Faculty Bibliography

There is a compelling need for an ultralong-acting local anesthetic. Previously, we demonstrated in mice and humans that encapsulation of bupivacaine into large multivesicular liposomes (Bupisome) prolongs drug residence time and analgesic duration at the injection site while reducing peak plasma concentration. However, we observed considerable leakage of bupivacaine from the liposomes during storage at 4 degrees C. This deficiency was overcome by modifying the lipid composition of Bupisome and by entrapping them in a Ca-alginate cross-linked hydrogel (Bupigel), forming stable, soft, injectable (3-5mm) beads. Bupisome are not released from Bupigel, but their encapsulated bupivacaine is released into the bulk solution. Adding 0.5% to 2.0% free bupivacaine to the Bupigel prevented net loss of bupivacaine from the Bupisome after storage at 4 degrees C for 2years, and at 37 degrees C enough bupivacaine was released to prolong analgesia. For injection subcutaneously into mice, the beads are drawn into a syringe, leaving the small amount of free bupivacaine behind. Both Bupisome and Bupigel formulations significantly prolonged analgesia in mice compared to standard bupivacaine, with Bupigel performing better than Bupisome.

Regional pain relief may be too risky in patients with coagulation disorders, whether they're induced by anticoagulants to manage or prevent adverse pregnancy outcomes linked with VTE or thrombophilia, or due to a coagulopathy. Benefits and risks can include a rare but catastrophic complication: spinal hematoma

Today's epidural and spinal options can make labor a far more pleasant experience than it once was. Techniques like the walking epidural not only greatly relieve pain; they also preserve motor strength

BACKGROUND: There is substantial evidence that cholinomimetic drugs increase pain threshold. However, the profound side effects of these agents have limited their clinical use either as analgesics or as analgesic adjuncts. A delivery system that would assure a slow and sustained drug release may be of value in ameliorating the problem of untoward effects. METHODS: The acetylcholinesterase inhibitor neostigmine was encapsulated into multilamellar lipid vesicles composed of phosphocholine and cholesterol. Three doses of plain or liposomal neostigmine were administered by the intrathecal route to mice (n=8-10/group), and analgesic duration was quantified by tail flick test. The doses were chosen based on preliminary experiments, which showed the maximum tolerated intrathecal doses of plain and liposomal neostigmine formulation were 0.625 microg and 80 microg, respectively. Two other doses for each formulation were then derived by 1:1 serial dilutions. Results were compared using survival analysis. RESULTS: The median antinociceptive duration for plain neostigmine was 0.33, 0.99 and 1.0 h for the 0.115, 0.312 and 0.625 microg doses, respectively. For the liposomal formulation, the median antinociceptive duration was 1.0, 1.5 and 6.0 h for the 20, 40 and 80 microg doses, respectively. CONCLUSIONS: Liposomal neostigmine provides prolonged spinal antinociception, and permits the safe administration of a relatively large dose, because drug is gradually released from the liposomal depot. This technology holds promise for the development of a clinically useful neostigmine formulation to provide spinal analgesia

BACKGROUND: The research on conductive analgesia induced by perineural opioids generated a large body of conflicting data. In this study we reassessed the antinociceptive response to perineural administration of morphine, fentanyl or meperidine in a rat model. METHODS: Analgesia was assessed using the hind paw withdrawal latency (HPWL) response to radiant heat. The opioid dose producing 20% of maximal possible effect (20%MPE) for systemic analgesia was calculated for each drug. Then sciatic blockade was performed with the dose corresponding to 20%MPE. The injected hind paw was used to measure direct perineural effect and the contralateral hind paw was used as an indicator of systemic effect. RESULTS: The response latency produced by morphine or fentanyl was not significantly different for ipsilateral (perineural effect) or contralateral (systemic effect) paw (27+/-11 vs. 28+/-16 and 3l+/-16 vs. 23+/-16 s, respectively). However, the meperidine group showed significantly higher %MPE for the ipsilateral paw (79+/-32 s) than for the contralateral paw (27+/-22 s). CONCLUSIONS: The results indicate that perineural fentanyl or morphine do not produce analgesia. Perineural block produced by meperidine was attributed to local anesthetic-like effect, rather than to drug interaction with opioid receptor

PURPOSE: To evaluate the dehydration-rehydration technique to prepare a formulation of liposomal bupivacaine, and to assess its analgesic efficacy. METHODS: Bupivacaine hydrochloride (BUP) was encapsulated into dehydration-rehydration vesicles (DRV) of varying phospholipid (PL) compositions. Two bilayer-forming phospholipids were used, the 'fluid' dimyristoyl-phosphatidylcholine and the 'solid' distearoyl-phosphatidylcholine (DSPC), with 20 or 40 mol% cholesterol, in the presence of bupivacaine at a 1.28 or 0.64 BUP/PL mole ratio. After rehydration, drug/lipid ratios were determined. The formulation with the highest drug/lipid ratio (DSPC/cholesterol in an 8:2 mole ratio prepared in the presence of bupivacaine in a 1.28 BUP/PL mole ratio) was adjusted to a final bupivacaine concentration of 3.5% or 0.5%. The duration of skin analgesia after subcutaneous injection in mice produced by these formulations was compared with the conventional administration of a plain 0.5% solution of BUP. In addition, the concentration of residual bupivacaine at the injection site was followed for 96 h. RESULTS: The relatively low organic solvent/aqueous phase and membrane/aqueous phase partition coefficients, together with liposomal trapped volume and BUP/PL mole ratio, indicated that most of the drug was encapsulated in the intraliposome aqueous phase of the DRV. The DSPC/cholesterol 8:2 mole ratio had the best drug encapsulation (BUP/PL = 0.36). Compared to plain BUP, these BUP-DRV produced significant prolongation of analgesia, which is explained by longer residence time of the drug at the site of injection. CONCLUSIONS: Bupivacaine-DRV may have a role in achieving safe, effective, and prolonged analgesia in humans