CRPS is a neuropathic pain disorder that occurs after tissue injuries and is known to cause tissue deterioration over time. Patients may present various symptoms, including severe pain, but the disease has been difficult to identify. Management of complications and symptoms has been so diverse that many different attempts have been made, but there has never been a standard treatment. Although the mechanism of the disease is not clear, it has been mainly treated with a variety of drugs, but recently, various methods, such as rehabilitation and nerve block, have also been tried.
The present analysis of all 72 RCTs on CRPS revealed a quantitative and qualitative improvement over time. However, the degree of improvement was suboptimal, and the identified deficiencies should be addressed in future studies.
Several previous investigations have focused on the issue of RCT quality (12, 21, 22, 24, 25). They found that the number of RCTs published in journals from the 1980s to the 2000s increased over time. They also found an improvement in RCT quality over time (24). However, the authors applied the Jadad scale only and no statistical analyses of the data were done. To address these issues, previous studies showed a quantitative increase in RCTs over time (21, 22). In the present study, we saw a recent increase in the number of RCTs published from the analysis of outcomes at 5-year intervals.
To evaluate adherence to the CONSORT statement, Uetani et al.(4) identified 98 RCTs and reported that only 11 of these 98 RCTs adhered to each item of the CONSORT statement. However, since the CONSORT statement is not a quality assessment tool, no statistical analysis of each article’s quality was possible. There are many tools for quantitatively assessing the quality of RCTs such as Moher (25), Chalmers (26), Jadad (12), van Tulder (14), Cochrane (15) and others. In this study, we used three tools, which were the Jadad scale, van Tulder scale, and CCRBT, which can comprehensively analyze the various elements of the CONSORT statement.
In an analysis of the methodological quality of RCTs published in Rheumatology International from 1981 to 2012, Lee et al.(21) confirmed that there was a quantitative increase in quality. However, the authors reported that the increase in quality was suboptimal. To fulfill the criteria for a high quality RCT, Lee et al.(21) proposed that authors should improve the reporting of allocation concealment, generation of randomization sequences, design of double blinded studies, and IRB approval. In the present study, double-blinded studies accounted for 76.4% of all RCTs published between 1998 and 2017 (Table 2). As in previous studies, inadequate explanations of blinding and the absence of any references to allocation concealment were factors that caused the evaluation of an RCT to be poor quality. Hewitt et al.(27) reported that 46% of the RCTs published in 2000 in the world’s four major medical journals (The British Medical Journal, The Journal of the American Medical Association, The Lancet, and The New England Journal of Medicine) had involved inappropriate or uncertain concealment of allocation. Moreover, Schulz et al.(23) suggested that without concealment of allocation, randomization could be compromised and distorted by more than 40% in the process of performing even if the randomization procedure is appropriate. Based on the present study, appropriate blinding and allocation concealment are associated with RCT quality, therefore, if the quality of these items are improved, the RCT quality will also be improved.
As shown in previous studies, articles published after IRB review had a relatively high quality (22). IRB approval is a valuable step in terms of ensuring valid study design and performance, and the benefit of establishing a study plan for the IRB approval process is likely to be shown in the observed increase in the publishing rate of high quality articles.
Clifford et al.(28) hypothesized that RCTs supported by funding would be of higher quality than those without funding, as they would be large-scale and well-designed. However, they found no association between funding source and article quality in an analysis of 100 RCTs published in a total of five high impact, peer-reviewed general medical journals. We investigated articles related to CRPS published over the past 20 years in the pain medicine field. Contrastingly, funding sources significantly impacted RCT quality, which was evaluated with the Jadad scale in the present study (P = 0.03, Table 4). In the case of research that received financial support, it is judged that there are many high-quality articles because it is possible to do well-designed research design and large-scale research.
Recently, many editors have requested clarification on the number of sample size of the research subjects. In this study, about 37 articles (51.4%) based on the Jadad method provided the basis for the sample size of the study subjects, of which 34 studies (91.9%) showed significantly higher quality than those which did not provide sample size calculation (P < 0.01, Table 2). The value of the van Tulder scale was 7.59 ± 1.44, and 36 studies (97.3%) showed a high quality evaluation, showing a significant difference (P < 0.01, Table 2).
In recent years, there has been a debate about whether the conflict of interest should be viewed as a new bias evaluation area or not (29). However, it is necessary to examine factors that have not been agreed to yet, and that may have an effect on bias.
Future RCTs should address the complexity of CRPS, which has the characteristics of spontaneous pain, allodynia, hyperalgesia of the limbs, and abnormal findings in the autonomic and motor nervous systems. CRPS potentially affects almost all systemic organs. Risk factors include smoking, genetic factors, psychological factors, and other factors that have not been yet been detailed. In 1994, the International Association for the Study of Pain (IASP) established diagnostic criteria for CRPSs. However, even after the development of the diagnostic criteria, disagreements persisted. There are two types of CRPS. Type 1 CRPS is not associated with obvious nerve damage and most patients belong to Type 1. There is no definite cure, and several therapies have been tested.
Although several RCTs have been reported for CRPS, the number and quality of papers may be lessened due to the rarity of the CRPS disease itself and the difficulty in designing the research. No definitive pathophysiology or treatment has been established yet for the disease. Therefore, the quality of the RCTs related to CRPS should be assessed for completeness and the information of each article should be validated.
This study had some limitations. As noted in previous RCT qualitative studies, no consensus has yet been reached concerning the optimal method of quality assessment, and no highly accurate and valid tools for quality assessment have been established (30). To overcome these limitations, the present study applied three different tools: the Jadad scale, the VTS, and the CCRBT.
The extraction and quality evaluation of RCTs may be influenced by the subjective judgement of the researcher. In the present study, thus, two independent researchers were responsible for data extraction and evaluation. Moreover, the data was evaluated and adjusted by a third researcher to optimize objectivity and reliability. To our knowledge, the present study represents the first systematic evaluation of all RCTs on CRPS published to date. The results suggest strategies to improve the quality of research on CRPS.