Abstract
This study evaluates the sustained analgesic effect of ketorolac-eluting thermosensitive biodegradable hydrogel in the plantar incisional pain model of the rat hind-paw. A ketorolac-embedded 2, 2'-Bis (2-oxazolin) (BOX) linking methoxy-poly(ethylene glycol) and poly(lactide-co-glycolide) (mPEG-PLGA) diblock copolymer (BOX copolymer) was synthesized as keto-hydrogel based on optimal sol-gel phase transition and in vitro drug release profile. The effect of keto-hydrogel on postoperative pain (POP) was assessed using the established plantar incisional pain model in hind-paw of rats and compared to that of ketorolac solution. Pain and sensory threshold, as well as pain scoring, were evaluated with behavioral tests by means of anesthesiometer and incapacitance apparatus, respectively. Pro-inflammatory cytokine levels (TNF-α, IL-6, VEGF, and IL-1β) around incisional wounds were measured by ELISA. Tissue histology was assessed using hematoxylin and eosin and Masson’s trichrome staining. Ten mg/mL (25 wt%) keto-hydrogel showed a sol-gel transition at 26.4°C with a 10-day sustained drug release profile in vitro. Compared to ketorolac solution group, the concentration of ketorolac in tissue fluid was higher in the keto-hydrogel group during the first 18 h of application. Keto-hydrogel elevated pain and sensory threshold, increased weight-bearing capacity, and significantly reduced the levels of TNF-α, IL-6, and IL-1β while enhanced VEGF in tissue fluid. Histologic analysis reveals greater epithelialization and collagen deposition around wound treated with keto-hydrogel. In conclusion, our study suggests that keto-hydrogel is an ideal compound to treat POP with a secondary gain of improved incisional wound healing.
Highlights
Surgical wound causes a localized tissue reaction which initiates a sequence of events from the periphery and transmits centrally to result in pain [1]
Since ketorolac is water soluble and hydrophilic in nature, it might enhance the sol-gel temperature by water structure breaking like other salts e.g. sodium thiocyanate (NaSCN) [28]
The 25 wt% and 30 wt% polymer solution containing 10 mg/mL ketorolac exhibited suitable sol-to-gel transition temperatures that are below body temperature (Table 3)
Summary
Surgical wound causes a localized tissue reaction which initiates a sequence of events from the periphery and transmits centrally to result in pain [1]. Systemic narcotics and/or non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstays of POP management. Systemic administration of these medications may have adverse effects, such as narcotic-induced nausea and vomiting, respiratory depression, inhibited intestinal peristalsis and constipation, dizziness, drowsiness, skin itching, and urinary retention and NSAID-induced upper gastrointestinal ulcer bleeding and nephrotoxicity [3, 4]. The local application of anesthetics/analgesics, e.g. via cream, lotion, gel, patch, or infiltration near the surgical site can minimize these adverse effects by delivering high concentrations of drugs to the site of pain origin while lowering drug concentration systemically [5]. The analgesic effects of such applications have been found to be insufficient in both strength and duration, leading to questions about their overall efficacy [6, 7]
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