Chapter 19 - Pain
Pain is the most common symptom bringing patients to medical attention. The objectives of this discussion are to describe the evaluation of the patient with pain and to discuss the different types of pain and their management from a neurologic perspective. Some of the conditions that predispose patients to pain will also be discussed. Particular attention will be paid to neuropathic pain, which is a particularly challenging issue in medical practice. Additionally, we will consider various treatments for this type of pain, and how these treatments might differ from the treatment of acute pain problems. Finally, we will also consider how suffering and pain are similar and how they are different.
There are a number of historical factors that are essential to the diagnosis and management of pain.
Where is the pain? The location may define the tissues from which pain is being generated, although referred pain (the perception of pain in a different, usually more distal) part of the body is common when deeper tissues are involved.
How did it start? The mechanism of onset (such as by injury) may give a great amount of information about the condition.
When did it start? The duration of the symptom can help define whether this is likely to be an acute, self-limited condition or whether it is now chronic, with probably complicating factors.
What has been the course? Most acutely painful conditions gradually improve with healing of the damaged tissues. Escalation of symptoms after the initial period can occur by one of three mechanisms. The condition may be prevented from healing by continued reaggravation; there may be significant inflammation that can continually irritate pain nerve fibers; or various processes that can lead to neuropathic pain may be developing.
What makes it better or worse? This is the particular question that is most likely to give you information about the specific mechanism of the pain and what might be done to treat it.
What has been the functional consequence of the pain? An understanding of the limitations produced by the pain will help you to understand the issues that the patient will be expecting assistance with.
What is the patient’s history of coping with painful conditions? This will help you to understand the barriers that the patient will need to overcome in order to recover.
What has been the effect of the pain on the patient’s psychological status? The more depression and anxiety that there is associated with the condition, the more that these have to be taken into consideration in the management of the pain.
What is the patient’s history of interaction with addicting substances? This is of prognostic significance and can also effect treatment decisions.
Fundamentally, pain can be divided into nociceptive and neuropathic pain. Nociceptive pain results from direct activation of pain nerve fibers, either due to chemical, inflammatory or mechanical mediators. Neuropathic pain refers to pain that is generated or sustained by the nervous system. These two types of pain are fundamentally different in mechanism and, therefore, require different treatment.
Nociceptive pain is the more common type of pain and is experienced by everyone suffering any kind of injury or localized inflammatory process. This kind of pain is due to activation of small diameter afferent nerve fibers that are sometimes called “pain” nerve fibers (more correctly termed “nociceptive” nerve fibers). There are two basic types of “pain fibers.” “Fast pain fibers” are lightly myelinated, Ad fibers (see table 21-2). These fibers relay a sharp, stinging sensation to nociceptive-specific neurons located at the margin of the dorsal horn. These fibers appear be responsible for alerting to the presence of pain but not necessarily transmitting its intensity. Smaller diameter (slower) nerve fibers in the range of C-fibers conduct information related aching, burning type pain. This pain has a wide range and appears to be responsible for relaying the intensity of the pain. The pain following these small nociceptive fibers is poorly localized in the nervous system since it is transmitted to higher centers by neurons in the dorsal horn that receive widely convergent input. See this discussion of the central pathways in relaying pain signals to higher centers.
The peripheral endings of nociceptive nerve fibers are usually activated by severe mechanical forces or by a variety of chemical mediators in the environment that are released by tissue damage, from nerves or from inflammatory cells (Table 19-1). It is important to note that sensory nerve fibers may release transmitters from their peripheral ends that can promote inflammation and that other nerve fibers (such as sympathetic nerve terminals) can also participate in the reaction. It is important to note that the activation of a nociceptive nerve fiber does not necessarily result in the experience of pain. There are several levels of the nervous system, notably the dorsal horn of the spinal cord and the thalamus, that have mechanisms for filtering the signal. Therefore, for example, activation of a few nociceptive fibers along with a large number of touch nerve fibers is unlikely to be experienced as pain. Treatment of nociceptive pain requires resolution of the conditions that are activating the nociceptive fibers. For example, if local inflammation is a major factor, suppression of the inflammatory reaction would be expected to resolve the pain.
Neuropathic pain is fundamentally different from nociceptive pain and is much more complex. This type of pain is generated or sustained by the nervous system. This can either relate to changes in the peripheral or central nervous systems. For example, peripheral nerve fibers can be altered in terms of sensitivity or response due to many factors. In the central nervous system, there may be reorganization of the pathways that transmit the signal or the functions of systems that normally filter or suppress pain. Of course, central and peripheral factors may combine to contribute to the genesis of neuropathic pain syndromes. Regardless of whether peripheral or central processes predominate, neuropathic pain responds poorly to normal pain treatments, and in fact may be complicated by normal acute pain treatments for it.
Neuropathic pain is, by definition, chronic and may escalate with time. This is as opposed to most acute, nociceptive pain problems that lesson with time and with healing. Neuropathic pain may augment associated with some structural or physiological changes in neurons of the pain pathways. Most conditions that cause pain are capable of triggering neuropathic pain in susceptible individuals. In addition to some inherent (possibly genetic) factors that may promote neuropathic pain, there are certain situations and conditions that appear to be more likely to do this than others. These conditions include diabetic neuropathy, postherpetic neuralgia, phantom limb pain, deafferntation and trigeminal neuralgia. The mechanisms responsible for neuropathic pain in these conditions are relatively well understood, while other conditions, such as trauma and other orthopedic problems, are less commonly understood triggers. Nonetheless, these represent significant contributions to neuropathic pain.
There are several different mechanisms for generation of neuropathic pain, some that affect the peripheral nervous system and some that affect central nervous system function. In the peripheral nervous system, there are three main mechanisms to consider: 1. Disorders that result in spontaneous firing of damaged nerve fibers; 2. Processes that result in oversensitivity of afferent pathways due to denervation; 3. Sympathetically maintained pain. Of the processes in the central nervous system, there may be sensitization at the synaptic level or through reorganization of higher processing mechanisms. We will discuss each of these processes.
Oversensitivity and even spontaneous activity of damaged fibers can often occur in concert with directly injured nociceptive nerve fibers. At the site of injury there can be changes in neuronal membranes that include augmentation of numbers of numbers of ion channels and insertion of additional types of receptors into the neuronal membrane. This process can result in sensitization of the nerve fiber to both mechanical and chemical mediators. Several well-known clinical conditions, such as trigeminal neuralgia, radiculopathy, plexopathies and certain compression injuries in nerves, can result in this type of sensitization. These conditions often result in projected pain, with pain being felt very specifically along the distribution of the peripheral sensory nerve fibers. Initial treatment for this type of neuropathic pain should be directed at the mechanical and chemical factors at the site of damage, though some of these changes may be chronic and resistant to improvement. For example, there may be ectopic foci of firing along and damaged nerve fiber. This type of pain is often described as shooting or stabbing and, when many nerve fibers are firing asynchronously, the pain may be described as a continuous burning pain. This is a process that can produce pain in an anesthetic part of the body (anesthesia dolorosa) and can be extremely bothersome. In many of these conditions, larger fibers may be completely absent, resulting in overall decrease in sensitivity (see the next section on deafferentation pain). Persistence of small nerve fibers (pain fibers) can result in magnification of pain due to spontaneous firing. These conditions may respond to treatments directed at stabilizing oversensitive nerve membranes, including anesthetics and anticonvulsant medications.
Deafferentation results from the interruption of sensory conduction due to damage to large diameter sensory nerve fibers (the ones that mediate touch and pressure sense). This process can increase sensitivity and irritability of neurons further along the sensory pathway. Some of this occurs as the direct result of loss of competition between the large-diameter “normal” sensory input and input from small diameter, nociceptive fibers. This can magnify the transmission and the perception of pain in much the same way as a sound being heard most acutely in an otherwise silent room. Additionally, a chronic lack of normal sensory input has been shown to be capable of actually decreasing the number of inhibitory neurons (presumably through transynaptic degeneration) in second and third order nuclei of the central nervous system. This, and other factors, can result in spontaneous firing of second and third order neurons. Therefore, there may be pain in the area of diminished or even completely lost sensation. This results in an extremely distressing kind of "central pain".
This group of conditions has gone by several names in the past (including complex regional pain, reflex sympathetic dystrophy, causalgia or sympathetically maintained pain), reflecting some variability in triggers and in presentation. These are all categorized by some irregularities in autonomic nervous system function, including changes in circulation and temperature as well as changes in sweating patterns. There may also be elements of neurogenic inflammation. Sympathetic nerve fibers not only secrete norepinephrine, but also certain inflammatory mediators such as prostaglandins and certain nerve growth factors. These may stimulate small diameter nociceptive fibers directly and may sensitize them (Table 19-1). This is particularly true when these nociceptive fibers have been damaged.
The sympathetic nervous system does appear to be involved in more general inflammatory reactions. This occurs with release of inflammatory mediators along with sympathetic neurotransmitters. These factors interact with tissue elements, and have been shown to contribute to inflammation in various experimental conditions (such as experimental models of inflammatory arthritis). Therefore, inflammation must be considered to be a complex interaction between tissue components and the nervous system.
It is known that neurotransmitters released from sensory nerve fibers in the periphery can also contribute to the inflammatory reaction. Many of these neurotransmitters sensitize other pain fibers and also can result in vasodilation, edema, infiltration of white blood cells and activation of other inflammatory cells. Therefore, the nervous system cannot be considered a passive participant in inflammation, but rather a pivotal factor in magnifying and sustaining inflammation. This may be why conditions that activate sensory nerve fibers and the sympathetic nervous system can aggravate local inflammation. It also may be why certain types of nerve blocks may be effective in abolishing chronic pain. This is clearly been shown in certain animal models of chronic pain. It is interesting to note that the chronic application of capsaicin (which depletes the number of small pain fibers in an area) may diminish this component of the inflammatory reaction.
This process of “neurogenic inflammation” may be central in many chronic pain problems. The family of conditions ranging from true causalgia (sustained pain and autonomic changes due to damage to nerve trunks) to various other types of sympathetically maintained pain may simply reflect differences in the specific tissues that neurogenic inflammation is acting upon.
Treatment of complex regional pain syndrome is quite difficult and sometimes frustrating. Early in the condition it is known that aggressive mobilization, and physiotherapy is helpful. Usually active exercises are better tolerated than passive, since there is often cutaneous hyperesthesia. Various methods of pain control, ranging from the use of physiotherapeutic modalities to anti-inflammatory medicines, are probably best considered to be ways to enhance the patient's tolerance for movement-related therapies. The mechanism whereby mobilization helps the condition is not clearly understood, but may involve the kind of low-frequency activation of normal sensory fibers that are known to promote long-term depression of synaptic transmission in overactive pain pathways (see the following section).
The central nervous system can participate in the generation of neuropathic pain. Central to this is the fact that neurons are plastic and change both structurally and functionally in response to injury. In many ways it can be stated that the nervous system can create a “memory” of pain. Many of the normal neural factors that are associated with memory in the cerebral cortex can take place in sensory nuclei as well. Convergence of high frequency, high-intensity stimulation appears to be necessary for this kind of memory and the most studied specific mechanism involves glutamate channels. High-intensity stimulation of these pathways results in "long-term potentiation." This may be enhanced by co-activation of various neurotransmitters associated with pain (such as substance P, neurokinin A, calcitonin gene-related peptide, and brain derived nerve growth factor). The resulting sensitized pain transmission neurons are activated much more readily and can even become spontaneously active within the pain pathway. Something that must be kept in mind is that these changes are quite robust and may even result in production of additional receptors and activation of various parts of the neuronal genome. Therefore, the effects of stimulation may be quite difficult to reverse.
Interestingly, low-frequency stimulation of the same pathways may result in long-term depression. Therefore, changes in the sensitivity of neurons are not necessarily immutable.
Although we've come to know many of the important receptors for this kind of pain memory at the neuronal level, it is becoming increasingly obvious that glial cells, may participate in this activation, producing cytokines and growth factors that are capable of enhancing and stabilizing some of these pathologic changes.
Changes in pain transmission pathways explain various clinical observations such as hyperalgesia. Neurons in sensory nuclei become excessively sensitive and may result in a painful experience to even light touch. Local reactions in the spinal cord are likely to be enhanced as well. This may explain local muscle spasm and overactivity of motor function. If the sensitization has been dramatic enough, it may result in spontaneous pain.
Changes in neuronal function have been demonstrated in various experimental models such as nerve root injury. There is also a strong suggestion that changes in the nervous system are occurring at many levels, including the spinal cord, areas of the brain stem that are involved in regulation of muscle tone and autonomic function as well as a levels of the thalamus and cerebral cortex that are involved in pain transmission and sensory and cognitive processing. I would hasten to add that this does not occur with all pain stimuli, and it is believed that some individuals are more likely to develop such chronic pain "memory." It is also clear that certain stimuli are more likely to produce changes, as well.
The implications of this understanding of pain memory are several. These include the fact that it is important to recognize the particular types of problems that are likely to become chronic and to treat them early and aggressively in order to attempt to interrupt conditioning at the beginning. Once problems become chronic, however, they are likely to require substantially more treatment, and treatment that takes into account this reorganization of sensory pathways.
The first step in managing neuropathic pain is identifying that it is a factor. Usually this is by recognizing the proper clinical setting, and accompanying physical signs. Neuropathic pain is much more likely to develop associated with conditions that damage the nervous system, including various direct nerve injuries and diseases such as diabetes, alcohol abuse, zoster, HIV, Lyme disease or conditions involving the central nervous system such as multiple sclerosis.
The character of pain may also be helpful. Neuropathic pain is much more likely to be described a shooting, stabbing, burning, or searing, and it's often worse at night (a potential distinction from most muscular pain). This is also distinct from inflammatory pain, which tends to be worse first thing in the morning, and during activity. The reason that neuropathic pain is often worse at night may relate to the lack of normal input to the nervous system as well as circadian rhythms in pain thresholds.
The distribution of pain can help identify neuropathic pain. When the cause is peripheral, symptoms often follow the route of the damaged peripheral nerve or nerve root (such as in cases of sciatica). When the cause is central, symptoms often involve large areas of the limb or body region. There may be changes in skin color, temperature or texture in the area. There may also be other evidence of damage to the nervous system (which may help to define a cause). Finally, there is likely to be a greater variety of pain related phenomena, including dysesthesias (painful paresthesias) and allodynia (pain generated by an innocuous stimulus), and there is also more likely to be autonomic changes.
Ideally, when a specific trigger is identified, treatment of the underlying disease should be initiated. Symptom control through local or regional measures is somewhat preferable to systemic treatment due to potential side effects of systemic treatment. Topical anesthetics with or without ionto- or phonophoresis may be helpful, and gradually escalating doses of capsaicin cream may be helpful as well (if tolerated). Regional anesthetic blocks, including sympathetic blocks, may be helpful. These interventions are more likely to be effective if they are accompanied by aggressive physical therapy interventions. Electrical stimulation, including transcutaneous electrical nerve stimulation, acupuncture-like stimulation, spinal cord stimulation or activation of local receptors by mobilization and massage may be quite useful. However, direct stimulation of painful areas may be poorly tolerated. In these cases, stimulation of adjacent areas, or even treatment of the opposite side of the body may be quite useful. These interventions may be useful in helping the person tolerate local therapy in the area of pain.
Unfortunately, nerve destructive procedures, which may be helpful on occasion, can worsen or even contribute to neuropathic pain. Various systemic treatments have been helpful, including certain anticonvulsants that calm abnormal nerve activity, as well as antidepressants that enhance serotonin and norepinephrine in the nervous system. In that regard, 5-hydroxytryptophan, which has similar effects on serotonin transmission, has not been specifically studied in neuropathic pain. There are various experimental treatments that have been attempted to interfere with some of the sensitization that occurs within the nervous system. However, these still remain on an experimental level.
Of interest, many of the acute pain medicines, especially those that act on opiate receptors, may actually result in further sensitization of neural pathways over the long run. Therefore, these should only be used in full recognition of this potential. While it appears that some individuals are more susceptible to this sensitization, it is not clear how to identify them. This is an active area of research interest in the pain medicine field, since it may help determine for whom opiates are appropriate in treatment of chronic, neuropathic pain.
Behavioral therapy is very important in chronic pain since stress amplifies pain and relaxation can reduce excitability of the autonomic nervous system. Additionally, sleep is quite abnormal in neuropathic pain patients, who have particularly disrupted slow-wave sleep. Various sleep interventions may be useful in these patients.
Although several different central and peripheral factors are described above, it is quite likely that many patients have a combination of factors. Therefore, it is not surprising that most patients with neuropathic pain require more than one type of therapy (e.g., pharmacologic, physical therapies and behavioral therapies).
These two terms are often used interchangeably. However, there are different mechanisms for each. While pain is a phenomenon that affects many levels of the nervous system, suffering is a cerebral cortical phenomenon and is highly individual. The frontal lobes (especially the medial aspect of the prefrontal cortex) appears to be the most importnat site for interpretation of the affective quality of the painful stimulus. Patients with damage to this region can still report the intensity of a painful stimulus but are generally less bothered by it (i.e., they appear to suffer less). These are the ares that are activated when normal individuals are attempting to assess the significance of a palinful stimulus.
It is clear that patients experience suffering in a highly individual manner and that there are both psychological and physical factors that go into this. Psychological factors can be conditioned by past painful experiences as well as by the significance of the pain to the individual. It can be affected by the patient’s psychological state as well as their individual coping style. Finally, it appears that some patients have much more activation of brain regions involved in suffering than others even when presented with painful stimuli that are identical. The foundation for this difference probably includes genetic makeup as well as a cumulation of life experiences and other factors.
Before concluding this discussion of pain, it would be appropriate to consider a condition that is common in medical and neurologic practice. Fibromyalgia is a condition of diffuse, chronic pain characterized by extreme sensitivity of muscles in several parts of the body. It may follow a minor injury or infection or may be spontaneous. It happens approximately ten times more often in women and usually begins in middle age. Symptoms wax and wane but are usually worsened by activity. It may resolve completely, but more often is associated with residual symptoms that can range from minor to very severe. Patients often complain of paresthesias (which may result in them seeing a neurologist) and extreme fatigue. Many patients have sleep disorders, migraine headaches and irritable bowel.
The diagnosis initially requires ruling out other diseases that cause chronic, diffuse pain Conditions that should be considered include Lyme disease, collagen vascular diseases, polymyositis, dermatomyositis and endocrine disorders (such as thyroid or adrenal disease). The diagnostic criteria are imperfect at best. However, chronic (>3 months), widespread (at least 3 body regions) pain, accompanied by abnormal sensitivity to relatively light pressure (<4kg/cm2) in at least 11 out of 18 standardized spots on the body. These spots include: the suboccipital muscles; the lower sternocleidomastoids; the second costochondral junctions; the insertions of the levator scapulae; the belly of the upper trapezius; two centimeters below the lateral epicondyle; the greater trochanter; the superolateral gluteal quadrant; and the medial knee. All these spots are bilateral, for a total of 18. Also, the sensitive spots must be distributed around the body, including spots above and below the waist and on both the left and right. It is important to note that, while these are research criteria, they only achieve slightly over 80% sensitivity and specificity for fibromyalgia.
The etiology of the condition is not clear. Speculation has included: a primary sleep disorder; a subtle endocrine dysfunction; a subtle immune dysfunction; a mood disorder; a disorder of serotonin metabolism; a disorder of muscle metabolism; an unrecognized infectious condition; or a neurologic disorder. There is some evidence for and against each of these possibilities and there also appears to be an inherited predisposition that must be considered (in addition to the clear gender difference).
Treatment includes a variety of pharmacological and nonpharmacological interventions. The necessary components of treatment probably should include education, certain medications, exercise, and cognitive/behavioral therapy. Additionally, the added components of sleep disorder, migraine and irritable bowel and bladder may require interventions on their own. The medications that may be useful tend to be included in the list of those that are used for neuropathic pain. Exercise appears to be particularly important, though poorly tolerated. A supervised, very gradually escalating program of cardiovascular conditioning exercises appears to be most useful, although there are many dropouts.
In summary, pain is the most common symptom in clinical practice. Nocicpetive pain, i.e., pain that results from direct activation of pain fibers, is an important symptom alerting to the presence of tissue damage. Although analgesic and anti-inflammatory medications may be appropriate, it is important to understand the underlying etiology.
Neuropathic pain is an important challenge in the management of many chronic pain patients. The cause or trigger may not be evident and pain may outlast the usual duration of recovery. The clinician should be should have heightened awareness to this possibility when there are certain accompanying conditions such as diabetes, zoster, multiple sclerosis, Lyme disease, HIV or radicular involvements. Pain that is worse at night, pain that is described as shooting, stabbing, burning or searing, and pain along non-anatomic distributions may represent early clues to neuropathic pain. This is also true when hyperalgia is prominent, when autonomic signs are apparent or when there is pain in hypoesthetic areas. The recognition of these features should lead to consideration of neuropathic pain.
Standard pain therapies are often less effective in neuropathic pain patients. Disease modification, local or regional measures, systemic therapies and behavioral interventions should be strongly considered in this group of patients.
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Define the following terms:Nocicpetive pain, neuropathic pain, postherepetic neuralgia, allodynia, dysesthesia, deafferentation pain , causalgia, substance P, hyperalgesia, fibromyalgia syndrome.
19-1. What tissue components interact with nociceptive nerve fibers to produce pain?
19-2. What are mechanisms of generation of neuropathic pain?
19-3. What is projected pain?
19-4. What is the mechanism of deafferentation pain?
19-5. How is sympathetically maintained pain recognized ?
19-6. What is "long-term potentiation"?
19-7. What is the character of neuropathic pain?
19-8. What are the theories for the etiology of fibromyalgia syndrome?
19-9. What kinds of treatments are available for fibromyalgia syndrome?
19-10. Who is most likely to deveop fibromyalgia syndrome?
19-11. What is the most important brain region with regard to suffering?