Transdermal administration of morphine to healthy subjects.

Abstract

1 Twelve healthy subjects received 10 mg morphine HCI delivered transdermally from an occlusive reservoir applied to a small area of skin, painlessly de-epithelialised by vacuum suction. On a separate occasion, 10 mg morphine HCI was given as an i.v. infusion over 20 min. 2 Venous blood samples were collected serially for 72 h and assayed for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) by h.p.l.c. Pupil size, salivation, and central nervous effects ( nausea, fatigue, headache, feeling of heaviness and dysphoria/euphoria) were also measured. 3 After transdermal application morphine was absorbed by a first-order process to produce relatively constant plasma drug concentrations over 11 h. The absolute bioavailability of transdermal morphine was 75% (65-85%; 95% CI). The plasma concentrations of both M6G and M3G were lower after transdermal administration than after i.v. infusion, and a considerable delay (of up to 1 h) was observed before the metabolites were detectable. AUC ratios for M3G and M6G relative to morphine were similar after both modes of administration. 4 Non-analgesic effects were less pronounced at the lower plasma drug and metabolite concentrations observed after transdermal delivery than after the i.v. infusion of morphine. 5 Transdermal administration of morphine warrants investigation as an alternative route of morphine delivery.

Analgesic and Nonanalgesic Effects of Intravenous Hydromorphone ‐ Relation to Plasma Concentrations in Healthy Volunteers

“…Saliva production was significantly reduced for more than 6 h following intravenous administration of hydromorphone. The inhibiting effect on saliva production was more pronounced and of longer duration compared with the reduction seen after intravenous infusion of 10 mg of morphine (23,31). Dry mouth was a common complaint during opioid therapy (32), but the mechanism for reduction of saliva production induced by morphine (25) and, as we have now shown, by hydromorphone, is unknown.…”

“…Measurement of pupil size is a convenient method for assessment of opioid receptor stimulation, but has only minor clinical importance. Photographic methods to assess pupil size are regarded as accurate (35) and were-used by Inturrisi et al (36), Miller et al (37), Strain et al (38) and Westerling et al (23,25) to evaluate miosis following opioid administration.…”

“…Fatigue, euphoria, dysphoria, headache, nausea and the feeling of heaviness were evaluated using category ratio scales (21)(22)(23) at the same time that blood samples were drawn (up to 30 h after drug administration).…”

“…The diameters of the pupil and the iris were measured on the negative film and the pupil:iris diameter ratio was calculated (23). The ratio was chosen to ascertain that the measurements were made in the same frontal plane.…”

“…Category rating scales with ratio properties, according to principles of Borg (21) and Borg et al (22), and previously used (23,25), were employed to evaluate feelings of fatigue, euphoria/dysphoria, headache, heaviness and nausea. The scale ranged from 'nothing at all' to 'maximal'.…”