Page 579 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 31 Opioid Agonists & Antagonists 565

antagonist-precipitated withdrawal, below). The potential for is to recouple opioid receptor function as described previously
physical and psychological dependence of the partial agonist- through the use of adjunctive nonopioid agents. NMDA-receptor
antagonist opioids appears to be less than that of the strong antagonists (eg, ketamine) have shown promise in preventing or
agonist drugs. reversing opioid-induced tolerance in animals and humans. Use of
ketamine is increasing because well-controlled studies have shown
1. Opioid tolerance—Opioid tolerance is the phenomenon clinical efficacy in reducing postoperative pain and opioid require-
whereby repeated doses of opioids have a diminishing analgesic ments in opioid-tolerant patients. Agents that independently
effect. Clinically, it has been described as an increasing opioid enhance μ-receptor recycling may also hold promise for improv-
dose requirement to achieve the analgesia observed at the initia- ing analgesia in the opioid-tolerant patient.
tion of opioid administration. Although development of tolerance
begins with the first dose of an opioid, tolerance may not become 2. Dependence—The development of physical dependence is an
clinically manifest until after 2–3 weeks of frequent exposure to invariable accompaniment of tolerance to repeated administration
ordinary therapeutic doses. Nevertheless, perioperative and critical of an opioid of the μ type. Failure to continue administering the
care use of ultrapotent opioid analgesics such as remifentanil have drug results in a characteristic withdrawal or abstinence syndrome
been shown to induce opioid tolerance within hours. Tolerance that reflects an exaggerated rebound from the acute pharmacologic
develops most readily when large doses are given at short intervals effects of the opioid.
and is minimized by giving small amounts of drug with longer The signs and symptoms of withdrawal include rhinorrhea,
intervals between doses. lacrimation, yawning, chills, gooseflesh (piloerection), hyperventila-
A high degree of tolerance may develop to the analgesic, tion, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea,
sedating, and respiratory depressant effects of opioid agonists anxiety, and hostility. The number and intensity of the signs and
(Table 31–3). It is possible to produce respiratory arrest in a symptoms are largely dependent on the degree of physical depen-
nontolerant person with a dose of 60 mg of morphine. However, dence that has developed. Administration of an opioid at this time
in a patient who is opioid-dependent or requires escalating opioid suppresses abstinence signs and symptoms almost immediately.
administration to manage intractable cancer pain, doses such as The time of onset, intensity, and duration of abstinence syn-
2000 mg of morphine taken over a 2- or 3-hour period may not drome depend on the drug previously used and may be related to
produce significant respiratory depression. Tolerance also develops its biologic half-life. With morphine or heroin, withdrawal signs
to the antidiuretic, emetic, and hypotensive effects but not to the usually start within 6–10 hours after the last dose. Peak effects are
miotic, convulsant, and constipating actions. Following discontin- seen at 36–48 hours, after which most of the signs and symptoms
uation of opioids, loss of tolerance to the sedating and respiratory gradually subside. By 5 days, most of the effects have disappeared,
effects of opioids is variable, and difficult to predict. However, but some may persist for months. In the case of meperidine, the
tolerance to the emetic effects may persist for several months after withdrawal syndrome largely subsides within 24 hours, whereas
withdrawal of the drug. Therefore, opioid tolerance differs by with methadone several days are required to reach the peak of
effect, drug, time, and the individual (genetic-epigenetic factors). the abstinence syndrome, and it may last as long as 2 weeks. The
Tolerance also develops to analgesics with mixed receptor slower subsidence of methadone effects is associated with a less
effects but to a lesser extent than to the agonists. Adverse effects intense immediate syndrome, and this is the basis for its use in
such as hallucinations, sedation, hypothermia, and respiratory the detoxification of heroin addicts. However, despite the loss of
depression are reduced after repeated administration of the mixed physical dependence on the opioid, craving for it may persist. In
receptor drugs. However, tolerance to the latter agents does not addition to methadone, buprenorphine and the α agonist cloni-
2
generally include cross-tolerance to the agonist opioids. It is also dine are FDA-approved treatments for opioid analgesic detoxifica-
important to note that tolerance does not develop to the antago- tion (see Chapter 32).
nist actions of the mixed agents or to those of the pure antagonists. A transient, explosive abstinence syndrome—antagonist-
Cross-tolerance is an extremely important characteristic of the precipitated withdrawal—can be induced in a subject physically
opioids, ie, patients tolerant to morphine often show a reduction dependent on opioids by administering naloxone or another
in analgesic response to other agonist opioids. This is particularly antagonist. Within 3 minutes after injection of the antagonist,
true of those agents with primarily μ-receptor agonist activity. signs and symptoms similar to those seen after abrupt discon-
Morphine and its congeners exhibit cross-tolerance not only with tinuance appear, peaking in 10–20 minutes and largely subsiding
respect to their analgesic actions but also to their euphoriant, seda- after 1 hour. Even in the case of methadone, withdrawal of which
tive, and respiratory effects. However, the cross-tolerance existing results in a relatively mild abstinence syndrome, the antagonist-
among the μ-receptor agonists can often be partial or incom- precipitated abstinence syndrome may be very severe.
plete. This clinical observation has led to the concept of “opioid In the case of agents with mixed effects, withdrawal signs and
rotation,” which has been used for many years in the treatment of symptoms can be induced after repeated administration followed
cancer pain. A patient who is experiencing decreasing effectiveness by abrupt discontinuance of pentazocine, cyclazocine, or nalor-
of one opioid analgesic regimen is “rotated” to a different opioid phine, but the syndrome appears to be somewhat different from
analgesic (eg, morphine to hydromorphone; hydromorphone that produced by morphine and other agonists. Anxiety, loss of
to methadone) and typically experiences significantly improved appetite and body weight, tachycardia, chills, increase in body
analgesia at a reduced overall equivalent dosage. Another approach temperature, and abdominal cramps have been noted.