Evidence Report/Technology Assessment

Number 45

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
2101 East Jefferson Street
Rockville, MD 20852

http://www.ahrq.gov/

Contract No. 290-97-0017

Prepared by:
McMaster University Evidence-based Practice Center
Alex Jadad, M.D.
Principal Investigator

Mary Ann O'Brien, MSc
Dean Wingerchuk, M.D.
Pam Angle, M.D.
Heather Biagi, BHSc
Matt Denkers, BHSc
Carmen Tamayo, M.D.
Mary Gauld, BA
Investigators

AHRQ Publication No. 01-E063

September 2001

ISBN: 1-58763-108-3
ISSN: 1530-4396

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. Endorsement by the Agency for Healthcare Research and Quality (AHRQ) or the U.S. Department of Health and Human Services (DHHS) of such derivative products may not be stated or implied.

AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps heath care decisionmakers -- patients and clinicians, health system leaders, and policymakers -- make more informed decisions and improve the quality of health care services.

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.

AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.

To evaluate (a) the measurement of central neuropathic pain (CNP) after traumatic spinal cord injury (TSCI), (b) the prevalence of acute and chronic CNP, (c) predictive factors for chronic CNP, and (d) the effectiveness and safety of various interventions for CNP.

Studies were identified by searching MEDLINE, EMBASE, and PsycINFO (to May 2000); CINAHL, HEALTHStar, and Sociological Abstracts (to November 1999); the Cochrane Library (issue 4, 1999); reference lists of eligible articles found in the searches; and personal files of advisory panel members.

Studies about the cause, management, or measurement of CNP were included. Exclusion criteria were participants without TSCI or CNP, children younger than 13 years, or inability to determine whether chronic pain was central and neuropathic.

Two reviewers independently extracted data for all studies except case reports. One reviewer extracted case report data, which was checked by another. Disagreements were resolved by consensus. The quality of data was assessed. Data were not pooled because clinical heterogeneity existed across studies, outcome measurements were inconsistent, studies had low methodological quality, and data reporting was incomplete.

132 unique studies (6 randomized controlled trials and 126 observational studies, including 47 case series and at least 56 single or multiple case reports) met the selection criteria. Few studies evaluated the management of CNP following TSCI in women; and no studies evaluated adolescents only, the role of treatment algorithms, or multidisciplinary approaches. Only two studies evaluated self-management strategies in cases of CNP following TSCI. Diagnosis, assessment and natural history: No discriminative or evaluative measurement instruments have been adequately investigated with respect to psychometric measurement properties in this setting. Pharmacological interventions: Little research has been done. The few studies available have such poor methods that it was not possible to evaluate interventions. It appears that local anesthetics, opioids, and clonidine given spinally may be effective in relieving CNP following TSCI, but better research is needed. Spinal cord and deep brain stimulation techniques: The studies had similar deficiencies to those described above. The limited evidence available suggests that spinal cord stimulation has a variable rate of early success and a low rate of long-term effectiveness. Deep brain stimulation has a low rate of early success and an even lower long-term success rate, coupled with significant adverse events. Dorsal root entry zone (DREZ) lesions and other surgical interventions: All studies on DREZ showed high rates of success but had poorly defined or no eligibility criteria, included no control groups, and did not report adequately the severity of adverse effects.

This report describes rigorous systematic reviews on the measurement and management of CNP after TSCI in adults and adolescents. The research on this topic is in its infancy. This report describes the limitations of the available evidence and provides recommendations for future research.

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.

Jadad A, O'Brien MA, Wingerchuk D, et al. Management of Chronic Central Neuropathic Pain Following Traumatic Spinal Cord Injury. Evidence Report/Technology Assessment Number 45. (Prepared by McMaster University Evidence-based Practice Center under Contract No. 290-97-0017.) AHRQ Publication No. 01-E063. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

Pain has been recognized for more than half a century as one of the many symptoms experienced by people who have suffered traumatic spinal cord injuries (TSCI). Efforts to estimate the prevalence, severity, and duration of pain after TSCI have led to variable results. This variation 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.

Great variability and little consensus have also plagued the classification of pain in people with TSCI. In 1997, however, a group of investigators developed a classification that seems to be gaining widespread acceptance. The first axis of this classification 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. Neuropathic pain is the focus of this report.

Neuropathic pain is defined as pain that occurs following damage to the central or peripheral nervous system. 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" (pain that occurs at the level of the SCI, in a segmental pattern with neuropathic features) and neuropathic pain "below level" (diffuse pain that is described by the words "burning," "tingling," "aching," "shooting," or "stabbing" and that should be present at least three segments below the level of injury). Neuropathic pain "at level" can be subdivided further into radicular (when it can be attributed to nerve root pathology) or central (when it is due to changes within the spinal cord or possible supraspinal structures), although the value of this subdivision has been questioned.

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, but it also may have even greater impact on the quality of life of patients than the extent of the injury itself. 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 Consortium for Spinal Cord Medicine (CSCM) and other interested organizations while building on existing work and focusing on answerable, clinically relevant questions.

A set of questions was initially proposed by the CSCM and further refined with input from members of the McMaster University Evidence-based Practice Center (MU-EPC) and the Task Order Officer (TOO). All questions, unless otherwise specified, relate to the assessment or management of chronic central neuropathic pain (CNP) following TSCI in adults and adolescents.

After multiple consultations, the following questions were selected as the focus of the evidence report. To maximize the efficiency of the process, they were grouped by theme.

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

The Technical Expert Panel (TEP) for this Task Order included individuals who represented professional organizations, providers of health care, purchasers of health services, researchers, and consumers. These individuals are recognized as national and international leaders in the management of pain or in issues related to spinal cord injury.

Initially, we used very liberal selection criteria. We regarded as potentially eligible any article that described a study: 1) in humans and 2) about the cause, management, or measurement of CNP in individuals after TSCI. There was no exclusion based on study design.

We excluded reports that were not primary studies and studies where the sample consisted of people without a TSCI, those without chronic neuropathic pain, or children younger than 13 years. We also excluded primary studies that did not contain data in the published report and studies in which the sample included individuals with TSCI as well as other types of CNP, but where the results were not presented separately for individuals with TSCI. In addition, we excluded studies that only used the term "chronic pain" without any other description of the pain experienced by the individuals in the study sample that could have helped us judge it as central and neuropathic.

We accepted any definition for CNP provided by the primary study authors. We developed a list of descriptions of CNP based on our preliminary searches. This list was used to guide the research team during the two-step screening process with six raters working in pairs. The first step was based upon the information available in titles and abstracts (where available) and was conducted by the same two raters working independently. The second step of the screening was based upon full text reports and involved all six raters randomly paired. Discrepancies were resolved by discussion.

Citations of potentially eligible studies were identified through a systematic search of:

• MEDLINE, EMBASE, and PsycINFO were searched from the date of their release to end of May 2000.
• CINAHL, HEALTHStar, and using Sociological Abstracts. All databases were searched from the date of their release to November 1999.
• The Cochrane Library (issue 4, 1999).
• The reference lists of any eligible article identified in any of the above sources.
• Personal files of all members of the local team and the TEP.

The development and refinement of the search strategy followed an iterative process using MEDLINE. The refined MEDLINE strategy was modified to meet the specific features of CINAHL, EMBASE and PsycINFO.

All data extraction forms were developed, pilot-tested, and revised by members of the local research team, including the team statisticians. After consultations with the TEP, our TOO, and our partners, the forms were approved for content. A general data extraction form was used with all studies, while individual forms were used for randomized controlled trials (RCTs), observational studies, and case reports. Items related to the quality of different study designs were embedded within the data extraction forms. Two reviewers completed data extraction independently for all studies except the case reports. For these studies, data were extracted by one reviewer and checked by another. Any disagreements were resolved by consensus. Following consensus on each item, the data forms were scanned into a Microsoft Access database using Teleform software.

Descriptive statistics were calculated for all fields of the database. Evidence tables were constructed to describe the most salient features of the included studies according to the review question. These tables are found at the end of each chapter along with the relevant supplementary tables.

The local research team at the MU-EPC, in consultation with members of the partner organizations and the TOO, evaluated the overall quantity and quality of the data available. This evaluation led to the conclusion that meta-analysis would be inappropriate to summarize the evidence on each of the research questions or for each of the main categories of interest. The main reasons for this decision were substantial clinical heterogeneity across the studies (e.g., interventions evaluated, patient samples, duration); inconsistency in outcome measurements; low methodological quality; and incomplete data reporting (see detailed descriptions within each category). Therefore, this report represents a systematic, qualitative review of the existing evidence, emphasizing the implications for clinical practice and the directions that future researchers could take to fill existing knowledge gaps.

For the purposes of this Evidence Report, the evidence syntheses were grouped in five chapters that included:

• The yield of the literature and the general characteristics of all the studies included;
• Studies on the diagnosis, assessment, and natural history of CNP after TSCI;
• Pharmacological interventions;
• Spinal cord and deep brain stimulation techniques; and
• DREZ lesions and other surgical interventions.

The analysis of the yield of the literature and the general characteristics of the studies showed that:

• A total of 591 full articles were retrieved and screened. After screening, 158 studies met the inclusion criteria. Of the 158 studies, 19 were reported in more than one publication. After several iterations, a total of 132 unique studies were included. These form the basis for the Evidence Report.
• Six studies were RCTs, and 126 were observational studies, including 47 case series and at least 56 single or multiple case reports.
• Overall, numerous deficiencies in the reporting of the studies limited the assessment of their validity, relevance, precision and, therefore, their clinical application. More than 50 percent of studies did not provide a definition for neuropathic pain, report the cause of the injuries, describe the use of surgical stabilization, state the onset time for pain after injury, or highlight the duration of pain. Fifty-four percent of the studies did not report the time from the injury to the inclusion in the study, the completeness of the injury, or the area of the body affected by pain.
• There was little information on the management of CNP following TSCI in women and adolescents.
• Thirty percent of studies had fewer than 25 patients. This limited their power to detect meaningful, clinically important differences among the interventions.
• There were no studies that evaluated the role of treatment algorithms or multidisciplinary approaches. Only two studies evaluated self-management strategies in cases of CNP following TSCI.
• Comparison or synthesis of data across studies was limited by the low quality of reporting and by the large number and heterogeneity of outcome measures and tests used in the studies.

The following is a description of the main conclusions and the implications from practice that could be derived from the evidence available to address the initial questions:

• Diagnosis, assessment, and natural history: There are no discriminative or evaluative measurement instruments that have been adequately investigated with respect to psychometric measurement properties in this context. Despite the serious limitations of most of the individual studies, most estimates of the prevalence of chronic pain after TSCI vary from 40 percent to 75 percent of patients. Pain is moderate to severe in 25 percent to 60 percent of these individuals, is often associated with psychological and psychiatric conditions, and is severe enough to impair or prevent optimal physical function and daily living.
• Pharmacological interventions: There is a dearth of research in this area, which includes most of the interventions that are regarded as the core for the management of other types of neuropathic pain. The few studies available have such small sample sizes, poor methodology, and incomplete reports that it was not possible to judge the value of any individual intervention or group of interventions. Although it appears that local anesthetics, opioids, and clonidine given spinally may be effective in relieving CNP following TSCI, better research is needed. While the needed evidence is gathered directly from patients with CNP after TSCI, clinicians interested in using pharmacological interventions will have to rely on research on these interventions in other patient populations.
• Spinal cord and deep brain stimulation techniques: These studies had similar deficiencies to those described above. The limited evidence available suggests that spinal cord stimulation has a variable rate of early success and a low rate of long-term effectiveness. Deep brain stimulation has a low rate of early success and an even lower long-term success rate, coupled with important adverse events. These findings make it difficult to justify the use of either procedure as a method of treating CNP after TSCI. Transcutaneous electrical nerve stimulation may reduce the sensation of "pain unpleasantness" if patients have positive expectations of treatment effectiveness.
• Dorsal root entry zone lesions and other surgical interventions: All studies on DREZ showed high rates of success, but had poorly defined (or lacked) inclusion and exclusion criteria, included no control groups, and did not report adequately the severity of the adverse effects experienced by patients. Even recognizing the problems regarding the validity and generalizability of the studies, some may look to DREZ lesioning or other spinal surgeries as a last resort when other palliative efforts have failed. Given that the studies did not adequately report the severity of the adverse effects experienced by patients, it is unknown whether DREZ lesioning and other spinal surgeries pose unwarranted risks to patients.

Research on the management of central CNP following TSCI is in its infancy. The following are some suggestions for future research:

• Multicenter collaboration to set a research agenda. The CSCM may be well-positioned to facilitate this level of collaboration, or alternative strategies may be needed to foster pragmatic working relationships, even among groups that do not have a tradition of cooperation. Such collaborative groups could study the research problems and provide training in clinical research to young investigators.
• Given the prevalence and severity of CNP following TSCI and the dearth of research to support any therapeutic strategy, it is imperative to develop effective strategies to improve the number, validity, precision, and relevance of future studies.
• Larger studies with more rigorous design, more comprehensive reports, and longer term followup are needed to establish the effectiveness and adverse effects of most of the interventions available. Special emphasis should be placed on gathering evidence on the effects of different interventions in women and adolescents.
• Research groups should make efforts to select a core set of validated and clinically relevant outcomes to be measured in all the studies, in addition to any other outcomes of interest to the specific groups of researchers.
• More rigorous studies, ideally large, double-blind, multicenter RCTs, are clearly needed to establish the relative effectiveness and safety of different pharmacological interventions. Priority should be given to interventions with established roles for the management of other types of neuropathic pain, such as tricyclic antidepressants, anticonvulsants, local anesthetics, and opioids. Studies designed to judge the added value of these interventions given in combination, through invasive routes (e.g., epidural and intrathecal infusions of opioids and local anesthetics), or using different formulations (e.g., sustained release preparations) should also be a priority.
• Since CNP is associated with psychosocial difficulties, other noninvasive approaches such as multidisciplinary or self-management approaches should be developed and evaluated for those with TSCI.
• More definitive studies are needed to determine the effectiveness and safety of non-pharmacological interventions. Based on the evidence available, the most promising interventions are spinal cord stimulation and DREZ lesions. These interventions, however, are also invasive and potentially harmful. The studies that are needed, however, will require complex, controlled designs with close attention to safety issues, substantial resources, and efficient collaboration among research groups.
• Studies are also needed to determine whether the response to treatment is influenced by the level and cause of the SCI; as well as by the duration, distribution, and characteristics of the pain; and by comorbid factors (e.g., anxiety and depressive disorders).
• There is a great opportunity for consumer groups to call for and support more research activities, given the number of important questions that remain unanswered.
• Funding and conducting the research that is required will not be easy, given the complexity of the disorder, the frequent presence of comorbidity, and the variety of interventions and outcomes available. Future research efforts will require commitment among different groups of stakeholders, some of which do not have a tradition of collaboration.

In summary, this report includes the first set of systematic reviews on the management of chronic CNP following TSCI. They incorporate state-of-the-art methodology and are ready for incorporation into evidence-based clinical practice guidelines or performance measures. The report also provides a detailed description of the many limitations of the evidence available and provides recommendations to fill existing knowledge gaps through rigorous research. Filling such gaps will not be easy and will require highly innovative efforts and collaboration among different groups of decisionmakers. If this field continues to produce few, small, incompletely reported studies with heterogeneous designs instead of the high quality collaborative efforts required, research in this area will continue to be of little value to guide important clinical and policy decisions.