DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

506 The use of fentanyl and sufentanil in chronic pain treatment been used successfully for longer neurosurgical procedures, where
rapid emergence from anesthesia may be important. However, in
cases where postprocedural analgesia is required, remifentanil alone
is a poor choice. In this situation, either a longer-acting opioid or
another analgesic modality should be combined with remifentanil
for prolonged analgesia, or another opioid should be used.
Remifentanil is not used intraspinally because of its formulation with
glycine, an inhibitory transmitter in the spinal dorsal horn.
SECTION II
NEUROPHARMACOLOGY
has become more widespread. The development of novel, minimally
invasive routes of administration for fentanyl has facilitated the use
of these compounds in chronic pain management. Transdermal
patches (DURAGESIC, others) that provide sustained release of fentanyl
for 48-72 hours are available. However, factors promoting increased
absorption (e.g., fever) can lead to relative overdosage and increased
side effects (see “Routes of Analgesic Drug Administration” later in
the chapter). Transbuccal absorption by the use of buccal tablets, soluble
buccal film, and lollypop-like lozenges permits rapid absorption
and has found use in the management of acute incident pain
(FENTORA, ACTIQ, ONSOLIS, others) and for the relief of breakthrough
cancer pain. As fentanyl is poorly absorbed in the GI tract, the optimal
absorption is though buccal absorption. Accordingly, there is little
opportunity for overdosing by that route.
Remifentanil
This compound was developed in an effort to create an
analgesic with a more rapid onset and predictable termination
of effect. The potency of remifentanil is
approximately equal to that of fentanyl. The pharmacological
properties of remifentanil are similar to those
of fentanyl and sufentanil. They produce similar incidences
of nausea, vomiting, and dose-dependent muscle
rigidity. Nausea, vomiting, itching, and headaches
have been reported when remifentanil has been used for
conscious analgesia for painful procedures. Intracranial
pressure changes are minimal when ventilation is controlled.
Seizures after remifentanil administration have
been reported (Beers and Camporesi, 2004).
Absorption, Fate, and Excretion. Remifentanil has a more rapid
onset of analgesic action than fentanyl or sufentanil. Analgesic
effects occur within 1-1.5 minutes following intravenous administration.
Peak respiratory depression after bolus doses of remifentanil
occurs after 5 minutes (Patel and Spencer, 1996). Remifentanil
is metabolized by plasma esterases, with a t 1/2
of 8-20 minutes (Burkle
et al., 1996); thus, elimination is independent of hepatic metabolism
or renal excretion. There is no prolongation of effect with repeated
dosing or prolonged infusion. Age and weight can affect clearance
of remifentanil, requiring that dosage be reduced in the elderly and
based on lean body mass. However, neither of these conditions
causes major changes in duration of effect. After 3- to 5-hour infusions
of remifentanil, recovery of respiratory function can be seen
within 3-5 minutes; full recovery from all effects of remifentanil is
observed within 15 minutes (Glass et al., 1999). The primary metabolite,
remifentanil acid, has 0.05-0.025% of the potency of the parent
compound, and is excreted renally.
Therapeutic Uses. Remifentanil hydrochloride (ULTIVA) is useful for
short, painful procedures that require intense analgesia and blunting
of stress responses; the drug is routinely given by continuous intravenous
infusion because its short duration of action makes bolus
administration impractical. The titratability of remifentanil and its
consistent, rapid offset make it ideally suited for short surgical procedures
where rapid recovery is desirable. Remifentanil also has
METHADONE AND PROPOXYPHENE
Methadone
Methadone (Figure 18–9) is a long-acting MOR agonist
with pharmacological properties qualitatively similar to
those of morphine. The analgesic activity of methadone,
a racemate, is almost entirely the result of its content
of L-methadone, which is 8-50 times more potent than
the D isomer. D-methadone also lacks significant respiratory
depressant action and addiction liability but possesses
antitussive activity.
CNS Effects. The outstanding properties of methadone
are its analgesic activity, its efficacy by the oral route,
its extended duration of action in suppressing withdrawal
symptoms in physically dependent individuals,
and its tendency to show persistent effects with repeated
administration. Miotic and respiratory-depressant
effects can be detected for >24 hours after a single dose;
on repeated administration, marked sedation is seen in
some patients. Effects on cough, bowel motility, biliary
tone, and the secretion of pituitary hormones are qualitatively
similar to those of morphine.
Absorption, Distribution, Metabolism, and Excretion. Methadone
is absorbed well from the GI tract and can be detected in plasma within
30 minutes of oral ingestion; it reaches peak concentrations at ~4 hours.
After therapeutic doses, ~90% of methadone is bound to plasma proteins.
Peak concentrations occur in brain within 1-2 hours of subcutaneous
or intramuscular administration, and this correlates well with
the intensity and duration of analgesia. Methadone also can be
absorbed from the buccal mucosa.
Methadone undergoes extensive biotransformation in the
liver. The major metabolites, the results of N-demethylation and
cyclization to form pyrrolidines and pyrroline, are excreted in the
urine and the bile along with small amounts of unchanged drug.
The amount of methadone excreted in the urine is increased when
the urine is acidified. The t 1/2
of methadone is long, 15-40 hours.
Methadone appears to be firmly bound to protein in various
tissues, including brain. After repeated administration, there is gradual
accumulation in tissues. When administration is discontinued,
low concentrations are maintained in plasma by slow release from
extravascular binding sites; this process probably accounts for the
relatively mild but protracted withdrawal syndrome.
Side Effects, Toxicity, Drug Interactions, and Precautions. Side
effects, toxicity, and conditions that alter sensitivity, as well as the