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Chapter: Basic & Clinical Pharmacology : Opioid Analgesics & Antagonists

The Opioid Antagonists

The pure opioid antagonist drugs naloxone, naltrexone, and nalmefene are morphine derivatives with bulkier substituents atthe N17 position.


The pure opioid antagonist drugs naloxone, naltrexone, and nalmefene are morphine derivatives with bulkier substituents atthe N17 position. These agents have a relatively high affinity for μ-opioid binding sites. They have lower affinity for the otherreceptors but can also reverse agonists at δ and κ sites.


Naloxone is usually given by injection and has a short duration of action (1–2 hours) when given by this route. Metabolic dis-position is chiefly by glucuronide conjugation like that of the agonist opioids with free hydroxyl groups. Naltrexone is well absorbed after oral administration but may undergo rapid first-pass metabolism. It has a half-life of 10 hours, and a single oral dose of 100 mg blocks the effects of injected heroin for up to 48 hours. Nalmefene, the newest of these agents, is a derivative of naltrexone but is available only for intravenous administration. Like naloxone, nalmefene is used for opioid overdose but has a longer half-life (8–10 hours).


When given in the absence of an agonist drug, these antagonists are almost inert at doses that produce marked antagonism of ago-nist opioid effects.

When given intravenously to a morphine-treated subject, the antagonist completely and dramatically reverses the opioid effects within 1–3 minutes. In individuals who are acutely depressed by an overdose of an opioid, the antagonist effectively normalizes respiration, level of consciousness, pupil size, bowel activity, and awareness of pain. In dependent subjects who appear normal while taking opioids, naloxone or naltrexone almost instanta-neously precipitates an abstinence syndrome.

There is no tolerance to the antagonistic action of these agents, nor does withdrawal after chronic administration precipitate an abstinence syndrome.

Clinical Use

Naloxone is a pure antagonist and is preferred over older weak agonist-antagonist agents that had been used primarily as antago-nists, eg, nalorphine and levallorphan.

The major application of naloxone is in the treatment of acute opioid overdose.  It is very important that therepeated whenever necessary. In using naloxone in the severely opioid-depressed newborn, it is important to start with doses of 5–10 mcg/kg and to consider a second dose of up to a total of 25 mcg/kg if no response is noted.

Low-dose naloxone (0.04 mg) has an increasing role in the treatment of adverse effects that are commonly associated with intravenous or epidural opioids. Careful titration of the naloxone dosage can often eliminate the itching, nausea, and vomiting while sparing the analgesia. For this purpose, oral naloxone, and more recently modified analogs of naloxone and naltrexone, have been approved by the FDA. These include methylnaltrexonebromide (Relistor) for the treatment of constipation in patientswith late-stage advanced illness and alvimopan (Entereg) for the treatment of postoperative ileus following bowel resection surgery. The principal mechanism for this selective therapeutic effect is believed to be inhibition of peripheral μ receptors in the gut with minimal CNS penetration.

Because of its long duration of action, naltrexone has been proposed as a maintenance drug for addicts in treatment pro-grams. A single dose given on alternate days blocks virtually all of the effects of a dose of heroin. It might be predicted that this approach to rehabilitation would not be popular with a large per-centage of drug users unless they are motivated to become drug-free. A related use is in combination with morphine sulfate in a controlled-release formulation (Embeda) in which 20–100 mg of morphine is slowly released over 8–12 hours or longer for the control of prolonged postoperative pain. Naltrexone, 0.4–4 mg, is sequestered in the center of the formulation pellets and is present to prevent the abuse of the morphine (by grinding and extraction of the morphine from the capsules).

There is evidence that naltrexone decreases the craving for alcohol in chronic alcoholics by increasing baseline β-endorphin release, and it has been approved by the FDA for this purpose . Naltrexone also facilitates abstinence from nicotine (cigarette smoking) with reduced weight gain. In fact, a combina-tion of naltrexone plus bupropion may also offer an effective and synergistic strategy for weight loss. If current trials demonstrate cardiovascular safety during prolonged use, this and other weight-loss medications compounded with naltrexone may eventually win FDA approval.


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