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Transcript
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