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.

Proteins and Peptides: Strategies for Delivery to and Across the Skin

“…This technique was developed by a group in Sweden in the 1990s and is now available as the commercial product Cellpatch which is used to deliver morphine in postoperative pain. 117 They also reported the application of the antidiuretic peptide 1-deamino-8-D-arginine vasopressin with close to 100% bioavailability in healthy human subjects 118 with recovery of the skin spot to normal after 6 weeks. No further research into this technique has been undertaken in the past 10 years or by other groups so it is unlikely that this technique will progress further for peptide delivery.…”

Should topical opioid analgesics be regarded as effective and safe when applied to chronic cutaneous lesions?

“…Unlike fentanyl, the transdermal absorption of morphine has not been widely published. An early report by Westerling et al [29] . suggested that the absolute bioavailability of transdermal morphine, across de‐epithelianised skin was 75%.…”

Concentration‐Effect Relationship after Intravenous Hydromorphone Administration: Use of An Effect Compartment Model and System Analysis to Minimize Hysteresis of Effects

“…Dryness of the mouth is a side effect of morphine (28,29) that was reported to be highly associated with morphine therapy in chronic pain patients (30). Following different routes of morphine administration to healthy volunteers, a significant reduction of saliva production was registered (9)(10)(11). Also, hydromorphone, given as an intravenous infusion over 20 mins, significantly reduced saliva production (12), which in the present analysis was shown to be well related to the estimated concentration of the opioid in a hypothetical effect compartment.…”

“…The analgesic effect of opioids is difficult to quantify and compare between individual subjects, whereas in healthy subjects, experimental pain lacks the emotional components of clinical pain. Unlike analgesia, side effects of opioids, such as miosis and decrease of saliva production, can be measured accurately (9)(10)(11)(12). The E max model (13,14) was applied after administration of morphine to healthy subjects (9,11), where these nonanalgesic effects were shown to be related to estimated effect compartment concentrations.…”

“…The right eye was photographed under standardized conditions, before and at regular intervals after administration of hydromorphone. The diameters of the pupil and iris were measured on the negative film and the pupil:iris diameter ratio was calculated (10). The ratio was chosen to ascertain that the measurements were made in the same frontal plane.…”