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1 [ Synovial Fluid Replacement ] Sodium Hyaluronate Aiding Recovery After Arthroscopy

[Post-arthroscopic changes to the Arthroscopy Arthroscopic surgery is a valuable technique that has brought significant benefit to millions of patients.

However, arthroscopy may be associated with some surgical trauma, the most important features of which are pain, swelling and reduced joint mobility.

distending the tissues, washing out debris and controlling any mild bleeding.

It is a biopolymer made of repeating disaccharide units, which gives the synovial fluid its characteristic viscoelastic properties.

2 [Post-arthroscopic changes to the Arthroscopy Arthroscopic surgery is a valuable technique that has brought significant benefit to millions of patients. The procedure minimises disruption of the tissues surrounding the joint and has fewer postoperative problems than open surgery. However, arthroscopy may be associated with some surgical trauma, the most important features of which are pain, swelling and reduced joint mobility. 1 Synovial fluid is flushed out of the joint during arthroscopy During arthroscopy, the joint is flushed with irrigating solution to improve visualisation by distending the tissues, washing out debris and controlling any mild bleeding. Irrigation also leads to a loss of the synovial fluid, which is vital for joint function. in the synovial fluid is an essential component of the synovial fluid. It is a biopolymer made of repeating disaccharide units, which gives the synovial fluid its characteristic viscoelastic properties. It enables the fluid to act as a lubricant, a shock absorber and a filter controlling the movement of cells and large molecules within the joint. 2,3 Under gradual shear stress, hyaluronan acts as a lubricant Under sudden loading, hyaluronan acts as a shock absorber acts as a filter, hindering the movement of potentially damaging cells and molecules

articular environment] in the cartilage and synovial membrane forms a coating over the surface of the articular cartilage and the synovial membrane.

5,6 In addition, the coating hinders the migration of free radicals and other inflammatory cells into the joint space.

3 articular environment] in the cartilage and synovial membrane forms a coating over the surface of the articular cartilage and the synovial membrane. 4 This coating acts as a viscoelastic shield, protecting the joint structures from mechanical damage. also protects from pain by masking the local nociceptors. 5,6 In addition, the coating hinders the migration of free radicals and other inflammatory cells into the joint space. 7 9 also forms the backbone of the proteoglycan aggregates that are essential for the structural and functional integrity of the articular cartilage. 1,11 Cartilage Synovial membrane layer Collagen Chondrocyte layer Pain receptor Macrophage-like synoviocyte Proteoglycan monomer Fibroblast-like synoviocyte backbone Consequences of the irrigation procedure During arthroscopy, the joint is flushed with irrigating solution, which washes out the synovial fluid and, therefore, hyaluronan from the joint. This displacement of hyaluronan leads to: loss of viscoelastic properties, shock absorption 1 and lubrication, causing stiffness and pain 8 loss of the protective hyaluronan coating of the cartilage and synovium, leaving these structures 6 open to inflammatory mediators and mechanical damage 4 loss of the masking effect on nociceptors, 2 resulting in increased pain. Index of cartilage metabolism p <.5 vs control In addition, the irrigating solutions used during arthroscopy may have a negative effect on the metabolism of articular cartilage Control Ringer s solution Ringer s glucose Ringer s lactate Normal saline The irrigating solutions used during arthroscopy impair cartilage metabolism 14 Betadine Post-arthroscopic symptoms may be associated with loss of hyaluronan from the joint Aiding Recovery After Arthroscopy

4 [Rationale for hyaluronan as a Once the synovial fluid is flushed out of the joint, the balance of the articular environment is lost. Replacement of the synovial fluid with hyaluronan may promote restoration of homeostasis inside the joint. Restoring the articular homeostasis Studies have shown that exogenous hyaluronan: restores cartilage metabolism following the physiological disturbance caused by irrigating solution 15,16 protects the articular cartilage and synovial membrane from damage through its functional and structural properties suppresses chondrolysis of cartilage by reducing penetration of fibronectin fragments 4 restores cartilage glycosaminoglycan content following 6 weeks of joint immobilisation; in addition, treatment with remobilisation and hyaluronan increased glycosaminoglycan content more than remobilisation alone 26 promotes repair of degraded cartilage, reverses the damage caused by exposure to fibronectin or interleukin-1, and restores proteoglycan to normal levels 27 promotes meniscal regeneration following meniscectomy and appears to inhibit degeneration of articular cartilage for up to 6 months 28,29 stimulates collagen remodelling and inhibits swelling during healing of meniscal tears in a rabbit model of total medial meniscectomy 3 stimulates the synthesis of endogenous hyaluronan 31 promotes wound healing 32 and the healing response following surgical laceration of the anterior cruciate ligament in rabbit models S-sulphate incorporation into proteoglycans (dpm) Control Saline (7 days) p <.1 Saline plus 5 mg/ml hyaluronan Saline irrigation significantly inhibits cartilage metabolism, as shown by reduced 35 S-sulphate incorporation into proteoglycans. It is restored to normal by the addition of hyaluronan 16 Meniscal regeneration (%) p <.5 Saline Proportion of cases (%) Not covered Saline Partially covered Completely covered Status of ACL laceration after 12 weeks Following partial meniscectomy, hyaluronan promotes meniscal regeneration compared with saline 29 Exogenous hyaluronan stimulates healing of damage to the anterior cruciate ligament (ACL) 33

5 synovial fluid replacement] Introduction of exogenous hyaluronan into the joint space immediately after arthroscopy decreases postoperative symptoms. has been shown to accelerate joint recovery by reducing pain and swelling, and improving joint function. Clinical benefit has also been shown to achieve symptomatic relief by: reducing pain in the joint caused by pain mediators. 5,34,35 3 p <.5 vs control Algesic score 2 1 Control 31 kda 86 kda 23 kda 5 mg/ml Exogenous hyaluronan reduces joint pain induced by pain mediators 5 In combination with arthroscopic surgery or lavage, hyaluronan is effective in: reducing pain and improving joint mobility in patients with chronic joint derangement protecting the joint and facilitating surgery 4 relieving postoperative pain of the knee joint. 39 Index of joint pain p <.5 vs pre-treatment Control Painless ROM Control Months after start of treatment Days after arthroscopy Exogenous hyaluronan reduces pain in patients with chronic joint derangement 38 improves painless range of movement (ROM) compared with standard procedure after arthroscopy 39 Post-arthroscopic recovery may be aided by administration of exogenous hyaluronan Aiding Recovery After Arthroscopy

6 [ : product characteristic What is? is indicated for relief of pain and promotion of joint recovery following arthroscopy or joint lavage. Composition is an isotonic solution of hyaluronan with a physiological ph that is designed to be used as a synovial fluid substitute. The concentration of hyaluronan in is.5%, similar to that in synovial fluid. Fermentation source The hyaluronan in is produced by bacterial fermentation. is a highly purified product; because it contains no animal protein contamination, the allergenic potential of is negligible. Presentation is presented in a 1-mL, mono-use container equipped with a Luer tip and packaged in a sealed sterile sachet. Sterility mono-use containers are terminally sterilised by autoclaving. The device is sterile when packaged in order to facilitate aseptic use in a surgery theatre.

s and administration] How does work? Following arthroscopy, displaces any irrigating solution left in the joint space, preventing this solution from impairing cartilage metabolism.

: restores the lubricating, shock-absorbing and filtering properties of the fluid re-establishes the protective coating over the surface of the cartilage and the synovial membrane, hindering the

7 s and administration] How does work? Following arthroscopy, displaces any irrigating solution left in the joint space, preventing this solution from impairing cartilage metabolism. acts as a temporary substitute for the synovial fluid, restoring normal physiological functions. : restores the lubricating, shock-absorbing and filtering properties of the fluid re-establishes the protective coating over the surface of the cartilage and the synovial membrane, hindering the migration of pro-inflammatory and catabolic mediators and protecting from mechanical damage reduces inflammation of the synovium alleviates pain by masking nociceptors enhances the production of endogenous hyaluronan. substitutes for synovial fluid and displaces the irrigating solution left in the joint How to administer? is introduced into the joint space at the end of arthroscopic surgery, immediately after completion of the irrigation procedure. can be administered by two alternative techniques: attach the Luer tip of the container to the portal already placed in the joint. Squeeze the container to introduce into the joint aspirate the contents of the container into a syringe. Inject into the joint cavity through a portal already placed in the joint. If a drain is placed in the operated joint, introduce and manipulate the joint for several minutes before opening the drain. is designed to aid recovery after arthroscopy Aiding Recovery After Arthroscopy

8 [ accelerates post- General pain relief 5 In a clinical study of patients who underwent knee arthroscopy, those treated with reported a significant reduction in pain, measured on the 1 mm visual analogue scale (VAS), compared with those who underwent the standard procedure with saline lavage only. The improvement was significant 1 week after surgery (p <.1) and was maintained for at least 1 month. 41 VAS p <.1 (n = 48) Control (n = 45) Days Post-surgery, reduces pain on the VAS compared to the standard procedure 41 Pain relief and functional improvement 6 5 p.1 Bupivacaine confers advantages over anaesthetic (bupivacaine) 3 6 weeks after arthroscopy. 42 In a randomised study, patients undergoing arthroscopy received 1 ml of bupivacaine.5% or following surgery. Patients who received had significantly less pain measured on the VAS, required significantly less analgesia and had a significant improvement in function demonstrated by a larger decrease in WOMAC score (p.5) than patients who received bupivacaine. VAS (cm) Pre-op 2 h Day 1 Day 7 Week 3 Week 6 reduces pain on weight bearing according to the 1 cm VAS compared with bupivacaine p.2 Bupivacaine 5 4 p <.5 Bupivacaine Number of tablets WOMAC score Pre-op 2 h Day 1 Day 7 Week 3 Week 6 Pre-op Day 1 Day 7 Week 3 Week 6 Post-arthroscopy, reduces the need for analgesics compared with bupivacaine 42 Post-arthroscopy, reduces the mean WOMAC score compared with bupivacaine 42

9 arthroscopic recovery] Reduction in joint swelling In another study involving patients who underwent arthroscopic partial meniscectomy and joint lavage, there was markedly less swelling in the joints of patients who received (n = 2), compared with those who did not (n = 2). This reduction in the severity of swelling remained apparent at day Patients without swelling (%) Control reduces postarthroscopic swelling compared with controls Days Effective in aiding recovery In the same study, patients treated with were more satisfied with their treatment than patients who underwent standard arthroscopy. Patients rated global efficacy over 1 month. At each time point, more patients in the arm rated efficacy as optimum/good than in the control arm. 43 Patients (%) Standard treatment Following arthroscopy, the percentage of patients who rated global efficacy as optimum or good was higher among the group than among the control group Day 7 Day 12 Day 28 promotes pain relief, reduces swelling and improves function in patients recovering from arthroscopy Aiding Recovery After Arthroscopy

10 [ : immediate and long- Rapid pain relief A synergistic effect is seen when is administered with a local anaesthetic. Following arthroscopic shoulder surgery, 58 patients were given either 1 ml plus 1 ml bupivacaine.5% or 2 ml bupivacaine alone. Patients treated with showed improved pain relief. Indeed, among 28 patients who received plus bupivacaine following arthroscopic shoulder surgery, 29% reported no pain 4 h after the operation compared with % in the bupivacaine group. 44 Number of patients No Following arthroscopy, pain relief was greater among patients who received than among those who did not 44 2 No pain Mild Moderate Severe Reduced analgesia consumption In the same study, at 4 h post-arthroscopy, 25% of patients who received plus bupivacaine required no further analgesia, whereas all of the patients in the bupivacaine arm required some form of analgesia. Moreover, only 11% of patients treated with plus bupivacaine required opiates compared with 33% of patients who received bupivacaine alone. 44 Number of patients No Following arthroscopy, patients who received required less analgesia than patients who received bupivacaine alone 44 None NSAIDs Paracetamol &/or Codeine NSAIDs & Coproxamol Opiates Reduced time to discharge from hospital In addition to experiencing less pain, the 28 patients who received plus bupivacaine were discharged in half the time taken to discharge those who received bupivacaine alone (5.2 vs 9.6 h; p =.1). 44

11 term outcomes] Long-lasting benefits Patients scheduled to undergo arthroscopy for degenerative osteoarthritis of the knee were randomised to (n = 36) or standard treatment (n = 38). 45 The relative benefit of on pain when walking remained apparent 1 year after arthroscopy. Patients without pain (%) Standard treatment reduced pain, when walking 1 m, for at least 1 year after arthroscopy 45 Pre-treatment 2 weeks 3 months 1 year Time after arthroscopy Patients in the arm also gave superior ratings for clinical global impression compared with those in the standard treatment arm. Patients (%) Standard treatment The percentage of patients who rated their global impression of treatment as clearly improved or no complaints was higher with than with standard treatment h 2 weeks 3 months 1 year Time after arthroscopy Safety The studies conducted with have demonstrated the excellent safety profile of treatment. No adverse events relating to have been reported in studies provides both short- and long-term post-arthroscopic efficacy and has an excellent safety profile Aiding Recovery After Arthroscopy

12 [ References ] 1. Arthroscopy. In: Metcalf RW, ed. Textbook of Rheumatology. 4th edition. Philadelphia: Saunders, 1993: Chapter Balasz EA, Denlinger JL. J Rheumatol 1993;29(Suppl 39): Peyron JG. Osteoarthritis Cartilage 1993;1: Homandberg GA et al. Osteoarthritis Cartilage 1997;5: Gotoh S et al. Ann Rheum Dis 1993;52: Miyazaki K et al. Pharmacometrics 1984;28: Abatangelo G et al. Eur J Cell Biol 1989;49(Suppl 28): Goto H et al. Tohoku J Exp Med 1999;187: Kvam BJ et al. Exp Cell Res 1995;218: Hardingham TE, Muir E. Biochem Biophys Acta 1972;279: Hascall VC J Supramol Struct 1977;7: Reagan BF et al. J Bone Joint Surg Am 1983;65: Straehley D et al. Trans Orthop Res Soc 1985;1: Bulstra SK et al. J Bone Joint Surg Br 1994;76: Bulstra SK et al. Presented at the Annual Meeting of the Dutch Orthopaedic Society. May 17 18, Bulstra SK et al. Presented at the 45th Annual Meeting of the Orthopedic Research Society. February 1 4, Ghosh P et al. J Rheumatol Suppl 1995;43: Kikuchi T et al. Osteoarthritis Cartilage 1996;4: Sonoda M et al. Am J Sports Med 1997;24: Yoshioka M et al. Osteoartritis Cartilage 1997;5: Asari A et al. Arch Histol Cytol 1998;61: Shimizu C et al. Osteoarthritis Cartilage 1998;6: Suzuki Y et al. Arch Orthop Trauma Surg 1998;117: Wenz W et al. Z Orthop Ihre Grenzgeb 1998;136: Shimizu C et al. J Rheumatol 1998;25: Fu LLK et al. Clin Rheumatol 21;2: Homandberg GA et al. Osteoarthritis Cartilage 23;11: Hope N et al. Semin Arthritis Rheum 1993;22: Kobayashi K et al. Osteoarthritis Cartilage 2;8: Sonoda M et al. Am J Sports Med 2;28: Smith MM, Ghosh P. Rheumatol Int 1987;7: Chen WYJ, Abatangelo G. Wound Rep Reg 1999;7: Wiig ME et al. J Orthop Res 199;8: Gotoh S et al. Nippon Yakurigaku Zasshi 1988;92: Yamashita I et al. Nippon Sikeigakka Gakkai Zasshi 1995;69: Miyamoto H et al. Austr Dent J 1998;43: Hirota W et al. Br J Oral Maxillofac Surg 1998;36: Sato S et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84: Dai GF et al. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 22;16: McCain JP et al. J Oral Maxillofac Surg 1989;47: Villamor A et al. Presented at the 9th World Congress of the Osteoarthritis Research Society International. December 2 5, 24; poster P Anand S et al. Presented at the 9th World Congress of the Osteoarthritis Research Society International. December 2 5, 24; poster P Mathies B. Presented at the 8th World Congress of the Osteoarthritis Research Society International. October 12 15, 23; poster P Funk L, Wykes PR. Presented at the 9th World Congress of the Osteoarthritis Research Society International. December 2 5, 24; poster P Hempfling H. Presented at the 8th World Congress of the Osteoarthritis Research Society International. October 12 15, 23; poster P22. Caudex Medical Oxford UK TBRO445 5/5 - [ Prescribing information ] - VISCOSEAL :.5% Sodium Hyaluronate Synovial fluid substitute. 1 ml mono-use container in a sterile sachet. Sterile by moist heat. Composition: Each 1ml of solution contains: sodium hyaluronate 5. mg, sodium chloride, disodium-hydrogenphosphate, monosodium-hydrogenphosphate and water for injections. The solution is isotonic. Indication: To relieve pain, improve mobility and promote joint recovery by flushing out irrigating solution and substituting the synovial fluid following arthroscopic procedures or joint lavage. Directions for use: The contents and outer surface of the VISCOSEAL mono-use container are sterile as long as the sachet remains unbroken. VISCOSEAL should be used at the end of the arthroscopy after completion of the normal irrigating procedure. Remove the container from the sachet. Twist off the cap and remove the air bubble by squeezing the container. Attach its luer tip to a portal already placed in the joint. Introduce VISCOSEAL into the joint cavity by squeezing the container. This will help to wash out the remaining irrigating solution. Precautions: The general precautions for arthroscopic procedures should be observed. VISCOSEAL should be instilled accurately into the joint cavity. As VISCOSEAL does not contain preservatives any solution not used immediately after opening should be discarded. Do not use if the mono-use container or sterile sachet are damaged. Store at below 25ºC. Do not use after the expiry date indicated on the box. Keep out of the reach of children. Contra-Indications: Known hypersensitivity to any of the constituents of the product. Interactions: No information on the incompatibility of VISCOSEAL with other solutions for intra-articular use is available to date. Characteristics and mode of action: Arthroscopy is a common procedure to visualise, diagnose and treat problems inside a joint. The joint is normally irrigated with solutions such as saline or Ringer lactate before and during arthroscopy in order to allow a clear view of the operation site and to rinse out debris. There is evidence that the presence of these solutions in the joint after irrigation may be detrimental to the cartilage. Furthermore, during the procedure the synovial fluid, which has particular viscoelastic and protective properties due to its hyaluronic acid content, is washed from the joint. Therefore, although the intervention may result in a long-term improvement of joint function, in the short-term patients may suffer from post-arthroscopy complaints like pain, swelling and impaired mobility of the joint. VISCOSEAL has been developed to relieve these symptoms and promote joint recovery. It contains a highly purified specific fraction of hyaluronic acid produced by fermentation and is devoid of animal protein. Flushing VISCOSEAL through the joint cavity will help remove the remaining irrigating solution and efficiently coat all surfaces of the joint. The VISCOSEAL left in the joint will act as a lubricant and a shock absorber and its macromolecular meshwork will prevent the free passage of inflammatory cells and molecules through the joint cavity. In addition, hyaluronic acid is able to promote wound healing. Presentation: 1 x 1ml mono-use container of VISCOSEAL in a sterile sachet. To be used under the direction of a physician. Med IC3 Keele University Science Park, Keele, Staffordshire, ST5 5NP Tel: Fax:

Restoring Synovial Balance Designed for long-term relief in OA

44343.qxd 7/11/6 1:47 am Page 1 Restoring Synovial Balance Designed for long-term relief in OA 44343.qxd 7/11/6 1:47 am Page 2 Ostenil Osteoarthritis is a degenerative joint disease that causes pain and