PAIN: PATHOPHYSIOLOGY AND MANAGEMENT 1

PAIN: PATHOPHYSIOLOGY AND MANAGEMENT

The task of medicine is to preserve and restore health and to relieve suffering. Understanding pain is essential to both these goals. Because pain is universally understood as a signal of disease, it is the most common symptom that brings a patient to a physician's attention. The function of the pain sensory system is to detect, localize, and identify tissue-damaging processes. Since different diseases produce characteristic patterns of tissue damage, the quality, time course, and location of a patient's pain complaint and the location of tenderness provide important diagnostic clues and are used to evaluate the response to treatment.

THE PAIN SENSORY SYSTEM

Pain is an unpleasant sensation localized to a part of the body. It is often described in terms of a penetrating or tissue-destructive process (e.g., stabbing, burning, twisting, tearing, squeezing) and/or of a bodily or emotional reaction (e.g., terrifying, nauseating, sickening). Furthermore, any pain of moderate or higher intensity is accompanied by anxiety and the urge to escape or terminate the feeling. These properties illustrate the duality of pain: it is both sensation and emotion. When acute, pain is characteristically associated with behavioral arousal and a stress response consisting of increased blood pressure, heart rate, pupil diameter, and plasma cortisol levels. In addition, local muscle contraction (e.g., limb flexion, abdominal wall rigidity) is often present.

THE PRIMARY AFFERENT NOCICEPTOR

A peripheral nerve consists of the axons of three different types of neurons: primary sensory afferents, motor neurons, and sympathetic postganglionic neurons .The cell bodies of primary afferents are located in the dorsal root ganglia in the vertebral foramina. The primary afferent axon bifurcates to send one process into the spinal cord and the other to innervate tissues. Primary afferents are classified by their diameter, degree of myelination, and conduction velocity. The largest-diameter fibers, A-beta (Ab), respond maximally to light touch and/or moving stimuli; they are present primarily in nerves that innervate the skin. In normal individuals, the activity of these fibers does not produce pain. There are two other classes of primary afferents: the small-diameter myelinated A-delta (Ad) and the unmyelinated (C fiber) axons . These fibers are present in nerves to the skin and to deep somatic and visceral structures. Some tissues, such as the cornea, are innervated only by Ad and C afferents. Most Ad and C afferents respond maximally only to intense (painful) stimuli and produce the subjective experience of pain when they are electrically stimulated; this defines them as primary afferent nociceptors (pain receptors). The ability to detect painful stimuli is completely abolished when Ad and C axons are blocked.

Individual primary afferent nociceptors can respond to several different types of noxious stimuli. For example, most nociceptors respond to heating, intense mechanical stimuli such as a pinch, and application of irritating chemicals.

Sensitization When intense, repeated, or prolonged stimuli are applied in the presence of damaged tissue or inflammation, the threshold for activating primary afferent nociceptors is lowered and the frequency of firing is higher for all stimulus intensities. Inflammatory mediators such as bradykinin, some prostaglandins, and leukotrienes contribute to this process, which is called sensitization. In sensitized tissues normally innocuous stimuli can produce pain. Sensitization is a clinically important process that contributes to tenderness, soreness, and hyperalgesia. A striking example of sensitization is sunburned skin, in which severe pain can be produced by a gentle slap on the back or a warm shower.

Under normal conditions, viscera are relatively insensitive to noxious mechanical and thermal stimuli. Hollow viscera do generate significant discomfort when distended. Furthermore, when affected by a disease process with an inflammatory component, deep structures such as joints or hollow viscera characteristically become exquisitely sensitive to mechanical stimulation.

A large proportion of Ad and C afferents innervating viscera are completely insensitive in normal noninjured, noninflamed tissue. That is, they cannot be activated by known mechanical or thermal stimuli and are not spontaneously active. However, in the presence of inflammatory mediators, these afferents become sensitive to mechanical stimuli. Such afferents have been termed silent nociceptors, and their characteristic properties may explain how under pathologic conditions the relatively insensitive deep structures can become the source of severe and debilitating pain and tenderness.

Nociceptor-Induced Inflammation One important concept to emerge in recent years is that afferent nociceptors also have a neuroeffector function. Most nociceptors contain polypeptide mediators that are released from their peripheral terminals when they are activated . An example is substance P, an 11-amino-acid peptide. Substance P is released from primary afferent nociceptors and has multiple biologic activities. It is a potent vasodilator, degranulates mast cells, is a chemoattractant for leukocytes, and increases the production and release of inflammatory mediators. Interestingly, depletion of substance P from joints reduces the severity of experimental arthritis. Primary afferent nociceptors are not simply passive messengers of threats to tissue injury but also play an active role in tissue protection through these neuroeffector functions.

CENTRAL PATHWAYS FOR PAIN

The Spinal Cord and Referred Pain The axons of primary afferent nociceptors enter the spinal cord via the dorsal root. They terminate in the dorsal horn of the spinal gray matter . The terminals of primary afferent axons contact spinal neurons that transmit the pain signal to brain sites involved in pain perception. The axon of each primary afferent contacts many spinal neurons, and each spinal neuron receives convergent inputs from many primary afferents.

From a clinical standpoint, the convergence of many sensory inputs to a single spinal pain-transmission neuron is of great importance because it underlies the phenomenon of referred pain. All spinal neurons that receive input from the viscera and deep musculoskeletal structures also receive input from the skin. The convergence patterns are determined by the spinal segment of the dorsal root ganglion that supplies the afferent innervation of a structure. For example, the afferents that supply the central diaphragm are derived from the third and fourth cervical dorsal root ganglia. Primary afferents with cell bodies in these same ganglia supply the skin of the shoulder and lower neck. Thus sensory inputs from both the shoulder skin and the central diaphragm converge on pain-transmission neurons in the third and fourth cervical spinal segments. Because of this convergence and the fact that the spinal neurons are most often activated by inputs from the skin, activity evoked in spinal neurons by input from deep structures is mislocalized by the patient to a place that is roughly coextensive with the region of skin innervated by the same spinal segment. Thus inflammation near the central diaphragm is usually reported as discomfort near the shoulder. This spatial displacement of pain sensation from the site of the injury that produces it is known as referred pain.

Ascending Pathways for Pain A majority of spinal neurons contacted by primary afferent nociceptors send their axons to the contralateral thalamus. These axons form the contralateral spinothalamic tract which lies in the anterolateral white matter of the spinal cord, the lateral edge of the medulla, and the lateral pons and midbrain. The spinothalamic pathway is crucial for pain sensation in humans. Interruption of this pathway produces permanent deficits in pain and temperature discrimination.

Spinothalamic tract axons connect to thalamic neurons that project to somatosensory cortex . This pathway from spinal cord to thalamus to somatosensory cortex appears to be particularly important for the sensory aspects of pain, i.e., its location, intensity, and quality. Spinothalamic tract axons also connect to thalamic and cortical regions linked to emotional responses, such as the cingulate gyrus and frontal lobe. This pathway is thought to subserve the affective or unpleasant emotional dimension of pain.

PAIN MODULATION

The pain produced by similar injuries is remarkably variable in different situations and in different people. For example, athletes have been known to sustain serious fractures with only minor pain, and Beecher's classic World War II survey revealed that many men were unbothered by battle injuries that would have produced agonizing pain in civilian patients. Furthermore, even the suggestion of relief can have a significant analgesic effect (placebo). On the other hand, many patients find even minor injuries (such as venipuncture) unbearable, and the expectation of pain has been demonstrated to induce pain without a noxious stimulus.

The powerful effect of expectation and other psychological variables on the perceived intensity of pain implies the existence of brain circuits that can modulate the activity of the pain-transmission pathways. Although there are probably several circuits that can modulate pain, only one has been studied extensively. This circuit has links in the hypothalamus, midbrain, and medulla, and it selectively controls spinal pain-transmission neurons through a descending pathway .

There is good evidence that this pain-modulating circuit contributes to the pain-relieving effect of opioid analgesic medications. Each of the component structures of the pathway contains opioid receptors and is sensitive to the direct application of opioid drugs. Furthermore, lesions of the system reduce the analgesic effect of systemically administered opioids such as morphine. Along with the opioid receptor, the component nuclei of this pain-modulating circuit contain endogenous opioid peptides such as the enkephalins and b-endorphin.

The most reliable way to activate this endogenous opioid-mediated modulating system is by prolonged pain and/or fear. There is evidence that pain-relieving endogenous opioids are released following operative procedures and in patients given a placebo for pain relief.

Pain modulation is bidirectional. Pain-modulating circuits not only produce analgesia but are also capable of increasing pain. Both pain-inhibiting and pain-facilitating neurons in the medulla project to and control spinal pain-transmission neurons. Since pain-transmission neurons can be activated by modulatory neurons, it is theoretically possible to generate a pain signal with no peripheral noxious stimulus. Some such mechanism could account for the finding that pain can be induced by suggestion alone and may provide a framework for understanding how psychological factors can contribute to chronic pain.

NEUROPATHIC PAIN

The normal nervous system transmits coded signals that result in pain. Thus lesions of the peripheral or central nervous system may result in a loss or impairment of pain sensation. Paradoxically, damage or dysfunction of the nervous system can produce pain. For example, damage to peripheral nerves, as occurs in diabetic neuropathy, or to primary afferents, as in herpes zoster, can result in pain that is referred to the body region innervated by the damaged nerves. Though rare, pain may also be produced by damage to the central nervous system, particularly the spinothalamic pathway or thalamus. Such neuropathic pains are often severe and are notoriously intractable to standard treatments for pain.

Neuropathic pains typically have an unusual burning, tingling, or electric shock-like quality and may be triggered by very light touch. These features are rare in other types of pain. On examination, a sensory deficit is characteristically present in the area of the patient's pain.

A variety of mechanisms contribute to neuropathic pain. As with sensitized primary afferent nociceptors, damaged primary afferents, including nociceptors, become highly sensitive to mechanical stimulation and begin to generate impulses in the absence of stimulation. There is evidence that this increased sensitivity and spontaneous activity is due to an increased concentration of sodium channels. Damaged primary afferents may also develop sensitivity to norepinephrine. Interestingly, spinal pain-transmission neurons cut off from their normal input may also become spontaneously active. Thus both central and peripheral nervous system changes may contribute to neuropathic pain.

Sympathetically Maintained Pain A certain percentage of patients with peripheral nerve injury develop a severe burning pain (causalgia) in the region innervated by the nerve. The pain typically begins after a delay of hours to days or even weeks. The pain is accompanied by swelling of the extremity, periarticular osteoporosis, and arthritic changes in the distal joints. A similar syndrome called reflex sympathetic dystrophy can be produced without obvious nerve damage by a variety of injuries, including fractures of bone, soft tissue trauma, myocardial infarction, and stroke. Although the pathophysiology of this condition is poorly understood, the pain can be relieved within minutes by blocking the sympathetic nervous system. This implies that sympathetic activity activates nociceptors even if they are not obviously damaged. These results also suggest that the sympathetic nervous system can, under some circumstances, play an active role in inflammation.

TREATMENT

The ideal treatment for any pain is to remove the cause. Sometimes this is possible, but more often after diagnosis and initiation of appropriate treatments for the cause, there is a lag period before the pain subsides. Furthermore, some conditions are so painful that rapid and effective analgesia is essential (e.g., the postoperative state, burns, trauma, cancer, sickle cell crisis). Analgesic medications are a first line of treatment in these cases, and their use should be familiar to all practitioners.

Aspirin, Acetaminophen, and Nonsteroidal Anti-Inflammatory Agents (NSAIDS) These drugs are considered together because they are used for similar problems and may have a similar mechanism of action. All these compounds inhibit cyclooxygenase (COX), and, except for acetaminophen, all have anti-inflammatory actions, especially at higher dosages. They are particularly effective for mild to moderate headache and for pain of musculoskeletal origin.

Since they are effective for these common types of pains and are available without prescription, COX inhibitors are by far the most commonly used analgesics. They are absorbed well from the gastrointestinal tract and, with occasional use, side effects are minimal. With chronic use, gastric irritation is a common side effect of aspirin and NSAIDs and is the problem that most frequently limits the dose that can be given. Gastric irritation is most severe with aspirin, which may cause erosion of the gastric mucosa, and because aspirin irreversibly acetylates platelets and interferes with coagulation of the blood, gastrointestinal bleeding is a risk. The NSAIDs are less problematic in this regard. Although toxic to the liver when taken in a high dose, acetaminophen rarely produces gastric irritation and does not interfere with platelet function. lists the dosages and durations of action of the commonly used drugs of this class.

The introduction of a parenteral form of NSAID, ketorolac, extends the usefulness of this class of compounds in the management of acute severe pain. Ketorolac is sufficiently potent and rapid in onset to supplant opioids for many patients with acute severe headache and musculoskeletal pain.

There are two major classes of COX: COX 1 is constitutively expressed, and COX 2 is induced in the inflammatory state. COX 2-selective drugs have recently been introduced for the treatment of arthritis and are associated with a significant reduction of gastric irritation. Whether COX 2-selective drugs have analgesic actions equivalent to other NSAIDs remains to be demonstrated.

Opioid Analgesics Opioids are the most potent pain-relieving drugs currently available. Furthermore, of all analgesics, they have the broadest range of efficacy, providing the most reliable method for rapidly relieving pain. Although side effects are common, they are usually not serious except for respiratory depression and can be reversed rapidly with the narcotic antagonist naloxone. The physician should not hesitate to use opioid analgesics in patients with acute severe pain. lists the most commonly used opioid analgesics.

Opioids produce analgesia by actions in the central nervous system. They activate pain-inhibitory neurons and directly inhibit pain-transmission neurons. Most of the commercially available opioid analgesics act at the same opioid receptor (mu receptor), differing mainly in potency, speed of onset, duration of action, and optimal route of administration. Although the dose-related side effects (sedation, respiratory depression, pruritus, constipation) are similar among the different opioids, some side effects are due to accumulation of nonopioid metabolites that are unique to individual drugs. One striking example of this is normeperidine, a metabolite of meperidine. Normeperidine produces hyperexcitability and seizures that are not reversible with naloxone. Normeperidine accumulation is much greater in patients with renal failure.

The most rapid relief with opioids is obtained by intravenous administration; relief with oral administration is significantly slower. Common acute side effects include nausea, vomiting, and sedation. The most serious side effect is respiratory depression. Patients with any form of respiratory compromise must be kept under close observation following opioid administration; an oxygen saturation monitor may be useful. The opioid antagonist, naloxone, should be readily available. These effects are dose-related, and there is great variability among patients in the doses that relieve pain and produce side effects. Because of this, initiation of therapy requires titration to optimal dose and interval. The most important principle is to provide adequate pain relief. This requires asking the patient whether the drug has relieved the pain and, if so, when the relief wears off. The most common error made by physicians in managing severe pain with opioids is to prescribe an inadequate dose. Since many patients are reluctant to complain, this practice leads to needless suffering. In the absence of sedation at the expected time of peak effect, a physician should not hesitate to repeat the initial dose to achieve satisfactory pain relief.

An innovative approach to the problem of achieving adequate pain relief is the use of patient-controlled analgesia (PCA). PCA requires a device that delivers a baseline continuous dose of an opioid drug, and preprogrammed additional doses whenever the patient pushes a button. The device can be programmed to limit the total hourly dose so that overdosing is impossible. The patient can then titrate the dose to the optimal level. This approach is used most extensively for the management of postoperative pain, but there is no reason why it should not be used for any hospitalized patient with persistent severe pain. PCA is also used for short-term home care of patients with intractable pain, such as is caused by metastatic cancer.

Many physicians, nurses, and patients have a certain trepidation about using opioids that is based on an exaggerated fear of patients becoming addicted. In fact, there is a vanishingly small chance of patients becoming addicted to narcotics as a result of their appropriate medical use.

The availability of new routes of administration has extended the usefulness of opioid analgesics. Most important is the availability of spinal administration. Opioids can be infused through a spinal catheter placed either intrathecally or epidurally. By applying opioids directly to the spinal cord, regional analgesia can be obtained using a relatively low total dose. In this way, such side effects as sedation, nausea, and respiratory depression can be minimized. This approach has been used extensively in obstetric procedures and for lower-body postoperative pain. Opioids can also be given intranasally (butorphanol), rectally, and transdermally (fentanyl), thus avoiding the discomfort of frequent injections in patients who cannot be given oral medication.

Opioid and Cyclooxygenase Inhibitor Combinations When used in combination, opioids and COX inhibitors have additive effects. Because a lower dose of each can be used to achieve the same degree of pain relief and their side effects are nonadditive, such combinations can be used to lower the severity of dose-related side effects. Fixed-ratio combinations of an opioid with acetaminophen carry a special risk. Dose escalation as a result of increased severity of pain or decreased opioid effect as a result of tolerance may lead to levels of acetaminophen that are toxic to the liver.