- Email: [email protected]
Therapeutic hip injections: Is the injection volume important?
Clinical Radiology 67 (2012) 55e60
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Original Paper
Therapeutic hip injections: Is the injection volume important? R. Young a, *, J. Harding b, A. Kingsly c, M. Bradley d a
Department of Radiology, Great Western Hospital, Swindon, UK Department of Radiology, University Hospital Coventry, Coventry, UK c Department of Mathematics and Statistics, Bristol Institue of Technology, University of the West of England, Bristol, UK d Department of Radiology, Southmead Hospital, Bristol, UK b
art icl e i nformat ion Article history: Received 10 January 2011 Received in revised form 18 June 2011 Accepted 5 July 2011
AIM: To assess whether an increased volume of local anaesthetic injection given with intraarticular steroids improves symptom relief in osteoarthritis of the hip. MATERIALS AND METHODS: One hundred and ten patients with hip osteoarthritis were randomized into two groups (A and B). All patients were given 40 mg triamcinolone and 2 ml bupivicaine, and patients from group B were also given 6 ml of sterile water for injection. Change in WOMAC (Western Ontario and McMaster University Osteoarthritis Index Version 3.1) scores from baseline to 3 months were calculated and assessed for clinical and statistical significance. The patients were assessed for pain at 2 weekly intervals using the Oxford pain chart. RESULTS: Patients from group B showed some reduction in stiffness (7%) and improved function (3%) compared with group A, and there were more clinical responders in these two categories. However, there was no significant statistical or clinical difference in WOMAC scores between the two groups at 3 months. There was also no statistical difference in pain symptoms between the two groups during the study period, measured at 2 weekly intervals. One hundred and two patients reached the study endpoint; eight patients who had bilateral hip injections were subsequently included in the analysis, and these patients did not alter the findings significantly. CONCLUSIONS: Published total injection volumes used for treating osteoarthritis of the hip with intra-articular steroids vary from 3 to 12 ml. The present study has shown that there is no detriment to using a larger volume of injectate, and recommends that practitioners use total volumes between 3 and 9 ml. Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Until recently there has been no robust evidence to support the efficacy of steroid injection for hip osteoarthritis, as no placebo-controlled trials had been performed.1 * Guarantor and correspondent: R. Young, Department of Radiology, Great Western Hospital, Marlborough Road, Swindon, Wiltshire SN3 6BB, UK. Tel.: þ44 1793 605874; fax: þ44 1793 604795. E-mail address: [email protected] (R. Young).
However, in 2007 a placebo-controlled trial involving 52 patients was published, finding benefit from steroid injection, with a primary endpoint at 2 months.2 There has also been another controlled trial showing benefit up to 1 month, but this study involved multiple injections over 2 week intervals.3 Additional studies without control groups have shown a degree of dose response with steroid treatment,4 and others have shown benefit up to 12 weeks, particularly with rest pain.5 Another small study of patients with hip osteoarthritis found little difference between three groups of saline, local
0009-9260/$ e see front matter Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2011.07.040
56
R. Young et al. / Clinical Radiology 67 (2012) 55e60
anaesthetic, or local anaesthetic with steroid.6 However, patients in this study were told that their surgery would be prioritized if their pain worsened after injection. There are two other studies that have looked at the duration of benefit of steroid hip injection, which can last for up to 3e6 months,7,8 but they were not specific for osteoarthritis of the hip. To the authors’ knowledge, there are no published studies that have studied the volumes used for injection of steroid with local anaesthetic in relation to pain relief efficacy. The total injection volumes used in published studies varies from 3 ml9 to 12 ml.8 The addition of an increased volume of fluid (local anaesthetic) to the standard steroid hip injection may improve distribution of steroid to the synovium. The aim of the present study was to verify that the additional volume improves symptoms from osteoarthritis, in order to provide guidance on the most appropriate volume for clinical practice. Previous studies evaluating hip steroid injection have used visual analogue pain scores for assessment5e7 but more recent studies2,4 have used the WOMAC (Western Ontario and McMaster University Osteoarthritis Index Version 3.1) osteoarthritis index to provide a more global assessment of pain, stiffness, and function. The WOMAC index is wellvalidated clinically10,11 and, therefore, has been used as the primary assessment tool in the present study.
Materials and methods After institutional ethics approval, all patients with osteoarthritis of the hip referred for intra-articular injection of steroid were invited to participate in the study. Patients were excluded if they had concurrent inflammatory arthropathy of the hip, a previous steroid hip injection 4 months previously, and/or any evidence of concurrent infection, uncorrectable coagulopathy, or allergy to contrast agent or local anaesthetic. Patients were also excluded if they could not understand the study in order to provide informed consent, of if they were referred for a diagnostic hip injection for investigation of knee pain.
Randomization and blinding Patients were randomized into two groups using a blocked randomization procedure. Group A was the low injection volume group (3 ml) and Group B was the higher volume group (9 ml). The patients were not allowed to see the specific volume of fluid injected. The medication was prepared in a syringe before the patient entered the room, according to the randomization procedure. The radiologist administering the treatment did not know the volume until the time of injection.
Procedure After obtaining informed consent, all patients underwent a fluoroscopically guided injection of the hip using aseptic technique and an anterior approach. The joint was accessed using a 22 G spinal needle, and position was confirmed using 0.5 ml of contrast agent (iohexol; Omnipaque 240; GE
Healthcare Canada Inc. Mississauga, Ontario, Canada 240 mg iodine/ml). Fellowship-trained musculoskeletal radiologists performed all the injections. The lead author (R.Y.) performed 28% of the injections and 40% were performed by an additional author (M.B.). Another musculoskeletal radiologist performed the remaining 32%. All patients were injected with 1 ml of 40 mg triamcinolone (Kenalog; Bristol-Myers Squibb Co. Uxbridge, Middlesex, UK) and 2 ml of 0.5% bupivicaine (Marcain; Hospira, Inc. Lake Forest, Ilinois 60045, USA), and patients from group B also received 6 ml sterile water for injection. All patients were advised to rest for 1e2 days after the procedure, maintaining minimal activity.
Study endpoint and outcome measures The patients filled in a baseline WOMAC LK 3.110 index questionnaire before the procedure. Subsequently patients completed an Oxford pain chart13 via telephone interview. The WOMAC index includes five questions regarding pain, two questions regarding stiffness, and 17 questions regarding difficulty performing daily activities. Each question carries a maximum score of four points. The Oxford pain chart reviews pain intensity and pain relief, using an ordinal scale. Patients were asked about pain intensity and pain relief alternately every 2 weeks. The study endpoint was at 3 months, when the patients completed the WOMAC index via telephone interview. The researcher who contacted the patient was separate to the researcher who injected the patient, and was therefore blinded to the volume of fluid injected. The primary outcome measure used was the WOMAC index.11 The difference in change in WOMAC scores at the study endpoint was compared between groups A and B. The rate and duration of pain relief measured using the Oxford pain chart was the secondary outcome measure. The use of telephone interviews was chosen to allow support and encouragement for the patients during the trial, and in order to reduce the drop out rate. The WOMAC index has been validated for such a use, and patients were shown to be very responsive to telephone follow-up, with a 100% completion rate.14 Data on age, gender, and additional potential confounding pathology (such as knee osteoarthritis and degenerative spinal disease) was used to stratify the groups as required (Table 1).
Clinical response prediction The OARSI/OMERACT (Osteoarthritis Research Society/ outcome measures in rheumatology responder criteria)1,12 have been developed to detect the “minimal perceptible clinical difference” between groups of patients. Patients are identified as “responders” if they show at least 50% improvement in pain or function and absolute change of more than 20 (0e100 scale). If these criteria are not met, then patients must meet two of the following three criteria: pain 20% and absolute change 10 (0e100 scale); function 20% and absolute change 10; and patient’s global
R. Young et al. / Clinical Radiology 67 (2012) 55e60
57
Results
Table 1 Baseline characteristics. Baseline characteristics
Group A
Group B
Total
Age (mean) Age Range Sex (M:F) % Female patients No. of patients No. of hips injected
62 20e93 27:32 54% 59 63
68 35e90 19:40 68% 59 63
65 46:72 61% 118 126
OA Hip only Lumbar spine OA & inflammatory conditiona OA secondary to DDH or AVNb
28 17 4 4
27 26 3 1
55 43 7 5
a Inflammatory condition ¼ rheumatoid arthritis, ankylosing spondylitis, polymyalgia rheumatica, chronic regional pain syndrome. b Osteoarthritis (OA) secondary to developmental dysplasia of the hip (DDH) or avascular necrosis (AVN).
assessment 20% and absolute change 10. The advantage of this system is that it considers both pain and function as important domains, but it also requires a minimum level of symptoms at baseline in order to determine a response.12 The effect size was also applied to the primary outcome measure to identify a potential perceptible clinical difference between each group. This was calculated using the Cohen D method: (mean of group B e mean of group A)/ pooled standard deviation. An effect size of 0.2 is considered small, 0.5 is moderate, and 0.8 is large.1 Clinical criteria were applied to the primary outcome measure only, as the Oxford pain chart used ordinal data.
Statistics In order to calculate an estimate of the number of patients required to detect the proposed benefit of increasing the volume of injection, an estimate of the variability of the primary outcome measure in both groups was required, in addition to the level expected in a control group. However, this information was not available for the present study at the time of study design; therefore, the effect size was used to estimate the power of the analysis. The two-by-two mixed analysis of variance (ANOVA) was chosen for analysis of the primary outcome. Differences in the mean of the WOMAC scores (pain, stiffness, and Activities of Daily Living (ADL)) were assessed over time and between group A and B simultaneously. Marginal means plots were generated to show this data graphically. An assessment of the normality of the data set was performed using the AndersoneDarling and KolmogoroveSmirnov tests. Although the data were not thought to be normal, use of the ANOVA is valid and reliable because the sample was large enough to provide an approximately normal distribution according to the central limit theorem. The differences in the Oxford pain chart variables between groups were assessed using the Chi-square test. Assessment of changes in pain intensity and pain relief over time was performed by analysing the percentage of patients who showed improvements over time, and constructing 95% confidence intervals for these percentages.
Baseline characteristics Three patients were initially excluded (Fig 1), one patient had a diagnostic injection for knee pain, one patient had reactive hip arthritis, and one was unable to consent. Eight patients referred for bilateral hip joint injections were also subsequently excluded to avoid potential inaccuracy in function assessment. Therefore, 110 patients were entered into the initial analysis. The baseline characteristic of all study patients are shown in Table 1. Most patients were referred from the orthopaedic outpatient clinic (90.7%) but a few were also referred from rheumatology (6.8%) and general practice (2.5%). After randomisation, three patients were withdrawn from group A before the Oxford pain chart analysis could be completed (Fig 1). An additional five patients were withdrawn from the primary outcome analysis before the final WOMAC index could be completed. Most of these patients were withdrawn because they underwent hip replacement surgery 2 weeks before the end of the study, but there were enough data from the Oxford pain charts to include them in the secondary outcome analysis (Fig 1).
Primary outcome measure Patients from group B showed some reduction in stiffness (7%) and improved function (3%) scores compared with group A (Table 2). There was also an increased number of clinical responders from group B, in these two categories, and overall (Table 5). However, there was no significant statistical or clinical difference in WOMAC scores between the two groups (Tables 2, 4, and 5). Groups A and B combined showed a statistically and clinically significant reduction in WOMAC scores in all three categories at the study endpoint (p < 0.001; Table 3). There was a medium effect size (0.55e0.7; Table 4) and an average reduction of symptoms by 20e29% in all categories (Table 2), indicating an average clinically perceptible response, according to OMERACT/OARSI criteria.12 These data correlate with a recent placebo-controlled trial showing benefit of steroid injection at 2 months.2
Secondary outcome measure Using the Chi-square test, there was no statistical difference between the groups in pain intensity or pain relief at any of the 2-week intervals (Table 6). As the data was ordinal, it was not possible to calculate effect sizes. When pain intensity and pain relief outcomes were recategorized into binary outcomes (i.e., no pain relief versus some pain relief, or no pain intensity versus some pain intensity), odds ratio analysis showed no difference between the groups.
Safety assessment There were no major side effects and no withdrawals secondary to adverse events. There were five minor side
58
R. Young et al. / Clinical Radiology 67 (2012) 55e60
121 patients referred 91% Orthopaedics 7% Rheumatology 2% GP
8 patients temporarily excluded from initial analysis
3 patients excluded 1 diagnostic injection for knee pain 1 reactive arthritis 1 unable to consent
8 double hip injections (4 in each group)
110 patients randomised
55 patients group A
55 patients group B
40 mg triamcinolone 2 ml 0.5% Marcaine
40 mg triamcinolone 2 ml 0.5% Marcaine 6 ml sterile water for injection
3 withdrawn 2 lost to follow up 1 additional injection
52 patients group A
55 patients group B
Oxford Pain Chart Every 2 weeks
Oxford Pain Chart Every 2 weeks
3 withdrawn
2 withdrawn
3 THR
1 THR = total hip replacement 1 too unwell
49 patients group A
53 patients group B
WOMAC at 3 months
WOMAC at 3 months
Figure 1 Distribution of patients in the clinical trial over 3 months.
effects post-procedure, including: one episode of temporary hyperglycaemia in a type 1 diabetic, one facial flush, one patient reported soft-tissue swelling, and two patients reported a temporary increase in pain.
Table 2 WOMAC category scores for both groups at baseline and at 3 months. WOMAC Categories
Group A
Group B
Patient Numbersa
49
53
Pain (baseline) Stiffness (baseline) Function difficulty (baseline)
12.2 5 42.1
12.3 5.2 44.3
Pain (3 months) Stiffness (3 months) Function difficulty (3 months)
8.8 3.9 33.8
8.9 3.7 34
Pain reduction Stiffness reduction Function difficulty reduction
3.4 (28%) 1.1 (22%) 8.3 (20%)
3.4 (28%) 1.5 (29%) 10.3 (23%)
There is some improvement in stiffness (e7%) and function (e3%) in group B compared with group A. a Patient numbers after exclusions, withdrawals and temporary exclusion of bilateral hip injection patients.
Discussion There is considerable variation in the volume of local anaesthetic used in combination with steroid for intraarticular injections of the hip. The total injection volumes Table 3 Analysis of variance for a two-way mixed design of the primary outcome measure. WOMAC
ANOVA Analysis
Mean Sq.
F
p
Pain
A vs. B (at baseline) A vs. B (at 3 months) All patients (Baseline vs. 3 months)
0.532 0.056 588.9
0.16 0.005 47.22
0.9 0.95 <0.001
Stiffness
A vs. B (at baseline) A vs. B (at 3 months) All patients (Baseline vs. 3 months)
0.001 2.54 86.72
<0.001 0.994 33.95
0.99 0.321 <0.001
Function Difficulty
A vs. B (at baseline) A vs. B (at 3 months) All patients (Baseline vs. 3 months)
84.33 55.61 4452.8
0.219 0.559 44.77
0.641 0.456 <0.001
There is a significant reduction in symptoms for both groups at 3 months, but this effect does not significantly differ between groups A and B.
R. Young et al. / Clinical Radiology 67 (2012) 55e60 Table 4 Effect sizes calculations for the primary outcome measure.
59
Table 6 Chi-square analysis of the secondary outcome measure.
Effect Scores (d)
Pain
Stiffness
Function
Category (Chi Square)
Gp A
Gp B
X2
p
Group A Group B Group BeA
0.69 0.7 0.01
0.56 0.7 0.14
0.66 0.58 0.08
Pain Pain Pain Pain Pain
52 52 52 52 51a
55 55 55 55 54a
1.09 5.89 1.24 5.53 1.25
0.778 0.208 0.743 0.237 0.742
9
8
used in published studies varies from 3 ml to 12 ml. The addition of local anaesthetic to a steroid hip injection was postulated to increase the level and duration of pain relief, as the additional injection volume may improve the distribution of steroid to the synovium. Therefore in the present study volumes of 3 ml versus 9 ml were compared in order to maximize the difference between both groups without potentially stretching the hip joint capsule. In order to measure differences in pain between patient groups, most previous studies have used a visual analogue scale5e7; however, in the present study the WOMAC index was used as it has been extensively validated10,11,14 and it incorporates the functional impact of treatment. For similar reasons it has also been used in more recent studies,2,4 and this allows a better comparison with the results of the present study. The primary group of patients studied were patients with osteoarthritis of the hip. Most patients were referred from the orthopaedic clinic (91%), but a few were from referrals from rheumatology and general practitioners. Half of the patients only had osteoarthritis of the hip. Just over one-third had osteoarthritis of the hip with osteoarthritis of the lumbar spine and/or knee. The remainder (11%) also had osteoarthritis of the hip secondary to developmental dysplasia or avascular necrosis, or with an additional inflammatory condition (Table 1). The study found patients given a greater volume of injectate had some improvement in function and stiffness at 3 months, but no improvement in pain relief. However, there was no significant statistical or clinical benefit of using a greater volume of injectate during the study, or at the study endpoint at 3 months post-injection. Although there was no statistical or clinical improvement in using a higher injectate volume, both groups showed an improvement in pain relief, stiffness and function at 3 months from baseline (Fig 2), which correlates with recent research.2 There were five minor side effects post-procedure, including one episode of hyperglycaemia in a type 1 diabetic, one facial flush, one patient reported soft-tissue
There was no significant difference between the groups with pain relief or pain intensity at any of the time points. Odds ratio analysis showed no difference between the groups when the above pain categories were recategorized into binary outcomes (i.e. no pain relief versus some pain relief, or no pain intensity versus some pain intensity). a One patient in each group had a hip replacement 10 weeks into the study.
swelling, and two patients reported an increased in hip joint pain. There was no reported infection, although infection is a rare complication, with an incidence ranging from 1 in 14,000 to 1 in 50,000,15 as quoted in studies where practitioners sterilized the skin but did not use gloves. Other reported side effects include a steroid flare (synovitis postinjection which occurs in 2%), fat necrosis or skin atrophy, and arthropathy, which is also rare.15 One of the limitations of the present study was that function was also likely to have been affected as one-third of patients also had osteoarthritis of the lumbar spine and knee. Other limitations of the study include the difficulty of using telephone follow-up for the Oxford pain chart, as not all patients were available at every 2 week window and some were lost to follow-up. Three different radiologists performed the hip injections in the study, allowing for potential variation in the amount of contrast given, as 0.5 ml is a small amount. Seven patients also had an inflammatory arthropathy affecting different joints, which may have also affected the hip, although this was not documented. Hip Stiffness Over Time
5.5 3 ml (A) 9 ml (B) WOMAC Stiffness Score
There is a moderate effect size at 3 months in both groups, but no clinically perceptibly difference in effect size between groups at 3 months.
Intensity at 2 weeks Relief at 4 weeks Intensity at 6 weeks Relief at 8 weeks Intensity at 10 weeks
5
4.5
4
Table 5 OARSI/OMERACT responder criteria12 for the primary outcome measure. Responders
No.
Pain
Stiffness
Function
Total
Group A Group B Both Groups Group BeA
49 53 102
26 (53%) 27 (51%) 53 (52%) 2%
23 (47%) 28 (53%) 51 (50%) 6%
22 (45%) 28 (53%) 50 (49%) 8%
24 (49%) 28 (53%) 52(51%) 4%
There were more “responders” in group B in the stiffness and function categories; however, this was not a clinically perceptible difference.
3.5 Baseline
3 months Time
Figure 2 WOMAC stiffness scores over time. There is a statistical and clinically significant reduction in scores in both groups combined at 3 months, but no significant difference between each group at 3 months.
60
R. Young et al. / Clinical Radiology 67 (2012) 55e60
In summary, there is no detriment to using an increased total volume of injectate for osteoarthritis of the hip. Therefore, the results of the present study indicate that practitioners should use total injectate volumes between 3 and 9 ml, which is in agreement with current literature. The present study cannot comment on volumes over 9 ml, which may lead to distension of the capsule and subsequent short-term pain, as has be seen with magnetic resonance arthrograms of the hip.
References 1. Zhang W, Doherty M, Arden N, et al. EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR standing committee for therapeutics international clinical studies including therapeutics (ESCISIT). Ann Rheum Dis 2005;64:669e81. 2. Lambert R, Hutchings EJ, Grace M, et al. Steroid injection for osteoarthritis of the hip. A randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2007;56:2278e87. 3. Qvistgaard E, Christensen R, Torp-Pederson S, et al. Intra-articular treatment of hip osteoarthritis: a randomized trial of hyaluronic acid, corticosteroid, and isotonic saline. Osteoarth Cartil 2006;14:163e70. 4. Robinson P, Keenan A-M, Conaghan PG. Clinical effectiveness and dose response of image-guided intra-articular corticosteroid injection for hip osteoarthritis. Rheumatology 2007;46:285e91. 5. Kullenberg B, Runesson R, Tuvhag R, et al. Intraarticular corticosteroid injection: pain relief in osteoarthritis of the hip? J Rheumatol 2004;31: 2265e8.
6. Flanagan J, Casale FF, Thomas TL, et al. Intra-articular injection for pain relief in patients awaiting hip replacement. Ann R Coll Surg Engl 1988;70:156e7. 7. Plant MJ, Borg AA, Dziedzic K, et al. Radiographic patterns and response to corticosteroid hip injection. Ann Rheum Dis 1997;56: 476e80. 8. Waseem M, Sadiq S, Gambhir AK, et al. Safety and efficacy of intraarticular injection of the hip. Hip International 2002;12:378e82. 9. Chitre AR, Fehily MJ, Bamford DJ. Total hip replacement after intraarticular injection of local anaesthetic and steroid. J Bone Joint Surg [Br] 2007;89-B:166e8. 10. Bellamy N, Buchanan WW, Goldsmith CH, et al. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 1998;15: 1833e40. 11. Bellamy N. WOMAC: a 20-year experiential review of a patient-centered self-reported health status questionnaire. J Rheumatol 2002; 29:2473e6. 12. Pham T, van der Heijde D, Lassere M, et al. Outcome variables for osteoarthritis clinical trials: the OMERACT-OARSI set of responder criteria. J Rheumatol 2003;30:1648e54. 13. Jadad AR, McQuay AR. The measurement of pain. In: Pynsent P, Fairbank J, Carr A, editors. Outcome measures in orthopaedics. Boston, MA: Butterworth Heinemann; 1993. p. 23e7. 14. Bellamy N, Campbell J, Hill J, et al. A comparative study of telephone versus onsite completion of the WOMAC 30 osteoarthritis index. J Rheumatol 2002;29:783e6. 15. Gray RG, Gottlieb NL. Intraarticular corticosteroids. An updated assessment. Clin Orthop RR 1983;177:253e63.
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Original Paper
Therapeutic hip injections: Is the injection volume important? R. Young a, *, J. Harding b, A. Kingsly c, M. Bradley d a
Department of Radiology, Great Western Hospital, Swindon, UK Department of Radiology, University Hospital Coventry, Coventry, UK c Department of Mathematics and Statistics, Bristol Institue of Technology, University of the West of England, Bristol, UK d Department of Radiology, Southmead Hospital, Bristol, UK b
art icl e i nformat ion Article history: Received 10 January 2011 Received in revised form 18 June 2011 Accepted 5 July 2011
AIM: To assess whether an increased volume of local anaesthetic injection given with intraarticular steroids improves symptom relief in osteoarthritis of the hip. MATERIALS AND METHODS: One hundred and ten patients with hip osteoarthritis were randomized into two groups (A and B). All patients were given 40 mg triamcinolone and 2 ml bupivicaine, and patients from group B were also given 6 ml of sterile water for injection. Change in WOMAC (Western Ontario and McMaster University Osteoarthritis Index Version 3.1) scores from baseline to 3 months were calculated and assessed for clinical and statistical significance. The patients were assessed for pain at 2 weekly intervals using the Oxford pain chart. RESULTS: Patients from group B showed some reduction in stiffness (7%) and improved function (3%) compared with group A, and there were more clinical responders in these two categories. However, there was no significant statistical or clinical difference in WOMAC scores between the two groups at 3 months. There was also no statistical difference in pain symptoms between the two groups during the study period, measured at 2 weekly intervals. One hundred and two patients reached the study endpoint; eight patients who had bilateral hip injections were subsequently included in the analysis, and these patients did not alter the findings significantly. CONCLUSIONS: Published total injection volumes used for treating osteoarthritis of the hip with intra-articular steroids vary from 3 to 12 ml. The present study has shown that there is no detriment to using a larger volume of injectate, and recommends that practitioners use total volumes between 3 and 9 ml. Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Until recently there has been no robust evidence to support the efficacy of steroid injection for hip osteoarthritis, as no placebo-controlled trials had been performed.1 * Guarantor and correspondent: R. Young, Department of Radiology, Great Western Hospital, Marlborough Road, Swindon, Wiltshire SN3 6BB, UK. Tel.: þ44 1793 605874; fax: þ44 1793 604795. E-mail address: [email protected] (R. Young).
However, in 2007 a placebo-controlled trial involving 52 patients was published, finding benefit from steroid injection, with a primary endpoint at 2 months.2 There has also been another controlled trial showing benefit up to 1 month, but this study involved multiple injections over 2 week intervals.3 Additional studies without control groups have shown a degree of dose response with steroid treatment,4 and others have shown benefit up to 12 weeks, particularly with rest pain.5 Another small study of patients with hip osteoarthritis found little difference between three groups of saline, local
0009-9260/$ e see front matter Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2011.07.040
56
R. Young et al. / Clinical Radiology 67 (2012) 55e60
anaesthetic, or local anaesthetic with steroid.6 However, patients in this study were told that their surgery would be prioritized if their pain worsened after injection. There are two other studies that have looked at the duration of benefit of steroid hip injection, which can last for up to 3e6 months,7,8 but they were not specific for osteoarthritis of the hip. To the authors’ knowledge, there are no published studies that have studied the volumes used for injection of steroid with local anaesthetic in relation to pain relief efficacy. The total injection volumes used in published studies varies from 3 ml9 to 12 ml.8 The addition of an increased volume of fluid (local anaesthetic) to the standard steroid hip injection may improve distribution of steroid to the synovium. The aim of the present study was to verify that the additional volume improves symptoms from osteoarthritis, in order to provide guidance on the most appropriate volume for clinical practice. Previous studies evaluating hip steroid injection have used visual analogue pain scores for assessment5e7 but more recent studies2,4 have used the WOMAC (Western Ontario and McMaster University Osteoarthritis Index Version 3.1) osteoarthritis index to provide a more global assessment of pain, stiffness, and function. The WOMAC index is wellvalidated clinically10,11 and, therefore, has been used as the primary assessment tool in the present study.
Materials and methods After institutional ethics approval, all patients with osteoarthritis of the hip referred for intra-articular injection of steroid were invited to participate in the study. Patients were excluded if they had concurrent inflammatory arthropathy of the hip, a previous steroid hip injection 4 months previously, and/or any evidence of concurrent infection, uncorrectable coagulopathy, or allergy to contrast agent or local anaesthetic. Patients were also excluded if they could not understand the study in order to provide informed consent, of if they were referred for a diagnostic hip injection for investigation of knee pain.
Randomization and blinding Patients were randomized into two groups using a blocked randomization procedure. Group A was the low injection volume group (3 ml) and Group B was the higher volume group (9 ml). The patients were not allowed to see the specific volume of fluid injected. The medication was prepared in a syringe before the patient entered the room, according to the randomization procedure. The radiologist administering the treatment did not know the volume until the time of injection.
Procedure After obtaining informed consent, all patients underwent a fluoroscopically guided injection of the hip using aseptic technique and an anterior approach. The joint was accessed using a 22 G spinal needle, and position was confirmed using 0.5 ml of contrast agent (iohexol; Omnipaque 240; GE
Healthcare Canada Inc. Mississauga, Ontario, Canada 240 mg iodine/ml). Fellowship-trained musculoskeletal radiologists performed all the injections. The lead author (R.Y.) performed 28% of the injections and 40% were performed by an additional author (M.B.). Another musculoskeletal radiologist performed the remaining 32%. All patients were injected with 1 ml of 40 mg triamcinolone (Kenalog; Bristol-Myers Squibb Co. Uxbridge, Middlesex, UK) and 2 ml of 0.5% bupivicaine (Marcain; Hospira, Inc. Lake Forest, Ilinois 60045, USA), and patients from group B also received 6 ml sterile water for injection. All patients were advised to rest for 1e2 days after the procedure, maintaining minimal activity.
Study endpoint and outcome measures The patients filled in a baseline WOMAC LK 3.110 index questionnaire before the procedure. Subsequently patients completed an Oxford pain chart13 via telephone interview. The WOMAC index includes five questions regarding pain, two questions regarding stiffness, and 17 questions regarding difficulty performing daily activities. Each question carries a maximum score of four points. The Oxford pain chart reviews pain intensity and pain relief, using an ordinal scale. Patients were asked about pain intensity and pain relief alternately every 2 weeks. The study endpoint was at 3 months, when the patients completed the WOMAC index via telephone interview. The researcher who contacted the patient was separate to the researcher who injected the patient, and was therefore blinded to the volume of fluid injected. The primary outcome measure used was the WOMAC index.11 The difference in change in WOMAC scores at the study endpoint was compared between groups A and B. The rate and duration of pain relief measured using the Oxford pain chart was the secondary outcome measure. The use of telephone interviews was chosen to allow support and encouragement for the patients during the trial, and in order to reduce the drop out rate. The WOMAC index has been validated for such a use, and patients were shown to be very responsive to telephone follow-up, with a 100% completion rate.14 Data on age, gender, and additional potential confounding pathology (such as knee osteoarthritis and degenerative spinal disease) was used to stratify the groups as required (Table 1).
Clinical response prediction The OARSI/OMERACT (Osteoarthritis Research Society/ outcome measures in rheumatology responder criteria)1,12 have been developed to detect the “minimal perceptible clinical difference” between groups of patients. Patients are identified as “responders” if they show at least 50% improvement in pain or function and absolute change of more than 20 (0e100 scale). If these criteria are not met, then patients must meet two of the following three criteria: pain 20% and absolute change 10 (0e100 scale); function 20% and absolute change 10; and patient’s global
R. Young et al. / Clinical Radiology 67 (2012) 55e60
57
Results
Table 1 Baseline characteristics. Baseline characteristics
Group A
Group B
Total
Age (mean) Age Range Sex (M:F) % Female patients No. of patients No. of hips injected
62 20e93 27:32 54% 59 63
68 35e90 19:40 68% 59 63
65 46:72 61% 118 126
OA Hip only Lumbar spine OA & inflammatory conditiona OA secondary to DDH or AVNb
28 17 4 4
27 26 3 1
55 43 7 5
a Inflammatory condition ¼ rheumatoid arthritis, ankylosing spondylitis, polymyalgia rheumatica, chronic regional pain syndrome. b Osteoarthritis (OA) secondary to developmental dysplasia of the hip (DDH) or avascular necrosis (AVN).
assessment 20% and absolute change 10. The advantage of this system is that it considers both pain and function as important domains, but it also requires a minimum level of symptoms at baseline in order to determine a response.12 The effect size was also applied to the primary outcome measure to identify a potential perceptible clinical difference between each group. This was calculated using the Cohen D method: (mean of group B e mean of group A)/ pooled standard deviation. An effect size of 0.2 is considered small, 0.5 is moderate, and 0.8 is large.1 Clinical criteria were applied to the primary outcome measure only, as the Oxford pain chart used ordinal data.
Statistics In order to calculate an estimate of the number of patients required to detect the proposed benefit of increasing the volume of injection, an estimate of the variability of the primary outcome measure in both groups was required, in addition to the level expected in a control group. However, this information was not available for the present study at the time of study design; therefore, the effect size was used to estimate the power of the analysis. The two-by-two mixed analysis of variance (ANOVA) was chosen for analysis of the primary outcome. Differences in the mean of the WOMAC scores (pain, stiffness, and Activities of Daily Living (ADL)) were assessed over time and between group A and B simultaneously. Marginal means plots were generated to show this data graphically. An assessment of the normality of the data set was performed using the AndersoneDarling and KolmogoroveSmirnov tests. Although the data were not thought to be normal, use of the ANOVA is valid and reliable because the sample was large enough to provide an approximately normal distribution according to the central limit theorem. The differences in the Oxford pain chart variables between groups were assessed using the Chi-square test. Assessment of changes in pain intensity and pain relief over time was performed by analysing the percentage of patients who showed improvements over time, and constructing 95% confidence intervals for these percentages.
Baseline characteristics Three patients were initially excluded (Fig 1), one patient had a diagnostic injection for knee pain, one patient had reactive hip arthritis, and one was unable to consent. Eight patients referred for bilateral hip joint injections were also subsequently excluded to avoid potential inaccuracy in function assessment. Therefore, 110 patients were entered into the initial analysis. The baseline characteristic of all study patients are shown in Table 1. Most patients were referred from the orthopaedic outpatient clinic (90.7%) but a few were also referred from rheumatology (6.8%) and general practice (2.5%). After randomisation, three patients were withdrawn from group A before the Oxford pain chart analysis could be completed (Fig 1). An additional five patients were withdrawn from the primary outcome analysis before the final WOMAC index could be completed. Most of these patients were withdrawn because they underwent hip replacement surgery 2 weeks before the end of the study, but there were enough data from the Oxford pain charts to include them in the secondary outcome analysis (Fig 1).
Primary outcome measure Patients from group B showed some reduction in stiffness (7%) and improved function (3%) scores compared with group A (Table 2). There was also an increased number of clinical responders from group B, in these two categories, and overall (Table 5). However, there was no significant statistical or clinical difference in WOMAC scores between the two groups (Tables 2, 4, and 5). Groups A and B combined showed a statistically and clinically significant reduction in WOMAC scores in all three categories at the study endpoint (p < 0.001; Table 3). There was a medium effect size (0.55e0.7; Table 4) and an average reduction of symptoms by 20e29% in all categories (Table 2), indicating an average clinically perceptible response, according to OMERACT/OARSI criteria.12 These data correlate with a recent placebo-controlled trial showing benefit of steroid injection at 2 months.2
Secondary outcome measure Using the Chi-square test, there was no statistical difference between the groups in pain intensity or pain relief at any of the 2-week intervals (Table 6). As the data was ordinal, it was not possible to calculate effect sizes. When pain intensity and pain relief outcomes were recategorized into binary outcomes (i.e., no pain relief versus some pain relief, or no pain intensity versus some pain intensity), odds ratio analysis showed no difference between the groups.
Safety assessment There were no major side effects and no withdrawals secondary to adverse events. There were five minor side
58
R. Young et al. / Clinical Radiology 67 (2012) 55e60
121 patients referred 91% Orthopaedics 7% Rheumatology 2% GP
8 patients temporarily excluded from initial analysis
3 patients excluded 1 diagnostic injection for knee pain 1 reactive arthritis 1 unable to consent
8 double hip injections (4 in each group)
110 patients randomised
55 patients group A
55 patients group B
40 mg triamcinolone 2 ml 0.5% Marcaine
40 mg triamcinolone 2 ml 0.5% Marcaine 6 ml sterile water for injection
3 withdrawn 2 lost to follow up 1 additional injection
52 patients group A
55 patients group B
Oxford Pain Chart Every 2 weeks
Oxford Pain Chart Every 2 weeks
3 withdrawn
2 withdrawn
3 THR
1 THR = total hip replacement 1 too unwell
49 patients group A
53 patients group B
WOMAC at 3 months
WOMAC at 3 months
Figure 1 Distribution of patients in the clinical trial over 3 months.
effects post-procedure, including: one episode of temporary hyperglycaemia in a type 1 diabetic, one facial flush, one patient reported soft-tissue swelling, and two patients reported a temporary increase in pain.
Table 2 WOMAC category scores for both groups at baseline and at 3 months. WOMAC Categories
Group A
Group B
Patient Numbersa
49
53
Pain (baseline) Stiffness (baseline) Function difficulty (baseline)
12.2 5 42.1
12.3 5.2 44.3
Pain (3 months) Stiffness (3 months) Function difficulty (3 months)
8.8 3.9 33.8
8.9 3.7 34
Pain reduction Stiffness reduction Function difficulty reduction
3.4 (28%) 1.1 (22%) 8.3 (20%)
3.4 (28%) 1.5 (29%) 10.3 (23%)
There is some improvement in stiffness (e7%) and function (e3%) in group B compared with group A. a Patient numbers after exclusions, withdrawals and temporary exclusion of bilateral hip injection patients.
Discussion There is considerable variation in the volume of local anaesthetic used in combination with steroid for intraarticular injections of the hip. The total injection volumes Table 3 Analysis of variance for a two-way mixed design of the primary outcome measure. WOMAC
ANOVA Analysis
Mean Sq.
F
p
Pain
A vs. B (at baseline) A vs. B (at 3 months) All patients (Baseline vs. 3 months)
0.532 0.056 588.9
0.16 0.005 47.22
0.9 0.95 <0.001
Stiffness
A vs. B (at baseline) A vs. B (at 3 months) All patients (Baseline vs. 3 months)
0.001 2.54 86.72
<0.001 0.994 33.95
0.99 0.321 <0.001
Function Difficulty
A vs. B (at baseline) A vs. B (at 3 months) All patients (Baseline vs. 3 months)
84.33 55.61 4452.8
0.219 0.559 44.77
0.641 0.456 <0.001
There is a significant reduction in symptoms for both groups at 3 months, but this effect does not significantly differ between groups A and B.
R. Young et al. / Clinical Radiology 67 (2012) 55e60 Table 4 Effect sizes calculations for the primary outcome measure.
59
Table 6 Chi-square analysis of the secondary outcome measure.
Effect Scores (d)
Pain
Stiffness
Function
Category (Chi Square)
Gp A
Gp B
X2
p
Group A Group B Group BeA
0.69 0.7 0.01
0.56 0.7 0.14
0.66 0.58 0.08
Pain Pain Pain Pain Pain
52 52 52 52 51a
55 55 55 55 54a
1.09 5.89 1.24 5.53 1.25
0.778 0.208 0.743 0.237 0.742
9
8
used in published studies varies from 3 ml to 12 ml. The addition of local anaesthetic to a steroid hip injection was postulated to increase the level and duration of pain relief, as the additional injection volume may improve the distribution of steroid to the synovium. Therefore in the present study volumes of 3 ml versus 9 ml were compared in order to maximize the difference between both groups without potentially stretching the hip joint capsule. In order to measure differences in pain between patient groups, most previous studies have used a visual analogue scale5e7; however, in the present study the WOMAC index was used as it has been extensively validated10,11,14 and it incorporates the functional impact of treatment. For similar reasons it has also been used in more recent studies,2,4 and this allows a better comparison with the results of the present study. The primary group of patients studied were patients with osteoarthritis of the hip. Most patients were referred from the orthopaedic clinic (91%), but a few were from referrals from rheumatology and general practitioners. Half of the patients only had osteoarthritis of the hip. Just over one-third had osteoarthritis of the hip with osteoarthritis of the lumbar spine and/or knee. The remainder (11%) also had osteoarthritis of the hip secondary to developmental dysplasia or avascular necrosis, or with an additional inflammatory condition (Table 1). The study found patients given a greater volume of injectate had some improvement in function and stiffness at 3 months, but no improvement in pain relief. However, there was no significant statistical or clinical benefit of using a greater volume of injectate during the study, or at the study endpoint at 3 months post-injection. Although there was no statistical or clinical improvement in using a higher injectate volume, both groups showed an improvement in pain relief, stiffness and function at 3 months from baseline (Fig 2), which correlates with recent research.2 There were five minor side effects post-procedure, including one episode of hyperglycaemia in a type 1 diabetic, one facial flush, one patient reported soft-tissue
There was no significant difference between the groups with pain relief or pain intensity at any of the time points. Odds ratio analysis showed no difference between the groups when the above pain categories were recategorized into binary outcomes (i.e. no pain relief versus some pain relief, or no pain intensity versus some pain intensity). a One patient in each group had a hip replacement 10 weeks into the study.
swelling, and two patients reported an increased in hip joint pain. There was no reported infection, although infection is a rare complication, with an incidence ranging from 1 in 14,000 to 1 in 50,000,15 as quoted in studies where practitioners sterilized the skin but did not use gloves. Other reported side effects include a steroid flare (synovitis postinjection which occurs in 2%), fat necrosis or skin atrophy, and arthropathy, which is also rare.15 One of the limitations of the present study was that function was also likely to have been affected as one-third of patients also had osteoarthritis of the lumbar spine and knee. Other limitations of the study include the difficulty of using telephone follow-up for the Oxford pain chart, as not all patients were available at every 2 week window and some were lost to follow-up. Three different radiologists performed the hip injections in the study, allowing for potential variation in the amount of contrast given, as 0.5 ml is a small amount. Seven patients also had an inflammatory arthropathy affecting different joints, which may have also affected the hip, although this was not documented. Hip Stiffness Over Time
5.5 3 ml (A) 9 ml (B) WOMAC Stiffness Score
There is a moderate effect size at 3 months in both groups, but no clinically perceptibly difference in effect size between groups at 3 months.
Intensity at 2 weeks Relief at 4 weeks Intensity at 6 weeks Relief at 8 weeks Intensity at 10 weeks
5
4.5
4
Table 5 OARSI/OMERACT responder criteria12 for the primary outcome measure. Responders
No.
Pain
Stiffness
Function
Total
Group A Group B Both Groups Group BeA
49 53 102
26 (53%) 27 (51%) 53 (52%) 2%
23 (47%) 28 (53%) 51 (50%) 6%
22 (45%) 28 (53%) 50 (49%) 8%
24 (49%) 28 (53%) 52(51%) 4%
There were more “responders” in group B in the stiffness and function categories; however, this was not a clinically perceptible difference.
3.5 Baseline
3 months Time
Figure 2 WOMAC stiffness scores over time. There is a statistical and clinically significant reduction in scores in both groups combined at 3 months, but no significant difference between each group at 3 months.
60
R. Young et al. / Clinical Radiology 67 (2012) 55e60
In summary, there is no detriment to using an increased total volume of injectate for osteoarthritis of the hip. Therefore, the results of the present study indicate that practitioners should use total injectate volumes between 3 and 9 ml, which is in agreement with current literature. The present study cannot comment on volumes over 9 ml, which may lead to distension of the capsule and subsequent short-term pain, as has be seen with magnetic resonance arthrograms of the hip.
References 1. Zhang W, Doherty M, Arden N, et al. EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR standing committee for therapeutics international clinical studies including therapeutics (ESCISIT). Ann Rheum Dis 2005;64:669e81. 2. Lambert R, Hutchings EJ, Grace M, et al. Steroid injection for osteoarthritis of the hip. A randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2007;56:2278e87. 3. Qvistgaard E, Christensen R, Torp-Pederson S, et al. Intra-articular treatment of hip osteoarthritis: a randomized trial of hyaluronic acid, corticosteroid, and isotonic saline. Osteoarth Cartil 2006;14:163e70. 4. Robinson P, Keenan A-M, Conaghan PG. Clinical effectiveness and dose response of image-guided intra-articular corticosteroid injection for hip osteoarthritis. Rheumatology 2007;46:285e91. 5. Kullenberg B, Runesson R, Tuvhag R, et al. Intraarticular corticosteroid injection: pain relief in osteoarthritis of the hip? J Rheumatol 2004;31: 2265e8.
6. Flanagan J, Casale FF, Thomas TL, et al. Intra-articular injection for pain relief in patients awaiting hip replacement. Ann R Coll Surg Engl 1988;70:156e7. 7. Plant MJ, Borg AA, Dziedzic K, et al. Radiographic patterns and response to corticosteroid hip injection. Ann Rheum Dis 1997;56: 476e80. 8. Waseem M, Sadiq S, Gambhir AK, et al. Safety and efficacy of intraarticular injection of the hip. Hip International 2002;12:378e82. 9. Chitre AR, Fehily MJ, Bamford DJ. Total hip replacement after intraarticular injection of local anaesthetic and steroid. J Bone Joint Surg [Br] 2007;89-B:166e8. 10. Bellamy N, Buchanan WW, Goldsmith CH, et al. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 1998;15: 1833e40. 11. Bellamy N. WOMAC: a 20-year experiential review of a patient-centered self-reported health status questionnaire. J Rheumatol 2002; 29:2473e6. 12. Pham T, van der Heijde D, Lassere M, et al. Outcome variables for osteoarthritis clinical trials: the OMERACT-OARSI set of responder criteria. J Rheumatol 2003;30:1648e54. 13. Jadad AR, McQuay AR. The measurement of pain. In: Pynsent P, Fairbank J, Carr A, editors. Outcome measures in orthopaedics. Boston, MA: Butterworth Heinemann; 1993. p. 23e7. 14. Bellamy N, Campbell J, Hill J, et al. A comparative study of telephone versus onsite completion of the WOMAC 30 osteoarthritis index. J Rheumatol 2002;29:783e6. 15. Gray RG, Gottlieb NL. Intraarticular corticosteroids. An updated assessment. Clin Orthop RR 1983;177:253e63.