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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.

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Hidden Metabolic Drivers of Pain

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Hidden metabolic drivers of pain

Hidden Metabolic Drivers of Pain

Dr Marc A. Russo


FPM Spring Meeting 2010

Traditional pharmacology

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

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

Areas to be Reviewed

  • ATP sensitive Potassium Channel

  • Nitric oxide signaling system

  • Magnesium

  • Drug efflux pump

  • Vitamin B12

Atp k channel

ATP K Channel

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

Hidden metabolic drivers of pain

  • Only fentanyl family and levorphanol activate MOR independent of the K channel.

    Clinical corollary: In diabetics Transdermal Fentanyl is the opioid of choice.

Hidden metabolic drivers of pain

  • 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

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

Reversing Nitroxidative Stress

  • Cox-2 inhibitors

  • Vitamin C

  • Allopurinol (xanthine oxidase)

  • GTN, nicorandil

Magnesium the ubiquitous ion

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

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

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 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

Hidden metabolic drivers of pain

  • 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

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

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 b121

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

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 clinic1

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

Other Investigational Areas

  • Visceral anticholinergic pathway (vagus) – meditation, nicotine

  • Gut inflammation – probiotics

  • Brain inflammation – tryptophan

  • Vitamin D3

In summary

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.

Hidden metabolic drivers of pain

  • 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 clinic2

In the Clinic

  • Consider:

  • Cholesterol, Testosterone, 25OH Vitamin D, Vitamin B12, Magnesium

  • Aim hsCRP<1mg/L ???

If all else fails

If All Else Fails




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