Long-term effect of epidural injection with sustained-release lidocaine particles in a rat model of postoperative pain T. Suto, H. Obata, M. Tobe, H.

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Long-term effect of epidural injection with sustained-release lidocaine particles in a rat model of postoperative pain T. Suto, H. Obata, M. Tobe, H. Oku, H. Yokoo, Y. Nakazato, S. Saito British Journal of Anaesthesia Volume 109, Issue 6, Pages 957-967 (December 2012) DOI: 10.1093/bja/aes302 Copyright © 2012 The Author(s) Terms and Conditions

Fig 1 Micrographs of SRLP-10 (a) and SRLP-25 (b). The distribution of the particle size of SRLP-10 and SRLP-25 was calculated from the micrographs using image analysis software (c). Scale bar = 100 μm. British Journal of Anaesthesia 2012 109, 957-967DOI: (10.1093/bja/aes302) Copyright © 2012 The Author(s) Terms and Conditions

Fig 2 The cumulative release of lidocaine from SRLPs in PBS was calculated. The percentage of lidocaine released from the SRLPs with regard to the actual lidocaine content in the SRLPs is shown as mean (sd) (n=4). British Journal of Anaesthesia 2012 109, 957-967DOI: (10.1093/bja/aes302) Copyright © 2012 The Author(s) Terms and Conditions

Fig 3 Withdrawal thresholds after the epidural injection of SRLP-10 (40 and 80 mg) in rats with paw incision determined with the von Frey test. The threshold of the group treated with SRLP-10 (80 mg) was higher than that of the control group (by two-way anova with the Student–Newman–Keuls post hoc test). The group treated with SRLP-10 (80 mg) showed anti-hypersensitivity for 7 days after the epidural injection. The threshold of the group treated with SRLP-10 (40 mg) was not different from that of the control group. Lidocaine (2 mg) only produced anti-hypersensitivity at 30 min after epidural injection. Data are shown as mean (sd) (n=6 each group). #P<0.05 compared with the control group. British Journal of Anaesthesia 2012 109, 957-967DOI: (10.1093/bja/aes302) Copyright © 2012 The Author(s) Terms and Conditions

Fig 4 Withdrawal thresholds after epidural injection of SRLP-25 (40 and 60 mg) in rats with paw incision were determined with the von Frey test. The thresholds of groups treated with SRLP-25 (40 and 60 mg) were higher than those of the control group (by two-way anova with the Student–Newman–Keuls post hoc test). The groups treated with SRLP-25 (60 mg) showed anti-hypersensitivity for 7 days, and the groups treated with SRLP-25 (40 mg) showed anti-hypersensitivity for 2 h after the epidural injection. The data are shown as the [mean (sd)] (n=6 each group). #P<0.05 compared with the control group. British Journal of Anaesthesia 2012 109, 957-967DOI: (10.1093/bja/aes302) Copyright © 2012 The Author(s) Terms and Conditions

Fig 5 (a) Motor paralysis after epidural injection of the SRLPs was assessed at 15, 30, 45, and 60 min after the epidural injection. Score: 0=normal, 1=weak hypotonia, 2=moderate hypotonia, and 3=complete paralysis. Data are shown as medians, inter-quartile range and 10th/90th percentiles (vertical lines) (n=4). #P<0.05 compared with the control group by the Kruskal–Wallis one-way anova on ranks and the Student–Newman–Keuls post hoc test. (b) The latency in the rota-rod test was examined at 15, 30, 45, and 60 min after epidural injection of the SRLPs. In the group treated with SRLP-10, latency was not different from the pre-injection value on the control group. Compared with the control group, the latency was significantly decreased at 15 and 30 min in the group treated with SRLP-25 (40 mg), and 15 min in the group treated with lidocaine (2 mg). Data are shown as the mean (sd) (n=4). #P<0.05 compared with the control group by one-way anova and the Student–Newman–Keuls post hoc test. C, control (PLA); L, lidocaine 2 mg; S25, SRLP-25 40 mg; S10, SRLP-10 80 mg. British Journal of Anaesthesia 2012 109, 957-967DOI: (10.1093/bja/aes302) Copyright © 2012 The Author(s) Terms and Conditions

Fig 6 Effect of SRLP-10 on paw withdrawal thresholds determined by the von Frey test (a) and effect of SRLP-10 on the pinprick test (b) in rats without paw incision compared with rats with back surgery without injection of SRLPs, and intact (normal) rats. Data are shown as the mean (sd) (n=8 each group). #P<0.05 compared with the sham surgery group by two-way anova with the Student–Newman–Keuls post hoc test. British Journal of Anaesthesia 2012 109, 957-967DOI: (10.1093/bja/aes302) Copyright © 2012 The Author(s) Terms and Conditions

Fig 7 Histopathology after epidural injection of SRLPs. (a) Specimen near the injection site 1 week after SRLP-10 injection. A foreign body reaction can be observed around the remaining SRLP-10 (arrowheads). (b) Specimen near the injection site 1 week after SRLP-25 injection. A foreign body reaction is seen around the remaining SRLP-25 (arrowheads). (c) The area near the injection site 1 week after PLA injection. A foreign body reaction can be seen around the remaining PLA (arrowheads). (d) The area near the injection site 1 week after the injection of lidocaine (2 mg). Scale bars=500 μm. SC, spinal cord; CE, cauda equina; DM, dura mater; PN, the origin of the peripheral nerve; SRLP, remaining sustained-release lidocaine particles; PLA, remaining polylactic acid. British Journal of Anaesthesia 2012 109, 957-967DOI: (10.1093/bja/aes302) Copyright © 2012 The Author(s) Terms and Conditions