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Chapter: Basic & Clinical Pharmacology : Opioid Analgesics & Antagonists

Strong Agonists

Morphine, hydromorphone, and oxymorphone are strong ago-nists useful in treating severe pain. These prototypic agents have been described in detail above.


The following section describes the most important and widely used opioid analgesics, along with features peculiar to specific agents. Data about doses approximately equivalent to 10 mg of intramuscular morphine, oral versus parenteral efficacy, duration of analgesia, and intrinsic activity (maximum efficacy) are pre-sented in Table 31–2.



Morphine, hydromorphone, and oxymorphone are strong ago-nists useful in treating severe pain. These prototypic agents have been described in detail above.

Heroin (diamorphine, diacetylmorphine) is potent and fast-acting, but its use is prohibited in the USA and Canada. In recent years, there has been considerable agitation to revive its use. However, double-blind studies have not supported the claim that heroin is more effective than morphine in relieving severe chronic pain, at least when given by the intramuscular route.


Methadone has undergone a dramatic revival as a potent andclinically useful analgesic. It can be administered by the oral, intra-venous, subcutaneous, spinal, and rectal routes. It is well absorbed from the gastrointestinal tract and its bioavailability far exceeds that of oral morphine.

Methadone is not only a potent μ-receptor agonist but its race-mic mixture of D- and L-methadone isomers can also block both NMDA receptors and monoaminergic reuptake transporters. These nonopioid receptor properties may help explain its ability to relieve difficult-to-treat pain (neuropathic, cancer pain), especially when a previous trial of morphine has failed. In this regard, when analgesic tolerance or intolerable side effects have developed with the use of increasing doses of morphine or hydromorphone, “opi-oid rotation” to methadone has provided superior analgesia at 10–20% of the morphine-equivalent daily dose. In contrast to its use in suppressing symptoms of opioid withdrawal, use of metha-done as an analgesic typically requires administration at intervals of no more than 8 hours. However, given methadone’s highly variable pharmacokinetics and long half-life (25–52 hours), initial admin-istration should be closely monitored to avoid potentially harmful adverse effects, especially respiratory depression. Because metha-done is metabolized by CYP3A4 and CYP2B6 isoforms in the liver, inhibition of its metabolic pathway or hepatic dysfunction has also been associated with overdose effects, including respiratory depres-sion or, more rarely, prolonged QT-based cardiac arrhythmias.

Methadone is widely used in the treatment of opioid abuse. Tolerance and physical dependence develop more slowly with methadone than with morphine. The withdrawal signs and symptoms occurring after abrupt discontinuance of methadone are milder, although more prolonged, than those of morphine. These properties make methadone a useful drug for detoxification and for maintenance of the chronic relapsing heroin addict.

For detoxification of a heroin-dependent addict, low doses of methadone (5–10 mg orally) are given two or three times daily for 2 or 3 days. Upon discontinuing methadone, the addict experiences a mild but endurable withdrawal syndrome.For maintenance therapy of the opioid recidivist, tolerance to 50–100 mg/d of oral methadone may be deliberately produced; in this state, the addict experiences cross-tolerance to heroin, which prevents most of the addiction-reinforcing effects of heroin. One rationale of maintenance programs is that blocking the reinforcement obtained from abuse of illicit opioids removes the drive to obtain them, thereby reducing criminal activity and making the addict more amenable to psychiatric and rehabilitative therapy. The pharmaco-logic basis for the use of methadone in maintenance programs is sound and the sociologic basis is rational, but some methadone pro-grams fail because nonpharmacologic management is inadequate.

The concurrent administration of methadone to heroin addicts known to be recidivists has been questioned because of the increased risk of overdose death secondary to respiratory arrest. Not only has the number of patients prescribed methadone for persistent pain increased, but the incidence of accidental overdose and complications related to respiratory depression have also increased. Buprenorphine, a partial μ-receptor agonist with long-acting properties, has been found to be effective in opioid detoxi-fication and maintenance programs and is presumably associated with a lower risk of such overdose fatalities.


Fentanyl is one of the most widely used agents in the family ofsynthetic opioids. The fentanyl subgroup now includes sufenta-nil, alfentanil, and remifentanil in addition to the parent com-pound, fentanyl.

These opioids differ mainly in their potency and biodisposi-tion. Sufentanil is five to seven times more potent than fentanyl. Alfentanil is considerably less potent than fentanyl, but acts more rapidly and has a markedly shorter duration of action. Remifentanil is metabolized very rapidly by blood and nonspecific tissue esterases, making its pharmacokinetic and pharmacodynamic half-lives extremely short. Such properties are useful when these com-pounds are used in anesthesia practice. Although fentanyl is now the predominant analgesic in the phenylpiperidine class, meperi-dine continues to be used. This older opioid has significant anti-muscarinic effects, which may be a contraindication if tachycardia would be a problem. Meperidine is also reported to have a nega-tive inotropic action on the heart. In addition, it has the potential for producing seizures secondary to accumulation of its metabo-lite, normeperidine, in patients receiving high doses or with con-current renal failure. Given this undesirable profile, use of meperidine as a first-line analgesic is becoming increasingly rare.


Levorphanol is a synthetic opioid analgesic closely resemblingmorphine in its action.

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