Is morphine-induced sedation synonymous with analgesia during intravenous morphine titration?

X. Paqueron*,1, A. Lumbroso1, P. Mergoni1, F. Aubrun1, O. Langeron1, P. Coriat1 and B. Riou1,2

1 Department of Anaesthesiology and Critical Care and 2 Department of Emergency Medicine and Surgery, Centre Hospitalier Universitaire Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Pierre et Marie Curie, Paris, France*Corresponding author: Département d’Anesthésie et de Réanimation, Centre Hospitalier Universitaire Pitié-Salpêtrière, 47 Boulevard de l’Hôpital, F-75651 Paris Cedex 13, France

Accepted for publication: May 25, 2002


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Postoperative morphine titration frequently induces sedation. The assumption is made that patients sleep when their pain is relieved. Some patients complain of persistent pain when they awake. We studied the time-course of sedation and analgesia to understand the determinants of patients’ sleep during morphine titration.

Methods. Seventy-three patients requiring morphine titration in a post-anaesthetic care unit after major surgery, were studied. Fifty-two patients slept (Sleep group) and 21 did not (Awake group). When a patient slept during titration, morphine was discontinued. Visual analogue pain scale (VAS), Ramsay score (RS), and the bispectral index (BIS) were recorded at the beginning of titration (STonset), at sleep onset (STsleep), then 5, 10, 20, and 30 min afterwards (ST4).

Results. In the Sleep group, mean (SD) RS increased from 1.7 (0.4) to 2.4 (0.6) (P<0.05 vs STonset) and BIS decreased from 95 (5.0) to 89.8 (10.2) between STonset and STsleep (P<0.05), RS remained stable thereafter. Conversely, RS and BIS remained unaltered in the Awake group. The reduction in VAS was comparable between groups (from 78 (17) to 39 (21), and from 64 (16) to 30.4 (11), respectively). Even though mean (SD) VAS was 39 (21) at ST4 in the Sleep group, 13 patients (25%) maintained a VAS above 50 mm.

Conclusion. We observed dissociated effects of morphine on the time-course of sedation and analgesia with sedation occurring first, followed by analgesia. Therefore, morphine-induced sedation should not be considered as an indicator of an appropriate correct level of analgesia during i.v. morphine titration.

Br J Anaesth 2002; 89: 697–701

Keywords: analgesia; analgesics opioid, morphine; monitoring, bispectral index; sedation


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Treatment of postoperative pain in the post-anaesthesia care unit (PACU) mainly relies on morphine titration, as it provides efficient and rapid onset of analgesia.1 Although the optimal dose of morphine is still a matter of debate, the usual recommendations for morphine titration include a short interval between two boluses (5–7 min) and no upper limit for the total administered dose.2 3 Among morphine-induced side-effects, sedation occurs in up to 60% of cases during morphine titration, and represents a common cause of discontinuation of titration for reasons of safety.3 The assumption is usually made that patients sleep when their pain has been relieved. Nevertheless, some patients complain of persistent pain when they awake and morphine titration is frequently resumed. Thus, sedation might not be synonymous with analgesia, and might even prolong the time to efficient pain relief, leading to extended stays in PACU.

Several behavioural scales assess depth of sedation. Among them, the Ramsay score (RS) is a validated and widely used technique.4 Nevertheless, its components are somewhat subjective, and prone to observer bias. The use of this scale is easy, for it does not require any device, but its accuracy in detecting deep sedation is questionable during the early postoperative period. Many patients in PACU are known to keep their eyes closed without being sedated. This corresponds to an RS of 3 in an apparently sleepy patient, leading to morphine discontinuation for safety reasons, independent of the visual analogue score (VAS) for pain.3 Therefore, we attempted to find methods measuring the depth of sedation in a way that avoids the observer interpretation of the RS and of the patient’s behaviour. The bispectral index (BIS) is a parameter derived from the electroencephalogram and has been validated in the assessment of the depth of anaesthesia5 and the depth of sedation in the intensive care unit.6 7 We felt that, as the technique is based on an analysis of electrical cortical activity, it could also provide a useful tool to assess the level of consciousness in awake patients. The BIS could also be useful to assess sedation in PACU, for it provides continuous information in contrast with the discontinuous assessment of behavioural scales.

Therefore, the current study was undertaken to provide a better assessment of the determinants of patient sedation during i.v. morphine titration in PACU, particularly in relation to the time-course of sedation and analgesia. The main goals of the study were to assess prospectively the temporal relationship between morphine titration, analgesia and sedation and to determine whether patients who sleep during i.v. morphine titration are simply sedated or are actually relieved from their pain.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
After institutional review board approval (CCPPRB Pitié-Salpêtrière), 73 patients admitted to the PACU after major orthopaedic or urological surgery under general anaesthesia, and who required i.v. morphine titration were studied. A list of surgical procedures considered as highly painful was established (i.e. spine fusion, total knee arthroplasty, total hip arthroplasty, ligamentoplasty, major shoulder surgery, pelvic surgery, total nephrectomy, and radical abdominal prostatectomy) before the study.

Regional anaesthesia was an exclusion criterion. Anaesthetic and postoperative analgesic procedures were not standardized and were left to the discretion of the attending anaesthetists in charge of the patient, according to local procedures.3 The only constraints placed upon anaesthetists were to use only sufentanil as the intraoperative opioid, and isoflurane as the volatile anaesthetic. Postoperative analgesia consisted mainly of a combination of propacetamol and ketoprofen (when not contraindicated) and morphine.

Local procedure for morphine titration
According to our local procedure,3 morphine titration was initiated when the pain VAS was higher than 30 mm on a 100 mm scale. Patients received oxygen via a facial mask at the rate of 5 litre min–1. Boluses of i.v. morphine were 3 or 2 mg when patient’s weight was above or below 60 kg, respectively. The interval between boluses was 5 min, without an upper dose limit. Morphine titration was discontinued when VAS was inferior to 30 mm, in case of side-effects such as nausea and/or vomiting, respiratory depression (SpO2 <92%, ventilatory frequency rate <10), or occurrence of deep sedation (eyes closed >3 min, RS >2). An RS on a 6-point scale was used (1=anxious and agitated patient; 2=cooperative patient; 3=asleep patient, brisk response to loud voice; 4=asleep patient, sluggish response to loud voice; 5=no response to loud voice; score of 6=no response to pain).

Among the 73 patients included, there was a group of patients who slept (Sleep group: eyes closed >3 min, RS >2) in whom i.v. morphine was discontinued, and a group of patients who did not sleep (Awake group). Morphine was not discontinued in the Awake group. The Awake group was designed to serve as a control group to assess the quality of BIS monitoring and to compare BIS and electromyographic (EMG) changes among patients who slept and those who stayed awake.

All patients were observed using a BIS monitor (A-2000 monitor; Aspect MS®, Leiden, The Netherlands). When a patient slept while receiving morphine, its administration was discontinued. The following variables were recorded: BIS value, RS, VAS, arterial oxygen saturation (SpO2), ventilatory frequency (VF), and the EMG recorded on the BIS monitor. We proceeded in the following order. First, the BIS and EMG values were recorded when the patient was asleep. Then, the patient was awoken and we assessed the RS. Finally, the VAS for pain was scored. After this, the patient usually fell asleep again. In the Sleep group, these variables were assessed just before the onset of titration (STonset), when patients started to sleep (STsleep), then 5 (ST1), 10 (ST2), 20 (ST3), and 30 min (ST4) after the onset of sleep. In the Awake group, the same variables were recorded just before the onset of titration (ATonset), then at 5 (AT0), 10 (AT1), 20 (AT2), 30 min (AT3), and at the end of titration (AT4).

Duration of surgery, total intraoperative sufentanil dose, administration of propacetamol and of ketoprofen, delay between tracheal extubation and onset of morphine titration, total dose of morphine administered, body temperature at onset of morphine titration and time of sleep after morphine titration were also measured.

Data are expressed as mean (SD), or as median and its 95% confidence interval when variables were not normally distributed (duration of surgery, delay between extubation, and onset of morphine titration). Continuous variables (age, weight, cumulative doses of sufentanil, total dose of morphine administered) were analysed using the Student’s t-test. Comparison of two medians was performed using the Mann–Whitney test. Changes in VAS, BIS, SpO2, ventilatory frequency, and EMG were analysed using an analysis of variance for repeated measures and a Bonferroni correction. The RS was analysed using Kruskall–Wallis test. Comparison of two numbers was performed using the chi-squared test. All P values were two-tailed and a P value of <0.05 was considered significant. Analyses were performed on a computer using NCSS 6.0 software (Statistical Solutions Ltd., Cork, Ireland).


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Seventy-three consecutive patients admitted to the PACU after major orthopaedic or urological surgical procedures and who received an i.v. morphine titration were studied. Among these patients, 52 slept (Sleep group) during morphine titration and 21 did not (Awake group). Patients’ characteristics, surgical data, onset time of morphine titration, and total administered dose of morphine, are shown in Table 1. There were significantly more men and the surgical duration was shorter in the Awake group compared with the Sleep group. In the Sleep group, the mean time to the sleep onset of initiation of morphine titration was 22 (10) min.


View this table:
[in this window]
[in a new window]
 
Table 1 Patients characteristics. Values are mean (SD or range) {and per cent} or median and [95% confidence interval]. *P<0.05 vs Sleep group
 
Values of RS were comparable with Tonset in both groups. The changes in RS were statistically different in the Sleep group compared with the Awake group. The RS increased in the Sleep group from 1.8 (0.4) at STonset to 3.2 (0.6) at ST2 then remained stable afterwards until ST4. Conversely, the RS remained unaltered throughout the whole study period (1.9 (0.3) at ATonset, 2.0 (0.4) at AT2, and 2.0 (0.4) at AT4) in the Awake group (P<0.05 vs Sleep group). Similarly, BIS was comparable at Tonset in both groups. Then, BIS dropped in the Sleep group (Fig. 1), whereas it remained stable throughout the study period in the Awake group (P<0.05 vs Sleep group).



View larger version (10K):
[in this window]
[in a new window]
 
Fig 1 Evolution of the BIS and of VAS in the Sleep and Awake groups. Values are mean (SD). In the Sleep group, BIS and VAS were assessed just before the onset of titration (STonset), when patients started to sleep (STsleep), then 5 (ST1), 10 (ST2), 20 (ST3), and 30 min (ST4) after the onset of sleep. In the Awake group, BIS and VAS were recorded just before the onset of titration (ATonset), then at 5 (AT0), 10 (AT1), 20 (AT2), 30 min (AT3), and at the end of titration (AT4). (A) BIS and VAS evolution in the Awake group: BIS value remained stable over the entire study period and VAS decreased regularly over time. (B) BIS and VAS evolution in the Sleep group: BIS decreased from 95 (5) at STonset to 90 (10) at STsleep then remained on a plateau until ST4 (P<0.05 vs Sleep group). The time-course of VAS was comparable with the evolution of VAS observed in the Awake group.

 
The time-course of VAS for pain was comparable in the Sleep and Awake groups (Fig. 1). Nevertheless, at STsleep, VAS was still 47 (19) mm in the Sleep group. Even though mean VAS at ST4 was 39 (21) in the Sleep group, 13 patients in this group (25%) still had a VAS above 50 mm, 14 patients (27%) a VAS of 30–49 mm and 25 patients only (48%) had a VAS below 30 mm (Fig. 2A). Individual analysis revealed that the patients who maintained a VAS above 50 mm after Tonset were the same at ST2, ST3, and ST4. However, the same analysis by sub-groups of VAS (below 30 mm, between 30 and 49, and above 50 mm) performed at AT2, AT3, and AT4 in the Awake group showed a constant and regular decrease of VAS over time (Fig. 2B).



View larger version (12K):
[in this window]
[in a new window]
 
Fig 2 Division into subgroups, according to VAS. Values are percentages. Patients in the Sleep group were separated into three subgroups according to their VAS, 10 (ST2), 20 (ST3) and 30 (ST4) min after onset of sleep. Similarly, the same analysis by subgroup was performed among the patients of the Awake group 20 (AT2) and 30 (AT3) min after the onset of morphine titration as well as at the end of titration (AT4). In the Sleep group (A), analgesia progressively improved over time in 25% of patients. Then, at ST4, VAS was below 30 mm in 48% of patients. Conversely, 25% of patients in Sleep group had a persistent high level of VAS, not decreasing over time. In the Awake group (B), a constant decrease in the percentage of patients with a VAS above 30 mm was observed over time. In the Awake group at AT4, VAS was below 30 mm in 95% of the patients.

 
The VF did not change significantly over the study period (15 (4) vs 14 (4), P ns) and no significant intergroup difference occurred. Similarly, the SpO2 did not change significantly, nor was SpO2 significantly different between the Sleep and Awake groups (99 (2) vs 99 (2), P ns, respectively). The EMG significantly decreased over time between STonset/ATonset and ST4/AT4 in both groups (from 56 (13) to 43 (10) in Sleep group, P<0.05 ST4 vs STonset; from 51 (8) to 46 (7), P<0.05 AT4 vs ATonset), but no significant intergroup difference was found.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The current study suggests that sedation during morphine titration occurs before patients have been completely relieved from their pain (as mean VAS at sleep onset was ~50 mm), and that sleep encountered during morphine titration is mainly related to the sedative properties of morphine. The second important finding of this study is that among patients in whom morphine titration is discontinued because of sedation, 25% still bear a high level of pain (VAS >50 mm) whereas only 50% have satisfactory pain relief (VAS <30 mm).

Sedation during i.v. morphine titration occurs in up to 60% of patients in PACU.3 This sedation is often arbitrarily attributed to the occurrence of an adequate level of analgesia, for the patient who sleeps does not spontaneously express any pain. Nevertheless, the meaning of this sedation is not obvious, as many causes of sedation, such as an incomplete elimination of general anaesthetics and/or intra-operative opioids, exist in the PACU that might interfere with or potentiate the effects of i.v. morphine titration. In our study, this factor is unlikely to be important for there was a long delay between tracheal extubation and the onset of morphine titration (~1 h in both groups). Nevertheless, the duration of surgery in the Sleep group was greater than in the Awake group and a larger dose of sufentanil was given and presumably a larger dose of isoflurane. Therefore, the patients who had a longer anaesthetic might be more likely to fall asleep when given the same dose of morphine as those receiving a shorter anaesthetic. Finally, morphine itself might also induce deep sedation.8 9 Therefore, occurrence of sedation during morphine titration does not necessarily imply that patients are relieved from their pain. In fact, the current study showed that at sleep onset during morphine titration, the VAS remained high (~50 mm).

The current study also identified three subgroups of patient among those who slept during titration: patients completely (VAS <30 mm), imperfectly (VAS between 30 and 50 mm) or not (VAS >50 mm) relieved at all from their pain, 30 min after morphine discontinuation. This last subgroup accounted for 25% of the patients who slept. An individual analysis (data not shown) showed that these were the same patients who had a VAS above 50 mm, 10, 20, and 30 min after the onset of sleep. Therefore, when a patient falls asleep while receiving morphine titration, failure of analgesia might probably be predicted early, when the VAS remains elevated 10 min after onset of sleep.

According to our local procedure, the PACU nurses discontinued i.v. morphine titration when the RS became greater than 2.3 This cut-off value was arbitrarily chosen for safety reasons, in order to avoid very deep sedation and respiratory depression.3 Nevertheless, neither respiratory depression as measured by SpO2 and ventilatory frequency, nor deep sedation (RS >4) was ever observed during the study period. Furthermore, in a previous study on 1200 patients, only one was given naloxone to reverse respiratory depression.3 It is possible that a cut-off value of the RS at three instead of two might allow patients to receive a little more morphine providing a better pain relief with no or little increment of respiratory depression. At the present time, however, no study currently supports this hypothesis from a safety point of view.

Interference between electroencephalographic activity and EMG is probably a major pitfall during BIS monitoring and has been reported previously as providing a false elevation of BIS values in anaesthetized patients.10 Also, BIS is usually artificially overestimated by the EMG activity in sedated and ventilated patients in the intensive care unit.7 This overestimation is not predictable and might therefore represent a possible bias in the interpretation of the BIS value in awake patients. As EMG activity is generally elevated in awake patients in PACU, the Awake group was designed as a control group in whom patients remained not sedated during morphine titration. Therefore, we could compare the changes in EMG in both the Sleep and Awake groups and then assess the influence of EMG on the BIS recording in these two groups. We did not find any significant difference in EMG between the groups. The results from the current study confirm that alteration in the EMG activity does not account for the decrease in the BIS observed in the Sleep group. The current study suggests that BIS monitoring might represent an interesting alternative to the RS in the assessment of depth of sedation in the PACU. The main value of the BIS over the RS is that it provides a continuous assessment of the sedation level.

Nevertheless, factors other than EMG activity limit the interpretation of the BIS in the intensive care unit and PACU. Hypothermia,11 shivering, poor signal quality (quality index signal <50%), spontaneous patient movements inducing signal loss, electrical interference from the forced-air warming systems12 or pacemakers13 are possible causes of misinterpretation of the BIS signal. In the current study, temperature was monitored and patients had a mean temperature of 36.2 and 35.8°C in the Sleep and Awake groups, respectively, which is compatible with an accurate recording of the BIS.14 We also considered possible electrical interference, and we particularly avoided the use of any forced-air warming blanket.

In conclusion, the current study provides new insights into the mechanisms of action of morphine during i.v. titration for acute postoperative pain in PACU. First, we showed that when patients sleep during morphine titration, sedation and analgesia have a different time-course, sedation occurring before analgesia. Secondly, only 48% of patients who sleep during morphine titration are relieved from their pain, 27% still express moderate pain (VAS between 30 and 50 mm). The remaining 25% of patients still endure high pain scores (VAS >50 mm) 30 min after the discontinuation of morphine titration. Finally, this study suggests that morphine-induced sedation should not be considered as an indirect indicator of a correct level of analgesia during i.v. morphine titration.


    Acknowledgement
 
We thank Dr David Baker MD, FRCA, of the Department of Anaesthesiology and Critical Care, CHU Necker-Enfants Malades, Paris, France, for reviewing the manuscript.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Edward WT, Breed RJ. The treatment of acute postoperative pain in postanesthesia care unit. Anesthesiol Clin 1990; 8: 235–65[ISI]

2 Owen H, Mather LE, Runciman WB, Carapetis RJ, Upton RN. The lockout interval in patient-controlled analgesia: a rationale basis for choice? Br J Anaesth 1987; 59: 1328–9

3 Aubrun F, Monsel S, Langeron S, Coriat P, Riou B. Postoperative titration of intravenous morphine. Eur J Anaesthesiol 2001; 18: 159–65[ISI][Medline]

4 Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974; 2: 656–9[ISI][Medline]

5 Gan TJ, Glass PS, Windsor A, et al. Bispectral index monitoring allows faster emergence and improved recovery from propofol, alfentanil, and nitrous oxide anesthesia. Anesthesiology 1997; 87: 808–15[ISI][Medline]

6 Simmons LE, Riker RR, Prato BS, Fraser GL. Assessing sedation during intensive care unit mechanical ventilation with the Bispectral Index and the Sedation-Agitation Scale. Crit Care Med 1999; 27: 1499–1504[ISI][Medline]

7 De Deyne C, Struys M, Decruyenaere J, et al. Use of continuous bispectral EEG monitoring to assess depth of sedation in ICU patients. Intensive Care Med 1998; 24: 1294–8[ISI][Medline]

8 Arunasalam K, Davenport HT, Painter S, Jones JG. Ventilatory response to morphine in young and old subjects. Anaesthesia 1983; 38: 529–33[ISI][Medline]

9 Catley DM, Thornton C, Jordan B, et al. Pronounced episodic oxygen desaturation in the postoperative period: its association with ventilatory pattern and analgesic regimen. Anesthesiology 1985; 63: 20–28[ISI][Medline]

10 Bruhn J, Bouillon TW, Shafer SL. Electromyographic activity falsely elevates the bispectral index. Anesthesiology 2000; 92: 1485–7[ISI][Medline]

11 Mychaskiw G, Heath BJ, Eichhorn JH. Falsely elevated bispectral index during deep hypothermic circulatory arrest. Br J Anaesth 2000; 85: 798–800[Abstract/Free Full Text]

12 Guignard B, Chauvin M. Bispectral index increases and decreases are not always signs of inadequate anesthesia. Anesthesiology 2000; 92: 903[ISI][Medline]

13 Gallagher JD. Pacer-induced artifact in the bispectral index during cardiac surgery. Anesthesiology 1999; 90: 636[ISI][Medline]

14 Lopez M, Ozaki M, Sessler DI, Valdes M. Mild core hyperthermia does not alter electroencephalographic responses during epidural-enflurane anesthesia in humans. J Clin Anesth 1993; 5: 425–30[ISI][Medline]