Article - Chronic Pain: A New Disease?

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Chronic Pain: A New Disease?

DANIEL BROOKOFF

Dr. Brookoff is Clinical Associate Professor of Medicine, University of

Tennessee College of Medicine, Memphis, and Associate Director,

Comprehensive Pain Institute, Methodist Hospitals of Memphis.

Chronic pain continues to be perceived as a characterologic disorder rather

than a serious, potentially fatal, medical disease. The general lack of

understanding of how persistent pain becomes magnified and ingrained

prevents many patients from receiving the level of care that they need to

regain control of their lives and resume normal activities.

In the United States, nearly one third of the population experiences severe

chronic pain at some point in life. It is currently the most common cause of

long-term disability, partially or totally disabling upwards of 50 million

people. As the population ages, the number of people needing treatment for

chronic pain from back disorders, degenerative joint diseases, rheumatologic

conditions such as fibromyalgia, visceral diseases, cancer, the effects of

cancer treatment, and other syndromes will undoubtedly grow.

The good news is that safe and effective medical treatment for chronic pain

is currently available. A major barrier to be overcome, however, is that

chronic pain is often not viewed as a physical illness worthy of treatment.

Recent studies demonstrating that specific changes occur in the peripheral

and central nervous systems of patients with chronic pain provide the

rationale for changing our approach to chronic pain syndromes and

instituting more aggressive and comprehensive treatment.

Normal Pain Pathways

Pain serves as an important alarm that warns us of threatened or ongoing

tissue damage. The ability to sense pain keeps us alive and functioning.

When that ability is compromised--for example, by diabetes or other causes

of sensory neuropathy--the risk of severe tissue damage and debility is

greatly increased.

Tissue injuries trigger the release of chemicals that give rise to an

inflammatory reaction that in turn triggers pain signals to the brain. These

signals, in the form of electrical impulses, are carried by thin

unmyelinated nerves called nociceptors (C-fibers) that synapse with neurons

in the dorsal horn of the spinal cord. From the dorsal horn, the pain signal

is transmitted via the spinothalamic tract to the cerebral cortex, where it

is perceived, localized, and interpreted.

This complex nociceptive system is balanced by an equally complex

antinociceptive system. Pain signals arriving from peripheral tissues

stimulate the release of endorphins in the periaqueductal gray matter of the

brain and enkephalins in the nucleus raphe magnus of the brainstem. The

endorphins inhibit propagation of the pain signal by binding to µ-opioid

receptors on the presynaptic terminals of nociceptors and the postsynaptic

surfaces of dorsal horn neurons. The enkephalins bind to delta-opioid

receptors on inhibitory interneurons in the substantia gelatinosa of the

dorsal horn, causing release of gamma-aminobutyric acid (GABA) and other

chemicals that dampen pain signals in the spinal cord.

Spinal interneurons release dynorphin, which activates kappa-opioid

receptors and leads to closure of N-type calcium channels in the spinal cord

cells that normally relay the pain signal to the brain. Following the

release of enkephalins, spinal cord cells release other small molecules,

including norepinephrine, oxytocin, and relaxin, that also inhibit pain

signal transmission.

Enkephalin is particularly notable in that it binds to delta-opioid

receptors that are selectively exposed on nociceptive nerves when they are

actively transmitting a pain signal. These receptors are usually localized

on presynaptic vesicles containing neurotransmitters. After the

neurotransmitters are released, the receptors are incorporated into the

presynaptic cell membrane. Active nociceptors thus become more sensitive

than inactive nociceptors to both endogenous and exogenous opiates, which

may explain how certain opioid analgesics relieve ongoing pain without

impairing the ability to sense the pain caused by new injuries.

This natural pain-relieving system may be as important to normal functioning

as the pain-signaling system. Because of it, minor injuries such as a cut

finger or stubbed toe make us upset and dysfunctional for only a few

minutes--not for days, as might be the case if the pain persisted until the

injury completely healed. We are thus able to cope with life's daily pains

without constantly suffering. But just as disorders of the pain-sensing

system can give rise to illness and dysfunction, so can disorders of the

pain-relieving system. Fibromyalgia, a condition that many clinicians

consider to be factitious, may be one example of a debilitating disease

caused by antinociceptive dysfunction.

Chronic Pain Pathways

Chronic pain is not just a prolonged version of acute pain. As pain signals

are repeatedly generated, neural pathways undergo physiochemical changes

that make them hypersensitive to the pain signals and resistant to

antinociceptive input. In a very real sense, the signals can become embedded

in the spinal cord, like a painful memory. The analogy to memory is

especially fitting since the generation of hypersensitivity in the spinal

cord and memory in the brain may share common chemical pathways.

Activation of NMDA Receptors. The main neurotransmitter used by nociceptors

synapsing with the dorsal horn of the spinal cord is glutamate, a versatile

molecule that can bind to several different classes of receptors. Those most

involved in the sensation of acute pain, AMPA

(alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic-acid) receptors, are

always exposed on afferent nerve terminals. In contrast, those most involved

in the sensation of chronic pain, NMDA (N-methyl-D-aspartate) receptors, are

not functional unless there has been a persistent or large-scale release of

glutamate. Repeated activation of AMPA receptors dislodges magnesium ions

that act like stoppers in transmembrane sodium and calcium channels of the N

MDA receptor complex. The conformational change in the neuronal membrane

that makes these receptors susceptible to stimulation is the first step in

central hypersensitization and marks the transition from acute to chronic

pain.

Activation of NMDA receptors has a number of important consequences. Because

activation causes spinal neurons carrying pain to be stimulated with less

peripheral input (a phenomenon known as windup), less glutamate is required

to transmit the pain signal, and more antinociceptive input is required to

stop it. Endorphins and other naturally occurring pain-relievers cannot keep

up with the demand and essentially lose their effectiveness. So do opioid

medications at the usually prescribed dosage. The clinical implications are

clear but underappreciated--inadequately treated pain is a much more

important cause of opioid tolerance than use of opioids themselves.

Activation of NMDA receptors can also cause neural cells to sprout new

connective endings. This neural remodeling can add new dimensions to old

sensations. The emotional component of pain may be increased, for example,

if the new connections channel more of the pain signal to the reticular

activating system of the brain. When that occurs, the signal's pathway into

the cerebral cortex is more splayed and the pain signal more diffuse and

difficult to localize.

Neural remodeling may also precipitate the destruction and loss of cells.

Some of the brain damage that occurs during strokes is believed to be caused

by the torrents of glutamate released from injured presynaptic cells, which

overstimulate NMDA receptors on adjacent postsynaptic cells and effectively

burn them out. The same phenomenon may occur in parts of the spinal cord

receiving persistent pain signals. There is also evidence that NMDA receptor

activation can stimulate normal apoptotic mechanisms. Although some of the

details have yet to be elucidated, the data obtained thus far suggest that

chronic pain is a destructive process that requires timely treatment in orde

r to limit the damage that it causes.

Activation of NK-I Receptors. A further effect of NMDA-receptor activation

is that it causes nociceptors to release the peptide neurotransmitter

substance P, which binds to neurokinin-1 (NK-1) receptors in the spinal

cord. Activation of these particular receptors amplifies the pain signal and

also stimulates nerve growth and regeneration. It is thus interesting to

note that the one chemical abnormality repeatedly documented in controlled

studies of patients with fibromyalgia syndrome is an elevated level of

substance P in the spinal fluid.

In animal models of chronic pain, substance P binding to NK-1 receptors

induces production of the c-fos oncogene protein, which in many respects can

be regarded as a biochemical footprint of chronic pain. The presence of

c-fos protein in spinal cord cells is a marker for central

hypersensitization. At first, it is detectable in afferent spinal cord cells

actively receiving pain signals. With persistence of the pain, the protein

spreads to progressively higher levels of the spinal cord until it

eventually reaches the thalamus, at which point the pain is virtually

untreatable.

This model explains why patients who have had uncontrolled pain for months

or years often find that their pain has spread beyond the originally

affected organ or dermatome. In these cases, physicians who are not familiar

with the concept of neural plasticity are apt to conclude that the pain is

psychogenic, because it does not conform to their preconceived map of the

nervous system.

Afferent Becomes Efferent.

Although most of us were taught that neuronal cells transmit signals in only

one direction, either towards (afferent) or away (efferent) from the brain,

we now know that many neurons can carry signals in both directions. With the

prolonged generation of pain signals, a dorsal root reflex can become

established. This is a pathologic condition in which afferent cells in the

dorsal horn release mediators that cause action potentials to fire

antidromically (i.e., backwards down the nociceptors). When this happens,

packets of chemicals located at the peripheral terminals of these cells are

released. Among these chemicals are nerve growth factor and substance P,

which is not only a neurotransmitter but also a potent inflammatory agent.

Nerve growth factor increases the excitability of nociceptors. Pain signals

from peripheral nerves are thus heightened, and the cycle of chronic pain is

continued.

Neurogenic Inflammation.

The release of substance P and nerve growth factor into the periphery causes

a tissue reaction termed neurogenic inflammation. In contrast to the classic

inflammatory response to tissue trauma or immune-mediated cell damage,

neurogenic inflammation is driven by events in the central nervous system

and does not depend on granulocytes or lymphocytes. Substance P causes

degranulation of mast cells, and its effects on the vascular endothelium

induce the release of bradykinin and production of nitric oxide, a potent

vasodilator. Biopsy specimens from neurogenically inflamed tissues--e.g.,

tendon insertion sites in fibromyalgia, the synovium in certain forms of

chronic arthritis, the bladder in interstitial cystitis, or the colon in

severe irritable bowel syndrome--typically show vasodilatation, plasma

extravasation, abnormal sprouting of peripheral nerve terminals, and an

accumulation of mast cells.

Hyperalgesia and Allodynia.

Chemosensitive afferent nerves may become so sensitized by persistent pain

that a low-intensity stimulus will provoke hyperalgesia. In certain

syndromes, the pain signals may also activate the usually quiet

mechanosensitive afferent nerves that are present in synovial tissue and all

viscus organs. Once activated, even slight movement or minimal deformity of

surrounding tissues can generate pain. This phenomenon, allodynia, is common

in chronic degenerative arthritis, low back pain, and severe irritable bowel

syndrome and interstitial cystitis.

Neuropathic Pain

Damage to sensory nerves can cause neuropathic pain syndromes that are

relatively insensitive to antinociceptive suppression. In patients who have

had a stroke or spinal cord injury, for example, the nerves that carry touch

signals may be destroyed. If enough pain-carrying fibers regenerate, tissues

presumed to be anesthetic can produce considerable pain if reinjured or

inflamed. This deafferentation pain is most common among patients with

spinal cord injuries. Although they may have no normal sensation below the

waist, surgery on decubitus ulcers or even a simple bladder infection can be

extremely painful. In postthoracotomy and other postoperative pain

syndromes, this type of pain is often associated with tactile hypesthesia.

Under certain conditions, usually after a tissue injury, the large

myelinated nerves (A fibers) that normally carry the sense of touch, sprout

new terminal branches that synapse with pain-sensing cells in the

superficial layers of the dorsal horn rather than with touch-sensing cells

located deeper in the spinal cord. Not only can these A fibers mediate

allodynia, but they are also resistant to the inhibiting effects of

endorphins or opioid medications because they do not have opioid receptors.

That would explain why patients with reflex sympathetic dystrophy have such

agonizing pain and do not respond to opioid medications.

Damage to the nociceptors themselves can also give rise to opioid-resistant

pain. When these nerve fibers are traumatized or severed, opioid receptor

proteins manufactured within the nerve cell body cannot be transported down

the axon to their final destination in the presynaptic membrane. That is why

surgical procedures designed to destroy or cut pain nerves are generally

unsuccessful in providing long-term pain relief. Neurodestructive

procedures, such as presacral neurectomies for pelvic pain, occipital

neurectomies for chronic headaches, and limb amputation for reflex

sympathetic dystrophy, that used to be common, have fallen out of favor.

Partial spinal cord transections and other neuroablative procedures continue

to be performed but are reserved primarily for end-stage cancer patients

with intractable pain and very grim prognoses.

Translating Science into Treatment

The generation of pain signals and consequent neural remodeling and

neurogenic inflammation may be slowed or stopped by activating normal

antinociceptive pathways at several points. Stimulation of opioid receptors

on peripheral nociceptors or postsynaptic neurons in the dorsal horn

inhibits the release of glutamate and prevents the transmission of pain

signals. This is the basic mode of action of opioid medications.

Drugs that block NMDA receptors can also have important pain-relieving

effects. In caring for patients who have illicitly used the potent NMDA

receptor-blocker phencyclidine ( " angel dust " ), I have been repeatedly

impressed by how many of them can tolerate the extreme pain of gunshot

wounds or fractures. Unfortunately, phencyclidine's psychotomimetic effects

make its use as a pain reliever impractical.

With careful use, other NMDA receptor-blockers such as ketamine can undo at

least some of the damage done by chronic pain. It is interesting to note

that, while nearly all of the powerful pain-relieving opioids are

levorotatory, their dextrorotatory isomers are often noncompetitive NMDA

receptor-bockers. One example is dextromethorphan, the D-isomer of

levorphanol. Another is methadone, which is formulated as a racemic mixture

that can both activate opioid receptors and block NMDA receptors. In

patients who have become tolerant to opioids, these drugs can often restore

sensitivity, even to small doses. Unfortunately, clinical use of these

drugs, with the exception of methadone, is currently limited because they

not only block NMDA receptors in the spinal cord but also in the brain,

where they can reverse learned inhibitions and induce transient psychosis.

Current research should soon yield ways of formulating and delivering NMDA

receptor-blockers that will ease most chronic pain syndromes without causing

such adverse effects.

The finding that enkephalins work by closing N-type calcium channels, which

are found only in neural tissue, prompted a search for drugs that would

block these channels specifically. One of the compounds isolated,

ziconotide, derived from the venom of a fish-hunting sea snail, has shown

promising results in clinical studies of patients with intractable

opioid-resistant pain.

Gabapentin, an anticonvulsant widely used for treatment of neuropathic pain,

also inhibits calcium flux through N-type channels. Despite its name,

gabapentin does not appear to have any effect on GABA receptors. However,

GABA-agonist medications such as baclofen are among the drugs being

investigated for GABA-like pain-relieving effects.

As new findings about the various elements of the antinociceptive system

have emerged, a number of other drugs are being reevaluated for analgesic

potential. The observation that alpha2-adrenergic receptors are involved in

inhibiting pain signals, led to reformulation of the oral hypertensive agent

clonidine as a potent intrathecal pain reliever. The demonstration of

clonidine's benefits in treating chronic pain syndromes has focused

attention on other alpha-adrenergic drugs. Both tizanidine, an antispasmodic

agent, and oxymetazoline, a nasal decongestant, are currently being assessed

for their utility as pain relievers.

Clinical Lessons

In tracing the pathways of acute and chronic pain, we see that they are very

different processes--so different that some investigators have proposed that

they be referred to by separate names, eudynia and maledynia. Chronic pain

(or maledynia), unlike normal everyday pain, is a destructive disease with

physical, psychological, and behavioral consequences.

Unlike patients with acute pain, those with chronic pain often appear to be

depressed, or even vegetative, and many show signs of psychomotor

impairment. Another characteristic of these patients is that, in the course

of giving their histories, they frequently refer to events and losses that

appear to be only peripherally related to the focus of their evaluation.

Although this is usually interpreted as evidence of a characterologic

disorder or psychiatric illness, it could be a manifestation of the

neurochemical link between pain and memory.

The failure to realize that behavioral and psychologic changes can reflect

pathologic changes in the nervous system often prevents patients with

chronic pain from getting the timely and aggressive care that they need. The

clinical take-home lesson is that we can reverse the signs and symptoms of

chronic pain with proper treatment. Part two of this article will make the

case that opioid medications, although broadly feared and highly restricted,

can be the mainstay of safe, effective treatment for chronic pain disease.

Selected Reading

Besson JM. The neurobiology of pain. Lancet 353:1610, 1999

Dickerson AH. NMDA receptor antagonists as analgesics. In Progress in Pain

Research, vol 1, Fields HL, Liebeskind VC (Eds), IASP Press, Seattle, 1994,

pp 173-188

Borsook D (Ed). Molecular Neurobiology of Pain. IASP Press, Seattle, 1997

Sicuteri F et al (Eds). Pain Versus Man. Raven Press, New York, 1992

Urban MO, Gebhart GF. Central mechanisms in pain. Med Clin North Am 83:585,

1999

Willis W (Ed). Hyperalgesia and Allodynia. Raven Press, New York, 1992