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© 1999 International Anesthesia Research Society
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Abstract |
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We studied the time course of clinical and pharmacokinetic effects after the rectal administration of diclofenac 100 mg in seven patients using patient-controlled morphine (PCA) on the first postoperative day after major spinal surgery. Plots of plasma diclofenac concentrations and pain intensity difference (PID) demonstrated counterclockwise hysteresis consistent with distribution to a central effect compartment such as the central nervous system. Mean ± SEM (range) maximum PID and its timing were 62% ± 10% (32%–98%) and 309 ± 20 (210–360) min after the administration of diclofenac, respectively. Minimal respiratory rates were significantly slower after the administration of diclofenac (P < 0.001), occurring at 197 ± 51.9 (60–360) min; arterial desaturations occurred in two patients without oxygen therapy. Plasma morphine and morphine-6-glucuronide (M6G) concentrations interpolated to the average time of minimal respiratory rate indicated decreases of 23% ± 13% (0%–79%) and 1% ± 9% (0%–32%) from their respective starting values. Plasma M6G concentrations were significantly different from baseline only 420 and 480 min after the administration of diclofenac. The potential opioid-sparing effects of a nonsteroidal antiinflammatory drug added during PCA morphine use may not be manifest for several hours. During this lag, plasma concentrations of M6G may reach and remain at levels high enough to increase the risk of respiratory depression and other opioid side effects for hours.
Implications: Plasma concentrations of morphine, morphine-6-glucuronide, and diclofenac were measured postoperatively after a single dose of rectal diclofenac 100 mg was added to morphine patient-controlled analgesia. Peak analgesia occurred 309 min and respiratory depression 197 min after diclofenac administration. Morphine consumption had decreased by 20%, but concentrations of the active metabolite morphine-6-glucuronide were unchanged. Vigilance is recommended in patients receiving patient-controlled analgesia opioids and nonsteroidal antiinflammatory drugs.
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Introduction |
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A knowledge of the pharmacokinetic properties of opioids can optimize their effective use in acute pain management (1). The steep plasma concentration-effect relationship, association of pain relief with a minimal effective analgesic concentration (MEAC), and the variation in MEAC for opioids have long been recognized (1–5). Patient-controlled IV opioid delivery (patient-controlled analgesia; PCA) reduces the effect of pharmacokinetic and pharmacodynamic variability by allowing patients to self-dose to achieve and maintain an appropriate plasma opioid concentration (1). PCA demands are made at essentially consistent blood concentrations (5).
There is also a relationship between plasma concentration and effect for nonsteroidal antiinflammatory drugs (NSAIDs). This is well established for aspirin in rheumatoid arthritis but may not be a simple relationship with other NSAIDs (6). It is difficult to extrapolate these data to acute and postoperative pain management because the pathophysiology is different. Further, there is evidence of dissociation between the analgesic and antiinflammatory effects of NSAIDs (7). Although increased serum concentrations of ibuprofen are associated with increased analgesia for patients with severe dental pain (8), there are little other data from postoperative pain management. Additional knowledge of pharmacokinetic and pharmacodynamic relationships would improve the scientific basis of NSAID dosing and delivery regimens. Such research should consider that NSAIDs are often given in combination with opioids.
The aims of this study were to investigate the plasma concentration-analgesic response relationship of a single rectal dose of diclofenac during morphine PCA in patients with moderate to severe postoperative pain (visual analog score [VAS] >40 mm) and to evaluate the effects of this single diclofenac dose on morphine consumption and plasma morphine and morphine-6-glucuronide (M6G) concentrations.
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Methods |
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After local ethics committee approval and written, informed consent, seven adult patients were entered into the study. All patients were scheduled for elective combined anterior and posterior lumbar vertebral fusions. Exclusion criteria included allergy or concurrent therapy with NSAIDs and abnormal preoperative hepatic or renal function. Patients were instructed preoperatively in the assessment of pain using a standard 100-mm VAS during a standard movement (reaching with a hand to touch the contralateral bedside). The use of a PCA device was also explained at this time.
Patients received a standardized anesthetic using propofol for induction and vecuronium for muscle relaxation as required, tracheal intubation, and mechanical ventilation of the lungs with 35% oxygen in nitrous oxide with added isoflurane. Intraoperative analgesia was provided initially with IV fentanyl 3–5 µg/kg, followed by IV morphine 0.1 mg/kg as determined by the anesthetist in charge of the case. All patients had a central venous catheter inserted into an internal jugular vein for intraoperative monitoring and later blood sampling.
In the recovery ward, nursing staff treated pain with increments of IV morphine titrated to patient comfort. Pain was assessed using a verbal 4-point ordinal scale (0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe pain). Patient comfort was taken as a score of 0 or 1. Patients were then allowed to use their PCA device to deliver IV morphine 1 mg on demand with a 5-min lockout time and no background infusion. Nausea and vomiting were treated as necessary with IV cyclizine 50 mg and/or IV ondansetron 4 mg. Patients were then discharged to a high-dependency unit and managed routinely by ward staff during the first postoperative night. All patients used their PCA device as required for at least 14 h before entering a formal 10-h study period at 8:00 AM on the day after surgery. Patients were not permitted any analgesics in addition to PCA before this time. Patients were eligible for the study period if their VAS score was >30 mm on movement, intraoperative blood loss was <15% of the total blood volume, postoperative hemoglobin concentration and urine output were >10 g/100 mL and 0.5 mL · kg-1 · h-1, respectively, and cardiovascular variables were stable.
Throughout the study period, normal activities such as washing, turning, and physiotherapy were allowed, and clinical data were recorded as follows: pain intensity (VAS during the standard movement) at 30-min intervals and hourly morphine consumption and respiratory rate. Continuous pulse oximetry was monitored. Venous blood sampling from the central venous cannula for later analysis of plasma morphine and M6G concentrations was performed every 60 min throughout the study period. Rectal diclofenac 100 mg was given at 10:00 AM (time 0). Additional venous blood was sampled for later analysis of plasma diclofenac concentrations 0, 5, 10, 15, 20, 30, 40, and 60 min after the administration of diclofenac and thereafter at 30-min intervals until the end of the study period (6:00 PM on the day after surgery; i.e., 480 min after the administration of diclofenac).
IV fluid therapy was maintained with crystalloid 1.5 mL · kg-1 · h-1. If the systolic blood pressure decreased to <100 mm Hg or the urine output to <0.5 mL · kg-1 · h-1, 250 mL of a urea-linked gelatin was given IV over 30 min as necessary (one patient). Patients breathed oxygen continuously via a variable performance mask.
Blood samples were centrifuged, and the plasma was stored at -70°C for later analysis using high-performance liquid chromatography techniques for plasma morphine, M6G (9), and diclofenac (10) concentrations.
For each patient, the median of five VAS scores over the 2 h before time 0 was used as the baseline pain intensity. The pain intensity difference (PID) at 30-min intervals after time 0 was calculated as the percent change in VAS score compared with the baseline pain intensity. Baseline values for time 0 for hourly morphine consumption and plasma morphine and M6G concentrations were also calculated using the data from the three time points immediately before diclofenac administration. If analysis of variance demonstrated no statistically significant difference at the 5% level, the mean of the three values was recorded as the baseline value.
It was assumed that the trough levels for plasma morphine concentration before the administration of diclofenac were an estimate of the MEAC for each patient. Previous estimates of the MEAC for morphine have been approximately 20 ng/mL, and pain relief has been associated with plasma concentrations on the order of 80 ng/mL (1,4,11). Blood sampling in this study was not controlled to avoid sampling during the initial distribution of morphine after an increment. Therefore, individual plasma morphine concentrations >100 nM/L (0.759 ng/mL = 1 nM/L) were excluded from analysis. Figure 1 shows the plasma morphine concentrations and excluded value for one patient.
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Hourly morphine consumption and plasma morphine and M6G concentrations were analyzed for changes after the rectal administration of diclofenac using analysis of variance with repeated measures. If a significant effect was demonstrated at the 5% level, pairwise comparisons using the paired t-test were performed where appropriate. Baseline and minimal respiratory rates after the administration of diclofenac were analyzed using the paired t-test. Statistical significance was assumed at P < 0.05.
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Results |
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The median (range) age and weight for the seven patients were 37 (26–48) yr and 83 (51–97) kg, respectively.
Plots of plasma diclofenac concentrations and PID for individuals demonstrated counterclockwise hysteresis loops. Figure 2 gives such a plot for an individual patient. Figure 3 plots the mean plasma diclofenac concentrations with a best fit curve and mean PID for all patients during the 480 min after the administration of diclofenac. The mean ± SEM maximal plasma diclofenac concentration was 1463 ± 201 nM/L. The mean ± SEM (range) time to maximal plasma diclofenac concentration was 64 ± 13 (30–120) min.
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Figure 3 also plots the maximal PID and its timing for each patient. The maximal PID was 62% ± 10% (32%–98%), and the time to maximal PID was 309 ± 20 (210–360) min.
The respiratory rate at time 0 was 10.3 ± 0.6 (8–13) breaths/min. The minimal respiratory rate after the administration of diclofenac was 5.4 ± 0.6 (4–8) breaths/min. Minimal respiratory rates occurred 197 ± 52 (60–360) min after the administration of diclofenac. Minimal respiratory rates were significantly lower than baseline (P < 0.001). All patients had pulse oximetry readings >94% during continuous oxygen therapy. Pulse oximetry readings of <85% for <1 min were observed over a 15-min period in two patients who had inadvertently removed their oxygen masks. These two patients had respiratory rates of 4 breaths/min, were sleeping and easily roused at this time, and had voluntarily stopped using the PCA. Other than oxygen therapy, no specific treatment was required.
Figure 4 gives the plasma morphine and M6G concentrations, and Figure 5 shows the changes in hourly morphine consumption and plasma morphine and M6G concentrations after the administration of diclofenac. There were statistically significant decreases in hourly morphine consumption and plasma morphine and M6G concentrations after the administration of diclofenac (P < 0.001). Hourly morphine consumption was significantly less than that at baseline at 300, 360, and 420 min; plasma morphine concentration was significantly less than that at baseline at 300, 360, 420, and 480 min; and plasma M6G concentration was significantly less than that at baseline at 420 and 480 min (P < 0.05).
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Table 1 gives the maximal change in hourly morphine consumption and plasma morphine and M6G concentrations, as well as the changes at the times of minimal respiratory rate and maximal PID after the administration of diclofenac. The mean plasma M6G concentration was not less than the baseline value until 300 min. Plasma M6G concentrations were significantly different from baseline at 420 and 480 min (P < 0.05).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We investigated the clinical and pharmacokinetic effects of a single rectal dose of diclofenac in patients receiving PCA with morphine for moderate to severe postoperative pain (VAS >40 mm). It is common clinical practice to administer a NSAID to such patients, and our patient cohort was chosen and managed deliberately to represent routine clinical practice.
Peak analgesic effect did not reflect peak plasma diclofenac concentration. A counterclockwise hysteresis plot is indicative of a time lag between plasma concentration and effect. Our data produced a small time lag between plasma concentration and effect. We considered this a partial counterclockwise hysteresis plot, probably a consequence of the rapid increase in plasma diclofenac concentration with rectal administration. A counterclockwise hysteresis plot may be explained by drug distribution phenomena or production of an active metabolite. Diclofenac is metabolized to a compound without important analgesic activity (12); however, the central action of NSAIDs is well established both at spinal (13) and supraspinal (14) levels. Further, there is clinical evidence that the analgesic and inflammatory effects of NSAIDs are dissociated and that additional actions produce analgesia in conjunction with cyclooxygenase inhibition, particularly in the spinal cord (7). Our results are consistent with diclofenac requiring distribution to a central effect compartment such as the spinal cord. Similar results have been demonstrated in humans with paracetamol (15), an analgesic known to have centrally mediated analgesia. The use of plasma concentration data to optimize NSAID delivery and analgesic effect for postoperative pain may therefore require complex concentration-effect modeling.
We were surprised by the magnitude of the delay to peak analgesia after the administration of diclofenac. Although there was an observed analgesic effect after 60 min (the mean hourly morphine consumption was reduced by approximately 20% between 60 and 120 min), the mean maximal effect occurred after 300 min. The co-administration of morphine may confound interpretation of this observation; however, the peak PID occurred despite decreased plasma morphine and M6G concentrations. Our patients seemed to be increasing their demand for morphine at the end of the study period, which suggests that the peak analgesic effect had already occurred and that an 8-h dosing interval is appropriate for rectal diclofenac.
Part of the rationale for using a NSAID with an opioid in acute pain management is to reduce opioid consumption and the risk of undesirable opioid side effects. Although the evidence for a reduction in opioid side effects is inconsistent, reduction of the risk of excessive sedation and respiratory depression is desirable. A reduction in arterial carbon dioxide concentrations in patients given NSAIDs in conjunction with PCA morphine has been demonstrated (16). Previous studies evaluating the clinical effects of NSAIDs during opioid use are often multiple-dose studies in which the opioid has been titrated after initiation of the NSAID. Our study suggests that a single dose of NSAID given to a patient already titrating an opioid for moderate to severe pain may increase the risk of respiratory depression.
The narrow therapeutic ratio for morphine is well known. The delicate relationship between analgesia and side effects can be altered by changes in pain intensity. This phenomenon has been previously described in a case report in which the performance of a local anesthetic block in a patient receiving opioid precipitated life-threatening respiratory depression (17). It is easy to appreciate this phenomenon after the rapid and often total analgesia produced by local anesthetics. However, the risk of inducing opioid-induced respiratory depression after the administration of a NSAID may not have been fully appreciated, as the clinical use of NSAIDs is influenced strongly by emphasis on opioid-sparing activity, lack of respiratory depression, and their secondary role in the management of moderate to severe postoperative pain.
This attitude may be inappropriate for patients who are titrating an opioid to a high pain intensity before dosing with a NSAID. NSAIDs are highly effective analgesics for postoperative pain (18). Four of our seven patients experienced a >50% reduction in the pain score during the 480-min period after diclofenac administration, despite already receiving morphine. Clearly, a NSAID can alter the MEAC for opioid significantly. Many patients may have NSAIDs withheld until some hours after surgery; for example, until the risk of bleeding is reduced. Perhaps after discharge from a high-dependency or postanesthesia care unit to a general surgical ward, such patients will have a lower perceived risk from their analgesic regimen and a lower level of nursing surveillance. Our observations suggest a need to modify the clinical approach to monitoring and the use of oxygen therapy in these patients, as hypoxemia may increase the risk of postoperative complications (19).
The mean time to minimal respiratory rate occurred when the mean morphine consumption and plasma morphine concentration had decreased by 20% and 23%, respectively. However, the mean plasma M6G concentration was essentially unchanged at this time. This delay is not surprising, as the peak plasma M6G concentration occurs at a mean time of 0.73 h after a single IV morphine injection in volunteers (20). Moreover, there is potential for kinetic interactions between analgesic drugs; NSAIDs may decrease the renal excretion of M6G after morphine administration (21). M6G has an analgesic potency many times that of morphine (22), and pharmacokinetic studies indicate that M6G has quantitative significance after all routes of administration (20). A considerable proportion of the clinical effects of parenteral morphine may be attributable to M6G. Therefore, the period of increasing analgesia after NSAID administration with little change in plasma M6G concentrations may represent a window of risk for patients. We observed that significant reductions in plasma M6G concentrations did not occur until 7 h after diclofenac administration. The potential benefits of opioid sparing may not therefore be realized until this time.
Plasma M6G concentrations have not usually been measured during studies evaluating morphine kinetics during PCA. The plasma M6G concentrations for each of our patients were remarkably constant. Given the clinical importance of M6G, it is possible that patients using PCA are titrating their morphine consumption to establish appropriate plasma and effect-site M6G concentrations. Determination of optimal site-specific concentrations of M6G may warrant a high priority in future research. Our data characterize the effective plasma concentration for M6G during PCA and the time course of changes after the administration of diclofenac.
In conclusion, patients with moderate to severe postoperative pain given rectal diclofenac during morphine PCA may experience analgesia sufficient to disturb the balance between opioid MEAC and side effects. The benefits of reduced morphine consumption may be delayed for at least 6 h until plasma M6G concentrations have decreased significantly. During this period, a higher level of monitoring should be considered for patients receiving a NSAID after titration of opioid for moderate to severe pain.
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Acknowledgments |
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The authors thank Mr. S. Ashmore and Mrs. J. Spendlove of the University Department of Anesthesia; and the staff of the Spinal Unit, Queens Medical Center, Nottingham.
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