Perineural Prolotherapy in Chronic Knee Osteoarthritis Pain.

Knee osteoarthritis (KOA) is a common musculoskeletal disorder characterized by pain, stiffness, and decreased function of the affected joint. Based on the severity of the disease, the therapeutic approach can be either conservative - minimally invasive, or surgical. One of the implemented conservative methods is the desensitization of the genicular nerves, via perineural injection of local anesthetic, as they provide sensory innervation to the knee joint and participate in the pathophysiology of neuropathic pain of KOA. Ultrasound guidance has significantly improved the precision of local anesthetic injections, thereby enhancing the effectiveness of therapeutic interventions targeting these nerves. Since the genicular nerves are very small, injections are often performed close to the genicular arteries, which are more easily identified with ultrasound. The documented limited therapeutic effect of this approach and the complications of neurodestructive techniques, like thermal radiofrequencies, necessitate the use of alternative methods for the treatment of chronic pain in KOA.

Prolotherapy was introduced as a regenerative treatment involving the injection of a glucose solution into or around the joint space to stimulate repair and promote functional restoration of the joint's soft tissues. Perineural prolotherapy (glucose concentration DW 5%) seems to exert therapeutic effects by inhibiting the activation of the TRPV1 pain receptor located at the terminals of nociceptive neurons, thereby reducing the neurogenic inflammation and destruction of surrounding tissues. Also, separating the nerve through the non-specific mechanical effect of fluid under force (hydrodissection) gradually reduce adhesions, enhance blood flow, and mobilize the nerve to promote neuroregeneration. However, these data were derived from studies regarding nerve entrapment, but not for anatomically intact nerves like KOA, while there is no direct evaluation of perineural prolotherapy until today in knee pain.

The purpose of this clinical study is to test the hypothesis that perineural injection of 5% dextrose and lidocaine into 4 genicular nerves (superomedial, superolateral, inferomedial, recurrent peroneal genicular nerve) is superior to lidocaine injection in the treatment of chronic pain in patients with KOA.

Sample size calculation is for the primary outcome measure (i.e. pain score 15 days after the 3rd injection). Based on bibliographic data of similar studies (Fu Y et al 2024) was found that the Pain score (VAS) of patients treated with peri-articular perineural injection (PG) was 4.80 ± 1.005 while from the work of Kim et al 2018 was found that the VAS score for patients injected with lidocaine alone was 40.4 ± 9.1 which was converted to10 scale (4.04±0.91). Based on this is expected an effect size equal to 0.79. Furthermore, by study design is expected equal patient allocation in the two arms, in addition we considered error probability 5%, study power 80% and two tailed tests. The total sample size based on the previous data is 52 patients (equally allocated in two arms), and in order to compensate for possible dropouts we will enroll 60 patients.

After sample of 60 patients (30 patients in each group) will be enrolled in the prospective, randomized, single-blind, superiority, controlled, clinical trial. After patients written informed consent, they will be randomized with allocation ratio 1:1 to either dextrose + lidocaine group (intervention group) or lidocaine group (active control group). Randomization will be performed using computer-generated sequences to ensure allocation concealment, minimizing selection bias. Participants will be blinded to group assignment, whereas clinicians administering the injections will not be blinded due to the nature of the intervention. This single-blind approach balances methodological rigor with practical feasibility. Before the perineural injections in both groups, the pain intensity and its impact on daily life, including general activity, mood, sleep and social interactions will be evaluated via the self-report questionnaire \<Brief Pain Inventory\> (BPI), followed by the calculation of the Pain Severity and Pain Interference Score. In addition, the physical function of patients will be assessed via the 30 seconds chair stand test and the severity of knee osteoarthritis will be estimated via the questionnaire \<Western Ontario and McMaster Universities arthritis index (WOMAC)\> and the respective score will be subsequently calculated.

Procedure:

No oral or intravenous medication will be administered at the beginning or during the procedure. The patients' vital signs will be monitored during the procedure and appropriate sterilized conditions will be ensured. The locations for the infiltration of the 5 genicular nerves will be firstly identified after ultrasound examination and the subsequent ultrasound-guided perineural injection will be accomplished.

In the Dextrose + Lidocaine group (group D+L) a perineural infusion of a total volume of 8 ml of DW 5% and lidocaine 1% will be performed at the 4 genicular nerves, which will be prepared as follows: 4 ml of lidocaine 2%, with 1.2 ml of DW 35% and 2.8 ml of NaCl 0.9%. In the Lidocaine group (group L) the respective infusion of a solution of 8 ml of lidocaine 1% at the 4 genicular nerves will be prepared as follows: 4 ml of lidocaine 2% with 4 ml of NaCl 0.9%. The perineural injections in each group will be executed 3 times (in 3 consecutive sessions): at their first assessment, 2 and 4 weeks later.

Measurements

* Pain Severity Score at 15 days after the 3rd infiltration. It is one of the two main components of Brief Pain Inventory (BPI) score, a numerical scale used to assess pain. The Severity Score is an average of pain intensity ratings (worst, least, average, and current pain). Patients rate their pain on a 0-10 scale, with 0 being "no pain and 10 being "pain as bad as you can imagine". * Pain Severity Score at baseline, 30 and 90 days after the 3rd infiltration. It will be estimated by the Brief Pain Inventory (BPI) score, as described above. * Pain Interference Score at baseline, 15, 30 and 90 days after the 3rd infiltration. It is a main component of the Brief Pain Inventory (BPI) score, based on how pain affects daily life. Patients rate the impact of pain on life domains (like mood, sleep, and activities) on a 0-10 scale, with 0 being "no interference" and 10 being "completely interferes". * Short-term changes 24h after the first infiltration. Approximately 24 hours after the 1st infiltration, a brief patient evaluation will be conducted. Specifically, pain intensity at the affected knee during movement will be assessed, according to Numerical Rating Scale (NRS), where patients assign a number from 0 to 10 to describe their pain level, with 0 meaning "no pain" and 10 meaning "the worst pain imaginable". Furthermore, the duration of the analgesia provided by the perineural injection will be recorded, along with the patient's level of optimism regarding the treatment's effectiveness and its impact on improving daily life. * WOMAC Questionnaire. Patients physical function will be evaluated by WOMAC questionnaire, which is divided into three subscales: pain (5 items), stiffness (2 items), and physical function (17 items). The 24-item questionnaire uses a 0-4 scale (None to Extreme), where scores are summed for each subscale (Pain 0-20, Stiffness 0-8, Function 0-68). Higher WOMAC scores indicate worse symptoms and greater functional limitations. Measurement will be made at: baseline, 30 and 90 days after completion of the therapy. Further subitems of WOMAC questionnaire might also be evaluated. * 30 seconds chair stand test (30CST). The number of successful attempts to stand up from a chair approximately 43 cm high, with a straight back and no arms for 30 seconds will be measured. Measurement will be made at: Baseline, 15, 30 and 90 days after completion of the therapy. * Global Impression of Change (GIC) scale, a subjective patient rating of overall improvement after treatment. It will be documented at 90 days after the 3rd infiltration. * Sub analyses of the scales used. Sub analyses of questions, eg. usage of analgesics.

Finally, any adverse events will be recorded.

STATISTICAL ANALYSIS Descriptive characteristics for the quantitative data will be expressed as median and Quartile 1 (Q1) to Quartile 3 (Q3), range or mean±standard deviation (SD) depending on normality as this will be checked by the Shapiro Wilk test. For the qualitative data will be reported the frequency of occurrence and the relevant percentage. Comparisons between the two arms at 15 days, depending on normality will be performed via the Mann Whitney U test or t-test. The significance level will be set to 0.05, and when applicable tests were two sided.

• Pain Severity Score (PSS) at baseline, 30 and 90 days after the 3rd infiltration [Time frame: A measurement before the first infiltration of the first participant up to 90 days after the 3rd infiltration of the last participant.]
• Pain Interference Score (PIS) [Time frame: From before the first infiltration of the first participant up to 3 months after the last infiltration of the last participant.]
• Short-term changes 24h after the first infiltration [Time frame: 24 hours after the first infiltration of the first participant up to 24 hours after the first infiltration of the last participant.]
• WOMAC Questionnaire [Time frame: Baseline, 15, 30 and 90 days after completion of the therapy of the first participant until 90 days after completion of therapy of the last participant.]
• 30 seconds chair stand test (30CST) [Time frame: Baseline, 15, 30 and 90 days after completion of the therapy of the first participant until 90 days after completion of therapy of the last participant.]
• The Global Impression of Change (GIC) scale [Time frame: 3 months after completion of therapy for the first participant up to 3 months after completion of therapy for the last participant.]