Ischemic pain affects millions of people worldwide. It is a detriment to quality of life and carries with it significant morbidity and mortality. Ischemic pain occurs when there is obstruction of the circulation to an area of the body. The myocardium, lower extremities, and mesentery can be affected primarily from the development of atherosclerosis obliterans. Pain management centers are becoming more involved in the care of patients with ischemic diseases because the centers can offer interventional procedures applicable to these diseases. This chapter provides a review of the pathophysiology of ischemic disease, existing and emerging therapies available and their efficacy, and the role of the pain specialist in the management of patients with peripheral, coronary, and mesenteric ischemic disease.

CHARACTERISTICS

Limb ischemia can be caused by atherosclerosis obliterans as well as atheroembolic or thromboembolic disease, vasculitis, trauma, and other disease processes. Limb ischemia affects macrovascular and microvascular circulation. Peripheral artery disease (PAD) is a marker for cardiovascular disease (CVD) and affects 8 million Americans.

Ischemic pain in PAD is insidious and gradual in onset. The pain is described as an aching and cramping sensation that is worse at night and improves when the legs are in a dependent position, which improves blood flow. Most patients have atherosclerotic changes for 5 to 10 years before they have symptoms. Intermittent claudication is the earliest sign of vascular insufficiency, which is characterized by cramping, tightness, and heaviness that increase with exercise. The pain is relieved with rest and the claudication distance remains fairly constant until further progression of the disease. The differential diagnosis for intermittent claudication is listed in Table 62-1.

In the early stages of PAD, collateral circulation develops and may maintain adequate perfusion to the affected limb, but may not provide sufficient blood flow to prevent symptoms, especially during exercise. Approximately 25% of patients with intermittent claudication will progress to critical ischemia and pain at rest, secondary to the primary and collateral vessels becoming stenotic or occluded. When rest pain occurs, the degree of vascular insufficiency is severe. When ischemic pain at rest, tissue necrosis, and/or gangrene develop, patients fall into the category of critical limb ischemia (CLI) and will likely require surgery or endovascular procedures for pain control, limb salvage, and wound healing. Diagnosis and treatment is essential to minimize these sequelae (Table 62-2).

The most common sites of atherosclerosis obliterans are the femoropopliteal arterial segment and the aortoiliac vessels, causing pain in the calves and buttocks, respectively. With progression of the disease, gangrene, ischemic ulcers, and trophic changes can occur in the more distal locations, namely the distal foot and toes. Ischemic ulcers can occur spontaneously; however, trauma is usually the inciting event leading to ulcer formation. The injury is unable to heal due to poor perfusion. Trophic changes, specifically dry scaly skin, loss of hair, and thick nails, are signs of arterial insufficiency.

TREATMENT

Management of PAD includes risk factor modification, antiplatelet, and antithrombotic drugs. Critical limb ischemia necessitates the addition of interventional treatments such as bypass surgery or angioplasty. Patients with CLI, refractory to or not amenable to surgery, or those seeking an alternative treatment, may be candidates for spinal cord stimulation (SCS).

MEDICAL

Current guidelines recommend smoking cessation which may include pharmacotherapy and/or enrollment in a smoking cessation program. Patients with PAD who continue to smoke have a greater risk of amputation, death, myocardial infarction (MI), and lower patency rates with angioplasty or surgical revascularization.¹

Diabetes contributes significantly to morbidity and mortality in patients with PAD. Additionally, diabetic patients are 20% to 30% more likely to develop PAD. Severity of diabetes and symptoms of PAD are directly correlated. Managing comorbidities such as hyperlipidemia, hypertension, and obesity are integral to the care of patients with PAD. Hypertension is associated with the development of atherosclerosis. Statins have been shown to diminish symptoms of claudication in patients with dyslipidemia and cardiac disease.² Protective and prophylactic care of the feet including good hygiene, avoidance of trauma, pressure points, and poorly fitting shoes is imperative to prevent ischemic ulceration and gangrene. Keeping the feet clean, dry, and free from infection is also important.

Antiplatelet therapy is a component of treatment of PAD to reduce risk of MI, stroke, and vascular death. Aspirin is recommended in doses of 75 to 325 mg per day. Clopidogrel can be used as an alternative to aspirin. The combination of these medications can also be used to decrease the aforementioned risks. Unless a patient has another proven indication for warfarin, it is not recommended as an addition to antiplatelet therapy.

INTERVENTIONAL/SURGICAL

In spite of these measures to slow the progression of atherosclerotic occlusive disease, 25% to 50% of patients will require more aggressive treatment.

The bypass versus angioplasty in severe ischemia of the leg (BASIL) trial is considered the most comprehensive randomized controlled trial to date.³ The study contrasted angioplasty to surgical vascular bypass examining overall survival and amputation-free survival. There was no significant difference after 2 years in amputation-free survival between the two arms of the study; however, bypass surgery, the first study, was associated with a significant increase in overall survival. Stenting and atherectomy are additional endovascular treatment options for patients with PAD.

For patients who are not candidates for surgical intervention, pain control, tissue salvage, and maintenance of an independent lifestyle are important issues. Unfortunately, limb amputation, which may have high perioperative mortality, may be the ultimate treatment option for some patients.

The success and efficacy of percutaneous transluminal angioplasty (PTA) has increased the number of patients treated for occlusive arterial disease who were not surgical candidates because of concomitant disease processes and substantial risk factors associated with surgery. PTA is a minimally invasive procedure that has fewer associated costs, shorter hospital stays, and fewer risks to the patient. The primary concern with PTA of the lower extremities is the long-term patency of the vessel.

Long-term success of iliac artery PTA is dependent on certain predictors as shown in Table 62-2. The early success rates of PTA for the iliac arteries range from 90% to 99% patency with 2-year patency rate of 80% to 95%. Angioplasty for femoropopliteal disease has a 2-year patency rate of 89% and a 4-year rate of 67%. Data indicate that PTA is a valuable and durable alternative to surgical revascularization (Table 62-3).

INTERVENTIONAL PAIN MANAGEMENT

Spinal Cord Stimulation

A large body of evidence now exists supporting the use of epidural SCS in the treatment of limb-threatening peripheral vascular disease as well as for intractable angina pectoris. SCS is now considered in patients who do not have surgical or other interventional options. The patients may have significant relief of their ischemic symptoms by undergoing this minimally invasive procedure with few risks to the patient with multiple comorbidities. The technique involves placement of the electrode at high lumbar or low thoracic levels.

Spinal cord stimulation was first used by Shealy et al in 1967.⁴ Early trials were plagued by equipment failures and malfunctions such as lead fracture and electrode movement. Patient selection was also poor because the specific mechanism of analgesia produced by SCS was and still is elusive. Regardless of the etiology of the pain, SCS was used in virtually any patient. The increase in the success rate of SCS over the ensuing years is a result of improved technology and better patient selection.

In the 1970s Cook et al used SCS to treat pain in patients with multiple sclerosis and noted that these patients had a significant improvement in lower extremity blood flow and a feeling of warmth in their lower extremities.⁵ Further studies showed clinical improvement in pain, microcirculation, and healing of ischemic ulcers in patients with inoperable peripheral vascular disease. Claudication distance, temperature, limb salvage rates, and exercise tolerance were substantially improved. Relief of ischemic pain appears to correlate well with an increase in microcirculatory changes and success rates of 70% to 100% pain relief are common. Macrocirculatory changes do not correlate well with relief of symptoms.

The most common use for SCS in the United States is for back pain with a predominant radicular component. The indications that may have the highest success rates are inoperable angina pectoris, peripheral vascular disease, and complex regional pain syndrome.

There are multiple theories as to how SCS improves blood flow in CLI. One postulated reason for benefit is improvement in microcirculation or nutritional blood flow. There is also support for suppression of efferent sympathetic activity causing peripheral vasodilation and secondary relief of pain. There may also be antidromic mechanism, whereby dorsal root stimulation causes activation of primary efferent fibers leading to peripheral release of CGRP and subsequent vasodilation^6–8 (Fig. 62-1).

Ubbink and Vermeulen analyzed all randomized controlled trials evaluating the effectiveness of SCS patient with nonreconstructable chronic critical leg ischemia. They concluded that there is evidence that SCS is better than conservative treatment to decrease amputation risk. There was a finding of benefit on ulcer healing and pain relief. It was found that limb salvage with SCS was comparable to distal bypass surgery. They intimated that future studies may include SCS versus bypass surgery in reconstructable CLI. Additional studies show pain reduction in patients with CLI.⁸

EMERGING THERAPIES

Future treatment therapies may include gene therapy, growth factors, and cellular therapy to stimulate collateral blood vessel growth into ischemic tissues. These therapies are currently investigational. Current research is also directed to the use of autologous endothelial progenitor cell transplantation.⁹