Vascular Pain and Medical Treatment of Intermittent Claudication Chp 37, 40

1. Vascular PainandMedical Treatment of Intermittent ClaudicationChp 37, 40 Maureen Tedesco, MD Vascular Surgery August 29, 2005

2. Pain • Nociceptive pain: associated with injurious stimulation • Neuropathic pain: transmitted in absence of injury • Location, duration, quality, severity, intensity • Can result from physical stimuli, or chemical effects (pH change, mediators)

3. Nociceptive pain • Transmitted in small unmyelinated A delta and C nerve fibers • Large and medium arteries have 2 types of innervation: afferent (sensory) and autonomic (sympathetic) nerves • arteries: stimulated by trauma, stretch or shear • Veins: stimulated by stretch • Relieved by resolution of stimuli

4. Intermittent Claudication (IC) • reduction of arterial perfusion to an extent that it is inadequate to meet the needs of working muscles • Common in Gastrocnemius-soleus muscle group • Never at rest, occurs post exertion of specific amount, disappears quickly after cessation • Burning, aching, cramping • No trophic lesions • Ischemic neuropathy (A delta and C fibers), lactic acidosis

5. Psuedoclaudication: Neurogenic claudication • lumbosacral neurospinal compression syndrome (spinal stenosis) • more common b/l, more diffuse pain (buttocks to feet), • associated with numbess/paresthesias; • relief with bending over while walking/ postural changes • minimal or no change in Doppler ankle pressure index during lower extremity pain while walking excludes arterial occlusive disease

6. popliteal entrapment syndrome: exercise induced pain in anterolateral aspect of leg; LE claudication in young pts • chronic compartment syndrome: ischemia d/t decreased AV pressure differential from venous engorgement and compartment tissue hypertension

7. Aortic and other larger artery pain • Aortic aneurysmal rupture: sudden, steady, burning, penetrating • Aortic dissection: substernal or interscapular tearing, ripping • Extracranial Carotid A dissection: burning pain in lateral neck

8. Vasculitic pain • Diffuse, aching pain • Diffuse pain over affected area (temple pain d/t temporal arteritis )

9. Rest Pain, Ulcers, Gangrene • Signals impending limb loss • Requires surgical intervention: arterial reconstruction or amputation • Mortality >50% over next 5 yrs

10. Rest Pain • Diffuse, poorly localized aching/burning in distal foot • Symptoms resolve if foot is hung over edge of bed or pt rises

11. Arterial Ulceration • (non-diabetic pt) Shallow, nonhealing, pallid erosion of skin • Unremitting and severe pain • Tx: urgent revascularization or amputation

12. Gangrene • Tissue death • Pain: ischemic neuropathy, skin and subcutaneuous tissue necrosis, osteomyelitis, and ascending infection • Paradoxically less pain than expected as distal feet may be insensate

13. Blue toe syndrome • Atheroembolism to toes or distal foot occurs b/c of digital or branch artery occlusion from clot/atheroma that has embolized into the distal circulation from a proximal source • Pain is uncommon until digital ischemia is severe

14. Diabetic foot • Chronic LE and foot pain, nonhealing ulceration, toe gangrene • underlying pathology - diabetic neuropathy - structural changes - inability to fight bacterial infections - not ischemia

15. Pain associated with Small artery Disease • Raynaud’s Syndrome: coolness, pallor, numbness, cyanosis, pain - Abnormal arterial reactivity - Dull acheness, fiery pain • Raynaud’s phenomenon: digital arterial occlusion due to rheumatoid conditions; digital vasoconstriction vasodilation -Fingertip ulceration and necrosis

16. Pain associated with Small artery Disease • Buerger’s Disease (thrombangiitis obliterans): nonatherosclerotic necrotizing process involving arteries, veins and nerves in the extremities; • severe, unremitting, aching, burning and agonizing foot and hand pain

17. Pain associated with Venous Disorders • DVT: painless LE edema, CP • Varicosities: diffuse aching pain or burning pain secondary to stretch stimulation • Postphlebitis syndrome: chronic LE edema, secondary venous varicosities, skin changes (stasis pigmentation, eczema, subcutaneous atrophy, skin breakdown, chronic nonhealing ulcerations) • Superficial phlebitis: chemical irritation of the intima of peripheral veins; IV’s, catheters; palpable cord, pain well localized, burning

18. Venous Stasis pigmentation

19. Pain associated with Lymphatic Dx • Lymphedema praecox- idiopathic nonvenous swelling of a lower extremity • Lymphedema not painful unless cellulitis or lymphangitis is present

20. Pain Associated with Amputation • Acute: related to surgery; resolves within weeks • Stump hematoma, necrosis • Limb sensation, phantom limb pain: diminishes within months-years; may need treatment • Late postamputation pain due to poor fitting prosthesis, neuroma, ischemia, DVT, progressive autonomic dysfunction

21. Medical Treatment of Intermittent Claudication • Platelet Inhibitors ASA, Plavix • Vasodilators • Trental, Pletal, Praxilene, Levocarnitine, Chelation Tx, Arginine, Ginko biloba, Buflomedil, Ketanserin, Niacin, Lovastatin

22. Intermittent claudication • Clinical condition of ischemic extremity muscular discomfort induced by exercise and relieved by short periods of rest • manifestation of PAD due to atherosclerosis • Consequence: serious lifestyle modifications • 15% deteriorate and progress to critical limb ischemia

23. Conservative treatment for mild-moderate disease • Lifestyle modifications: smoking cessation, diet • Lengthen pain-free and maximal walking distance by walking exercise program • Strict supervised exercise regimen

24. Platelet Inhibitors: ASA • reduces secondary events in pts with atherosclerotic dx; improves graft patency • Has NOT been shown to improve pain free walking distance (PFWD), maximal walking distance (MWD) or symptoms in pts with IC • Not indicated for symptoms of claudication • Due to reduction of secondary events all pts w/ PAD should be on ASA

25. Platelet Inhibitors: Clopidogrel (Plavix) • Antiplatelet agent; better than ASA in reducing secondary events in pts with atherosclerosis • CAPRIE trial: showed reduction in stroke, MI, death • No evidence that symptoms of IC are reduced with Plavix

26. Vasodilators • Former theory: Dilate BV more blood to ischemic limb • Reality: Ischemic tissue metabolic byproducts maximal dilation of vessels distal to a lesion • Vasodilators cause proximal and parallel vessels to dilate steal phenomenon • Vasodilators decreased SVR decreased perfusion pressure

27. CCB (verapamil): increases PFWD and MWD in one study (Bagger et al) • No change in ABI’s • CCB has another effect: changes oxygen extraction/utilization capacity improve efficiency of oxygen use in the extremity • Pure Vasodilators not recommended for IC

28. Pentoxifylline (Trental) • Methylxanthine derivative • Improvement of RBC deformity, decreases blood viscosity, platelet aggregation inhibition, reduction in fibrinogen levels • 2 studies: increased PFWD, as did placebo, with no change in pt quality of life/ subjective symptoms; • May wear off with long term use • Monitor drug levels and activity if pt is on other methylxanthine derivatives (theophylline, aminophylline)

29. Cilostazol (Pletal) • Phosphodiesterase type III inhibitor inhibits cAMP phosphodiesterase ↑cAMP platelet aggregation inhibition and ↑SMC relaxation • ↑HDL, ↓ triglycerides • ↓SMC proliferation (in vitro studies only) • Large double blind trial: 100 mg po bid  ↑MWD + subjective improvement

30. Cilostazol (Pletal) • Side effects: HA, GI c/o, palpitations, ↑ HR • Start at low dose (50mg qd) • Contraindicated in pts with CHF • Liver metabolism may reduce dose if pt is on erythromycin, antifungals, SSRI, omeprazole • Increases PFWD, MWD: Keep reasonable expectations

31. Naftidrofuryl (Praxilene) • Serotonin antagonist; vasodilatory properties and improved efficiency of aerobic mechanism • Increases PFWD, not MWD • GI c/o • Not available in US, used frequently in Europe

32. Levocarnitine • improves availability of substrates required for energy production, increasing efficiency of Kreb cycle • Significant PFWD increase and subjective improvement shown • Carnitine supplements available in health food stores • Use not currently scientifically supported

33. Chelation therapy • Binds with Ca+2 prevents progression of/ reverses atherosclerotic dx • EDTA • Data not convincing • Requires monitoring of Chemistry and hematology • May function as an Antioxidant • New FDA study to evaluate its benefit • Currently not recommended for IC

34. Arginine • aa, precursor for nitric oxide formation • May ↑PFWD, ↑ MWD • Further studies needed • Available as oral supplement in most health food stores • Not currently recommended for IC

35. Ginkgo biloba • Meta-analysis of randomized double-blind, placebo controlled trials comparing Ginkgo biloba with placebo • Ginkgo biloba↑PFWD, ↑MWD • GI c/o most common • More large scale trials needed

36. Buflomedil • Vasoactive drug, platelet inhibition, improves RBC deformity • Improves efficiency of muscle cell metabolism • Improved PFWD, MWD (Trubestein et al) • Side effects: GI c/o, HA, dizziness, erythema and pharyngitis • Not available in US (Europe and LA)

37. Ketanserin • Serotonin S-2 receptor antagonist • Extensive testing in Europe • One study: no improvement of PFWD • Not currently recommended

38. Niacin and Lovastatin • Combined positive effects on total cholesterol, LDL, triglycerides, and HDL’s, combined with reduction in fibrinogen levels improve IC symptoms • Inositol niacinate (niacin derivative) improved PFWD in small study • GI c/o, flushing • Awaiting large-scale results

39. Summary • Numerous and at time serious lifestyle consequences of IC • FDA approved treatment for IC: pentoxifylline (Trental) and cilostazol (Pletal) • Lifestyle modification is key • Only nonoperative tx consistently shown to lengthen MWD and PFWD is a supervised exercise regimen