Bioavailabilities of rectal and oral methadone in healthy subjects

Abstract

Br J Clin PharmacolBritish Journal of Clinical Pharmacology DOI:10.1111DOI:10. /j.1365DOI:10. -2125DOI:10. .2004 Bioavailabilities of rectal and oral methadone in healthy subjects AimsRectal administration of methadone may be an alternative to intravenous and oral dosing in cancer pain, but the bioavailability of the rectal route is not known. The aim of this study was to compare the absolute rectal bioavailability of methadone with its oral bioavailability in healthy humans. MethodsSeven healthy subjects (six males, one female, aged 20-39 years) received 10 mg d 5 -methadone-HCl rectally (5 ml in 20% glycofurol) together with either d 0 -methadone intravenously (5 mg) or orally (10 mg) on two separate occasions. Blood samples for the LC-MS analyses of methadone and it's metabolite EDDP were drawn for up to 96 h. Noninvasive infrared pupillometry was peformed at the same time as blood sampling. ResultsThe mean absolute rectal bioavalability of methadone was 0.76 (0.7, 0.81), compared to 0.86 (0.75, 0.97) for oral administration (mean (95% CI)). Rectal absorption of methadone was more rapid than after oral dosing with Tmax values of 1.4 (0.9, 1.8) vs. 2.8 (1.6, 4.0) h. The extent of formation of the metabolite EDDP did not differ between routes of administration. Single doses of methadone had a duration of action of at least 10 h and were well tolerated. ConclusionsRectal administration of methadone results in rapid absorption, a high bioavailability and long duration of action. No evidence of presystemic elimination was seen. Rectal methadone has characteristics that make it a potential alternative to intravenous and oral administration, particularly in cancer pain and palliative care.

Effect of Steady-State Faldaprevir on the Pharmacokinetics of Steady-State Methadone and Buprenorphine-Naloxone in Subjects Receiving Stable Addiction Management Therapy

“…Faldaprevir at 240 mg BID has been shown to be a moderate inhibitor of CYP3A and has no effect on CYP2B6 in healthy volunteers (5); hence, the limited effect of faldaprevir on methadone is consistent with the suggestion that CYP3A4 may not be important in methadone metabolism. Methadone may also be a relatively insensitive substrate for CYP450 inhibition, since it has a lower first-pass effect (oral bioavailability, 86%) than midazolam (oral bioavailability range, 31 to 72%) (20,21). Buprenorphine has low to moderate bioavailability by the sublingual and oral routes (estimated at 51% and 28%, respectively [22]) and is extensively metabolized by N-dealkylation to norbuprenorphine, primarily through CYP3A4 (10,23).…”

Comparison of Intravenous Buprenorphine and Methadone Self-Administration by Recently Detoxified Heroin-Dependent Individuals

“…The maximal doses were chosen to be those that would be safely tolerated in opioid-experienced, nondependent individuals. For methadone, studies have shown a roughly 2:1 ratio in steady-state plasma concentrations after oral and intravenous administration, respectively (Dale et al, 2004). Clinical experience suggests that substantial toxicity, including death, may occur in nonopioid-dependent individuals receiving a starting dose of 30 to 40 mg of methadone orally (Senay, 1999).…”

Methadone-associated long QT syndrome: improving pharmacotherapy for dependence on illegal opioids and lessons learned for pharmacology

“…The racemic mix of methadone hydrochloride is highly soluble in water. Overall bioavailability is 86% for oral administration and 76% for rectal administration [13]. Protein binding is 86 -89% [14].…”