Saturday, July 26, 2008


Pain: Pathophysiology and Management: Introduction

(Harrison's Internal Medicine 17ed> Chapter 12. 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 protect the body and maintain homeostasis. It does this by detecting, localizing, and identifying 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. Once this information is obtained, it is the obligation of the physician to provide rapid and effective pain relief.


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.

Peripheral Mechanisms
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 (Fig. 1). The cell bodies of primary sensory 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 (Aβ), 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 (Aδ) and the unmyelinated (C fiber) axons (Fig.1). 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 Aδ and C afferents. Most Aδ 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 Aδ and C axons are blocked

Fig.1 Components of a typical cutaneous nerve. There are two distinct functional categories of axons: primary afferents with cell bodies in the dorsal root ganglion, and sympathetic postganglionic fibers with cell bodies in the sympathetic ganglion. Primary afferents include those with large-diameter myelinated (Aβ ), small-diameter myelinated (Aδ), and unmyelinated (C) axons. All sympathetic postganglionic fibers are unmyelinated. (Click for Larger View)

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


When intense, repeated, or prolonged stimuli are applied to damaged or inflamed tissues, 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, nerve growth factor, 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.

Sensitization is of particular importance for pain and tenderness in deep tissues. Viscera are normally relatively insensitive to noxious mechanical and thermal stimuli, although hollow viscera do generate significant discomfort when distended. In contrast, 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 Aδ 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. Low pH, prostaglandins, leukotrienes, and other inflammatory mediators such as bradykinin play a significant role in sensitization.

Nociceptor-Induced Inflammation

Primary afferent nociceptors also have a neuroeffector function. Most nociceptors contain polypeptide mediators that are released from their peripheral terminals when they are activated (Fig. 2). 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.

Fig. 2. Events leading to activation, sensitization, and spread of sensitization of primary afferent nociceptor terminals. A. Direct activation by intense pressure and consequent cell damage. Cell damage induces lower pH (H+) and leads to release of potassium (K+) and to synthesis of prostaglandins (PG) and bradykinin (BK). Prostaglandins increase the sensitivity of the terminal to bradykinin and other pain-producing substances. B. Secondary activation. Impulses generated in the stimulated terminal propagate not only to the spinal cord but also into other terminal branches where they induce the release of peptides, including substance P (SP). Substance P causes vasodilation and neurogenic edema with further accumulation of bradykinin. Substance P also causes the release of histamine (H) from mast cells and serotonin (5HT) from platelets. (click for larger view)

Central Mechanisms

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 (Fig. 3). The terminals of primary afferent axons contact spinal neurons that transmit the pain signal to brain sites involved in pain perception. When primary afferents are activated by noxious stimuli, they release neurotransmitters from their terminals that excite the spinal cord neurons. The major neurotransmitter they release is glutamate, which rapidly excites dorsal horn neurons. Primary afferent nociceptor terminals also release peptides, including substance P and calcitonin gene-related peptide, which produce a slower and longer-lasting excitation of the dorsal horn neurons. The axon of each primary afferent contacts many spinal neurons, and each spinal neuron receives convergent inputs from many primary afferents

Fig. 3. The convergence-projection hypothesis of referred pain. According to this hypothesis, visceral afferent nociceptors converge on the same pain-projection neurons as the afferents from the somatic structures in which the pain is perceived. The brain has no way of knowing the actual source of input and mistakenly "projects" the sensation to the somatic structure.(click for larger view)

The convergence of 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 ascend to several regions of the thalamus. There is tremendous divergence of the pain signal from these thalamic sites to broad areas of the cerebral cortex that subserve different aspects of the pain experience (Fig. 4). One of the thalamic projections is to the somatosensory cortex. This projection mediates the purely sensory aspects of pain, i.e., its location, intensity, and quality. Other thalamic neurons project to cortical regions that are linked to emotional responses, such as the cingulate gyrus and other areas of the frontal lobes, including the insular cortex. These pathways to the frontal cortex subserve the affective or unpleasant emotional dimension of pain. This affective dimension of pain produces suffering and exerts potent control of behavior. Because of this dimension, fear is a constant companion of pain.

Fig. 4. Pain transmission and modulatory pathways. A. Transmission system for nociceptive messages. Noxious stimuli activate the sensitive peripheral ending of the primary afferent nociceptor by the process of transduction. The message is then transmitted over the peripheral nerve to the spinal cord, where it synapses with cells of origin of the major ascending pain pathway, the spinothalamic tract. The message is relayed in the thalamus to the anterior cingulate (C), frontal insular (F), and somatosensory cortex (SS). B. Pain-modulation network. Inputs from frontal cortex and hypothalamus activate cells in the midbrain that control spinal pain-transmission cells via cells in the medulla. (click for larger view)

Pain Modulation

The pain produced by injuries of similar magnitude is remarkably variable in different situations and in different individuals. 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 soldiers in battle were unbothered by 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) frightening and 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. One of these circuits has links in the hypothalamus, midbrain, and medulla, and it selectively controls spinal pain-transmission neurons through a descending pathway (Fig. 4).

Human brain imaging studies have implicated this pain-modulating circuit in the pain-relieving effect of attention, suggestion, and opioid analgesic medications. Furthermore, each of the component structures of the pathway contains opioid receptors and is sensitive to the direct application of opioid drugs. In animals, 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 β-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 surgical procedures and in patients given a placebo for pain relief.

Pain-modulating circuits can enhance as well as suppress 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. In fact, human functional imaging studies have demonstrated increased activity in this circuit during migraine headache. A central circuit that facilitates pain could account for the finding that pain can be induced by suggestion or enhanced by expectation, and it could provide a framework for understanding how psychological factors can contribute to chronic pain.

Neuropathic Pain

Lesions of the peripheral or central nervous pathways for pain typically result in a loss or impairment of pain sensation. Paradoxically, damage to or dysfunction of these pathways 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. Hyperpathia is also characteristic of neuropathic pain; patients often complain that the very lightest moving stimuli evoke exquisite pain (allodynia). In this regard it is of clinical interest that a topical preparation of 5% lidocaine in patch form is effective for patients with postherpetic neuralgia who have prominent allodynia.

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 cord pain-transmission neurons cut off from their normal input may also become spontaneously active. Thus, both central and peripheral nervous system hyperactivity contribute to neuropathic pain.

Sympathetically Maintained Pain

Patients with peripheral nerve injury can 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. The pain is dramatically and immediately relieved by blocking the sympathetic innervation of the affected extremity. Damaged primary afferent nociceptors acquire adrenergic sensitivity and can be activated by stimulation of the sympathetic outflow. 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 and the signs of inflammation are rapidly relieved by blocking the sympathetic nervous system. This implies that sympathetic activity can activate undamaged nociceptors when inflammation is present. Signs of sympathetic hyperactivity should be sought in patients with posttraumatic pain and inflammation and no other obvious explanation.

Acute Pain: Treatment

The ideal treatment for any pain is to remove the cause; thus, diagnosis should always precede treatment planning. Sometimes treating the underlying condition does not immediately relieve pain. 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 all practitioners should be familiar with their use.

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 (Table 1). 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.

Table 1 Drugs for Relief of Pain

Generic Name

Dose, mg




Acetylsalicylic acid

650 PO

q 4 h

Enteric-coated preparations available


650 PO

q 4 h

Side effects uncommon


400 PO

q 4–6 h

Available without prescription


250–500 PO

q 12 h

Delayed effects may be due to long half-life


200 PO

q 4–6 h

Contraindicated in renal disease


25–50 PO

q 8 h

Gastrointestinal side effects common


15–60 IM/IV

q 4–6 h

Available for parenteral use


100–200 PO

q 12–24 h

Useful for arthritis


10–20 PO

q12–24 h

Removed from U.S. market in 2005

(click the following images to view other pain relieving agents)

aAntidepressants, anticonvulsants, and antiarrhythmics have not been approved by the U.S. Food and Drug Administration (FDA) for the treatment of pain. bGabapentin in doses up to 1800 mg/d is FDA approved for postherpetic neuralgia. Note: 5-HT, serotonin; NE, norepinephrine.

Since they are effective for these common types of pain 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, have only minimal side effects. 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 and ulceration of the gastric mucosa leading to bleeding or perforation. Because aspirin irreversibly acetylates platelets and thereby interferes with coagulation of the blood, gastrointestinal bleeding is a particular risk. Increased age and history of gastrointestinal disease increase the risks of aspirin and NSAIDs. In addition to NSAIDs' well-known gastrointestinal toxicity, nephrotoxicity is a significant problem for patients using them on a chronic basis, and patients at risk for renal insufficiency should be monitored closely. NSAIDs also cause an increase in blood pressure in a significant number of individuals. Long-term treatment with NSAIDs requires regular blood pressure monitoring and treatment if necessary. Although toxic to the liver when taken in a high dose, acetaminophen rarely produces gastric irritation and does not interfere with platelet function.

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 moderate analgesic potency and produce less gastric irritation than the nonselective COX inhibitors. It is not yet clear whether the use of COX-2–selective drugs is associated with a lower risk of nephrotoxicity compared to nonselective NSAIDs. On the other hand, COX-2–selective drugs offer a significant benefit in the management of acute postoperative pain because they do not affect blood coagulation. This is a situation in which the nonselective COX inhibitors would be contraindicated because they impair platelet-mediated blood clotting and are thus associated with increased bleeding at the operative site. COX-2 inhibitors, including celecoxib (Celebrex), and valdecoxib (Bextra), are associated with increased cardiovascular risk. It is possible that this is a class effect of NSAIDs, excluding aspirin. These drugs are contraindicated in patients in the immediate period after coronary artery bypass surgery and should be used with caution in patients having a history of or significant risk factors for cardiovascular disease.

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 and effective method for rapid pain relief. 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. Table 1 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 (µ-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 increased in patients with renal failure.

The most rapid relief with opioids is obtained by intravenous administration; relief with oral administration is significantly slower. Common side effects include nausea, vomiting, constipation, 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. Opioid 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 determining whether the drug has adequately relieved the pain and the duration of the relief. 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 can deliver a baseline continuous dose of an opioid drug, as well as preprogrammed additional doses whenever the patient pushes a button. 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 that caused by metastatic cancer.

Because of patient variability in analgesia requirement, intravenous PCA is generally begun after the patient's pain has been controlled. The bolus dose of the drug (typically 1 mg morphine or 40 µg fentanyl) can then be delivered repeatedly as needed. To prevent overdosing, PCA devices are programmed with a lockout period after each demand dose is delivered (5–10 min) and a limit on the total dose delivered per hour. While some have advocated the use of a simultaneous background infusion of the PCA drug, this increases the risk of respiratory depression and has not been shown to increase the overall efficacy of the technique.

Many physicians, nurses, and patients have a certain trepidation about using opioids that is based on an exaggerated fear of addiction. 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. The fentanyl transdermal patch has the advantage of providing fairly steady plasma levels, which maximizes patient comfort.

Opioid and COX 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.


Managing patients with chronic pain is intellectually and emotionally challenging. The patient's problem is often difficult to diagnose; such patients are demanding of the physician's time and often appear emotionally distraught. The traditional medical approach of seeking an obscure organic pathology is usually unhelpful. On the other hand, psychological evaluation and behaviorally based treatment paradigms are frequently helpful, particularly in the setting of a multidisciplinary pain-management center.

There are several factors that can cause, perpetuate, or exacerbate chronic pain. First, of course, the patient may simply have a disease that is characteristically painful for which there is presently no cure. Arthritis, cancer, migraine headaches, fibromyalgia, and diabetic neuropathy are examples of this. Second, there may be secondary perpetuating factors that are initiated by disease and persist after that disease has resolved. Examples include damaged sensory nerves, sympathetic efferent activity, and painful reflex muscle contraction. Finally, a variety of psychological conditions can exacerbate or even cause pain.

There are certain areas to which special attention should be paid in the medical history. Because depression is the most common emotional disturbance in patients with chronic pain, patients should be questioned about their mood, appetite, sleep patterns, and daily activity. A simple standardized questionnaire, such as the Beck Depression Inventory, can be a useful screening device. It is important to remember that major depression is a common, treatable, and potentially fatal illness.

Other clues that a significant emotional disturbance is contributing to a patient's chronic pain complaint include: pain that occurs in multiple unrelated sites; a pattern of recurrent, but separate, pain problems beginning in childhood or adolescence; pain beginning at a time of emotional trauma, such as the loss of a parent or spouse; a history of physical or sexual abuse; and past or present substance abuse.

On examination, special attention should be paid to whether the patient guards the painful area and whether certain movements or postures are avoided because of pain. Discovering a mechanical component to the pain can be useful both diagnostically and therapeutically. Painful areas should be examined for deep tenderness, noting whether this is localized to muscle, ligamentous structures, or joints. Chronic myofascial pain is very common, and in these patients deep palpation may reveal highly localized trigger points that are firm bands or knots in muscle. Relief of the pain following injection of local anesthetic into these trigger points supports the diagnosis. A neuropathic component to the pain is indicated by evidence of nerve damage, such as sensory impairment, exquisitely sensitive skin, weakness and muscle atrophy, or loss of deep tendon reflexes. Evidence suggesting sympathetic nervous system involvement includes the presence of diffuse swelling, changes in skin color and temperature, and hypersensitive skin and joint tenderness compared with the normal side. Relief of the pain with a sympathetic block is diagnostic.

A guiding principle in evaluating patients with chronic pain is to assess both emotional and organic factors before initiating therapy. Addressing these issues together, rather than waiting to address emotional issues after organic causes of pain have been ruled out, improves compliance in part because it assures patients that a psychological evaluation does not mean that the physician is questioning the validity of their complaint. Even when an organic cause for a patient's pain can be found, it is still wise to look for other factors. For example, a cancer patient with painful bony metastases may have additional pain due to nerve damage and may also be depressed. Optimal therapy requires that each of these factors be looked for and treated.

Chronic Pain: Treatment

Once the evaluation process has been completed and the likely causative and exacerbating factors identified, an explicit treatment plan should be developed. An important part of this process is to identify specific and realistic functional goals for therapy, such as getting a good night's sleep, being able to go shopping, or returning to work. A multidisciplinary approach that utilizes medications, counseling, physical therapy, nerve blocks, and even surgery may be required to improve the patient's quality of life. There are also some newer, relatively invasive procedures that can be helpful for some patients with intractable pain. These procedures include implanting intraspinal cannulae to deliver morphine or intraspinal electrodes for spinal stimulation. There are no set criteria for predicting which patients will respond to these procedures. They are generally reserved for patients who have not responded to conventional pharmacologic approaches. Referral to a multidisciplinary pain clinic for a full evaluation should precede any invasive procedures. Such referrals are clearly not necessary for all chronic pain patients. For some, pharmacologic management alone can provide adequate relief.

Antidepressant Medications

The tricyclic antidepressants [amitriptyline, imipramine, nortriptyline, desipramine (TCAs; Table 1)] are extremely useful for the management of patients with chronic pain. Although developed for the treatment of depression, the tricyclics have a spectrum of dose-related biologic activities that include the production of analgesia in a variety of clinical conditions. Although the mechanism is unknown, the analgesic effect of TCAs has a more rapid onset and occurs at a lower dose than is typically required for the treatment of depression. Furthermore, patients with chronic pain who are not depressed obtain pain relief with antidepressants. There is evidence that tricyclic drugs potentiate opioid analgesia, so they may be useful adjuncts for the treatment of severe persistent pain such as occurs with malignant tumors. Table 2 lists some of the painful conditions that respond to tricyclics. TCAs are of particular value in the management of neuropathic pain such as occurs in diabetic neuropathy and postherpetic neuralgia, for which there are few other therapeutic options.

Table 2 Painful Conditions that Respond to Tricyclic Antidepressants

Postherpetic neuralgiaa

Diabetic neuropathya

Tension headachea

Migraine headachea

Rheumatoid arthritisa,b

Chronic low back painb


Central post-stroke pain

aControlled trials demonstrate analgesia.

bControlled studies indicate benefit but not analgesia.

The TCAs that have been shown to relieve pain have significant side effects.Some of these side effects, such as orthostatic hypotension, drowsiness, cardiac conduction delay, memory impairment, constipation, and urinary retention, are particularly problematic in elderly patients, and several are additive to the side effects of opioid analgesics. The serotonin-selective reuptake inhibitors such as fluoxetine (Prozac) have fewer and less serious side effects than TCAs, but they are much less effective for relieving pain. It is of interest that venlafaxine (Effexor) and duloxetine (Cymbalta), which are nontricyclic antidepressants that block both serotonin and norepinephrine reuptake, appear to retain most of the pain-relieving effect of TCAs with a side-effect profile more like that of the serotonin-selective reuptake inhibitors. These drugs may be particularly useful in patients who cannot tolerate the side effects of tricyclics.

Anticonvulsants and Antiarrhythmics

These drugs are useful primarily for patients with neuropathic pain. Phenytoin (Dilantin) and carbamazepine (Tegretol) were first shown to relieve the pain of trigeminal neuralgia. This pain has a characteristic brief, shooting, electric shock–like quality. In fact, anticonvulsants seem to be helpful largely for pains that have such a lancinating quality. Newer anticonvulsants, gabapentin (Neurontin) and pregabalin (Lyrica), are effective for a broad range of neuropathic pains.

Antiarrhythmic drugs such as low-dose lidocaine and mexiletine (Mexitil) can also be effective for neuropathic pain. These drugs block the spontaneous activity of damaged primary afferent nociceptors.

Chronic Opioid Medication

The long-term use of opioids is accepted for patients with pain due to malignant disease. Although opioid use for chronic pain of nonmalignant origin is controversial, it is clear that for many such patients opioid analgesics are the best available option. This is understandable since opioids are the most potent and have the broadest range of efficacy of any analgesic medications. Although addiction is rare in patients who first use opioids for pain relief, some degree of tolerance and physical dependence are likely with long-term use. Therefore, before embarking on opioid therapy, other options should be explored, and the limitations and risks of opioids should be explained to the patient. It is also important to point out that some opioid analgesic medications have mixed agonist-antagonist properties (e.g., pentazocine and butorphanol). From a practical standpoint, this means that they may worsen pain by inducing an abstinence syndrome in patients who are physically dependent on other opioid analgesics.

With long-term outpatient use of orally administered opioids, it is desirable to use long-acting compounds such as levorphanol, methadone, or sustained-release morphine (Table 1). Transdermal fentanyl is another excellent option. The pharmacokinetic profile of these drug preparations enables prolonged pain relief, minimizes side effects such as sedation that are associated with high peak plasma levels, and reduces the likelihood of rebound pain associated with a rapid fall in plasma opioid concentration. Constipation is a virtually universal side effect of opioid use and should be treated expectantly.

Treatment of Neuropathic Pain

It is important to individualize treatment for patients with neuropathic pain. Several general principles should guide therapy: the first is to move quickly to provide relief; a second is to minimize drug side effects. For example, in patients with postherpetic neuralgia and significant cutaneous hypersensitivity, topical lidocaine (Lidoderm patches) can provide immediate relief without side effects. Anticonvulsants (gabapentin or pregabalin, see above) or antidepressants can be used as first-line drugs for patients with neuropathic pain. Antiarrhythmic drugs such as lidocaine and mexiletene can be effective (see above). There is no consensus on which class of drug should be used as a first-line treatment for any chronically painful condition. However, because relatively high doses of anticonvulsants are required for pain relief, sedation is very common. Sedation is also a problem with the tricyclic antidepressants but is much less of a problem with serotonin/norepinephrine reuptake inhibitors (SNRIs, e.g., venlafaxine and duloxetine). Thus, in the elderly or in those patients whose daily activities require high-level mental activity, these drugs should be considered as the first line. In contrast, opioid medications should be used as a second- or third-line drug class. While highly effective for many painful conditions, opioids are sedating, and their effect tends to lessen over time, leading to dose escalation and, occasionally, a worsening of pain due to physical dependence. Drugs of different classes can be used in combination to optimize pain control.

It is worth emphasizing that many patients, especially those with chronic pain, seek medical attention primarily because they are suffering and because only physicians can provide the medications required for pain relief. A primary responsibility of all physicians is to minimize the physical and emotional discomfort of their patients. Familiarity with pain mechanisms and analgesic medications is an important step toward accomplishing this aim.


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