Chronic Spinal Cord Injury Pain

Chronic pain following spinal cord injury (SCI) is estimated to occur in 65% to 81% of SCI patients, wherein about one third of patients rate it as severe.^2,7 The addition of intractable pain to deficits in voluntary motor functions and autonomic dysfunction following SCI severely diminishes patient social and psychologic well-being.⁸ In order to improve patient quality of life, pain relief is an important consideration along with other SCI-related complications in an overall treatment and rehabilitation strategy.

Despite increasing understanding of the cellular and molecular processes that mediate chronic pain in general, effective treatment for SCI pain in particular is lacking. At least two impositions thwart attempts to effectively ameliorate SCI pain. First, SCI pain is a heterogeneous condition with a number of possible interacting neurologic and inflammation-mediated mechanisms. Secondly, although chronic SCI pain shares striking similarities in terms of symptoms with other chronic pain states such as peripheral nerve injury pain, it appears that distinct mechanisms distinguish chronic neuropathic SCI pain from that of other types of neuropathic pain. For example, there is a striking lack of parallelism between peripheral neuropathic pain and neuropathic SCI pain in terms of clinical pharmacology. The first steps toward effective analgesic treatment for SCI pain will involve not only involve careful clinical diagnosis but also consideration of SCI pain as a distinct chronic pain syndrome.

Spinal Cord Injury Pain Classification

The International Association for the Study of Pain (IASP) has proposed a taxonomy that attempts to group SCI pain states to assist consistent clinical diagnosis and aid in designing effective pain management strategies (Table 103–1).⁹ In addition, classification also aids researchers in designing appropriate experiments that will uncover mechanisms underlying SCI pain and hopefully uncover new analgesic targets.

TABLE 103-1 Proposed IASP Classification of Pain Following Spinal Cord Injury

Table 103–1 first divides pain into two general “types,” nociceptive and neuropathic, and further divides these pain types by possible underlying pathologies. The classification of the various pains (musculoskeletal, visceral, and neuropathic pain based on spinal lesion level) does not suggest definitive mechanisms, and the construct validity of the divisions has yet to be confirmed in clinical studies. However, such an uncomplicated taxonomy is a positive first step in systematically addressing the cause of SCI pain and developing useful therapies.

The first type of SCI pain, nociceptive pain, arises from stimulation of either somatic or visceral primary afferent nociceptors. Musculoskeletal pain has been characterized as dull aching pain that worsens with movement and eases with rest.⁷ In addition, this particular pain is localized to musculoskeletal structures. Sources of musculoskeletal pain include injury to muscles or ligaments related to the initial injury, overuse of the shoulders and arms of a wheelchair-bound patient, and vertebral instability and osteoporosis due to SCI.¹⁰ Given the initial challenges of novel self-propulsion and injury-associated pain, the onset of musculoskeletal pain is comparatively rapid, within weeks of the injury, and is the most commonly reported SCI-associated pain.¹¹ Chronic musculoskeletal pain has been noted long after the injury (at least 5 years) and could be associated with the long-term skeletal changes in posture due to injury.⁷ Visceral pain has been described as spontaneous, dull, poorly localized, or cramping apparently originating from deep visceral structures.⁷ The occurrence of pain may or may not be coupled with visceral pathology and, unlike musculoskeletal pain, the onset of visceral pain may be months or years following SCI.^7,12 Although the incidence of chronic visceral SCI pain is low, the pain is described as either severe or excruciating.⁷

The second type of SCI pain is neuropathic pain, which results from trauma or disease to the nervous system. Neuropathic pain has been described as unevoked pain characterized as sharp, burning, shooting, stabbing, and electric, occurring continuously or as paroxysms. In addition to spontaneous pain, there may also be exaggerated painfulness evoked by non-noxious stimulation (e.g., allodynia). Spontaneous and evoked neuropathic pain may occur at the level of injury due to a combination of damaged segmental spinal nerve roots or disinhibited spinal dorsal horn nociceptive neurons. About 40% of SCI patients experience at-level neuropathic pain.⁷ In contrast to at-level pain, below-level pain appears to have a delayed onset post-SCI and this could be due to dysfunction of brain regions postsynaptic to the spinothalamic tract.⁷ Below-level pain is as severe and persistent as at-level neuropathic SCI pain.⁷ Despite a lack of cutaneous thermal detection (either cold or heat) below the lesion, below-level neuropathic pain occurs in about one third of SCI patients. Interestingly, at-level and below-level cutaneous hypersensitivity correlates with the presence of below-level spontaneous pain, which suggests a common mechanism underlying these symptoms.^13,14 A positive correlation between spontaneous pain and cutaneous mechanical hypersensitivity of the painful area has been reported for other neuropathic pain states.¹⁵ Such a correlation suggests that it may be possible to use defined stimuli to quantify spontaneous pain, beyond a subjective patient report, and objectively compare and contrast the efficacies of pain treatments.

General Mechanism

A general outline of the normal pain “pathway” will be presented. Detailed neuroanatomic and neurochemical schemes have been elaborated elsewhere.¹⁶ Noxious cutaneous stimuli (either thermal or mechanical) stimulate myelinated or unmyelinated small diameter primary afferents, conducting the “noxious signal” to the spinal cord superficial dorsal horn (or in the face, to the brainstem trigeminal sensory nucleus). Within the dorsal horn, excitatory neurotransmitters released from primary afferent central terminals stimulate postsynaptic dorsal horn neurons. A number of neuroactive substances (e.g., adenosine 5′-triphosphate [ATP]), excitatory amino acids, and neuropeptides activate their respective receptors on the postsynaptic neuron. By contrast, non-nociceptive, large-diameter, primary afferents terminate in deep dorsal horn and also in the brainstem dorsal column nuclei.

Axons of dorsal horn nociceptive neurons ascend to the brain via a number of tracts. Axons of nociceptive neurons decussate in the spinal cord and ascend via the contralateral ventral funiculus (spinothalamic tract) and terminate in the ventroposterior lateral thalamus. The pain signal may be dispersed from the thalamic nucleus to various brain areas with diverse functions such as the sensory cortex, hypothalamus, limbic lobes, and motor nuclei. Although there are a number of indirect pathways between the spinal dorsal horn and brain, direct projections of dorsal horn neurons to a number of brain areas have also been reported.¹⁷ By virtue of the numerous direct and indirect connections between nociceptive neurons to higher brain areas, pain evokes multiple physiologic and psychologic responses. Given human genetic diversity, it is apparent that the pain experience, as well as potential treatment strategies, differs between individuals and groups.^18,19

In the normally functioning pain system, the excitatory component is counterbalanced by endogenous inhibitory components such that the initial pain sensation is not permanently propagated or does not evoke an exaggerated response. Primary afferents not only synapse with dorsal horn nociceptive neurons but also inhibitory interneurons, which, in turn, synapse with spinal nociceptive neurons, thus moderating pain transmission.²⁰ Also, axons of nociceptive spinal neurons that terminate in the brainstem activate serotonergic, catecholaminergic, and GABAergic (gamma-aminobutyrate) neurons, which in turn send axons down to the dorsal horn. Because terminals are found presynaptic to primary afferents and spinal nociceptive neurons, activation of these brainstem neurons leads to diminished pain perception. Direct application by intrathecal injection of inhibitory neurotransmitters and opioid neuropeptides reduce spinal nociceptive neuron responses to noxious peripheral stimulation and are antinociceptive in rats.²¹ Analgesia is also observed in humans, following intrathecal injection of similar substances (α-adrenergic, GABAergic, and opioid receptor agonists).²² These findings a considerable parallel between the human and rat spinal dorsal horn neurochemistry, which, furthermore, points out the utility of preclinical models in evaluating drugs for possible clinical use.

In contrast to the normal state, experimental evidence suggests that decreased inhibition, increased excitation, or a combination of both initiates and perpetuates a chronic pain state because of the pathology of the nervous system. For example, acute lumbar intrathecal injection of an antagonist to either the GABA_A or GABA_B receptor subtype or the glycine receptor leads to a transient yet robust hind paw hypersensitivity and vocalization in rats. This indicates that a tonic inhibition is present in the normal state, which “dampens” responses to peripheral stimulation. Similarly, intrathecal injection of an excitatory glutamate receptor agonist (e.g., N-methyl-D-aspartate) induces a long-lasting hind paw hypersensitivity.²³ The sustained excitation of nociceptive neurons may lead to increased intracellular cation levels, upregulation of second messenger systems, and gene expression.¹⁶ These intracellular processes then lead to persistent hyperactivity and increased responsiveness to peripheral stimulation. Furthermore, such abnormal activity may be found throughout the pain neuraxis. Preclinical pain models have demonstrated considerable changes to normal neuroanatomy and neurochemistry following painful peripheral nerve injury or inflammation. For example, the central terminals of non-nociceptive primary afferents extend to spinal laminae normally receiving nociceptors, and these same afferents now express neuropeptides typically found in nociceptors.^24,25 Changes in brain activity response to peripheral stimulation following an injury, including an SCI, have been observed.²⁶

On the basis of findings in preclinical pain models, to attenuate clinical chronic pain states, it would be reasonable to increase inhibition (e.g., intrathecal GABA_B receptor agonist baclofen) or decrease excitation (e.g., intrathecal [N-methyl-D-aspartate] NMDA receptor antagonist ketamine) at the level of the spinal cord, the first site of interaction between the peripheral and central nervous systems (see later).^22,27 Even though such acute measures may prove efficacious, they are temporary. It is likely that a number of regions within the nervous system may express abnormal excitation and that these changes have been made permanent via genetic and structural mechanisms. Implantation of cells that continuously release endogenous analgesic substances and gene therapy may provide long-term pain relief.^28–32

Most experimental pain studies have focused on neural function for obvious reasons. However, glial cells (e.g., microglia, astrocytes) vastly outnumber neurons in the central nervous system (CNS). Accumulating evidence indicates that glia have a key role in maintaining the neuropathic SCI pain state.³³ In the normal state, glia appear to maintain the homeostasis of the extracellular milieu. Because glia express receptors and ion channels, similar to neurons, they may respond to neuroactive substances. Following exposure to these substances, activated glia may release, in turn, a number of neuroactive substances and proinflammatory cytokines. The glial response following injury has been intensely characterized because modulating the response is believed to be crucial to promoting motor and sensory recovery.³⁴ Injury of the thoracic spinal cord leads to dramatic increases in microglia and astrocytes not only at the site of injury but at the level of the lumbar enlargement, several segments away.^35,36 Interestingly, similar increases in spinal glial activity in the lumbar spinal cord are observed in models of painful peripheral neuropathies.³⁷ Treatments designed to decrease glial function following SCI in order to improve motor function may also have a secondary effect of reducing SCI-induced pain. Such treatment studies should include sensory outcomes if the patient has SCI pain.

Neuropathic Spinal Cord Injury Animal Models

The majority of preclinical SCI pain experiments have been done in rodents, not only because of the convenient availability of near homogenous subjects but also because general clinical aspects of the histopathology following an SCI can be replicated in rats.³⁸ In addition, numerous analgesic treatments initially screened in peripheral-injury chronic pain models have gone on to demonstrate clinical efficacy. Thus animal models of SCI pain may also be useful in both elucidating SCI pain mechanisms and developing novel clinical treatments.