR 1.9 (1.0–3.4), P < 0.05] were significantly associated with the need for rescue sc morphine.
Conclusion: Sedation during titration and an initial VAS 60 are characteristics of the patients who require rescue (less than two hours) sc morphine after iv morphine titration.
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Introduction |
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The recommended delay between the end of iv morphine titration and the onset of administration of sc morphine remains debatable. In our previous study,1 we compared the administration of sc morphine at two and four hours after the end of iv titration, and concluded that a delay of two hours provides better pain control than a delay of four hours. However, some patients complain of pain before the two hour period has elapsed. Therefore, in a prospective observational study, we assessed patients’ pain scores during and after iv morphine titration and tried to identify variables associated with the need for rescue (less than two hours) sc morphine.
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Methods |
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All nurses in the PACU and in the wards have been trained to assess pain using unidimensional scales and to perform iv morphine titration (PACU) followed by sc administration (PACU and wards). They use the visual analogue scale (VAS; 0 to 100, hand-held slide-rule type)6 and a special form for data collection. When patients have difficulties in manipulating the VAS, nurses are allowed to use a numerical rating scale (from 0 to 100),7 since these two methods are equivalent.7,8 A strict protocol of iv morphine titration has been implemented in the PACU after a previous study had determined the optimal regimen of morphine titration.1,2 This protocol defined the dose of iv boluses, the interval between boluses, the absence of limitation of the total dose, the VAS threshold required to administer morphine and the criteria to stop titration. After arrival in the PACU and immediately after the patients underwent tracheal extubation and were awake, they were questioned as to the presence of pain (at least every 15 min before the onset of morphine titration) and asked to rate pain intensity (VAS). When the pain score was greater than 30, iv morphine was titrated every five minutes in 3-mg increments (2 mg in patients weighing 
60 kg) and pain was assessed every five minutes until pain relief, defined as a VAS score of 30 or less. When the patient was asleep, no attempt at arousal was made. In this case the patient was considered as having effective pain relief and was assigned a VAS score of 0. When pain was too severe to obtain a VAS score (patient refusal), it was scored as 100. Clinical monitoring included respiratory rate measurements, oxygen saturation measured by pulse oximetry, sedation according to the Ramsay score,9 arterial blood pressure, and heart rate. All patients received oxygen supplementation. Morphine titration was stopped if the patient had a respiratory rate lower than 12 breaths·min–1, had an oxygen saturation measured by pulse oximetry lower than 95%, and/or experienced a serious adverse event related to morphine administration (allergy with cutaneous rash and/or hypotension, vomiting, severe pruritus). In case of severe ventilatory depression (respiratory rate < 10 breaths·min–1), naloxone (iv boluses of 0.04 mg) was administered until the respiratory rate was greater than 12 min and this was defined as a severe morphine-related adverse effect. Sedation was defined as a Ramsay score9 of more than 2 and the percentage of sedated patients during morphine titration was also recorded. A strict protocol of sc administration of morphine was also implemented after iv titration. Morphine was administered every four hours and the dose was adjusted according to the VAS and patient’s weight. The first administration of sc morphine was planned to occur two hours after the end of iv morphine titration, as previously reported.1–3,10 However, during this study, the VAS score was systematically measured every 15 min up to two hours after iv morphine titration. Therefore, the requirement for additional sc morphine during this two-hour period was also recorded. Patients were divided into two groups, those who required additional sc morphine before the two hour delay and those who did not.
During the data collection period, consecutive patients who fulfilled the following criteria were included: 1) VAS score > 30; 2) understanding of the unidimensional methods. Thus patients with minor pain (defined as a VAS score 30), with delirium or dementia, or who were non-French speaking were not included in the study. The criterion for exclusion was interruption of morphine titration because of the occurrence of severe morphine adverse effects. Sedation was not considered a severe morphine adverse effect, as previously reported.1,2 Patients who received other analgesics (or regional anesthesia) as a rescue procedure because of lack of pain relief with morphine were also excluded. The decision to leave the PACU was taken by the anesthesiologist after the nurse had checked that the patient fulfilled the Aldrete criteria,11 and did not suffer from emesis, severe pain or major postoperative bleeding.
Statistical analysis
The main end-point of the study was the determination of variables significantly associated with the need for rescue morphine using multivariable analysis. In a preliminary study (n = 100 patients), we observed that 19% of patients required rescue morphine. To avoid overfit of the regression model, we decided to include 400 patients, enabling us to enter up to eight variables with at least ten patients per cell and a ratio of variables to outcome events greater than 10.
Data are expressed as means ± SD or medians and their 95% confidence interval (CI) for non-Gaussian variables (time delay and duration). The Student t test was used to compare two means and the Mann-Whitney test to compare two medians. Fisher’s exact method was used for categorical variables. For multivariate analysis, a forward step-by-step logistic regression was used and odds ratios (OR) with 95% CI were calculated. All comparisons were two-tailed and a P value of less than 0.05 was required to rule out the null hypothesis. Statistical analysis was performed using NCSS 6.0 software (Statistical Solutions Ltd., Cork, Ireland).
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Results |
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During the first two hours after iv morphine titration, the cumulative number of patients requiring rescue sc morphine increased progressively up to 84 (21%; Figure 1
). The comparison between patients who required additional sc morphine before the two-hour delay, and those who did not is shown in the Table. Evolution of the VAS during the postoperative period in these two groups is shown in Figure 2. Using univariate analysis, patients requiring rescue sc morphine received a greater perioperative dose of sufentanil, had more severe postoperative pain as shown by their higher initial VAS, and experienced more frequent sedation during iv morphine titration (Table). There were no significant differences in heart rate between the two groups from 15 min (74 ± 16 vs 73 ± 14 beats·min–1, NS) to 120 min (76 ± 15 vs 75 ± 14 beats·min–1, NS). Respiratory rate was higher in patients who required sc morphine at 15 min (16 ± 3 vs 15 ± 3 breaths·min–1, P < 0.01) and 30 min (16 ± 3 vs 15 ± 3 breaths·min–1, P < 0.01) but not after and up to 120 min (16 ± 4 vs 16 ± 3 breaths·min–1, NS). There were no significant differences between the two groups regarding the expected postoperative pain (minor, moderate, major). The postoperative temperature and the delay to morphine titration had no influence on the need for rescue sc analgesia. Using a multivariate analysis, only an initial VAS score 60 [OR = 1.9 (95% CI: 1.0–3.4), P = 0.049] and the occurrence of sedation during titration [OR = 2.3 (95% CI: 1.4–3.8), P = 0.001] were significantly associated with the need for rescue sc morphine. There was a significant difference between the two groups regarding the combination of a VAS 60 and sedation during titration [34 patients (40%) in the rescue sc group vs 63 patients (20%), P < 0.001].
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Discussion |
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The ideal analgesic regimen after iv morphine titration in the PACU remains a matter for debate. PCA has been advocated as the method of choice. However, a sc regimen of morphine has also been shown to be effective, provided that the dose of sc morphine is adapted to the level of pain according to a strict protocol.3,10 Moreover, some recent studies have suggested that sc morphine administration may be considered as efficient as PCA.4,5 Apart from this controversy, the appropriate sc morphine regimen following iv morphine titration has been poorly investigated, and little information is available concerning the delay between the end of iv titration and the first administration of sc morphine. The plasma half-life of iv morphine is about 1.5 hr while the duration of useful analgesia is three to five hours.12 In contrast, Upton et al.13 observed that the duration of iv morphine analgesia (defined as the length of time the concentration is above 80% of its maximum level) is approximately 96 min. In a previous study, we used a four-hour interval between the end of titration and the onset of sc morphine, but we observed that the mean VAS was too high and the percentage of pain relief too low at the end of the PACU stay.1 We therefore decided to reduce this interval to two hours, producing a marked improvement in the number of patients with pain relief without any significant increase in morphine-related adverse effects.1 Nevertheless, despite the administration of sc morphine at two hours, we observed that pain relief was still not obtained in 27% of patients at the end of the PACU period.1 In the present study, we confirmed that 21% of our patients required additional sc morphine during the two-hour period after iv titration.
We identified two factors that predict the need for rescue (less than two hours) sc morphine: 1) the occurrence of sedation during iv morphine titration and 2) an initial VAS 60. In accordance with our titration protocol, patients received an unlimited number of boluses of iv morphine until pain relief (VAS 30) was obtained. However, iv morphine titration was stopped when severe morphine-related adverse effects or sedation (Ramsay score > 2) occurred.1,2,14 In a previous study, up to 62% of patients receiving iv morphine titration experienced sedation.1 Sedation was considered a sign of pain relief but also an early manifestation of morphine overdose leading to interruption of morphine administration. This position was justified by the absence of a significant increase in morphine-related adverse effects.1 Nevertheless, we recently evaluated sedated patients during iv morphine titration15 and observed that 25% of these sedated patients still bear a high level of pain. We also observed that the time course of sedation and analgesia differed, sedation occurring before analgesia. The conclusion of that study was that morphine-induced sedation should not always be considered an indicator of appropriate pain relief during iv morphine titration.15 In the present study, our results are in agreement with this assumption since sedation was a significant risk factor for the requirement of additional sc morphine before the two-hour delay period. Do these results suggest that morphine iv titration should be continued in sedated patients? We believe that it should not because of a potential increase in the incidence of severe morphine-related adverse effects if the significance of sedation, which should be considered as an early warning of potential morphine overdosage, is not taken into account. Our present and previous15 studies only indicate that sedation may not always mean pain relief and that 25% of sedated patients may thus require rescue sc morphine administration or another analgesic regimen [non-steroidal anti-inflammatory drugs (NSAIDs), NMDA antagonists, local anesthetic blocks, etc.]. Strategies to decrease opioid sedation include techniques to decrease opioid requirements while keeping the same level of analgesia. Multimodal and prophylactic analgesia, using synergistic analgesic regimens with morphine (NSAIDs, ketamine, regional analgesia with local anesthetics) may reduce postoperative morphine consumption and morphine sedation.16 Recently, Cepeda et al. assessed the attractive concept of using an opioid antagonist to decrease opioid side effects.17 The addition of ultra low dose naloxone (0.6 µg·mL–1) to morphine PCA (1 mg·mL–1) was compared to morphine PCA (1 mg·mL–1) in the postoperative period during 24 hr. The combination of ultra low dose naloxone to morphine did not decrease the incidence of sedation.17 Further studies are required to determine the most appropriate analgesic regimen in these sedated, but not pain-free, patients.
We also observed that an initial VAS 60 was a significant predictor for the requirement of rescue sc morphine. We have assessed the relationship between initial VAS and morphine requirements during iv titration in the PACU.14 Although there was a weak individual correlation between initial VAS and morphine consumption, we observed a significant dose-response relationship when patients were grouped according to range of VAS (from 30–41 to 91–100). The value of 60 corresponded to the mid-point of this dose-response curve which was associated with a morphine requirement 0.13 mg·kg–1.14 Our present results indicate that patients with more severe pain and requiring a greater dose of morphine to achieve pain relief required rescue sc morphine more frequently. This suggests that the concentration of morphine at the effect site should be higher and that the length of time the concentration is above this threshold is reduced in these patients. Although the dose of morphine administered during iv titration was higher in patients who required rescue sc morphine, this difference did not reach statistical significance. Nevertheless, considering the extraordinarily large individual variation in morphine requirements,14 we cannot exclude the hypothesis that the sample size of our study did not provide us sufficient power to detect a significant difference. Further studies of blood morphine concentrations are mandatory to confirm this hypothesis.
Some remarks must address the limitations of our study. First, we excluded patients who experienced morphine-related adverse effects and those who were unable to understand VAS. We have recently observed that our nurses had to use a simple verbal rating scale in 10% and a subjective behavioural scale in 7% of our patients.18 The analgesic regimen after such morphine titration remains to be determined. Second, the VAS assumes that pain is a unidimensional experience. Although intensity is a very important dimension of pain, pain refers to a variety of sensations that cannot be categorized under a single linguistic label.19
In conclusion, we identified two risk factors for requiring rescue (less than two hours) sc morphine after iv morphine titration: an initial VAS 60 and the occurrence of sedation during iv titration. These findings should lead to a more rational management of postoperative pain.
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Acknowledgments |
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Footnotes |
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2 Aubrun F, Monsel S, Langeron O, Coriat P, Riou B. Postoperative titration of intravenous morphine in the elderly patient. Anesthesiology 2002; 96: 17–23.[Medline]
3 Aubrun F, Kalfon F, Mottet P, et al. Adjunctive analgesia with intravenous propacetamol does not reduce morphine-related adverse effects. Br J Anaesth 2003; 90: 314–9.
4 Choinière M, Rittenhouse BE, Perreault S, et al. Efficacy and costs of patient-controlled analgesia versus regularly administered intramuscular opioid therapy. Anesthesiology 1998; 89: 1377–88.[Medline]
5 Keïta H, Geachan N, Dahmani S, et al. Comparison between patient-controlled analgesia and subcutaneous morphine in elderly patients after total hip replacement. Br J Anaesth 2003; 90: 53–7.
6 Huskisson EC. Measurement of pain. Lancet 1974; 9: 1127–31.
7 Jensen MP, Karoly P, Braver S. The measurement of clinical pain intensity: a comparison of six methods. Pain 1986; 27: 117–26.[Medline]
8 DeLoach LJ, Higgins MS, Caplan AB, Stiff JL. The visual analog scale in the immediate postoperative period: intrasubject variability and correlation with a numeric scale. Anesth Analg 1998; 86: 102–6.[Abstract]
9 Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974; 2: 656–9.
10 Aubrun F, Bunge D, Langeron O, Saillant G, Coriat P, Riou B. Postoperative morphine consumption in the elderly patient. Anesthesiology 2003; 99: 160–5.[Medline]
11 Aldrete JA, Kroulik D. A postanesthetic recovery score. Anesth Analg 1970; 49: 924–34.
12 Twycross RG. Narcotics. In: Wall PD, Melzack R (Eds). Texbook of Pain. New York: Churchill Livingstone; 1984: 514–25.
13 Upton RN, Semple TJ, Macintyre PE. Pharmacokinetic optimisation of opioid treatment in acute pain therapy. Clin Pharmacokinet 1997; 33: 225–44.[Medline]
14 Aubrun F, Langeron O, Quesnel C, Coriat P, Riou B. Relationships between measurement of pain using visual analog score and morphine requirements during postoperative intravenous morphine titration. Anesthesiology 2003; 98: 1415–21.[Medline]
15 Paqueron X, Lumbroso A, Mergoni P, et al. Is morphine-induced sedation synonymous with analgesia during intravenous morphine titration? Br J Anaesth 2002; 89: 697–701.
16 Hanna MH, Elliott KM, Stuart-Taylor ME, Roberts DR, Buggy D, Arthurs GJ. Comparative study of analgesic efficacy and morphine-sparing effect of intramuscular dexketoprofen trometamol with ketoprofen or placebo after major orthopaedic surgery. Br J Clin Pharmacol 2003; 55: 126–33.[Medline]
17 Cepeda MS, Alvarez H, Morales O, Carr DB. Addition of ultralow dose naloxone to postoperative morphine PCA: unchanged analgesia and opioid requirement but decreased incidence of opioid side effects. Pain 2004; 107: 41–6.[Medline]
18 Aubrun F, Paqueron X, Langeron O, Coriat P, Riou B. What pain scales do nurses use in the postanaesthesia care unit? Eur J Anaesthesiol 2003; 20: 745–9.[Medline]
19 Katz J, Melzack R. Measurement of pain. Surg Clin North Am 1999; 79: 231–52.[Medline]
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