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Inflammation and the Spine: Mediators to Modulators J. Scott Bainbridge, M.D. Denver Back Pain Specialists, LLC www.DenverBackPainSpecialists.com

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Overview Nociceptive vs Neuropathic Pain Vs Inflammatory Pain Lines blurred Stimuli and Mediators of Inflammation Inflammation soup Multi-level Processing of Pain Neuro-plasticity Multi-level modulation of inflammatory response Treatment Strategies and Options

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Objectives Elucidate evidence for role of inflammation in pain of spinal origin. Describe chemical pathways, mediators, and pharmacological treatments of inflammation. List side effects of commonly used anti- inflammatory drugs. Introduce basis for use of exercise, CAM, mindfulness, nutritional, and other treatments for inflammatory pain.

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Disclosure Principal investor in Nutrakinetics, LLC. Nutraceutical company with interest in anti- inflammatory products Spouse, Professor Jacquelyn Bainbridge, Pharm.D., involved in team building and distribution of Mona Vie nutritional products

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Scholz and Woolf; 2002

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Plasticity Peripheral sensitization Altered sensory neuron excitability Wind-up Central sensitization Synaptic reorganization Long term potentiation Disinhibition Glial activation

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Kwon; 2004

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Hall; 2004

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Hall and Springer; 2004

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Scholz and Woolf; 2002

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Kwon et al; 2004

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Clinical uses of glucocorticoids Acute whiplash: + one trial IV Acute spinal cord inj: + high dose methylprednisolone IM or PO: negative (spine pain) Spinal: mixed Intraoperative (HNP/radic): +

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Glucocorticoid Action Decrease Inflammation decrease prostaglandin, leukotriene synthesis decrease PMN migration Direct Membrane Stabilization Modulation of Periph Nociceptor Neurons Mod of Spinal Cord Dorsal Horn Cells Slight Anesthetic Effect

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Pharmacologic Properties of Commonly Used Corticosteroids Relative Potency

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Corticosteroid Side Effects Fever Myalgia Malaise Fluid and electrolyte imbalance Hypertension Hyperglycemia Myopathy Ulcers Immunosuppression Behavioral changes Allergic reaction Pituitary-adrenal suppression Abrupt withdrawal after prolonged use: acute adrenal insufficiency

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Corticosteroid Side Effects Cardiovascular System Prolonged Use: hypertension due to Na+ uptake Direct effects due to steroid receptors on heart and smooth muscle cardiac output and vascular tone

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Corticosteroid Side Effects Musculoskeletal Avascular necrosis Bone mineral density loss Muscle weakness and wasting Case report of steroid myopathy after one epidural injection (Boonen S et al. Br J Rheumatol 1995;34:385-6)

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Corticosteroid Side Effects Central Nervous System Euphoria Behavioral changes; psychosis EEG abnormalities Excitability of nervous tissue

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Corticosteroid Side Effects Gastrointestinal System Gastric acid secretion Risk ulcer especially if on NSAIDs Fat absorption Endocrine System ACTH, TSH, FSH, Testosterone

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Adrenal Suppression Intra-articular glucocorticoid injection Serum cortisol suppressed at 1 week independent of dose 40mg triamcinolone Duration of local and systemic effect increase with decreased solubility (Armstrong RD et al. Ann Rheum Dis 1981;40:571-4)

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Adrenal Suppression Epidural steroid injection (ESI) Suppresses adrenal function 3 weeks 25 mg Hydrocortisone/80 or 160 mg Methylprednisolone (Benzon HT. Pain 1986;24:277-95)

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Adrenal Suppression ESI Study of 2 individuals, single dose 160mg methylprednisolone, steroid naive Complete cortisol suppression 6 days Incomplete at least 4 weeks Therefore, epidural dosing similar systemic availability to low daily oral glucocorticoid (Dubois EF et al. Clin Rheumatol 2003;22:12-7)

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Osteocalcin Depression with Oral Prednisone Wilson AM et al. Chest 1998;114:1022-7.

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Bone Mineral Density and ESI Does ESI cause bone loss? Cross-sectional study of relationship between cumulative ESI dose and BMD Inconclusive dose relationship Osteoporosis/osteopenia higher than general population Could be that all doses caused decreased BMD (Dubois EF et al. Clin Rheumatol 2003;22:12-7)

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Bone Mineral Density and ESI Prospective study 204 patients, 123 follow-up at one year No change in BMD after standard doses spinal steroids All spinal injections included DXA at forearm Calcium/Vit D ? (Manchikanti L. Pain Physician 2000 Oct;3(4):357-66)

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Bone Mineral Density and ESI If ESI = 10-20mg PO x 4 weeks, THEN: ACR 2001 update for oral steroids Ca ++ /Vit D all starting low/moderate dose Bisphosphonates 5mg/day for > 3 mo Bisphosphonates 5mg/d long term with osteoporosis or osteoporotic fracture

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Local Anesthetics Hematologic effects Epidural inhibit platelets, fibrinolysis, and leukocyte function Granulocyte migration /metabolic activation at surgical sites (Naguib M et al. Drug Safety 1998 Apr; 18(4)221- 50)

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Local Anesthetics Tissue Effects Cytotoxic to chondrocytes Bupivicaine 0.5%, 15-30 min in vitro Intact cartilage provided partial protection (Chu CR et al. Arthroscopy 2006; 22:693-9) Inhibit Fibroblasts Myotoxic (Hogan Q. Regional Anesthesia 1996;21:43-50)

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Local Anesthetics Neural Toxicity Intrathecal lidocaine more neurotoxic than epidural Dose-dependent toxicity found in rats Doses studied much higher than those used in humans (Kirihara Y et al. Anesthesiology 2003;99:961-8)

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Local Anesthetics Overall safety Large scale surveys attest to overall safety of spinal anesthetics (Hodgson P et al. Anesth Analg 1999;88:797-809)

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Tumor Necrosis Factor (TNF- ) TNF is a principal mediator of acute inflammatory responses Macrophages: primary source Mediator of inflammation, tissue destruction, and organ injury Lipopolysaccharide is a strong inducer of TNF- release from macrophages Homotrimer structure (3 protein chains) Membrane-bound and soluble forms of TNF-

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NSAIDs Good evidence for efficacy in acute or episodic back pain

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NSAID Cardiovascular Toxicity Nonselective NSAIDs as a class associated with increased risk of acute MI Relative risk 1.19, 95% CI 1.08-1.31 This meta-analysis limited by heterogeneity

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NSAID Gastrointestinal Toxicity 1.3-1.6% annual risk of hospitalization or death due to NSAID-associated gastropathy 1 in 3 RA patients over course of disease Long-term NSAID users: 10% Nonspecific dyspepsia 1-10% Serious GI bleeding or ulceration < 1% Kidney toxicity and others

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NSAIDs Renal Toxicity Aspirin doses as low as 75 mg/day may still have adverse renal effects Study of elderly patients given aspirin 75 mg/day for 1 week, 150 mg/day for 1 week, 325 mg/day for 1 week, then no aspirin for 1 week All aspirin doses reduced creatinine clearance and uric acid secretion, especially in patients with low albumin levels or taking diuretics Risk of NSAID toxicity increased with diminished renal function or decreased effective intravascular volume due to diuretic therapy, cirrhosis, or congestive heart failure

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NSAIDs and Pregnancy NSAIDs may be associated with increased risk for miscarriage Association of NSAIDs with miscarriage based on prescription use of NSAIDs in 63 (1.5%) of 4,268 women who had a miscarriage and 318 (1.5%) of 21,750 women who had a live birth which shows no significant difference but there were significant differences in subgroups when accounting for use of NSAIDs in the preceding 1-9 weeks In utero exposure to analgesics may be associated with increased risk of developing schizophrenia Large cohort study found > 4 times increased risk of schizophrenia in persons with analgesic exposure during second trimester Use of NSAIDs during third trimester may cause premature closure of ductus arteriosus and persistant pulmonary hypertension; uncommon if drug discontinued 6-8 weeks before delivery Use of NSAIDs during third trimester may cause premature closure of ductus arteriosus and persistant pulmonary hypertension; uncommon if drug discontinued 6-8 weeks before delivery

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Other NSAID ADRs CNS changes (dizziness, aseptic meningitis) Hepatotoxicity (especially with diclofenac) Severe rashes (e.g., Steven Johnsons Syndrome)

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Nutrients/Supplements Anti-oxidants Anti-inflammatory (COX inhibition or other mechanisms)

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Recommendations for patients Diet high in antioxidants (multicolored food choices) Diet high in good fats (polyunsaturated, omega-3) Supplement vitamin D3, Omega-3, possibly concentrates of antioxidants Avoid trans-fats, excessive alcohol or simple sugars/starches (pro-inflammatory)

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Bibliography Alper, A. B., Jr., H. Tomlin, et al. (2006). "Effects of the selective cyclooxygenase-2 inhibitor analgesic celecoxib on renal carbonic anhydrase enzyme activity: a randomized, controlled trial." Am J Ther 13(3): 229-235. Autio, R. A., J. Karppinen, et al. (2006). "The effect of infliximab, a monoclonal antibody against TNF-alpha, on disc herniation resorption: a randomized controlled study." Spine (Phila Pa 1976) 31(23): 2641-2645. Ballantyne, J., S. Fishman, et al. (2010). Bonica's management of pain. Philadelphia, PA, Lippincott, Williams & Wilkins. Bombardier, C., L. Laine, et al. (2000). "Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group." N Engl J Med 343(21): 1520-1528, 1522 p following 1528. Boswell, M. V., R. V. Shah, et al. (2005). "Interventional techniques in the management of chronic spinal pain: evidence-based practice guidelines." Pain Physician 8(1): 1-47. Chou, R., J. D. Loeser, et al. (2009). "Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain: an evidence-based clinical practice guideline from the American Pain Society." Spine (Phila Pa 1976) 34(10): 1066-1077. Chou, R., A. Qaseem, et al. (2007). "Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society." Ann Intern Med 147(7): 478-491. Cohen, S. P., N. Bogduk, et al. (2009). "Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica." Anesthesiology 110(5): 1116-1126. Doidge, N. (2007). The brain that changes itself : stories of personal triumph from the frontiers of brain science. New York, Viking. Dubois, E. F., M. F. Wagemans, et al. (2003). "Lack of relationships between cumulative methylprednisolone dose and bone mineral density in healthy men and postmenopausal women with chronic low back pain." Clin Rheumatol 22(1): 12-17. Hall, E. D. and J. E. Springer (2004). "Neuroprotection and acute spinal cord injury: a reappraisal." NeuroRx 1(1): 80-100.

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Bibliography Hurwitz, E. L., E. J. Carragee, et al. (2008). "Treatment of neck pain: noninvasive interventions: results of the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders." Spine (Phila Pa 1976) 33(4 Suppl): S123-152. Jensen, G. S., X. Wu, et al. (2008). "In vitro and in vivo antioxidant and anti-inflammatory capacities of an antioxidant-rich fruit and berry juice blend. Results of a pilot and randomized, double-blinded, placebo-controlled, crossover study." J Agric Food Chem 56(18): 8326-8333. Kay, J., J. W. Findling, et al. (1994). "Epidural triamcinolone suppresses the pituitary-adrenal axis in human subjects." Anesth Analg 79(3): 501-505. Korhonen, T., J. Karppinen, et al. (2006). "The treatment of disc-herniation-induced sciatica with infliximab: one-year follow-up results of FIRST II, a randomized controlled trial." Spine (Phila Pa 1976) 31(24): 2759-2766. Kwon, B. K., W. Tetzlaff, et al. (2004). "Pathophysiology and pharmacologic treatment of acute spinal cord injury." Spine J 4(4): 451- 464. LeDoux, J. E. (2002). Synaptic self : how our brains become who we are. New York, Viking. Lefkowith, J. B., G. S. Geis, et al. (2000). "Safety of celecoxib vs other nonsteroidal anti-inflammatory drugs." JAMA 284(24): 3123- 3124. Manchikanti, L. (2002). "Role of neuraxial steroids in interventional pain management." Pain Physician 5(2): 182-199. Manchikanti, L., V. Pampati, et al. (2000). "The effect of neuraxial steroids on weight and bone mass density: a prospective evaluation." Pain Physician 3(4): 357-366. Pappagallo, M. (2005). The neurological basis of pain. New York, McGraw-Hill, Medical Pub. Division. Scholz, J. and C. J. Woolf (2002). "Can we conquer pain?" Nat Neurosci 5 Suppl: 1062-1067. Scuderi, G. J., J. M. Cuellar, et al. (2009). "Epidural interferon gamma-immunoreactivity: a biomarker for lumbar nerve root irritation." Spine (Phila Pa 1976) 34(21): 2311-2317. Silverstein, F. E., G. Faich, et al. (2000). "Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study." JAMA 284(10): 1247-1255. Whelton, A., J. L. Lefkowith, et al. (2006). "Cardiorenal effects of celecoxib as compared with the nonsteroidal anti-inflammatory drugs diclofenac and ibuprofen." Kidney Int 70(8): 1495-1502.