1. Background
Knee osteoarthritis (KOA) is a degenerative disease leading to painful joints, articular stiffness, and decreased function (1). The high prevalence of KOA, especially in older persons, makes it a costly health-care problem. Radiologic changes of osteoarthritis (OA) are usually observed at around 65 years, the age at which almost 11% of patients become symptomatic (2-4). The exact mechanism of pain and disability is not well recognized. The origin of pain has been attributed to various body parts such as the articular capsule, ligaments, synovium, bone, lateral part of the meniscus, and extraarticular ligaments and tendons (5, 6). Total knee arthroplasty (TKA) is the definitive treatment of KOA in severe cases. However, surgeons tend to delay TKA as much as possible because of the limited survival of knee prostheses. In addition, revision surgery is a complicated and difficult procedure. The nonoperative treatment of these patients is a multimodal approach that includes physical therapy, anti-inflammatory drug use, intraarticular injections, acupuncture, and use of wedge insoles; this approach has resulted in satisfactory outcomes in patients at the earlier stages of the disease (7, 8). However, none of these modalities completely relieves the knee pain and dissolves the symptoms. In a recent report, none of these treatments was shown to have an advantage over the others (4). Prolotherapy was first introduced by Hackett in 1950, followed by several preclinical and clinical studies (9). Prolotherapy seems to stimulate the healing process of tissues with chronic injuries (10, 11). In some animal models, prolotherapy resulted in increased inflammatory markers (12). The mechanism of action of dextrose prolotherapy is not clearly understood. Hypertonic dextrose can cause the osmotic rupture of local cells (13). Increased extracellular glucose leads to increased growth factors in different types of human cells (14-16). In addition, a hypertonic environment results in increased DNA-encoding growth factors (17). Although some studies have demonstrated the promising effects of prolotherapy with hypertonic dextrose on pain and function in patients with KOA (18-22), more prospective randomized studies are required to prove the efficacy and safety of this treatment method for KOA.
The medical effects of ozone are increasingly being considered in recent years especially for musculoskeletal disorders, including low back pain, lumbar disk herniation, failed back surgery syndrome, degenerative spinal disease, shoulder disorders, and KOA (23-31). There is limited evidence on the efficacy of ozone therapy for patients with KOA, and its mechanism of action is unknown. Several biological effects have been suggested for ozone. The increased oxygenation of tissues, and analgesic and anti-inflammatory effects through the stimulation of the antinociceptive system may explain the therapeutic effects of ozone in musculoskeletal disorders (26, 32).
2. Objectives
In the current randomized clinical trial, we compared the effects of prolotherapy with hypertonic dextrose and prolotherapy with ozone on pain and function in patients with KOA.
3. Patients and Methods
During 2013, 80 patients with mild to moderate OA of the medial knee compartment (Kellgren-Lawrence grade I and II), aged 40 - 75 years, were enrolled in the current randomized clinical trial. All patients gave their written informed consent before the study. The diagnosis of KOA was made on the basis of the results of clinical examination and anteroposterior standing radiography. The exclusion criteria included pregnancy, severe underlying diseases such as diabetes, anticoagulant use, being a candidate for knee joint replacement (Kellgren-Lawrence grade III and IV), OA of the lateral knee compartment, previous prolotherapy or any intraarticular injection during the last year, with suspicion for infectious or inflammatory arthritis, and daily use of opioid or nonopioid analgesic drugs. Before the treatment, the pain intensity was determined by using a 10-cm ruler (visual analogue scale). In this scale, 0 indicated no pain and 10 indicated the worst pain. Moreover, all patients completed the Western Ontario and McMaster university arthritis index (WOMAC) assessment, which varies between 0 and 100 points and in which lower scores indicate better knee status.
Patients were randomly assigned equally into two groups: the ozone prolotherapy (OP) group and the hypertonic dextrose prolotherapy (HDP) group. Through the inferomedial approach, 15 g/mL of ozone-oxygen mixture (5 - 7 cm3) was injected intraarticularly in the OP group, and 7 cm3 of 12.5% hypertonic dextrose was injected intraarticularly in the HDP group, by using a 25-G needle under ultrasound guidance. Before the prolotherapy, 1% lidocaine was injected as a local anesthetic to the skin and underlying tissues. The injections were repeated three times with 7–10 days interval for each patient. Three months after the last injection, the pain intensity was measured and the WOMAC scores were determined. Finally, the pretreatment and posttreatment outcomes were compared in each group and between the two groups.
3.1. Statistics
Statistical analysis was performed by using SPSS statistical software ver. 15.0. The pretreatment and posttreatment outcomes were compared by using a paired t-test for quantitative data and the McNemar test for qualitative data. The two groups were compared by using an independent-samples t-test for quantitative data and the 2 test for qualitative data. P < 0.05 was considered significant.
4. Results
The demographic characteristics of the patients are presented in Table 1, which shows no statistically significant difference between the two groups. In addition, before the treatment, the pain intensity and WOMAC scores were the same between the two groups (P < 0.05) (Table 2). After the treatment, the pain and function significantly improved in the two groups (P < 0.001) (Table 2). However, there was no statistically significant difference in pain and WOMAC scores at the last visit between the two groups (P < 0.05) (Table 2).
Table 1. Comparison of Demographic Findings between the Two Groups (n = 40)
| Variable | Ozone | Hypertonic Dextrose | P Value |
|---|---|---|---|
| Age, y | 59.1 ± 12.3 | 57.3 ± 15.1 | 0.349 |
| Sex | 0.491 | ||
| Male | 17 | 14 | |
| Female | 23 | 26 | |
| Body mass index, kg/m2 | 31.2 ± 1.1 | 31.8±0.9 | 0.751 |
| Duration of pain (before injection), months | 7.6 ± 0.8 | 8.1 ± 0.9 | 0.1 |
Table 2. Comparison of the Visual Analogue Scale and WOMAC Scores in Each Group and between the Two Groups (n = 40)
| Group | Ozone | Hypertonic Dextrose | P Value (Intergroup) | P Value (Intragroup) |
|---|---|---|---|---|
| Visual analogue scale | < 0.001 | |||
| Before | 7.6 ± 1.3 | 8.1 ± 1.1 | 0.146 | |
| After | 2.8 ± 1.1 | 3 ± 1.2 | 0.512 | |
| WOMAC score | < 0.001 | |||
| Before | 56.3 ± 11.5 | 58.5 ± 13.3 | 0.835 | |
| After | 81.6 ± 13.7 | 83.7 ± 15.3 | 0.173 |
5. Discussion
The current study shows that prolotherapy with hypertonic dextrose or prolozone (intraarticular ozone injection) can be effectively used in the nonoperative management of patients with KOA. Prolotherapy is an injection therapy for the management of chronic musculoskeletal disorders such as KOA (10). Although prolotherapy is being increasingly used worldwide, its mechanism of action in pain relief is not yet clearly understood. Several mechanisms have been proposed, such as accelerating the healing process of damaged tissue (10, 11), releasing growth factors (14-16), having a positive effect on the nociceptive system (33), and the effect of needle insertion and volume enhancement (34).
Reeves and Hassanein found that prolotherapy with 10% dextrose resulted in significant pain relief, decrease in knee swelling, decrease in bulking episodes, and improvement in the knee range of motion. They also found, on the basis of radiographic images, that prolotherapy was associated with improvement in OA severity.
In recent years, the treatment of several musculoskeletal disorders with ozone has increasingly attracted attention. Ozone is a toxic and soluble gas with high oxidative activity (35). Ozone has an antinociceptive effect with several mechanisms (35, 36). Paoloni et al. treated patients with lumbar disc herniation by using intramuscular oxygen-ozone injection. They observed that 61% of the patients became pain free compared with 33% of the control group (30). Li et al. and Mishra et al. reported improved function and decreased pain intensity after intraarticular injection of ozone in patients with KOA (24, 25). To our knowledge, there is no study comparing the effects of prolotherapy with hypertonic dextrose and injection of ozone. Therefore, it is possible to compare the outcomes of the current study with those of others. However, our findings confirmed the outcome of previous studies indicating the pain killing and therapeutic effects of prolotherapy with ozone or dextrose. In our study, the pain intensity was significantly reduced after the treatment. However, there was no statistically significant difference between the two groups.
We believe that our study is limited by the small sample size; if more patients were investigated, it is possible that we could have found some differences between the two groups. In addition, we only investigated the short-term results; mid-term and long-term follow-up are required.
5.1. Conclusion
Intraarticular injection of hypertonic dextrose or ozone could significantly decrease pain in patients with mild to moderate KOA, and improve their functional status. There was no significant difference between dextrose and ozone in the outcomes, and more studies are required in the future.
