This is a randomized controlled trial employing a 2x3 repeated measure design with two groups and three assessment periods (pre-intervention, 1 month and 3 months follow up) conducted in the pain clinic of the Department of Anaesthesia and Intensive care of a tertiary care Institute. The study period was from 15th May2020 -15th August 2020.
Ethics approval and trial registration
The study was approved by the Institute Ethics Committee and collaborative Yoga University (SVYASA). The study was registered with the Clinical Trial Registry of India dated 30/04/2020 with CTRI registration number as: CTRI/2020/04/024951 http://ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=42947&EncHid=84466.70773&modid=1&compid=19%27,%2742947det%27) and has adopted the CONSORT standard guidelines for clinical trial reporting.
All consecutive patients with CLBP attending the pain clinic were screened for the inclusion criteria. Inclusion criteria were patients with lumbosacral CLBP of more than 3 months duration not responding to conservative management with a verbal numerical rating scale of ≥ 5 at the time of enrolment. The eligible adult CLBP patients were shortlisted at the pain clinic outpatient department (OPD). Based on the initial evaluation of physician for symptoms and radio-diagnostic methods, the selected patients were further approached by the researcher confirming on their diagnosis and pain status. The patients were given a detailed explanation regarding the study (potential risks/benefits, voluntary participation, procedures, etc.) and were provided with adequate time to reflect on the information. The enrolled patients were called in 4 batches, taking care of all the social distancing measures and COVID appropriate behavior.
The assessment of patients was based on comprehensive clinical evaluation and assessing their symptoms, the degree of functional limitation, and psychological wellbeing. Radio-diagnostic methods involved MRI scans of the lumbosacral spine.
During the pre-treatment assessment, written informed consent was obtained from the patients. An initial pain history interview was conducted along with the administration of the baseline questionnaires.
The patients were randomly divided into the two groups. Control group received the usual care of treatment as per institutional protocol. The yoga group received IAYT as an adjunct to usual care.
The study used a block randomization design. A random allocation sequence was generated by the statistician. For each participant, an opaque envelope was opened, in consecutive order, by an external research assistant not involved in the inclusion process. The participants did not know the content of the different intervention arms. The yoga leader was not blinded. However, the research group assessing the study's outcome was blinded during the data collection and data analysis.
After randomization, the participants received information about the offered intervention from a research assistant not involved in the offered interventions. Yoga, strength training, and evidence-based advice were all presented as well-established interventions, to equalize the participants' expectations.
Participants then completed the 3-months treatment program that they were allotted into, while both the groups continued with their routine medical care. These patients were allowed to interact and communicate with the physician, the study investigator, and the therapist via telecommunication method whenever the need arise. Follow-up assessments were conducted in-person in four batches at one month and three months intervals post-treatment.
The chosen IAYT protocol was designed for CLBP patients based on extensive research and contribution towards the promotion of health and efficiently treating pathologies for more than 30 years now. The protocol was planned with the inputs from the previous studies, yoga experts, expert medical professionals, physiotherapists and was further streamlined with the help of literature review, Yoga investigators, physiotherapists, and expert medical professionals.
IAYT is a treatment protocol with a combination of modern scientific approaches blended with ancient wisdom, based on the basic principle of Panchkoshas, that is, five layers of existence to human beings. These practices were aimed at body level (Annamaya Kosa) include loosening stretches, asanas (postures); at subtle energy level (Pranamaya Kosa) including pranamaya (breathing practices), and the mind level (Manomaya Kosa) including meditation and relaxation techniques.
The series of 60 minutes IAYT classes using all of the components of yoga (body, subtle energy, and mind level), was conducted for 2 weeks (6 sessions/week, 12 sessions total). The sessions were designed for participants to gradually progress from simple poses to more challenging poses adjusting to the patient's development. No props were used. Before the session, the participants were advised to keep their bowel and bladder empty. During the practice, care was taken regarding individual body limitations, and was advised not to strain too much to attain the correct posture with advice to suggest that.
It was followed by yoga practice at home and follow-ups at the set intervals for a total span of three months. Home practice for at least 45 mins was strongly encouraged throughout the intervention period after sessions ended. We provided the participants with a four-page all-inclusive colored IAYT pamphlet with pictorial presentations depicting practices as well as the audio recordings of the complete protocol to be used at home.
Patients in the control group were provided with usual care as per institutional protocol involving education about disease process and role of self-care, ergonomic and posture advice, advice to stay physically active, lifestyle modification, provision of a back care booklet (developed and validated at the part taking site) , medications as per the decision of treating physician, etc. They adhered to the treatment protocol for the same duration, under the guidance of a pain physician and physiotherapist.
Adherence to the yoga protocol was defined as attending at least 9 of the 12 yoga classes. For the usual care group, adherence was defined as reading at least three-fourths of the book by self-report.
The participants were assessed to adherence to home sessions by keeping a logbook of record the time spent on practicing and surprise video callings. A WhatsApp group was created for encouragement and motivation at regular intervals.
Clinical Assessment and Follow up
Baseline assessments included pain intensity using Verbal Numerical rating scale (VNRS)functional ability using Modified Oswestry Disability Questionnaire (MODQ),types of pain using Douleur neuropathic- 4 questionnaire (DN4)and Pain Disability Questionnaire (PDQ),pain catastrophizing using pain catastrophizing scale (PCS), Quality of life using EuroQol (EQ-5D- 5L)  5patients mental and emotional state using Hospital Anxiety and Depression Scale (HADS)  and fear of movement related to CLBP using Tampa Scale of Kinesiophobia (TSK) .Patients were followed up at 1 and 3 months and the abovementioned assessment were recorded. Medications prescribed by pain physician for CLBP were also assessed at all the three-time points. These drug therapies were reported as 'mono therapy' for 1 medication and 'dual therapy' for 2 medications. Further; medicine dosages were also evaluated to assess the changes in the overall dosage requirement. The patients rated their change on this 7-point scale that ranged from "very much improved" to "very much worse," with "no change" as the mid-point. [28, 29] The investigators recording data at baseline and follow-up were blinded to the treatment group.
Data collection on any unfavorable outcomes or serious health events was also collected.
We measured ß-Endorphin and TNF-α from the blood samples; and CGRP from the saliva of the CLBP patients to study the mechanistic role of yoga at baseline, one month and three months. ß-Endorphin is involved in pain management and is a chief natural suppressor of hyperexcitability.[30, 31]TNF- α is an inflammatory marker that can interact with other neurotrophic factors and modify pain sensation.32 CGRP is involved in the transmission of pain and pain perception.[33, 34]
5ml of blood was collected early morning (empty stomach) at baseline, 1 and 3 months. The samples were collected in a serum separator vacutainers kept at room temperature for half an hour followed by centrifugation at 2500 rpm for 30 minutes. The serum was then separated, aliquoted, coded and subsequently stored at -80°C until use.
For the saliva collection, the participants were instructed to rinse their mouth with distilled deionized water to remove debris and moisture, before the collection. Post 10 minutes of rest, the salivary collection process was commenced. During the collection, the participants were asked to keep their eyes open during salivation and not to speak or mentally stimulate salivary flow. The participants were instructed to sit upright and with their head slightly titled forward, non-stimulated whole saliva pooling at the floor of the mouth was gathered in a collection tube.
The expression level of ß-Endorphin, and TNF-α in the serum and CGRP in the saliva was analyzed using commercially available ELISA kits (Qayee Bio, China). The OD was observed at 450nm on the ELISA reader.
SAMPLE SIZE AND STATISTICAL ANALYSIS
In the absence of available published data comparing IAYT with usual care in Indian CLBP patients for management as well as assessing the mechanistic molecular role of IAYT, we performed this pilot feasibility study. We performed post hoc power analysis to calculate the power of study. We conducted both intentions to treat (ITT) and per-protocol analysis with ITT being primary. Data of all patients having one follow-up at one month was included with the last observation carried forward imputation for missing data.
Descriptive statistics including means, medians, and standard deviations for continuous variables, and the number and proportions for categorical variables are reported. Data are presented as mean±SD and median (IQR) and were analyzed for normality using Kolmogorov-Smirnov Z test. Between-group (Yoga Group vs Control Group) comparisons of normally distributed variables were performed using an independent t-test; while the Wilcoxon-Mann-Whitney test was used for non-normally distributed variables. Categorical data were analyzed by χ2 test or Fischer exact test where appropriate. Generalized estimating equations (GEE) was used for the analysis of repeatedly measured data at a various time interval (NRS, MODI, DN4, PDQ, PCS, EuroQOL, HADS, and TSK) using linear regression to estimate mean change from baseline. GEE was used to include all available data, and account for intra-subject correlations on repeated measurements, and explore the overall average effect. For GEE, all observed data was used without imputation for missing values. The analysis was considered to be unbiased under a missing at-random (MAR) assumption. To account for correlation among repeated measures for the same individual, an unstructured covariance for the initial model was assumed. A simpler model was used for the covariance if appropriate. Results are presented as between-group differences in adjusted mean with 95% confidence intervals (CI) of the differences and effect sizes (ES) (adjusted mean difference/pooled baseline SD). The analysis was carried at a 5% level of significance level (α = 0.05). SPSS software version 22 (Chicago, Illinois: SPSS Inc.) was used for data analysis.