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

508 doses of 20-25 mg morphine given subcutaneously. The use of
higher doses of propoxyphene is accompanied by untoward effects
including toxic psychoses. Very large doses produce some respiratory
depression in morphine-tolerant addicts, suggesting that crosstolerance
between propoxyphene and morphine is incomplete.
Abrupt discontinuation of chronically administered propoxyphene
hydrochloride (up to 800 mg/day given for almost 2 months) results
in mild abstinence phenomena, and large oral doses (300-600 mg)
produce subjective effects that are considered pleasurable by postaddicts.
The drug is quite irritating when administered either intravenously
or subcutaneously, so abuse by these routes results in
severe damage to veins and soft tissues.
SECTION II
NEUROPHARMACOLOGY
Therapeutic Uses. In 2009, the European Medicines Agency completed
a review of the safety and effectiveness of dextropropoxyphene-containing
medicines and concluded that the benefits
do not outweigh the risks and recommended a gradual withdrawal of
marketing authorization throughout the EU (European Medicines
Agency, 2009). The conclusion reached by the agency included an
assessment that dextropropoxyphene-containing medicines are weak
painkillers with a limited effectiveness in the treatment of pain and a
narrow therapeutic index. Furthermore, the agency judged acetaminophen
(paracetamol) containing combinations with dextropropoxyphene
to be no more effective than acetaminophen alone. In
the U.S., propoxyphene has been approved for mild to moderate pain
since 1957. Recently the drug has been labeled with additional warnings
related to the risk of rapidly fatal effects in the event of an overdose
(FDA, 2009). Thus, in the U.S., propoxyphene should not be
prescribed to patients who are suicidal or have a history of suicidal
ideation. In addition, higher than expected serum levels of
propoxyphene should be anticipated from the concommitant administration
of strong CYP3A4 inhibitors such as ritonavir, ketoconazole,
itraconazole, clarithromycin, nelfinavir, nefazadone, amiodarone,
amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir,
grapefruit juice, and verapamil. Propoxphene alternatives
should be considered for patients receiving a strong CYP3A4
inhibitor and others at risk for overdose, particularly those with preexisting
heart disease.
Other Opioid Agonists
Tramadol. Tramadol (ULTRAM) is a synthetic codeine analog that is
a weak MOR agonist. Part of its analgesic effect is produced by inhibition
of uptake of norepinephrine and serotonin. In the treatment
of mild to moderate pain, tramadol is as effective as morphine or
meperidine. However, for the treatment of severe or chronic pain,
tramadol is less effective. Tramadol is as effective as meperidine in
the treatment of labor pain and may cause less neonatal respiratory
depression.
Pharmacokinetics. Tramadol is 68% bioavailable after a single oral
dose and 100% available when administered intramuscularly. Its
affinity for the μ opioid receptor is only 1/6000 that of morphine.
However, the primary O-demethylated metabolite of tramadol is
two to four times as potent as the parent drug and may account for
part of the analgesic effect. Tramadol is supplied as a racemic
mixture, which is more effective than either enantiomer alone. The
(+)-enantiomer binds to the receptor and inhibits serotonin uptake.
The (–)-enantiomer inhibits norepinephrine uptake and stimulates
α 2
adrenergic receptors (Lewis and Han, 1997). Tramadol undergoes
extensive hepatic metabolism by a number of pathways, including
CYP2D6 and CYP3A4, as well as by conjugation with subsequent
renal excretion. The rate of formation of the active metabolite is
dependent on CYP2D6 and therefore is subject to both metabolic
induction and inhibition. The elimination t 1/2
is 6 hours for
tramadol and 7.5 hours for its active metabolite. Analgesia begins
within an hour of oral dosing and peaks within 2-3 hours. The duration
of analgesia is ~6 hours. The maximum recommended daily
dose is 400 mg.
Side Effects and Adverse Effects. Common side effects of tramadol
include nausea, vomiting, dizziness, dry mouth, sedation, and
headache. Respiratory depression appears to be less than with
equianalgesic doses of morphine, and the degree of constipation
is less than that seen after equivalent doses of codeine (Duthie,
1998). Tramadol can cause seizures and possibly exacerbate
seizures in patients with predisposing factors. While tramadolinduced
analgesia is not entirely reversible by naloxone, tramadolinduced
respiratory depression is reversed by naloxone. However,
the use of naloxone increases the risk of seizure in patients
exposed to tramadol. Misuse, diversion, physical dependence,
abuse, addiction, and withdrawal have been reported in conjunction
with the use of tramadol. Tramadol has been shown to reinitiate
physical dependence in some patients who have previously
been dependent on other opioids, thus it should be avoided in
patients with a history of addiction. Precipitation of withdrawal
necessitates that tramadol be tapered prior to discontinuation.
Tramadol should not be used in patients taking MAO inhibitors
(Lewis and Han, 1997), SSRIs, or other drugs that lower the
seizure threshold (described earlier).
Tapentadol. Tapentadol (NUCYNTA) is structurally and mechanistically
similar to tramadol. It displays a mild opioid activity and possesses
monoamine reuptake inhibitor activity. It is considered similar
to tramadol in activity, efficacy, and side-effect profile. Like tramadol,
it should not be used concurrently with agents that enhance
monamine activity or lower the seizure threshold, such as MAO
inhibitors and SSRIs. The major pathway of tapentadol metabolism
is conjugation with glucuronic acid; ~70% of the dose is excreted in
urine in the conjugated form.
OPIOID AGONISTS/ANTAGONISTS
AND PARTIAL AGONISTS
The drugs described in this section differ from clinically
used μ opioid receptor agonists. Drugs such as nalbuphine
and butorphanol are competitive MOR antagonists but
exert their analgesic actions by acting as agonists at KOR
receptors. Pentazocine qualitatively resembles these
drugs, but it may be a weaker MOR receptor antagonist
or partial agonist while retaining its KOR agonist activity.
Buprenorphine, on the other hand, is a partial agonist
at MOR. The stimulus for the development of mixed
agonist–antagonist drugs was a desire for analgesics with
less respiratory depression and addictive potential.
However, the clinical use of these compounds is limited
by undesirable side-effects and limited analgesic effects.