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Toxicity & Undesired Effects
Direct toxic effects of the opioid analgesics that are extensions of their acute pharmacologic actions include respiratory depression, nausea, vomiting, and constipation (Table 31–4). In addition, tolerance and dependence, diagnosis and treatment of overdosage, and contraindications must be considered.
Drug dependence of the opioid type is marked by a relatively specific withdrawal or abstinence syndrome. Just as there are pharmacologic differences between the various opioids, there are also differences in psychological dependence and the severity of withdrawal effects. For example, withdrawal from dependence on a strong agonist is associ-ated with more severe withdrawal signs and symptoms than with-drawal from a mild or moderate agonist. Administration of an opioid antagonist to an opioid-dependent person is followed by brief butsevere withdrawal symptoms (see antagonist-precipitated withdrawal, below). The potential for physical and psychological dependence of the partial agonist-antagonist opioids appears to be less than that of the strong agonist drugs.
1. Tolerance—Although development of tolerance begins withthe first dose of an opioid, tolerance generally does not become clinically manifest until after 2–3 weeks of frequent exposure to ordinary therapeutic doses. Nevertheless, perioperative and critical care use of ultrapotent opioid analgesics such as remifentanil have been shown to induce opioid tolerance within hours. Tolerance develops most readily when large doses are given at short intervals and is minimized by giving small amounts of drug with longer intervals between doses.
Depending on the compound and the effect measured, the degree of tolerance may be as great as 35-fold. Marked tolerance may develop to the analgesic, sedating, and respiratory depressant effects. It is possible to produce respiratory arrest in a non-tolerant person with a dose of 60 mg of morphine, whereas in addicts maximally tolerant to opioids as much as 2000 mg of morphine taken over a 2- or 3-hour period may not produce significant respiratory depression. Tolerance also develops to the antidiuretic, emetic, and hypotensive effects but not to the miotic, convulsant, and constipating actions (Table 31–3).
Tolerance to the sedating and respiratory effects of the opioids dissipates within a few days after the drugs are discontinued. Tolerance to the emetic effects may persist for several months after withdrawal of the drug. The rates at which tolerance appears and disappears, as well as the degree of tolerance, may also differ con-siderably among the different opioid analgesics and among indi-viduals using the same drug. For instance, tolerance to methadone develops more slowly and to a lesser degree than to morphine.
Tolerance also develops to analgesics with mixed receptor effects but to a lesser extent than to the agonists. Such effects as hallucinations, sedation, hypothermia, and respiratory depression are reduced after repeated administration of the mixed receptor drugs. However, tolerance to the latter agents does not generally include cross-tolerance to the agonist opioids. It is also important to note that tolerance does not develop to the antagonist actions of the mixed agents or to those of the pure antagonists.
Cross-tolerance is an extremely important characteristic of the opioids, ie, patients tolerant to morphine often show a reduction in analgesic response to other agonist opioids. This is particularly true of those agents with primarily μ-receptor agonist activity. Morphine and its congeners exhibit cross-tolerance not only with respect to their analgesic actions but also to their euphoriant, sedative, and respiratory effects. However, the cross-tolerance existing among the μ-receptor agonists can often be partial or incomplete. This clinicalobservation has led to the concept of “opioid rotation,” which has been used in the treatment of cancer pain for many years. A patient who is experiencing decreasing effectiveness of one opioid analgesic regimen is “rotated” to a different opioid analgesic (eg, morphine to hydromorphone; hydromorphone to methadone) and typically experiences significantly improved analgesia at a reduced overall equivalent dosage. Another approach is to “recouple” opioid recep-tor function through the use of adjunctive nonopioid agents. NMDA-receptor antagonists (eg, ketamine) have shown promise in preventing or reversing opioid-induced tolerance in animals and humans. Use of ketamine is increasing because well-controlled stud-ies have shown clinical efficacy in reducing postoperative pain and opioid requirements in opioid-tolerant patients. Agents that inde-pendently enhance μ-receptor recycling may also hold promise to improve analgesia in the opioid-tolerant patient.
The novel use of δ-receptor antagonists with μ-receptor agonists is also emerging as a strategy to avoid the development of tolerance. This idea has developed around the observation that mice lacking the δ-opioid receptor fail to develop tolerance to morphine.
2. Dependence—The development of physical dependence isan invariable accompaniment of tolerance to repeated administra-tion of an opioid of the μ type. Failure to continue administering the drug results in a characteristic withdrawal or abstinence syn-drome that reflects an exaggerated rebound from the acute phar-macologic effects of the opioid.
The signs and symptoms of withdrawal include rhinorrhea, lac-rimation, yawning, chills, gooseflesh (piloerection), hyperventila-tion, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety, and hostility. The number and intensity of the signs and symptoms are largely dependent on the degree of physical depen-dence that has developed. Administration of an opioid at this time suppresses abstinence signs and symptoms almost immediately.
The time of onset, intensity, and duration of abstinence syn-drome depend on the drug previously used and may be related to its biologic half-life. With morphine or heroin, withdrawal signs usually start within 6–10 hours after the last dose. Peak effects are seen at 36–48 hours, after which most of the signs and symptoms gradually subside. By 5 days, most of the effects have disappeared, but some may persist for months. In the case of meperidine, the withdrawal syndrome largely subsides within 24 hours, whereas with methadone several days are required to reach the peak of the abstinence syndrome, and it may last as long as 2 weeks. The slower subsidence of methadone effects is associated with a less intense immediate syndrome, and this is the basis for its use in the detoxification of heroin addicts. However, despite the loss of physical dependence on the opioid, craving for it may persist. In addition to methadone, buprenorphine and clonidine (an α2-noradrenergic receptor agonist) are FDA-approved treatments for opioid analgesic detoxification .
transient, explosive abstinence syndrome— antagonist-precipitated withdrawal—can be induced in a subject physicallydependent on opioids by administering naloxone or another antagonist. Within 3 minutes after injection of the antagonist, signs and symptoms similar to those seen after abrupt discontinu-ance appear, peaking in 10–20 minutes and largely subsiding after 1 hour. Even in the case of methadone, withdrawal of which results in a relatively mild abstinence syndrome, the antagonist-precipitated abstinence syndrome may be very severe.
In the case of agents with mixed effects, withdrawal signs and symptoms can be induced after repeated administration followed by abrupt discontinuance of pentazocine, cyclazocine, or nalor-phine, but the syndrome appears to be somewhat different from that produced by morphine and other agonists. Anxiety, loss of appetite and body weight, tachycardia, chills, increase in body temperature, and abdominal cramps have been noted.
3. Addiction—The euphoria, indifference to stimuli, and seda-tion usually caused by the opioid analgesics, especially when injected intravenously, tend to promote their compulsive use. In addition, the addict experiences abdominal effects that have been likened to an intense sexual orgasm. These factors constitute the primary reasons for opioid abuse liability and are strongly rein-forced by the development of physical dependence. This disorder has been linked to dysregulation of brain regions mediating reward and stress .
Obviously, the risk of causing dependence is an important consideration in the therapeutic use of these drugs. Despite thatrisk, under no circumstances should adequate pain relief ever be with-held simply because an opioid exhibits potential for abuse or because legislative controls complicate the process of prescribing narcotics.Furthermore, certain principles can be observed by the clinician to minimize problems presented by tolerance and dependence when using opioid analgesics:
· Establish therapeutic goals before starting opioid therapy. This tends to limit the potential for physical dependence. The patient and his or her family should be included in this process.
· Once an effective dose is established, attempt to limit dosage to this level. This goal is facilitated by use of a written treatment contract that specifically prohibits early refills and having mul-tiple prescribing physicians.
· Instead of opioid analgesics—especially in chronic manage-ment—consider using other types of analgesics or compounds exhibiting less pronounced withdrawal symptoms on discon-tinuance.
· Frequently evaluate continuing analgesic therapy and the patient’s need for opioids.
Intravenous injection of naloxone dramatically reverses coma due to opioid overdose but not that due to other CNS depressants. Use of the antagonist should not, of course, delay the institution of other therapeutic measures, especially respiratory support.
C. Contraindications and Cautions in Therapy
1. Use of pure agonists with weak partial agonists—Whena weak partial agonist such as pentazocine is given to a patient also receiving a full agonist (eg, morphine), there is a risk of diminish-ing analgesia or even inducing a state of withdrawal; combining full agonist with partial agonist opioids should be avoided.
2. Use in patients with head injuries—Carbon dioxide reten-tion caused by respiratory depression results in cerebral vasodila-tion. In patients with elevated intracranial pressure, this may lead to lethal alterations in brain function.
3. Use during pregnancy—In pregnant women who arechronically using
opioids, the fetus may become physically dependent in utero and manifest
withdrawal symptoms in the early postpartum period. A daily dose as small as 6
mg of heroin (or equivalent) taken by the mother can result in a mild
with-drawal syndrome in the infant, and twice that much may result in severe
signs and symptoms, including irritability, shrill crying, diarrhea, or even
seizures. Recognition of the problem is aided by a careful history and physical
examination. When withdrawal symptoms are judged to be relatively mild,
treatment is aimed at control of these symptoms using such drugs as diazepam;
with more severe withdrawal, camphorated tincture of opium (parego-ric; 0.4 mg
of morphine/mL) in an oral dose of 0.12–0.24 mL/kg is used. Oral doses of
methadone (0.1–0.5 mg/kg) have also been used.
4. Use in patients with impaired pulmonary function— Inpatients with borderline respiratory reserve, the depressant proper-ties of the opioid analgesics may lead to acute respiratory failure.
5. Use in patients with impaired hepatic or renal function—Because morphine and its congeners are metabolized primarily in the liver, their use in patients in prehepatic coma may be questioned. Half-life is prolonged in patients with impaired renal function, and morphine and its active glucuronide metabolite may accumulate; dosage can often be reduced in such patients.
6. Use in patients with endocrine disease—Patients withadrenal insufficiency (Addison’s disease) and those with hypothy-roidism (myxedema) may have prolonged and exaggerated responses to opioids.
Because seriously ill or hospitalized patients may require a large number of drugs, there is always a possibility of drug interactions when the opioid analgesics are administered. Table 31–5 lists some of these drug interactions and the reasons for not combining the named drugs with opioids.
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