Brainstem Modulators

  • Sergio Canavero
  • Vincenzo Bonicalzi


These drugs modulate the release of aminergic and non-aminergic neurotransmitters from brainstem (e.g., locus coeruleus, raphe nuclei, etc.) and basal forebrain (e.g., Meynert’s nucleus) nuclei. Fibers leaving these nuclei fan out both upward into the brain and downward to the cord. These regulate the function and activation state of the brain, both diffusely and focally. However, other mechanisms of action are possible and are differentiated according to individual drugs (Tables 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 14.10, and 14.11).


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  1. 1.
    Leijon G, Boivie J. Central post-stroke pain—a controlled trial of amitriptyline and carbamazepine. Pain. 1989;36:27–36.CrossRefPubMedGoogle Scholar
  2. 2.
    Cardenas DD, Warms CA, Turner JA, Marshall H, Brooke MM, Loeser JD. Efficacy of amitriptyline for relief of pain in spinal cord injury: results of a randomized controlled trial. Pain. 2002;96:365–73.CrossRefPubMedGoogle Scholar
  3. 3.
    Lampl C, Yazdi K, Röper C. Amitriptyline in the prophylaxis of central poststroke pain. Preliminary results of 39 patients in a placebo-controlled, long-term study. Stroke. 2002;33:3030–2.CrossRefPubMedGoogle Scholar
  4. 4.
    Rintala DH, Holmes SA, Courtade D, Fiess RN, Tastard LV, Loubser PG. Comparison of the effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal cord injury. Arch Phys Med Rehabil. 2007;88:1547–60 (Erratum in: Arch Phys Med Rehabil. 2008;89:1206).Google Scholar
  5. 5.
    Agarwal N, Joshi M. Effectiveness of amitriptyline and lamotrigine in traumatic spinal cord injury-induced neuropathic pain: a randomized longitudinal comparative study. Spinal Cord. 2017;55:126–30 (in press).Google Scholar
  6. 6.
    Chitsaz A, Janghorbani M, Shaygannejad V, Ashtari F, Heshmatipour M, Freeman J. Sensory complaints of the upper extremities in multiple sclerosis: relative efficacy of nortriptyline and transcutaneous electrical nerve stimulation. Clin J Pain. 2009;25(4):281–5.CrossRefPubMedGoogle Scholar
  7. 7.
    Richards JS, Bombardier CH, Wilson CS, Chiodo AE, Brooks L, Tate DG, Temkin NR, Barber JK, Heinemann AW, McCullumsmith C, Fann JR. Efficacy of venlafaxine XR for the treatment of pain in patients with spinal cord injury and major depression: a randomized, controlled trial. Arch Phys Med Rehabil. 2015;96(4):680–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Richards JS, Bombardier C, Fann J, et al. The effect of venlafaxine on neuropathic and non-neuropathic pain in persons with spinal cord injury: results from a randomized controlled trial. Paper presented at: 4th International Congress on Neuropathic Pain. Toronto, ON, Canada; 2013.Google Scholar
  9. 9.
    Vranken JH, Hollmann MW, van der Vegt MH, Kruis MR, Heesen M, Vos K, Pijl AJ, Dijkgraaf MG. Duloxetine in patients with central neuropathic pain caused by spinal cord injury or stroke: a randomized, double-blind, placebo-controlled trial. Pain. 2011;152(2):267–73.CrossRefPubMedGoogle Scholar
  10. 10.
    Vollmer TL, Robinson MJ, Risser RC, Malcolm SK. A randomized, double-blind, placebo-controlled trial of duloxetine for the treatment of pain in patients with multiple sclerosis. Pain Pract. 2014;14(8):732–44.CrossRefPubMedGoogle Scholar
  11. 11.
    Brown TR, Slee A. A randomized placebo-controlled trial of duloxetine for central pain in multiple sclerosis. Int J MS Care. 2015;17(2):83–9.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Davidoff G, Roth E, Guarracini M, Sliwa J, Yarkony G. Function-limiting dysesthetic pain syndrome among traumatic spinal cord injury patients: a cross-sectional study. Pain. 1987;29(1):39–48.CrossRefPubMedGoogle Scholar
  13. 13.
    Vestergaard K, Andersen G, Jensen TS. Treatment of central post-stroke pain with a selective serotonin reuptake inhibitor. Eur J Neurol. 1996;3(Suppl 5):169.Google Scholar
  14. 14.
    Heilporn A. Two therapeutic experiments on stubborn pain in spinal cord lesions: coupling melitracen-flupenthixol and the transcutaneous nerve stimulation [proceedings]. Paraplegia. 1978;15(4):368–72.CrossRefPubMedGoogle Scholar
  15. 15.
    Clifford DB, Trotter JL. Pain in multiple sclerosis. Arch Neurol. 1984;41(12):1270–2.CrossRefPubMedGoogle Scholar
  16. 16.
    Tourian AY. Narcotic responsive “thalamic” pain treatment with propranolol and tricyclic antidepressants. Pain. 1987;30(Suppl 4):411.CrossRefGoogle Scholar
  17. 17.
    Moulin DE, Foley KM, Ebers GC. Pain syndromes in multiple sclerosis. Neurology. 1988;38(12):1830–4.CrossRefPubMedGoogle Scholar
  18. 18.
    Kluger NJ, Clifford JS, Cavanagh RJ, Griffith WL. A case of a chemically dependent patient with a thalamic pain syndrome treated with amitriptyline. J Addict Dis. 1991;10(3):97–102.CrossRefPubMedGoogle Scholar
  19. 19.
    MacGowan DJ, Janal MN, Clark WC, Wharton RN, Lazar RM, Sacco RL, Mohr JP. Central poststroke pain and Wallenberg’s lateral medullary infarction: frequency, character, and determinants in 63 patients. Neurology. 1997;49(1):120–5.CrossRefPubMedGoogle Scholar
  20. 20.
    Bowsher D. The time factor in tricyclic treatment of postherpetic neuralgia (PHN) and central post-stroke pain (CPSP). In: 10th world congress on pain, book of abstracts. Seattle: IASP Press; 2002. p. A890–P160.Google Scholar
  21. 21.
    Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Therapeutic outcome in neuropathic pain: relationship to evidence of nervous system lesion. Eur J Neurol. 2004;11(8):545–53.CrossRefPubMedGoogle Scholar
  22. 22.
    Li W, Ma DR. Randomized controlled trial on antidepressant drugs treating patients with central pain. China J Modern Med. 2005;15:2660–2.Google Scholar
  23. 23.
    Cardenas DD, Jensen MP. Treatments for chronic pain in persons with spinal cord injury: a survey study. J Spinal Cord Med. 2006;29(2):109–17.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Jiang CJ, Tan YC, Yang YJ, Zhang EZ, Liu J, Yao SQ, Yu JL. Sequential drugs treatment for central pain following spinal cord injury. Zhongguo Gu Shang. 2009;22(6):458–9.PubMedGoogle Scholar
  25. 25.
    Kopsky DJ, Liebregts R, Keppel Hesselink JM. Central neuropathic pain in a patient with multiple sclerosis treated successfully with topical amitriptyline. Case Rep Med. 2012;2012:471835.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Djaldetti R, Yust-Katz S, Kolianov V, Melamed E, Dabby R. The effect of duloxetine on primary pain symptoms in Parkinson disease. Clin Neuropharmacol. 2007;30(4):201–5.PubMedGoogle Scholar
  27. 27.
    Michel D, Laurent B, Convers P, Garcia-Larrea L, Le Bas JF, Mauguiere F, Schott B. Douleurs corticales: étude clinique, électrophysiologique et topographique de 12 cas. Rev Neurol (Paris). 1990;146(6–7):405–14.Google Scholar
  28. 28.
    Shimodozono M, Kawahira K, Kamishita T, Ogata A, Tohgo S, Tanaka N. Reduction of central poststroke pain with the selective serotonin reuptake inhibitor fluvoxamine. Int J Neurosci. 2002;112(10):1173–81.CrossRefPubMedGoogle Scholar
  29. 29.
    Canavero S, Bonicalzi V, Paolotti R. Reboxetine for central pain: a single-blind prospective study. Clin Neuropharmacol. 2002;25(4):238–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Schott GD, Loh L. Anticholinesterase drugs in the treatment of chronic pain. Pain. 1984;20(2):201–6.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Sergio Canavero
    • 1
  • Vincenzo Bonicalzi
    • 2
  1. 1.HEAVEN/GEMINI International Collaborative GroupTurinItaly
  2. 2.AOUCittà della Salute e della Scienza di Torino, Department of Neurosciences, Rita Levi MontalciniUniversità di TorinoTurinItaly

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