Inflammation and the Spine: Mediators to Modulators

of 57 /57
Inflammation and the Spine: Mediators to Modulators J. Scott Bainbridge, M.D. Denver Back Pain Specialists, LLC

Embed Size (px)


Inflammation and the Spine: Mediators to Modulators. J. Scott Bainbridge, M.D. Denver Back Pain Specialists, LLC Overview. Nociceptive vs Neuropathic Pain Vs Inflammatory Pain Lines blurred Stimuli and Mediators of Inflammation Inflammation “soup” - PowerPoint PPT Presentation

Transcript of Inflammation and the Spine: Mediators to Modulators

Inflammation: Mediators to Management

Inflammation and the Spine: Mediators to Modulators

J. Scott Bainbridge, M.D.

Denver Back Pain Specialists, LLC


Nociceptive vs Neuropathic Pain

Vs Inflammatory Pain

Lines blurred

Stimuli and Mediators of Inflammation

Inflammation soup

Multi-level Processing of Pain


Multi-level modulation of inflammatory response

Treatment Strategies and Options


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.


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

Scholz and Woolf; 2002


Peripheral sensitization

Altered sensory neuron excitability


Central sensitization

Synaptic reorganization

Long term potentiation


Glial activation

Kwon; 2004

Hall; 2004

Hall and Springer; 2004

Scholz and Woolf; 2002

Kwon et al; 2004

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): +

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

Pharmacologic Properties of Commonly Used Corticosteroids

Relative Potency

Click to edit Master text styles

Second level

Third level

Fourth level

Fifth level

Corticosteroid Side Effects




Fluid and electrolyte imbalance






Behavioral changes

Allergic reaction

Pituitary-adrenal suppression

Abrupt withdrawal after prolonged use: acute adrenal insufficiency

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

Corticosteroid Side Effects


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)

Corticosteroid Side Effects

Central Nervous System


Behavioral changes; psychosis

EEG abnormalities

Excitability of nervous tissue

Corticosteroid Side Effects

Gastrointestinal System

Gastric acid secretion

Risk ulcer especially if on NSAIDs

Fat absorption

Endocrine System

ACTH, TSH, FSH, Testosterone

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)

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)

Adrenal Suppression


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)

Osteocalcin Depression with Oral Prednisone

Wilson AM et al. Chest 1998;114:1022-7.

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)

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)

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

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)

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


(Hogan Q. Regional Anesthesia 1996;21:43-50)

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)

Local Anesthetics

Overall safety

Large scale surveys attest to overall safety of spinal anesthetics

(Hodgson P et al. Anesth Analg 1999;88:797-809)

Tumor Necrosis Factor (TNF-)

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- release from macrophages

Homotrimer structure (3 protein chains)

Membrane-bound and soluble forms of TNF-


Point of Slide: Background on general immune functions of TNFa (if required, otherwise move to backup slides)

TNF-alpha (or simply TNF) is the principal mediator of the acute inflammatory response. [Abbas p247] It is produced by macrophages and lymphocytes, but its primary source is macrophages. TNF-alpha functions with interleukin-1 to mediate inflammation. [Abbas p253] Tumor necrosis factor has a broad spectrum of biologic activity. [Bazzoni 1996 p1717] It is a mediator of inflammation, tissue destruction, and organ injury. [Harris 2005 p940]

All members of the TNF family, including TNF-alpha, are believed to consist of 3 polypeptide (protein) chains (shown in different colors on this illustration). [Bazzoni 1996 p1717] This structure of 3 protein chains is called a homotrimer.

Tumor necrosis factor exists in both membrane-bound and soluble (circulating) forms. [Janeway, online book] The membrane-bound form is cleaved by a molecule called TACE, and is freed from the cell membrane.

The secreted molecules then aggregate into the trimolecular complex of TNF, which can bind to and activate receptors. [Papadakis 2000 p1148] Both membrane-bound and soluble forms of TNF bind to TNF receptors on cell surfaces. [Harris 2005 p380]


Good evidence for efficacy in acute or episodic back pain

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

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

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

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


CNS changes (dizziness, aseptic meningitis)

Hepatotoxicity (especially with diclofenac)

Severe rashes (e.g., Steven Johnsons Syndrome)



Anti-inflammatory (COX inhibition or other mechanisms)

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)


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.


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.