The two principal competitive antagonists of morphine and of morphine analogues, without agonist effect, are naloxone and naltrexone. These two compounds have similar properties but have different indications.
- They reverse the effects of morphine: respiratory depression, analgesia, euphoria, drowsiness, miosis.
- Administered to a morphine addict under the effect of morphine, they elicit an acute withdrawal syndrome.
- Administered to a normal subject, they do not modify painful perceptions, which suggests that the physiological role of enkephalins is low.
- They can reduce addiction to other compounds, in particular alcohol. Enkephalin release and mu and delta receptor stimulation appear to be involved in alcoholic addiction leading to dopamine release in the nucleus accumbens.
Different therapeutic uses
Naloxone, Narcan*, which is largely inactivated by first-pass metabolism after oral administration, is used by parenteral route to treat respiratory depression induced by opioid agonists. It does not improve the other respiratory depressions. Its duration of action is short, about thirty minutes and readministration can be necessary. Naloxone could also be used for the diagnosis of morphine overdose or misuse by eliciting a withdrawal syndrome, but this is neither useful nor very desirable. After administration of strong doses of naloxone, cases of arterial hypertension were observed.
Naltrexone is given by oral route in the treatment of morphine dependence to avoid relapses. After seven to ten days of abstinence, the morphine addict treated by naltrexone becomes insensitive to a possible intake of a morphinomimetic agent. In other words, morphine intake is without effect in an addict treated by naltrexone. But, administered to a non-abstinent morphine addict, it elicits a withdrawal syndrome.
Naltrexone is also used as an adjunct to support the maintenance of abstinence in patients dependant on alcohol. It indeed decreases the desire for drinking and the pleasure of consuming alcohol.
Naltrexone is quite well absorbed after administration by oral route. Its plasma half-life is about four hours, that of its principal active metabolite, ß-naltrexol, about twelve hours, which explains its sustained effect.
Various but not very specific adverse effects generally without severity were observed during treatment with naltrexone.
Nalorphine, which has agonist and antagonist effects, was largely used as antidote of the respiratory depression caused by morphine. Currently, one prefers naloxone, pure antagonist, but nalorphine has effects at the same time
- At a subject not having received morphine, nalorphine induce a respiratory depression, a miosis, a low analgesic effect, an euphoric or dysphoric state can. Its repeated administration elicits tolerance and its discontinuation a withdrawal syndrome.
- In a subject treated by morphine, nalorphine opposes the effects of morphine, including respiratory depression.
- In a morphine addict, it elicits a withdrawal syndrome.
Nalmefene, chemically quite similar to naltrexone, is an opioid antagonist of long duration of action.