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One learns quickly in dealing with patients that not all pain is the consequence of serious disease. Every day, healthy persons of all ages have pains that must be taken as part of normal sensory experience. To mention a few, there are the "growing pains" of presumed bone and joint origin of children; the momentary shock-like pains over an eye or in the temporal or occipital regions ("ice-pick" pain), which strike with such suddenness as to raise the suspicion of a ruptured intracranial aneurysm; inexplicable split-second jabs of pain elsewhere; the more persistent ache in the shoulder, hip, or extremity that subsides spontaneously or in response to a change in position; the fluctuant precordial discomfort of gastrointestinal origin, which conjures up fear of cardiac disease; and the breathtaking "stitch in the side" caused by intercostal or diaphragmatic cramp during exercise. These "normal pains," as they may be called, tend to be brief and to depart as obscurely as they came. Such pains come to notice only when elicited by an inquiring physician or when experienced by a patient given to worry and introspection. They must always be distinguished from the pain of disease.
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Whenever pain—by its intensity, duration, and the circumstances of its occurrence—appears to be abnormal or when it constitutes the chief complaint or one of the principal symptoms, the physician must attempt to reach a tentative decision as to its mechanism and cause. This is accomplished by a thorough interrogation of the patient, with the physician carefully seeking out the main characteristics of the pain in terms of the following:
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Knowledge of these factors in every common disease is the lore of medicine. The severity of pain is often difficult to assess. Extreme degrees of pain are betrayed by the patient's demeanor but lesser degrees can be roughly estimated by the extent to which the pain has interfered with the patient's sleep, work, and other activities, or by the patient's need for bed rest. Some physicians find it helpful, particularly in gauging the effects of analgesic agents, to use a "pain scale," i.e., to have the patient rate the intensity of his pain on a scale of zero (no pain) to 10 (worst pain) or to mark it on a line (the Visual Analog Pain Scale). It has been our experience that this effort to quantify pain is often unhelpful to the neurological analysis as patients rarely rate pain as trivial, when they have already decided to consult a physician about the problem. For most patients, pain that necessitates medical consultation is, by definition, severe. This general approach is put to use every day in the practice of general medicine. Together with the physical examination, including maneuvers designed to reproduce and relieve the pain and ancillary diagnostic procedures, it enables the physician to identify the source of most pains and the diseases of which they are a part. Whether the earlier mentioned functional imaging techniques will offer an additional tool to evaluate pain remains to be determined.
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Once the pains caused by the more common and readily recognized diseases of each organ system are eliminated, there remain a significant number of chronic pains that fall into one of four categories: (1) pain from an obscure medical disease, the nature of which has not yet been disclosed by diagnostic procedures; (2) pain associated with disease of the central or peripheral nervous system (i.e., neurogenic, or neuropathic pain); (3) pain associated with psychiatric disease; and (4) pain of unknown cause.
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Pain Caused by Undiagnosed Medical Disease
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Here the source of the pain is usually in a bodily organ and is caused by a lesion that irritates and destroys nerve endings. Consequently, the term nociceptive pain is often used even though it is ambiguous. It usually means an involvement of structures bearing the origin of pain fibers. Cancer is the most frequent example. Osseous metastases, tumors of the kidney, pancreas, or liver, peritoneal tumor implants, invasion of retroperitoneal tissues or the hilum of the lung, and infiltration of nerves of the brachial or lumbosacral plexuses can be extremely painful, and the origin of the pain may remain obscure for a long time. Sometimes it is necessary to repeat all diagnostic procedures after an interval of a few months, even though at first they were negative. From experience one learns to be cautious about reaching a diagnosis from insufficient data. Treatment in the meantime is directed to the relief of pain, at the same time instilling in the patient a need to cooperate with a program of expectant observation.
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Neurogenic, or Neuropathic Pain
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These terms are generally used interchangeably to designate pain that arises from direct stimulation of nervous tissue itself, central or peripheral, exclusive of pain as a consequence of stimulation of C fibers by lesions of other bodily structures (i.e., the nociceptive pain described above). This category comprises a variety of disorders involving single and multiple nerves, notably trigeminal neuralgia and those caused by herpes zoster, diabetes, and trauma; neuromas and neurofibromas, a number of polyneuropathies of diverse type; root irritation, e.g., from a prolapsed disc; spinal arachnoiditis and spinal cord injuries; the thalamic pain syndrome of Dejerine-Roussy; and, rarely, parietal lobe infarction such as the ones described by Schmahmann and Leifer. As a rule, lesions of the cerebral cortex and white matter are associated not with pain but with hypalgesia. Schott (1995) reviewed the clinical features that characterize central pain. Particular diseases giving rise to neuropathic pain are considered in their appropriate chapters but the following remarks are of a general nature, applicable to all of the painful states that compose this group.
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The sensations that characterize neuropathic pain vary and are often multiple—burning, gnawing, aching, and shooting or lancinating qualities are described. There is an almost invariable association with one or more of the symptoms of hyperesthesia, hyperalgesia, allodynia, and hyperpathia (see above). The abnormal sensations coexist in many cases with a sensory deficit and local autonomic dysfunction. Furthermore, the pain generally responds poorly to treatment, including the administration of opioid medications.
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Peripheral Nerve Pain
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Painful states that fall into this category are in most cases related to disease of the peripheral nerves, and it is to pain from this source that the term neuropathic is more strictly applicable. Pain states of peripheral nerve origin far outnumber those caused by spinal cord, brainstem, thalamic, and cerebral disease. Although the pain is localized to a sensory territory supplied by a nerve, plexus or nerve root, it often radiates to adjacent areas. Sometimes the onset of pain is immediate on receipt of injury; more often it appears at some point during the evolution or recession of the disorder. The disease of the nerve may be obvious, expressed by the usual sensory, motor, reflex, and autonomic changes, or these changes may be undetectable by standard tests. In the latter case, the term neuralgia is used.
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The postulated mechanisms of peripheral nerve pain are diverse and differ from those of central diseases. Some of the major ideas were mentioned in the earlier section on chronic pain. One mechanism is denervation hypersensitivity, first described by Walter Cannon. He noted that when a group of neurons is deprived of its natural innervation, they become hyperactive. Others point to a reduced density of certain types of fibers in nerves supplying a causalgic zone as the basis of the burning pain but the comparison of the density of nerves from painful and nonpainful neuropathies has not proved to be consistently different. For example, Dyck and colleagues, in a study of painful versus nonpainful axonal neuropathies, concluded that there was no difference between them in terms of the type of fiber degeneration. Also, the occurrence of ectopic impulse generation all along the surface of injured axons and the possibility of ephaptic activation of unsheathed axons seem applicable particularly to some causalgic states. Stimulation of the nervi nervorum of larger nerves by an expanding intraneural lesion or a vascular change was postulated by Asbury and Fields as the mechanism of nerve trunk pain. The sprouting of adrenergic sympathetic axons in response to nerve injury has already been mentioned and is an ostensible explanation for the abolition of causalgic pain by sympathetic blockade. This has given rise to the term sympathetically sustained pain for some cases of causalgia, as discussed below.
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Regenerating axonal sprouts, as in a neuroma, are also hypersensitive to mechanical stimuli. On a molecular level, it has been shown that voltage-gated sodium channels accumulate at the site of a neuroma and all along the axon after nerve injury, and that this gives rise to ectopic and spontaneous activity of the sensory nerve cell and its axon. Such firing has been demonstrated in humans after nerve injury. This mechanism is concordant with the relief of neurogenic pain by sodium channel-blocking anti-epileptic drugs. Spontaneous activity in nociceptive C fibers is thought to give rise to burning pain; firing of large myelinated A fibers is believed to produce dysesthetic pain induced by tactile stimuli. The abnormal response to stimulation is also influenced by sensitization of central pain pathways, probably in the dorsal horns of the spinal cord, as outlined in the review by Woolf and Mannion. Hyperalgesia and allodynia are thought to result from such a spinal cord mechanism. Several observations have been made regarding the neurochemical mechanisms that might underlie these changes but none provides a consistent explanation. Possibly more than one of these mechanisms is operative in a given peripheral nerve disease.
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Evidence that the sodium channel can generate neural pain is given by the extraordinary disease "paroxysmal extreme pain disorder" also known as "familial rectal pain syndrome." Here, a mutation of the sodium channel gene, SCN9A, leads to the early onset of paroxysmal autonomic changes and attacks of excruciating deep burning pain in the rectum, eye, or jaw, or diffusely, as described by Fertleman and coworkers. Similar but more diffuse painful states such as erythromelalgia and paroxysmal extreme pain disorder are being uncovered that are predicated on similar voltage-gated sodium channel mutations and more impressively, by the congenital absence of the ability to experience pain due to a loss of function mutation in a sodium channel gene and a mutation in the tyrosine kinase receptor gene. Fischer and Waxman provide a summary of the mutations in the sodium channel gene and their clinical presentations.
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Causalgia and Reflex Sympathetic Dystrophy (Complex Regional Pain Syndrome)
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Causalgia is the name that Weir Mitchell applied to a rare (except in time of war) type of peripheral neuralgia consequent upon trauma, with partial interruption of the median or ulnar nerve and, less often, the sciatic or peroneal nerve (see also "Chronic Pain" further on and discussion in Chap. 46). It is characterized by persistent, severe pain in the hand or foot, most pronounced in the digits, palm of the hand, or sole. The pain has a burning quality and frequently radiates beyond the territory of the injured nerve. The painful parts are exquisitely sensitive to contact, so the patient cannot bear the pressure of clothing or drafts of air; even ambient heat, cold, noise, or emotional stimuli intensify the causalgic symptoms. The affected extremity is kept protected and immobile, often wrapped in a cloth moistened with cool water. Sudomotor, vasomotor, and, later, trophic abnormalities are usual accompaniments of the pain. The skin of the affected part is moist and warm or cool and soon becomes shiny and smooth, at times scaly, devoid of hair, and discolored.
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A number of theories have been proposed to explain the causalgic syndrome. For many years it was attributed to a short-circuiting of impulses, the result of an artificial connection between efferent sympathetic and somatic afferent pain fibers at the point of the nerve injury. The demonstration that causalgic pain could be abolished by depletion of neurotransmitters at sympathetic adrenergic endings shifted the presumed site of sympathetic-afferent interaction to the nerve terminals and suggested that the abnormal cross-excitation is chemical rather than electrical in nature. Another possible explanation is that an abnormal adrenergic sensitivity develops in injured nociceptors and that circulating or locally secreted sympathetic neurotransmitters trigger the painful afferent activity. Another theory holds that a sustained period of bombardment by sensory pain impulses from one region results in the sensitization of central sensory structures. "True causalgia" of this type can be counted on to respond favorably, if only temporarily, to procaine block of the appropriate sympathetic ganglia and, for a longer time, to regional sympathectomy. Prolonged cooling and the intravenous injection of guanethidine, a sympathetic-blocking drug, into the affected limb (with the venous return blocked for several minutes) may alleviate the pain for days or longer. Epidural infusions, particularly of analgesics or ketamine, intravenous infusion of bisphosphonates, and spinal cord stimulators are other forms of treatment (see Kemler et al). The roles of the central and sympathetic nervous systems in causalgic pain have been critically reviewed by Schott and by Schwartzman and McLellan.
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Increasingly, reflex sympathetic dystrophy has been reported after limb and bone injury but in the absence of evident damage to adjacent nerves. Oaklander and Fields have speculated that this is due to an induced small fiber neuropathy; limited confirmation of this notion is given by those authors.
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Recent investigations have begun to define the molecular changes that occur in sensory neurons and the spinal cord in cases of chronic pain of this type. Alterations in N-methyl-D-aspartate (NMDA) receptors, induction of cyclooxygenase and prostaglandin synthesis, and changes in gabanergic inhibition in the dorsal horns are all implicated (Woolf).
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The term causalgia is, in our view, best reserved for the syndrome described above—i.e., persistent burning pain and local abnormalities of autonomic innervation from trauma to a major nerve in an extremity. Some neurologists use "causalgia" to describe only the burning feature of pain due to partial nerve injury. Others have applied the term to a wide range of conditions that are characterized by persistent burning pain but have only an inconstant association with sudomotor, vasomotor, and trophic changes and an unpredictable response to sympathetic blockade. These latter states, which have been described under a plethora of terms (e.g., complex regional pain syndrome type 2, Sudeck atrophy of bone, minor causalgia, shoulder–hand syndrome, algodystrophy, or algoneurodystrophy), may follow non-traumatic lesions of the peripheral nerves or even lesions of the CNS ("mimocausalgia").
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We have no explanation for the so-called causalgia–dystonia syndrome (Bhatia et al) in which a fixed dystonic posture is engrafted on a site of causalgic pain. The clinical features of both the causalgic and dystonic elements of the syndrome have been somewhat unusual in the cases reported. The degree of injury was often trivial or nonexistent and no signs of a neuropathic lesion were evident. Remarkably, both the causalgia and dystonia spread from their initial sites to widely disparate parts of the limbs and body. The syndrome did not respond to any form of treatment, although some patients recovered spontaneously. Another interesting type of causalgia and reflex sympathetic dystrophy follows deep venous thrombosis in a leg and had in the literature been recorded as "algodystrophy." It may be similar to the left shoulder and hand changes that come on months after a myocardial infarction ("shoulder–hand syndrome").
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The treatment of reflex sympathetic dystrophy is largely unsatisfactory, although a certain degree of improvement can be expected if treatment is started early and the limb is mobilized. The options for treatment are discussed further on.
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Central Neurogenic Pain
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There are several configurations of central lesions that damage the sensory system and produce severe pain. Deafferentation of secondary neurons in the posterior horns or of sensory ganglion cells that terminate on them may cause the deafferented cells to become continuously active and, if stimulated by a microelectrode, to reproduce pain. In the patient whose spinal cord has been transected, there may be intolerable pain in regions below the level of the lesion. It may be exacerbated or provoked by movement, fatigue, or emotion and projected to areas disconnected from suprasegmental structures (akin to the phantom pain in the missing part of an amputated limb). Here, and in the rare cases of intractable pain with lateral medullary or pontine lesions, loss of the descending inhibitory systems seems a likely explanation. This may also explain the pain of the Dejerine-Roussy thalamic syndrome described in Chap. 9. Altered sensitivity and hyperactivity of central neurons are alternative possibilities.
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Further details concerning the subject of neuropathic pain can be found in the older but still informative writings of Scadding and of Woolf and Mannion.
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Pain in Association with Psychiatric Diseases
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It is not unusual for patients with depression to have pain as a dominant symptom. As emphasized previously, most patients with chronic pain of all types are depressed. Wells and colleagues, in a survey of a large number of depressed and chronic pain patients, have corroborated this clinical impression. Fields has elaborated a theoretical explanation of the overlap of pain and depression. In such cases, one is faced with an extremely difficult clinical problem—that of determining whether a depressive state is primary or secondary. Complaints of weakness and fatigue, depression, anxiety, insomnia, nervousness, irritability, palpitations, etc., are woven into the clinical syndrome, attesting to the prominence of a psychiatric disorder. In some instances the diagnostic criteria for depression cited in Chap. 52 provide some insight, but in others it is impossible to make this determination and may not be necessary as depression and pain are so often coincident. Empiric treatment with antidepressant medication or, failing this, with electroconvulsive therapy is one way out of the dilemma.
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Intractable pain may also be the leading symptom of both somatization and conversion reactions. Experienced physicians are familiar with the patient who has undergone multiple surgical procedures to address painful complaints (so-called Briquet disease). The recognition and management of this group of disorders are discussed in Chap. 51.
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The desire for compensation (e.g. workman's compensation, disability status) is usually colored by persistent complaints of headaches, neck pain (whiplash injuries), low back pain, and other painful conditions. The question of ruptured disc is often raised, and laminectomy and spinal fusion may be performed (sometimes more than once) on the basis of dubious radiologic findings. Long delay in the settlement of litigation, allegedly to determine the seriousness of the injury, only enhances the symptoms and prolongs the disability. The medical and legal professions have no certain approach to such problems and often work at cross-purposes. We have found that a frank, objective appraisal of the injury, an assessment of any psychiatric problem, and encouragement to settle the legal claims as quickly as possible work in the best interests of all concerned. Although hypersuggestibility and relief of pain by placebos may reinforce the physician's belief that there is a prominent factor of hysteria or malingering (see Chap. 51), such data are difficult to interpret.
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The possibility of drug addiction as a motivation for visiting the physician and reporting severe pain should be addressed. It is impossible to assess pain in addicted individuals, for their complaints are woven into their need for medication. Temperament and mood should be evaluated carefully; the physician must remember that the depressed patient often denies feeling dysphoric and may even occasionally smile. The use of alcohol to self-medicate for pain usually indicates a depressive illness or lifelong alcohol dependence. When no medical, neurologic, or psychiatric disease can be established, one may be resigned to managing the painful state by the use of nonnarcotic medications and periodic clinical reevaluations. Such a course, though not altogether satisfactory, is preferable to prescribing excessive opioids or subjecting the patient to ablative surgery.
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Chronic Pain of Indeterminate Cause
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Pain in the thorax, abdomen, flank, back, face, head, or other part that cannot be traced to any visceral abnormality can create challenging clinical problems. In most cases, obscure neurologic sources, such as a spinal cord tumor and neuroma, have been excluded by repeated examinations and imaging procedures. A psychiatric disorder to which the patient's symptoms and behavior might be attributed cannot be discerned. Yet the patient complains continuously of pain, is disabled, and spends a great deal of effort and resources seeking medical aid.
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In such a circumstance, some physicians and surgeons, rather than concede their helplessness, may resort to extreme measures, such as exploratory thoracotomy, laparotomy, or laminectomy. Or they may injudiciously attempt to alleviate the pain and avoid drug addiction by severing roots and spinal tracts, often with the result that the pain moves to an adjacent segment or to the other side of the body.
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This type of patient benefits from being seen more than once by the physician. All the medical facts should be reviewed and the clinical and laboratory examinations repeated if some time has elapsed since they were last done. Tumors in the hilum of the lung or mediastinum; in the retropharyngeal, retroperitoneal, and paravertebral spaces; or in the uterus, testicle, kidney, or prostate pose a special difficulty in diagnosis, often being undetected for many months. More than once, we have seen a patient for months before a kidney or pancreatic tumor became apparent. Neurofibroma causing pain in an unusual site, such as one side of the rectum or vagina, is another type of tumor that may defy diagnosis for a long time. Truly neurogenic pain is almost invariably accompanied by alterations in cutaneous sensation and other neurologic signs, the finding of which facilitates diagnosis; however, the appearance of the neurologic signs may be delayed—for example, in brachial neuritis.
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Because of the complexity and difficulty in diagnosis and treatment of chronic pain, most medical centers have found it advisable to establish pain clinics. Here a staff of internists, anesthesiologists, neurologists, neurosurgeons, and psychiatrists can review each patient in terms of drug dependence, neurologic disease, and psychiatric problems. Success is achieved by treating each aspect of chronic pain, and addressing the individual's problem rather than treating it generically with emphasis on increasing the patient's tolerance of pain by means of biofeedback, meditation, and related techniques; by using special analgesic procedures (discussed later in the chapter); by establishing a regimen of pain medication that does not lead to a rebound exaggeration of pain between doses; and by controlling depressive illness.
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Rare and Unusual Disturbances of Pain Perception
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Lesions of the parietooccipital regions of one cerebral hemisphere sometimes have peculiar effects on the patient's capacity to feel and react to pain. Under the title of pain hemiagnosia, Hecaen and Ajuriaguerra described several cases of left-sided paralysis from a right parietal lesion, which, at the same time, rendered the patient hypersensitive to noxious stimuli. When pinched on the affected side, the patient, after a delay, became agitated, moaned, and seemed distressed but made no effort to fend off the painful stimulus with the other hand or to withdraw from it. In contrast, if the good side was pinched, the patient reacted normally and moved the normal hand at once to the site of the stimulus to remove it. The motor responses seemed no longer to be guided by sensory information from one side of the body.
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There are also two varieties of rare individuals who from birth are totally indifferent to pain coupled with anhidrosis ("congenital insensitivity to pain") or are incapable of feeling pain ("universal analgesia"). The former have been found by Indo and colleagues to have a mutation in the a neural tyrosine kinase receptor, a nerve growth factor receptor; those in the second group suffer from either a congenital lack of pain neurons in dorsal root ganglia, or to a mutation in the sodium channel discussed earlier. A similar loss of pain sensibility is encountered in the Riley-Day syndrome (congenital dysautonomia, see Chap. 26).
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The phenomenon of asymbolia for pain is another rare and unusual condition wherein the patient, although capable of distinguishing the different types of pain stimuli from one another and from touch, is said to make none of the usual emotional, motor, or verbal responses to pain. The patient seems totally unaware of the painful or hurtful nature of stimuli delivered to any part of the body, whether on one side or the other. The current interpretation of asymbolia for pain is that it represents a particular type of agnosia (analgognosia) or apractagnosia (see Chap. 22), in which the person loses his ability to adapt his emotional, motor, and verbal actions to the consciousness of a nociceptive impression. Pre-frontal lobe lesions from stroke, trauma, tumor, or in former times frontal lobotomy, can produce a version of this syndrome.
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Treatment of Intractable Pain
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Once the nature of the patient's pain and underlying disease has been determined, therapy must include some type of pain control. Initially, of course, attention is directed to the underlying disease with the idea of eliminating the source of the pain by appropriate medical, surgical, or radiotherapeutic measures. When the primary disease is not treatable, the physician should, if time and the circumstances permit, attempt to use the milder measures for pain relief first—for example, nonnarcotic analgesics and antidepressants or anti-epileptic drugs before resorting to narcotics, local nerve blocks or contemplating surgical approaches for pain relief. Not all situations allow this graduated approach, and large doses of narcotics may be required early in the course of illness—for example, to treat the pain of visceral and bone cancer. The same measured strategy is appropriate in the treatment of neuropathic pain and of pain of unclear origin except that one generally stops short of ablative procedures that irrevocably damage nerves or parts of the central nervous system.
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The field of pain relief has been changed by the introduction of analgesic procedures that block nerves, alter neural conduction, or administer conventional medications in new ways. These have become the province of pain clinics and hospital pain services usually led by departments of anesthesiology. In addition, a number of special procedures or unique medications are highly effective for pain relief but are unique to specific situations. These include certain forms of headache and limb pain (temporal arteritis and polymyalgia rheumatica treated with corticosteroids, or migraine relief with "triptan" drugs); trigeminal neuralgia, which may be relieved by microvascular decompression of a branch of the basilar artery or by controlled damage of the gasserian ganglion; and painful dystonic disorders that are relieved by the injection of botulinum toxin. Special procedures that have been devised to treat various forms of spinal back pain fall into the same category. The following discussion provides some guidance for the physician who is asked to undertake or participate in the treatment of chronic pain or of neuropathic pain.
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Narcotics (Opioids and Opiates)
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A useful way in which to undertake the management of chronic pain that affects several parts of the body, as in the patient with metastases, is with codeine or oxycodone taken together with aspirin, acetaminophen, or another nonsteroidal antiinflammatory drug (NSAID), or tramadol. The analgesic effects of these types of drugs are additive, which is not the case when narcotics are combined with diazepam or phenothiazine. Antidepressants and antiepileptic drugs, as discussed further on, may have a beneficial effect on pain even in the absence of overt depression. This is true particularly in cases of neuropathic pain (painful polyneuropathy and some types of radicular pain). Sometimes these non-narcotic agents may, in themselves or in combination with these treatment modalities, be sufficient to control the patient's pain and the use of narcotics can then be kept in reserve.
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Should the foregoing measures prove to be ineffective, one must turn to narcotic agents. Methadone and levorphanol are sometimes useful drugs with which to begin, because of their effectiveness by mouth and the relatively slow development of tolerance. Some pain clinics prefer the use of shorter-acting drugs such as oxycodone, given more frequently through the day. The oral route should be used whenever possible, as it is more comfortable for the patient than the parenteral route. Also, the oral route is associated with fewer side effects except for nausea and vomiting, which tend to be worse than with parenteral administration. Should the latter become necessary, one must be aware of the ratios of oral-to-parenteral dosages required to produce equivalent analgesia. The main medications used in the treatment of pain are summarized in Table 8-3.
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If oral medication fails to control the pain, the parenteral administration of codeine or more potent opioids becomes necessary. One may begin with methadone, dihydromorphine (Dilaudid), or levorphanol, given at intervals of 4 to 6 h because of their relatively long duration of action (particularly in comparison to meperidine). Alternatively, one may first resort to the use of transdermal patches of drugs such as fentanyl, which provide relief for 24 to 72 h and which we have found particularly useful in the treatment of pain from brachial or lumbosacral plexus invasion by tumor and of painful neuropathies such as those caused by diabetes and systemic amyloidosis. Long-acting morphine preparations are useful alternatives.
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Should long-continued injections of opiates become necessary, the optimal dose for the relief of pain should be established and the drug then given at regular intervals around the clock, rather than "as needed." The administration of morphine (and other narcotics) in this way represents a laudable shift in attitude among physicians. For many years it was widely believed that the drug should be given in the smallest possible doses, spaced as far apart as possible, and repeated only when severe pain reasserted itself. It has become clear that this approach results in unnecessary discomfort and, in the end, the need to use larger doses. Most physicians now realize that the fear of creating narcotic dependence and the expected phenomenon of increasing tolerance must be balanced against the overriding need to relieve pain. The most pernicious aspect of addiction, that of compulsive drug-seeking behavior with its attendant sociopathic behaviors, occurs only rarely in this setting and usually in patients with a previous history of addiction or alcoholism, with depression as the primary problem, or with certain characterologic disorders that have been loosely referred to as "addiction proneness." Even in patients with severe acute or postoperative pain, the best results are obtained by allowing the patient to determine the dose and frequency of intravenous medication, a method known as patient-controlled analgesia (PCA). Again, the danger of producing addiction is minimal.
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Guidelines for the use of orally and parenterally administered opioids for cancer-related pain are contained in the article of Cherny and Foley and in the publication of the U.S. Department of Health and Human Services, which unfortunately, is no longer easily obtained.
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The approach outlined above conforms to our understanding about pain-control mechanisms. Aspirin and other NSAIDs are believed to prevent the activation of nociceptors by inhibiting the synthesis of prostaglandins in skin, joints, viscera, and other structures in the peripheral nervous system. Morphine and meperidine given orally, parenterally, or intrathecally presumably produce analgesia by acting as "false" neurotransmitters at opiate receptor sites in the posterior horns of the spinal cord—sites that are normally activated by endogenous opioid peptides. The separate sites of action of NSAIDs and opioids provide an explanation for the therapeutic usefulness of combining these drugs. Opioids not only act directly on the central pain-conducting sensory systems but also exert a powerful action on the affective component of pain.
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Supplemental Medications for the Treatment of Pain
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Tricyclic antidepressants, especially the methylated forms (imipramine, amitriptyline, and doxepin), block serotonin reuptake and thus enhance the action of this neurotransmitter at synapses and putatively facilitate the action of the intrinsic opiate analgesic system. As a general rule, relief is afforded with tricyclic antidepressants in the equivalent dose range of 75 to 125 mg daily of amitriptyline, but little benefit accrues with higher amounts. The specific serotonin reuptake inhibitors (SSRI) antidepressants seem not to be as effective for the treatment of chronic neuropathic pain (see review by McQuay and colleagues) but these agents have not yet been extensively investigated in this clinical condition.
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Antiepileptic drugs (AEDs) have a beneficial effect on many central and peripheral neuropathic pain syndromes but are generally less effective for causalgic pain caused by partial injury of a peripheral nerve. The mode of action of phenytoin, carbamazepine, gabapentin, levetiracetam, and other AEDs in suppressing the lancinating pains of tic douloureux and certain polyneuropathies, as well as pain after spinal cord injury and myelitis, is not fully understood, but they are widely used. Their action has been attributed to the blocking of sodium channels on axons, thereby reducing the evoked and spontaneous activity in nerve fibers. The full explanation is certainly more complex and related to separate central and peripheral sites, as summarized by Jensen. Often, large doses must be utilized—for example, more than 2,400 mg per day for gabapentin for full effect—but the soporific and ataxic effects may be poorly tolerated.
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Most often a combination of medications is used for the treatment of intractable chronic pain. A common combination is the addition of gabapentin to an opioid such as morphine, and perhaps not surprisingly, this was superior to either drug alone in a crossover trial in patients with postherpetic neuralgia and diabetic neuropathy conducted by Gilron and colleagues but at the expense of side effects and lower tolerated doses of both drugs.
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Table 8-3 summarizes the main analgesics (nonnarcotic and narcotic), antiepileptics, and antidepressant drugs in the management of chronic pain.
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Treatment of Cancer Pain
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If the patient is ridden with neoplastic disease and will not live longer than a few weeks or months and has widespread pain, surgical measures are usually not advisable. Pain from widespread osseous metastases, even in patients with hormone-insensitive tumors, may be relieved by radiation therapy or by hypophysectomy. If these are not feasible, opioid medications are required and are effective, but they must be prescribed in adequate doses. Many patients prefer transdermal fentanyl to oral or intravenous agents. Usually, nerve section is not a satisfactory way of relieving restricted pain of the trunk and limbs because the overlap of adjacent nerves prevents complete denervation. Other procedures to be considered are the regional delivery of narcotic analogues, such as fentanyl or ketamine by means of an external pump and a catheter that is implanted percutaneously in the epidural space in proximity to the dorsal nerve roots of the affected region; this device can be used safely at home.
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Treatment of Neuropathic Pain
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The treatment of pain induced by nerve root or intrinsic peripheral nerve disease is a challenge for the neurologist and employs several techniques that are generally administered by an anesthesiologist. One usually resorts first to one of the antiepileptic drugs discussed earlier and listed in Table 8-3. The next simplest treatments are topical; if the pain is regional and has a predominantly burning quality, capsaicin cream can be applied locally, care being taken to avoid contact with the eyes and mouth. The irritative effect of this chemical, which releases substance P, seems in some cases to mute the pain. We have also had success with several concoctions of "eutectic" mixtures of local anesthetic (EMLA) creams or the simpler lidocaine gel with ketorolac, gabapentin, and other medications; these are applied directly to the affected area, usually the feet, in the morning and evening. Concoctions such as topical Ketamine mixed in soy lecithin to produce a gel with drug concentration of 5 mg/ml, have been reportedly useful in treating post herpetic neuralgia according to Quan and associates in a small randomized trial. Aspirin mixed with chloroform in cold cream is said to be very effective in the topical treatment of post herpetic neuralgia, as suggested by King (see Chap. 10). These preparations may provide considerable relief in postherpetic neuralgia and some painful peripheral neuropathies, but they are totally ineffective in others.
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Several types of spinal injections, including epidural, root, and facet blocks, have long been used for the treatment of pain. Injections of epidural corticosteroids or mixtures of analgesics and steroids are helpful in selected cases of lumbar or thoracic nerve root pain, and occasionally in painful peripheral neuropathy, but precise criteria for the use of this measure are not well established. Several studies do not support a beneficial effect but there is little doubt, in our view, that quite a few patients are helped, if only for several days or weeks (see Chap. 11). Nerve root blocks with lidocaine or with longer-acting local anesthetics are sometimes helpful in establishing the precise source of radicular pain. Their main therapeutic use in our experience has been for thoracic radiculitis from shingles, chest wall pain after thoracotomy, and diabetic radiculopathy. Similar local injections are used in the treatment of occipital neuralgia. Injection of analgesic compounds into and around facet joints and the extension of this procedure, radiofrequency ablation of the small nerves that innervate the joint, are as controversial as epidural injections, with most studies failing to find a consistent benefit. Despite these drawbacks, we have found both of these approaches very useful when pain can be traced to a derangement of these joints, as discussed in Chap. 11.
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The intravenous infusion of lidocaine has a brief beneficial effect on many types of pain, including neuropathic varieties, localized headaches, trigeminal neuralgia, and other facial pains; it is said to be useful in predicting the response to longer-acting agents such as mexiletine, its oral analogue, although this relationship has been erratic in our experience (see Table 8-3). Mexiletine is given in an initial dose of 150 mg per day and slowly increased to a maximum of 300 mg three times daily; it should be used very cautiously in patients with heart block and has fallen very much out of favor in many centers, partly due to cardiac conduction abnormalities during and after the infusion.
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Reducing sympathetic activity within somatic nerves by direct injection of the sympathetic ganglia in affected regions of the body (stellate ganglion for arm pain and lumbar ganglia for leg pain) has met with mixed success in neuropathic pain, including that of causalgia and reflex sympathetic dystrophy. A variant of this technique uses regional intravenous infusion of a sympathetic-blocking drug (bretylium, guanethidine, reserpine) into a limb that is isolated from the systemic circulation by the use of a tourniquet. This is known as a "Bier block," after the developer of regional anesthesia for single-limb surgery. These techniques, as well as the administration of clonidine by several routes and the intravenous infusion of the adrenergic blocker phentolamine, is predicated on the concept of "sympathetically sustained pain," meaning pain that is mediated by the interaction of sympathetic and pain nerve fibers or by the sprouting of adrenergic axons in partially damaged nerves. These forms of treatment have been under study for many decades and have given variable results but the most consistent responses to regional sympathetic blockade are obtained in cases of true causalgia resulting from partial injury of a single nerve.
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A number of other treatments have proven successful in some patients with reflex sympathetic dystrophy and other neuropathic pains but the clinician should be cautious about their chances of success over the long run. A novel one of these has been the use of bisphosphonates (pamidronate, alendronate), which have been beneficial in painful disorders of bone, such as Paget disease and metastatic bone lesions. It is theorized that this class of drug reverses the bone loss consequent to reflex sympathetic dystrophy but how this relates to pain control is unclear (Schott, 1997). Electrical stimulation of the posterior columns of the spinal cord by an implanted device, as discussed below, has become popular. Another treatment of last resort is the intravenous or epidural infusion of drugs such as ketamine; sometimes this has a lasting effect on causalgic pain.
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The approaches enumerated here are usually undertaken in sequence; a combination of drugs—such as gabapentin, narcotics, and clonidine—in addition to anesthetic techniques—is usually required. The ongoing attention and support of the neurologist often becomes the patient's mainstay. Further references can be found in the thorough review by Katz.
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Ablative Surgery in the Control of Pain
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It is our considered opinion that a program of medical therapy should always precede ablative surgical measures. Only when a variety of analgesic medications (including opioids) and only when certain practical measures, such as regional analgesia or anesthesia, have completely failed, should one turn to neurosurgical procedures. Also, one should be very cautious in suggesting a procedure of last resort for pain that has no established cause as, for example, limb pain that has been incorrectly identified as causalgic because of a burning component but where there has been no nerve injury.
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The least-destructive procedure consists of surgical exploration for a neuroma if a prior injury or operation may have partially sectioned a peripheral nerve. Magnetic resonance imaging of the region should be performed first and will demonstrate most such lesions, but we are uncertain if all small neuromas are visualized, and it is this ambiguity that justifies exploration. Another nondestructive procedure is implantation of a spinal electrical stimulator, usually adjacent to the posterior columns. This procedure, in which there is now a resurgence of interest, has afforded only incomplete relief in our patients and may be difficult to maintain in place. However Kemler and colleagues found a sustained reduction in pain intensity and an improved quality of life in patients with intractable reflex sympathetic dystrophy, even after 2 years in a randomized trial. It is clear that careful selection of patients is the best assurance of a good outcome. We can add from experience with our patients that a temporary trial of the stimulator is advisable before committing to its permanent use. The ill-advised use of nerve section and dorsal rhizotomy as definitive measures for the relief of regional pain was discussed above under "Treatment of Intractable Pain."
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Spinothalamic tractotomy, in which the anterior half of the spinal cord on one side is sectioned at an upper thoracic level, effectively relieves pain in the opposite leg and lower trunk. This may be done as an open operation or as a transcutaneous procedure in which a radiofrequency lesion is produced by an electrode. The analgesia and thermoanesthesia may last a year or longer, after which the level of analgesia tends to descend and the pain tends to return. Bilateral tractotomy is also feasible but with greater risk of loss of sphincteric control and, at higher levels, of respiratory paralysis. Motor power is nearly always spared because of the position of the corticospinal tract in the posterior part of the lateral funiculus.
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Pain in the arm, shoulder, and neck is more difficult to relieve surgically. High cervical transcutaneous cordotomy has been used successfully, with achievement of analgesia up to the chin. Commissural myelotomy by longitudinal incision of the anterior or posterior commissure of the spinal cord over many segments has also been performed, with variable success. Dorsal root entry zone (DREZ) lesions may relieve pain in the distribution of one or two nerve roots. Lateral medullary tractotomy is another possibility but must be carried almost to the mid-line to relieve cervical pain. The risks of this latter procedure and also of lateral mesencephalic tractotomy (which may actually produce pain) are so great that neurosurgeons have abandoned these operations.
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Stereotactic surgery on the thalamus for one-sided chronic pain is still used in a few centers and the results have been instructive. Lesions placed in the ventroposterior nucleus are said to diminish pain and thermal sensation over the contralateral side of the body while leaving the patient with all the misery or affective experience of pain; lesions in the intralaminar or parafascicular-centromedian nuclei relieve the painful state without altering sensation (Mark). Because these procedures have not yielded predictable benefits to the patient, they are now seldom used. The same unpredictability pertains to cortical ablations. Patients in whom a severe depression of mood is associated with a chronic pain syndrome have been subjected to bilateral stereotactic cingulotomy or the equivalent—subcaudate tractotomy. A considerable degree of success has been claimed for these operations but the results are difficult to evaluate. Orbito-frontal leukotomy has been discarded because of the personality change that it produces.
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Non-Medical Methods for the Treatment of Pain
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Included under this heading are certain techniques such as biofeedback, meditation, imagery, acupuncture, spinal manipulation, as well as transcutaneous electrical stimulation. Among the most intriguing treatments has been mirror therapy in which the patient is instructed to perform movements in the painful arm while watching the same moves in a mirror, made by the unaffected arm. The majority of patients in one blinded trial benefitted in terms of pain and mobility, but this study by Cacchio and coworkers included only patients with strokes and paretic limbs, not those with peripheral nerve injury. Each of these may be of value in the context of a comprehensive pain management program, usually conducted in a pain clinic as a means of providing relief from pain and suffering, reducing anxiety, and diverting the patient's attention, even if only temporarily, from the painful body part. Attempts to quantify the benefits of these techniques—judged usually by a reduction of drug dosage—have given mixed or negative results. Nevertheless, it is unwise for physicians to dismiss these methods, as well-motivated and apparently psychologically stable persons have reported subjective improvement with one or another of these methods and in the final analysis, this is what really matters. Conventional psychotherapy in combination with the use of medication and, at times, electroconvulsive therapy can be of benefit in the treatment of associated depressive symptoms, as discussed above (under "Pain in Association with Psychiatric Diseases") but it should not otherwise be expected to change the experience of pain.
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Whatever treatment is undertaken, medical, procedural or surgical, the objective should be to allow and encourage increased use and mobilization of the affected limb or part, as success at this is most closely associated with relief of pain and reduced suffering.