Glasgow Meeting - May 2003

Opioid pharmacology in special patient groups: covariate analysis and clinical implications

F Servin

Thinking in concentration has been a major improvement in designing adequate dosage scheme for anaesthetic drugs administration. It is usually done through pharmacokinetic estimation of predicted drug concentrations. Nevertheless, most available pharmacokinetic models used for these calculations are based on specific, usually normal, populations and include only a small number of covariates to account for the population interindividual variability. It is therefore important in clinical practice to know were these models may be at a loss to properly estimate the value and accuracy of the predicted concentration in a specific individual.

1. Opioid pharmacokinetics (PK):

a. Metabolism

Fentanyl, alfentanil and sufentanil are metabolised through the P450 cytochrome system (CYP450), and those enzymes are very sensitive to induction or inhibition. This will not affect fentanyl or sufentanil clearance since the hepatic extraction coefficient of those drugs is high, and their clearance mainly correlated to liver blood flow. On the other hand, alfentanil clearance is much lower and therefore sensitive to variations of CYP450 action. As a consequence, a reduction in liver blood flow will enhance and lengthen fentanyl and sufentanil, and at a lesser degree alfentanil action (1), but changes in enzymes activity (inhibition or induction) will only modify alfentanil clearance. In cirrhotic patients, alfentanil pharmacokinetics will be modified earlier in the time course of hepatic failure than that of fentanyl or sufentanil(2).

Remifentanil pharmacokinetics are characterised by a very high clearance related to its hydrolysis by tissue esterases, which action is independent from most physiologic or pathologic circumstances (3). These esterases are different from the pseudo cholinesterases which metabolise for example muscle relaxants, and thus remifentanil clearance is independent from pseudo cholinesterase activity. Possibly due to the progressive shrinking of "noble" tissues with age, remifentanil clearance is reduced in very old patients, which calls for a reduction in maintenance infusion rates in this population.

Some opioids have active metabolites which in normal patients have little influence on the time course of action of the drug, but may become significant in circumstances such as renal failure where they accumulate. Hepatic conjugation of morphine generates among others the morphine-6- glucuronide which µ agonist action is 13 times as much as that of morphine if administered spinally (4) and which CNS concentration decreases very slowly. This metabolite might contribute more than morphine itself in the prolonged analgesic and respiratory actions of the drug (5). Water soluble, it accumulates in case of renal failure(6). Remifentanil is predominantly metabolised by non specific esterases to an acid metabolite GI-90291(7). GI-90291 is an analgesic, but its potency (about 0.1% of that of remifentanil) renders its clinical impact negligible. It is excreted through the kidney. Even when accumulation occurs in renal failure patients, the concentrations obtained after a few hours infusion are not sufficient to generate pharmacological effects (8).

b. Identified covariates

Population pharmacokinetics analysis may identify covariate which have a significant influence on PK parameters of the studied drug and therefore incorporate them into the PK model. It is always better when estimating drug concentration in a patient to use a model incorporating those covariates.

Many dosing schemes use total body weight to estimate the amount of drug to be given to the patients. Nevertheless this can be grossly misleading if the drug does not distribute in fat tissue. For example, alfentanil or remifentanil dosages should be calculated on lean body mass and not total body weight.

Extremes of age usually modify the pharmacokinetics of drugs, and the knowledge of such changes are mandatory to design appropriate dosing schemes in the elderly. Clinical implications in special patient groups

2. Clinical implications in special patient groups

a. Obese patients

 Apart from the (expected) high clearance, another important feature of remifentanil pharmacokinetics is its quasi independency from body weight, with only the lean body mass appearing as a significant morphological covariate of the model(9). As a consequence, remifentanil pharmacokinetics are not appreciably different in obese versus lean subjects and in clinical practice, remifentanil dosing regimens should be based on lean body mass and not on total body weight (9). The most recent PK model published for sufentanil does not include body weight as a significant covariate(10). Interestingly, it performed well when used for sufentanil TCI in morbidly obese patients despite a slight overestimation of plasma sufentanil concentrations specifically for body mass indexes greater than 40. The authors concluded that this pharmacokinetic parameters set derived from a normal-weight population accurately predicted plasma sufentanil concentrations in morbidly obese patients (11) .

b. Elderly patients

Advanced age does not modify all opioids pK in the same way. Alfentanil duration of action in enhanced because its clearance is reduced(12). Changes in liver blood flow will reduce fentanyl clearance (13). Remifentanil clearance is reduced but its overall duration of action is not modified, the main consequence of this clearance reduction being lesser maintenance requirements for this drug(14).

c. Renal failure

Renal failure modifies alfentanil PK : clinical efficiency is enhanced through the reduction in initial volume of distribution and an increase in unbound fraction, but duration of action is not prolonged (15). Remifentanil pharmacokinetics are unaffected by renal disease (8). Nevertheless in this situation, the elimination of the active metabolite is markedly reduced (8). Morphine 6 glucuronide accumulation prolongs morphine duration of action in renal failure patients.

d. Liver failure

Remifentanil clearance is independent from the liver function, and thus is not modified by severe chronic liver disease (16), or even by the anhepatic phase of liver transplant (17).

e. Co medications interacting with the CYP 450 system

Since alfentanil has small distribution volumes, its context sensitive half time reaches quickly equilibrium and clearance becomes rapidly the predominant limiting factor for termination of action of the drug. With an intermediate hepatic extraction coefficient, alfentanil clearance will depend on both liver blood flow and CYP450 activity(18). Many drugs such as for example cimetidine or erythromycin interact with alfentanil hepatic metabolism and prolong its duration of action (19)

f. New born

Remifentanil crosses the placenta (20) but disappears rapidly from the neonate blood due to a high metabolic clearance (21). It can therefore be used in pregnant women without deleterious effects on the neonate.

g. Children

Remifentanil pharmacokinetics are very similar in children and in adult patients (21).

3. Transfer to effect site

One of the key issues of the time course of action of opioids is the onset time. It differs widely among opioids(22). An adequate estimation of the onset time is mandatory to titrate and improve the hemodynamic stability during anaesthesia.

a. Influence of age

Ageing delays the onset of action of many drugs, possibly through a reduction in regional blood flows. Remifentanil is no exception to this rule(14). Even if the influence of age on the transfer time of the other opioids has not been published, it seems fair to assess that this onset time will be increased in the elderly, specifically for alfentanil which enters the CNS at an early stage after injection.

b. Cardiac output

If the leading factor which delays the onset time of anaesthetic drugs in the elderly is the reduction in blood flow, all patients with reduced cardiac output should be considered as having delayed onsets at least for remifentanil and alfentanil, even if so far no data have been published on this point.

4. Pharmacokinetics of opioids

a. Influence of age

Effective opioid concentrations are much reduced in elderly patients and dosages should be reduced accordingly in this population. EEG changes appear in elderly patients at lower morphine, fentanyl, alfentanil or remifentanil concentrations than in younger adults (14,23).

b. Chronic alcoholism, addiction - chronic opioid therapy

On the contrary, opioid requirements are frequently increased in chronic alcoholic patients, at least when no acute alcohol intoxication is present(24). Similarly, opioid tolerance may lead to very high opioid requirements in drug addicts or in patients with chronic opioid pain treatment(25).

In conclusion, when available, the best way to administer opioids in special patients groups is to use a target controlled infusion based on a model which takes into account the appropriate covariates. This allows the practitioner to deal directly with the effect / concentration relationship and to efficiently titrate the drug to effect whatever the pharmacodynamic variability.

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