open access

Vol 13, No 3 (2019)
Review articles
Published online: 2019-09-13
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Neuropathic pain: new mechanisms of action of old drugs

Zbigniew Zylicz
DOI: 10.5603/PMPI.2019.0016
·
Palliat Med Pract 2019;13(3):123-128.

open access

Vol 13, No 3 (2019)
Review articles
Published online: 2019-09-13

Abstract

Approximately 7–10% of the general population and 30% of cancer patients suffer from neuropathic
pain, which is induced by the damage or disease of the neurologic structures. Sometimes neuropathic
pain is caused by the pressure on a nerve but more often pain is due to the sensitization of the centers in
the spinal cord and brain. Some structures become so sensitive to the peripheral pain impulses that they
become totally independent of them. Recently neuropathic pain is seen as an activation process of the
innate immunologic system. In this area the Toll-like receptors seems to play an important role and many
drugs are able to inhibit their activation. Treatment of neuropathic pain depends on the possibility of nerve
decompression. However, in many cases, the sensitization is the target for treatment. For this purpose,
most useful are gabapentinoids that inhibit influx of calcium across the membrane. Antidepressants (SNRI)
such as duloxetine and venlafaxine are also useful as well as tricyclic antidepressants, although the latter
are characterized by significant adverse effects. In some types of neuropathic pain 8% capsaicin, as well as
5% lidocaine plasters or different opioids, are successfully used although there is still a lack of sufficient,
good quality controlled clinical trials. The description of the role of Toll-like receptors in the pathophysiology
of neuropathic pain is a breakthrough in thinking and hope for the future to elaborate new, more
effective treatment methods.


Palliat Med Pract 2019; 13, 3: 123–128

Abstract

Approximately 7–10% of the general population and 30% of cancer patients suffer from neuropathic
pain, which is induced by the damage or disease of the neurologic structures. Sometimes neuropathic
pain is caused by the pressure on a nerve but more often pain is due to the sensitization of the centers in
the spinal cord and brain. Some structures become so sensitive to the peripheral pain impulses that they
become totally independent of them. Recently neuropathic pain is seen as an activation process of the
innate immunologic system. In this area the Toll-like receptors seems to play an important role and many
drugs are able to inhibit their activation. Treatment of neuropathic pain depends on the possibility of nerve
decompression. However, in many cases, the sensitization is the target for treatment. For this purpose,
most useful are gabapentinoids that inhibit influx of calcium across the membrane. Antidepressants (SNRI)
such as duloxetine and venlafaxine are also useful as well as tricyclic antidepressants, although the latter
are characterized by significant adverse effects. In some types of neuropathic pain 8% capsaicin, as well as
5% lidocaine plasters or different opioids, are successfully used although there is still a lack of sufficient,
good quality controlled clinical trials. The description of the role of Toll-like receptors in the pathophysiology
of neuropathic pain is a breakthrough in thinking and hope for the future to elaborate new, more
effective treatment methods.


Palliat Med Pract 2019; 13, 3: 123–128

Get Citation

Keywords

neuropathic pain, sensitization of the central nervous system, tricyclic antidepressants, gabapentin, pregabalin, opioids

About this article
Title

Neuropathic pain: new mechanisms of action of old drugs

Journal

Palliative Medicine in Practice

Issue

Vol 13, No 3 (2019)

Pages

123-128

Published online

2019-09-13

DOI

10.5603/PMPI.2019.0016

Bibliographic record

Palliat Med Pract 2019;13(3):123-128.

Keywords

neuropathic pain
sensitization of the central nervous system
tricyclic antidepressants
gabapentin
pregabalin
opioids

Authors

Zbigniew Zylicz

References (53)
  1. Breivik H, Collett B, Ventafridda V, et al. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006; 10(4): 287–333.
  2. Jensen T, Baron R, Haanpää M, et al. A new definition of neuropathic pain. Pain. 2011; 152(10): 2204–2205.
  3. van Hecke O, Austin SK, Khan RA, et al. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain. 2014; 155(4): 654–662.
  4. Roberto A, Deandrea S, Greco MT, et al. Prevalence of Neuropathic Pain in Cancer Patients: Pooled Estimates From a Systematic Review of Published Literature and Results From a Survey Conducted in 50 Italian Palliative Care Centers. J Pain Symptom Manage. 2016; 51(6): 1091–1102.e4.
  5. Fallon MT. Neuropathic pain in cancer. Br J Anaesth. 2013; 111(1): 105–111.
  6. Scheib J, Höke A. Advances in peripheral nerve regeneration. Nat Rev Neurol. 2013; 9(12): 668–676.
  7. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009; 10(9): 895–926.
  8. Williams KS, Killebrew DA, Clary GP, et al. Differential regulation of macrophage phenotype by mature and pro-nerve growth factor. J Neuroimmunol. 2015; 285: 76–93.
  9. DeLeo JA, Yezierski RP. The role of neuroinflammation and neuroimmune activation in persistent pain. Pain. 2001; 90(1-2): 1–6.
  10. Singson RD, Feldman F, Slipman CW, et al. Postamputation neuromas and other symptomatic stump abnormalities: detection with CT. Radiology. 1987; 162(3): 743–745.
  11. Salemis NS. Traumatic neuroma as a rare cause of intractable neuropathic breast pain following cancer surgery: Management and review of the literature. Intractable Rare Dis Res. 2018; 7(3): 185–190.
  12. De Nardo D. Toll-like receptors: Activation, signalling and transcriptional modulation. Cytokine. 2015; 74(2): 181–189.
  13. Jurga AM, Rojewska E, Piotrowska A, et al. Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model. Neural Plast. 2016; 2016: 5238730.
  14. Lewis SS, Loram LC, Hutchinson MR, et al. (+)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats. J Pain. 2012; 13(5): 498–506.
  15. Hutchinson MR, Zhang Y, Brown K, et al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). Eur J Neurosci. 2008; 28(1): 20–29.
  16. Harrison NA, Brydon L, Walker C, et al. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry. 2009; 66(5): 407–414.
  17. Moresco EM, LaVine D, Beutler B. Toll-like receptors. Curr Biol. 2011; 21(13): R488–R493.
  18. Velasquez-Manoff M. Gut microbiome: the peacekeepers. Nature. 2015; 518(7540): S3–11.
  19. Doorn KJ, Moors T, Drukarch B, et al. Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson's disease patients. Acta Neuropathol Commun. 2014; 2: 90.
  20. Fitzpatrick JMK, Downer EJ. Toll-like receptor signalling as a cannabinoid target in Multiple Sclerosis. Neuropharmacology. 2017; 113(Pt B): 618–626.
  21. Rich T, Zhao F, Cruciani RA, et al. Association of fatigue and depression with circulating levels of proinflammatory cytokines and epidermal growth factor receptor ligands: a correlative study of a placebo-controlled fatigue trial. Cancer Manag Res. 2017; 9: 1–10.
  22. Grace P, Maier S, Watkins L. Opioid-Induced Central Immune Signaling: Implications for Opioid Analgesia. Headache: The Journal of Head and Face Pain. 2015; 55(4): 475–489.
  23. Due MR, Piekarz AD, Wilson N, et al. Neuroexcitatory effects of morphine-3-glucuronide are dependent on Toll-like receptor 4 signaling. J Neuroinflammation. 2012; 9: 200.
  24. Lewis SS, Hutchinson MR, Rezvani N, et al. Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta. Neuroscience. 2010; 165(2): 569–583.
  25. Hutchinson MR, Zhang Y, Shridhar M, et al. Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain Behav Immun. 2010; 24(1): 83–95.
  26. Dellemijn PL, Vanneste JA. Randomised double-blind active-placebo-controlled crossover trial of intravenous fentanyl in neuropathic pain. Lancet. 1997; 349(9054): 753–758.
  27. Bleeker CP, Bremer RC, Dongelmans DA, et al. Inefficacy of high-dose transdermal fentanyl in a patient with neuropathic pain, a case report. Eur J Pain. 2001; 5(3): 325–9; discussion 329.
  28. Wang X, Zhang Y, Peng Y, et al. Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4. Br J Pharmacol. 2016; 173(5): 856–869.
  29. Hutchinson MR, Loram LC, Zhang Y, et al. Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity. Neuroscience. 2010; 168(2): 551–563.
  30. Suarez-Roca H, Silva JA, Arcaya JL, et al. Role of mu-opioid and NMDA receptors in the development and maintenance of repeated swim stress-induced thermal hyperalgesia. Behav Brain Res. 2006; 167(2): 205–211.
  31. Felsby S, Nielsen J, Arendt-Nielsen L, et al. NMDA receptor blockade in chronic neuropathic pain: a comparison of ketamine and magnesium chloride. Pain. 1996; 64(2): 283–291.
  32. Mei XP, Zhou Y, Wang W, et al. Ketamine depresses toll-like receptor 3 signaling in spinal microglia in a rat model of neuropathic pain. Neurosignals. 2011; 19(1): 44–53.
  33. Chincholkar M. Analgesic mechanisms of gabapentinoids and effects in experimental pain models: a narrative review. Br J Anaesth. 2018; 120(6): 1315–1334.
  34. Sills GJ. The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol. 2006; 6(1): 108–113.
  35. Berlin RK, Butler PM, Perloff MD. Gabapentin Therapy in Psychiatric Disorders: A Systematic Review. Prim Care Companion CNS Disord. 2015; 17(5).
  36. Zylicz Z. Krajnik, M., : The effect of gabapentin and pregabalin on symptoms other than pain and seizures. A review of the evidence. Adv Pall Med. 2008; 4: 179–184.
  37. Loblaw DA, Perry J, Chambers A, et al. Systematic review of the diagnosis and management of malignant extradural spinal cord compression: the Cancer Care Ontario Practice Guidelines Initiative's Neuro-Oncology Disease Site Group. J Clin Oncol. 2005; 23(9): 2028–2037.
  38. Żylicz Z. Diagnosis and treatment of nerve entrapment neuropathiesin Palliative Medicine. Ból. 2018; 19(1): 37–41.
  39. Attal N. Pharmacological treatments of neuropathic pain: The latest recommendations. Rev Neurol (Paris). 2019; 175(1-2): 46–50.
  40. Park SH, Wackernah RC, Stimmel GL. Serotonin syndrome: is it a reason to avoid the use of tramadol with antidepressants? J Pharm Pract. 2014; 27(1): 71–78.
  41. van Nooten F, Treur M, Pantiri K, et al. Capsaicin 8% Patch Versus Oral Neuropathic Pain Medications for the Treatment of Painful Diabetic Peripheral Neuropathy: A Systematic Literature Review and Network Meta-analysis. Clin Ther. 2017; 39(4): 787–803.e18.
  42. Suchorzewski M, Wujtewicz M. Opioidy w leczeniu bólu neuropatycznego. Medycyna Paliatywna w Praktyce. 2007; 1(2): 49–53.
  43. Bechakra M, Moerdijk F, van Rosmalen J, et al. Opioid responsiveness of nociceptive versus mixed pain in clinical cancer patients. Eur J Cancer. 2018; 105: 79–87.
  44. Davis AM, Inturrisi CE. d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia. J Pharmacol Exp Ther. 1999; 289(2): 1048–1053.
  45. McNicol ED, Ferguson MC, Schumann R. Methadone for neuropathic pain in adults. Cochrane Database Syst Rev. 2017; 5: CD012499.
  46. Induru RR, Davis MP. Buprenorphine for neuropathic pain--targeting hyperalgesia. Am J Hosp Palliat Care. 2009; 26(6): 470–473.
  47. Butler S. Buprenorphine-Clinically useful but often misunderstood. Scand J Pain. 2013; 4(3): 148–152.
  48. Wiffen PJ, Derry S, Moore RA, et al. Buprenorphine for neuropathic pain in adults. Cochrane Database Syst Rev. 2015(9): CD011603.
  49. Duehmke RM, Derry S, Wiffen PJ, et al. Tramadol for neuropathic pain in adults. Cochrane Database Syst Rev. 2017; 6: CD003726.
  50. Galiè E, Villani V, Terrenato I, et al. Tapentadol in neuropathic pain cancer patients: a prospective open label study. Neurol Sci. 2017; 38(10): 1747–1752.
  51. Yang Mi, Zhou M, He Li, et al. Non-antiepileptic drugs for trigeminal neuralgia. Cochrane Database Syst Rev. 2011(1): CD004029.
  52. Zhou M, Chen N, He Li, et al. Oxcarbazepine for neuropathic pain. Cochrane Database of Systematic Reviews. 2017.
  53. Fallon MT, Wilcock A, Kelly CA, et al. Oral Ketamine vs Placebo in Patients With Cancer-Related Neuropathic Pain: A Randomized Clinical Trial. JAMA Oncol. 2018; 4(6): 870–872.

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