Inflammation - Denver Back Pain Specialists
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Transcript Inflammation - Denver Back Pain Specialists
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 antiinflammatory 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 antiinflammatory 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
Corticosteroid Side Effects
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Fever
Myalgia
Malaise
Fluid and electrolyte
imbalance
Hypertension
Hyperglycemia
Myopathy
Ulcers
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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
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)22150)
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-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
NSAID’s
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 Johnson’s
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)
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