RESUMO
BACKGROUND: Previous research suggests that the α2 adrenergic agonist clonidine, a centrally acting analgesic and antihypertensive, may also have direct effects on peripheral pain generators. However, aqueous injections are limited by rapid systemic absorption leading to off target effects and a brief analgesic duration of action. PURPOSE: The aim of this study was to examine the efficacy of a sustained-release clonidine depot, placed in the wound bed, in a pig incisional pain model. METHODS: The depot was a 15 mm ×5 mm ×0.3 mm poly(lactide-co-caprolactone) polymer film containing 3% (w/w) clonidine HCl (MDT3). Fifty-two young adult mix Landrace pigs (9-11 kg) were divided into seven groups. All subjects received a 6 cm, full-thickness, linear incision into the left lateral flank. Group 1 served as a Sham control group (Sham, n=8). Group 2 received three placebo strips (PBO, n=8), placed end-to-end in the subcutaneous wound bed before wound closure. Group 3 received one MDT3 and two PBO (n=8), Group 4 received two MDT3 and one PBO (n=8), and Group 5 received three MDT3 (n=8). Positive control groups received peri-incisional injections of bupivacaine solution (Group 6, 30 mg/day bupivacaine, n=8) or clonidine solution (Group 7, 225 µg/day, n=4). RESULTS: The surgical procedure was associated with significant peri-incisional tactile allodynia. There was a dose-dependent effect of MDT3 in partially reversing the peri-incisional tactile allodynia, with maximum pain relief relative to Sham at 72 hours. Daily injections of bupivacaine (30 mg), but not clonidine (up to 225 µg), completely reversed allodynia within 48 hours. There was a statistically significant correlation between the dose of MDT3 and cumulative withdrawal threshold from 4 hours through the conclusion of the study on day 7. CONCLUSION: These data suggest that a sustained-release clonidine depot may be a viable nonopioid, nonamide anesthetic therapy for the treatment of acute postsurgical nociceptive sensitization.
RESUMO
BACKGROUND: Epidural steroid injections have shown efficacy in short-term pain relief, but often require repeated injections in order to provide continued pain relief. It has been suggested that a continuous, locally administered dose of an anti-inflammatory compound may provide sustained pain relief at doses lower than those needed with injections. OBJECTIVE: To evaluate the distribution of clonidine after transforaminal placement of a biodegradable drug delivery depot system. STUDY DESIGN: A preclinical animal study. METHODS: A biodegradable polymer drug depot designed to provide sustained delivery of clonidine was placed in or near a single lumbar neural foramen in 12 farm pigs. Clonidine tissue concentrations were measured at the implant site and at incremental distances from the implant over a time period of 12 weeks. Plasma clonidine levels were measured at 4 hours postimplantation on days 1, 2, 3, 5, and 7, and then weekly until the termination of the study. RESULTS: Clonidine was detectable up to 6 cm away from the drug depot. The highest concentrations of clonidine were present within the targeted spinal nerve; the concentration decreased with increasing distance from the depot. Clonidine was undetectable in plasma from all animals at all time points. LIMITATIONS: While clonidine was detected up to 6 cm from the drug depot, it is unknown if the drug concentration has clinical relevance. CONCLUSIONS: The results indicate that a biodegradable depot designed to be placed in a specific location to provide local sustained release of an anti-inflammatory and analgesic drug may be a feasible new approach to treat radicular pain associated with intervertebral disc pathology and other spinal conditions.
