Andrew D Lawson, MSc, FRCA, FANZCA, and Sally-Ann Ryder, MBBS, FRCA, Consultants in Pain Medicine, Royal Berkshire Hospital, London Road, Reading RG1 5AN, UK

The authors discuss the possible treatments for chronic refractory angina. Like many other chronic pain syndromes, refractory angina cannot be banished, yet the symptoms may produce great functional disability. The possible treatments discussed here should be seen as complementary to standard medical and interventional techniques. They include counselling, psychotherapy, transcu­taneous electrical nerve stimulation, stellate ganglion block, paravertebral block, spinal cord stimulation, laser therapy and opioids. The treatment of patients with chronic stable angina should be directed towards improving their quality of life as well as preventing ischaemic events.

Background 
Chronic refractory angina is a clinical diagnosis based on the symptoms of stable angina that are thought to be caused by ischaemia due to advanced coronary disease and not controllable by combinations of maximal anti-anginal medication, angioplasty or coronary bypass surgery. There is also a small group of people who have normal coronary arteries but who experience angina (syndrome X) for whom some of the treatments mentioned below may be beneficial.
As ischaemic heart disease becomes more common, there will be increasing numbers of people for whom conventional treatments of angina are no longer effective. In the USA there are an estimated 2.4 million patients with coronary artery disease not suitable for revascularisation, and there is an estimated incidence of 1:5000 patients with ischaemic heart disease. Following coronary revascularisation, there is a 50% incidence of recurrent angina in the decade after surgery. The effective management of these patients is therefore important, as the condition is becoming more common, particularly in an ageing population.
Chronic refractory angina can be described as an ischaemia-related chronic pain syndrome and, like many other chronic pain syndromes, refractory angina cannot permanently be banished. Symptoms may produce great functional disability, rendering people housebound, reducing their ability to perform activities of daily living and leading to depression, sleep deprivation and alteration of mood. Disorders of sleep function are well documented in chronic pain, and are not believed to be a function of a depressed mood but rather to be secondary to the pain.1 The American Society of Anesthesiologists has defined chronic pain as ‘persistent or episodic pain of a duration or intensity that adversely affects the function or well-being of the patient, attributable to any non-malignant aetiology’.2
Chronic pain serves no biological purpose and creates an environment of pain, disability economic and societal dysfunction, with psychological sequelae. With this sort of pain, the symptom has become the disease itself. Long-term pain can cause hopelessness, depression, isolation, family breakdown and crippling disability.3 Patients with refractory angina may develop a vicious circle of pain leading to reduced physical activity which, of itself, may further reduce exercise tolerance. Then attempts to increase physical activity cause more chest pain and reduction in activity. Episodes of pain lead to repeated hospital and primary care attendances and admissions for suspected myocardial infarction.
In the UK, a draft chronic refractory angina care pathway was proposed in 2001, outlining the current consensual evidence. It addresses all the important issues in the management of refractory angina and leads clinicians through the care pathway (http://www.angina.org/source/pro/ guideline.htm).
The symptoms of angina are thought to be due to activation of nociceptors by ischaemia, resulting in an imbalance in myocardial oxygen supply and demand. The perception of chest pain activates the sympathetic nervous system via the cardiac sympathetic nerves (T1 to T5). This in turn produces tachycardia and hypertension, increasing myocardial oxygen requirement and so further exacerbating the imbalance between supply and demand. Stress, anger and excitement, all known precipitants of angina, can also produce such sympathetic stimulation through activation of the limbic system.

Treatment of refractory angina
Outpatient counselling and rehabilitation
This involves a discussion about the diagnosis of refractory angina and an explanation of the management plan, including lifestyle advice about diet, smoking and physical activity if the patient has not already received it. In addition, relaxation training has an important role.

Psychotherapy
All patients with refractory angina should have a psychological assessment. There are a number of reasons why people presenting with refractory angina benefit from some form of psychotherapy. These individuals may have undergone several episodes of cardiac surgery. There is an accepted incidence of cognitive dysfunction following cardiopulmonary bypass surgery which, when severe, may modify pain perception and behaviour. Some patients may be suitable for treatment with cognitive behavioural therapy, whereas others may respond to measures such as stress reduction programmes and relaxation training. An 8-week angina management programme has been reported to demonstrate reductions in anginal episodes and improvements in quality of life.

Transcutaneous electrical nerve stimulation
Transcutaneous electrical nerve stimulation (TENS) can be of use in the treatment of refractory angina. The exact mechanism by which it has its effect is unknown, although it can generally be explained by the gate-control theory of pain. Available data suggest that the effect is in addition to (and possibly separate from) analgesia produced by simple counterstimulation, perhaps by stimulating release of endogenous opioids. It is often thought that the pain relief obtained by TENS is mainly a placebo effect. However, a study has demonstrated the analgesic effect of TENS intraoperatively in unconscious patients, when there is no subjective input. All the work studying angina has involved continuous, high-frequency TENS. The electrodes are applied to the chest so that the main area where the patients experience their pain lies between them. Patients are advised to use their TENS for at least 1 hour three times a day, and are encouraged to use it during acute angina attacks. Typically the latter situation requires a stronger intensity of stimulation than is required for pain prevention. When TENS is effective, the benefit is almost immediate and is rapidly followed by full resolution of the angina. If the angina continues for longer than 15 minutes, patients are advised to seek medical attention. Use of TENS has been reported to reduce the incidence of ischaemic attacks and to increase exercise tolerance.4
As a therapy, TENS is very safe in most cases. Contact dermatitis is uncommon but, if it occurs, the types of electrode, jelly and adhesive tape can all be changed. Permanent cardiac pacemakers are not a contraindication to TENS; however, care must be taken as they may need reprogramming, and the TENS should not stimulate directly over the pacemaker. The individual with the pacemaker is instructed about their TENS machine in the pacemaker clinic, where both devices can be checked for safety.

Temporary sympathectomy
The pathogenesis of angina and myocardial infarction pain involves the activation of the afferent sympathetic pathway, leading to the typical clinical picture of a patient who is cold, clammy and anxious owing to the action of efferent sympathetic nerves. By interrupting the link in this sympathetic loop, a prolonged effect on the pain can be obtained. Beneficial reduction in angina can be achieved with repeated sympathetic blocks, but the duration of benefit after successive blocks is unpredictable.

Stellate ganglion block
Left-sided stellate ganglion block is a technique that has been used widely by specialists for treating chronic pain syndromes for many years, and it seems to be effective.5 A small, placebo-controlled, randomised trial in 1966 showed that the block can reduce symptoms of angina, and this has been repeated in further studies. A double-blind, randomised, placebo- controlled study is underway at present to confirm this role.

Paravertebral block
Until the 1950s, paravertebral injection of alcohol was a common treatment for the angina of individuals too unwell to undergo cervicothoracic sympathectomy. Advances in cardiothoracic surgery and in medical therapies have reduced the role of para- vertebral block. However, this is being re-evaluated in cases of refractory angina. Epidural anaesthesia is also effective, and almost certainly works by a similar mechanism.6

Destructive sympathectomy
In some cardiothoracic centres treating patients with refractory angina, cardiothoracic surgeons have performed thoracoscopic diathermy of the upper thoracic chain, with promising results.7 However, more data are required before a full evaluation can be made.

Spinal cord stimulation
The gate-control theory of pain led to the first spinal cord stimulator being implanted for cancer pain, and its use in angina was reported as a chance finding in a patient who had a stimulator for another reason in 1984. Spinal cord stimulators were originally implanted for intractable angina in Australia in 1987, and since then there have been over 70 publications on spinal cord stimulation (SCS) in refractory angina. These studies have confirmed improvement in quality of life of these patients, with fewer ischaemic episodes and reduced frequency of hospital admission. Moreover, these effects are long lasting and obtained at negligible risk. Clinicians are naturally concerned about the potential risks of masking myocardial ischaemia by SCS. Studies have demonstrated that SCS does not mask the pain of a myocardial infarction, but increases exercise duration, increases time to angina, decreases ischaemic episodes, decreases the number of anginal attacks and reduces nitrate consumption.8,9
The mechanism of action of SCS is multifactorial. There is a reduction in pain, maybe by a direct effect on the spinal cord possibly mediated by an increase in gamma-aminobutyric acid in the dorsal horn and also through beta-endorphin release. It has been proposed that beta-endorphin receptors may exist on presynaptic terminals of cardiac sympathetic neurones.
A reduction in sympathetic tone is observed during SCS, together with homogenisation of regional myocardial blood flow and redistribution of blood flow to areas that were previously ischaemic. Improvement in coronary microcirculatory flow and an alteration in the sympathetic/ parasympathetic balance during SCS seems to decrease myocardial oxygen consumption. These effects all result in decreased myocardial ischemia.
The technique requires inserting SCS electrodes under fluoroscopic guidance into the epidural space. The electrodes are positioned at the level of T1 to T3 and then connected to an external stimulator to produce paraesthesiae where the patient feels the pain.

Laser therapy
Transmyocardial laser revascularisation (TMLR) was devised as a method of directly perfusing the myocardium with oxygenated blood from the left ventricle, either via the transthoracic approach or percutaneously. This technique is based on the principle of reptilian circulation where there are no epicardial coronary arteries, just intramyocardial sinusoids that directly connect the ventricle, arteries and veins. These channels are also thought to stimulate new vessel growth (angiogenesis) in the myocardium. Some positron emission tomography studies have shown a significant increase in myocardial perfusion, particularly in the subendocardial region. TMLR is often performed in conjunction with conventional coronary bypass surgery. The first report of laser therapy alone was in the case of a 55-year-old man with severe angina, who is still alive 12 years later. Initially the Food and Drugs Administration (FDA) advisory panel rejected TMLR as a therapy, but conditional approval was granted in the spring of 1998.
TMLR is expensive, with a high but improving mortality.10 There have been many case reports of lasting benefits, yet there does appear to be a decrease in efficacy after a year. The mechanism of action is not clearly defined, and there is no consensus available from either animal or human studies about the exact effects of TMLR on myocardial perfusion and left ventricular function.

Opioids
There is now increasing acceptance of the role of opioids in the treatment of chronic non-cancer pain. The development of novel drug formulations and routes of administration have helped. There is little published work on the treatment of chronic refractory angina with strong opioids, although there are anecdotal reports of treatment with sustained-release morphine or trans­dermal fentanyl. The introduction of implantable refillable pumps, that can deliver minute volumes of intrathecal opioids, may offer an alternative route of administration that could limit troublesome side effects. Effective analgesia by the epidural or intrathecal administration of opioids has been reported for up to 7 years.11

Intramyocardial gene therapy
Direct intramyocardial administration of genes encoding for or capable of stimulating production of angiogenic cytokines may provide an alternative revascularisation strategy for people with refractory angina. Preclinical studies in myocardial ischaemia have provided evidence of significant improvement in collateral perfusion following intramuscular administration of naked DNA encoding for vascular endothelial growth factor (VEGF). This therapy has been associated with a dramatic reduction in angina frequency, 70% of patients being free of angina at 6 months. Results from a phase II trial suggest that VEGF gene transfer is safe and might produce an anti-ischaemic effect in cases of chronic, stable myocardial ischaemia.12

Enhanced external counterpulsation
Recently evidence has been published demonstrating a significant decrease in angina and an improved quality of life after enhanced external counterpulsation (EECP), with benefits still evident at 2 years in cases of severe left ventricular dysfunction and refractory angina. Like the intra-aortic balloon pump, this non-invasive technique augments diastolic blood flow and coronary blood flow by the serial inflation of three sets of cuffs which wrap around the calves, thighs and buttocks. Inflation and deflation are timed to the patient's ECG. The haemodynamic effect is to decrease afterload and hence myocardial oxygen demand and to increase venous return and cardiac output.13

Partial fatty acid oxidation inhibition
The partial fatty acid oxidation (pFOX) inhibitor ranolazine has been suggested as a novel treatment for refractory angina, and was given FDA approval in January 2006. It is thought to exert its effect by altering cardiac metabolism, and is anti-anginal and anti-ischaemic.14

Conclusions
The above therapies should be seen as complementary to standard medical and interventional techniques in the treatment of chronic angina. They should not be seen as therapies of last resort, and may be indicated earlier in the therapeutic pathway when problems exist with compliance or unwanted effects of standard treatments. The treatment of the person with chronic stable angina should be directed towards improvement of quality of life as well as prevention of ischaemic events. In some respects it represents a long-term palliation of distressing and limiting symptoms.