To assess the quality of information in each study, we developed a 15-point scoring technique modeled on the Downs and Black checklist for assessing methodological quality of nonrandomized studies (Appendix 1, available online as supplemental digital content at http://links.lww.com/PAIN/A506).24 Specifically, we assessed the clarity of the surgery performed, the precision of the outcomes reported, whether information on potential confounders was reported, whether complications of bad outcomes were reported, and quality of bias analysis. Recognizing the limitations of quality scoring to account for bias among studies,35,40,43 detailed data were collected on study characteristics thought most likely to bias study results, namely objectivity of the outcome reported, follow-up duration, the proportion of patients lost to follow up, and known confounders for successful relief of pain when available. Using this scale, a higher number equates with higher quality of information presented.
2.4. Statistical analysis
Raw categorical data from relevant studies were used to calculate proportions with 95% confidence intervals (CIs) of patients who experienced a meaningful reduction of pain. Individual proportions were combined by means of DerSimonian-Laird random-effects models, given the variety of surgical techniques, geographic locations, and patient populations among studies.21,65 A continuity correction of 0.1 was used for studies with a proportion of 0 or 1. Cochran Q and Higgins I 2 tests were used to assess heterogeneity among studies. Given the modest statistical power of these tests, we considered heterogeneity as significant if P < 0.1 or I 2 > 30%.
We explored sources of heterogeneity with stratified analysis of group differences when significant heterogeneity was noted among studies for a confounder and when more than 15 studies reported the confounder of interest. Stratified analyses examining surgical group differences were performed for confounding variables. For studies with multiple surgical groups, confounding information for each surgical group was used when available. Otherwise, mean or median data from each study as a whole was applied to each group to allow categorization. Analysis of variance was performed using a Bonferroni correction to compare multiple groups.
Meta-regression was also used to explore sources of heterogeneity. After calculating the log odds ratio of patients with meaningful reduction of pain and standard error of the log odds ratio, a forward, step-wise meta-regression was performed with potential confounding variables as covariates. Confounders were considered significant in the model if they altered the β-coefficient for surgery type by more than 10%.58 We assessed publication bias graphically using Hunter's method for creating funnel plots and formally tested funnel asymmetry using Peters' test.42,71 All statistical analyses were performed using StataIC 13 (StataCorp, College Station, TX) and the METAPROP, METAREG, and METAFUNNEL software packages.
Our electronic literature search and review of bibliographies identified 1328 studies. After abstract review excluding duplications and studies not relevant to the subject of interest, 85 full-text studies were reviewed. After exclusion of studies not meeting the inclusion criteria, 54 studies reporting 74 treatment groups and results for 1381 patients were included in the final analysis (Fig. 1).
The reviewed studies were conducted over a period of more than 30 years (1976-2015), in 16 countries, reflecting a variety of medical practices and reporting techniques. Among the 54 included studies, 4 studies (7%) were conducted prospectively. Thirty-nine (72%) studies reported outcomes for a single surgical technique, 11 (20%) reported outcomes for 2 techniques, 3 (6%) presented 3 techniques, and 1 (2%) reported 4 techniques. In general, each technique correlated with a treatment group; however, 6 studies described multiple techniques that were categorized into the same treatment group. Excision and transposition was the most commonly reported technique for treating neuroma, with 34 studies (63%) including this group. Nineteen studies (35%) included an excision-only group, 11 studies (20%) included a neurolysis and coverage group, 10 studies (19%) included an excise and repair group, and 4 studies (7%) included an excise and cap group (Table 1).
Thirty-five studies (65%) reported treatment of neuromas in the upper extremity, 12 (22%) reported on lower extremity neuromas, and 6 (11%) reported on neuromas in both upper and lower extremities. One study (2%) did not specify neuroma location but did include intraoperative photographs of the upper extremities. Thirty-six studies (67%) reported results after treatment of cutaneous sensory nerve neuromas, 11 studies (20%) reported results after treatment of major nerve (e.g., ulnar, median, sciatic) neuromas, and 5 studies (9%) reported results for both. Two studies (4%) did not specify if major or cutaneous nerve were treated.
In the included studies, the mean age of patients was 41.6 ± 7.1 years. The median follow-up was 24 months (interquartile range [IQR]: 17-31), and the median duration of symptoms prior to surgery reported was 21 months (IQR: 10-41). The median percentage of patients who had one or more prior operations for neuroma pain among studies was 29% (IQR: 0-1).
3.2. Patient identification
Forty-eight studies (89%) reported clearly how they diagnosed neuromas in their patients. In all cases, the physical examination was the primary method of neuroma identification. Twenty-nine studies (54%) supplemented this with a diagnostic nerve block. Three studies (6%) also used an MRI or ultrasound to aid in diagnosis.
3.3. Outcomes reporting
Outcomes reporting and duration of follow-up varied widely across studies. Many studies reported numerous outcomes. Thirty-eight studies (70%) used a nonstandard ordinal scale such as no pain, mild pain, moderate pain, or severe pain as their primary outcome. Only 15 studies (28%) included a 10-point VAS to report pain, and only 8 (15%) used it as a primary outcome. Four studies (8%) used patient satisfaction as a primary outcome. Four studies (8%) reported a reduction in pain on physical examination or improved functional status as the primary outcome. One study (2%) reported only that all patients had complete pain relief and were able to return to normal activities. One study (2%) determined success of treatment from decreased use of analgesic pain medication.
Forty-four studies (81%) explicitly reported partial vs complete pain relief. Five studies (9%) reported scores on the DASH scale before and after treatment. Fifteen studies (28%) reported patient satisfaction. Most studies (40 of 54 [74%]) reported only mean follow-up duration rather than the timing of outcome assessment. Three studies (6%) reported only a follow-up range, and 2 studies (4%) reported minimum follow-up only. Only one study (2%) reported the exact time of outcome assessment.
3.4. Quality of studies
Among the 54 studies included, the quality of information reported was inconsistent, limiting our ability to analyze confounding variables as sources of heterogeneity. On a scale from 0 to 15, with 0 representing no important information presented and 15 representing most important information presented, the median score was 8.0 (IQR: 6.4-10.0). Studies consistently reported their aims, hypotheses, patient identification criteria, and surgical technique. Patient selection, outcomes assessment, and complications were rarely clearly reported.
3.5. Sources of confounding bias
Based on the literature review, we considered the following confounding variables important when assessing outcomes for treatment of painful neuromas: sex, age, duration of symptoms, timing of outcome assessment, number of prior neuroma pain operations, nerve involved, employment status, workers' compensation claims or pending litigation, smoking status, body mass index, and socioeconomic status. No study reported all of these variables and no study reported why or how confounders were selected. Among studies reporting confounders, only 9 studies (17%) considered confounding in their analysis.
3.6. Meaningful reduction of pain by surgery type
Among all studies, the proportion of patients with a meaningful reduction in pain was 77% (95% CI: 73-83). When stratified by the treatment group, there were no significant differences between treatment groups in the outcome of meaningful reduction in pain (P > 0.05). However, the excision and transposition group had the highest proportion of patients with a meaningful pain reduction (81% [95% CI: 75-86]) and the most consistent results. Despite this, a large amount of heterogeneity was observed in all treatment groups, I 2 range 85.7% to 95.6% (Fig. 2).
3.7. Stratified analyses
To tease out possible guidelines for future surgical treatment of neuromas, stratified analyses examining surgical group differences were performed for confounding variables. These included age, follow-up duration, symptom duration prior to definitive neuroma surgery, proportion of patients with 1 or more prior neuroma pain surgeries, neuroma location, affected nerve caliber (major nerve vs cutaneous nerve), primary outcome, study quality, and study publication year. Study groups were categorized according to the mean symptom duration reported prior to neuroma surgery into: duration less than 12 months, duration of 12 to 23 months, duration greater than 24 months, and not reported. Among groups with mean symptoms duration greater than 24 months, excision and transposition (74% patients improved [95% CI: 0.65-0.83]) and neurolysis and coverage (91% patients improved [95% CI: 0.80-1.00]) were significantly better than excision and repair (20% patients improved [95% CI: 0.05-0.34]), P < 0.05 for both comparisons. Among groups with mean symptom duration less than 12 months, or 12 to 23 months, there were no significant differences between surgery types.
Study groups were categorized according to the proportion of patients who had one or more surgeries for neuroma pain prior to the reported surgery (0%-15%, 16%-30%, 31%-45%, 46%-60%, and greater than 60%). Among studies with greater than 60% patients with one or more prior surgeries specifically for neuroma pain, excision and transposition (78% patients improved [95% CI: 0.66-0.90]) and neurolysis and coverage (96% patients improved [95% CI: 0.90-1.00]) were significantly better than excision-only (30% patients improved [95% CI: 0.02-0.59]), P < 0.05 for both comparisons. No significant differences were seen between surgery types in groups with less than 60% patients with one or more prior operations for pain. No significant differences in the proportion of patients with a meaningful pain reduction among study groups were seen regardless of age, follow-up duration, location (upper vs lower extremity), affected nerve caliber, primary outcome used, study quality, or publication year.
3.8. Regression analysis
Meta-regression was performed to examine for confounding effects of mean age, mean follow-up duration, mean symptom duration, proportion of patients with one or more prior operations, nerve caliber, and primary outcome reported. Within the multiple regression models, the primary outcome reported, mean patient age, and proportion of patients with 1 or more prior operations altered the effect estimate of surgery type on proportion of patients with meaningful improvement after neuroma surgery by more than 10%, suggesting that these factors do confound treatment effect.
3.9. Bias analysis
Funnel plot analysis of study groups was symmetric, suggesting that there was no publication bias among studies (Appendix 2, available online as supplemental digital content at http://links.lww.com/PAIN/A506). Peters' test for publication bias confirmed these results (P = 0.24).
A wide variety of surgical techniques are described in the literature to treat painful neuroma. Thus, the goal of this meta-analysis of 54 studies reporting outcomes after surgical treatment of painful neuromas was to evaluate surgical effectiveness, establish a hierarchy of effective techniques, and delve into the impact of confounders on effective surgical treatment. When evaluating the studies that met the inclusion criteria, our data demonstrate that clinically meaningful improvement of pain can be achieved with surgical intervention. However, the most effective surgical technique was not elucidated, as we found no significant differences between the various surgical techniques. Further, the overall quality of most of the studies reviewed was low and excitement for these results must be tempered.
Despite the low quality of most of the studies, the large number of studies, surgical groups, and patients included in this meta-analysis allowed for exploration of the role of confounding variables on neuroma surgery outcomes. There was no evidence of publication bias, suggesting that the reported outcomes are reliable. Our categorization schema and subdividing patients into surgical groups by technique is a reflection of the surgical literature, descriptions, and experience. This meta-analysis cannot assess if our categorization schema by technique was meaningful and this is a limitation to the study. Subtle differences in technique are not well addressed with a meta-analysis and would require a well-designed trial to flush out. Therefore, we recommend ongoing thoughtful analysis of outcomes and technique by surgeons in conjunction with pain specialists.
Overall, our data suggest that most patients with a painful neuroma deemed appropriate surgical candidates by the surgeon will have a meaningful decrease in pain with surgical intervention and that in appropriately selected cases, the dogma that “operating for pain will only result in more pain” may not apply.12,13,67 No information is included about patients with painful neuromas that were not offered surgery. Therefore, any conclusions about the effectiveness of surgery have to be limited to patients deemed appropriate for surgical management, ie, indicated for surgery by the surgeon. We believe that patient selection and careful attention to correct diagnosis is the key to successful outcomes.
When evaluating patients with painful neuromas, it is essential to distinguish between neuropathic pain because of compression neuropathy, direct nerve injury, or both, bearing in mind the distinct possibility of an associated double-crush phenomenon.90,94 Surgical treatment will vary significantly for compression and neurotmetic injury.15,69 The distinction requires a detailed history and physical examination. Identifying the appropriate nerve(s) involved in pain generation is critical, especially considering overlap of nerve dermatomes and frequent plexus formation between cutaneous nerves.23,54,79 The importance of active patient participation in correct diagnosis cannot be overemphasized.32 Further, a multidisciplinary approach to these patients with pain is essential. We recommend the involvement of pain management specialists, physical therapists, and psychological therapists in coming to the diagnosis and decision for surgical intervention. In our experience, misdiagnosis coupled with surgery can make a patient's pain worse.
Stratified analyses revealed 2 interesting findings. The first was that excision of a neuroma and transposition of the distal nerve end into muscle, bone, or vein or neurolysis of a neuroma and coverage with healthy vascularized tissue were superior to excision-only or excision and capping in patients who had neuroma pain for more than 2 years and in patients who had more than one previous surgery specifically to deal with neuroma pain. Why these procedures are superior in these patient populations cannot be answered by this meta-analysis and deserves further study. However, these populations are believed to be the most recalcitrant to surgical treatment because of centralization of their pain.20,30 Therefore, because of their severity, these groups may allow the best evaluation of the surgical treatments.
Numerous authors have suggested that the microenvironment can affect painful neuroma formation.33,45,72,96 Placing the cut nerve end into muscle is shown to decrease neuroma size and myofibroblast infiltration, potentially decreasing pain signaling.57,95 Placing the cut nerve end deep within a muscle or under a vascularized flap also protects it from external stimuli and blocks axon regeneration to the skin.50,57 Skin may serve as both a mechanical and biological irritant, especially in an inflamed, multiply operated wound bed.61,70 Other mechanical irritants should also be carefully observed by limiting tension and motion on the cut nerve end.20 Our clinical experience with vascularized tissue coverage of a neuroma has not been positive unless the source of neuroma pain is addressed with neuroma excision or neuroma excision and repair.88
The results of this study are consistent with previously published work stating that 20% to 30% of neuromas will be refractory to treatment, regardless of the type of surgery performed.36,64 Initial results can be misleading, and reoperation rates as high as 65% have been reported in some studies.36,37,52 Unfortunately, reoperation rates can be difficult to track and were rarely reported in the included studies. Studies also suggest that neuroma location or size can affect outcomes.20,31,36 In this study, neuroma location in the lower vs upper extremity made no difference. Neuroma size was rarely reported, which precluded a meaningful interpretation of its impact.
As with all systematic reviews and meta-analyses, our ability to draw conclusions is limited by the quality of information in the primary studies included. Studies only reported a median of 8, out of 15 possible, key factors pertinent to patient outcome. All studies failed to include at least one important factor, and most studies failed to report or perform any bias analysis with their results. Although included data were sufficient to perform stratified and multivariate regression analysis, our inability to detect significant differences among treatment groups does not confirm equivalence of these techniques. Rather, this lack of difference is likely an indication of the granularity of our data and heterogeneity in outcomes and confounding variables reporting among studies.
Therefore, one of the major conclusions of this study that is we must improve the quality of data reporting in the literature to improve the acceptance and validity of surgical treatment for painful neuromas. In particular, studies need to include clear descriptions of how a neuroma is diagnosed, clear inclusion and exclusion criteria, and data about confounders such as age, ethnicity, smoking status, socioeconomic status, employment status, and litigation or workers' compensation claims. These data should include precision estimates and not just ranges. Similarly, outcomes reporting should be standardized. We suggest using a pre- and post-operative VAS in conjunction with a pain diagram and list of pain adjectives. We use a standardized pain assessment sheet at every visit (Appendix 3, available online as supplemental digital content at http://links.lww.com/PAIN/A506). It is essential that future studies collect long-term follow-up data on patients and include nonbiased reporting of reoperative rates and treatment failures.
Surgical management of painful neuromas led to clinically meaningful improvement of pain in approximately 77% of cases regardless of surgical technique used. Although no technique proved to be clearly superior, these data demonstrate that surgical intervention should be considered in the treatment algorithm for patients suffering from painful neuroma refractory to medical management. Future studies evaluating the surgical treatment of neuroma, or those comparing surgical techniques, need to be careful to define their treatment, outcomes, inclusion/exclusion criteria, and should account for confounding variables to provide meaningful data and to facilitate the evidence-based treatment of our patients with painful neuromas.
Conflict of interest statement
The authors have no conflict of interest to declare.
R. P. Parikh is supported by a NIH Ruth L. Kirschstein National Research Service Award Institutional Research Training Grant (T32CA190194, PI Colditz).
The authors thank the National Center for Advancing Translational Sciences for grant UL1 TR000448 that helped make this work possible.
Supplemental digital content
Supplemental digital content associated with this article can be found online at http://links.lww.com/PAIN/A506.
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Neuroma; Surgery; Operation; Operate; Reconstruction; Restoration; Procedure; Surgical intervention; Allodynia; Burning; Hyperalgesia; Extremity; Peripheral; Hand; Arm; Leg; Foot; Neurectomy; Transposition; Transpos*; Excision; Excis*; Pain relief; Pain management; Outcome; Analgesia; Treatment outcome; Therapy; Visual analogue scale; VAS; Faces pain scale; Pain scale; Quality of life; Health related quality of life; Dash questionnaire; Dash score; Disabilities of the arm shoulder and hand
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