Chapter 6. Sacroiliac joint intra-articular infiltration- randomized double-blind study. Karolina M. Szadek. Wouter W. A. Zuurmond. Stephan A.

Transcription

1 Chapter 6 Sacroiliac joint intra-articular infiltration- randomized double-blind study. Karolina M. Szadek Wouter W. A. Zuurmond Stephan A. Loer Roberto S.G.M. Perez Submitted

2 Abtract Low back pain originating from the SI joint is addressed by injecting a local anesthetic with or without corticosteroid in this joint. Thirty-four patients (8 men, 26 women), mean age 47 years (SD 10.98), with SI joint pain and three or more positive provocation tests for SI joint pain, were randomly assigned to one of the following treatment groups: A) 2ml of 2% lidocaine, B) lidocaine 2%, 1ml + 40mg methylprednisolone acetate (DM), or C) 2ml of 0.9% NaCl (placebo). The infiltration was performed under the fluoroscopy. The effect of the infiltration was evaluated with the daily pain scores as the primary outcome measure, whereby pain relief of >2 point was interpreted as clinically relevant. Secondary outcome measures included the Oswestry Disability Index (ODI), Roland- Morris Disability Questionnaire (RM), COOP WONCA (CW) and SF36, the duration of pain free period/clinically relevant pain relief, and medication use. The study took minimum five weeks for each patient, with the maximum follow-up of 3 months. Thereafter, patients were offered post-experimental intra-articular and peri-articular infiltration of the SI joint. Mean pain relief after the infiltration was 0.2 (SD 3.27) in the lidocaine group, 1.08 (SD 2.36) in the placebo group, and 2.5 (SD 3.01) in de lidocainemethylprednisolone group. A statistically significant the mean pain relief between the groups observed at the day 3, 7, 9, 12, and 28, which was clinically relevant for the DM group. A significant difference between the groups on the ODI was observed at four weeks in favor of the DM group. A clinically relevant and statistically significant improvement on the RM was found at 2 and 4 weeks only for the DM group. We found no statistically significant difference between the groups regarding the quality of life measured with CW. A statistically significant difference between groups was found in improvement on the physical dimension of the SF-36, in favor of the DM group. Differences between the groups were not consistent during the follow-up; however, these results provide an indication that infiltration with lidocaine- methylprednisolone could be superior for pain relief and reduction in functional impairment compared to placebo and lidocaine. The post-experimental interventions had no additional value. The effects are temporary, and require further scientific support.

3 Introduction According to a large epidemiological study, low back pain is a leading contributor to years lived with disability, with a global prevalence in both genders estimated at 10.7% (men 9.46%, women 8,7%). 1 It was also one of the four most common disorders in all world regions, and was the leading cause of YLDs in all developed countries 1. The annual prevalence of back pain is estimated at % 2. Almost every adult will experience an episode of back pain (70-85 % of the population). Financial costs associated with low back pain include the medical care, insurance payment, productivity loss, employee reeducation, administrative expenses and litigation. 3 The average societal costs per patient with chronic low back pain in the Netherlands are estimated at 8533 a year 4. In only approximately 5 15% of cases low back pain can be attributed to a specific cause. 5 If trauma or physical abnormalities such as malignancies, neurological or infectious diseases (the red flags) are excluded, low back pain can be considered to originate from benign causes, such as sacroiliac joint (SI joint) pain. However, making the right diagnosis, and subsequently the choice for the appropriate treatment is often difficult in practice. In particular, the relationship between symptoms and objective findings, such as physical and radiographic examination is often unclear or absent. 6 The therapy for benign low back pain is not standardized and varies by institution and by practitioner. 7 The current therapy in many pain practices consists of invasive and non- invasive methods. Non-invasive methods include physical therapy, revalidation programs, medications, or trans cutaneous nerve stimulation. Invasive methods include nerve or joint blockades/infiltrations. 8,9 With respect to treatment of SI joint paint there is a little known about the effect of injection techniques when compared with non-invasive treatment, or combinations of techniques and other treatments. Also, the effectiveness of the SI joints infiltration has not been investigated in a placebo-controlled study. Pain that emanates from the SI joint can be reduced by injection of drugs into the joint. However, there is no consensus in the literature regarding the used agents. In general, lidocaine or bupivacaine, with or without corticosteroids is used. 7 Therefore, in this study we would like to compare the effectiveness of standard used medications with the placebo. Our goal was to determine the effect and the duration of the effect of the infiltration of the SI joint in patients with benign chronic low back pain.

4 Finally, there is enough new evidence, basically from anatomical and histological studies to presume that the peri-articular structures can be involved in pain from SI joint region 10,11. Therefore, secondary goal of our study was to compare the effectiveness of intra-articular infiltration with peri-articular one. Methods The study was performed in the outpatient clinic of the VU University Medical Center in Amsterdam from September November It was approved by medical ethical committee and registered in the trial register (ISRCTN ). Verbal and written information was provided before the procedure. Patients in the age years, suffering from chronic low back pain (>3 months), presumably originating from SI joint were screened for participation in the study. Patients with the most intense pain below the spinal level L5, in the anatomical region of the SI joint, pressure pain at the posterior aspect of a sacroiliac joint, with unilateral pain, whereby three or more out of five provocation tests were positive (distraction test, compression test, thigh trust test, posterior shear test, Gaenslen test, Patrick's sign) were included. 12 The exclusion criteria were: hypersensitivity to contrast medium, lidocaine and/or methylprednisolone, pregnancy, or the presence of a specific cause of low back pain (malignancy, vertebral, pelvic fracture, active inflammation of the sacroiliac joint, or neurological impairment (motor loss, sensory loss and/or malnutrition disorders). Injection technique. The patient is positioned in a prone position on the fluoroscopic table, the dorso-caudal edge of the SI joint is identified in the antero-posterior projection, and the puncture place marked on the skin. The sacroiliac joint is approached under intermittent fluoroscopy guidance with a 23 G 100mm needle (Cotop International B.V.). The intra-articular position of the needle is confirmed with a small amount of contrast (see picture 1), and documented in three other projections: right and left anterior oblique and, and the lateral, and stored in the VU University Medical Centricity Enterprise Web page. Thereafter the SI joint is infiltrated with randomly assigned medications: A. 2ml of lidocaine2%; B. 1ml Lidocaine 2% + 1ml methylprednisolone acetate 40 mg/1ml or C. 2ml of 0.9% NaCl (the control

5 intervention). Following the intervention, the patients were monitored at the recovery unit for at least two hours, and then discharged home. Picture 1. Spreading of the contrast medium through the intra-articular space of SI joint. Randomization. The hospital pharmacist performed the block randomization of the study medication, in the groups of three patients. The medications were prepared in blinded syringes, so that neither the patient, nor researchers were aware of the drug the patient has got administered. Success of blinding was assessed after termination of the study by asking patients and researchers what they thought they have received. According to standard power analysis, whereby the difference of 2 points as measured with 11 points scale between the groups was held (SD = 2), with an accuracy of 5% and a power of 80%, 21 patients were required per group 13,14. Considering 10% dropout during the follow up, our goal was to include 67 patients in the study.

6 Primary and secondary outcomes and data collection Patients were requested to keep a pre- and post-intervention diary, one week before, and maximal up to three months post intervention. The primary outcome was the pain relief, measured 3 times a day with an 11 point scale (pain intensity numerical rating scale) using the anchors 0=no pain and 10=the worst imaginable pain. A positive outcome of the SI joint infiltration was 50% pain relief. Pain reduction of 2 points, compared to baseline was considered clinically relevant 13,14. Secondary results, were differences in functional impairment and health-related quality of life, measured with the SF-36, COOP-Wonca charts, Oswestry Low Back Pain Disability Index (ODI) and Roland-Morris Disability Questionnaire (RM). Health-related quality of life was evaluated with the SF-36 questionnaire (every four weeks) and Coop- Wonca charts (every two weeks). The SF-36 covers eight different scales: physical functioning, role physical, bodily pain, general health perceptions, vitality, social functioning, role emotional, and mental health, whereby higher scores are associated with better quality of life and state of health 13,14. These eight scales can be further converted into mental (MCS) and physical (PCS) dimensions, which subsequently were compared to Dutch norms for mental and physical dimension. 15 The mean (SD) normal values for Dutch population are: Physical Function 83.0 (22.8); Role-Physical 76.4 (36.3); Bodily Pain 74.9 (23.4); General Health 70.7 (20.7); Vitality 68.6 (19.3); Social Functioning 84.0 (22.4); Role-Emotional 84.0 (22.4); Mental Health 76.8 (17.4). 16 The Coop-Wonca charts comprises six single-item scales, each representing a different aspect of functional ability: physical fitness, feelings, daily activities, social activities, change in health and overall health. 17 Each chart consists of five-point ordinal scale ranging from 1 ( no impairment ) to 5 ( severely impaired ), illustrated with a simple drawing. The global score reflects functional capacity, from 6 (no limitation at all) to 30 (severely limited). A change of 6 percentage points in global score was interpreted as a clinically relevant improvement. 18 Functional impairment was assessed every two weeks with a 24 points Roland-Morris Questionnaire (RMQ), and Oswestry Disability Index (ODI). Considering the RMQ, a sum score ranging from 0 to 24 was calculated by adding positive answers together,

7 whereby higher scores indicate severe disability. A decrease of more than 2,5 points compared to baseline was considered clinically relevant. 19 The ODI is a selfadministered questionnaire divided into ten sections, whereby each section is scored on a 0 5 scale, 5 representing the greatest disability. The index is calculated by dividing the summed score by the total possible score, which is then multiplied by 100 and expressed as a percentage. A change of 10 % was interpreted a minimal clinically important change. 20 Finally, patients were asked to report their daily analgesic consumption and other treatments, which could influence the results of SI joint blockade. Once a week, any potential side effects of the treatment were recorded. Post-Experimental follow up study. After completion of the study, patients were offered additional treatment with another intra-articular infiltration, whereby with the technique as described above 2cc of lidocaine 2% and DepoMedrol 40mg were infiltrated. Finally, peri-articular infiltration of the SI joint was offered. Hereby the interosseous and dorsal SI joint ligaments were targeted under fluoroscopic guidance. A 10cc solution of 8cc lidocaine 2% and 80mg DepoMedrol (2cc) was infiltrated in the ligamentous tissue using two approaches, the cranial and caudal, whereby the periarticular nerve structures were targeted 10,11. Data analysis. The data were processed and analyzed using IBM SPSS version The data was analyzed by means of parametric (t-test) or non-parametric test (Mann- Whitney and Kruskal Wallis) where appropriate, whereby a two-sided p <0.05 was considered statistical significant. For the change of pain in time as measured with 11 point scale we used a linear mixed model analysis, whereby we looked closely at changes in pain during different parts of the day (morning, afternoon and evening). Results We included 34 patients (8 man en 26 women) in mean age 47 years (SD 10.98) (see diagram 1). All patients experienced chronic pain of the SI-joint with a median duration of pain of 31 months (IQR ). Thirty patients had unilateral pain (22-right, and 8-left), and the remaining four patients had bilateral pain. Twenty-eight patients complained about the pain radiation, but not of radicular character. In the majority of patients (N=31) pain was persistent, which often lead to poor night rest (N=27). During

8 physical examination, the patients pain was provoked by thigh thrust test (N=33), Gaenslen`s test (N=29), Patrick`s sign (N=29), distraction test (N=18), and compression test (N=14). Three positive tests were found in 20 patients (58.8%), four in 7 (20.65%) and, five in remaining 7 patients (20.65%). The baseline (T0) pain score was mean 6,39 (SD 1.58), and it was highest in the lidocaine-dm group 6.75 (SD 1.47). (See figure 1) The mean pain relief after the SI joint blockade was 0.2 (SD 3.27) in the lidocaine group, 1.08 (SD 2.36) in the placebo group, and 2.5 (SD 3.01) in de lidocaine-dm group. Clinically relevant pain relief was found only in the lidocaine-dm group, and only up to day 12 after intervention. A statistically significant difference in pain relief between the groups was observed only at the day 3 (p=0,034), day 7 (p=0,013), day 9 (p=0,021), day 12(p=0,02), and day 28 (p=0,004). The difference at four weeks between the groups as tested with the Kruskal Wallis test was not statistically significant (p=0,387). In the post hoc analysis performed with Mann- Whitney test we found the statistically significant differences between the groups, in favor of the DM group compared to placebo at the day 3, 7, and 28. Between the placebo and lidocaine group was this difference statistically significant only at the day 12; whereas between DM and lidocaine at the day 7, 9, 12, 28. One patient experienced arrhythmia and complained about the fever, and as we have learned later, this patient was treated with corticosteroids.

9 Enrollment Assessed for eligibility (n=197) Excluded (n=158) - Not meeting inclusion criteria (n=74) - Declined to participate (n=30) - Other reasons (n=59) Allocation Randomized (n=34) Allocated to placebo and received intervention (n=13) Allocated to DM and received intervention (n=13) Allocated to lidocaine and received intervention (n=8) Follow-Up Lost to follow-up (n=0) Discontinued intervention n=0) Analysis Analysed (n=34) Excluded from analysis (n=0) Diagram 1. Flow of the progress through the phases of the parallel-randomized three groups in our study.

10 T0 T1 1 T1 2 T1 3 T1 4 T1 5 T1 6 T1 7 T2 1 T2 2 T2 3 T2 4 T2 5 T2 6 T2 7 T3 1 T3 2 T3 3 T3 4 T3 5 T3 6 T3 7 T4 1 T4 2 T4 3 T4 4 T4 5 T4 6 T4 7 P DM L Figure 1. Mean daily pain scores per randomization group. In the figure 2, the differences in mean daily pain scores between baseline and follow up points are shown. The differences between the groups as tested with Kruskal Wallis test were statistically significant at the 3rd (p=0.034), 7th (p=0.013), 9th (p=0.012), 12th (p=0.020) and 28th (p=0.004) day after the blockade P M L Figure 2. The differences in mean daily pain scores between the baseline and follow up. The change in pain during different parts of the day between the groups as tested with linear mixed model analysis was not statistically significant (morning p=0.901, the afternoon p=0.052, and the evening p=0.246). During inclusion 9 patients used no medication at all, 15 used acetaminophen, 14 used NSAIDs (ibuprofen, naproxen or diclofenac), and 9 used tramadol. In two cases strong opioids were prescribed prior the inclusion, of which in one case methadone was prescribed for treatment of persistent facial pain due to trigeminal neuralgia. In the

11 other case fentanyl was prescribed for a persistent low back pain after sacroiliac joint arthrodesis by means of two screws, for treatment of pelvic instability, which later were removed due to nerve irritation. As fentanyl appeared not to be effective and the patient was motivated to stop to use it, it was advised the switch of opiates, from fentanyl to methadone. Four patients used co-analgesics like pregabalin and carbamazepine. Four weeks after SI joint infiltration, the number of patients not using any analgesics increased to 13 patients. We observed no changes in analgesics consumption in 18 patients, including the use of strong opiates. Five patients stopped the analgesics consumption, they have been using during enrolment. There was no case of initiation of opioid use during the study. In table 1 the mean and median scores of Coop-Wonca questionnaire are given. The scores increase slightly in the placebo group and decrease in both, lidocaine and lidocaine-dm groups, but they do not reach the clinically relevant reduction. The differences between the groups as tested with Kruskal-Wallis test were not statistically significant. In table 2, the results of the Roland-Morris questionnaire are presented. The mean difference was clinically relevant only in the DM group and was 3.67 (SD 6.31) and 3.1 (SD 6.54) after two and four weeks respectively. The differences between the groups as tested with Kruskal-Wallis test were statistically significant after two (p=0.016) and four weeks (p=0.012). As can be seen in table 3, the DM group had the worst baseline score, as measured with ODI, which means the highest impairment, but became better after four weeks; whereas in the placebo group was just the opposite. The improvement in the lidocaine and DM group was not clinically relevant. The differences between the groups were statistically significant after four weeks (p=0.045), but not after two weeks (p=0.071).

12 CW T0 T2 T4 Mean (SD) Placebo (2.78) Lidocaine (2.79) DM (2.50) Median (IQR) 19 ( ) 20 (18-23) 19 (17-20) Mean (SD) (3.35) (4.50) (4.09) Median (IQR) 20 ( ) 19.5 ( ) 18 ( ) Mean (SD) (3.40) (5.06) (4.05) Median (IQR) 19 ( ) 19 (13-20) 17 ( ) Table 1. Results of Coop-Wonca (CW) questionnaire. DM- DepoMedrol; T0-baseline, T2, T4 measurement two and four weeks after treatment; SD-Standard deviation; IQR-interquartile range. RM T0 T2 T4 Mean Median Mean Median Mean (SD) (IQR) (SD) (IQR) (SD) Placebo (5.38) ( ) (4.16) (11-18) (3.80) Lidocaine (2.88) ( ) (3.65) ( ) (2.76) DM (2.91) ( ) (5.42) (8-16) (8.75) Median (IQR) 16 (13-18) 14 (12-18) 14 ( ) Table 2. The results of Roland-Morris (RM) questionnaire. DM- DepoMedrol, T0-baseline, T2, T4 measurement two and four weeks after treatment, SD-Standard deviation, IQR- interquartile range

13 ODI T0 T2 T4 Mean (SD) Median (IQR) Mean (SD) Median (IQR) Mean (SD) Median (IQR) Placebo 56 (14.81) 56 (44-65) (17.34) 60 (44-74) (17.31) 62 (49-74) Lidocaine 64.5 (10.84) 64 (60-72) 63 (14.30) 64 (57-72) 60 (12.38) 60 (56-66) DM (10.62) 68 (60-72) (16.48) 58 (53-68) (16.81) 61 ( ) Table 3. Results of Oswestry disability index (ODI). DM- DepoMedrol, T0-baseline, T2, T4 measurement two and four weeks after treatment, SD-Standard deviation, IQR-interquartile range. Dutch national scores T0 P T4 P T0 DM T4 DM T0 L T4 L Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) PF 83.0 (22.8) 59.6 (15.2) 52.3 (11.8) 42.1 (15.1) 50.2 (20.0) 46.2 (11.2) 54.3 (13.4) RP 76.4 (36.3) 61.5 (34.8) 46.2 (28.6) 48.6 (30.5) 75.0 (42.6) 59.4 (37.6) 57.1 (34.5) BP 74.9 (23.4) 35.5 (14.8) 39.1 (13.9) 30.9 (16.1) 39.7 (23.9) 30.9 (25.9) 31.6 (26.1) GH 70.7 (20.7) 55.8 (18.3) 49.2 (19.2) 57.9 (15.9) 60.9 (13.9) 62.5 (15.8) 60.2 (18.6) VT 68.6 (19.3) 34.2 (7.6) 41.2 (16.0) 32.3 (12.3) 35.8 (10.2) 35.4 (11.2) 30.0 (14.6) SF 84.0 (22.4) 64.4 (11.2) 68.3 (15.0) 63.5 (11.9) 55.8 (15.0) 68.7 (25.9) 70.3 (27.5) RE 82.3 (32.9) 48.7 (37.5) 35.9 (37.2) 51.5 (27.3) 52.8 (36.1) 37.5 (37.5) 33.3 (38.5) MH 76.8 (17.4) 46.5 (7.7) 48.3 (8.7) 44.3 (9.3) 43.3 (9.2) 47.0 (7.3) 44.6 (5.9) PCS 42.4 (7.0) 39.9 (5.9) 36.8 (7.5) 42.8 (8.4) 40.5 (8.2) 41.1 (8.0) MCS 35.2 (4.1) 36.5 (5.3) 37.5 (5.8) 34.8 (5.0) 36.1 (6.5) 35.3 (9.6) Table 4. Results of SF-36 questionnaire; physical functioning (PF), role limitations due to physical health problems (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social functioning (SF), role limitations due to emotional problems (RE), and general mental health (MH); mental (MCS) and physical (PCS) dimensions. P-placebo, DM- DepoMedrol, L-lidocaine, T0-baseline, T4- measurement four weeks after treatment, SD- Standard deviation

14 In table 4 the results of multi-item scores of SF-36 health survey are presented. For convenience also the results of mean national Dutch scores are given. 16 In general, our study population scored much worse comparing to general results of Dutch population, indicating poorer mental and physical status. According to the results of physical component summary score, at the baseline, the DM group was physically most impaired one, whereas the placebo group scored the worst regarding the mental impairment. The change in time between the groups as tested with Kuskal-Wallis test was statistically significant for physical functioning (p=0.025), role limitations due to physical health problems (p=0.004), and physical component dimension (p=0.045). According to the results of Patients' Global Impression of Change scale, 10 patients improved, whereof 3 reported to improve greatly. Two of these patients were from the DM group and remaining patient received lidocaine. Fourteen patients did not notice any change, and 5 patients reported worsening of their complaint. Post-Experimental follow up study Twenty patients were treated with the second intra-articular infiltration. Median pain relief as calculated per week is shown in table 5. The pain relief as tested with Wilcoxon test was statistically significant up to the 4th week after the infiltration, but not clinically relevant. The results of Coop-Wonca, Roland-Morris are summarized in table 6. There was no difference between the pre and post intra-articular intervention measurements as established with CW. Difference in functional impairment (RM), tested with the Wilcoxon test was statistically significant after 2 (p=0.037) and 4 weeks (0.023) post-intervention, but this difference was not clinically relevant. The physical component summary score improved and was mean (SD 7.59), and the mental component summary deteriorated, mean (SD 3.75). The difference of physical component of SF-36 was statistically significant (p=0.025), but not the mental component (p=0.10). Finally, patients were treated with peri-articular infiltrations. The median pain relief up to 4 weeks following the injection is shown in table 5. The pain relief was not clinically relevant. As tested with Wilcoxon test there was no statistically significant difference between the pre and post-intervention of pain relief, neither measurements of RM, CW and SF-36 (see table 6).

15 PET1 PET2 PET3 PET4 Pain relief after intraarticular infiltration median (IQR) N= ( ) p= ( ) p= ( ) p= ( ) p=0.022 Pain relief after periarticular infiltration median (IQR) (N=20) 0.86 ( ) p= ( ) p= ( ) p= ( ) p=0.22 Table 5. The summary of the pain relief after the intra-articular infiltration and peri-articular infiltration during follow-up. N- number of patients; PET1, PET2, PET3, PET4 measurement one, two, three and four weeks after post-experimental treatment (PET); IQRinterquartile range. Intra-articular infiltration Peri-articular infiltration PET2 PET4 PET2 PET4 Mean Median Mean Median Mean Median Mean Median (SD) (IQR) (SD) (IQR) (SD) (IQR) (SD) (IQR) CW 15.9 (3.9) 15 (13-19) 16 (4.24) 15 ( ) 16.4 (4.8) 15.0 ( ) 17.8 (5.56) 18.0 ( ) RM (5.1) 14 ( ) (5.2) 14 ( ) (4.98) 13.5 ( ) (5.4) 14 ( ) Table 6. The results of Coop-Wonca (CW) and Roland-Morris (RM) questionnaire. PET2, PET4 measurement two and four weeks after post-experimental treatment; SD- standard deviation; IQR-interquartile range.

16 Discussion The goal of this study was to find out the difference between the effectiveness, in particular pain relief after an intra-articular infiltration of SI joint using frequently used medication local anesthetics and corticosteroids. We performed this RCT to compare the effect of the medication with a placebo. The aim was to measure a long time pain relief, whereby 2 points relief as measured with an 11 points scale was considered clinically relevant. Although we have seen pain reduction in all the groups, the pain reduction was only clinically relevant in the group treated with lidocaine and corticosteroids. The clinical relevancy of pain relief can be a point of discussion. For positive outcome of diagnostic SI joint blocks different cut off points are described in the literature, varying from 50% 21,22 up to 90% 23 pain relief. In three studies a certain duration of pain relief after the infiltration was required, namely two hours in case of the study of Maigne 24, and four hours in the studies of Van der Wurff et al. 21,22. In contrast to our study, none of the previous studies was designed to measure the duration of pain relief after the blockade. Based on our results when local anesthetics are combined with corticosteroids, the pain relief prolongs up to 12 days after intervention. However, we observed no changes in analgesics consumption in 18 patients, including the use of strong opiates, 5 patients stopped the analgesics consumption. This is comparable to findings from other studies evaluating SI joint injections. In the study of Borowsky et al., whereby patients received intra- and periarticular SI joint injections, only 3 out of 120 patients lowered their daily opioid dosage. In the study of Cohen et al. 17 out of 77 included patients reduced their opioid intake or completely stopped a non-opioid analgesic 25. The argumentation for using corticosteroids in treatment of spinal pain comes from their ability to suppress inflammatory reactions related to the inhibition of phospholipase 2 (PLA2), and as a result inhibition of neural transmission in nociceptive C-fibers, i.e. analgesic effects [3]. From our previous study we have learned that nociceptors can be found in the synovial part of the joint, as well as the peri-articular ligamentous structures [33,34]. Therefore we extended the treatment of our patients with peri-articular infiltration. The efficacy of peri-articular infiltrations was previously studied for different purposes [5,19,20,23]. The retrospective studies of Luukkainen et al. were designed to investigate the efficacy of peri-articular methylprednisolon

17 injections in non-spondylarthropathic patients with chronic pain in the region of the SI joint. The effectiveness of corticosteroids was significant compared to placebo [19,20]. In the retrospective study of Yin et al. peri-articular injections were used for diagnostic purpose, prior the sensory stimulation-guided radiofrequency neurotomy of the SI joint, whereby patients were treated with two separate injections containing bupivacaine and triamcinolone, in SI joint interosseous ligament [44]. Fourteen patients with 70% pain relief were allocated to radiofrequency neurotomy procedure, whereof after 6 months 36% of patients experienced complete pain relief. Murakami et al. compared the efficacy of lidocaine intra-articular infiltration with peri-articular one in the prospective study, whereby one or more sections of the posterior part of the SI joint were infiltrated [23]. The positive outcome was the improvement in daily activities assessed after infiltration. Also in this study peri-articular infiltration had better success rate than intra-articular one. Finally, in the retrospective review of Borowsky et al. case series comparing patient responses to intra-articular injection versus combined intra-articular and peri-articular injection of anesthetic and corticosteroid were described [5]. They found statistically significant differences between the changes in VAS pain scores at the 3-week and 3- month follow-ups, when comparing sacroiliac intra-articular injection to the combined procedure intra-articular plus S1 3 lateral branch block injections. However, despite these positive findings we did not find an additional benefit effect of peri-articular infiltration compared to intra-articular infiltration. This may be related to the use of a different infiltration technique compared to other studies (i.e. selective lateral branch blocks vs. ligamentous). In a recent publication, new insights with respect to the SI joint innervation were described, based on cadaveric dissection [28]. According to this study, sacral nerves S1-S2 contribute to the innervation in all specimens, S3 in 88%, L5 in 8%, and S4 in 4%. Also, our study was not set up as a direct comparison between intra- and peri-articular injection techniques, and both interventions were performed sequentially. These studies are therefore still warranted, as are studies comparing different peri-articular infiltration techniques. Another point is of consideration in the targeted structure. With the intra-articular technique the synovial part of the joint and the ventral SI joint capsule can be reached, whereas with peri-articular infiltration the dorsal ligamentous complex of the SI joint is reached. With present diagnostic techniques for SI joint pain this remains difficult to

18 establish, therefore more specificity regarding the origin of the SI joint pain in an individual patient is therefore still required. There is only a little evidence for use of corticosteroids for SI joint injections, and they are mainly focused on the benefits rather than the side effects of corticosteroids 23,26,27. Nowadays it is an on-going debate of safe use of corticosteroids for spinal injections which mainly considers the side effects of epidural corticosteroid injections 28. Is it safe then to inject corticosteroids in SI joint? In our experimental study population we noted one incident of fever and a feeling of arrhythmia, unfortunately not objectified by ECG, which solved within 24 hours after the infiltration. After high-dose (1000mg) intravenous methylprednisolone cardiac arrhythmias, like sinus arrest and atrial fibrillation have been reported 29. Corticosteroids are potent drugs used for many indications and causing a number well known side effects. The most common are deregulation of fluid and electrolyte balance, muscle weakness and atrophy, osteoporosis, peptic ulcer with possible perforation and hemorrhage, delayed wound healing, thin fragile skin leading to petechiae, leukocytosis, and different endocrine effects 30. However, in the case of spinal corticosteroids injections cardiac effects are uncommon, and even if they occur, corticosteroids are not to blame According to one study, the most frequently reported adverse effects of SI joint injections involve the discomfort of the injection-site, pain exacerbation, and facial flushing and/or sweating 31. Therefore, we cannot explain the arrhythmia occurring in our patient. If the SI joint blockade is performed for diagnostic purposes, a second confirmatory blockade is usually performed, with a different local anesthetic agent 21,22,24, The argument for this practice is that patients may respond positively to single block for other reasons than the action of a local anesthetic. In the case of the lumbar facet joint blocks for instance, it has been shown that from only 31% out of 100 patients responding positively a first lumbar facet blocks respond positively to the second one. The false-positive rate of uncontrolled diagnostic blocks of the lumbar zygapophysial joints was reported to be 38% 36, leading to incorrect diagnoses. In our study we performed single injections, what can be suspected for high number of false positive responses. However, to avoid the misinterpretation of the effect of the injections we pre-screened our patients with validated SI joint pain provocation tests 21,33.

19 In an earlier systematic review we established that the thigh thrust test and 3 or more positive provocation tests have the highest diagnostic value 12. Relying on the presence of pain in the SI joint region alone could lead to over-diagnosing of SI joint pain 12. Based on these data, we applied strict inclusion criteria and selected patients whose pain could be provoked by 3 or more stressing tests. As a consequence, we managed to include only 34 patients from 197 screened, which result was well below the required sample size estimated for this study, namely 67 patients. This has serious consequences for the ability to draw conclusions from the present study. However, even with these limited numbers we found indications for efficacy in the group infiltrated with corticosteroids, and not in the other two groups. However, as this could be related to sampling error, adequately powered studies evaluating the interventions used in our study are still required. Another problem encountered in our study is the internal allocation mistake due to the use of different randomization lists, which resulted in unequal distribution of patients over the groups. However, as the treatment allocation was performed in a blinded manner, this has probably not influenced the random nature of the allocation to groups. Finally, in this study possible psychological factors affecting prognosis of SI joint pain have not been taken into account. Since there is ample evidence indicating poorer outcome of low back treatment in patients with depression and autonomous coping, 37 our results may be influenced by the psychological factors, for which the study results were not adjusted. In conclusion, for patients with chronic SI joint pain as confirmed by physical examination this study provides are some indications that intra-articular infiltration with a combination of lidocaine and methylprednisolone may provide short-term benefit. Adequately powered studies are still required to establish benefits and risks of this intervention, and for the additional value of peri-articular blockade techniques.

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