Management of frozen shoulder: a systematic review and cost-effectiveness analysis

Outcomes

Pain was measured using several different outcome scales; therefore, the standardised mean difference (SMD) was calculated. Final value and change scores were not combined together as SMDs, as the difference in SD reflects differences in measurement. Scales were amended, where necessary, so that an increase in score equated to an increase in pain according to the Cochrane Handbook. 48 The SMD measure used was Hedges’ g as this is considered appropriate for studies with small sample sizes. 49

The interpretation of the SMD is not as intuitive as the interpretation of the original measures of treatment effect. To address this issue, the pooled SMD was back transformed to an original measure by multiplying it with a ‘typical’ SD of one of the pain measures. A visual analogue scale (VAS) 0–100 mm was chosen, as this measure of pain, compared with others used by studies included in the review, had the largest volume of literature regarding minimum clinically important differences (MCIDs) in pain. This included one study performed in a shoulder-specific population. 50 Transformation from SMD to VAS 0–100 mm was made using a representative pooled SD at baseline from one of the included trials. 51 It should be noted that this was only appropriate for pooled rather than individual study SMDs. 52 The reduction in pain recorded as a SMD can be interpreted on a VAS 0–100 mm using Table 5. No data could be located on the MCID in pain for individuals with frozen shoulder; however, it is suggested that a difference of 14 mm on a 100-mm VAS scale is the MCID for individuals with rotator cuff disease, a shoulder disorder also characterised by pain and restricted range of movement. 50 Given that the between-group MCID is thought to approximate 40% of that within individuals,6,53 the MCID between groups for rotator cuff disorder can be estimated to be approximately 5.6 mm. This value is therefore used as a proxy for the between-group MCID for frozen shoulder.

A wide range of function and disability scales were reported in the studies. These outcomes were not converted to a SMD as they were not considered similar enough. This was because there were differences between some scales in the aspects of function and disability assessed and in the weighting given to similar components. In addition, the correlation between some of the included scales was at best moderate. 54–56

Because of the large number of different range of movement measures used, following discussion with the advisory group these were prioritised for the analyses. The passive range of movement outcomes of interest were passive external rotation, passive internal rotation and passive abduction; and the active range of movement outcomes were active external rotation, active internal rotation and active abduction. When passive and active range of movement was not reported separately, unspecified external rotation, internal rotation and abduction were used in the synthesis. When active internal rotation was not reported but hand behind back was, this was used as a proxy measure, although there is some evidence that the correlation between the two is low to moderate. 57

Interventions

As stated above, studies were grouped by type of intervention in the narrative synthesis and pair-wise comparisons. In addition, subgroups were created within interventions. These subgroups were specified a priori to identify clinically similar studies for pooling in the pair-wise comparisons and MTC to guide the exploration of similarities and differences within classes of interventions in the narrative synthesis. These subgroups were as follows:

• Active physical therapy and physical therapy without mobilisation. Active physical therapy (or physical therapy with mobilisation) was defined as an intervention in which at least part of the intervention involved the patient’s body being wholly or partly in motion, such as exercise, mobilisation and stretching (with or without passive techniques such as heat treatment). Interventions in which there was no such active mobilisation or stretching and the participant was the passive recipient of a therapy such as laser therapy, TENS, ultrasound, heat treatment or ice packs alone were classified as physical therapy without mobilisation.

• Steroid injections were grouped by the number of injections – three or fewer injections and more than three injections. This was based on advice from the advisory group that patients in the UK are unlikely to receive more than three injections for frozen shoulder; therefore, this was the cut-off used.

Length of follow-up

Follow-up of ≤ 4 weeks was not included in the analysis as it was not considered to be informative. Where studies did not report the same length of follow-up, outcomes were pooled grouped by short-, medium- and long-term follow-up. For short-term follow-up the data point from each study at 3 months’ follow-up or the closest data point before 3 months’ follow-up was used. For the outcome of pain, where pair-wise comparisons were possible, the same short-term follow-up data used for the MTC at 3 months were pooled. This was to enable comparison of results from the pair-wise comparisons and the MTC. For medium-term follow-up the data point at 6 months or the closest data point before 6 months was used. For long-term follow-up the data point at 12 months or the closest data point before 12 months was used. Data were also presented (when reported) at multiple times within a follow-up period (e.g. 6 weeks and 3 months). When only a narrative synthesis was possible, data were discussed using the same categories.

Unit of analysis error

Some of the included studies had a unit of analysis error, that is, patients were randomised to the intervention but outcome was reported by shoulder when a participant had two frozen shoulders. In these instances the number of patients was used as the denominator in the analysis as only a few patients had more than one shoulder involved; therefore, the difference between number of shoulders and number of participants was small. 58

Multi-arm trials

Where pooling of multi-arm trials required the use of a control group more than once in the same meta-analysis, the number of participants in the control group was divided approximately evenly among the comparisons, with the means and SDs left unchanged. Where different arms were assessing minor variations of a class of intervention these were combined before pooling. 37

Subgroup analyses

Subgroup analyses were planned to explore the influence of the following study characteristics in the MTC and pair-wise comparisons:

• inclusion of patients with diabetes

• stage of frozen shoulder

• study quality (with studies stratified by concealment of allocation and by blinding of outcome assessors).

Because of the small number of studies suitable for pooling it was only possible to explore these factors in the narrative.

Study characteristics

Six RCTs investigated steroid injections, with or without the addition of physiotherapy, in the treatment of primary frozen shoulder. A summary of the study characteristics is reported in Table 6, with further details available in Appendix 6. All were full papers of studies conducted in the UK,41,67 Turkey,66,68 Canada35 and the USA42 between 1981 and 2008. There was one two-armed trial,68 one three-armed trial67 and four four-armed trials35,41,42,66

The steroids administered were methylprednisolone acetate and triamcinolone hexacetonide. Two studies used a single injection of 20 mg triamcinolone hexacetonide,41,67 one of which also administered lidocaine,67 and three studies used a single injection of 40 mg methylprednisolone acetate or triamcinolone hexacetonide. 35,66,68 The remaining study administered three 40-mg injections of methylprednisolone acetate plus lidocaine, one each week for 3 weeks. 42 In one of the studies the injection was guided using fluoroscopy. 35 Five of the studies reported administering an intra-articular injection,35,41,42,66,68 one of which compared an anterior and a lateral approach,42 and in one study it was unclear. 67

The comparators were steroid injection plus physiotherapy,35,41,67 placebo injection,35,41,42,68 physiotherapy with35,41 and without66,67 placebo injection and home exercise alone. 66

Five of the six trials evaluated a physical therapy regimen as part of the intervention. 35,41,42,66,67 These varied between studies but all consisted of physiotherapy modalities. They included combinations of exercises, mobilisation techniques, TENS, ultrasound, ice, heat packs and interferential therapy. All of the studies appeared to include some form of mobilisation as part of the physiotherapy, although details were scant in some studies. The duration of physiotherapy ranged from 4 to 11 weeks, although, with the exception of one study, duration was < 6 weeks. One study tailored the physiotherapy depending on whether participants had acute or chronic-like symptoms. 35

Five studies reported that participants in all groups were asked to undertake home exercises, although the level of detail reported varied between studies. Bal et al. 68 had a substantial home exercise programme: participants were asked to undertake shoulder stretching and stabilising exercises five times per day over 12 weeks, using a heat pack before exercise and a cold pack after. Carette et al. 35 asked participants to carry out active and auto-assisted exercises twice daily over 12 weeks. In the study by Calis et al. 66 stretching and Codman’s exercises were performed. Details of home exercise were not reported in the other two studies. 41,42 The study by Dacre et al. 67 did not have a home exercise component.

There was also some variability between studies in concomitant treatments. Four studies reported that paracetamol of varying doses was available to participants: 1500 mg per day when needed in one study,68 a supply (dose unspecified) in one study,35 one to two tablets every 4–6 hours (a maximum of eight per day) in another study41 and paracetamol when needed in the remaining study. 66 Another study stated that all participants were advised to continue NSAIDs. 42 One study did not report whether participants received concomitant treatment. 67

The inclusion criteria varied between the six studies, although four of the studies used similar criteria for the extent of restriction of movement. 35,41,66,68 Three of the studies included participants with frozen shoulder of < 6 months’ duration. 35,41,42 Where reported, frozen shoulder was diagnosed through presence of pain and range of movement, clinical diagnosis, presence of symptoms, laboratory tests and radiography. The method of diagnosis was unclear in two studies. 42,68 Three studies included a small number of participants with diabetes: 6% in the study by Carette et al. ,35 5% in the study by Dacre et al. 67 and 6% in the study by Ryans et al. 41 None of the studies reported results separately for patients with diabetes. The participants’ stage of frozen shoulder at baseline was not reported in any of the studies. Where reported, the mean duration of frozen shoulder amongst the included participants ranged from 1342 to 2135 weeks. None of the studies reported whether participants had received any previous treatment for frozen shoulder. The mean age of participants ranged from 54 to 57 years and the proportion of women ranged from 42% to 63%.

Quality assessment

Quality varied between the included studies. Four studies did not report the method of randomisation;42,66–68 therefore, it was unclear whether these were truly randomised studies as stated by the authors. In addition, in two of these studies it was unclear whether the intervention groups were comparable at baseline. 67,68 These four studies therefore have a potentially high risk of bias even though they met other criteria such as blinding of outcome assessment. Only one of these studies was adequately powered for at least one outcome. 67 Bal et al. 68 also reported substantial loss to follow-up (20%, all in the placebo group). Dacre et al. 67 and Rizk et al. 42 reported considerably less loss to follow-up (6% and 8% respectively), whereas Calis et al. 66 reported that there were no dropouts.

The remaining two studies were considered of satisfactory quality although one had some risk of bias. 41 Both reported an adequate method of randomisation and Carette et al. 35 also reported an adequate method of allocation concealment; it was unclear whether Ryans et al. 41 used an adequate method because, although sealed envelopes were used, it was not stated whether these were opaque or sequentially numbered. Both studies met most of the remaining criteria including reported blinding of outcome assessment. Ryans et al. 41 reported that participants were blinded to type of injection. Carette et al. 35 attempted to blind the injection; however, the method used (covering the syringe with foil) may not have been reliable. Blinding of the physiotherapy treatment was not possible. Carette et al. 35 also reported an intention-to-treat analysis. The main limitation of this study was that it may not have been sufficiently powered; 17% were lost to follow-up and there appears to be an imbalance between treatment groups, with greater loss to follow-up in the steroid group. Ryans et al. 41 did not report an intention-to-treat analysis and there was also a high proportion lost to follow-up (27%), with a higher number of dropouts in the steroid only and placebo groups. As with the Carette study, the Ryans study may not have been sufficiently powered. Full details of study quality are reported in Appendix 8.

Pain

All six studies assessed pain but Calis et al. 66 and Dacre et al. 67 reported data in graphical form only (Table 7). Consequently, a SMD could not be calculated and these two studies could not be included in a meta-analysis. Calis et al. 66 reported that there was significantly greater improvement in pain in the steroid group than in the placebo group (p = 0.02). Dacre et al. 67 evaluated steroid, steroid and physiotherapy, and physiotherapy alone. This study reported that all three groups showed a significant reduction in pain after 6 weeks (p < 0.001) with mean measures improving by 49–66%, and further improvements at 6 months. Improvements were reported to be similar in all three treatment groups.

Of the four remaining studies, three reported final mean values and SDs were reported or could be imputed. Both Carette et al. 35 and Rizk et al. 42 reported pain overall and Ryans et al. 41 reported daytime pain at rest (Table 7). Each of the three studies reported pain using a different scale.

The study by Bal et al. 68 reported mean change and SDs at 12 weeks for pain at night measured on the VAS 0–100 mm. Although a SMD could be calculated for this study, it was inappropriate to pool this SMD with those SMDs calculated from final value means, as the difference in SD reflects not differences in measurement scale, but differences in the reliability of the measurements. 48

Table 8 provides the SMDs and 95% CIs. The outcome data for individual groups in the included trials are available in Appendix 7.

Steroid versus placebo

Three studies reported pain at short-term follow-up. Two studies reported final value mean pain for short-term follow-up: Carette et al. 35 reported data at 6 weeks and 3 months and Ryans et al. 41 reported data at 6 weeks (Table 8). As stated in the methods section, to allow comparison of the results of the meta-analysis with the MTC for pain, time points closest to 3 months were pooled, that is, 3-month data for Carette et al. 35 were pooled with 6-week data for Ryans et al. 41 There was a significant decrease in pain with steroid injection compared with placebo: pooled SMD –1.15, 95% CI –1.62 to –0.67 (Figure 2). When back transformed to a 0–100 mm VAS scale, this equates to a mean difference (MD) of 21 mm (95% CI –29.7 to –12.3 mm). No data could be located on the MCID in pain for individuals with frozen shoulder. However, it is suggested that a difference of 14 mm on a 100-mm VAS scale is the MCID for individuals with rotator cuff disease, a shoulder disorder also characterised by pain and restricted range of movement. 50 Given that the between-group MCID is thought to approximate 40% of that within individuals,6,53 the MCID between groups for rotator cuff disorder can be estimated to be approximately 5.6 mm. Using this as a proxy for between-group MCID for frozen shoulder, this suggests that there is a clinically significant decrease in pain with steroid compared with placebo. There was no statistical heterogeneity between the studies (I² = 0%). When 6-week data for Carette et al. 35 and Ryans et al. 41 were pooled the results were similar (pooled SMD –1.30, 95% CI –1.78 to –0.81; MD 23.8 mm, 95% CI 32.6 to 14.8 mm).

FIGURE 2.

Standardised mean difference at up to 3 months: steroid vs placebo.

Bal et al. 68 reported mean change in pain at 12 weeks. There was no significant difference in pain with steroid compared with placebo (Table 8).

Steroid versus physiotherapy combined with placebo

Two studies reported data at short-term follow-up: Carette et al. 35 reported data at 6 weeks and 3 months and Ryans et al. 41 reported data at 6 weeks (Table 8). In both studies physiotherapy was combined with placebo. When 3-month data from Carette et al. 35 were pooled with 6-week data from Ryans et al. 41 there was no significant difference in pain between steroid and physiotherapy (Figure 3). When back transformed to a 0–100 mm VAS scale, this equates to a MD of –4 mm (95% CI –11.9 to 3.7 mm), which suggests that there may be no clinically significant difference between treatments. There was no statistical heterogeneity between studies (I² = 0%). When 6-week data for Carette et al. 35 and Ryans et al. 41 were pooled there was a marginally significant decrease in pain with steroid compared with physiotherapy combined with placebo (pooled SMD –0.51, 95% CI –0.94 to –0.07). However, when back transformed to a 0–100 mm VAS scale, this equates to a MD of –9.3 mm (95%–17.2 to –1.2 mm), which, as with the pooled 3-month and 6-week data, suggests that there may be no clinically significant difference between treatments.

FIGURE 3.

Standardised mean difference at up to 3 months: steroid vs physiotherapy combined with placebo.

Steroid combined with physiotherapy versus placebo

Two studies reported pain at short-term follow-up: Carette et al. 35 reported data at 6 weeks and 3 months and Ryans et al. 41 reported data at 6 weeks (Table 8). When 3-month data from Carette et al. 35 were pooled with 6-week data from Ryans et al. 41 there was a statistically significant decrease in pain with steroid combined with physiotherapy compared with placebo: pooled SMD –1.88, 95% CI –2.43 to –1.33 (Figure 4). When back transformed to a 0–100 mm VAS scale, this equates to a MD of –34.40 mm (95% CI –44.47 to –24.34 mm). This suggests that there is a clinically significant decrease in pain with steroid combined with physiotherapy compared with placebo. There was no statistical heterogeneity between studies (I² = 3%). When 6-week data for Carette et al. 35 and Ryans et al. 41 were pooled the results were similar (pooled SMD –2.31, 95% CI –2.89 to –1.72; MD –42.3 mm, 95% CI –52.9 to –31.5 mm).

FIGURE 4.

Standardised mean difference at up to 3 months: steroid combined with physiotherapy vs placebo.

Steroid combined with physiotherapy versus physical therapy combined with placebo

Three studies reported pain for short-term follow-up. In all studies physiotherapy was combined with a placebo injection. Carette et al. 35 reported pain at 6 weeks and 3 months, Rizk et al. 42 reported pain at 11 weeks and Ryans et al. 41 reported pain at 6 weeks (Table 8).

When 3-month data from Carette et al. 35 were pooled with 11-week data from Rizk et al. 42 and 6-week data from Ryans et al. 41 there was a significant decrease in pain with steroid combined with physiotherapy compared with physiotherapy: pooled SMD –0.57, 95% CI –0.94 to –0.20 (Figure 5). However, there was evidence of substantial statistical heterogeneity (I² = 79%). When 6-week data for Carette et al. 35 were pooled with 11-week data from Rizk et al. 42 and 6-week data from Ryans et al. ,41 the results were similar (pooled SMD –0.86, 95% CI –1.25 to –0.47, I² = 89%). Potential sources of heterogeneity may be the type of steroid used, different lengths of follow-up and proportion of patients with diabetes. Furthermore, the studies by Carette et al. 35 and Ryans et al. 41 were assessed to have a potentially lower risk of bias than the study by Rizk et al. 42

FIGURE 5.

Standardised mean difference at up to 3 months: steroid combined with physiotherapy vs physiotherapy combined with placebo.

Given the differences in study quality, a sensitivity analysis was performed by excluding Rizk et al. 42 from the meta-analyses (Figure 6). Pooling 3-month data from Carette et al. 35 and 6-week data from Ryans et al. 41 resulted in a significant decrease in pain with steroid combined with physiotherapy compared with physiotherapy: pooled SMD –0.98, 95% CI –1.43 to –0.52. Furthermore, there was no longer evidence of statistical heterogeneity (I² = 0%). When back transformed to a 0–100 mm VAS, the pooled SMD equates to a MD of –17.93 mm (95% CI –26.2 to –9.5 mm), which suggests that there is also a clinically significant decrease in pain with steroid combined with physiotherapy compared with physiotherapy. When 6-week data for Carette et al. 35 and Ryans et al. 41 were pooled the results were similar (pooled SMD –1.51, 95% CI –2.00 to –1.02; MD 27.6 mm, 95% CI 36.6 to 18.7 mm).

FIGURE 6.

Standardised mean difference at up to 3 months (sensitivity analysis): steroid combined with physiotherapy vs physiotherapy combined with placebo.

The study by Rizk et al. 42 also reported pain for medium-term follow-up. At 24 weeks there was no significant difference between steroid combined with physiotherapy and physiotherapy (see Table 8).

Steroid combined with physiotherapy versus steroid

Carette et al. 35 reported data at 6 weeks and 3 months and Ryans et al. 41 reported data at 6 weeks (Table 8). When 3-month data from Carette et al. 35 were pooled with 6-week data from Ryans et al. 41 there was a significant difference in pain with steroid combined with physiotherapy compared with steroid alone: pooled SMD –0.75, 95% CI –1.20 to –0.29 (Figure 7). When back transformed to a 0–100 mm VAS, this equates to a MD of –13.7 mm (95% CI –21.96 to –5.3 mm), which suggests that there may be no clinically significant difference between treatments. However, there was evidence of substantial statistical heterogeneity (I² = 70%); therefore, this result should be interpreted with caution. When 6-week data for Carette et al. 35 and Ryans et al. 41 were pooled, there was a significant decrease in pain with steroid combined with physiotherapy compared with steroid alone (pooled SMD –1.00, 95% CI –1.47 to –0.53). When back transformed to a 0–100 mm VAS, this equates to a MD of –18 mm (95% CI 26.9 to 9.7 mm). This suggests that there may be a clinically significant reduction in pain with steroid combined with physiotherapy compared with steroid alone. Furthermore, there was no evidence of statistical heterogeneity (I² = 0%).

FIGURE 7.

Standardised mean difference at up to 3 months: steroid combined with physiotherapy vs steroid.

Function and disability

Four of the six studies assessed function and disability; however, only the Shoulder Pain and Disability Index (SPADI) total score and SPADI 8-item disability subscales were common to more than one study and follow-up times varied (Table 9). Results were presented as change from baseline data for all but one of the studies. 66 Table 10 provides the between-group difference in means and 95% CIs. The outcome data for the individual groups in the included trials are available in Appendix 7.

Steroid versus placebo

Two studies reported SPADI total score and SPADI 8-item subscale score for steroid versus placebo injection (Table 10). 35,68

Carette et al. 35 reported SPADI total score at 6 weeks and found a significant effect in favour of the steroid injection group (MD –17.8, 95% CI –31.96 to –3.64).

Both studies reported 3-month follow-up and were pooled at this time point, although it should be noted that the study by Bal et al. 68 was at high risk of bias. When the two studies were pooled (Figure 8) statistical heterogeneity was high (I² = 80%); therefore, the treatment effect should be treated with considerable caution. The study by Carette et al. 35 reported a significantly greater decrease in SPADI total score in the steroid group than in the placebo and home exercise group (MD –16.10, 95% CI –30.26 to –1.94), whereas in the Bal et al. study68 the treatment effect was in favour of placebo and home exercise, although the CIs crossed the line of no effect. Only Carette et al. 35 reported SPADI total score for medium- and long-term follow-up; there was no significant difference between groups for these later follow-up times (Table 10).

FIGURE 8.

Shoulder Pain and Disability Index total score at 3 months: steroid vs placebo.

Carette et al. 35 reported SPADI 8-item disability subscale score at 6 weeks and found a significant effect in favour of the steroid injection group (MD –13.80, 95% CI –27.53 to –0.07).

As with SPADI total score, the same two studies reported SPADI 8-item disability subscale score and were available for meta-analysis at 3 months. 35,68 Again, the pooled treatment effect should be treated with considerable caution because of high heterogeneity (Figure 9). Carette et al. 35 reported a significantly greater decrease in SPADI 8-item subscale score in the steroid group than with placebo and home exercise (MD –14.30, 95% CI –28.03 to –0.57), whereas in the Bal et al. study68 the treatment effect was in favour of placebo and home exercise, although the CIs crossed the line of no effect.

FIGURE 9.

Shoulder Pain and Disability Index 8-item subscale score at 3 months: steroid vs placebo.

Only Carette et al. 35 reported SPADI 8-item subscale score for medium- and long-term follow-up; there was no significant difference between groups for this outcome (Table 10).

Ryans et al. 41 reported results of the Shoulder Disability Questionnaire (SDQ) and global function at 6 and 16 weeks. There was no significant difference between the steroid group and the placebo group at either time point for either outcome (Table 10). Bal et al. 68 reported University of California Los Angeles (UCLA) Shoulder score with steroid injection versus placebo and both groups were similar at the 3-month follow-up [steroid group median 32.5, interquartile range (IQR) 6.2; placebo group median 31.5, IQR 7.7; no p-value reported].

Range of movement

The range of movement measurements of interest in the review were external rotation, internal rotation and abduction (both passive and active); if internal rotation was not available but hand behind back was reported, this was used as a proxy measure. Five studies reported at least one of these measures (Table 11). Change from baseline data was available from three of these studies35,41,68 and final value data was available from one study. 66 A fifth study, by Rizk et al. ,42 reported only means with no measures of variance or p-values with which to impute SDs. Table 12 provides the between-group differences in means and 95% CIs. The outcome data for the individual groups in the included trials are available in Appendix 7.

Steroid versus placebo

One study by Bal et al. 68 reported passive internal rotation at 12 weeks. There was a significantly greater improvement in the placebo group compared with steroid injection (MD –28.50°, 95% CI –41.56° to –15.44°). This result contradicts the original analysis in the paper, which reported that there was no statistically significant difference between the two groups, using the Mann–Whitney U-test.

Three studies reported passive external rotation at short-term follow-up, two at 6 weeks35,41 and two at 3 months. 35,68 Improvement in passive external rotation was significantly greater with steroid injection than with placebo injection at 6 weeks (pooled MD 9.48°, 95% CI 2.76° to 16.19°; two RCTs) (Figure 10). There was no significant heterogeneity between these studies (I² = 0%)

FIGURE 10.

Passive external rotation at 6 weeks: steroid vs placebo.

Meta-analysis of the two studies that reported passive external rotation at 3 months showed no significant difference between the steroid and the placebo groups (Figure 11)35,68 This pooled result was associated with substantial heterogeneity (I² = 80%) and should therefore be treated with caution. The study by Carette et al. 35 showed a significant improvement in passive external rotation in the steroid group compared with placebo whereas the study by Bal et al. 68 showed no significant difference between groups (Table 11). There were several possible sources of heterogeneity, in particular differences in the risk of bias.

FIGURE 11.

Passive external rotation at 3 months: steroid vs placebo.

Two RCTs reported passive external rotation for medium-term follow-up: 16 weeks41 and 6 months. 35,41 There was no significant difference between steroid and placebo groups in passive external rotation (MD 4.67°, 95% CI –2.21° to 11.55°) (Figure 12). There was some evidence of moderate statistical heterogeneity (I² = 43%). Both studies appeared clinically similar although the follow-up time points differed. Carette et al. 35 was the only study to examine passive external rotation at long-term follow-up and found no significant difference between steroid and placebo groups (Table 12). 35

FIGURE 12.

Passive external rotation at up to 6 months: steroid vs placebo.

Carette et al35 reported passive abduction and hand behind back at 6 weeks and 3, 6 and 12 months. There was no significant difference between groups at any of the time points for either outcome (Table 11).

Steroid versus physiotherapy combined with placebo

Three studies reported passive external rotation at time points up to 3 months. 35,41,66 Two of the studies involved physiotherapy sessions over 12 weeks and in both physiotherapy groups a placebo injection was also given. 35,41 Both studies reported data at 6 weeks and one35 reported data at 3 months; 6-week data were pooled. There was no significant difference in passive external rotation between groups at 6 weeks (Figure 13). There was substantial statistical heterogeneity between the studies (I² = 64%).

FIGURE 13.

Passive external rotation at 6 weeks: steroid vs physiotherapy combined with placebo.

Carette et al. 35 reported passive external rotation, and passive abduction at 3 months. There was no significant difference between treatment groups for both outcomes (Table 12).

Medium-term follow-up data were available for the studies by Carette et al. 35 and Ryans et al. 41 Carette et al. 35 reported passive external rotation at 6 months and Ryans et al. 41 at 16 weeks. There was no significant difference between groups (Figure 14). There was no significant difference between groups in passive external rotation at 12 months in the Carette et al. study. 35 Similarly, the same study showed no significant difference between treatment groups in passive abduction or hand behind back at medium- or long-term follow-up (Table 12).

FIGURE 14.

Passive external rotation at up to 6 months: steroid vs physiotherapy combined with placebo.

Steroid combined with physiotherapy versus placebo

Two studies reported passive external rotation at time points up to 3 months. 35,41 Both studies reported data at 6 weeks and one35 reported data at 3 months. Data at 6 weeks were pooled. The meta-analysis (Figure 15) indicated that passive external rotation was significantly greater with steroid injection plus physiotherapy than with placebo injection at 6 weeks (pooled MD 16.99°, 95% CI 10.01° to 23.97°).

FIGURE 15.

Passive external rotation at 6 weeks: steroid combined with physiotherapy vs placebo.

Passive external rotation was significantly greater with steroid injection plus physiotherapy than with placebo injection at 3 months (MD 17.60°, 95% CI 7.90° to 27.30°) in the study by Carette et al. 35

Medium-term follow-up data were also available up to 6 months: Carette et al. 35 reported passive external rotation at 6 months and Ryans et al. 41 at 16 weeks. The pooled estimate showed that passive external rotation was significantly greater with steroid injection plus physiotherapy than with placebo injection at medium-term follow-up (pooled MD 8.14°, 95% CI 0.18° to 16.09°); however, there was substantial statistical heterogeneity (I² = 70%) (Figure 16). There were a number of possible sources of heterogeneity including the dose of steroid used, different length of follow-up and the proportion of participants with diabetes. There was no significant difference between groups at 12 months in the single study reporting long-term follow-up (Table 12). 35

FIGURE 16.

Passive external rotation at up to 6 months: steroid combined with physiotherapy vs placebo.

Carette et al. 35 reported passive abduction at 6 weeks and 3, 6 and 12 months. Improvement of passive abduction was significantly greater in the steroid plus physiotherapy group than with placebo injection at 6 weeks (MD 15.30°, 95% CI 7.14° to 23.46°), 3 months (MD 16.30°, 95% CI 8.14° to 24.46°) and 6 months (MD 13.00°, 95% CI 4.84° to 21.16°). There was no significant difference between treatment groups at 12 months (Table 12).

In the same study there was a significantly greater improvement in hand behind back for the steroid with physiotherapy group than with placebo injection at 6 weeks (MD –9.00 cm, 95% CI –15.80 cm to –2.20 cm) and 3 months (MD –7.10 cm, 95% CI –13.90 cm to –0.30 cm), but not at any of the other time points (Table 12).

Steroid combined with physiotherapy versus physiotherapy combined with placebo

Three studies reported passive external rotation at time points up to 3 months. 35,41,42 All studies reported data at 6 weeks35,41,42 and two also reported data at 3 months. 35,42 Because of SDs not being available for one study,42 data were pooled from two of the studies for 6-week follow-up. 35,41 The increase in passive external rotation was significantly greater with steroid injection plus physiotherapy than with physiotherapy (plus placebo injection) at 6 weeks (pooled MD 10.80°, 95% CI 4.02° to 17.58°) (Figure 17). There was moderate to high heterogeneity between the studies (I² = 70%); the results of this analysis should therefore be considered with caution.

FIGURE 17.

Passive external rotation at 6 weeks: steroid combined with physiotherapy vs physiotherapy combined with placebo.

The study by Carette et al. 35 also showed that the increase in passive external rotation was significantly greater with steroid injection plus physiotherapy than with physiotherapy at 3 months (MD 13.00°, 95% CI 3.56° to 22.44°).

Medium-term data were also available from Carette et al. 35 and Ryans et al. 41 The pooled estimate (Figure 18) showed that passive external rotation was significantly greater with steroid injection plus physiotherapy than with physiotherapy at up to 6 months (pooled MD 7.36°, 95% CI 0.04° to 14.68°). The study by Carette et al. 35 showed no significant difference between groups at 12 months (Table 12).

FIGURE 18.

Passive external rotation at up to 6 months: steroid combined with physiotherapy versus physical therapy combined with placebo.

Carette et al. 35 reported passive abduction at 6 weeks and 3, 6 and 12 months. Improvement of passive abduction was significantly greater in the steroid plus physiotherapy group than with physiotherapy at 6 weeks (MD 11.30°, 95% CI 3.40° to 19.20°), 3 months (MD 10.40°, 95% CI 2.50° to 18.30°) and 6 months (MD 7.90°, 95% CI –0.00° to 15.80°). There was no significant difference between treatment groups at 12 months (Table 12).

Steroid versus steroid and physiotherapy

Two studies reported passive external rotation for short-term follow-up;35,41 both studies reported data at 6 weeks and one35 reported data at 3 months; the 6-week data were pooled. Passive external rotation was significantly greater with steroid injection plus physiotherapy than with steroid alone at 6 weeks (pooled MD –7.52°, 95% CI –14.70° to –0.34°). This analysis was not associated with statistical heterogeneity (I² = 0%) (Figure 19). The study by Carette et al. 35 showed no significant difference between treatment groups at 3 months (Table 12).

FIGURE 19.

Passive external rotation at 6 weeks: steroid versus steroid and physiotherapy.

Data were also available for medium-term follow-up for the same two studies. The pooled analysis showed no significant difference between groups and the analysis was not associated with statistical heterogeneity (I² = 0%) (Figure 20). The study by Carette et al. 35 showed no significant difference between treatment groups at long-term follow-up (Table 12).

FIGURE 20.

Passive external rotation at up to 6 months: steroid versus steroid and physiotherapy.

Carette et al. 35 reported passive abduction at 6 weeks and 3, 6 and 12 months. At 6 weeks improvement of passive abduction was significantly greater in the steroid plus physiotherapy group than with steroid alone (MD –8.10, 95% CI –16.26 to 0.06); there were no significant differences between treatment groups at later follow-up times (Table 12).

Similarly, for hand behind back, there was a significantly better improvement in the steroid with physiotherapy group than with steroid alone at 6 weeks (MD 8.50, 95% CI 1.70 to 15.30) but not at later follow-up (Table 12).

Quality of life

Only Carette et al. 35 reported quality of life data following treatment (Table 13). 35 Table 14 provides between-group differences in means and associated 95% CIs. Further outcome data can be found in Appendix 7.

There was a statistically significant improvement in the physical component of the SF-36 with steroid plus physiotherapy compared with placebo at 6 months (MD 7.10, 95% CI 0.86 to 13.34). There was no statistically significant difference between these two groups at any of the other time points evaluated.

There was a statistically significant improvement with steroid plus physiotherapy compared with physiotherapy (plus placebo injection) in the physical component at 6 weeks (MD 5.30, 95% CI 0.03 to 10.57) and in the mental component at 6 months (MD 8.20, 95% CI 1.98 to 14.42) and 12 months (MD 6.90, 95% CI 0.68 to 13.12). There was no statistically significant difference between these two treatments groups at any of the other time points evaluated.

For the comparisons steroid compared with placebo, steroid compared with physiotherapy (plus placebo injection) and steroid compared with physiotherapy plus steroid, the study by Carette et al. 35 showed no statistically significant difference between treatment groups at any of the time points evaluated.

Adverse events

Three of the studies that investigated steroids reported adverse events. 42,67,68 There was a limited amount of information reported regarding adverse events in the included studies (Table 15). None of the studies reported any details regarding how adverse event data were collected or recorded; therefore, the data should be treated with caution. Two reported that no adverse effects were reported in any of the treatment groups67,68 and one reported that there were no withdrawals due to adverse effects. 42

Summary

The six included steroid injection studies were diverse in terms of the intervention: two used a single steroid injection of 20 mg, three a single injection of 40 mg and one used three injections of 40 mg administered over 3 weeks. Five of the studies reported using an intra-articular injection. There was also some variation between studies in the physiotherapy provided, although most of the studies used a programme of < 6 weeks’ duration that included mobilisation and home exercise for all groups. Five of the studies were multi-armed trials. Steroid injection was compared with placebo in three studies, home exercise in one study and physiotherapy alone in four studies (with or without placebo). The effect of steroid injection followed by physiotherapy was also assessed. This combined intervention was compared with placebo, steroid alone and physiotherapy (with placebo) alone.

Information about previous treatments that participants had received and stage of frozen shoulder was limited. Outcomes were not reported by stage of frozen shoulder or by whether or not participants had diabetes. As a result, it was not possible to explore in the synthesis the effect of these variables on outcome. It was unclear whether four of the studies were truly randomised and therefore these studies had a potentially high risk of bias. 42,66–68 The fifth study was of adequate quality,35 whereas the sixth was of reasonable quality but may have a risk of bias. 41

For most of the comparisons, data were available from only one or two studies, which may have been underpowered to detect an effect. There were sufficient data to pool the two best-quality studies for some of the outcomes, although in some instances statistical heterogeneity was high. In addition, although both studies used a single intra-articular injection, one evaluated a guided injection of 40 mg of steroid35 and the other used a 20-mg dose and the injection appeared to be unguided. 41 For most outcomes and comparisons it was necessary to undertake a narrative synthesis.

Study characteristics

Three RCTs investigated sodium hyaluronate in the treatment of primary frozen shoulder. A summary of the study characteristics is reported in Table 16. All were full papers of studies conducted in Turkey,66 Italy69 and Japan70 between 1996 and 2006. There were two two-armed trials69,70 and one four-armed trial. 66

Calis et al. 66 used a 30-mg injection once weekly for 2 weeks, Takagishi et al. 70 used 2 mg injected once weekly for 5 weeks and Rovetta et al. 69 used 20 mg of sodium hyaluronate coadministered with 20 mg of steroid (triamcinolone acetonide) injected at 15-day intervals for the first month then monthly for 6 months and physical therapy (mobilisation or exercises) for 4–12 weeks. The comparators were steroid injection,66,70 steroid injection and physiotherapy,69 physiotherapy66 and no intervention except for home exercise. 66

Two of the three studies included physiotherapy. 66,69 Both studies differed in the duration and content of the regimen, but each contained some form of active exercise or mobilisation. Calis et al. 66 had a regimen of 10 daily sessions consisting of a heat pack applied for 20 minutes, ultrasonic therapy for 5 minutes (1.5 W/cm2 intensity), TENS for 20 minutes at the patient’s level of tolerance, and stretching exercises. In comparison, Rovetta et al. 69 had a 4- to 12-week regimen of the most appropriate therapy for the individual (passive mobilisation, active exercises and facilitation exercises), which was chosen by a physiotherapist. Only Calis et al. 66 reported that participants had a home exercise programme, which consisted of stretching and Codman exercises, but did not provide any further details.

Two studies reported that patients received concomitant treatments. 69,70 Rovetta et al. 69 allowed paracetamol (dose unspecified) to be taken if necessary, whereas Takagishi et al. 70 stated that participants who were using topical NSAIDs prior to commencing the study were allowed to continue to do so. Calis et al. 66 allowed paracetamol to be taken if necessary.

The inclusion criteria varied between the three studies. Rovetta et al. 69 reported that none of the participants had diabetes, whereas Calis et al. 66 and Takagishi et al. 69 did not report whether or not any of the participants had diabetes. Frozen shoulder was diagnosed through physical examination, laboratory tests, subacromial impingement test, clinical history, radiography or ultrasound when described. The method of diagnosis was unclear in one study. 70 The participants’ stage of frozen shoulder at baseline was not reported in any of the studies and it was unclear whether participants had received any previous treatments. The mean age of participants ranged from 48 years to 65.8 years. The proportion of women ranged from 63% to 75%.

Quality assessment

None of the studies reported the method of randomisation or allocation concealment, and only one stated that blinded outcome assessment was performed; therefore, all three studies have a potentially high risk of bias. The study by Calis et al. 66 was of higher quality and fulfilled five criteria: the number of participants randomised, treatment groups that were comparable at baseline, blinded outcome assessors, use of intention-to-treat analysis and no unexpected imbalances in dropouts. Rovetta et al. 69 fulfilled two criteria, stating the number of participants randomised and also having treatment groups that were comparable at baseline, whereas Takagishi et al. 70 fulfilled only one criterion, which was stating the number of patients randomised. Full details of study quality are reported in Appendix 8.

Pain

All three studies evaluating sodium hyaluronate assessed pain; however, the study by Calis et al. 66 reported pain in graphical form and therefore could not be included in the analysis. Calis et al. 66 did, however, report that there was significant improvement in pain severity at 3 months within each of the treatment groups, including the no intervention group (p < 0.001). Rovetta et al. 69 and Takagishi et al. 70 both used a VAS but assessed different types of pain at different time points (Table 17); therefore, it was inappropriate to pool the two studies. Table 18 provides the SMDs and 95% CIs. The outcome data for the individual groups in the included trials are available in Appendix 7.

Function and disability

Calis et al. 66 and Takagishi et al. 70 both assessed function and disability. Calis et al. assessed function and disability using the Constant score (Table 19), whereas Takagishi et al. 70 used a Japanese-specific activities of daily living questionnaire. However, Takagishi et al. reported baseline values and a p-value for the within-group change from baseline only and therefore could not be included in the analysis. Table 20 provides the MD and 95% CIs. The outcome data for the individual groups in the included trial are available in Appendix 7.

At 3 months Calis et al. 66 found a significantly greater improvement in the Constant score with sodium hyaluronate compared with no treatment (MD 8.90, 95% CI 2.62 to 15.18), but no significant difference in Constant score between sodium hyaluronate and physiotherapy (MD –6.00, 95% CI –12.16 to 0.16) or between sodium hyaluronate and steroid injection (MD –0.20, 95% CI –5.86 to 5.46).

Range of movement

The range of movement measurements of interest were external rotation, internal rotation and abduction (both passive and active); if internal rotation was not available but hand behind back was reported, this was used as a proxy measure of active internal rotation. All three studies that evaluated sodium hyaluronate reported at least one of these measurements (Table 21). Table 22 provides the between-group difference in means and 95% CIs. The outcome data for the individual groups in the included trials are available in Appendix 7.

Quality of life

None of the three studies that evaluated sodium hyaluronate assessed quality of life.

Adverse events

None of the three studies evaluating sodium hyaluronate reported whether or not participants experienced any adverse events.

Summary

The three included studies investigating sodium hyaluronate used variable doses and in one study sodium hyaluronate was combined with steroid injection and physiotherapy. Because of variations in outcomes reported and comparators used it was not possible to pool data in a meta-analysis. For most outcome measures data were available from a single study only. The studies did not report participants’ stage of frozen shoulder or previous treatments received.

All of the studies had a potentially high risk of bias; none reported the method of randomisation and therefore it was unclear whether they were truly randomised. Because it was unclear whether all studies had enough participants to detect a statistically significant treatment effect, it should be kept in mind that where studies did not report a statistically significant benefit (i.e. the CI crossed the line of no difference) this should not be interpreted as evidence of no difference between the groups.

One study reported a medium-term benefit in pain outcome when sodium hyaluronate was added to steroid and physiotherapy. The same study also reported a significant benefit at medium-term follow-up for internal rotation but not for external rotation or abduction. Another study reported a benefit for function and disability with sodium hyaluronate compared with home exercise but not with physiotherapy or steroid. The same study reported significantly better short-term passive external rotation and abduction with sodium hyaluronate than with home exercise and physiotherapy but not steroid injection. A second study reported no evidence of a benefit for external rotation with sodium hyaluronate compared with steroid.

In conclusion, a small number of diverse studies of sodium hyaluronate were identified, all of which may have had a high risk of bias. There was insufficient evidence to make conclusions with any certainty about the effectiveness of sodium hyaluronate for primary frozen shoulder and in what situations it is likely to be effective.

Study characteristics

Eleven RCTs and one controlled trial investigated various types of physical therapy in the treatment of primary frozen shoulder. A summary of the study characteristics is reported in Table 23, with further details available in Appendix 6. Eleven were full papers and one71 was available in abstract form only. One was a Chinese-language paper. 72 The studies were published in the Netherlands,40,73 Turkey,51,66,74 Hong Kong,75 Singapore,76 Thailand,77 Greece,16 Taiwan,78 China72 and the UK71 between 1994 and 2009. There were nine two-armed trials,16,40,51,72–74,76–78 two three-armed trials71,75 and one four-armed trial. 66

A variety of physical therapy regimens were used, most of which were physiotherapy modalities. These included various combinations of exercises (up to and beyond the pain threshold), stretching, manipulation of the glenohumeral joint, ultrasound, superficial heat, SWD, laser therapy, Codman’s exercises, wall-climbing exercises, continuous passive motion, manual therapy, dumb-bell gymnastics and massage. For the purposes of the synthesis, the interventions were grouped based on whether or not at least one component involved mobilisation (of any type) under the supervision of a therapist. Therapies that involved some form of mobilisation (with or without other physical therapies) are described as active therapies. Studies using interventions such as laser therapy or TENS without any supervised mobilisation or exercise were classified as therapy without mobilisation.

Seven compared at least two forms of physical therapy. 40,71,72,74–76,78 One of the studies had what was described as a ‘supervised neglect’ intervention. 73 This study by Diercks and Stevens was the only study identified that explicitly used a supervised neglect intervention; therefore, this study was included although it was not a RCT. 73 Undertaken in the Netherlands, a physiotherapy intervention of unspecified duration was used that involved a standardised protocol, carried out by a therapist, of active exercises up to and beyond the pain threshold. The supervised neglect comparator involved providing patients with an explanation of the natural course of the disease and instructions not to exercise in excess of their pain threshold, to undertake pendulum exercises and active exercises within the painless range and to resume all activities that were tolerated. In the Calis et al. study, physiotherapy was compared with sodium hyaluronate and steroid injection;66 and in the Pajareya et al. study, physiotherapy was compared with no intervention. 77

A single study did not have an arm with an active mobilisation component. This study by Stergioulas16 compared laser therapy with placebo laser (with home exercise). The remaining studies compared multiple active physical therapies. One compared ultrasound and physiotherapy with sham ultrasound and physiotherapy;51 one compared 1-hour sessions of continuous passive motion with physiotherapy;74 one compared osteopathy with physiotherapy and with breathing exercises, massage and range of movement exercises;71 one compared end-range mobilisation (ERM) and mid-range mobilisation (MRM) with mobilisation with movement (MWM) and MRM;78 one compared passive joint mobilisations and exercises with exercises only;76 one compared SWD plus stretching with heat pack plus stretching;75 one compared dumb-bell gymnastics with barehanded exercises;72 and one compared high-grade mobilisation techniques (HGMT) with low-grade mobilisation techniques (LGMT) (both followed by Codman pendular exercises). 40 All of the physiotherapy arms included an active mobilisation component. The intervention duration ranged from 2 weeks to 3 months.

Six studies reported that home exercise was used as part of the intervention, although details were limited in some studies. Where specified the home exercise routines included daily Codman and stretching exercises,66 Codman, stretching and active range of movement exercises,51 daily passive range of movement and pendulum exercises,74 pendulum and pain-free exercises16 and daily stretches. 75 Home exercise was discouraged in one study. 78 Analgesic use also differed between studies where reported. NSAIDs or other analgesics were prescribed when necessary in one study,73 paracetamol was taken when necessary in another,66 paracetamol was allowed to a maximum of 1000 mg daily in another,51 400 mg of ibuprofen was given daily for 3 weeks in one study77 and prescribed and non-prescribed pain medication was allowed in one study. 40 No NSAIDs or other analgesics were allowed in one RCT, with a week washout period before the study commenced. 74

The inclusion criteria varied between the studies. All included patients with some limitation of movement, although the extent of this varied where reported. Primary frozen shoulder was diagnosed through range of movement, biochemical analyses, radiography and clinical diagnosis where reported. Four studies did not report how frozen shoulder was diagnosed. 40,71,77,78 Three included participants with diabetes: 37% in the study by Dogru et al. ,51 16% in the study by Vermeulen et al. 40 and 33% in the study by Pajareya et al. 77 Separate data were not presented for this subgroup. The mean duration of frozen shoulder at baseline ranged from 3 months to 6.8 years. The stage of frozen shoulder included was reported by few studies: stage 1 or 2 in the study by Dundar et al. ,74 ‘stiff stage’ in the studies by Yan72 and Leung and Cheing75 and late stage 2 or 3 in the study by Maricar and Chok. 76 Outcome was not reported separately by stage of frozen shoulder. Only one study, Vermeulen et al. ,40 reported on whether participants had received any previous treatment for frozen shoulder. In this study 81% of participants had previously received physical therapy, 61% steroid injections and 6% surgery. The proportion of female participants ranged from 20% to 86% and the mean age of participants ranged from 50 to 62.5 years.

Quality assessment

The quality of the studies was generally poor. Only one was of satisfactory quality, reporting the number randomised and both an appropriate method of randomisation and adequate allocation concealment. 78 This study by Yang et al. also met most of the remaining criteria including comparability at baseline, blinding of outcome assessors and intention-to-treat analysis; however, the study may not be adequately powered to detect significant differences between groups and there was a large number of dropouts (23%). The main limitation of this study was the study design for the purposes of our review; only limited data were suitable for inclusion in our analysis as different sequences of the three same mobilisations were compared at end of treatment (see Appendix 6). 78

Leung and Cheing,75 Stergioulas16 and Vermeulen et al. 40 reported an appropriate method of randomisation; Leung and Cheing75 and Vermeulen et al. 40 did not report whether an adequate method of allocation concealment was used; and Stergioulas16 reported that allocation was performed using opaque envelopes but it was unclear whether the envelopes were numbered sequentially. Although these three studies fulfilled other criteria, such as comparability at baseline and blinding of outcome assessors, there was still a possible risk of bias. Leung and Cheing75 reported that there was no loss to follow-up and loss to follow-up was 15% in the Stergioulas study16 (the majority in the laser group) and 4% in the Vermeulen study40 (with equal numbers from each group). Vermeulen et al. 40 also used intention-to-treat analysis and was adequately powered for one outcome.

Calis et al. ,66 Dogru et al. ,51 Dundar et al. ,74 Pajareya et al. 77 and Yan72 reported the number of participants randomised. It was unclear whether the method of assignment was truly random in any of these studies and allocation concealment was not reported; therefore, they potentially have high risk of bias. These studies also fulfilled few of the remaining criteria. Dogru et al. 51 and Calis et al. 66 reported blinding of outcome assessment. Dropouts were relatively high in the Pajareya study77 (12%, the majority in the control group) and the reporting of satisfaction results was also unclear. There were no or very few dropouts in the Calis et al. ,66 Dogru et al. ,51 Yan72 and Dundar et al. 74 studies. Calis et al. 66 also used intention-to-treat analysis.

The number of participants randomised was inconsistently reported in the study by Maricar and Chok. 76 Neither Maricar and Chok76 or Wies et al. 71 reported the method of randomisation or allocation concealment, so were at high risk of bias. Few of the remaining criteria were met. Dropouts were high in the study by Maricar and Chok (41%)76 and not reported by Wies et al. 71

Allocation to groups was not randomised in the study by Diercks and Stevens73 and met none of the quality criteria (including blinding of outcome assessment) except comparability at baseline (there were no significant differences in age, sex or duration of disease). This study was quasi-experimental with a successive cohort as the physical therapy group. This study was therefore at a high risk of bias. The paper reported that there was no loss to follow-up.

Pain

Six studies assessed pain (Table 24). The study by Pajareya et al. 77 reported analgesic use at 3 weeks only and was therefore excluded from the synthesis. Calis et al. 66 reported data in graphical form only; consequently, the SMD could not be calculated and this study could not be included in a meta-analysis. Calis et al. 66 did, however, report that there was significant improvement in pain severity at 3 months within both the physical therapy group and the no intervention group (p < 0.001).

The remaining four studies each evaluated different physical therapies using different comparators; therefore, it was not appropriate to pool the studies in a meta-analysis. 16,40,51,74

Table 25 provides the SMDs and 95% CIs. The outcome data for individual groups in the included trials are available in Appendix 7.

Function and disability

Ten of the twelve studies that assessed physical therapies reported function and disability outcomes (Table 26). SPADI score16,51,71,74,77 and Constant score66,73,74 were common to several studies; however, the data could not be pooled in meta-analysis as the comparisons varied substantially. Short- and medium-term data were available from these studies. Final value data were available from six studies. 16,51,66,73–75 Pajareya et al. 77 included only baseline data, so this study was not included in the analysis. Change from baseline data was available from the study by Vermeulen et al. 40 Yang et al. 78 reported mean percentage of change only. Table 27 provides between-group differences and 95% CIs. Because of differences between interventions and comparators it was not appropriate to pool these studies. Outcome data for individual studies are available in Appendix 7.

Range of movement

Eleven of the included studies that investigated physical therapy reported a range of movement measure of interest (Table 28). All of the studies except two reported short- or medium-term follow-up. One presented data at 24 months73 and one at 12 months. 40 Six studies reported final value data and one77 presented data that were not included in the analysis as follow-up was l < 4 weeks. One study reported change from baseline data. 40 Maricar and Chok76 reported only graphs and p-values, presented narratively. Because of the differences between the interventions and comparators meta-analyses were not performed. Table 29 provides between-group differences and 95% CIs. Outcome data for individual studies are available in Appendix 7.

Quality of life

Two studies, one by Dogru et al. 51 and the other by Vermeulen et al. ,40 reported quality of life using the physical and mental components of the SF-36 (Table 30). Data at 3 months’ follow-up were available (Table 31). As the interventions varied substantially these studies were not pooled. Outcome data for the individual groups are available in Appendix 7.

Other

Two studies reported other outcomes of interest (Table 32). Pajareya et al. 77 reported satisfaction with treatment and percentage of patients reporting treatment success. Yan72 also reported the percentage of patients describing their rate of improvement as bad, average, good and excellent at 3 months. These data are summarised in Table 33 and further information for the individual studies is available in Appendix 7.

Adverse events

Two studies reported adverse events. 74,77 In the study by Pajareya et al. 77 patients in the physiotherapy group were asked whether they had pain that persisted for > 2 hours after treatment or more disability the next morning. There were 10 episodes of pain in the physiotherapy group (in four patients) that persisted for > 2 hours after treatment. Patients were also asked whether the trial drugs and/or treatment programme upset them in any way and were examined for signs of echymosis or burn during range of movement evaluation. Side effects of NSAIDs were reported but it was unclear which treatment groups these applied to (see Appendix 6). Dundar et al. 74 stated that no side effects were observed during the study. No further information regarding how adverse events were measured or assessed was reported. The study by Stergioulas16 reported that there were no complications. Adverse events did not appear to have been assessed in the remaining nine studies.

Summary

Twelve studies were included that investigated various types of physical therapy, without use of steroid injection. They were very diverse in the physical therapies evaluated, although most evaluated physiotherapy modalities. The comparators were another physical therapy or control. With the exception of one study,16 at least one component of the intervention involved active mobilisation or exercise. Half the studies reported that participants were advised to undertake home exercise.

One study of satisfactory quality was identified and three studies were of reasonable quality but had some risk of bias. The other studies had a potentially high risk of bias. Because of the considerable variability of the interventions investigated in the studies and different outcomes measures used it was not appropriate to pool any studies in a meta-analysis. The studies did not report outcome by stage of frozen shoulder or the presence of diabetes and information was very limited regarding previous treatments received.

Study characteristics

Three RCTs investigated acupuncture in the treatment of primary frozen shoulder. A summary of study characteristics is reported in Table 34. All were full papers of studies conducted in Hong Kong,79 China80 and Taiwan81 between 2006 and 2008. There was one two-armed trial80 and two three-armed trials. 79,81 Sample sizes ranged from 74 to 360.

One study used acupuncture81 and two studies used electroacupuncture,79,80 The number of acupuncture points needled ranged from three to five. Although needle point prescriptions varied between studies, two studies both included Hegu (LI4) and Jianyu (LI15) needle points. 80,81 In the acupuncture study, acupuncture was administered in a course of eight sessions. In both studies of electroacupuncture, the intervention was administered in a course of 10 sessions, with acupuncture points needled to a depth of 15–25 mm and electricity administered when ‘De qi’ sensation was felt. Further details of the electrical stimulation used were reported in one study only79 and consisted of 2–100-Hz electrical stimulation at a pulse of 100–400 microseconds for 20 minutes. The comparators were interferential electrotherapy,79 waiting list control,79 TENS,80 physiotherapy81 and acupuncture with physiotherapy. 81

One study included a physiotherapy regimen. 81 This consisted of a heat pack for 15 minutes, joint mobilisation for 5–10 minutes and active shoulder exercises for 5–10 minutes, five times per week for 4 weeks. One study reported concomitant treatment of a home exercise programme of mobilisation exercises five times a day over 6 months. 79 Two studies did not report whether participants received any concomitant treatment. 80,81

The inclusion criteria varied between the three studies. It was unclear in all studies whether they included participants with diabetes. Frozen shoulder was diagnosed by an orthopaedic surgeon, through clinical examination and through clinical history. The participants’ stage of frozen shoulder was not reported in two studies. 79,81 In the other study participants were reported to have either stage 1 (described by the authors as pre-adhesive) frozen shoulder, that is, they had shoulder pain that increased at night with range of motion normal or only slightly affected, or stage 2 (described by the authors as adhesive) frozen shoulder, that is, a reduction in pain but severely affected range of motion. 80 None of the studies reported whether participants had received previous treatment for frozen shoulder. Where reported, the mean age of participants ranged from 51.5 to 56.4 years and the proportion of women from 52% to 55%.

Quality assessment

None of the studies reported the method of randomisation or allocation concealment; therefore, these three studies are potentially at high risk of bias. The study by Cheing et al. 79 was of the highest quality and fulfilled five criteria: the number randomised, the comparability of treatment groups at baseline, double blinded, blinding of outcome assessors to treatment allocation and no unexpected imbalances in dropouts between groups. This study, however, did not use intention-to-treat analysis. Fang et al. 80 fulfilled two criteria: the number of participants randomised and the blinding of participants. Ma et al. 81 also fulfilled two criteria: the number of participants randomised and the comparability of treatment groups at baseline for important prognostic factors.

The studies by Fang et al. 80 and Ma et al. 81 reported outcome measures at ≤ 4 weeks from baseline and are therefore excluded from the subsequent synthesis. Furthermore, the waiting list control arm for the study by Cheing et al. 79 reported outcomes at 4 weeks from baseline only. The following synthesis is therefore based on the study by Cheing et al. 79 and compares electroacupuncture with interferential therapy only. This study reported on the outcomes of pain and of function and disability only.

Pain

Cheing et al. 79 reported results of ‘pain at the moment’ at approximately 2, 4 and 7 months using a 0–10 cm VAS. There was no significant difference in pain between the electroacupuncture and interferential therapy groups at 2 months (SMD 0.35, 95% CI –0.23 to 0.93), 4 months (SMD 0.21, 95% CI –0.37 to 0.78) or 7 months (SMD 0.21, 95% CI –0.37 to 0.78).

Function and disability

Cheing et al. 79 reported results of the Constant score at 2, 4 and 7 months. There was no significant difference in Constant score between the electroacupuncture and interferential therapy groups at 2 months (MD –2.80, 95% CI –5.88 to 0.28), 4 months (MD 3.10, 95% CI –1.53 to 7.73) or 7 months (MD –1.70, 95% CI –4.76 to 1.36).

Adverse events

None of the three studies that evaluated acupuncture or electroacupuncture reported on whether or not participants experienced any adverse events.

Summary

Three studies compared acupuncture with another treatment, although only one provided data beyond 4 weeks’ follow-up. This study had a potentially high risk of bias and it was unclear whether it had enough participants to detect a difference between groups. Based on a single study, there was no statistically significant difference between electroacupuncture and inferential electrotherapy in pain or function and disability at short-, medium- or long-term follow-up. There was insufficient evidence to make conclusions with any certainty about the effectiveness of acupuncture for primary frozen shoulder and in what situations it is likely to be effective.

Study characteristics

Four RCTs investigated MUA in the treatment of primary frozen shoulder. A summary of study characteristics is available in Table 35 and full details are provided in Appendix 6. All were full papers of studies conducted in Pakistan,82 the UK38,83 and Finland39 between 2007 and 2009. All were two-arm trials and sample sizes ranged from 3638 to 125. 39

The MUA procedure was described in three of the RCTs38,39,83 and was performed by a physician39 or, in the two UK studies, by an orthopaedic surgeon. 38,83 In two studies participants received a steroid injection (triamcinolone) in conjunction with MUA, 30 mg38 in one of the UK studies and 80 mg82 in the study from Pakistan.

A single study, by Amir-us-Saqlain et al. ,82 reported use of a physiotherapy programme following MUA. The other three studies advised participants in the intervention and control groups to undertake home exercises. Kivimaki et al. 39 appeared to have the most intensive home exercise programme, although details were scanty in all the studies; participants in this study received physiotherapy advice in two sessions and written instructions for a daily training programme including pendulum and stretching exercises. Quraishi et al. 38 reported a home exercise programme of pendulum exercises and wall-climbing movements; specific details were not provided by Jacobs et al. 83

Each of the studies had a different comparator. In the study by Amir-us-Saqlain et al. 82 from Pakistan, the intervention being assessed was the effect of keeping the manipulated extremity in abduction and external rotation for 24 hours following MUA. Both groups received MUA, including a steroid injection, followed by physical therapy and the experimental group also had the extremity kept in a fixed position following MUA. In the two UK studies, Jacobs et al. 83 compared MUA with distension in combination with steroid injection; and Quraishi et al. 38 compared MUA, including a steroid injection, with arthrographic distension. Kivimaki et al. 39 compared MUA (plus home exercise) with home exercise alone, which involved physiotherapy advice in two sessions and written instructions for home exercise.

The inclusion criteria varied between studies in terms of extent of restriction of movement. 38,39,82 Jacobs et al. 83 did not specify the symptomatic inclusion criteria other than that patients with primary frozen shoulder were included. Quraishi et al. 38 included only patients with stage 2 frozen shoulder. The stage of frozen shoulder was described as painful and stiff or in the ‘freezing’ phase in two RCTs,39,83 and the majority of participants reported pain and stiffness in one RCT (the remainder had either pain or stiffness). 82 At baseline the duration of frozen shoulder ranged from a mean or median of 10 weeks to 40 weeks. Two studies reported on whether participants had received previous treatment for frozen shoulder. Quraishi et al. 38 reported that 44% had previously received physical therapy, 61% a steroid injection and 31% physical therapy combined with steroid injections. Kivimaki et al. 39 alluded to participants having received previous treatment by reporting that in the 3 months prior to randomisation there was no difference between treatment groups in terms of physical therapy, massage or chiropractic manipulations received. The mean or median age of the participants ranged from 53 to 57 years and the proportion of women ranged from 58% to 68%. It was unclear whether participants with diabetes were included in one study,82 one study reported that there were no participants with diabetes83 and in the remaining two studies the proportions with diabetes were 14%39 and 17%. 38

Quality assessment

The included RCTs generally varied in quality. All of the studies reported the number of participants randomised and comparability at baseline, although one reported only comparability for range of movement. 82 The Amir-us-Saqlain et al. 82 and Jacobs et al. 83 studies did not report the method of randomisation and so it was unclear whether these studies were truly randomised, and they did not report allocation concealment or whether the outcome assessors were blinded, although this would not have been possible in the study by Amir-us-Saqlain et al. 82 These studies therefore had a potentially high risk of bias. Additionally, Jacobs et al. 83 was not adequately powered, loss to follow-up was high (19%) and it was unclear whether imbalances in dropouts were adjusted for. Although the authors stated that intention-to-treat analysis was performed, not all patients were included in the analysis. It was unclear whether the study by Amir-us-Saqlain et al. 82 was adequately powered and loss to follow-up was high (23%).

Both Kivimaki et al. 39 and Quraishi et al. 38 reported appropriate randomisation methods; however, only Kivimaki et al. 39 reported allocation concealment and blinding of outcome assessors and was therefore classified as of adequate quality. Loss to follow-up was high in this study (34% at 6 months) and was greater in the MUA group than in the control group; the analysis did not appear to be intention to treat. The study did not appear to be adequately powered at the 6- and 12-month follow-ups. Although Quraishi et al. 38 reported that the investigator was blinded, it was not clear whether outcome assessment was blinded or whether there was allocation concealment and therefore this study may be at risk of bias. Loss to follow-up was relatively low in this study (8%) although it was unclear whether the study was adequately powered. Full details of study quality are reported in Appendix 8.

Pain

There was no significant difference in pain intensity between MUA and home exercise at 6 weeks or 3, 6 or 12 months (Table 37).

Function and disability

There was no significant difference in Constant score between treatment groups at 6 weeks or 3, 6 or 12 months (Table 37).

Range of movement

There was no significant difference in passive abduction, passive internal rotation or external rotation between treatment groups at 6 weeks or 3, 6 or 12 months (Table 37).

Working ability

There was no significant difference in the change in working ability between treatment groups at 6 weeks or 3, 6 or 12 months (Table 37).

Adverse events

The authors reported that there were no major complications during manipulation.

Pain

The study by Jacobs et al. 83 showed no significant difference in pain intensity between treatment groups up to 16 weeks. The mean regression coefficient (SE) was –2.77 (0.33) for MUA and –2.75 (0.42) for distension combined with steroid injection (95% CI –1.11 to 1.15).

In the study by Quraishi et al. 38 at 2 months’ follow-up the mean VAS score was 4.7 (range 0 to 8.5) in the MUA plus steroid arm and 2.4 (range 0 to 8) in the arthrographic distension arm (p-value not reported). At 6 months there was a significantly greater improvement in VAS in the arthrographic distension group than in the MUA group (SMD 1.52, 95% CI 0.75 to 2.30) (Table 39).

Function and disability

The study by Jacobs et al. 83 found no significant difference between treatment groups in the Constant score up to 16 weeks: mean regression coefficient (SE) 3.13 (0.24) for MUA and 3.23 (0.42) for distension plus steroid injection (95% CI –1.09 to 0.81).

In the study by Quraishi et al. 38 at 2 months’ follow-up the mean Constant score was 58.5 (range 24 to 90) in the MUA plus steroid arm and 57.4 (range 17 to 80) in the arthrographic distension arm. At 6 months the Constant score was significantly improved in the arthrographic distension group compared with the MUA group (–6.40, 95% CI –6.56 to –6.24) (Table 39).

Range of movement

Quraishi et al. 38 reported no statistically significant difference between groups in external rotation (p = 0.13), internal rotation (p = 0.48) and abduction at 6 months’ follow-up (p = 0.62) (data available only in a graph).

Quality of life

Jacobs et al. 83 reported that all components of the SF-36 improved for all patients during the course of treatment, with the greatest improvements shown in the physical role and bodily pain components. There was no statistically significant difference with respect to change in SF-36 scores between the treatment groups (data available only in graph format, no p-values reported).

Satisfaction

Quraishi et al. 38 reported that at final follow-up 81% of MUA patients were satisfied or very satisfied compared with 94% of patients who received arthrographic distension. All of the patients with diabetes were satisfied with their outcome (three in both the MUA and arthrographic distension groups).

Adverse events

The study by Jacobs et al. 83 reported that no systemic or local complications were noted in either treatment group. Quraishi et al. 38 did not report any information on adverse events.

Range of movement

Passive abduction (MD 22.49°, 95% CI 13.14° to 31.84°), passive internal rotation (MD 1.00 cm, 95% CI 0.71 cm to 1.29 cm), active abduction (MD 28.99°, 95% CI 17.07° to 40.91°) and active internal rotation (MD 0.91 cm, 95% CI 0.49 cm to 1.33 cm) were significantly greater at 12 weeks post treatment in the MUA combined with steroid injection plus manipulated extremity and physiotherapy group than in the MUA combined with steroid injection plus physiotherapy group. There was no significant difference in passive or active external rotation between treatment groups.

Summary

The four included studies of MUA were diverse in terms of the intervention and the comparator. Some studies used a steroid injection (triamcinolone) in conjunction with MUA. The studies were not considered clinically similar enough to be pooled in a meta-analysis. Across all of the studies information about previous treatments that participants had received and stage of frozen shoulder was limited. It was not possible to explore variation between those with and without diabetes.

Because it was unclear whether all studies had enough participants to detect a statistically significant treatment effect, it should be kept in mind that where studies did not report a significant benefit (i.e. the CI crossed the line of no difference) this should not be interpreted as evidence of no difference between the groups. A single study of adequate quality reported no statistically significant difference between MUA (and home exercise) and home exercise alone in pain, function and disability, range of movement or working ability at 6 weeks and 3, 6 and 12 months. 39 Follow-up at 6 months and beyond in this study should be treated with some caution because of high loss to follow-up, which was somewhat higher in the MUA group, and also the lack of intention-to-treat analysis. Two studies comparing MUA with distension had mixed findings. One, with a potentially high risk of bias, found no significant difference in pain or function and disability between MUA and distension (which included steroid) up to 16 weeks post treatment. 83 The second, which had some risk of bias, found a significantly greater improvement in pain and function and disability at 6 months with arthrographic distension than with MUA in conjunction with steroid. 38 The fourth study, with a potentially high risk of bias, reported that keeping the manipulated extremity in abduction and external rotation for 24 hours following MUA was superior to MUA without this additional process for passive and active abduction and internal rotation at 12 weeks. 82

In conclusion, there was very little evidence available for MUA and most of the studies identified had limitations. The single adequate study found no evidence of benefit of MUA over home exercise alone. Generalisability is somewhat unclear because of the limited information about previous interventions that participants had received and stage of frozen shoulder.

Study characteristics

Three RCTs investigated distension with steroid injection in the treatment of primary frozen shoulder. A summary of study characteristics is reported in Table 42, with further details available in Appendix 6. All were full papers of studies conducted in Australia,43 Denmark84 and Norway36 and published between 1998 and 2008. All were two-armed trials.

The two most recent studies by Buchbinder et al. 43 and Tvetia et al. 36 used arthrographic distension. One injected 40 mg of steroid (in 1 ml) and up to 82 ml of saline on a single occasion43 and the other injected 20 mg of steroid (2 ml), 4 ml of local anaesthetic and 10 ml of saline on three occasions at 2-week intervals,36 along with contrast medium in the arthrographic distension groups. Both of these studies stated that the procedure continued until rupture occurred. Buchbinder et al. 43 had the additional end points of patient termination of the procedure and a maximum of 90 ml having been injected. The older study by Gam et al. 84 stated that the injection was confirmed by ultrasound and participants were injected with 20 mg of steroid with 19 ml of lidocaine once per week for up to 6 weeks. Details were not provided in this study as to whether distension occurred or how this was established. The two studies of arthrographic distension used different comparators: Buchbinder et al. 43 used a placebo comparator of arthrogram only, whereas Tveita et al. 36 used steroid injection (with local anaesthetic).

Home exercise of pendular exercises and scapular setting were given in the study by Buchbinder et al. 43 and no manual treatment (e.g. physiotherapy, massage) or other medical interventions were allowed. In contrast, in the Tvetia et al. study36 patients were allowed to continue with their current physiotherapy programme; no patients were prescribed new physiotherapy programmes during the study. The study of non-arthrographic distension did not report any information regarding home exercise. 84

There was some variability in concomitant treatments. Buchbinder et al. 43 allowed paracetamol and codeine preparations but NSAIDs were not allowed, Tveita et al. 36 allowed pain medication organised by the patients’ primary care physicians and Gam et al. 84 reported that analgesics were permitted.

The inclusion criteria varied between studies; however, the two most recent studies of arthrographic distension required similar extent of restriction in shoulder movement. 36,43 The duration of frozen shoulder at baseline ranged from a median or mean of 114 days (approximately 4 months) to 7 months, although the stage at baseline was not reported by any of the studies. Diagnosis was by measuring passive range of movement to onset of pain,43 clinical examination, blood samples and radiography or ultrasound,84 and clinical history and radiography. 36

A substantial proportion of patients (28%) had diabetes in the Buchbinder study;43 the remaining two studies had no patients with diabetes. Buchbinder et al. 43 also included a small proportion (2.2%) with secondary frozen shoulder. Buchbinder et al. 43 and Tveita et al. 36 also reported that patients had undergone treatment for frozen shoulder before the study: in the Buchbinder study 28% of patients had received corticosteroid injections whereas in the Tveita study 17% had undergone physiotherapy. The ages of patients ranged from a mean or median of 47 years to 57.3 years and the proportion of women was either 59% or 80%.

Quality assessment

Buchbinder et al. 43 was considered of satisfactory quality as the risk of bias was minimised through computerised randomisation and allocation concealment by a biostatistician who kept the assignment scheme. An intention-to-treat analysis was also performed. Patients were blinded to treatment and outcome assessors were also blinded. The treatment groups were also comparable at baseline. The main limitation of this study is that it was not sufficiently powered after dropouts (9%). The intention-to-treat analysis used in the study was adequately powered based on the authors’ power calculation (the sample size to detect a difference in SPADI scores).

Both Gam et al. 84 and Tveita et al. 36 reported a reliable method of randomisation; however, it was not clear whether an adequate method of allocation concealment had been used. Tveita et al. 36 reported that patients were not informed of their actual assignment until the first injection was to be given, and no information regarding allocation concealment was reported by Gam et al. 84 Therefore, these studies are potentially at risk of bias. Gam et al. 84 reported that outcome assessors were blinded and that the groups were comparable at baseline. In the study by Tveita et al. 36 there appeared to be a higher proportion with previous shoulder problems and who were on sick leave in the steroid injection group. Tveita et al. 36 also reported using statistical adjustment to control for baseline differences for the function and disability SPADI outcome but not for range of movement. Tveita et al. 36 used intention-to-treat analysis and both studies reported the same rate of loss to follow-up (9%), with similar numbers in each arm.

Pain

Two studies, one by Buchbinder et al. 43 and one by Gam et al. ,84 assessed pain. Buchbinder et al. 43 reported change from baseline data at 3, 6 and 12 weeks using a 10-point Likert scale (Table 43). However, the study by Gam et al. 84 reported data for VAS pain scores at rest and VAS pain scores on function in graphical form only. This study was described narratively.

There was no significant difference in pain between arthrographic distension with steroid and placebo (arthrogram) at 6 weeks (SMD –0.40, 95% CI –0.99 to 0.19) or 12 weeks (SMD –0.15, 95% CI –0.73 to 0.44) in the study by Buchbinder et al. 43

In the study by Gam et al. 84 there was no significant difference between the steroid and distension groups for VAS pain score on function (p = 0.1) or VAS pain score at rest (p = 0.1) (time points unclear). The authors reported that there was a tendency toward less pain in the distension group. Additionally, the authors reported that analgesic consumption was significantly lower at week 11 in the distension group than in the steroid group (p = 0.008). These results were presented in graphical form only.

Function and disability

Two of the three included studies assessed function and disability. 36,43 Both reported SPADI total score and one43 reported a problem elicitation technique score, a patient preference disability measure in which patients identify their own problems related to the disease that they would like to see improve as a result of treatment. Change from baseline data were available from Buchbinder et al. 43 and final value data were available from Tveita et al. 36 (Table 44). These were not pooled as the comparator arms were different between studies: Buchbinder et al. 43 compared arthrographic distension with placebo whereas Tveita et al. 36 used steroid injection as a comparator. Table 45 provides the between-group MDs and 95% CIs. The outcome data for individual groups are available in Appendix 7.

Range of movement

The range of movements of interest in this review that were reported by the studies of distension were passive and active abduction, passive and unspecified external rotation, passive internal rotation and hand behind back. Change from baseline data were available from Buchbinder et al. 43 and final value data were available from Tveita et al. 36 (Table 46). It was considered inappropriate to pool the two studies as one had a placebo comparator and one a steroid injection comparator. The study by Gam et al. 84 provided limited data for extraction and these were summarised narratively. Table 47 summarises the between-group MDs and 95% CIs. The outcome data for individual groups are available in Appendix 7.

Adverse events

All of the studies investigating distension reported adverse events. These were reported in detail in the study by Buchbinder et al. 43 and to a lesser extent by Gam et al. 84 and Tveita. 36 The adverse events reported by all studies are summarised in Table 48.

Buchbinder et al. 43 reported that open-ended questions were used to assess the extent of adverse events. More patients in the arthrographic distension group than in the placebo group reported pain associated with the procedure (16% vs 5%) and pain lasting up to 48 hours (12% vs 5%). None of the adverse events was reported as serious and a number of additional adverse events were reported (Table 48).

Gam et al. 84 reported that the number and type of side effects were recorded. The only adverse events reported in this study were two cases of unacceptable pain after injection (one in each treatment group); these patients dropped out of the study.

In the study by Tveita et al. 36 the patients recorded pain intensity related to the injection procedures. Six patients in the steroid group and five in the distension group felt that the injections were very painful. Flushing and disturbances in heat regulation were also common in both groups and a number of other non-serious adverse events were reported (Table 48).

Summary

Three studies were included that investigated the effects of distension with steroid injection. Two of these studies investigated arthrographic distension36,43 and the other investigated non-arthrographic distension. 84 The comparators evaluated were steroid alone36,84 and placebo (arthrogram only). 43 Only one study was judged to be of satisfactory quality,43 whereas the remainder were potentially at risk of bias. Because of the variability in the interventions and comparators it was not considered appropriate to pool any of the studies. Stage of frozen shoulder was not reported in any of these studies; however, previous treatments were described in two of the studies. 36,43

Quality assessment

Both studies were case series, which are inherently at high risk of bias because of the lack of a control group. The Bradford Hill criteria (a group of minimal conditions necessary to provide adequate evidence of a causal relationship between an incidence and a consequence) state that there must be a temporal relationship between the incidence of the factor (in this case surgery) and consequence (recovery). For a condition such as frozen shoulder, which for most people will resolve over a 1- to 3-year period, this relationship cannot be ascertained without a control group. 87 Austgulen et al. 85 was considered better quality as this study reported inclusion criteria, the population appeared representative of the frozen shoulder population, SDs were reported and patients were recruited prospectively, although the extent of this was unclear. The number of dropouts was unclear. Chen et al. 86 met only one criterion (reporting of inclusion criteria); the remainder were unclear or not met. There were no dropouts in this study. Further details of quality assessment are available in Appendix 8.

Pain

Only one study reported any data regarding pain. Chen et al. 86 reported that two-thirds of patients complained of pain exacerbation after arthroscopic brisement; 5% had pain duration of longer than a few weeks. Half of patients had pain relief within 1 month whether in motion or not. After 3 months all except eight shoulders were pain free in any direction of shoulder movement (data were not reported).

Function and disability

Austgulen et al. 85 reported a significant improvement in the Oxford Shoulder score from a baseline mean of 41.0 (SD 7.5) to 18.4 (SD 7.3) postoperatively (p < 0.001), a scale for which the best possible outcome is 12 and worst possible outcome is 60 (Table 51).

Similarly, Chen et al. 86 reported that an improvement in the mean modified ASES score from a baseline score of 41 (SD 13) to 87 (SD 11) was significant (p < 0.005) at follow-up (Table 51).

Austgulen et al. 85 reported significant improvements from baseline to follow-up (p < 0.001) on a 10-point scale in mean working ability (baseline 2.4, SD 2.6; follow-up 7.4, SD 2.5), mean physical activity (baseline 2.3, SD 2.5; follow-up 7.4, SD 2.4) and sleep at night (baseline 1.7, SD 2.5; follow-up 7.2, SD 2.6). This study also reported high satisfaction postoperatively (8.6, SD 1.6 on a 10-point scale) (Table 51).

Range of movement

Austgulen et al. 85 reported that there was a significant improvement in mean external rotation from 3° (SD 5°) to 39° (SD 23°) (p < 0.001) and in mean abduction from 34° (SD 8°) to 154° (SD 37°) (p < 0.001) postoperatively.

Chen et al. 86 reported a similar average gain in external rotation of 35°. The gain in internal rotation was 30°.

Adverse events

Austgulen et al. 85 reported that two patients had frozen shoulder again and had repeat surgery. No deep infections, nerve damage or other complications were reported. Chen et al. 86 found that only one patient experienced complications (superficial wound infection). No further information regarding how adverse events had been assessed was reported in either study.

Summary

Two studies investigated capsular release. Both were case series and therefore inherently at high risk of bias. One of the studies stated that debrisement was a component of the capsular release procedure and both reported that physiotherapy was undertaken post procedure.

One case series reported that the majority of patients were pain free at movement at short-term follow-up. Statistical significance was not reported. There was evidence of benefit for function and disability from both studies. Each study reported a significant improvement in one function and disability scale. Additionally, one study reported significant benefits in working ability, physical activity, sleep at night and satisfaction with capsular release. One study reported evidence of significant benefit in two measures of range of movement with capsular release; the other study reported an improvement in two measures of range of movement, but did not report whether or not these were significant.

In conclusion, although the evidence available suggested potential benefit from capsular release, these studies were at high risk of bias and cannot be used to draw conclusions regarding the efficacy of this treatment for frozen shoulder.

Homogeneity

The assumption of homogeneity is that trials are sufficiently homogeneous to be quantitatively combined. In the analysis presented, placebo included sham distension, saline injections and placebo laser. Although we believed that it was appropriate to pool different types of placebo, it could be argued that these are not similar enough because of the differing degree of invasiveness. Furthermore, there were differences in the populations of the included studies. For all studies of conservative treatments, it was not reported whether participants had received any previous treatment for frozen shoulder. However, for both studies of invasive treatments (MUA combined with physical therapy, and arthrographic distension with steroid) it was reported that at least some participants had undergone previous treatments for frozen shoulder including corticosteroid injections or some form of physical therapy. This would suggest that the populations of the invasive studies had a longer duration and possibly more treatment-resistant forms of frozen shoulder than those in the conservative treatment studies.

Consistency

The assumption of consistency is that had treatment C been included in a trial comparing interventions A and B then the treatment effect dAC would be equivalent to that obtained from a trial of interventions A and C. 33 Assuming consistency, the treatment effect dAC is the sum of the treatment effects dAB and dBC. However, this assumption requires that the treatments involved belong to closed loops in the network of evidence, such as that seen in a connected polygonal structure. 88 Given that the structure of the network presented here was of a radiating star, with only one loop of evidence, it was not feasible to assess consistency.

Methodological similarity

Of the nine studies included in the analysis, five were of at least satisfactory quality (method of randomisation was adequate and outcome assessment was blinded)16,35,39,41,43 and four were not. 42,51,70,79 To assess the effect of quality on the estimates, a network of studies that were at least of satisfactory quality was evaluated (network 2). However, this model was unstable and, although presented in Appendix 10, the reliability of the data included in the analysis presented is uncertain and does not allow a robust assessment of the impact of quality.

Steroid injections

Six RCTs investigated steroid injections in the treatment of primary frozen shoulder, either alone or in combination with physical therapy. 35,41,42,66–68 Steroid injections can be delivered by a number of different practitioners using different approaches. We have broken these down into a guided injection delivered by an orthopaedic surgeon, a rheumatologist or a radiologist in a hospital setting; unguided injection delivered by a physiotherapist or a GP in a non-hospital setting; and unguided injection delivered by a physiotherapist, an orthopaedic surgeon or a rheumatologist in a hospital setting. Given the nature of the condition and the individual nature of treatments, it was not possible to be precise about the number of injections that an average individual may receive. It was also suggested by our advisory group that the number of patients receiving guided injection within the NHS was likely to be low.

Sodium hyaluronate injection

Three trials evaluating sodium hyaluronate were identified in the effectiveness review. 66,69,70 In a recent UK-based survey of treatment recommendations by health-care professionals involved in managing frozen shoulder, sodium hyaluronate injection was recommended by < 1% for treating the early ‘painful’ phase or ‘resolution’ phase of frozen shoulder. 18 It was further suggested by the clinical advisory group that one injection would typically be delivered over two sessions in a hospital setting. The injection was likely to be delivered by a consultant. However, the costs were not available for sodium hyaluronate for provision under the NHS. It was felt that this intervention was likely to be delivered in a hospital setting, but we were unable to ascertain any costs associated to its delivery that would be borne by the NHS.

Physical therapy

The broader range of physical therapies are not available through the NHS and therefore have not been costed. Two categories of physiotherapy were costed, physiotherapy with mobilisation (active) and physiotherapy without mobilisation. It was felt by the advisory group that physiotherapy without mobilisation would not be delivered on its own in an NHS setting, but may be used to complement another therapy. Therefore, for the purpose of resource-use estimation, physiotherapy without mobilisation has been considered only as an add-on delivered alongside other therapies.

Acupuncture

Three trials evaluating acupuncture were identified in the effectiveness review. 79–81

It was felt by the clinical advisory group that acupuncture, like other physiotherapies, would in clinical practice rarely be given in isolation of other treatments. We have therefore assumed that acupuncture would be delivered in physiotherapy sessions, in either a hospital or a community setting, over the same duration as active physiotherapy, that is, six sessions of 20–30 minutes’ duration at a total cost ranging from £117.75 to £126.75.

Manipulation under anaesthesia

The review identified four RCTs investigating MUA in the treatment of primary frozen shoulder. 38,39,82,83 The resource implications of MUA were difficult to firmly establish. The actual cost of MUA has been estimated at £424 (range £191–500) based on the HD24C code, which was obtained from the NHS Reference Costs. 95 In addition, there is a need for extensive rehabilitation physiotherapy, which was estimated on average to consist of two 30-minute sessions per week for 4 months, plus a final review, which would take place with the orthopaedic surgeon. Therefore, in total, the estimated cost of MUA is £1446. If steroid injections are also used this cost would increase accordingly.

Arthrographic distension

Three trials evaluating arthrographic distension with steroid injection were identitied in the effectiveness review. 36,43,84 Arthrographic distension is assumed to be delivered in the hospital setting by a radiologist or an orthopaedic surgeon and involves the use of radiological imaging (e.g. fluoroscopy) to ensure that the injection is accurately placed. The procedure was assumed to require around 15 minutes based on the clinical literature. Because there are no UK trials in the clinical review it is unclear how many visits for injections might be needed. We have therefore conservatively estimated the cost as involving one hospital outpatient visit with injection. The estimated cost of this procedure has been derived from the NHS Reference Costs95 at £113 (range £78–133) based on code RA16Z, plus the cost of a combined injection of triamcinolone and lidocaine (£1.49 + £0.35), giving a total of £114.845 (range £79.84–134.84).

Capsular release

Two studies evaluating capsular release were identified in the effectiveness review. 85,86 Capsular release is performed in the hospital setting and delivered by a surgical team, which is likely to comprise anaesthetist, orthopaedic surgeon, anaesthetic nurse, scrub nurse and assistant and recovery nurse. The procedure is likely to take 30–45 minutes, followed by a further 15 minutes for recovery from anaesthetic. The estimated cost of this procedure has been derived from the NHS Reference Costs95 at £1182 (range £787–1489) based on code HB62C. Like MUA, capsular release requires a follow-up of intensive physiotherapy. We have estimated that the physiotherapy following capsular release would be the same as that following MUA. On average this would consist of two 30-minute sessions per week for 4 months, plus a final review that would take place with the orthopaedic surgeon. Therefore, in total, the estimated cost of capsular release is £2204 (range £1809–2511).

Summary

Average costs were estimated for the interventions included in the review. These ranged from £36.18 for an unguided steroid injection to £2204 for capsular release. Where possible, these estimated average costs will be used to inform tentative cost-effectiveness ratios, which will be presented later in the report. They will be combined with HRQoL data estimated by means of a mapping exercise, which is presented in the following section. The aim is to estimate HRQoL by mapping from three clinical outcomes to EQ-5D using an available data set. The main focus of the mapping is to explore the nature and direction of the relationship between different clinical and HRQoL outcome measures. We will then use the EQ-5D estimates to obtain HRQoL outcomes for a subset of clinical trials identified in the review that have presented data on the three relevant outcomes.

Methods

The following sections present the methods used in estimating HRQoL data to inform our tentative analysis and potentially inform other economic evaluations.

Results from the mapping exercise

Pattern of EQ-5D, pain visual analogue scale and SF-36 PCS and MCS scores

EQ-5D and pain visual analogue scale

The mean EQ-5D scores (ordered according to health state severity) in the SAPPHIRE population vary over a wide range (e.g. from negative utility values to ‘perfect health’ as indicated by utility values of 1.0; Table 61 and Figure 25). In contrast, the SAPPHIRE trial mean pain VAS scores vary over a narrower range (e.g. highest mean VAS score = 60, when a maximum pain VAS of 100 is possible). An increasing EQ-5D score (i.e. better health status) appears to be generally accompanied by decreasing pain VAS scores (i.e. lower scores = less pain).

TABLE 61 - Pattern of EQ-5D scores and pain VAS scores within the SAPPHIRE data set (with complete responses at 3 months)

All values were equal to 1.0, i.e. full index.

EQ-5D grouping	n	EQ-5D (mean)	Pain VAS (mean)
< 0	8	–0.05	18.13
0–0.249	15	0.08	60
0.25–0.499	1	0.26	50
0.5–0.699	52	0.63	41.87
0.7–0.799	24	0.75	40.17
0.8–0.899	26	0.83	38.88
0.9–1.0a	15	1.0	34.67
Full index	15	1.0	34.67
Overall	141	0.63	37.63

FIGURE 25.

Pattern of EQ-5D scores and pain VAS scores within the SAPPHIRE data set (for complete responses) at 3 months’ follow-up (base case).

EQ-5D and SF-36 PCS and MCS

Figure 26 and Table 62 show that mean EQ-5D scores (ordered according to health state severity) in the SAPPHIRE population vary over a wide range. In contrast, the SAPPHIRE trial mean SF-36 PCS and MCS scores vary over a relatively narrow range. An increasing EQ-5D score (i.e. better health status) appears to be generally accompanied by increasing SF-36 PCS and MCS scores (i.e. higher scores = a better quality of life).

FIGURE 26.

Pattern of EQ-5D scores and SF-36 PCS and MCS scores within the SAPPHIRE data set (for complete responses) at 3 months’ follow-up (base case).

TABLE 62 - Pattern of EQ-5D scores and SF-36 PCS and MCS scores within the SAPPHIRE data set (with complete responses at 3 months)

NA, not applicable (no values fell within this grouping).

All values were equal to 1.0, i.e. full index.

EQ-5D grouping	n	EQ-5D (mean)	SF-36 PCS (mean)	SF-36 MCS (mean)
< 0	10	–0.07	35.96	45.70
0–0.249	18	0.11	39.18	47.35
0.25–0.499	1	0.26	36.64	41.14
0.5–0.699	44	0.63	39.68	42.01
0.7–0.799	21	0.75	44.07	50.23
0.8–0.899	28	0.82	42.91	53.2
0.9–1.0a	0	NA	NA	NA
Full index	11	1.0	40.68	48.95
Overall	133	0.59	40.79	47.21