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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 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 Spinal Opiate Analgesia Discovery of CNS opiate receptors Identification of endogenous opiate peptides Isolation of receptors Endogenous Opioid Peptides Proopiomelanocortin (POMC) Endorphins Beta-lipotropin Proenkephalin A Met-enkephalin, leu-enkephalin Other enkephalins, peptide E Prodynorphin dynorphin A & B neoendorphins ( and ) Opioid Receptors and Ligands Opioid Receptor Endogenous Agonist Synthetic Agonists Antagonists ß-Endorphin Endomorphins Morphine DAMGO Naloxone ß-FNA Delta (20-30%) Met-Enkephalin Leu-Enkephalin DPDPE SNC-80 DSTBULET Naltrindole Naloxone Kappa (5-10%) Dynorphine A Dynorphine B Mu (70%) hORL1 Nociceptin/OFQ None 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 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 Opioid Recptor Physiology G-protein-coupled receptor family Synthesized in DRG Second messenger using camp Negative coupling Inhibit camp via Giprotein And - opening of K+ channels - Closing of ca2+ Opioid Receptor Physiology And - opening of K+ channels - Closing of ca2+ Opiate Receptors Distributed pre- and post-synaptically High affinity binding Binding stereospecific Optimal binding in ph range 7-8 Opioid Recetors Analgesia Dorsal horn Lamina I Substantia gelatinosa Brainstem Nucleus caudalis Supraspinal PAG Medial and intralaminar thalamic nuclei Striatum Opioid Recptors Autonomic 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 Opioid Receptors Miscellaneous Effects Endocrine effects Posterior pituitary – inhibition of vasopressin Hormonal effects – hypothalamic infundibulum Behavioral effects Amygdala, hippocampus, nucleus accumbuns, basal ganglia Motor rigidity Striatum 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 Spinal Opiate Analgesia Pre-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 Spinal Opiate Analgesia Post-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 Spinal Opiate Analgesia Disinhibitory 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 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 Descending Modulation 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 Factors Affecting Drug Distribution Patient characteristics CSF properties Drug properties Injection technique Injection Factors Site of injection Subarachnoid vs. Epidural Velocity of injection Turbulence (barbotage) Bolus vs. continuous infusion Drug Properties Lipid solubility Dose and volume Baricity Vasoconstrictors Pharmacokinetics of IT Opioids Uptake by spinal cord Depends lipid solubility of drug Rostral - caudal distribution by bulk flow Transdural absorption systemic uptake Continuous IT Drug Infusion Hydrophilic 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 Continuous IT Drug Infusion Lipophilic 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 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 Intraspinal Morphine Conversion Ratios 300 mg oral morphine = 100 mg parenteral morphine = 10 mg epidural morphine = 1 mg intrathecal morphine * May not be accurate at high doses 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 - 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 Calcium Channel Blockers SNX-111 Antagonists of N-type Ca+2 channels antinociceptive in animals models of acute, chronic, & neuropathic pain synthetic form of -conopeptide MVIIA Inhibits evoked nociceptive behavior in rats when given IT Staats Et Al, 1998 Chronic,intractable neuropathic Pain: Marked Analgesic Efficacy of ziconotide Randomized, prospective, double-blind, placebocontrolled trial N=102, VASPI score 50 Response = 30% reduction in VASPI from baseline without an inc. in opiate requirements Percent reduction from baseline in VASPI 40 30 20 10 0 SNX-111 Placebo Penn et al, 1992 Octreotide for Cancer Pain 25 20 15 Octreotide Pain level 10 5 0 0 10 20 30 40 50 60 Drug Selection 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) Exclusion Criteria Major psychological issues Substance abuse history Unresolved secondary gain issues Medical contraindication for surgery Spinal pathology precluding catheter placement Allergy to opiates 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 • A SUCCESSFUL TRIAL DOES NOT GUARANTEE LONG-TERM SUCCESS OF IT INFUSION Trial Assessment Goals 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 Trialing for IT Therapy What do we know about screening? Multiple accepted methods No consensus as to the single best method Screening Methods* Single bolus Multiple boluses Continuous infusion, “functional trial” *Intrathecal or epidural Survey of Trialing Methods epidural infusion 35.3% 1999Continous Survey of Academic Teaching Programs 52%Bolus usingITcontinuous injection infusion 33.7% 59% using IT route Bolus epidural injection 17% using epidural route only 22%Continuous using bothITroutes infusion 24.5% 6.4% 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 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 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 Epidural vs. Intrathecal CRITERIA EPIDURAL INTRATHECAL Onset of Action Slower onset of analgesia Faster onset of analgesia Systemic Effects Greater systemic effects Minimal systemic effects Shorter-lasting Longer-lasting Higher dose to achieve effect Lower dose required (1/10 epidural dose) Higher incidence of Post-LP headache systemic side effects Risk of epidural abscess Respiratory depression Duration of Effect Dose Adverse Effects/Risks Meningitis 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 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 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 Monitoring During Trial Vital signs, pulse oximetry, apnea monitor Pain reduction VAS Percent pain relief Assessment of mood Functional assessments SF-36 MPQ Oswestry disability index Drug-related side effects Supplemental opioid use Side Effects of Spinal Opioids Pruritis Urinary retention Nause/vomiting Sedation Respiratory depression Continuous Epidural Infusion Trial Tunneled epidural catheter Morphine infusion, 0.2mg/cc Starting dose, 0.2mg/hr (1cc/hr) Dose titration for 36-48 hours Final dose: 4.8-48mg/day IT dose: 0.48 – 4.8mg MS/day Continuous IT Trial Tunneled IT catheter Algoline catheter, 33.5 inches .0156 m./in = 0.5226 ml catheter volume Calculate IT equi-analgesic dose Morphine used as 1st line agent Reduce systemic opioids by 50% Assess VAS scores every 2 hours Monitor development of side effects Titrate infusion to analgesic effect Quantitative Crossover Doubleblind IT Trial Phase I – Dose Escalation Trial Baseline VAS score Bolus injections of IT morphine separated by 30 minute Drop in VAS < 3, repeat IT morphine Drop in VAS > 3, proceed to Phase II Levy R, M.D, Ph.D. Quantitative Crossover Doubleblind IT Trial Phase II – Double-Blind Crossover Trial IT Morphine vs. Saline Day 1 Drug A – VAS scores for 6 hours VAS scores within 1 point of baseline Drug B Day 2 Drug A – VAS scores for 6 hours VAS scores within 1 point of baseline Drug B Levy R, M.D, Ph.D. IT Bolus (ITB) vs. Continuous Epidural Infusion (CEI) 86 patient screened for inclusion 28 excluded from inclusion 58 patients approached 18 declined inclusion 40 patients randomized ITB (n=18) or CEI (n=19) 27 successful trial - pump implantation ITB, 67% (12/18) CEI, 79% (15/19) 3 patients lost to follow-up ITB (n=10), CEI (n=14 Anderson V, Burchiel K, Cooke B: A Prospective Randomized Trial of Intrathecal Injection vs. Epidural Infusion in the Selection of Patients for Continuous Intrathecal Opioid Therapy. Neuromodulation, 2003 IT Bolus vs. CEI No significant difference in 6 month outcomes between ITB and CEI ITB – 60% “successful” response CEI – 64% “successful” response Drug-related complications more common in ITB group (88%) vs. CEI group (70%) CEI 2.5 times more costly ($4,762 vs. 1,862) CONCLUSION: Differences in pain and functional response to long-term IT opioids among patients selected by either trial method are not large IT Bolus vs. CEI VAS Pain Scores 100 80 60 IT CEI 40 20 0 Baseline 6 Months % Change Anderson V, Burchiel K, Cooke B: A Prospective Randomized Trial of Intrathecal Injection vs. Epidural Infusion in the Selection of Patients for Continuous Intrathecal Opioid Therapy. Neuromodulation, 2003 Questions Regarding Trialing Screening method Duration of trial Drug and dose Use of placebo Systemic opioids Criteria for success Pump Implantation Catheter insertion Tunneling and anchoring of catheter Pump pocket preparation Preparation and filling of pump Connection of catheter to pump Anchoring of pump Catheter Complications Fractures Occur around spinous processes with midline catheter placement Withdrawal of catheter through needle Kinks Occur at connections and anchors from lack of slack and/or not using a strain relief sleeve Holes Missing or failed strain relief sleeve at pump connector on one-piece catheter Several reports of small holes in one-piece catheter under pump. No reports of holes under the pump with the two-piece catheter Dislodgements Occur from pump movement and lack of slack at pump and catheter causing the catheter to slip through anchor Occur from ligament motion or CSF pressure and no anchor or purse string suture at fascial entry point 5/23/2017 Confidential 62 Catheter Complications Medtronic Clinical Study 7.0% 0.061 6.0% 0.051 5.0% 0.04 4.0% 0.03 3.0% 2.0% 1.0% 0.0% 0.007 0.004 0.003 0.003 0.001 0.001 0.001 Catheter Complications 20-25% incidence 20,000 implants annually 5,000 catheter revisions annually Estimated revision cost $10,000 $50,000,000 yearly revision cost Proper catheter placement is probably the single most important aspect of pump implantation for avoiding device-related complications Catheter Fracture - Midline Insertion Midline Two Piece Catheter (8731) Pre-attached catheter anchor/connecting pin Sutureless strain relief sleeve (distal) Pre-attached pump connector 8711 catheter 8731 Catheter Pre-attached proximal strain relief sleeve Catheter Insertion Technique Paramedian entry 1.5-2 cm off midline toward side of pump pocket 1 to 1 ½ vertebral levels caudal to dural entry Avoid midline insertion Shallow angle of insertion, 30 degrees Facilitates catheter insertion Position catheter just below conus Catheter Insertion ~ 30° Catheter Insertion Catheter Fracture/Tears Pulling the catheter back through the introducer needle may shear or create holes in the catheter Gently remove stylet with catheter fully stretched; Using excessive force can produce tears in the catheter Expose Lumbodorsal Fascia 5-6 cm incision down to fasica Leave needle in place to avoid cutting catheter Undermine each side to facilitate anchoring Pump Pocket Upper quadrant of abdomen; 2 inches below/parallel to costal margin Big enough, but not too big AVOID incision directly over refill port site of current/future surgery site of previous radiation iliac crest, rib cage placing directly beneath beltline Tunneling and Anchoring Back-to-Front Strain relief loop of catheter Anchor at fascial insertion site Anchoring Pump Connect catheter to pump and secure Coil excess tubing behind pump Place pump in pocket and secure with nonabsorbable sutures Suture loop Dacron pouch Aspirate/inject through CAP to confirm patency Catheter tip Dural puncture Pump anchored with sutures or pouch Paramedian Oblique Entry V-wing anchor 5 cm of slack in catheter Loop of excess catheter under pump Catheter connector which also functions as the primary anchor Complications Infection most often occurs at pump pocket REMOVE the system Post-dural puncture headache CSF leak Mechanical problems Misplaced catheter Catheter disconnection Catheter migration Pump pocket seroma Spinal Opiates for Benign Pain Accepted yet controversial Mixed reviews and results Long-term effectiveness is unclear given the non-uniformity of reporting outcomes No definitive end-point for therapy Spinal Opiates For Non-Cancer Pain PAIN DISTRIBUTION Axial lower back pain Diffuse bilateral leg pain Unilateral leg pain failed trial of spinal cord stimulation Spinal Opiates Non-Malignant Pain U.S. experience, 1981-1992 14 authors, 156 patients 69% (107) good-excellent pain relief 75% (126 of 169) with cancer pain had good-excellent pain relief Krames E: Spinal Administration of Opioids for Nonmalignant Pain Syndromes: A U.S. Experience Spinal Opiates Non-Malignant Pain 120 patients 63% (n=76) with FBSS or LBP Mean age: 54.0 + 11.2 years (28-79) Follow-up period mean: 3.4 + 1.3 years (0.5 - 5.7 years) Winkellmuller et al.: J Neurosurgery 85:458-467, 1996 Spinal Opiates Non-malignant Pain Mean morphine dose initial: 2.7 mg/day (0.3-12 mg/day) after 3.4 years: 4.7 mg/day (0.3-12 mg/day) 28 patients followed more than 4 years 64% (n=18) constant dosage history 36% (n=10) increase in morphine dose > 6mg/day after 1 year Winkellmuller et al.: J Neurosurgery 85:458-467, 1996 Mean Pain Scores 100 Mean VAS 80 • 74% benefit from therapy •Avg. pain reduction • 67% at 6 months •58% last follow-up 60 40 • 81% improve quality of life 20 •92% “satisfied” 0 Before 1st FU Last FU Winkellmuller et al.: J Neurosurgery 85:458-467, 1996 Mean IT Morphine Dose (mg/day) Mean Daily Morphine Dose 5 LBP 4.5 4 3.5 3 2.5 2 Initial exam First FU Last FU Winkellmuller et al.: J Neurosurgery 85:458-467, 1996 Totals Multicenter Review of Spinal Opiates Retrospective review of 429 patients 66% non-malignant pain Physician assessment global pain relief scores percent pain relief VAS scores for pain intensity ADL, overall activity level Employment Paice: J Pain Symptom Management, 1996 Global Pain Relief 43% Excellent 52.4% 5% Good 42.9% Poor 4.8% 52% Paice: J Pain Symptom Management, 1996 Changes in ADL 14% 4% 82% Increased 82% No Change 14% Decreased 4% Paice: J Pain Symptom Management, 1996 Daily Opiate Dosage Mean daily dose, 9.2 mg/day Initial dose higher for non-malignant pain Gradual linear dose escalation in nonmalignant pain At 24 months, dosages similar in patients with non-malignant and cancer pain Paice: J Pain Symptom Management, 1996 Conclusions of Multicenter Review Nociceptive pain responds best to spinal opiates Neuropathic pain responds to spinal opiates but may require higher dosages Addition of local anesthetics may by synergistic in neuropathic pain Prospective Study - Spinal Opiates 40 patients with non-malignant pain mostly FBSS with > 3 operations Mean duration of pain, 8 + 9 years (6mos-40yrs) 30 (75%) had successful screening trial minimum of 50% pain reduction by VAS Follow-up 6, 12, 18, 24 months complete data for 20 patients followed for 2 years Outcome by VAS, CIPI, BDI, MPQ Anderson V,Burchiel K: Neurosurgery, Feb. 1999 Results VAS for pain and pain coping scores remained improved CIPI and MPQ scores improved and persisted Initial morphine dose 1.96 + 1.8 mg/day, inc. to 6.0 + 7.0 at 3 months, 9.43 + 8.8 at 15 months Device complications, 20% Anderson V,Burchiel K: Neurosurgery, Feb. 1999 Visual Analog Scores Mean initial VAS 78.5 ± 15.9 (39-100) Percent change in VAS significantly decreased at each interval Decrease in VAS greatest during the initial 3 months Reduction in VAS remained relatively constant 80 70 60 50 40 30 20 10 0 Initial Anderson V,Burchiel K: Neurosurgery, Feb. 1999 6-mo 18-mo McGill Pain Scores 40 35 30 25 PRI 20 MP Q-s 15 10 5 0 Baseline 3 6 12 18 24 Anderson V,Burchiel K: Neurosurgery, Feb. 1999 CIPI Scores 30 CIPI improved for 1218 months 25 Several CIPI subscales showed trends toward sustained improvement 15 20 10 5 0 Initial Anderson V,Burchiel K: Neurosurgery, Feb. 1999 6 18 Medication Intake Daily IT morphine dose 25mg Mean equianalgesic opioid dose increased significantly over time initial: 1.96 ± 1.75 mg/day 24 months: 14.59 ± 20.52 mg/day Dose escalation most rapid during initial 3 months Oral narcotic intake initial: 90% (28/30) 24 months: 30% (6/30) Spinal Opiates for Benign Pain Maron J, Loeser J: The Clinical Journal Pain, 1996 Data insufficient to permit formal analysis The proper role of intraspinal opioids in the treatment of non-malignant pain cannot be determined from the existing literature Spinal opiates for benign pain should be considered experimental All patients who receive such therapy should be part of a clinical protocol Unresolved Issues How should outcome be measured? Management of tolerance Question of neurotoxicity Development of hyperalgesia Indefinite requirement for medical care The Dilemma of Outcomes A lack of consensus complicates the interpretation of many if not the majority of efficacy studies The Bottom Line There can be no substitute for sound clinical judgement based on a detailed assessment of each patient ! Conclusions Intraspinal opiates can be safely used in patients with non-malignant pain syndromes without fear of drug abuse Intraspinal opiates are effective in reducing pain in carefully selected patients with non-malignant pain syndromes including FBSS Most patient with non-malignant pain express satisfaction with the therapy Patients experience improvements in ADL Whether intraspinal opiates improve return to work rates in patients with FBSS remain unresolved Conclusions Spinal opiates are effective in patients with pain due to cancer Long term issues regarding tolerance, neurotoxicity, etc. are generally irrelevant Choice of device depends on anticipated life expectancy