Injection Therapy – The Evidence

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Section 1 Injection Therapy – The Evidence

The evidence base for injection therapy


Injection therapy is the treatment of musculoskeletal disorders by the targeted injection of drugs into joints and soft tissues.

Corticosteroid and local anaesthetic injection therapy has been in use for 60 years, and has stood the ‘test of time’.1 There is a wealth of anecdotal evidence for its efficacy, but few, if any, definitive studies,15 and few studies comparing injection therapy with other treatments; the comparative studies that do exist mainly concern the shoulder and elbow, and their conclusions are contradictory.620 Consequently, there are few facts and a mass of opinions – many of them dogmatic and contradictory – about almost every aspect of injection therapy2124 and published guidelines for joint and soft tissue injections are based more on personal experience and anecdote than on evidence.1,4 This state of affairs is surprising, because injection therapy is the most common therapeutic intervention in rheumatological practice.25

Interpretation of injection therapy studies is compounded by a disconcerting lack of expert agreement about definitions, diagnosis, and outcome measures in musculoskeletal medicine,1,2631 coupled with wide variations in methodology and quality between trials. Because of this, most authoritative reviews tend to be conservative in their estimates of the presence and size of treatment effects in injection therapy.3,5,3243

Nonetheless, injection therapy is recommended for musculoskeletal (mainly knee and shoulder) disorders in national and international guidelines 3,4448 and is used extensively for other musculoskeletal conditions.49,50 Given its relative safety,1,3,5,5153 ease of application in trained hands and cost-effectiveness,3 plus the frequent lack of convincing systematic evidence for the effectiveness of alternatives,38 injection therapy is a very useful treatment modality.54 This is supported by the collective experience of the majority of clinicians in primary care and the locomotor specialties.55

Remarkably, there are hardly any double blind randomized controlled trials of intra-articular versus systemic corticosteroid injection therapy for the treatment of any inflammatory arthropathies. The superior clinical efficacy of joint injection therapy has been reported only recently in two trials comparing intra-articular to systemic injection of the same total dosage of triamcinolone in rheumatoid arthritis.

In the first randomized study, patients with polyarticular disease who were treated with intra-articular injections of triamcinolone demonstrated significantly better pain control and range of motion than did those who were treated with the same total dosage of mini-pulse systemic steroids. Patient evaluation of disease activity, tender joint count, blood pressure, side effects, physician contacts, and hospital visits were significantly better for those treated with intra-articular steroids.56

The second study compared the efficacy and safety of intra-articular corticosteroid injection with systemic injection of the same dose of triamcinolone for the treatment of monoarthritis of the knee in rheumatoid arthritis patients. The intra-articular approach showed better results in terms of local inflammatory variables and improvement evaluation by the patient and physician.57

However, in both studies the systemic treatment was given with triamcinolone acetonide, while the joints were injected with the far less soluble and longer acting triamcinolone hexacetonide. It could be argued that what these studies demonstrate is the superiority of the hexacetonide formulation of triamcinolone, rather than the route of administration.

The definitive randomized trial to demonstrate the superiority of the intra-articular route of corticosteroid administration in inflammatory joint disease is still awaited. Nonetheless, authoritative international guidelines recommend that intra-articular corticosteroid injections should be considered for the relief of local symptoms in patients with inflammatory arthritis.58

As with other treatment modalities, the challenge for all clinicians delivering injection therapy is to implement evidence-based practice by applying the best research-based treatments, tempered by clinical experience and patients’ values.59 Where good research evidence is lacking, clinicians should become involved in research that will provide that evidence.

Problems with injection therapy may arise when:

The art of good injection therapy is to select the appropriate patient, and to place the minimal effective amount of an appropriate drug into the exact site of the affected tissue at an appropriate time. This means that the clinician using injection therapy must possess a high level of diagnostic and technical skill.

Delivery of injection therapy

Doctors in rheumatology, orthopaedics, musculoskeletal medicine, sports medicine, and pain management are the main medical specialists who deliver injection therapy.

Most general practitioners (GPs) in the UK carry out some joint and soft tissue injections, but limit themselves to knees, shoulders and elbows.60 A small highly active group receives referrals from colleagues.60,61 Most of the injections in the community are performed by just 5–15 % of GPs.61,62 The main perceived barriers to performing these injections are inadequate training, the inability to maintain injection skills and discomfort or lack of confidence with the performance of the technique.6062 Training improves GPs’ injection activity and their level of confidence.63

In 1995 chartered physiotherapists in the UK were granted the right to use injection therapy, whereupon the authors of this textbook developed the first training programme in this field and were lead contributors to the only published injection therapy guidelines.64

Injections administered by physiotherapists have been shown to be part of a very effective way of managing orthopaedic65 and rheumatology 66 outpatients and patients in the community with musculoskeletal lesions.67 Extended Scope Practitioners in physiotherapy have been shown to be as effective as orthopaedic surgeons and to generate lower initial direct hospital costs.68 Podiatrists also deliver injection therapy for lower limb disorders and nurses have also been trained in musculoskeletal injection therapy.69,70

Current controversies in injection therapy

Almost every aspect of injection therapy is non-standardized. Notwithstanding controversies about diagnosis, there is no universal agreement about the following:

How useful is imaging? (See pages 44–59 and Appendix 1, Landmark technique accuracy and outcome studies.)

The research agenda in injection therapy

Whither injection therapy? Given the large number of questions listed above we might reflect on why, after six decades, there is such a dearth of first-rate evidence for a therapeutic approach that is so well established and widely utilized. Certainly the research agenda should seek to address the points raised above, but why are published studies in the recent medical literature concerning injection therapy with corticosteroid and local anaesthetic so relatively sparse? It may be that to some the benefits are so well established and self-evident that further research is unnecessary (we would vigorously disagree).

Certainly, newer agents may attract more interest because of their novelty value and (often unfulfilled) theoretical potential (see page 31, Other substances used for injection therapy).77 Perhaps research into novel treatments is generously funded by manufacturers (with the potential for partial reporting of results), while research into inexpensive, familiar treatments attracts little or no support from industry and academia. There are undoubtedly other reasons.

Recommendations for future research abound in the papers cited in this book (far too numerous to mention here). A particular issue is that double blind randomized controlled studies comparing corticosteroid injection therapy with a placebo or another treatment all test a single injection (or initial cluster of injections) at the outset with the comparator, but in real life most clinicians empirically use repeated injections; the strategy of repeating the injection as required has never been explicitly tested for efficacy, safety and cost-effectiveness in a prospective trial.

One suggestion we fully endorse is that those systematically reviewing and meta-analysing the musculoskeletal literature should provide model research protocols, methodologies and frameworks that could be taken ‘off the shelf’ and utilized by anyone sufficiently enthused to participate in injection therapy research.

November 2010 was the 350th anniversary of that bastion of scientific enquiry, The Royal Society. Anyone who aspires to best evidence based practice should bear in mind the society’s motto: ‘nulius in verba’ – take nobody’s word for it.


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3. National Collaborating Centre for Chronic Conditions. Osteoarthritis: national clinical guideline for care and management in adults. London: Royal College of Physicians; 2008. (NICE Guideline)

4. Speed C.A. Injection therapies for soft-tissue lesions. Best Pract Res Clin Rheumatol. 2007;21:2333-2347.

5. Cole B.J., Schumacher H.R. Injectable corticosteroids in modern practice. J Am Acad Orthop Surg. 2005;139:137-146.

6. Skedros J.G., Hunt K.J., Pitts T.C. Variations in corticosteroid/anesthetic injections for painful shoulder conditions: comparisons among orthopaedic surgeons, rheumatologists, and physical medicine and primary-care physicians. BMC Musculoskelet Disord. 2007;8:63. doi:10.1186/1471-2474-8-63

7. Gaujoux-Viala C., Dougados M., Gossec L. Efficacy and safety of steroid injections for shoulder and elbow tendonitis: a meta-analysis of randomised controlled trials. Ann Rheum Dis. 2009;68(12):1843-1849.

8. Crashaw D.P., Helliwell P.S., Hensor E.M.A., et al. Exercise therapy after corticosteroid injection for moderate to severe shoulder pain: large pragmatic randomised trial. Br Med J. 2010;340:c3037.

9. Karthikayan S., Kwong H.T., Upadyhay P.K. A double-blind randomized controlled study comparing subacromial injection of tenoxicam or methylprednisolone in patients with subacromial impingement. J Bone Joint Surg Br. 2010;92(1):77-82.

10. Ryans I., Montgomery A., Galway R., et al. A randomized controlled trial of intra-articular triamcinolone and/or physiotherapy in shoulder capsulitis. Rheumatology. 2005;44(4):529-535.

11. Hay E.M., Thomas E., Paterson S.M., et al. A pragmatic randomised controlled trial of local corticosteroid injection and physiotherapy for the treatment of new episodes of unilateral shoulder pain in primary care. Ann Rheum Dis. 2003;62:394-399.

12. van der Windt D.A.W.M., Bouter L.M. Physiotherapy or corticosteroid injection for shoulder pain? Ann Rheum Dis. 2003;62:385-387.

13. Carette S., Moffet H., Tardif J., et al. Intraarticular corticosteroids, supervised physiotherapy, or a combination of the two in the treatment of adhesive capsulitis of the shoulder: A placebo-controlled trial. Arthritis Rheum. 2003;48:829-838.

14. Winters J.C., Jorritsma W., Groenier K.H., et al. Treatment of shoulder complaints in general practice: long term results of a randomised, single blind study comparing physiotherapy, manipulation, and corticosteroid injection. Br Med J. 1999;318:1395-1396.

15. van der Windt D.A.W.M., Koes B.W., Deville W., et al. Effectiveness of corti-costeroid injections versus physiotherapy for treatment of painful stiff shoulder in primary care: randomised trial. Br Med J. 1998;317:1292-1296.

16. Winters J.C., Sobel J.S., Groenier K.H., et al. Comparison of physiotherapy manipulation and corticosteroid injection for treating shoulder complaints in general practice: randomised single blind study. Br Med J. 1997;314:1320-1325.

17. Tonks J.H., Pai S.K., Murali S.R. Steroid injection therapy is the best conservative treatment for lateral epicondylitis: a prospective randomised controlled trial. Int J Clin Pract. 2007;61:2240.

18. Bisset L., Beller E., Jull G., et al. Mobilisation with movement and exercise, corticosteroid injection, or wait and see for tennis elbow: randomized trial. Br Med J. 2006;333:939.

19. Hay E.M., Paterson S.M., Lewis M., et al. Pragmatic randomised controlled trial of local corticosteroid injection and naproxen for treatment of lateral epicondylitis of elbow in primary care. Br Med J. 1999;319:964-968.

20. Verhaar J.A.N., Walenkamp G.H.I.M., van Mameren H., et al. Local corticosteroid injection versus Cyriax type physiotherapy for tennis elbow. J Bone Joint Surg Br. 1995;77:128-132.

21. Charalambous C.P., Tryfonidis M., Sadiq S., et al. Septic arthritis following intra-articular glucocorticoid injection of the knee – a survey of current practice regarding antiseptic technique used during intra-articular glucocorticoid injection of the knee. Clin Rheumatol. 2003;22:386-390.

22. Haslock I., Macfarlane D., Speed C. Intraarticular and soft tissue injections: a survey of current practice. Br J Rheumatol. 1995;34:449-452.

23. Cluff R., Mehio A., Cohen S., et al. The technical aspects of epidural steroid injections: a national survey. Anesth Analg. 2002;95:403-408.

24. Masi A.T., Driessnack R.P., Yunus M.B., et al. Techniques for “blind” glucocorticosteroid injections into glenohumeral joints. J Rheumatol. 2007;34(5):1201-1202. [letter]

25. Bamji A.M., Dieppe P.A., Haslock D.I., et al. What do rheumatologists do? A pilot audit study. Br J Rheumatol. 1990;29:295-298.

26. Kassimos G., Panayi G., van der Windt D.A.W.M. Differences in the management of shoulder pain between primary and secondary care in Europe: time for a consensus and Author’s reply. Ann Rheum Dis. 2004;63:111-112.

27. Hoving J.L., Buchbinder R., Green S., et al. How reliably do rheumatologists measure shoulder movement?. Ann Rheum Dis, 7. 2002: 612-616.

28. Nørregaard J., Krogsgaard M.R., Lorenzen T., et al. Diagnosing patients with longstanding shoulder joint pain. Ann Rheum Dis. 2002;61:646-649.

29. Carette S. Adhesive capsulitis – research advances frozen in time? J Rheumatol. 2000;27:1329-1331.

30. Marx R.G., Bombardier C., Wright J.G. What do we know about the reliability and validity of physical examination tests used to examine the upper extremity? J Hand Surg. 1999;24A:185-193.

31. Bamji A.N., Erhardt C.C., Price T.R., et al. The painful shoulder: can consultants agree? Br J Rheumatol. 1996;35:1172-1174.

32. Gaujoux-Viala C., Dougados M., Gossec L. Efficacy and safety of steroid injections for shoulder and elbow tendonitis: a meta-analysis of randomised controlled trials. Ann Rheum Dis. 2009;68:1843-1849.

33. Dorrestijn O., Stevens M., Winters J.C., et al. Conservative or surgical treatment for subacromial impingement syndrome: a systematic review. J Shoulder Elbow Surg. 2009;18(4):652-660.

34. Buchbinder R., Green S., Youd J.M. Corticosteroid injections for shoulder pain. Cochrane Database Sys Rev. (1):2003. Art. No.: CD004016. doi: 10.1002/14651858. CD004016. [Edited (no change to conclusions), published in Issue 1, 2009]

35. Shah N., Lewis M. Shoulder adhesive capsulitis: systematic review of randomised trials using multiple corticosteroid injections. Br J Gen Pract. 2007;57:662-667.

36. Koester M.C., Dunn W.R., Kuhn J.E., et al. The efficacy of subacromial corticosteroid injection in the treatment of rotator cuff disease: a systematic review. J Am Acad Orthop Surg. 2007;15(1):3-11.

37. Faber E., Kuiper J.I., Burdorf A., et al. Treatment of impingement syndrome: a systematic review of the effects on functional limitations and return to work. J Occup Rehabil. 2006;16(1):7-25.

38. Assendelft W., Green S., Buchbinder R., et al. Clinical review Extracts from Concise Clinical Evidence Tennis elbow. Br Med J. 2003;327:329.

39. Hepper C.T., Halvorson J.J., Duncan S.T. The efficacy and duration of intra-articular corticosteroid injection for knee osteoarthritis: A systematic review of Level I Studies. J Am Acad Orthop Surg. 2009;17(10):638-646.

40. Bellamy N., Campbell J., Welch V., et al. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Sys Rev. (2):2006. Art. No.: CD005328. DOI: 10.1002/14651858. CD005328.pub2 [Edited – no change to conclusions – published in Issue 2, 2009]

41. Godwin M., Dawes M. Intra-articular steroid injections for painful knees: systematic review with meta-analysis. Can Fam Physician. 2004;50:241-248.

42. Arroll B., Goodyear-Smith F. Corticosteroid injections for osteoarthritis of the knee: meta-analysis. Br Med J. 2004;328:869-870.

43. Gossec L., Dougados M. Review: Intra-articular treatments in osteoarthritis: from the symptomatic to the structure modifying. Ann Rheum Dis. 2004;63:478-482.

44. Geraets J.J., de Jongh A.C., Boeke A.J., et al. Summary of the practice guideline for shoulder complaints from the Dutch College of General Practitioners. Ned Tijdschr Geneeskd. 2009;153:A164. [Article in Dutch]

45. New Zealand Guidelines Group. Diagnosis and management of soft tissue shoulder injuries and related disorders. Best Practice Evidence Based Guideline. 2004.

46. American College of Rheumatology subcommittee on osteoarthritis guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum. 2000;43:1905-1915.

47. Jordan M., Arden N.K., Doherty M., et al. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2003;62:1145-1155.

48. American Academy of Orthopaedic Surgeons Clinical Practice Guideline on Treatment of Carpal Tunnel Syndrome. Rosemont (IL): American Academy of Orthopaedic Surgeons (AAOS); 2008.

49. Creamer P. Intra-articular corticosteroid injections in osteoarthritis: do they work, and if so, how? Ann Rheum Dis. 1997;56:634-636.

50. Fanciullo G.J., Hanscom B., Seville J., et al. An observational study of the frequency and pattern of use of epidural steroid injection in 25,479 patients with spinal and radicular pain. Reg Anesth Pain Med. 2001;26(1):5-11.

51. Nichols A.W. Complications associated with the use of corticosteroids in the treatment of athletic injuries. Clin J Sport Med. 2005;15(5):E370.

52. Kumar N., Newman R. Complications of intra- and peri-articular steroid injections. Br J Gen Pract. 1999;49:465-466.

53. Seror P., Pluvinage P., Lecoq F., et al. Frequency of sepsis after local corticosteroid injection (an inquiry on 1,160,000 injections in rheumatological private practice in France). Rheumatology. 1999;38:1272-1274.

54. Holden J., Wooff E. Is our evidence-based practice effective? Review of 435 steroid injections given by a general practitioner over eight years. Clinical Governance: An International Journal. 2005;4:276-280.

55. Croft P. Admissible evidence. Ann Rheum Dis. 1998;57:387-389.

56. Furtado R.N., Oliveira L.M., Natour J. Polyarticular corticosteroid injection versus systemic administration in treatment of rheumatoid arthritis patients: a randomized controlled study. J Rheumatol. 2005;32:1691-1698.

57. Konai M.S., Vilar Furtado R.N., Dos Santos M.F., et al. Monoarticular corticosteroid injection versus systemic administration in the treatment of rheumatoid arthritis patients: a randomized double-blind controlled study. Clin Exp Rheumatol. 2009;27:214-221.

58. Combe B., Landewe R., Lukas C., et al. EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2007;66:34-45.

59. Haynes R.B., Devereaux P.J., Guyatt G.H. Physicians’ and patients’ choices in evidence based practice. Br Med J. 2002;324:1350.

60. Liddell W.G., Carmichael C.R., McHugh N.J. Joint and soft tissue injections: a survey of general practitioners. Rheumatology. 2005;44(8):1043-1046.

61. Gormley G.J., Corrigan M., Steele W.K., et al. Joint and soft tissue injections in the community: questionnaire survey of general practitioners’ experiences and attitudes. Ann Rheum Dis. 2003;62:61-64.

62. Jolly M., Curran J.J. Underuse of intra-articular and periarticular corticosteroid injections by primary care physicians: discomfort with the technique. J Clin Rheumatol. 2003;9(3):187-192.

63. Gormley G.J., Steele W.K., Stevenson M. A randomised study of two training programmes for general practitioners in the techniques of shoulder injection. Ann Rheum Dis. 2003;62:1006-1009.

64. ACPOM. A Clinical Guideline for the Use of Injection Therapy by Physiotherapists. London: The Chartered Society of Physiotherapy; 1999.

65. Weale A., Bannister G.C. Who should see orthopaedic outpatients – physiotherapists or surgeons? Ann R Coll Surg Engl. 1994;77(suppl):71-73.

66. Dyce C., Biddle P., Hall K., et al. Evaluation of extended role of physio and occupational therapists in rheumatology practice. Br J Rheumatol, April, suppl. 1: abstracts. 1996: 130.

67. Hattam P., Smeatham A. An evaluation of an orthopaedic screening service in primary care. British Journal of Clinical Governance. 1999;42:45-49.

68. Daker-White G., Carr A.J., Harvey I., et al. A randomised controlled trial – shifting boundaries of doctors and physiotherapists in orthopaedic outpatient departments. J Epidemiol Community Health. 1999;53:643-650.

69. Edwards J., Hannah B., Brailsford-Atkinson K., et al. Intra-articular and soft tissue injections: assessment of the service provided by nurses. Ann Rheum Dis. 2002;61:656-657. (Letter)

70. Edwards J., Hassell A. Intra-articular and soft tissue injections by nurses: preparation for expanded practice. Nurs Stand. 2000;33(14):43-46.

71. Yelland M.J., Glasziou P.P., Bogduk N., et al. Prolotherapy injections, saline injections, and exercises for chronic low-back pain: a randomized trial. Spine. 2004;29:9-16.

72. Rosseland L.A., Helgesen K.G., Breivik H., et al. Moderate-to-severe pain after knee arthroscopy is relieved by intra-articular saline: a randomized controlled trial. Anesth Analg. 2004;98:1546-1551.

73. Koes B.W. Corticosteroid injection for rotator cuff disease. Br Med J. 2009;338:a2599.

74. Ekeberg O.M., Bautz-Holter E., Tveita E.K., et al. Subacromial ultrasound guided or systemic steroid injection for rotator cuff disease: randomised double blind study. Br Med J. 2009;338:a3112.

75. Ghahreman A., Ferch R., Bogduk N. The efficacy of transforaminal injection of steroids for the treatment of lumbar radicular pain. Pain Medicine. 2010;11(8):1149-1168.

76. van der Windt D.A.W.M., Bouter L.M. Physiotherapy or corticosteroid injection for shoulder pain? Ann Rheum Dis. 2003;62:385-387.

77. Gerwin N., Hops C., Lucke A. Intraarticular drug delivery in osteoarthritis. Adv Drug Deliv Rev. 2006;2:226-242.

Corticosteroids and local anaesthetics


Corticosteroids were first administered systemically in 1948 by Philip Hench in the USA7 and were hailed as the new ‘universal panacea’, but it soon became apparent that there were major side-effects that greatly limited their systemic use.1,2 In 1951 Hollander in the USA reported the first use of local hydrocortisone injections for arthritic joints.8

The commonly used injectable corticosteroids are synthetic analogues of the adrenal glucocorticoid hormone cortisol (hydrocortisone), which is secreted by the innermost layer (zona reticularis) of the adrenal cortex. Cortisol has many important actions including anti-inflammatory activity. Corticosteroids influence the cells involved in the immune and inflammatory responses primarily by modulating the transcription of a large number of genes. They act directly on nuclear steroid receptors to control the rate of synthesis of mRNA.3 However, they also reduce the production of a wide range of pro-inflammatory mediators including cytokines and other important enzymes.1,2,46

Rationale for using corticosteroids

We know surprisingly little about the precise pharmacological effects of corticosteroids when they are injected directly into joints and soft tissues.911

Local steroid injections are thought to work by:

Suppressing inflammation in inflammatory systemic diseases such as rheumatoid or psoriatic arthritis, gout, etc.2,4,1215 Synovial cell infiltration and proinflammatory cytokine expression are reduced in a multifaceted manner by intra-articular corticosteroid injection.4
Suppressing inflammatory flares in degenerative joint disease.3,14,16 However, the pathophysiology of osteoarthritis is poorly understood,17 and there are no reliable clinical features that predict which osteoarthritic joints will respond to injection. Often, the only way to find out is with an empirical trial of injection therapy.14,16
Direct analgesic effect: inflammation is a complex cascade of molecular and cellular events.29,30 The precise role of inflammation in ‘tendinitis’ is the subject of considerable debate, and many authors prefer the terms ‘tendinosis’ or ‘tendinopathy’ to describe the pathological changes.29,30 Tendon pain may not be due to inflammation (tendinitis) or structural disruption of the tendon fibres (tendinosis), but might instead be caused by the stimulation of nociceptors by chemicals such as glutamate, substance P and chondroitin sulphate released from the damaged tendon.31,32 Corticosteroids (and possibly local anaesthetics) may inhibit release of noxious chemicals and/or the long-term behaviour of local nociceptors. In vitro, corticosteroids have also been shown to inhibit the transmission of pain along unmyelinated C-fibres by direct membrane action.33