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An audit of the safety and effectiveness of an alfentanil:morphine mixture in the postanaesthesia care unit
Acute Pain (2007) 9, 13—19
An audit of the safety and effectiveness of an alfentanil:morphine mixture in the postanaesthesia care unit Waleed K. Alkhazrajy, Pamela E. Macintyre, Richard N. Upton, Jennifer Ong ∗, Guy L. Ludbrook Discipline of Anaesthesia and Intensive Care, School of Medicine, Royal Adelaide Hospital and University of Adelaide, North Terrace, Adelaide, SA 5000, Australia Received 20 July 2006 ; received in revised form 11 October 2006; accepted 13 October 2006 Available online 17 January 2007 KEYWORDS Alfentanil; Analgesia; Dose to comfort; Morphine; Postoperative pain; Time to comfort
Summary Background: After an initial clinical investigation of the effectiveness of an alfentanil—morphine mixture (AM) for the treatment of postoperative pain in the recovery setting, an audit was conducted to look at the effectiveness, safety and incidence of adverse opioid-related side effects of this mixture compared with morphine (M) alone. Assessment of effectiveness included the time and dose required to achieve patient comfort, the time to discharge from the postanaesthesia care unit (PACU) and pain scores; assessment of safety and side effects included measurement of sedation scores, oxygen saturation and respiratory rate as well as incidence of nausea and vomiting, and pruritus. Methods: A total of 453 patients were recruited: the M group (221 patients) received a standard IV morphine regimen (morphine concentration 1 mg/ml; bolus doses of between 0.5 and 4 ml IV given every 3 min as needed by nursing staff according to the hospital protocol—–see Appendix A); the AM group (232 patients) received a similar IV regimen using the alfentanil:morphine mixture (alfentanil 50 g and morphine 0.75 mg/ml; bolus doses given as for morphine). Results: In the M group, the mean time to comfort was 40.9 ± 34 min whilst in the AM group, it was 32.8 ± 26 min (significant at p = 0.004). The mean (S.D.) volume required to achieve comfort was similar and the mean time to discharge from the PACU was 105.3 ± 75 min for the M group and 88.4 ± 55 min for the AM group (p = 0.5). Neither the sedation scores or pain scores at comfort differed significantly between the groups. The minimum respiratory rates recorded in the PACU were 12 ± 3.2 breaths/min for the M group and 11.9 ± 3.1 breaths/min for patients given
∗ Corresponding author at: Discipline of Anaesthesia and Intensive Care, School of Medicine, University of Adelaide, Frome Road, Adelaide, SA 5005, Australia. Tel.: +61 8 8303 5163; fax: +61 8 8303 3909. E-mail address: [email protected] (J. Ong).
1366-0071/$ — see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.acpain.2006.10.001
14
W.K. Alkhazrajy et al. AM. There was no significant difference between the two groups in patients’ reports of nausea, vomiting or pruritus. Conclusion: Compared with morphine alone, the use of an alfentanil:morphine mixture can reduce the time taken to achieve patient comfort without increasing the risk of opioid-related adverse effects. © 2006 Elsevier B.V. All rights reserved.
1. Introduction Providing rapid but safe management of postoperative pain is a vital goal in the immediate postsurgical period. However, despite the best efforts of anaesthesiologists and nurses, many patients still experience moderate to severe pain in the postanaesthesia care unit (PACU). Even with an increased focus on pain management programmes, including the development of new standards and guidelines, inadequate pain management is common and postoperative pain continues to be under-treated [1,2]. Opioids remain the cornerstone of acute pain treatment in this setting, in spite of adverse effects such as respiratory depression, nausea and vomiting. Yet an opioid with the desirable pharmacokinetic characteristics of rapid onset and prolonged duration of effect is not clinically available. Intravenous protocols, using repeated bolus doses of opioids prescribed by doctors and titrated by nursing staff, are a common technique for the management of pain in the PACU (see example in Appendix A). For safety, when bolus doses of opioids are given at intervals during IV titration regimens, it has been suggested that the interval between these doses should allow for the peak effect of each dose to be seen before another is given [3]. Although this reduces the risk of excess drug accumulation and excessive sedation, it can result in a delay before adequate analgesia is achieved, especially if drugs such as morphine are used. However, if an opioid with a faster onset of action is given, such as alfentanil, the duration of analgesia may be too short, as offset of action is also more rapid. Morphine enters the central nervous system (CNS) slowly [4] and has a relatively slow onset to peak effect, even after IV bolus dose administration. Alfentanil has a much faster onset of action due to its greater lipid solubility and high unionized fraction at physiological pH [5]. A mixture of opioids, such as a mixture of alfentanil and morphine, may allow a more rapid onset of action, providing more rapid relief of postoperative pain compared with morphine alone, whilst still maintaining a reasonable duration of effect.
In our earlier study, pharmacokinetic modelling of estimated CNS opioid concentrations was used to devise the optimal mixture of morphine and alfentanil in the treatment of postoperative pain [6]. Our study of 58 patients in the PACU who were randomly allocated to receive analgesia using IV titration regimens of either morphine (M) or alfentanil and morphine (AM) revealed that an IV alfentanil—morphine mixture of 55 g:0.75 mg/ml provided effective pain relief that was more rapid in onset compared with morphine alone. This is thought to be the result of combining the rapid CNS penetration of alfentanil with the prolonged duration of effect of morphine. In order to confirm the finding of improved analgesia and to examine the safety of AM mixture versus morphine protocols, both regimens were made freely available to anaesthesiologists in the operating suite. We have now conducted a larger and more detailed audit of the effectiveness and safety of IV titration regimens using M and AM in a large group of patients in the PACU of a large teaching hospital.
2. Patients and methods Approval for the audit was obtained from the Human Research Ethics Committee of the Royal Adelaide Hospital. Patients considered by their anaesthesiologist as likely to require postoperative IV opioid analgesia in the PACU were identified preoperatively and enrolled in the audit. Those reporting any prior adverse reactions to morphine or alfentanil, or patients with a poor understanding of English, were excluded.
2.1. Dose selection and recruitment of patients Power analysis, using the incidence of adverse respiratory effects reported in the PACU (personal communication—–audit data), suggested that 200 patients would be needed in each group. This was performed using the known incidence of respiratory depression and sedation in patients
Alfenanil:morphine mixture in the PACU
15
receiving the morphine protocol, providing approximately 80% power to detect a 30% difference with a standard significance level of p < 0.05. The concentration of M used was 1 mg/ml; the concentration of AM was 50 g alfentanil plus 0.75 mg morphine per ml. Both solutions were colourless and appeared identical in the syringes. Earlier pharmacokinetic—pharmacodynamic analysis suggested these two regimens were equipotent on a volume basis. Doses of between 0.5 and 4 ml were administered at intervals no closer than every 3 min according to the flow chart reproduced in Appendix A. These intervals were used to minimize the risk of opioid accumulation after repeated boluses over time and are based approximately on clinical experience [7]. Protocols were commenced and managed at the discretion of the PACU nurses. A total of 453 patients (excluding the 58 patients in our initial study [6]) scheduled for surgery under anaesthesia were recruited and enrolled in this audit over a 20-week period and were allocated by their attending anaesthesiologists to receive M (221 patients) or AM (232 patients) as needed by nursing staff, according to the institutional IV opioid protocol (see Appendix A). Patient characteristics were similar between the two treated groups. In the AM group, the mean age was 52 ± 18.9 years and the gender ratio (male/female) was 100/132. In the M group, the mean age was 54 ± 18.2 years and the gender ratio (male/female) was 101/120. However, the patients were not matched for weight, ASA criteria, surgical procedure or anaesthetic type. Allocation to M or AM was at the discretion of the anaesthesiologist.
2.2. Postoperative monitoring Postoperatively, the following were recorded and assessed: the time to achieve comfort (reported following direct questioning of the patient), the total dose volume required to achieve comfort and the time to discharge from the PACU. In addition, the pain score (VAS, 0—10) at the point of comfort was reported, and the highest sedation score and the incidence of nausea, vomiting and itching were also recorded.
Verbal numerical pain scores were used to assess pain (0—10 where 0 = no pain and 10 = worst pain imaginable). Onset of CNS depression, if any, was assessed using sedation scores (0 = wide awake, 1 = occasionally drowsy, easy to rouse (and can stay awake), 2 = constantly drowsy, easy to rouse (but cannot stay awake) and 3 = somnolent, difficult to rouse) [3]. A sedation score of 3 was considered to be a significant predictor of respiratory depression potentially requiring opioid antagonism. A sedation score of 2 was indicative of a risk of significant respiratory depression if further opioids were given. Peripheral oxygen saturation (SpO2 ) levels and respiratory rates were also monitored and the lowest values were recorded, although respiratory rate is known to be much less reliable indicator of early respiratory depression than increasing sedation [8].
2.3. Statistical analysis In order to compare between the two treatment groups, the data from each group were pooled and compared using an unpaired Student’s t-test, and the results are expressed as mean and standard deviation (S.D.). p-Values were calculated where appropriate, and a value of p < 0.05 was considered statistically significant.
3. Results All patients in both groups reached the point of reporting comfort, but the patients who were given AM became comfortable more rapidly than those given M (Table 1). The mean (S.D.) time to comfort was 40.9 ± 34 min with M compared with 32.8 ± 26 min for AM (significance at p = 0.004). However, there was no significant difference in the mean (S.D.) volume required to achieve comfort: 15.2 ± 11 ml in the M group and 15 ± 17 ml in the AM group (p = 0.92; Table 1). This equated to doses of 15.2 mg of morphine in the first group, and 11.25 mg of morphine and 0.75 mg alfentanil in the second group. The mean time to discharge from the PACU was 88.4 ± 55 min for
Table 1 Comparison of mean time to comfort, mean dose volume to achieve comfort and mean time to discharge from the postanaesthesia care unit (PACU) between alfentanil:morphine (AM) mixture and morphine (M) groups
Time to comfort (min) Volume to achieve comfort (ml) Time to discharge (min) Results are expressed as mean ± S.D.
AM group
M group
p-Value
32.8 ± 26 15 ± 17 88.4 ± 55
40.9 ± 34 15.2 ± 11 105.3 ± 75
0.004 0.92 0.5
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W.K. Alkhazrajy et al.
Table 2 Comparison of the mean pain score at the time comfort was reported, sedation score, minimum mean respiration rate, lowest median SpO2 levels and incidence of adverse events between alfentanil:morphine (AM) mixture and morphine (M) groups AM group (n = 232)
M group (n = 221)
Mean pain score
3.4 ± 1.9
3.3 ± 1.8
Sedation score 0 1 2 3
33 (14.2%) 144 (62%) 52 (22.4%) 3 (1.3%)
22 (9.95%) 144 (65.2%) 52 (23.5%) 3 (1.4%)
11.9 ± 3.1
12 ± 3.2
98% ± 3.2
98% ± 3.3
9% 2.2% 3.9%
9.5% 2.8% 4.5%
Minimum respiration rate (number of breaths/min) Lowest SpO2 (% saturation) Nausea Vomiting Itching
Results are expressed as mean ± S.D. Mean pain score (p = 0.67).
M and 105.3 ± 75 min for AM (not significant at p = 0.5). As shown in Table 2, there was no difference in the mean pain scores at the time comfort was reported between the two groups; 3.3 ± 1.8 for M and 3.4 ± 1.9 for AM (p = 0.67). Sedation scores remained below 3 for all but three patients in each group. Overall, the sedation scores for the two groups had a similar profile (Table 2). The average lowest respiratory rate recorded was 12.0 breaths/min in patients given M (mean = 12 ± 3.2) and 11.9 breaths/min in those given AM (mean = 11.9 ± 3.1), respectively. In both groups, the lowest median oxygen saturation levels were 98% (AM group: 98 ± 3.2%; M group: 98 ± 3.3%), and considered to be within the clinically acceptable range (Table 2). The incidence of nausea, vomiting or itching was similar between the two groups (Table 2). With the types of operations, the surgical data and spread of surgical procedures were generally similar between the two study groups, with the exception of orthopaedic surgery (major joint replacement) and laparoscopic surgery (Table 3). In the AM group, the number of patients with laparoscopic surgery was considerably higher than those in the M group. By contrast, the number of patients with major joint replacement surgery was lower in the AM group when compared to the M group.
Table 3 Comparison of the number and type of surgical procedures between alfentanil:morphine (AM) mixture and morphine (M) groups Surgical procedures Major joint replacement Back or neck surgery Other orthopaedic Laparotomy Laparoscopic surgery Breast surgery Gynaecological laparotomy Gynaecological—–other Head and neck Other Total
AM group
M group
14 18 26 20 32 12 13 8 41 48
28 12 24 19 9 12 13 12 44 48
232
221
Data represent the number of patients who had undergone surgeries indicated for the two groups.
4. Discussion Control of pain in the PACU is still one of the major challenges in anaesthetic practice. In a recent study, a positive correlation between the severity of side effects (pain and nausea) and decrease in the quality of recovery in the immediate postoperative period has been found, and decreasing the severity of postoperative pain or nausea may potentially improve patient recovery and outcomes [9]. A national survey of 250 US adults who had undergone a recent surgical procedure was conducted and the participants were asked about their postoperative pain experience [1]. In this survey, approximately 80% of patients experienced pain after surgery, and of these patients, 86% reported moderate, severe or extreme pain. Postoperative pain can have significant effects on patient recovery and very few studies have examined the effect of postoperative pain, nausea and other symptoms on patient-oriented outcomes in the immediate postoperative period. In this audit, we have demonstrated the effectiveness and safety of a mixture of alfentanil combined with morphine administered using our standard IV opioid regimen. Our study showed that administration of the AM mixture offered a more rapid achievement of comfort than morphine alone. The dose volume to achieve comfort and the discharge time from the recovery ward were not statistically significantly different between these two groups, suggesting groups were well matched for analgesic requirements. We were unable to demonstrate any differences in the sedation score or the mean pain score at the time comfort was reported. There were no differences in respiratory depression and oxygen saturation between the two
Alfenanil:morphine mixture in the PACU groups, and the incidence of side effects such as vomiting, itching and nausea was similar in both groups. From the pharmacokinetic perspective, use of an AM mixture should be advantageous, based on the previous determination of the optimal ratio of the two drugs that gave an apparent time-course of CNS concentrations with an earlier time to the peak CNS concentration and onset of analgesia, but relatively long duration of action [6]. In our earlier study, an IV alfentanil:morphine mixture of 55 g:0.75 mg/ml provided effective pain relief that was more rapid in onset compared with morphine alone. We chose a ratio of 50 g:0.75 mg/ml alfentanil:morphine mixture in the current study because this simplified preparation of the mixture. However, concentrations were comparable to those employed in the pharmacokinetic modelling study with respect to their analgesic efficacies from clinical experience [6]. Alfentanil is a short-acting opioid receptor agonist with an equilibration half-life of about 1 min between plasma and its site of action [7,10]. In contrast, morphine equilibrates with a half-life of up to 2—3 h and has a much slower transfer rate between plasma and effect site than alfentanil [10]. It takes a longer time until the peak effect of morphine is seen but analgesia will be more prolonged because of its slower efflux from the site of action and from plasma. With different opioids, the concentration—effect relationship is elusive because analgesia lags behind plasma concentration to varying degrees, and the extent of hysteresis is dependent upon the physicochemical characteristics of the drug. In the case of alfentanil, the hysteresis is minimal due to its rapid CNS penetration, whilst with morphine the hysteresis is most marked because of its slow CNS equilibration [11]. Indeed, the slower cerebral uptake and low lipophilicity of morphine contributes to its prolonged relative duration with little delay in relative onset (time of relative onset for morphine is 6 min versus alfentanil of 1 min, whilst relative tmax and relative duration for morphine are 19 and 96 min, respectively, and for alfentanil,
17 this is 2 min for both) [7]. This delayed equilibration becomes of particular clinical significance in postoperative patients in whom multiple doses of parenteral opioids are titrated against pain levels. Furthermore, there is a possibility that a pharmacodynamic synergy between the two drugs contributes to their improved effectiveness as a combination. However, the similar incidence of opioid-related adverse effects is not consistent with this mechanism. It is acknowledged that this study has some methodological limitations. Patients were not randomised to receive M or AM, but allocation was at the discretion of the anaesthesiologist. However, there was a similarity between the equipotent volumes of drug required to achieve comfort, and the similarity of the pain scores reported at the time of comfort. Staff were not blinded to the drug they were administering which raises the potential for bias in the dose selection and timing. The use of protocols (see Appendix A) minimizes the variation in dose regimen permitted, thus reducing any risk of bias. A randomised double-blinded trial can circumvent these limitations, and is being planned. Despite the limitations, the data from our two trials provide evidence that an AM mixture provides more rapid analgesia than a conventional morphine pain protocol, without increasing the risk of opioidrelated side effects.
Conflict of interest There is no conflict of interest in this study.
Acknowledgements We would like to thank the general theatre recovery suite staff and the staff anaesthesiologists of the Royal Adelaide Hospital for their co-operation in the conduct of this audit. This study was funded by a grant from the Australian Society of Anaesthetists. Financial source: Funded by a grant from the Australian Society of Anaesthetists.
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Appendix A
W.K. Alkhazrajy et al.
Alfenanil:morphine mixture in the PACU
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References [1] Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be under-managed. Anesth Analg 2003;97:534—40. [2] Wu CL, Berenholtz SM, Pronovost PJ, Fleisher LA. A systematic review and analysis of postdischarge complications after ambulatory surgery. Anesthesiology 2002;96: 994—1003. [3] Macintyre PE, Ready LB. Acute pain management a practical guide. 2nd ed. London: W.B. Saunders; 2001. [4] Ederoth P, Tunblad K, Bouw R, Lundberg CJ, Ungerstedt U, Nordstrom CH, et al. Blood-brain barrier transport of morphine in patients with severe brain trauma. Br J Clin Pharmacol 2004;57:427—35. [5] Hull CJ. The pharmacokinetics of alfentanil in man. Br J Anaesth 1983;55:157S—64S. [6] Ludbrook GL, Macintyre PE, Douglas H, Ong L, Upton RN. A mixture of alfentanil and morphine for rapid postopera-
[7]
[8] [9]
[10]
[11]
tive loading with opioid: theoretical basis and initial clinical investigation. Anaesthesia 2001;56:1—7. Upton RN, Semple TJ, Macintyre PE. Pharmacokinetic optimisation of opioid treatment in acute pain therapy. Clin Pharmacokinet 1997;33:225—44. ANZCA acute pain guidelines: http://www.anzca.edu.au/ publications/acutepain.htm; 2005. Wu CL, Rowlingson AJ, Partin AW, Kalish MA, Courpas GE, Walsh PC, et al. Correlation of postoperative pain to quality of recovery in the immediate postoperative period. Reg Anesth Pain Med 2005;30:516—22. Lotsch J. Pharmacokinetic—pharmacodynamic modelling of opioids. J Pain Symptom Manage 2005;29:S90— 103. Chapman CR, Hill HF, Saeger L, Garvin J. Profiles of opioid analgesia in humans after intravenous bolus administration: alfentanil, fentanyl and morphine compared in experimental pain. Pain 1990;43:47—55.
An audit of the safety and effectiveness of an alfentanil:morphine mixture in the postanaesthesia care unit Waleed K. Alkhazrajy, Pamela E. Macintyre, Richard N. Upton, Jennifer Ong ∗, Guy L. Ludbrook Discipline of Anaesthesia and Intensive Care, School of Medicine, Royal Adelaide Hospital and University of Adelaide, North Terrace, Adelaide, SA 5000, Australia Received 20 July 2006 ; received in revised form 11 October 2006; accepted 13 October 2006 Available online 17 January 2007 KEYWORDS Alfentanil; Analgesia; Dose to comfort; Morphine; Postoperative pain; Time to comfort
Summary Background: After an initial clinical investigation of the effectiveness of an alfentanil—morphine mixture (AM) for the treatment of postoperative pain in the recovery setting, an audit was conducted to look at the effectiveness, safety and incidence of adverse opioid-related side effects of this mixture compared with morphine (M) alone. Assessment of effectiveness included the time and dose required to achieve patient comfort, the time to discharge from the postanaesthesia care unit (PACU) and pain scores; assessment of safety and side effects included measurement of sedation scores, oxygen saturation and respiratory rate as well as incidence of nausea and vomiting, and pruritus. Methods: A total of 453 patients were recruited: the M group (221 patients) received a standard IV morphine regimen (morphine concentration 1 mg/ml; bolus doses of between 0.5 and 4 ml IV given every 3 min as needed by nursing staff according to the hospital protocol—–see Appendix A); the AM group (232 patients) received a similar IV regimen using the alfentanil:morphine mixture (alfentanil 50 g and morphine 0.75 mg/ml; bolus doses given as for morphine). Results: In the M group, the mean time to comfort was 40.9 ± 34 min whilst in the AM group, it was 32.8 ± 26 min (significant at p = 0.004). The mean (S.D.) volume required to achieve comfort was similar and the mean time to discharge from the PACU was 105.3 ± 75 min for the M group and 88.4 ± 55 min for the AM group (p = 0.5). Neither the sedation scores or pain scores at comfort differed significantly between the groups. The minimum respiratory rates recorded in the PACU were 12 ± 3.2 breaths/min for the M group and 11.9 ± 3.1 breaths/min for patients given
∗ Corresponding author at: Discipline of Anaesthesia and Intensive Care, School of Medicine, University of Adelaide, Frome Road, Adelaide, SA 5005, Australia. Tel.: +61 8 8303 5163; fax: +61 8 8303 3909. E-mail address: [email protected] (J. Ong).
1366-0071/$ — see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.acpain.2006.10.001
14
W.K. Alkhazrajy et al. AM. There was no significant difference between the two groups in patients’ reports of nausea, vomiting or pruritus. Conclusion: Compared with morphine alone, the use of an alfentanil:morphine mixture can reduce the time taken to achieve patient comfort without increasing the risk of opioid-related adverse effects. © 2006 Elsevier B.V. All rights reserved.
1. Introduction Providing rapid but safe management of postoperative pain is a vital goal in the immediate postsurgical period. However, despite the best efforts of anaesthesiologists and nurses, many patients still experience moderate to severe pain in the postanaesthesia care unit (PACU). Even with an increased focus on pain management programmes, including the development of new standards and guidelines, inadequate pain management is common and postoperative pain continues to be under-treated [1,2]. Opioids remain the cornerstone of acute pain treatment in this setting, in spite of adverse effects such as respiratory depression, nausea and vomiting. Yet an opioid with the desirable pharmacokinetic characteristics of rapid onset and prolonged duration of effect is not clinically available. Intravenous protocols, using repeated bolus doses of opioids prescribed by doctors and titrated by nursing staff, are a common technique for the management of pain in the PACU (see example in Appendix A). For safety, when bolus doses of opioids are given at intervals during IV titration regimens, it has been suggested that the interval between these doses should allow for the peak effect of each dose to be seen before another is given [3]. Although this reduces the risk of excess drug accumulation and excessive sedation, it can result in a delay before adequate analgesia is achieved, especially if drugs such as morphine are used. However, if an opioid with a faster onset of action is given, such as alfentanil, the duration of analgesia may be too short, as offset of action is also more rapid. Morphine enters the central nervous system (CNS) slowly [4] and has a relatively slow onset to peak effect, even after IV bolus dose administration. Alfentanil has a much faster onset of action due to its greater lipid solubility and high unionized fraction at physiological pH [5]. A mixture of opioids, such as a mixture of alfentanil and morphine, may allow a more rapid onset of action, providing more rapid relief of postoperative pain compared with morphine alone, whilst still maintaining a reasonable duration of effect.
In our earlier study, pharmacokinetic modelling of estimated CNS opioid concentrations was used to devise the optimal mixture of morphine and alfentanil in the treatment of postoperative pain [6]. Our study of 58 patients in the PACU who were randomly allocated to receive analgesia using IV titration regimens of either morphine (M) or alfentanil and morphine (AM) revealed that an IV alfentanil—morphine mixture of 55 g:0.75 mg/ml provided effective pain relief that was more rapid in onset compared with morphine alone. This is thought to be the result of combining the rapid CNS penetration of alfentanil with the prolonged duration of effect of morphine. In order to confirm the finding of improved analgesia and to examine the safety of AM mixture versus morphine protocols, both regimens were made freely available to anaesthesiologists in the operating suite. We have now conducted a larger and more detailed audit of the effectiveness and safety of IV titration regimens using M and AM in a large group of patients in the PACU of a large teaching hospital.
2. Patients and methods Approval for the audit was obtained from the Human Research Ethics Committee of the Royal Adelaide Hospital. Patients considered by their anaesthesiologist as likely to require postoperative IV opioid analgesia in the PACU were identified preoperatively and enrolled in the audit. Those reporting any prior adverse reactions to morphine or alfentanil, or patients with a poor understanding of English, were excluded.
2.1. Dose selection and recruitment of patients Power analysis, using the incidence of adverse respiratory effects reported in the PACU (personal communication—–audit data), suggested that 200 patients would be needed in each group. This was performed using the known incidence of respiratory depression and sedation in patients
Alfenanil:morphine mixture in the PACU
15
receiving the morphine protocol, providing approximately 80% power to detect a 30% difference with a standard significance level of p < 0.05. The concentration of M used was 1 mg/ml; the concentration of AM was 50 g alfentanil plus 0.75 mg morphine per ml. Both solutions were colourless and appeared identical in the syringes. Earlier pharmacokinetic—pharmacodynamic analysis suggested these two regimens were equipotent on a volume basis. Doses of between 0.5 and 4 ml were administered at intervals no closer than every 3 min according to the flow chart reproduced in Appendix A. These intervals were used to minimize the risk of opioid accumulation after repeated boluses over time and are based approximately on clinical experience [7]. Protocols were commenced and managed at the discretion of the PACU nurses. A total of 453 patients (excluding the 58 patients in our initial study [6]) scheduled for surgery under anaesthesia were recruited and enrolled in this audit over a 20-week period and were allocated by their attending anaesthesiologists to receive M (221 patients) or AM (232 patients) as needed by nursing staff, according to the institutional IV opioid protocol (see Appendix A). Patient characteristics were similar between the two treated groups. In the AM group, the mean age was 52 ± 18.9 years and the gender ratio (male/female) was 100/132. In the M group, the mean age was 54 ± 18.2 years and the gender ratio (male/female) was 101/120. However, the patients were not matched for weight, ASA criteria, surgical procedure or anaesthetic type. Allocation to M or AM was at the discretion of the anaesthesiologist.
2.2. Postoperative monitoring Postoperatively, the following were recorded and assessed: the time to achieve comfort (reported following direct questioning of the patient), the total dose volume required to achieve comfort and the time to discharge from the PACU. In addition, the pain score (VAS, 0—10) at the point of comfort was reported, and the highest sedation score and the incidence of nausea, vomiting and itching were also recorded.
Verbal numerical pain scores were used to assess pain (0—10 where 0 = no pain and 10 = worst pain imaginable). Onset of CNS depression, if any, was assessed using sedation scores (0 = wide awake, 1 = occasionally drowsy, easy to rouse (and can stay awake), 2 = constantly drowsy, easy to rouse (but cannot stay awake) and 3 = somnolent, difficult to rouse) [3]. A sedation score of 3 was considered to be a significant predictor of respiratory depression potentially requiring opioid antagonism. A sedation score of 2 was indicative of a risk of significant respiratory depression if further opioids were given. Peripheral oxygen saturation (SpO2 ) levels and respiratory rates were also monitored and the lowest values were recorded, although respiratory rate is known to be much less reliable indicator of early respiratory depression than increasing sedation [8].
2.3. Statistical analysis In order to compare between the two treatment groups, the data from each group were pooled and compared using an unpaired Student’s t-test, and the results are expressed as mean and standard deviation (S.D.). p-Values were calculated where appropriate, and a value of p < 0.05 was considered statistically significant.
3. Results All patients in both groups reached the point of reporting comfort, but the patients who were given AM became comfortable more rapidly than those given M (Table 1). The mean (S.D.) time to comfort was 40.9 ± 34 min with M compared with 32.8 ± 26 min for AM (significance at p = 0.004). However, there was no significant difference in the mean (S.D.) volume required to achieve comfort: 15.2 ± 11 ml in the M group and 15 ± 17 ml in the AM group (p = 0.92; Table 1). This equated to doses of 15.2 mg of morphine in the first group, and 11.25 mg of morphine and 0.75 mg alfentanil in the second group. The mean time to discharge from the PACU was 88.4 ± 55 min for
Table 1 Comparison of mean time to comfort, mean dose volume to achieve comfort and mean time to discharge from the postanaesthesia care unit (PACU) between alfentanil:morphine (AM) mixture and morphine (M) groups
Time to comfort (min) Volume to achieve comfort (ml) Time to discharge (min) Results are expressed as mean ± S.D.
AM group
M group
p-Value
32.8 ± 26 15 ± 17 88.4 ± 55
40.9 ± 34 15.2 ± 11 105.3 ± 75
0.004 0.92 0.5
16
W.K. Alkhazrajy et al.
Table 2 Comparison of the mean pain score at the time comfort was reported, sedation score, minimum mean respiration rate, lowest median SpO2 levels and incidence of adverse events between alfentanil:morphine (AM) mixture and morphine (M) groups AM group (n = 232)
M group (n = 221)
Mean pain score
3.4 ± 1.9
3.3 ± 1.8
Sedation score 0 1 2 3
33 (14.2%) 144 (62%) 52 (22.4%) 3 (1.3%)
22 (9.95%) 144 (65.2%) 52 (23.5%) 3 (1.4%)
11.9 ± 3.1
12 ± 3.2
98% ± 3.2
98% ± 3.3
9% 2.2% 3.9%
9.5% 2.8% 4.5%
Minimum respiration rate (number of breaths/min) Lowest SpO2 (% saturation) Nausea Vomiting Itching
Results are expressed as mean ± S.D. Mean pain score (p = 0.67).
M and 105.3 ± 75 min for AM (not significant at p = 0.5). As shown in Table 2, there was no difference in the mean pain scores at the time comfort was reported between the two groups; 3.3 ± 1.8 for M and 3.4 ± 1.9 for AM (p = 0.67). Sedation scores remained below 3 for all but three patients in each group. Overall, the sedation scores for the two groups had a similar profile (Table 2). The average lowest respiratory rate recorded was 12.0 breaths/min in patients given M (mean = 12 ± 3.2) and 11.9 breaths/min in those given AM (mean = 11.9 ± 3.1), respectively. In both groups, the lowest median oxygen saturation levels were 98% (AM group: 98 ± 3.2%; M group: 98 ± 3.3%), and considered to be within the clinically acceptable range (Table 2). The incidence of nausea, vomiting or itching was similar between the two groups (Table 2). With the types of operations, the surgical data and spread of surgical procedures were generally similar between the two study groups, with the exception of orthopaedic surgery (major joint replacement) and laparoscopic surgery (Table 3). In the AM group, the number of patients with laparoscopic surgery was considerably higher than those in the M group. By contrast, the number of patients with major joint replacement surgery was lower in the AM group when compared to the M group.
Table 3 Comparison of the number and type of surgical procedures between alfentanil:morphine (AM) mixture and morphine (M) groups Surgical procedures Major joint replacement Back or neck surgery Other orthopaedic Laparotomy Laparoscopic surgery Breast surgery Gynaecological laparotomy Gynaecological—–other Head and neck Other Total
AM group
M group
14 18 26 20 32 12 13 8 41 48
28 12 24 19 9 12 13 12 44 48
232
221
Data represent the number of patients who had undergone surgeries indicated for the two groups.
4. Discussion Control of pain in the PACU is still one of the major challenges in anaesthetic practice. In a recent study, a positive correlation between the severity of side effects (pain and nausea) and decrease in the quality of recovery in the immediate postoperative period has been found, and decreasing the severity of postoperative pain or nausea may potentially improve patient recovery and outcomes [9]. A national survey of 250 US adults who had undergone a recent surgical procedure was conducted and the participants were asked about their postoperative pain experience [1]. In this survey, approximately 80% of patients experienced pain after surgery, and of these patients, 86% reported moderate, severe or extreme pain. Postoperative pain can have significant effects on patient recovery and very few studies have examined the effect of postoperative pain, nausea and other symptoms on patient-oriented outcomes in the immediate postoperative period. In this audit, we have demonstrated the effectiveness and safety of a mixture of alfentanil combined with morphine administered using our standard IV opioid regimen. Our study showed that administration of the AM mixture offered a more rapid achievement of comfort than morphine alone. The dose volume to achieve comfort and the discharge time from the recovery ward were not statistically significantly different between these two groups, suggesting groups were well matched for analgesic requirements. We were unable to demonstrate any differences in the sedation score or the mean pain score at the time comfort was reported. There were no differences in respiratory depression and oxygen saturation between the two
Alfenanil:morphine mixture in the PACU groups, and the incidence of side effects such as vomiting, itching and nausea was similar in both groups. From the pharmacokinetic perspective, use of an AM mixture should be advantageous, based on the previous determination of the optimal ratio of the two drugs that gave an apparent time-course of CNS concentrations with an earlier time to the peak CNS concentration and onset of analgesia, but relatively long duration of action [6]. In our earlier study, an IV alfentanil:morphine mixture of 55 g:0.75 mg/ml provided effective pain relief that was more rapid in onset compared with morphine alone. We chose a ratio of 50 g:0.75 mg/ml alfentanil:morphine mixture in the current study because this simplified preparation of the mixture. However, concentrations were comparable to those employed in the pharmacokinetic modelling study with respect to their analgesic efficacies from clinical experience [6]. Alfentanil is a short-acting opioid receptor agonist with an equilibration half-life of about 1 min between plasma and its site of action [7,10]. In contrast, morphine equilibrates with a half-life of up to 2—3 h and has a much slower transfer rate between plasma and effect site than alfentanil [10]. It takes a longer time until the peak effect of morphine is seen but analgesia will be more prolonged because of its slower efflux from the site of action and from plasma. With different opioids, the concentration—effect relationship is elusive because analgesia lags behind plasma concentration to varying degrees, and the extent of hysteresis is dependent upon the physicochemical characteristics of the drug. In the case of alfentanil, the hysteresis is minimal due to its rapid CNS penetration, whilst with morphine the hysteresis is most marked because of its slow CNS equilibration [11]. Indeed, the slower cerebral uptake and low lipophilicity of morphine contributes to its prolonged relative duration with little delay in relative onset (time of relative onset for morphine is 6 min versus alfentanil of 1 min, whilst relative tmax and relative duration for morphine are 19 and 96 min, respectively, and for alfentanil,
17 this is 2 min for both) [7]. This delayed equilibration becomes of particular clinical significance in postoperative patients in whom multiple doses of parenteral opioids are titrated against pain levels. Furthermore, there is a possibility that a pharmacodynamic synergy between the two drugs contributes to their improved effectiveness as a combination. However, the similar incidence of opioid-related adverse effects is not consistent with this mechanism. It is acknowledged that this study has some methodological limitations. Patients were not randomised to receive M or AM, but allocation was at the discretion of the anaesthesiologist. However, there was a similarity between the equipotent volumes of drug required to achieve comfort, and the similarity of the pain scores reported at the time of comfort. Staff were not blinded to the drug they were administering which raises the potential for bias in the dose selection and timing. The use of protocols (see Appendix A) minimizes the variation in dose regimen permitted, thus reducing any risk of bias. A randomised double-blinded trial can circumvent these limitations, and is being planned. Despite the limitations, the data from our two trials provide evidence that an AM mixture provides more rapid analgesia than a conventional morphine pain protocol, without increasing the risk of opioidrelated side effects.
Conflict of interest There is no conflict of interest in this study.
Acknowledgements We would like to thank the general theatre recovery suite staff and the staff anaesthesiologists of the Royal Adelaide Hospital for their co-operation in the conduct of this audit. This study was funded by a grant from the Australian Society of Anaesthetists. Financial source: Funded by a grant from the Australian Society of Anaesthetists.
18
Appendix A
W.K. Alkhazrajy et al.
Alfenanil:morphine mixture in the PACU
19
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