Background: Peripheral opioid receptor targeting has been well established as a novel target in clinical
pain management for acute and chronic peripheral inflammatory pain. The physiochemical properties of
the peripheral mu-opioid receptor agonist, loperamide HCl, limit the use of the free drug as an analgesic
or anti-inflammatory agent, particularly for dermal delivery across intact skin.
Objective: Our objective was to manufacture an effective topical formulation containing loperamide
using liposomal delivery that would allow loperamide to produce analgesia and anti-inflammatory effects,
by penetrating the epidermis to reach peripheral opioid receptors within the dermis of intact skin.
Study Design: A randomized, double blind, controlled animal trial.
Methods: Thirty-five adult male Wistar rats (200 – 250 g) were randomly divided into 5 groups: loperamide
HCl-encapsulated liposomal gel, naloxone methiodide + loperamide HCl-encapsulated liposomal gel, free
loperamide gel, empty liposomal gel, and 1% diclofenac gel (Voltaren®). Diclofenac gel was used as a
positive control as it is clinically used as a topical analgesic and anti-inflammatory drug. Animals received an
intraplantar injection of 150 µl Complete Freund’s Adjuvant (CFA) into the right hindpaw and experiments
were performed 5 days post-CFA injection, which corresponded to the peak inflammatory response. All
manufactured formulations were applied topically on both hind paws twice daily, whereas Voltaren gel
was applied 3 times a day in accordance with the manufacturer’s instructions. The dose administered
was 50 µl, which equated to 0.4 mg of loperamide HCl for the loperamide HCl treatment groups (low
dose). Naloxone methiodide (1 mg/kg) was administered via intraplantar injection, 15 minutes prior to
application of loperamide HCl-encapsulated liposomal gel to determine opioid receptor dependent activity.
An investigator blinded to the treatment administered assessed time course of the antinociceptive and antiinflammatory effects using a paw pressure analgesiometer and plethysmometer, respectively.
Results: Application of loperamide HCl in a liposomal gel formulation exerted analgesic and antiinflammatory effects exclusively in peripheral painful inflamed tissue. This formulation produced highly
significant analgesic and anti-inflammatory effects over the 48-hour time course studied following
topical administration in rats with CFA-induced inflammation of the paw. As expected, the diclofenac
gel group showed significant antinociception over the duration of the study; however, this effect was
lower in comparison to the loperamide HCl liposomal gel formulation. All other control groups showed
no significant antinociceptive effects. In addition, all control groups (1% diclofenac gel, free loperamide
gel, and empty liposomal gel) did not demonstrate a significant change in paw volume over 48 hours.
Limitations: In vivo studies were performed in the well-established rodent model of acute inflammatory
pain. We are currently studying this approach in chronic pain models known to have clinical activation of
the peripheral immune-derived opioid response.
Conclusions: The study demonstrates that topically applied loperamide encapsulated within liposomal
systems has improved therapeutic efficacy over conventional formulations for the local treatment of acute
peripheral inflammatory pain conditions where the skin has remained intact. Once in the inflamed peripheral
tissue, loperamide provides analgesic and anti-inflammatory effects in a similar manner to peripheral
endogenous opioids. This preparation optimises the retention of drug at the site where action is required.
Key words: Pain, inflammation, opioids, loperamide, liposomes, topical drug delivery, peripheral opioid
receptors
Subcellular Pathways of β-Endorphin Synthesis, Processing, and Release from Immunocytes in Inflammatory Pain