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Inrathecal Drug Delivery What have we learned ?

Inrathecal Drug Delivery What have we learned ?. David L. Caraway, M.D., Ph.D. CEO, Medical Director Center for Pain Relief, Tri-State St. Mary’s Regional Medical Center Huntington, WV. Disclosure. I make my living providing medical services to patients

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Inrathecal Drug Delivery What have we learned ?

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  1. Inrathecal Drug DeliveryWhat have we learned? David L. Caraway, M.D., Ph.D. CEO, Medical Director Center for Pain Relief, Tri-State St. Mary’s Regional Medical Center Huntington, WV

  2. Disclosure I make my living providing medical services to patients Industry: Consulting, speaking, research Medtronic, Inc., Boston Scientific Inc., Spinal Modulation, Inc., Vertos Inc. Leadership NANS ASIPP

  3. Intrathecal Pumps Intrathecal drug delivery systems are not a “therapy.” They are a delivery system for a therapy. Opioids are the most commonly used intrathecal therapy. Three questions to explore: Is there any good evidence that opioids - regardless of the route of delivery – are safe and effective? What are the advantages and disadvantages of the intrathecal route of delivery? How can we improve outcomes?

  4. Short term efficacy Clear efficacy in multiple RCT’s (up to 8 months) demonstrate improvement in pain No evidence to support dosing of higher than 180 mg morphine equivalent per day Long term efficacy No PCRTs for longer than 8 months None for pump vs oral Overall evidence is weak Studies mostly look at VAS, little evidence of improved function Is Opioid Therapy Effective? Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med November 13, 2003;349:1943-53

  5. Dose Escalation Tolerance Physiological Opioid Induced Hyperalgesia Solid evidence in animal models Emerging clinical data Disease progression Perception Goals of therapy Comorbid psychological/behavioral pathology

  6. Side effects Dysphoria, constipation, urinary retention, somnolence, cognitive changes Immune and hormonal function Testosterone, estrogen, cortisol suppression, decreased libido, infertility (1) Addiction Social, psychological, physical and financial consequences Is Opioid Therapy Safe? 1. Lee C, et al. Low serum cortisol associated with opioid use: Case report and review of the literature. Endocrinologist 2002;12:5-8.

  7. U.S. with 4.6% of world’s population • Produces 80% of Lawyers • Consumes almost 30% of Global Oil supply (CIA) • Consumes 80% of Global Opioid supply Patricia Good, Divisionof Drug Diversion Control, DEA • Consumes 99% of Global Hydrocodone supply JAMA, 2007 • Fatal opioid overdoses tripled to nearly 14,000 deaths from 1999 to 2006 (CDC) • 2008 alone 305,885 ER visits related to opioids 7

  8. Intrathecal Opioids Advantages: Achieves steady-state, around the clock dosing Reduced side effects (1), Use of intermittent dosing to reduce tolerance Intrathecal Adjuvants Compliance Eliminate systemic opioids Can provide patient activated rescue dosing Reduction in longitudinal costs, diversion 1. Smith, T. J Clin Oncology, 2002

  9. Intrathecal Opioids Disadvantages: More invasive More difficult to discontinue therapy Acquisition costs If positioned as a salvage therapy for patients who have failed but remain on high dose systemic opioids outcomes are diminished Practice of David Caraway, MD. St. Mary’s Regional Medical Center Huntington, WV.

  10. Intrathecal Opioids Requires same strategies as systemic delivery Early titration to achieve analgesia and goals of therapy Careful consideration of dose increases Maintain moderate doses Monitor for side effects, efficacy IT adjuvants Physician remains in control of dosing Practice of David Caraway, MD. St. Mary’s Regional Medical Center Huntington, WV.

  11. QUALITY OF PAIN • Easy first choices for PUMP • Cancer • Diffuse pain, eg Rh. Arthritis • Elderly axial spinal pain • Good analgesia with systemic opioids but intolerable side effects Practice of David Caraway, MD. St. Mary’s Regional Medical Center Huntington, WV.

  12. QUALITY OF PAIN • Difficult choices for PUMP Minimal baseline pain with intermittent severe pain (PCA?) Poorly defined etiology Poor compliance to previous therapies Poor response to escalating doses of opioids Young age Practice of David Caraway, MD. St. Mary’s Regional Medical Center Huntington, WV.

  13. Goals of Therapy Create a treatment plan with specific goals eg: Manageable constipation Gardening, shopping, holding grandchildren Increased range of motion, ambulation Reduced hospital, ER visits

  14. Psychological Evaluation Consider recommendations and treat if indicated - prior to trial Ability to understand appropriate expectations Has patient come to terms with status, expected life span Is this someone you are willing to “marry”? Major active psychosis, current drug addiction, some personality disorders, cognitive deficits, progressive organic brain disorders, suicidal, homicidal behavior

  15. Dr. Caraway Know When To Quit

  16. And… When never to start!

  17. What are the goals of trialing? To increase the odds that the goals of therapy are met

  18. Continuous vs single shot and intermittent bolus Consistent with standard of care, however: Titration Interpreting adverse events Multiple procedures Does not model steady-state characteristics of intended therapy

  19. Continuous Epidural vs Continuous Intrathecal Screening Advantages Disadvantages Intrathecal More closely approximates Increased risk of:l pharmacodynamics of PDPH system to be implanted CSF leak Does not require epidural Serious infection space (fusion, mets) Overdose Neurological complication during placement Epidural May allow outpatient Less predictive? Management Risk of migration to SAS Extended trials Increased systemic uptake Less risks

  20. Use of Systemic Pain Medications with IDDS: CLBP Key Findings: While at 12 months 42% decreased or discontinued systemic opioids 58% had no change or increased n=136 Deer T, Chapple I, Classen A, 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.

  21. Are supplemental systemic opioids necessary? Methylnaltrexone data in treatment of opioid induced constipation (OIC)1 Blockade of peripheral mu receptors does not: change pain scores induce withdrawal increase opioid requirements 1. Slatkin N, Thomas J, Lipman AG. Methylnaltrexone for treatment of opiod-induced constipation in advanced illness patients. J Support Oncol. 2009 Jan-Feb;7(1):39-46

  22. Do we need oral opioids after pump implant? Vertebral Compression Fractures, N=24 Failed systemic opioids Compare before implant to one year follow up VAS, DW, ambulation, PHS Results None required systemic opioids All showed significant improvement and reduced side effects Neuromodulation Volume 10 Issue 2 Page 167-176, April 2007

  23. Intrathecal Opioid Safety “Mortality associated with implantation and management of intrathecal opioid drug infusion systems to treat noncancer pain.” Anesthesiology 2009 “…higher mortality than after spinal cord stimulation implants or after lumbar diskectomy in community hospitals.” Is this an appropriate comparator? Coffey R, Owens M, Broste S, et al. Mortality Associated with Implantation and Management of Intrathecal Opioid Drug Infusion Systems to Treat Noncancer Pain. Anasthesiology. 2009; 111:881-91

  24. Intrathecal Opioid Safety Excess morbidity/mortality not due to surgical complications No reports of device malfunctioning to cause overdose Respiratory arrest caused or contributed to cause of death in all cases Management issues Continued self-administered medications Lack of monitoring when initiating dose Coffey R, Owens M, Broste S, et al. Mortality Associated with Implantation and Management of Intrathecal Opioid Drug Infusion Systems to Treat Noncancer Pain. Anasthesiology. 2009; 111:881-91

  25. Compounding and polypharmacy “…clinical reports of inflammatory mass lesions and direct spinal cord toxicity that appear to have been caused by compounded and/or impure drugs, or the long-term administration of drug formulations not specifically tested and approved for chronic intrathecal use” • ↵Jones TF, Feler CA, Simmons BP, et al. Neurological complications including paralysis after a medication error involving implanted intrathecal catheters. ;:–6. • Levin GZ, Tabor DR. Paraplegia secondary to progressive necrotic myelopathy in a patient with an implantable morphine pump. ;:–6. • Knox S, Atkinson RP, Stephens R, et al. Myelopathy as a complication of intrathecal drug infusion systems. ;:–7.

  26. Polyanalgesia Consensus Conference 2007 Neuromodulation Vol 10 Issue 4 page 300 – 328 October 2007

  27. Recommended Maximum Intrathecal Dosages and Concentrations* * These represent general recommendations and are dependent upon the specific patient and the clinical experience of the physician and thus, maximum dosage and/or concentrations may vary from these. Neuromodulation Vol 10 Issue 4 page 300 – 328 October 2007

  28. Novel pump implant location

  29. An Approach Continuous infusion trial Consider an overnight observation for implant Start with lower than anticipated analgesic dose Discontinue systemic opioids Titrate to achieve goals within 6- 8 weeks of initiation of opioid therapy 20 – 30% dose increases Document attainment of goals

  30. An Approach Failure to achieve moderate stable dose warrants re-examination of treatment plan Trial of IT adjuvant while holding opioid dose steady Episodic pain and “rescue dosing” Reduction or discontinuation Surveillance Progression of disease Complications eg: IG, catheter failure

  31. Dosing “Micro Dosing” Discontinuation of oral opioids prior to trial Initiate opioid at low dose Maybe useful for highly opioid tolerant patients

  32. Drug target Posterior for pain drugs Several spinal segments sensitized Anatomical barriers to distribution Dorsal septum Dentate ligaments CSF effects Thoracic higher CSF velocities Lumbar less CSF movement Where to Place the Catheter Tip? Atlas of Human Anatomy 3rd ed. By Frank H. Netter, M.D.ICON Learning Systems, Tereboro, NJ

  33. Afferents enter into local dorsal horn and project rostral / caudal 4-6 segments Normal - Modest drive on neurons in distal segments Sensitization > Recruitment of adjacent afferent neurons and spinal segments Result> Often not a single pain or spasticity generator Ideally the drug would spread out over several vertebral segments. Drug targets: Chronic Pain Hydrophilic Drug Cervical Desired profile Thoracic Lipophilic Drug Lumbar _ _ _ _ _ Drug Concentration Sacrum

  34. Anatomy: Compartmentalization Dura Arachnoid Dorsal Septum Nerve Roots Dentate Ligaments Davson & Segal, Physiology of the CSF and Blood-Brain Barriers, 1996

  35. CSF Flow Does NOT simply flow rostral to caudal Does NOT flow down posterior and up anterior surface Protein, ionic and drug concentrations DO vary along spine and CSF – nonhomogeneous Atlas of Human Anatomy 3rd ed. By Frank H. Netter, M.D.ICON Learning Systems, Tereboro, NJ

  36. CSF Oscillates with Cardiac Cycle Davson & Segal, Physiology of the CSF and Blood-Brain Barriers, 1996

  37. Visualization of CSF Flow Cine MRI CSF oscillates more at high (rostral) vertebral levels compared to caudal levels Complex flow patterns C2 T1 T6 T10 T12 L2 Unpublished data; Hai Ying Liu, University of Minnesota

  38. Spinal Drug Distribution: CM Bernards Posterior T12 catheter 8 Hour infusion Infusion rates: 21ml/hr or 1ml/hr 3H-bupivacaine 14C-baclofen Baclofen – more hydrophilic;bupivicaine – more lipophilic CSF - Microdialysis probes Anterior and posterior T12 (0 cm), 5 cm caudal, 5 and 10 cm cephalad, cerebral (parietal lobe) Tissue - Spinal cord sections 1 cm segments Anterior and posterior Bernards CM, Anesthesiology, 105, Jul 2006, 169-178.

  39. CSF Bupivacaine Concentrations vs Flow Rate . • 21 ml/hr: 120-240 min to steady state (posterior vs anterior) • Regardless of flow – large difference in posterior vs anterior concentrations • High flow – drug distributes 5 cm from tip with less difference between posterior anterior Data also published in Bernards C.M. Anesthesiology. 2006 Jul;105(1):169-78.

  40. Spinal Tissue Drug Levels Cephalad N=8 • Low flow – narrow longitudinal distribution pattern vs. high flow – greater distribution (yellow bars) • Low flow – posterior to anterior ratio is large vs high flow narrow (blue arrows) Bernards CM, Anesthesiology, 105, Jul 2006, 169-178.

  41. Lack of Distribution with Slow Infusion Posterior catheter Methylene Blue 20 µl/hour 8 hours No anterior distribution Catheter Tip 1 cm Bernards CM, Anesthesiology, 105, Jul 2006, 169-178. Rostral

  42. Chronic Infusion in Ambulatory Pigs Does duration of infusion and normal movement and position changes make a difference in spinal drug distribution? • 14-day infusion of morphine • (1 mg/mL) at 20 μl/h • Rostral distribution ~ caudal distribution • Catheter tip ~ 9000 ng/g • vs. 10 cm 500 ng/g ~ 6% of tip levels • Qualitatively similar to 8-hr model: • Drug is highly concentrated near catheter tip (log scale) • Drug levels fall off rapidly with distance from tip • 8 hours vs 14 days • Drug levels are detectable 15 cm beyond catheter tip in spinal tissue after 14 days 9000 500 Flack SH, Anderson CM, Bernards CM: Anesthesia and Analgesia (In Press) 2010.

  43. Normalized: Slow vs. Fast Infusion vs. Bolus – Tissue Content Data published also in: Bernards C.M. Anesthesiology. 2006 Jul;105(1):169-78.

  44. Effect of IT Bolus Volume on Drug Efficacy Rat hind paw on heat source; measure latency of withdrawal Bolus equal dose of morphine as High volume / Low concentration (A) Low volume / High concentration (B) Place intrathecal catheter with tip at L6 (sciatic nerve entry zone) Low volume / High concentration had greatest effect Move catheter tip from L6 High volume /Low concentration had greatest effect A B _ _ _ _ _ Drug Concentration Frank H. Netter, M.D. et al., Nervous System vol 1, (1972), pp.49 Tony Yaksh, UCSD, unpublished data

  45. Conclusions CSF flow patterns vary along spinal canal CSF volume and local anatomy may be important CSF oscillations due to cardiac cycle Limited tissue distribution with slow infusion Flexible dosing using high-flow intermittent boluses may provide improved drug distribution

  46. Summary: Clinical Considerations • Catheter tip near level of pathology • Use higher flow rates and lower concentrations • Bolus dosing • Eliminate or reduce systemic opioids • Failure to achieve moderate stable dose warrants re- examination of treatment plan • Trial of adjuvant medications • Episodic pain and “bolus dosing” • Reduction or discontinuation • Surveillance • Progression of disease • Complications eg: IG, catheter failure

  47. Technical ability does not always assure attainment of goals

  48. THE END THANK YOU

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