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Acetaminophen combined with tramadol is more effective than acetaminophen or tramadol to reduce neuropathic root pain: an experimental study with application of nucleus pulposus in a rat model

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Abstract

Introduction

Various drugs are used to treat patients with neuropathic pain; however, optimal treatment using acetaminophen (A) and/or tramadol (T) remains unclear. The evidence supporting the drug choice and the timing of administration is insufficient. Therefore, the objective of the present study was to investigate the effect of T and/or A on pain-related behavior in a nucleus pulposus (NP) rat model.

Materials and methods

Sprague–Dawley rats (n = 180) were divided into NP-A (52 mg/kg), NP-T (6 mg/kg), NP-AT (combined A and T), NP-S (saline), and sham groups (n = 36 per group). The rats received 0.2 mL of treatment solution orally once daily for 7 days after application of NP on the left L5 dorsal root ganglion (DRG). Behavioral testing and immunohistochemistry analysis for some markers’ expressions in DRGs and the spinal cord were performed.

Results

Pain thresholds in the NP-AT group did not significantly differ from the sham at all time points, while those were significantly lower in the NP-A and in the NP-T groups at D7 and/or D14 (p < 0.05). Tumor necrosis factor-α in the NP-S group was significantly higher at D2 and D7 (p < 0.05). Among the three treatment groups, activating transcriptional factor 3 and growth-associated protein 43 showed a tendency toward an increase at D7–D21.

Conclusion

Combined administration of acetaminophen and tramadol maintained in the pain threshold in the rat NP model. These findings suggest that the combination of acetaminophen and tramadol might be a potential therapeutic modality for patients with lumbar disc herniation.

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References

  1. Aoki Y, Rydevik B, Kikuchi S, Olmarker K (2002) Local application of disc-related cytokines on spinal nerve roots. Spine (Phila Pa 1976) 27:1614–1617

    Article  Google Scholar 

  2. Boden SD, McCowin PR, Davis DO, Dina TS, Mark AS, Wiesel S (1990) Abnormal magnetic-resonance scans of the cervical spine in asymptomatic subjects. A prospective investigation. J Bone Jt Surg Am 72:1178–1184

    Article  CAS  Google Scholar 

  3. Boos N, Rieder R, Schade V, Spratt KF, Semmer N, Aebi M (1995) 1995 Volvo Award in clinical sciences. The diagnostic accuracy of magnetic resonance imaging, work perception, and psychosocial factors in identifying symptomatic disc herniations. Spine (Phila Pa 1976) 20:2613–2625

    Article  CAS  Google Scholar 

  4. Bouhassira D, Lanteri-Manet M, Attal N et al (2008) Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 136:380–387

    Article  Google Scholar 

  5. Chou R, Huffman LH (2007) Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med 147:505–514

    Google Scholar 

  6. Chou R, Qaseem A, Snow V, Casey D, Cross JT Jr, Shekelle P, Owens DK (2007) Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med 147:478–491

    Article  Google Scholar 

  7. Gey M, Wanner R, Schilling C, Pedro MT, Sinske D, Knoll B (2016) Atf3 mutant mice show reduced axon regeneration and impaired regeneration-associated gene induction after peripheral nerve injury. Open Biol. https://doi.org/10.1098/rsob.160091

    Article  PubMed  PubMed Central  Google Scholar 

  8. Grasselli G, Strata P (2013) Structural plasticity of climbing fibers and the growth-associated protein GAP-43. Front Neural Circuits 7:25. https://doi.org/10.3389/fncir.2013.00025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Handa J, Sekiguchi M, Krupkova O, Konno S (2016) The effect of serotonin-noradrenaline reuptake inhibitor duloxetine on the intervertebral disk-related radiculopathy in rats. Eur Spine J 25:877–887. https://doi.org/10.1007/s00586-015-4239-9

    Article  PubMed  Google Scholar 

  10. Igarashi T, Kikuchi S, Shubayev V, Myers RR (2000) 2000 Volvo Award winner in basic science studies: Exogenous tumor necrosis factor-alpha mimics nucleus pulposus-induced neuropathology. Molecular, histologic, and behavioral comparisons in rats. Spine (Phila Pa 1976) 25:2975–2980

    Article  CAS  Google Scholar 

  11. Imai S, Narita M, Miyashita K (2010) New aspect about mechanism of analgesic effect on acetaminophen. Pain Clin 31:503–505 (in Japanese)

    Google Scholar 

  12. Kaneuchi Y, Sekiguchi M, Kameda T, Kobayashi Y, Konno S (2018) Temporal and spatial changes of μ-opipod receptors in the brain, spinal cord and dorsal root ganalion in a rat lumbar disc herniation model. Spine (Phila Pa 1976). https://doi.org/10.1097/brs.0000000000002776

    Article  Google Scholar 

  13. Kameda T, Sekiguchi M, Kaneuchi Y, Konno SI (2017) Investigation of the effect of diabetes on radiculopathy induced by nucleus pulposus application to the DRG in a spontaneously diabetic rat model. Spine (Phila Pa 1976). https://doi.org/10.1097/brs.0000000000002299

    Article  Google Scholar 

  14. Kato K, Kikuchi S, Konno S, Sekiguchi M (2008) Participation of 5-hydroxytryptamine in pain-related behavior induced by nucleus pulposus applied on the nerve root in rats. Spine (Phila Pa 1976) 33:1330–1336. https://doi.org/10.1097/brs.0b013e318173298b

    Article  Google Scholar 

  15. Kato K, Kikuchi S, Shubayev VI, Myers RR (2009) Distribution and tumor necrosis factor-alpha isoform binding specificity of locally administered etanercept into injured and uninjured rat sciatic nerve. Neuroscience 160:492–500. https://doi.org/10.1016/j.neuroscience.2009.02.038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kobayashi H, Kikuchi S, Konno S, Kato K, Sekiguchi M (2011) Interaction of 5-hydroxytryptamine and tumor necrosis factor-alpha to pain-related behavior by nucleus pulposus applied on the nerve root in rats. Spine (Phila Pa 1976) 36:210–218. https://doi.org/10.1097/brs.0b013e3181fea618

    Article  Google Scholar 

  17. Kobayashi Y, Sekiguchi M, Konno SI (2017) Effect of an acid-sensing ion channels inhibitor on pain-related behavior by nucleus pulposus applied on the nerve root in rats. Spine (Phila Pa 1976) 42:E633–E641. https://doi.org/10.1097/brs.0000000000001918

    Article  Google Scholar 

  18. Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23–36

    Article  CAS  Google Scholar 

  19. Miyoshi S, Sekiguchi M, Konno S, Kikuchi S, Kanaya F (2011) Increased expression of vascular endothelial growth factor protein in dorsal root ganglion exposed to nucleus pulposus on the nerve root in rats. Spine (Phila Pa 1976) 36:E1–E6

    Article  Google Scholar 

  20. Moore DL, Goldberg JL (2011) Multiple transcription factor families regulate axon growth and regeneration. Dev Neurobiol 71:1186–1211. https://doi.org/10.1002/dneu.20934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Murata Y, Nannmark U, Rydevik B, Takahashi K, Olmarker K (2008) The role of tumor necrosis factor-alpha in apoptosis of dorsal root ganglion cells induced by herniated nucleus pulposus in rats. Spine (Phila Pa 1976) 33:155–162. https://doi.org/10.1097/brs.0b013e3181605518

    Article  Google Scholar 

  22. Murata Y, Onda A, Rydevik B, Takahashi K, Olmarker K (2004) Selective inhibition of tumor necrosis factor-alpha prevents nucleus pulposus-induced histologic changes in the dorsal root ganglion. Spine (Phila Pa 1976) 29:2477–2484

    Article  Google Scholar 

  23. Nakagawa T, Kaneko S (2010) Spinal astrocytes as therapeutic targets for pathological pain. J Pharmacol Sci 114:347–353

    Article  CAS  Google Scholar 

  24. Olmarker K, Brisby H, Yabuki S, Nordborg C, Rydevik B (1997) The effects of normal, frozen, and hyaluronidase-digested nucleus pulposus on nerve root structure and function. Spine (Phila Pa 1976) 22:471–475 (discussion 476)

    Article  CAS  Google Scholar 

  25. Olmarker K, Larsson K (1998) Tumor necrosis factor alpha and nucleus-pulposus-induced nerve root injury. (Phila Pa 1976) 23:2538–2544

    Article  CAS  Google Scholar 

  26. Olmarker K, Rydevik B (2001) Selective inhibition of tumor necrosis factor-alpha prevents nucleus pulposus-induced thrombus formation, intraneural edema, and reduction of nerve conduction velocity: possible implications for future pharmacologic treatment strategies of sciatica. Spine (Phila Pa 1976) 26:863–869

    Article  CAS  Google Scholar 

  27. Onda A, Yabuki S, Kikuchi S (2003) Effects of neutralizing antibodies to tumor necrosis factor-alpha on nucleus pulposus-induced abnormal nociresponses in rat dorsal horn neurons. Spine (Phila Pa 1976) 28:967–972. https://doi.org/10.1097/01.brs.0000061984.08703.0c

    Article  Google Scholar 

  28. Otoshi K, Kikuchi S, Konno S, Sekiguchi M (2010) The reactions of glial cells and endoneurial macrophages in the dorsal root ganglion and their contribution to pain-related behavior after application of nucleus pulposus onto the nerve root in rats. Spine (Phila Pa 1976) 35:264–271. https://doi.org/10.1097/brs.0b013e3181b8b04f

    Article  Google Scholar 

  29. Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL (1992) Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther 260:275–285

    CAS  PubMed  Google Scholar 

  30. Reeves RR, Burke RS (2008) Tramadol: basic pharmacology and emerging concepts. Drugs Today (Barc, Spain: 1998) 44:827–836. https://doi.org/10.1358/dot.2008.44.11.1289441

    Article  CAS  Google Scholar 

  31. Saito H, Wakai J, Sekiguchi M, Kikuchi S, Konno S (2014) The effect of selective serotonin reuptake inhibitor (SSRI) on pain-related behavior in a rat model of neuropathic pain. Eur Spine J 23:2401–2409. https://doi.org/10.1007/s00586-014-3392-x

    Article  PubMed  Google Scholar 

  32. Sakakiyama M, Maeda S, Isami K, Asakura K, So K, Shirakawa H, Nakagawa T, Kaneko S (2014) Preventive and alleviative effect of tramadol on neuropathic pain in rats: roles of alpha(2)-adrenoceptors and spinal astrocytes. J Pharmacol Sci 124:244–257

    Article  CAS  Google Scholar 

  33. Sasaki N, Kikuchi S, Konno S, Sekiguchi M, Watanabe K (2007) Anti-TNF-alpha antibody reduces pain-behavioral changes induced by epidural application of nucleus pulposus in a rat model depending on the timing of administration. Spine (Phila Pa 1976) 32:413–416. https://doi.org/10.1097/01.brs.0000255097.18246.bc

    Article  Google Scholar 

  34. Sasaki N, Sekiguchi M, Kikuchi S, Konno S (2011) Effects of asialo-erythropoietin on pain-related behavior and expression of phosphorylated-p38 map kinase and tumor necrosis factor-alpha induced by application of autologous nucleus pulposus on nerve root in rat. Spine (Phila Pa 1976) 36:E86–E94. https://doi.org/10.1097/brs.0b013e3181f137a8

    Article  Google Scholar 

  35. Scholz J, Woolf CJ (2007) The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 10:1361–1368

    Article  CAS  Google Scholar 

  36. Seijffers R, Mills CD, Woolf CJ (2007) ATF3 increases the intrinsic growth state of DRG neurons to enhance peripheral nerve regeneration. J Neurosci 27:7911–7920. https://doi.org/10.1523/jneurosci.5313-06.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Seki S, Sekiguchi M, Konno SI (2017) Association between neurotrophic factor expression and pain-related behavior induced by nucleus pulposus applied to rat nerve root. Spine (Phila Pa 1976). https://doi.org/10.1097/brs.0000000000002223

    Article  Google Scholar 

  38. The committee for the guideline for the pharmacological management of neuropathic pain of japan society of pain clinicians (2016) Guidelines for the pharmacologic management of neuropathic pain, 2nd edn. Department Shinko Trading Co., Ltd., Tokyo

    Google Scholar 

  39. The Committee for Clinical Practice Guideline for Chronic Pain (2018) Clinical practice guideline for chronic pain. Department Shinko Trading Co., Ltd., Tokyo

    Google Scholar 

  40. The Japanese Orthopaedic Association Guideline Committee (2012) JOA clinical practice guideline for the management of low back pain. Nankodo Co., Ltd., Tokyo (in Japanese)

    Google Scholar 

  41. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424:778–783

    Article  CAS  Google Scholar 

  42. van Tulder M, Becker A, Bekkering T, Breen A, del Real MT, Hutchinson A, Koes B, Laerum E, Malmivaara A (2006) Chapter 3. European guidelines for the management of acute nonspecific low back pain in primary care. Eur Spine J 15(Suppl 2):S169–S191. https://doi.org/10.1007/s00586-006-1071-2

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wuertz K, Quero L, Sekiguchi M, Klawitter M, Nerlich A, Konno S, Kikuchi S, Boos N (2011) The red wine polyphenol resveratrol shows promising potential for the treatment of nucleus polposus medicated pain in vitro and in vivo. Spine 36(12):E1373–E1384

    Article  Google Scholar 

  44. Yamashita T, Takahashi K, Yanenobu K, Kikuchi S (2014) Prevalence of neuropathic pain in case with chronic pain realated to spinal disocrders. J Orthop Sci 19:15–21. https://doi.org/10.1007/s00776-013-0496-9

    Article  PubMed  Google Scholar 

  45. Yamashita T, Yamamoto S, Zhang J, Kometani M, Tomiyama D, Kohno K, Tozaki-Saitoh H, Inoue K (2016) Duloxetine inhibits microglial P2X4 receptor function and alleviates neuropathic pain after peripheral nerve injury. PLoS ONE 11:e0165189

    Article  Google Scholar 

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Funding

The device(s)/drug(s) is/are FDA-approved or approved by corresponding national agency for this indication. No funds were received in support of this work. No relevant financial activities outside the submitted work.

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  1. Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, 1-Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan

    Ryohei Sato, Miho Sekiguchi & Shin-ichi Konno

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  1. Ryohei Sato
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Correspondence to Miho Sekiguchi.

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Sato, R., Sekiguchi, M. & Konno, Si. Acetaminophen combined with tramadol is more effective than acetaminophen or tramadol to reduce neuropathic root pain: an experimental study with application of nucleus pulposus in a rat model. Eur Spine J 29, 169–178 (2020). https://doi.org/10.1007/s00586-019-06190-z

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