My Draft Book for HARRISON INTERNAL MEDICINE

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Vitamins/Minerals
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Vitamin A: Massive studies in a number of developing nations proved that vitamin A deficiency is prevalent and associated with increased risks of mortality in young children. Prospective trials showed that 100,000 to 200,000 IU of vitamin A twice a year can reduce the overall death rate significantly.
Folic Acid: Rates of neural tube defects are significantly diminished if the diet is supplemented with folic acid during pregnancy.
Folic acid, vitamin B6, and vitamin B12: Randomized, double-blind, controlled trials suggest that this vitamin combination lowers serum homocysteine levels and the risk of myocardial infarction.
Vitamins C and E, β-carotene, and zinc: A large, randomized controlled trial showed that these supplements combined reduce the progression of age-related macular degeneration.
Even vitamins and minerals, which are presumed safe in moderate doses, can have unexpected adverse effects. Two large controlled trials of β-carotene for prevention of cancer or retinal diseases found increased rates of lung cancer in those randomized to the supplement. Ongoing are large prospective trials seeking benefits from ingestion of supplements on rates of prostate cancer (vitamin E and selenium) and Alzheimer's disease (vitamin E).

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Herbals and Other Natural Products
Glucosamine and/or chondroitin sulfate: Systematic surveys of controlled trials concluded that these products of animal joints are superior to placebo in improving performance and slowing the narrowing of the joint space in patients with osteoarthritis of the knee.
Ginkgo biloba: Americans consumed nearly $250 million of this herbal product in 2000. The literature shows no evidence that it improves cognition, but it may decrease the risk of dementia.
Saw palmetto (Serenoa repens) and African plum (Pygeum africanum): Each of these botanicals is likely effective for the symptomatic treatment of benign prostatic hyperplasia. Sales of saw palmetto are growing, with an estimated $131 million of the product consumed by Americans in 2000.
St.-John's-wort (Hypericum perforatum): Among the most popular herbal product worldwide, numerous small studies and systematic reviews suggested it to benefit patients with a wide range of depressive syndromes. High-quality, randomized, placebo-controlled trials, found St.-John's-wort to not be superior to placebo for treatment of major depression of moderate severity, a spectrum of illness that clearly warrants professional evaluation and treatment.
Echinacea species: Echinacea roots are widely used to treat or prevent respiratory infections, with over $200 million in sales in 2000. Although in vitro studies have shown that Echinacea constituents stimulate humoral and cellular immune responses, systematic reviews of the clinical trials have not concluded that they are beneficial.

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Other Modalities
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Acupuncture: A frequently cited NIH-led consensus development conference in 1997 concluded that evidence exists that acupuncture relieves nausea from chemotherapy and pain following extraction of molars. Some subsequent studies have confirmed these earlier impressions regarding acute nausea and vomiting, but the data regarding pain management have been mixed, with little evidence that it benefits neuropathic pain.
Mind-body medicine: Clinical trials support the use of biofeedback for incontinence, headache, and stroke rehabilitation. Hypnosis may be beneficial in relieving pain due to minor surgical interventions, chemotherapy-associated nausea, and irritable bowel syndrome.
Spinal manipulation: Systematic reviews of fairly well designed trials concluded that chiropractic or osteopathic manipulation provides significant improvement for patients with uncomplicated acute back pain. No proof exists that they are superior to, or more cost-effective than, other conventional approaches, nor do they alter the long-term outcome.

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SUMMARY
An array of unproven modalities will always be used by the patients under our care. Physicians must approach each encounter as an opportunity to better understand patients, their beliefs, and their expectations and as an opportunity to help guide their choices in a constructive way. Many of these choices are entirely innocuous and can be accommodated in the context of the larger diagnostic and therapeutic intervention. Some should be actively discouraged. Along the way, scientific evidence will drive many CAM approaches out of favor. Some modalities will garner sufficient support to become part of mainstream care: the next generation of physicians will never know they were once controversial.

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too slow in my reading speed

[ 本帖最后由 zhangheng1020 于 2006-3-8 15:04 编辑 ]

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11
Pain: Pathophysiology and Management
Howard L. Fields
Joseph B. Martin
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.

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

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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. 11-1).
The cell bodies of primary afferents are located in the dorsal root ganglia in the
vertebral foramina. The primary afferent axon bifurcates to send one process into the
spinal cord and the other to innervate tissues. Primary afferents are classified by their
diameter, degree of myelination, and conduction velocity. The largest-diameter fibers,
A-beta (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. 11-
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.
Individual primary afferent nociceptors can respond to several different types of noxious
stimuli. For example, most nociceptors respond to heating, intense mechanical stimuli
such as a pinch, and application of irritating chemicals.

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Sensitization
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, 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.

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Nociceptor-Induced Inflammation
One important concept to emerge in recent years is that afferent nociceptors also have
a neuroeffector function.
Most nociceptors contain polypeptide mediators that are released from their peripheral
terminals when they are activated (Fig. 11-2). An example is substance P, an 11-aminoacid
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.

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Nociceptor-Induced Inflammation
One important concept to emerge in recent years is that afferent nociceptors also have
a neuroeffector function.
Most nociceptors contain polypeptide mediators that are released from their peripheral
terminals when they are activated (Fig. 11-2). An example is substance P, an 11-aminoacid
peptide. Substance P is released from primary afferent nociceptors and has
multiple biologic activities. It is a potent vasodilator, degranulates mast cells, is a
chemoattractant for leukocytes, and increases the production and release of
inflammatory mediators. Interestingly, depletion of substance P from joints reduces the
severity of experimental arthritis. Primary afferent nociceptors are not simply passive
messengers of threats to tissue injury but also play an active role in tissue protection
through these neuroeffector functions.
CENTRAL 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. 11-3). The terminals of
primary afferent axons contact spinal neurons that transmit the pain signal to brain
sites involved in pain perception. The axon of each primary afferent contacts many
spinal neurons, and each spinal neuron receives convergent inputs from many primary
afferents.
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.

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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. 11-4).
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. 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.

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PAIN MODULATION
The pain produced by similar injuries 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.
T he 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 paintransmission
neurons through a descending pathway (Fig. 11-4).
Human brain imaging studies have implicated this pain-modulating circuit in the painrelieving
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, 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 and could provide a framework for
understanding how psychological factors can contribute to chronic pain.

[ 本帖最后由 zhangheng1020 于 2006-3-8 16:27 编辑 ]

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NEUROPATHIC PAIN
Lesions of the peripheral or central nervous pathways for pain typically result in a loss
or impairment of pain sensation. Paradoxically, damage 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.

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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 (Chap. 354). 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.