Pain: Moving from Symptom Control toward Mechanism-Specific Pharmacologic Management

Clinical Principles Nociceptive pain: transient pain in response to a noxious stimulus. Inflammatory pain: spontaneous pain and hypersensitivity to pain in response to tissue damage and inflammation. Neuropathis pain: spontaneous pain and hypersensitivity to pain in association with damage to or a lesion of the nervous system. Functional pain: hypersensitivity to pain resulting from abnormal central processing of normal input. Physiologic Principles Nociception Peripheral sensitization Phenotype switch Central sensitization Neuron glial interaction Increased facilitation Structural reorganization Decreased inhibition Pain is a multidimensional sensory experience that is intrinsically unpleasant and associated with hurting and soreness. It may vary in intensity (mild, moderate, or severe), quality (sharp, burning, or dull), duration (transient, intermittent, or persistent), and referral (superficial or deep, localized or diffuse). Although it is essentially a sensation, pain has strong cognitive and emotional components; it is linked to, or described in terms of, suffering. It is also associated with avoidance motor reflexes and alterations in autonomic output. All of these traits are inextricably linked in the experience of pain. Although we tend to think of pain as a homogeneous sensory entity, several distinct types exist: nociceptive, inflammatory, neuropathic, and functional (Figure 1). The neurobiological mechanisms responsible for these different pains are beginning to be defined (1-3), providing insight into how distinct types of pain are generated by diverse etiologic factors, and in which patients (4). Moreover, we can now realistically expect to move from an empirical therapeutic approach to one that it is targeted specifically at the particular mechanisms of the type of pain experienced by an individual patient. Although current analgesic treatment is aimed at suppressing or controlling symptoms (5), interventions that can abort the development of pain mechanisms are beginning to be conceivable (1). Figure 1. The 4 primary types of pain. Pain: The Good, the Bad, and the Ugly Pain can be essentially divided into 2 broad categories: adaptive and maladaptive. Adaptive pain contributes to survival by protecting the organism from injury or promoting healing when injury has occurred. Maladaptive pain, in contrast, is an expression of the pathologic operation of the nervous system; it is pain as disease. The sensory experience of acute pain caused by a noxious stimulus is mediated by a specialized high-threshold sensory system, the nociceptive system. This system extends from the periphery through the spinal cord, brain stem, and thalamus to the cerebral cortex, where the sensation is perceived. To prevent damage to tissue, we have learned to associate certain categories of stimuli with danger that must be avoided if at all possible. This association is formed by linking noxious stimuli with a sensation that is intense and unpleasant: that is, pain. The sensation of pain must be strong enough that it demands immediate attention. This nociceptive pain system is a key early warning device, an alarm system that announces the presence of a potentially damaging stimulus. Nociceptive pain must be controlled only under specific clinical situations, such as during surgery or medical procedures that damage tissue and after trauma. It is important that this system not be chronically disabled, because loss of its protective function inevitably leads to tissue damage, including self-induced mutilation of the tongue and lips, destruction of joints, loss of the tips of fingers, and pressure ulcers. Nociceptive pain is therefore a vital physiologic sensation. Lack of it in patients with congenital insensitivity to pain due to a mutation of the nerve growth factor tyrosine kinase A receptor, which results in a loss of high-threshold sensory neurons, reduces life expectancy (6). If tissue damage occurs despite the nociceptive defensive system (for example, through trauma, surgery, or inflammatory diseases), the body's imperative shifts from protecting against noxious, potentially damaging stimuli to promoting healing of the injured tissue. Inflammatory pain is used to accomplish this goal. In this state, sensitivity is increased such that stimuli to the affected part that would normally not cause pain now do so. As a result, we prevent contact with or movement of the injured part until repair is complete, minimizing further damage. Inflammatory pain typically decreases as the damage and inflammatory response resolve (Figure 1). Although inflammatory pain is adaptive, evolution has not taken into account the ability to inflict elective injury (that is, to undergo surgery) or survive severe trauma. We need to be able to actively manage inflammatory pain after surgery or trauma as well as in patients with inflammatory diseases, such as rheumatoid arthritis, without removing or severely blunting the warning system of nociceptive pain or impairing the healing process by allowing excessive inflamed or damaged tissue to form. The aim is to normalize pain sensitivity, not remove it. Maladaptive pain is uncoupled from a noxious stimulus or healing tissue. Such pain may occur in response to damage to the nervous system (neuropathic pain) or result from abnormal operation of the nervous system (functional pain) (Figure 1). Maladaptive pain is the expression of abnormal sensory processing and usually is persistent or recurrent. This is an area of enormous unmet clinical need because treatment options are limited and our understanding incomplete. Essentially, in maladaptive pain, the fire alarm system is constantly switched on even though there is no emergency, or repeated false alarms occur. Neuropathic pain may result from lesions to the peripheral nervous system, as in patients with diabetic or AIDS polyneuropathy, post-herpetic neuralgia, or lumbar radiculopathy, or to the central nervous system, such as in patients with spinal cord injury, multiple sclerosis, or stroke (7). Functional pain is an evolving concept. In this form of pain sensitivity, no neurologic deficit or peripheral abnormality can be detected. The pain is due to an abnormal responsiveness or function of the nervous system, in which heightened gain or sensitivity of the sensory apparatus amplifies symptoms. Several common conditions have features that may place them this category: for example, fibromyalgia, irritable bowel syndrome, some forms of noncardiac chest pain, and tension-type headache (8-10). It is not known why the central nervous system of patients with functional pain displays abnormal sensitivity or hyperresponsiveness. Classic migraine is in a category of its own. It is an episodic neurologic condition related to abnormal cortical activity that alters sensory input from dural and cerebrovascular sensory fibers and is associated with an abnormal sensory processing in the brain stem. It possesses features of inflammatory and functional pain, as well as of objective neurologic dysfunction (11, 12). Pain caused by cancer varies greatly in character and source; it depends on the tumor, its location, and its proximity to other tissues. In some cases, tumor cells produce chemical signals that contribute directly to the pain, as in osteosarcomas. In other tumors, the pain may be due to mechanical compression or invasion of a nerve, distention of an organ, ischemia, or an inflammatory reaction to tissue necrosis. It may also represent a neurotoxic side effect of chemotherapy (13). Although inflammatory, neuropathic, and functional pain each have different causes, they share some characteristics. The pain in these syndromes may arise spontaneously in the apparent absence of any peripheral stimulus, or it may be evoked by stimuli. Evoked pain may arise from a low-intensity, normally innocuous stimulus, such as a light touch to the skin in a patient with post-herpetic neuralgia or vibration during an acute attack of gout, or it may be an exaggerated and prolonged response to a noxious stimulus. The former condition is called allodynia and the latter hyperalgesia. Spontaneous pain and changes in sensitivity to stimuli are fundamental features of clinical pain, distinguishing it from nociceptive pain, in which pain occurs only in the presence of an intense or noxious stimulus. Because nociceptive pain constitutes our everyday experience of pain, the lack of an identifiable peripheral stimulus in some patients can lead to the assumption that their pain is hysterical in origin. However, the increased sensitivity of the nervous system during inflammatory, neuropathic, or functional pain can lead to pain in the absence of any peripheral noxious stimulus. Two major challenges in pain management are to identify the mechanisms responsible for producing hypersensitivity to pain and to find a means of normalizing sensitivity or preventing hypersensitivity from becoming established. Mechanisms of Pain Multiple mechanisms that can produce pain have been identified; they include nociception, peripheral sensitization, phenotypic switches, central sensitization, ectopic excitability, structural reorganization, and decreased inhibition (1, 2, 14, 15). Nociception is the sole mechanism that causes nociceptive pain and comprises the processes of transduction, conduction, transmission, and perception. Transduction is the conversion of a noxious thermal, mechanical, or chemical stimulus into electrical activity in the peripheral terminals of nociceptor sensory fibers. This process is mediated by specific receptor ion channels expressed only by nociceptors (Figure 2A). Conduction is the passage of action potentials from the peripheral terminal along axons to the central terminal of nociceptors in the central nervous system, and transmission is the synaptic transfer and modulation of input from one neuron to another. Ectopic excitability, structural reorganization, and decreased inhi