Repeated measures ANOVA indicated no significant between-group differences or time by treatment interaction in performance of any of the functional tasks at any of the data collection time points. The analysis also indicated a significant time effect on the performance of 6-MW (F = 11.39, P = .00), TCS (F = 20.99, P = .00), and Down stair (F = 6.61, P = .01), functional tasks between the pre- and postapplication time points. Post hoc analysis indicated that performance of the 6-MW, TCS, and Down stairs significantly improved as a result of applying the 3.5% menthol gel. This same post hoc analysis indicated that the placebo treatment resulted in improved performance of the Down stairs task only (see Table 3). Significant treatment effect sizes (partial eta square ηp2)58 ranged from medium (ηp2 = 0.090) on the Stair up task to large (ηp2 = 0.36) for the TCS task.
The analysis indicated no significant between-group differences or time by treatment interaction in pain while performing any of the functional tasks at any of the data collection time points. The analysis also indicated a significant time effect on the pain reported during the TUG (F = 4.90, P = .03), TCS (F = 7.41, P = .01), Up stairs (F = 16.60, P = .00), and the Down stairs (F = 4.99, P = .03) functional tasks. The post hoc analysis found that the menthol condition resulted in significant decline in pain (see Table 4) during the performance of the TUG, TCS, Up stairs, and Down stairs functional tasks. The placebo condition did not result in any changes in pain while performing any functional tasks. The effect sizes on pain while performing these functional tasks as a result of applying the menthol ranged from moderate (ηp2 = 0.12) for the TUG and the Down stairs task to large (ηp2 = 0.30) for the Up stairs functional task.
These findings do not support the study hypotheses that a 3.5% menthol gel applied to an osteoarthritic knee joint will result in improved performance of functional tasks or pain while performing functional tasks compared to the application of a placebo control. The significant improvements in functioning and pain as a result of the menthol treatment appear to indicate further discussion. The application of 3.5% menthol to the affected osteoarthritic knee joint resulted in improved performance of 3 of 5 functional tasks, whereas the placebo improved the performance of only 1 of the 5 functional tasks assessed. As well, the application of 3.5% menthol resulted in significantly less pain while performing 4 of the 5 functional tasks, whereas the placebo condition did not significantly change the subject's pain while performing any of the functional tasks. These promising findings must be tempered by the result that performance of functional tasks and pain was not significantly different following application of the menthol or the placebo conditions. These promising findings may be attributable to a number of factors. By selecting a sample who was functioning at a relatively high level, the effect of the intervention may not of had the potential to substantially improve their functioning or decrease their pain. That is a ceiling effect may have confounded the findings. Another explanation may be that the intervention was not able to produce results beyond the placebo effect of the control condition. Hróbjartsson and Gøtzsche59 in their Cochrane Review reported in their study of more than 200 trials that placebo interventions were not found to have important clinical effects in general but may influence patient-reported pain, although it was “difficult to distinguish patient-reported effects of placebo from response bias.” These authors reported the pooled relative effect for a placebo to be 0.93 (effect of only 7%) but significant. The findings of this study seem to be consistent with what these authors would anticipate to be the effect the placebo effect on patient reports of pain (mean change in pain with the placebo = 12.8%). The observed difference in pain resulting from the menthol treatment observed in this trial appears clinically meaningful (mean change in pain with the menthol = 33.8%) and is perhaps attributable to the menthol intervention.
Although statistically significant the improvement in functioning observed in this study as a result of the menthol intervention may not meet the threshold for clinical significance. Previous authors have established a threshold for clinically significant difference of the 6-MWT to be 25–54 meters60,61 The statistically significant improvement in the 6-MWT as a result of the menthol did not appear to reach this threshold. Although there is no similar threshold established for TCS and the Down stairs tasks, the clinical importance of 7.42% and 8.66% improvements in these tasks, respectively, as a result of the menthol is debatable. Another possible explanation for the significant improvement in the 6-MWT and the TCS test under the menthol condition was that the subjects could easily gauge their performance on these functional tasks (distance walked and repetitions performed) whereas the other functional tasks were timed, and their performance was not disclosed to them by the research staff conducting the assessments. Since the menthol gel has a distinct odor and produces a cooling or “tingling” sensation when applied topically, it was likely that the subjects were aware of which condition contained the menthol content. With this knowledge, subjects may have attempted to increase their performance on the 6-MWT and TCS following application of the menthol treatment. Future researchers conducting similar studies may wish to assess the effect of topical menthol in such a way that the subjects cannot detect the content of the menthol in the gel.
The declines in pain during the functional tasks appear to be clinically significant ranging from 27% to 37% decline in pain following the application of the menthol treatment. These observed decreases in pain with the application of the menthol are consistent with the findings of previous investigators who have reported that afferent thermosensitive neurons are stimulated by menthol,7,12–16 which in turn inhibit or block the nociceptive afferent neurons, which conduct pain impulses.19 This proposed analgesic mechanism of menthol is validated by the results of this study and is consistent with the findings of Gaudioso et al.62 who reported that low concentrations of menthol cause analgesia in mice, blocking pain voltage-gated Na1 channels in dorsal root ganglion. These authors concluded that menthol is a state-selective blocker of Na1 of nociceptive afferent neurons channels and may have utility as a topical analgesic compound. Thus, the analgesic effects of menthol observed in this study are consistent with the biochemical mechanism of action observed in previous studies and support anecdotal reports that the topical application of menthol produces an analgesic effect.
The results of this study must be interpreted cautiously for a number of reasons. First, neither the researcher nor the subjects were blinded to the treatment conditions or the purposes of the study. This lack of blinding may have resulted in an expectation bias or the Hawthorne effect from both the subject and the researcher collecting the data. Second, the sample was consuming daily dosages of pain-relieving medications, which may have contaminated the findings. The research team considered purposely evoking pain within the sample by asking the subjects not to take their pain medication on the data collection days to be unethical. To minimize the effect of subjects taking their pain medication, they were instructed to take their scheduled pain medications at the same time of day on the days when data were collected and data were collected at the same time of day from each individual subject. This approach maintained the consistency of any effect of the subject's consumption of pain medication on the outcome variables over the data collection points. Furthermore, the results of the WOMAC pain subscale and the functional tasks indicated that the subjects were in mild pain over the previous week with high levels of functional ability similar to previously studied groups of patients with knee OA. These finding may indicate a ceiling effect that any treatment may not be able to reduce the subject's pain or improve their functioning because they were experiencing only mild levels of pain in the previous week and were functioning at a high level. It is interesting to observe that the topical menthol condition resulted in significant reductions in pain in addition to the subject's scheduled pain medications. This additive analgesic effect of topical menthol with the subject's scheduled pain medications supports the validity of the “complimentary” effect of topical menthol to relieve pain. This observation suggests that the analgesic mechanism of action is different between menthol and oral pain medications subjects in this study were consuming and indicates further study in the area. These results provide only the immediate effects of the intervention and clinical applicability to situations where an immediate pain-relieving response is indicated. This immediate analgesic effect may be desirable prior to pain-evoking treatments including maintaining flexibility or strength of the affected knee joint.
The final limitation of the study was that the repeated-measures nature of the design may have resulted in a familiarization effect with the data collection protocol. Subjects may have performed differently on the functional tasks and had different pain during their second visit to the laboratory based upon becoming familiar with the data collection protocol during their first visit to the laboratory. The impact of this familiarization effect was minimized by randomly assigning the ordering of the menthol and placebo conditions during the first visit to the laboratory and evaluating subjects while they performed familiar functional tasks. The repeated measures design was also selected to minimize wide anticipated differences between knee OA patients on their functional ability and pain previously reported in the literature.63 If the small sample in this study were randomized to receive either only a treatment or a control condition, the wide variability in functioning and pain exhibited by knee OA patients may have diluted the statistical power of the findings. Future randomized clinical trials may wish to directly compare the effects of the topical menthol and a placebo control among large randomly assigned groups of knee OA patients to minimize the effect of variability.
The results of this preliminary study may indicate the efficacy of topical menthol to improve the functioning and decrease the pain among knee OA patients. These findings are consistent with previous investigators who have proposed a biochemical mechanism of action for topical menthol as an analgesic. This consistent evidence regarding the effectiveness of topical menthol to relieve pain provides the clinician with another approach to treating pain among knee OA patients. Standard treatment of knee OA pain includes nonsteroidal anti-inflammatory drugs, which are accompanied by significant gastrointestinal, renal, and neurological side effects.6 Using topical menthol to compliment standard pharmacological treatment of knee OA may contribute to enhance pain relief and improve functional ability particularly during pain-evoking activities. Further study is needed to determine how long the pain-impacting effect of the menthol lasts and to provide more insights into the extent to which its effectiveness represents more than a placebo effect.
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functioning; menthol; osteoarthritis; pain