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ORIGINAL ARTICLES
Prolonged Nerve Block by Microencapsulated Bupivacaine Prevents Acute Postoperative Pain in Rats
  1. Rachit Ohri, PhD*,
  2. Phillip Blaskovich, BS*,
  3. Jeffrey Chi-Fei Wang, MD†,
  4. Lan Pham, MS*,
  5. Gary Nichols, PhD‡,
  6. William Hildebrand, MS‡,
  7. Daniel Costa, BS*,
  8. Nelson Scarborough, PhD*,
  9. Clifford Herman, PhD‡ and
  10. Gary Strichartz, PhD†
  1. From the *COVIDIEN Surgical Solutions, Bedford, MA; and
  2. †Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; and
  3. ‡COVIDIEN Pharmaceuticals, St Louis, MO.
  1. Address correspondence to: Gary Strichartz, PhD, MRB 613/BWH 75 Francis St, Boston, MA 02115-6110 (e-mail: gstrichz{at}zeus.bwh.harvard.edu).

Abstract

Background and Objectives To minimize acute postoperative pain, a new formulation of slowly released bupivacaine was developed.

Methods Bupivacaine was microencapsulated at 60% (wt/wt) in poly-lactide-co-glycolide polymers and characterized for physicochemical properties and bupivacaine release kinetics. This formulation was injected around the rat sciatic nerve to produce an antinociceptive effect to toe pinch. Mechanical hyperalgesia following lateral plantar paw incision in rats was assessed for 7 to 14 days when the bupivacaine slow-release formulation was placed at the ipsilateral sciatic nerve and compared with the hyperalgesia that developed with various controls.

Results Bupivacaine was released in vitro at a relatively constant rate over a period of ∼72 to 96 hours. Complete antinociception, shown as no response to toe pinch, lasted for 23 ± 7 hours, with a half-recovery time of 42 ± 8 hours after sciatic nerve injection of 0.4 mL of the microspheres delivering 34 mg of bupivacaine. Solutions of 0.5% (wt/vol) bupivacaine-HCl (0.1 mL) produced complete antinociception for less than 2 hours and recovery half-times of 2 hours. Postincisional mechanical hyperalgesia, shown by increased withdrawal responses to von Frey filaments, was absent for 24 hours and was lower than control for 96 hours, when the sciatic nerve was blocked by bupivacaine microspheres, whereas the 0.5% bupivacaine solution reduced postincisional pain for only 4 hours.

Conclusions Corresponding to its far greater functional blocking time, the microsphere-bupivacaine formulation was able to significantly reduce postoperative pain below control levels for up to 4 days. These findings of several days of postoperative pain relief, for an injectable formulation containing a single active agent, present an improved and potentially promising therapy to prevent acute pain after surgery.

https://doi.org/10.1097/AAP.0b013e3182680f35

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    Footnotes

    • The authors contributed to this article as follows: R.O.: experimental design, data analysis, and writing; P.B.: preparation of materials and intellectual input for microsphere characterization; J.C.F.W.: animal surgery, testing, data collection, and statistical analysis; L.P.: material preparation and intellectual input for microsphere characterization; G.N.: analytical characterization of microsphere batches; W.H.: scanning electron microscopy; D.C.: HPLC analysis and particle size distribution analysis; N.S.: experimental design; C.H.: oversight in optimizing microsphere formulation, analytical characterization, and experimental design; G.S.: study design, data analysis, and writing.

    • The authors declare no conflict of interest.