This study aimed to assess efficacy and usability of Cannabidiol (CBD) infused tampons for the relief of primary dysmenorrhea, a condition affecting 50–95% assigned female at birth. While primary dysmenorrhea affects a significant percentage of females, there remains a notable absence of specialized medications or devices to alleviate the intense pain that hinders daily activities. We have developed a CBD-infused tampon, lubricated for comfort and ease, recognising the potential benefits of cannabinoids in pain management.
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Materials and methods
A randomized, single-blinded, placebo-controlled, non-interventional study was conducted with 63 participants, screened against an inclusion and exclusion criteria, following a review of their medical history, gynecological examination, and confirmation of the absence of pregnancy and sexually transmitted infections (STIs). Out of 114 screened individuals, 83 were eligible. Participants self-reported their pain levels and satisfaction with the CBD tampon using a modified Mankoski scale (1–10) for pain assessment.
Results
63 participants completed the study, following through three consecutive menstruations. The CBD-infused tampon achieved statistically significant pain reduction during the first and third months of the study (p < 0.05). Less than 5% of participants experienced CBD-infused tampon-related irritation. Between 37 and 40% of the participants reported improvement in the level of vaginal dryness.
Conclusion
This study supports the efficacy and usability of the CBD-infused tampon. The findings indicate the potential of CBD-infused tampons as a promising option for managing menstrual pain. Further research and exploration of this innovative product can contribute to the management of primary dysmenorrhea.
Keywords
Primary dysmenorrhea
CBD-infused tampon
Pain-relief
1. Introduction
Dysmenorrhea stands as a commonly occurring gynecological ailment in adolescent females, with its prevalence varying globally, spanning from 50% to 95% [1]. The primary therapeutic intervention for primary dysmenorrhea presently involves the use of anti-inflammatory agents [2]. These medications, however, are often administered at higher dosages in females compared to males to achieve optimal efficacy, particularly in cases of severe or disabling primary dysmenorrhea [3]. The frequent use of high doses of anti-inflammatory drugs can result in notable adverse effects, including gastric irritation and primary dysregulation of gut microbiota [4].
Historically, cannabinoids have been used by women to alleviate menstrual pain [6]. The endocannabinoid system (ECS), which plays a significant role in neuropathic pain and the reproductive system, offers a potential mechanism for the therapeutic effects of cannabinoids [7,8]. Within the ECS, the two main endocannabinoid receptors, CB1 and CB2, can interact with phytocannabinoids extracted from hemp to alleviate inflammation [9]. Research has shown that CB1 and CB2 receptors are widely distributed throughout the uterine tissue, making it an ideal target for localized deposition of cannabinoids to alleviate pain [10]. The study conducted by Russo et al. highlights the potential of this approach in effectively relieving primary dysmenorrhea without the usual systemic effects associated with conventional treatments [4].
The evolution of menstrual hygiene products, from ancient makeshift solutions to today's commercial offerings, reveals a history marked by limited innovation. While pivotal developments like the introduction of tampons in an advert in 1933 signified a milestone, the fundamental designs of these products have seen minimal alteration [13]. While adjustments in size, comfort, and additional features have been made, they have failed to adequately address concerns of user comfort and negative effects such as vaginal dryness and epithelial disruption [5]. Materials and designs of tampons have previously demonstrated a role in reducing the drying effects to the vaginal epithelium [11].
An innovative concept of a CBD-infused tampon believed to have fewer side effects than anti-inflammatories, while producing a similar pain-relieving effect in patients with primary dysmenorrhea was recently introduced to the market. A rigorous biocompatibility assessment, in line with the U.S. FDA's requirements (ISO 10993), has been conducted to confirm the tampon's safety. This evaluation involved examining various parameters, including vaginal irritation, sensitisation, systemic toxicity, material-mediated pyrogenicity, and potential toxic shock syndrome risk. All tests were passed, confirming the safety profile of the CBD-infused tampons.
This study aims to investigate the efficacy and usability of a CBD-infused tampon as an alternative method for relieving primary dysmenorrhea.
2. Materials and methods
2.1. Study design
For this randomized, single-blinded, placebo-controlled, non-interventional study, 114 female subjects were enrolled between the ages of 18 and 45 years old at the Institute for Medical Research, Sofia, Bulgaria. Subjects were screened against the inclusion and exclusion criteria in Supplementary Table S1, following a review of their medical history and gynecological examination to confirm the absence of pregnancy and STIs. The total duration of the study was 3 months. The study scheme and inclusion/exclusion criteria are presented in Fig. 1 and Table S1.
Fig. 1. Study time and events scheme. FC, follow-up call; ICF, informed consent form; M, menstruation; STI, sexually transmitted infection; V, visit.
All study procedures were explained to participants and written informed consent was obtained. All study protocols and documents were reviewed and approved by the institutional review boards at the Diagnostic and Consultative Center “Ascendent” Ltd., Sofia, Bulgaria with a reference number 5/28.03.2019.
2.2. Method
2.2.1. Efficacy measurements
Data were collected via self-reporting in participant diaries. Participants were asked to rate their pain levels. Pain was measured using a modified Mankoski scale (10-point scale, 1 lowest to 10 highest intensities of pain; Supplementary material Box 1). Entries were completed 3 times per day of tampon usage, through 3 consecutive menstrual cycles.
2.2.2. Usability measurements
Data were collected via self-reporting in participant diaries (Table S2). The diary consisted of 10 questions assessing self-reported vaginal dryness, irritation related to use of tampon, comfort when using the tampon, satisfaction, and overall well-being. The questionnaire used is available upon request.
2.2.3. Adverse effects notifications
Any adverse events were reported directly to the PI.
2.2.4. Statistical analysis
All statistical analyses were performed in R 4.0 (2020), STATA 14.2 and Microsoft Excel (2019). Statistical significance was identified when P < 0.05. In addition, confidence intervals were calculated (95% CI = mean difference ± 1.96 X standard error). Standard error (SE) was calculated using pooled standard deviation (SD). The mean pain difference was calculated as basal pain minus post-tampon application pain. Change in pain was expressed as the difference of two measurements as percent of basal pain. Additionally, positive differences were labeled as “improved”, negative ones as “worsened”, and zero differences as “no change”. Basal is the pain sensitivity the patient experiences prior to using the CBD-tampon or placebo (measured at first occurrence of pain each day using the modified Mankoski scale). The change in pain was calculated by taking the mean pain difference as a percentage of basal pain. The mean percent change in pain (2 h after tampon application) was compared using a t-test.
Additionally, factorial ANOVA model was built with post-hoc tests for variables with statistically significant effect. The оutcome variable was percent change (%change), and the independent variables were study group, day, and month, with the last two as interaction terms (study group#day, study group#month).
Since effects were statistically significant only for ‘day’ and the interaction term ‘study group# day’, data was also explored in a two-way ANOVA model with the three months combined. Once more, the effects of ‘day’ and the interaction term were statistically significant. Post-hoc (Tukey) tests indicated the location of these differences (see Tables S3 and S4, column 'Pain change').
All completed visits were used (rows with missing data were eliminated). Participant status 'improved' was included only. Entries with baseline pain equal to 0 and no change were eliminated.
2.3. Ethics approval and consent to participate
This study was conducted in compliance with ethical guidelines and principles established by the Bulgarian Health Law. The research protocol was reviewed and approved by Ascendent Medical Center before data collection commenced. All necessary measures were taken to ensure the protection of the rights, dignity, and well-being of the participants involved.
Prior to participation, informed consent was obtained from all individuals included in this study. Participants were provided with a detailed explanation of the study objectives, procedures, potential risks and benefits, and their right to withdraw from the study at any point without consequences. Furthermore, they were assured of the confidentiality and anonymity of their personal information.
To protect the privacy and confidentiality of the participants, all data collected during this study was coded and stored securely. Any identifying information was removed or anonymized to maintain the privacy of the participants. Only authorized researchers had access to the data, and the information obtained was solely used for the purposes of this study
3. Results
This efficacy and usability study was designed to determine whether use of a CBD-infused tampon can alleviate menstrual cycle pain, or primary dysmenorrhea, by comparing data with use of a placebo regular tampon. Of the 114 subjects screened, 83 were eligible and 63 completed the study. Results are presented in Fig. 2, Fig. 3 and Table 1, Table 2, and Tables S3–7.
Fig. 2. Clinical Trial: Average change in pain as % of basal pain 2 h after tampon application,
by month and day (all completed visits are included).
Fig. 3. Flow chart representing the recruitment and randomisation of participants.
Table 1. Pain experienced 2 h after tampon application, analyzed through mean difference comparison using a t-test. The data is presented by month and day, encompassing all completed visits* and assessed with the Modified Mankoski Pain Scale.
Day | CBD tampons (mean) | placebo (mean) | t | p (two way) | p (one way >0) | CBD tampons (n) | placebo (n) |
Month 1 | |||||||
1 | 2.08 | 2.05 | 0.05 | 0.96 | 0.48 | 31 | 29 |
2 | 2.13 | 1.80 | 0.66 | 0.51 | 0.26 | 31 | 32 |
3 | 1.54 | 1.54 | 0.00 | 0.99 | 0.49 | 26 | 27 |
4 | 1.43 | 1.17 | 0.46 | 0.65 | 0.33 | 14 | 18 |
5 | 1.2 | 0.64 | 1.02 | 0.32 | 0.16 | 10 | 11 |
6 | 1 | 1.5 | −0.41 | 0.70 | 0.65 | 3 | 4 |
7 | 2 | −0.5 | – | – | – | 1 | 2 |
Month 2 | |||||||
1 | 2.54 | 1.84 | 1.62 | 0.11 | 0.06 | 29 | 31 |
2 | 2.26 | 1.47 | 1.62 | 0.11 | 0.06 | 29 | 29 |
3 | 2.39 | 1.56 | 1.59 | 0.12 | 0.06 | 23 | 25 |
4 | 1.47 | 1.47 | 0 | 1 | 0.5 | 15 | 15 |
5 | 1.46 | 1.11 | 0.49 | 0.63 | 0.31 | 12 | 9 |
6 | 2 | 1 | – | – | – | 2 | 2 |
7 | 2 | – | – | – | – | – | – |
Month 3 | |||||||
1 | 2.80 | 1.90 | 1.49 | 0.14 | 0.07 | 28 | 29 |
2 | 1.8 | 1.30 | 1.10 | 0.28 | 0.14 | 30 | 26 |
3 | 1.44 | 1.29 | 0.33 | 0.74 | 0.37 | 25 | 21 |
4 | 1.27 | 1.06 | 0.32 | 0.76 | 0.38 | 15 | 16 |
5 | 1.22 | 0.86 | 0.44 | 0.67 | 0.33 | 9 | 7 |
6 | 1 | 2 | −0.67 | 0.54 | 0.73 | – | – |
7 | 2 | – | – | – | – | – | – |
CBD, cannabidiol.
*
Including all completed visits and "improved" status only.
Table 2. Comparison of the change in experienced pain as a percentage of basal pain 2 h after tampon application* using a t-test.
Empty Cell | N | Mean | SE | SD | 95% CI | Empty Cell | t test | p (2-way) | p (1-way>0) |
Month 1 Day 2 | |||||||||
CBD tampon | 20 | 68.74 | 6.60 | 29.53 | 54.92 | 82.56 | |||
Placebo | 26 | 51.35 | 5.42 | 27.64 | 40.18 | 62.52 | |||
diff | 17.38 | 8.47 | 0.32 | 34.45 | 2.05 | 0.05a | 0.02 | ||
Month 3 Day 1 | |||||||||
CBD tampon | 22 | 67.29 | 5.48 | 25.72 | 55.89 | 78.70 | |||
Placebo | 22 | 49.27 | 5.99 | 28.09 | 36.82 | 61.73 | |||
diff | 18.01 | 8.12 | 1.63 | 34.40 | 2.22 | 0.03a | 0.02 | ||
Month 3 Day 2 | |||||||||
CBD tampon | 20 | 70.83 | 5.51 | 24.66 | 59.30 | 82.38 | |||
Placebo | 18 | 47.26 | 6.51 | 27.60 | 33.54 | 60.99 | |||
diff | 23.57 | 8.48 | 6.38 | 40.77 | 2.78 | 0.01a | 0.00 |
CBD, cannabidiol; SE, Standard Error; SD, Standard Deviation; 95% CI, confidence interval.
*Including all completed visits and "improved" status only.
3.1. Efficacy analysis
A comparative t-test was performed on the mean differences in pain (observed 2 h post tampon application) between both study groups. The CBD-infused tampons demonstrated a statistically significant reduction in pain on the day 2 of month 1, and on the days 1 and 2 of month 3, as outlined in Table 2. Furthermore, a consistent exponential escalation in pain relief was observed over the duration of each menstrual cycle, reaching its peak of 100% on the seventh day. This pattern of pain alleviation was observed in both the CBD-infused tampon and placebo groups across all three menstrual cycles (as illustrated in Fig. 2).
Additional data checks were performed to assess the validity of the main ANOVA assumptions:
1
2
3
The above assumptions were not fully met by non transformed data.
Factorial two-way ANOVA model (pooled monthly data) was built to evaluate the effect of ‘study group’ and ‘day’ on the percent change in pain score (outcome variable). Post-hoc tests (Bonferroni; Tukey) were performed for variables with statistically significant effect on the outcome variable (Tables S3 and S6).
A statistically significant effect of 'day' on the outcome variable was demonstrated by the pooled data analysis (Table 2) as well as for each month. Nevertheless, the post-hoc test (Bonferroni) supported the above only for the following pairs: month 1 - Period day 1 vs. Period day 4 (p < 0.1), Period day 1 vs. Period day 5 (p < 0.05); month 2 - Period day 1 vs. Period day 4 (p < 0.05), Period day 1 vs Period day 5 (p < 0.05), Period day 2 vs Period day 5 (p < 0.05) (see Table S3).
Although the effect of the study group was not demonstrated in this model (rather as part of the interaction term ‘study group# day’, p < 0.009), post-hoc tests (Bonferroni) on monthly data suggested that the mean change in pain score was different between the study groups (month 1 and 3) and showed that pain relief was greater among the CBD group (with 9.55, p < 0.048 and 12.59, p < 0.012 percentage points respectively). For the pooled data, the paired variables’ (‘day’ and ‘study group’) effect was statistically significant for several combinations, although mostly when comparing the two groups on different days (except for day 2, p < 0.018) (Table S4).
Since differences in daily baseline pain between groups were not statistically significant, and ‘month’ did not have effect neither as a single independent variable nor as an interaction pair, mean percent change was compared between groups for each separate day using pooled data. The results suggested that the mean percent change in pain score was different between groups in day 1 (p < 0.0024) and 2 (p < 0.0003) of the menstrual cycle, and the CBD tampon seemed to provide greater pain relief than the regular one (Table S7).
3.2. Usability and comfort evaluation
Analysis of the qualitative data collected from participant diaries disclosed the following observations. Less than 5% reported any irritation associated with the CBD-infused tampon. In contrast, between 37% and 40% of the participants identified noticeable improvements in vaginal dryness. A significant portion of participants, ranging from 37% to 70%, experienced improvements in mood or overall well-being. In terms of overall comfort, more than 80% of participants classified the product as satisfactory or enjoyable.
3.3. Adverse events
A comprehensive assessment of the participant diaries, which were utilized to track any adverse effects and overall user comfort, revealed that adverse events were reported by three participants who completed the study. Specifically, in the CBD-infused tampon group, one participant experienced vertigo on the initial day of each menstrual cycle post tampon usage, and another reported vertigo during the first menstrual cycle along with discomfort and itching unrelated to the CBD-infused tampons. The events elapsed rapidly without need for medical attention after removal of the CBD-tampon. Additionally in the placebo group, one participant reported experiencing pain after the first day of usage during the third menstrual cycle.
4. Discussion
In our study, we investigated the potential of localized deposition of cannabinoids for alleviating pain associated with primary dysmenorrhea. The wide distribution of CB1 and CB2 receptors in uterine tissue provided a rationale for targeting this region [10]. While our investigation did not directly explore the interaction between phytocannabinoids and endocannabinoid receptors within the ECS, our findings corroborate previous research by Russo et al., suggesting that a targeted approach may effectively relieve primary dysmenorrhea symptoms without causing typical systemic effects observed with conventional treatments [6].
This study examined vaginal delivery of CBD infused into a tampon as an alternative method of pain relief and suggested an efficacy profile of a CBD-infused tampon. As seen in Fig. 2, the change in pain as a percentage of basal pain increases and reaches 100% in the final days of menstruation. This can be explained by natural alleviation of primary dysmenorrhea throughout the 7 days [12].
The data used to produce Fig. 2 includes percentage change in pain score 2 h after tampon application compared to baseline pain (measured at first occurrence of pain each day using a modified Mankoski scale). The purpose of this graph was to demonstrate the magnitude of improvement in those participants whose score 2 h after tampon application was greater than 0.
Although the use of parametric tests for analysis of ordinal data (Mankoski scale could be considered as such) is a topic of discussion, some authors advise on the use of parametric tests when the number of ordinal categories is large than four" [15].
As demonstrated in Table 1, there was no significant difference observed, nevertheless, the CBD-infused tampon group had a visible advantage over the placebo group. It is crucial to note the variability in these values, attributable to the individualized nature of basal pain amongst participants. In contrast, the t-test comparison of the percentage change in pain, recorded 2 h post tampon application (Table 2), offered a more nuanced insight into pain dynamics. Here, we observed a statistically significant reduction in pain on the second day of the first month, and the first and second days of the third month, attributable to the CBD-infused tampon. Given that the onset of menstruation typically accompanies the most severe cases of primary dysmenorrhea, it is reasonable to anticipate a more prominent divergence during this period [14]. Factorial two-way ANOVA model was built with post-hoc tests for variables with statistically significant effect on the outcome variable, demonstrating that pain relief was greater in days 2–7 compared with day 1 (Table S3) and that pain relief was greater among the CBD group (Table S7). However, to thoroughly explore the differences in pain scores it could also be appropriate to look at the results taking into account the decreasing pain intensity from day 1 till day 7, in the background of equal daily baseline pain for both groups.
Potential limitations of this study include a small sample size and the absence of study replication. Furthermore, the research design could benefit from enhancements, such as capturing pain data both prior to and following the application of the CBD-infused tampon. We can improve the study design by introducing a cross-over design.
Future clinical research recommendations would include understanding the effectiveness of using CBD tampons against menstrual pain. To further investigate the effects of CBD on pain, a metabolomics study to evaluate pain serum biomarkers or to assess the levels of CBD and painkillers in blood samples would be recommended.
In conclusion, these findings highlight the potential of the CBD-infused tampon as a viable intervention for primary dysmenorrhea, strengthening the case for continued exploration of the interrelationship between cannabinoids and menstrual pain.
Author contributions (CRediT roles)
Valentina Milanova - Conceptualization; Data curation; Formal analysis; Funding acquisition; Project administration; Roles/Writing - original draft; Writing – review & editing.
Kalina Mihaylova - Conceptualization; Data curation; Formal analysis; Methodology; Project administration; Roles/Writing – original draft; Writing – review & editing.
Iva Lazarova - Formal analysis; Methodology; Validation; Visualization; Roles/Writing – original draft; Writing – review & editing.
Teodora Georgieva - Roles/Writing – original draft; Writing – review & editing.
Harold Baxter - Conceptualization; Data curation Resources; Project administration Roles/Writing – original draft.
Dafina Dobreva - Software; Formal analysis.
Consent for publication
Annes Daye LTD consents to the publication of the study “Efficacy and Usability of a Cannabidiol-Infused Tampon for the Relief of Primary Dysmenorrhea”.
Funding
Anne's Day Ltd. This research did not receive any other specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interests
Valentina Milanova reports a relationship with Anne’s Day Ltd. that includes: employment and equity or stocks. Kalina Mihaylova reports a relationship with Anne’s Day Ltd. that includes: employment. Iva Lazarova reports a relationship with Anne’s Day Ltd. that includes: employment. Teodora Georgieva reports a relationship with Anne’s Day Ltd. that includes: employment. Harold Baxter reports a relationship with Anne’s Day Ltd. that includes: employment. Dafina Dobreva reports a relationship with Anne’s Day Ltd. that includes: non-financial support. Valentina Milanova has patent issued to Anne’s Day Ltd. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Availability of data and materials
The data that supports the findings of this study are available in Appendix A and upon request.
Acknowledgements
We extend our heartfelt gratitude to everyone who contributed to the successful completion and realization of this study, “Efficacy and Usability of a Cannabidiol-Infused Tampon for the Relief of Primary Dysmenorrhea".
Special thanks to Dr. Dimitar Georgiev, without whose expertise and supervision we wouldn’t have been able to complete this study.
Finally, our thanks also extend to all the volunteer participants who contributed to this study.
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