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
◦
◦
◦
◦
◦
◦
◦
◦
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
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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
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