Summary

Triamcinolone intra-articular corticosteroid injection is approved as an adjunctive, short-term treatment for pain relief in patients with knee osteoarthritis (OA). Long-term use is not supported by current evidence, including recently published 2-year clinical data showing that repeat intra-articular triamcinolone injections every 12 weeks, as used in clinical practice, lead to cartilage loss and do not reduce pain in patients with knee OA.

Key points

  • Triamcinolone, and several other intra-articular corticosteroid injections, can be used for short-term pain relief for people with knee OA.
  • In a 2-year clinical study, intra-articular triamcinolone injections every 12 weeks led to cartilage loss and did not reduce pain for patients with knee OA.
  • In OA, improvements in knee pain after intra-articular corticosteroid injections have been shown to be moderate at 1–2 weeks, small at 13 weeks and not evident at 26 weeks.
  • Management of OA should aim to optimise the patient’s physical function, maximise their quality of life, enable their ability to cope with pain and reduce symptoms.
  • If considered, intra-articular corticosteroid injections should generally be administered short term, and as an adjunct to core treatments.

Two-year data do not support injectable triamcinolone for knee OA

Triamcinolone, and several other intra-articular corticosteroid injections, can be used for short-term pain relief for people with knee OA.1-7

However, results of a 2-year clinical study that was published in 2017 do not support the use of intra-articular triamcinolone injected every 12 weeks for the treatment of symptomatic knee OA.8

What can we take from this study, and how should we manage knee OA? 

Triamcinolone increased cartilage loss, but did not improve pain

In the double-blind study, 140 patients with symptomatic knee OA (and ultrasonic features of synovitis) were randomised to receive either intra-articular injections of triamcinolone acetonide 40 mg or saline (0.9% sodium chloride; placebo) every 12 weeks for 2 years.8

Changes in knee cartilage volume loss (using cartilage thickness) and pain were co-primary outcomes.8

Study participants

Patients included in the study were aged ≥ 45 years with a diagnosis of OA defined using clinical diagnostic criteria from the American College of Rheumatology.8

Patients were required to have knee pain, radiological features of OA, ultrasonographic evidence of effusion synovitis, and pain from the knee joint confirmed by clinical examination.8

Patients were excluded from the study if they had symptoms suggestive of an alternative diagnosis (such as inflammatory joint disease or osteonecrosis).8

Based on the above eligibility criteria, the included patients can be considered as having ‘typical’ knee OA (see ‘How should knee OA be diagnosed?’ for more information).

Co-primary outcomes

The first co-primary outcome, change in cartilage volume, was assessed in the compartment with greatest joint space narrowing (the ‘index’ compartment), using cartilage thickness.8

Cartilage volume was assessed every 12 months, using MRI.8

The study authors advised that they used MRI to enable direct quantitation of cartilage and soft-tissue structures, because radiography is insensitive to OA progression and does not directly image critical soft-tissue structures or bone marrow lesions in OA.8

However, the amount of change in cartilage volume that represents a minimal clinically important difference has not been established.8

The second co-primary outcome, pain, was assessed every 12 weeks using the Western Ontario and McMaster Universities (WOMAC) OA Index pain subscale.8

Using the WOMAC pain subscale, a score of 0 represents no pain and a score of 20 represents extreme pain.8

A 3.94-point improvement is considered to represent a minimal clinically important difference.8

Cartilage loss was statistically significantly greater with triamcinolone than with the placebo, with a between-group difference of –0.11 mm (95% confidence interval [CI] –0.20 to –0.03, p = 0.01).8

Knee pain reduction was not significantly different between triamcinolone and the placebo, with a between-group difference of –0.64 (95% CI –1.6 to 0.29, p = 0.17).8

Triamcinolone’s effect on cartilage volume and pain are not unexpected (see the study limitations below and ‘How should knee OA be managed?’ for more information).

Secondary outcomes

A validated volumetric cartilage damage index was also used to quantitate cartilage loss.8

Using the cartilage damage index, cartilage loss was significantly greater with triamcinolone than with the placebo (between-group difference of −61.25 µm3).8

However, changes in area of denudation, bone marrow lesion volume and effusion volume were not significantly different between the two treatment groups.8

There were also no significant differences in knee function or stiffness between the treatment groups.8

Safety

There were significantly more adverse events with saline than with triamcinolone (63 versus 52 patients, 182 versus 131 events; p = 0.02 for both comparisons).8

Eight events were treatment-related, three with saline (one cellulitis, two injection site pain) and five with triamcinolone (one facial flushing, four injection site pain).8

Serious adverse events were similar between the two treatment groups (p = 0.06).8

Limitations

The study authors acknowledged that treatment responses could potentially have been affected by high expectations of active treatment, large placebo responses to saline injection, and patients being allowed to continue their usual medicines.8

In addition, because corticosteroids typically have only short-term effects on pain, transient responses could have been missed because pain was not measured within the 4-week period after each injection.8

How should knee OA be diagnosed?

A diagnosis of knee OA is nearly 100% likely if a patient has all of the following signs and symptoms:9

  • persistent activity-related knee pain
  • limited morning stiffness
  • reduced function
  • crepitus
  • restricted movement
  • bony enlargement.

Although age of onset, symptoms and progression of OA will vary between patients, there are several ‘typical features’ of OA.10,11

These are considered to be age > 40 years, activity-related joint pain, short duration of (or no) morning stiffness, and symptoms affecting only one or a few joints.11

Knee OA can be diagnosed using these typical features, without X-ray or MRI, assuming no alternative or additional diagnoses are suspected.11-13

Radiological features of OA typically have a low correlation to OA symptoms, and MRI should be considered only if there is suspicion of serious pathology not detected by X-ray.12,14

How should knee OA be managed?

Overall, management of OA should aim to maintain or optimise the patient’s physical function, maximise their quality of life, enable their ability to cope with pain and reduce symptoms.14

If analgesics are considered, then they should be recommended to help enable physical function, rather than to abolish pain.14

Although management will differ for each patient – because patients’ needs and responses to different OA management options will vary – weight management and exercise are recommended for all people with OA.14

If required, weight loss and regular exercise can help to reduce pain and improve physical function in people with knee OA.14

Whatever intervention is selected, it should be assessed regularly against individual goals, to determine whether it is safe and beneficial.14

What about intra-articular corticosteroid injections for knee OA?

Corticosteroid injections approved in Australia are generally indicated as adjunctive therapies for short-term administration (see Table 1).1-7

For example, because of their rapid onset of action, intra-articular corticosteroid injections may be useful if patients have to travel and are concerned about pain from their OA.14

According to Australian guidelines on the use of intra-articular corticosteroid injections:

  • no more than four injections should be administered to a single joint in a year, due to the potential for increased risk of cartilage damage15
  • if there is no response after two consecutive injections, further injections should be avoided15
  • a single injection may provide symptom relief lasting 4–12 weeks for patients with knee OA14
  • clinical trials supporting intra-articular corticosteroid use may have a high or unclear risk of bias14
  • corticosteroids are used for a wide range of conditions, often without substantial evidence of their effectiveness.15

In a meta-analysis of 26 randomised controlled trials, intra-articular corticosteroid injections in patients with knee OA were found to lead to small or moderate improvements in knee pain.16

Improvements were moderate at 1–2 weeks after the end of treatment (standardised mean difference [SMD] –0.48, 95% CI –0.70 to –0.27), small to moderate at 4–6 weeks (SMD –0.41, 95% CI –0.61 to –0.21), and small at 13 weeks (SMD –0.22, 95% CI –0.44 to 0.00).16

However, the quality of evidence was low, results were inconclusive and there was no evidence of reduced pain 26 weeks after injection (SMD –0.07, 95% CI –0.25 to 0.11).16

Table 1: PBS-listed injectable glucocorticoids for systemic use, and TGA-approved intra-articular indications for patients with OA

PBS listed for injectiona PBS restrictions TGA-approved indication for injection in OA

Triamcinolone1,17,b

Available brand: 
Kenacort-A10 

  • Alopecia areata
  • Chronic discoid lupus erythematosus
  • Granulomata (dermal)
  • Keloid
  • Lichen planus hypertrophic
  • Lichen simplex chronicus
  • Local intra-articular or peri-articular infiltration
  • Necrobiosis lipoidica
  • Psoriasis
Intra-articular injection is indicated as an adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in synovitis of OA or post-traumatic OA

Betamethasone acetate + betamethasone sodium phosphate3,18,b

Available brand: 
Celestone Chronodose

  • Alopecia areata
  • Chronic discoid lupus erythematosus
  • Granulomata (dermal)
  • Keloid
  • Lichen planus hypertrophic
  • Lichen simplex chronicus
  • Local intra-articular or peri-articular infiltration
  • Necrobiosis lipoidica
  • Uveitis

Intra-articular injection is a recommended route of administration in patients with OA

Indicated for the treatment of both severe and moderate conditions, in acute and chronic self-limiting diseases responsive to systemic corticosteroid therapy, especially in patients for whom treatment with oral corticosteroid medication is not feasible

OA is not included as a ‘Representative condition’ under ‘Indications’ (other rheumatic disorders are), but recommendations for OA and knee dosing are mentioned in ‘Local administration’

Dexamethasone sodium phosphate4,5,19,c

Available brands:
  • Dexamethasone Mylan
  • DBL Dexamethasone (Hospira)
No restrictions

Both brands are indicated as an adjunctive therapy for short-term administration during an acute episode or exacerbation of OA

Both brands include dosing for intra-synovial or soft-tissue injections. Intra-articular dosing is not directly specified, but doses for injection into large and small joints, and precautions for intra-articular use, are described

Methylprednisolone6,7,20-23,d

Available brands:
  • Depo-Medrol
  • Depo-Nisolone
  • Methylpred
  • Methylprednisolone Alphapharm
  • Solu-Medrol
  • No restrictions (Methylpred, Methylprednisolone Alphapharm, Solu-Medrol)
  • Local intra-articular or peri-articular infiltration (Depo-Medrol, Depo-Nisolone)

Depo-Medrol & Depo-Nisolone

Intra-articular injection is indicated as an adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in synovitis of OA or post-traumatic OA

Methylpred, Methylprednisolone Alphapharm & Solu-Medrol

Not indicated for intra-articular injection

Instead, indicated for intravenous or intramuscular use as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in synovitis of OA or post-traumatic OA

Intravenous or intramuscular use is indicated when oral therapy is not feasible, and the strength, form and route of administration of the drug reasonably lend the preparation to the treatment of the condition


OA, osteoarthritis.

a. The following medicines are also listed on the PBS (Body System H, SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS; H02 - CORTICOSTEROIDS FOR SYSTEMIC USE; H02A - CORTICOSTEROIDS FOR SYSTEMIC USE, PLAIN; H02AB - Glucocorticoids), but they are listed only for oral use: cortisone (Cortate), dexamethasone (Dexamethasone), hydrocortisone (Hysone 4, Hysone 20), prednisolone (Panafcortelone, Predsolone, Solone), prednisolone sodium phosphate (PredMix, Redipred) and prednisone (Predsone, Panafcort, Sone). Hydrocortisone sodium succinate (Solu-Cortef) is not indicated for intra-articular injection, but is instead indicated for intravenous or intramuscular use as adjunctive therapy for short-term administration in synovitis of OA or post-traumatic OA.

b. The restrictions listed here are for medical and nurse practitioners. The restricted benefits for dental practitioners are local intra-articular or peri-articular infiltration, keloid and lichen planus hypertrophic only.

c. Prescription by medical or nurse practitioners only. No code for dental practitioners.

d. All brands can be prescribed by medical and nurse practitioners. Only Depo-Medrol and Depo-Nisolone have a code for dental practitioners.

table-striped

What about ‘regenerative’ injectables for knee OA?

Despite their increased use for OA, Australian therapeutic guidelines do not recommend intra-articular platelet-rich plasma (PRP), adipocyte cell suspensions or mesenchymal stem cell injections for treatment of OA.14

They advise that results from studies investigating intra-articular PRP injections should be interpreted with caution due to the high risk of bias.14

In addition, evidence to support the use of adipocyte cell suspensions and mesenchymal stem cells is also weak.14

In 2014, the Australian Rheumatology Association released a position statement on stem cell therapies.24

It advised that there is currently insufficient evidence to recommend stem cell therapy/autologous cell-based interventions for OA outside of a clinical trial setting.24

In October 2017, the TGA advised that it will change how autologous human cell and tissue products (including stem cell therapies) will be regulated in Australia.25

These products have previously not been regulated by the TGA.25

However, there is growing concern about the advertising of unproven treatments to consumers, and potential safety risks due to increasing treatment complexity.25

The TGA has therefore proposed the following changes for the regulation of autologous human cell and tissue products:25

  • prohibit direct advertising to consumers
  • exclude from regulation only those products manufactured and used in a hospital by a medical or dental practitioner, for a patient in the care of the same practitioner
  • regulate products that are minimally manipulated, and for homologous use only, and manufactured and used outside a hospital by a medical or dental practitioner, and for a patient in the same practitioner’s care
  • regulate under the Biologicals Regulatory Framework products that are manufactured and used outside an accredited hospital, and more than minimally manipulated, or for non-homologous use.


Information for patients

All patients with knee OA are encouraged to seek education about their condition and advice on self-management.14

You may find the following information useful when discussing knee OA and its management with your patients.

References

  1. Aspen Pharma Pty Ltd. Triamcinolone acetonide (Kenacort-A10 injection): Product information. 2015 (accessed 1 September 2017).
  2. Aspen Pharma Pty Ltd. Triamcinolone acetonide (Kenacort-A40 injection): Product information. 2015 (accessed 1 September 2017).
  3. Merck Sharp & Dohme (Australia) Pty Ltd. Betamethasone (Celestone Chronodose injection): Product information. 2015 (accessed 1 September 2017).
  4. Hospira Australia Pty Ltd. Dexamethasone phosphate (DBL dexamethasone sodium phosphate injection): Product information. 2012 (accessed 1 September 2017).
  5. Alphapharm Pty Ltd. Dexamethasone sodium phosphate (Dexamethasone Mylan injection): Product information. 2015 (accessed 1 September 2017).
  6. Kenral. Methylprednisolone acetate (Depo-Nisolone): Product information. 2015 (accessed 1 September 2017).
  7. Pfizer Australia Pty Ltd. Methylprednisolone acetate (Depo-Medrol): Product information. 2015 (accessed 1 September 2017).
  8. McAlindon TE, LaValley MP, Harvey WF, et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: A randomized clinical trial. JAMA 2017;317:1967-75.
  9. Zhang W, Doherty M, Peat G, et al. EULAR evidence-based recommendations for the diagnosis of knee osteoarthritis. Ann Rheum Dis 2010;69:483-9.
  10. Doherty M, Abhishek A. Clinical manifestations and diagnosis of osteoarthritis. UpToDate. Wolters Kluwer, 2017 (accessed 20 June 2017).
  11. Sakellariou G, Conaghan PG, Zhang W, et al. EULAR recommendations for the use of imaging in the clinical management of peripheral joint osteoarthritis. Ann Rheum Dis 2017;76:1484-94.
  12. Australian Commission on Safety and Quality in Health Care. Osteoarthritis of the Knee Clinical Care Standard. Sydney: Australian Commission on Safety and Quality in Health Care, 2017 (accessed 25 May 2017).
  13. National Institute for Health and Care Excellence. Osteoarthritis: Care and management in adults. Clinical guideline [CG177]. UK: National Institute for Health and Care Excellence, 2014 (accessed 5 June 2017).
  14. Rheumatology Expert Group. Therapeutic Guidelines: Osteoarthritis. West Melbourne, Victoria: Therapeutic Guidelines Ltd, 2017 (accessed 5 June 2017).
  15. Australian Medicines Handbook. Immunomodulators and antineoplastics. Adelaide: Australian Medicines Handbook Pty Ltd, 2017 (accessed 30 August 2017).
  16. Juni P, Hari R, Rutjes AW, et al. Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev 2015:CD005328.
  17. Australian Government Department of Health. PBS Schedule. Triamcinolone. 2017 (accessed 1 September 2017).
  18. Australian Government Department of Health. PBS Schedule. Betamethasone acetate + betamethasone sodium phosphate. 2017 (accessed 1 September 2017).
  19. Australian Government Department of Health. PBS Schedule. Dexamethasone sodium phosphate. 2017 (accessed 1 September 2017).
  20. Australian Government Department of Health. PBS Schedule. Methylprednisolone. 2017 (accessed 1 September 2017).
  21. Alphapharm Pty Ltd. Methylprednisolone (as sodium succinate) (Methylprednisolone Alphapharm powder for injection): Product information. 2016 (accessed 1 September 2017).
  22. Alphapharm Pty Ltd. Methylprednisolone (as sodium succinate) powder for injection (Methylpred): Product information. 2016 (accessed 1 September 2017).
  23. Pfizer Australia Pty Ltd. Methylprednisolone sodium succinate (Solu-Medrol and Solu-Medrol Act-O-Vial): Product information. 2017 (accessed 1 September 2017).
  24. Australian Rheumatology Association. AOA/ARA position statement on stem cell therapy. 2014 (accessed 6 February 2018).
  25. Australian Government Department of Health. Therapeutic Goods Administration. Media releases & statements: Regulation of autologous cell and tissue products. 2017 (accessed 9 November 2017).