Perineural Prolotherapy in Chronic Knee Osteoarthritis Pain: A Randomized Controlled Trial.

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.