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Original Contribution

February 6, 2013

Effect of Corticosteroid Injection, Physiotherapy, or Both on Clinical Outcomes in Patients With Unilateral Lateral EpicondylalgiaA Randomized Controlled Trial

Brooke K. Coombes, PhD; Leanne Bisset, PhD; Peter Brooks, MD, FRACP; et alAsad Khan, PhD; Bill Vicenzino, PhD

Author Affiliations Article Information

JAMA. 2013;309(5):461-469. doi:10.1001/jama.2013.129

Abstract

Importance Corticosteroid injection and physiotherapy, common treatments for lateral epicondylalgia, are frequently combined in clinical practice. However, evidence on their combined efficacy is lacking.

Objective To investigate the effectiveness of corticosteroid injection, multimodal physiotherapy, or both in patients with unilateral lateral epicondylalgia.

Design, Setting, and Patients A 2 × 2 factorial, randomized, injection-blinded, placebo-controlled trial was conducted at a single university research center and 16 primary care settings in Brisbane, Australia. A total of 165 patients aged 18 years or older with unilateral lateral epicondylalgia of longer than 6 weeks' duration were enrolled between July 2008 and May 2010; 1-year follow-up was completed in May 2011.

Interventions Corticosteroid injection (n = 43), placebo injection (n = 41), corticosteroid injection plus physiotherapy (n = 40), or placebo injection plus physiotherapy (n = 41).

Main Outcome Measures The 2 primary outcomes were 1-year global rating of change scores for complete recovery or much improvement and 1-year recurrence (defined as complete recovery or much improvement at 4 or 8 weeks, but not later) analyzed on an intention-to-treat basis (P < .01). Secondary outcomes included complete recovery or much improvement at 4 and 26 weeks.

Results Corticosteroid injection resulted in lower complete recovery or much improvement at 1 year vs placebo injection (83% vs 96%, respectively; relative risk [RR], 0.86 [99% CI, 0.75-0.99]; P = .01) and greater 1-year recurrence (54% vs 12%; RR, 0.23 [99% CI, 0.10-0.51]; P < .001). The physiotherapy and no physiotherapy groups did not differ on 1-year ratings of complete recovery or much improvement (91% vs 88%, respectively; RR, 1.04 [99% CI, 0.90-1.19]; P = .56) or recurrence (29% vs 38%; RR, 1.31 [99% CI, 0.73-2.35]; P = .25). Similar patterns were found at 26 weeks, with lower complete recovery or much improvement after corticosteroid injection vs placebo injection (55% vs 85%, respectively; RR, 0.79 [99% CI, 0.62-0.99]; P < .001) and no difference between the physiotherapy and no physiotherapy groups (71% vs 69%, respectively; RR, 1.22 [99% CI, 0.97-1.53]; P = .84). At 4 weeks, there was a significant interaction between corticosteroid injection and physiotherapy (P = .01), whereby patients receiving the placebo injection plus physiotherapy had greater complete recovery or much improvement vs no physiotherapy (39% vs 10%, respectively; RR, 4.00 [99% CI, 1.07-15.00]; P = .004). However, there was no difference between patients receiving the corticosteroid injection plus physiotherapy vs corticosteroid alone (68% vs 71%, respectively; RR, 0.95 [99% CI, 0.65-1.38]; P = .57).

Conclusion and Relevance Among patients with chronic unilateral lateral epicondylalgia, the use of corticosteroid injection vs placebo injection resulted in worse clinical outcomes after 1 year, and physiotherapy did not result in any significant differences.

Abstract

중요성 외측 상과 통증의 일반적인 치료법인 코르티코스테로이드 주사와 물리 치료는 임상에서 종종 병행됩니다. 그러나 두 치료법의 병용 효과에 대한 증거는 부족합니다.

목적 일측성 외측 상과통 환자에서 코르티코스테로이드 주사, 복합 물리 치료 또는 두 가지 치료의 효과를 조사합니다.

설계, 환경 및 환자 호주 브리즈번의 한 대학 연구 센터와 16개 일차 진료 환경에서 2×2 요인, 무작위 배정, 주사 맹검, 위약 대조 임상시험을 실시했습니다. 2008년 7월부터 2010년 5월까지 6주 이상 지속된 일측성 외측 상 과통을 가진 18세 이상의 환자 총 165명이 등록되었으며, 2011년 5월에 1년간의 추적 관찰이 완료되었습니다.

중재 코르티코스테로이드 주사(n = 43), 위약 주사(n = 41), 코르티코스테로이드 주사와 물리치료(n = 40) 또는 위약 주사와 물리치료(n = 41).

주요 결과 측정

두 가지 주요 결과는 치료 의향에 따라 분석된

1년 후 완전 회복 또는

매우 호전된 상태와

1년 후 재발(4주 또는 8주 후 완전 회복 또는 매우 호전된 상태로 정의)에 대한

글로벌 변화 점수 평가였습니다(P < .01).

2차 결과에는

4주 및 26주 시점의 완전 회복 또는 현저한 개선이 포함되었습니다.

결과

코르티코스테로이드 주사는

위약 주사 대비 1년 후 완전 회복 또는 크게 개선된 비율이 낮았고

(각각 83% 대 96%; 상대 위험도[RR], 0.86 [99% CI, 0.75-0.99]; P = .01),

1년 후 재발이 더 적었습니다(54% 대 12%; RR, 0.23 [99% CI, 0.10-0.51]; P < .001).

물리치료를 받은 그룹과 물리치료를 받지 않은 그룹은

1년 후 완전 회복 또는 큰 개선(각각 91% 대 88%; RR, 1.04 [99% CI, 0.90-1.19]; P = .56)

또는 재발(29% 대 38%; RR, 1.31 [99% CI, 0.73-2.35]; P = .25)에 대한 평가에서 차이가 없었고

물리치료를 받은 그룹과 물리치료를 받지 않은 그룹은 1년 후에도 차이가 없었습니다.

26주째에도 비슷한 패턴이 발견되었는데,

코르티코스테로이드 주사 후 완전 회복률이 낮거나

위약 주사 후 훨씬 개선되었으며(각각 55% vs 85%; RR, 0.79 [99% CI, 0.62-0.99]; P < .001),

물리 치료 그룹과 물리 치료를 받지 않은 그룹 간에 차이가 없었습니다

(각각 71% vs 69%; RR, 1.22 [99% CI, 0.97-1.53]; P = .84).

4주 시점에서

코르티코스테로이드 주사와 물리 치료 간에 유의미한 상호작용이 있었으며(P = .01),

위약 주사와 물리 치료를 받은 환자는

물리 치료를 받지 않은 환자보다 완전히 회복되거나 훨씬 개선되었습니다

(각각 39% vs 10%; RR, 4.00 [99% CI, 1.07-15.00]; P = .004).

그러나

코르티코스테로이드 주사와 물리치료를 병행한 환자와

코르티코스테로이드만 투여한 환자 간에는 차이가 없었습니다(각각 68% vs 71%; RR, 0.95 [99% CI, 0.65-1.38]; P = .57).

결론 및 관련성

만성 편측 상과통 환자 중

코르티코스테로이드 주사와 위약 주사를 사용한 경우

1년 후 임상 결과가 악화되었으며,

물리 치료는 유의미한 차이를 보이지 않았습니다.

Trial Registration anzctr.org Identifier: ACTRN12609000051246

Use of corticosteroid injections to treat lateral epicondylalgia is increasingly discouraged,1,2 partly because evidence of long-term efficacy has not been found,3-5 and due to high recurrence rates.3,6 In a randomized controlled trial with 1-year follow-up,3 recurrence was evident in 72% of patients receiving corticosteroid injection compared with 8% after physiotherapy.

Combining corticosteroid injection with physiotherapy to compensate for the poor long-term outcomes of corticosteroid injections has been eval‎uated only in 2 small studies.7,8 One of the studies reported no benefit at 6 months after corticosteroid injection when added to ice massage plus physiotherapy-prescribed exercise.7 The other study found no significant effect of a progressive resistance training and graduated exercise program when added to corticosteroid injection; however, this study was underpowered, reported a high dropout rate, and did not assess outcomes beyond 7 weeks.8 The long-term effects of corticosteroid injection combined with physiotherapy are not known.

In contrast to the poor long-term outcomes, corticosteroid injections produce substantial pain relief in the short-term,3,5,9 which is counterintuitive, given their anti-inflammatory mode of action juxtaposed against the lack of inflammatory markers in tendinopathy.10-12 A plausible explanation is that these corticosteroid injections are associated with strong placebo effects.13 A systematic review14 found significant heterogeneity for studies comparing corticosteroid injection with placebo injection, with 3 of the 4 studies showing no difference. However, the use of lidocaine and bupivacaine injections as placebo comparators might have exerted a therapeutic effect.13 There is a critical need to eval‎uate the efficacy of corticosteroid injection compared with a placebo injection of normal saline.

The primary objectives of this study were 2-fold: to eval‎uate at 1 year the clinical efficacy of (1) corticosteroid injection vs placebo injection and (2) physiotherapy vs no physiotherapy in patients with unilateral lateral epicondylalgia. The primary outcomes were (1) patient-rated 1-year global change scores for complete recovery or much improvement and (2) 1-year recurrence (defined as complete recovery or much improvement at 4 or 8 weeks, but not at 8, 12, 26, or 52 weeks).

외측 상과 통 치료에

코르티코스테로이드 주사를 사용하는 것은

점점 더 권장되지 않고 있습니다.1,2

부분적으로는

장기적인 효능에 대한 증거가 발견되지않았고3-5

재발률이 높기 때문입니다.3,6

1년간 추적 관찰한 무작위 대조시험에서3

코르티코스테로이드 주사를 맞은 환자의 72%에서

재발이 분명한 반면

물리 치료 후 8%에서 재발이 나타났습니다.

코르티코스테로이드 주사의 좋지 않은 장기 결과를 보완하기 위해 코르티코스테로이드 주사와 물리 치료를 병행하는 것은 2건의 소규모 연구에서만 평가되었습니다.7,8 한 연구에서는 얼음 마사지와 물리 치료 처방 운동을 추가했을 때 코르티코스테로이드 주사 후 6개월이 지나도 효과가 없다고 보고했습니다.7 다른 연구에서는 점진적 저항 훈련과 점진적 운동 프로그램을 코르티코스테로이드 주사에 추가했을 때 유의미한 효과를 발견하지 못했지만, 이 연구는 규모가 작고 중도 탈락률이 높았으며 7주 이후의 결과를 평가하지 않았습니다.8 물리 치료와 병행한 코르티코스테로이드 주사의 장기적인 효과는 알려지지 않았습니다.

장기적인 결과가 좋지 않은 것과는 대조적으로,

코르티코스테로이드 주사는

단기간에 상당한 통증 완화 효과를 나타내며,3,5,9

이는 건 병증의 염증 마커 부족과 항염증 작용 방식을 고려할 때 직관에 반하는 것입니다.10-12

이러한 코르티코스테로이드 주사가 강력한 위약 효과와 관련이 있다는 그럴듯한 설명이 있습니다.13

체계적인 검토14에서는 코르티코 스테로이드 주사와 위약을 비교하는 연구에 대해 상당한 이질성이 발견되었으며, 4 개의 연구 중 3 개는 차이가 없음을 보여주었습니다. 그러나 리도카인과 부피바카인 주사를 위약 비교군으로 사용함으로써 치료 효과를 발휘했을 수 있습니다.13 생리식염수 위약 주사와 비교하여 코르티코스테로이드 주사의 효능을 평가할 필요가 있습니다.

이 연구의 주요 목표는 두 가지로, 일측 외측 상과 통증 환자에서 (1) 코르티코스테로이드 주사 대 위약 주사, (2) 물리 치료 대 물리 치료 없음의 임상적 효능을 1년 시점에서 평가하는 것이었습니다.

주요 결과는 (1) 완전 회복 또는 현저한 개선에 대한 환자 평가 1년 글로벌 변화 점수, (2) 1년 재발(4주 또는 8주에 완전 회복 또는 현저한 개선으로 정의되었으나 8, 12, 26, 52주에는 그렇지 않음)이었습니다.

Methods

A randomized, blinded, placebo-controlled trial with a 2 × 2 factorial design and 1 year of follow-up was performed in a community setting in Brisbane, Australia, as per the published protocol.13 Injection and physiotherapy factors were combined to constitute 4 treatment groups: (1) corticosteroid injection, (2) placebo injection, (3) corticosteroid injection plus multimodal physiotherapy, and (4) placebo injection plus multimodal physiotherapy. This trial was approved by the University of Queensland medical research ethics committee.

Patients

Adults aged 18 years or older with unilateral lateral epicondylalgia of longer than 6 weeks' duration, who responded to public advertisements between August 2008 and May 2010, were invited to participate. Inclusion criteria were pain over the lateral humeral epicondyle with pain severity of greater than 30 mm on a 100-mm visual analog scale (VAS), provoked by at least 2 of the following: gripping, palpation, resisted wrist or middle finger extension, or stretching of forearm extensor muscles with reduced pain-free grip.

Exclusion criteria were receipt of injection (during preceding 6 months); receipt of a course of physiotherapy (during preceding 3 months); concomitant neck or other arm pain necessitating treatment or preventing participation in usual work or recreational activities (during preceding 6 months); symptoms suggesting radicular, neurological, or systemic arthritic conditions; pregnancy; breastfeeding; or contraindication to injection. Eligibility was determined by telephone interview and physical examination by one researcher (B.K.C.) and confirmed by a second researcher (B.V.).

Randomization

After written informed consent was obtained, randomization was performed by concealed allocation using a computer-generated schedule developed by the Queensland Clinical Trials Center, an independent, offsite organization. Randomization was stratified according to pain severity of greater or less than 57.5 mm on a 100-mm VAS, which was based on the mean score from a previous study.3 A research assistant not involved in data collection or analysis, administered the randomization schedule and arranged all study appointments.

Blinding

The researcher who assessed outcomes and performed the intention-to-treat analysis was blinded to both injection and physiotherapy assignment. Patients were masked to injection type (corticosteroid or placebo) but not to physiotherapy due to its nature. To eval‎uate the success of blinding, patients were asked at 8 weeks whether they were confident of which injection they received, and those who responded yes were asked to report the suspected injection type. The outcome assessor guessed both injection and physiotherapy assignment of all patients.

Interventions

Injection Types. Patients received a single injection of either placebo (0.5 mL of 0.9% isotonic saline) or corticosteroid and local anesthetic medication (10 mg/mL of triamcinolone acetonide in a 1 mL injection plus 1 mL of 1% lignocaine) by 1 of 5 medical practitioners within 10 days of randomization. The injection was applied to the site of greatest palpable tenderness at the common extensor origin.

All patients received standardized advice to avoid activities that caused or provoked pain and to refrain from performing strenuous activity for 2 weeks after receipt of injection. Following this 2-week period, a gradual return to normal activities was encouraged (even if substantial initial relief was obtained) to minimize potential recurrence. Patients could use an analgesic or anti-inflammatory medication, heat or cold pack, or braces as needed, but were discouraged from seeking treatments other than those assigned.

Physiotherapy. The physiotherapy groups underwent eight 30-minute sessions of treatment during an 8-week period, with the first session scheduled prior to the injection. Eleven physiotherapy practitioners with postgraduate qualifications underwent 2 hours of training with 2 of the authors (B.K.C. and B.V.) to standardize the treatment according to a published protocol,13 which comprised local elbow manual therapy and exercise.

To individualize treatment, practitioners chose manual therapy and exercises from the protocol and progressed the program based on the patients' capabilities to allow for optimal exercise volume and load setting without exacerbating pain. The specific elbow manipulation (mobilization with movement) techniques were applied in combination with gripping as described by Vicenzino.15

The comprehensive exercise program included twice daily sensorimotor retraining of gripping and concentric and eccentric exercise to progressively load the wrist extensors using resistive elastic latex bands. The home program was regularly reviewed and exercise diaries were monitored to facilitate program adherence.

물리 치료.

물리치료 그룹은 8주 동안

30분씩 8회의 치료를 받았으며,

첫 번째 세션은 주사 전에 예약되었습니다.

대학원 자격을 갖춘 물리치료사 11명은

국소 팔꿈치 도수 치료와 운동으로 구성된 공개된프로토콜13에 따라

치료를 표준화하기 위해 저자들 중 2명(B.K.C. 및 B.V.)과 함께 2시간 동안 교육을 받았습니다.

치료를 개별화하기 위해 의사는

프로토콜에서 도수 치료와 운동을 선택하고

환자의 능력에 따라 프로그램을 진행하여 통증을 악화시키지 않고

최적의 운동량과 부하를 설정할 수 있도록 했습니다.

특정 팔꿈치 조작(움직임을 통한 동원) 기술은 비첸지노가 설명한 대로 그립과 함께 적용되었습니다.15

종합적인 운동 프로그램에는

매일 두 번 파지에 대한 감각 운동 재훈련과 저항성 탄성 라텍스 밴드를 사용하여

손목 신근에 점진적으로 부하를 주는

동심 및 편심 운동이 포함되었습니다.

홈 프로그램을 정기적으로 검토하고

운동 일기를 모니터링하여 프로그램 준수를 촉진했습니다.

Outcome Measures

Patients estimated their global rating of change at each trial visit (at 4, 8, 12, 26, and 52 weeks) using a 6-point Likert scale, ranging from “complete recovery” to “much worse.”3,13 A priori primary outcomes were 1-year global rating of change scores of complete recovery or much improvement and 1-year recurrence (defined as global rating of change scores of complete recovery or much improvement at 4 or 8 weeks, but not at 8, 12, 26, or 52 weeks).

The secondary outcomes were global rating of change scores of complete recovery or much improvement at 4 and 26 weeks; severity of current resting pain and worst pain over the preceding week (on a 100-mm VAS); a condition-specific, validated questionnaire of pain and disability (Patient-Rated Tennis Elbow Eval‎uation score range: 0-100, in which 100 represents the worst imaginable pain with a very significant functional disability)16,17; health-related quality of life (EuroQol EQ-5D score range: 0-1, in which 1 represents perfect health)18 at 4, 26, and 52 weeks; use of analgesic or anti-inflammatory medication or other nonallocated treatments; and adverse events. Minimum clinically important changes in pain and disability (as measured using the Patient-Rated Tennis Elbow Eval‎uation) of 37% of baseline scores are reported for clinical significance defined as “much better” or “completely recovered” in patients with lateral epicondylalgia.19

Statistical Analysis

The primary hypotheses of this 2 × 2 factorial study design were that after 1 year, clinical outcomes would be worse in patients receiving an injection of corticosteroid (vs placebo), whereas outcomes would be better in those receiving physiotherapy (vs no physiotherapy). At the outset of the trial, we did not anticipate an interaction between the 2 interventions.20 A total sample size of 120 patients (α = .05, β = .20) was initially estimated to detect a clinically meaningful difference of 25% for the 2 factorial (at margin) comparisons (corticosteroid vs placebo; physiotherapy vs no physiotherapy) for all primary hypotheses based on previous studies.3,5

However, at a trial steering committee meeting (before recruitment ended), we decided to inflate the sample size to 165 to permit adequate power for the following a priori pairwise comparisons21: corticosteroid injection vs placebo injection alone; corticosteroid injection plus physiotherapy vs placebo injection plus physiotherapy; placebo injection vs placebo injection plus physiotherapy; and corticosteroid injection vs corticosteroid injection plus physiotherapy; and to account for loss to follow-up. No interim analyses were performed during the study period.

The statistical analyses were performed on a blinded, intention-to-treat basis using SPSS version 20.0 (SPSS Inc) with a priori 2-sided significance as a P value of less than .01 due to the multiple comparisons. The effects of injection and physiotherapy on complete recovery or much improvement and 1-year recurrence were analyzed using binary logistic regression, including baseline worst pain as a covariate (measured by the VAS), which is a recognized prognostic factor.22

We investigated for interactions between injection and physiotherapy factors and interpreted results of pairwise comparisons when a significant interaction was found. We calculated the relative risk (RR) of complete recovery or much improvement by dividing the corticosteroid (or physiotherapy) risk by the placebo (or no physiotherapy) risk. We also calculated the RR of recurrence by dividing the placebo (or no physiotherapy) risk by the corticosteroid (or physiotherapy) risk. The numbers needed to treat (NNT) were generated as a meaningful indicator of treatment efficacy for practitioners.23

Continuous outcomes were analyzed using linear regression, including baseline values of the dependent variable as a covariate. Main effects or pairwise comparisons (when there was a significant interaction)21 were expressed as standardized mean differences (SMDs) and calculated using RevMan statistical software version 5.0 (Nordic Cochrane Centre, Cochrane Collaboration). A beneficial effect of corticosteroid and physiotherapy were defined as a RR of greater than 1, or a SMD and NNT of greater than 0, whereas a harmful effect of corticosteroid injection and physiotherapy were defined as a RR of less than 1, or a SMD and NNT of less than 0. A SMD between 0.2 and 0.5 was defined as a small effect, a SMD between 0.5 and 0.8 as a medium effect, and a SMD of greater than 0.8 as a large effect.24

Results

A total of 165 patients with unilateral lateral epicondylalgia were enrolled between July 2008 and May 2010. Figure 1 summarizes patient recruitment, participation, and attrition. The most common reasons for exclusion of patients with suspected lateral epicondylalgia were recent treatment (22%), other elbow condition (19%), concomitant neck or shoulder pain (14%), refused to participate (13%), bilateral elbow pain (12%), or resolution of lateral epicondylalgia (5%). Elbow surgery, a history of repeated corticosteroid injection, neurological symptoms, and other contraindications made up the remaining 15% of excluded patients.

The trial was completed in May 2011, with 163 patients (99%) completing primary outcomes at 1 year; there were 2 deaths due to cancer. Because of the small proportion of missing values (n = 3; 2%), we did not perform any data imputation. The omitted cases had similar baseline characteristics as the total sample. No significant differences in baseline characteristics were found among the 4 study groups (Table 1). The median duration of lateral epicondylalgia was 16 weeks (range: 6 weeks-4 years) and 76% presented with their first episode.

Four patients did not receive the allocated injection (1 in the placebo group and 3 in the corticosteroid group) due to nonattendance (n = 2; 1%) or alternative medical advice (n = 2; 1%). The mean (SD) number of physiotherapy sessions attended was 7.5 (1.9). Seven patients (9%) completed less than 4 physiotherapy sessions; the reasons included nonattendance, moving interstate, or recovery from pain. Of patients in the physiotherapy groups, 70% were compliant with their home exercise program during at least 5 of 7 weeks. Two patients (2%) in the corticosteroid group received an additional corticosteroid injection, and 7 patients (8%) not allocated to physiotherapy, pursued physiotherapy outside of the trial.

Treatment allocation was correctly guessed by the outcome assessor in 53% (20/38) of cases receiving the placebo injection only, 39% (16/41) of cases receiving the placebo injection plus physiotherapy, 44% (18/41) of cases receiving the corticosteroid injection only, and 39% (15/38) of cases receiving the corticosteroid injection plus physiotherapy. Of 137 patients, 50 (37%) stated they were confident of which injection they received and correct responses were identified by 71% (20/28) of patients in the corticosteroid injection group and 73% (16/22) of patients in the placebo injection group. No differences were found among the 4 interventions.

Descriptive statistics for the 4 randomized groups for a priori time points (at 4, 26, and 52 weeks) are presented in Table 2 and Table 3 while additional data are provided in the (eTable ).

Primary Outcomes

There was no interaction between injection (corticosteroid vs placebo) and physiotherapy (yes vs no) at 1 year (P = .99). Corticosteroid injection demonstrated lower complete recovery or much improvement at 1 year compared with placebo injection (68/82 [83%] vs 78/81 [96%], respectively; RR, 0.86 [99% CI, 0.75 to 0.99]; NNT, −7.5 [99% CI, −150.9 to −3.7]; P = .01) and greater recurrence (44/81 [54%] vs 10/81 [12%]; RR, 0.23 [99% CI, 0.10 to 0.51]; NNT, −2.4 [−4.3 to −1.8]; P < .001) (Figure 2).

There were no differences between physiotherapy and no physiotherapy at 1 year for complete recovery or much improvement (73/80 [91%] vs 73/83 [88%], respectively; RR, 1.04 [99% CI, 0.90-1.19]; P = .56) or recurrence (23/80 [29%] vs 31/82 [38%]; RR, 1.31 [99% CI, 0.73-2.35]; P = .25) (Figure 2).

Secondary Outcomes

At 4 Weeks. There was a significant interaction at 4 weeks between corticosteroid injection and physiotherapy for complete recovery or much improvement (P = .01; Figure 2), worst pain (P < .001), pain and disability (P < .001), and quality of life (P = .004) (Figure 3).

In the absence of physiotherapy, complete recovery or much improvement was greater following corticosteroid injection compared with the placebo injection (RR, 7.32 [99% CI, 2.1-25.5]; NNT, 1.6 [99% CI, 1.3-2.9]; P < .001). Corticosteroid injection alone was associated with large benefits for all secondary outcomes: worst pain (SMD, 1.77 [99% CI, 1.09-2.44]; P < .001), resting pain (SMD, 0.87 [99% CI, 0.28-1.46]; P < .001), pain and disability (SMD, 1.81 [99% CI, 1.13-2.48]; P < .001), and quality of life (SMD, 1.14 [99% CI, 0.53-1.76]; P < .001).

When physiotherapy was present, there were no differences between the corticosteroid injection and placebo injection groups for the outcomes of complete recovery or much improvement (RR, 1.73 [99% CI, 0.97 to 3.08]; P = .02), worst pain (SMD, 0.51 [99% CI, −0.08 to 1.09]; P = .03), resting pain (SMD, 0.21 [99% CI, −0.36 to 0.79]; P = .29), and quality of life (SMD, 0.30 [99% CI, −0.27 to 0.88]; P = .08). There was a medium-sized benefit for pain and disability when physiotherapy was combined with corticosteroid injection (vs placebo injection combined with physiotherapy) (SMD, 0.63 [99% CI, 0.04 to 1.22]; P < .001).

Physiotherapy plus corticosteroid (vs corticosteroid alone) had no effect on the outcomes of complete recovery or much improvement (RR, 0.95 [99% CI, 0.65 to 1.38]; P = .57), worst pain (SMD, −0.38 [99% CI, −0.96 to 0.19]; P = .10), resting pain (SMD, −0.05 [99% CI, −0.62 to 0.52]; P = .91), pain and disability (SMD, −0.40 [99% CI, −0.97 to 0.18]; P = .12), and quality of life (SMD, −0.30 [99% CI, −0.88 to 0.27]; P = .29).

Patients who received the placebo injection plus physiotherapy had greater complete recovery or much improvement compared with the no physiotherapy group (RR, 4.00 [99% CI, 1.07-15.00]; NNT, 3.4 [99% CI, 2.0-21.4], P = .004), and medium-sized benefits for worst pain (SMD, 0.88 [99% CI, 0.29-1.48]; P < .001), resting pain (SMD, 0.60 [99% CI, 0.02-1.19]; P = .01), and pain and disability (SMD, 0.77 [99% CI, 0.18-1.37]; P = .001).

At 26 Weeks. There were no significant interaction effects at 26 weeks. The corticosteroid injection demonstrated lower complete recovery or much improvement compared with the placebo injection (45/82 [55%] vs 69/81 [85%], respectively; RR, 0.79 [99% CI, 0.62 to 0.99]; NNT −5.5 [99% CI, −123.1 to −2.9]; P < .001).

Patients who received the corticosteroid injection had medium-sized deficits for worst pain (SMD, −0.77 [99% CI, −1.19 to −0.35]; P < .001), resting pain (SMD, −0.61 [99% CI, −1.02 to −0.19]; P < .001), pain and disability (SMD, −0.76 [99% CI, −1.18 to −0.34]; P < .001), and quality of life (SMD, −0.55 [99% CI, −0.97 to −0.14]; P = .004).

Physiotherapy compared with no physiotherapy demonstrated no effects on the outcomes of complete recovery or much improvement (57/80 [71%] vs 57/83 [69%], respectively; RR, 1.22 [99% CI, 0.97 to 1.53]; P = .84), worst pain (SMD, 0.04 [99% CI, −0.36 to 0.44]; P = .79), resting pain (SMD, 0.05 [99% CI, −0.35 to 0.46]; P = .74), pain and disability (SMD, 0.07 [99% CI, −0.33 to 0.48]; P = .25), and quality of life (SMD, 0.33 [99% CI, −0.08 to 0.74]; P = .13).

At 52 Weeks. There were no significant interaction effects at 52 weeks. Consistent with the primary outcomes, worst pain remained significantly higher for the corticosteroid injection compared with the placebo injection at 1 year, although the differences were small (SMD, −0.44 [99% CI, −0.85 to −0.03]; P = .005).

No differences were found between the 2 injection types for resting pain (SMD, −0.17 [99% CI, −0.58 to 0.23]; P = .29), pain and disability (SMD, −0.36 [99% CI, −0.76 to 0.05]; P = .02), and quality of life (SMD, −0.22 [99% CI, −0.63 to 0.18]; P = .21). Physiotherapy compared with no physiotherapy demonstrated no effects on the outcomes of complete recovery or much improvement (73/80 [91%] vs 73/83 [88%], respectively; RR, 1.04 [99% CI, 0.90 to 1.19]; P = .56), worst pain (SMD, −0.07 [99% CI, −0.47 to 0.34]; P = .66), resting pain (SMD, −0.07 [99% CI, −0.47 to 0.34]; P = .64), pain and disability (SMD, 0.05 [99% CI, −0.36 to 0.45]; P = .51), and quality of life (SMD, 0.00 [99% CI, −0.40 to 0.40]; P = .70).

Use of an analgesic or anti-inflammatory medication did not differ between injection of corticosteroid or placebo (26/83 [31%] vs 23/82 [28%], respectively; P = .57), whereas it was less frequently used by patients allocated to physiotherapy compared with those not allocated to physiotherapy (16/81 [20%] vs 33/84 [39%], respectively; NNT, 5.1 [99% CI, 2.8-84.8]; P = .008) (Table 2). Nonprotocol medical consultations did not significantly differ between injection types (corticosteroid vs placebo) (15/83 [18%] vs 8/82 [10%], respectively; P = .13) or physiotherapy (yes vs no) (7/81 [9%] vs 16/84 [19%], respectively; P = .06).

Adverse events reported in this study were minor, transient, and not significantly different between injection or physiotherapy factors (Table 2). Skin depigmentation (4/83; 5%) and subcutaneous atrophy (3/83; 4%) occurred exclusively in patients receiving corticosteroid injection, showed a delayed onset (evident on examinations at 8 or 12 weeks), and was resolved by 26 weeks.

Comment

In this placebo-controlled study, a single, blinded injection of corticosteroid medication was associated with poorer long-term outcomes and higher recurrence rates 1 year after receiving an injection in patients with unilateral lateral epicondylalgia. Eight weeks of multimodal physiotherapy, comprising elbow mobilization with movement and exercise, did not optimize long-term outcomes, but was beneficial in the short-term in the absence of corticosteroid injection. Significantly fewer patients receiving physiotherapy consumed an analgesic or anti-inflammatory medication.

A systematic review (search date: March 2010)4 reported it was not possible to make a definitive declaration regarding the efficacy of corticosteroid injection beyond placebo, largely due to significant heterogeneity for studies making this comparison. Our current study provides evidence of the short-term effectiveness of corticosteroid injection alone compared with placebo injection. Notwithstanding this, differences in complete recovery or much improvement were not significant when patients also received physiotherapy, a finding echoed by Newcomer et al7 in a study of lateral epicondylalgia of less than 6 weeks' duration. This evidence does not support the clinical practice of using corticosteroid injection to facilitate active rehabilitation.

Results were reversed at 6 months, with corticosteroid injection displaying moderate to large inferior effects consistently across measures of complete recovery or much improvement, pain, disability, and quality of life. At 1 year, most patients (90%) in the study reported complete recovery or much improvement, which reflects the natural history of the condition.3,5,9 However, in patients who received the corticosteroid injection, significantly fewer reported being completely recovered or much improved, and worst pain levels remained higher 1 year after receipt of the corticosteroid injection.

Furthermore, more than half of all patients treated with a single corticosteroid injection experienced a recurrence, a substantially greater proportion than the placebo group. In clinical terms, this represented an NNT of 2.4 (ie, for every 2 or 3 people treated with corticosteroid injection vs placebo, 1 person experienced recurrence during the year). While high recurrence rates after corticosteroid injection have been previously reported,3,5 our current study provides evidence that it may be the effect of the medication and not merely a manifestation of the condition or the injection.

The biological basis for the clinical effect of corticosteroids in lateral epicondylalgia is still largely unknown. Corticosteroids are potent in suppressing inflammation,25 but the prevailing opinion is that no histological evidence of acute inflammation has been documented,11,12,26,27 although inflammatory cells have been detected by newer studies using immunohistochemistry.28,29 The early response of corticosteroids may be due to an analgesic effect on the neuropeptides, calcitonin gene-related peptide, and substance P, which are increased in tendinopathy.27

Recurrence may occur because corticosteroids do not address key features of tendinopathy, which is traditionally thought to be associated with overuse, cumulative trauma weakening the collagen cross-linking, and the noncollagenous matrix and vascular elements of the tendon.27 Corticosteroids might be deleterious to the tendon through an effect on fibroblasts' role in collagen and extracellular matrix protein production.25 Others have proposed that the poor long-term clinical effect of corticosteroid injection might be related to the immediate pain relief and conceivable excessive or inappropriate early activity.3,27

Contrary to our hypothesis and to a generally held clinical view,2 we found that multimodal physiotherapy provided no beneficial long-term effect on complete recovery or much improvement, recurrence, pain, disability, or quality of life, thereby not supporting the hypothesis that the combined approach is superior. However, physiotherapy should not be dismissed altogether because in the absence of the corticosteroid, it provided short-term benefit across all outcomes, as well as the lowest recurrence rates (4.9%) and 100% complete recovery or much improvement at 1 year.

At 4 weeks, the magnitude of improvement on the Patient-Rated Tennis Elbow Eval‎uation, a validated, condition-specific measure of pain and disability, exceeded previously reported minimum clinically important differences19 for patients receiving corticosteroid injection and/or physiotherapy, but not for those receiving placebo injection alone. A previous study showed a similar multimodal physiotherapy program was superior to wait and see in the short-term.3

The strengths of this study lie in the high retention (99.8%) of patients after extended follow-up and the consistency of findings across validated condition-specific and generic outcomes.

This study also has limitations. First, results may not be generalized to other clinical contexts in which treatments are reserved for specific individuals or combined in a different sequence or manner (for example, injection of patients who have not recovered after a period of wait and see or physiotherapy; or treatment with physiotherapy in patients with poor late outcomes after injection).

Second, it is common for lateral epicondylalgia to present bilaterally or be associated with concomitant symptoms of the neck or upper limb.22 We limited our study population to patients with unilateral lateral epicondylalgia without significant neck or other upper limb symptoms, which needs to be considered in applying our findings to clinical practice.

Third, we excluded patients who had received recent treatment or repeated corticosteroid injection because inclusion may have biased the findings. Excluding patients who received prior corticosteroid injection suggests that our findings are the best-case scenario in terms of long-term outcomes. A previous study found a poorer long-term effect of repeated corticosteroid injection (mean of 4.3 injections in 18 months) on reduction of pain vs treatment with a single injection.30

Fourth, it should be acknowledged that while the assessor was blinded to treatments received by the patients, the lack of patient and therapist blinding to physiotherapy might have biased estimates of the benefit of physiotherapy, the mitigation of which should be considered in future study designs.31

In conclusion, among patients with chronic unilateral lateral epicondylalgia, there was a worse clinical outcome 1 year after corticosteroid injection compared with placebo, despite its short-term benefits. Physiotherapy did not result in any significant 1-year differences.

코멘트

이 위약 대조 연구에서는 일측 외측 상과염 환자에서 코르티코스테로이드 약물을 맹검으로 1회 주사하는 것이 주사 1년 후 장기 예후가 나쁘고 재발률이 높은 것과 관련이 있는 것으로 나타났습니다. 팔꿈치 운동과 운동으로 구성된 8주간의 복합 물리치료는 장기적인 결과를 최적화하지는 못했지만, 코르티코스테로이드 주사를 받지 않은 단기적인 치료에는 도움이 되었습니다. 물리치료를 받은 환자 중 진통제나 소염제를 복용한 환자 수는 훨씬 적었습니다.

한 체계적 문헌고찰(검색 날짜: 2010년 3월)4에서는 위약을 넘어서는 코르티코스테로이드 주사의 효능에 대해 결론을 내릴 수 없다고 보고했는데, 이는 이러한 비교를 한 연구의 이질성이 상당하기 때문이었습니다. 이번 연구는 위약 주사와 비교하여 코르티코스테로이드 주사 단독의 단기적 효과에 대한 증거를 제공합니다. 그럼에도 불구하고, 환자가 물리 치료를 받은 경우 완전한 회복이나 큰 개선의 차이는 크지 않았으며, 이는 6주 미만의 외측 상과통에 대한 연구에서 Newcomer 등7이 발견한 결과를 반영한 것입니다. 이러한 증거는 적극적인 재활을 촉진하기 위해 코르티코스테로이드 주사를 사용하는 임상 관행을 뒷받침하지 않습니다.

6개월이 지나자 결과는 반전되어 코르티코스테로이드 주사는 완전 회복 또는 대폭 개선, 통증, 장애 및 삶의 질 측정에서 일관되게 중간 정도에서 크게 열등한 효과를 나타냈습니다. 1년 후, 연구에 참여한 대부분의 환자(90%)가 완전히 회복되었거나 많이 호전되었다고 보고했는데, 이는 질환의 자연 경과를 반영하는 결과입니다.3,5,9 그러나 코르티코스테로이드 주사를 맞은 환자에서는 완전히 회복되었거나 많이 호전되었다고 보고한 환자 수가 훨씬 적었으며 코르티코스테로이드 주사를 맞은 후 1년이 지나도 최악의 통증 수준이 여전히 높게 유지되었습니다.

또한 코르티코스테로이드 주사를 한 번만 맞은 환자의 절반 이상이 재발을 경험했으며, 이는 위약 그룹보다 훨씬 많은 비율이었습니다. 임상적으로 볼 때 이는 2.4의 NNT(위약 대비 코르티코스테로이드 주사로 치료받은 환자 2~3명당 1명이 1년 동안 재발을 경험했다는 의미)를 나타냅니다. 코르티코스테로이드 주사 후 높은 재발률은 이전에 보고된 바 있지만,3,5 이번 연구는 단순히 질환이나 주사의 증상이 아니라 약물의 효과일 수 있다는 증거를 제공합니다.

외측 상과 통증에서 코르티코스테로이드의 임상적 효과에 대한 생물학적 근거는 아직 거의 알려지지 않았습니다. 코르티코 스테로이드는 염증을 억제하는 데 강력하지만,25 면역 조직 화학을 사용한 최신 연구에서 염증 세포가 발견되었지만 급성 염증의 조직 학적 증거는 문서화되지 않았다는 것이 지배적 인 의견입니다 .11,12,26,27.28,29 코르티코 스테로이드의 초기 반응은 건 병증에서 증가하는 신경 펩티드, 칼시토닌 유전자 관련 펩티드 및 물질 P에 대한 진통제 효과 때문일 수 있습니다 .27

코르티코스테로이드는 전통적으로 과다 사용, 누적된 외상으로 인한 콜라겐 교차 결합 약화, 힘줄의 비콜라겐 기질 및 혈관 요소와 관련이 있다고 생각되는 건병증의 주요 특징을 해결하지 못하기 때문에 재발이 발생할 수 있습니다.27 코르티코스테로이드는 콜라겐 및 세포 외 기질 단백질 생산에서 섬유아세포의 역할에 영향을 미쳐 힘줄에 해로울 수 있습니다.25 다른 사람들은 코르티코스테로이드 주사의 열악한 장기 임상 효과가 즉각적인 통증 완화 및 생각할 수있는 과도하거나 부적절한 초기 활동과 관련이있을 수 있다고 제안했습니다.3,27

우리의 가설과 일반적으로 알려진 임상적 견해와는 달리,2 복합 물리 치료는 완전한 회복이나 재발, 통증, 장애 또는 삶의 질에 장기적으로 유익한 효과를 제공하지 않았으며, 따라서 복합 접근법이 우수하다는 가설을 뒷받침하지 못한다는 것을 발견했습니다.

그러나

코르티코스테로이드가 없는 경우 물리치료는

모든 결과에서 단기적인 이점을 제공했을 뿐만 아니라

가장 낮은 재발률(4.9%)과 1년 후 100% 완전 회복 또는 큰 개선을 보였기 때문에

물리치료를 완전히 무시해서는 안 됩니다.

4주 후, 통증 및 장애에 대한 검증된 상태별 척도인 환자 평가 테니스 엘보 평가에서 개선 정도는 코르티코스테로이드 주사 및/또는 물리 치료를 받은 환자의 경우 이전에 보고된 임상적으로 중요한 최소 차이19를 초과했지만 위약 주사만 받은 환자의 경우 그렇지 않은 것으로 나타났습니다. 이전 연구에서는 유사한 복합 물리치료 프로그램이 단기간에 대기하고 지켜보는 것보다 더 우수한 것으로 나타났습니다.3

이 연구의 강점은 장기 추적 관찰 후 환자의 높은 유지율(99.8%)과 검증된 질환별 및 일반적 결과 전반에 걸쳐 일관된 결과를 보인다는 점입니다.

이 연구에도 한계가 있습니다. 첫째, 특정 개인에게만 치료를 시행하거나 다른 순서나 방식으로 치료를 병행하는 다른 임상 상황에 결과를 일반화할 수 없습니다(예: 일정 기간 경과 관찰 또는 물리 치료 후 회복되지 않은 환자에게 주사 또는 주사 후 후기 결과가 좋지 않은 환자에게 물리 치료를 병행하는 경우).

둘째, 외측 상 과통은 양측으로 나타나거나 목 또는 상지의 수반되는 증상과 연관되는 것이 일반적입니다.22 우리는 연구 대상을 목 또는 기타 상지 증상이 없는 일측 외측 상 과통 환자로 제한했으며, 이는 연구 결과를 임상 진료에 적용할 때 고려할 필요가 있습니다.

셋째, 최근 치료를 받았거나 반복적으로 코르티코스테로이드 주사를 맞은 환자를 포함하면 연구 결과에 편향이 있을 수 있으므로 제외했습니다. 이전에 코르티코스테로이드 주사를 맞은 환자를 제외했다는 것은 이번 연구 결과가 장기적인 결과 측면에서 가장 좋은 시나리오임을 시사합니다. 이전 연구에서는 반복적인 코르티코스테로이드 주사(18개월 동안 평균 4.3회 주사)가 한 번의 주사로 치료하는 것보다 통증 감소에 대한 장기적인 효과가 더 좋지 않다는 것을 발견했습니다.30

넷째, 평가자는 환자가 받은 치료에 대해 맹목적이었지만, 환자와 치료사가 물리치료에 대해 맹목적이었기 때문에 물리치료의 이점에 대한 평가가 편향되었을 수 있으며, 향후 연구 설계에서 이를 완화하는 것이 고려되어야 합니다.31

결론적으로, 만성 일측 외측 상 과염 환자 중 코르티코스테로이드 주사 1년 후 위약에 비해 임상 결과가 더 나빴지만, 단기적인 이점에도 불구하고 위약에 비해 임상 결과가 더 나빴습니다. 물리 치료는 1년간 유의미한 차이를 보이지 않았습니다.

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Article Information

Corresponding Author: Bill Vicenzino, PhD, School of Health and Rehabilitation Sciences, University of Queensland, Bldg 84A, St Lucia QLD 4072, Australia (b.vicenzino@uq.edu.au).

Author Contributions: Dr Vicenzino had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Coombes, Bisset, Brooks, Vicenzino.

Acquisition of data: Coombes, Bisset, Vicenzino.

Analysis and interpretation of data: Coombes, Bisset, Brooks, Khan, Vicenzino.

Drafting of the manuscript: Coombes, Brooks, Vicenzino.

Critical revision of the manuscript for important intellectual content: Coombes, Bisset, Brooks, Khan, Vicenzino.

Statistical analysis: Coombes, Khan, Vicenzino.

Obtained funding: Bisset, Brooks, Vicenzino.

Administrative, technical, or material support: Coombes, Vicenzino.

Study supervision: Bisset, Vicenzino.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bisset reported receiving payment from the Australian Catholic University for lectures on physiotherapy assessment and management of the elbow. Dr Vicenzino reported receiving payment from various conferences for lectures on a range of musculoskeletal and sports health-related topics, including lateral epicondylalgia, physiotherapy, injections, and exercise; receiving travel reimbursement when serving as a keynote speaker or when providing workshop presentations; and receiving royalties from Elsevier for a book that covers some of the treatments in the treatment program described in this article. No other authors reported disclosures.

Funding/Support: This study was supported by the Australian National Health and Medical Research Council grant 511238 awarded to Drs Bisset, Brooks, and Vicenzino.

Role of the Sponsor: The Australian National Health and Medical Research Council had no role in the design or conduct of the study; the collection, management, analysis, or interpretation of the data; the preparation, review, or approval of the manuscript; or approval authority over the content of the article.

Additional Contributions: We thank all of the patients for their valuable contributions to the study.

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Bisset L, Beller E, Jull G, Brooks P, Darnell R, Vicenzino B. Mobilisation with movement and exercise, corticosteroid injection, or wait and see for tennis elbow: randomised trial.  BMJ. 2006;333(7575):93917012266PubMedGoogle ScholarCrossref