Clinical Pharmacokinetics of Narcotic Agonist-Antagonist Drugs

Abstract

Narcotic agonist-antagonist drugs are able specifically to reverse the effects of morphine and other opiate agonists in some pharmacological preparations. They also have some agonist properties which in some cases may be extensive and provide useful clinical properties such as analgesia, or may be minimal. Thus pentazocine, buprenorphine, nalbuphine and butorphanol all demonstrate definite analgesic properties. Naltrexone, in contrast, has only limited agonist action, as shown for example in pupil constriction, and is perhaps better regarded as an antagonist.After intravenous administration of buprenorphine there is an initially rapid early distribution phase with a half-life of about 2 minutes. Studies on butorphanol and pentazocine had insufficient early samples to allow accurate analysis of this phase. Otherwise, the intravenous pharmacokinetics for ali these drugs show bi-or tri-exponential decay with terminal half-lives of between 3 and 5 hours, plasma clearances of between 1200 and 2800 ml/min, and apparent volumes of distribution of 200 to 400L. These values for plasma clearance and terminal ha(f-l!fe have been confirmed in oral and intramuscular studies.There is only limited information about the rate or extent of absorption after intramuscular administration. For buprenorphine peak plasma concentrations are reached between 2 and 5 minutes; for pentazocine and butorphanol the peak is later, at between 15 and 60 minutes for pentazocine and 45 minutes for butorphanol. Systemic availability of intramuscular buprenorphine is in the range of 40 to 100%, but is generally greater than 90%. Availability of intramuscular butorphanol has been reported to be complete.Oral systemic availability for drugs with a high plasma clearance is predictably low because of a significant first-pass effect through the liver. The oral availabilities of pentazocine and nalbuphine have been calculated to be about 20%, and although there are no pharmacokinetic data, some evidence of clinical efficacy suggests a similar figure for butorphanol and buprenorphine. For naltrexone however, the available data suggest that this drug is completely absorbed after oral administration.Only buprenorphine has been studied by the sublingual route. The systemic availability was variable (16 to 94%), but on average it was 55% in a study of long duration; the absorption half-life from the buccal cavity was estimated to be 76 minutes. Over a limited dose range there appeared to be linear increases in the maximum rise in plasma concentration and A UC with buprenorphine administered by this route. There have been no pharmacokinetic studies of the narcotic agonist-antagonist drugs by other routes of administration, such as after intrathecal or extradural administration, or rectally or transcutaneously.Pharmacodynamic data for these drugs are incomplete. AnalgeSia in man appears to be dose-related for pentazocine, butorphanol, buprenorphine and nalbuphine; morphine antagonism is dose-related for naltrexone. The appearance of opiate side effects (nausea and...

Comparison of the opioid receptor antagonist properties of naltrexone and 6β-naltrexol in morphine-naïve and morphine-dependent mice

“…The metabolite is maximally found at 2 to 3-fold higher concentrations than naltrexone in plasma following oral administration (Ferrari et al, 1998). Given the large acute potency difference, 6β-naltrexol may not contribute after naltrexone administration, although it may be responsible for the long duration of naltrexone action (Bullingham et al, 1983). Consequently differential pharmacokinetic profiles of the two compounds may explain why 6β-naltrexol produces a less severe withdrawal than naltrexone and thus be a preferable antagonist for the treatment of overdose.…”

Buprenorphine alters ethanol self-administration in rats: dose-response and time-dependent effects

“…The plasma half-life of buprenorphine is 3 h compared with 2 h for morphine (Jaffe and Martin 1990). The plasma half-life of buprenorphine, however, does not appear to be related to its time course of agonist effects (Bullingham et al 1983;Jaffe and Martin 1990). Interestingly, diprenorphine (0.003-3.0 mg/kg), an opioid antagonist which has a chemical structure similar to buprenorphine, has also been shown to increase EtOH intake , with the maximum effect occurring with the 0.1 mg/kg dose.…”

Why do Pain Physicians Not Routinely Use Mixed Opioids for the Prevention of Neuraxial Opioid-induced Pruritus?

“…Nalbuphine may produce the same degree of respiratory depression as equianalgesic doses of morphine. Moreover, Nalbuphine exhibits a ceiling clinical effect such that increases in a dose greater than 30 mg do not produce further respiratory depression, always in the absence of other CNS active medications affecting patient respiration [23].…”