Intra-articular Injections

National Clinical Guideline Centre (UK)

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National Clinical Guideline Centre (UK). Osteoarthritis: Care and Management in Adults. London: National Institute for Health and Care Excellence (UK); 2014 Feb. (NICE Clinical Guidelines, No. 177.)

A new version of this title is available

Update information: December 2020: in the recommendation on adding opioid analgesics NICE added links to other NICE guidelines and resources that support discussion with patients about opioid prescribing and safe withdrawal management. For the current recommendations, see www.nice.org.uk/guidance/CG177/chapter/recommendations.

Update information: December 2020: in the recommendation on adding opioid analgesics NICE added links to other NICE guidelines and resources that support discussion with patients about opioid prescribing and safe withdrawal management. For the current recommendations, see www.nice.org.uk/guidance/CG177/chapter/recommendations.

Osteoarthritis: Care and Management in Adults.

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10Intra-articular Injections

10.1. Introduction

Corticosteroids

Corticosteroid injections are used to deliver high doses of synthetic corticosteroids to a specific joint, while minimising systemic side effects. Corticosteroids have marked anti-inflammatory effects, and it is assumed that their analgesic action in osteoarthritis is in some way related to their anti-inflammatory properties. Certainly intra-articular corticosteroids can reduce the volume of synovitis of osteoarthritis³³⁸, however the relationship between osteoarthritis synovitis and pain is less clear. It is recognised that clinical examination is not sensitive in detecting inflammation (synovial hypertrophy or effusions) when compared with imaging methods such as ultrasonography or MRI⁹⁷, so clinical prediction of response to a corticosteroid injection is unreliable. The presence of an effusion is not in itself an indication for corticosteroid injection, unless there is significant restriction of function associated with the swelling. Rather, the indication should be based on severity of pain and disability.

Hyaluronans

Endogenous hyaluronan (HA, previously known as hyaluronic acid) is a large, linear glycosaminoglycan and is a major non-structural component of both the synovial and cartilage extracellular matrix. It is also found in synovial fluid and is produced by the lining layer cells of the joint. HA is removed from the joint via the lymphatic circulation and degraded by hepatic endothelial cells. Its key functions in the joint are to confer viscoelasticity, lubrication and help maintain tissue hydration and protein homeostasis by preventing large fluid movements and by acting as an osmotic buffer. Synthetic HA was isolated from roosters’ comb and umbilical cord tissue and developed for clinical use in ophthalmic surgery and arthritis in the 1960s. The beneficial effects in ophthalmic surgery were followed by the use of HA in osteoarthritis: the rationale was to replace the properties lost by reduced HA production and quality as occurs in osteoarthritis joints, a concept known as viscosupplementation. Commercial preparations of HA have the same structure as endogenous HA although cross-linked HA molecules (known as hylans) were later engineered by linking HA molecules in order to obtain greater elasto-viscosity and intra-articular dwell-time. However, the mechanism by which HA exerts its therapeutic effect, if any, is not certain, and evidence for restoration of rheological properties is lacking. It has been suggested that two stages might be involved; an initial biomechanical stage followed by a physiological stage. It is suggested that biomechanical mechanisms initially come into effect when the synovial fluid in the osteoarthritic joint is replaced by the higher molecular weight exogenous HA. Clinical studies report that exogenous HA is able to assist in restoring the elastoviscosity, and the lubricating and shock absorbing abilities, of synovial fluid. It is noted that physiological mechanisms may account for the clinical benefits of intra-articular administration of HA that persist beyond the residence time of HA, although evidence has largely been obtained from preclinical studies. Given the relatively short intra-articular residency (hours to days), any hypothesis for its mechanism of action must account for the sometime reported long-duration of clinical efficacy (months). CG 59 did not recommend the use of intra-articular hyaluronan injections. This update has prioritised a review of evidence published since CG59.

10.1.1. Methodological introduction: corticosteroids

We looked for studies that investigated the efficacy and safety of intra-articular injection of corticosteroid compared with placebo with respect to symptoms, function and quality of life in adults with osteoarthritis. One Cochrane systematic review and meta-analysis on knee osteoarthritis patients ²⁶ and 3 additional RCTs on osteoarthritis of the hip¹⁴⁶ ³⁶⁸^,³⁶⁸ or thumb ³⁰¹ were found. No relevant cohort or case-control studies were found.

The meta-analysis assessed the RCTs for quality and pooled together all data for the outcomes of symptoms, function and AEs. However, the outcome of quality of life was not reported. The results for quality of life have therefore been taken from the individual RCTs included in the systematic review.

The meta-analysis included 12 RCTs (with N=653 participants) on comparisons between intra-articular corticosteroids and intra-articular placebo injections in patients with knee osteoarthritis. Studies included in the analysis differed with respect to:

Type of corticosteroid used (1 RCT prednisolone acetate; 4 RCTs triamcinolone hexacetonide; 1 RCT methylprednisolone; 3 RCTs hydrocortisone solution; 2 RCTs triamcinolone acetonide; 1 RCT cortivazol; 1 RCT methylprednisolone acetate)
Treatment regimens
Trial design, size and length.

Tests for heterogeneity were performed for any pooled results, but no evidence of heterogeneity was found between studies that were combined. Unless otherwise stated, all evidence statements are derived from data presented in the systematic review and meta-analysis.

The three additional RCTs focused on the outcomes of symptoms, function and quality of life. The three included RCTs were similar in terms of osteoarthritis diagnosis (radiologically).

However, they differed with respect to osteoarthritis site, corticosteroid agent, and sample size.

10.1.2. Evidence statements: Intraarticular (IA) corticosteroids vs placebo

Knee

Overall, the evidence appraised by the Cochrane review suggests a short-term benefit (up to one week) in terms of pain reduction and patient global assessment after IA injections with corticosteroids in the knee. Beyond this period of time there were non-significant differences between IA corticosteroids and IA placebo as reported by most of the studies identified.

There was evidence of pain reduction between two weeks to three weeks but a lack of evidence for efficacy in functional improvement.

No significant differences between corticosteroids and placebo were reported at any time point by studies evaluating the following outcomes in patients with knee OA:

functional improvement (e.g. walking distance, range of motion)
Stiffness
quality of life
safety
study withdrawals.

Hip and Thumb

No conclusive results were observed in studies evaluating IA injections of corticosteroids and placebo in other joints affected by OA (i.e. hip and thumb).

Table 201

Pain in knee OA.

Table 202

Global assessment in knee OA.

Table 203

Pain in hip OA.

Table 204

Pain in thumb OA.

Table 205

Function in hip OA.

Table 206

Global assessment in hip OA.

Table 207

Global assessment in thumb OA.

Table 208

Adverse events in hip OA.

Table 209

Total withdrawals in thumb OA.

10.1.3. From evidence to recommendations

Corticosteroids

Generally the research evidence demonstrates that intra-articular corticosteroid injections provide short-term (1–4 weeks) reduction in osteoarthritis pain, although effects on function appear less marked. The effects have been best demonstrated for knee osteoarthritis, although there are some data for efficacy in hip and hand osteoarthritis. The GDG noted that these injections are widely used in many osteoarthritis sites. There is no clear message from this evidence on whether any particular corticosteroid preparation is more effective than another, or on which dose of a given preparation is most effective. In clinical practice, the short-term pain relief may settle flares of pain and also allow time for patients to begin other interventions such as joint-related muscle strengthening.

The risks associated with intra-articular corticosteroid injection are generally small. A small percentage of patients may experience a transient increase in pain following injection. Subcutaneous deposition of steroid may lead to local fat atrophy and cosmetic defect. Care should always be taken when injecting small joints (such as finger joints) to avoid traumatising local nerves. There is a very small risk of infection. The question of steroid-arthropathy, that is, whether intra-articular steroids may increase cartilage loss, remains controversial and is currently based on animal model and retrospective human studies. Nevertheless, caution should be applied if injecting an individual joint on multiple occasions and other osteoarthritis therapies should be optimised

10.1.4. Recommendations

33.: Intra-articular corticosteroid injections should be considered as an adjunct to core treatments for the relief of moderate to severe pain in people with osteoarthritis. [2008]

10.2. Intra-articular injections of hyaluronic acid/hyaluronans in the management of OA in the knee, hand, ankle, big toe and hip

10.2.1. What is the clinical and cost effectiveness of intra-articular injections of hyaluronic acid/hyaluronans in the management of OA in the knee, hand, ankle, big toe and hip?

For full details see review protocol in Appendix C.

Table 210

PICO characteristics of review question.

10.2.2. Clinical evidence

Due to the volume of evidence pertaining to hyaluronan intra-articular injections evidence statements are only presented for the outcomes predefined as critical by the GDG i.e pain, adverse events and quality of life. The full forest plots can be found in appendix I.5. The GDG noted that any degree of structure modification should be taken as clinically important, thus the MID chosen for structural modification outcomes was the line of no effect or zero.

OA Knee

One Cochrane review which included 76 studies ²⁷ comparing hyaluronans to placebo or active treatment in knee osteoarthritis was identified. In addition, 20 studies that were published after the Cochrane review were also identified⁶^,¹²^,³¹^,⁷²^,⁸⁴^,¹¹⁷^,²⁰⁰^,²¹⁰^,²²⁵^,²³⁴^,²⁴⁸^,²⁵⁷^,²⁷⁰^,³²⁸^,³⁴⁶^,³⁵⁶^,³⁵⁷^,⁴¹⁷^,⁴¹⁹^,⁴²⁰. Evidence from these are summarised in the clinical GRADE evidence profiles below. See also the study selection flow chart in Appendix D, forest plots in Appendix I, study evidence tables in Appendix G and exclusion list in Appendix J.

The protocol for this evidence review (see Appendix C) differed slightly from the protocol for the Cochrane review ²⁷. Any differences were agreed with the GDG. Due to this, we have excluded some papers that were included in the Cochrane review¹⁷^,²⁵^,¹¹⁸^,¹⁷⁰^,¹⁹⁹^,²³⁰^,³⁷⁴^,⁵⁰⁶. The reasons for exclusion are fully listed in Appendix J.
This review included all hyaluronan products, including those that are licensed and unlicensed for use in the UK, as requested by NICE
The comparisons reported in this review include placebo (saline) injections, NSAIDs, steroid injections, physiotherapy, exercise, conventional or appropriate care. There were eleven studies that compared one HA product to another and two studies that compared different numbers of injections of the same HA product.
The doses and treatment schedules used in the studies varied (see evidence tables, Appendix G).
No studies included in this review reported time to joint replacement
One study published after the Cochrane review was included but could not be analysed because it did not report data in a form that could be extracted³⁵⁶ (see Appendix G)
Where more than one result was reported for a time point the latest result was used. The only study where this was different was for Petrella (2006), who reported results at 6 and 12 weeks; results from week 6 were used in the meta-analysis because the 12 weeks results could not be used.
A fixed effects model was used for analysis unless there was significant heterogeneity which was unexplained by subgroup analysis, in which case a random effects model was used.

OA Hip

Five studies were identified which evaluated the use of hyaluronans in osteoarthritis of the hip. Four of these studies included licensed preparations ¹⁶^,¹⁶^,³⁶⁸^,⁴²⁸^,⁴⁴⁹ and one study looked at unlicensed preparations ³⁸³.
The comparisons included placebo (saline injections) and steroid injections.
The doses and treatment schedules used in the studies varied (see evidence tables, Appendix G).
One study reported data for efficacy measures in graphs and only adverse event data was extracted from this study for analysis ¹⁶.
None of the studies reported mean/minimum joint space width or time to joint replacement.

OA Ankle

Six studies were identified which evaluated the use of hyaluronans in osteoarthritis of the ankle. Three of these studies included licensed preparations ⁸²^,³⁹⁶^,⁵⁰⁰ and two studies used unlicensed preparations ¹⁰⁸^,²³².
The doses and treatment schedules used in the studies varied (see evidence tables, Appendix G).One study compared different doses and treatment schedules for the same hyaluronan (Orthovisc), but the efficacy measures were reported as medians and could not be included in the analysis. Only adverse event data was extracted from this study ⁵⁰⁰.
One study reported data for efficacy measures as percentage change from baseline in graphs. Data for only adverse events was extracted from this study ⁸². Another study also reported data for responder rate in graphs and this was not extracted or analysed ³⁹⁶.
None of the studies reported mean/minimum joint space width or time to joint replacement.

OA Base of thumb

Four studies were identified which evaluated the use of hyaluronans in osteoarthritis of the trapezio-metacarpal joint. All studies included licensed preparations ¹⁸
One study reported the Mann-Whitney test scores for its efficacy measures and not the actual results, hence was not included in the analysis ¹⁵⁶. Another study was an open label study ¹⁸.
The doses and treatment schedules used in the studies varied (see evidence tables, Appendix G).
None of the studies reported WOMAC pain, WOMA function, WOMAC stiffness, mean/minimum joint space width or time to joint replacement.

OA Great toe

Two studies were identified which evaluated the use of hyaluronans in osteoarthritis of the first metatarsophalangeal joint. Both included licensed preparations ³²⁰^,³⁶⁴.
Both studies compared single injections of hyaluronans. However, the products used were different and one study compared hyaluronan to saline injection ³²⁰ whereas the second study compared it to triamcinolone acetonide ³⁶⁴.
Neither study reported WOMAC pain, WOMAC function, WOMAC stiffness, mean/minimum joint space width or time to joint replacement.

Table 211

Summary of studies included in the review.

Knee OA

Table 212

Clinical evidence profile Knee OA- Hyalgan (licensed product) vs placebo.

Table 213

Clinical evidence profile: Knee OA-Hylan GF 20 (licensed product) vs placebo.

Table 214

Clinical evidence profile: Knee OA-Orthovisc (licensed product) vs placebo.

Table 215

Clinical evidence profile: Knee OA-BioHy (licensed product) vs placebo.

Table 216

Clinical evidence profile: Knee OA-Durolane (licensed product) vs placebo.

Table 217

Clinical evidence profile: Knee OA-Suplasyn (licensed product) vs placebo.

Table 218

Clinical evidence profile: Knee OA-Hyalgan (licensed product) vs NSAID.

Table 219

Clinical evidence profile: Knee OA-Hylan GF-20(licensed product) vs NSAID.

Table 220

Clinical evidence profile: Knee OA-Suplasyn (licensed product) vs NSAID.

Table 221

Clinical evidence profile: Knee OA-Hylan GF 20 (licensed product) vs Triamcinolone.

Table 222

Clinical evidence profile: Knee OA- Durolane (licensed product) vs Triamcinolone.

Table 223

Clinical evidence profile: Knee OA- Ostenil (licensed product) vs triamcinolone.

Table 224

Clinical evidence profile: Knee OA- Hyalgan (licensed product) vs methylprednisolone.

Table 225

Clinical evidence profile: Knee OA- Orthovisc (licensed product) vs methylprednisolone.

Table 226

Clinical evidence profile: Knee OA- Orthovisc (licensed product) vs betamethasone.

Table 227

Clinical evidence profile: Knee OA- Hylan GF-20 (licensed product) vs Physiotherapy.

Table 228

Clinical evidence profile: Knee OA- Orthovisc (licensed product) vs Physiotherapy.

Table 229

Clinical evidence profile: Knee OA-Hyalgan (licensed product) following knee arthroscopy with lavage vs conventional treatment (knee arthroscopy with lavage alone).

Table 230

Clinical evidence profile: Knee OA-Hylan GF-20 (licensed product) vs ‘conventional treatment for osteoarthritis’ (the paper provides no more detail on the control arm).

Table 231

Clinical evidence profile: Knee OA- Artz (unlicensed product) vs placebo.

Table 232

Clinical evidence profile: Knee OA- Adant (unlicensed product) vs placebo.

Table 233

Clinical evidence profile: Knee OA- NRD-101 (unlicensed product) vs placebo.

Table 234

Clinical evidence profile: Knee OA- Artz (unlicensed product) vs corticosteroid.

Table 235

Clinical evidence profile: Knee OA- Artz (unlicensed product) vs exercise.

Table 236

Clinical evidence profile: Knee OA- Hyalgan (licensed product) vs Hylan GF-20 (licensed product).

Table 237

Clinical evidence profile: Knee OA-BioHy (licensed product) vs Hylan GF-20 (licensed product).

Table 238

Clinical evidence profile: Knee OA- Orthovisc (licensed product) vs Hylan GF-20 (licensed product).

Table 239

Clinical evidence profile: Knee OA- Hylan GF20 (licensed product) vs Sinovial (licensed product).

Table 240

Clinical evidence profile: Knee OA- Adant (unlicensed product) vs Hyalgan (licensed product).

Table 241

Clinical evidence profile: Knee OA- Fermathron (licensed product) vs Hyalart (unlicensed product).

Table 242

Clinical evidence profile: Knee OA- Hylan GF 20 (licensed product) vs Variofill (unlicensed product).

Table 243

Clinical evidence profile: Knee OA-Hyruan (unlicensed product) vs Hyalart (unlicensed product).

Table 244

Clinical evidence profile: Knee OA- Go-On (unlicensed product) vs Hyalgan (licensed product).

Table 245

Clinical evidence profile: Knee OA- SLM-10 (unlicensed product) vs Artz (unlicensed product).

Table 246

Clinical evidence profile: Knee OA- Zeel compositum (unlicensed product) vs Hyalart (unlicensed product).

Table 247

Clinical evidence profile: Knee OA- Hylan GF 20 (licensed product): 1 × 6mL injection vs 1 × 4mL injection vs 2 × 4mL injections vs 3 × 4mL injections vs 3 × 2mL injections.

Table 248

Clinical evidence profile: Knee OA- Hyalgan (licensed product): 5 injections vs 3 injections.

Table 249

Clinical evidence profile: Knee OA- Orthovisc (licensed product): 4 injections vs 3 injections.

Table 250

Clinical evidence profile: Knee OA- HA- no product specified (unlicensed product): 6 injections vs 3 injections.

Hip OA

Table 251

Clinical evidence profile: Hip OA- Hyalgan (licensed product) vs Saline.

Table 252

Clinical evidence profile: Hip OA- Durolane(licensed product) vs Saline.

Table 253

Clinical evidence profile: Hip OA: Hyalgan (licensed product) vs Methylprednisolone.

Table 254

Clinical evidence profile: Hip OA- Hylan G-F 20 (licensed product) vs Methylprednisolone.

Table 255

Clinical evidence profile: Hip OA-Durolane (licensed product) vs Methylprednisolone.

Table 256

Clinical evidence profile: Hip OA- Durolane (licensed product) vs Standard care.

Table 257

Clinical evidence profile: Hip OA- Adant (unlicensed product) vs Saline.

Table 258

Clinical evidence profile: Hip OA- Ostenil (licensed product) vs Hylan G-F 20.

Ankle OA

Table 259

Clinical evidence profile: Ankle OA-Hyalgan (licensed product) vs Saline.

Table 260

Clinical evidence profile: Ankle OA- Supartz (unlicensed product) vs Saline.

Table 261

Clinical evidence profile: Ankle OA- Adant (unlicensed product) vs Exercise.

Base of thumb OA

Table 262

Clinical evidence profile: Base of thumb OA- Synvisc (licensed product) vs Saline.

Table 263

Clinical evidence profile: Base of thumb OA- Ostenil (licensed product) vs Triamcinolone.

Table 264

Clinical evidence profile: Base of thumb OA- Orthovisc (licensed product) vs Methylprednisolone.

Table 265

Clinical evidence profile: Base of thumb OA- Synvisc (licensed product) vs Betamethasone.

First MTP joint OA

Table 266

Clinical evidence profile: First MTP joint OA- Synvisc (licensed product) vs Saline.

Table 267

Clinical evidence profile: First MTP joint OA- Ostenil (licensed product) vs Triamcinolone.

10.2.3. Economic evidence

Evidence from CG59

Published literature

Four studies comparing hyaluronans with a relevant comparator were included²²⁸^,⁴⁵⁶^,⁴⁷⁸^,⁵⁰⁵. Three of the studies compared hyaluronans with some form of conventional care⁴⁵⁶^,²²⁸^,⁴⁷⁸, and one study compared hyaluronan with celecoxib and naproxen⁵⁰⁵.

However due to methodological limitations, the use of these papers was limited, and evidence statements could not be made from them. Therefore, these papers have been excluded from the guideline update – reasons for exclusion are summarised in Appendix K.

Original analysis

Additionally, an original cost-effectiveness analysis was conducted in CG59 which calculated the cost-effectiveness of hyaluronans using three placebo (saline) controlled RCTs⁴^,¹⁰⁰^,³⁶⁸ (included in the original guideline review). WOMAC scores were taken from the RCTs and mapped onto EQ-5D using the formula from Barton 2008²². Only direct costs of the interventions were considered, assuming one GP consultation per injection.

A summary of this CG59 analysis can be found in Appendix M. Evidence statements have not been drafted for the CG59 analysis as this has not been updated in this guideline update, and more weight was placed by the GDG on cost effectiveness and clinical evidence from the update guideline.

Evidence from update guideline

Published literature

One study was identified with the relevant intervention²⁸⁵. This study was selectively excluded due to a poor study design, lack of comparator, and non-UK setting. This study is summarised in Appendix H, with reasons for exclusion given.

Unit costs

Relevant unit costs are provided in Table 268 below to aid consideration of cost effectiveness.

Table 268

Unit cost of hyaluronan and steroid products.

The table below shows an example of the costs of some of the hyaluronan products available, and also the cost of some steroid injection products for comparison.

Economic considerations

As well as the cost of the product, the time needed by the professional to administer the injection is also an additional cost, and the more injections needed then the higher the cost.

As an estimate, the average GP surgery consultation costs around £36.^h The injection may be given by a specialist such as a rheumatologist, instead of a GP, which will probably be associated with a higher cost.

The possibility of adverse events from the hyaluronan injections have also been highlighted in the cinical review. These would have treatment costs as well as health consequences associated with them.

10.2.4. Evidence statements

Clinical

10.2.4.1. OA Knee- licensed hyaluronans

Hyaluronan vs Placebo

Hyalgan

One study with 177 people with osteoarthritis of the knee suggested that Hyalgan and placebo may be similarly effective in reducing WOMAC pain at follow up less of than 13 weeks [LOW].

Two studies with 372 people with osteoarthritis of the knee suggested that Hyalgan and placebo may be similarly effective in reducing WOMAC pain at follow-up of more than 13 weeks [LOW].

Three studies with 482 people with osteoarthritis of the knee suggested that there may be fewer people with painful injections or injection site pain in the placebo group compared to the Hyalgan group at follow-up of more than 13 weeks, although there was some uncertainty surrounding this effect [LOW].

Hylan GF20

One study with 94 people with osteoarthritis of the knee suggested that Hylan GF20 and placebo may be similarly effective in reducing global pain measured on a VAS scale at follow up less of than 13 weeks [MODERATE].

Four studies with 233 people with osteoarthritis of the knee suggested that Hylan GF20 may be clinically more effective than placebo in improving WOMAC pain at follow up less of than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

One study with 30 people with osteoarthritis of the knee suggested that multiple injections of Hylan GF20 may be more clinically effective than placebo in improving WOMAC pain at follow-up of more than 13 weeks, although there was some uncertainty surrounding this effect [LOW].

One study with 243 people with osteoarthritis of the knee suggested that single injections of Hylan GF20 may not be more clinically effective than placebo in improving WOMAC pain at follow-up of more than 13 weeks, although there was some uncertainty surrounding this effect [LOW].

Five studies with 417 people with osteoarthritis of the knee suggested that there may be fewer patients with local reactions in the placebo group compared to people in the Hylan GF20 group at a follow up of less than 13 weeks [VERY LOW].

One study with 52 people with osteoarthritis of the knee suggested that there may be fewer patients with local reactions in the placebo group compared to people in the Hylan GF20 group at a follow up of more than 13 week, although there was some uncertainty surrounding this effect s [VERY LOW].

Orthovisc

Six studies with 449 people with osteoarthritis of the knee suggested that Orthovisc may be clinically more effective than placebo at reducing WOMAC pain at follow up less of than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

Five studies with 408 people with osteoarthritis of the knee suggested that Orthovisc may be clinically more effective than placebo at reducing WOMAC pain at follow-up of more than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

Three studies with 719 people with osteoarthritis of the knee suggested that there may be fewer people with adverse events (local skin rash) in the Orthovisc group compared to people in the placebo or arthroscopy (alone) groups at follow up of more than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

BioHy

One study with 588 people with osteoarthritis of the knee suggested that BioHy and placebo may be similarly effective in reducing WOMAC pain at follow-up of more than 13 weeks [MODERATE].

One study with 588 people with osteoarthritis of the knee suggested that and placebo may be similarly effective at improving health related quality of life (using SF 36) at follow-up of more than 13 weeks [MODERATE].

One study with 59 people with osteoarthritis of the knee suggested that there were fewer adverse events (injection site pain) in people in the placebo group compared to people in the BioHy group at follow-up of more than 13 weeks, although there was some uncertainty surrounding this effect [LOW].

Durolane

Two studies with 692 people with osteoarthritis of the knee suggested that Durolane and placebo may be similarly effective in improving WOMAC pain at follow up less of than 13 weeks [MODERATE].

One study with 346 people with osteoarthritis of the knee suggested that Durolane and placebo may be similarly effective in improving WOMAC pain at follow-up of more than 13 weeks [MODERATE].

One study with 347 people with osteoarthritis of the knee suggested there were fewer adverse events related to the injection in the Durolane group compared to the placebo group at follow-up of more than 13 weeks, although there was some uncertainty surrounding this effect [LOW].

Suplasyn

One study with 53 people with osteoarthritis of the knee suggested that Suplasyn and placebo may be similarly effective in reducing WOMAC pain at follow up of less than 13 weeks [MODERATE].

Hyaluronan vs NSAIDs

Hyalgan

One study with 240 people with knee osteoarthritis suggested that Hyalgan and Naproxen may be similarly effective in the reduction of pain measured on the VAS scale at follow up of less than 13 weeks [MODERATE].

One study with 216 people with knee osteoarthritis suggested that Hyalgan and Naproxen may be similarly effective in the reduction of pain measured on the VAS scale at follow up of more than 13 weeks follow up [MODERATE].

One study with 327 people with knee osteoarthritis showed that there may have been fewer people with injection site pain in the Naproxen group compared to the Hyalgan group at follow up of more than 13 weeks [MODERATE].

Hylan GF20

One study with 57 people with knee osteorarthritis suggested that Hylan GF20 and NSAID may be similarly effective in reducing pain measured on a VAS scale at follow up of less than 13 weeks [VERY LOW ].

One study with 58 people with knee osteoarthritis suggested that Hylan GF20 and NSAID may be similarly effective in reducing pain measured on a VAS scale at follow up of more than 13 weeks [VERY LOW].

One study with 108 people with knee osteoarthritis suggested that Hylan GF20 and NSAID may be similarly effective in reducing pain measured with a WOMAC scale at follow up of less than 13 weeks [LOW].

One study with 102 people with knee osteoarthritis suggested that fewer people had local adverse reactions in the NSAID group compared to people in the Hylan GF20 at follow up of less than 13 weeks [VERY LOW].

Suplasyn

One study with 54 people with knee osteoarthritis suggested that suplasyn and NSAID may be similarly effective in the reduction of pain measured on the WOMAC scale at follow up of less than 13 weeks [MODERATE].

Hyaluronan vs Triamcinolone

Hylan GF20

One study with 215 people with knee osteoarthritis suggested that Hylan GF20 and triamcinolone may be similarly effective in reducing pain measured on a WOMAC scale at follow up of less than 13 weeks [LOW].

One study with 215 people with knee osteoarthritis suggested that Hylan GF20 and triamcinolone may be similarly effective in reducting pain measured on a WOMAC scale at follow up of more than 13 weeks [LOW].

Durolane

One study with 60 people with knee osteoarthritis suggested that durolane and triamcinolone may be similarly effective in reducing pain measured on a VAS scale at follow up of less than 13 weeks [VERY LOW].

Ostenil

One study with 42 people with osteoarthritis of the knee suggested that ostenil and placebo may be similarly effective in the reduction of pain measured on a VAS scale as follow up of less than 13 weeks [VERY LOW].

Hyaluronan vs steroid

Hyalgan

No study included in this review reported critical outcomes of global pain (VAS or WOMAC), quality of life or adverse events.

Orthovisc

One study with 55 people with knee osteoarthritis suggested that people may have fewer skin adverse events in the methylprednisolone group compared to people who took orthovisc at follow up of more than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

One study with 55 people with knee osteoarthritis suggested orthovisc and methyprednislone may be similarly effective in the number of patients reporting knee pain at follow up of more than 13 weeks [VERY LOW].

Orthovisc vs betamethasone

No study in this comparison reported critical outcomes of global pain (VAS or WOMAC), quality of life or adverse events.

Hyaluronan vs physiotherapy

Hylan GF20

One study with 40 people with knee osteoarthritis suggested that Hylan GF20 may be clinically more effective than physiotherapy in reduction in pain measured on a WOMAC scale at follow up of less than 13 weeks, but there was some uncertainty [VERY LOW].

One study with 40 people with osteoarthritis of the knee suggested that Hylan GF 20 may be more clinically effective than physiotherapy at reducing pain measured on a WOMAC scale at follow up of more than 13 weeks [VERY LOW].

One study with 40 people with osteoarthritis of the knee suggested that Hylan GF20 and physiotherapy may be similarly effective at improving quality of life measured with SF36 (physical functioning domain) at follow up of less than 13 weeks [VERY LOW].

Orthovisc

One study with 40 people with osteoarthritis of the knee suggested that orthovisc and physical therapy may be similarly effective at reducing pain measured on the WOMAC scale at follow up of less than 13 weeks [VERY LOW].

One study with 40 people with osteoarthritis of the knee suggested that orthovisc may be more clinically effective than physical therapy in the reduction of pain measured on the WOMAC scale at follow up of more than 13 weeks, but there was some uncertainty [LOW].

One study with 40 people with osteoarthritis of the knee suggested that physical therapy may be more clinically effective than orthovisc in improving quality of life measured by SF36 (physical functioning domain) at follow up of less than 13 weeks, but there was some uncertainty [VERY LOW].

One study with 40 people with osteoarthritis of the knee suggested that physical therapy may be more clinically effective than orthovisc in improving quality of life measured by SF36 (physical functioning domain) at follow up of more than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

Hyaluronan vs conventional treatment

Hyalgan

One study with 36 people with osteoarthritis of the knee suggested that Hyalgan may be more clinically effective than conventional treatment in reducing pain measured on a VAS scale at follow up of more than 13 weeks, but there was some uncertainty [VERY LOW].

One study with 36 people with osteoarthritis of the knee suggested that Hyalgan and conventional treatment may be similarly effective at improving quality of life as measured by AIMS at follow up of more than 13 weeks [VERY LOW].

Hyaluronan vs appropriate treatment

Hylan GF 20

One study with 497 people with osteoarthritis of the knee suggested that Hylan GF 20 may be more clinically effective than appropriate care in reducing pain measured on the WOMAC scale at follow up of more than 13 weeks, although there was some uncertainty surrounding this effect [LOW].

10.2.4.2. OA Knee-unlicensed hyaluronans

Hyaluronan vs placebo

Artz

Three studies with 507 people with osteoarthritis of the knee showed that Artz and placebo may be similarly effective at reducing pain measured on the VAS scale at follow up of less than 13 weeks [HIGH].

Two studies with 312 people with osteoarthritis of the knee showed that Artz and placebo may be similarly effective at reducing pain measured on the VAS scale at follow up of more than 13 weeks [MODERATE].

One study with 223 people with osteoarthritis of the knee suggested that artz and placebo may be similarly effective at reducing pain measured on the WOMAC scale at follow up of less than 13 weeks [VERY LOW].

Adant

No study included in this comparison reported critical outcomes of global pain (VAS or WOMAC), quality of life or adverse events.

NRD-101

One study with 174 people with osteoarthritis of the knee showed that NRD-101 and placebo may be similarly effective at reducing pain measured on the VAS scale at follow up of more than 13 weeks [HIGH].

One study with 216 people with osteoarthritis of the knee suggested that fewer people who received oral placebo and placebo injection reported knee pain during or after injection compared to NRD-101 at follow up of more than 13 weeks, although there was some uncertainty surrounding this effect [LOW].

Hyaluronan vs steroid

Artz

One study with 51 people with osteoarthritis of the knee suggested that artz and corticosteroids are similarly effective in the reduction of pain measured on a VAS scale as follow up of less than 13 weeks [VERY LOW].

Hyaluronan vs exercise

Artz

One study with 87 people with osteoarthritis of the knee showed that artz and exercise may be similarly effective at reducing pain measured on a VAS scale as follow up of more than 13 weeks [LOW].

10.2.4.3. OA Knee: Hyaluronan product vs another Hyaluronan product- unlicensed or licensed

Hyalgan vs Hylan GF20

One study with 54 people with osteoarthritis of the knee suggested that people receiving hyalgan injections may have fewer local reactions (acute inflammation and pain) than people receiving Hylan GF20 at follow up of less than 13 weeks [VERY LOW].

BioHy vs Hylan GF20

One study with 321 people with osteoarthritis of the knee showed that BioHy and Hylan GF20 are similarly effective in the reduction of pain as measured with the WOMAC scale at follow up of less than 13 weeks [HIGH].

Orthovisc vs Hylan GF20

Three studies with 121 people with osteoarthritis of the knee suggested that Orthovisc and Hylan GF20 may be similarly effective in the reduction of pain as measured with the WOMAC scale at follow up of less than 13 weeks [VERY LOW].

Two studies with 81 people with osteoarthritis of the knee suggested that Orthovisc and Hylan GF20 may be similarly effective in the reduction of pain as measured with the WOMAC scale at follow up of more than 13 weeks [VERY LOW].

One study with 40 people with osteoarthritis of the knee showed that Hylan GF20 may be more clinically effective than Orthovisc at improving quality of life (physical functioning domain) measured with SF36 at follow up of less than 13 weeks [LOW].

One study with 40 people with osteoarthritis of the knee suggested that Hylan GF20 may be more clinically effective than Orthovisc at improving quality of life (physical functioning domain) measured with SF36 at follow up of more than 13 weeks, but there was some uncertainty [VERY LOW].

Two studies with 92 people with osteoarthritis of the knee suggested that there may be fewer local adverse events in the hylan GF20 group compared to the orthovisc group at follow up of more than 13 weeks [VERY LOW].

Hylan GF20 vs Sinovial

One study with 380 people with osteoarthritis of the knee suggested that Hylan GF 20 and Sinovial may be similarly effective in reducing WOMAC pain at follow up of less than 13 weeks [MODERATE].

One study with 381 people with osteoarthritis of the knee suggested that Hylan GF 20 and Sinovial and are similarly effective in the reduction of WOMAC pain at follow up of more than 13 weeks [MODERTE]

One study with 381 people with osteoarthritis of the knee suggested that people had fewer adverse events relating to injections in the Synovial group compared to the Hylan GF 20 group at follow up of more than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

Adant vs hyalgan

One study with 49 people with osteoarthritis of the knee suggested that people had fewer painful injections in the Hyalan group compared to the Adant group at follow up of less than 13 weeks [VERY LOW].

Fermathron vs hyalart

One study with 233 people with osteoarthritis of the knee suggested that fermathron and hylart were similarly effective in the reduction in pain measured on the VAS scale at follow up of less than 13 weeks [HIGH].

Hylan GF 20 vs Variofill

One study with 20 people with bilateral knee OA (40 knees) showed that Hylan GF 20 and Variofill may be similarly effective in improving VAS pain at follow up of less than 13 weeks [VERY LOW]

One study with 20 people with bilateral knee OA (40 knees) suggested that Variofill may be clinically more effective in improving VAS pain than Hylan GF 20 at follow up of more than 13 weeks, but there was some uncertainty [LOW]

One study with 20 people with bilateral knee OA (40 knees) showed that Hylan GF 20 and Variofill may be similarly effective in improving WOMAC pain at follow up of less than 13 weeks [LOW]

One study with 20 people with bilateral knee OA (40 knees) suggested that Variofill may be clinically more effective at improving WOMAC pain than Hylan GF 20 at follow up of more than 13 weeks, but there was some uncertainty [LOW]

Hyruan vs Hyal

One study which assessed 182 people with osteoarthritis of the knee suggested that there may be no clinically important difference between Hyruan and Hyal in the number of knees with swelling at injection site at follow up of less than 13 weeks [Very low quality].

One study which assessed 146 people with osteoarthritis of the knee suggested that there may be no clinically important difference between Hyruan and Hyal in the number of knees with tenderness at injection site at follow up of less than 13 weeks [Low quality].

Go-on vs Hyalgan

One study with 426 people with osteoarthritis of the knee showed that Go-on and Hyalgan may be similarly effective at improving VAS pain at follow up of more than 13 weeks [HIGH]

One study with 426 people with osteoarthritis of the knee showed that Go-on and Hyalgan may be similarly effective at improving WOMAC pain at follow up of more than 13 weeks [HIGH]

One study with 436 people with osteoarthritis of the knee showed that there may be no clinically important difference between Go-on and Hyalgan in the total number of people reporting adverse events at follow up of more than 12 weeks [MODERATE].

One study with 436 people with osteoarthritis of the knee suggested that there may be fewer patients who discontinue treatment due to adverse events in the Go-on group compared to the Hyalgan group at follow up of more than 12 weeks, although there was some uncertainty surrounding this effect [LOW].

SLM-10 vs artz

One study with 164 people with osteoarthritis of the knee suggested that there may be fewer local adverse events related to study drug resulting in withdrawals in the SLM-10 group compared to the artz group at follow up of less than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

One study with 164 people with osteoarthritis of the knee suggested that there may be no difference between SLM-10 and Artz in the number of local adverse events with no specific relationship to the study drug at follow up of less than 13 weeks [VERY LOW].

Zeel compositum vs hylart

No study included in this comparison reported critical outcomes of global pain (VAS or WOMAC), quality of life or adverse events.

10.2.4.4. OA knee: Hyaluronan product vs different doses of same Hyaluronan product

Hylagan: 5 injections vs 3 injections

No study included in this comparison reported critical outcomes of global pain (VAS or WOMAC), quality of life or adverse events.

Hylan GF 20: 1 ×6mL injection vs 1 × 4mL injection vs 2 × 4mL injection vs 3 × 4mL injection

One study with 41 people in the intervention groups of interest who had osteoarthritis of the knee suggested that fewer people had adverse events related to the injection in the 1 × 6mL injection group compared to the 1 × 4mL injection group at follow up of more than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

One study with 39 people in the intervention groups of interest who had osteoarthritis of the knee suggested that there was no difference between 1 × 6mL injection group and 2 × 4mL injection group in the number of people that experienced adverse event related to the injection [VERY LOW].

One study with 40 people in the intervention groups of interest who had osteoarthritis of the knee suggested that fewer people had adverse events related to the injection in the 1 × 6mL injection group compared to the 3 × 4mL injection group at follow up of more than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

One study with 40 people in the intervention groups of interest who had osteoarthritis of the knee suggested that there was no difference between 1 × 6mL injection and 3 × 2mL injection in the number of people that experienced adverse event related to the injection at follow up of more than 13 weeks [VERY LOW].

One study with 40 people in the intervention groups of interest who had osteoarthritis of the knee suggested that fewer people experienced adverse events related to the injection in the 1 ×4mL injection group compared to the 2 × 4mL injection group at follow up of more than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

One study with 41 people in the intervention groups of interest who had osteoarthritis of the knee suggested that fewer people had adverse events in the 1 × 4mL injections group compared to the 3 × 4mL injection group at follow up of more than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

One study with 41 people in the intervention groups of interest who had osteoarthritis of the knee suggested that fewer people receiving 3 × 2mL injection had fewer adverse events than people receiving the 1 × 4mL injection at follow up of more than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

One study with 39 people in the intervention groups of interest who had osteoarthritis of the knee suggested that fewer people receiving the 2 × 4mL injection experienced adverse events relating to the injection compared to people receiving 3 × 4mL injections at follow up of more than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

One study with 39 people in the intervention groups of interest who had osteoarthritis of the knee suggested that there was no difference between people receiving 2 × 4mL injections or the 3 × 2mL injection in the number of people experiencing adverse events related to the injection at follow up of more than 13 weeks [VERY LOW].

One study with 40 people in the intervention groups of interest who had osteoarthritis of the knee suggested that there may be fewer people who experienced adverse events relating to the injection in the 3 × 2mL injection group compared to the 3 × 4mL injection group at follow up of more than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

Orthovisc: 4 injections vs 3 injections

One study with 247 people with osteoarthritis of the knee suggested that there may be fewer patients with skin adverse events in the group who had 3 injections of orthovisc compared to the group who had 4 injections of orthovisc at follow up of more than 13 weeks [VERY LOW].

HA (no formulation stated): 6 injections vs 3 injections

One study with 106 people with osteoarthritis of the knee showed that there may be no clinically important difference between HA and placebo in the reduction of pain as measured on the WOMAC scale at follow up of less than 13 weeks [MODERATE].

One study with 106 people with osteoarthritis of the knee suggested that HA and placebo may be similarly effective in improving quality of life as measured by SF36 (physical function domain) at follow up of less than 13 weeks [MODERATE].

One study with 106 people with osteoarthritis of the knee suggested that HA and placebo may be similarly effective in improving quality of life as measured by SF36 (vitality domain) at follow up of less than 13 weeks [MODERATE].

Hyaluronan (no product stated): 6 injections vs 3 injections

One study with 106 people with osteoarthritis of the knee suggested that 6 injection and 3 injections of hyaluronan were similarly effective in the reduction in WOMAC pain at follow up of less than 13 weeks [MODERATE].

One study with 106 people with osteoarthritis of the knee suggested that 6 injection and 3 injections of hyaluronan are similarly effective in the improvement of SF36 (physical function) at follow up of less than 13 weeks [MODERATE].

One study with 106 people with osteoarthritis of the knee suggested that 6 injection and 3 injections of hyaluronan may be similarly effective in the improvement of SF36 (vitality) at follow up of less than 13 weeks [MODERATE].

10.2.4.5. OA Hip- licensed hyaluronans

Hyaluronan vs Saline

Hyalgan

One study with 69 people with osteoarthritis of the hip suggested that Hyalgan and saline may be similarly effective in reducing pain on walking measured on the visual analogue scale at follow up less of than 13 weeks [LOW].

Durolane

One study with 38 people with osteoarthritis of the hip suggested that people may have fewer adverse events in the saline group compared to Durolane with respect to adverse event profile at follow up less of than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

Hyaluronan vs Steroid

Hyalgan

One study with 65 people with osteoarthritis of the hip suggested that Hyalgan and methylprednisolone may be similarly effective in reducing pain on walking measured on the visual analogue scale at follow up less of than 13 weeks [LOW].

Hylan G-F 20

One study with 312 people with osteoarthritis of the hip showed that Hylan G-F 20 and methylprednisolone may be similarly effective at reducing pain measured on the WOMAC scale at follow up greater than 13 weeks [MODERATE].

One study with 312 people with osteoarthritis of the hip suggested that there may be no difference between Hylan G-F 20 and methylprednisolone with respect to adverse event profile at follow up greater than 13 weeks [LOW].

Durolane (licensed)

One study with 39 people with osteoarthritis of the hip suggested that people may experience fewer adverse events in the methylprednisolone group compared to the Durolane group with respect to adverse event profile at follow up less than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

Hyaluronan vs Standard care

Durolane

One study with 39 people with osteoarthritis of the hip suggested that standard care may be clinically more effective than Durolane with respect to adverse profile at follow up less than 13 weeks, but there was some uncertainty [VERY LOW]

10.2.4.6. OA Hip- unlicensed hyaluronans

Hyaluronan vs Saline

Adant

One study with 85 people with osteoarthritis of the hip suggested that Adant and saline may be simllarly effective in reducing pain measured on the WOMAC scale at follow up less of than 13 weeks [HIGH].

One study with 85 people with osteoarthritis of the hip suggested that Adant and saline may be similarly effective in reducing pain measured on the visual analogue scale at follow up less of than 13 weeks [HIGH].

One study with 85 people with osteoarthritis of the hip suggested that people may have fewer events in the saline group may be clinically more effective than Adant with respect to adverse event profile at follow up less of than 13 weeks [High quality].

10.2.4.7. OA Hip: Hyaluronan vs Hyaluronan (licensed preparations)

Ostenil vs Hylan G-F 20

One study with 43 people with osteoarthritis of the hip suggested that Ostenil and Hylan G-F 20 may be similarly effective in reducing pain measured on the visual analogue scale at follow up less than 13 weeks [VERY LOW].

One study with 56 people with osteoarthritis of the hip suggested people may have fewer adverse events in the Ostenil group compared to the Hylan G-F 20 group with respect to adverse event profile at follow up greater than 13 weeks [VERY LOW].

10.2.4.8. OA Ankle- licensed hyaluronans

Hyaluronan vs Saline

Hyalgan

One study with 17 people with osteoarthritis of the ankle suggested that Hyalgan may be clinically more effective than saline in improving quality of life measured by EQ5D (domain: no problem) at follow up greater than 13 weeks, but there was some uncertainty [VERY LOW].

One study with 17 people with osteoarthritis of the ankle suggested Hyalgan and saline may be similarly effective in improving quality of life measured by EQ5D (domain: some problem) at follow up greater than 13 week, although there was some uncertainty surrounding this effect s [LOW].

One study with 17 people with osteoarthritis of the ankle suggested that Hyalgan and saline may be similarly effective in improving quality of life measured by EQ5D (domain: unable to perform) at follow up greater than 13 weeks [LOW].

Two studies with 47 people with osteoarthritis of the ankle suggested that saline may be clinically more effective than Hyalgan with respect to adverse event profile at follow up greater than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].

10.2.4.9. OA Ankle- unlicensed hyaluronans

Supartz

One study with 56 people with osteoarthritis of the ankle suggested that Supartz and saline may be similarly effective in reducing pain measured on the visual analogue scale at follow up less than 13 weeks [LOW].

One study with 56 people with osteoarthritis of the ankle suggested that there may be no clinically important difference between Supartz and saline with respect to adverse event profile at follow up less than 13 weeks [LOW].

Hyaluronan vs Exercise

Adant

One study with 30 people with osteoarthritis of the ankle suggested that Adant and exercise may be similarly effective in reducing pain on activity measured on the visual analogue scale at follow greater than 13 weeks [VERY LOW].

One study with 30 people with osteoarthritis of the ankle suggested that Adant and exercise may be similarly effective in reducing pain at rest measured on the visual analogue scale at follow greater than 13 weeks [VERY LOW].

One study with 30 people with osteoarthritis of the ankle showed that there may be no clinically important difference between Adant and exercise with respect to adverse event profile at follow greater than 13 weeks [VERY LOW].

10.2.4.10. OA Base of thumb- licensed hyaluronans

Hyaluronan vs Saline

Synvisc

One study with 38 people with osteoarthritis of the base of thumb showed that there may be no clinically important difference between Synvisc and saline with respect to adverse event profile at follow up greater than 13 weeks [LOW].

Hyaluronan vs Steroid

Ostenil vs Triamcinolone

One study with 40 people with osteoarthritis of the base of thumb suggested that triamcinolone may be clinically more effective than Ostenil in reducing pain measured on the visual analogue scale at follow up less than 13 weeks, but there was some uncertainty [VERY LOW].

One study with 40 people with osteoarthritis of the base of thumb suggested that triamcinolone may be clinically more effective than Ostenil in reducing pain measured on the visual analogue scale at follow up of greater than 13 weeks, but there was some uncertainty [VERY LOW].

One study with 40 people with osteoarthritis of the base of thumb suggested that there may be no difference between Ostenil and triamcinolone with respect to adverse event profile at follow greater than 13 weeks [LOW].

Orthovisc vs Methylprednisolone

One study with 52 people with osteoarthritis of the base of thumb suggested that Orthovisc and methylprednisolone may be similarly effective in reducing pain on activity measured on the visual analogue scale at follow up less than 13 weeks [VERY LOW].

One study with 52 people with osteoarthritis of the base of thumb suggested that Orthovisc and methylprednisolone may be similarly effective in reducing pain at rest measured on the visual analogue scale at follow up less than 13 weeks [VERY LOW].

One study with 52 people with osteoarthritis of the base of thumb showed that there may be no difference between Orthovisc and methylprednisolone with respect to adverse event profile at follow up greater than 13 weeks [LOW].

Synvisc vs Betamethasone

One study with 42 people with osteoarthritis of the base of thumb showed that there may be no difference between Synvisc and betamethasone with respect to adverse event profile at follow up greater than 13 weeks[Low quality].

10.2.4.11. OA first MTP joint- licensed hyaluronans

Hyaluronan vs Saline

Synvisc

One study with 151 people with osteoarthritis of the first metatarsophalangeal joint suggested that Synvisc and saline may be similarly effective in improving quality of life measured by the physical component of SF36 at follow up less than 13 weeks [MODERATE].

One study with 151 people with osteoarthritis of the first metatarsophalangeal joint suggested that Synvisc and saline may be similarly effective in improving quality of life measured by the mental component of SF36 at follow up less than 13 weeks [LOW].

One study with 151 people with osteoarthritis of the first metatarsophalangeal joint suggested that Synvisc and saline may be similarly effective in improving quality of life measured by the mental component of SF36 at follow up greater than 13 weeks [MODERATE].

One study with 151 people with osteoarthritis of the first metatarsophalangeal joint suggested that people may have fewer adverse events in the Synvisc group compared to the saline group with respect to adverse event profile at follow up greater than 13 weeks, but there was some uncertainty [LOW].

Hyaluronan vs Steroid

Ostenil vs Triamcinolone

One study with 36 people with osteoarthritis of the first metatarsophalangeal joint suggested that Ostenil may be clinically more effective than triamcinolone in reducing pain on walking 20 metres measured on the visual analogue scale at follow up less than 13 weeks, but there was some uncertainty [VERY LOW].

One study with 36 people with osteoarthritis of the first metatarsophalangeal joint suggested that Ostenil and triamcinolone may be similarly effective in reducing pain at rest or palpation measured on the visual analogue scale at follow up less than 13 weeks [VERY LOW].

Economic

No relevant economic evaluations were identified.

10.2.5. Recommendations and link to evidence

Recommendations	34. Do not offer intra-articular hyaluronan injections for the management of osteoarthritis. [2014]
Relative values of different outcomes	The GDG considered that pain measured on WOMAC or a visual analogue scale (VAS), function, quality of life and adverse events profile to be the critical outcomes for decision-making. Other important outcomes were stiffness, structure modification, the OMERACT OARSI responder criteria and the patient’s global assessment.
Trade off between clinical benefits and harms	The GDG considered the comparison of hyaluronan injections to placebo to be the most appropriate comparator to judge clinical effectiveness and adverse events. Results were presented stratified by joint type and data was available on knee, hip, ankle, base of thumb and great toe joints. The vast majority of the data related to injections of the knee. Results were also presented separately for those hyaluronan injections which are licenced in the UK. In looking at interventions appropriate controls are needed the GDG considered the evidence for the efficacy of a given therapy, the primary comparison for decision making involved looking at active therapies versus placebo, and in the case of device studies versus sham control. They then also considered other comparators where placebo or shams were not available or inappropriate, such as when looking at toxicity and cost effectiveness. The GDG understand and were aware of the considerable effect size of contextual response in clinical trials and in practice for all therapies. Where possible they tried to discern the specific treatment efficacy element that relates to the treatment rather than contextual response. Where such trials exist as to allow for the effective measurement of contextual response they must form the primary comparator for decision making, to ensure we are recording a therapy with a scientific treatment response. The GDG therefore believe that saline is the appropriate comparator to elicit the specific treatment efficacy for hyaluronans injections. The GDG considered that the benefits of reduction in pain would be balanced by the potential for adverse events/local reactions to the injection. The number of injections required would also need to be considered. The GDG noted that any degree of structure modification should be taken as clinically important, thus the MID chosen for structural modification outcomes was the line of no effect or zero. However, the relative lack of data, inconsistent effects on structural modification and radiological method of measurement of structure modification were noted and it was the critical outcomes that guided the GDG decision making in this area Knee OA Licensed HA injections Clinically important reduction in pain compared to placebo was demonstrated for Hylan G-F20 on WOMAC scales at up to three months. At over three months clinically important reductions in pain where shown when multiple injections were used, this effect was not demonstrated for single injections. Clinically important reduction in pain compared to placebo was demonstrated for Orthovisc on the WOMAC pain scale at all time points. However all these effects were surrounded by uncertainty and the quality ranged from low to very low. No clinically important difference was demonstrated over placebo on any pain scale at any time point for Durolane, Hyalgan, BioHy and Suplasyn. Quality of life data comparing HA injections with placebo was only available for BioHy. No clinically important difference was demonstrated over placebo. Hyalgan and Hyalan G-F20 both demonstrated higher rates of local adverse reactions/pain at injection sites compared to placebo. Unlicensed HA injections No clinically important difference was demonstrated over placebo on any pain scale at any time point for Artz and NRD-101. No quality of life data was available on the comparison of unlicensed hyaluronan injections compared to placebo. NRD-101 demonstrated higher rates of pain during injection compared to placebo Hip OA Licensed hyaluronan injections No clinically important difference was demonstrated over placebo on any pain scale at any point for Hyalgan No quality of life data was available on the comparison of licenced hyaluronan injections compared to placebo Durolane demonstrated rates of higher local adverse events than placebo Unlicensed hyaluronan injections No clinically important difference was demonstrated over placebo on any pain scale at any point for Adant No quality of life data was available on the comparison of unlicensed hyaluronan injections compared to placebo Adant demonstrated rates of higher adverse events than placebo Ankle OA Licensed hyaluronan injections No pain data was available on the comparison of licenced hyaluronan injections compared to placebo Clinically important improvement in the EQ5D domains of no problem and some problem were demonstrated for Hyalgan over placebo, although there was uncertainty surrounding the effects and the quality ranged from low to very low Hyalgan demonstrated rates of higher local adverse events than placebo Unlicensed hyaluronan injections No clinically important difference was demonstrated over placebo on any pain scale at any point for Supartz No quality of life data was available on the comparison of unlicensed hyaluronan injections compared to placebo No adverse event data was available on the comparison of unlicensed hyaluronan injections compared to placebo Base of thumb OA Data available for the critical outcomes of pain, quality of life and adverse events compared to placebo suggested there was no clinically important difference in adverse events of the licensed hyaluronan Synvisc versus placebo. Base of thumb OA Data available for the critical outcomes of pain, quality of life and adverse events compared to placebo suggested there was no clinically important difference in quality of life of the licenced hyaluronan Synvisc versus placebo.
Economic considerations	An economic analysis from the previous guideline looked at the cost-effectiveness of hyaluronan injections compared with placebo (saline). This found that hyaluronans were unlikely to be cost effective, as the incremental cost-effectiveness ratios were outside of the £20,000 per QALY threshold. This analysis was rated as having potentially serious limitations. As no costs of placebo were included in the analysis, this could be interpreted as a comparison with usual care, using placebo controlled trials. It is widely accepted that large pragmatic randomised trials are the best study design on which to base an economic evaluation, as this will capture the cost-effectiveness of an intervention as it would be used in practice, compared to what is currently standard care or in addition/as an adjunct to standard care. The cost-effectiveness of hyaluronans versus placebo is not of interest, since we are interested in the benefits and opportunity costs that would occur in practice. However an intervention must first be shown to have a clinical benefit, and the best comparator to prove this would be a placebo or sham where possible in order to identify the magnitude of effect over and above the contextual/placebo response. Only if effect has been proven above placebo/sham, should cost effectiveness evidence be considered. Saline is considered to be the appropriate placebo for hyaluronan injections to elicit the treatment efficacy. One study was identified from the update search as potentially includable²⁸⁵. However it was rated as having potentially serious/very serious limitations and the GDG felt it should be excluded. Reasons include; poor study design, lack of comparator, and non-UK setting. Given no economic evidence, some assessment of cost-effectiveness is described below. The incremental cost of Suplasyn for example versus no treatment would be £214.50 (assuming 3 injections and 3 GP consultations for Suplasyn and no costs for no treatment). At this incremental cost, a QALY of 0.0107 would be needed to achieve an ICER of £20,000. Although the incremental QALY gain for hyaluronans versus no treatment would be higher than that of hyaluronans versus placebo (as placebo’s have a small effect), we do not think it will reach the 0.0107 threshold, as those compared to placebo were lower than 0.005 (see appendix M). When we compare hyaluronans with steroids, the incremental cost of suplasyn versus a steroid injection is £100.32 (as one course of suplasyn (3 injections) costs £106.50, and one course of steroids (1 injection but can have more if necessary) costs £6.18. The healthcare professional cost of administering the injections is not considered as this is common to both interventions). At this incremental cost, a QALY of 0.005 would be needed to achieve an ICER of £20,000. As the effectiveness of hyaluronans over saline is roughly the same as that of hyaluronans over steroids according to the clinical review, we can compare this QALY gain with those reported in the CG59 analysis as a reference (see appendix M). We can see that the incremental QALYs are generally lower than 0.005. It seems unlikely that hyaluronans would be cost effective given these figures, particularly if more expensive products are used – as they can vary in price significantly. The GDG felt that the clinical evidence was not strong enough to warrant a positive recommendation as the evidence varied. Had there been positive evidence on the effectiveness of hyaluronans, then above are some examples of assessment of cost-effectiveness given the lack of published cost effectiveness evidence. As mentioned above, cost effectiveness evidence based on pragmatic trials are preferred, so the comparators are steroids, and no treatment. Based on these considerations the GDG concluded that hyaluronan injections are not likely to be cost effective
Quality of evidence	Knee OA Licensed preparations of hyaluronans For hyalgan versus conventional treatment at less than 13 weeks follow up the evidence was of very low quality. For hylan GF 20 versus placebo at less than 13 weeks the evidence was of very low quality and for Hylan GF 20 versus placebo at more than 13 weeks the evidence was of low quality. For Hylan GF 20 versus physical therapy and appropriate care the evidence was of very low quality at more than 13 weeks. For orthovisc versus placebo at less than and more than 13 weeks follow up the evidence was of very low quality. For orthovisc versus physical therapy at long term follow the evidence was of low quality evidence)and for improving quality of life at short and long term follow up the evidence was of very low quality. For Hyalgan versus placebo or NSAIDs, Hylan GF 20 versus NSAID or triamcinolone, BioHy vs placebo, Durolane versus placebo or triamcinolone, suplasyn versus placebo or NSAID, ostenil versus triamcinolone the evidence was mostly of low and very low quality. Unlicensed preparations of hyaluronans For Artz versus placebo, steroid or exercise for any outcome the evidence was of low and very low quality and for NRD_101 versus placebo the evidence was of high quality. The majority of studies comparing one HA product to another were relatively small and there was generally only one study per comparison. The quality of the evidence ranged from very low to high, depending on the comparison and the study. Four studies compared a different number of injections of the same or different HA products. The studies were generally small and the results imprecise, allocation concealment and blinding was not well reported in the studies. The evidence was of very low, low and moderate quality and there was generally no difference between the different number of injections of HA products. Hip OA The licensed HA products compared for Hip OA (Hylagan or Durolane vs saline, Hyalgan, Hylan or Durolane vs methylprednisolone and Durolane vs standard care) included evidence that was mostly low and very low quality. The unlicensed HA product Adant was compared to saline (High and moderate quality evidence) and Ostenil was compared to Hylan GF 20 (Very low quality evidence). Ankle OA For Hyalgan vs saline, the evidence was of very low quality. Another study compared the use of Supartz to saline in ankle OA, and the evidence was of low and moderate quality. Another study compared adant to exercise and the evidence was of very low quality. Base of thumb OA For Synvisc vs saline or betamethasone the evidence was of low quality. For ostenil vs triamcinolone the evidence was very low and low quality and for Orthovisc vs methylprednisolone it was very low and low quality. 1^st metacarpal joint OA For Synvisc vs saline or Ostenil vs triamcinolone for people with OA of the 1^st MTP joint the evidence was of very low, low and moderate quality.
Other considerations	The GDG noted the findings of the evidence review and in particular commented that the quality of the evidence that demonstrated a possible benefit from the use of Hyalgan over placebo in improving pain in people with OA of the knee was of low quality. They therefore felt that it would not be appropriate to name a particular preparation within a recommendation especially when the evidence for this product was of varying quality They noted also that the increased adverse events profile associated with injections versus placebo. The GDG decided that the recommendation made in the original OA guideline (CG59) remained valid for the NHS and as such chose not to recommend the use of hyaluronans. The GDG noted that evidence was absent in relation to whether there were specific groups of people who may respond better to hyaluronan injections than others and as such chose to make a research recommendation in this area Research recommendation The GDG agreed to draft a research recommendation on identification of predictors of response to individual treatments in people with osteoarthritis. For further details on research recommendations, see Appendix M.

Footnotes

h: Source: Unit costs of health and social care, PSSRU (2011). This cost includes direct care staff costs (without qualifications).

Bookshelf ID: NBK333060

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National Clinical Guideline Centre (UK). Osteoarthritis: Care and Management in Adults. London: National Institute for Health and Care Excellence (UK); 2014 Feb. (NICE Clinical Guidelines, No. 177.) 10, Intra-articular Injections.
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Introduction
Intra-articular injections of hyaluronic acid/hyaluronans in the management of OA in the knee, hand, ankle, big toe and hip

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