Intraspinal Drug Infusion

  • Sergio Canavero
  • Vincenzo Bonicalzi


Several drugs have been administered intrathecally (IT) in attempting to treat CP. Unfortunately, no well-designed studies with homogeneous groups of patients and long-term follow-up are available for definite conclusions. However, drug combinations (e.g., midazolam/clonidine/bupi- or ropivacaine or baclofen/clonidine/bupi- or ropivacaine) may be more effective; tolerance may develop more slowly. Since the dosage of each single drug is reduced, side effects might be fewer—although not necessarily. Intraspinal infusion is not risk-free: aside from generic ones (catheter dislodgement [IT>epidural], root irritation [IT>epidural], reactive arachnoiditis [IT>epidural]), infective complications are the most feared, with occasional mortality; bleeding, neurological injury, and cerebrospinal leaks are also possible. Intermittent boluses or continuous infusion shows no difference in predicting trial and long-term success, at least for opioids [1]; a positive preimplantation test does not guarantee long-term relief.


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  1. 1.
    Hamza M, Doleys DM, Saleh IA, Medvedovsky A, Verdolin MH, Hamza M. A prospective, randomized, single-blinded, head-to-head long-term outcome study, comparing Intrathecal (IT) boluses with continuous infusion trialing techniques prior to implantation of drug delivery systems (DDS) for the treatment of severe intractable chronic nonmalignant pain. Neuromodulation. 2015;18:636–48.CrossRefPubMedGoogle Scholar
  2. 2.
    Lind G, Schechtmann G, Winter J, Meyerson BA, Linderoth B. Baclofen-enhanced spinal cord stimulation and intrathecal baclofen alone for neuropathic pain: long-term outcome of a pilot study. Eur J Pain. 2008;12:132–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Schechtmann G, Lind G, Winter J, Meyerson B, Linderoth B. Intrathecal clonidine and baclofen enhance the pain-relieving effect of spinal cord stimulation: a comparative placebp-controlled, randomized trial. Neurosurgery. 2010;67:173–81.CrossRefPubMedGoogle Scholar
  4. 4.
    Pollock LJ, Brown M, Boshes B, Finkelman I, Chor H, Arieff AJ, Finkle JR. Pain below the level of injury of the spinal cord. Arch Neurol Psychiatr. 1951;65:319–22.CrossRefGoogle Scholar
  5. 5.
    Davis L. Treatment of spinal cord injuries. AMA Arch Surg. 1954;69:488–95.CrossRefPubMedGoogle Scholar
  6. 6.
    Waltz TA, Ehni G. The thalamic syndrome and its mechanisms. Report of two cases, one due to arteriovenous malformation in the thalamus. J Neurosurg. 1966;24:735–42.CrossRefPubMedGoogle Scholar
  7. 7.
    Portenoy RK, Foley KM, Inturrisi CE. The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid infusions. Pain. 1990;43:273–86.CrossRefPubMedGoogle Scholar
  8. 8.
    Crisologo PA, Neal B, Brown R, McDanal J, Kissin I. Lidocaine-induced spinal block can relieve central poststroke pain: role of the block in chronic pain diagnosis. Anesthesiology. 1991;74:184–5.CrossRefPubMedGoogle Scholar
  9. 9.
    Loubser PG, Donovan WH. Diagnostic spinal anaesthesia in chronic spinal cord injury pain. Paraplegia. 1991;29:25–36.PubMedGoogle Scholar
  10. 10.
    Lema MJ, Shady JA, Zoll JG, West CR. Management of intractable back pain from caudal ependymoma with spinal methylprednisolone, bupivacaine and morphine. Pain. 1992;48:245–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Loubser PG, Clearman RR. Evaluation of central spinal cord injury pain with diagnostic spinal anesthesia. Anesthesiology. 1993;79:376–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Nitescu P, Dahm P, Appelgren L, Curelaru I. Continuous infusion of opioid and bupivacaine by externalized intrathecal catheters in long-term treatment of “refractory” nonmalignant pain. Clin J Pain. 1998;14:17–28.CrossRefPubMedGoogle Scholar
  13. 13.
    Dahm PO, Nitescu PV, Appelgren LK, Curelaru I. Long-term intrathecal (i.t.) infusion of bupivacaine relieved intractable pain and spasticity in a patient with multiple sclerosis. Eur J Pain. 1998;2:81–5.CrossRefPubMedGoogle Scholar
  14. 14.
    Huntoon MA, Hurdle MFB, Marsh RW, Reeves RK. Intrinsic spinal cord catheter placement: implications of new intractable pain in a patient with a spinal cord injury. Anesth Analg. 2004;99:1763–5.CrossRefPubMedGoogle Scholar
  15. 15.
    Bruel BM, Burton AW, Ting J, Mosura M. Rapid titration of ziconotide for the treatment of severe intractable back pain from metastatic spinal anaplastic ependymoma. Eur J Pain. 2007;11:S142–143 A321.Google Scholar
  16. 16.
    Papadopoulos G, Tzimas P, Zigouris A, Voulgaris S, Karanikolas M. Subarachnoid clonidine for treatment of central neuropathic pain persisting for twenty-four years after spinal cord injury. A case report. Eur J Pain. 2010;54:102 A359.Google Scholar
  17. 17.
    Canavero S, Bonicalzi V. The neurochemistry of central pain: evidence from clinical studies, hypothesis and therapeutic implications. Pain. 1998;74(2–3):109–14.CrossRefPubMedGoogle Scholar
  18. 18.
    Canavero S, Bonicalzi V, Clemente M. No neurotoxicity from long-term (5 years) intrathecal infusion of midazolam in humans. J Pain Symptom Manag. 2006;32:1–3.CrossRefGoogle Scholar
  19. 19.
    Kumru H, Kofler M, Flores MC, Portell E, Robles V, Leon N, Vidal J. Effect of intrathecal baclofen on evoked pain perception: an evoked potentials and quantitative thermal testing study. Eur J Pain. 2013;17:1039–47.CrossRefPubMedGoogle Scholar
  20. 20.
    Boehm UL, Wyart C. Spinal sensory circuits in motion. Curr Op Neurobiol. 2016;41:38–43.CrossRefGoogle Scholar
  21. 21.
    Herman RM, D’Luzansky SC, Ippolito R. Intrathecal baclofen suppresses central pain in patients with spinal lesions. A pilot study. Clin J Pain. 1992;8:338–45.CrossRefPubMedGoogle Scholar
  22. 22.
    Taira T, Tanikawa T, Kawamura H, Iseki H, Takakura K. Spinal intrathecal baclofen suppresses central pain after a stroke. J Neurol Neurosurg Psychiatry. 1994;57:381–2.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Taira T, Kawamura H, Tanikawa T, Iseki H, Kawabatake H, Takakura K. A new approach to control central deafferentation pain: spinal intrathecal baclofen. Stereotact Funct Neurosurg. 1995;65:101–5.CrossRefPubMedGoogle Scholar
  24. 24.
    Loubser PG, Akman NM. Effects of intrathecal baclofen on chronic spinal cord injury pain. J Pain Symptom Manag. 1996;12:241–7.CrossRefGoogle Scholar
  25. 25.
    Middleton JW, Siddall PJ, Walker S, Molloy AR, Rutkowski SB. Intrathecal clonidine and baclofen in the management of spasticity and neuropathic pain following spinal cord injury: a case study. Arch Phys Med Rehabil. 1996;77:824–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Meglio M. Evaluation and management of central and peripheral deafferentation pain. In: Gildenberg PL, Tasker RR, editors. Textbook of stereotactic and functional Neurosurgery. New York: McGraw-Hill; 1998. p. 1631–6.Google Scholar
  27. 27.
    Becker R, Uhle EI, Alberti O, Bertalanffy H. Continuous intrathecal baclofen infusion in the management of central deafferentation pain. J Pain Symptom Manag. 2000;20:313–5.CrossRefGoogle Scholar
  28. 28.
    Que JC, Siddall PJ, Cousins MJ. Pain management in a pateint with intractable spinal cord injury pain: a case report and literature review. Anesth Analg. 2007;105:1462–73.CrossRefPubMedGoogle Scholar
  29. 29.
    Sadiq SA, Poopatana CA. Intrathecal baclofen and morphine in multiple sclerosis patients with severe pain and spasticity. J Neurol. 2007;254:1464–5.CrossRefPubMedGoogle Scholar
  30. 30.
    Koulousakis A, Kuchta J, Bayarassou A, Sturm V. Intrathecal opioids for intractable pain syndromes. Acta Neurochir (Wien) Suppl. 2007;97:45–8.Google Scholar
  31. 31.
    Ruis Ortiz S, Galvez R, Romero Cotelo J, Lopez Tapia Fa, Martin de Rosales J, Romero Rodriguez Y. Intrathecal ziconotide combined with other two drugs in two cases of refractory spinal cord injury pain. Eur J Pain. 2009;13:S260 (A917).Google Scholar
  32. 32.
    Margot-Duclot A, Silhouette B, Thiebaut JB. Intrathecal baclofen for intractable neuropathic pain-predictive study of efficacy and long term results. Eur J Pain Suppl. 2010;4:104 A364.Google Scholar
  33. 33.
    D’Hardemare V, Bruxelle J, Margot-Duclos A, Bachelart M, Thiebaut JB. Intrathecal baclofen on central and peripheric neuropathic pain: a retrospective, multicenter, single-blind study on 23 patients. Stereotact Funct Neurosurg. 2014;92(suppl 2):A251.Google Scholar
  34. 34.
    Ho JK, Sadiq SA. Use of intrathecal clonidine in patients with multiple sclerosis or spastic paraparesis. J Neurol. 2012;259:982–4.CrossRefPubMedGoogle Scholar
  35. 35.
    Glynn CJ, Jamous MA, Teddy PJ, Moore RA, Lloyd JW. Role of spinal noradrenergic system in transmission of pain in patients with spinal cord injury. Lancet. 1986;2:1249–50.CrossRefPubMedGoogle Scholar
  36. 36.
    Glynn CJ, Jamous MA, Teddy PJ. Cerebrospinal fluid kinetics of epidural clonidine in man. Pain. 1992;49:361–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Uhle EI, Becker R, Gatscher S, Bertalanffy H. Continuous intrathecal clonidine administration for the treatment of neuropathic pain. Stereotact Funct Neurosurg. 2000;75:167–75.CrossRefPubMedGoogle Scholar
  38. 38.
    Siddall PJ, Molloy AR, Walker S, Mather LE, Rutkowski SB, Cousins MJ. The efficacy of intrathecal morphine and clonidine in the treatment of pain after spinal cord injury. Anesth Analg. 2000;9:1493–8.CrossRefGoogle Scholar
  39. 39.
    Siddall PJ, Gray M, Rutkowski S, Cousins MJ. Intrathecal morphine and clonidine in the management of spinal cord injury pain: a case report. Pain. 1994;59:147–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Coombs DW, Saunders RL, Gaylor MS, Block AR, Colton T, Harbaugh R, Pageau MG, Mroz W. Relief of continuous chronic pain by intraspinal narcotics infusion via an implanted reservoir. JAMA. 1983;250(17):2336–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Tutak U, Doleys DM. Intrathecal infusion systems for treatment of chronic low back and leg pain of noncancer origin. South Med J. 1996;89(3):295–300.CrossRefPubMedGoogle Scholar
  42. 42.
    Noble M, Tregear SJ, Treadwell JR, Schoelles K. Long-term opioid therapy for chronic noncancer pain: a systematic review and meta-analysis of efficacy and safety. J Pain Symptom Manag. 2008;35:214–28.CrossRefGoogle Scholar
  43. 43.
    Hook M, Woller S, Bancroft E, Aceves M, Funk MK, Hartman J, Garraway SM. Neurobiological effects of morphine following spinal cord injury. J Neurotrauma. 2017 (in press).Google Scholar
  44. 44.
    Namba S, Nakao Y, Matsumoto Y, Ohmoto T, Nishimoto A. Electrical stimulation of the posterior limb of the internal capsule for treatment of thalamic pain. Appl Neurophysiol. 1984;47:137–148 (see also J Neurosurg 1985, 63, 224–234). Google Scholar
  45. 45.
    Auld AW, Maki-Jokela A, Murdoch DM. Intraspinal narcotic analgesia in the treatment of chronic pain. Spine. 1985;10:777–81.CrossRefPubMedGoogle Scholar
  46. 46.
    Penn RD, Paice JA. Chronic intrathecal morphine for intractable pain. J Neurosurg. 1987;67:182–6.CrossRefPubMedGoogle Scholar
  47. 47.
    Brazenor GA. Long term intrathecal administration of morphine: a comparison of bolus injection via reservoir with continuous infusion by implanted pump. Neurosurgery. 1987;21:484–91.CrossRefPubMedGoogle Scholar
  48. 48.
    Triggs WJ, Beric A. Sensory abnormalities and dysaesthesias in the anterior spinal artery syndrome. Brain. 1992;115:189–98.CrossRefPubMedGoogle Scholar
  49. 49.
    Reig E. Spinal infusion of morphine for the treatment of neuropathic pain. Medtronic Conference on Advances in Chronic Pain Treatment, Padova, 1993 Nov 27.Google Scholar
  50. 50.
    Fenollosa P, Pallares J, Cervera J, Pelegrin F, Inigo V, Giner M, Forner V. Chronic pain in the spinal cord injured: statistical approach and pharmacological treatment. Paraplegia. 1993;31:722–9.Google Scholar
  51. 51.
    Hassenbusch SJ, Stanton-Hicks M, Covington EC, Walsh JG, Guthrey DS. Long-term intraspinal infusions of opioids in the treatment of neuropathic pain. J Pain Symptom Manag. 1995;10:527–43.CrossRefGoogle Scholar
  52. 52.
    Winkelmuller M, Winkelmuller W. Long-term effects of continuous intrathecal opioid treatment in chronic pain of nonmalignant etiology. J Neurosurg. 1996;85:458–67.CrossRefPubMedGoogle Scholar
  53. 53.
    Angel IF, Gould HJ Jr, Carey ME. Intrathecal morphine pump as a treatment option in chronic pain of nonmalignant origin. Surg Neurol. 1998;49:92–8.CrossRefPubMedGoogle Scholar
  54. 54.
    Anderson VC, Burchiel KJ. A prospective study of long-term intrathecal morphine in the management of chronic nonmalignant pain. Neurosurgery. 1999;44:289–301.CrossRefPubMedGoogle Scholar
  55. 55.
    Gatscher S, Becker R, Uhle E, Bertalanffy H. Combined intrathecal baclofen and morphine infusion for the treatment of spasticity related pain and central deafferentation pain. Acta Neurochir. 2002;79(Suppl):75–6.Google Scholar
  56. 56.
    Ridgeway B, Wallace M, Gerayli A. Ziconotide for the treatment of severe spasticity after spinal cord injury. Pain. 2000;85:287–9.CrossRefPubMedGoogle Scholar
  57. 57.
    Mironer YE, Tollison CD. Methadone in the intrathecal treatment of chronic nonmalignant pain resistant to other neuroaxial agents: the first experience. Neuromodulation. 2001;4:25–31.CrossRefPubMedGoogle Scholar
  58. 58.
    Kumar K, Kelly M, Pirlot T. Continuous intrathecal morphine treatment for chronic pain of nonmalignant etiology: long-term benefits and efficacy. Surg Neurol. 2001;55(2):79–86.CrossRefPubMedGoogle Scholar
  59. 59.
    Rogano L, Teixeira MJ, Lepski G. Chronic pain after spinal cord injury: clinical characteristics. Stereotact Funct Neurosurg. 2003;81:65–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Nuti C, Peyron R, Garcia-Larrea L, Brunon J, Laurent B, Sindou M, Mertens P. Motor cortex stimulation for refractory neuropathic pain: four year outcome and predictors of efficacy. Pain. 2005;118:43–52.CrossRefPubMedGoogle Scholar
  61. 61.
    Saulino M. Successful reduction of neuropathic pain associated with spinal cord injury via a combination of intrathecal hydromorphone and ziconotide: a case report. Spinal Cord. 2007;45:749–52.CrossRefPubMedGoogle Scholar
  62. 62.
    Shankar V, Kabazie A, Boyle A. Use of an implantable intrathecal morphine pump in the treatment of refractory pain caused by thalamic syndrome. J Pain. 2009;10:41 (A261).Google Scholar
  63. 63.
    Tsai MD, Wang ADJ, Wei CP, Tsai MC. Neuropathic pain following spinal cord trauma treated with cingulotomy: report of two cases. Eur J Pain. 2010;(Suppl 4):121 (A428).Google Scholar
  64. 64.
    Morishita T, Foote KD, Archer DB, Coombes SA, Vaillancourt DE, Hassan A, Haq IU, Wolf J, Okun MS. Smile without euphoria induced by deep brain stimulation: a case report. Neurocase. 2015;21:674–8.CrossRefPubMedGoogle Scholar
  65. 65.
    Belfrage M, Segerdahl M, Arner S, Sollevi A. The safety and efficacy of intrathecal adenosine in patients with chronic neuropathic pain. Anesth Analg. 1999;89:136–42.PubMedGoogle Scholar
  66. 66.
    Rauck RL, North J, Eisenach JC. Intrathecal clonidine and adenosine: effects on pain and sensory processing in patients with chronic regional pain syndrome. Pain. 2015;156:88–95.CrossRefPubMedGoogle Scholar
  67. 67.
    Horazeck C, Huh AS, Huh BK. Acute rhabdomyolysis in a patient with long-term exposure to intrathecal ziconotide: a case report. Pain Pract. 2015 Mar;15(3):E34–9.CrossRefPubMedGoogle Scholar
  68. 68.
    McDowell GC 2nd, Pope JE. Intrathecal Ziconotide: dosing and administration strategies in patients with refractory chronic pain. Neuromodulation. 2016;19:522–32.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Penn RD, Paice JA. Adverse effects associated with the intrathecal administration of ziconotide. Pain. 2000;85:291–6.CrossRefPubMedGoogle Scholar
  70. 70.
    Saulino M, Burton AW, Danyo DA, Frost S, Glanzer J, Solanki DR. Intrathecal ziconotide and baclofen provide pain relief in seven patients with neuropathic pain and spasticity: case reports. Eur J Phys Rehabil Med. 2009;45:61–7.PubMedGoogle Scholar
  71. 71.
    Voirin J, Darie I, Fischer D, Simon A, Rohmer-Heitz I, Proust F. Ziconotide intrathecal delivery as treatment for secondary therapeutic failure of motor cortex stimulation after 6 years. Neurochirurgie. 2016;62:284–8.CrossRefPubMedGoogle Scholar
  72. 72.
    Prusik J, Argoff C, Peng S, Pilitsis JG. Use of low dose Ziconotide as first-line Intrathecal Monotherapy. Neuromodulation. 2017 (in press).Google Scholar
  73. 73.
    Bonicalzi V, Canavero S. Intrathecal ziconotide for chronic pain. JAMA. 2004;13(292):1681–2.Google Scholar
  74. 74.
    Rauck RL, Wallace MS, Leong MS, Mineheart M, Webster LR, Charapata SG, Abraham JE, Buffington DE, Ellis D, Kartzinel R, the Ziconotide 301 Study Group. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manag. 2006;31:393–406.CrossRefGoogle Scholar
  75. 75.
    Wallace MS, Charapata SG, Fisher R, Byas-Smith M, Staats PS, Mayo M, McGuire D, Ellis D. The ziconotide nonmalignant pain study 96-002 group. Intrathecal ziconotide in the treatment of chronic nonmalignant pain: a randomized, double-blind, placebo-controlled clinical trial. Neuromodulation. 2006;9:75–86.CrossRefPubMedGoogle Scholar
  76. 76.
    Wallace MS, Rauck R, Fisher R, Charapata SG, Ellis D. Dissanayake S for the Ziconotide 98-022 study group. Intrathecal ziconotide for severe chronic pain: safety and tolerability results of an open-label, long term trial. Anesth Analg. 2008;106:628–37.CrossRefPubMedGoogle Scholar
  77. 77.
    Ellis DJ, Dissanayake S, McGuire D, Charapata SG, Staats PS, Wallace MS, Grove GW, Vercruysse P. The Elan study 95-002 group. Continuous intrathecal infusion of ziconotide for treatment of chronic malignant and nonmalignant pain over 12 months: a prospective, open-label study. Neuromodulation. 2008;11:40–9.CrossRefPubMedGoogle Scholar
  78. 78.
    Webster LR, Fisher R, Charapata S, Wallace MS. Long-term intrathecal ziconotide for chronic pain: an open label study. J Pain Symptom Manag. 2009;37:363–72.CrossRefGoogle Scholar
  79. 79.
    Sang CN, Barnabe KJ, Kern SE. Phase IA clinical trial evaluating the tolerability, pharmacokinetics, and analgesic efficacy of an Intrathecally administered Neurotensin a Analogue in central neuropathic pain following spinal cord injury. Clin Pharmacol Drug Dev. 2016;5(4):250–8.CrossRefPubMedGoogle Scholar
  80. 80.
    Taira T, Hori T. Intrathecal baclofen in the treatment of post-stroke central pain, dystonia, and persistent vegetative state. Acta Neurochir Suppl. 2007;97:227–9.PubMedGoogle 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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