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Intrathecal Analgesia for Chronic Refractory Pain: Current and Future Prospects

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Abstract

The intrathecal drug-delivery system (IDDS) is one mode of infusing analgesic medications directly into the cerebrospinal fluid in close proximity to their site of action. This modality has been employed in patients with refractory pain either due to malignant or non-malignant causes for over 30 years. Unfortunately, and despite the number of years it has been in use, there is still a scarcity of rigorous evidence to guide its integration into clinical practice. Current best evidence is inconclusive as to the comparative effectiveness and harms of the IDDS relative to routine medical care of patients. There are far more systematic reviews than high-quality primary comparative studies of the IDDS vs. conventional pain treatment. Existing clinical practice recommendations are best viewed as expert opinion with competing interests. This article will review the existing literature for indications, contraindications, consensus statements, different technologies, and complications of the IDDS. Although approved analgesics for IDDS delivery are limited to morphine and ziconotide, many other analgesics, alone or in combination, are routinely used in this setting. This review will also focus on the pharmacology, clinical efficacy, and safety of intrathecal medications extensively used in clinical practice; including agents approved, unapproved, and under development.

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References

  1. Phillips CJ, Harper C. The economics associated with persistent pain. Curr Opin Support Palliat Care. 2011;5(2):127–30.

    Article  PubMed  Google Scholar 

  2. Langley P, Muller-Schwefe G, Nicolaou A, Liedgens H, Pergolizzi J, Varrassi G. The societal impact of pain in the European Union: health-related quality of life and healthcare resource utilization. J Med Econ. 2010;13(3):571–81.

    Article  PubMed  Google Scholar 

  3. Lemay K, Wilson KG, Buenger U, Jarvis V, Fitzgibbon E, Bhimji K, et al. Fear of pain in patients with advanced cancer or in patients with chronic noncancer pain. Clin J Pain. 2011;27(2):116–24.

    Article  PubMed  Google Scholar 

  4. Reitsma ML, Tranmer JE, Buchanan DM, Vandenkerkhof EG. The prevalence of chronic pain and pain-related interference in the Canadian population from 1994 to 2008. Chronic Dis Inj Can. 2011;31(4):157–64.

    CAS  PubMed  Google Scholar 

  5. Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain. 2012;13(8):715–24.

    Article  PubMed  Google Scholar 

  6. International Association for the Study of Pain. Declaration that access to pain management is a fundamental human right. [Internet]. 2015. http://www.iasp-painorg/Advocacy/Content.aspx?ItemNumber=1821. Cited 30 Apr 2015.

  7. 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.

    CAS  PubMed  Google Scholar 

  8. Yaksh TL, Rudy TA. Analgesia mediated by a direct spinal action of narcotics. Science. 1976;192(4246):1357–8.

    Article  CAS  PubMed  Google Scholar 

  9. Jones TF, Feler CA, Simmons BP, Melton K, Craig AS, Moore WL, et al. Neurologic complications including paralysis after a medication error involving implanted intrathecal catheters. Am J Med. 2002;112(1):31–6.

    Article  PubMed  Google Scholar 

  10. Gourlay GK. Advances in opioid pharmacology. Support Care Cancer. 2005;13(3):153–9.

    Article  PubMed  Google Scholar 

  11. Kieffer BL, Gaveriaux-Ruff C. Exploring the opioid system by gene knockout. Prog Neurobiol. 2002;66(5):285–306.

    Article  CAS  PubMed  Google Scholar 

  12. Ansari M, Smyth C, Ahmadzai N, Coyle K, Brener S, Sandhu S et al. Intrathecal drug delivery systems for noncancer pain: an evidence-based analysis [under review].

  13. Ansari M, Smyth C, Ahmadzai N, Coyle K, Brener S, Alisic S et al. Intrathecal drug delivery systems for cancer pain: an evidence-based analysis [under review].

  14. Deer TR, Prager J, Levy R, Rathmell J, Buchser E, Burton A, 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.

    Article  PubMed  Google Scholar 

  15. Deer TR, Prager J, Levy R, Burton A, Buchser E, Caraway D, et al. Polyanalgesic Consensus Conference, 2012: recommendations on trialing for intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation. 2012;15(5):420–35.

    Article  PubMed  Google Scholar 

  16. Deer TR, Prager J, Levy R, Rathmell J, Buchser E, Burton A, et al. Polyanalgesic Consensus Conference—2012: consensus on diagnosis, detection, and treatment of catheter-tip granulomas (inflammatory masses). Neuromodulation. 2012;15(5):483–95.

    Article  PubMed  Google Scholar 

  17. Deer TR, Levy R, Prager J, Buchser E, Burton A, Caraway D, 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.

    Article  PubMed  Google Scholar 

  18. Prager J, Deer T, Levy R, Bruel B, Buchser E, Caraway D, et al. Best practices for intrathecal drug delivery for pain. Neuromodulation. 2014;17(4):354–72.

    Article  PubMed  Google Scholar 

  19. Falco FJ, Patel VB, Hayek SM, Deer TR, Geffert S, Zhu J et al. Intrathecal infusion systems for long-term management of chronic non-cancer pain: an update of assessment of evidence. Pain Physician. 2013;16(2 Suppl):SE185-SE216.

  20. Deer TR, Caraway DL, Wallace MS. A definition of refractory pain to help determine suitability for device implantation. Neuromodulation. 2014;17(8):711–5.

    Article  PubMed  Google Scholar 

  21. Stearns L, Boortz-Marx R, Du PS, Friehs G, Gordon M, Halyard M, et al. Intrathecal drug delivery for the management of cancer pain: a multidisciplinary consensus of best clinical practices. J Support Oncol. 2005;3(6):399–408.

    CAS  PubMed  Google Scholar 

  22. Kurita GP, Kaasa S, Sjogren P, European Palliative Care Research Collaborative (EPCRC). Spinal opioids in adult patients with cancer pain: a systematic review: a European Palliative Care Research Collaborative (EPCRC) opioid guidelines project. Palliat Med. 2011;25(5):560–77.

    Article  PubMed  Google Scholar 

  23. Myers J, Chan V, Jarvis V, Walker-Dilks C. Intraspinal techniques for pain management in cancer patients: a systematic review. Support Care Cancer. 2010;18(2):137–49.

    Article  PubMed  Google Scholar 

  24. Krames ES. Practical issues when using neuraxial infusion. Oncology (Williston). 1999;13(5 Suppl 2):37–44.

    CAS  Google Scholar 

  25. Krames ES. Intraspinal opioid therapy for chronic nonmalignant pain: current practice and clinical guidelines. J Pain Symptom Manage. 1996;11(6):333–52.

    Article  CAS  PubMed  Google Scholar 

  26. Ballantyne JC, Carr DB, Berkey CS, Chalmers TC, Mosteller F. Comparative efficacy of epidural, subarachnoid and intracerebroventricular opioids in patients with pain due to cancer (DARE structured abstract). Reg Anesth. 1996;21:542–56.

    CAS  PubMed  Google Scholar 

  27. Williams JE, Louw G, Towlerton G. Intrathecal pumps for giving opioids in chronic pain: a systematic review. Health Technol Assess Database. 2000;4:1.

    Google Scholar 

  28. Horlocker TT, Wedel DJ, Rowlingson JC, Enneking FK, Kopp SL, Benzon HT, et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (third edition). Reg Anesth Pain Med. 2010;35(1):64–101.

    Article  CAS  PubMed  Google Scholar 

  29. Jamison RN, Edwards RR. Pain control procedures: stimulators and intrathecal pumps. In: Block A, Sarwer D, editors. Presurgical psychological screening: understanding patients, improving outcomes. Washington DC: American Psychological Association; 2013. p. 85.

    Chapter  Google Scholar 

  30. Schatman M. Selection criteria for intrathecal opioid therapy: a re-examination of the “science”. Pract Pain Manag. 2005;5(1):1–9.

    Article  Google Scholar 

  31. Malhotra VT, Root J, Kesselbrenner J, Njoku I, Cubert K, Gulati A, et al. Intrathecal pain pump infusions for intractable cancer pain: an algorithm for dosing without a neuraxial trial. Anesth Analg. 2013;116(6):1364–70.

    Article  CAS  PubMed  Google Scholar 

  32. Kim D, Saidov A, Mandhare V, Shuster A. Role of pretrial systemic opioid requirements, intrathecal trial dose, and non-psychological factors as predictors of outcome for intrathecal pump therapy: one clinician’s experience with lumbar postlaminectomy pain. Neuromodulation. 2011;14(2):165–75.

    Article  PubMed  Google Scholar 

  33. Burton AW, Rajagopal A, Shah HN, Mendoza T, Cleeland C, Hassenbusch SJ, et al. Epidural and intrathecal analgesia is effective in treating refractory cancer pain. Pain Med. 2004;5(3):239–47.

    Article  PubMed  Google Scholar 

  34. Lin CP, Lin WY, Lin FS, Lee YS, Jeng CS, Sun WZ. Efficacy of intrathecal drug delivery system for refractory cancer pain patients: a single tertiary medical center experience. J Formos Med Assoc. 2012;111(5):253–7.

    Article  CAS  PubMed  Google Scholar 

  35. Duarte RV, Raphael JH, Sparkes E, Southall JL, LeMarchand K, Ashford RL. Long-term intrathecal drug administration for chronic nonmalignant pain. J Neurosurg Anesthesiol. 2012;24(1):63–70.

    Article  PubMed  Google Scholar 

  36. Lara NA Jr, Teixeira MJ, Fonoff ET. Long term intrathecal infusion of opiates for treatment of failed back surgery syndrome. Acta Neurochir Suppl. 2011;108:41–7.

    Article  PubMed  Google Scholar 

  37. 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.

    Article  PubMed  Google Scholar 

  38. Hassenbusch SJ, Stanton-Hicks M, Covington EC. Spinal cord stimulation versus spinal infusion for low back and leg pain. Acta Neurochir Suppl. 1995;64:109–15.

    Article  CAS  PubMed  Google Scholar 

  39. Hassenbusch SJ, Pillay PK, Magdinec M, Currie K, Bay JW, Covington EC, et al. Constant infusion of morphine for intractable cancer pain using an implanted pump. J Neurosurg. 1990;73(3):405–9.

    Article  CAS  PubMed  Google Scholar 

  40. Shetter AG, Hadley MN, Wilkinson E. Administration of intraspinal morphine sulfate for the treatment of intractable cancer pain. Neurosurgery. 1986;18(6):740–7.

    Article  CAS  PubMed  Google Scholar 

  41. Raphael JH, Duarte RV, Southall JL, Nightingale P, Kitas GD. Randomised, double-blind controlled trial by dose reduction of implanted intrathecal morphine delivery in chronic non-cancer pain. BMJ Open. 2013;3(7):1–9. doi:10.1136/bmjopen-2013-003061.

    Article  Google Scholar 

  42. Hamza M, Doleys D, Wells M, Weisbein J, Hoff J, Martin M, et al. Prospective study of 3-year follow-up of low-dose intrathecal opioids in the management of chronic nonmalignant pain. Pain Med. 2012;13(10):1304–13.

    Article  PubMed  Google Scholar 

  43. Rauck RL, Cherry D, Boyer MF, Kosek P, Dunn J, Alo K. Long-term intrathecal opioid therapy with a patient-activated, implanted delivery system for the treatment of refractory cancer pain. J Pain. 2003;4(8):441–7.

    Article  CAS  PubMed  Google Scholar 

  44. Valentino L, Pillay KV, Walker J. Managing chronic nonmalignant pain with continuous intrathecal morphine. J Neurosci Nurs. 1998;30(4):233–9, 243–4.

    Article  CAS  PubMed  Google Scholar 

  45. Medtronic for Healthcare Professionals. MRI information for SynchroMed II pump. [Internet]. 2015. http://professional.medtronic.com/pt/neuro/itb/fpi/mri-guidelines/index.htm. Cited 27 Apr 2015.

  46. De Andres J, Villanueva V, Palmisani S, Cerda-Olmedo G, Lopez-Alarcon MD, Monsalve V, et al. The safety of magnetic resonance imaging in patients with programmable implanted intrathecal drug delivery systems: a 3-year prospective study. Anesth Analg. 2011;112(5):1124–9.

    Article  PubMed  CAS  Google Scholar 

  47. Flowonix. After your procedure [Internet]. 2015. http://www.backpainonline.com/patientcare-giver/the-prometra-procedure/after-your-procedure. Cited 20 Oct 2015.

  48. Kosturakis A, Gebhardt R. SynchroMed II intrathecal pump memory errors due to repeated magnetic resonance imaging. Pain Physician. 2012;15(6):475–7.

    PubMed  Google Scholar 

  49. Wilkes D. Programmable intrathecal pumps for the management of chronic pain: recommendations for improved efficiency. J Pain Res. 2014;7:571–7.

    Article  PubMed Central  PubMed  Google Scholar 

  50. Medtronic. SynchroMed II. Infusion system patient manual. [Internet]. 2015. http://www.medtronic.com/wcm/groups/mdtcom_sg/@mdt/@neuro/documents/documents/synch-ii-8637-pat-manual.pdf. Cited 28 Apr 2015.

  51. Gebhardt R, Ludwig M, Kirsner S, Kisling K, Kosturakis AK. Implanted intrathecal drug delivery systems and radiation treatment. Pain Med. 2013;14(3):398–402.

    Article  PubMed  Google Scholar 

  52. Brant JM. The use of access devices in cancer pain control. Semin Oncol Nurs. 1995;11(3):203–12.

    Article  CAS  PubMed  Google Scholar 

  53. Bottros MM, Christo PJ. Current perspectives on intrathecal drug delivery. J Pain Res. 2014;7:615–26.

    PubMed Central  PubMed  Google Scholar 

  54. Turner JA, Sears JM, Loeser JD. Programmable intrathecal opioid delivery systems for chronic noncancer pain: a systematic review of effectiveness and complications (DARE structured abstract). Clin J Pain. 2007;23:180–95.

    Article  PubMed  Google Scholar 

  55. SynchroMed II Programmable Infusion Pump. [Internet]. 2015. http://professional.medtronic.com/pt/neuro/itb/prod/synchromed-ii/#VTfTrK3BzGc. Cited 28 Apr 2015.

  56. Arrambide J. Prometra post-approval study. [Internet]. 2015. https://clinicaltrials.gov/show/NCT01854229. Cited 8 Jan 2015.

  57. Rauck R, Deer T, Rosen S, Padda G, Barsa J, Dunbar E, et al. Accuracy and efficacy of intrathecal administration of morphine sulfate for treatment of intractable pain using the Prometra® Programmable Pump. Neuromodulation. 2010;13(2):102–8.

    Article  PubMed  Google Scholar 

  58. Jackson TP, Lonergan DF, Todd RD, Martin PR. Intentional intrathecal opioid detoxification in 3 patients: characterization of the intrathecal opioid withdrawal syndrome. Pain pract. 2013;13(4):297–309.

    Article  PubMed  Google Scholar 

  59. Winkelmuller M, Winkelmuller W. Long-term effects of continuous intrathecal opioid treatment in chronic pain of nonmalignant etiology. J Neurosurg. 1996;85(3):458–67.

    Article  CAS  PubMed  Google Scholar 

  60. Ferrante FM. Neuraxial infusion in the management of cancer pain. Oncology (Williston). 1999;13(5 Suppl 2):30–6.

    CAS  Google Scholar 

  61. Engle MP, Vinh BP, Harun N, Koyyalagunta D. Infectious complications related to intrathecal drug delivery system and spinal cord stimulator system implantations at a comprehensive cancer pain center. Pain Physician. 2013;16(3):251–7.

    PubMed  Google Scholar 

  62. Byers K, Axelrod P, Michael S, Rosen S. Infections complicating tunneled intraspinal catheter systems used to treat chronic pain. Clin Infect Dis. 1995;21(2):403–8.

    Article  CAS  PubMed  Google Scholar 

  63. Holmfred A, Vikerfors T, Berggren L, Gupta A. Intrathecal catheters with subcutaneous port systems in patients with severe cancer-related pain managed out of hospital: the risk of infection. J Pain Symptom Manage. 2006;31(6):568–72.

    Article  PubMed  Google Scholar 

  64. Roberts LJ, Finch PM, Goucke CR, Price LM. Outcome of intrathecal opioids in chronic non-cancer pain. Eur J Pain. 2001;5(4):353–61.

    Article  CAS  PubMed  Google Scholar 

  65. Brogan SE. Intrathecal therapy for the management of cancer pain. Curr Pain Headache Rep. 2006;10(4):254–9.

    Article  PubMed  Google Scholar 

  66. Nitescu P, Sjoberg M, Appelgren L, Curelaru I. Complications of intrathecal opioids and bupivacaine in the treatment of “refractory” cancer pain. Clin J Pain. 1995;11(1):45–62.

    Article  CAS  PubMed  Google Scholar 

  67. Bican O, Minagar A, Pruitt AA. The spinal cord: a review of functional neuroanatomy. Neurol Clin. 2013;31(1):1–18.

    Article  PubMed  Google Scholar 

  68. Hodgson PS, Neal JM, Pollock JE, Liu SS. The neurotoxicity of drugs given intrathecally (spinal). Anesth Analg. 1999;88(4):797–809.

    CAS  PubMed  Google Scholar 

  69. Hocking G, Wildsmith JA. Intrathecal drug spread. Br J Anaesth. 2004;93(4):568–78.

    Article  CAS  PubMed  Google Scholar 

  70. Perruchoud C, Eldabe S, Durrer A, Bovy M, Brookes M, Madzinga G, 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.

    Article  PubMed  Google Scholar 

  71. Osman H. Neuraxial opioids. Alex J Anaesth Intensiv Care. 2015;9(2):1–3.

    Google Scholar 

  72. US Food and Drug Administration. Medtronic drug infusion pumps: recall—intermittent or permanent pump motor stall. [Internet]. 2015. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm333251.htm. Cited 11 May 2015.

  73. Hassenbusch SJ, Portenoy RK, Cousins M, Buchser E, Deer TR, Du Pen SL, et al. Polyanalgesic Consensus Conference 2003: an update on the management of pain by intraspinal drug delivery—report of an expert panel. J Pain Symptom Manag. 2004;27(6):540–63.

    Article  Google Scholar 

  74. 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.

    Article  CAS  PubMed  Google Scholar 

  75. Medi-Span. Trissel's IV-Chek™ API v3.1. [Internet]. http://www.medispan.com/trissels-iv-chek-api/. Accessed 13 Oct 2015.

  76. Frawley G, Smith KR, Ingelmo P. Relative potencies of bupivacaine, levobupivacaine, and ropivacaine for neonatal spinal anaesthesia. Br J Anaesth 2009;103(5):731–8.

    Article  CAS  PubMed  Google Scholar 

  77. Mercadante S, Intravaia G, Villari P, Ferrera P, Riina S, David F, et al. Intrathecal treatment in cancer patients unresponsive to multiple trials of systemic opioids. Clin J Pain. 2007;23(9):793–8.

    Article  PubMed  Google Scholar 

  78. 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.

    Article  PubMed  Google Scholar 

  79. Smith TJ, Coyne PJ, Staats PS, Deer T, Stearns LJ, Rauck RL, et al. An implantable drug delivery system (IDDS) for refractory cancer pain provides sustained pain control, less drug-related toxicity, and possibly better survival compared with comprehensive medical management (CMM). Ann Oncol. 2005;16(5):825–33.

    Article  CAS  PubMed  Google Scholar 

  80. Gilmer-Hill HS, Boggan JE, Smith KA, Frey CF, Wagner FC Jr, Hein LJ. Intrathecal morphine delivered via subcutaneous pump for intractable pain in pancreatic cancer. Surg Neurol. 1999;51(1):6–11.

    Article  CAS  PubMed  Google Scholar 

  81. 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.

    Article  PubMed  Google Scholar 

  82. Yaksh TL, Hassenbusch S, Burchiel K, Hildebrand KR, Page LM, Coffey RJ. Inflammatory masses associated with intrathecal drug infusion: a review of preclinical evidence and human data. Pain Med. 2002;3(4):300–12.

    Article  PubMed  Google Scholar 

  83. Deer TR. A prospective analysis of intrathecal granuloma in chronic pain patients: a review of the literature and report of a surveillance study. Pain Physician. 2004;7(2):225–8.

    PubMed  Google Scholar 

  84. Gock SB, Wong SH, Stormo KA, Jentzen JM. Self-intoxication with morphine obtained from an infusion pump. J Anal Toxicol. 1999;23(2):130–3.

    Article  CAS  PubMed  Google Scholar 

  85. Guy J, Hindman BJ, Baker KZ, Borel CO, Maktabi M, Ostapkovich N, et al. Comparison of remifentanil and fentanyl in patients undergoing craniotomy for supratentorial space-occupying lesions. Anesthesiology. 1997;86(3):514–24.

    Article  CAS  PubMed  Google Scholar 

  86. 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.

    Article  CAS  PubMed  Google Scholar 

  87. Brown J, Klapow J, Doleys D, Lowery D, Tutak U. Disease-specific and generic health outcomes: a model for the evaluation of long-term intrathecal opioid therapy in noncancer low back pain patients. Clin J Pain. 1999;15(2):122–31.

    Article  CAS  PubMed  Google Scholar 

  88. 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.

    Article  CAS  PubMed  Google Scholar 

  89. Deer T, Chapple I, Classen A, Javery K, Stoker V, Tonder L, et al. Intrathecal drug delivery for treatment of chronic low back pain: report from the National Outcomes Registry for Low Back Pain. Pain Med. 2004;5(1):6–13.

    Article  PubMed  Google Scholar 

  90. Backryd E, Larsson B. Movement-evoked breakthrough cancer pain despite intrathecal analgesia: a prospective series. Acta Anaesthesiol Scand. 2011;55(9):1139–46.

    Article  CAS  PubMed  Google Scholar 

  91. Duse G, Davia G, White PF. Improvement in psychosocial outcomes in chronic pain patients receiving intrathecal morphine infusions. Anesth Analg. 2009;109(6):1981–6.

    Article  CAS  PubMed  Google Scholar 

  92. Du Pen S, Du PA, Hillyer J. Intrathecal hydromorphone for intractable nonmalignant pain: a retrospective study. Pain Med. 2006;7(1):10–5.

    Article  PubMed  Google Scholar 

  93. 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.

    Article  PubMed  Google Scholar 

  94. Goucke CR, Dusci LJ, Van LS, Fairclough D, Ilett KF. Stability and tolerability of high concentrations of intrathecal bupivacaine and opioid mixtures in chronic noncancer pain: an open-label pilot study. Pain Med. 2010;11(11):1612–8.

    Article  PubMed  Google Scholar 

  95. Kumar K, Bodani V, Bishop S, Tracey S. Use of intrathecal bupivacaine in refractory chronic nonmalignant pain. Pain Med. 2009;10(5):819–28.

    Article  PubMed  Google Scholar 

  96. 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.

    Article  PubMed  Google Scholar 

  97. Dahm P, Lundborg C, Janson M, Olegard C, Nitescu P. Comparison of 0.5 % intrathecal bupivacaine with 0.5 % intrathecal ropivacaine in the treatment of refractory cancer and noncancer pain conditions: results from a prospective, crossover, double-blind, randomized study. Reg Anesth Pain Med. 2000;25(5):480–7.

    CAS  PubMed  Google Scholar 

  98. van Dongen RT, Crul BJ, 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):166–72.

    Article  PubMed  Google Scholar 

  99. 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. 2002;5(4):208–13.

    Article  PubMed  Google Scholar 

  100. Baaijens PF, Dongen RT, Crul BJ. Intrathecal midazolam for the treatment of chronic mechanical low back pain: a randomized double-blind placebo-controlled study [abstract]. Br J Anaesth. 1995;74(Suppl 1):143.

    Google Scholar 

  101. 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.

    Article  PubMed  Google Scholar 

  102. van Dongen RT, Crul BJ, De BM. 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.

    Article  PubMed  Google Scholar 

  103. Kuthiala G, Chaudhary G. Ropivacaine: a review of its pharmacology and clinical use. Indian J Anaesth. 2011;55(2):104–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Carrillo-Ruiz JD, Andrade P, Godinez-Cubillos N, Montes-Castillo ML, Jimenez F, Velasco AL, et al. Coupled obturator neurotomies and lidocaine intrathecal infusion to treat bilateral adductor spasticity and drug-refractory pain. J Neurosurg. 2010;113(3):528–31.

    Article  PubMed  Google Scholar 

  105. Mercadante S, Villari P, Ferrera P, Arcuri E. Local anesthetic switching for intrathecal tachyphylaxis in cancer patients with pain. Anesth Analg. 2003;97(1):187–9 (table).

    Article  CAS  PubMed  Google Scholar 

  106. Elia N, Culebras X, Mazza C, Schiffer E, Tramer MR. Clonidine as an adjuvant to intrathecal local anesthetics for surgery: systematic review of randomized trials. Reg Anesth Pain Med. 2008;33(2):159–67.

    CAS  PubMed  Google Scholar 

  107. Engelman E, Marsala C. Efficacy of adding clonidine to intrathecal morphine in acute postoperative pain: meta-analysis. Br J Anaesth. 2013;110(1):21–7.

    Article  CAS  PubMed  Google Scholar 

  108. Ackerman LL, Follett KA, Rosenquist RW. Long-term outcomes during treatment of chronic pain with intrathecal clonidine or clonidine/opioid combinations. J Pain Symptom Manag. 2003;26(1):668–77.

    Article  CAS  Google Scholar 

  109. Bevacqua BK, Fattouh M, Backonja M. Depression, night terrors, and insomnia associated with long-term intrathecal clonidine therapy. Pain Pract. 2007;7(1):36–8.

    Article  PubMed  Google Scholar 

  110. Hassenbusch SJ, Gunes S, Wachsman S, Willis KD. Intrathecal clonidine in the treatment of intractable pain: a phase I/II study. Pain Med. 2002;3(2):85–91.

    Article  PubMed  Google Scholar 

  111. Liu H-J, Gao X-Z, Liu X-M, Xia M, Li W-Y, Jin Y. Effect of intrathecal dexmedetomidine on spinal morphine analgesia in patients with refractory cancer pain. J Palliat Med. 2014;17(7):837–40.

    Article  PubMed  Google Scholar 

  112. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2012;11:CD003351. doi:10.1002/14651858.CD003351.pub2.

    PubMed  Google Scholar 

  113. Newsome S, Frawley BK, Argoff CE. Intrathecal analgesia for refractory cancer pain. Curr Pain Headache Rep. 2008;12(4):249–56.

    Article  PubMed  Google Scholar 

  114. Vranken JH, Troost D, de Haan P, Pennings FA, van der Vegt MH, Dijkgraaf MG, et al. Severe toxic damage to the rabbit spinal cord after intrathecal administration of preservative-free S(+)-ketamine. Anesthesiology. 2006;105(4):813–8.

    Article  CAS  PubMed  Google Scholar 

  115. Vranken JH, Troost D, Wegener JT, Kruis MR, van der Vegt MH. Neuropathological findings after continuous intrathecal administration of S(+)-ketamine for the management of neuropathic cancer pain. Pain. 2005;117(1–2):231–5.

    Article  CAS  PubMed  Google Scholar 

  116. Hocking G, Cousins MJ. Ketamine in chronic pain management: an evidence-based review (DARE structured abstract). Anesth Analg. 2003;97:1730–9.

    Article  CAS  PubMed  Google Scholar 

  117. Wermeling D, Drass M, Ellis D, Mayo M, McGuire D, O’Connell D, et al. Pharmacokinetics and pharmacodynamics of intrathecal ziconotide in chronic pain patients. J Clin Pharmacol. 2003;43(6):624–36.

    Article  CAS  PubMed  Google Scholar 

  118. Staats PS, Yearwood T, Charapata SG, Presley RW, Wallace MS, Byas-Smith M, 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.

    Article  CAS  PubMed  Google Scholar 

  119. Rauck RL, Wallace MS, Leong MS, Minehart M, Webster LR, Charapata SG, et al. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manag. 2006;31(5):393–406.

    Article  CAS  Google Scholar 

  120. Wallace MS, Charapata SG, Fisher R, Byas-Smith M, Staats PS, Mayo M, 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.

    Article  PubMed  Google Scholar 

  121. Pope JE, Deer TR. Intrathecal pharmacology update: novel dosing strategy for intrathecal monotherapy ziconotide on efficacy and sustainability. Neuromodulation. 2015 (epub ahead of print).

  122. Rauck R, Coffey RJ, Schultz DM, Wallace MS, Webster LR, McCarville SE, et al. Intrathecal gabapentin to treat chronic intractable noncancer pain. Anesthesiology. 2013;119(3):675–86.

    Article  PubMed  Google Scholar 

  123. Paice JA, Penn RD, Kroin JS. Intrathecal octreotide for relief of intractable nonmalignant pain: 5-year experience with two cases. Neurosurgery. 1996;38(1):203–7.

    Article  CAS  PubMed  Google Scholar 

  124. Long JB. Spinal subarachnoid injection of somatostatin causes neurological deficits and neuronal injury in rats. Eur J Pharmacol. 1988;149(3):287–96.

    Article  CAS  PubMed  Google Scholar 

  125. Deer TR, Penn R, Kim CK, Bowman RG, Norris M, Stewart CD, et al. The use of continuous intrathecal infusion of octreotide in patients with chronic pain of noncancer origin: An evaluation of efficacy in a prospective double-blind fashion. Neuromodulation. 2006;9(4):284–9.

    Article  PubMed  Google Scholar 

  126. Bader P, Echtle D, Fonteyne V, Livadas K, De Meerleer G, Paez Borda A et al. Guidelines on pain managment. [Report]. pp. 1–92. 2010. European Association of Urology.

  127. Hammond DL. J.J. Bonica lecture—2001: role of spinal GABA in acute and persistent nociception. Reg Anesth Pain Med. 2001;26(6):551–7.

    CAS  PubMed  Google Scholar 

  128. 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(1):132–6.

    Article  CAS  PubMed  Google Scholar 

  129. Lind G, Meyerson BA, Winter J, Linderoth B. Intrathecal baclofen as adjuvant therapy to enhance the effect of spinal cord stimulation in neuropathic pain: a pilot study. Eur J Pain. 2004;8(4):377–83.

    Article  CAS  PubMed  Google Scholar 

  130. Sciubba DM, Lin LM, Conway JE, Bydon A, Gokaslan ZL, Kebaish K. Development of scoliosis following intrathecally placed opioid pump for chronic low back pain. Spine. 2007;32(24):E718–22.

    Article  PubMed  Google Scholar 

  131. Watve SV, Sivan M, Raza WA, Jamil FF. Management of acute overdose or withdrawal state in intrathecal baclofen therapy. Spinal Cord. 2012;50(2):107–11.

    Article  CAS  PubMed  Google Scholar 

  132. Cardoso AL, Quintaneiro C, Seabra H, Teixeira C. Cardiac arrest due to baclofen withdrawal syndrome. BMJ Case Rep. 2014.

  133. Edwards M, Serrao JM, Gent JP, Goodchild CS. On the mechanism by which midazolam causes spinally mediated analgesia. Anesthesiology. 1990;73(2):273–7.

    Article  CAS  PubMed  Google Scholar 

  134. Yaksh TL, Allen JW. The use of intrathecal midazolam in humans: a case study of process. Anesth Analg. 2004;98(6):1536–45.

    Article  PubMed  Google Scholar 

  135. Schoeffler P, Auroy P, Bazin JE, Taxi J, Woda A. Subarachnoid midazolam: histologic study in rats and report of its effect on chronic pain in humans. Reg Anesth. 1991;16(6):329–32.

    CAS  PubMed  Google Scholar 

  136. 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.

    Article  CAS  PubMed  Google Scholar 

  137. Morr S, Heard CM, Li V, Reynolds RM. Dexmedetomidine for acute baclofen withdrawal. Neurocrit Care. 2015;22(2):288–92.

    Article  CAS  PubMed  Google Scholar 

  138. 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(1):136–42.

    CAS  PubMed  Google Scholar 

  139. Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of intrathecal neostigmine methylsulfate in humans. Anesthesiology. 1995;82(2):331–43.

    Article  CAS  PubMed  Google Scholar 

  140. Lauretti GR. The evolution of spinal/epidural neostigmine in clinical application: thoughts after two decades. Saudi J Anaesth. 2015;9(1):71–81.

    Article  PubMed Central  PubMed  Google Scholar 

  141. Rijsdijk M, van Wijck AJ, Kalkman CJ, Yaksh TL. The effects of glucocorticoids on neuropathic pain: a review with emphasis on intrathecal methylprednisolone acetate delivery. Anesth Analg. 2014;118(5):1097–112.

    Article  CAS  PubMed  Google Scholar 

  142. Moberg-Wolff E. Potential clinical impact of compounded versus noncompounded intrathecal baclofen. Arch Phys Med Rehabil. 2009;90(11):1815–20.

    Article  PubMed  Google Scholar 

  143. Centers for Disease Control and Prevention (CDC). Exophiala infection from contaminated injectable steroids prepared by a compounding pharmacy—United States, July–November 2002. MMWR Morb Mortal Wkly Rep. 2002;51(49):1109–12.

    Google Scholar 

  144. Hayes C, Jordan MS, Hodson FJ, Ritchard L. Ceasing intrathecal therapy in chronic non-cancer pain: an invitation to shift from biomedical focus to active management. PLoS One. 2012;7(11):e49124.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  145. MedtronicNeuro. Post-market study of intrathecal morphine compared to conventional medical management for pain control and improvement of opioid-related side effects (CONVERT TDD). [Intenet]. 2015. https://clinicaltrials.gov/show/NCT01924182. Cited 8 Jan 2015.

  146. Erdeck M. Standard pain control or intrathecal therapy in controlling pain in patients with locally advanced, unresectable, or metastatic pancreatic cancer. [Internet]. 2015. https://clinicaltrials.gov/show/NCT00660348. Cited 8 Jan 2015.

  147. MedtronicNeuro. etPost-market Study of Intrathecal Morphine Compared to Conventional Medical Management for Pain Control and Improvement of Opioid-related Side Effects (CONVERT TDD). [Internet]. 2015. https://clinicaltrials.gov/ct2/show/NCT01924182. Cited 29 Apr 2015.

  148. Mamet J, Klukinov M, Yaksh TL, Malkmus SA, Williams S, Harris S, et al. Single intrathecal administration of the transcription factor decoy AYX1 prevents acute and chronic pain after incisional, inflammatory, or neuropathic injury. Pain. 2014;155(2):322–33.

    Article  CAS  PubMed  Google Scholar 

  149. Holzer P. The pharmacological challenge to tame the transient receptor potential vanilloid-1 (TRPV1) nocisensor. Br J Pharmacol. 2008;155(8):1145–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  150. Smith R. Resiniferatoxin to treat severe pain associated with advanced cancer. [Interent]. 2015. https://clinicaltrials.gov/show/NCT00804154. Cited 8 Jan 2015.

  151. Sorrento Therapeutics Inc. Resiniferatoxin to treat severe pain associated with advanced cancer. [Internet]. 2015. https://clinicaltrials.gov/ct2/show/NCT00804154. Cited 29 Apr 2015.

  152. 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.

    Article  CAS  PubMed  Google Scholar 

  153. Karai L, Brown DC, Mannes AJ, Connelly ST, Brown J, Gandal M, et al. Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control. J Clin Invest. 2004;113(9):1344–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  154. Brown DC, Agnello K, Iadarola MJ. Intrathecal resiniferatoxin in a dog model: efficacy in bone cancer pain. Pain. 2015;156(6):1018–24.

    PubMed  Google Scholar 

  155. Bevan S, Quallo T, Andersson DA. TRPV1. Handb Exp Pharmacol. 2014;222:207–45.

    Article  CAS  PubMed  Google Scholar 

  156. Lewis RJ, Dutertre S, Vetter I, Christie MJ. Conus venom peptide pharmacology. Pharmacol Rev. 2012;64(2):259–98.

    Article  CAS  PubMed  Google Scholar 

  157. Lewis RJ. Discovery and development of the chi-conopeptide class of analgesic peptides. Toxicon. 2012;59(4):524–8.

    Article  CAS  PubMed  Google Scholar 

  158. Kern SE, Allen J, Wagstaff J, Shafer SL, Yaksh T. The pharmacokinetics of the conopeptide contulakin-G (CGX-1160) after intrathecal administration: an analysis of data from studies in beagles. Anesth Analg. 2007;104(6):1514–20 (table).

    Article  CAS  PubMed  Google Scholar 

  159. Wermeling D, Drass M, Ellis D, Mayo M, McGuire D, O’Connell D, et al. Pharmacokinetics and pharmacodynamics of intrathecal ziconotide in chronic pain patients. J Clin Pharmacol. 2003;43(6):624–36.

    Article  CAS  PubMed  Google Scholar 

  160. Guyatt GH, Oxman AD, Schunemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol. 2011;64(4):380–2.

    Article  PubMed  Google Scholar 

  161. Dean MM, Cellarius V, Henry B, Oneschuk D, Librach Canadian Society Of Palliative Care Physicians Taskforce SL. Framework for continuous palliative sedation therapy in Canada. J Palliat Med. 2012;15(8):870–9.

    Article  PubMed  Google Scholar 

  162. Kurita GP, Benthien KS, Nordly M, Mercadante S, Klepstad P, Sjogren P. The evidence of neuraxial administration of analgesics for cancer-related pain: a systematic review. Acta Anaesthesiol Scand 2015;59(9):1103–15.

    Article  CAS  PubMed  Google Scholar 

  163. 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.

    PubMed  Google Scholar 

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Acknowledgments

The Ottawa Hospital Anesthesia Alternate Funds Association provided support to prepare this article. The authors would like to thank the Centre for Practice Changing Research at the Ottawa Hospital Research Institute, Mr. Raymond Daniel, Mr. Danny Jenkins, and Dr. Gregory Bryson for their advice and assistance preparing the article for publication.

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Authors and Affiliations

  1. Department of Anesthesiology, University of Ottawa and Ottawa Hospital Research Institute, The Ottawa Hospital—General Campus, 501 Smyth Rd., CCW 1551, Ottawa, ON, K1H 8L6, Canada

    Catherine Smyth

  2. Knowledge Synthesis Group, Ottawa Hospital Research Institute, Ottawa, ON, Canada

    Nadera Ahmadzai

  3. Department of Pharmacy, The Ottawa Hospital, Ottawa, ON, Canada

    Jason Wentzell & Tiffany Nguyen

  4. Department of Anesthesiology, University of Ottawa, The Ottawa Hospital—General Campus, 501 Smyth Rd., CCW 1551, Ottawa, ON, K1H 8L6, Canada

    Ashley Pardoe, Andrew Tse, Yvette Goddard & Shona Nair

  5. Departments of Anesthesiology and Psychology, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada

    Patricia A. Poulin

  6. Ottawa, Canada

    Becky Skidmore

  7. Faculty of Medicine, School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, ON, Canada

    Mohammed T. Ansari

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  1. Catherine Smyth
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Correspondence to Catherine Smyth.

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Conflict of interest

In 2012–13, the University of Ottawa received unrestricted donations from Medtronic Inc., Reckitt Benckiser, and Purdue Pharma to devote to The Ottawa Hospital Pain Clinic’s knowledge translation projects for primary care entitled “PainConnect” and “AddictionConnection”. Dr. Smyth is the medical lead and principal investigator on these projects. None of the other authors have a conflict of interest to declare.

Funding

The Ottawa Hospital Anesthesia Alternate Funds Association (TOHAAFA) supported Dr. Catherine Smyth’s non-clinical time used to work on this article. TOHAAFA also supported several research staff from the Centre for Practice Changing Research at the Ottawa Hospital Research Institute to assist with the preparation of the article (e.g., search strategy, article retrieval, article screening using Distiller SR, obtaining author permissions to reproduce tables/figures, and preparation of references).

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Smyth, C., Ahmadzai, N., Wentzell, J. et al. Intrathecal Analgesia for Chronic Refractory Pain: Current and Future Prospects. Drugs 75, 1957–1980 (2015). https://doi.org/10.1007/s40265-015-0471-1

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