Intra-articular Hyaluronic Acid Treatment for Golfer's Toe Keeping Older Golfers on Course Robert J. Petrella, MD, PhD; Anthony Cogliano, MD THE PHYSICIAN AND SPORTSMEDICINE - VOL 32 - NO. 7 - JULY 2004 BACKGROUND: Osteoarthritis of the great toe can lead to a progressive decrease in range of motion (ROM) and pain at the first metatarsophalangeal (MTP) joint. This condition, observed in older golfers, results in reduced participation and enjoyment of this popular activity. OBJECTIVE: To assess the efficacy, safety, and patient satisfaction with a series of intra-articular injections of hyaluronic acid (HA) into the first MTP joint in older patients who reported osteoarthritis-associated pain, loss of MTP joint ROM, and disability that interfered with golf participation. METHODS: Forty-seven consecutive male golfers met the inclusion criteria and were given a weekly intra-articular HA injection for 8 weeks. Baseline measures of MTP joint ROM, pain at rest and immediately after tiptoe walking for 10 m, and global patient satisfaction (GPS) were compared with measures at 9 and 16 weeks and at presentation for a second injection series. RESULTS: Adverse events (only local injection site pain was noted) were <0.01%. At 9 weeks, significant improvement in pain at rest, pain after tiptoe walking, ROM, and GPS were observed. These changes were maintained for all measures at 16 weeks. At presentation for the second series, GPS was significantly higher than at baseline and at 16 weeks. Pain at rest, tiptoe walking pain, and ROM were significantly improved from baseline, but tiptoe-walking pain was significantly reduced at 16 weeks. CONCLUSION: Intra-articular HA injection significantly improved pain tolerance at rest and with activity. Patient acceptance of the treatment was high, with very few adverse events in golfers who had osteoarthritis of the first MTP joint. Osteoarthritis of the first metatarsophalangeal (MTP) joint can lead to progressive reduction in range of motion (ROM) and pain with activity that can affect walking and recreational activity. In particular, older golfers appear to have a predisposition for this condition that limits their participation in this increasingly popular recreational activity. The treatment algorithm developed for osteoarthritis includes initial nonpharmacologic approaches followed by oral analgesic medication and nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroid injection, and surgical manipulation.2 Recently, intra-articular hyaluronic acid (HA) injection use at all stages of osteoarthritis progression has been proposed by the American College of Rheumatology and the European League Against Rheumatism.2 The efficacy of intra-articular HA injection has been described in the osteoarthritic knee,3-5 but experience with other joints is limited.6 The potential benefits of HA injection over traditional NSAID and intra-articular corticosteroid use in older patients include the low incidence of systemic adverse effects, absence of drug interaction, and nearly unlimited frequency of use. Whether intra-articular HA use in a smaller joint, such as the first MTP, provides efficacy and a low side-effect profile similar to the knee is unknown. Study Design The protocol and written informed consent for studies involving human subjects were approved by the University of Western Ontario Review Board. The study was a single-center, single-arm, open-label trial with an 8-week treatment phase. Within 12 months, orthopedic and primary care physicians referred patients who had pain in the first MTP joint (unilateral only) and disability (described as reduced golfing activity without an acute injury event) for at least 3 months. In addition, all patients had radiographic evidence of osteoarthritis of the first MTP joint (ie, grade 1 to 3 hallux rigidus using the Regnauld classification of joint-space narrowing and osteophyte formation). The subjects provided informed consent, had not taken NSAIDs for 2 weeks prior to entry, had not received intra-articular corticosteroid injection in the first MTP joint within the previous 3 months, did not have other lower-extremity musculoskeletal disability or pain, and had pain exceeding 45 mm on a 100-mm visual analogue scale (VAS) immediately following tiptoe walking for 10 m. After screening and enrollment, patients completed assessments and received a 1.0-mL intra-articular injection of HA (Suplasyn, Bioniche Life Sciences Inc, Belleville, Ontario; 20 mg/2 mL) in the first MTP joint. An experienced physician delivered the injections using a 27-gauge needle. The toe was semiflexed and held in gentle traction without topical or local anesthesia during injection. One dose was administered each week (± 2 days) for 8 consecutive weeks in an unblinded fashion. Patients returned at 9 and 16 weeks and then self-selected a follow-up visit when they would request a second series of injections based on return of symptoms that interfered with their golf activity. Assessments Clinical assessments were performed prior to injection at baseline, at each of seven subsequent weekly treatment visits, at 16 weeks, and at the second series visit (28 to 76 weeks after the eighth injection). Adverse events were recorded at each study visit and classified using standard World Health Organization terminology and coding. The primary efficacy measures were first MTP joint pain after 5 minutes of seated rest and following completion of 10 m of tiptoe walking (assessed by VAS), range of plantar flexion and dorsiflexion of the first MTP joint (measured from the metatarsal to the proximal phalanx with a goniometer), and global patient satisfaction (GPS) (measured on a 5-point categorical scale, with 1 representing completely unsatisfied and 5 completely satisfied). In addition to HA injection therapy, patients were permitted to use standard nonpharmacologic therapies, including rest, ice, compression, and elevation, (RICE) and orthoses, aspirin for cardiovascular disease prophylaxis up to 325 mg/day, and general analgesia using acetaminophen up to 1 g/day. NSAIDs were not allowed during HA treatment but were allowed at patient discretion during the follow-up posttreatment. Use of alternate treatment modalities was recorded at 16 weeks and at follow-up visits. Statistical Analysis Changes in pain scores were evaluated using analysis of variance (ANOVA) for repeated measures. GPS was evaluated to determine the proportion of treatment responders at each treatment and at follow-up visits. Frequency of adverse events over the treatment period and during follow-up were also recorded. Level of statistical significance was accepted at P<0.05. Results Fifty-six patients were referred over the study period, and 47 subjects met entry criteria and provided informed consent. All 47 patients completed each treatment session and reported for follow-up assessments. All subjects were men, with mean age of 71 (± 4.3) years and a mean body mass index of 26.3 (± 1.7) kg/m2. Osteoarthritis of the first MTP joint was found in 37 patients on the right foot and in 11 patients on the left foot. One patient had bilateral osteoarthritis, but data from only the left foot were used in the study; osteoarthritis in the right foot was found incidentally at the end of the study. Radiographs of the first MTP joint showed 36% had grade 1, 42% had grade 2, and 22% had grade 3 osteoarthritis (Regnauld classification). Baseline demographic characteristics and additional therapies used over the treatment phase and during follow-up were recorded (table 1). No significant difference was observed from prestudy and follow-up levels of the use of orthoses, acetaminophen, or NSAIDs.

TABLE 1. Demographics and Other Characteristics of Study Participants Who Had Golfer's Toe Assessment Referrals Screened (n = 56) Enrolled (n = 47) Age (years) Male BMI (kg/m2) Duration of MTP pain (days) Used NSAID prior to enrollment Used NSAID in follow-up 70.5 ± 3.1 56 (100%) 27.1 ± 1.4 189.8 ± 23.2 31 Data not collected 71 ± 4.3 47 (100%) 26.3 ± 1.7 142.6 ± 28.7 30 6 Severity of pain immediately after walking 10 m on tiptoe (measured on a 100-mm visual analog scale) Moderate (> 60 mm) Mild (45-60 mm) < Mild (< 45 mm) 67% 32% 1% 66% 34% 0% Osteoarthritis assessment by Regnauld classification Grade 1 Grade 2 Grade 3 41% 40% 19% 36% 42% 22% Used nonpharmacologic therapies during study (eg, RICE, orthoses) Data not collected 2 BMI = body mass index; MTP = first metatarsophalangeal joint; NSAID = nonsteroidal anti-inflammatory drug; RICE = rest, ice, compression, and elevation

The mean number of golf sessions of at least 9 holes was 3.1 per week at enrollment, 4.7 at 4 months, and 4.2 at 9 months. Golf participation was not related to season, because all participants had an equal opportunity to play throughout the year. Primary efficacy measures. A significant reduction from baseline pain at rest and tiptoe-walking pain was observed at 9 weeks (VAS 29.4 mm/40.2 mm, P<0.01/P<0.001), 16 weeks (30.4 mm/32.8 mm, P<0.01/P<0.001) and follow-up (26.1 mm/59 mm; P<0.01/P<0.05) (figure 1). GPS showed significant improvement from the sixth visit assessment (4.6 ± 0.3; P<0.002) and was maintained at 9 weeks (4.86 ± 0.2; P<0.001), 16 weeks (4.51 ± 0.31; P<0.001), and follow-up (4.6 ± 0.13; P<0.002). ROM was increased by 16° flexion at 9 weeks (P<0.01), 22° at 16 weeks (P<0.007), and 18° at follow-up (P<0.009) (table 2). At final follow-up, three patients had requested injection with intra-articular corticosteroid during the 16-week follow-up period, because their pain at rest was more than 60 mm (VAS). Examination of these three subjects showed no significant difference in demographics from the total group. Two subjects had no improvement in pain at rest or tiptoe walking pain at 9 and 16 weeks, and these were defined as treatment failures.

TABLE 2. Primary Efficacy Measures of Hyaluronic Acid Injection for Golfer's Toe Baseline (n = 47) 9 Wk (n = 47) 16 Wk (n = 47) Follow-up (n = 47) Rest pain (mm)* 41.2 ± 3.1† 29.4 ± 3.3† 30.4 ± 2.9† 26.1 ± 2.6† Tiptoe-walking pain (mm)* 68.9 ± 5.9 40.2 ± 4.1‡ 32.8 ± 3.1‡ 59.0 ± 18.4§ Range of motion (degrees) 6.3 ± 4.1 26.3 ± 10.5† 32.6 ± 9.7‡ 28.7 ± 7.5‡ Increase from baseline — 16° 22° 18° Global patient satisfaction (5-point scale) 3.1 ± 1.3 4.86 ± 0.2 4.51 ± 0.3 4.6 ± 0.13|| Adverse events, pain only (number of patients) N/A 2 0 0 *Measured on a 100-mm visual analog scale. † P<0.01 ‡ P<0.001 § P<0.05 || P<0.002

Adverse events. No local or systemic adverse events were reported during the treatment phase of the trial. Two patients who took NSAIDs during the follow-up phase experienced gastrointestinal pain that necessitated discontinuation of these medications. Discussion Musculoskeletal trauma and injury are common among recreational athletes, including golfers. Repeated mechanical injury during activity or sport is a possible nidus for osteoarthritis in larger joints7-9 and may also affect smaller weight-bearing joints, such the first MTP joint in golfers. Current, well-established, and efficacious therapy for osteoarthritis includes the use of topical and oral analgesics, such as nonselective NSAIDs and selective cyclo-oxygenase-2 (COX-2) inhibitors to relieve symptoms and disability. However, long-term nonselective NSAID and COX-2 inhibitor use is also associated with adverse gastrointestinal and cardiovascular events,10,11 a point that is of particular concern with older patients. HA is a natural, complex component of synovial fluid and cartilage that decreases in concentration and molecular weight in osteoarthritis.12 Replacement of HA (ie, viscosupplementation) has multiple effects on molecular weight and HA concentration in synovial fluid that, in part, relates to improved symptoms.2 Hence, determining the efficacy of intra-articular HA therapy should include assessment of functional changes (eg, symptoms with walking and stepping activity) in addition to standard pain and disability assessment.13 Viscosupplementation with intra-articular HA appears to extend pain relief beyond the product's biological kinetics.14 The structure-modifying effects (eg, improved chondrocyte density, reduced synovial inflammation, increased synovial repair process) in the osteoarthritic joint may relate to pain relief,4,12,15 and this is an area of active investigation. While the evidence regarding viscosupplementation with HA in the knee continues to evolve,2 limited evidence and experience exist with other joints, and none, to our knowledge, is known in small articular joints. In two limited studies6,16 in patients who had painful shoulders, intra-articular HA injection improved pain and function; therefore, similar efficacy in other articular joints requires ongoing investigation. Limitations. The present study had several limitations that could affect the general applicability of the results. This unblinded, open-label, unrandomized trial had no active comparator among a small number of otherwise healthy subjects. Future studies should include larger subject numbers to achieve appropriate statistical power and use a randomized design that would include an active comparator treatment arm to further address efficacy and safety. We used a 1.0-mL HA intra-articular injection administered once weekly over 8 consecutive weeks. This was based on the clinical experience of the primary investigator with differing volumes and treatment schedules in this population and was in accordance with previous weekly treatment schedules for HA in the knee. Formal dose-response studies would determine the optimal treatment course for osteoarthritis of the first MTP joint. Conclusions and Recommendations HA injection produced a significant, long-term improvement in pain and function in older patients who had osteoarthritis of the first MTP joint. Because of the small articular space, we used 1.0 mL of HA without any associated local and systemic adverse events. The regimen used in this study produced high patient satisfaction, was associated with limited need for concomitant therapies during follow-up, and appeared acceptable as a repeated, long-term therapeutic option. References Creamer P, Hochberg MC: Osteoarthritis. Lancet 1997;350(9076):503-508 Maheu E, Ayral X, Dougados M: A hyaluronan preparation (500-730 kDa) in the treatment of osteoarthritis: a review of clinical trials with Hyalgan. Int J Clin Pract 2002;56(10):804-813 Petrella RJ, DiSilvestro MD, Hildebrand C: Effects of hyaluronate sodium on pain and physical functioning in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled clinical trial. Arch Intern Med 2002;162(3):292-298 Frizziero L, Govoni E, Bacchini P: Intra-articlar hyaluronic acid in the treatment of osteoarthritis of the knee: clinical and morphological study. Clin Exp Rheumatol 1998;16(4):441-449 Altman RD, Moskowitz R: Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteoarthritis of the knee: a randomized clinical trial. Hyalgan Study Group. J Rheumatol 1998;25(11):2203-2212 Leardini G, Perbellini A, Franceschini M, et al: Intra-articular injections of hyaluronic acid in the treatment of painful shoulder. Clin Ther 1988;10(5):521-526 Spector TD, Cicuttini F, Baker J, et al: Genetic influences on osteoarthritis in women: a twin study. BMJ 1996;312(7036):940-943 Kujala UM, Kaprio J, Sarna S: Osteoarthritis of weight bearing joints of lower limbs in former elite male athletes. BMJ 1994;308(6923):231-234 Carrabba M, Paresce E, Angelini M, et al: The safety and efficacy of different dose schedules of hyaluronic acid in the treatment of painful osteoarthritis of the knee with joint effusion. Eur J Rheumatol Inflam 1995;15:25-31 White WB, Whelton A: Cardiovascular events and COX-2 inhibitors. JAMA 2001;286(22):2811-2812 Johnson AG, Nguyen TV, Day RO: Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med 1994;121(4):289-300 Listrat V, Ayral X, Patarnello F, et al: Arthroscopic evaluation of potential structure modifying activity of hyaluronan (Hyalgan) in osteoarthritis of the knee. Osteoarthritis Cartilage 1997;5(3):153-160 Bellamy N, Kirwan J, Boers M, et al: Recommendations for a core set of outcome measures for future phase III clinical trials in knee, hip, and hand osteoarthritis: consensus development at OMERACT III. J Rheumatol 1997;24(4):799-802 Kotz R, Kolarz G: Intra-articular hyaluronic acid: duration of effect and results of repeated treatment cycles. Am J Orthop 1999;28(11 suppl):5-7 Pasquali Ronchetti I, Guerra D, Taparelli F, et al: Morphological analysis of knee synovial membrane biopsies from a randomized controlled clinical study comparing the effects of sodium hyaluronate (Hyalgan) and methylprednisolone acetate (Depomedrol) in osteoarthritis. Rheumatology (Oxford) 2001;40(2):158-169 Rovetta G, Monteforte P: Intraarticular injection of sodium hyaluronate plus steroid versus steroid in adhesive capsulitis of the shoulder. Int J Tissue React 1998;20(4):125-130 Dr Petrella is the medical director at the Canadian Centre for Activity and Ageing and associate professor at the University of Western Ontario, both in London, Ontario. Dr Cogliano is staff physician at the Fowler-Kennedy Sport Medicine Clinic at the University of Western Ontario. Address correspondence to Robert J. Petrella, MD, PhD, Heart Health and Exercise Laboratory, Centre for Activity and Ageing, 1490 Richmond St, London, Ontario, Canada N6G 2M3; e-mail to petrella@uwo.ca. Disclosure information: Drs Petrella and Cogliano disclose no significant relationship with any manufacturer of any commercial product mentioned in this article. No drug is mentioned in this article for an unlabeled use. RETURN TO JULY 2004 TABLE OF CONTENTS HOME  |   JOURNAL  |   PERSONAL HEALTH  |   RESOURCE CENTER  |   CME  |   ADVERTISER SERVICES  |   ABOUT US  |   SEARCH