The Nature of Pain

Pain has been described by the International Association for the Study of Pain as an “unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Although pain is a reaction of the body to harmful stimuli and is therefore a protective early warning system, the sensation of pain in postoperative patients, cancer patients, and other chronic pain patients has little positive effect. The stress response to pain can alter the healing process by evoking massive sympathetic discharge that in turn alters blood flow, tissue perfusion, and immune function. In addition, in certain painful conditions the patient has reduced respiratory function. Hence, the term pain, derived from the Latin poena for punishment, reflects the deleterious effects that can be inflicted upon the body. Since millions of Americans suffer from some form of pain each year, resulting in the expenditure of billions of dollars for various treatment modalities, pain and its underlying causes are a major public health problem.

The nature of pain is highly subjective. Pain has both sensory (somatic) and psychological (affective) components. One person may feel pain in response to noxious stimuli, while another person may disregard the stimuli. The affective (psychological) aspects of pain play a critical role in pain perception. A patient under external stress or other significant psychological problems often cannot handle the additional stress of pain. Anxiety exacerbates the perception of pain. Pain in turn exacerbates anxiety, decreases the comfort of the patient, and results in disturbances in sleeping, eating, and locomotion, creating a cycle of related medical problems. The drugs described in this chapter are used to interrupt such a cycle. The nonopioid analgesics act to decrease the generation of the mediators of pain at the site of tissue damage, although several of the drugs also have some effects within the central nervous system (CNS). The opioid analgesics are unique in that they not only block the incoming nociceptive signals to the brain but also act at higher brain centers, controlling the affective components of the pain. The drugs described in this chapter do not constitute the entirety of the armamentarium of therapies for pain relief. Many patients respond best to a combination of therapies. Therapeutic modalities in addition to the drugs described in this chapter include antidepressants, adrenergic agonists (e.g., clonidine), transcutaneous electrical nerve stimulation, physical therapy, massage therapy, acupuncture, meditation, and behavior modification. The treatment regimen is generally based upon the type of pain.

Cells in the substantia gelatinosa (lamina II contains highest levels of opioid binding) of the dorsal horn of the spinal cord respond to incoming nociceptive stimuli and regulate, or gate, the transmission of nociceptive impulses to other pathways within the CNS via the spinothalamic tract. Opioids also can elicit analgesic effects by stimulating the release of norepinephrine from a descending noradrenergic pathway, which extends from the locus ceruleus to the dorsal horn of the spinal cord.

In general, pain can be described as either acute or chronic. Acute pain, which does not outlast the initiating painful stimulus, has three generally encountered origins. The most common type of acute pain is of superficial origin from wounds, chemical irritants, and thermal stimuli, such as burns. Acute pain of deep somatic origin usually arises from injection of chemical irritants or from ischemia, such as with myocardial infarction. Acute pain of visceral origin is most often associated with inflammation. Chronic pain, by contrast, outlasts the initiating stimulus, which in many cases is of unknown origin. Chronic pain is often associated with diseases such as cancer and arthritis. Treatment of chronic pain presents a challenge to the physician in that the underlying cause is often not readily apparent. Neuropathic pain, a type of chronic pain, responds poorly to opioids. Some causes of neuropathic pain include diabetic neuropathies, shingles (herpes zoster), ischemia following stroke, and phantom limb pain. Neuropathic pain responds well in many cases to therapies other than the use of opioids and nonsteroidal antiinflammatory drugs (NSAIDs).

Pain thus has several etiologies, and transmission of nociceptive inputs from diverse nociceptors occurs via different fiber bundles. Aδ-fibers are the site for rapid transmission of sharp, painful stimuli. Such fibers are myelinated and enter the dorsal horn, from which point the ascending systems of the spinothalamic tract are activated. C-fibers, which also enter the dorsal horn and synapse on spinothalamic tract neurons, are responsible for the slower transmission (fibers are not myelinated) of nociceptive impulses, resulting in a dull, aching sensation. The Aδ-fibers and C-fibers are activated by mechanoreceptors. Aδ-fibers and C-fibers are also activated by other types of nociceptors, such as those responding to heat and chemicals. Current studies on the plasticity of pain-modulating systems that contribute to the chronic long-lasting nature of pain have been reviewed in detail by Julius and Basbaum (2001) and include alterations in numerous intracellular signaling systems beyond the scope of this post. However, what is becoming apparent is that novel analgesics may be designed in the future to target the modulation of intracellular targets in pain processing and neuronal plasticity.

The loss of quality of life for a patient with either acute or chronic pain has led to extensive development of various drugs to treat pain. Such drugs eliminate pain by either decreasing the underlying cause of the pain (as do the nonopioid analgesics described later) or decreasing the transmission of nociceptive impulses and pain perception (as do the opioids).