Inflammation: Mediators to Management

Inflammation and the Spine: Mediators to Modulators

J. Scott Bainbridge, M.D.

Denver Back Pain Specialists, LLC

www.DenverBackPainSpecialists.com

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

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.

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

Scholz and Woolf; 2002

Plasticity

Peripheral sensitization

Altered sensory neuron excitability

Wind-up

Central sensitization

Synaptic reorganization

Long term potentiation

Disinhibition

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

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Second level

Third level

Fourth level

Fifth level

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

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

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)

Corticosteroid Side Effects

Central Nervous System

Euphoria

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

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)

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

Myotoxic

(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-

33

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]

NSAIDs

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

Other NSAID ADRs

CNS changes (dizziness, aseptic meningitis)

Hepatotoxicity (especially with diclofenac)

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

Nutrients/Supplements

Anti-oxidants

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)

Bibliography

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Bibliography

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