OnTop Dose of a Either Alfentanil or Remifentanil in an Opioid Based Anesthetic Regimen

The demand to ensure a sufficient analgesic level up to the very last minute of an operation, without inducing an overhang of effects, with a delay in recovery, has led to the development of opioid agents, which are characterized by a short duration of action. Due to the pharmacokinetic and physicochemical properties the opioid fentanyl, which is being used most often in neuroleptanalgesia and in an opioid-based anesthetic regimen, often projects into the postoperative period with

1000

• Concentration in plasma

M Infusion

1 ^

Spectral edge

frequency

I

1 " 1

0 5

15 25

Time (min)

0 Spectral edge frequency 5 (Hz)

Concentration in plasma

Infusion

Spectral edge

frequency

\y

""V

V_ /-••

Computed concentration

frequency (Hz)

Figure III-25. Plasma concentration and the corresponding EEG-spectral edge frequency following a 5-minute infusion of alfentanil (1500 |j,g/min) and remifentanil (150 |j,g/min) respectively (Adapted from [83, 84])

Table III-9. Comparison of pharmacokinetics of different opioids among each other

Opioid

Elimination

Clearance (Cl)

Distribution

Protein

Non-Ionized

half life t1/2e

(ml/min/kg)

coefficient Vd

Binding (%)

(%)

(min)

(L/kg)

Fentanyl

219

13.0

4.0

84

9

Alfentanil

94

6.4

0.86

92

89

Sufentanil

64

12.7

2.9

92

20

Morphine

77

14.7

3.2

60

24

Pethidine

92

12.0

2.9

?

5

Meptazinol

124

132

4.99

27

10

Adapted from [70, 75]

Adapted from [70, 75]

insufficient recovery of spontaneous ventilation and consciousness. The cause for such overhang is the larger distribution coefficient (Vd) of fentanyl in the peripheral compartment of the body (skin, musculature, and fatty tissue), whereby it hides from the biodegradation resulting in high amounts in the biophase and a long terminal elimination half-life (t1/2B) with a long duration of action (Table III-9).

To circumvent this disadvantage the anesthesiologist can use the short-acting opioid alfentanil or the ultra-short acting opioid remifentanil. Both of them are fentanyl analogs derived from the group of 4-aniline-piperidines, which are able to blunt the stress response in the very last minute of an operation. Since stress during operation results in a cascade of events, which have been implicated in increasing patient morbidity and/or mortality this results in an improvement of patient care. In comparison to the other potent narcotic analgesics, alfentanil is characterized by a smaller volume of distribution (Vd) and due to the higher clearance rate (Cl), it also results in a shorter elimination half-life (t1/2B; Figure III-26). Because alfentanil in comparison to the other opioids also has a higher portion of non-ionized molecules, more fractions of the pharmacologically active agent are able to penetrate the blood-brain barrier, reaching the opioid receptor sites within the CNS (Table III-9), thereby inducing an immediate and powerful analgesic effect.

When using the opioid remifentanil, elimination half-life is only 7min, having an onset of action of about 1 min, which is similar to alfentanil. Independent of liver function, degradation is done by blood and tissue esterase, whereby repetitive doses or an infusion does not result in an overhang of effects.

Figure III-26. Low volume of distribution of alfentanil (Vd), when compared to fentanyl, results in more molecules available for degradation, a higher clearance (Cl) via the liver, and a shorter elimination half-life (t1/2B)

Alfentanyl Comparison Fenatnyl
Figure III-27. Principle of the "on-top" administration of alfentanil or remifentanil when given at the end of classical neuroleptanalgesia or an opioid-based anesthetic technique with fentanyl

Due to such a preferable profile, alfentanil or remifentanil can be used to potentiate analgesia when used on-top a preexisting, low analgesic level without inducing an overhang of respiratory depression into the postoperative period (Figure III-27).

The reasons for using either one of these two agents are more obvious than using the potent opioid fentanyl or sufentanil. First, and most of all, the time to maximum effect (onset of action; Figure III-28) is that of circulation time, where after intravenous injection the opioid rapidly enters brain tissue [85] [86]. The opioid can be applied whenever there is a need for an increase in analgesia, directly related to the stage of operation, when there is an increase in nociceptive afferences. Contrary, onset of action of fentanyl starts at 2 min with a maximal analgesic effect clinically seen only after 5min [77].

Thiopental Alfentanil Sufentanil Fentanyl

Morphine

Minutes

Figure III-28. Comparison of maximal onset times of various opioids compared to a barbiturate. Alfentanil, similar to remifentanil has the shortest onset time till maximal effect, which is comparable to a barbiturate

The obvious advantages of alfentanil as well as remifentanil are also demonstrated in its Context-Sensitive Half Time, reflecting the time at which a drug will induce a biological effect in a patient. Being particularly useful for understanding the impact of a continuous infusion of an opioid and the time until recovery, the "three compartment" phamacological model can be used. Although being derived from data of single dose applications in patients and using a computer stimulation program, it reflects the potential behavior of a drug in patients [87]. There it can be seen that opioids being metabolized by the liver accumulate over time resulting in a longer recovery period. This is especially demonstrated for the opioid fentanyl, which tends to accumulate in the peripheral compartment. Such findings are of clinical significance, as a long infusion time corresponds with a longer duration until the drug decreases by 50% in the CNS (Figure III-29).

A similar beneficial effect is seen with the opioid remifentanil, which does not accumulate in the peripheral compartment since it is an esterase-metabolized opioid (EMO), maintaining a brief period of biological effect without risk of accumulation, regardless of the disease and the time or the duration of infusion [88]. Remifentanil may even be superior to alfentanil since after a similar infusion time, the decay in plasma level of both agents is much faster after remifentanil than after alfentanil. Therefore, regardless of the metabolic status of the patient, a fast decrease in plasma levels can be anticipated with this non-specific esterase metabolized opioid (Figure III-30).

While remifentanil's short duration of action is explained by its rapid degradation via non-pseudocholinesterases, the time that limits the effects of alfentanil is the metab-olization by the liver. Due to its high lipophilicity and the higher portion of non-ionized molecules (Table III-9) the blood-brain barrier is rapidly penetrated resulting in immediate binding to the receptor site and the initiation of effects. However, the speed by which alfentanil enters the brain is also in the reverse direction. Alfen-tanil rapidly leaves the CNS back to the central compartment of the blood, from where the liver eliminates the agent by metabolism [75]. Although being redistributed to protein-rich organ sites (i.e. musculature, liver, kidney, lungs) as other opioids like fentanyl, the amount of this redistribution is much less. Therefore alfen-tanil cannot hide from metabolism as fentanyl does, resulting in a faster elimination with a loss of effects. Its short duration on respiratory drive is demonstrated in mean end-expiratory CO2-concentrations in volunteers following different dosages of alfentanil, while using the rebreathing technique as originally described by Read [89]. There it can be seen that a dose of 10^g/kg body weight of alfentanil, the respiratory depressive effect is of short duration and of lesser magnitude as an equianalgesic dose of fentanyl (2 ^g/kg body weight). The respiratory depressive effect of fentanyl was 13fold more intense and of longer duration (Figure III-31).

Since theoretically "on-top" administration of alfentanil on a fentanyl-based anesthesia results in an interaction of both opioids on receptor sites, this may provoke a prolongation in an impaired respiratory drive and a long-lasting impairment of vigilance. In a clinical study alfentanil (10 ^g/kg body weight) or fentanyl (1.5 ^g/kg body weight) was given to patients during classical neuroleptanalgesia

Figure III-29. Difference in time required for a 20%, a 50% or an 80% decrease in the biophase, when using different opioids at different infusion times (Data adapted from [87])

with fentanyl within the last 50min of the procedure [91]. Postoperatively the electroencephalogram was used to determine any difference in vigilance, while plasma levels were determined to evaluate difference in the metabolic rate of the liver.

Alfentanil as well as fentanyl initially induce a characteristically slowing in EEG activity with dominance of delta-waves (0.5-3 Hz) as described by others

Time (mln)

Figure III-30. Decay in plasma concentration following similar infusion times of alfentanil (0.5 |ig/kg/min) and remifentanil (0.05 ig/kg/min) (Adapted from [84])

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lec

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t t •

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tio.

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lOOjigkg giertary

iw-l

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Figure III-31. Mean end-expiratory CO2-concentrations in volunteers receiving either fentanyl or alfentanil, while the responsiveness of the respiratory center was evaluated using an inspiratory concentration of 4% CO2 at four different time intervals. Sensitivity of the respiratory center was only reduced 10 and 20 min after alfentanil. After an equianalgesic dose of fentanyl respiratory impairment lasted significantly longer (Adapted from [90])

Figure 111-32. Comparative power (picoWatt) in EEG activity in the fast beta-band (13-30 Hz) in two groups of patients having received either on-top alfentanil or fentanyl respectively. Note the significant (*p < 0.05; **p < 0.01) higher activity after the additional dose of alfentanil (Adapted from [91])

Figure 111-32. Comparative power (picoWatt) in EEG activity in the fast beta-band (13-30 Hz) in two groups of patients having received either on-top alfentanil or fentanyl respectively. Note the significant (*p < 0.05; **p < 0.01) higher activity after the additional dose of alfentanil (Adapted from [91])

[17, 81]. However, contrary to "on-top" fentanyl, alfentanil "on-top" resulted in a faster recovery. This was reflected in the fast beta-domain (13-30 Hz) of the EEG, reflecting a higher state of vigilance in the postoperative period (Figure III-32).

Following "on-top" alfentanil and similar to the faster recovery in vigilance, patients also had a faster recovery of spontaneous respiratory drive (Table III-10). Although the dose of alfentanil necessary to induce a sufficient analgesia in a non-premeditated patients is 40 ± 20^g/kg body weight [85, 92], a low dose of 10 ^g/kg body weight is sufficient to potentiate analgesia in patients with receptor sites already preoccupied by fentanyl.

While the electroencephalogram reflects the state of vigilance in a patient, the sensory-evoked potential mirrors the depth of analgesia and the degree of blockade

Table 111-10. Postoperative spontaneous respiration (L/min) in patients, following "on-top" alfentanil versus "on-top" fentanyl

Postoperative time (min)

"On-top" alfentanil (L/min)

"On-top" fentanyl (L/min)

10

5.1 ±0.5

5.4 ± 0.8

20

6.4 ± 0.6

6.3 ± 0.8

30

5.9±0.5

5.5 ± 1.1

40

4.4±0.5

4.6 ± 1.5

50

5.9±0.6

5.0 ± 1.5

Adapted from [91]

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Figure III-33. Different peaks of the somatosensory-evoked potential in patients undergoing classical neuroleptanesthesia with fentanyl and a concomitant intraoperative "on-top" administration of alfentanil. Note, the short-term depression of the late peak 5 (> 100m) and its recovery 40min after administration (DHB = dehydrobenzperidol) (Adapted from [97])

Figure III-33. Different peaks of the somatosensory-evoked potential in patients undergoing classical neuroleptanesthesia with fentanyl and a concomitant intraoperative "on-top" administration of alfentanil. Note, the short-term depression of the late peak 5 (> 100m) and its recovery 40min after administration (DHB = dehydrobenzperidol) (Adapted from [97])

of the electrically-induced stimulus at the median nerve on its way to the cerebral cortex by opioid receptor occupancy [93, 94, 95, 96]. A representative example shows the changes in amplitude height of the late (> 100 ms) evoked peak during neuroleptanesthesia, before and after alfentanil (Figure III-32). From such data it can be concluded, that alfentanil when given "on-top" an opioid based anesthetic regimen, is a safe agent because it induces a short-time increase of analgesia within the last period of an operation, without, however, resulting in an overhang with a depressed vigilance or a prolongation in recovery of spontaneous respiratory drive. With an analgesic potency 40-70fold that of morphine, alfentanil is an agent for short-term potentiation of analgesia given within the last 30 min of operation, while opioids like fentanyl and/or sufentanil should only be given during the anesthetic course, when the duration of operation is expected to last one hour and longer.

Both opioids, alfentanil and remifentanil can safely be given "on-top" an opioid-based anesthesia whenever a reduction in analgesia becomes apparent: 1. Any increase in systolic blood pressure > 15% above the preoperative level before premedication.

2. An increase in heart rate above 90 beats/min, presumed that the patient does not experience hypovolemia.

3. All other vegetative signs of an insufficient depth of analgesia such as lacrimation, transpiration or involuntary movement of extremities.

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