MAJOR NEUROLOGIC SYMPTOMS AND THEIR TREATMENT

OPIOID ANALGESICS AND ANTAGONISTS (Narcotic Analgesics and Antagonists)

The concept of specific opioid receptors in the brain and discovery of the endogenous ligands for these receptors has greatly enhanced understanding of analgesic mechanisms. "Opioid" is a generic term describing substances, natural or synthetic, that bind to these receptors to produce an agonist action. Opioid antagonists are opioid-like substances that bind to opioid receptors, but produce little or no agonist activity.

Available opioids and antagonists are described here; principles and details of their clinical use are described under TREATMENT OF ACUTE POSTOPERATIVE PAIN and CANCER PAIN, below.

Natural Opioid Analgesics

Morphine, an opium alkaloid, is the prototype of the opioid analgesics. In the nontolerant patient with acute pain, it provides analgesia at a dose (about 10 mg IM) that does not result in severe alterations in consciousness. Morphine affects both the initial perception of pain and the emotional response to it. Total relief of pain is difficult to achieve, but reducing the level of distress or suffering is achievable. Patients with severe pain rarely obtain pleasant, euphoric sensations from morphine, but may become drowsy and relaxed, partly because of decreased distress. Paradoxically, in patients without pain, morphine may produce dysphoria.

Traditionally, oral morphine has been considered ineffective. It is rapidly transformed, principally in the liver, and excreted in the urine. However, with upward titration of the dose, oral morphine can be very effective for chronic pain; it is the drug most commonly used to treat severe cancer pain. A slow-release tablet that dispenses morphine over 8 to 12 h and a concentrated oral solution have been developed in attempts to make oral morphine more acceptable. Morphine sulfate is the most commonly used water-soluble salt. Very low doses of intraspinal morphine (eg, 5 to 10 mg epidurally or 0.5 to 1 mg intrathecally) can provide long-lasting (up to 24 h) pain relief postoperatively and in selected nontolerant cancer patients.

Adverse effects of morphine are dose-related and include respiratory depression, de-creased cough reflex, nausea, vomiting, constipation, itch, sedation, and confusion. Mor-phine also produces miosis and causes contraction of peripheral smooth muscle, the most important effect of which is decreased propulsive movements in the GI tract, causing con-stipation (a useful effect in the treatment of diarrhea with opioids). Morphine causes the venules (capacitance vessels) to dilate, and hypotension may occur in hypovolemic patients or those who suddenly assume an upright position. This effect is rare with chronic use. Morphine 6-glucuronide, a morphine metabolite, is active, potent, and renally excreted. It may explain the exaggerated response seen in some patients with renal failure who receive multiple doses of morphine, which should thus be used cautiously in such patients. Morphine and other opioids should also be used with caution in patients with chronic obstructive pulmonary disease; patients with liver disease should receive smaller starting doses and careful titration. Neonates, especially premature infants, are unusually sensitive to morphine and other opioids, because they lack adequate metabolic pathways to elim-inate them.

The development of tolerance to morphine and other opioids varies from one physio-logic system to another; eg, tolerance develops slowly to the constipating effect, whereas respiratory depression or nausea typically wanes soon after treatment begins. During chronic therapy, it may become necessary to increase the dose to achieve the same degree of pain relief, since the duration of action shortens and the peak analgesic effect decreases.

Codeine, an opium derivative, has good oral potency; 65 mg is equianalgesic to about 600 mg of aspirin. However, since codeine acts centrally, it can provide analgesia additive to aspirin, acetaminophen, and other peripherally-acting analgesics. It is also useful to treat cough and diarrhea. Unwanted effects (respiratory depression, nausea, vomiting, and constipation) are similar to those of other opioids.

Synthetic Opioid Analgesics Meperidine: Between 75 and 100 mg parenterally is equianalgesic to 10 mg of morphine sulfate, but its duration of action (about 3 h) is shorter. Its oral potency is poor. Meperidine is metabolized to an active metabolite (normeperidine) that causes dysphoria and CNS excitation, including myoclonus, tremulousness, and seizures. Accumulation of nor-meperidine occurs for days after dosing begins or is increased, particularly in those with renal failure. For this reason, meperidine is not preferred in the management of chronic cancer pain.

Methadone has a very long half-life that is longer than its duration of analgesia and good oral bioavailability. It is most often used for short-term treatment of heroin withdrawal (see DEPENDENCE OF THE OPIOID TYPE in Ch. 137), long-term maintenance therapy of opioid addiction, and analgesia in cancer patients. Methadone provides long action, oral effectiveness, and ability at high dosage to block heroin-induced euphoria. Adverse effects resemble those of morphine and are reversible by opioid antagonists. Both its duration of analgesia and CNS (ie, respiratory) effects persist longer than those of morphine. Therefore, unless tolerance has developed, the patient should be closely monitored for several days or more after increasing the methadone dose or its frequency, as serious respiratory depression may result.

Propoxyphene is related chemically to methadone. Propoxyphene hydrochloride 65 mg has central-type analgesic activity equivalent to 650 mg of aspirin, and 100 mg of propoxyphene napsylate is equivalent to 65 mg of propoxyphene hydrochloride. The napsylate salt is available in suspension and tablet formulations allowing more flexibility in dosage and administration. Propoxyphene is used alone or in combination with aspirin or acetaminophen to treat mild to moderate pain. Its toxicity resembles that of other opioid analgesics.

Levorphanol has good oral potency and can be used instead of morphine for all indications. Despite a relatively long half-life (14 to 16 h), the duration of effect is usually 4 h.

Hydromorphone is a potent opioid with a rapid onset of action and a short half-life. It can be used instead of morphine and is available in oral, injectable, and rectal formulations. A concentrated solution (10 mg/mL) is available and is useful in the management of tolerant patients with cancer pain who require parenteral drugs.

Oxymorphone is a potent agonist available in injectable and rectal formulations; 10 mg rectally is about as potent as morphine 10 mg IM.

Oxycodone is a synthetic morphine congener that has a high oral potency; 30 mg orally is equipotent to morphine 10 mg IM. Although available alone, it is usually combined with aspirin or acetaminophen. Brompton's cocktail (a mixture of oral morphine or heroin, an antiemetic, a stimulant, and alcohol), no more effective to treat chronic cancer pain than oral morphine alone, is not recommended.

Opioid Antagonists and Agonist-Antagonists

Antagonists: Naloxone, an almost pure opioid antagonist without significant agonist action, is virtually free of the undesirable effects of the opioid agonist-antagonists. It does not cause respiratory depression or psychotomimetic effects when given alone, and can reverse the effects of opioids. It acts within minutes when given IV and slightly less rapidly when given IM. However, the duration of antagonism is usually shorter than that of opioid-induced respiratory depression, so that clinical vigilance and repeated doses of naloxone may be necessary. A common starting dosage in the nontolerant patient with acute opioid overdosage is 0.4 mg IV q 2 to 3 min prn.

Naltrexone, an orally active opioid antagonist, has recently been approved as an adjunct in opioid dependence. Its long duration of action is generally well tolerated. Other potentially important applications remain to be studied.

Agonist-antagonists: Pentazocine, a weak antagonist with considerable analgesic activity, is available in a parenteral formulation and in tablets combined with naloxone, aspirin, or acetaminophen. The analgesic activity of pentazocine 60 mg IM is comparable to 10 mg of morphine. There is a ceiling effect to analgesia at higher doses. This characteristic, the potential for opioid withdrawal if pentazocine is given to patients already physically dependent on agonist drugs, and the risk of psychotomimetic effects limit the use of this drug to nontolerant, nonphysically dependent patients with acute pain. Pentazocine overdosage is reversible by naloxone, but not by other opioid antagonists.

Butorphanol is a parenteral drug with a spectrum of effects similar to pentazocine. Nalbuphine has psychotomimetic effects less prominent than with pentazocine, but more likely to occur than with morphine. A parenteral formulation is available.
Buprenorphine is a very potent analgesic with a relatively long (6 h) duration. Psychotomimetic effects are less prominent than with the other agonist-antagonist drugs, but other effects are similar. The clinician should be aware that respiratory depression induced by buprenorphine may not be fully reversible with naloxone.

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