Efficacy of Majoon Chobchini versus Majoon Ushba with Roghane Surkh in Post Chikungunya Arthritis - A Randomized Single Blind Comparative Clinical Trial

Introduction

Post Chikungunya Arthritis (PCA) is a sequel of Chikungunya fever caused by RNA virus. It has been identified as a widespread viral infection, and many patients report persistent but self-limiting tendinitis, arthritis and arthralgia as their primary symptoms. Cases of chronic inflammation mimic rheumatoid arthritis. Numerous people around the world have been impacted by the moderate to severe arthropathy caused by Chikungunya.¹

Although there is no definitive cure, the condition is currently managed using non-steroidal, anti-inflammatory medicines (NSAIDs), corticosteroids, hydroxychloroquine, sulfasalazine, methotrexate, and biologic therapies, either alone or in combination.^1,2 These drugs cause gastro intestinal disturbances, allergies and nephropathy, etc.³

The symptoms of Chikungunya resemble those of Hummae Khilti. As per the doctrine of Unani system of medicine, fever either resolves on its own or progresses to a state of crisis (Buhran). In most cases, the fever resolves naturally; however, certain fevers may take form of a crisis (Buhran-Inteqali). The symptoms of Buhrane Inteqali manifest in the form of epistaxis, or local irritation, painful joints, Isterkha, Tashannuj, etc.⁴ Waja ul Mafsil is one of the characteristics of Buhran Inteqali in certain fevers (Hummae Khilti).⁴ Painful conditions of joints are described as Waja ul Mafasil in Unani medicine, and based on the involvement of the joint, they are termed differently. Regardless of the cause of painful joints, they have been treated with several single agents like Suranjaan, Asgand, Kundur, Muqil, Boazidaan, etc and compound formulations such as Majoon Suranjan, Majoon Jograj Gugal, Majoon Ushba, Habbe Muquil, Habbe Suranjan, Safoof-e Chobchini, Safoofe Surnjaan, Habe Mufasil, Majoon Gheeghawar, Jawarishe Hindi, Habe Sibr, Majoone Azraqi, etc.^{3,5-11,12,13,14} In this study, Majoone Chobchini was selected based on its ingredients and indications. It was hypothesized that this formulation is effective in alleviating pain in joints, and also aids in eliminating blood impurities.

In Unani medicine, several drugs are indicated for painful joints, particularly when accompanied with infection. Among these, Majoon Chobchini, Majoon Ushba are commonly administered orally, while Roghane Surkh is frequently recommended for local application.

It is hypothesized that these formulations may be beneficial in managing post Chikungunya arthritis, associated with joint pain, swelling, and soreness, based on the properties of their individual constituents. In light of the current therapy options, this clinical trial entitled "Efficacy of Majoon Chobchini versus Majoon Ushba with Roghane Surkh in Post Chikungunya Arthritis-A Randomised Single Blind Comparative Clinical Trial" was planned to compare the efficacy of Majoon Chobchini and Majoon Ushba with Roghane Surkh.

Materials and Methods

This trial was approved by the Institutional Ethical Committee for Biomedical Research vide IEC number NIUM/IEC/2019-20/006/IMR/01, dated 03/06/2020 and CTRI vide No CTRI/2021/11/037727, conducted between November 2021 and July 2023.

Study participants

Patients of both genders, aged between 18-50 years, with P/H/O Chikungunya fever about three months back, with Disease Activity Score (DAS 28) >3.2 and Clinical Disease Activity Index (CDAI) > 10 were included in the study. Participants were excluded from the study if they were below 18 years or above 50 years of age; had a DAS 28 <3.2 and/or CDAI <10; had arthritis not related to Chikungunya fever; were diagnosed with autoimmune diseases or systemic illnesses such as hypertension, diabetes mellitus, malignancy, liver or kidney dysfunction; had received systemic or intra-articular corticosteroids, hydroxychloroquine, sulfasalazine, methotrexate, NSAIDs or any form of complementary and alternative medicine (CAM) therapy within two weeks prior to enrolment; or were pregnant and lactating.

Study design

Parallel arm, single-blind, randomized, comparative clinical trial.

Sample size

The sample size was estimated using the formula,¹⁵ N= r+1 (Zα/2 + Z1-β)²σ²/ rd², as 82 patients. Considering 20% dropout rate, the total sample size was estimated as 99 patients, with 50 allocated to the test group and 49 to the control group.

Randomization

The randomization list was generated using computerized software, and a total of 99 patients were enrolled in the study.

Interventions

Interventions for both the groups were purchased from Hamdard laboratory (GMP certified). Patients in Group A received Majoon Chobchini 7 g twice a day with water, one hour after meals, with local application of 5-10 mL of Roghane Surkh over the affected area twice a day. Group B patients received Majoon Ushba 7 g twice a day with water, one hour after meals, with local application of 5-10 mL of Roghane Surkh over the affected area twice a day.

Assessment of study outcomes

The efficacy outcomes of the study were assessed on the objective parameters like, DAS 28 (Disease Activity Score), CDAI (Clinical Disease Activity Index), Indian HAQ (Health Assessment Questionnaire) and C-reactive protein (CRP) levels.^18,19,20 Safety assessment was carried out based on clinical symptoms and reporting of side effects, if any, along with haematological and biochemical laboratory investigations viz. haemogram, liver function tests (LFT)- SGOT, SGPT, Kidney function tests (KFT)- blood urea, serum creatinine.

Study procedure

Patients fulfilling the inclusion criteria were enrolled after obtaining written informed consent. They were randomly allocated into two groups viz. Group A (n=50) and Group B (n=49). Patients in Group A were given Majoon Chobchini (oral) + Roghane Surkh (local), while the patients in Group B were given Majoon Ushba (oral) + Roghane Surkh (local) in the dosage form as mentioned previously, for a duration of four weeks. Tablet Paracetamol 650 mg was allowed to use as a rescue medication. Follow-up assessments for efficacy were conducted on 7th, 14th, 21st and 28th days of the study. The investigations were done before and after the completion of trial. The pre and post treatment objective f indings (effects) were assessed statistically. Patients who failed to follow the protocol therapy, who used more than two doses of rescue medication per week, and the cases in which adverse drug reactions were noticed, were withdrawn from the study.

Statistical analysis

Efficacy analysis was performed on intention-to treat (ITT) principles using the last observation carry forward method (LOCF), on participants who received interventions and completed two follow-up visits after the baseline visit. The study data were analyzed statistically with appropriate tests. Changes in various parameters were assessed for statistical evaluation by using Fisher’s exact test (on categorical scale, non-parametric setting for qualitative data analysis) while, Student ‘t’ test (on continuous scale) was used for both intergroup and intragroup analysis at every follow-up visit. Leven’s test was performed to assess the homogeneity of variance. Results on continuous measurements were presented on Mean±SD (Min-Max) and results on categorical measurements were presented in Number (%). P value of less than 0.05 was considered statistically significant.

Results

Demographic Characteristics The demographic characteristics of the study patients were analyzed using Chi square test and Fisher Exact test between both groups and data were found statistically not significant (P >0.05) both before and after the study.

Effect of Intervention on DAS 28 (Disease Activity Score)

The mean DAS 28 score for Group A improved significantly from baseline to 4th follow-up visit, with mean values of 4.86±0.86 and 3.44±0.94, respectively (P <0.001). Similarly, significant improvement was observed in Group B with a mean value of 5.21±2.52 at baseline and 3.40±0.83 at 4th follow-up visit (P <0.001). However, no significant difference was found between the two groups, implying that they were both equally effective (P =0.716).

Effect of Intervention on HAQ (Health Assessment Questionnaire)

It was observed that mean HAQ score decreased significantly from 1.61±0.47 at baseline to 0.53±0.48 at 4th follow-up in Group A, while a significant reduction was also found in Group B with a mean value 1.93±2.68 at baseline and 0.563±0.56 at 4th follow-up (P <0.001). The two groups did not differ substantially in intragroup analysis (P =0.899)

Effect of Intervention on CDAI SCORE (Clinical Disease Activity Index Score)

Significant improvement in CDAI score was observed in both Group A and Group B (P <0.001). The mean score in Group A reduced from 23.48±5.12 at baseline to 13.18±5.26 at 4th follow-up and in Group B, mean score reduced from 22.64±5.98 to 13.04±5.59 at baseline and 4th follow-up, respectively. Improvement in CDAI score was similar in both the groups with a P value of 0.570.

Effect of Intervention on C-Reactive protein (CRP)

The mean±SD of CRP in Group A was 8.46±4.77 at baseline, which significantly improved to 5.95±2.013 after treatment with Majoon Chobchini (P <0.001). Even in Group B, it decreased significantly from baseline 10.44±7.25 to 6.13±3.53, following therapy with Majoon Ushba (P <0.001).

There was no significant difference between the values of safety parameters before and after the treatment, except for hemoglobin percentage and Erythrocyte sedimentation rate (ESR). Significant improvement in Hb% in Group A was observed with a mean value of 12.16±1.68 at baseline to 12.40±1.52 after treatment (P =0.006). Similarly, at baseline, the mean ± SD of ESR in Group A was 26.4±16.9, which significantly improved to 19.94±13.56 (P <0.001) after the study completion.

Discussion

The results of our study demonstrated that Majoon Chobchini effectively improved the objective parameters viz. DAS 28 score, HAQ score, CDAI score and CRP value (P <0.001) in both the groups, but there was no difference among the groups pertaining to the improvement of any of the parameters. Samarpita et al., observed similar anti-arthritic activity of Majoon Chobchini in their study with reduced paw swelling, restored body weight, and analgesic activity in rats. They also discovered that Majoon Chobchini suppressed the production of pro-inflammatory cytokines (TNF-, IL 6, IL-1, and IL-17), slowing the onset and progression of arthritis.²¹ Nadeem Md. et al., also observed highly significant improvement in DAS 28 score in comparison with placebo and attributed it to the analgesic (Musakkine A’lam), anti-inflammatory (Muhallil) effect of Majoon Chobchini as mentioned in Unani literature.¹⁵

HAQ score also showed a highly significant reduction in each group of the study. Nadeem Md et al., also observed similar findings in relation to HAQ score.¹⁵ Samarpita et al., in their study noted that oral treatment of Majoon Chobchini reversed cartilage degradation and prevented bone erosion and joint deformity. Moreover, it reduced osteoclast formation significantly.²¹

Improvement in CDAI score also corresponds with the f indings of Samarpita et al., where the authors observed improvement in inflammation and also reported analgesic effect of Majoon Chobchini.²¹

The improvement in CRP was comparable in both the groups, indicating equal effectiveness in both the groups. Nadeem et al., also observed significant reduction in levels of CRP and ESR following therapy with Majoon Chobchini.¹⁵ The findings of Group A also corroborate with the observations of Samarpita et al., where oral administration of Majoon Chobchini significantly reduced pro-inflammatory markers, ROS and reversed the increased expression of iNOS and COX-2, contributing to its anti-inflammatory properties.²¹

No significant change in the safety parameters suggests that the test drug is neither hepatotoxic nor nephrotoxic; rather it exhibits heptatonic action as noted in this trial where it was observed to increase hemoglobin concentration. Moreover, the anti-inflammatory effect of the test drug was further supported by a reduction in ESR levels. Thus, it can be concluded that Majoon Chobchini is safe for therapeutic use in patients with post Chikungunya arthralgia.

The strength of our study lies in its potential to offer therapeutic alternatives that may reduce the patients’ dependence on analgesic medications. While this study provides valuable insights into the efficacy of Majoon Chobchini versus Majoon Ushba with Roghane Surkh in post Chikungunya arthralgia, it is important to acknowledge certain limitations that may affect the interpretation of the results and the generalizability of the findings. Due to the shortage of funds, viral markers for Chikungunya could not be assessed and also post treatment follow-up was not conducted to determine the residual effect of the drug. The study focused on post Chikungunya arthritis, and the findings may not be applicable to other forms of arthritis with different etiologies. Moreover, the study primarily evaluated clinical outcomes and did not delve into the underlying mechanisms of action of Majoon Chobchini, Majoon Ushba and Roghane Surkh. Further research is needed to elucidate the mechanisms by which these interventions may exert their effects.

Further large-scale, multi-centric studies can be conducted to evaluate the management of post Chikungunya arthralgia using Unani and other alternative medicines, with viral markers included as assessment parameters.

Conclusion

The results of this study provide compelling evidence of the efficacy and safety of Majoon Chobchini as a therapeutic intervention for patients suffering from post Chikungunya arthralgia. Our findings revealed significant improvements in key objective parameters, including DAS 28 score, HAQ score, CDAI score, and CRP values, in both the treatment groups. These improvements suggest that Majoon Chobchini effectively alleviates the clinical manifestations of the condition, including pain, functional impairment, and inflammation.

In conclusion, the study results provide strong evidence that Majoon Chobchini is a safe and effective therapeutic option for patients with post Chikungunya arthralgia. These findings have significant implications in clinical practice, offering a potential remedy for the debilitating symptoms associated with this condition. Further research and clinical trials are warranted to validate and build upon these promising findings, with the ultimate goal of improving outcomes for patients suffering from post Chikungunya arthralgia.

Conflict of interest

The authors declare that there are no conflicts of interest associated with this research study. All aspects of this study, including its design, execution, analysis, and reporting, have been conducted with the highest standards of objectivity, integrity, and transparency. No competing financial interests or personal relationships have influenced the conduct or outcomes of this research.

Acknowledgement

The authors would like to acknowledge the Grant in Aid Advanced Research Project of RGUHS for their f inancial support under the Collaborative Research Project for the Year 2020-21. Their invaluable funding played a crucial role in facilitating the execution of this research and in advancing our understanding of the subject matter. Furthermore, the authors would also like to acknowledge the institutions and organizations that provided access to research facilities, equipment, and resources essential for conducting the investigations and analyses presented in this study.