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Intrathecal Therapy: The Age Factor

Intrathecal Therapy: The Age Factor. Salim Hayek, MD, PhD Division of Pain Medicine University Hospitals Case Medical Center. Related Conflicts of Interest. Research/Fellowship Support Medtronic. Learning Objectives. Indications for Intrathecal Therapy Pharmacokinetics of Intrathecal Meds

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Intrathecal Therapy: The Age Factor

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  1. Intrathecal Therapy:The Age Factor Salim Hayek, MD, PhD Division of Pain Medicine University Hospitals Case Medical Center

  2. Related Conflicts of Interest • Research/Fellowship Support • Medtronic

  3. Learning Objectives • Indications for Intrathecal Therapy • Pharmacokinetics of Intrathecal Meds • Cancer vs. Non-Cancer Pain • The Effect of Age

  4. Indications and Theory of Intrathecal Analgesia • Pain • Intractable • Uncontrolled with oral agents • Significant side effects with oral agents • The intrathecal route • Bypasses the blood brain barrier • Compared to the epidural route • higher rates of satisfactory pain relief • lower rates of treatment failures • lower rates of technical complications E. Krames. Intraspinal Opioid Therapy for Chronic Nonmalignant Pain: Current Practice and Clinical Guidelines. JPSM 1996;11(6):333-352.

  5. Krames E. Med Clin North Am. 1999;83:787-808

  6. Pain Management:A More Flexible Approach • Different time frames • Multiple therapies at one time • Different starting points Corrective surgery Complementary medicine, behavioral programs, adjuvant meds Long-term oral opioids Intrathecal therapy orneurostimulation Physical therapy, TENS NSAIDs, over-the-counter drugs Chronic Pain Patient Neuroablation Prager J and Jacobs M. Evaluation of patients for implantable pain modalities: medical and behavioral assessment. Clin J Pain. 2001 Sep;17(3):206-14.

  7. Intrathecal Therapy for Pain: Patient Selection • Objective evidence of pathology • Failure to achieve adequate resultsfrom oral opioid therapy • Inability to tolerate the side effectsof oral opioids • Psychological evaluation • Age? Krames E. Journal of Pain and Symptom Management;1996, Vol 11, No 6: 333-352

  8. IDDS Trial Procedure • Final step in patient selection: patient’sresponse to the opioid during a screening test • Several Methods of Trial • Single bolus • Multiple injections • Continuous infusion • Patients who experience 50% or greaterpain relief, generally are candidates forpermanent implant Krames E. Journal of Pain and Symptom Management;1996, Vol 11, No 6: 333-352

  9. Pharmacological Considerations • Receptors for the agents have to be at the spinal level • Drug considerations • Lipid solubility • Density and baricity • Bolus vs. continuous • Location of catheter/receptors

  10. Opioids Clonidine Ziconotide Bupivacaine Synapses Mechanism of Action--IT • CSF ~ ISF • Most receptors are in the substantia gelatinosa 1-2 mm from surface of dorsal horn • Hydrophilic>Hydrophobic • Longer ½ life • Deeper penetration • Smaller volume of distribution • Rostral spread Kroin JS. Clin.Pharmacokinet. 22:319-326, 1992 Nordberg G. Acta Anaesthesiol.Scand.Suppl 79:1-38, 1984

  11. Bupivacaine Opioids Clonidine Ziconotide

  12. Pharmacokinetics-lipophilicity • Moderately hydrophilic agents (such as morphine, baclofen or clonidine)  concentration gradient in the CNS whereby the cisternal CSF drug concentration is 1/3 to 1/7 that in the lumbar CSF • Much lower supratentorial effects Kroin JS et al: The distribution of medication along the spinal canal after chronic intrathecal administration. Neurosurgery 33:226-230, 1993

  13. Morphine • Receptors in the substantia gelatinosa • Only FDA approved opioid for ITP • IT MSO4a higher concentration in the cerebrospinal fluid (CSF) compared to epidural administration • Lower volume of distribution (70 ml) • Lower vascular absorption Hayek, S., P. Joseph and N. Mekhail (2004) Pharmacology of Intrathecally administered agents for the treatment of pain and spasticity. Seminars in Pain Medicine 1(4):238-253

  14. Reduce Dose – Reduce Side Effects • 1 mg intrathecal morphine = 300 mg oral morphine Krames ES. J Pain Symptom Manage. 1996 Jun;11(6):333-52.

  15. IT MSO4--Myth • Administration of low doses of intrathecal opiates will eliminate the problems associated with high oral or parenteral doses • Similar to oral opioids, problems with tolerance, pruritus, sedation and respiratory depression occur with intrathecal administration especially in patients with chronic benign pain

  16. Unique IT Opioid Side Effects • Pruritus: IT>>oral or parenteral • Intrathecal granuloma (at the tip of intrathecal catheters) is a serious complication that can occur with chronic intrathecal opioid infusions • Opioid-induced hyperalgesia • R/O granuloma • Peripheral edema • hypogonadotrophic hypogonadism, central hypocorticism and growth hormone deficiency Hayek, S. et al., Seminars in Pain Medicine 1(4):238-253

  17. IT Opioid Dose Escalation Paice J et al., Paice et al., J Pain Symptom Manage 11, 1996

  18. Cancer Pain Smith TJ. J Clin Oncol. 2002 Oct 1;20(19):4040-9

  19. Cancer-Related Pain Studies: Limited by Survival • 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):441-447 • Of the 119 patients implanted, 15 made it to 13 months

  20. IT Granuloma • Typical histopathology • Macrophages, neutrophils and monocytes • Necrotic center • No evidence of infectious process • Granulation tissue

  21. American Jouranal of Roentgenology 2007; 189: W375-W381.

  22. Contrast-enhanced sagittal T1-weighted American Journal of Roentgenology 2007; 189: W375-W381.

  23. Deer T. et al. (2007), Neuromodulation 10 (4): 300-328

  24. Dose Recommendations Deer T. et al. (2007), Neuromodulation 10 (4): 300-328

  25. Predictive Value of Trialing Dominguez E et al., Pain Practice, Volume 2, Number 4, 2002 315–325

  26. Predictive Value of Trialing Dominguez E et al., Pain Practice, Volume 2, Number 4, 2002 315–325

  27. Gender Dominguez E et al., Pain Practice, Volume 2, Number 4, 2002 315–325

  28. Age

  29. Influence of age on the effect of reference analgesics in rats (mechanical threshold) British Journal of Pharmacology (2002) 137, 813 - 820

  30. Influence of age on the effect of reference analgesics in rats (thermal threshold) British Journal of Pharmacology (2002) 137, 813 - 820

  31. Wang Y et al., Anesth Analg. 2005 Jun;100(6):1733-9

  32. Wang Y et al., Anesth Analg. 2005 Jun;100(6):1733-9

  33. Wang Y et al., Anesth Analg. 2005 Jun;100(6):1733-9

  34. Wang Y et al., Anesth Analg. 2005 Jun;100(6):1733-9

  35. Age as an Outcome Factor? CCF IDDS Implants 2000-2006  171 Patients Excluded 13 12 11 Malignancy ITB No opioids  135 Patients

  36. Patient Population

  37. Indications for implant

  38. Pain Relief

  39. Opioid Doses

  40. Age Effect

  41. Age Effect

  42. NRS Scores

  43. Age Effect

  44. Oral Opioid Dose

  45. Age Effect

  46. * p<0.001 * p<0.05 p<0.055 IT Opioid Dose

  47. Conclusions • Judicial application of intrathecal infusion therapies can be helpful in the management of cancer and non-cancer related pain • Thorough understanding of the pharmacology and physiology is crucial to ensure optimal outcomes • Age may be an important consideration in algorithmic management of patient with IDDS in non-cancer pain

  48. Thank You

  49. 60 patients D dose (D12m-D0)/D0 *100 * D0= dose at implant date * * Paired t test demonstrates a significant difference IT med used at the last recorded treatment (and 3m, 6m) vs implant date. T value -2.9611282427 P value 0.0072151033 Degrees of Freedom 22

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