Abstract
Pain may be the most common reason patients seek treatment from physicians. When persistent and unrelieved, pain can frustrate both the person suffering with this condition and the physician trying to alleviate it. Relief from chronic pain may be particularly difficult to achieve and fraught with mis-conceptions. Treatment usually requires trials of physical, pharmacologic, and surgical interventions to achieve resolution. In cases that remain insoluble, patients must accept partial relief and seek adaptive strategies.
The source of persistent pain may be nociceptive or neuropathic. Both utilize the same nervous system pathways for transmission, but significant physiologic differences exist in the mechanism through which the body processes and resolves these painful stimuli. Nociceptive pain that results from a known or obvious source (eg, trauma, cancer metastasis, ischemia, arthritis) is often easy to identify. Neuropathic pain, however, may occur in the absence of an identifiable precipitating cause. Physicians must remain alert to differences in presentation and course of neuropathic pain syndromes, some of which may be subtle or unusual.
The International Association for the Study of Pain defines neuropathic pain as “initated or caused by a primary lesion or dysfunction in the nervous system” and due to disordered peripheral or central nerves.
1 The disorder can be caused by compression, transection, infiltration, ischemia, or metabolic injury to neuronal cell bodies, or in combination. Neuropathic pain may be classified as either peripheral or deafferentation (central) in origin.
2 Examples of the former include diabetic peripheral neuropathy (DPN), postherpetic neuralgia (PHN), antineoplastic therapy– or HIV-induced sensory neuropathy, tumor infiltration neuropathy, phantom limb pain, postmastectomy pain, complex regional pain syndromes (reflex sympathetic dystrophy), and trigeminal neuralgia. Deafferentation syndromes resulting in neuropathic pain include multiple sclerosis (MS), spinal cord injury (SCI), central poststroke pain, and Parkinson disease.
Bennett
3 provided incidence estimates of common types of neuropathic pain and concluded that if neuropathic low back pain is included in the total, approximately 3.8 million individuals in the United States alone suffer from this disorder. Bowsher
4 calculated that there might be as many as 1 million patients with PHN in the United States. Such painful conditions are likely to increase as the population continues to age; eg, herpes zoster, diabetes mellitus, cerebrovascular accidents, Parkinson disease, and cancer are diseases of aging.
Diabetic peripheral neuropathy, second only to low back pain–associated neuropathy, is estimated to account for 600 cases per 100,000 (
Table 1); these cases are certain to increase as the population of those with diabetes mellitus continues to increase.
Response to an acute painful stimulus is an important adaptive mechanism that protects a person from further injury. Considering characteristics that nociceptive and neuropathic pain have in common will help clarify their differences. Pain signals resulting from noxious stimuli (wounds, thermal or inflammatory insults) are converted into electrical impulses within tissue nociceptors whose cell bodies are found in dorsal root ganglions; both nociceptive and neuropathic pain signals utilize the same pain pathways.
Information regarding intensity, quality, and location of pain is conveyed to the sensory cortex from the somatosensory thalamus. The central nervous system utilizes descending inhibitory pathways via the dorsolateral fasciculus (Lissauer's tract) of the spinal cord and the periaqueductal gray matter to modulate transmission of nociceptive stimuli.
5,6 Namaka et al
7 characterize this as a complex equilibrium of pain-signaling and pain-relieving pathways connecting peripheral and central nervous systems.
Efficient, rapid transmission of acute responses to a painful stimulus is a self-protection process. Pain signals an “alarm” that leads to subsequent protective responses. Neuropathic pain, however, signals no imminent danger. The operative difference is that neuropathic pain represents a delayed, ongoing response to damage that is no longer acute which continues to be expressed as painful sensations.
Sensory neurons damaged by injury, disease, or drugs produce spontaneous discharges that lead to sustained levels of excitability. These ectopic discharges begin to “cross talk” with adjacent uninjured nerve fibers, resulting in amplification of the pain impulse (peripheral sensitization). This hyperexcitability leads to increased transmitter release causing increased response by spinal cord neurons (central sensitization). The process, known as “windup,” accounts for the fact that the level of perceived pain is far greater than what is expected based on what can be observed.
8,9
Painful nerve stimulation leads to activation of N-methyl-
d-aspartate (NMDA) receptors on the postsynaptic membrane in the dorsal horn of the spinal cord.
6(pp207-228) Release of NMDA, a modulating neurotransmitter, is coupled with subsequent release of glutamate, an excitatory neurotransmitter. The resultant extended depolarization (influx of calcium and sodium and efflux of potassium) produces much larger than usual postsynaptic potentials, known as
synaptic potentiation. Spinal windup has been described as “continuous increased excitability of central neuronal membranes with persistent potentiation”
9,10 Neurons of the peripheral and central nervous system continue to transmit pain signals beyond the original injury, thus activating an ongoing, continuous central pain response (
Figure 1). Devor et al
11 presented evidence showing that damaged sensory fibers have a higher concentration of sodium channels, an alteration that would increase spontaneous firing.
The symptoms described by persons with neuropathic pain are myriad (see
Sidebar, p S15), representing a variety of possible nerve injuries implicated in the etiology.
2 Neuropathic pain sufferers complain of numbness, burning, or tingling, or a combination; they describe electric shock–like, prickly, or pins and needles sensations. In 1990, Boureau et al
12 identified six adjectives used substantially more frequently to describe neuropathic pain.
Electric shock, burning, and
tingling were most commonly used (53%, 54%, and 48% respectively), in addition to
cold, pricking, and
itching. These terms should suggest a neuropathic etiology for pain.
Several common types of responses are elicited from patients with neuropathic pain (
Table 2). These abnormal sensations, or dysesthesias, may occur alone, or they may occur in addition to other specific complaints. Unlike the usual response to nociceptive pain, the irritating or painful sensation occurs completely in the absence of an apparent cause. A common example is the severe, aching, “toothache-like” response elicited by a cool draft of air on the cheek of a patient suffering from trigeminal neuralgia.
Table 2
Sensory Symptoms and Signs Associated With Neuropathic Pain
Symptom or Sign
| Description
|
---|
▪ Allodynia | Pain due to nonnoxious stimuli (clothing, light touch) when applied to the affected area. May be mechanical (eg, caused by light pressure), dynamic (caused by nonpainful movement of a stimulus), or thermal (caused by nonpainful warm, or cool stimulus) |
▪ Anesthesia | Loss of normal sensation to the affected region |
▪ Dysesthesia | Spontaneous or evoked unpleasant abnormal sensations |
▪ Hyperalgesia | Exaggerated response to a mildly noxious stimulus applied to the affected region |
▪ Hyperpathia | Delayed and explosive response to a noxious stimulus applied to the affected region |
▪ Hypoesthesia | Reduction of normal sensation to the affected region |
▪ Paresthesias | Nonpainful spontaneous abnormal sensations |
▪ Phantom Pain | Pain from a specifc site that no longer exists (eg, amputated limb) or where there is no current injury |
▪ Referred Pain | Occurs in a region remote from the source |
Table 2
Sensory Symptoms and Signs Associated With Neuropathic Pain
Symptom or Sign
| Description
|
---|
▪ Allodynia | Pain due to nonnoxious stimuli (clothing, light touch) when applied to the affected area. May be mechanical (eg, caused by light pressure), dynamic (caused by nonpainful movement of a stimulus), or thermal (caused by nonpainful warm, or cool stimulus) |
▪ Anesthesia | Loss of normal sensation to the affected region |
▪ Dysesthesia | Spontaneous or evoked unpleasant abnormal sensations |
▪ Hyperalgesia | Exaggerated response to a mildly noxious stimulus applied to the affected region |
▪ Hyperpathia | Delayed and explosive response to a noxious stimulus applied to the affected region |
▪ Hypoesthesia | Reduction of normal sensation to the affected region |
▪ Paresthesias | Nonpainful spontaneous abnormal sensations |
▪ Phantom Pain | Pain from a specifc site that no longer exists (eg, amputated limb) or where there is no current injury |
▪ Referred Pain | Occurs in a region remote from the source |
×
Allodynia is the term given to a painful response to an otherwise benign stimulus. Taken to the extreme (eg, inability to remove the stimulus), this response can result in the agonizing neuropathic symptom known as hyperpathia. Another example of allodynia is touch sensitivity of badly sunburned skin, where even light stroking of the inflamed area causes extreme discomfort; like neuropathic pain, this response seems out of proportion to the injury.
With respect to anesthesia or hypoesthesia, pharmacologic induction of this condition by lidocaine hydrochloride or fentanyl produces predictable half-lives and duration of action; this is not the case with neuropathic-induced anesthesia or hypoesthesia. The discomfort of one's foot “falling asleep” is a common paresthesia. That uncomfortable sensation is self-limiting and resolves spontaneously, unlike the continuous, self-perpetuating and annoying sensation of pins and needles caused by neuropathic pain.
Tricyclic antidepressants have been used for treatment of patients with DPN since the 1970s. These agents have documented pain-control efficacy
27 but are limited by a slow onset of action (analgesia in days to weeks), anticholinergic side effects (dry mouth, blurred vision, confusion/sedation, and urinary retention), and potential cardiac toxicity. Amitriptyline hydrochloride is the most extensively studied of the TCAs, at oral doses of 10 mg to 25 mg at bedtime. This dose can be slowly titrated with escalating doses every 4 to 7 days. Frail and elderly patients may be unable to tolerate therapeutic doses because of sedation. Desipramine and nortriptyline are less-sedating alternatives to amitryptiline; plasma drug levels are available for the latter.
The advent of selective serotonin reuptake inhibitors (SSRIs) gave hope that they could be used for chronic pain without the concerns of cardiac toxicity and anticholinergic side effects. However, results have been disappointing. With the exception of duloxetine hydrochloride, SSRIs are not indicated for neuropathic pain; they may be useful adjuncts to treat patients who have pain with depression when TCAs are contraindicated. Duloxetine is a new SSRI which has received US Food and Drug Administration (FDA) approval for the PHN indication.
Patients with neuropathic pain are prone to depression, drug dependency, and insomnia. Interrupted sleep is one of the most difficult problems facing patients with neuropathy, as there is no way to escape the discomforting symptom. Antidepressants and sedative-hypnotic medications may be prescribed as important adjunctive therapy for neuropathy.