Current limited evidence suggests that carbamazepine and phenytoin may be effective in the treatment of Fabry disease-related neuropathic pain. Only one author extracted the data, hence some data may have been missed. In addition, methodological quality of the included studies was not assessed or addressed in the review. Further large, high-quality, long duration studies that used robust endpoints and measured the effectiveness of different analgesic drugs in Fabry disease neuropathic pain were required.
Overall summary High risk of bias in the review
Data were extracted by only one author, hence some data may have been missed. Only search terms were provided, but the full search strategy was not reported, therefore it could not be assessed if this was appropriate. Methodological quality of the included studies was not assessed in the review.
|A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4?||Probably no|
|B. Was the relevance of identified studies to the review's research question appropriately considered?||Probably yes|
|C. Did the reviewers avoid emphasizing results on the basis of their statistical significance?||Probably yes|
|Risk of bias in the review||High|
|Number of studies||26|
|Number of participants||55|
|Last search date||September 2014|
|Objective||To give an overview of existing strategies for managing neuropathic pain in Fabry disease.|
|Population||Children as well as adults with Fabry disease and neuropathic pain.|
|Interventions||Pain medication (carbamazepine, phenytoin, gabapentin, neurotropin, pethidine, opioids etc.).
Studies on the effect of enzyme replacement therapy on pain and reviews were not included.
Analgesics (acetaminophen and non-steroidal anti-inflammatory drugs) were excluded.
|Comparator||Placebo or other interventions (ASA).|
|Outcome||Primary outcome: chronic pain reduction after any treatment period.
Secondary outcomes: reduction of the frequency of pain attacks as reported by the patient, any pain-related outcome that indicated improvement or worsening, treatment withdrawals due to lack of effect, and any (serious) adverse event while on treatment.
|Study design||Clinical trials, case series and case reports.|
Out of 16 studies reporting on 24 patients with Fabry disease and neuropathic pain undergoing treatment with carbamazepine, 5 out of 24 (20.8%) patients reported complete pain relief; 16 out of 24 (66.7%) patients reported partial pain relief; and 3 out of 24 (12.5%) patients reported no pain relief. Out of three studies reporting on four patients receiving carbamazepine, two patients reported dose-related autonomic complications (leading to dose reduction in one patient, and discontinuation in the other), and one patient discontinued due to drowsiness.
Out of seven studies reporting on 19 patients with Fabry disease and neuropathic pain undergoing treatment with phenytoin, 1 out of 19 (5.3%) patients reported complete pain relief; 12 out of 19 (63.2%) patients reported partial pain relief; and 6 out of 19 patients (31.6%) reported no pain relief. One study in eight patients also reported a reduction in the frequency of painful crises in 7 out of 8 (87.5%) patients. In one study reporting on 27 patients, one patient experienced dizziness, drowsiness and headache, and one patient discontinued due to poor compliance.
Out of two studies reporting on seven patients with Fabry disease and neuropathic pain undergoing treatment with gabapentin, 6 out of 7 (85.7%) reported partial pain relief, and 1 out of 7 (14.3%) reported no pain relief.
One study reported that two out of two (100%) patients undergoing treatment with neurotropin reported partial pain relief.
One study reported that two out of two (100%) patients undergoing treatment with pethidine reported partial pain relief.
One study reported that two out of two (100%) patients undergoing treatment with lidocaine reported partial pain relief.
The research objective was clearly stated and appropriate eligibility criteria were defined. No restrictions were imposed based on the sources of information and study characteristics.
|1.1 Did the review adhere to pre-defined objectives and eligibility criteria?||Probably yes|
|1.2 Were the eligibility criteria appropriate for the review question?||Probably yes|
|1.3 Were eligibility criteria unambiguous?||Probably yes|
|1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)?||Probably yes|
|1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)?||Probably yes|
|Concerns regarding specification of study eligibility criteria||Low|
Searches were conducted in PubMed and EMBASE databases to identify relevant literature. Reference lists of retrieved papers were checked for additional studies. ClinicalTrials.gov was also searched to identify further published and unpublished data. Search terms were provided but a full search strategy was not reported and therefore the effectiveness of the strategy could not be assessed. There were no reported date, publication format or language restrictions. It was not reported if screening was undertaken independently by more than one reviewer.
|2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports?||Probably yes|
|2.2 Were methods additional to database searching used to identify relevant reports?||Yes|
|2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible?||No information|
|2.4 Were restrictions based on date, publication format, or language appropriate?||Probably yes|
|2.5 Were efforts made to minimise error in selection of studies?||No information|
|Concerns regarding methods used to identify and/or select studies||Unclear|
Data were extracted by only one author. Sufficient characteristics were available for interpretation of the results. The study results were appropriately collected for the synthesis. Methodological quality of the included studies was not assessed in the review.
|3.1 Were efforts made to minimise error in data collection?||No|
|3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results?||Probably yes|
|3.3 Were all relevant study results collected for use in the synthesis?||Probably yes|
|3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria?||No|
|3.5 Were efforts made to minimise error in risk of bias assessment?||No|
|Concerns regarding methods used to collect data and appraise studies||High|
All studies included in the review contributed to the synthesis. It was inappropriate to pool the case reports/series and clinical trials, hence the meta-analyses were not conducted. A narrative synthesis was undertaken for the review. Methodological quality of the included studies was not considered in the synthesis.
|4.1 Did the synthesis include all studies that it should?||Yes|
|4.2 Were all pre-defined analyses reported or departures explained?||Probably yes|
|4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies?||Probably yes|
|4.4 Was between-study variation minimal or addressed in the synthesis?||Probably yes|
|4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses?||Probably yes|
|4.6 Were biases in primary studies minimal or addressed in the synthesis?||No|
|Concerns regarding synthesis and findings||High|
- Cyclohexanecarboxylic Acids
- Fabry Disease
- gamma-Aminobutyric Acid