PHARMACOKINETICS OF FENTANYL DURING CONSTANT RATE I.V. INFUSION FOR THE RELIEF OF PAIN AFTER SURGERY

Br. J. Anaesth. (1986), 58, 950-956 PHARMACOKINETICS OF FENTANYL DURING CONSTANT RATE I.V. INFUSION FOR THE RELIEF OF PAIN AFTER SURGERY D. J. R. DUTHIE, A. D. McLAREN AND W. S. NIMMO Acute pain after surgery is managed conventionally by the intermittent administration of opioid drugs, often with a dosing interval determined by patient request. Drug is given only when pain is experienced, which ensures that this regimen is ineffective (Utting and Smith, 1979; Hug, 1980). Fear of inducing respiratory depression or physical dependence, and a prescribed minimum interval between injections, may persuade nursing staff against administering further opioid drug when requested to do so (Cartwright, 1985). Delivery of drug to its receptor site is influenced by the absorption and disposition of the drug as well as by the dosing interval. If opioids are given i.m., their absorption may vary greatly. In a study of morphine concentrations after i.m. injections, Rigg and colleagues (1978) showed that the peak plasma concentration varied 5-fold, and the time taken to reach peak concentrations varied 15-fold. Similar variations have been demonstrated for pethidine (Mather et al., 1975). This variation is less when the drug is injected to the arm rather than the thigh (Stanski, Greenblatt and Lowenstein, 1978). I.v. infusion of opioids ensures that the prescribed dose is received by the patient and avoids variability in the absorption of the drugs. However, distribution, metabolism and excretion may be affected by disturbances in physiology caused by anaesthesia and surgery. The aim of the present study was to investigate the pharmaco- DAVID J. R. DUTHIB,* M.B., OLB., F.F.A.R.CJ.; A. DOUGLAS MCLAREN, M.B., CH.B., FJ-AJLCJ.; WALTER S. NIMMO,* BSC, M.D., F.R.C.P., F.F-A.R.CS; University Department and Divisionof Anaesthesia, Western Infirmary.GlasgowGl 16NT. *Present address: Department of Anaesthesia, Sheffield University Medical School, Beech Hill Road, Sheffield S 2RX. SUMMARY Forty-five patients in four groups undergoing orthopaedic, upper abdominal, prolonged or cardiac surgery received a constant rate i.v. infusion of fentanyl 0 fig h~\ for 24 h starting 2 h before surgery. A single bolus dose was given i.v. at the induction of anaesthesia. Plasma fentanyl concentrations, measured by radioimmunoassay were between 1 and 3 ng ml' 1 until the infusions were discontinued. Clearance of fentanyl was decreased in the cardiac surgery group only. The elimination half-life was 7.3-9.7 h. This simple regimen produced effective analgesia. kinetics and effects of a constant rate i.v. infusion of fentanyl 0 ug h" 1 in patients undergoing different types of surgery. PATIENTS AND METHODS Patients and anaesthesia The study was approved by the local Ethics Advisory Committee. All patients gave informed written consent to participate. Patients studied underwent joint replacement surgery to the knee or hip (orthopaedic group); surgery to the stomach or gall bladder through a midline epigastric incision (upper abdominal group; surgery expected to last longer than 4 h (prolonged group) or surgery involving cardiopulmonary bypass (cardiac group). Patients were excluded if they were aged less than 18 yr or more than 70 yr, or had pre-existing respiratory disease. An infusion of fentanyl 0 ug h" 1 was delivered from a Baxter Travenol infusor (Nimmo and

PHARMACOKINETICS OF CONSTANT RATE FENTANYL 951 Todd, 1985) to a peripheral vein through an 18-gauge cannula dedicated exclusively to the infusion. The infusion was begun 2 h before the induction of anaesthesia and continued for 24 h (26 h in the cardiac group). Anaesthesia was standardized. Premedication additional to the infusion of fentanyl was not given. Anaesthesia was induced with thiopentone 5 mg kg" 1 and neuromuscular blockade was produced by pancuronium 0.07 mg kg" 1. The trachea was intubated and the patient's lungs were ventilated with 67% nitrous oxide and 1-2% enflurane in oxygen. The minute volume of ventilation was related to body weight. Before skin incision, a single bolus dose of fentanyl 0 ug (500 ig in the cardiac group) was given. Additional bolus doses of pancuronium were given as required; its effects were antagonized at the end of surgery using neostigmine 2.5 mg given with atropine 1.2 mg. After surgery, morphine mg i.m. was available to any patient whose pain was not relieved by the infusion of fentanyl. Prochlorperazine 12.5 mg i.m. was prescribed to treat vomiting. The total doses of morphine and prochlorperazine received by each patient in the first 24 h after surgery were recorded. Blood sampling Venous blood was sampled from a peripheral vein in a limb other than that bearing the fentanyl infusion at the following times: before and 0.5, 1, 2, 4, 8, 12 and 24 h after the infusion was established. Further samples were taken 0.25, 0.5 and 1 h after the bolus dose of fentanyl, and 0.5, 1, 2 and 4 h after the infusion was discontinued. Plasma was separated and stored at 20 C until plasma fentanyl concentrations were measured by radioimmunoassay (Michiels, Hendricks and Heykants, 1977; Schiittler and White, 1984). The coefficients of variation for the radioimmunoassay were 4.4% within an assay and 12% between assays. The assay was sensitive enough to detect fentanyl 0.1 ng ml" 1 in plasma. Pharmacokinetic calculations The pharmacokinetic parameters clearance, volume of distribution, elimination half-life and elimination rate constant were calculated for each patient from the plasma fentanyl concentrations. The areas under fentanyl concentration-time curves (AUC) were calculated by a linear trapezoidal method (Yeh and Kwan, 1978). The area from the last sample until infinity was estimated by extrapolation of the concentrationtime curve (Rowland and Tozer, 1980). The following equations were used in the calculations. Cl = x _ AUC ^R In2 (2) (3) where Cl = clearance; X 1 = total dose administered; AUC = total area under concentration-time curve; j/o area = volume of distribution; k = elimination rate constant; 7iP = slow half-life. The elimination rate constant was calculated from the slope of the plasma concentration-time curve after stopping the infusion. Respiration Respiratory function was assessed by measurements of respiratory rate (over 1 min) and peak expiratory flow rate (PEFR) before, and at 8, 12 and 24 h after surgery. Arterial blood-gas tensions were measured at 12 and 24 h. Analgesia At 8, 12 and 24 h, patients were asked to describe their experience of pain. This was recorded on a 4-point scale: 0 = no pain; 1 = slight pain; 2 = moderate pain; 3 = severe pain. Any nausea or vomiting was recorded. Statistical analysis Serial measurements within each group were compared using the paired two-sample t test. Simultaneous measurements between groups were compared by one-way analysis of variance and Wilcoxon's rank sum test. Statistical significance was accepted when P < 0.05. RESULTS Forty-five patients were studied. There were no significant differences in the age, weight and height of patients in any of the four groups (table I).

952 BRITISH JOURNAL OF ANAESTHESIA TABLE I. Patient data (mean ± SD). *P < 0.05 compared with all other groups Upper abdominal Cardiac 13 12 Weight Height Duration ASA Surgery Age (yr) (kg) (cm) (min) grades 5 Hip 5 Knee 61 ±8 69±12 170± 120±50 I, II 4 Stomach 9 Gallbladder 49±14 65±14 160± 0±30 I, II 5 Head and 58±11 69±11 170± 340±180* II, III neck 5 Chest wall 6 Valve replacement 6 Vein graft 55±12 69±9 170± 200±70* Bypass time 80±40 III, IV E? 2- Anaesthesia ~ 3-} Anaesthesia 1-1 2 4 0-ugboiis 12 24 26 28 Time (h) 0- ug h' 1 infusion 2 4 12 0-ugbolus 24 26 28 Time (h) 0-pgh" 1 infusion FIG. 1. Mean (±SEM) plasma fentanyl concentrations in patients undergoing orthopaedic surgery. All patients received fentanyl 0 ug h~' from 0 to 24 h. A bolus dose of 0 ug was given i.v. at 2 h. 3-i E3 ' Anaesthesia r 2 4 loo-yg bolus 12 24 26 28 Time(h) 0-uq h" 1 infusion FIG. 2. Mean (±SEM) plasma fentanyl concentrations in 13 patients undergoing upper abdominal surgery. Dose regimen as infigure.1. FIG. 3. Mean (±SEM) plasma fentanyl concentrations in patients undergoing prolonged surgery. Dose regimen as in figure 1. Pharmacokinetics The variation in plasma fentanyl concentrations between patients in each group was marked. In a two-way analysis of variance for sampling time and patient, these differences were significant in the orthopaedic, upper abdominal and prolonged groups {P < 0.001) and of borderline significance in the cardiac group (0.05 < P < 0.). The mean plasma fentanyl concentrations are illustrated in figures 1 to 4. Between the groups, there were no significant differences in the plasma fentanyl concentrations at any sampling time. Within the orthopaedic group, from 30 min after the bolus dose until the infusions were discontinued, there were no significant differences in the plasma fentanyl concentrations. In the upper abdominal, prolonged and cardiac groups, the plasma fentanyl concentrations were significantly greater at 24 h than at 12 h (table II).

PHARMACOKINETICS OF CONSTANT RATE FENTANYL 953 I 2 1- Anaesthesia The calculated model-independent values and the correlation coefficients of the data used to calculate k l0 are shown in table III. Although the clearance of fentanyl in the upper abdominal group was less than that in the orthopaedic and prolonged groups, the difference did not achieve statistical significance. Clearance in the cardiac group was significantly less than that in the orthopaedic and prolonged groups, but not significantly different from that in the upper abdominal group. The elimination half-life of fentanyl ranged from 7.3 to 9.7 h. 500-U bolus 14 Time (h) 0-ug ' 1 bolus 26 28 30 FIG. 4. Mean (±SEM) plasma fentanyl concentrations in 12 patients undergoing cardiac»urgery. All patients received fentanyl 0 ug h" 1 from 0 to 26 h. A bolus dose of 500 ng was given i.v. at 2 h. TABLE II. Plasma fentanyl concentration] (mean t For difference between 12 h and 24 h Upper abdominal Cardiac 12 h 1.8 ±0.2 1.8 ±0.2 1.4±0.1 2.0±0.1 24 h 2.0±0.3 2.2 ±0.2 1.7±0.2 2.8±0.2 ±SEM). P\ ns <0.02 <0.01 < 0.005 Respiration Because artificial ventilation was used after cardiopuknonary bypass, respiratory function was not measured, and pain was not assessed subjectively, in the cardiac group. There were no significant differences in respiratory rates within or between the other groups but, after surgery, PEFR were significantly lower in the upper abdominal group than in the other two groups. At 24 h the PEFR in the prolonged group were less than the respective preoperative flow rates. Arterial blood-gas tensions were similar at 12 and 24 h in the three groups (table IV). There were no significant differences between the groups at either time. TABLE III. Calculated pharmacokinetic values {mean ± SEM). *P < 0.05 cardiac compared with orthopaedic or prolonged groups. Cl - Plasma clearance; k,, = elimination rate constant; YD""* = volume of distribution ;Tf = elimination half-life n Cl (ml min" 1 ) (litre) T* (h) Correlation coefficient of hi data with slope *, Upper abdominal Cardiac 13 12 960±140 720 ±70 9O0±70 660 ±30* 0.13 ±0.02 0.11 ±0.01 0.16 ±0.04 0.13 ±0.02 500±60 470 ±70 6±0 380±60 7.5±1.7 8.5±2.0 9.7±2.1 7.3±1.4 0.88 ±0.03 0.80 ±0.03 0.90 ±0.03 0.89 ±0.03 TABLE IV. Respiratory function {mean ±SEM). *P < 0.01 compared with orthopaedic and prolonged groups; fp < 0.05 compared with orthopaedic group Respiratory rates (b.p.m.) Peak expiratory flow rates (% of preop. value) Arterial blood-gas tension (k Pa) 12 h 24 h Upper abd. 0 16±1 16±1 19±1 8h 15±1 18±1 15±2 12 h 13±1 13±1 14±2 24 h 15±1 15±1 14±2 8h 85±6 42 ±4* 70±4 12 h 82±5 42 ±4* 70±4 24 h 86±5 45 ±6* 66±5t Pco, 5.8 ±0.2 5.8±0.2 6.0 ±0.2 Po, 8.7 ±0.3 8.6 ±0.5 8.7 ±0.5 Pco, 5.9 ±0.2 5.9±0.2 5.7 ±0.3 Po, 8.9 ±0.4 8.5 ±0.4 8.9±0.5

954 S 50-777s Upper abdominal FIG. 5. Pain experience recorded in patients: open columns = none or mild; cross-hatched columns = severe. TABLE V. Mean additional ijn. morphine and prochlorperaznu administered {mean ± SEM) Morphine (mg) ProchJorperazine (mg) 5±2 11 ±3 Upper abdominal 19±4 5±2 6 ±3 ±3 Cardiac 14±4 Analgesia Subjective assessments of pain (on three occasions after surgery) elicited complaints of severe pain in 7% of observations in the orthopaedic group and in 15 % of the observations in the upper abdominal group (fig. 5). Nausea and vomiting were experienced by 20% of the orthopaedic group, 15% of the upper abdominal group and 30% of the prolonged group. The mean additional morphine and prochlorperazine required in all groups was less than two doses of morphine and one dose of prochlorperazine (table V). DISCUSSION An infusion of fentanyl 0 ugh" 1 supplemented by a bolus of 0 ug produced plasma fentanyl concentrations which ranged from 1.4 to 2.8 ng ml" 1 from the end of surgery until the infusion was discontinued at 24 h. Fentanyl demonstrates a close concentration-response relationship. The concentrations measured were within the range 1-3 ng ml" 1, which has been shown to produce analgesia with less than 50% decrease in the ventilatory response to carbon dioxide (Andrews et al., 1983). Infusing a drug to steady-state requires both BRITISH JOURNAL OF ANAESTHESIA rate-controlled drug administration and a recipient whose clearance is unchanging. During any 24-h period which includes anaesthesia and surgery, many acute perturbations may occur in a patient's physiology. Despite this, the measured plasma fentanyl concentrations were similar to those which would be anticipated at steady-state. Theoretical steady-state concentrations were calculated from the equation: (4) where k J t = infusion rate; Cl = clearance; Cj 8 = steady state plasma concentration. The expected mean steady-state concentrations (ng ml" 1 ) (measured concentrations at 24 h in parentheses, table II) were orthopaedic 1.8 (2.0); upper abdominal 2.4 (2.2); prolonged 1.8 (1.7); and cardiac 2.5 (2.8). After infusion for five elimination half-lives, plasma concentrations of a drug, subject to first-order elimination, should be within 98 % of the eventual steady-state concentration. The elimination half-life of fentanyl varied from 7.3 to 9.7 in the four groups (table III). After 24 h of constant rate infusion, plasma concentrations would be expected to be 82-90 % of their steady-state value. However, in this study patients received a supplementary bolus dose of fentanyl which modified the plasma concentrations. Opioid infusions begun after anaesthesia have been characterized by a failure to relieve pain until plasma concentrations have increased to within the therapeutic range (Stapleton, Austin and Mather, 1979). Regimens to overcome this delay which utilize large loading doses, sequential infusion rates and microprocessor-controlled infusion pumps have achieved steady-state rapidly (Vaughan and Tucker, 1975; Wagner, 1975). Complex apparatus and a knowledge of the pharmacokinetic indices of the infused drug are required. Large loading doses may result in initial plasma concentrations within the toxic concentration range (Mitenko and Ogilvie, 1972). The infusion regimen described is simple, and achieves the desired result with a disposable pump requiring no external power source. The clearances of fentanyl in the orthopaedic and prolonged groups were similar to those reported in volunteers and patients using bolus doses or i.v. infusions of less than 4 h duration (Hug, 1984). The clearance of fentanyl tended to be lower in the upper abdominal group and was

PHARMACOKINETICS OF CONSTANT RATE FENTANYL 955 reduced significantly in the cardiac group. Fentanyl is metabolized principally in the liver by N-dealkylation and hydroxylation (McClain and Hug, 1980). Clearance is greater than 50% of liver blood flow and, therefore, flow dependent. Anaesthesia and surgery decrease liver blood flow intra-abdominal surgery more than surgery to the body surface (Gelman, 1976). Alterations in liver blood flow in upper abdominal surgery and during surgery involving cardioputmonary bypass may be responsible for the reduced clearances in these groups. The increase in mean plasma concentrations between 12 and 24 h varied from only 0.3 ng ml" 1 in the prolonged group to 0.8 ng ml" 1 in the cardiac group. These differences were statistically significant in the upper abdominal, prolonged and cardiac groups. The percentage increases by groups in 12 h were: orthopaedic 11%; upper abdominal 22%; prolonged 21% and cardiac 40%. With an elimination half life of 7.3-9.7 h, mean plasma fentanyl concentrations would be expected to increase from 58-68% to 82-90% of steady-state concentrations during the last 12 h of infusion. A proportional increase in plasma concentration of 32-41 % would be expected, which is larger than the increase of 11-40% measured, possibly as a result of the additional bolus dose given. The half-life of 7.3-9.7 h is longer than that reported in healthy volunteers and patients given less fentanyl than 8 ug kg" 1 (Hug, 1984). Plasma fentanyl concentrations measured for 4 h after the infusions were discontinued, were used to calculate the rate constant of elimination, k l0. Elimination half-life is given by 0.693/)fe. This method requires that samples are taken for three times the half-life and that the correlation coefficient of the log plasma concentration-time data is greater than 0.98. The 4 h sampling time in our study was less than the elimination half-life, but concentrations would have been too small to measure 22-30 h after the infusions were discontinued. The mean correlation coefficients for the slope k l0 were 0.80-0.90. Metabolites of fentanyl are thought not to be active pharmacologically (Soudijn, Van Wijngarden and Janssen, 1974). After prolonged infusion, metabolites can interfere with drug metabolism and may prolong the elimination half-life. Elimination half-lives comparable to those reported here, have been found in patients receiving fentanyl 60 ng kg" 1 (Bovill and Sebel, 1980). These patients underwent surgery involving cardiopulmonary bypass. It is possible that, in studies using smaller doses of fentanyl over a shorter time, distribution was still occurring at the time blood was sampled for calculation of elimination half-life. The large apparent volumes of distribution obtained are appropriate for a lipophilic drug. Measurements of respiratory function (table IV) showed no difference in the mean respiratory rates after surgery compared with those measured in the preoperative period. Arterial blood-gas tensions at 12 and 24 h were similar to reported values in patients after surgery, whose pain was relieved by regular i.m. injection of morphine (Spence and Logan, 1975; Nimmo and Todd, 1985). The peak expiratory flow rates of patients who had undergone upper abdominal surgery were significantly worse after surgery than those in the orthopaedic and prolonged groups. The results of the assessment of pain, and nausea and vomiting, are given in figure 5 and the text. This was principally a pharmacokinetic study, so these assessments were made in an open manner and are subject to the limitations that imposes. The mean requirement for additional analgesia or antiemetic agent, or both, was less than two doses of morphine and one of prochlorperazine, respectively. Analgesia was considered satisfactory in the great majority of observations. In conclusion, fentanyl by constant rate infusion supplemented by a single bolus dose produces concentrations that approach the eventual steadystate concentrations within the first 24 h of infusion. Mean plasma fentanyl concentrations within the range 1 3 ng ml" 1 throughout. ACKNOWLEDGEMENTS were obtained We are grateful to Mr P. D. Henderson for technical assistance, to Mrs C. M. King for typing this paper and to Professor C. J. Hull for his help in the preparation of the manuscript. The co-operation of our surgical and anaesthetic colleagues is gratefully acknowledged. REFERENCES Andrews, C. J. H., Sinclair, M., Prys-Roberts, C, and Dye, A. (1983). Ventilatory effects during and after continuous infusion of fentanyl or alfentanil. Br.J. Anaesth., 55, 21 IS. Bovill, J. G., and Sebel, P. S. (1980). Pharmacokinetics of high-dose fentanyl. A study in patients undergoing cardiac surgery. Br. J. Anaesth., 52, 795. Cartwright, P. D. (1985). Pain control after surgery: a survey of current practice. Arm. R. Coll. Surg. Engl., 67, 13.

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