Principles and Practice of Intraspinal Drug Infusion for Chronic Pain

1. Principles and Practice of Intraspinal Drug Infusion for Chronic Pain Richard K. Osenbach, M.D. Director of Neurosciences and Neurosurgery Cape Fear Valley Health System Fayetteville, NC

2. History of Opiate Analgesia • 1901 - intrathecal injection of morphine • 1915 - antagonist of morphine discovered • 1951 - 1st human use of morphine antagonists • 1976 - 1st use of IT morphine in animals • 1980 - spinal morphine used for cancer pain

3. Spinal Opiate Analgesia • Discovery of CNS opiate receptors • Identification of endogenous opiate peptides • Isolation of receptors

4. Endogenous Opioid Peptides • Proopiomelanocortin (POMC) • Endorphins • Beta-lipotropin • Proenkephalin A • Met-enkephalin, leu-enkephalin • Other enkephalins, peptide E • Prodynorphin • dynorphin A & B • neoendorphins ( and )

5. Opioid Receptors and Ligands

6. Mu Receptor • Defined by affinity for morphine • Less affinity for other receptor subtypes • Most clinically important opioids selective for Mu receptor • Cross react at higher doses • 1 - supraspinal 2 – spinal • Most analgesic effects of systemic morphine mediated through 1 effects • 70% located pre-synaptically

7. Morphine • High affinity for the Mu receptor • 50x less affinity for delta receptor • Minimal affinity for kappa, hORL1 receptor • Most physiological effects through action at Mu receptor • Non-Mu effects with very high doses • No evidence fo Mu-Delta cross tolerance

8. Opioid Recptor Physiology • G-protein-coupled receptor family • Synthesized in DRG • Second messenger using camp • Negative coupling • Inhibit camp via Gi-protein •  And  - opening of K+ channels •  - Closing of ca2+

9. Opioid Receptor Physiology •  And  - opening of K+ channels •  - Closing of ca2+

10. Opiate Receptors • Distributed pre- and post-synaptically • High affinity binding • Binding stereospecific • Optimal binding in ph range 7-8

11. Opioid RecetorsAnalgesia • Dorsal horn • Lamina I • Substantia gelatinosa • Brainstem • Nucleus caudalis • Supraspinal • PAG • Medial and intralaminar thalamic nuclei • Striatum

12. Opioid RecptorsAutonomic Effects • Cough suppression, orthostatic hypotension • Nucleus tractus solitarius and ambiguous, locus ceruleus • Respiratory depression • Nucleus tractus solitarius, parabrachial nucleus • Nausea/vomiting • Area postrema • Meiosis • Superior colliculus, pretectal nuclei

13. Opioid ReceptorsMiscellaneous Effects • Endocrine effects • Posterior pituitary – inhibition of vasopressin • Hormonal effects – hypothalamic infundibulum • Behavioral effects • Amygdala, hippocampus, nucleus accumbuns, basal ganglia • Motor rigidity • Striatum

14. Actions of Spinal Opiates • Application to spinal cord produces rapid and potent analgesia • Reduction in activity in spinal projection neurons in lamina V • Increases latency of pain behavior responses in animals • Effects reversed with naloxone

15. Spinal Opiate AnalgesiaPre-synaptic Actions • Presynaptic action at neuron terminals • C-fiber terminal zones in lamina I & II • Receptors synthesized in DRG • rhizotomy - 70% reduction • Activation - inhibition of nerve terminal • Reduction in transmitter release • tachykinins, excitatory AA, SP • Opening of K+ channels • Closing of ca+2 channels

16. Spinal Opiate AnalgesiaPost-synaptic Actions • Receptors on neuronal cell body or dendritic projections • Post-synaptic hyperpolarization • identical ionic mechanisms • Reduction in evoked electrical activity • 25% Mu and Delta receptors located on neurons • Requires higher doses of systemic morphine • eg. A-fiber mediated allodynia

17. Spinal Opiate AnalgesiaDisinhibitory Effect • Indirect post-synaptic action involving 3 neuron circuit • Enkephalin neurons in SG • GABA effect • Inhibition of inhibitory interneuron • Increased activity of second inhibitory interneuron (release from inhibition) • Depression of activity in output neurons

18. Supraspinal Descending Modulation 1) wall: transection of spinal cord results in increased activity of lamina V neurons to noxious input  Bulbospinal pathway exerts tonic inhibitory control on nociceptive neurons 2) stimulation of specific brainstem sites produces a highly specific suppression of the responses to noxious stimuli that is reversed by monoamine receptor antagonists 3) discreet lesions of the DLF block the inhibitory effects of stimulation-produced analgesia 4) microinjection of local anesthetics into the NRM blocks stimulation-produced analgesia from PAG stimulation

19. Descending Modulation

20. Rationale for IT Drug Delivery Provide high concentration of drug at the site of interaction with spinal receptors and minimize spread to other regions in the brain

21. Factors Affecting Drug Distribution • Patient characteristics • CSF properties • Drug properties • Injection technique

22. Injection Factors • Site of injection • Subarachnoid vs. Epidural • Velocity of injection • Turbulence (barbotage) • Bolus vs. continuous infusion

23. Drug Properties • Lipid solubility • Dose and volume • Baricity • Vasoconstrictors

24. Pharmacokinetics of IT Opioids • Uptake by spinal cord • Depends lipid solubility of drug • Rostral - caudal distribution by bulk flow • Transdural absorption - systemic uptake

25. Continuous IT Drug InfusionHydrophilic Drugs • Concentration gradually increases and concentration gradient develops • 5 -7 half-lives to reach steady state • Distribution ratio constant regardless of drug concentration • Final steady state concentration proportional to dose infused

26. Continuous IT Drug InfusionLipophilic Drugs • Rapidly absorbed after contacting cell membranes, blood vessels, BBB • Rapidly lost from CSF and systemically redestributed • Localized distribution • catheter tip must be close to intended site of action or high infusion dates must be used

27. Epidural Infusion • Epidural space acts as a reservoir for slow release of drug • Release variable • Timing of drug effects more unpredictable • 2 - 3% epidural morphine crosses dura into CSF • Equi-analgesic effect requires 10x the amount of drug given epidurally

28. Intraspinal MorphineConversion Ratios • 300 mg oral morphine = • 100 mg parenteral morphine = • 10 mg epidural morphine = • 1 mg intrathecal morphine * May not be accurate at high doses

30. Alternative Agents • Alpha-2 agonists • clonidine, tizanidine, dexmedotomidine • Local anesthetics • Bupivicaine, ropivicaine • Somatostatin analogs • octreotide • Calcium channel blockers • SNX-111 (zicontide) • NMDA Antagonists • ketamine, dextrmethorphan, methadone • Miscellaneous agents • Adenosine, midazolam, gabapentin, aspirin

31.  - 2 Adrenergic Agonists • Inhibition of SP release • Inhibition of nociceptive neurons • Site of action separate from opiates and local anesthetics • Synergistic with opiates • Approved for medium-term epidural infusion for cancer pain • Daily dose 50 - 900 g • Side effects: hypotension

32. Calcium Channel Blockers SNX-111 • Antagonists of N-type Ca+2 channels anti-nociceptive in animals models of acute, chronic, & neuropathic pain • synthetic form of -conopeptide MVIIA • Inhibits evoked nociceptive behavior in rats when given IT

33. Staats Et Al, 1998Chronic,intractable neuropathic Pain: Marked Analgesic Efficacy of ziconotide • Randomized, prospective, double-blind, placebo-controlled trial • N=102, VASPI score  50 • Response =  30% reduction in VASPI from baseline without an inc. in opiate requirements

34. Penn et al, 1992Octreotide for Cancer Pain

35. Drug Selection

36. Patient Selection • Observable concordant pathology • Opioid-responsive pain • Failure of less invasive, complex therapy • Failure of long-acting oral opioids • Surgically-correctable pathology excluded • Psychological clearance • Successful screening trial • Life expectancy > 3 months (cancer pain)

37. Exclusion Criteria • Major psychological issues • Substance abuse history • Unresolved secondary gain issues • Medical contraindication for surgery • Spinal pathology precluding catheter placement • Allergy to opiates

38. Principles of Screening • Accurately select candidates for long-term IT drug delivery • Physician and patient should define goals for IT drug delivery BEFORE proceeding with a trial • Goals defined on a case-by-case basis • Theoretically, the trial should approximate as closely as possible the conditions of long-term therapy • IT drug delivery is represents only a SINGLE element in overall long-term pain management for a given patient

39. A SUCCESSFUL TRIAL DOES NOT GUARANTEE LONG-TERM SUCCESS OF IT INFUSION

40. Trial AssessmentGoals of Screening • Success of an IT drug trial must be defined in the context of the goals that are set • Analgesic response • What is significant? • “One man’s junk is another man’s treasure” • Drug-related side effects • Mood • Functional improvement

41. Trialing for IT Therapy What do we know about screening? • Multiple accepted methods • No consensus as to the single best method

42. Screening Methods* • Single bolus • Multiple boluses • Continuous infusion, “functional trial” *Intrathecal or epidural

43. Survey of Trialing Methods 1999 Survey of Academic Teaching Programs 52% using continuous infusion 59% using IT route 17% using epidural route only 22% using both routes • Continous epidural infusion 35.3% • Bolus IT injection 33.7% • Bolus epidural injection 24.5% • Continuous IT infusion 6.4%

44. Single IT Bolus Trial ADVANTAGES • Procedurally simple • Low cost • Low risk and morbidity DISADVANTAGES • Sub-analgesic drug levels; “false negative trial” • Side effects may obscure analgesic response • Higher likelihood of placebo response • Inability to determine accurate starting dose • Inability to evaluate ADL

45. Multiple Bolus Injections ADVANTAGES • Ability to titrate dose • Establish dose-response curve • Placebo injections for comparison with active drug administration DISADVANTGES • Increased incidence of side effects • Transient vs. sustained • Lack of correlation with continuous infusion • Multiple dural punctures required for IT delivery unless temporary catheter used • More costly and time-consuming

46. Functional (Continuous) Trial ADVANTAGES • Controlled dose titration • Assess starting dose for IT therapy • Reduce risk of drug-related side effects • Dissipates placebo effect over time • Assessment of functional outcome DISADVANTGES • Procedurally more complicated • Requires greater expertise • Higher morbidity • More costly

47. Epidural vs. Intrathecal

48. Placebo Administration • Rationale: reduce the likelihood of a false positive trial • Normal individuals may exhibit a placebo response • Difficulty interpreting placebo response • A positive placebo response should not necessarily mean “no pump” • Functional trialing with dose titration dissipates the placebo response over time

49. Dosing • Primary determinants: • Route of administration • Current dose of systemic opioids • Large doses of systemic opioids will confer some degree of tolerance • Higher IT dose tolerated (required) • Convert total daily dose of opioid to intraspinal morphine equivalent • Epidural: 10% systemic dose • Intrathecal: 0.5-1% systemic dose

50. Oral Opioids During Trial • No consensus on alteration of systemic opioids during the trial • Maintaining the patient on a portion of their daily dose will lessen the likelihood of withdrawal • Withdrawal from systemic opioids may result in reduction in opioid-induced hyperalgesia • May produce a “false positive” result • 50-75% reduction in systemic dose • Liberal use of “breakthrough” medication • Minimal use of “breakthough” medication can be taken as one objective measure of pain relief