10-05-07 - Chronic Pain - A New Disease

8/6/2019 10-05-07 - Chronic Pain - A New Disease

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Normal Pain Pathways

Pain serves as an important alarm that warns us of threatened or ongoing tissue damage. Theability 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 damageand debility is greatly increased.

Tissue injuries trigger the release of chemicals that give rise to an inflammatory reaction that inturn triggers pain signals to the brain. These signals, in the form of electrical impulses, arecarried by thin unmyelinated nerves called nociceptors (C-fibers) that synapse with neurons inthe dorsal horn of the spinal cord. From the dorsal horn, the pain signal is transmitted via thespinothalamic tract to the cerebral cortex, where it is perceived, localized, and interpreted(Figure 1).

Figure 1(opens graphic in new window)
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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 theperiaqueductal 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 -opioidreceptors on the presynaptic terminals of nociceptors and the postsynaptic surfaces of dorsalhorn neurons. The enkephalins bind to delta-opioid receptors on inhibitory interneurons in thesubstantia 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)


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Spinal interneurons release dynorphin, which activates kappa-opioid receptors and leads toclosure of N-type calcium channels in the spinal cord cells that normally relay the pain signal tothe 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 selectivelyexposed on nociceptive nerves when they are actively transmitting a pain signal. These receptorsare usually localized on presynaptic vesicles containing neurotransmitters. After theneurotransmitters are released, the receptors are incorporated into the presynaptic cell


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membrane. Active nociceptors thus become more sensitive than inactive nociceptors to bothendogenous and exogenous opiates, which may explain how certain opioid analgesics relieveongoing 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 upsetand dysfunctional for only a few minutes--not for days, as might be the case if the pain persisteduntil the injury completely healed. We are thus able to cope with life's daily pains withoutconstantly suffering. But just as disorders of the pain-sensing system can give rise to illness anddysfunction, so can disorders of the pain-relieving system. Fibromyalgia, a condition that manyclinicians consider to be factitious, may be one example of a debilitating disease caused byantinociceptive dysfunction.

Chronic Pain Pathways

Chronic pain is not just a prolonged version of acute pain. As pain signals are repeatedlygenerated, neural pathways undergo physiochemical changes that make them hypersensitive tothe pain signals and resistant to antinociceptive input. In a very real sense, the signals canbecome embedded in the spinal cord, like a painful memory. The analogy to memory isespecially fitting since the generation of hypersensitivity in the spinal cord and memory in thebrain may share common chemical pathways.

Activation of NMDA Receptors. The main neurotransmitter used by nociceptors synapsingwith 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 onafferent 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 persistentor large-scale release of glutamate. Repeated activation of AMPA receptors dislodgesmagnesium ions that act like stoppers in transmembrane sodium and calcium channels of theNMDA receptor complex. The conformational change in the neuronal membrane that makesthese 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)


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Activation of NMDA receptors has a number of important consequences (Table 1). Becauseactivation causes spinal neurons carrying pain to be stimulated with less peripheral input (aphenomenon known as windup), less glutamate is required to transmit the pain signal, and moreantinociceptive 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 opioidmedications at the usually prescribed dosage. The clinical implications are clear butunderappreciated--inadequately treated pain is a much more important cause of opioid tolerance

than use of opioids themselves.

Table 1. Results of NMDA-Receptor Activation

Normal

Windup

Reduced opioid effects

Neuropathic


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Injury discharge

Hyperalgesia

Allodynia


Inflammatory

Neuronal responses

Hyperalgesia

Reduced opioid effects (time-dependent)

Long-Term

Gene induction

Novel neurotransmission

Cell death

Pain memory


Adapted from Dickerson, 1994

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 tothe reticular activating system of the brain. When that occurs, the signal's pathway into thecerebral 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 braindamage that occurs during strokes is believed to be caused by the torrents of glutamate releasedfrom injured presynaptic cells, which overstimulate NMDA receptors on adjacent postsynapticcells and effectively burn them out. The same phenomenon may occur in parts of the spinalcord receiving persistent pain signals. There is also evidence that NMDA receptor activation canstimulate 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


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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 causesnociceptors 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 painsignal and also stimulates nerve growth and regeneration. It is thus interesting to note that theone chemical abnormality repeatedly documented in controlled studies of patients withfibromyalgia 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 ofthe c-fosoncogene protein, which in many respects can be regarded as a biochemical footprint ofchronic pain. The presence ofc-fosprotein in spinal cord cells is a marker for centralhypersensitization. At first, it is detectable in afferent spinal cord cells actively receiving painsignals. 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 virtuallyuntreatable.

This model explains why patients who have had uncontrolled pain for months or years oftenfind that their pain has spread beyond the originally affected organ or dermatome. In thesecases, physicians who are not familiar with the concept of neural plasticity are apt to concludethat the pain is psychogenic, because it does not conform to their preconceived map of thenervous 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 nowknow that many neurons can carry signals in both directions. With the prolonged generation ofpain signals, a dorsal root reflex can become established. This is a pathologic condition in whichafferent cells in the dorsal horn release mediators that cause action potentials to fireantidromically (i.e., backwards down the nociceptors). When this happens, packets of chemicalslocated at the peripheral terminals of these cells are released. Among these chemicals are nervegrowth factor and substance P, which is not only a neurotransmitter but also a potentinflammatory agent. Nerve growth factor increases the excitability of nociceptors. Pain signalsfrom peripheral nerves are thus heightened, and the cycle of chronic pain is continued (Figure4).

Figure 4(opens figure in a new window)


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Neurogenic Inflammation. The release ofsubstance P and nerve growth factor into the periphery causes a tissue reaction termedneurogenic inflammation. In contrast to the classic inflammatory response to tissue trauma orimmune-mediated cell damage, neurogenic inflammation is driven by events in the centralnervous system and does not depend on granulocytes or lymphocytes. Substance P causesdegranulation of mast cells, and its effects on the vascular endothelium induce the release ofbradykinin and production of nitric oxide, a potent vasodilator. Biopsy specimens fromneurogenically inflamed tissues--e.g., tendon insertion sites in fibromyalgia, the synovium incertain forms of chronic arthritis, the bladder in interstitial cystitis, or the colon in severeirritable bowel syndrome--typically show vasodilatation, plasma extravasation, abnormalsprouting of peripheral nerve terminals, and an accumulation of mast cells.

Hyperalgesia and Allodynia. Chemosensitive afferent nerves may become so sensitized by


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persistent pain that a low-intensity stimulus will provoke hyperalgesia. In certain syndromes, thepain signals may also activate the usually quiet mechanosensitive afferent nerves that are presentin synovial tissue and all viscus organs. Once activated, even slight movement or minimaldeformity of surrounding tissues can generate pain. This phenomenon, allodynia, is common in

chronic degenerative arthritis, low back pain, and severe irritable bowel syndrome and interstitialcystitis.

Neuropathic Pain

Damage to sensory nerves can cause neuropathic pain syndromes that are relatively insensitiveto antinociceptive suppression. In patients who have had a stroke or spinal cord injury, forexample, the nerves that carry touch signals may be destroyed. If enough pain-carrying fibersregenerate, tissues presumed to be anesthetic can produce considerable pain if reinjured orinflamed. 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 oreven a simple bladder infection can be extremely painful. In postthoracotomy and otherpostoperative 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) thatnormally carry the sense of touch, sprout new terminal branches that synapse with pain-sensingcells in the superficial layers of the dorsal horn rather than with touch-sensing cells locateddeeper in the spinal cord. Not only can these A fibers mediate allodynia, but they are alsoresistant to the inhibiting effects of endorphins or opioid medications because they do not haveopioid 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 thesenerve fibers are traumatized or severed, opioid receptor proteins manufactured within the nervecell body cannot be transported down the axon to their final destination in the presynapticmembrane. That is why surgical procedures designed to destroy or cut pain nerves are generallyunsuccessful in providing long-term pain relief. Neurodestructive procedures, such as presacralneurectomies for pelvic pain, occipital neurectomies for chronic headaches, and limbamputation 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 grimprognoses.

Translating Science into Treatment

The generation of pain signals and consequent neural remodeling and neurogenic inflammationmay be slowed or stopped by activating normal antinociceptive pathways at several points.Stimulation of opioid receptors on peripheral nociceptors or postsynaptic neurons in the dorsalhorn inhibits the release of glutamate and prevents the transmission of pain signals. This is thebasic mode of action of opioid medications.


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Drugs that block NMDA receptors can also have important pain-relieving effects. In caring forpatients 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 ofgunshot 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 ofthe damage done by chronic pain. It is interesting to note that, while nearly all of the powerfulpain-relieving opioids are levorotatory, their dextrorotatory isomers are often noncompetitiveNMDA 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 opioidreceptors and block NMDA receptors. In patients who have become tolerant to opioids, thesedrugs can often restore sensitivity, even to small doses. Unfortunately, clinical use of thesedrugs, 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 learnedinhibitions and induce transient psychosis. Current research should soon yield ways offormulating and delivering NMDA receptor-blockers that will ease most chronic painsyndromes without causing such adverse effects.

The finding that enkephalins work by closing N-type calcium channels, which are found only inneural tissue, prompted a search for drugs that would block these channels specifically. One ofthe compounds isolated, ziconotide, derived from the venom of a fish-hunting sea snail, hasshown promising results in clinical studies of patients with intractable opioid-resistant pain.

Gabapentin, an anticonvulsant widely used for treatment of neuropathic pain, also inhibitscalcium flux through N-type channels. Despite its name, gabapentin does not appear to haveany effect on GABA receptors. However, GABA-agonist medications such as baclofen areamong the drugs being investigated for GABA-like pain-relieving effects.

As new findings about the various elements of the antinociceptive system have emerged, anumber of other drugs are being reevaluated for analgesic potential. The observation thatalpha2-adrenergic receptors are involved in inhibiting pain signals, led to reformulation of theoral hypertensive agent clonidine as a potent intrathecal pain reliever. The demonstration ofclonidine's benefits in treating chronic pain syndromes has focused attention on other alpha-

adrenergic drugs. Both tizanidine, an antispasmodic agent, and oxymetazoline, a nasaldecongestant, 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 adestructive disease with physical, psychological, and behavioral consequences.

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


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vegetative, and many show signs of psychomotor impairment. Another characteristic of thesepatients is that, in the course of giving their histories, they frequently refer to events and lossesthat appear to be only peripherally related to the focus of their evaluation. Although this isusually 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 inthe nervous system often prevents patients with chronic pain from getting the timely andaggressive care that they need. The clinical take-home lesson is that we can reverse the signs andsymptoms of chronic pain with proper treatment. Part two of this article will make the case thatopioid 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

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