Vascular PainVascular Painandand

Medical Treatment of Medical Treatment of Intermittent ClaudicationIntermittent Claudication

Chp 37, 40 Chp 37, 40 Maureen Tedesco, MDMaureen Tedesco, MD

Vascular SurgeryVascular Surgery

August 29, 2005August 29, 2005

PainPain

Nociceptive pain: associated with injurious Nociceptive pain: associated with injurious stimulationstimulation

Neuropathic pain: transmitted in absence Neuropathic pain: transmitted in absence of injury of injury

Location, duration, quality, severity, Location, duration, quality, severity, intensity intensity

Can result from physical stimuli, or Can result from physical stimuli, or chemical effects (pH change, mediators)chemical effects (pH change, mediators)

Nociceptive painNociceptive pain

Transmitted in small unmyelinated A delta Transmitted in small unmyelinated A delta and C nerve fibersand C nerve fibersLarge and medium arteries have 2 types Large and medium arteries have 2 types of innervation: afferent (sensory) and of innervation: afferent (sensory) and autonomic (sympathetic) nervesautonomic (sympathetic) nervesarteries: stimulated by trauma, stretch or arteries: stimulated by trauma, stretch or shear shear Veins: stimulated by stretch Veins: stimulated by stretch Relieved by resolution of stimuli Relieved by resolution of stimuli

Intermittent Claudication (IC) Intermittent Claudication (IC)

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

Psuedoclaudication: Neurogenic Psuedoclaudication: Neurogenic claudicationclaudication

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

popliteal entrapment syndrome: exercise popliteal entrapment syndrome: exercise induced pain in anterolateral aspect of leg; induced pain in anterolateral aspect of leg; LE claudication in young pts LE claudication in young pts

chronic compartment syndrome: ischemia chronic compartment syndrome: ischemia d/t decreased AV pressure differential d/t decreased AV pressure differential from venous engorgement and from venous engorgement and compartment tissue hypertensioncompartment tissue hypertension

Aortic and other larger artery painAortic and other larger artery pain

Aortic aneurysmal rupture: sudden, Aortic aneurysmal rupture: sudden, steady, burning, penetrating steady, burning, penetrating

Aortic dissection: substernal or Aortic dissection: substernal or interscapular tearing, rippinginterscapular tearing, ripping

Extracranial Carotid A dissection: burning Extracranial Carotid A dissection: burning pain in lateral neckpain in lateral neck

Vasculitic pain Vasculitic pain

Diffuse, aching painDiffuse, aching pain

Diffuse pain over affected area (temple Diffuse pain over affected area (temple pain d/t temporal arteritis )pain d/t temporal arteritis )

Rest Pain, Ulcers, GangreneRest Pain, Ulcers, Gangrene

Signals impending limb lossSignals impending limb loss

Requires surgical intervention: arterial Requires surgical intervention: arterial reconstruction or amputationreconstruction or amputation

Mortality >50% over next 5 yrs Mortality >50% over next 5 yrs

Rest PainRest Pain

Diffuse, poorly localized aching/burning in Diffuse, poorly localized aching/burning in distal footdistal foot

Symptoms resolve if foot is hung over Symptoms resolve if foot is hung over edge of bed or pt risesedge of bed or pt rises

Arterial UlcerationArterial Ulceration

(non-diabetic pt) (non-diabetic pt) Shallow, nonhealing, Shallow, nonhealing, pallid erosion of skinpallid erosion of skin

Unremitting and Unremitting and severe pain severe pain

Tx: urgent Tx: urgent revascularization or revascularization or amputation amputation

GangreneGangrene

Tissue death Tissue death

Pain: ischemic Pain: ischemic neuropathy, skin and neuropathy, skin and subcutaneuous tissue subcutaneuous tissue necrosis, osteomyelitis, necrosis, osteomyelitis, and ascending and ascending infectioninfection

Paradoxically less pain Paradoxically less pain than expected as distal than expected as distal feet may be insensate feet may be insensate

Blue toe syndrome Blue toe syndrome

Atheroembolism to toes Atheroembolism to toes or distal foot occurs b/c of or distal foot occurs b/c of digital or branch artery digital or branch artery occlusion from occlusion from clot/atheroma that has clot/atheroma that has embolized into the distal embolized into the distal circulation from a circulation from a proximal sourceproximal source

Pain is uncommon until Pain is uncommon until digital ischemia is severe digital ischemia is severe

Diabetic footDiabetic foot

Chronic LE and foot Chronic LE and foot pain, nonhealing pain, nonhealing ulceration, toe ulceration, toe gangrenegangreneunderlying pathologyunderlying pathology- diabetic neuropathy - diabetic neuropathy - structural changes- structural changes

- inability to fight - inability to fight bacterial infections bacterial infections - not ischemia- not ischemia

Pain associated with Small artery Pain associated with Small artery DiseaseDisease

Raynaud’s Syndrome: Raynaud’s Syndrome: coolness, pallor, numbness, coolness, pallor, numbness, cyanosis, paincyanosis, pain- Abnormal arterial reactivity- Abnormal arterial reactivity- Dull acheness, fiery pain - Dull acheness, fiery pain Raynaud’s phenomenon: Raynaud’s phenomenon: digital arterial occlusion due digital arterial occlusion due to rheumatoid conditions; to rheumatoid conditions; digital vasoconstrictiondigital vasoconstriction vasodilation vasodilation

-Fingertip ulceration and -Fingertip ulceration and necrosis necrosis

Pain associated with Small artery Pain associated with Small artery DiseaseDisease

Buerger’s Disease (thrombangiitis Buerger’s Disease (thrombangiitis obliterans): nonatherosclerotic necrotizing obliterans): nonatherosclerotic necrotizing process involving arteries, veins and process involving arteries, veins and nerves in the extremities; nerves in the extremities;

severe, unremitting, aching, burning and severe, unremitting, aching, burning and agonizing foot and hand pain agonizing foot and hand pain

Pain associated with Venous Pain associated with Venous DisordersDisorders

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

Venous Stasis pigmentation Venous Stasis pigmentation

Pain associated with Lymphatic DxPain associated with Lymphatic Dx

Lymphedema praecox- idiopathic Lymphedema praecox- idiopathic nonvenous swelling of a lower extremity nonvenous swelling of a lower extremity

Lymphedema not painful unless cellulitis Lymphedema not painful unless cellulitis or lymphangitis is present or lymphangitis is present

Pain Associated with AmputationPain Associated with Amputation

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

Medical Treatment of Intermittent Medical Treatment of Intermittent Claudication Claudication

Platelet InhibitorsPlatelet Inhibitors

ASA, PlavixASA, Plavix

VasodilatorsVasodilators

Trental, Pletal, Praxilene, Levocarnitine, Trental, Pletal, Praxilene, Levocarnitine, Chelation Tx, Arginine, Chelation Tx, Arginine, Ginko bilobaGinko biloba, , Buflomedil, Ketanserin, Niacin, LovastatinBuflomedil, Ketanserin, Niacin, Lovastatin

Intermittent claudicationIntermittent claudication

Clinical condition of ischemic extremity Clinical condition of ischemic extremity muscular discomfort induced by exercise muscular discomfort induced by exercise and relieved by short periods of restand relieved by short periods of restmanifestation of PAD due to manifestation of PAD due to atherosclerosis atherosclerosis Consequence: serious lifestyle Consequence: serious lifestyle modificationsmodifications15% deteriorate and progress to critical 15% deteriorate and progress to critical limb ischemia limb ischemia

Conservative treatment for mild-Conservative treatment for mild-moderate diseasemoderate disease

Lifestyle modifications: smoking cessation, Lifestyle modifications: smoking cessation, diet diet

Lengthen pain-free and maximal walking Lengthen pain-free and maximal walking distance by walking exercise programdistance by walking exercise program

Strict Strict supervisedsupervised exercise regimen exercise regimen

Platelet Inhibitors: ASAPlatelet Inhibitors: ASA

reduces secondary events in pts with reduces secondary events in pts with atherosclerotic dx; improves graft patencyatherosclerotic dx; improves graft patencyHas NOT been shown to improve pain free Has NOT been shown to improve pain free walking distance (PFWD), maximal walking distance (PFWD), maximal walking distance (MWD) or symptoms in walking distance (MWD) or symptoms in pts with ICpts with ICNot indicated for symptoms of claudicationNot indicated for symptoms of claudicationDue to reduction of secondary eventsDue to reduction of secondary events all all pts w/ PAD should be on ASApts w/ PAD should be on ASA

Platelet Inhibitors: Clopidogrel Platelet Inhibitors: Clopidogrel (Plavix)(Plavix)

Antiplatelet agent; better than ASA in Antiplatelet agent; better than ASA in reducing secondary events in pts with reducing secondary events in pts with atherosclerosis atherosclerosis

CAPRIE trial: showed reduction in stroke, CAPRIE trial: showed reduction in stroke, MI, death MI, death

No evidence that symptoms of IC are No evidence that symptoms of IC are reduced with Plavixreduced with Plavix

VasodilatorsVasodilators

Former theory: Dilate BVFormer theory: Dilate BV more blood to more blood to ischemic limbischemic limbReality: Ischemic tissueReality: Ischemic tissue metabolic metabolic byproductsbyproducts maximal dilation of vessels maximal dilation of vessels distal to a lesiondistal to a lesionVasodilators cause proximal and parallel Vasodilators cause proximal and parallel vessels to dilatevessels to dilate steal phenomenon steal phenomenonVasodilatorsVasodilators decreased SVR decreased SVR decreased perfusion pressure decreased perfusion pressure

CCB (verapamil): increases PFWD and CCB (verapamil): increases PFWD and MWD in one study (Bagger et al)MWD in one study (Bagger et al)

No change in ABI’sNo change in ABI’s

CCB has another effect: changes oxygen CCB has another effect: changes oxygen extraction/utilization capacityextraction/utilization capacity improve improve efficiency of oxygen use in the extremityefficiency of oxygen use in the extremity

Pure Vasodilators not recommended for IC Pure Vasodilators not recommended for IC

Pentoxifylline (Trental)Pentoxifylline (Trental)

Methylxanthine derivative Methylxanthine derivative Improvement of RBC deformity, decreases blood Improvement of RBC deformity, decreases blood viscosity, platelet aggregation inhibition, viscosity, platelet aggregation inhibition, reduction in fibrinogen levelsreduction in fibrinogen levels2 studies: increased PFWD, as did placebo, with 2 studies: increased PFWD, as did placebo, with no change in pt quality of life/ subjective no change in pt quality of life/ subjective symptoms; symptoms; May wear off with long term useMay wear off with long term useMonitor drug levels and activity if pt is on other Monitor drug levels and activity if pt is on other methylxanthine derivatives (theophylline, methylxanthine derivatives (theophylline, aminophylline)aminophylline)

Cilostazol (Pletal)Cilostazol (Pletal)

Phosphodiesterase type III inhibitorPhosphodiesterase type III inhibitor inhibits cAMP phosphodiesteraseinhibits cAMP phosphodiesterase ↑cAMP↑cAMP platelet aggregation inhibitionplatelet aggregation inhibition and and ↑SMC relaxation↑SMC relaxation

↑↑HDL, ↓ triglyceridesHDL, ↓ triglycerides

↓↓SMC proliferation (in vitro studies only)SMC proliferation (in vitro studies only)

Large double blind trial: 100 mg po bid Large double blind trial: 100 mg po bid ↑MWD + subjective improvement↑MWD + subjective improvement

Cilostazol (Pletal)Cilostazol (Pletal)

Side effects: HA, GI c/o, palpitations, Side effects: HA, GI c/o, palpitations, ↑ HR↑ HR

Start at low dose (50mg qd)Start at low dose (50mg qd)

Contraindicated in pts with CHFContraindicated in pts with CHF

Liver metabolismLiver metabolism may reduce dose if pt may reduce dose if pt is on erythromycin, antifungals, SSRI, is on erythromycin, antifungals, SSRI, omeprazole omeprazole

Increases PFWD, MWD: Increases PFWD, MWD: Keep reasonable Keep reasonable expectationsexpectations

Naftidrofuryl (Praxilene)Naftidrofuryl (Praxilene)

Serotonin antagonist; vasodilatory Serotonin antagonist; vasodilatory properties and improved efficiency of properties and improved efficiency of aerobic mechanism aerobic mechanism

Increases PFWD, not MWDIncreases PFWD, not MWD

GI c/o GI c/o

Not available in US, used frequently in Not available in US, used frequently in EuropeEurope

improves availability of substrates required improves availability of substrates required for energy production, increasing for energy production, increasing efficiency of Kreb cycleefficiency of Kreb cycle

Significant PFWD increase and subjective Significant PFWD increase and subjective improvement shownimprovement shown

Carnitine supplements available in health Carnitine supplements available in health food stores food stores

Use not currently scientifically supportedUse not currently scientifically supported

Levocarnitine Levocarnitine

Chelation therapy Chelation therapy

Binds with CaBinds with Ca+2+2 prevents progression of/ prevents progression of/ reverses atherosclerotic dxreverses atherosclerotic dx

EDTA EDTA

Data not convincing Data not convincing

Requires monitoring of Chemistry and Requires monitoring of Chemistry and hematology hematology

May function as an Antioxidant May function as an Antioxidant

New FDA study to evaluate its benefitNew FDA study to evaluate its benefit

Currently not recommended for IC Currently not recommended for IC

Arginine Arginine

aa, precursor for nitric oxide formationaa, precursor for nitric oxide formation

May May ↑PFWD, ↑ MWD↑PFWD, ↑ MWD

Further studies neededFurther studies needed

Available as oral supplement in most Available as oral supplement in most health food stores health food stores

Not currently recommended for ICNot currently recommended for IC

Ginkgo bilobaGinkgo biloba

Meta-analysis of randomized double-blind, Meta-analysis of randomized double-blind, placebo controlled trials comparing placebo controlled trials comparing Ginkgo Ginkgo biloba biloba with placebowith placebo

Ginkgo bilobaGinkgo biloba ↑PFWD, ↑MWD↑PFWD, ↑MWD

GI c/o most commonGI c/o most common

More large scale trials neededMore large scale trials needed

BuflomedilBuflomedil

Vasoactive drug, platelet inhibition, Vasoactive drug, platelet inhibition, improves RBC deformityimproves RBC deformity

Improves efficiency of muscle cell Improves efficiency of muscle cell metabolismmetabolism

Improved PFWD, MWD (Trubestein et al)Improved PFWD, MWD (Trubestein et al)

Side effects: GI c/o, HA, dizziness, Side effects: GI c/o, HA, dizziness, erythema and pharyngitiserythema and pharyngitis

Not available in US (Europe and LA)Not available in US (Europe and LA)

KetanserinKetanserin

Serotonin S-2 receptor antagonistSerotonin S-2 receptor antagonist

Extensive testing in EuropeExtensive testing in Europe

One study: no improvement of PFWDOne study: no improvement of PFWD

Not currently recommended Not currently recommended

Niacin and LovastatinNiacin and Lovastatin

Combined positive effects on total Combined positive effects on total cholesterol, LDL, triglycerides, and HDL’s, cholesterol, LDL, triglycerides, and HDL’s, combined with reduction in fibrinogen combined with reduction in fibrinogen levelslevels improve IC symptoms improve IC symptoms

Inositol niacinate (niacin derivative)Inositol niacinate (niacin derivative) improved PFWD in small studyimproved PFWD in small study

GI c/o, flushingGI c/o, flushing

Awaiting large-scale results Awaiting large-scale results

SummarySummary

Numerous and at time serious lifestyle Numerous and at time serious lifestyle consequences of ICconsequences of ICFDA approved treatment for IC: FDA approved treatment for IC: pentoxifylline (Trental) and cilostazol pentoxifylline (Trental) and cilostazol (Pletal)(Pletal)Lifestyle modification is keyLifestyle modification is keyOnly nonoperative tx consistently shown to Only nonoperative tx consistently shown to lengthen MWD and PFWD is a lengthen MWD and PFWD is a supervised exercise regimensupervised exercise regimen