The Two Faces of Pain: Acute and Chronic
What is pain? The International Association for the Study of Pain
defines it as: An unpleasant sensory and emotional experience
associated with actual or potential tissue damage or described
in terms of such damage.
It is useful to distinguish between
two basic types of pain, acute and chronic, and they differ greatly.
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Acute
pain, for the most part, results from disease,
inflammation, or injury to tissues. This type of pain generally
comes on suddenly, for example, after trauma or surgery, and
may be accompanied by anxiety or emotional distress. The cause
of acute pain can usually be diagnosed and treated, and the
pain is self-limiting, that is, it is confined to a given
period of time and severity. In some rare instances, it can
become chronic.
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Chronic
pain is widely believed to represent disease itself.
It can be made much worse by environmental and psychological
factors. Chronic pain persists over a longer period of time
than acute pain and is resistant to most medical treatments.
It can—and often does—cause severe problems for
patients. |
What
is the Role of Age and Gender in Pain?
Gender and Pain
It is now widely believed that pain affects men and women differently.
While the sex hormones estrogen and testosterone certainly play
a role in this phenomenon, psychology and culture, too, may account
at least in part for differences in how men and women receive
pain signals. For example, young children may learn to respond
to pain based on how they are treated when they experience pain.
Some children may be cuddled and comforted, while others may be
encouraged to tough it out and to dismiss their pain.
Many investigators are turning their
attention to the study of gender differences and pain. Women,
many experts now agree, recover more quickly from pain, seek help
more quickly for their pain, and are less likely to allow pain
to control their lives. They also are more likely to marshal a
variety of resources-coping skills, support, and distraction-with
which to deal with their pain.
Research in this area is yielding
fascinating results. For example, male experimental animals injected
with estrogen, a female sex hormone, appear to have a lower tolerance
for pain-that is, the addition of estrogen appears to lower the
pain threshold. Similarly, the presence of testosterone, a male
hormone, appears to elevate tolerance for pain in female mice:
the animals are simply able to withstand pain better. Female mice
deprived of estrogen during experiments react to stress similarly
to male animals. Estrogen, therefore, may act as a sort of pain
switch, turning on the ability to recognize pain.
Investigators know that males and
females both have strong natural pain-killing systems, but these
systems operate differently. For example, a class of painkillers
called kappa-opioids is named after one of several opioid receptors
to which they bind, the kappa-opioid receptor, and they include
the compounds nalbuphine (Nubain®) and butorphanol
(Stadol®). Research suggests that kappa-opioids provide better
pain relief in women.
Though not prescribed widely, kappa-opioids
are currently used for relief of labor pain and in general work
best for short-term pain. Investigators are not certain why kappa-opioids
work better in women than men. Is it because a woman's estrogen
makes them work, or because a man's testosterone prevents them
from working? Or is there another explanation, such as differences
between men and women in their perception of pain? Continued research
may result in a better understanding of how pain affects women
differently from men, enabling new and better pain medications
to be designed with gender in mind.
A
Pain Primer: What Do We Know About Pain?
We may experience pain as a prick, tingle, sting, burn, or ache.
Receptors on the skin trigger a series of events, beginning with
an electrical impulse that travels from the skin to the spinal
cord. The spinal cord acts as a sort of relay center where the
pain signal can be blocked, enhanced, or otherwise modified before
it is relayed to the brain. One area of the spinal cord in particular,
called the dorsal horn is important in the reception of
pain signals.
The most common destination in the
brain for pain signals is the thalamus and from there to the cortex,
the headquarters for complex thoughts. The thalamus also serves
as the brain's storage area for images of the body and plays a
key role in relaying messages between the brain and various parts
of the body. In people who undergo an amputation, the representation
of the amputated limb is stored in the thalamus.
Pain is a complicated process that
involves an intricate interplay between a number of important
chemicals found naturally in the brain and spinal cord. In general,
these chemicals, called neurotransmitters, transmit nerve
impulses from one cell to another.
There are many different neurotransmitters
in the human body; some play a role in human disease and, in the
case of pain, act in various combinations to produce painful sensations
in the body. Some chemicals govern mild pain sensations; others
control intense or severe pain.
The body's chemicals act in the transmission
of pain messages by stimulating neurotransmitter receptors
found on the surface of cells; each receptor has a corresponding
neurotransmitter. Receptors function much like gates or ports
and enable pain messages to pass through and on to neighboring
cells. One brain chemical of special interest to neuroscientists
is glutamate. During experiments, mice with blocked glutamate
receptors show a reduction in their responses to pain. Other important
receptors in pain transmission are opiate-like receptors. Morphine
and other opioid drugs work by locking on to these opioid receptors,
switching on pain-inhibiting pathways or circuits, and thereby
blocking pain.
Another type of receptor that responds
to painful stimuli is called a nociceptor. Nociceptors
are thin nerve fibers in the skin, muscle, and other body tissues,
that, when stimulated, carry pain signals to the spinal cord and
brain. Normally, nociceptors only respond to strong stimuli such
as a pinch. However, when tissues become injured or inflamed,
as with a sunburn or infection, they release chemicals that make
nociceptors much more sensitive and cause them to transmit pain
signals in response to even gentle stimuli such as breeze or a
caress. This condition is called allodynia -a state in
which pain is produced by innocuous stimuli.
The body's natural painkillers may
yet prove to be the most promising pain relievers, pointing to
one of the most important new avenues in drug development. The
brain may signal the release of painkillers found in the spinal
cord, including serotonin, norepinephrine, and opioid-like chemicals.
Many pharmaceutical companies are working to synthesize these
substances in laboratories as future medications.
Endorphins and enkephalins
are other natural painkillers. Endorphins may be responsible for
the "feel good" effects experienced by many people after
rigorous exercise; they are also implicated in the pleasurable
effects of smoking.
Similarly, peptides, compounds
that make up proteins in the body, play a role in pain responses.
Mice bred experimentally to lack a gene for two peptides called
tachykinins-neurokinin A and substance P-have a reduced
response to severe pain. When exposed to mild pain, these mice
react in the same way as mice that carry the missing gene. But
when exposed to more severe pain, the mice exhibit a reduced pain
response. This suggests that the two peptides are involved in
the production of pain sensations, especially moderate-to-severe
pain. Continued research on tachykinins, conducted with support
from the NINDS, may pave the way
for drugs tailored to treat different severities of pain.
Scientists are working to develop
potent pain-killing drugs that act on receptors for the chemical
acetylcholine. For example, a type of frog native to Ecuador
has been found to have a chemical in its skin called epibatidine,
derived from the frog's scientific name, Epipedobates tricolor.
Although highly toxic, epibatidine is a potent analgesic and,
surprisingly, resembles the chemical nicotine found in cigarettes.
Also under development are other less toxic compounds that act
on acetylcholine receptors and may prove to be more potent than
morphine but without its addictive properties.
The idea of using receptors as gateways
for pain drugs is a novel idea, supported by experiments involving
substance P. Investigators have been able to isolate a tiny population
of neurons, located in the spinal cord, that together form a major
portion of the pathway responsible for carrying persistent pain
signals to the brain. When animals were given injections of a
lethal cocktail containing substance P linked to the chemical
saporin, this group of cells, whose sole function is to communicate
pain, were killed. Receptors for substance P served as a portal
or point of entry for the compound. Within days of the injections,
the targeted neurons, located in the outer layer of the spinal
cord along its entire length, absorbed the compound and were neutralized.
The animals' behavior was completely normal; they no longer exhibited
signs of pain following injury or had an exaggerated pain response.
Importantly, the animals still responded to acute, that is, normal,
pain. This is a critical finding as it is important to retain
the body's ability to detect potentially injurious stimuli. The
protective, early warning signal that pain provides is essential
for normal functioning. If this work can be translated clinically,
humans might be able to benefit from similar compounds introduced,
for example, through lumbar (spinal) puncture.
Another promising area of research
using the body's natural pain-killing abilities is the transplantation
of chromaffin cells into the spinal cords of animals bred experimentally
to develop arthritis. Chromaffin cells produce several of the
body's pain-killing substances and are part of the adrenal medulla,
which sits on top of the kidney. Within a week or so, rats receiving
these transplants cease to exhibit telltale signs of pain. Scientists,
working with support from the NINDS,
believe the transplants help the animals recover from pain-related
cellular damage. Extensive animal studies will be required to
learn if this technique might be of value to humans with severe
pain.
One way to control pain outside of
the brain, that is, peripherally, is by inhibiting hormones called
prostaglandins. Prostaglandins stimulate nerves at the
site of injury and cause inflammation and fever. Certain drugs,
including NSAIDs, act against such
hormones by blocking the enzyme that is required for their synthesis.
Blood vessel walls stretch or dilate
during a migraine attack and it is thought that serotonin plays
a complicated role in this process. For example, before a migraine
headache, serotonin levels fall. Drugs for migraine include the
triptans: sumatriptan (Imitrix®), naratriptan (Amerge®),
and zolmitriptan (Zomig®). They are called serotonin
agonists because they mimic the action of endogenous (natural)
serotonin and bind to specific subtypes of serotonin receptors.
Ongoing pain research, much of it
supported by the NINDS, continues
to reveal at an unprecedented pace fascinating insights into how
genetics, the immune system, and the skin contribute to pain responses.
The explosion of knowledge about
human genetics is helping scientists who work in the field of
drug development. We know, for example, that the pain-killing
properties of codeine rely heavily on a liver
enzyme, CYP2D6, which helps convert codeine into morphine. A small
number of people genetically lack the enzyme CYP2D6; when given
codeine, these individuals do not get pain relief. CYP2D6 also
helps break down certain other drugs. People who genetically lack
CYP2D6 may not be able to cleanse their systems of these drugs
and may be vulnerable to drug toxicity. CYP2D6 is currently
under investigation for its role in pain.
In his research, the late John C.
Liebeskind, a renowned pain expert and a professor of psychology
at UCLA, found that pain can kill by delaying healing and causing
cancer to spread. In his pioneering research on the immune system
and pain, Dr. Liebeskind studied the effects of stress-such as
surgery-on the immune system and in particular on cells called
natural killer or NK cells. These cells are thought
to help protect the body against tumors. In one study conducted
with rats, Dr. Liebeskind found that, following experimental surgery,
NK cell activity was suppressed, causing the cancer to spread
more rapidly. When the animals were treated with morphine, however,
they were able to avoid this reaction to stress.
The link between the nervous and
immune systems is an important one. Cytokines, a type of protein
found in the nervous system, are also part of the body's immune
system, the body's shield for fighting off disease. Cytokines
can trigger pain by promoting inflammation, even in the absence
of injury or damage. Certain types of cytokines have been linked
to nervous system injury. After trauma, cytokine levels rise in
the brain and spinal cord and at the site in the peripheral nervous
system where the injury occurred. Improvements in our understanding
of the precise role of cytokines in producing pain, especially
pain resulting from injury, may lead to new classes of drugs that
can block the action of these substances.
What
is the Future of Pain Research?
In the forefront of pain research are scientists supported by
the National Institutes of Health (NIH), including the NINDS.
Other institutes at NIH that support pain research include the
National Institute of Dental and Craniofacial Research, the National
Cancer Institute, the National Institute of Nursing Research,
the National Institute on Drug Abuse, and the National Institute
of Mental Health. Developing better pain treatments is the primary
goal of all pain research being conducted by these institutes.
Some pain medications dull the patient's
perception of pain. Morphine is one such drug. It works through
the body's natural pain-killing machinery, preventing pain messages
from reaching the brain. Scientists are working toward the development
of a morphine-like drug that will have the pain-deadening qualities
of morphine but without the drug's negative side effects, such
as sedation and the potential for addiction. Patients receiving
morphine also face the problem of morphine tolerance, meaning
that over time they require higher doses of the drug to achieve
the same pain relief. Studies have identified factors that contribute
to the development of tolerance; continued progress in this line
of research should eventually allow patients to take lower doses
of morphine.
One objective of investigators working
to develop the future generation of pain medications is to take
full advantage of the body's pain "switching center"
by formulating compounds that will prevent pain signals from being
amplified or stop them altogether. Blocking or interrupting pain
signals, especially when there is no injury or trauma to tissue,
is an important goal in the development of pain medications. An
increased understanding of the basic mechanisms of pain will have
profound implications for the development of future medicines.
The following areas of research are bringing us closer to an ideal
pain drug.
Systems and Imaging: The idea
of mapping cognitive functions to precise areas of the brain dates
back to phrenology, the now archaic practice of studying bumps
on the head. Positron emission tomography (PET), functional magnetic
resonance imaging (fMRI), and other imaging technologies offer
a vivid picture of what is happening in the brain as it processes
pain. Using imaging, investigators can now see that pain activates
at least three or four key areas of the brain's cortex-the layer
of tissue that covers the brain. Interestingly, when patients
undergo hypnosis so that the unpleasantness of a painful stimulus
is not experienced, activity in some, but not all, brain areas
is reduced. This emphasizes that the experience of pain involves
a strong emotional component as well as the sensory experience,
namely the intensity of the stimulus.
Channels: The frontier in
the search for new drug targets is represented by channels. Channels
are gate-like passages found along the membranes of cells that
allow electrically charged chemical particles called ions to pass
into the cells. Ion channels are important for transmitting signals
through the nerve's membrane. The possibility now exists for developing
new classes of drugs, including pain cocktails that would act
at the site of channel activity.
Trophic Factors: A class of
"rescuer" or "restorer" drugs may emerge from
our growing knowledge of trophic factors, natural chemical substances
found in the human body that affect the survival and function
of cells. Trophic factors also promote cell death, but little
is known about how something beneficial can become harmful. Investigators
have observed that an over-accumulation of certain trophic factors
in the nerve cells of animals results in heightened pain sensitivity,
and that some receptors found on cells respond to trophic factors
and interact with each other. These receptors may provide targets
for new pain therapies.
Molecular Genetics: Certain
genetic mutations can change pain sensitivity and behavioral responses
to pain. People born genetically insensate to pain-that is, individuals
who cannot feel pain-have a mutation in part of a gene that plays
a role in cell survival. Using "knockout" animal models-animals
genetically engineered to lack a certain gene-scientists are able
to visualize how mutations in genes cause animals to become anxious,
make noise, rear, freeze, or become hypervigilant. These genetic
mutations cause a disruption or alteration in the processing of
pain information as it leaves the spinal cord and travels to the
brain. Knockout animals can be used to complement efforts aimed
at developing new drugs.
Plasticity: Following injury,
the nervous system undergoes a tremendous reorganization. This
phenomenon is known as plasticity. For example, the spinal cord
is "rewired" following trauma as nerve cell axons make
new contacts, a phenomenon known as "sprouting." This
in turn disrupts the cells' supply of trophic factors. Scientists
can now identify and study the changes that occur during the processing
of pain. For example, using a technique called polymerase chain
reaction, abbreviated PCR, scientists can study the genes that
are induced by injury and persistent pain. There is evidence that
the proteins that are ultimately synthesized by these genes may
be targets for new therapies. The dramatic changes that occur
with injury and persistent pain underscore that chronic pain should
be considered a disease of the nervous system, not just prolonged
acute pain or a symptom of an injury. Thus, scientists hope that
therapies directed at preventing the long-term changes that occur
in the nervous system will prevent the development of chronic
pain conditions.
Neurotransmitters: Just as
mutations in genes may affect behavior, they may also affect a
number of neurotransmitters involved in the control of pain. Using
sophisticated imaging technologies, investigators can now visualize
what is happening chemically in the spinal cord. From this work,
new therapies may emerge, therapies that can help reduce or obliterate
severe or chronic pain.
Hope
for the Future
Thousands of years ago, ancient peoples attributed pain to spirits
and treated it with mysticism and incantations. Over the centuries,
science has provided us with a remarkable ability to understand
and control pain with medications, surgery, and other treatments.
Today, scientists understand a great deal about the causes and
mechanisms of pain, and research has produced dramatic improvements
in the diagnosis and treatment of a number of painful disorders.
For people who fight every day against the limitations imposed
by pain, the work of NINDS-supported scientists holds the promise
of an even greater understanding of pain in the coming years.
Their research offers a powerful weapon in the battle to prolong
and improve the lives of people with pain: hope.
Appendix
Spine Basics: The Vertebrae,
Discs, and Spinal Cord
Stacked on top of one another in the spine are more than 30 bones,
the vertebrae, which together form the spine. They are divided
into four regions:
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the seven cervical
or neck vertebrae (labeled C1-C7) |
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the 12 thoracic
or upper back vertebrae (labeled T1-T12) |
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the five lumbar
vertebrae (labeled L1-L5), which we know as the lower back |
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the sacrum and coccyx,
a group of bones fused together at the base of the spine |
The vertebrae are linked by ligaments,
tendons, and muscles. Back pain can occur when, for example, someone
lifts something too heavy, causing a sprain, pull, strain, or
spasm in one of these muscles or ligaments in the back.
Between the vertebrae are round,
spongy pads of cartilage called discs that act much like
shock absorbers. In many cases, degeneration or pressure from
overexertion can cause a disc to shift or protrude and bulge,
causing pressure on a nerve and resultant pain. When this happens,
the condition is called a slipped, bulging, herniated, or ruptured
disc, and it sometimes results in permanent nerve damage.
The column-like spinal cord is divided
into segments similar to the corresponding vertebrae: cervical,
thoracic, lumbar, sacral, and coccygeal. The cord also has nerve
roots and rootlets which form branch-like appendages leading from
its ventral side (that is, the front of the body) and from its
dorsal side (that is, the back of the body). Along the dorsal
root are the cells of the dorsal root ganglia, which are critical
in the transmission of "pain" messages from the cord
to the brain. It is here where injury, damage, and trauma become
pain.
The Nervous
Systems
The central nervous system (CNS) refers to the brain and spinal
cord together. The peripheral nervous system refers to the cervical,
thoracic, lumbar, and sacral nerve trunks leading away from the
spine to the limbs. Messages related to function (such as movement)
or dysfunction (such as pain) travel from the brain to the spinal
cord and from there to other regions in the body and back to the
brain again. The autonomic nervous system controls involuntary
functions in the body, like perspiration, blood pressure, heart
rate, or heart beat. It is divided into the sympathetic and parasympathetic
nervous systems. The sympathetic and parasympathetic nervous systems
have links to important organs and systems in the body; for example,
the sympathetic nervous system controls the heart, blood vessels,
and respiratory system, while the parasympathetic nervous system
controls our ability to sleep, eat, and digest food.
The peripheral nervous system also
includes 12 pairs of cranial nerves located on the underside of
the brain. Most relay messages of a sensory nature. They include
the olfactory (I), optic (II), oculomotor (III), trochlear (IV),
trigeminal (V), abducens (VI), facial (VII), vestibulocochlear
(VIII), glossopharyngeal (IX), vagus (X), accessory (XI), and
hypoglossal (XII) nerves. Neuralgia, as in trigeminal neuralgia,
is a term that refers to pain that arises from abnormal activity
of a nerve trunk or its branches. The type and severity of pain
associated with neuralgia vary widely.
Phantom Pain:
How Does the Brain Feel?
Sometimes, when a limb
is removed during an amputation, an individual will continue to
have an internal sense of the lost limb. This phenomenon is known
as phantom limb and accounts describing it date back to the 1800s.
Similarly, many amputees are frequently aware of severe pain in
the absent limb. Their pain is real and is often accompanied by
other health problems, such as depression.
What causes this phenomenon? Scientists
believe that following amputation, nerve cells "rewire"
themselves and continue to receive messages, resulting in a remapping
of the brain's circuitry. The brain's ability to restructure itself,
to change and adapt following injury, is called plasticity (see
section on Plasticity).
Our understanding of phantom pain
has improved tremendously in recent years. Investigators previously
believed that brain cells affected by amputation simply died off.
They attributed sensations of pain at the site of the amputation
to irritation of nerves located near the limb stump. Now, using
imaging techniques such as positron emission tomography (PET)
and magnetic resonance imaging (MRI), scientists can actually
visualize increased activity in the brain's cortex when an individual
feels phantom pain. When study participants move the stump of
an amputated limb, neurons in the brain remain dynamic and excitable.
Surprisingly, the brain's cells can be stimulated by other body
parts, often those located closest to the missing limb.
Treatments for phantom pain may include
analgesics, anticonvulsants, and other types of drugs; nerve blocks;
electrical stimulation; psychological counseling, biofeedback,
hypnosis, and acupuncture; and, in rare instances, surgery.
Chili Peppers,
Capsaicin, and Pain
The hot feeling, red face,
and watery eyes you experience when you bite into a red chili
pepper may make you reach for a cold drink, but that reaction
has also given scientists important information about pain. The
chemical found in chili peppers that causes those feelings is
capsaicin (pronounced cap-SAY-sin), and it works its unique
magic by grabbing onto receptors scattered along the surface of
sensitive nerve cells in the mouth.
In 1997, scientists at the University
of California at San Francisco discovered a gene for a capsaicin
receptor, called the vanilloid receptor. Once in contact with
capsaicin, vanilloid receptors open and pain signals are sent
from the peripheral nociceptor and through central nervous system
circuits to the brain. Investigators have also learned that this
receptor plays a role in the burning type of pain commonly associated
with heat, such as the kind you experience when you touch your
finger to a hot stove. The vanilloid receptor functions as a sort
of "ouch gateway, " enabling us to detect burning hot
pain, whether it originates from a 3-alarm habanera chili or from
a stove burner.
Capsaicin is currently available
as a prescription or over-the-counter cream for the treatment
of a number of pain conditions, such as shingles. It works by
reducing the amount of substance P found in nerve endings and
interferes with the transmission of pain signals to the brain.
Individuals can become desensitized to the compound, however,
perhaps because of long-term damage to nerve tissue. Some individuals
find the burning sensation they experience when using capsaicin
cream to be intolerable, especially when they are already suffering
from a painful condition, such as postherpetic neuralgia. Soon,
however, better treatments that relieve pain by blocking vanilloid
receptors may arrive in drugstores.
Marijuana
As a painkiller, marijuana or, by its Latin name, cannabis,
continues to remain highly controversial. In the eyes of many
individuals campaigning on its behalf, marijuana rightfully belongs
with other pain remedies. In fact, for many years, it was sold
under highly controlled conditions in cigarette form by the Federal
government for just that purpose.
In 1997, the National Institutes
of Health held a workshop to discuss research on the possible
therapeutic uses for smoked marijuana. Panel members from a number
of fields reviewed published research and heard presentations
from pain experts. The panel members concluded that, because there
are too few scientific studies to prove marijuana's therapeutic
utility for certain conditions, additional research is needed.
There is evidence, however, that receptors to which marijuana
binds are found in many brain regions that process information
that can produce pain.
Nerve Blocks
Nerve blocks may involve local anesthesia, regional anesthesia
or analgesia, or surgery; Pain Management Specialists routinely
use them for traditional dental procedures. Nerve blocks can also
be used to prevent or even diagnose pain.
In the case of a local nerve block,
any one of a number of local anesthetics may be used; the names
of these compounds, such as lidocaine or novocaine, usually have
an aine ending. Regional blocks affect a larger area of
the body. Nerve blocks may also take the form of what is commonly
called an epidural, in which a drug is administered into the space
between the spine's protective covering (the dura) and the spinal
column. This procedure is most well known for its use during childbirth.
Morphine and methadone are opioid narcotics (such drugs end in
ine or one) that are sometimes used for regional analgesia and
are administered as an injection.
Neurolytic blocks employ injection
of chemical agents such as alcohol, phenol, or glycerol to block
pain messages and are most often used to treat cancer pain or
to block pain in the cranial nerves
Surgical blocks are performed on
cranial, peripheral, or sympathetic nerves. They are most often
done to relieve the pain of cancer and extreme facial pain, such
as that experienced with trigeminal neuralgia. There are several
different types of surgical nerve blocks and they are not without
problems and complications. Nerve blocks can cause muscle paralysis
and, in many cases, result in at least partial numbness. For that
reason, the procedure should be reserved for a select group of
patients and should only be performed by skilled surgeons. Types
of surgical nerve blocks include:
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Neurectomy
(including peripheral neurectomy) in which a damaged peripheral
nerve is destroyed.
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Spinal
dorsal rhizotomy in which the surgeon cuts the
root or rootlets of one or more of the nerves radiating from
the spine. Other rhizotomy procedures include cranial rhizotomy
and trigeminal rhizotomy, performed as a treatment
for extreme facial pain or for the pain of cancer.
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Sympathectomy,
also called sympathetic blockade, in which a drug or
an agent such as guanethidine is used to eliminate pain in
a specific area (a limb, for example). The procedure is also
done for cardiac pain, vascular disease pain, the pain of
reflex sympathetic dystrophy syndrome, and other conditions.
The term takes its name from the sympathetic nervous system |
