Hidden Metabolic Drivers of Hidden Metabolic Drivers of PainPain

Dr Marc A. RussoDr Marc A. RussoMBBS DA FANZCA FFPMANZCAMBBS DA FANZCA FFPMANZCA

FPM Spring Meeting 2010FPM Spring Meeting 2010

Traditional PharmacologyTraditional Pharmacology

• Proven efficacy as single agent in Proven efficacy as single agent in controlled animal studies. All other controlled animal studies. All other variables kept the same.variables kept the same.

• Often 80-100% reduction in outcome.Often 80-100% reduction in outcome.

• Why do we see 10-40% reduction in Why do we see 10-40% reduction in clinical practice?clinical practice?

Why do our drugs work so Why do our drugs work so poorly?poorly?

• Non controlled conditions, complianceNon controlled conditions, compliance

• Diet, sleep, mood variabilityDiet, sleep, mood variability

• Multiple drugsMultiple drugs

• Multiple different genetic strains of humanMultiple different genetic strains of human

Areas to be ReviewedAreas to be Reviewed

• ATP sensitive Potassium ChannelATP sensitive Potassium Channel

• Nitric oxide signaling systemNitric oxide signaling system

• MagnesiumMagnesium

• Drug efflux pumpDrug efflux pump

• Vitamin B12Vitamin B12

ATP K ChannelATP K Channel

K ChannelK Channel

• Channel must be open for G protein Channel must be open for G protein coupling to mu opioid receptorcoupling to mu opioid receptor

• Closed channel inhibits opioid induced Closed channel inhibits opioid induced antinociceptionantinociception

• High BSL, diabetic drugs close channelHigh BSL, diabetic drugs close channel

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

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

• Cholesterol blocks the channelCholesterol blocks the channel• Lee SY Cholesterol inhibits M-type K+ channels via protein kinase Lee SY Cholesterol inhibits M-type K+ channels via protein kinase

C phosphorylation in sympathetic neurons J Biol Chem 2010 Apr C phosphorylation in sympathetic neurons J Biol Chem 2010 Apr 285(14) 10939-50285(14) 10939-50

• Level required in patch clamp Level required in patch clamp corresponds to serum level of 6.0 corresponds to serum level of 6.0 mmol/Lmmol/L

Nitric Oxide, Reactive Oxygen Nitric Oxide, Reactive Oxygen SpeciesSpecies

• Morphine inhibits super oxide dismutase Morphine inhibits super oxide dismutase (SOD)(SOD)

• More super oxide combines with nitric More super oxide combines with nitric oxide to form peroxynitrite which disrupts oxide to form peroxynitrite which disrupts pre and post opioid receptor synaptic pre and post opioid receptor synaptic functionfunction

• Salvemini D Peroxynitrite: a strategic linchpin of opioid analgesic Salvemini D Peroxynitrite: a strategic linchpin of opioid analgesic tolerance Trends in Pharmacol Sci 2009 Apr 30(4) 194-202tolerance Trends in Pharmacol Sci 2009 Apr 30(4) 194-202

• End result: Opioid ToleranceEnd result: Opioid Tolerance

Reversing Nitroxidative Reversing Nitroxidative StressStress• Cox-2 inhibitorsCox-2 inhibitors

• Vitamin CVitamin C

• Allopurinol (xanthine oxidase)Allopurinol (xanthine oxidase)

• GTN, nicorandilGTN, nicorandil

Magnesium – The Ubiquitous Magnesium – The Ubiquitous IonIon

• Multiple roles in regulation in the Multiple roles in regulation in the bodybody

• Serum levels do not well reflect body Serum levels do not well reflect body tissue stores except at extreme low tissue stores except at extreme low levelslevels

Poster IASP Montreal 2010Poster IASP Montreal 2010

• 50% of CRPS patients were magnesium deficient 50% of CRPS patients were magnesium deficient as defined by an inadequate urinary excretion of as defined by an inadequate urinary excretion of magnesium compared to healthy controls after an magnesium compared to healthy controls after an IV magnesium load.IV magnesium load.

• Does this explain the failure rate of IV Ketamine Does this explain the failure rate of IV Ketamine infusions in treating CRPS?infusions in treating CRPS?

• Could one Mg load in CRPS patients prior to Could one Mg load in CRPS patients prior to commencing ketamine infusion improve commencing ketamine infusion improve outcomes?outcomes?

Mg DeficiencyMg Deficiency

• Serum magnesium levels below Serum magnesium levels below 0.85mmol/l associated with systemic 0.85mmol/l associated with systemic inflammatory responseinflammatory response

• Nielsen FH Magnesium,Inflammation and Obesity in chronic Nielsen FH Magnesium,Inflammation and Obesity in chronic disease Nutrit Rev 2010 Jun 68(6) 333-40disease Nutrit Rev 2010 Jun 68(6) 333-40

Magnesium and PainMagnesium and Pain

• Magnesium blocks the development Magnesium blocks the development of morphine toleranceof morphine tolerance

• Habibi-Asl B Development of morhpine induced tolerance and Habibi-Asl B Development of morhpine induced tolerance and withdrawal symptoms is attenuatedby lamotrigene and withdrawal symptoms is attenuatedby lamotrigene and magnesium sulphate in mice Pak J Biol Sci 2010 May 15 12(10) magnesium sulphate in mice Pak J Biol Sci 2010 May 15 12(10) 798-803798-803

P-GylcoproteinP-Gylcoprotein

• Acts as a drug efflux pumpActs as a drug efflux pump

• Normally acts as an extrusion mechanism Normally acts as an extrusion mechanism for removing intracellular debrisfor removing intracellular debris

• Can be upregulated by contact with drugs Can be upregulated by contact with drugs thus leading to multidrug resistancethus leading to multidrug resistance

• Prednisone is one of the major activators of Prednisone is one of the major activators of the drug efflux pumpthe drug efflux pump

• Dilger K Identification of budesonise and prednisone as substrates of the Dilger K Identification of budesonise and prednisone as substrates of the intestinal drug efflux pump P Glycoprotein Inflammat Bowel Dis 2004 Sep intestinal drug efflux pump P Glycoprotein Inflammat Bowel Dis 2004 Sep 10(5)578-8310(5)578-83

• Clinical Corollary: Once on steroids your drugs Clinical Corollary: Once on steroids your drugs won’t work wellwon’t work well

• This can be reversed by Sulfasalazine This can be reversed by Sulfasalazine increasing glucocorticoid receptor expressionincreasing glucocorticoid receptor expression

• Oerlmans R Ann Rheum Dis 2007 Oct 66(10) 1289-95Oerlmans R Ann Rheum Dis 2007 Oct 66(10) 1289-95

In the ClinicIn the Clinic

• Don’t do lots of steroid blocks close Don’t do lots of steroid blocks close together. You will make the patient together. You will make the patient refractory to their benefit.refractory to their benefit.

• Use SparinglyUse Sparingly

Vitamin B12Vitamin B12

• 26% of >65 year olds have evidence of 26% of >65 year olds have evidence of peripheral neuropathy, rises to 54% in age>85peripheral neuropathy, rises to 54% in age>85

• Loss of ankle reflex, fine touch discriminationLoss of ankle reflex, fine touch discrimination

• OR >2 for Vitamin B12 deficiency, Rheumatoid OR >2 for Vitamin B12 deficiency, Rheumatoid Arthritis, Diabetes Mellitus Arthritis, Diabetes Mellitus

• Mold JW The prevalence, predictors and consequences of peripheral sensory Mold JW The prevalence, predictors and consequences of peripheral sensory neuropathy in older patients J Am Board Fam Pract 2004 Sep/Oct 17(5) 309-18neuropathy in older patients J Am Board Fam Pract 2004 Sep/Oct 17(5) 309-18

Vitamin B12Vitamin B12

• Is an antineuropathic drug!Is an antineuropathic drug!

• Reduced tactile allodynia in a spinal Reduced tactile allodynia in a spinal nerve ligation model in dose nerve ligation model in dose dependant manner.dependant manner.

• Granados-Soto V Proc West Pharmacol Soc 2004 47 92-4Granados-Soto V Proc West Pharmacol Soc 2004 47 92-4

Human DataHuman Data

• 7 RCTs with positive effects on 7 RCTs with positive effects on diabetic neuropathy.diabetic neuropathy.

• Pain and paraesthesia improvedPain and paraesthesia improved

• Acta Neurol Taiwan Effectiveness of Vtamin B12 on diabetic Acta Neurol Taiwan Effectiveness of Vtamin B12 on diabetic neuropathy:systematic review of clinical controlled trials 2005 neuropathy:systematic review of clinical controlled trials 2005 Jun 14(2) 48-54Jun 14(2) 48-54

In the ClinicIn the Clinic

• In a patient with neuropathic pain In a patient with neuropathic pain should an empirical trial of Vitamin should an empirical trial of Vitamin B12 be considered?B12 be considered?

• If not should B12 level be measured If not should B12 level be measured with a trigger for supplementation?with a trigger for supplementation?

Other Investigational AreasOther Investigational Areas

• Visceral anticholinergic pathway (vagus) – Visceral anticholinergic pathway (vagus) – meditation, nicotinemeditation, nicotine

• Gut inflammation – probioticsGut inflammation – probiotics

• Brain inflammation – tryptophanBrain inflammation – tryptophan

• Vitamin D3Vitamin D3

In SummaryIn Summary

• Things are much more complex than Things are much more complex than one realises.one realises.

• Drug trials really do have to be done Drug trials really do have to be done on an individual basis – you never on an individual basis – you never can tell.can tell.

• Don’t just attend to the drugs.Don’t just attend to the drugs.

• Attend to the metabolic milieu in Attend to the metabolic milieu in which these drugs are going to exist.which these drugs are going to exist.

• Become comfortable with being a Become comfortable with being a metabologistmetabologist

In the ClinicIn the Clinic

• Consider:Consider:

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

• Aim hsCRP<1mg/L ???Aim hsCRP<1mg/L ???

If All ElseIf All Else Fails Fails

ENCOURAGE AENCOURAGE A

HEALTHYHEALTHY

LIFESTYLELIFESTYLE