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Jadad A, O'Brien MA, Wingerchuk D, et al. Management of Chronic Central Neuropathic Pain Following Traumatic Spinal Cord Injury. Rockville (MD): Agency for Healthcare Research and Quality (US); 2001 Sep. (Evidence Reports/Technology Assessments, No. 45.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Management of Chronic Central Neuropathic Pain Following Traumatic Spinal Cord Injury.

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1Pain as a Problem Following Traumatic Spinal Cord Injury

Introduction

Pain has been recognized for more than half a century as one of the many symptoms experienced by people who have suffered spinal cord injuries (SCI) (Backonja and Galer, 1998; Bedbrook, 1981; Beric, Dimitrijevic, and Lindblom, 1988; Botterell, Callaghan, and Jousse, 1953; Britell and Mariano, 1991; Burke, 1976; Davidoff, Roth, Guarracini, et al., 1987; Davis and Martin, 1947; Davis, 1975; Kaplan, Grynbaum, Lloyd, et al., 1962; Kennedy, 1946; Levi, Hultling, Nash, et al., 1995; Melzack and Loeser, 1978; Michaelis, 1970; Nashold, 1991; Pollock, 1951; Riddoch, 1938; Roth, 1994; Tunks, 1986). Estimates of the prevalence of pain in this group, however, have varied widely. Studies have reported that pain is experienced by 1 to 94 percent of people at some point after suffering an SCI (Ravenscroft, Ahmed, and Burnside, 1999; Roth, 1994; Siddall, Taylor, and Cousins, 1997). Attempts to estimate the severity and duration of pain after SCI have also led to variable results. It has been reported, for instance, that pain can become chronic in 1 to 70 percent and can be severe or disabling in 5 to 37 percent of people after SCI (Kaplan, Grynbaum, Lloyd, et al., 1962; Nepomuceno, Fine, Richards, et al., 1979; Ravenscroft, Ahmed, and Burnside, 1999). This variation in estimates of prevalence, severity, and duration, which has also been shown across institutions within multicenter studies, has been explained by differences among the studies in terms of pain definitions, terminology, classification, inclusion criteria, variability in reporting methods, as well as several etiological, demographic, and cultural factors (Roth, 1994).

Independently of the problems to estimate its prevalence, severity, and duration, it has been shown that pain can be very disabling after SCI. A study has revealed that, depending on the level of the lesion, 23 to 37 percent of people with pain after SCI would, if they had the chance, trade pain relief for loss of bladder, bowel, or sexual function (Nepomuceno, Fine, Richards, et al., 1979).

Classification of Pain After SCI

Studies in animal models have suggested a variety of pathophysiological mechanisms that occur after SCI, from intraspinal sprouting of C, A delta, and A beta primary afferent fibers to alterations in ion channels and transmitter receptor activation state leading to permanent central sensitization of cells in the pain pathway (spinothalamic tract neurons) (Bennett, 1993). Yezierski (1996) reviewed the results of three experimental models of SCI (ischemic, mechanical, and excitotoxic) and concluded that "there are neurochemical, anatomical, and physiological changes that collectively constitute a central injury cascade responsible for the development of clinical symptoms" (Yezierski, 1996). He suggests that it is unlikely that any one mechanism is solely responsible for the onset of central pain following SCI. The clinical field is well positioned to learn from the mammalian studies and model therapeutic interventions based on mechanisms that are known to occur. In the clinic, however, the classification of pain in people with SCI has been plagued by great variability and little consensus.

In 1997, a group of investigators developed a method of classification that seems to be gaining widespread acceptance, as it was built upon the existing literature and designed to provide simple guidance to research and management decisions (Siddall, Taylor, and Cousins, 1997). We will follow this classification, as much as possible, throughout this evidence report.

The first axis of the classification (Axis 1) includes four major categories or divisions of pain: "musculoskeletal," "visceral," "neuropathic," and "other." These categories are based on the system affected, which can be readily identifiable in clinical settings. The following is almost a verbatim description of each of these categories, as stated in the original article (Siddall, Taylor, and Cousins, 1997).

Musculoskeletal Pain

This is pain that arises from damage or overuse in structures such as bones, ligaments, muscles, intervertebral discs, and facet joints. This category also includes mechanical pain due to damage of spinal structures such as that occurring before spinal stabilizing surgery. Musculoskeletal pain can be identified by location (at or above lesion level in those with complete spinal cord lesions) and by features (dull, aching, worse with activities, eased by rest).

Visceral Pain

This is pain associated with visceral pathology. It can be identified by location (e.g., abdomen) and features (dull, poorly localized, cramping, related to visceral function or pathology).

Neuropathic Pain

This is pain that occurs following damage to the central or peripheral nervous system (Merskey and Bogduk, 1994). This pain can be identified by site (region of sensory disturbance) and by features (sharp, shooting, electric, burning, stabbing). Neuropathic pain can be further broken down by site (Axis 2) into neuropathic pain "at level" and neuropathic pain "below level."

Neuropathic At Level Pain

As its name indicates, this is pain that occurs at the level of the SCI, in a segmental pattern with neuropathic features. This type of pain may be attributed to nerve root pathology or changes within the spinal cord or possibly supraspinal structures. Siddall and colleagues (1997) also suggest that pain that is described as "burning," "tingling," "sharp," "aching," or "shooting" in a dermatomal distribution at the level of the lesion, with or without hyperesthesia, should be classified as neuropathic at level pain. "At level" should include two segments above and below the level of SCI, because input from several segments may be disrupted or disturbed following injury at any particular level (Siddall, Taylor, and Cousins, 1997).

Neuropathic Below Level Pain

This type of pain refers to diffuse pain that is described by the words "burning," "tingling," "aching," "shooting," or "stabbing." In distinction to neuropathic at level pain, this pain should be present at least three segments below the level of injury. This type of pain has been labeled by other classification systems as "central pain" or "deafferentation pain."

Neuropathic pain is the focus of this report. Neuropathic pain not only is one of the most challenging conditions in chronic pain management and one of the most promising areas in pain research (Jadad, 1993), but also, it may have even greater impact on the quality of life of patients than the extent of the injury itself (Westgren and Levi, 1998).

Other Types of Pain

This is a category created to include other specific types of pain that are not included in the categories listed above, such as pains that are a "consequence" of SCI. This group includes pains such as those associated with syringomyelia, compressive mononeuropathies, and reflex sympathetic dystrophy.

This classification system excludes sensations following SCI that are not regarded as pain, such as phantom phenomena.

The Role of Systematic Reviews in the Study of Neuropathic Pain After Traumatic Spinal Cord Injury

Pain arguably is the best studied of all symptoms. There is a rich tradition of pain relief research spanning the past 50 years. Each year, the body of literature expands by thousands of new articles published in hundreds of journals and books and, increasingly, on the Internet. During the second half of the 20th century, the number of randomized controlled trials (RCTs) in pain relief doubled every 10 years. In January of 2000, a search of the Cochrane Controlled Trials Register (Cochrane Library, 1999), the largest collection of clinical trials in the world, found that "pain" or "analgesia" were mentioned in more than 23,000 citations of RCTs or almost 9 percent of the total. Not surprisingly, keeping up with existing and new knowledge in pain relief has become a difficult task.

The explosion of information on pain and its management, and the need to use it efficiently, has led to an increasing interest in the use of the principles of evidence-based health care to guide clinical decisions and resource allocation around pain relief.

One of the strongest manifestations of the interest in evidence-based decisionmaking has been the considerable increase in the number of systematic reviews addressing a wide variety of pain relief topics. For instance, systematic reviews have been used to evaluate the evidence on the effectiveness and safety of interventions for chronic pain such as transcutaneous electrical nerve stimulation (McQuay and Moore, 1998), intravenous regional sympathetic blockade (Jadad, Carroll, Glynn, et al., 1995; McQuay and Moore, 1998), opioids (Jadad, 1998); anticonvulsant drugs (McQuay, Carroll, Jadad, et al., 1995), antidepressants (McQuay, Tramer, Nye, et al., 1996), systemic local anesthetic-type drugs (Kalso, Tramer, McQuay, et al., 1998; McQuay and Moore, 1998) and cognitive behavior therapy (Morley, Eccleston, and Williams, 1999).

The impetus for the use of systematic reviews to guide decisions in pain relief has been strengthened by the availability of powerful tools such as the Oxford Pain Database (Jadad, Carroll, Moore, et al., 1996), validated tools to assess the quality of analgesic trials (Jadad, Moore, Carroll, et al., 1996), specialized Web sites and textbooks (McQuay and Moore, 1998; Oxford Pain Web Site, 1999), special interest groups within professional organizations (International Association for the Study of Pain, 1999), and the Cochrane Collaboration (Cochrane PaPas Group, 0).

Despite the increasing amount of collaborative work represented by these efforts, however, no systematic reviews have been identified to address issues specifically related to the management of neuropathic pain after TSCI.

Commissioning of This Report

Neuropathic pain is perhaps one of the most promising areas for the development of strong partnerships and for profound breakthroughs in clinical treatment. For these efforts to be efficient, it is essential that all the potential partners count with a rigorous synthesis of the best available evidence from clinical research to provide a common platform for their deliberations.

The McMaster University EPC (MU-EPC) was notified in September 1999 that it was successful in its bid to undertake the development of an evidence report on the "Management of Chronic Central Neuropathic Pain Following Traumatic Spinal Cord Injury." This topic was nominated by the Consortium for Spinal Cord Medicine (CSCM), an organization that includes representation from 18 partners (Appendix A). The CSCM plans to use this report as part of its guideline development process.

The objectives of this Task Order were to conduct a comprehensive systematic review of the literature on this important topic and to support guideline development initiatives by the CSCM, while building upon existing work and focusing on potentially answerable, clinically relevant questions.

The absence of a widely accepted definition for "chronic central neuropathic pain," including specific issues related to the chronicity and the traumatic nature of pain, forced a liberal approach to the questions posed by the CSCM in relation to the selection of studies (otherwise we would have had no articles to review). It was decided that the questions would apply to people who had suffered a direct traumatic injury to the spinal cord, that had pain described as chronic (regardless of the duration), and that fit the classification proposed by Siddall et al., 1997.

Review Questions

All questions were initially formulated by the CSCM and further refined with input from members of the MU-EPC and the AHRQ Task Order Officer (TOO). By request from the CSCM and the TOO, all questions, unless otherwise specified, relate to the assessment or management of chronic central neuropathic pain (CNP) following traumatic spinal cord injury (TSCI) in adults.

Group I: Issues Related to Assessment

  1. What are the measurement properties (reliability, validity, sensitivity to change) of:
    1. assessment approaches for chronic central neuropathic pain per se (including criteria and tools such as inventories, questionnaires, and scales to measure pain intensity or relief);
    2. other outcome measures or assessments (related to the experience of pain, such as impact of pain on mood, sleep, and independence); and
    3. assessment approaches (including criteria and tools such as inventories, questionnaires, and scales) to identify new onset musculoskeletal pain against a background of chronic central neuropathic pain?
  2. What is the strength of evidence for strategies for the differential diagnosis of chronic central neuropathic pain from other types of pain?

Group II: Issues Related to Natural History

3.

What is the strength of evidence supporting strategies to estimate the prevalence of acute and chronic central neuropathic pain and factors that could predict the development of chronic central neuropathic pain?

Group III: Issues Related to Interventions for Treatment

4.

a) What is the evidence for the effectiveness and safety of each of the following classes of medications: simple analgesics (including nonsteroidal anti-inflammatory drugs [NSAIDs] and acetaminophen); antidepressants (including tricyclics and seratonin reuptake inhibitors [SSRIs]); antiseizure medication; narcotics; muscle relaxants; N-methyl-D-aspartate (NMDA) antagonists; and local anesthetics?
b) How do these classes of medications compare with one another?
c) What is the strength of evidence for the effectiveness and safety of treatment algorithms including these classes of medication?

5.

What is the evidence of effectiveness and safety of: (a) electrical stimulation (TENS); (b) regional anesthetic interventions (nerve blocks); (c) surgery, including dorsal root entry zone (DREZ); (d) multidisciplinary pain treatment approaches; (e) pain management approaches; (f) comprehensive pain management clinics; and (g) psychosocial interventions?

6.

What is the evidence for the effectiveness and safety of self-management approaches to chronic pain management (e.g., Catalano's workbook, Caudill's workbook, Aspen's pain management education manual, and Tollison's pain management patient guide)?

7.

What are the costs (if available) associated with pharmacologic, technological and other interventions listed in questions 4, 5, and 6 above?

To our knowledge, there have been no systematic reviews specifically designed to answer any of the questions formulated by the CSCM.

Anticipated Challenges for This Task Order

Studying the natural history, prevalence, and treatment of neuropathic pain through the research evidence available to date was regarded as a complex task from the outset. The first major challenge for any effort to review the evidence from research on the management of pain following TSCI emanates from the nature of neuropathic pain, its definition, and our understanding of its underlying pathophysiology. Although there is a surprising degree of agreement around the definition of neuropathic pain within the clinical community, neuropathic pain is not a discrete physiologically measurable phenomenon, but a construct (or concept) derived from clinical observations (Portenoy, 1998). Although useful from the clinical perspective, the current construct of neuropathic pain is likely to be overly simplistic (Portenoy, 1998). In fact, there has been no confirmation that a constellation of "neuropathic mechanisms" actually exists (Portenoy, 1998). If such mechanisms exist, they are likely to be complex and highly variable, both within and across pain syndromes (Bennett, 1993; Portenoy, 1998). On the other hand, multiple mechanisms can be present within any given diagnostic category and even within individual patients (Fields and Rowbotham, 1994).

Another expected challenge to the application of the principles of evidence-based decision-making to the study of pain following TSCI is related to the amount and quality of the research data available. A recent analysis of specialized journals revealed that less than 1 percent of articles specifically addressed pain after TSCI (Siddall, Taylor, and Cousins, 1997). In addition, systematic reviews and empirical methodological studies have repeatedly shown that research in pain relief in general is incompletely reported, addresses few clinically relevant questions, and is prone to bias (Jadad and Cepeda, 1999). If these problems were also to be present in the small subset of research studies on pain after TSCI, the value of the little knowledge available would be reduced even further.

Lastly, other barriers were expected to emanate from the lack of a systematic approach to the management of neuropathic pain in general that could be applied to the management of pain following TSCI. To date, treatment decisions have been described as "largely hit or miss, mostly miss" (Fields, 1994), as clinicians have been forced to administer the same group of treatments to patients, regardless of the origin of the pain, hoping to find at least one that could give patients adequate relief (Max, 1990).

The Collaborative Team

The team that developed the Task Order included a local executive team, a Technical Expert Panel (TEP), representatives from the CSCM (Appendix A) and the TOO. The TEP included a group of prominent professionals, purchasers, and patients who agreed to participate in this Task Order, as well as members of the CSCM.

By applying state-of-the-art methodology and by building on the accumulated experience of evidence-based decisionmaking in pain relief, this Task Order will not only support the production of guidelines by the CSCM and other interested organizations, but could also provide valuable information to support the decisions of clinicians, policy makers, researchers, advocates, consumers, journal editors, and any other group of individuals interested in the management of pain after TSCI.

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