Introduction: The Universal Disorder

You know it at once. It may be the fiery sensation of a burn moments after your finger touches the stove. Or it’s a dull ache above your brow after a day of stress and tension. Or you may recognize it as a sharp pierce in your back after you lift something heavy.

It is pain. In its most benign form, it warns us that something isn’t quite right, that we should take medicine or see a doctor. At its worst, however, pain robs us of our productivity, our well-being, and, for many of us suffering from extended illness, our very lives. Pain is a complex perception that differs enormously among individual patients, even those who appear to have identical injuries or illnesses.

In 1931, the French medical missionary Dr. Albert Schweitzer wrote, “Pain is a more terrible lord of mankind than even death itself.” Today, pain has become the universal disorder, a serious and costly public health issue, and a challenge for family, friends, and health care providers who must give support to the individual suffering from the physical as well as the emotional consequences of pain.

How is Pain Diagnosed?

There is no way to tell how much pain a person has. No test can measure the intensity of pain, no imaging device can show pain, and no instrument can locate pain precisely. Sometimes, as in the case of headaches, physicians find that the best aid to diagnosis is the patient’s own description of the type, duration, and location of pain. Defining pain as sharp or dull, constant or intermittent, burning or aching may give the best clues to the cause of pain. These descriptions are part of what is called the pain history, taken by the physician during the preliminary examination of a patient with pain.

Physicians, however, do have a number of technologies they use to find the cause of pain. Primarily these include:

  • Electrodiagnostic procedures include electromyography (EMG)nerve conduction studies, and evoked potential (EP) studies. Information from EMG can help physicians tell precisely which muscles or nerves are affected by weakness or pain. Thin needles are inserted in muscles and a physician can see or listen to electrical signals displayed on an EMG machine. With nerve conduction studies the doctor uses two sets of electrodes (similar to those used during an electrocardiogram) that are placed on the skin over the muscles. The first set gives the patient a mild shock that stimulates the nerve that runs to that muscle. The second set of electrodes is used to make a recording of the nerve’s electrical signals, and from this information the doctor can determine if there is nerve damage. EP tests also involve two sets of electrodes – one set for stimulating a nerve (these electrodes are attached to a limb) and another set on the scalp for recording the speed of nerve signal transmission to the brain.
  • Imaging, especially magnetic resonance imaging or MRI, provides physicians with pictures of the body’s structures and tissues. MRI uses magnetic fields and radio waves to differentiate between healthy and diseased tissue.
  • neurological examination in which the physician tests movement, reflexes, sensation, balance, and coordination.
  • X-rays produce pictures of the body’s structures, such as bones and joints.

How is Pain Treated?

The goal of pain management is to improve function, enabling individuals to work, attend school, or participate in other day-to-day activities. Patients and their physicians have a number of options for the treatment of pain; some are more effective than others. Sometimes, relaxation and the use of imagery as a distraction provide relief. These methods can be powerful and effective, according to those who advocate their use. Whatever the treatment regime, it is important to remember that pain is treatable. The following treatments are among the most common.

Acetaminophen is the basic ingredient found in Tylenol® and its many generic equivalents. It is sold over the counter, in a prescription-strength preparation, and in combination with codeine (also by prescription).

Acupuncture dates back 2,500 years and involves the application of needles to precise points on the body. It is part of a general category of healing called traditional Chinese or Oriental medicine. Acupuncture remains controversial but is quite popular and may one day prove to be useful for a variety of conditions as it continues to be explored by practitioners, patients, and investigators.

Analgesic refers to the class of drugs that includes most painkillers, such as aspirin, acetaminophen, and ibuprofen. The word analgesic is derived from ancient Greek and means to reduce or stop pain. Nonprescription or over-the-counter pain relievers are generally used for mild to moderate pain. Prescription pain relievers, sold through a pharmacy under the direction of a physician, are used for more moderate to severe pain.

Anticonvulsants are used for the treatment of seizure disorders but are also sometimes prescribed for the treatment of pain. Carbamazepine in particular is used to treat a number of painful conditions, including trigeminal neuralgia. Another antiepileptic drug, gabapentin, is being studied for its pain-relieving properties, especially as a treatment for neuropathic pain.

Antidepressants are sometimes used for the treatment of pain and, along with neuroleptics and lithium, belong to a category of drugs called psychotropic drugs. In addition, anti-anxiety drugs called benzodiazepines also act as muscle relaxants and are sometimes used as pain relievers. Physicians usually try to treat the condition with analgesics before prescribing these drugs.

Antimigraine drugs include the triptans – sumatriptan (Imitrex®), naratriptan (Amerge®), and zolmitriptan (Zomig®) – and are used specifically for migraine headaches. They can have serious side effects in some people and therefore, as with all prescription medicines, should be used only under a doctor’s care.

Aspirin may be the most widely used pain-relief agent and has been sold over the counter since 1905 as a treatment for fever, headache, and muscle soreness.

Biofeedback is used for the treatment of many common pain problems, most notably headache and back pain. Using a special electronic machine, the patient is trained to become aware of, to follow, and to gain control over certain bodily functions, including muscle tension, heart rate, and skin temperature. The individual can then learn to effect a change in his or her responses to pain, for example, by using relaxation techniques. Biofeedback is often used in combination with other treatment methods, generally without side effects. Similarly, the use of relaxation techniques in the treatment of pain can increase the patient’s feeling of well-being.

Capsaicin is a chemical found in chili peppers that is also a primary ingredient in pain-relieving creams (see Chili Peppers, Capsaicin, and Pain in the Appendix).

Chemonucleolysis is a treatment in which an enzyme, chymopapain, is injected directly into a herniated lumbar disc (see Spine Basics in the Appendix) in an effort to dissolve material around the disc, thus reducing pressure and pain. The procedure’s use is extremely limited, in part because some patients may have a life-threatening allergic reaction to chymopapain.

Chiropractic care may ease back pain, neck pain, headaches, and musculoskeletal conditions. It involves “hands-on” therapy designed to adjust the relationship between the body’s structure (mainly the spine) and its functioning. Chiropractic spinal manipulation includes the adjustment and manipulation of the joints and adjacent tissues. Such care may also involve therapeutic and rehabilitative exercises.

Cognitive-behavioral therapy involves a wide variety of coping skills and relaxation methods to help prepare for and cope with pain. It is used for postoperative pain, cancer pain, and the pain of childbirth.

Counseling can give a patient suffering from pain much needed support, whether it is derived from family, group, or individual counseling. Support groups can provide an important adjunct to drug or surgical treatment. Psychological treatment can also help patients learn about the physiological changes produced by pain.

COX-2 inhibitors may be effective for individuals with arthritis. For many years scientists have wanted to develop a drug that works as well as morphine but without its negative side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) work by blocking two enzymes, cyclooxygenase-1 and cyclooxygenase-2, both of which promote production of hormones called prostaglandins, which in turn cause inflammation, fever, and pain. The newer COX-2 inhibitors primarily block cyclooxygenase-2 and are less likely to have the gastrointestinal side effects sometimes produced by NSAIDs.

In 1999, the Food and Drug Administration approved a COX-2 inhibitor – celecoxib – for use in cases of chronic pain. The long-term effects of all COX-2 inhibitors are still being evaluated, especially in light of new information suggesting that these drugs may increase the risk of heart attack and stroke. Patients taking any of the COX-2 inhibitors should review their drug treatment with their doctors.

Electrical stimulation, including transcutaneous electrical stimulation (TENS), implanted electric nerve stimulation, and deep brain or spinal cord stimulation, is the modern-day extension of age-old practices in which the nerves of muscles are subjected to a variety of stimuli, including heat or massage. Electrical stimulation, no matter what form, involves a major surgical procedure and is not for everyone, nor is it 100 percent effective. The following techniques each require specialized equipment and personnel trained in the specific procedure being used:

  • TENS uses tiny electrical pulses, delivered through the skin to nerve fibers, to cause changes in muscles, such as numbness or contractions. This in turn produces temporary pain relief. There is also evidence that TENS can activate subsets of peripheral nerve fibers that can block pain transmission at the spinal cord level, in much the same way that shaking your hand can reduce pain.
  • Peripheral nerve stimulation uses electrodes placed surgically on a carefully selected area of the body. The patient is then able to deliver an electrical current as needed to the affected area, using an antenna and transmitter.
  • Spinal cord stimulation uses electrodes surgically inserted within the epidural space of the spinal cord. The patient is able to deliver a pulse of electricity to the spinal cord using a small box-like receiver and an antenna taped to the skin.
  • Deep brain or intracerebral stimulation is considered an extreme treatment and involves surgical stimulation of the brain, usually the thalamus. It is used for a limited number of conditions, including severe pain, central pain syndrome, cancer pain, phantom limb pain, and other neuropathic pains.

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 (see section on Spine Basics in the Appendix), 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. (For a discussion of the thalamus and its role in this phenomenon, called phantom pain, see section on Phantom Pain in the Appendix.)

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 receptorsfound 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.

Where Can I Get More Information?

For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute’s Brain Resources and Information Network (BRAIN) at:

BRAIN

P.O. Box 5801
Bethesda, MD 20824
(800)352-9424
http://www.ninds.nih.gov

Information also is available from the following organizations:

American Chronic Pain Association (ACPA)

P.O. Box 850
Rocklin, CA 95677-0850
ACPA@pacbell.net
http://www.theacpa.org
Tel: 916-632-0922 / 800-533-3231
Fax: 916-652-8190

American Pain Foundation

201 North Charles Street
Suite 710
Baltimore, MD 21201-4111
info@painfoundation.org
http://www.painfoundation.org
Tel: 888-615-PAIN (7246)
Fax: 410-385-1832

National Institute of Arthritis and Musculoskeletal and Skin Diseases Information Clearinghouse

1 AMS Circle
Bethesda, MD 20892-3675
NIAMSinfo@mail.nih.gov
http://www.niams.nih.gov
Tel: 877-22-NIAMS (226-4267) / 301-565-2966 (TTY)
Fax: 301-718-6366

American Association of Neurological Surgeons

5550 Meadowbrook Drive
Rolling Meadows, IL 60008-3852
info@aans.org
http://www.aans.org
Tel: 847-378-0500 / 888-566-AANS (2267)
Fax: 847-378-0600

American Academy of Orthopaedic Surgeons/ American Association of Orthopaedic Surgeons

6300 North River Road
Rosemont, IL 60018
hackett@aaos.org
http://www.aaos.org
Tel: 847-823-7186
Fax: 847-823-8125

American Academy of Family Physicians

11400 Tomahawk Creek Parkway
Suite 440
Leawood, KS 66211-2672
fp@aafp.org
http://www.aafp.org
Tel: 913-906-6000 / 800-274-2237
Fax: 913-906-6095

Alzheimer’s Association

225 North Michigan Avenue
17th Floor
Chicago, IL 60601-7633
info@alz.org
http://www.alz.org
Tel: 312-335-8700 / 1-800-272-3900 (24-hour helpline)
TDD: 312-335-5886
Fax: 866-699-1246

American Academy of Neurological and Orthopaedic Surgeons

10 Cascade Creek Lane
Las Vegas, NV 89113
aanos@aanos.org
http://www.aanos.org
Tel: 702-388-7390
Fax: 702-871-4728

American Academy of Physical Medicine & Rehabilitation

330 North Wabash Ave.
Suite 2500
Chicago, IL 60611-7617
info@aapmr.org
http://www.aapmr.org
Tel: 312-464-9700
Fax: 312-464-0227

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