Musculoskelet Surg DOI 10.1007/s12306-015-0364-1

ORIGINAL ARTICLE

Co-analgesic therapy for arthroscopic supraspinatus tendon repair pain using a dietary supplement containing Boswellia serrata and Curcuma longa: a prospective randomized placebo-controlled study G. Merolla1,2 • F. Dellabiancia2 • A. Ingardia3 • P. Paladini1 • G. Porcellini1

Received: 21 January 2015 / Accepted: 14 March 2015 Ó Istituto Ortopedico Rizzoli 2015

Abstract Background The cuff tendon that is most prone to fullthickness rotator cuff tears is the supraspinatus (SSP). Arthroscopic SSP repair ensures good to satisfactory midto long-term clinical outcomes. However, the intense postoperative pain reduces rehabilitation compliance and is cause of patient dissatisfaction. Many natural compounds act by inhibiting inflammatory pathways in a similar way to anti-inflammatory drugs Materials and methods This was a prospective randomized trial designed to assess the analgesic effect of a dietary supplement (DS) containing Boswellia serrata and Curcuma longa in a population of subjects with full-thickness SSP tendon tear treated by arthroscopy. Three weeks before surgery, patients were randomized to receive TendisulfurÒ (group T) or a placebo (group P) for 2 months. The primary outcome measure was subjective VAS pain. Secondary outcomes measures were Constant– Murley score simple shoulder test, and patient global assessment (PGA) scores. Patients were assessed

immediately at baseline and subsequently at 1, 2, 4, 6, 8, 12, and 24 weeks. Results Stratification of pain scores and subscores demonstrated significantly lower overall pain scores in group T versus group P at 1 week (p = 0.0477), and lower but not significantly different scores on week 2 (p = 0.0988); at subsequent time points, differences were not significant (p [ 0.05). PGA scores were good in all subjects. Conclusions In conclusion, this study provides objective data on the effect of a DS containing natural substances, added to standard analgesics, on postoperative RC pain. DS alleviated short and partially mid-term pain, while longterm pain was unchanged. This limitation can probably be addressed by a dosage increase over the first 4 weeks and by extending treatment by 1 or 2 months. Keywords Supraspinatus pain
Arthroscopy
Co-analgesia
Dietary supplements

Introduction & G. Merolla [email protected]; [email protected] 1

Unit of Shoulder and Elbow Surgery, ‘‘D. Cervesi’’ Hospital, Hospital, Cattolica - AUSL della Romagna Ambito Territoriale di Rimini, Via L. v. Beethoven 5, 47841 Cattolica, Italy

2

‘‘Marco Simoncelli’’ Biomechanics Laboratory, ‘‘D. Cervesi’’ Hospital, Cattolica, Cattolica, Italy

3

Unit of Anesthesiology and Intensive Care, Riccione and Cattolica Hospitals - AUSL della Romagna Ambito Territoriale di Rimini, Cattolica, Italy

Rotator cuff tears (RCTs) are major causes of pain and disability. They range in prevalence from 30 to 50 % in patients more than 50 years old and are frequently asymptomatic and progressive [2, 3]. According to recent findings, most RCTs are caused by primary intrinsic rotator cuff (RC) degeneration [4] due to a variety of factors including natural aging, limited vascularity, altered biology, poor mechanical properties, and genetic factors [5–7]. RCTs do not heal spontaneously and tend to grow larger over time [2, 8]. The cuff tendon that is most prone to fullthickness RCTs is the supraspinatus (SSP) [9]. RCT diagnosis is essential to optimize surgical treatment and

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improve prognosis. Arthroscopic SSP repair ensures good to satisfactory mid- to long-term clinical outcomes [10– 12]. However, the intense postoperative pain reduces rehabilitation compliance and promotes shoulder stiffness, besides being a cause of patient dissatisfaction [13]. Despite their well-known side effects, non-steroidal anti-inflammatory drugs (NSAIDs) are still the keystone treatment of joint-related inflammatory pain for most classically taught clinicians. NSAIDs act primarily by interacting with proinflammatory cytokines, interfering with prostaglandin and thromboxane production [14–16]. However, side effects are significant [17–19] and may include delayed muscle regeneration and impaired ligament, tendon, and cartilage healing [20, 21]. These disadvantages have prompted research into natural compounds, such as herbal remedies, that can reduce postoperative pain and inflammation [22, 23]. Many natural compounds act by inhibiting inflammatory pathways in a similar way to antiinflammatory drugs [16, 22]. This study was devised to assess the analgesic effect of a dietary supplement (DS) containing Boswelliaserrata and Curcumalonga (TendisulfurÒ, LaborestSpA, Nerviano, Italy) in a population of subjects with full-thickness SSP tendon tear treated by arthroscopy.

Materials and methods Study design This was a prospective randomized trial designed to assess the analgesic effect of TendisulfurÒ on postoperative pain due to arthroscopic SSP tendon repair. All patients gave their informed consent to be included in the study, and which complies with the Ethical Standards of the 1964 Helsinki Declaration as revised in 2000. Study population and inclusion criteria The intent-to-treat population included 122 patients who underwent surgical SSP repair from May 01 to December 31, 2013. Three weeks before surgery, they were randomized to receive TendisulfurÒ (group T) or a placebo (group P) for 2 months using a software-generated block list (Research Randomizer, version 3.0, 2011) and a standard randomization procedure (1:1). The SSP tear was examined preoperatively by a trained musculoskeletal radiologist by magnetic resonance imaging (MRI) with T2weighted oblique coronal and sagittal views [24, 25] and classified arthroscopically according to Snyder et al. [26]. Patients considered eligible for the study were aged C18 years, had a full-thickness SSP tear [27] diagnosed

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clinically, confirmed by MRI, and repaired by arthroscopy, and grade 0–2 fatty degeneration according to Fuchs et al. [28], they had received neither preoperative nor postoperative treatment with articular or subacromial steroid injections over the previous 4 months, and were available for the duration of the study. Exclusion criteria were refusal to agree to study conditions, preoperative shoulder fracture, irreparable (or [40 mm) SSP tendon tear, calcifying tendinitis, shoulder instability, acromioclavicular joint disorder, infection, neoplasm, symptomatic cervical spine disease, rheumatoid arthritis or immune disease, gout or uric acid disease, severe medical conditions, or pregnancy. Patients were also assessed for mental status and excluded in case of cognitive limitations that could prevent a valid consent or subjective and objective evaluation. Clinical evaluation was consistently performed by two independent observers (FD, IA) who had not taken part in the surgical procedure. In all, 18 patients did not agree to take the DS or the placebo or failed to meet the inclusion criteria, leaving 104 patients. Group T received a preparation containing TendisulfurÒ (2 daily sachets for 15 days and 1 sachet for the next 45 days) starting from the first postoperative day. Patients of both groups were also prescribed a conventional analgesic therapy with tramadol and/or paracetamol (maximum daily dosage 400 mg and 4 g, respectively) which they were asked to suspend 24 h prior to each follow-up visit. This was specifically checked by the clinician at each visit, and the amount of conventional pain medications taken by each patient was recorded. Power and sample size calculation The aim of the study was to demonstrate a pain improvement of 20 mm on a 100 mm visual analog scale (VAS) between group T and P, with a standard deviation (SD) of 0.7 mm. Detecting a 0.5 effect size and reaching a power of 80 % (a = 0.05) were calculated to require 45 patients per group. Preparations TendisulfurÒ is a commercially available DS containing a high dose of methylsulfonylmethane (MSM), type I and II collagen, glycosaminoglycans (GAG), the amino acids Larginine and L-lysine, dry extract of B. serrata titrated to 30 % inacetyl-11-keto-b-boswellic acid (AKBA), and dry extract of C. longa titrated to 95 % in curcuminoids. The placebo contained the following natural constituents: sorbitol, acesulfame K, sucralose, silicon dioxide, xanthan gum, orange aroma, passion fruit flavor, b-carotene 1 %, E 120, and anhydrous citric acid.

Musculoskelet Surg

Arthroscopic procedure

Follow-up

All operations were carried out by three experienced shoulder surgeons (GM, PP, and GP). Patients were placed in the lateral decubitus position with a traction of 5 kg. Three portals (anterior, lateral, and posterior) were used for the arthroscopic procedure. After looking for long head of biceps (LHB) tears, medial instability, or subscapularis lesions, the subacromial bursa was removed and SSP mobility evaluated by pulling the tendon laterally toward the footprint region. If anatomical reinsertion was feasible, the patient was included in the study, whereas irreparable SSP tendon tears involved exclusion. The SSP tendon was reattached using 1 or 2 triple-loaded, metal suture anchors (Threvo; ConMed, Largo, FL-USA). LHB tears or instability were managed by LHB tenotomy; acromioplasty was performed before RC repair in patients with acromial spurs. The SSP footprint was flattened with a burr without making a significant trough. The rehabilitation program merely required wearing a sling over the first 3 weeks from surgery; this was followed by passive mobilization and assisted-active exercises in a pool within the pain-free range of motion (ROM) up to the sixth week; finally, active exercises with and without resistance were allowed.

Patients were assessed immediately before the operation (baseline) and subsequently at 1, 2, 4, 6, 8, 12, and 24 weeks. The subjective pain score was recorded by each patient using a printed analogical scale. Data were entered in an electronic worksheet (Microsoft Excel for Mac Os 2011) which calculated overall average pain scores and subscores. The CMS was the numeric sum of subjective and objective evaluations using an electronic version of the scales (www.orthopaedicscores.com) that gave the final score at the end of the questionnaire. A printed version of the SST was filled out by each patient and finally reported on an Excel sheet. The CMS and SST were administered on weeks 8 and 12, when all the items could be applied.

Outcome measures The primary outcome measure was subjective VAS pain. Secondary outcomes measures were Constant–Murley Score (CMS) [1], simple shoulder test (SST) [29], and Patient Global Assessment (PGA) scores, and preparation tolerability, including any adverse events after each administration. All measurements were taken independently by two examiners who had not been involved in the surgical procedures. Pain included overall pain, pain at night, pain with activity, and pain without activity rated on a scale from 0 (no pain) to 100 mm (severe pain). Patients were asked to record the average pain experienced in the previous 48 h. The CMS included a subjective questionnaire for pain, the ability to perform activities of daily living (ADLs), an objective evaluation of active ROM, and strength. Pain was rated on a 15-point scale (0 severe pain, 15 no pain); ADLs were scored on a 20-point scale, with lower scores associated with greater impairment. The ROM was measured using a standard goniometer between the upper arm and the upper part of the chest. Shoulder strength was assessed using a Lafayette handheld dynamometer (Lafayette Instruments, Lafayette, IN, USA), whose microprocessor has a resolution of 0.4 lb (0.2 kg) in the pound 0–50 (0–22.6 kg) range, and 0.03 % accuracy with two calibration points: 0.25 and 50 lb (0.11 and 22.6 kg). A point was given for each 0.5 kg of strength. Data were recorded and analyzed using SPSS v.10 software (SPSS Inc, Chicago, IL, USA).

Statistical analysis A descriptive analysis (absolute and percentage frequency tables, averages, SD, minimum and maximum) was performed for all variables and separately for each group. The groups were compared for both demographics and clinical variables, including pain scores at different time points. Pre- and postoperative CMS and SST scores were also compared. The v-square test was applied to categorical variables, the t test to normal quantitative variables, and the Mann–Whitney U test was used for all scores. The threshold of significance was set at 0.05. The Bravais– Pearson correlation coefficient was calculated to analyze inter-rater and intra-rater variability. Data were expressed as mean ± SD.

Results Of the 104 fully randomized patients, 1 from group T and 3 from group P were excluded due to incomplete follow-up, leaving 100 subjects (50 per group). The enrollment flow diagram is reported in Fig. 1. No significant differences between the groups were found for demographic or anthropometric data (Table 1). Age, gender, body mass index, and SSP tear size were not related to clinical outcomes. Primary outcomes The overall pain scores of group T showed a significant reduction at all time points (weeks 1, 2, 4, 6, 8, 12, and 24; p \ 0.05) (Fig. 2). The night pain subscores showed a similar trend, with significantly lower values at all time points (p \ 0.05) (Fig. 3). The scores for pain during activity were significantly lower on weeks 12 (p = 0.0017) and 24 (p = 0.0013) (Fig. 4).

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Musculoskelet Surg Fig. 1 Flow diagram of the patients included in the study

Table 1 Demographic and anthropometric data of the study population

Variable

Data Group T

Group P

p value

Patients (N)

50

50

0.972

Mean age (years ± SD)

53.3 ± 7.6

55.4 ± 9.4

0.223

Gender (M/F) (%)

27/23 (85.2/14.8)

28/22 (78.6/21.4)

0.224

BMI

26.7 ± 3.7

25.8 ± 4.0

0.223

Shoulder Right/left (%)

41/9 (82/18)

35/15 (70/30)

Dominant

43

39

0.052

SSP tear size (mm)

2.9 ± 0.8

2.7 ± 1.1

0.102

Follow-up week (days)

1 (7 ± 0.8)

1 (7 ± 0.6)

2 (14 ± 0.7)

2 (14 ± 1.0)

4 (28 ± 0.9) 6 (42 ± 1.2)

4 (28 ± 0.8) 6 (42 ± 1.1)

8 (57 ± 0.9)

8 (57 ± 0.8)

12 (88 ± 2.1)

12 (88 ± 2.3)

24 (169 ± 2.2)

24 (168 ± 2.9)

One patient from group T and 3 from group P did not complete the follow-up and were excluded. The final population included 100 subjects SD standard deviation, BMI body mass index, SSP supraspinatus

The overall pain scores of group P did not decrease significantly at the first two time points (week 1, p = 0.598; week 2, p = 0.653), but they did show significantly lower values at all subsequent time points (p \ 0.05). Similarly, the night pain subscores showed non-significant differences at the first two time points and significant reductions thereafter (p \ 0.05). Pain during

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activity was significantly decreased on weeks 12 (p = 0.0018) and 24 (p = 0.0010) (Figs. 2, 3, 4). Secondary outcomes The CMS and SST were measured at 12 and 24 weeks. In group T, both were significantly different compared with

Musculoskelet Surg Fig. 2 Overall pain scores

Fig. 3 Night pain scores

baseline at either time point (12 weeks, p = 0.00023 and p = 0.00012, respectively; 24 weeks, p = 0.00011 and p = 0.00021, respectively). Trends were similar in group P (week 12: CMS p = 0.00017, SST p = 0.00014; week 24: CMS p = 0.00014 and SST p = 0.00013) (Table 2). Consumption of rescue medication was significantly higher in group P on week 1 (180 mg/die of Tramadol in the group P versus 130 mg in the group T) and higher (albeit not significantly so) on week 2; it then became similar in the two groups.

Comparison of TendisulfurÒ and Placebo groups The baseline pain scores were not significantly different in the groups (p = 0.2846). Pain scores and subscores Stratification of pain scores and subscores demonstrated significantly lower overall pain scores in group T versus group P at 1 week (p = 0.0477), and lower but not

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Musculoskelet Surg Fig. 4 Pain during activity scores

Table 2 Constant–Murley and simple shoulder test scores of the two groups Follow-up Baseline

12 weeks

p value

24 weeks

p value

Patient global assessment and adverse events

Constant–Murley score Group T

33.3 ± 4.7

60.3 ± 8.6

0.0002

71.6 ± 8.1

0.0001

Group P

31.3 ± 5.2

59.3 ± 8.8

0.0001

69.9 ± 7.2

0.0001

Simple shoulder test Group T 3.2 ± 0.89

7.7 ± 1.8

0.0001

8.2 ± 1.7

0.0002

Group P

6.9 ± 2.7

0.0001

8.1 ± 0.9

0.0001

3.4 ± 1.0

Values are mean ? standard deviation (SD)

significantly different scores on week 2 (p = 0.0988); at subsequent time points differences were not significant (p [ 0.05). Night pain baseline scores were similar in both groups; they were significantly lower in group T on week 1 (p = 0.0113), lower but not significantly different in this group on week 2 (p = 0.3059), and showed non-significant differences thereafter (p [ 0.05). Pain during activity was not significantly different either at 12 or at 24 weeks (p [ 0.05). Secondary outcomes Intergroup CMS and SST differences were not significant, either at 12 (p = 0.884 and p = 0.352, respectively) or at 24 weeks (p = 0.523 and p = 0.292, respectively).

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K values ranged from 0.81 to 0.83 (CMS), from 0.82 to 0.84 (SST), and from 0.83 to 0.85 (strength measurements), reflecting good interobserver agreement. The k value for intra-observer agreement ranged from 0.82 to 0.88.

PGA scores were good in all subjects. Compliance was high and no adverse events were recorded.

Discussion Plant and herbal medications have been providing effective pain relief for hundreds of years and are becoming increasingly popular due to their relatively few side effects [22]. This study assessed the analgesic properties of a DS administered to patients subjected to arthroscopic SSP repair, whose persistent postoperative pain can compromise functional recovery. In addition to the analgesic effect, the preparation has the potential to reduce the intake of antiinflammatory drugs, which can interfere with healing of the repaired tendons [20, 21]. Our findings indicate that in the short-term (week 1) overall pain scores were significantly lower in subjects receiving the DS compared with those of the placebo group and that they were lower though not significantly so in the middle term (weeks 2 and 4). A similar trend was found for pain at night. Pain during activity and the two clinical scores (CMS and SST) were not significantly different in the longer term (12 and 24 weeks). Consumption of rescue medication in the first

Musculoskelet Surg

two weeks was also lower in the group receiving TendisulfurÒ. These findings have clinical implications, because pain in the immediate postoperative period after arthroscopic SSP repair is severe [13, 30–33]. The main factors influencing the pain pattern after RC repair seem to be preoperative VAS score and pain type (i.e., acute versus chronic) and postoperative stiffness of internal rotation [13]; this is a well-known problem that often leads surgeons to recommend early rehabilitation, to limit the risk of shoulder stiffness and patient dissatisfaction [34–38]. The significantly lower pain scores recorded at 1 week and the lower scores found at 2 weeks in the group receiving TendisulfurÒ enhanced rehabilitation, minimized complications, and increased compliance. The ingredients of this nutraceutical preparation have documented analgesic and trophic effects on tendons, muscles, ligaments, and cartilage [22, 23, 39–43]. MSM is the first oxidized metabolite of dimethylsulfoxide (DMSO), which seems to have antiinflammatory and chemopreventive properties and to inhibit prostacyclin (PGI2) synthesis and free radical scavenging activity [43–46]. DMSO has been shown to ameliorate some inflammatory conditions such as rheumatoid arthritis, osteoarthritis, lupus and lymphoproliferative disease [47–49]. The amino acid constituents of collagen (glycine, proline and lysine) are the starting point for the synthesis of new collagen, which supports connective tissue regeneration and may contribute to the dominant mechanism of load transfer [50, 51]. Tenocytelike cells isolated from SSP tendon express type I collagen, the most common collagen type in tendons [52]. Recent in vitro findings have documented an anti-inflammatory effect of oral collagen on human tenocytes [53]. The noncollagenous matrix consists of water, proteoglycans and their protein core, and GAG chains. Proteoglycan core proteins bind to collagen fibrils, and their GAG chains span between the fibrils and can bind to other GAG chains or proteoglycan core proteins on adjacent fibrils [54, 55]. A relationship between altered GAG composition and SSP tendon overuse has recently been hypothesized [56]; in addition GAG depletion increases the stress-relaxation response of tendon fascicles [57]. L-arginine is a physiological precursor of nitric oxide (NO), an important mediator of vasodilation that contributes to enhance tissue perfusion [58]. NO is synthesized in endothelial cells by endothelial NO synthase (NOS) from the guanidino-nitrogen terminal of L-arginine [59]. The onset and duration of the vasodilator effect of L-arginine and its action on NO production closely match the plasma concentration half-life of L-arginine [60]. Inhibition of NOS activity by oral administration of N omega-nitro-L-arginine methyl ester (LNAME) results in a significant reduction in cross-sectional area and failure load of healing Achilles tendon constructs [61]. Oleo-gum-resin of Boswellia species has been

demonstrated to have anti-inflammatory effects in patients with RA or inflammatory diseases [62]. AKbBA inhibits cytokine production in human monocytes in vitro [63] and exerts a cytotoxic activity that seems to be attributable to inhibition of nuclear factor kappa B(NF-jB) signaling, resulting in reduction of NF-jB-dependent antiapoptotic gene expression [64]. Curcumin (diferuloylmethane) is a natural polyphenol derived from the rhizome of C. longa Linn; it has documented potential to treat various diseases via NF-jB inhibition [65, 66]. Commercially available curcumin preparations contain three major components, curcumin (77 %), demethoxycurcumin (17 %), and bisdemethoxycurcumin (3 %), collectively referred to as ‘‘curcuminoids’’ [66–68]. Recent studies show that curcumin exerts its effects by modulating several important molecular targets, including transcription factors (e.g., NFjB, AP-1, b-catenin, and peroxisome proliferator-activated receptor-c), enzymes (e.g., COX-2, 5-LOX, and inducible NOS), pro-inflammatory cytokines (e.g., TNF-a, IL-1b, and IL-6), and cell surface adhesion molecules. The ability of curcumin to modulate the expression of these targets has prompted investigation of its therapeutic value in several conditions, including inflammatory diseases [67, 69]. Its anti-inflammatory and free radical scavenging properties have also been explored in clinical trials [65]. The reduced postoperative pain reported by our T group after arthroscopic SSP repair agrees in part with the findings of a randomized controlled trial by Gumina et al. [40], where the group treated with an oral DS showed greater pain improvement and greater repair integrity up to 6 months after arthroscopic RC repair, but not significantly different SST and CMS scores. The latter findings and the lack of longer-term effects on postoperative pain may be explained by the fact that the preparation used by the authors, though similar to TendisulfurÒ, lacked both Curcuma and Boswellia, which seem to provide an additional anti-inflammatory action via arginine and MSM. The evidence for the clinical effect of herbal medications and other natural substances on human muscles and tendons is still limited [39, 40, 70, 71]. To our knowledge, only Gumina and coworkers investigated the effect of an oral preparation containing natural substances on pain and tendon healing after arthroscopic RC repair [40]. The effects of a DS also containing B. serrata and C. longa on arthroscopic RC tendon repair have never been assessed before the present study. Our findings prompt the following considerations: 1.

2.

this is the first placebo-controlled study of a commercial oral supplement in a population of patients subjected to SPP tendon arthroscopic repair; all procedures were performed by three skilled shoulder surgeons who did not take part in enrollment or evaluation;

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3.

4.

5.

6.

the effect of TendisulfurÒ chiefly involved early postoperative pain, which is recognized as the most critical phase in the management of patients undergoing RC repair; B. serrata and C. longa seem to have played a major role in pain relief, even though a definite conclusion cannot be drawn due to the various ingredients contained in the DS; pain reduction was accompanied by reduced intake of standard analgesics and NSAIDs, which exert nonnegligible adverse effects; TendisulfurÒ is not expensive; in addition, by reducing pain it also increased patient satisfaction and reduced recourse to national health service resources.

Our data indicate that TendisulfurÒdid not alleviate longer-term pain. This limitation can probably be addressed by a dosage increase over the first 4 weeks and by extending treatment by 1 or 2 months. Furthermore, the effects of TendisulfurÒ on RC tendon healing could be investigated with MRI or less expensive ultrasound examination. In conclusion, this study provides objective data on the effect of a DS containing natural substances, added to standard analgesics, on postoperative RC pain.

7.

8.

9.

10.

11.

12.

13.

14.

15. Acknowledgments The authors are grateful to Word Designs (www.silviamodena.com) for the language revision. Conflict of interest of interest.

The authors declare that they have no conflict

Human and animal rights This article does not contain any studies with human or animal subjects performed by any of the authors.

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