Adequate analgesic treatment of both acute perioperative pain and chronic pain in dogs is recognized by the veterinary profession
and the general public as imperative to appropriate and humane medical care.1-3 Because of modern veterinary medicine's more sophisticated invasive surgical procedures (e.g. thoracotomy), moderate to severe perioperative pain can be expected to last at least 48 to 72 hours after surgery. Also,
because of improved veterinary preventive care, dogs have an increased life expectancy, and with increasing age comes painful
age-related conditions such as osteoarthritis.
Wanted: A perfect analgesic
Of the available analgesic regimens in veterinary medicine, opioids remain the gold standard for moderate to severe pain in
dogs.4 Most injectable opioids require dosing every three to six hours (or more often) to maintain therapeutic serum concentrations.
Currently available oral formulations of opioids, such as morphine sulfate controlled-release tablets (MS Contin—Purdue Frederick),
have a significant first-pass effect in dogs, rendering the actual analgesic efficacy of this formulation questionable.5
Transdermal fentanyl patches have gained popularity in veterinary medicine, with effective serum fentanyl concentrations being
achieved within 24 hours and maintained for about 72 hours after patch application.6 When a dog is sent home with a fentanyl patch, however, there is a risk of access to the patch by caretakers or children
in the household.7,8 In addition, the patch's effectiveness varies depending on how well it sticks to the dog's skin, and the dog can become profoundly
sedated if it ingests the patch.
No currently available formulations of opioids for use in dogs or other species meet all the desirable characteristics of
adequate analgesia: effectiveness, predictable therapeutic serum concentrations, a convenient dosing interval, minimal side
effects, and no risk of diverting the drug to a person or accidental ingestion by the pet or by children.
Liposomal opioid formulations: A possible solution?
Our group, which consists of a clinical anesthesiologist (L.J. Smith) and a laboratory animal veterinarian (L.A. Krugner-Higby),
at the University of Wisconsin's School of Veterinary Medicine, in collaboration with chemists at the University of Wisconsin's
School of Pharmacy, has been developing novel liposome-encapsulated formulations of both oxymorphone and hydromorphone. These
formulations are synthesized such that the opioid is surrounded by onion-skin–like layers of lipid bilayer membranes, with
opioid sandwiched between layers (Figure 1). The drug is released by both slow leakage across the lipid membranes, depending on the drug's lipid solubility, and by
membrane degradation by local tissue macrophages after the drug is injected into the animal.
Figure 1. A scanning electron micrograph of the type of liposomes being formulated in our lab. The liposomal membranes were
stained with 2% phosphotungstic acid in this preparation to highlight the membrane structure.
These formulations show promise as extended-release preparations of opioids, providing therapeutic drug concentrations for
up to seven days after a single subcutaneous injection.9 Our initial work involved the synthesis of liposomal oxymorphone by using egg phosphatidylcholine, with about 80% recapture
of the oxymorphone hydrochloride base.9 This simple egg phosphatidylcholine liposome had in vitro release characteristics that suggested a potential analgesic duration
of five to seven days.9