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Hidden Metabolic Drivers of Pain
Dr Marc A. Russo
MBBS DA FANZCA FFPMANZCA
FPM Spring Meeting 2010
Traditional Pharmacology
• Proven efficacy as single agent in
controlled animal studies. All other
variables kept the same.
• Often 80-100% reduction in outcome.
• Why do we see 10-40% reduction in
clinical practice?
Why do our drugs work so poorly?
• Non controlled conditions, compliance
• Diet, sleep, mood variability
• Multiple drugs
• Multiple different genetic strains of human
Areas to be Reviewed
• ATP sensitive Potassium Channel
• Nitric oxide signaling system
• Magnesium
• Drug efflux pump
• Vitamin B12
ATP K Channel
K Channel
• Channel must be open for G protein
coupling to mu opioid receptor
• Closed channel inhibits opioid induced
antinociception
• High BSL, diabetic drugs close channel
• Only fentanyl family and levorphanol
activate MOR independent of the K
channel.
Clinical corollary: In diabetics Transdermal
Fentanyl is the opioid of choice.
• Cholesterol blocks the channel
• Lee SY Cholesterol inhibits M-type K+ channels via protein kinase C
phosphorylation in sympathetic neurons J Biol Chem 2010 Apr 285(14)
10939-50
• Level required in patch clamp corresponds
to serum level of 6.0 mmol/L
Nitric Oxide, Reactive Oxygen
Species
• Morphine inhibits super oxide dismutase (SOD)
• More super oxide combines with nitric oxide to
form peroxynitrite which disrupts pre and post
opioid receptor synaptic function
• Salvemini D Peroxynitrite: a strategic linchpin of opioid analgesic tolerance Trends
in Pharmacol Sci 2009 Apr 30(4) 194-202
• End result: Opioid Tolerance
Reversing Nitroxidative Stress
• Cox-2 inhibitors
• Vitamin C
• Allopurinol (xanthine oxidase)
• GTN, nicorandil
Magnesium – The Ubiquitous Ion
• Multiple roles in regulation in the body
• Serum levels do not well reflect body
tissue stores except at extreme low levels
Poster IASP Montreal 2010
• 50% of CRPS patients were magnesium deficient as
defined by an inadequate urinary excretion of
magnesium compared to healthy controls after an IV
magnesium load.
• Does this explain the failure rate of IV Ketamine
infusions in treating CRPS?
• Could one Mg load in CRPS patients prior to commencing
ketamine infusion improve outcomes?
Mg Deficiency
• Serum magnesium levels below
0.85mmol/l associated with systemic
inflammatory response
• Nielsen FH Magnesium,Inflammation and Obesity in chronic disease
Nutrit Rev 2010 Jun 68(6) 333-40
Magnesium and Pain
• Magnesium blocks the development of
morphine tolerance
• Habibi-Asl B Development of morhpine induced tolerance and withdrawal
symptoms is attenuatedby lamotrigene and magnesium sulphate in mice
Pak J Biol Sci 2010 May 15 12(10) 798-803
P-Gylcoprotein
• Acts as a drug efflux pump
• Normally acts as an extrusion mechanism
for removing intracellular debris
• Can be upregulated by contact with drugs
thus leading to multidrug resistance
• Prednisone is one of the major activators of the
drug efflux pump
• Dilger K Identification of budesonise and prednisone as substrates of the intestinal
drug efflux pump P Glycoprotein Inflammat Bowel Dis 2004 Sep 10(5)578-83
• Clinical Corollary: Once on steroids your drugs
won’t work well
• This can be reversed by Sulfasalazine increasing
glucocorticoid receptor expression
• Oerlmans R Ann Rheum Dis 2007 Oct 66(10) 1289-95
In the Clinic
• Don’t do lots of steroid blocks close
together. You will make the patient
refractory to their benefit.
• Use Sparingly
Vitamin B12
• 26% of >65 year olds have evidence of
peripheral neuropathy, rises to 54% in age>85
• Loss of ankle reflex, fine touch discrimination
• OR >2 for Vitamin B12 deficiency, Rheumatoid
Arthritis, Diabetes Mellitus
• Mold JW The prevalence, predictors and consequences of peripheral sensory
neuropathy in older patients J Am Board Fam Pract 2004 Sep/Oct 17(5) 309-18
Vitamin B12
• Is an antineuropathic drug!
• Reduced tactile allodynia in a spinal nerve
ligation model in dose dependant manner.
• Granados-Soto V Proc West Pharmacol Soc 2004 47 92-4
Human Data
• 7 RCTs with positive effects on diabetic
neuropathy.
• Pain and paraesthesia improved
• Acta Neurol Taiwan Effectiveness of Vtamin B12 on diabetic
neuropathy:systematic review of clinical controlled trials 2005 Jun 14(2)
48-54
In the Clinic
• In a patient with neuropathic pain should
an empirical trial of Vitamin B12 be
considered?
• If not should B12 level be measured with
a trigger for supplementation?
Other Investigational Areas
• Visceral anticholinergic pathway (vagus) –
meditation, nicotine
• Gut inflammation – probiotics
• Brain inflammation – tryptophan
• Vitamin D3
In Summary
• Things are much more complex than one
realises.
• Drug trials really do have to be done on
an individual basis – you never can tell.
• Don’t just attend to the drugs.
• Attend to the metabolic milieu in which
these drugs are going to exist.
• Become comfortable with being a
metabologist
In the Clinic
• Consider:
• Cholesterol, Testosterone, 25OH Vitamin
D, Vitamin B12, Magnesium
• Aim hsCRP<1mg/L ???
If All Else
Fails
ENCOURAGE A
HEALTHY
LIFESTYLE