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,¹^–⁵ 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.⁶^–²⁰ Consequently, there are few facts and a mass of opinions – many of them dogmatic and contradictory – about almost every aspect of injection therapy²¹^–²⁴ 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,^1,²⁶^–³¹ 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,^5,³²^–⁴³

Nonetheless, injection therapy is recommended for musculoskeletal (mainly knee and shoulder) disorders in national and international guidelines ^3,⁴⁴^–⁴⁸ and is used extensively for other musculoskeletal conditions.^49,⁵⁰ Given its relative safety,^1,^3,^5,⁵¹^–⁵³ 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:

• an inappropriate drug is chosen

• too large a dose or volume is given

• the drug is put into the wrong tissue

• poor technique allows spread of drugs to adjacent tissue

• injections are given too frequently

• insufficient attention is directed to the cause of the lesion

• no regard is given to aftercare and rehabilitation.

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.⁶⁰^–⁶² 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 orthopaedic ⁶⁵ 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:

• What are we treating – what is the pathological/biochemical cause for the pain?

• Are we always treating inﬂammation, or is the drug doing something else, e.g. modifying the action of nociceptors?

• Are there subgroups of potential injection responders within broad diagnostic categories e.g. ‘shoulder pain’ or ‘back pain’ and if so how can we identify them?

• Which options – which drug, dosage, volume, technique, venue, aftercare, co-intervention and/or rehabilitation should we advocate?

• When is the optimal time to inject in the course of any disorder?

• Should injections be repeated – if so at what intervals and how often?

• Who should be followed up – at what intervals and for how long?

• How much benefit is due to the placebo, the acupuncture or the ﬂuid volume effect as opposed to any specific pharmacological effect?

• What is the role of other injectable drugs besides steroid and local anaesthetic?

• Is injected saline an analgesic? This may influence the interpretation of trials where saline was used as an (assumed) inactive control.^71,⁷²

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

• Is a targeted injection more effective than a non-specific systemic one?⁷³^–⁷⁵

• How much do patients’ expectations and preferences affect the outcome?⁷⁶

• How much mythology is there about injection therapy and how can we correct it?

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.

References

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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]

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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.

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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]

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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.

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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.

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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.

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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.

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Corticosteroids and local anaesthetics

Corticosteroids

Corticosteroids were first administered systemically in 1948 by Philip Hench in the USA ⁷ 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,^2,⁴^–⁶

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.⁹^–¹¹

Local steroid injections are thought to work by:

• Suppressing inflammation in inflammatory systemic diseases such as rheumatoid or psoriatic arthritis, gout, etc.^2,^4,¹²^–¹⁵ 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

• Breaking up the inflammatory damage–repair–damage cycle which is postulated to set up a continuous low-grade inflammatory response, inhibiting tissue repair and sound scar formation, while forming adverse adhesions.^18,¹⁹ There is little direct evidence to support this, however.¹⁰

• Protecting cartilage: there may be a direct chondroprotective effect on cartilage metabolism or other effects not related to anti-inflammatory activity of the steroids e.g. promotion of articular surfactant production.^3,^6,²⁰^–²⁸

• 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