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ANESTHETIC PHARMACOLOGY

The Concentration-Effect Relationship of the Respiratory Depressant Effects of Alfentanil and Fentanyl

Leena H. Mildh, MD^*, Harry Scheinin, MD PhD, and Olli A. Kirvelä, MD PhD

*Department of Anesthesia and Intensive Care, Helsinki University Hospital, Helsinki, Finland; and Department of Clinical Pharmacology and Department of Anesthesia, Turku University Hospital, Turku, Finland

Address correspondence and reprint requests to Leena Mildh, MD, Department of Anesthesia, Helsinki University Hospital, Hospital for Children and Adolescents, PO BOX 281, FIN-00029 HUS, Finland. Address e-mail to leena.mildh{at}hus.fi

	Abstract

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The relative potencies of fentanyl and alfentanil for respiratory depression were determined in eight healthy male volunteers in a double-blinded, randomized study with a cross-over design. The drugs were delivered by computer-driven infusion with logarithmically ascending plasma concentrations until the respiratory rate reached 2/min and/or oxygen saturation decreased below 85% with subjects breathing room air. Ventilation was measured with respiratory inductive plethysmography, indirect calorimetry, and arterial blood gas analysis, and plasma drug concentrations were determined. Pharmacodynamic modeling was performed using a fractional E_max model for minute volume and respiratory rate and the concentrations producing 50% depression (i.e., apparent 50% effective concentration [EC₅₀] values) were determined. Both drugs decreased ventilation in a similar manner, and drug infusions were terminated at mean ± SD measured plasma concentrations of 254 ± 88 ng/mL and 5.1 ± 1.7 ng/mL for alfentanil and fentanyl, respectively. Alfentanil decreased minute volume from baseline by 54% ± 19% and respiratory rate by 40% ± 11% with EC₅₀ values of 234 ± 57 ng/mL and 195 ± 101 ng/mL. The respective decreases for fentanyl were 50% ± 11%, 41% ± 15%, and the estimated EC₅₀ values were 6.1 ± 1.4 ng/mL and 3.5 ± 1.4 ng/mL, respectively. Using the apparent EC₅₀ values, the calculated potency ratio for alfentanil:fentanyl was (mean and 95% confidence interval) 1:39 (1:31–1:46) for minute volume and 1:51 (1:34–1:68) for respiratory rate. This is analogous to the analgesic effect studied earlier. The findings support the notion of parallel analgesic and respiratory depressant effects of alfentanil and fentanyl. Therefore equianalgesic concentrations of both drugs will lead to equally pronounced respiratory depression.

IMPLICATIONS: This double-blinded, randomized study evaluated the potency ratio of alfentanil and fentanyl-induced respiratory depression. The findings support the notion of parallel analgesic and respiratory depressant effects of alfentanil and fentanyl. Therefore equianalgesic concentrations of both drugs will lead to equally pronounced respiratory depression.

	Introduction

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Alfentanil and fentanyl are widely used and extensively studied opioids. The potency ratio of these two drugs has been estimated previously by different methods, the ratio varying somewhat depending on the pharmacological end point used. The alfentanil:fentanyl analgesic concentration potency ratio for skin incision was estimated as 1:57 (1,2) and for experimental pain 1:48 (3). The respiratory depressant effects of alfentanil and fentanyl have been studied separately (4–7), but their relative potencies have not been quantified properly. However, there are clinical studies suggesting that for a given level of analgesia alfentanil might cause less respiratory depression than fentanyl (8–10).

In many of the previous studies, responsiveness to carbon dioxide (4,6) or hypoxia (5) was used to measure respiratory depression. Responsiveness to carbon dioxide is a well-documented and sensitive test for drug-induced respiratory depression. However, this method is associated with some problems (11). In this study, respiratory inductive plethysmography (12,13) and indirect calorimetry (14) were used for monitoring of resting ventilation to obtain continuous data and to not disturb the drug effect by the monitoring system (11). To obtain stable target plasma concentrations, a computer-driven infusion pump with escalating drug plasma concentrations was used for drug delivery. Thus, the aim of this study was to determine the potency ratio for respiratory depression induced by alfentanil and fentanyl using a continuous, noninvasive monitoring technique.

	Methods

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Eight healthy male volunteers were enrolled in the study. Subjects ranged in age from 22 to 28 yr and were within normal weight limits (range, 65–94 kg). None had a history of alcohol and/or drug abuse and none was currently using any medication. A screening test for drugs (cocaine, amphetamine, cannabis, opioids, and benzodiazepines) was performed for each volunteer before participating in the study. This study was approved by the Institutional Ethics Committee of Turku University Hospital and written informed consent from each volunteer was obtained before recruitment.

Each subject was randomly allocated to receive two different treatments according to a balanced, cross-over and double-blinded design with 5–7 days washout period. The order of drug administration was assigned using random permutation. The volunteers received fentanyl and alfentanil as a continuous infusion delivered with a computer-driven (STANPUMP; developed by Steven L. Shafer, MD; Palo Alto, CA) infusion pump (Harward 22 Basic Syringe Pump; Harward Apparatus, South Natick, MA). Nonweight-adjusted pharmacokinetic variables were used (15,16). Ascending logarithmic escalations of pseudo steady-state plasma concentrations of 5, 8, 12.5, 20, 31.5, 50, 80, 125, 200, 315, and 500 ng/mL for alfentanil and 0.1, 0.16, 0.25, 0.4, 0.63, 1, 1.6, 2.5, 4, 6.3, and 10 ng/mL for fentanyl were accomplished at 10-min intervals (i.e., 10 concentrations over a 100-fold concentration range). The study drugs were prepared and administered by an independent person not participating in the study by diluting them with 50 mL physiological saline.

Before each session, food, caffeinated drinks, and chocolate were not allowed for 12 h preceding the study. Both sessions for each subject were performed at the same time of day to avoid possible diurnal variation. After admission to the study site, a radial artery and a forearm vein were cannulated. The plethysmograph belts were fitted around the chest wall and abdomen, and the subjects were asked to breathe through the pneumotachometer for at least 2 min to have a volume reference for the plethysmograph. Then the canopy of the indirect calorimetry was placed over each subjects’ head. After a 15-min stabilization period, baseline values for all variables were recorded. The drug infusion was started according to the method described above. The infusions were terminated when respiratory rate decreased to 2/min or oxygen saturation (SpO₂) decreased below 85%. After terminating the drug infusion, the volunteers were asked to take a few deep breaths and were given IV naloxone 0.4 mg and/or, in case of emesis, IV tropisetron 2 mg. The subjects were observed at the study site until no adverse drug effect was seen according to standard outpatient criteria.

Respiratory inductive plethysmography (RIP), (RESPITRACE; NIMS, Miami Beach, FL) (12,13) was used for respiratory monitoring. Changes in rib cage (RC) and abdominal circumferences (AB) were simultaneously measured using two differential linear transformers connected to tight fitting belts around the chest at nipple level and around the abdomen at umbilical level. The RC and AB signals were summed electronically to provide a signal equivalent to tidal volume (VT). The calibration was done semiquantitatively before each measurement in each subject by first collecting baseline breathing data for 5 min and thereafter by calibrating against a known volume reference (17). A heated pneumotachometer (Hans Rudolph Inc., Kansas City, MO) connected to a differential pressure transducer (VALIDYNE MP 45, ± 2.0 cm H₂O; Validyne, Northridge, CA) was used as the volume reference. Flow, volume, and analog RC+AB signals were amplified and recorded using a physiologic recording system (DIREC; Raytech Instruments, Vancouver, BC). At least five breaths were sampled for calibration. The calibrated RC+AB signal was analyzed with the software program (Respievents) provided with the RIP. Minute volume (E) was calculated from VT and respiratory rate. Mean inspiratory flow (VT/Ti), an indicator of respiratory drive, was calculated by dividing VT by inspiratory time (Ti). The proportion of total ventilation that can be attributed to expansion of rib cage (RC%) was also measured with RIP. Both VT/Ti and RC% are standardized and validated variables produced by the Respievents and are described in detail elsewhere (13,18,19). The data were analyzed by including every breath from a 2-min period.

Indirect calorimetry (DELTATRAC; Datex, Helsinki, Finland) is an open system device designed for measuring oxygen consumption (O₂) and carbon dioxide production (CO₂) in both spontaneously breathing and mechanically ventilated subjects, with a relative error of O₂ and CO₂ of ± 5% (14). The Deltatrac flow generator entrains room air through the canopy at a rate of 40 L/min. The sampling is done from a side-stream port at the proximal side of the canopy. The difference between the inspired and expired oxygen fractions (FIO₂ and FeO₂), analyzed from the mixed expiratory gas flowing through the monitor, was measured with a fast-response paramagnetic differential oxygen sensor. The expired CO₂ fraction (FeCO₂), analyzed from the mixed expiratory gas, was measured with an infrared CO₂ sensor. The gas exchange monitor was calibrated before each study session with a standardized, certified gas mixture (95% O₂, 5%CO₂). The values of O₂ were produced every 60 s from the Deltatrac and collected online to a computer for further analysis. The CO₂ values were used for calculation of alveolar ventilation (V_A).

In summary, the following respiratory variables were recorded during the study: PaO₂(kPa), PaCO₂(kPa), SpO₂(%), V_A(L/min), E(L/min), VT(mL), RR(/min), RC%(%), VT/Ti(mL/s), and O₂(mL/min).

Mean arterial blood pressure and heart rate were directly measured from the radial artery and monitored along with SpO₂ using a Cardiocap monitor (Datex). Data from these variables were also recorded online to a computer every 10 s for further analysis.

Data from minutes 7–9 at each concentration level were used for analysis. RIP data were analyzed from a representative 120-s period within this time period and Deltatrac data as mean value of the two successive 1-min values from minutes 7–9. Data from the Cardiocap monitor were analyzed as a mean value of all values produced during minutes 8–9.

Arterial blood samples were drawn at the end of each concentration level from the radial artery for measurements of PaO₂ and PaCO₂ as well as for plasma drug concentration determinations. Alveolar ventilation was calculated as V_A (L/min) = 0.115 x CO₂ (mL/min)/PaCO₂ (kPa) (18,20).

Plasma concentrations of fentanyl and alfentanil were determined using radioimmunoassay methods (21,22). The intra- and interassay coefficients of variations were 3.7% and 3.3% for alfentanil and 6.0% and 6.9% for fentanyl. The measured, not predicted, concentrations of alfentanil and fentanyl were used for pharmacodynamic modeling and for determining the cutoff values.

To determine the potency of respiratory depression induced by the opioids, pharmacodynamic modeling was performed separately for each subject using the nonlinear regression program PCNONLIN (Version 4.2; Scientific Consulting Inc., Apex, NC) without weighting. The concentrations producing 50% of the maximal decrease in E and respiratory rate (i.e., apparent EC₅₀ values) were estimated by fitting the fractional E_max and sigmoidal E_max models to the data according to Equations 1 and 2, respectively,

equation

equation

where E = effect, E₀ = baseline effect (maximal drug effect, E_max is equal to E₀), C = drug concentration, EC₅₀ = concentration at 50% of E_max and = sigmoidicity (Hill) factor (7). The goodness of the fit was determined by Akaike’s information criterion and by assessment of scatter of the observed data points in relation to the fitted function. In addition, the increase in PaCO₂ was fitted to a linear model, i.e.;,

equation

where k = the slope of the line relating effect to concentration. Potency ratios were calculated by dividing the respective EC₅₀ values.

Statistical Analysis
Data are presented as mean ± SD. The different pharmacodynamic responses were analyzed using analysis of variance for crossover design with repeated measures within periods. In this analysis, a significant step effect was indicative for concentration-dependent effects, and the two factor interaction sequence*period or the three factor interaction sequence*period*step indicative for differences between the two study drugs. To assess the sensitivity of the various respiratory variables to detect drug-induced respiratory depression, the analysis was continued in case of a significant concentration effect by calculating paired contrasts vs baseline and by correcting corresponding P values for multiple comparisons (Bonferroni correction). A P value <0.05 was considered as statistically significant. In addition, 95% confidence intervals were calculated for the estimated EC₅₀ values and potency ratios. Statistical computing was performed using the SAS system for Windows (Release 6.12, 1996; SAS Institute Inc., Cary, NC).

	Results

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The cutoff for respiratory depression was reached and the infusion terminated at targeted concentration levels of 200–500 ng/mL during alfentanil sessions and at concentration levels of 2.5–6.3 ng/mL during fentanyl sessions. Mean measured cutoff concentrations were 254 ± 88 ng/mL and 5.1 ± 1.7 ng/mL for alfentanil and fentanyl, respectively. The measured alfentanil concentrations were slightly below and fentanyl concentrations slightly above the targeted concentrations (Fig. 1). Mean ± SD total alfentanil dose was 4.48 ± 1.30 mg and fentanyl dose 0.47 ± 0.13 mg. SpO₂ was used as a cutoff variable in 15 sessions and respiratory rate in one session.

View larger version (14K): [in this window] [in a new window]   Figure 1. Targeted (solid lines) and mean (SD) measured (filled squares) alfentanil and fentanyl plasma concentrations in 8 healthy subjects. Concentrations were escalated logarithmically at 10-min intervals using a computer-driven infusion pump.

Both drugs depressed ventilation in a concentration-dependent manner in a nonlinear way (Fig. 2, Table 1). SpO₂ decreased from 97% ± 1% (baseline) to 83% ± 4% (at cessation of the infusion) during alfentanil treatment and from 97% ± 1% to 84% + 3% during fentanyl treatment. E decreased from 8.9 ± 1.5 L/min to 4.4 ± 1.6 L/min and from 9.9 ± 1.7 L/min to 4.9 ± 1.2 L/min during alfentanil and fentanyl, respectively. VT increased slightly and RC% more clearly toward the end of both infusions. There were no clear changes in VT/Ti, but statistical analysis revealed a significant time (concentration) effect in analysis of variance (P = 0.037). Changes in all other respiratory variables were highly significant for the concentration effect (P < 0.001). However, there were no significant differences between the study drugs except for V_A (P = 0.029) and SpO₂ (P = 0.003), which were both decreased slightly earlier during fentanyl treatment (Table 1). O₂ decreased during alfentanil infusion by 8% ± 9% and during fentanyl by 15% ± 14% (Table 1). No differences were found between the treatments. Heart rate remained at baseline level throughout both sessions. There were no significant differences between the treatments in either heart rate or mean arterial blood pressure, but statistical analysis revealed a significant concentration effect in mean arterial blood pressure (Table 1).

View larger version (30K): [in this window] [in a new window]   Figure 2. Individual curves of eight healthy subjects for minute volume (E), respiratory rate, and arterial carbon dioxide pressure (PaCO2) during each concentration step of alfentanil and fentanyl infusions.

	Discussion

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Fentanyl and alfentanil caused respiratory depression in an almost similar fashion. However, the apparent EC₅₀ values for alfentanil obtained in the present study are strikingly higher than EC₅₀ values reported by other groups. In the study by Glass et al. (6), alfentanil-induced respiratory depression was studied with healthy volunteers using the minute ventilation response to 7.5% CO₂, administered via "bag in the box" system and the EC₅₀ was 49.4 ng/mL. In the study of Bouillon et al. (7), the increase of PaCO₂ was used as a determinant of respiratory depression in a sophisticated indirect response model and the EC₅₀ for V_A "corrected to normocapnia" was 60.3 ng/mL. The discrepancy in the derived EC₅₀ values was a result of different end points. In unstimulated resting ventilation, which was used in this study, both hypercarbia and hypoxia can considerably stimulate ventilation and affect the potency estimates. Thus, our (apparent) EC₅₀ values can even be considered as biased estimates of the true potency of the opioids (7). However, our primary goal was to determine the potency ratio of the two drugs. The current results clearly show that the potency of ventilatory depression of opioids (i.e., EC₅₀ values) is highly dependent on the physiological conditions in which the measurements are made, and different estimates can be obtained with concomitantly measuring and modeling or standardizing CO₂ levels in the body (7). However, both kind of studies, i.e., ventilatory challenges where PaCO₂ is controlled and measurements of resting ventilation, are needed to extend the knowledge of respiratory depression induced by different opioids (11).

Fentanyl is not as widely studied as alfentanil in respect to the EC₅₀ values for respiratory depression. In the study of Cartwright et al. (4), the EC₅₀ for fentanyl-induced respiratory depression in surgical patients was estimated to range between 1.5 and 3.1 ng/mL measured with responsiveness for CO₂. These values are lower than the "apparent" EC₅₀ values obtained from our study; the reason is probably the same as with alfentanil. In the study of Fung and Eisele (25), where a single bolus of fentanyl was given to healthy volunteers, the EC₅₀ for respiratory depression was 4.6 ng/mL. However, the use of a single bolus, instead of a steady-state infusion, makes direct comparisons difficult.

The most sensitive variable was V_A, which was significantly decreased even at quite small plasma drug concentrations. A significant decrease in respiratory rate and an increase of PaCO₂ were also detected at small plasma drug concentrations that were clearly below anesthetic and even analgesic drug concentrations (1). The decrease of E was largely accounted for by the reduced respiratory rate because VT increased toward the end of the study. In previous studies, the decrease in E was the result of either decrease in VT or respiratory rate, depending on the dose of opioid administered (5,21,26). In our study, wide concentration ranges were used; the result was a decrease of respiratory rate. The mode of the monitoring system, e.g., resting ventilation, can account for this decrease in respiratory rate (27).

Despite the large amount of opioids infused, no chest wall rigidity was detected during either of the infusions as seen by the continuous increase of RC%. This is in accordance with previous studies in which chest wall rigidity was mostly seen with rapid bolus doses rather than infusions (9,28). No paradoxical chest movement was detected in any of the subjects, which indicates patent airway. The developing respiratory depression in this study was thus a result of central apnea, not upper airway obstruction. In our study, VT/Ti increased slightly but significantly during both drug infusions, suggesting maintained respiratory drive (19). However, this increase was most probably caused by the stimulatory effect of increased PaCO₂, which masks the opioid-induced depression in respiratory drive. The increase of mean inspiratory flow has been associated with increasing activation of respiratory muscle and progressive increase in lung volume (29). This is in line with our observation of increasing VT and RC%.

The respiratory effects were assessed by indirect calorimetry and respiratory inductive plethysmography because they were validated, noninvasive monitoring systems for continuous respiratory monitoring (12–14,17). The use of a nondisturbing system to measure respiratory pattern and ventilation creates a setting close to the clinical situation. This monitoring system allows natural breathing without any external stimuli from the equipment. In addition, use of these methods enabled the measurement of V_A, determined by the rate of CO₂ and the alveolar partial pressure of CO₂, which is closely related to PaCO₂. V_A thus depicts the actual gas exchange in lungs and the efficacy of breathing. Tobin et al. (19) have compared VT/Ti, measured with RIP to standard indices of respiratory center outputP measured with mouth occlusion pressure and demonstrated a close correlation between the two measurements. We did not measure sedation, as it is difficult to do properly without disturbing these respiratory measurements.

A computer-driven infusion pump (STANPUMP-Harvard 22) was used in the present study to rapidly achieve and maintain the desired pseudo steady-state plasma concentrations of the opioids. The 10-minute time period we used in the present study was, however, not quite sufficient to achieve equilibration with the effect site during fentanyl infusion. Based on a STANPUMP simulation the effect site concentration at pharmacologically relevant concentrations was approximately 90% of the plasma concentrations at the end of the 10-minute period. Thus the true EC₅₀ values of fentanyl may be slightly less than those reported and may underestimate the respiratory depression caused by fentanyl. A 10-minute interval was chosen to reduce the total dose.

In conclusion, both alfentanil and fentanyl produced respiratory depression in a similar fashion with escalating drug plasma concentrations. Using a continuous measurement of resting ventilation, the potency ratio for respiratory depression was between 1:39 and 1:51 (alfentanil:fentanyl). This is analogous to the potency ratio for pain stimulation studied elsewhere. Thus, the respiratory depressant effects of alfentanil and fentanyl are identical at equianalgesic drug plasma concentrations.

	Acknowledgments

 
Supported, in part, by institutional funding of Turku University Hospital, Turku, Finland.

We would like to thank Elina Kahra for excellent technical assistance, Hans Helenius and Lauri Sillanmäki for performing the statistical analyses, and Janssen Pharma for analyzing plasma drug concentrations.

	Footnotes

 
Presented as an abstract in the meeting of Scandinavian Society of Anesthesiologists, Århus, Denmark, June 7th-11th, 1999.

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