Mixed Opioid Agonist–Antagonists
or Partial Agonists
The mixed opioid
agonist–antagonists are potent anal-gesics in opioid-naive patients but
precipitate with-drawal in patients who are physically dependent on opi-oids.
They are useful for the treatment of mild to moderate pain. They were developed
to reduce the ad-diction potential of the opioids while retaining the
anal-gesic potency of the drugs. Their analgesic effect is gen-erally
attributed to an interaction at the κ- and to a lesser extent the μ-opioid receptor.
Interaction at the μ-receptor increases the
sedative effects of the drugs. The euphoric effects are due to in-teraction
with the κ-receptor. The dysphoric and psy-chotomimetic side effects of the
drugs are attributed to interaction at the σ-receptor.
The mixed agonist–antagonists
and partial agonists differ from morphine in that they (1) produce excita-tory
and hallucinogenic effects, (2) produce a low de-gree of physical dependence,
(3) induce withdrawal signs that differ from those of morphine, and (4)
pro-duce excitatory effects related to the sympathetic dis-charge of
norepinephrine and therefore are positive in-otropic agents in the heart.
Pentazocine (Talwin) is a potent analgesic with
an-tagonistic activity in opioid-addicted patients. It incom-pletely blocks the
effects of morphine in such patients but will precipitate withdrawal. To
eliminate abuse of the drug via IV administration, pentazocine is com-bined
with naloxone (Talwin-NX). IV
administration of Talwin-NX will produce no analgesic or euphoric ef-fects
because naloxone blocks the pentazocine moiety. However, the drug will retain
its analgesic potency when administered orally, since naloxone is not active
orally. Pentazocine produces as much respiratory de-pression as morphine but
does not produce the same degree of constipation or the biliary constriction
ob-served with morphine. Pentazocine may increase GI motility if used in high
doses. Unlike morphine, penta-zocine increases heart rate and blood pressure by
re-leasing norepinephrine. Pentazocine also may increase uterine contractions
in pregnancy.
Absorption of pentazocine
following oral administra-tion is rapid. The onset of action occurs within
approxi-mately 15 minutes, and the half-life is 2 to 3 hours. Pentazocine is
extensively metabolized in the liver and thus has a high first-pass effect
following oral administra-tion; its half-life differs considerably from patient
to pa-tient. Oxidation of the methyl groups followed by conju-gation to
glucuronides in the liver terminates the effects of pentazocine. Excretion
occurs through the kidney.
Pentazocine is indicated for
relief of moderate pain in patients not receiving large doses of opioids. It is
also used as premedication for anesthesia and as a supple-ment to surgical
anesthesia.
The most common side effect
of pentazocine is se-dation resulting from an interaction with the κ-receptor. Also observed are
sweating, dizziness, psychotomimetic effects, anxiety, nightmares, and
headache. Nausea and vomiting are less frequent than with morphine. Respiratory
depression and increased heart rate, body temperature, and blood pressure
accompany overdose. Naloxone is effective in reducing the respiratory
de-pression but requires the use of higher doses than for morphine overdose.
Most of the contraindications
specific to penta-zocine stem from its excitatory effects. Other
con-traindications are similar to those for morphine. Pentazocine is
contraindicated in patients with myo-cardial infarction because it increases
heart rate and cardiac load. Similarly, it is contraindicated in epileptic
patients because it decreases seizure threshold. In addi-tion, in head trauma
patients, it can increase intracranial pressure and brain injury. Pentazocine use
in patients with psychoses is contraindicated because of its psy-chotomimetic
side effects.
The combination of
pentazocine with the antihista-mine tripelennamine results in a combination
known to drug abusers as T’s and blues. This combination pro-duces heroinlike
subjective effects, and heroin addicts use it in the absence of heroin. In
addition, the use of pentazocine in combination with alcohol or barbitu-rates
greatly enhances its sedative and respiratory de-pressant effects.
Tolerance to the analgesic
effects of pentazocine de-velops. Withdrawal signs are milder than those seen
with morphine, and they produce more excitatory effects.
Butorphanol (Stadol) is chemically related to
levor-phanol but pharmacologically similar in action to pen-tazocine. As an
opioid antagonist it is nearly 30 times as potent as pentazocine and has
one-fortieth the potency of naloxone. It is a potent opioid analgesic indicated
for the relief of moderate to severe pain. Its potency is 7 times that of
morphine and 20 times that of pentazocine as an analgesic. Its onset of action
is similar to that of morphine. The side effects and signs of toxicity are
sim-ilar to those produced by pentazocine. It produces exci-tatory effects and
sedation and precipitates withdrawal in opioid-dependent patients. Although
generally ad-ministered parenterally because of its low bioavailabil-ity
following oral administration, it is also unique in that a nasal spray
formulation is available. The nasal spray is indicated for the relief of
postoperative pain and mi-graine headache. The low molecular weight of
butor-phanol, its high lipophilicity, and its lack of vasocon-strictor effects
make it particularly suitable for nasal administration.
Nasal administration of
butorphanol decreases the onset of action to 15 minutes and decreases the
first-pass effect of the drug, which increases bioavailability. Generally the
patient sprays a set dose of 1 mg per hour for 2 hours. The duration of action
is 4 to 5 hours. The convenience of such administration is a major advantage to
patients requiring repeat dosing. The abuse potential following such
administration has not been extensively studied, although it is thought to be
small. Butorphanol is not a federally controlled (“scheduled”) drug, so
physicians are not required to obtain the licenses and security safeguards
required for other opioid analgesics.
Adverse effects,
contraindications, and drug interac-tions are similar to those for pentazocine
and morphine.
Nalbuphine (Nubain) is a mixed agonist–antagonist
that is similar in structure to both the antagonist naloxone and the agonist
oxymorphone. It is administered par-enterally and is equipotent to morphine and
5 times as potent as pentazocine. Although the pharmacological ef-fects
(analgesia, respiratory depression, sedation, and so on) are similar to those
produced by pentazocine, nal-buphine produces fewer psychotomimetic effects. It
dif-fers from pentazocine in that it has far greater antagonist than agonist
effect. Thus, its use is likely to precipitate se-vere withdrawal in
opioid-dependent patients. It is used much as pentazocine is, that is, for
moderate to severe pain, postsurgical anesthesia, and obstetrical analgesia.
Nalbuphine’s abuse potential is less than that of codeine and propoxyphene,
although tolerance and dependence have been shown following chronic
administration. High doses are perceived by addicts as being like those of the
barbiturates. Drug interactions and contraindications are similar to those for
pentazocine and morphine.
Buprenorphine (Temgesic) is a mixed agonist–antago-nist
and a derivative of the naturally occurring opioid thebaine. Buprenorphine is
highly lipophilic and is 25 to 50 times more potent than morphine as an
analgesic. The sedation and respiratory depression it causes are more intense
and longer lasting than those produced by morphine. Its respiratory depressant
effects are not readily reversed by naloxone. It binds to the μ-receptor with high affinity
and only slowly dissociates from the receptor, which may explain the lack of
naloxone rever-sal of respiratory depression.
Buprenorphine has more
agonist than antagonist ef-fects and is often considered a partial agonist
rather than a mixed agonist–antagonist, although it precipi-tates withdrawal in
opioid-dependent patients. Its phar-macological effects are similar to those
produced by both morphine and pentazocine. Indications for its use are similar
to those of pentazocine, that is, for moderate to severe pain. Sublingual
preparations are available, but have a slow onset and erratic absorption.
The abuse potential of
buprenorphine is low. While high doses of the drug are perceived by addicts as
being morphinelike, it does reduce the craving for morphine and for the
stimulant cocaine. Thus, buprenorphine is a potential new therapy for the
treatment of addiction to both classes of drugs.
Drug interactions and
contraindications are similar to those described for pentazocine and morphine.
Dezocine (Dalgan) is a synthetic aminotetralin
deriva-tive with potent agonist–antagonist effects. The onset of activity and
potency as an analgesic are comparable to those of morphine. Although the drug
requires glu-curonidation during metabolism, patients with hepatic
insufficiency clear it normally. The main route for clear-ance is the kidney.
Thus, patients with renal dysfunction are prone to buildup of dezocine over
time. As an an-tagonist, dezocine is more potent than pentazocine. As an
agonist, dezocine produces analgesia and respiratory depression (which is
readily reversed by naloxone), but unlike pentazocine, it has little if any
effect on the car-diovascular system.
Dezocine is indicated as an
analgesic for moderate to severe pain. In addition, it shows promise in chronic
pain states, such as with victims of severe burns. Contraindications and
adverse effects of the drug are similar to those described for morphine. No
tendency toward abuse has been demonstrated thus far.
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