By late middle age 5% of men and women will have developed peripheral arterial disease and within 5 years 25% of these will develop pain at rest, ulceration, and gangrene (critical limb ischemia).¹ Physicians who practice in the specialty of pain medicine need to be familiar with the causes and treatment of pain due to peripheral vascular disease because it has a high prevalence. Appropriate therapy and management can significantly improve the quality of life for patients. Pain medicine physicians, by encouraging secondary or tertiary preventive therapy, have the opportunity to improve the life expectancy of their patients with symptomatic peripheral vascular disease of whom more than 50% have disease of the coronary and/or carotid arteries. This chapter will outline the disease conditions and treatments for pain associated with peripheral vascular disease.²

The ischemic pain of peripheral vascular disease can be approximated by sustained tourniquet inflation on an extremity. In experimental studies, as time passes, tissue oxygenation levels fall, metabolic byproducts accumulate, reactive cellular agents are released, nociceptive signals entering the central nervous system (CNS) increase, and patients report increasing intensity of pain. The affective descriptors for this pain differ and are more difficult to tolerate than pain produced by other experimental modalities. Patients with peripheral vascular disease experience this type of pain without the ability to restore blood flow by releasing the tourniquet. Effective management of this pain can restore quality of life for these patients.

Arterial insufficiency is most commonly the result of occlusive diseases with atheroma formation (arteriosclerosis obliterans), but less commonly occurs in thromboangiitis obliterans (Buerger disease), Raynaud syndrome, diabetic arteritis, and arteritis associated with collagen disease. Other diseases with vascular-related causes such as migraine and cluster headache are discussed elsewhere (see Chapter 3).

ATHEROMA AND ITS CONSEQUENCES: ARTERIOSCLEROSIS

The role of lipids was suggested with the early appearance of fatty streaks in young soldiers during emergency surgery and at autopsy in the 1970s. The role of lipids distinguishes arteriosclerosis from other arterial disease. Primary and secondary prevention strategies are available to reduce the incidence and/or aggressively treat the known risk factors of hypercholesterolemia, hypertension, cigarette smoking, and poor control of diabetes. As the disease progresses, plaque formation tends to occur at bifurcations in large and medium-sized arteries where turbulence, alteration of laminar flow, and shear stress may provoke an endothelial and/or vascular smooth muscle response. Arteriosclerosis is a dynamic process that involves vascular and inflammatory tissue responses with decreased release of nitric oxide (NO) and other protective secretions, increased release of cytokines by inflammatory cells responding to exposed matrix, and release of growth factors from the endothelium, as well as platelet activation. Arteries may respond initially to this process with an increase in size, but arterial remodeling may not be sustained in the face of ongoing plaque accumulation. Although a full discussion of arteriosclerosis is beyond the scope of this chapter, understanding of the causes at the gene and cellular level will suggest effective treatment options.

PROGRESSION OF ATHEROMATOUS PLAQUES

Although arteriosclerosis is most prominent at bifurcations, the straight femoropopliteal segment is involved in 60% of lower limb disease; the upper limbs are less often involved. Initially, as vessel diameter decreases, flow can be maintained if velocity increases. Vessel size also may increase, specifically at the arteriolar level, forming a collateral supply. As vessel diameter continues to decrease beyond 70%, the patient may develop symptoms, especially if the process is affecting collateral vessels as well. Initial symptoms usually occur during exercise when the circulation is stressed. Even in patients with severe claudication, blood flow may be near normal at rest. With progression, critical limb ischemia develops with an incidence of 0.5 to 1 per 1000.³

MECHANISM OF PAIN FROM ARTERIAL DISEASE

Oxygen is the most flow-limited nutrient for muscle and skin. Striated muscle is capable of working anaerobically, with delayed repayment of the oxygen debt. Lactate and pyruvate levels rise as oxygen debt continues. It is assumed that the accumulation of these products of metabolism trigger firing of C-fiber nociceptors, thus triggering the pain cascade.

As oxygen tissue levels fall, hypoxia triggers altered Ca²⁺ signaling in vascular smooth muscle,⁴ gene transcription for expression of inflammatory cytokines such as tumor necrosis factor,⁵ Interleukin-1 and 10 (IL-1, IL-10),⁶ and cytokine factors promoting vessel growth,^7,8 particularly growth of small vessels less than 200 microns in diameter.⁹ Endothelial dysfunction is associated with altered release of a mediator such as NO, eicosanoid, endothelium-derived hyperpolarizing factor, endothelin, and angiotensin II.¹⁰ Inflammatory cytokines also affect the coagulation system; for example, hypoxia-triggered release of IL-1 can decrease tissue plasminogen activator and stimulate release of plasminogen activator inhibitor-1.¹¹ Decreased release of NO leads to increased endothelial adhesiveness to circulating white blood cells.¹² Inflammatory mediators may both directly and indirectly trigger C-fiber nociceptor barrage into the CNS.

CLINICAL PICTURE OF OCCLUSIVE ARTERIAL DISEASE

The patient may have complaint of claudication and/or rest pain. Claudication is defined as pain in a muscle group (commonly the calf, less often the thigh, instep or buttock) that occurs while walking and forces the patient to stop. Pain is rapidly relieved by rest after which walking can be resumed. Walking distance typically decreases as the disease progresses. The diagnosis can often be made with a careful history. Another disease such as arthritis may produce infirmity so the patient is unable to tolerate exercise. In these patients the diagnosis may be made by examination. In patients with severe coronary disease, the angina linked to very low-effort walking may occur before claudication, masking this presentation of the disease. Often the reverse is true, and the presence of claudication may limit the patient’s exercise tolerance so that even significant coronary disease may remain quiescent. Because 50% of patients with symptomatic peripheral vascular disease have coronary artery disease, patients with claudication have a 50% 10-year survival rate with most deaths due to myocardial infarction.¹³ Patients with claudication should receive preventive treatment to reduce the risk of myocardial infarction.

The differential diagnosis of claudication includes venous and neurogenic claudication. The latter is often associated with stenosis of the central spinal canal. In spinal stenosis during walking or standing, the cauda equina can become constricted within the narrowed canal, with decreased perfusion causing progressively intense lower extremity. In this case, pain may be worse with trunk extension and better with flexion. Watch for this clinical pearl when the patient reports that walking downhill (extending the spine) is more painful than walking uphill, especially in the setting where peripheral pulses are strong on examination. Lack of spina canal stenosis on computed tomography (CT) or magnetic resonance imaging (MRI) makes this diagnosis less likely. If the history is adequate, the site of claudication may also indicate the level of occlusion (Table 61-1). Intermittent claudication is more common in men than in women in whom it is rare before menopause.

Pedal ischemia rest pain occurs in the toes or forefoot with or without ulceration or gangrene. The history of ischemic pain is invariably that of pain occurring at night (after a variable recumbent period), which causes the patient to arise and is relieved by limb dependency. The patient may indicate that sleep is better in a chair. As the condition progresses, pain becomes continuous and the toes deteriorate. Ulceration or gangrene may occur. Spontaneous tissue necrosis may occur in the most peripheral distribution and is likely to affect the toes. It may also occur following trauma, overzealous chiropody, or orthopedic procedures including bunionectomy and treatment for ingrown toenails. Usually preceded by claudication, pedal ischemia may appear in patients who have little or no claudication pain.

OTHER RELEVANT HISTORY

Arteriosclerosis is a systemic disease and the history may be positive for myocardial ischemia (infarcts or angina), stroke, hypertension, arrhythmias, and transient ischemic attacks (in the form of focal neurologic deficits resolving within 24 h). A careful medication history may reveal the extent to which secondary prevention efforts have been successful. The extent of aspirin use and monitoring of cholesterol concentration in a follow-up of patients in the British regional heart study showed that most patients with intermittent claudication without history of myocardial infarction (MI), angina, cerebrovascular accident (CVA), were not receiving appropriate secondary prevention.¹⁴ Behavioral interventions may be helpful if a history of tobacco use is elicited and psychosocial stressors are present.¹⁵ An excellent review of the effect of smoking and cessation on mortality, morbidity, and quality of life was published in 2010.¹⁶ In an 11-hospital study, 711 consecutive Dutch patients with surgical treatment of peripheral arterial disease were followed prospectively for 5 years. Interestingly, there was a negative result for the primary aim among 5-year survivors.

PHYSICAL EXAMINATION

The general examination includes blood pressure measurement, cardiac auscultation, and funduscopy. Local examination will reveal ischemic tissue loss and poor capillary circulation. Low input arterial pressure can be enhanced by elevating the legs above the heart for 2 minutes while the patient repeatedly dorsoplantar flexes the ankles; this will produce elevation pallor.

All accessible pulses should be palpated and large vessels (e.g., femoral) should be auscultated for presence of a bruit as indication of proximal stenosis. The data should be charted, as shown in Table 61-2.

INVESTIGATIONS

The general assessment of the patient is aided by chest radiography, cardiography, complete blood count (CBC), and blood chemistries that include a lipid profile. Echocardiography¹⁷ testing of coagulation activity includes prothrombin time (PT), partial prothrombin time (PTT), and international normalized ratio (INR) for patients on coumarin. Testing fibrinogen and plasminogen activator inhibitor-1 levels has been suggested.¹⁸ Noninvasive localization of disease by technology such as combined echo-Doppler (duplex) is preferred both for diagnosis and choosing between surgery and percutaneous transluminal angioplasty (PTA).¹⁹ Magnetic resonance technologies are capable of providing high quality noninvasive studies with sensitivity and specificity comparing favorably to digital subtraction angiography.²⁰ The standard test remains the ankle-to-arm ratio (ankle-brachial-index [ABI]). Systolic pressure at the ankle is compared with systemic arterial pressure measured in the arm. This measure is far more sensitive than pulse oximetry.²¹ Observed values are related to clinical state (Table 61-3). When distal vessels are calcified and poorly compressible, the ABI may prove unhelpful and values greater than 1.50 may be obtained. Angiography is generally performed prior to reconstructive surgery.

MANAGEMENT OF MAJOR ARTERIAL OCCLUSION

Management of a patient with an ischemic lower limb is summarized in the flow chart

TREATMENT OF CLAUDICATION

Conservative treatment includes observation and treatment of associated conditions such as diabetes, anemia, or polycythemia. Efforts to assist patients with smoking cessation and to engage in regular exercise have been shown to improve outcome and quality of life.²² Over 3 months of supervised treadmill exercise (at claudication threshold for 30 to 40 minutes three times each week), marked improvement was demonstrated with increased time to claudication, increased peak walking and improved endothelial function.²³ Thought to mediate these positive changes, NO concentration increases with exercise but for patients with claudication, a reduction in NO stores may limit this effect. Might it be possible to boost the benefit of exercise in these patients by increasing NO stores, for example by increasing the concentration of its immediate precursor, plasma nitrite (NO2−)? This may be the case when increased oral consumption of dietary nitrates (NO3−), converted by a salivary enzyme to (NO2−), results in increased time to claudication and exhaustion, 32 and 65 seconds, respectively (Fig. 61-1).²⁴

The severity of claudication, response (or lack of response) to medical management, impact on lifestyle, and quality of life must be weighed against the risks before proceeding with a surgical treatment or percutaneous transluminal angioplasty (PTA.) The PTA procedure has high success rates for large vessels with short lesions such as the common iliac, and may be performed as a same-day procedure. Stenting may improve success rates when lesions are more complex or repeat therapy is required. In smaller vessels, PTA is less effective so that, for example, prominent pedal ischemia mandates consideration of vascular surgery if it is technically feasible. Arterial reconstruction may utilize endarterectomy, in situ or reverse venous or synthetic grafting material. The many variations and details are beyond the scope of this chapter; however, the efficacy of bypass surgery for treatment of lower limb ischemia is supported by evidence-based medicine review.²⁵

SYMPATHECTOMY

Interruption of the lumbar sympathetic chain has a time-honored place in the treatment of peripheral ischemia. Before the advent of arterial reconstruction, it was the only surgical measure that produced pain relief. The indications for sympathectomy have diminished considerably over the last 50 years. Currently this treatment has a limited role.^26,27 Reports of the procedure performed successfully by laparoscopy and with chemical sympathectomy continue to appear in the literature.^28,29 Sympathectomy may improve blood flow to the foot and may improve rest pain, heal ulceration, and prevent skin necrosis.