Abstract
Purpose
Gamma-aminobutyric acid analogues are commonly used to treat neuropathic and chronic pain before and after spinal surgery in recent years. Aim of this study is to investigate the influence of pregabalin on spinal fusion and to determine the proper pregabalin dose for postoperative utilization in a validated rat intertransverse spinal fusion.
Methods
Lumbar intertransverse fusion surgeries performed in four groups of rats according to a previously established rat model for posterolateral spinal fusion. All rats were followed up for 6 weeks at the postoperative period by administering oral pregabalin doses of 10 (D10), 30 (D30) and 100 mg/kg/day (D100) except the control group. All rats were killed after 6 weeks and evaluated in terms of manual palpation, radiographic investigation and histological analysis to investigate posterolateral fusion.
Results
Assessment of fusion with manual palpation revealed lower fusion rates in D100 group. In histological analysis, scores were significantly lower in D30 and D100 groups compared to the control group; this finding was interpreted as inhibition of spinal fusion. Radiographic evaluation did not reveal any significant statistical difference between groups.
Conclusions
Histological analysis and manual palpation results showed inhibition of spinal fusion formation with high doses of pregabalin. According to these results, administration of high-dose pregabalin should be avoided at the postoperative period until successful fusion is obtained in patients who undergo spinal fusion surgery.
Graphic abstract
These slides can be retrieved under electronic supplementary material.
Similar content being viewed by others
References
Gajraj NM (2007) Pregabalin: its pharmacology and use in pain management. Anesth Analg 105(6):1805–1815
Enke O, New HA, New CH, Mathieson S, McLachlan AJ, Latrimer J, Maher CG, Lin CC (2018) Anticonvulsants in the treatment of low back pain and lumbar radicular pain: a systematic review and meta-analysis. CMAJ 190(26):E786–E793
Mathieson S, Valenti L, Maher CG, Britt H, Li Q, McLachlan AJ, Lin CC (2018) Worsening trends in analgesics recommended for spinal pain in primary care. Eur Spine J 27(5):1136–1145
Bydon M, De la Garza-Ramos R, Macki M, Baker A, Gokaslan AK, Bydon A (2014) Lumbar fusion versus nonoperative management for treatment of discogenic low back pain: a systematic review and meta-analysis of randomized controlled trials. J Spinal Disorders Tech 27(5):297–304
Turan A, Karamanlioglu B, Memis D, Hamamcioglu MK, Tukenmez B, Pamukcu Z, Kurt I (2004) Analgesic effects of gabapentin after spinal surgery. Anesthesiology 100(4):935–938
Siemienow KB, Muschler GF (2011) Principles of bone fusion. In: Herkowitz HN, Garfin SR, Eismont FJ, Bell GR, Balderston RA (eds) The spine, 6th edn. Saunders, Philadelphia, pp 1130–1158
Perinpanayagam J, Abu-Asi MJ, Bustamante S, Kunnumpurath S (2015) Opioid-sparing drugs (ketamine, gabapentin, pregabalin, and clonidine). In: Kaye AD, Vadivelu N, Urman RD (eds) Substance abuse, 1st edn. Springer, Heidelberg, pp 319–330
European Medicines Agency (EMEA) (2005) Initial marketing-authorization documents. https://www.ema.europa.eu/en/medicines/human/EPAR/lyrica. Accessed 25 July 2019
Gezici AR, Ergun R, Gurel K, Yilmaz F, Okay O, Bozdogan O (2009) The effect of risedronate on posterior lateral spinal fusion in a rat model. J Korean Neurosurg Soc 46(1):45–51
Grauer JN, Patel TC, Erulkar JS, Troiano NW, Panjabi MM, Friedlander GE (2001) Evaluation of OP-1 as a graft substitute for intertransverse process lumbar fusion. Spine 26(2):127–133
Boden SD, Schimandle JH, Hutton WC (1995) An experimental lumbar intertransverse process spinal fusion model. Radiographic, histologic, and biomechanical healing characteristics. Spine 20(4):412–420
Schimandle JH, Boden SH, Hutton WC (1995) Experimental spinal fusion with recombinant human bone morphogenetic protein-2. Spine 20(12):1326–1337
Kiter E, Er E, Sen Turk N, Oto M, Akkaya S (2014) Efficacy of 5-Fluorouracil in inhibition of unintended bone formation in spinal surgery: a histological evaluation on a rat model of spontaneous spinal fusion. Acta Orthop Traumatol Turc 48(1):86–91
Emery SE, Brazinski MS, Koka A, Bensusan JS, Stevenson S (1994) The biological and biomechanical effects of irradiation on anterior spinal bone grafts in a canine model. J Bone Joint Surg Am 76(4):540–548
He Y, Revel M, Loty B (1995) A quantitative model of post-laminectomy scar formation. Effects of a nonsteroidal anti-inflammatory drug. Spine 20(5):557–563
Kanda J, Izumo N, Kobayashi Y, Onodera K, Shimakura T, Yamamoto N, Takahashi HE, Wakabayashi H (2017) Effects of the antiepileptic drugs phenytoin, gabapentin, and levetiracetam on bone strength, bone mass, and bone turnover in rats. Biol Pharm Bull 40(11):1934–1940
Yamaguchi K, Kumakura S, Someya A, Iseki M, Inada E, Nagaoka I (2017) Anti-inflammatory actions of gabapentin and pregabalin on the substance P-induced mitogen-activated protein kinase activation in U373 MG human glioblastoma astrocytoma cells. Mol Med Rep 16(5):6109–6115
Ishida W, Elder BD, Holmes C, Lo SL, Witham TF (2016) Variables affecting fusion rates in the rat posterolateral spinal fusion model with autogenic/allogenic bone grafts: a meta-analysis. Ann Biomed Eng 44(11):3186–3201
Hahm TS, Ahn HJ, Ryu S, Gwak MS, Choi SJ, Kim JK, Yu JM (2012) Combined carbamazepine and pregabalin therapy in a rat model of neuropathic pain. Br J Anaesth 109(6):968–974
Sandhu HS, Khan SN, Suh DY, Boden SD (2001) Demineralized bone matrix, bone morphogenetic proteins, and animal models of spine fusion: an overview. Eur Spine J 10(Suppl 2):S122–S131
Kockara N, Sofu H, Issın A, Cetinkaya M (2017) Pregabalin does not affect fracture healing adversely. Eklem Hastalik Cerrahisi 28(1):19–24
Carano RA, Filvaroff EH (2003) Angiogenesis and bone repair. Drug Discovery Today 8(21):980–989
Verma V, Singh N, Singh Jaggi A (2014) Pregabalin in neuropathic pain: evidences and possible mechanisms. Curr Neuropharmacol 12(1):44–56
Fehrenbacher JC, Taylor CP, Vasko MR (2003) Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain 105(1–2):133–141
Ha Y, Carragee E, Cheng I, Kwon SE, Kim YH (2011) Pregabalin as a neuroprotector after spinal cord injury in rats: biochemical analysis and effect on glial cells. J Korean Med Sci 26(3):404–411
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
İmre, E., Çiftdemir, M. & Taştekin, E. Effects of pregabalin on spinal fusion. Eur Spine J 29, 332–339 (2020). https://doi.org/10.1007/s00586-019-06226-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00586-019-06226-4