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Chronic Pain: Basic Science
Pain sensation is an important physiologic means by which an organism is informed about the immediate external environment and internal bodily function. The pain “experience” is the integration of a number of neurologic functions. In response to a brief painful stimulus, a rapid unconscious reflex and subsequent purposeful movement steer the organism away from the source of pain. The painful experience may be paired with a cue and remembered to generate avoidance behavior and evoke profound emotions. Pain from internal organs may signal either imminent or ongoing tissue damage, which can prompt a patient to seek medical attention. In a sense, acute pain assists survival.
However, chronic pain, pain that persists long after tissue healing due to injury or in tandem with disease, serves no useful biologic function. Chronic pain leads to heightened anxiety and diminished social functioning. The economic costs, in terms of both health care costs and lost productivity, are staggering and expected to rise even further as the population ages. Thus there is a vital need to understand the mechanism of chronic pain and to develop mechanism-based analgesic therapies.
Chronic Spinal Cord Injury Pain
Chronic pain following spinal cord injury (SCI) is estimated to occur in 65% to 81% of SCI patients; approximately one third of those patients rate it as severe. The addition of intractable pain to deficits in voluntary motor functions and autonomic dysfunction following SCI severely diminishes patient social and psychologic well-being. 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 conditions 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. Second, although chronic SCI pain shares striking similarities in terms of symptoms with other chronic pain states, such as peripheral nerve injury pain, 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 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 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 107.1 ). In addition, classification also aids researchers in designing appropriate experiments that will uncover mechanisms underlying SCI pain and hopefully uncover new analgesic targets.
TABLE 107.1
Proposed International Association for the Study of Pain Classification of Pain After Spinal Cord Injury
From Siddall PJ. Management of neuropathic pain following spinal cord injury: now and in the future. Spinal Cord. 2009;47:352–359.
| Broad Type (Tier 1) | Broad System (Tier 2) | Specific Structures/Pathology (Tier 3) |
|---|---|---|
| Nociceptive | Musculoskeletal | Bone, joint, muscle trauma, or inflammation |
| Mechanical instability | ||
| Muscle spasm | ||
| Secondary overuse syndromes | ||
| Visceral | Renal calculus, bowel, sphincter dysfunction, etc. | |
| Dysreflexic headache | ||
| Neuropathic | Above level | Compressive mononeuropathies |
| Complex regional pain syndromes | ||
| At level | Nerve root compression (including cauda equina) | |
| Syringomyelia | ||
| Spinal cord trauma/ischemia (central dysesthesia syndrome, etc.) | ||
| Below level | Spinal cord trauma/ischemia (central dysesthesia syndrome, etc.) |
As shown in Table 107.1 , SCI pain can be divided into two general types, nociceptive and neuropathic. These pain types can be further divided by possible underlying pathologies. The classification of the various pain types (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. In addition, this particular pain is localized to musculoskeletal structures. Examples of musculoskeletal pain sources 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. 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. 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. Visceral pain has been described as spontaneous, dull, poorly localized, or cramping, apparently originating from deep visceral structures. 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. Although the incidence of chronic visceral SCI pain is low, the pain is described as either severe or excruciating.
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 that is sharp, burning, shooting, stabbing, and electric, occurring continuously or as paroxysms. In addition to spontaneous pain, there may also be exaggerated painfulness evoked by nonnoxious 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. In contrast to at-level pain, below-level pain appears to have a delayed onset after SCI, which could be due to dysfunction of brain regions postsynaptic to the spinothalamic tract. Below-level pain is as severe and persistent as at-level neuropathic pain. 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. A positive correlation between spontaneous pain and cutaneous mechanical hypersensitivity of the painful area has been reported for other neuropathic pain states. 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 efficacy of pain treatments.
General Mechanism
This chapter presents a general outline of the normal pain pathway. Detailed neuroanatomic and neurochemical schemes have been published elsewhere. 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, nonnociceptive, large-diameter, primary afferents terminate in the 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. 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 among individuals and groups.
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 synapse with dorsal horn nociceptive neurons as well as inhibitory interneurons that, in turn, synapse with spinal nociceptive neurons, thus moderating pain transmission. Also, axons of nociceptive spinal neurons that terminate in the brainstem activate serotonergic, catecholaminergic, and GABAergic (γ-aminobutyric acid) 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 reduces spinal nociceptive neuron responses to noxious peripheral stimulation and is antinociceptive in rats. Analgesia is also observed in humans following intrathecal injection of similar substances (α-adrenergic, GABAergic, and opioid receptor agonists). These findings show a considerable parallel between the human and rat spinal dorsal horn neurochemistry that further 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 [NMDA]) induces a long-lasting hind paw hypersensitivity. The sustained excitation of nociceptive neurons may lead to increased intracellular cation levels, upregulation of second messenger systems, and gene expression. 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 nonnociceptive primary afferents extend to spinal laminae normally receiving nociceptors, and these same afferents express neuropeptides typically found in nociceptors. Changes in brain activity response to peripheral stimulation following an injury, including an SCI, have been observed.
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 NMDA receptor antagonist ketamine) at the level of the spinal cord, the first site of interaction between the peripheral nervous system and the central nervous system (CNS; see later). 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. Cellular transplantation may be able to address some of these permanent changes and can be modified to target multiple aspects of CNS dysfunction. For example, transplantation of embryonic cells, such as neural progenitor cells or GABAergic neural progenitor cells, improves neuropathic pain symptoms, possibly through replacement of lost cells and promotion of increased inhibition. Also, embryonic cells can be altered to continuously release endogenous analgesic substances, either through bioengineering or biomaterial platforms, which could be utilized to provide long-term pain relief. This is particularly promising given the extensive preclinical and clinical research with cellular transplantation for functional recovery after SCI (for a review, see Yousefifard et al. ). Adjunct therapies, such as locomotor or cardiac training, may also improve long-term pain relief by targeting multiple aspects of SCI, including injury-evoked inflammatory processes, activation of endogenous analgesic systems, reduction of primary afferent sprouting, and normalization of neurotrophic factors within the spinal cord and affected musculature.
Recombinant Analgesic Peptides
Naturally occurring peptides with analgesic properties are increasingly becoming the focus of preclinical pain research for several reasons, such as (1) their high specificity and affinity to pain-related target receptors, (2) their involvement as substrates of metabolism, and (3) their potential use in cellular and gene-based therapies. Vector-mediated delivery of possible analgesic molecules, such as opioid peptides, antiinflammatory cytokine interleukin-10, calcium channel binding peptide CBD3, brain-derived neurotrophic factor, and the GABA-synthetic enzyme GAD, have shown promising outcomes in rodent neuropathic pain models. Herpes simplex virus–mediated opioid peptide gene delivery has recently undergone clinical trials for cancer pain. A previous study described selection of promising therapeutic molecules. Since then, exciting preclinical studies have demonstrated that naturally occurring peptides could be used to attenuate SCI-induced dorsal horn neuronal dysfunction underlying the SCI neuropathic pain state.
Intrathecal administration of histogranin, a peptide found in the medullary adrenal gland, ameliorated cutaneous hypersensitivity associated with neuropathic pain, possibly through reducing the activity of NMDA. A recombinant synthetic version of histogranin, serine-histogranin (SHG), was expressed in vivo in rats by using a lentivirus expression system and reduced acute pain perception. Naturally occurring µ-opioid receptor ligands, endomorphin-1 and -2 (EM-1 and EM-2) have also demonstrated efficacy in preclinical pain models. The preclinical findings of efficacy recently led to the initiation of a phase I clinical trial in which a viral vector delivered an opioid peptide gene to subjects with cancer pain. Intraspinal injections of lentiviruses encoding SHG, EM-1 and EM-2, either singly or in combination, produced robust analgesic effects in SCI rats without decrement of efficacy over time (tolerance), as observed with some clinical analgesics. Furthermore, the analgesic effects of the combination of SHG and EM appeared to be additive, which suggests a potential for greater analgesia with a combination compared with either peptides alone. The data suggest that delivery of therapeutic genes could be a useful approach in managing clinical neuropathic SCI pain.
The use of viruses to deliver therapeutic genes could be contraindicated in some patients. Thus, as an alternative, recombinant cell therapy offers the possibility of focal delivery of analgesic substances within the CNS. The recombinant cellular approach allows for the generation of genes encoding multiple copies of a peptide, which in turn allows for varying quantities of peptide to be produced. Genetically modified rat embryonic GABAergic cells expressing SHG significantly reduced thermal and mechanical hypersensitivity in rats with neuropathic SCI pain. The GABAergic cells were capable of encoding from one to six copies of the SHG gene. Antinociception was observed, even when the cells were transplanted long after the injury. Intrathecal injection of an antibody to SHG attenuated the antinociceptive effect of the transplants, demonstrating that significant amounts of SHG were released from the transplants. Levels of SHG released by the cells were confirmed by immunoblotting and immunocytochemistry. These data highlight the potential use of gene and cellular therapies in providing long-lasting pain relief in patients with neuropathic SCI pain.
For obvious reasons, most experimental pain studies have focused on neural function. However, glial cells (e.g., microglia, astrocytes) vastly outnumber neurons in the CNS. Accumulating evidence indicates that glia have a key role in maintaining the neuropathic SCI pain state. 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. Injury of the thoracic spinal cord leads to dramatic increases in microglia and astrocytes, not only at the site of injury, but also at the level of the lumbar enlargement several segments away. Interestingly, similar increases in spinal glial activity in the lumbar spinal cord are observed in models of painful peripheral neuropathies. Treatments designed to decrease glial function following SCI 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.
There is a compelling need for nonpharmaceutical treatment options for SCI patients through the identification of new and novel therapeutic strategies such as physical rehabilitation. Physical rehabilitation is a peripheral treatment that provides increased endogenous production of neurotrophic factors associated with spinal plasticity and functional recovery to the CNS, which can be difficult to deliver exogenously due to the impermeability of these neurotrophic factors across the blood-brain barrier. Clinically, physical rehabilitation such as locomotor training (cycling and treadmill training) is prescribed to prevent muscle atrophy in the affected limbs and promote locomotor recovery in SCI patients. However, aside from the known locomotor benefits, preclinical research has shown that moderate levels of locomotor training in rodent models of SCI provide partial reduction of neuropathic pain, and increased levels of exertion under an intensive locomotor training protocol significantly reduced multiple symptoms of neuropathic pain not seen with moderate exertion. These benefits are in part due to changes in endogenous opioid production, µ-opioid receptor expression, the bulbospinal serotonergic system, inflammatory markers, and aberrant sprouting of central terminals of nociceptive primary afferents. Preclinical research findings suggest a dual role for physical rehabilitation to combat both neuropathic pain and locomotor dysfunction, thereby maximizing the potential for postinjury recovery, improving patient independence, and increasing productivity and participation in normal daily activities. Currently, physical rehabilitation is only prescribed to manage pain resulting from peripheral injury and is rarely used for the management of central neuropathic pain. Clinical trials in SCI patients are underway.
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-homogeneous subjects, but also because general clinical aspects of the histopathology following an SCI can be replicated in rats. 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.
Considerations
A degree of controversy exists surrounding the clinical relevance of rodent models of pain. Such controversy plagues other fields of neurologic research as well. The main clinical diagnosis of pain is based on the patient's verbal report, which would include pain severity, duration, and frequency. By contrast, in chronic pain models, a specific response to a given stimulus is interpreted as pain by experimenters. An exaggerated change in response to either nonnoxious or noxious (hyperalgesia) cutaneous stimuli is interpreted to mean a pathologic alteration in the underlying pain mechanism. However, such changes in sensory perception may not always be reported by patients, who primarily present with unevoked spontaneous pain.
An additional controversy that arises concerning animal models is deciding which would be best to use for preclinical research such that the information obtained could be readily translated into clinical practice. In terms of evaluating new therapeutics, predictive validity and reliability are crucial. A model with predictive validity allows one to accurately foresee the effect of a treatment in humans.
If the animal displays behaviors that are analogous to clinical symptoms, the model is said to have face validity. In pain research, however, the outcome measures in preclinical and clinical situations may not be identical. Most preclinical analgesic drug studies measure changes in response to stimulation, whereas few clinical drug trials have solely used quantitative sensory testing. Despite the stark difference in outcome measures, the concordance between the animal and clinical results is between 61% and 88%. In general, the high concordance suggests that the presence of cutaneous sensitivity (e.g., withdrawal threshold) is predictive of spontaneous pain (e.g., pain rating on a visual analog scale), but the wide range also indicates that some models may have better predictive value over others.
In an attempt to bridge the divide between clinical and preclinical outcome measures, basic scientists are working to quantify spontaneous pain-related behavior and changes in mood associated with chronic pain in animals. As mentioned earlier, changes in affect may impair SCI rehabilitation, further degrading overall well-being. Some of the well-defined experimental methods used in other behavioral research fields such as psychiatry and drug addiction have been adopted to detect and quantify spontaneous pain-related behavior, with varying degrees of success. For example, the University of Michigan developed a mechanical conflict-avoidance system (Coy MCS; Noldus Information Technology) that provides an operant method of pain testing that complements reflexive methods by addressing cognitive and motivational processing in rodents. Given the current level of concordance between preclinical and clinical results and the difficulty of quantifying affect in animals, it is not entirely clear how much more translational or clinical value will be gained with the addition of nonspontaneous measures to current testing procedures.
If a model has face validity, the assumption that follows is that it also has construct validity. Although it is desirable to mimic the clinical pathology in the rat, this may not always be possible. Demonstrating construct validity requires knowledge of the clinical mechanism, which is often lacking and incompletely understood. Also, as Geyer and Markou point out, the theoretical basis of neurologic disorders is constantly evolving. Thus construct validity should not be the sole determinant to judge the usefulness of a model.
Finally, reliability refers to the “consistency and stability” of both the experimental procedure and the symptoms resulting from it. On the one hand, this quality is highly desirable in basic science research because a highly predictable outcome following a manipulation reduces the chance of error and the need to use large numbers of subjects. On the other hand, clinical SCI is not homogeneous, and although many SCI patients have chronic pain, some do not.
Ultimately, the first consideration in choosing a model should be the scientific purpose of the model. Then, on the basis of the three main criteria (face, predictive, construct validity), the experimenter can determine whether the model is appropriate for the objectives.
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