Effects of the complexation of various fentanyl analogs in hydroxypropyl‐β‐cyclodextrin after epidural and intrathecal administration in rats

Abstract

Complexation of various equipotent doses of fentanyl-like opioids in hydroxypropyl-6-cyclodextrin (HP-P-CD) results in a potentiation of the spinal activity of these opioids after both epidural and intrathecal administration in a fixed diluent volume o f 10 p,l. The first active and most optimal concentrations of HP-(3-CD after epidural administration differed between the opioids and varied from 1 to 20% HP-P-CD. The duration of deep surgical analgesia increased at optimal concentrations of HP-P-CD with a factor 3 for fentanyl (15% HP-P-CD), 3.6 for sufentanil (5-10% HP-p-CD), and 2.2, 6.0, and 1.4 for carfentanil (5% HP-P-CD), alfentanil (20% HP-p-CD), and lofentanil (15% HP-P-CD), respectively. Increasing the concentrations of HP-P-CD above these optimal concentrations did not further potentiate the analgesic activity of the opioids. The complexation of the opioids in HP-P-CD also increased the duration o f supraspinal side-effects. However, except for lofentanil, the potentiations o f the analgesic activity were always longer lasting than those for the secondary side-effects. As a consequence, there was a gain in the total time of analgesia without side-effects. After intrathecal administration, there was no gain in the duration of deep surgical analgesia after complexation of fentanyl, carfentanil, and alfentanil in HP-P-CD. For both sufentanil and lofentanil, maximal potentiation of analgesia was measured at 10% HP-P-CD with, respectively, 2.8-and 1.7-fold increases in the duration of analgesia. Also intrathecally, there was some gain in the duration o f duration o f analgesia without supraspinal side-effects. These results on the potentiation of the opioids with HP-P-CD are discussed in relation to the lipophilicity of the tested opioids. o 1993 Wiley-Liss, Inc

Pharmaceutical Applications of Cyclodextrins. 2. In Vivo Drug Delivery

“…The effects of HP--CD in altering the activity of a number of opioids and model drugs after intracerebral, intrathecal, and epidural administration have been mixed. [94][95][96][97][98][99] The results indicated that the effects of HP--CD varied with concentration. No dramatic long-term sustaining effect was observed in any of the studies although some interesting observations were made.…”

Cyclodextrin Drug Carrier Systems

“…A retinal−dextran conjugate solubilized by β-cyclodextrin was reported to be less cytotoxic and retained the ability to inhibit the growth of cancer cells . 2-Hydroxypropyl-β-cyclodextrin serves as a benign vehicle for the delivery of drugs which are directed at sites in the central nervous system. , When opioids were administered intrathecally in rats, 2-hydroxypropyl-β-cyclodextrin prolonged the duration of analgesia and reduced the supraspinal side effects such as the incidence of catalepsy and blockade of the pinna reflex. 2-Hydroxypropyl-β-cyclodextrin appears to provide a slow release reservoir, diminishing the redistributional loss of spinally administered drug from the locus of desired effect to systemic circulation and extraspinal tissues.…”