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© 1999 International Anesthesia Research Society
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Abstract |
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Using a patient-controlled analgesia (PCA) delivery system, we evaluated the clinical advantages and disadvantages of morphine PCA compared with morphine plus lysine acetyl salicylate (LAS), a soluble aspirin. After major orthopedic surgery, 50 adult patients were enrolled in a prospective, randomized, and double-blinded study. When a patient in the recovery room complained of pain, an initial dose of morphine or the morphine/LAS mixture was titrated to achieve analgesia of visual analog score
3 in 30 min. An equivalent volume PCA dose of either morphine 1 mg/mL or morphine 0.5 mg + LAS 90 mg/mL was used with a lockout interval of 10 min. Pain score, patient satisfaction, vital signs, and adverse effects were observed for 48 h. Adequate analgesia (visual analog scale score 3) was achieved with either drug. Morphine consumption in the morphine/LAS group was significantly less than in morphine group (13.9 vs 18.4 mg in 24 h and 24.3 vs 32.4 mg in 48 h). Significantly more sedation was evident with the morphine group (P < 0.05). We conclude that injectable LAS can be used as an effective and safe adjuvant to morphine for PCA. This combination reduces dose requirements of morphine and hence some of its adverse effects. Implications: Injectable aspirin could be used as an effective and safe adjuvant to morphine for patient-controlled analgesia. This combination reduces the dose requirement of morphine and therefore some of the morphine-related untoward effects.
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Introduction |
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The combinations of opioids with aspirin or acetaminophen in an oral preparation are often used for analgesia. However, the efficacy of parenteral aspirin combined with opioid for the relief of acute pain, especially by patient-controlled analgesia (PCA) delivery is unknown. We therefore undertook this double-blinded, randomized, prospective study to evaluate the analgesic efficacy and safety of IV lysine acetyl salicylate (LAS) in combination with morphine provided by PCA in patients after major orthopedic surgeries.
Kweekel-De Vries et al. (1) reported that 1.8 g of LAS, given IM, was at least as good as 10 mg of morphine given IM in the treatment of postoperative pain and was associated with less nausea, vomiting, and respiratory depression than morphine. Jones et al. (2) reported that IV LAS 1.8 g, given at 6-h intervals after major thoracic surgery, provided equipotent analgesia compared with 10 mg morphine given at 6-h intervals, and was not associated with any significantly greater blood loss in the period after surgery. We used the same dose ratio of 180:1 for aspirin versus morphine in our study.
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Methods |
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With the approval of the hospital’s research committee and written, informed consent, 50 adult patients scheduled for elective total hip or total knee arthroplasty were enrolled in the study. All the patients were ASA physical status I and II. Exclusion criteria included: 1) allergy to the study drugs, 2) inability to use the PCA, 3) difficulty in communication, 4) refusal to participate, 5) history of significant liver or kidney diseases, 6) history of substance abuse, 7) history of peptic ulcer disease, or 8) bleeding disorders. All patients were instructed on the use of the PCA pump during a preoperative consultation session as well as the use of the visual analog scale (VAS), with 0 being no pain and 10 being the most excruciating pain. All patients received general anesthesia induced with thiopental and succinylcholine and maintained with isoflurane in 60% N2O and 40% O2. No local anesthesia, opioids, antiemetics, or nonsteroidal antiinflammatory drugs (NSAID) were used 24 h before or during surgery.
In the postanesthesia care unit (PACU) as soon as patients complained of pain and the VAS score was >5, they were divided randomly into two equal groups of 25 each. Group 1 received morphine and Group 2 received morphine plus LAS (Lybrile® lysine acetyl salicylate; Yung Shin Pharmaceutical Industrial Co., Ltd., Taiwan, Republic of China). An identical syringe containing an equal volume of either morphine 1 mg/mL or morphine 0.5 mg plus LAS 90 mg/mL was prepared by a pharmacist and given to the investigator who was blinded to the identity of the drug(s). The initial dose of either group was given in increments for 30 min until adequate analgesia was achieved with a VAS score 3. The patient was then attached to the PCA pump (Lifecare Infusor-4200; Abbott Laboratories, North Chicago, IL) with the respective study drug(s). The PCA dose was set at 1 mL bolus with a lockout interval of 10 min. No continuous background infusion and 4-h maximal limit was given. Rescue analgesia with titration of meperidine 25–50 mg IV was allowed if the patient could not obtain adequate pain relief from the above PCA regimen. Drug compatibility in mixing morphine with LAS had been verified by the hospital pharmacy.
VAS at rest was assessed every 6 h for the first 24 h after starting the PCA and every 12 h for the subsequent 24 h by the investigator. At the last interview at each 24-h period, the patient was also asked to rate his or her overall satisfaction with the pain relief using a Global Satisfaction Score which was divided into very good, good, fair, and poor. Data of PCA demand, dose delivered, and total dose used were retrieved from the computer memory of the PCA device.
All adverse effects were recorded during the 48-h observation period. Persistent nausea for more than 3 h or vomiting more than twice was treated with IV metoclopramide 10 mg every 4 h as needed. The degree of sedation was rated on a 4-point scale with 0 = awake, 1 = drowsy, 2 = asleep but responded to verbal commands, or 3 = unarousable sleep. The respiratory depression was defined as a respiratory rate <10/min, which was treated with incremental doses of IV naloxone. Urinary retention could not be assessed because of the presence of the indwelling Foley catheter in all the patients. Pruritus was treated with IV diphenhydramine 10 mg every 6 h as needed. Daily blood loss via the surgical drain was measured for the assessment of bleeding tendency of the two groups until the drains were removed.
Data for age, body weight, height, morphine demand, and consumption were analyzed with the Student’s t-test and reported as mean ± SD. VAS scores were analyzed with the Mann-Whitney U-test. The 
2 test was used for sex, type of surgery, and satisfaction score. Analysis of adverse effects was done by the Fisher’s exact test. A P value <0.05 was considered statistically significant.
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Results |
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The demographic data and the types of operations for the two groups were comparable and without significant difference (Table 1).
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The average time from arrival in the PACU to the time when the patients complained of pain that necessitated analgesia was 22 ± 14 min for Group I and 23 ± 12 min for Group 2. Before the initial dose, the mean baseline VAS score in the PACU was 7.1 ± 1.2 in Group 1 and 6.9 ± 0.9 in Group 2. The onset time of either drug was within 5 min. After the initial dose, all of the patients had a satisfactory analgesia in the PACU in 30 min, with a VAS score of 2.3 ± 1.3 in Group 1 and 2.8 ± 1.0 in Group 2. Group 1 consumed significantly more morphine (8.7 ± 3.7 mg) than Group 2 (5.5 ± 2.1 mg).
Both study drugs provided effective postoperative analgesia throughout the 48 h. The pain relief by VAS at each assessment was not statistically different between the two groups (Fig. 1).
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There was no statistically significant difference between the two groups on all three satisfaction score assessments (PACU, 24 h, 48 h) (Table 2). There were two patients in the morphine group who complained of persistent nausea and one patient in the morphine/LAS group who complained of dizziness and rated the satisfaction score "poor" in 24 h. The two patients with nausea were treated with metoclopramide 10 mg IV, and the patient with dizziness was advised to withhold further PCA until the dizziness subsided. None of them requested a termination of PCA.
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The morphine/LAS group showed a statistically higher frequency in PCA demand than morphine group (31.5 vs 23.2 times in 24 h and 46.9 vs 38.1 in 48 h) (Table 3). The morphine consumption in the morphine/LAS group, however, was significantly less than in the morphine group (Table 3).
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Urinary retention was not assessed because of the presence of urinary catheters (Table 4). No patient in either group had unarousable sleep or respiratory rate
10 breaths/min; however, there was significantly more sedation observed with the morphine group. The amount of blood loss from the surgical drain was similar, 774 ± 366 mL in the morphine group and 685 ± 319 mL in the morphine/LAS group, representing no significant difference between the two groups. None of the patients in either group complained of dyspepsia or tinnitus.
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Discussion |
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Despite the introduction of many new NSAIDs, aspirin is still the most widely prescribed and commonly used household analgesic and is the gold standard with which others must be compared. Many NSAIDs have been studied for postoperative pain control (3–6). However, there are no reports regarding the combined use of morphine and aspirin by PCA.
Postoperative pain has been treated successfully with PCA opioids, most commonly morphine. which, unfortunately, may cause a number of serious side effects, including mental confusion, constipation, physical dependency, and respiratory depression. This especially causes concern in wards where nursing supervision of the patient may not be optimal. Thus, either inadequate dosing or untoward effects may result.
Aspirin, like other NSAIDs, reduces pain by interruption of the arachidonic acid pathway at the cyclo-oxygenase level and has no central opioid effects; therefore it is associated with significantly less sedation, nausea, vomiting, and respiratory depression. In a preliminary, unpublished study, we found that aspirin alone could not provide effective analgesia in some patients with severe postoperative pain regardless of the dose. In our study, however, the morphine-sparing effect of aspirin when combined with morphine is quite evident. Kweekel-De Vries et al. (1) and Jones et al. (2) reported that the equipotency of morphine to LAS was 1:180. Using the same potency ratio, our study showed that the morphine consumption in the morphine/LAS group was reduced by about one fourth, as shown in Table 3. This seems to indicate that the effect of morphine/LAS combination is additive and not synergistic. The use of the large doses of LAS in the combination group did not cause any significant postoperative bleeding problem compared with that of the morphine alone group. This finding is consistent with the finding of Jones et al. (2), and was explained as a paradoxical effect on the bleeding time as a result of a dose-dependent differential action of aspirin on the platelet aggregating inhibitor, prostacyclin, and the proaggregating thromboxane. An acute dose of <1 g of LAS has been shown to prolong bleeding time, whereas larger doses are associated with no prolongation of bleeding time (2). However, clinical monitoring for potential bleeding and other side effects, such as bronchospasm on IV administration of LAS, should be exercised. We consider a reduction in morphine consumption that leads to less sedation to be an improved feature of morphine PCA because the sedation can be a sign of central depression before life-threatening respiratory depression.
The morphine-sparing effect of LAS does not affect much of the cost changes because both morphine and LAS have a similar cost at a 1:180 mg (equal potency) ratio. Ketorolac was also found to have a morphine-sparing effect when combined with morphine (7). When compared with ketorolac, LAS has a lower cost. As demonstrated by Morley-Forster et al. (4), ketorolac should be compared with other NSAIDs at equipotent doses to allow clinicians to decide on the best postoperative analgesia at the lowest cost.
In summary, our study showed that injectable LAS can be used as an effective and safe adjuvant to morphine for PCA. This combination reduces dose requirements of morphine, and, hence, some of its adverse effects. This combination may be particularly helpful if less sedation is desired.
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Acknowledgments |
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The authors thank Rainy Chih-Cheng Lin, MSc, for statistical calculations, Shu-Hui Yang, chief CRNA, Min-Fei Liao, MSc, for data collection, and all other members of our department who corroborated this work.
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References |
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Kweekel-De Vries WJ, Spierdijk J, Mattie H, Hermans JMH. A new soluble acetyl salicylic acid derivative in the treatment of post-operative pain. Br J Anaesth 1974;46:133–5.
[Abstract/Free Full Text] -
Jones RM, Cashman JN, Foster JMG, et al. Comparison of infusions of morphine and lysine acetyl salicylate for the relief of pain following thoracic surgery. Br J Anaesth 1985;57:259–63.
[Abstract/Free Full Text] - Catado PA, Senagore AJ, Kilbride MJ. Ketorolac and patient controlled analgesia in the treatment of postoperative pain. Surg Gynecol Obstet 1993;176:435–8.[Web of Science][Medline]
- Morley-Foster P, Newton PT, Cook MJ. Ketorolac and indomethacin are equally efficacious for the relief of minor postoperative pain. Can J Anaesth 1993;40:1126–30.[Web of Science][Medline]
- Kostamovaara PA, Laitimen JO, Nuutinen LS, Koivuranta MK. Intravenous ketoprofen for pain relief after total hip or knee replacement. Acta Anaesthesiol Scand 1996;40:697–703.[Web of Science][Medline]
- Insel PA. Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout. In: Hardman JG, Limbird LE, eds. The pharmacological basis of therapeutics. 9th ed. New York:McGraw-Hill, 1996:617–57.
- Picard P, Bazin JE, Conio N, et al. Ketorolac potentiates morphine in postoperative patient-controlled analgesia. Pain 1997;73:401–6.[Web of Science][Medline]
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