Syndromes, Injuries and Diseases
 
Cancer Pain
Mark J. Lema, MD, PhD
Professor and Chair
Department of Anesthesiology
State University of New York at Buffalo

Miles R. Day, MD
Assistant Professor
Department of Anesthesiology
Texas Tech University

David P. Myers, MD
Clinical Assistant Professor of Anesthesiology
State University of New York at Buffalo

Victor A. Filadora II, MD
Clincal Fellow in Anaesthesia
Harvard Medical School

Edward T. Plata, DC, MD

Advances in cancer treatment continue to lengthen survival among cancer patients. As patients live longer, the need for effective pain control has gained increased importance for improving the quality of life. Patients with advanced cancer often have pain as their chief complaint. The incidence of pain varies, depending on the type if neoplasm, stage, and the extent of spread. Because pain is a common symptom in cancer patients, next to incurability, it is the most feared complication.

With the current therapeutic modalities available to the clinician, about 80% to 90% of cancer pain can be controlled. However, studies by Cleeland, using Eastern Cooperative Oncology Group (ECOG) physicians, show that most cancer pain is under-treated, especially in regard to women, minorities, and the elderly. Major barriers to effective cancer pain control include:

1. Inadequate assessment by practitioners.
2. Under-reporting by patients and families.
3. Lack of knowledge regarding current treatment by practitioners.
4. Lack of accountability for effectively treating pain.
5. Fear if over-regulation by government officials.
6. Inadequate reimbursement or excessive paperwork by payers for treatment of pain by
health care providers.

In an attempt to rectify the problems, the World Health Organization (WHO), the American Society of Anesthesiologists, and the Agency for Health Care Policy and Research (AHCPR) have developed guidelines for the treatment of cancer pain.

Pathophysiology

Etiology

There are essentially five different causes of pain in cancer patients:

1. Acute cancer-related pain.
2. Chronic cancer-related pain.
3. Pain unrelated to cancer.
4. Chronic nonmalignant pain in opioid-tolerant patients.
5. End-of-life pain.

Classification

Cancer pain is classified according to pain duration and pain quality. Pain duration denotes the degree of chronicity. The three temporal conditions are acute pain, chronic pain, and incidental pain. Pathophysiological components are:

1. somatic (nociceptive) pain,
2. visceral pain,
3. neuropathic pain,
4. central pain, and
5. sympathetic pain.

Breakthrough pain is a clinical term describing the episodic exacerbations of pain above the established baseline, which is experienced in up to 93% of cancer patients. Doses of morphine, oxycodone, or hydromorphone, for example, are given every 2 to 4 hours, as needed, to combat breakthrough pain while the patient continues taking a long-acting oral opioid agent. If a patient routinely uses breakthrough medications, the daily total amount should be converted to a sustained-release dosage and added to the current maintenance dose.

Cancer Pain Syndromes

Although clinicians classify pain according to its onset, duration, and nature, cancer pain is often experienced as several different types of pain, with combined somatic and neuropathic types the most frequent. During the course of the disease, the pain changes as a result of tumor progression or regression after treatment. These changes may occur rapidly and illustrate the dynamic nature of cancer pain.

Acute Pain

Pain is often the presenting symptom of a patient with cancer. If it occurs early in the disease, patients may endure high levels of pain in the expectation that adequate anticancer therapy will relieve their symptoms. If it occurs late in the course, pain often signifies disease recurrence, which is associated with anxiety, apprehension, and suffering.

Pain is also associated with diagnostic procedures such as lumbar puncture or bone marrow biopsy, for example. In addition, postoperative pain can persist after surgery for tumor recurrence and may be complicated in patients who are tolerant of opioids.

Anticancer therapy is frequently associated with painful sequelae such as skin burns, mucositis, pharyngitis, and cystitis after radiation therapy. Similarly, while receiving drug chemotherapy, some patients experience myalgias, gastrointestinal distention, or local irritation, for example. Acute pain caused by the treatment occasionally progresses to chronic pain. Usually, acute pain is self-limiting and is most effectively treated with opioid analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs).

Chronic Pain Related to Cancer

Chronic pain related to cancer can be considered according to the following categories:

1. Tumor-induced Pain
2. Chemotherapy-induced Pain
3. Radiation Therapy-induced Pain

Postsurgical Pain Syndromes

Pain After Thoracotomy

After thoracotomy, pain develops in the distribution of the intercostal nerves in a small number or patients as a result of partial or complete injury from retractors, sutures, wires, or transaction. Pain usually develops 1 to 2 months after the operation and is described as constant in the area of sensory loss, with occasional lancinating pain.

Pain After Mastectomy

Patients who have has a radical mastectomy may experience pain in the posterior part of the arm, axilla, and anterior chest wall as a result of damage to the intercostobrachial nerve. Pain typically develops 1 to 2 months after the operation and is tight, constricting, and burning in mature. Patients will tend to keep the arm in a flexed position close to the chest wall, because movement exacerbates the pain. As a result, a frozen shoulder may develop from reduced joint motion. Reports of phantom breast pain occasionally appear in the literature.

Pain After Radical Neck Dissection

Pain can arise as a result of surgical intervention, including radical neck dissection. This pain is characterized as being constant, with dysesthesia and shock-like sensation as a result of interruption of the cervical plexus nerves and peripheral nerves serving those areas.]

Phantom Limb Pain

Phantom limb pain occurs in a large number of patients after amputation and usually produces a burning and cramping sensation in the area of the original limb. It can easily be differentiated from stump pain, which occurs at the site of the amputation and is elicited by palpation or percussion of the stump area.

Pain Unrelated To Cancer

Approximately 3% of the pain syndromes that occur in cancer patients have no relation to the underlying cancer or cancer treatment] Most commonly, pain is caused by degenerative disk disease, arthritis, fibromyalgia, or migraine and has often predated the diagnosis of cancer. In these patients, pain does not necessarily signify recurrent disease; however, a chronic illness behavior has already developed in many patients. Careful assessment and early psychological intervention are required.

Cancer Pain And Opioid-Tolerant Patients

Opioid-tolerant pain patients a challenging group. These patients may have used opioids illicitly in the past, but are no longer using them. Many are reluctant to take opioids for their cancer pain, fearing an addiction potential. These patients require support and understanding of the necessity to treat the pain. The liberal use of adjuvant therapies allowing for decreased opioid does is also beneficial.

Cancer pain that develops in patients who have been taking opioids for other medical conditions requires higher doses of opioids] In these cases, the use of adjuvants and early intervention with block techniques or the use of more potent opioid receptor agonists may avoid dose escalation without good pain control] Patients who use more than 50 mg of oral morphine for longer than 3 months often require three times more drug for a three-times-longer duration than opioid-naive patients after surgery]

Assessment Of Cancer Pain

Assessment of cancer pain begins with a thorough understanding of the complex nature of pain. The International Association for the Study of Pain defined pain in 1979 as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage." This definition stresses the importance of the emotional and suffering aspects of pain.

Clinical Assessment

Treatment failure can often be directly attributed to an inadequate assessment by the physician of the patient with cancer pain. Initial treatment should be based on the cause and type of pain. Prior to beginning treatment, the clinician should perform a detailed history and physical examination. Based on the findings of the examination, diagnostic studies should be ordered; a preliminary diagnosis, treatment goals, and a treatment plan are then established. Following the initial evaluation, on subsequent visits, the patient's status should be reassessed, as tumor growth is a dynamic and evolving process.

History And Physical Examination

To determine what further testing a patient may require, the location, quality, and duration of the patient's pain should be elicited. A complete review of the past medical history and what, if any, therapeutic measures have been previously tried to relieve pain may provide valuable information for developing a treatment plan. Physical examination should include a complete neurological examination. Neurological deficits from direct tumor invasion or compression are common and are frequently painful.

In addition to pain, most patients with cancer have numerous other symptoms. They often suffer from insomnia, depression, fatigue, and the side effects from therapeutic intervention such as headache and nausea, for example. One should take into account all the symptoms and develop a therapeutic plan that will improve quality of life for the patient.

Pain Intensity

One of the most difficult aspects of pain control is the accurate assessment of pain intensity. Although intensity is difficult to gauge, it is important because it provides a basis for developing a treatment plan and evaluating the effectiveness of therapeutic interventions. Also, if a patient's pain level increases during treatment, it may indicate disease progression. The best methods for determining pain intensity are the Verbal Scale or the Visual Analogue Pain Scale (VAPS) and the McGill Pain Questionnaire.

Treatment Strategies

Following a thorough review of the patient's medical condition, a preliminary treatment plan should be established. Functional status and quality-of-life issues are also critically important to assess. Provisions for supportive care should be discussed and the emotional stress on family members as well as the psychological well being of the patient should be considered.

Goals

After a treatment plan has been established, the patient's expectations in terms of pain control should be discussed. Often patient's have unrealistic goals and may not understand the extent of the disease. If necessary, the help of the primary care physician can be obtained to communicate with the patient.

Treatment Options

Oral And Parenteral Analgesia

Pharmacotherapy is the most widely used method of pain control. Three categories of analgesic medications are commonly available: NSAIDs, opioid analgesics, and adjuvant agents.

Nonsteroidal Anti-Inflammatrory Drugs

The peripheral effects of NSAIDs inhibit the enzyme cyclooxygenase, decreasing tissue levels of prostaglandins, which are the inflammatory mediators that sensitize peripheral nociceptors in the skin. NSAIDS have an anti-inflammatory action and an inhibitory effect on bone tumor growth by the inhibition of prostaglandin E2 release. They may also have a centrally medicated analgesic effect.

Acetaminophen has an analgesic effect by inhibiting nitric oxide synthetase, an action that is centrally and spinally mediated and similar in efficacy to that of aspirin. Also, NSAIDs possess a therapeutic ceiling dose, above which further dose increments provide little relief. Toxicity, however, increases and includes nausea, gastritis, and platelet dysfunction.

Opioid Analgesics

Opioid analgesics are the mainstay of therapy for cancer pain. The objective is to control pain while minimizing distressing side effects. The success of this therapy depends on the expertise of the prescriber, who must know the nuances of pharmacological features among various opioids and must be experienced in their use to make an appropriate selection for each patient.

Patients who don't respond to second-step opioids are switched to opioids on the third step of the ladder, most often morphine, hydromorphine, oxycodone, or fentanyl. Morphine has been used extensively worldwide and has been endorsed by the WHO. It is also available in several formulations and lends itself to administration by different routes.

When a physician selects a route for administration, factors such as gastrointestinal upset or obstruction, outpatient versus inpatient setting, and patient compliance should be addressed. Oral administration is the preferred and most economical route, although some medications may be given rectally when doses by both routes are considered equivalent.

A widely accepted principle of effective management of cancer pain with opioids is dosage administration at fixed intervals on an around-the-clock basis. This approach provides sustained analgesia and avoids the peak and trough effects of medication given as needed. When sustained-release agents are used, additional opioids should also be available for breakthrough pain at all times during the course of treatment. Doses must be titrated to the patient's need, thereby avoiding side effects from overdosing or persistent pain from inadequate analgesia.

Adjuvant Therapy

• Adjuvant medications are used in conjunction with oral or parenteral analgesics. They
may have inherent analgesic action, improve mood or sleep, or alleviate nausea,
anxiety, and somnolence. The tricyclic antidepressants are known to have analgesic action. They alleviate depression, improve sleep, and benefit patients with neuropathic
pain.
• Anticonvulsive drugs and the antispasmodic baclofen are helpful in patients with
lancinating pain.
• Mexiletine has been used in neuropathic pain from cancer after its success in the
treatment of painful diabetic neuropathy.
• Corticosteriods are useful adjuvants and have been shown to improve analgesia,
mood, and appetite in the short term.

Transdermal Delivery

The transdermal therapeutic system with fentanyl (patch) has simplified the concept of continuos parenteral administration of opioid by using a noninvasive method. This method has been beneficial in the treatment of cancer pain with high patient preference. Fentanyl is the sole opioid available by this method because of its high lipid solubility.

After initial application of the patch, serum levels gradually increase to peak concentration in 12 to 24 hours, and effective analgesia occurs as early as 6 hours. The patches are marketed in dosages of 25, 50, 75, and 100 mg/hr and are applied for 72 hours. Because these dosages are additive, a patient requiring 150 mg/hr of transdermal fentanyl may have two 75-mg/hr patches.

Patient-Controlled Analgesia

Patient-controlled analgesia (PCA) allows patients to treat their own pain by self-administering prescribed doses of opioids parenterally by means of a small, sophisticated programmable, computerized pump. The pump can be programmed to deliver a continuous infusion; in addition, the patient can administer bolus injections at a preset dose and time interval. There appears to be no difference in the effects on respiratory function compared with other therapies.

Neurosurgical Procedures

With the development of the multidisciplinary approach to pain management and with an increasing range of available pharmcological agents, fewer patients require surgical intervention. The aim of surgery is to interrupt the nociceptive pathways in the peripheral nerves or at certain sites in the neuraxis.

The most common performed surgical procedure for cancer pain relief is anterolateral cordotomy, which targets the spinothalamic tract. This can be done by open technique, which carries significant morbidity; complications include hemiparesis, urinary retention, and sexual impotence. Percutaneous cordotomy has largely replaced the open method. It is usually performed with the patient under local anesthesia by advancement of a thermal coagulation probe with fluroscopic guidance. It is ineffective for those with neuropathic pain caused by a central mechanism and has only limited use for visceral pain.

Intraspinal Therapies

Intraspinal administration of opioids is frequently used in the treatment of pain, especially pain that in not controlled with oral medications. Opioids can be delivered by the spinal or epidural route. Advantages include profound analgesia, often at a much lower opioid dose without the motor, sensory, or sympathetic block associated with intraspinal local anesthetic administration. The opioid dosage is usually much lower; approximately 20% to 40% of the systemic dose is given epidurally, and only 10% of the epidural dose is used if given intrathecally, thereby lowering the risk of side effects. Placement of an intrathecal pump initially is a much more complex and costly procedure in comparison to epidural catheter placement. However, the high cost of implantation may be negated by the sustained home maintenance costs of epidural infusion after 4 to 6 months.

Three systems used for chronic intraspinal opioid administration include:

1. Percutaneous tunneled epidural catheters
2. Tunneled epidural or spinal catheters connected to subcutaneously implanted
injection ports

Regional Blocks

Patients suffering from cancer pain localized in a certain area of the body, which manifests as peripheral neuralgia or visceral pain, are excellent candidates for regional block with neurolytic agents. These techniques are also appropriate in patients who are extremely ill or debilitated.

3. Implanted spinal infusion pump systems

The management of patients with cancer pain can be a challenging task, even for physicians trained in cancer pain management. The use of a systemic approach in assessing such pain can simplify management. Without a thorough assessment, the possibility of misdiagnosis and undertreatment exists. Appropriate and frequently times assessments form the basis for the development of an effective pain treatment plan. An understanding of the various etiological mechanisms of cancer and the different types of pain that they can produce is essential to providing appropriate therapeutic interventions. Finally, a multidisciplinary approach addressing pain, anger, anxiety, depression, and associated symptoms is essential in providing the best quality of life during this life-threatening experience.

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