Mechanisms of cancer pain

Two major pain categories exist: nociceptive pain and neuropathic pain. Nociceptive pain results from tissue damage and can be further subdivided into somatic and visceral pain. Somatic pain may originate from multiple sites—including skin, muscle, joints, connective tissue, or bone—and is mediated by somatic afferent fibers (Aδ and C fibers). Somatic pain is most often described as sharp, throbbing, and well localized if it is superficial, or it is described as dull, aching, and less well localized if it is deep. Visceral pain originates from solid or hollow visceral organs and is mediated by visceral nociceptive afferent fibers that travel along with visceral sympathetic efferent fibers. Visceral pain is often described as a dull diffuse pain that is frequently referred in a dermatomal fashion.

Neuropathic pain occurs when there is damage to or dysfunction of nerves in the peripheral or central nervous system. The pain frequently has dysesthetic (e.g., burning, pricking) or paroxysmal (e.g., stabbing, shooting, electric shock-like) qualities and may be associated with sensory, motor, or autonomic dysfunction. Neuropathic pain may be centrally or peripherally generated. When the pain is coupled with loss of sensory input, it is referred to as deafferentation pain (e.g., phantom limb pain). When dysregulation of the autonomic nervous system plays a major role, the pain is referred to as sympathetically mediated pain (e.g., complex regional pain syndrome). Sympathetically mediated pain may occur after a nerve or limb injury; the patient often has diffuse burning pain of the affected extremity associated with allodynia, hyperpathia, sudomotor dysfunction, and signs of impaired blood flow regulation to the extremity. This pain is believed to be mediated, at least in part, by sympathetic efferent fibers. Deafferentation pain and sympathetically mediated pain are examples of centrally generated neuropathic pain. Examples of peripherally generated pain include polyneuropathies and mononeuropathies. Compared with nociceptive pain, neuropathic pain is often less responsive to conventional pharmacologic therapy.

One or more of these mechanisms may contribute to a patient’s pain and may occur as a result of the primary cancerous lesion, metastatic disease, neural compression, or treatments, such as radiation therapy, chemotherapy, or surgery. Pain may also originate from secondary nonmalignant sources (e.g., herniated nucleus pulposus, spinal stenosis, myofascial pain syndrome).

Medical therapy

The World Health Organization’s three-step analgesic ladder is a validated, clinical pain treatment algorithm that is very helpful in outlining a therapeutic pain management strategy for patients with cancer. The analgesic ladder progresses in a stepwise approach as pain increases and is utilized to meet individual needs. The approach begins with nonopioids; then, as necessary, it progresses to intermediate-potency opioids for moderate pain and then to more potent opioids for severe pain. Nonopioid medications and adjuvant medications may be used at each step depending on the type or types of pain being treated.

Adjuvant analgesic agents play a major role in treating patients with malignancies (Table 215-1). Most of these medications have a primary indication other than pain but have analgesic properties. The choice of adjuvant is made based on several assessments, including the type of pain, pharmacologic characteristics and adverse effects of the drug, interactions with other medications, and patient comorbid conditions (e.g., depression). Adjuvant agents comprise a diverse group of medications and can be broadly classified into multipurpose adjuvant analgesic agents and adjuvants specific for neuropathic pain, bone pain, musculoskeletal pain, and bowel obstruction.

Tricyclic antidepressants are the most common antidepressant used in the treatment of chronic pain conditions; however, their use may be limited by the frequent occurrence of associated adverse effects, such as orthostatic hypotension, sedation, cardiotoxicity, and drug-induced confusion. Corticosteroids are useful for bone pain, neuropathic pain, headaches secondary to increased intracranial pressure, spinal cord compression, and pain due to obstruction of a hollow viscus or organ-capsule distention. Corticosteroids may have other benefits, including improvement in appetite, nausea, malaise, and overall quality of life. The α₂-adrenergic agonists clonidine and tizanidine are also useful. Intraspinally administered clonidine has been shown to be beneficial in severe, intractable cancer pain. Neuroleptic agents, such as olanzapine, have been found to decrease pain and opioid consumption and to improve cognitive function and anxiety.

Cancer-related neuropathic pain is widely treated with anticonvulsants. Gabapentin is considered a first-line agent. Pregabalin is a similar anticonvulsant with evidence of analgesic efficacy in certain neuropathic pain states. Orally and parenterally administered local anesthetic agents have analgesic properties in patients with neuropathic pain. The NMDA (N-methyl-D-aspartic acid) receptor antagonists have been shown to have analgesic effects, with ketamine, specifically, being found to reduce opioid requirements and relieve cancer pain.

Bone pain and pathologic fractures are common in patients with cancer. Radiation therapy is administered when possible. Adjuvants that have been found to be valuable in treating bone pain include calcitonin, bisphosphonates, and certain radiopharmaceuticals (radionuclides that are absorbed at areas of high bone turnover).

If surgical decompression is not feasible in patients with a malignant bowel obstruction, the use of the somatostatin analog octreotide, anticholinergic drugs (hyoscine, glycopyrrolate), and corticosteroids may be beneficial.

Other systemically administered drugs such as baclofen, cannabinoids, benzodiazepines, and psychostimulants have also been used as adjuvant analgesics. The 5% lidocaine patch, EMLA cream (a eutectic mixture of the local anesthetic agents prilocaine and lidocaine), and capsaicin (an ingredient in chili pepper that causes release of substance P) may be useful in patients with localized pain syndromes, such as chest pain after mastectomy, radiation-induced dermatitis, post-thoracotomy pain, and others.

Not all cancer-related pain can be managed with orally or parenterally administered medications alone. Pain may be inadequately controlled, or doses may be limited by intolerable systemic adverse effects of the analgesic agent. In these situations, interventional therapy is often undertaken.

Interventional therapy

Given that the use of the World Health Organization’s analgesic ladder does not provide adequate analgesia for all patients with cancer, a revised stepwise approach has been developed that includes the use of interventional techniques (Figure 215-1).

For those patients with pain that is refractory to treatment with medications, multiple interventional therapies exist to provide relief. Options include nerve blocks and other injection therapies (e.g., joint and trigger-point injections), neurolytic blocks, epidurally and intrathecally administered analgesia, neuromodulation (e.g., spinal cord stimulator), and advanced neurosurgical techniques (e.g., cordotomy, midline myelotomy, rhizotomy, neurostimulation).

Other approaches

Therapies other than medications and procedures have been effective for treating cancer-related pain. Relaxation techniques, massage, therapeutic exercise, heat, ice, electrical stimulation, counseling, and other modalities may be valuable. A multidisciplinary or team approach to the management of cancer-related pain, with the participation of oncologists, nurses, psychologists, palliative care specialists, and pain management specialists, will likely produce the most beneficial treatment program.