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Chronic Pain: 1. A New Disease?
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 (Figure 1).
Figure 1 (opens graphic in new window)
This complex nociceptive system is balanced by an equally complex antinociceptive system (Figure 2). 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.
Figure 2 (opens graphic in new window)
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 NMDA receptor complex. The conformational change in the neuronal membrane that makes these receptors susceptible to stimulation is the first step in central hypersensitization (Figure 3) and marks the transition from acute to chronic pain.
Figure 3 (opens graphic in new window)
Activation of NMDA receptors has a number of important consequences (Table 1). 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 order 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 (Figure 4).
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.
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.
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.
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