Partial agonists Subject

Morphine antagonists and partial agonists. The effects of opioids can be abolished by the antagonists naloxone or naltrexone (A), irrespective of the receptor type involved. Given by itself, neither has any effect in normal subjects however, in opioid-dependent subjects, both precipitate acute withdrawal signs. Because of its rapid presystemic elimination, naloxone is only suitable for parenteral use. Naltrexone is metabolically more stable and is given orally. Naloxone is effective as antidote in the treatment of opioid-induced respiratory paralysis. Since it is more rapidly eliminated than most opioids, repeated doses may be needed. Naltrexone may be used as an adjunct in withdrawal therapy. 

From the published clinical studies, it would appear that the partial agonists bretazenil and abercamil are less likely to cause physiological dependence, have lower reinforcing effects and a lower incidence of subjective effects associated with abuse liability than the conventional 1,4-benzodiazepine sedative-hypnotics. It is presently unclear whether the full agonists for the GABA-A receptor, zolpidem and zopiclone, offer a real advance in the treatment of insomnia although their adverse effect profiles and abuse liability may be lower than that of the conventional benzodiazepines. 

A low-efficacy opioid can reduce the effectiveness of a high-efficacy opioid by successfully competing with the latter for receptors. Partial agonist (agonist/antagonist) opioids, e.g. pentazocine, will also antagonise the action of other opioids, e.g. heroin, and may even induce the withdrawal syndrome in dependent subjects. 

Naloxone is a pure competitive antagonist at all opioid receptors, notably the p- and K- receptors it has no agonist activity. Naloxone antagonises both agonist and partial agonist opioids (although it may not be sufficient to reverse the effects of buprenorphine in overdose, so tenaciously does the latter drug bind to receptors). It induces an acute withdrawal syndrome in opioid-dependent subjects. 

Tomlinson B, Cruickshank JM, Hayes Y, Renondin JC, Lui JB, Graham BR, Jones A, Lewis AD, Prichard BN. Selective beta-adrenoceptor partial agonist effects of pindolol and xamoterol on skeletal muscle assessed by plasma creatine kinase changes in healthy subjects. Br J Clin Pharmacol 1990 30(5) 665-72. 

Compounds (28), (29), and (30) are BZD receptor partial agonists which are anxiolytic in mice subjected to an operant punishment test and protect against PTZ-induced seizures in mice and rats [67], They cause minimum motor impairment in rodents and do not cause withdrawal in mice and squirrel monkeys. 

The major side effects of dezocine are dizziness, vomiting, euphoria, dysphoria, nervousness, headache, pruritus, and sweating. Normal volunteers and recovered addicts report the subjective effects of single doses of dezocine to be like morphine. Because of the partial agonist mechanism of dezocine, one would not expect it to have a high abuse potential. 

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