The 1995 study by Felsby and colleagues examined the effects of N-methyl-D-aspartate (NMDA) receptor blockade on spontaneous pain and the area of tactile allodynia in patients with peripheral neuropathic disorders. Two distinct mechanisms of NMDA receptor blockade were investigated: 1) a physiological blockade using Mg2+ to block the ion channel coupled to the NMDA receptor, and 2) a blockade of the phencyclidine site via a subanesthetic dose of the non-competitive NMDA receptor antagonist, ketamine.

The key findings were that ketamine produced a significant reduction in spontaneous pain (57%) and the area of allodynia (33%) compared to placebo, while magnesium chloride failed to show a significant reduction in pain (29%) and allodynia (18%). Importantly, there was a significant correlation between the reduction in spontaneous pain and the reduction in the area of tactile allodynia following ketamine administration, suggesting that these two phenomena are interrelated and mediated by the same NMDA receptor-mediated mechanism.

This comprehensive dataset from the Felsby et al. study was carefully extracted and analyzed, allowing for its inclusion in the current systematic review and meta-analysis on the efficacy of magnesium sulfate in the management of neuropathic pain. The detailed analysis presented in this R Markdown provides valuable insights into the underlying mechanisms of neuropathic pain and the potential role of NMDA receptor modulation as a therapeutic target.

Felsby S, Nielsen J, Arendt-Nielsen L, Jensen TS. NMDA receptor blockade in chronic neuropathic pain: a comparison between ketamine and magnesium chloride. Pain. 1995;64(2):283-291. doi:10.1016/0304-3959(95)00113-1

Baseline pain

The baseline pain scores for the 10 patients were reported in Table 1 of the original publication (1). To standardize these values to a 0-100 scale, as is common for visual analog pain scales (2), the raw scores were divided by 10. This transformation allows for easier interpretation and comparison of the pain scores, as the resulting values would range from 0 to 10, with 0 representing no pain and 10 representing the worst imaginable pain.

The individual baseline pain scores were extracted from the data presented in Figure 1 and stored in the variable “dolorbasal”. The mean baseline pain score was then calculated by taking the mean of these values and dividing by 10 to obtain the standardized mean baseline pain score of 4.66. Similarly, the standard deviation of the baseline pain scores was calculated and divided by 10 to get the standardized baseline pain score standard deviation of 1.53.

Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken). 2011;63 Suppl 11:S240-S252. doi:10.1002/acr.20543

Data Extraction using WebPlotDigitizer

The data points representing the mean and the upper and lower bounds of the standard deviation intervals for the visual analog pain scale scores in the ketamine, magnesium sulfate, and placebo groups were extracted from Figure 3 of the Felsby et al. study using the WebPlotDigitizer tool (1).

WebPlotDigitizer is a widely used and validated software application that allows for the accurate extraction of data from published figures and plots (2). This method of data extraction is particularly useful when the original study does not report the numeric values in the text, as was the case for the detailed pain score results presented in the graphical format of Figure 3 in the Felsby et al. publication.

To calculate the standard deviation from the extracted mean values and the reported 95% confidence intervals, the difference between the upper and lower bounds of the interval was divided by 4. This is because the 95% confidence interval represents approximately 2 standard deviations above and 2 standard deviations below the mean (3). Therefore, the absolute difference between the interval bounds corresponds to 4 standard deviations, and dividing this difference by 4 provides the estimated standard deviation.

The extracted mean values and standard deviation ranges for the reduction in pain scores and allodynia area following the interventions were then used as the input data for the meta-analysis conducted in the current review. This approach of digitizing figure data and calculating standard deviations from confidence intervals has been employed in previous systematic reviews and meta-analyses when the original study authors did not provide the complete numeric results (4,5). By utilizing the detailed information captured through WebPlotDigitizer, the current meta-analysis was able to incorporate the comprehensive dataset from the Felsby et al. study, enhancing the robustness and reliability of the pooled estimates.

References:

  1. Rohatgi A. WebPlotDigitizer: Web based tool to extract data from plots, images, and maps. Version 4.5. 2023. https://automeris.io/WebPlotDigitizer. Accessed [date accessed].

  2. Drevon D, Fursa SR, Malcolm AL. Intercoder reliability and validity of WebPlotDigitizer in extracting graphed data. Behav Modif. 2017;41(2):323-339. doi:10.1177/0145445516673998

  3. Altman DG, Bland JM. Confidence intervals illuminate absence of evidence. BMJ. 2004;329(7464):384-385. doi:10.1136/bmj.329.7464.384

  4. Xu J, Hu J, Cao Y, et al. Efficacy and safety of intravenous lidocaine for postoperative pain management: A systematic review and meta-analysis. Medicine (Baltimore). 2020;99(1):e18583. doi:10.1097/MD.0000000000018583

  5. Jiang L, Li L, Shen V, Wang Q, Xiong X. Efficacy of intravenous lidocaine on pain relief in patients undergoing laparoscopic cholecystectomy: A meta-analysis from randomized controlled trials. Int J Surg. 2015;16(Pt A):68-74. doi:10.1016/j.ijsu.2015.02.012

#deviation of the Ketamine group

ketamine_mean <- 3.769230769230771
ketamine_lower <- 1.3076923076923084 
ketamine_upper <- 6.256410256410257

# Calculate the standard deviation: a range of 4 is used as this represents a 95% confidence interval (+2 and -2 standard deviations)

ketamine_sd <- (ketamine_upper - ketamine_lower) / 4
print(ketamine_sd)
## [1] 1.237179
ketamine <- data.frame(Ketamine = c("mean", "standard_deviation"),
                       value = c(ketamine_mean, ketamine_sd))
knitr::include_graphics("ketamina.png")

# Calculation for the mean and standard deviation of the Magnesium Sulfate group  
magnesium_mean <- 3.7247380928473417
magnesium_lower <- 1.1274224319710804
magnesium_upper <- 6.218261538976469

# Calculate the standard deviation: a range of 4 is used as this represents a 95% confidence interval (+2 and -2 standard deviations)
magnesium_sd <- (magnesium_upper - magnesium_lower) / 4
knitr::include_graphics("magnesium.png")

summary(cars)
##      speed           dist       
##  Min.   : 4.0   Min.   :  2.00  
##  1st Qu.:12.0   1st Qu.: 26.00  
##  Median :15.0   Median : 36.00  
##  Mean   :15.4   Mean   : 42.98  
##  3rd Qu.:19.0   3rd Qu.: 56.00  
##  Max.   :25.0   Max.   :120.00
# Calculation for the mean and standard deviation of the Placebo group
placebo_mean <- 4.400073926145726
placebo_lower <- 1.9900199703268662
placebo_upper <- 6.785023794978155

# Calculate the standard deviation
placebo_sd <- (placebo_upper - placebo_lower) / 4
print(placebo_sd)
## [1] 1.198751
placebo <- data.frame(Placebo = c("mean", "standard_deviation"),
                      value = c(placebo_mean, placebo_sd))
knitr::include_graphics("placebo.png")

Results

The data points from the figures in the Felsby et al. study were carefully extracted using the WebPlotDigitizer tool. This allowed for the precise capture of the mean values and confidence interval ranges presented in the original publication’s graphical displays. By digitizing the figure data, the key information could be incorporated into the current analysis, ensuring a comprehensive and transparent representation of the study findings.

##           treatment     mean standard_deviation
## 1          Baseline 4.660000           1.531303
## 2          Ketamine 3.769231           1.237179
## 3 Magnesium Sulfate 3.724738           1.272710
## 4           Placebo 4.400074           1.198751

Note that the echo = FALSE parameter was added to the code chunk to prevent printing of the R code that generated the plot.