(788) Topical morphine bioavailability in volunteers

J Paice, J Von Roenn, J Hudgins, L Luong, T Krejcie, M Avram; Northwestern

University; Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
Although most patients with cancer-related pain obtain relief with
available therapies, swallowing difculties or intestinal obstruction pre-
clude oral analgesic delivery. Topical morphine may provide an alter-
nate delivery form but morphine bioavailability from a topical gel for-
mulation has not been reported in humans. Therefore, we conducted a
randomized, placebo controlled, double-blind, crossover study of ve
healthy volunteers after they provided institutionally approved written
informed consent. They were admitted to the General Clinical Research
Center (GCRC) of Northwestern University twice, being randomly as-
signed to receive either one mL of morphine compounded at 10 mg/mL
in pluronic lecithin organogel (PLO) base (ExcelleRx, Philadelphia, PA)
applied to the wrist and one mL of normal saline administered subcuta-
neously or one mL of topical drug-free PLO base and one mL of subcu-
taneous morphine 3 mg/mL on the rst occasion and the opposite com-
bination on the second occasion. Seventeen blood samples were
collected from5 min to 10 h after dose administration for determination
of plasma morphine concentrations. Plasma samples were prepared by
solid-phase extraction and morphine concentrations measure by an LC-
MS-MS technique with a linear range of 0.5 500 ng/ml. Bioavailability
of the topical formulation was estimated from doses and areas under
the curves, assuming the subcutaneous dose bioavailability was 100%.
The median bioavailability of morphine compounded in a PLO base and
administered topically to volunteers was less than 2%. Despite a report
that topical morphine is effective in controlling chronic arthritis pain,
the present results are consistent with the report that morphine was
minimally absorbed transdermally from a PLO formulation in dogs.
These results suggest that transdermal administration of morphine com-
pounded in a PLO base is unlikely to provide relief of cancer-related
pain. Supported in part by a grant from ExcelleRx.
(789) An open-label pharmacokinetic study in humans of a
4% amitriptyline 2% ketamine topical cream
D Everton, D Bhagwat, M Damask; EpiCept Corporation, Englewood Cliffs, NJ
Topically delivered pain medications can provide adequate pain relief
without the side-effects of systemically delivered drugs. This open-label,
pharmacokinetic study in 36 healthy adults was designed to determine
plasma levels of a topically delivered creamcontaining 4%amitriptyline
and 2%ketamine (NP-1). The level of quantitation was (0.5 ng/mL). 4 mL
of NP-1 cream were applied b.i.d. during a 48 hour period. Safety/toler-
ability were assessed and blood samples were collected up to 96 hours
after rst application. Plasma amitriptyline levels were above 0.500
ng/mL after the second application, through 60 hours after the last
application. The mean Cmax of 1.676 ng/mL occurred 72 hours after the
rst application. The highest amitriptyline concentration observed at
any one time point was 5.91 ng/mL. The terminal elimination phase for
amitriptyline had not been reached in most of the subjects. Plasma
ketamine levels were above 0.500 ng/mL within several hours after the
rst application up to the last observation at 96 hours. The highest single
ketamine concentration was 10.7 ng/mL. The mean ketamine Cmax of
5.198 ng/mL occurred at 41.4 hours. Terminal elimination was ongoing
during the nal 48 h of the study in the majority of the subjects. The PK
parameter values for both drugs were age-group independent. NP-1
was found to be safe and well tolerated across all groups. Mild, transient
application site irritation was the most common adverse event and oc-
curred in 11% of subjects. Prior studies utilizing a twice-daily local ap-
plication of NP-1 in the treatment of various neuropathies suggest that
signicant pain relief can be achieved. This study conrms that the
efcacy is due to topical action as only sub-therapeutic blood levels of
both drugs are observed.
(790) Effect of lidocaine patch on thermal thresholds and
experimental pain
M Wallace, V Lam, G Schulteis; University of California San Diego, La Jolla, CA
Currently, there is a growing interest in the use of topical agents for the
treatment of pain; therefore, there is a need to validate the use of
human experimental pain using topical analgesics. This study evaluated
the effects of topical lidocaine on intradermal capsaicin induced pain
and hyperalgesia. Thirteen subjects entered into a double-blind,
placebo-controlled, randomized study. A baseline quantitative neuro-
sensory test (QST) was performed on the volar aspect of each forearm. A
placebo patch and a lidocaine patch was applied to the volar aspect of
each forearm. The arms were randomized to placebo and lidocaine
patch. After four hours of application the right forearm patch was re-
moved, QST was repeated, and capsaicin (10l, 10 mg/ml) was injected
intradermally at the site of application. Pain scores were measured at
the time of injection and every 2.5 minutes for 10 minutes. Ten minutes
after the capsaicin injection, the hyperalgesic area and are response
were mapped and QST was repeated. At the completion of the testing
on the right forearm, the left forearm patch was removed and the
procedures described for the right forearm were repeated for the left
forearm. Prior to the capsaicin injection the lidocaine patch resulted in a
signicant increase in the cool and warm thresholds and a signicant
decrease in hot pain thresholds from baseline. There was no effect on
cold pain thresholds. Although there was a trend for increase in touch
and touch pain thresholds, it did not reach statistical signicance. The
lidocaine patch had no effect on the pain, are or hyperalgesia, This
study demonstrated differential effects of the lidocaine patch on skin
sensation. Since there was a lowering of the hot pain thresholds, it is not
surprising that lidocaine patch had no effect on intradermal capsaicin
induced pain and hyperalgesia.
D30 - Other
(791) Hyperbaric oxygen treatment decreases edema and me-
chanical hypersensitivity in animal models of acute in-
ammation and arthritis
H. Wilson; University of Texas at Arlington, Arlington, TX
Society for Neuroscience abstract
S48 Abstracts