Decreased Low Back Pain Intensity and Differential Gene Expression Following CalmareW: Results From a Double-Blinded Randomized Sham-Controlled Study Angela R. Starkweather, Patrick Coyne, Debra E. Lyon, R. K. Elswick, Jr., Kyungeh An, Jamie Sturgill Correspondence to Angela R. Starkweather E-mail: astarkweathe@vcu.edu Angela R. Starkweather Associate Professor and Chair Department of Adult Health and Nursing Systems Virginia Commonwealth University School of Nursing 1100 East Leigh Street P.O. Box 980567 Richmond, VA 23298-0567 Patrick Coyne Clinical Director of Palliative Care Virginia Commonwealth University Richmond, VA Debra E. Lyon Executive Associate Dean Thomas M. and Irene B. Kirbo Endowed Chair University of Florida Gainesville, FL , Note: Additional authors are listed on the last page. Abstract: In this double-blinded, randomized controlled trial we evaluated the effects of Calmare1, a non-invasive neurocutaneous electrical pain intervention, on lower back pain intensity as measured by the “worst” pain score and on pain interference using the Brief Pain Inventory-Short Form, on measures of pain sensitivity assessed by quantitative sensory testing, and on mRNA expression of pain sensitivity genes. Thirty participants were randomized to receive up to 10 sessions of Calmare1 treatment (n¼15) or a sham treatment (n¼15) using the same device at a non-therapeutic threshold. At 3 weeks after conclusion of treatment, compared with the sham group, the Calmare1 group reported a significant decrease in the “worst” pain and interference scores. There were also significant differences in pain sensitivity and differential mRNA expression of 17 pain genes, suggesting that Calmare1 can be effective in reducing pain intensity and interference in individuals with persistent low back pain by altering the mechanisms of enhanced pain sensitivity. Further study of long-term pain outcomes, particularly functional status, analgesic use and health care utilization, is warranted. 2015 Wiley Periodicals, Inc. Keywords: low back pain; chronic pain; Calmare1; scrambler; gene expression Research in Nursing & Health, 2015, 38, 29–38 Accepted 24 October 2014 DOI: 10.1002/nur.21632 Published online in Wiley Online Library (wileyonlinelibrary.com).
Results The demographic characteristics of the participants in each group did not differ significantly, as shown in Table 1. Most participants were working part- or full-time, had a collegelevel education, and reported LBP duration between 6 and 12 months. In both groups, 80% of participants reported using non-steroidal anti-inflammatory drugs (NSAIDs) intermittently for pain (<4 times per week), and 20% reported using NSAIDs more regularly (>4 times per week). At the 1- and 3-week follow-up visits, there was a statistically significant difference in the “worst” pain score between the Calmare1 and sham groups (Table 2). Similarly, pain interference was significantly different between groups at the 3-week follow-up visit, with significantly lower pain interference in the Calmare1 group. The “worst” pain and interference scores of the BPI showed a significant decrease in the Calmare1 group from baseline to the 3-week follow-up visit, whereas the scores of the shamtreatment group did not change over time. In the Calmare1 group, seven (47%) participants had a >50% reduction in the “worst” pain score from baseline to the 3-week followup visit, five (33%) participants had a 30–49% reduction, and three (20%) had a 20–29% reduction. Measures of pain sensitivity (heat pain threshold, single stimulus rating, and pressure pain threshold) were significantly different between groups at the 3-week follow-up visit (Table 3). The higher-level thresholds to heat pain and pressure pain in the Calmare1 group at 3 weeks reflected the higher-stimulus intensity required to cause a perception of pain. Consistent with less pain sensitivity, they also rated their perception of pain with the single heat stimulus aslower. Although the Calmare1 group showed less pain sensitivity compared to the sham group at the 3-week followup visit, the within-group changes in pain sensitivity measures in the Calmare1 group from baseline to 3 weeks did not reach a level of statistical significance. Differential expression of 10 candidate genes between the Calmare1 and sham groups was observed between baselineand 3 weeks post-intervention, while baseline mRNA levels of the 84 candidate genes did not differ. Using a p-value threshold of <.01, the fold regulation of the following genes was significantly different between the Calmare1 and sham group: BDKRB1, CACNA1B, CHRNA4, GDNF, GRM1, NGF, NTRK1, OPRD1, PENK, and PLA2G1B. Table 4 shows the differential fold regulation in the Calmare1 group at 3 weeks post-intervention. In exploration of the success of blinding of participants to treatment assignment, both Calmare1 and sham groups reported a significant reduction in pain in withingroup analyses during the 10-day intervention period, as measured by a numerical rating scale administered by the IDTA before each treatment session, consistent with shortterm placebo analgesic effects of the sham control. We also asked whether participants believed they had received Calmare1 therapy (and not the sham treatment) after the three-week follow-up appointment. Participants were asked to respond using one of three categories: “definitely not,” “unsure,” or “definitely.” In the sham treatment group, 66%The primary aim of this study was to compare the intensity and pain interference of LBP over time, measured by the BPISF, between participant groups randomized to Calmare1 or sham. The Calmare1 group reported significantly lower pain intensity, as measured by the “worst” pain score, at the 1- and 3-week follow-up visits, and lower pain interference at the 3-week follow-up. The finding of decreased pain intensity after Calmare1 is consistent with previous investigations in participants with other types of chronic pain, although different pain indicators, such as pain “now” or “average,” were used in those studies (Coyne et al., 2013; Ricci et al., 2011; Smith et al., 2010; Smith & Marineo, 2013). The presence of short-term placebo analgesic effects in response to the sham control supports the use of the sham protocol. Placebo analgesic responses are modulated through expectations regarding pain treatment and are regulated through responses to noxious stimuli in the spinal cord and brain as well as activation of descending pain inhibitory pathways (Benedetti, 2009). While it may be assumed that these effects also contributed to the change in pain scores of participants who received the Calmare1 intervention, the effects of the neurocutaneous electrical stimulation appeared more gradually. In particular, although the Calmare1 group did not have a statistically significant decrease in the “worst” pain score from baseline to 1 week post-intervention, the reduction was significant at 3 weeks post-intervention. Given that the “worst” pain score reflects temporal pain variability, or the “memory” of pain, these findings suggest the Calmare1 intervention may influence peripheral and central pain processing.
There are currently 3 studies that are double-blind studies that are completed and waiting for results to be published.
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