Differential sensitivity of three experimental pain models in detecting the analgesic effects of transdermal fentanyl and buprenorphine

Abstract

This is the first randomized controlled trial that tests the analgesic efficacy of transdermally delivered opioids in healthy volunteers and that assesses the sensitivity of different experimental pain tests to detect analgesia in this setting. Transdermal application of the full agonist fentanyl (TDF: 12.5 or 25 microg/h) and the partial agonist buprenorphine (TDB: 35 microg/h) was compared in three experimental models of acute pain (heat pain, painful electrical stimulation, cold pressor) in a double-blind, randomized, placebo-controlled, 4-arm crossover study with 20 healthy subjects (15 men, 5 women). Patches were administered for 72 h and pain levels measured at baseline and 24 and 72 h, with an 11-day wash-out. The cold pressor test was most sensitive to analgesic effects, with significant reductions in area under the pain intensity curve for all active compounds at 24 h (average reductions: 14% TDF 12.5 microg/h, 35% TDF 25 microg/h, 43% TDB 35 microg/h). There were significant increases in heat pain threshold for TDF 25 microg/h and TDB 35 microg/h. Painful electrical stimulation failed to demonstrate an analgesic effect. The magnitude of analgesia in the cold pressor model showed some correlation with TDF dosage and comparable effects for the full agonist fentanyl and the partial agonist buprenorphine. We conclude that the cold pressor test was most sensitive to analgesic effects in healthy subjects and that a transdermal dose of 12.5 microg/h fentanyl achieved significant pain reduction compared with placebo. Subjects experienced opioid-typical AEs including dizziness, nausea and vomiting. No serious AEs occurred.

Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone

“…Oxycodone also increased the heat pain threshold and decreased the cold pain sensitivity, but these changes were not altered by itraconazole. The minor effect of itraconazole on oxycodone-induced pharmacological response despite the clear changes in its pharmacokinetics is well in line with the log-linear relationship between drug concentration and effect and the relatively small dose of oxycodone used in our study [31,32]. Azole antimycotics are known to have significant interactions with several substrates of CYP3A [15,16,[33][34][35].…”

Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs

“…10). Three studies found that fentanyl attenuated this parameter, which was contradictory to the finding of Tucker et al (Tucker et al, 2005;Koltzenburg et al, 2006;Andresen et al, 2010). Repetitive heat pain was unaffected by fentanyl, whereas repetitive cold pain was attenuated by fentanyl (Ilkjaer et al, 1996;Price et al, 2002).…”

“…Fentanyl has been tested against electrical and thermal (heat and cold) skin pain. Electrical pain was unaffected by fentanyl in two studies, whereas two studies found effect on this pain modality (Ginosar et al, 2003;Tucker et al, 2005;Koltzenburg et al, 2006;Andresen et al, 2010). Effects on heat pain have been tested through various stimulation paradigms and conflicting results exist.…”

Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review

“…The analgesic effect was shown more robustly when assessed as the area under the VAS curve compared with the peak pain intensity and the mean pain intensity [58].…”