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The Department of Anaesthesiology and Intensive Care, Karolinska Hospital and Institute, Stockholm, Sweden
Address correspondence and reprint requests to Åsa Österlund, MD, Department of Anaesthesiology and Intensive Care, Karolinska Hospital and Institute, SE-171 76 Stockholm, Sweden.
| Abstract |
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E) and tidal volume (VT) were reduced in the S-Large group, and
E was reduced in the morphine group. End-tidal CO2 increased in both groups (P < 0.05), but respiratory rates remained unchanged. In the S-Small group, no ventilatory changes were recorded. In the S-Large group, the median sedation score was 6.8 cm with corresponding values in the morphine and S-Small groups of 3.3 and 2.5 cm, respectively. There was a relationship between the plasma concentration of sameridine and the depression of ventilation. We conclude that sameridine influences resting ventilation and that this effect is directly related to plasma concentrations of sameridine. From a ventilatory aspect, a clinical dose of sameridine with both local anesthetic and opioid properties seems safe. Implications: Sameridine, a molecule with both local anesthetic and analgesic properties, impaired resting ventilation after a large IV dose (0.73 mg/kg), more so than 0.10 mg/kg IV morphine. A clinical dose of sameridine (0.15 mg/kg) did not have any effects on ventilation.
| Introduction |
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Intrathecal administration of opioids produces excellent postoperative analgesia, but several case reports have documented severe respiratory depression (7). In a recent study using intrathecal sameridine doses of 1025 mg in adult patients undergoing arthroscopic knee surgery, no negative influences on respiratory rate or peripheral oxygen saturation were observed (8). Because sameridine has intrinsic opioid characteristics, its ventilatory effects were examined.
The main purpose of this study was to evaluate the influence of two doses of sameridine on resting ventilation in healthy volunteers. Based on previous tolerability data, a large dose of sameridine (0.73 mg/kg) was selected, whereas the small clinical dose (0.15 mg/kg) was chosen to achieve plasma concentrations in the range observed in patients after intrathecal administration. Morphine (0.10 mg/kg) was chosen for comparisons because it is standard for postoperative pain management.
| Methods |
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The subjects were studied in a single-blinded, randomized, three-way cross-over design with at least 7 days between the investigations. The subjects and the laboratory technician monitoring the ventilatory measurements were blinded to the test drug given. The investigator was unaware of the randomization until the experimental day. Venous cannulas were placed in the left and right cubital veins. One was used for infusion of the study drug and the other for blood sampling. The subjects rested in a comfortable bed with a 15o head-up tilt and were not allowed to leave the bed for 4 h after the start of drug infusion. The subjects received 20-min IV infusions of 0.15 mg/kg sameridine (S-Small), 0.73 mg/kg sameridine (S-Large), and 0.10 mg/kg morphine. During the study sessions, noninvasive blood pressure and heart rate were recorded 5 min before the start of drug infusion (baseline) and were repeated at 5-min intervals up to 30 min and thereafter at 40, 60, 90, 120, 180, and 240 min after the start of drug infusion.
Resting ventilation was recorded with the subjects breathing air via a modified transparent face mask tightly positioned over their noses and mouths. The subjects were allowed an initial resting period of approximately 2030 min for adaptation in a relaxed atmosphere. An in-line infrared capnometer (Model 14360 A; Hewlett-Packard, Palo Alto, CA) and a pneumotachograph (Fleisch 2; Siemens Elema, Solna, Sweden) (linear for flows up to 2.4 L/s) were placed in the circuit dead space. The dead space of the system was 70 mL as measured by water displacement. Inspiratory and expiratory resistances of the measuring apparatus were 2 cm H2O · L-1 · s-1. Tidal volume (VT) was measured by integration of the flow signal from the pneumotachograph. Minute ventilation (
E) was the result of VT and respiratory rate (RR). Flow (V), VT, and in-line ETCO2 were registered on an ink-jet recorder, and the signals were stored in a computer. Inspired and expired concentrations of O2 were continuously recorded by a device that also measured SpO2 by finger pulse oximetry. Ventilation volumes were presented at body temperature and pressure saturated. The in-line Hewlett-Packard capnometer was calibrated with certified gases before each experiment. Calibration of the pneumotachograph was performed before and after each experiment using a high-precision syringe. Ventilatory variables were recorded 5 min before the start of drug infusion (baseline) and were repeated at 5-min intervals up to 30 min and thereafter at 40, 60, 90, 120, 180, and 240 min after the start of drug infusion. The time points 20 and 120 min were selected for the statistical evaluation because the highest plasma concentration was expected at 20 min (end of infusion), whereas a reasonable recovery period had elapsed at 120 min after the start of infusion.
The degree of sedation, as rated by the subject, was recorded by using a 10-cm visual analog scale with the end points of 0 = awake, not tired and 10 = asleep.
Five milliliters of peripheral blood was collected before drug administration (<15 min), every 5 min up to 40 min, and thereafter at 1, 1.5, 2, 3, 4, 6, and 8 h after the start of infusion. The samples were collected in heparinized tubes and centrifuged; plasma was frozen at -20°C within 1 h of collection.
Sameridine was assayed by capillary gas chromatography using nitrogen-sensitive detection (9). The precision, given as the coefficients of variation, was between 5% and 10% at three concentration levels: 50, 300, and 2000 nmol/L. The limit of quantification (LOQ) of the method was set at 10 nmol/L.
Morphine was assayed by using a method based on liquid chromatography-mass spectrometry, with a stable isotopic-dilution technique. The precision (coefficient of variation) was between 5% and 7% at three concentration levels: 4, 25, and 50 nmol/L. The LOQ of the method was set at 1.5 nmol/L.
Pharmacokinetics of sameridine and morphine were determined using noncompartmental analysis and a computer program (PHA 176 release 5.0.1; Bolt Beranek and Newman Software Products Corp., Cambridge, MA). The peak plasma concentration (Cmax) was observed directly from the individual plasma concentration-time curves. The terminal slope of the log-linear plasma concentration time (
) was estimated by linear regression of three to six concentration time points. The total area under the plasma concentration-time curve (AUC) was estimated by using the log-linear trapezoidal rule up to the last plasma concentration that was above the LOQ. Total AUC was calculated as AUC + AUCextrapolated where AUCextrapolated was calculated as Ccalc/
. Ccalc is the plasma concentration calculated (by using linear regression) at the final sampling. The terminal half-life (t
) was calculated by ln/
. Plasma clearance (CL) was calculated by dose/AUC.
For the evaluation of the relationship between plasma concentrations and effects on ventilation in the sameridine groups, ETCO2 was chosen as a representative variable for the effects on ventilation.
The statistical analyses of the effects on ventilation were based on the within-subject differences by using nonparametric procedures. The absolute changes in ventilatory variables from baseline to 20 and 120 min after the start of infusion were studied. Besides descriptive statistics and graphs, formal comparisons were made by pairwise sign test corrected for multiplicity (i.e., corrected for the three possible pairs) according to Bonferroni-Holm. Ventilatory variables and sedation data are presented as median (range or quartiles). Pharmacokinetics are presented as mean ± SD.
| Results |
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In the S-Large group,
E was reduced 28% (P < 0.05) and VT was reduced 18% at the end of the 20-min drug infusion (Fig. 1; Table 1). This was associated with an 11% increase in ETCO2 (P < 0.01); that is, 0.55 mm Hg (1st and 3rd quartiles 0.41, 0.72) (Fig. 2). By 2 h,
E had returned to the baseline value, whereas ETCO2 remained slightly increased by 0.13 mm Hg (0.05, 0.20). In the S-Small group, none of the ventilatory variables
E, VT, or ETCO2deviated significantly from the baseline recording (Table 1).
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E (P < 0.01) at the end of drug infusion with a corresponding 5% increase in ETCO2 (P < 0.01). At 2 h,
E had returned to baseline, whereas ETCO2 remained slightly increased at 0.20 mm Hg (0.20, 0.30) RRs showed no changes at any time or in any dose group (Table 1).
The increase in ETCO2 was most pronounced in the S-Large group (P < 0.05 versus morphine and S-Small). The changes in
E were not different between any of the sameridine groups and the morphine group, whereas the difference between the two sameridine groups was significant (P < 0.05).
At the end of infusion, the median sedation score was 6.8 cm (4.08.5) in the S-Large group. In the S-Small group, the sedation score was 2.5 cm (0.05.0), and the corresponding value in the morphine group was 3.3 cm (2.06.0). Sedation scores were somewhat higher for a longer time period in the morphine group (Fig. 3).
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of 3.6 (0.9) h and plasma CL was 1.68 (0.48) L/min.
After infusion of morphine, the mean Cmax was 237 ± 72 nmol/L. The mean terminal t
was 2.0 ± 0.2 h with a clearance of 2.22 ± 0.61 L/min.
There was a relationship between the plasma concentration and the effects on ETCO2 (Fig. 4). The levels of plasma concentration observed in the S-small group had no effects on ventilation. The maximal median increase in ETCO2 was observed 25 min after the start of infusion, whereas the median maximal plasma concentration was observed 18 min after the start of infusion. A time dependency illustrated by the counterclockwise hysteresis was seen for the relationship between concentration and effect (Fig. 4). This counterclockwise hysteresis indicates a distribution delay between the effect compartment and the changes in plasma concentration (10).
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| Discussion |
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All subjects in this investigation received the two different infusions of sameridine and the infusion of morphine in random order, which makes the results comparable as far as biological variations are concerned. Studies on resting ventilation in the awake state are, however, influenced by many additional factors, such as stress, time of the day, food, and exercise, resulting in interindividual variations (11). Many of these factors were eliminated by the design of the study, but they should be kept in mind when interpreting effects on respiration in awake humans. It is important that the laboratory routines be strict and that the subject be allowed enough time to get accustomed to the breathing apparatus. In the current study, at least 30 min was allowed for adaptation before control measurements were performed. The subjects were comfortably resting in a semirecumbent position, and soft music and low-intensity illumination were provided to improve satisfaction and relaxation.
In the evaluation of drug-dependent respiratory depression, morphine is often used as a reference drug. Hence, morphine was also chosen in the current study as an active control to position sameridine with regard to its potential respiratory depressant action. However, whether morphine, with its active metabolites, is an ideal reference drug is debatable because other analgesics often are of short duration and lack active metabolites, e.g., fentanyl (12). The influence of morphine metabolites on pharmacodynamics is not clearly understood. The major metabolite of morphine, morphine-3-glucuronide (M3G) has a very low affinity for the µ-opioid receptor. Another metabolite, morphine-6-glucuronide (M6G), that binds to the µ-opioid receptor has analgesic properties and can induce respiratory depression of a lesser degree than equianalgesic doses of morphine (13,14). In our study, there was a tendency to prolonged sedation and later-occurring side effects in the morphine group compared with the sameridine groups; this may have been caused by morphine metabolites.
The pharmacokinetics of morphine (15,16) and sameridine (6) in our study are similar to previous studies in healthy volunteers.
On a molar basis, the small sameridine dose was three quarters of the morphine dose, whereas the large sameridine dose was 6.5 times greater. Hence, when given in equimolar doses, sameridine seems less prone than morphine to induce ventilatory depression, which could be explained by their difference in µ-agonist activity (3). The analgesic effect, which also is dependent on µ-agonist activity, has been investigated in mice and showed that morphine was 23 times more potent than sameridine (17).
In Jorfeldt et al.'s (18) classic study, resting ventilation in humans was not affected by the local anesthetics lidocaine, mepivacaine, or bupivacaine. Furthermore, Johnson and Löfström (19) found that neither lidocaine, mepivacaine, nor bupivacaine affected resting ventilation or ventilation stimulated by hypercarbia. Based on these reports, local anesthetics are unlikely to have negative effects on ventilation.
In humans, the ventilatory effects of sameridine have been documented after its intrathecal administration to patients undergoing arthroscopic knee surgery (8). That study did not show any negative effects on ventilation based on the monitoring of RRs and peripheral O2 saturation, which are in agreement with the results of the small-dose group in the present study. Additionally, several of the patients in that study received IV morphine postoperatively without concomitant respiratory effects.
After spinal administration, there is also a systemic uptake, often characterized by a long terminal half-life, reflecting the absorption from the intrathecal space (20). Both intrathecal and systemic concentrations could have effects on ventilation (21,22). According to the concentration-effect relationship in this study, systemic concentrations obtained in the range of those in the small-dose group seem safe from a ventilatory point of view. The plasma concentrations after the larger dose of sameridine impaired respiration with a reduced
E and increased ETCO2, together with increased sedation. Both the ventilatory effects and sedation seen in the large-dose group were more pronounced than those after the IV morphine dose of 0.10 mg/kg. This difference indicates that the large dose of sameridine is inappropriate for clinical use, bearing in mind that this dose was 6.5 times greater than the morphine dose on a molar basis. Because local anesthetic drug effects do not result in respiratory depression, the ventilatory effects seen after the large dose of sameridine are most probably caused by the built-in µ-agonist properties that may result in a depressed central ventilatory responsiveness.
We conclude that the IV administration of sameridine, a drug with combined local anesthetic and partial µ-opioid agonistic properties, may influence respiration in a plasma-concentrationdependent fashion. From a ventilatory aspect, a clinical dose (0.15 mg/kg) of this new drug seems safe.
| Acknowledgments |
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Many thanks to Anette Ebberyd and Ringvor Hägglöf for their contributions as laboratory technicians; Pär Karlsson for statistical evaluation; and Carina Norsten-Höög and Caroline Borgström for bioanalytical work.
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