Osteoarthritis (OA) is the most common joint disease in adults, and its prevalence increases with age causing disability in the elderly population (Felson et al., 2000[11]). The most common symptoms of OA are pain, joint stiffness, crepitation on motion and limitation of joint motion (Hochberg et al., 1995[12]). Pain is a debilitating symptom of OA which causes significant impairment to the quality of life of afflicted patients. Routinely administered medications for OA include analgesics and non-steroidal anti-inflammatory drugs, but these drugs may introduce gastrointestinal and renal complications in long-term use (Smalley et al., 1995[24]; Felson et al., 2000[11]). Therefore, there is a demand for novel anti-nociceptive and anti-inflammatory medications that could control OA-associated chronic pain in an effective and safe fashion (Walzer et al., 2015[26]; Chen et al., 2015[8]; Panahi et al., 2014[20]; Sahebkar and Henrotin, 2015[22]).

Medicinal plants have always been regarded as an indispensible source for finding natural medicines with multi-faceted actions and minimal adverse events (Cameron et al., 2009[7]). The plants belonging to the genus Elaeagnus (Elaeagnaceae) grow widely over vast swathes of land from the Northern regions of Asia to the Himalayas and Europe. One species of this genus, Elaeagnus angustifolia (EA), also known as Russian olive, has been reported in the Iranian folk medicine to be used for its anti-inflammatory and analgesic properties in the treatment of patients with rheumatic diseases (Mirhydar, 1998[17]). Other conditions for which EA has been traditionally used as a medicine include fever, amoebic dysentery, gastrointestinal problems (nausea, vomiting and jaundice), jaundice, tetanus and asthma (Mirhydar, 1998[17]). Noteworthy, pharmacological investigations have revealed that EA extract has potent anti-inflammatory, analgesic and muscle relaxant effects (Ahmadiani et al., 2000[1]; Ramezani et al., 2001[21]; Hosseinzadeh et al., 2003[13]). Nevertheless, reports on the efficacy of EA in the management of OA in clinical practice have been very scarce (Ebrahimi et al., 2014[9]) and no previous head-to-head comparison with an NSAID exists. The present study set out to address this question in a randomized clinical trial controlled with ibuprofen as a standard medication routinely used for the management of OA symptoms.

Of the initial 99 patients who met the inclusion criteria, 97 (97.9 %) finished the study comprising 33 in the low-dose EA (300 mg/day), 32 in the high-dose EA (600 mg/day) and 32 in the ibuprofen group (Figure 1(Fig. 1)). There was no significant difference in age and gender, as well as baseline BMI, VAS, LPFI, WOMAC and PGA scores among the three studied groups (p > 0.05) (Table 1(Tab. 1)). The amount of kaempferol in the extract was determined by HPLC method to be 0.21 % w/w (Figure 2(Fig. 2)).

There were significant reductions in the total WOMAC score following 7-week treatment in all three studied groups. With respect to subscales, there were significant reductions in the pain and stiffness subscales in the high-dose (600 mg/day) (p=0.028) and low-dose (300 mg/day) (p=0.035) E. angustifolia group, respectively. Physical function was improved in the ibuprofen (p=0.038) and high-dose E. angustifolia (p=0.009) groups. VAS, LPFI and PGA scores were all improved by either of administered EA doses and ibuprofen (Table 2(Tab. 2)).

Between-group comparisons indicated that the changes in total and subscale WOMAC, VAS and LPFI scores were comparable among the three studied groups. However, there was a greater reduction in the PGA score in the low-dose E. angustifolia group compared with the ibuprofen group (p=0.048), whilst the difference with the high-dose vs. low-dose E. angustifolia groups, and between the high-dose and ibuprofen groups did not reach statistical significance (Table 3(Tab. 3)).

No significant differences were seen in adverse reactions or tolerability between the study groups. No significant gastrointestinal adverse reactions were seen in the patients treated in the three treatment groups.

The goal of this study was to evaluate the efficacy of E. angustifolia extract in the treatment of knee osteoarthritis pain and clinical symptoms. The results showed a significant decrease in pain and other symptoms of osteoarthritis by E. angustifolia extract, with an efficacy comparable to that of ibuprofen as a standard analgesic.

Although there are many studies conducted on the efficacy of E. angustifolia in gastrointestinal disorders, few studies have assessed the analgesic and anti-inflammatory effects of this medicinal plant in clinical settings. Ebrahimi et al. (2014[9]) reported significant improvements in WOMAC total score as well as subscales of pain and physical function following 8 weeks of supplementation with E. angustifolia medulla powder in females with knee osteoarthritis. However, no improvement versus placebo was observed with the whole fruit powder (Ebrahimi et al., 2014[9]). In the same study, measurement of circulating levels of a number of cytokines including tumor necrosis factor-alpha (TNF-α), interleukine-1β, interleukine-10, matrix metalloproteinase-1 and -13 did not suggest any significant change compared with placebo (Nikniaz et al., 2014[19]).

Previous experimental studies have shown that different constituents of E. angustifolia seeds possess anti-nociceptive activity in hot-plate and writhing tests, therefore suggesting the involvement of both peripheral and central nervous mechanisms (Ahmadiani et al., 2000[1]; Ramezani et al., 2001[21]). Also, it has been reported that E. angustifolia can suppress both cyclooxygenase-1 and -2 enzymes with a comparable efficacy to indomethacin (Farahbakhsh et al., 2011[10]). This could be an important mechanism for the efficacy of the plant in OA, as cyclooxygenase enzymes are responsible for the production of a range of pro-inflammatory and nociceptive mediators, particularly prostaglandin E₂ (PGE₂) (Bensen et al., 1999[5]).

The aqueous and ethanol extracts of E. angustifolia have a high content of flavonoids and tannins. Kaempferol, ferulic acid and cumaric acid are the major polyphenolic components of E. angustifolia extract (Bucur et al., 2009[6]). The action of kaempferol is of particular interest owing to the efficacy of this flavonoid in suppressing the production and release of inflammatory cytokines (TNF-α and interleukin-6), mediators (nitric oxide and PGE₂) and signaling molecules (Src, Syk and IRAK4), and release of reactive oxygen species (Kim et al., 2015[16]).

Aqueous and ethanol extracts of the plant have been reported to possess muscle-relaxant activity in a dose-dependent manner. Interestingly, this effect of E. angustifolia (at the dose of 2 mg/kg) was comparable to that of diazepam (Hosseinzadeh et al., 2003[13]). Muscle-relaxant effect of the extract can be a potential mechanism for the pain-relieving effects of E. angustifolia in patients with OA as peri-articular muscles weakness is common in this disease (Hurley, 1999[14]). However, muscle-relaxant effects may be harmful in long-term because strengthening the quadriceps muscles is required for the treatment of OA (Serrão et al., 2012[23]; van der Esch et al., 2012[25]). Hence, it is required to evaluate muscle torque changes after treatment with E. angustifolia to confirm the mentioned possible side-effect.

In conclusion, findings of the present trial suggested the efficacy and safety of E. angustifolia extract in alleviating the clinical symptoms of OA. Although the present study was limited by its pilot nature, the results supported comparable efficacy of E. angustifolia with ibuprofen that was observed in this study is of particular importance owing to the side effects associated with the long-term use of NSAIDs. According to the present results, E. angustifolia extract could be regarded as an alternative to NSAIDs in subjects suffering from OA symptoms.

The authors would like to thank Clinical Trial Research Center (Tehran, Iran) for the financial support of this study.

None declared.