Inflammation and the Spine: Mediators to Modulators

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

2. Overview • Nociceptivevs 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

3. 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.

4. 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

5. Scholz and Woolf; 2002

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

9. Kwon; 2004

10. Hall; 2004

11. Hall and Springer; 2004

12. Scholz and Woolf; 2002

13. Kwon et al; 2004

14. 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): +

15. 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

16. Pharmacologic Properties of Commonly Used Corticosteroids Relative Potency

17. 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 Corticosteroid Side Effects

18. 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

19. 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)

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

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

22. 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)

23. 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)

24. 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)

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

26. 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)

27. 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)

28. 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

29. 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)

30. 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)

31. 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)

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

33. Tumor Necrosis Factor (TNF-α) • TNFa 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-α release from macrophages • Homotrimer structure (3 protein chains) • Membrane-bound and soluble forms of TNF-α

37. NSAID’s • Good evidence for efficacy in acute or episodic back pain

40. 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

41. 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

42. 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

43. 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

44. Other NSAID ADRs • CNS changes (dizziness, aseptic meningitis) • Hepatotoxicity (especially with diclofenac) • Severe rashes (e.g., Steven Johnson’s Syndrome)

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