Comparison of antinociceptive effects of plain lidocaine versus lidocaine complexed with hydroxypropyl-β-cyclodextrin in animal models of acute and persistent orofacial pain

  • Stéphani Batista de Oliveira
  • Erika Ivanna Araya
  • Eder Gambeta
  • Luiz Eduardo Nunes Ferreira
  • Michele Franz-Montan
  • Rafaela Franco Claudino
  • Juliana Geremias ChichorroEmail author
Original Article


Herein, it was investigated whether a complex of lidocaine with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) would present a better antinociceptive profile in vivo when compared with plain lidocaine in models of orofacial pain. Plain lidocaine (LDC) and complexed lidocaine (LDC:HP-β-CD) were initially evaluated in vitro to determine the release rate of the two formulations. Subsequently, the effect of both formulations was evaluated in independent groups of rats submitted to the orofacial formalin test, induction of facial heat hyperalgesia by capsaicin and carrageenan, and induction of facial heat and mechanical hyperalgesia by constriction of the infraorbital nerve. LDC:HP-β-CD led to a reduction in the lidocaine release assessed in the in vitro release assay compared to plain LDC. Both formulations presented an antinociceptive effect in all models, but LDC:HP-β-CD showed a better effect in the second phase of the formalin response, in carrageenan-induced heat hyperalgesia, and in the heat hyperalgesia associated to infraorbital nerve constriction. Our results show that complexation improved in vivo antinociceptive effects of LDC, but further studies are necessary to elucidate what properties contribute to the better effect of the complexed formulation on this models and/or what characteristics of the pain model facilitate the action of the complexed formulation.


Lidocaine Trigeminal neuropathic pain Capsaicin Carrageenan Formalin Hyperalgesia 


Author contribution

JGC and RFC conceived and designed research. SBO, EIA, and EG conducted the in vivo experiments. LENF and MFM prepared lidocaine complexed formulation and conducted the in vitro assay. JGC analyzed data and wrote the manuscript. All authors read, revised, and approved the manuscript.


This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) - Finance Code 001.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures were conducted in accordance with the Institutional Committee on the Ethical Use of Animals (authorization no. 1039) and performed in accordance with ethical guidelines, including the policies and recommendations of the International Association for the Study of Pain and according to the recommendations of the Brazilian Agency CONCEA (National Council of Control in Experimental Animals).

Supplementary material

210_2018_1609_Fig5_ESM.png (616 kb)
Supplementary Figure 1

Experimental procedures timeline. In the formalin test animals received plain lidocaine (LDC, 2% in 50 μL), complexed lidocaine (LDC:HP-β-CD, 2% in 50 μL) or vehicle (VEH, 50 μL) into the right upper lip, and after 10 minutes, formalin (FOR, 2.5% in 50 μL) or saline (SAL, 50 μL) in the same site. The grooming response was assessed for 30 min (first phase: 0-3 minutes, second phase: 12-30 min). In the capsaicin test, heat hyperalgesia was assessed (BL), and animals was treated with plain lidocaine (LDC, 2% in 50 μL), complexed lidocaine (LDC:HP-β-CD, 2% in 50 μL) or vehicle (VEH, 50 μL) into the right upper lip, and after 10 minutes, capsaicin (CAP, 3 μg in 50 μL) or saline (SAL, 50 μL) was injected in the same site. Heat hyperalgesia was measured 0.5, 1, 2, 3 and 4 h after CAP/SAL injection. In the Carrageenan test, animals were subjected to the same procedure, but the treatments were performed 150 min after carrageenan (CAR, 100 μg in 50 μL) or saline (SAL, 50 μL) into the right upper lip. Heat and mechanical hyperalgesia were evaluated 5 and 15 days, respectively, after CION, as well as hourly after treatments with plain lidocaine (LDC, 2% in 50 μL), complexed lidocaine (LDC:HP-β-CD, 2% in 50 μL) or vehicle (VEH, 50 μL) into the right upper lip. (PNG 615 kb)

210_2018_1609_MOESM1_ESM.tif (119 kb)
High resolution image (TIF 119 kb)
210_2018_1609_Fig6_ESM.png (50 kb)
Supplementary Figure 2

Effect of plain lidocaine (LDC) and lidocaine complexed with 2-hydroxypropyl-β-cyclodextrin (LDC:HP-β-CD) in control animals (related to Fig 2). Animals was pre-treated with plain lidocaine (LDC, 2% in 50 μL) or complexed lidocaine (LDC:HP-β-CD, 2% in 50 μL) into the right upper lip, and after 10 minutes, vehicle (VEH, 50 μL) was injected in the same site. The grooming response was assessed for 30 minutes after VEH injection, and the first phase was considered from 0-3 minutes and the second phase was considered from 12-30 minutes. Data are expressed as mean ± SEM. Two-way ANOVA with repeated measures followed by the Bonferroni post hoc test (n=9-11). (PNG 50 kb)

210_2018_1609_MOESM2_ESM.tif (36 kb)
High resolution image (TIF 36 kb)
210_2018_1609_Fig7_ESM.png (38 kb)
Supplementary Figure 3

Effect of plain lidocaine (LDC) and lidocaine complexed with 2-hydroxypropyl-β-cyclodextrin (LDC:HP-β-CD) in control animals (related to Fig 3). Heat hyperalgesia baseline (BL) was assesses and animals was treated with plain lidocaine (LDC, 2% in 50 μL) or complexed lidocaine (LDC:HP-β-CD, 2% in 50 μL) into the right upper lip, and 10 or 150 minutes later they were treated with capsaicin vehicle (50 μL, Panel A) or with carrageenan vehicle (50 μL, Panel B), respectively. Data are expressed as mean ± SEM. Two-way ANOVA with repeated measures followed by the Bonferroni post hoc test (n=6-10). (PNG 37 kb)

210_2018_1609_MOESM3_ESM.tif (28 kb)
High resolution image (TIF 27 kb)
210_2018_1609_Fig8_ESM.png (40 kb)
Supplementary Figure 4

Effect of plain lidocaine (LDC) and lidocaine complexed with 2-hydroxypropyl-β-cyclodextrin (LDC:HP-β-CD) in SHAM animals (related to Fig 4). Heat or mechanical hyperalgesia baseline (BL) was assessed and SHAM surgery was performed. The heat and mechanical hyperalgesia was measured 5 or 15 days after surgery, respectively. Animals was treated with plain lidocaine (LDC, 2% in 50 μL) or complexed lidocaine (LDC:HP-β-CD, 2% in 50 μL) into the right upper lip, and heat or mechanical hyperalgesia (Panel A and B, respectively) was assessed for up to 4 hours after treatment. Data are expressed as mean ± SEM. Two-way ANOVA with repeated measures followed by the Bonferroni post hoc test (n=6-10). (PNG 40 kb)

210_2018_1609_MOESM4_ESM.tif (28 kb)
High resolution image (TIF 28 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Stéphani Batista de Oliveira
    • 1
  • Erika Ivanna Araya
    • 1
  • Eder Gambeta
    • 1
  • Luiz Eduardo Nunes Ferreira
    • 2
  • Michele Franz-Montan
    • 3
  • Rafaela Franco Claudino
    • 1
  • Juliana Geremias Chichorro
    • 1
    Email author return OK on get
  1. 1.Department of Pharmacology, Biological Sciences SectorFederal University of ParanaCuritibaBrazil
  2. 2.School of NurseGuarulhos UniversityGuarulhosBrazil
  3. 3.Department of Physiological Sciences, Piracicaba Dental SchoolUniversity of CampinasSao PauloBrazil

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