Intrathecal Pharmacology

  • Lucas W. Campos


Intrathecal therapy (IT) is a vital component in the treatment of moderate to severe refractory cancer or noncancer pain. Knowledge and clinical experience using targeted intrathecal drug delivery have continued to grow as evidenced in the writings of the Polyanalgesic Consensus Conference (PACC). The distinguished authors of the PACC guidelines point out that IT is not a salvage therapy for high-dose opioid failure and recommend earlier IT trials for appropriate patient populations. They emphasize that treatment should be based on disease indications with known mechanisms so that appropriate drug selection can take place. Currently, there are only two FDA-approved medications for IT: morphine and ziconotide. Use of other medications such as bupivacaine, clonidine, and baclofen to treat chronic pain states is off-label. This chapter focuses on the pharmacokinetics, pharmacodynamics, and evidence for use of these and other medications in the intrathecal space. Current research continues to explore both new medications and medication combinations with the aim of improving patient safety and sustainable outcomes.


Intrathecal therapy Targeted drug delivery Pharmacodynamics Pharmacokinetics Cerebrospinal fluid 

Recommended Reading

  1. 1.
    Abrahams M, Higgins P, Whyte P, Breen P, Muttu S, Gardiner J. Intact proprioception and control of labour pain during epidural analgesia. Acta Anaesthesiol Scand. 1999;43(1):46–50.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Åkerman B, Arweström E, Post C. Local anesthetics potentiate spinal morphine Antinociception. Anesthesia & Analgesia. 1988;67(10):943.Google Scholar
  3. 3.
    Allen JW, Horais KA, Tozier NA, Yaksh TL. Opiate pharmacology of intrathecal granulomas. Anesthesiology. 2006;105(3):590–8.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Artru AA. CSF dynamics, cerebral edema and intracranial pressure. In: Textbook of neuroanesthesia: with neurosurgical and neuroscience perspectives. New York: McGraw-Hill; 1997. p. 61–115.Google Scholar
  5. 5.
    Atli A, Theodore BR, Turk DC, Loeser JD. Intrathecal opioid therapy for chronic nonmalignant pain: a retrospective cohort study with 3-year follow-up. Pain Med. 2010;11(7):1010–6.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Balédent O, Henry-Feugeas MC, Idy-Peretti I. Cerebrospinal fluid dynamics and relation with blood flow: a magnetic resonance study with semiautomated cerebrospinal fluid segmentation. Invest Radiol. 2001;36(7):368–77.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Behar M, Magora F, Olshwang D, Davidson JT. Epidural morphine in treatment of pain. Lancet. 1979;1(8115):527–9.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Belverud S, Mogilner A, Schulder M. Intrathecal pumps. Neurotherapeutics. 2008;5(1):114–22.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Berg A, Barsa J, Deer T, et al. Efficacy of morphine sulfate infusion via the Prometra® intrathecal infusion pump. A prospective multicenter evaluation: 5th World Congress Institute of Pain; 2009.Google Scholar
  10. 10.
    Bernards CM. Understanding the physiology and pharmacology of epidural and intrathecal opioids. Best Pract Res Clin Anaesthesiol. 2002;16(4):489–505.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Bernards CM. Recent insights into the pharmacokinetics of spinal opioids and the relevance to opioid selection. Curr Opin Anaesthesiol. 2004;17(5):441–7.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Bernards CM. Cerebrospinal fluid and spinal cord distribution of baclofen and bupivacaine during slow intrathecal infusion in pigs. Anesthesiology. 2006;105(1):169–78.CrossRefGoogle Scholar
  13. 13.
    Bhadelia RA, Bogdan AR, Kaplan RF, Wolpert SM. Cerebrospinal fluid pulsation amplitude and its quantitative relationship to cerebral blood flow pulsations: a phase-contrast MR flow imaging study. Neuroradiology. 1997;39(4):258–64.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Boswell MV, Iacono RP, Guthkelch AN. Sites of action of subarachnoid lidocaine and tetracaine: observations with evoked potential monitoring during spinal cord stimulator implantation. Reg Anesth. 1992;17(1):37–42.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Brill S, Gurman GM, Fisher A. A history of neuraxial administration of local analgesics and opioids. Eur J Anaesthesiol. 2003;20(9):682–9.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Brown DC, Agnello K, Iadarola MJ. Intrathecal resiniferatoxin in a dog model: efficacy in bone cancer pain. Pain. 2015;156(6):1018–24.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Calthorpe N. The history of spinal needles: getting to the point. Anaesthesia. 2004;59(12):1231–41.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389(6653):816–24.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Coffey RJ, Owens ML, Broste SK, et al. Mortality associated with implantation and management of intrathecal opioid drug infusion systems to treat noncancer pain. Anesthesiology. 2009;111(4):881–91.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Coffey RJ, Owens ML, Broste SK, et al. Medical practice perspective: identification and mitigation of risk factors for mortality associated with intrathecal opioids for non-cancer pain. Pain Med. 2010;11(7):1001–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Cohen SP, Dragovich A. Intrathecal analgesia. Anesthesiol Clin. 2007;25(4):863–82, viii.PubMedCrossRefGoogle Scholar
  22. 22.
    Corning JL. Local anaesthesia in general medicine and surgery. D. Appleton; 1886.Google Scholar
  23. 23.
    Covino BG. The pharmacology of local anesthetic agents. In: Stanley TH, Clayton Petty W, editors. Anesthesiology 1986. Developments in critical care medicine and anesthesiology: Springer Netherlands; 1986. p. 6–10.Google Scholar
  24. 24.
    Dahm P, Nitescu P, Appelgren L, Curelaru I. Efficacy and technical complications of long-term continuous intraspinal infusions of opioid and/or bupivacaine in refractory nonmalignant pain: a comparison between the epidural and the intrathecal approach with externalized or implanted catheters and infusion pumps. Clin J Pain. 1998;14(1):4–16.PubMedCrossRefGoogle Scholar
  25. 25.
    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(1):81–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Deer TR. A critical time for practice change in the pain treatment continuum: we need to reconsider the role of pumps in the patient care algorithm. Pain Med. 2010;11(7):987–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Deer TR. History of intrathecal drug delivery. In: Atlas of implantable therapies for pain management. New York: Springer; 2011. p. 139–41.CrossRefGoogle Scholar
  28. 28.
    Deer TR, Pope JE. Factors to consider in the choice of intrathecal drug in the treatment of neuropathic pain. Expert Rev Clin Pharmacol. 2015;8(5):507–10.PubMedCrossRefGoogle Scholar
  29. 29.
    Deer TR, Serafini M, Buchser E, Ferrante FM, Hassenbusch SJ. Intrathecal bupivacaine for chronic pain: a review of current knowledge. Neuromodulation. 2002;5(4):196–207.PubMedCrossRefGoogle Scholar
  30. 30.
    Deer TR, Caraway DL, Kim CK, Dempsey CD, Stewart CD, McNeil KF. Clinical experience with intrathecal bupivacaine in combination with opioid for the treatment of chronic pain related to failed back surgery syndrome and metastatic cancer pain of the spine. Spine J. 2002;2(4):274–8.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Deer TR, Kim C, Bowman R, Tolentino D, Stewart C, Tolentino W. Intrathecal ziconotide and opioid combination therapy for noncancer pain: an observational study. Pain Physician. 2009;12(4):E291–6.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Deer TR, Krames E, Levy RM, Hassenbusch SJ 3rd, Prager JP. Practice choices and challenges in the current intrathecal therapy environment: an online survey. Pain Med. 2009;10(2):304–9.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Deer TR, Smith HS, Cousins M, et al. Consensus guidelines for the selection and implantation of patients with noncancer pain for intrathecal drug delivery. Pain Physician. 2010;13(3):E175–213.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Deer TR, Prager J, Levy R, et al. Polyanalgesic consensus conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation. 2012;15(5):436–64; discussion 464–466.CrossRefGoogle Scholar
  35. 35.
    Deer TR, Levy R, Prager J, et al. Polyanalgesic Consensus Conference--2012: recommendations to reduce morbidity and mortality in intrathecal drug delivery in the treatment of chronic pain. Neuromodulation. 2012;15(5):467–82; discussion 482.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    van der Plas AA, Marinus J, Eldabe S, Buchser E, van Hilten JJ. The lack of efficacy of different infusion rates of intrathecal baclofen in complex regional pain syndrome: a randomized, double-blind, crossover study. Pain Med. 2011;12(3):459–65.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    van Dongen RTM, Crul BJP, van Egmond J. Intrathecal Coadministration of Bupivacaine Diminishes Morphine Dose Progression During Long-term Intrathecal Infusion in Cancer Patients. Clin J Pain. 1999;15(3):166.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Du Pen S, Du Pen A, Hillyer J. Intrathecal hydromorphone for intractable nonmalignant pain: a retrospective study. Pain Med. 2006;7(1):10–5.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Duarte RV, Raphael JH, Southall JL, Baker C, Hanu-Cernat D. Intrathecal inflammatory masses: is the yearly opioid dose increase an early indicator? Neuromodulation. 2010;13(2):109–13.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Feng X, Zhang F, Dong R, et al. Intrathecal administration of clonidine attenuates spinal neuroimmune activation in a rat model of neuropathic pain with existing hyperalgesia. Eur J Pharmacol. 2009;614(1-3):38–43.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Fukushima S, Takenami T, Yagishita S, Nara Y, Hoka S, Okamoto H. Neurotoxicity of intrathecally administered fentanyl in a rat spinal model. Pain Med. 2011;12(5):717–25.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Ghafoor VL, Epshteyn M, Carlson GH, Terhaar DM, Charry O, Phelps PK. Intrathecal drug therapy for long-term pain management. Am J Health Syst Pharm. 2007;64(23):2447–61.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Goldstein A, Lowney LI, Pal BK. Stereospecific and nonspecific interactions of the morphine congener levorphanol in subcellular fractions of mouse brain. Proc Natl Acad Sci U S A. 1971;68(8):1742–7.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Greenberg HS, Taren J, Ensminger WD, Doan K. Benefit from and tolerance to continuous intrathecal infusion of morphine for intractable cancer pain. J Neurosurg. 1982;57(3):360–4.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Grider JS, Harned ME, Etscheidt MA. Patient selection and outcomes using a low-dose intrathecal opioid trialing method for chronic nonmalignant pain. Pain Physician. 2011;14(4):343–51.Google Scholar
  46. 46.
    Hayek SM, Hanes MC. Intrathecal therapy for chronic pain: current trends and future needs. Curr Pain Headache Rep. 2014;18(1):388.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Hayek SM, Joseph PN, Mekhail NA. Pharmacology of intrathecally administered agents for treatment of spasticity and pain. Seminars in Pain Medicine. 2003;1(4):238–53.CrossRefGoogle Scholar
  48. 48.
    Hayek SM, Deer TR, Pope JE, Panchal SJ, Patel VB. Intrathecal therapy for cancer and non-cancer pain. Pain Physician. 2011;14(3):219–48.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Hayek SM, Veizi IE, Narouze SN, Mekhail N. Age-dependent intrathecal opioid escalation in chronic noncancer pain patients. Pain Med. 2011;12(8):1179–89.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Herz A, Teschemacher HJ. Activities and sites of antinociceptive action of morphine-like analgesics and kinetics of distribution following intravenous, intracerebral and intraventricular application. Adv Drug Res. 1971;6:79–119.Google Scholar
  51. 51.
    Hildebrand KR, Elsberry DD, Deer TR. Stability, compatibility, and safety of intrathecal bupivacaine administered chronically via an implantable delivery system. Clin J Pain. 2001;17(3):239–44.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Hoederath P, Gautschi OP, Land M, Hildebrandt G, Fournier JY. Formation of two consecutive intrathecal catheter tip granulomas within nine months. Cent Eur Neurosurg. 2010;71(1):39–42.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Holzer P. The pharmacological challenge to tame the transient receptor potential vanilloid-1 (TRPV1) nocisensor. Br J Pharmacol. 2008;155(8):1145–62.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Hsu Y, Hettiarachchi HDM, Zhu DC, Linninger AA. The frequency and magnitude of cerebrospinal fluid pulsations influence intrathecal drug distribution: key factors for interpatient variability. Anesth Analg. 2012;115(2):386–94.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Johansen MJ, Satterfield WC, Baze WB, Hildebrand KR, Gradert TL, Hassenbusch SJ. Continuous intrathecal infusion of hydromorphone: safety in the sheep model and clinical implications. Pain Med. 2004;5(1):14–25.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Karai L, Brown DC, Mannes AJ, et al. Deletion of vanilloid receptor 1_expressing primary afferent neurons for pain control. J Clin Invest. 2004;113(9):1344–52.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Kongkam P, Wagner DL, Sherman S, et al. Intrathecal narcotic infusion pumps for intractable pain of chronic pancreatitis: a pilot series. Am J Gastroenterol. 2009;104(5):1249–55.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Krames ES. Intrathecal infusional therapies for intractable pain: patient management guidelines. J Pain Symptom Manage. 1993;8(1):36–46.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Krames ES, Olson K. Clinical realities and economic considerations: patient selection in intrathecal therapy. J Pain Symptom Manage. 1997;14(3 Suppl):S3–S13.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Krashin DL, Merrill JO, Trescot AM. Opioids in the management of HIV-related pain. Pain Physician. 2012;15(3 Suppl):ES157–68.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Kroin JS. Intrathecal drug administration. Clin Pharmacokinet. 1992;22(5):319–26.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Kumar K, Hunter G, Demeria DD. Treatment of chronic pain by using intrathecal drug therapy compared with conventional pain therapies: a cost-effectiveness analysis. J Neurosurg. 2002;97(4):803–10.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Kumar K, Bodani V, Bishop S, Tracey S. Use of intrathecal bupivacaine in refractory chronic nonmalignant pain. Pain Med. 2009;10(5):819–28.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Li DF, Bahar M, Cole G, Rosen M. Neurological toxicity of the subarachnoid infusion of bupivacaine, lignocaine or 2-chloroprocaine in the rat. Br J Anaesth. 1985;57(4):424–9.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Lundborg C, Dahm P, Nitescu P, Biber B. High intrathecal bupivacaine for severe pain in the head and neck. Acta Anaesthesiol Scand. 2009;53(7):908–13.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Mironer YE, Haasis JC, Chapple I, Brown C, Satterthwaite JR. Efficacy and safety of intrathecal opioid/bupivacaine mixture in chronic nonmalignant pain: a double blind, randomized, crossover, multicenter study by the National Forum of Independent Pain Clinicians (NFIPC). Neuromodulation Technol Neural Interface. 2002;5(4):208–13.CrossRefGoogle Scholar
  67. 67.
    Netter FH. Atlas of human anatomy. Elsevier Health Sciences; 2010.Google Scholar
  68. 68.
    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(1):17–28.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    North RA. Drug receptors and the inhibition of nerve cells. Br J Pharmacol. 1989;98(1):13–28.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    North RB, Cutchis PN, Epstein JA, Long DM. Spinal cord compression complicating subarachnoid infusion of morphine: case report and laboratory experience. Neurosurgery. 1991;29(5):778–84.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Onofrio BM, Yaksh TL, Arnold PG. Continuous low-dose intrathecal morphine administration in the treatment of chronic pain of malignant origin. Mayo Clin Proc. 1981;56(8):516–20.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Papisov MI, Belov VV, Gannon KS. Physiology of the intrathecal bolus: the leptomeningeal route for macromolecule and particle delivery to CNS. Mol Pharm. 2013;10(5):1522–32.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Patel VB, Manchikanti L, Singh V, Schultz DM, Hayek SM, Smith HS. Systematic review of intrathecal infusion systems for long-term management of chronic non-cancer pain. Pain Physician. 2009;12(2):345–60.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Penn RD, Paice JA. Chronic intrathecal morphine for intractable pain. J Neurosurg. 1987;67(2):182–6.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Perruchoud C, Eldabe S, Durrer A, et al. Effects of flow rate modifications on reported analgesia and quality of life in chronic pain patients treated with continuous intrathecal drug therapy. Pain Med. 2011;12(4):571–6.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science. 1973;179(4077):1011–4.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Pope JE, Deer TR. Ziconotide: a clinical update and pharmacologic review. Expert Opin Pharmacother. 2013;14(7):957–66.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Pope JE, Deer TR, Bruel BM, Falowski S. Clinical uses of intrathecal therapy and its placement in the pain care algorithm. Pain Pract. 2016; Scholar
  79. 79.
    Prager J, Deer T, Levy R, et al. Best practices for intrathecal drug delivery for pain. Neuromodulation. 2014;17(4):354–72; discussion 372.CrossRefGoogle Scholar
  80. 80.
    Rainov NG, Heidecke V, Burkert W. Long-term intrathecal infusion of drug combinations for chronic back and leg pain. J Pain Symptom Manage. 2001;22(4):862–71.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Ramsey CN, Owen RD, Witt WO, Grider JS. Intrathecal granuloma in a patient receiving high dose hydromorphone. Pain Physician. 2008;11(3):369–73.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Rauck RL, Wallace MS, Leong MS, et al. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage. 2006;31(5):393–406.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Reig E, Abejón D. Continuous morphine infusion: a retrospective study of efficacy, safety, and demographic variables. Neuromodulation. 2009;12(2):122–9.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Rennels ML, Blaumanis OR, Grady PA. Rapid solute transport throughout the brain via paravascular fluid pathways. Adv Neurol. 1990;52:431–9.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Resiniferatoxin to Treat Severe Pain Associated with Advanced Cancer – Full Text View – Accessed 13 Sept 2017.
  86. 86.
    Saltari MR, Shaladi A, Piva B, et al. The management of pain from collapse of osteoporotic vertebrae with continuous intrathecal morphine infusion. Neuromodulation. 2007;10(2):167–76.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Schmidtko A, Lötsch J, Freynhagen R, Geisslinger G. Ziconotide for treatment of severe chronic pain. Lancet. 2010;375(9725):1569–77.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Scott DB, McClure JH, Giasi RM, Seo J, Covino BG. Effects of concentration of local anaesthetic drugs in extradural block. Br J Anaesth. 1980;52(10):1033–7.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Sjoberg M, Nitescu P, Appelgren L, Curelaru L. Long-term intrathecal morphine and bupivacaine in patients with refractory cancer pain-results from a morphine-bupivacaine dose regimen of 0.5/4.75 mg/ml. Anesthesiology. 1994;80(2):284–97.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Staats PS, Yearwood T, Charapata SG, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA. 2004;291(1):63–70.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Stockman HW. Effect of anatomical fine structure on the flow of cerebrospinal fluid in the spinal subarachnoid space. J Biomech Eng. 2006;128(1):106–14.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Tobias G, Sands RP Jr, Bacon DR. Continuous spinal anesthesia: a continuous history? Reg Anesth Pain Med. 1999;24(5):453–7.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Tuohy CEB. Costinuous spinal anesthesiaits usefitiisess and technic involved. Anesthesiology. 1944;5(2):142–8.CrossRefGoogle Scholar
  94. 94.
    Uhle EI, Becker R, Gatscher S, Bertalanffy H. Continuous intrathecal clonidine administration for the treatment of neuropathic pain. Stereotact Funct Neurosurg. 2000;75(4):167–75.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Ummenhofer WC, Arends RH, Shen DD, Bernards CM. Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil. Anesthesiology. 2000;92(3):739–53.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Van Dongen RT, Crul BJ, De Bock M. Long-term intrathecal infusion of morphine and morphine/bupivacaine mixtures in the treatment of cancer pain: a retrospective analysis of 51 cases. Pain. 1993;55(1):119–23.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Veizi IE, Hayek SM, Narouze S, Pope JE, Mekhail N. Combination of intrathecal opioids with bupivacaine attenuates opioid dose escalation in chronic noncancer pain patients. Pain Med. 2011;12(10):1481–9.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Waara-Wolleat KL, Hildebrand KR, Stewart GR. A review of intrathecal fentanyl and Sufentanil for the treatment of chronic pain. Pain Med. 2006;7(3):251–9.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Wagemans MF, van der Valk P, Spoelder EM, Zuurmond WW, de Lange JJ. Neurohistopathological findings after continuous intrathecal administration of morphine or a morphine/bupivacaine mixture in cancer pain patients. Acta Anaesthesiol Scand. 1997;41(8):1033–8.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Wallace MS, Charapata SG, Fisher R, et al. Intrathecal ziconotide in the treatment of chronic nonmalignant pain: a randomized, double-blind, placebo-controlled clinical trial. Neuromodulation. 2006;9(2):75–86.CrossRefGoogle Scholar
  101. 101.
    Wallace MS, Rauck R, Fisher R, et al. Intrathecal ziconotide for severe chronic pain: safety and tolerability results of an open-label, long-term trial. Anesth Analg. 2008;106(2):628–37, table of contents.PubMedCrossRefGoogle Scholar
  102. 102.
    Wallace MS, Kosek PS, Staats P, Fisher R, Schultz DM, Leong M. Phase II, open-label, multicenter study of combined intrathecal morphine and ziconotide: addition of ziconotide in patients receiving intrathecal morphine for severe chronic pain. Pain Med. 2008;9(3):271–81.PubMedCrossRefGoogle Scholar
  103. 103.
    Webster LR, Fakata KL, Charapata S, Fisher R, MineHart M. Open-label, multicenter study of combined intrathecal morphine and ziconotide: addition of morphine in patients receiving ziconotide for severe chronic pain. Pain Med. 2008;9(3):282–90.PubMedCrossRefGoogle Scholar
  104. 104.
    Webster LR, Fisher R, Charapata S, Wallace MS. Long-term intrathecal ziconotide for chronic pain: an open-label study. J Pain Symptom Manage. 2009;37(3):363–72.PubMedCrossRefGoogle Scholar
  105. 105.
    Wermeling DP. Ziconotide, an intrathecally administered N-type calcium channel antagonist for the treatment of chronic pain. Pharmacotherapy. 2005;25(8):1084–94.PubMedCrossRefGoogle Scholar
  106. 106.
    Wermeling D, Drass M, Ellis D, et al. Pharmacokinetics and pharmacodynamics of intrathecal ziconotide in chronic pain patients. J Clin Pharmacol. 2003;43(6):624–36.PubMedCrossRefGoogle Scholar
  107. 107.
    Yaksh TL, Rudy TA. Analgesia mediated by a direct spinal action of narcotics. Science. 1976;192(4246):1357–8.PubMedCrossRefGoogle Scholar
  108. 108.
    Yaksh TL, Jessell TM, Gamse R, Mudge AW, Leeman SE. Intrathecal morphine inhibits substance P release from mammalian spinal cord in vivo. Nature. 1980;286(5769):155–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Yaksh TL, Horais KA, Tozier NA, et al. Chronically infused intrathecal morphine in dogs. Anesthesiology. 2003;99(1):174–87.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Lucas W. Campos
    • 1
  1. 1.Interventional Pain PhysiciansChicoUSA

Personalised recommendations