Chapter 51. Advances in the Management of Ischemic Pain

Ischemic pain is pain caused by obstruction of the circulation to a body part. Pain management centers have only recently become involved in the care of patients with ischemic diseases such as peripheral vascular disease and angina pectoris because now these centers have something unique to offer. This chapter provides a review of the pathophysiology of ischemic disease, the therapies available and their efficacy, and the role of the pain specialist in the management of patients with peripheral and coronary ischemic disease.

Atherosclerosis obliterans is the principal cause of ischemic pain associated with peripheral vascular disease and coronary artery disease. Ischemic pain in peripheral vascular disease is insidious and gradual in onset. It usually begins with intermittent claudication. Most patients have atherosclerotic changes for 5 to 10 years before they have symptoms. Approximately 25% of patients with intermittent claudication will progress to critical ischemia and pain at rest.

Intermittent claudication is the earliest sign of vascular insufficiency, which is characterized by cramping, tightness, and heaviness that increases with exercise. The pain is relieved with rest and the claudication distance remains fairly constant until further progression of the disease. In the early stages of the disease, 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. Over time, both the primary and collateral vessels become stenotic or occluded and critical ischemia develops with pain at rest.

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 also a sign of arterial insufficiency.

Conservative therapy for treatment of intermittent claudication includes smoking cessation and the control of contributing diseases such as hypertension, diabetes, and hyperlipidemia. 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 of infection is also important. In spite of these measures to slow the progression of atherosclerotic occlusive disease, 25% to 50% of patients will require more aggressive treatment

Ischemic pain is described as an achy and crampy sensation that is worse at night and improves when the legs are in a dependent position, which improves blood flow. When rest pain occurs, the degree of vascular insufficiency is severe and these patients are also at increased risk for diffuse atherosclerotic disease of the coronary and cerebral arteries. The differential diagnosis for intermittent claudication is shown in Table 51-1.

Atherosclerotic occlusive disease of the lower extremities can lead to intermittent claudication, ischemic pain at rest, tissue necrosis, and gangrene. In most cases, vascular reconstruction procedures are the treatment of choice. In approximately 10% to 20% of patients, revascularization procedures are not technically feasible or fail secondary to poor outflow. For patients who are not surgical candidates, pain control, tissue salvage, and maintenance of an independent lifestyle are important issues. Unfortunately, limb amputation, which may have a high perioperative mortality, may be the ultimate treatment in some of these patients.

Several noninvasive therapies are in use to treat peripheral vascular disease including antiplatelet, antithrombotic, and fibrinolytic therapies. If a patient has an underlying hereditary predisposition to a hypercoagulable disorder, this should be evaluated and treated first. The most commonly used agents are aspirin, dipyridamole, and sulfinpyrazone. Although aspirin has been shown to be useful in decreasing the incidence of thrombosis in coronary artery disease, the effectiveness of this and other antiplatelet drugs has not been clearly demonstrated for peripheral vascular disease. The fibrinolytic agents urokinase, streptokinase and tissue plasminogen activator have been tested and used extensively for the treatment of acute myocardial infarction. Their efficacy for arterial insufficiency in peripheral vascular disease has not been proven, and may be related to the fact that peripheral vascular disease is not an acute process, but rather a slow and insidious process.

Over recent years, 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 51-2. The early success rate of PTA for the iliac arteries ranges from 90% to 99% patency with a 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%. These data indicate that PTA is a valuable and durable alternative to surgical revascularization.

Operative management is still the ultimate therapy if other more conservative efforts fail. Ischemic pain at rest, and not intermittent claudication alone, is the primary indication for surgical intervention. Ischemic rest pain may lead to tissue or limb loss in 20% of patients if untreated. Only 5% of patients with intermittent claudication will require amputation if untreated. In the past, chemical lumbar sympathectomy followed by surgical sympathectomy was widely used for treatment of peripheral vascular disease. Currently, the primary operative interventions are arterial bypass surgery using the saphenous vein or polytetrafluoroethylene grafts and endarterectomy with patch graft.

A large body of evidence now exists supporting the use of epidural spinal cord stimulation (SCS) in the treatment of limb-threatening peripheral vascular disease as well as for intractable angina pectoris. SCS may be a satisfactory alternative to operative revascularization and PTA since the specific anatomy of the arterial stenosis or occlusion is irrelevant. Many patients who were previously not candidates for any type of intervention or who had failed with other therapies may have significant relief of their ischemic symptoms with a SCS device. Since SCS is a minimally invasive procedure and is placed percutaneously under local anesthesia, there are few risks to the patient.

Spinal cord stimulation was first used by Shealy and coworkers in 1967.1 Early trials were plagued by equipment failures and malfunctions such as lead fracture and electrode movement. Patient selection was also poor since the specific mechanism of analgesia produced by spinal cord stimulation was and still is elusive. SCS was utilized in virtually any patient regardless of the etiology of their pain. The increase in the success rate of spinal cord stimulation over the ensuing years is a result of the combination of improved technology and better patient selection.

In the 1970s Cook et al were using 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.2 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 appear to correlate well with relief of symptoms.

The most common use for spinal cord stimulation 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 is much theory and speculation regarding the physiologic mechanism by which spinal cord stimulation improves symptoms from arterial insufficiency. In general, most researchers concur that relief of ischemic pain is the result of improved microcirculation, since in most studies measurements of macrocirculation were not reliable predictors of long-term success.

Macrocirculatory arterial flow is measured by a variety of noninvasive techniques including segmental pressures, ankle-brachial indices, systolic toe pressures, and duplex scanning. Segmental pressures use a cuff to measure systolic pressures at two different levels of the limb and normally there should be <20 mm Hg difference in any two pressures. The ankle-brachial index, expressed as a percentage, measures the systolic ankle pressure and divides it by the brachial artery systolic pressure. The normal value is 1.0% to 1.2%. The systolic toe pressure should be 80% to 90 % of the brachial artery pressure. Duplex scanning is a combination of ultrasonic imaging of the underlying blood vessel with the capability of estimating velocity changes at different sites and evaluating distal arterial waveform morphology.

The changes that occur during SCS are primarily to the microcirculation or nutritional blood flow. The two techniques used most frequently to measure microcirulatory changes after SCS are transcutaneous oximetry and capillary microscopy. Transcutaneous oximetry measures the oxygen diffusing from the skin (TcPO2). Skin blood flow is determined by the patency of proximal arteries and TcPO2 approaches arterial PO2 when O2 delivery is high relative to consumption. TcPO2 will be low when O2 delivery is low compared with O2 consumption. Capillary microscopy is used to measure capillary diameter, red blood count (RBC) velocity, peak RBC velocity after a 1-minute occlusion, time-to-peak RBC velocity, and the density of perfused capillaries.

The Fontaine classification of peripheral vascular disease, as shown in Table 51-3, can be used to determine which patients may benefit most from SCS. Studies have shown that patients in the Fontaine class III are the most likely patients to benefit from SCS. Those patients with only intermittent claudication do respond to SCS but not to the same degree as class III patients. Patients that are already experiencing tissue loss may have pain relief from SCS, but the overall limb salvage for the class IV patient is poor.

In a study by Jacobs et al, 20 patients with inoperable ischemic rest pain were evaluated for macro- and microcirculatory changes before and after SCS.3 These patients had failed other therapies and were not candidates for any further surgical interventions. The macrocirculatory parameters of ankle-brachial index and systolic toe pressure did not change after the SCS procedure. The microcirculatory parameters measured in this study showed dramatic improvements that were statistically significant. Although the diameter of the capillaries did not increase, RBC velocity and peak RBC velocity improved within 24 hours of SCS. The long-term limb salvage was 80% at 1 year and 56% at 2 years. The mean hospital stay for patients with SCS implants was 16 days, and for patients with amputations, 91 days.

Positive prognostic factors for success of SCS for peripheral vascular disease in this study included good immediate pain relief after the SCS procedure and for Fontaine class III patients. Patients with existing tissue loss had poorer response to SCS. For patients with gangrene and ischemic ulcers of >3 cm diameter, the limb-saving effect of SCS is minimal. Patients who had no immediate relief of their pain and those who had recurrence of their pain had poorer outcomes and required amputation.

A recent study by Kumar et al included 46 patients with severe limb-threatening ischemia.4 This study found a significant increase in RBC velocity after 24 hours of SCS. An increase in peak flow velocity of at least 10 cm/second at the level of the common femoral artery was shown to correlate with good long-term success. This study also found that the combination of at least a 75% decrease in pain and an increase of TcPO2 of 10 mm after SCS, when compared with baseline values, were also good predictors of long-term success.

Increases in capillary density, capillary RBC velocity after occlusion, and a decrease in time to peak RBC velocity correlate with a decrease in ischemic pain. Measures of macrocirculation such as ankle-brachial index and systolic toe pressures do not change significantly and do not correlate with long-term success of the SCS procedure.

The actual mechanism of how SCS improves microcirculation is not well understood. There are some theories that postulate that SCS works through inhibition of preganglionic sympathetic activity. This would imply that SCS decreases, or inhibits, the maladaptive responses that occur in the microvasculature distal to an occlusion. Changes in preganglionic autonomic activity is thought to be responsible for the changes seen in ischemic disease. However, if this were the case, then patients who have had either a surgical or chemical sympathectomy would not respond to SCS. In actuality these patients do respond with the microvascular changes previously mentioned. In general, it appears that SCS alters sympathetic outflow, but whether these changes are mediated by a central or peripheral mechanism is unknown. The actual neurohumoral changes that occur with SCS are also poorly understood. There is general agreement that a decrease in ischemic pain correlates well with improved microcirculation after SCS, but is the decreased pain a result of improved circulation or is circulation improved because SCS has relieved pain and lessened the autonomic response to the pain. More research is needed to better understand the underlying mechanisms of SCS.

Angina pectoris is a syndrome that results from an imbalance in myocardial oxygen consumption and myocardial oxygen supply. The disease process can produce severe incapacitating pain, or pressure in the chest, arms, neck, or jaw. Atherosclerotic coronary artery disease is one of the leading causes of morbidity and mortality in westernized countries. The arteries that are most commonly affected by atherosclerosis are the large epicardial arteries; however small vessel disease may also contribute to the overall clinical picture. Atherosclerosis may affect a single vessel and cause a discrete lesion, or it may affect multiple vessels diffusely. There appears to be no correlation between the severity of anginal pain and the severity of atherosclerosis. A single lesion in the left artery descending may produce extreme pain and disability, whereas multiple diffuse lesions affecting several vessels may only produce mild to moderate anginal symptoms or complete absence of symptoms.

Antianginal therapies have focused on decreasing myocardial oxygen consumption while increasing oxygen delivery in an effort to restore the natural balance between supply and demand. The long-term goals of antianginal therapy are to decrease the frequency of anginal attacks, reduce the severity of the attacks, and to prevent the ischemic event from progressing to myocardial damage. Control of anginal symptoms not only preserves the independence and lifestyle of patients, but also improves their long-term prognosis.

Treatment for atherosclerotic coronary artery disease has focused on drug therapy, catheter-based revascularization techniques, surgical revascularization, and more recently, transmyocardial laser revascularization and spinal cord stimulation. The mainstay of pharmacologic treatment has been nitrates, beta-adrenergic blockers, and calcium channel blockers. Beta blockers decrease myocardial oxygen demand and oxygen consumption by decreasing ventricular wall tension, heart rate, and myocardial ionotropic state. Calcium channel blockers work by inhibiting the reuptake of calcium in slow calcium channels, thereby producing vasodilatation. This vasodilatory effect works to increase coronary artery perfusion and oxygen supply. This vasodilation also decreases afterload and increases cardiac output and in effect reduces cardiac work. Nitroglycerin acts as a vasodilator also, and it not only dilates coronary arteries but reduces afterload and preload secondary to its venous pooling effects. Nitrates and the calcium channel blockers both relieve vasospasm, which may contribute to ischemic attacks. These drugs may also be used for patients who have anginal pain but no objective signs of ischemia and normal coronary arteriograms. This syndrome, known as syndrome X, may be the result of small vessel disease and/or coronary vasospasm.

Most patients with atherosclerotic coronary artery disease and anginal pain respond to the medical therapies previously mentioned; however, for those that still have pain and decreased function because of their pain, more aggressive therapies are needed. One new therapy is long-term intermittent urokinase therapy. Urokinase activates circulating and bound plasminogen, which is converted to plasmin. Plasmin degrades fibrin, producing thrombolysis and improving blood rheology. Urokinase may also initiate regression of coronary plaques. The therapy is begun in the hospital with intravenous doses of urokinase three times per week. Once target fibrinogen levels are reached, the patient is discharged to home and the therapy is continued for a total of 12 weeks. Some patients have shown a 70% reduction in anginal attacks with a 20% improvement in exercise tolerance. Patients’ symptoms improve for approximately 3 months after the termination of treatment.

More invasive techniques for anginal pain include revascularization procedures such as surgical coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA). The first successful PTCA was performed in 1977, and since then the success rate and the indications for its use have expanded. The current indications for PTCA can be found in Table 51-4. Originally, it was felt that the actual mechanism of PTCA was that the balloon compressed the plaque and caused dilatation or aneurysm formation in the stenosed vessel. Now it is known that the pressure created by the balloon fractures the plaque, and releases the deeper medial and adventitial layers that were previously trapped in the plaque. Once released from the plaque, the vessel wall has improved compliance.

The advantages of PTCA for anginal pain are similar to those for peripheral vascular disease. It is less invasive than surgery, hospital stay is shorter, the procedure can be repeated multiple times, and patients who were not candidates for CABG because of concurrent diseases may be candidates for a less invasive procedure because the risks are less.

PTCA requires certain anatomical considerations for the procedure to be successful. The lesion should be focal, concentric, proximal, noncalcified, and located on a relatively straight portion of the artery. The long-term restenosis rate is better if the vessel is at least 2.5 mm in diameter, the lesion is at least 50% occlusive, and the occlusion is a focal and not a diffuse stenosis. The complications of PTCA include acute perforation, rupture, total occlusion, dissection, and embolization. The most common complication is acute occlusion at the site of PTCA, which may require emergent CABG. The long-term restenosis rates suggest that approximately 30% of patients will have a return of their symptoms with restenosis in the first 6 months after PTCA. Approximately 70% of patients will have no return of their symptoms at 6 months, and most of these patients will be symptom-free at 5 to 7 years. These success rates refer to single vessel PTCA. Patients with multivessel PTCA have higher long-term restenosis rates and have increased risks associated with PTCA.

The most recent technique in cardiac revascularization is transmyocardial laser revascularization, (TMLR). This technique is based on the fact that myocardial perfusion comes from not only the epicardial arteries but also from ventriculocoronary anastomosis. The technique of artificially creating transmyocardial channels is not new, and was first performed in 1967. The interest in this technique waned because of the advent of CABG and because the channels produced mechanically tended to fibrose and occlude. The development of laser technology has made TMLR a viable technique. The technique uses a carbon dioxide laser to penetrate the myocardium in 50-millisecond discharges. The procedure is done through a thoracotomy incision and can be completed in approximately 2 to 3 hours. The surgeon makes approximately 40 transmyocardial channels that are confirmed using intraoperative transesophageal echocardiography. There is no need for cardiopulmonary bypass to perform the procedure, and the laser portion of the operation may take as little as 15 minutes. The epicardial portion of the 1-mm channel closes almost immediately with compression. The endocardial portion of the channel remains patent. The CO2 laser vaporizes tissue with minimal thermal damage, which contributes to the long-term success of the treatment. In 1997 the results of an FDA-approved multicenter trial of TMLR showed improvement of symptoms in approximately 79% of patients at 12 months, and approximately 30% of patients were completely symptom-free at 12 months after TMLR. The advantage of this technique over other revascularization procedures is that there are no coronary artery anatomical constraints and patients who were not candidates for CABG or PTCA because of the specific anatomy of their coronary artery lesions may now be candidates for TMLR.

Spinal cord stimulation (SCS), as mentioned earlier, has been used for the treatment of various pain syndromes.5 Over the past 10 years, SCS has been found to have efficacy in the treatment of intractable angina pectoris in patients refractory to medical therapy who are not candidates for further revascularization procedures. The mechanism by which SCS relieves anginal pain is a subject of much speculation. Various theories suggest that SCS works through a spinothalamic mechanism, which may inhibit neuronal transmission at a segmental level. It is possible that SCS inhibits sympathetic outflow and decreases circulating levels of epinephrine and this in turn reduces cardiac work load and myocardial oxygen consumption. The sympatholytic effect may act directly or indirectly through stimulation of large dorsal column nerve fibers, which inhibit the smaller pain-transmitting fibers. Perhaps the most interesting theory was postulated through the use of positron emission tomography. A recent study evaluating angina patients 6 weeks after SCS showed that patients had no increase in overall myocardial perfusion.6 There was, however, increased perfusion in previously ischemic regions. This would imply that SCS redistributed microvascular perfusion from non-ischemic areas of the myocardium to ischemic areas.

When SCS was first introduced for anginal pain, it was feared that SCS was merely abolishing nociceptive input and not affecting myocardial oxygen demand or supply. If this were the case, then SCS would obscure or conceal the warning sign of ischemia, namely anginal pain, and not affect the underlying cause of the ischemia. This is not the case and, in fact, SCS seems to work by improving myocardial function through a poorly understood mechanism that decreases myocardial oxygen consumption. Several studies have shown that SCS increases tolerance to pacing, myocardial lactate metabolism, and decreases the duration and magnitude of ST changes during maximal pacing with SCS.7

Mannheimer et al looked at the effects of SCS in 20 patients who were on maximal medical therapy and who were not candidates for revascularization procedures.8 These patients had angina and ST depression during a bicycle ergometry test performed prior to the start of the SCS trial. The investigators used coronary sinus pacing and blood samples to determine the effects of SCS on the parameters of lactate production and coronary sinus blood flow. The investigators evaluated the parameters of coronary sinus blood flow, lactate metabolism, rate pressure product, time to angina, time to ST segment depression, recovery time from angina, and ST segment depression. They measured these parameters before and during the SCS procedure. The results of this study showed that all parameters including tolerance to pacing, time to angina, time to ST segment depression, lactate metabolism, and rate-pressure product improved during SCS. In addition, recovery time from angina and ST segment depression was decreased. Perhaps the most important outcome of this study was that at a maximum pacing rate, all patients experienced anginal pain and ST segment depression comparable to ST segment changes seen in the control. Therefore, SCS not only increases cardiac function, perhaps by decreasing myocardial oxygen consumption, but when there was myocardial ischemia, SCS did not prevent patients from having angina and ST segment depression.

A thorough knowledge of ischemic disease is necessary in order to provide care for these patients. The development of SCS as an option for pain specialists now enables us to render effective and relatively low-risk treatment to these patients that was not previously available. SCS for both peripheral vascular and coronary artery disease is efficacious and has been critically investigated with proven and predictable results and complications.