Description

Background and Rationale Chronic non-specific low back pain (CNSLBP) is among the most prevalent and disabling musculoskeletal conditions in the world, with approximately 60-80% of individuals developing it at some point during their lifetime. Unlike specific etiologies for back pain, e.g., fracture, infection, or radiculopathy, CNSLBP has no explicitly diagnosable pathological or structural cause. Yet, it often leads to chronic pain, functional disability, and reduced quality of life. The economic burden of CNSLBP extends beyond the patient, with high socioeconomic costs in healthcare consumption, lost productivity, and disability-related absenteeism. Despite extensive use of conventional treatments, e.g., pharmacologic treatments, physiotherapy, and interventions, most patients are only temporarily or partially relieved, indicating an urgent requirement for an improved long-term management regimen.

Traditional Western medical interventions have a proclivity to address inflammatory or structural causes, and conventional pharmacotherapy generally provides transient symptom relief of limited duration. NSAIDs, muscle relaxants, and opioids can abate acute symptoms but are side-affected and of little long-term efficacy. Similarly, interventional therapies, i.e., epidural steroid injection or radiofrequency ablation, may be targeted at specific anatomical structures but do not address the multifactorial causation of CNSLBP and resultant recurrence or chronicity of pain. Complementary treatments, e.g., exercise, cognitive behavior therapy, and acupuncture, are inconsistently effective, and integration into mainstream clinical practice is frequently disrupted by complexity, cost, or the need for special training.

Prolotherapy, or proliferative therapy, is a new regenerative therapy for chronic musculoskeletal pain. Hypertonic dextrose solution injections near ligaments, tendons, and periarticular tissue is postulated to enhance local repair of tissue, collagen production, and modulation of neurogenic inflammation in dextrose prolotherapy. Targeted injections, based on recent studies, reduce pain and improve function, particularly in chronic low back pain that is resistant to conventional treatment. Of note, many of the anatomic sites treated with prolotherapy are also points for acupuncture, which have been shown to influence neurovascular physiology, endogenous opioid release, and pain modulatory systems. This overlap provides a unique venue for the convergence of the mechanistic benefits of both interventions.

Despite encouraging early findings, few studies have assessed the efficacy of prolotherapy in patients with CNSLBP systematically. There is not much evidence to support prolotherapy; that's why it has not been widely practiced. The treatment site is also non-uniform. This is why we would like to conduct this study, as a way of finding out whether the protocol of prolotherapy to and from universally recognized lumbar acupoints can provide clinically meaningful reductions in pain severity and improvement in functional capability, and thus address a highly important unmet need in the treatment of chronic low back pain.

Study Objectives and Hypotheses The primary study objective is to determine the clinical effectiveness of combinational prolotherapy injectate delivered to standardized acupuncture points for the management of adults with chronic non-specific low back pain (CNSLBP). Specifically, we wish to determine whether the intervention has a significant impact on reducing pain intensity and enhancing functional ability compared with the use of local anesthetic injections alone. By stimulating acupoints that correspond to the lumbar region, this approach is designed to combine regenerative, neuromodulatory, and analgesic mechanisms that may offer a more comprehensive solution for those who remain symptomatic despite conventional therapies.

Secondary objectives are to assess the impact of the intervention on quality of life, patient-reported disability, and global physical performance, as measured by validated instruments of pain and mobility assessment, such as:

• the Oswestry Disability Index (ODI)
• the Numeric Rating Scale (NRS)
• the BPI (Brief Pain Inventory) scale
• the TUG (Timed UP and Go Functional Low Back Pain Test)
• the Roland-Morris (Low Back Pain disability questionnaire)
• the GIC (Global Impression of Change) Scale Safety and tolerability will be tracked by reporting of injection-related adverse events. We also wish to ascertain whether treatment at specific acupoints is linked with differential effects, thereby providing initial data concerning point-specific efficacy.

The study aims to test the following hypotheses:

1. Primary Hypothesis: The patients treated with prolotherapy at standardized lumbar acupuncture points will experience a clinically appreciable reduction in pain intensity and improved functional outcomes compared to those treated with local anesthetic injections alone.
2. Secondary Hypotheses:
   • Patient-reported disability and quality of life scores will be improved by the intervention.
   • The treatment will be safe and well-tolerated with minimal adverse effects. By setting out these well-defined objectives and hypotheses, this study seeks to provide robust evidence on the effectiveness and safety of combinational prolotherapy for CNSLBP, a highly needed area in the management of chronic musculoskeletal pain.

Study Design This study is a prospective, single-blind, randomized controlled trial (RCT) with the aim of determining the effectiveness of combinational prolotherapy in patients with chronic non-specific low back pain (CNSLBP). 60 adult participants will be enrolled and randomized in a 1:1 ratio to the intervention group ("Prolo Group") or active control group ("Lido Group"). Randomization will be achieved using computer-generated sequences to allow allocation concealment, minimizing selection bias. Participants will be blinded to group assignments, but clinicians who will be giving the injections will not be blinded due to the nature of the intervention. This single-blind design balances methodological rigor and practicality.

The Prolo Group will receive injections of hypertonic dextrose solution (15% D-glucose) with 1% lidocaine, injected into up to 15 lumbar acupuncture points per session. The Lido Group will receive injections of 1% lidocaine, the same procedure, as an active comparator to control for mechanical needle and local anesthetic effects. For each injection, a 23G, 25 mm needle with 1 mL of solution will be used. Ultrasound guidance will be employed to accurately identify anatomical targets, while palpation will be used to locate tender or Ashi points consistent with the standardized protocol.

Treatment will be administered in three sessions: one baseline session, a second session at two weeks, and a third session at four weeks. Follow-up visits will occur at 15, 30, and 90 days after the last injection to determine both short- and medium-term effects. The design provides the opportunity to observe cumulative effects, temporal characteristics of pain relief, and functional change.

Participants The research will recruit 60 adult patients with chronic non-specific low back pain (CNSLBP) as a defined condition of persistent lumbar pain greater than three months' duration without apparent structural, inflammatory, neoplastic, or neurological pathology. Recruitment will be by referral from outpatient pain clinics and primary care physicians and through targeted advertisements in health centers, providing a representative sample akin to real-life patient populations.

Baseline measurements will include demographic data, medical history, and initial pain and disability scores. Tender points will be systematically mapped consistent with the uniform acupuncture protocol, so that identical targeting is achieved on injection. Participants will also be provided advice on permissible concomitant treatments, and limits will be imposed on the initiation of new interventional treatments or alteration of current analgesic therapy during the study.

This clearly delineated participant population ensures that the research examines combinational prolotherapy effects in a representative CNSLBP cohort with rigorous safety protocols. Strict inclusion and exclusion criteria and methodical baseline assessments will allow for accurate measurement of treatment outcomes and replicability of the results.

Intervention Procedures The intervention protocol in this study is to determine the effects of combinational prolotherapy injected at standardized lumbar acupuncture points, consisting of regenerative and analgesic processes. Two groups will be randomized for participants: the Prolo Group, in which the participants will be injected with combinational prolotherapy with hypertonic dextrose and lidocaine, and the Lido Group, in which participants will be injected with local anesthetic injections alone. The purpose is to see whether the administration of dextrose provides additional clinical value beyond mechanical needle effects and local anesthetic action.

Injection Materials and Preparation

• Prolo Group: All participants will receive 15% dextrose (D-glucose) with 1% lidocaine.
• Lido Group: All participants will receive 1% lidocaine alone. Solutions will be prepared fresh in a sterile environment immediately before each session. All injections are 1 mL per location.

Point Selection Injection sites are standardized based on a modified acupoint protocol for the most widely utilized lumbar points associated with chronic low back pain. These include BL23 (Shenshu), BL25 (Dachangshu), BL31 (Shangliao), BL54 (Zhibian), GV3 (Yaoyangguan), GV4 (Mingmen), and patient-specific Ashi points accessed by palpation.

Procedural Steps

1. Localization: Points will be found before injection by means of ultrasound and palpation.
2. Injection Technique: The needle will be inserted perpendicularly into the target site, following skin antisepsis, and the solution to be administered will be injected slowly over the course of a few seconds. Gently used tissue manipulation can facilitate diffusion.
3. Session Schedule: There will be three sessions administered to the subjects: a baseline injection as the initial session, the second session in two weeks' time, and the third session four weeks later. The sessions should last approximately 25-30 minutes.
4. Post-procedure Care: The participants will be observed for 15-20 minutes post-injection for side effects. Routine post-procedure care, like activity modification and watchful waiting for late reactions, will be provided.

   Measurements

Change in pain, measured through:

• the BPI (Brief Pain Inventory) scale: Baseline evaluation and d90 following the end of the infiltrations (injection sessions). Patients are asked to rate their pain on a 0 (no pain) to 10 (worst possible pain) scale.
• the Numeric Rating Scale (NRS): 15 minutes after every infiltration (1st, 2nd and 3rd), d15 and d30 after the 3rd infiltration. This measure provides a valid, sensitive, patient-centered measure of pain experience with the ability to detect clinically significant change over time.

Functional Disability (activity limitations due to low back pain), measured through:

• the Oswestry Disability Index (ODI): Baseline evaluation, d15, d30 and d90 after 3rd infiltration. It is a ten-item self-administered questionnaire covering personal care, lifting, walking, and social life, scored in percentages. The higher score indicates more disability.
• the TUG (Timed UP and Go Functional Low Back Pain Test): Baseline evaluation, 15 minutes before and after 1st Infiltration and d15, d30, and d90 after 3rd infiltration
• Pain reduction, duration of analgesia, and optimism at 24h after the end of the first session. Pain reduction after the first session will be analyzed as a predictor of the pain improvement 1 month after the end of the 3 sessions.
• the Roland-Morris (Low Back Pain disability questionnaire): Baseline evaluation, d15 and d90 after 3rd infiltration
• the GIC (Global Impression of Change) Scale: d90 after 3rd Infiltration. Participants will provide a rating of overall change on a 7-point Likert scale, indicating subjective assessment of the effectiveness of the treatment.

Safety and Tolerability Adverse events will be recorded routinely at all sessions and follow-up. Minor common reactions should be short-lasting injection-site pain or bruising. Serious adverse events, though unlikely given the minimally invasive procedure, will be reported immediately and reviewed by the study's safety monitoring committee.

Assessment Schedule

• Baseline: Demographics, medical history, and tender points and initial questionnaires.
• During Intervention: Pre-injection NRS scores at each session (weeks 0, 2, and 4) and follow-up for immediate adverse events.
• Follow-Up: Global reassessment at 15, 30, and 90 days post-last injection, encompassing the aforementioned questionnaires and scales.

Contact and questions 24h after the first intervention.

This multi-level evaluation strategy ensures robust analysis of short- and medium-term impact, providing extensive insight into the intervention's clinical effect and safety profile. The study captures both objective and subjective treatment response with the combination of established quantitative measures and patient-reported outcomes.

Statistical Analysis Statistical analysis design is attracted to critically evaluate the safety and efficacy of combinational prolotherapy in treating chronic non-specific low back pain (CNSLBP), with proper regard to transparency, reproducibility, and concomitance with standard clinical research methods.

Sample Size Calculation Sample size was estimated based on previous studies on prolotherapy and injection therapy for CNSLBP (Maniquis-Smigel 2017; Sirh et al. 2022). To adress potential dropouts and keep enough power, the study will include 60 participants divided evenly between the Prolo Group (dextrose + lidocaine) and the Lido Group (lidocaine alone).

The trial shall be run for a duration of about 18-24 months with separate phases of recruitment, intervention, follow-up, and analysis of data. Time has been factored in for anticipated recruitment rates, retention among the participants, and the sequential nature of the intervention protocol.

Possible Benefits Participants of the study can anticipate various benefits in terms of clinical outcomes. The most anticipated benefit is the reduction in pain severity as assessed with the Numeric Rating Scale (NRS), and this can enhance daily functioning and quality of life. Secondary benefits could include enhanced mobility, reduced disability as measured by the Oswestry Disability Index (ODI), and improvements in physical and psychosocial status. The targeted injections also have the capability to produce localized effects via modulation of peripheral nerve sensitization, tissue repair, and enhancement of microcirculation within the affected tissue. Furthermore, the study will create standardized protocols for combinational prolotherapy at common acupuncture points, which would be applicable to future clinical treatments and result in evidence-based practices for treating chronic low back pain. Participants will also profit from structured education, exercise teaching, and lifestyle counseling, part of the study, which will support extended self-management practice.

Potential Risks This therapy does not entail any risks at all, being non-systemic in practice and executed under aseptic conditions. Slight, usual side effects are brief discomfort, slight bruising, or soreness at the injection sites. Some may also experience temporary local swelling or erythema. Use of a mixture of dextrose and lidocaine is intended to reduce discomfort during the injections. Serious complications, such as infection, bleeding, or nerve injury, are highly unlikely due to the superficiality of the injections and adherence to strict aseptic protocol.

Ethical Considerations Participating individuals shall be completely informed about the potential risks and benefits prior to providing their written consent. The study shall adhere to strict ethical principles, including ongoing safety monitoring, participants' right to withdraw at any time, and provision for rescue therapies in the event of an inadequate response.

In summary, the potential benefits of relief from pain, enhanced functioning, and the gain in scientific information considerably outweigh the minimal and manageable risks of the intervention and hence justify the ethical justification for conducting this study.