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The clinical course of low back pain: a meta-analysis comparing outcomes in randomised clinical trials (RCTs) and observational studies

  • Majid Artus1Email author,
  • Danielle van der Windt1,
  • Kelvin P Jordan1 and
  • Peter R Croft1
BMC Musculoskeletal Disorders201415:68

DOI: 10.1186/1471-2474-15-68

Received: 17 August 2013

Accepted: 25 February 2014

Published: 7 March 2014

Abstract

Background

Evidence suggests that the course of low back pain (LBP) symptoms in randomised clinical trials (RCTs) follows a pattern of large improvement regardless of the type of treatment. A similar pattern was independently observed in observational studies. However, there is an assumption that the clinical course of symptoms is particularly influenced in RCTs by mere participation in the trials. To test this assumption, the aim of our study was to compare the course of LBP in RCTs and observational studies.

Methods

Source of studies CENTRAL database for RCTs and MEDLINE, CINAHL, EMBASE and hand search of systematic reviews for cohort studies. Studies include individuals aged 18 or over, and concern non-specific LBP. Trials had to concern primary care treatments. Data were extracted on pain intensity. Meta-regression analysis was used to compare the pooled within-group change in pain in RCTs with that in cohort studies calculated as the standardised mean change (SMC).

Results

70 RCTs and 19 cohort studies were included, out of 1134 and 653 identified respectively. LBP symptoms followed a similar course in RCTs and cohort studies: a rapid improvement in the first 6 weeks followed by a smaller further improvement until 52 weeks. There was no statistically significant difference in pooled SMC between RCTs and cohort studies at any time point:- 6 weeks: RCTs: SMC 1.0 (95% CI 0.9 to 1.0) and cohorts 1.2 (0.7to 1.7); 13 weeks: RCTs 1.2 (1.1 to 1.3) and cohorts 1.0 (0.8 to 1.3); 27 weeks: RCTs 1.1 (1.0 to 1.2) and cohorts 1.2 (0.8 to 1.7); 52 weeks: RCTs 0.9 (0.8 to 1.0) and cohorts 1.1 (0.8 to 1.6).

Conclusions

The clinical course of LBP symptoms followed a pattern that was similar in RCTs and cohort observational studies. In addition to a shared ‘natural history’, enrolment of LBP patients in clinical studies is likely to provoke responses that reflect the nonspecific effects of seeking and receiving care, independent of the study design.

Background

Well-conducted randomised clinical trials (RCTs) generally provide the strongest evidence for the effectiveness of treatments. RCTs on the effectiveness of treatments for non-specific low back pain have not found evidence for a clear superiority of any treatment [13]. Yet, low back pain symptoms tend to improve in RCTs regardless of the treatment provided. Such improvement seems to follow a pattern common to all treatment arms, of rapid early improvement within the first 6 weeks reaching a plateau over the following 12 months [4]. This is explained at least partly by the ‘natural history’ (i.e. the propensity for symptoms to improve without treatment). With the use of treatment this is referred to as the ‘clinical course’ of symptoms. The clinical course of back pain has been assessed in observational (cohort) studies [5, 6]. It was also found to follow a pattern of general improvement that starts rapidly and plateaus over time. Although this suggests a similarity between RCTs and cohort studies, there is no clear evidence for this from direct comparison. More importantly, it is not clear whether the size of overall symptom improvement is the same in these two groups of studies. There is only a limited evidence for a direct comparison, mainly comparing RCTs with non-randomised trials and observational studies that included comparator groups [7].

There is an assumption that the course of symptoms in RCTs is different from that in cohort studies. It has been suggested that the mere participation in a trial influences the course of symptoms [8, 9]. This might be explained by benefits perceived by participants and assumed to be related to the intensive assessment and monitoring. The so called ‘Hawthorne effect’ was quoted as an example of how individuals change behaviour due to the attention they receive from researchers. [1012]. Although this is expected to apply to all studies, it might be relatively more pronounced in RCTs compared with cohort studies.

Another issue is whether participants in RCTs are in some way different from the average person presenting for care in usual clinical practice. Whether their willingness to be randomly allocated to a treatment or a placebo makes these individuals different from the average patient to whom the results of RCTs will be applied. If true, this raises the issue of whether participants in RCTs are less representative of the average patients compared with participants in observational studies in which patients are not randomised.

It is therefore important to establish the evidence for the similarity or otherwise, in the pattern and the size of back pain symptom improvement in these two types of studies. This would test the assumption that mere willingness to enrol in RCTs and be randomised to treatments would influence the clinical course of symptoms. This would have potentially important implications on interpreting the results of RCTs and their generalizability in clinical practice.

The aim of this systematic review and meta-analysis was to compare changes in low back pain symptoms over time in RCT participants with those of participants in observational cohort studies.

Methods

Criteria for inclusion

Included were studies (RCTs and prospective observational cohort studies) conducted for primary care treatment for LBP (e.g. analgesia, exercises, manipulation therapy) among individuals aged 18 or over. Studies had to provide baseline and follow-up data on the designated primary outcome measure of pain intensity, measured on a Numerical Rating Scale (NRS) or Visual Analogue Scale (VAS). Only studies published in English were included. Also excluded were studies conducted among patients with specific LBP (e.g. cancer or inflammatory arthritis), post-operative or post-traumatic back pain, or back pain associated with pregnancy or labour.

Searching and selection of studies

To meet the specific aims of the study, the literature search did not have to be exhaustive, but to provide sufficiently large pool of studies. The Cochrane Central Register of Controlled Trials (CENTRAL) was therefore chosen as a sufficient data source for RCTs.. This search was an update (up to April 2012) of a strategy previously used and described elsewhere [4]. For observational studies, a literature search was conducted for the same time period using the databases of AMED, EMBASE, MEDLINE and CINAHL based on the keywords ‘low back pain’, ‘back pain’, ‘spinal pain’, ‘primary care’, ‘general practice’, ‘population’, ‘cohort’, ‘observational’, ‘prognosis’, predictor’ and ‘course’. The detailed search strategy is shown in Additional file 1. References accompanying relevant systematic reviews and included cohort studies were also hand-checked to identify additional eligible studies.

The literature search was conducted by MA and screening of citations/abstracts ad selection of RCTs and cohort studies applying the inclusion criteria was conducted by MA, DVdW & KPJ.

Data extraction

The extracted data included:
  1. 1.

    Study characteristics (publication year, country of study, clinical setting, study design, sample size).

     
  2. 2.

    Participants’ characteristics (mean age;% female; duration of symptoms).

     
  3. 3.

    Interventions: name, dose and provider.

     
  4. 4.

    Outcome: baseline and follow up mean scores (and baseline standard deviation (SD)) for pain intensity.

     

Analysis

Firstly, RCTs as a single group were compared with observational studies. Secondly, RCTs were sub-grouped into efficacy and pragmatic trials, based on whether the trial included a placebo, sham or no treatment, with such trials being grouped as efficacy trials. RCTs that included comparator treatment of usual care or waiting list arms were classified as pragmatic trials. To compare studies groups that are similar with regard to the type of treatment, a separate analysis was conducted to compare cohort studies with RCT arms that received ‘usual care’. Each RCT sub-group was compared separately with observational studies.

Pain intensity scores were converted to a zero to 100 scale (least to most severe) where necessary by multiplication. Meta-analysis using a random effects model was performed using STATA/IC 11 software to compute pooled mean pain intensity scores (and 95% confidence intervals) at baseline and follow up, separately for RCT treatment arms and for observational studies. Commonly used follow-up times of 6, 13, 27 and 52 weeks were selected for comparison. Data on other time points were considered to fall within the selected points if they were within a three-week range.

To compare the size of improvement in outcome scores in RCTs and observational studies, the standardized mean change (SMC) [13] was calculated for each RCT treatment arm and observational study by subtracting the follow-up mean outcome score from the baseline mean score and dividing by the standard deviation (SD) of baseline scores. Pooled SMCs were calculated using random effects meta-analysis. SMCs over 0.8 were considered large, 0.5 – 0.8 moderate and less than 0.5 small [14]. The 95% Confidence Intervals for SMCs were calculated using the formula described by Hozo et al. [15]. The variance (squared standard deviation, σ2) of response size was calculated using the following formula [15]:
σ 2 = 2 1 ρ / n n 1 / n 3 1 + n / 2 1 ρ δ 2 δ 2 / c n 1 2

Where: c (n-1) approximates 1 - [3 / 4(n-1) –1], ρ is the population correlation between baseline and follow-up scores which was estimated as 0.5, n is sample size and δ is the SMC. Heterogeneity of studies’ estimates was assessed by computing I 2 statistic [16], where zero indicates no variation between studies and 100% indicates that all variation is the result of variation between studies. Meta-regression analyses were conducted to test the significance of the difference in the size of SMCs between RCTs and observational studies at the selected follow up points.

Results

Included studies

The updated search for RCTs yielded a total of 1134 citations of which papers for 70 RCTs (165 treatment arms) satisfied the inclusion criteria and provided pain intensity data useful for analysis (Figure 1). The search for observational studies yielded a total of 653 citations (Figure 2), and data for pain intensity useful for analysis were provided in 15 papers. Relevant data were obtained for further four papers by contacting authors, allowing analysis of pain intensity data from papers for a total of 19 observational studies.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2474-15-68/MediaObjects/12891_2013_Article_2051_Fig1_HTML.jpg
Figure 1

Identification and inclusion of RCTs in the systematic review.

https://static-content.springer.com/image/art%3A10.1186%2F1471-2474-15-68/MediaObjects/12891_2013_Article_2051_Fig2_HTML.jpg
Figure 2

Identification and inclusion of observational cohort studies in the systematic review.

Characteristics of study setting and population

A list of the included RCTs and observational studies and their population characteristics are presented in Tables 1 & 2. They were conducted in more than13 countries including the USA, Australia, and European countries during a period spanning two decades. They are comparable in terms of age distribution, gender composition and mean baseline pain intensity (Table 3). It appears that compared with observational studies, RCTs included a larger percentage of participants described as having chronic low back pain (57% in RCTs vs 11% in cohorts). However, these figures need to be interpreted with caution as observational studies often included a mixture of patients with acute and chronic back pain (19% in RCTs vs 63% in cohorts).
Table 1

Characteristics of included observational cohort studies (n 19)

Author and country

Population and setting

Age, mean (y)

Female%

Type of back pain

Sample size

Bakker et al., Netherlands [17]

GP consulters

41

48

Acute

97

Bekkering et al., Netherlands [18]

Physiotherapy consulters

45

52

Mixed

500

Carey et al., USA [19]

GP and chiropractic consulters

42

52

Acute

1628

Chenot et al., Germany [20]

GP consulters

44

 

Mixed

1342

Coste et al., France [21]

GP consulters

46

40

Acute

103

Demmelmeir et al., Sweden [22]

General population

42

55

Mixed

379

Dunn et al., UK [23]

GP consulters

  

Mixed

206

Grotle et al., Norway [24]

Primary care

38

55

Acute

123

Hass et al., Netherlands [25]

Community chiropractic clinics

43

53

Mixed

2780

Kovacs et al., Spain [26]

GP consulters

46

52

Mixed

648

McGuirk et al., Australia [27]

GP consulters

53

57

Acute

83

Miller et al., UK [28]

GP consulters

39

60

Mixed

211

Nyiendo et al., USA [29]

Medical and chiropractic clinics

  

Chronic

835

Perreault et al., Canada [30]

Physiotherapy departments

51

 

Mixed

78

Sefarlis et al., Sweden [31]

GP consulters

39

 

Acute

60

Sharma et al., USA [32]

Medical and chiropractic clinics consulters

40

50

Mixed

2872

Tamcan et al., Switzerland [33]

General population

42

50

Chronic

340

van Hoogan et al., Netherlands [34]

GP consulters

44

55

Mixed

443

van Tulder et al., Netherlands [35]

GP consulters

41

49

Mixed

368

Table 2

Characteristics of included RCTs (n 70)

Author and country

Setting

Treatment

Age, mean (y)

Female (%)

Duration of back pain, mean (weeks)

Sample size of trial arms

Albaladejo et al., Spain [36]

Primary care

Education & physiotherapy

51

68

 

100

  

Education

51

63

 

139

  

Usual GP care

53

72

 

109

Arribas et al., Spain [37]

National health centres

GDS physical therapy

39

64

 

78

  

Electrotherapy

39

64

 

67

Bendix et al., Denmark [38]

General practice

Functional restoration (PT + OT + Psychological)

40

66

 

48

  

Outpatient intensive physical training: Aerobics + strengthening exercises + fitness machines

43

69

 

51

Bronfort et al., USA [39]

College outpatient clinic

Spinal manipulation & trunk strengthening exercise

41

54

156

71

  

NSAID & Trunk strengthening exercise

40

44

104

52

  

Spinal manipulation & Stretching exercise

41

39

120

51

Bronfort et al., USA [40]

Physical therapy clinic

Supervised exercises

45

57

249

100

  

Chiropractic

45

66

250

100

  

Home exercises

46

58

250

101

Browder et al., USA [41]

Physical therapy clinics

Extension orientated exercises

40

31

9

26

  

Strengthening exercises

38

32

9

22

Burton et al., UK [42]

General practice

The Back Book + usual care (GP & osteopathic care)

 

11

 

83

  

The traditional Handy Hints & usual care (GP & osteopathic care)

 

12

 

79

Cambron et al., USA [43]

Chiropractic clinic + hospital clinic + General population

Chiropractic flexion distraction procedure

42

34

 

123

  

Active trunk exercise program

41

41

 

112

Cecchi et al., Italy [44]

Rehabilitation department

Spinal manipulation

58

69

 

70

  

Individual physiotherapy

61

61

 

70

  

Back school

58

70

 

70

Chan et al., Hong Kong [45]

Physiotherapy

Aerobic training

47

79

54

24

  

Usual physiotherapy

46

77

63

22

Chang et al., Taiwan [46]

General population

Piroxicam sachet

34

30

 

23

  

Piroxicam tablets

34

26

 

19

Chok et al., Singapore [47]

Physiotherapy + Orthopaedic clinics + A/E

Physical therapy (endurance exercise at the PT department) + back hot pack

38

20

4

38

  

Back hot pack (Home)

34

29

4

28

Costa et al., Australia [48]

Physical therapy clinics

Exercise

55

58

335

77

  

Detuned diathermy and detuned USS

53

62

328

77

Constant et al., France [49]

General practice

Spa therapy & usual GP care

   

63

  

Waiting list group & usual GP care

   

63

Critchley et al., UK [50]

Physiotherapy department

Individual physiotherapy

45

59

275

71

  

Spinal stabilisation

44

71

346

72

  

Pain management

44

62

348

69

Di Cesare et al., Italy [51]

Physical therapy clinics

Trigger point mesotherapy

53

55

22

29

  

Acupuncture point mesotherapy

53

55

21

33

Djavid et al., Iran [52]

Occupational clinic

Low level laser (LLL)

40

56

118

20

  

LLL + exercise

38

37

110

21

  

Placebo LLL + exercise

36

17

106

20

Dufour et al., Denmark [53]

Rheumatology clinics

Group based multidisciplinary therapy

41

57

514

142

  

Individual therapist assisted exercises

41

56

540

144

Dundar et al., Turkey [54]

Physical therapy clinics

Aquatic exercise

35

47

 

32

  

Land based exercise

35

48

 

33

Fritz et al., USA [55]

Physical therapy clinics

Traction plus EOT

42

55

 

31

  

Extension orientated therapy (EOT)

41

58

 

33

Frost et al., UK [56]

Physiotherapy

Routine physiotherapy & advice book

42

58

 

144

  

Advice from physiotherapist & advice book

40

47

 

142

Geisser et al., USA [57]

University spinal programme

Manual therapy & Specific exercise (self corrections, stretching, strengthening)

39

67

284

26

  

Sham Manual therapy & Specific exercise

39

56

370

25

  

Manual Therapy & Non-specific exercise

37

80

370

24

  

Sham Manual Therapy & non-specific exercise

46

61

284

25

George et al., USA [58]

Physical therapy

Standard care physical therapy

37

53

4

32

  

Fear-avoidance based physical therapy

40

62

4

34

Glasov et al., Australia [59]

General population

Laser acupuncture

58

95

 

45

  

Sham laser

49

62

 

45

Glomsrod et al., Norway [60]

Physicians clinics and General population

Active back school (Lectures and back exercises)

41

65

 

37

  

Usual medical care

39

57

 

35

Goldby et al., UK [61]

General practice + hospital physicians

Spinal stabilisation & Attending the back school

43

68

 

84

  

Manual therapy & Attending the back school

41

70

 

89

  

Education (Booklet: Back in action) & Attending the back school

42

68

 

40

Hay et al., UK [62]

General practice

A brief programme of pain management (general fitness and exercise at clinic and home, explanation about pain mechanisms, distress, encouragement of positive coping strategies, overcoming fear of “hurt = harm”, and implementation of a graded return to usual activities)

40

50

 

201

  

Physiotherapy including manual therapy techniques

41

55

 

201

Heymans et al., Netherlands [63]

Occupational healthcare

Usual Dutch occupational physician care

41

17

35

103

  

Low intensity back school

41

22

35

98

  

High intensity back school

40

23

35

98

Hseih et al., USA [64]

General population

Joint manipulation & myofascial therapy

48

33

12

52

  

Joint manipulation

47

33

12

48

  

Myofascial therapy

49

33

12

51

  

Back school

48

40

11

48

Hurley et al., UK [65]

Physiotherapy + General practice + self referral

Manipulation therapy (Passively move intervertebral joint within or beyond its range)

40

57

8

80

  

Interferential therapy (Electrical stimulation)

40

62

8

80

  

Manipulation & interferential therapy

41

60

8

80

Hurwitz et al., USA [66]

Managed care facility

Chiropractic care only

52

49

 

169

  

Chiropractic care & physical modalities (Heat/cold, USS)

54

58

 

172

  

Medical care (excluding physical treatment) only

49

47

 

170

  

Medical care & physical modalities (Heat/cold, USS)

49

54

 

170

Hurwitz et al., USA [67]

Network of healthcare

Chiropractic care only

52

49

 

340

  

Chiropractic care & physical modalities (Heat/cold, USS)

53

58

 

340

Jellema et al., Netherlands [68]

General practice

Minimal intervention strategy (Assessing psychosocial risks, providing information on back pain and treatments & advice on self care)

43

48

2

143

  

Usual GP care

42

47

2

171

Kaapa H., Finland [69]

Occupational healthcare

Multidisciplinary rehabilitation: guided, group programme. : CBT, relaxation, back school education & physical therapy

46

100

72

59

  

Individual physiotherapy

47

100

63

61

Kankaanpaa, Finland [70]

Occupational healthcare

Active rehabilitation: guided exercises in a dept + behavioural support

40

34

 

30

  

Passive treatment: which they considered as minor to the active arm, e.g. massage and thermal treatment

39

33

 

24

Kapitza et al., Germany [71]

General population

Contingent biofeedback

53

67

655

21

  

Non-contingent biofeedback (placebo)

54

62

800

21

Karjalainen et al., 2003 & 2004, Finlands [72, 73]

General practice

Mini-intervention (Specific back exercises, reduce patient concerns & encourage physical activity)

44

59

 

56

  

Mini-intervention & worksite visit

44

57

 

51

  

Usual GP care

43

60

 

57

Kennedy et al., UK [74]

Primary care

Acupuncture + back book

47

46

 

24

  

Sham acupuncture + back book

45

58

 

24

Kerr et al., UK [75]

General practice

Acupuncture

43

50

86

30

  

Placebo TENS (non-functioning)

43

65

73

30

Kovacs et al., Spain [76]

Nursing home consulters

Back book education

80

66

 

233

  

Back guide education

81

63

 

199

  

Pamphlet with cardiovascular health advice

80

64

 

241

Kuukkanen et al., Finland [77]

Occupational healthcare

Intensive training: intensive progressive exercises guided at the gym + home exercises

 

62

 

29

  

Home exercise only: same as intensive, but unguided

 

48

 

29

  

Control: usual activities, no trial exercises

 

54

 

28

Leclaire et al., Canada [78]

Private physiatrist clinic

Standard care (rest, analgesics, physio) & Swedish back school

32

43

 

82

Standard care (rest, analgesics, physio)

32

41

 

86

Lindstrom et al., Sweden [79]

Occupational healthcare

Swedish back school & workplace visit + graded exercise (CBT approach)

 

24

 

51

  

Usual care: rest& analgesics & physical treatment

 

38

 

52

Linton et al., Sweden [80]

General practice + general population

Back pain pamphlet

45

71

 

70

  

Comprehensive information package

44

74

 

66

  

CBT intervention

44

70

 

107

Luijsterburg et al., Netherlands [81]

Primary care

Physical therpay + GP care

42

57

 

67

  

Usual GP care

43

40

 

68

Machado et al., Brazil [82]

Physiotherapy

Psychotherapy

45

81

356

16

  

Exercise

42

59

206

17

Mannion et al., 1999 & 2001, Finland [83, 84]

General population

Modern active individual physiotherapy: strengthening, coordination and aerobics exercises, instructions on ergonomic principles + home exercises

46

61

520

46

  

Muscle reconditioning on training devices (small groups)

45

54

504

47

  

Low impact aerobic/stretching (groups)

44

55

676

44

Maul et al., Switzerland [85]

Occupational healthcare

Back school & exercise

38

  

97

  

Back school

39

  

86

Mehling et al., USA [86]

General practice

Breath therapy

50

70

51

16

  

Physical therapy: soft tissue mobilisation, joint mobilisation and exercises

49

58

57

12

Moseley L, Australia [87]

Physiotherapy + General practice

Physiotherapy

43

64

 

29

  

Usual GP care

38

54

 

28

Niemisto et al., 2003 & 2005, Finland [88, 89]

General population

Manipulation, exercise & physician consultation

37

55

312

102

  

Physician consultation only

37

53

312

102

Nordeman et al., Sweden [90]

General practice + physical therapy dept

Early access to physio (Individualised, exercise, advice, group education)

39

63

 

32

  

Waiting list control

41

50

 

28

Paatelma et al., Finland [91]

Occupational clinic

Orthopaedic manual therapy

44

42

 

45

  

McKenzie technique

44

29

 

52

  

Advice only

44

35

 

37

Peloso et al., USA [92]

Outpatients

Tramadol & Acetamenophen combination tablets 375/325 2 PRN

58

64

 

167

  

Placebo tablets 2 PRN

58

61

 

169

Rantonen et al., Finland [93]

Occupational clinic

Physical therapy

44

35

676

43

  

Exercise

45

28

520

43

  

Back book education

44

32

728

40

Rasmussen-Barr et al., Sweden [94]

Physiotherapy

Graded exercises

37

50

468

36

  

Advice and walking

40

50

572

35

Rasmussen-Barr et al., Sweden [95]

Physiotherapy

Stabilizing training (Individual) (Cognitive + stabilisation of spinal muscles)

39

70

 

24

Manual treatment (Individual) (Other muscles exercises, no manipulation)

37

78

 

23

Rittweger et al., Germany [96]

General population

Isodynamic lumbar extension

50

44

603

30

Vibration exercise (On a machine with a vibrating platform)

54

52

754

30

Ritvanen et al., Finland [97]

General population

Traditional chiropractic bone setting

41

45

 

33

  

Physical therapy

42

43

 

28

Rossignol et al., Canada [98]

Workers compensation board

Coordination of primary healthcare program

37

33

 

54

Usual GP care

38

23

 

56

Sahin et al., Turkey [99]

Physical therapy clinics

Back school

47

75

30

75

  

Physical therapy

51

78

32

75

Soukup et al., Norway [100]

General practice + general population + referrals

Mensediesk exercise group intervention

40

53

676

34

  

Waiting list group

40

49

578

35

Staal et al., & Hlobil et al., Netherlands [101, 102]

Occupational healthcare

Graded activity (Physiotherapy + OT)

39

5

9

67

  

Usual OT care

37

8

8

67

Torstensen et al., Norway [103]

Social security offices

Medical exercise therapy (MET)

42

52

 

71

Conventional physiotherapy (CP)

43

48

 

67

Self exercise

40

51

 

70

Tsui et al., Hong Kong [104]

Physiotherapy

Electro-acupuncture & back exercise

40

76

39

14

  

Electrical heat acupuncture + back exercise

39

71

54

14

  

Back exercise only

41

62

50

14

Turner et al., USA [105]

General practice + physicians + general population

Relaxation training (group)

   

24

  

Cognitive therapy (group)

   

23

  

Cognitive therapy & Relaxation training (group)

   

25

  

Waiting list control

   

30

Unsgaard-Tondel et al., Norway [106]

Primary care

Low load exercise

41

81

312

36

  

High load sling exercise

43

64

468

36

  

General exercise

36

65

312

37

van der Roer et al., Netherlands [107]

Physiotherapy

Intensive protocol training

42

55

54

60

  

Guidelines based physiotherapy

42

48

47

54

Wand et al., UK [108]

General practice + A/E patients

Assess & Advice & Physiotherapy

34

44

 

43

  

Assess & Advice & wait

35

55

 

51

Werners et al., Germany [109]

General practice

Interferential therapy: electrotherapy, to stimulate muscles fibres

38

43

 

68

  

Motorised lumbar traction & massage

39

49

 

72

Yelland et al., Australia [110]

General practice

Glucose lignocaine injection

52

59

770

28

  

Exercise (Alternating: flexion and extension of spine and hips)

49

55

718

26

  

Saline injection

50

56

759

27

  

Normal activity

51

58

733

29

Table 3

Comparison of population characteristics of included RCTs and observational cohort studies

  

Cohort studies

RCTsa

Publication year

 

1994-2012

1993-2012

Sample size, Median (range)

 

368 (60, 2872)

128 (28, 681)b

67 (12, 340)c

Age, mean d (SD)

 

43 (4.1)

44 (7.9)

Female, mean percentage (SD)

 

52 (4.8)

53 (16.9)

Type of pain, n (%)

Acute

5 (26)

34 (20)

 

Chronic

2(11)

94 (57)

 

Mixed

12(63)

31 (19)

 

Unclear

0

6 (4)

Baseline pain intensity, mean d (SD)

 

49.6 (12.7)

49.9 (12.9)

aRCTs that provided data on pain intensity outcome. bSample size of RCT. cSample size of arm. dMean of all cohort/RCT means.

The setting of RCTs included general practice (18 RCTs), occupational health care departments (15 RCTs) and physiotherapy departments (19 RCTs). Eight trials were conducted among the general population and 10 in mixed settings. 13 RCTs (34 treatment arms) were classified by one of the authors (MA) as efficacy trials and the remaining 57 (131 treatment arms) as pragmatic trials. Eight RCTs included ‘usual care’ arms. The19 observational studies included consulters in general practice (11 studies) and other allied primary care services such as chiropractic clinics and physiotherapy departments, as well as cohorts sampled from the general population in two studies. All participants were described in the papers as receiving ‘usual’ or ‘standard care’.

The course of pain intensity scores over time

Pooled mean pain intensity scores at baseline and follow up for RCTs and observational studies are presented in Figure 3 and Table 4. They show a similar pattern of symptom change over time in both groups. This is represented by a substantial rapid early improvement of mean pain intensity within the first 13 weeks of follow-up followed by a smaller further improvement over the follow-up period to 52 weeks.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2474-15-68/MediaObjects/12891_2013_Article_2051_Fig3_HTML.jpg
Figure 3

Pooled mean pain intensity scores (95% confidence interval) for the included RCTs and observational cohort studies from baseline to 52 week follow up.

Table 4

Pooled mean pain intensity scores (95% CI) for included RCTs and observational cohort studies using random effects meta-analysis

 

Baseline

6 weeks

13 weeks

27 weeks

52 weeks

RCTs

     

Pain

48.1 (45.8, 50.5)

34.1 (31.0, 37.2)

27.8 (25.1, 30.6)

26.4 (24.3, 28.6)

28.9 (25.7, 32.0)

Arms, n

165

58

94

97

78

Sample size*

10655

3577

6109

6640

4499

Cohorts

     

Pain

47.3 (38.6, 56.0)

31.7 (18.5, 44.8)

30.7 (25.6, 35.8)

24.7 (12.9, 36.4)

26.7 (19.8, 33.6)

n

19

6

10

10

12

Sample size*

13096

6122

6848

5496

6284

*The total number of participants included in trials or cohort studies providing data for the analysis.

Regarding the size of symptom change over time, pooled SMCs (Table 5) confirm the substantial improvement in pain symptoms in both groups. These range from 0.9 to 1.2 for RCTs and from 1.0 to 1.2 for observational studies.
Table 5

Pooled estimates of SMCs (95% confidence interval) for pain intensity for included RCTs and observational cohort studies

 

Pooled SMCs (95% CI)

 

6 weeks

13 weeks

27 weeks

52 weeks

 

n

 

I 2

 

I 2

n

 

I 2

n

 

I 2

Cohorts

6

1.2 (0.7, 1.7)

99

9

1.0 (0.8, 1.3)

99

9

1.2 (0.8, 1.7)

99

11

1.1 (0.8, 1.6)

99

RCTs

60

1.0 (0.9, 1.0)

99

94

1.2 (1.1, 1.3)

100

101

1.1 (1.0, 1.2)

100

78

0.9 (0.8, 1.0)

99

p-value*

 

0.651

  

0.735

  

0.878

  

0.721

 

Efficacy RCTs

15

1.0 (0.9, 1.1)

99

13

1.2 (1.0, 1.4)

100

16

0.9 (0.7, 1.2)

100

14

0.7 (0.5, 0.8)

100

p-value**

 

0.663

  

0.549

  

0.574

  

0.104

 

Pragmatic RCTs

43

1.0 (0.9, 1.1)

99

81

1.2 (1.1, 1.4)

100

81

1.2 (1.0,1.3)

100

64

0.9 (0.8, 1.1)

100

p-value***

 

0.628

  

0.466

  

0.899

  

0.642

 

Usual Care RCT arms

   

8

1.2 (1.0, 1.3)

99

7

1.3 (1.7, 1.4)

99

7

1.0 (0.8, 1.2)

99

Number of cohort studies and RCTs treatment arms. *Meta-regression comparison between cohort studies and RCTs. efficacy RCTs, **Meta-regression comparison between cohort studies and efficacy RCTs. ***Meta-regression comparison between cohort studies and pragmatic RCTs.

There was a large between-study variation in the sizes of pain improvement from baseline within both observational studies and RCT treatment arms demonstrated by the high I 2 values (99%).

Meta-regression analysis showed no statistically significant difference in the change in pain intensity (SMC) between all RCTs and observational studies at any follow up point. There was also no statistically significant difference in the change in pain intensity when considering the two types of RCTs (pragmatic and efficacy) separately compared with observational studies. Comparing cohort studies and usual care arms of RCTs also did not show any difference in the pattern or course of LBP between these groups.

Discussion

This study directly compared the course of non-specific low back pain symptoms in observational studies with RCTs on primary care treatments for back pain. The results showed no significant difference in the size of symptom improvement and the pattern of this improvement over time.

Investigating whether any difference is concentrated between observational studies and efficacy RCTs failed to show any difference in the size of symptom improvement. This was to test the assumption that compared with pragmatic RCTs, efficacy RCTs are characterised by higher level of attention and adherence to treatment protocol as well as stricter criteria for patient selection and inclusion [111, 112]. Guidelines and tools are available to describe clinical trials as efficacy or pragmatic. The purpose of some of these tools is to inform trial design [111] while others are for the purpose of systematic reviews [112]. RCTs, however, are very rarely purely pragmatic or efficacy trials and could often be described along a continuum between these two ends and most include features of both with possible dominance of either. To satisfy the specific aims of our study related to the care and attention received in studies, the approach adopted was to describe trials that included placebo, sham or no treatment arms as efficacy trials.

A separate comparison between observational studies and the ‘usual treatment’ arms of RCTs was assumed to provide a comparison of groups receiving similar types of treatments. This comparison also failed to show any difference in the pattern or size of the clinical course of symptoms in these groups. This echoes what we have previously demonstrated of the absence of a significant difference in the pattern or size of symptom improvement in RCTs comparing usual care with active treatment arms [4].

One of the findings in this study was the large heterogeneity among cohort studies and RCT arms. Conducting meta-analysis in the presence of a large heterogeneity is potentially problematic. Using random effects model would have ameliorated this problem to an extent, but not completely. For this reason, the outcome of the meta-analysis will need to be interpreted within the specific context and aim of this study, namely to study the general trend of the clinical course of symptoms. The heterogeneity could be explained by a number of potential methodological as well as clinical characteristics. Formally studying such potential sources of heterogeneity is important and is beyond the aims of this study.

Meta-analyses comparing RCTs and observational studies have been conducted with varying aims including comparing treatment effects [111], adverse effects of treatments [112, 113] and prognostic factors [114]. However, although the clinical course of low back pain has been studied in observational studies [10, 11], we are not aware of a direct comparison with the clinical course of symptoms in RCTs. Furlan et al. [12] compared matching pairs of RCTs and non-randomised studies and included cohort studies but only those that had comparison groups. More significantly, the main aim of Furlan et al’s work was to compare RCTs with non-randomised studies regarding their methodological quality rather than to study the clinical course of symptoms.

A number of factors have been suggested to influence the course of symptoms in clinical trials, related to the participants (e.g. cultural background, health literacy) [115117], the practitioner/researcher (e.g. communication skills and experience with the use of the treatment) [115, 118] and the characteristics of the treatment (e.g. invasiveness, physical contact and psychological component) [119]. Another factor is suggested to relate to the actual enrolment in a trial. This is assumed to be related to the factual and perceived extensive care and attention provided in the trial - the ‘Hawthorne effect’, the ‘care effect’ or the unique strict adherence to the treatment protocol ‘protocol effect’. Such effects are assumed to contribute to extra improvement among participants in clinical trials compared with other studies or usual clinical practice [5].

The clinical course of back pain in observational studies might simply represent an extension of our earlier findings in RCTs [4]. This represents an average ‘general response to health care’ which dominates any individual responses to treatments. This general response overwhelms any additional effect of being in a trial, observational study or in fact seeking usual routine care. It is true that specific treatments are provided in RCTs as opposed to observational studies where no particular treatments are specified. In fact none of the observational studies included in our review included a specific treatment. However, conservative treatments for non-specific low back pain investigated in RCTs are not new but already available in clinical practice [1, 3]. This might mean that expectations of novel and big effects among those participating in RCTs of back pain are not generally high.

Alternatively, differences may exist between RCTs and observational studies in the care and attention provided. But the effect on the clinical course of symptoms lies in outcomes other than those captured by pain intensity. Outcomes that may specifically represent components of a ‘trial effect’, and their measurement was beyond the scope of this paper.

Participants of observational studies are arguably similar to patients presenting in usual clinical practice. This means that our findings suggest that RCTs participants are not different from the average patients with regard to the clinical course of LBP. This challenges the assumption that participants in clinical trials are somehow different from the average patients. Or that their symptoms run a course that is to an extent influenced by mere participation in the trial. In other words, or findings would support the generalizability of the trials’ findings to patients in usual clinical practice. The findings also throws in doubt the assumption related to the effect of mere participation in a trial, although our study did not specifically aims to study this effect.

Limitations

A large number of observational studies and RCTs on a wide range of treatments for non-specific low back pain were included to study the overall size of change in pain symptoms over time. The study, however, has a number of limitations.

For literature search, we adopted the same strategy that was adopted in a previous study conducted and published by the same group to examine the course of LBP in RCTs [4]. This was an updated access to the CENTRAL database. Although this might have limited the number of RCTs included in the study, it is unlikely that this represented a very large number that would have impacted the study outcome. Adopting the same strategy also provides the opportunity for a continuity of comparison between the two studies.

Also, as the aim of the study was to investigate the overall clinical course of LBP rather than to estimate the effectiveness of a particular treatment, an exhaustive inclusion of all trials on back pain treatments was not required. The aim was to have a large and representative pool of clinical trials that would vary sufficiently with respect to the types of treatments to achieve the objectives in this review and the CENTRAL database satisfied this aim. As a similar data base does not exist for observational cohort, a different search strategy was conducted for this group of studies.

The numbers of included RCTs and observational studies were not comparable. This might raise the concern that the outcome of the comparison is inaccurate. Although this is an arguably valid concern, the comparison with smaller subgroups of RCTs (efficacy RCTs and usual care arms) provided a more comparable numbers. The outcome of these comparisons confirmed the outcome of comparing the total groups of RCTs and cohort studies, which should help alleviate the related concerns.

The focus in our study was on pain intensity outcome using a Numerical Rating Scale (NRS) or Visual Analogue Scale (VAS). This was because of the lack of data on other outcome measures such as functional disability outcomes that would allow for a satisfactory comparison. The forced focus on one outcome measure in meta-analysis is common in systematic reviews of observational studies because of the lack of data on other outcome measures [11]. Excluding studies that did not provide data relevant to the analysis used in this study might have influenced our results. However, we have no evidence to suggest that this has led to systematic exclusion of studies with either large or small improvement in symptoms. We found in a previous review that the overall course of symptoms using functional disability outcomes (Roland Morris disability questionnaire, RMDQ and Oswestry Disability Inventory ODI) was similar to that when using pain intensity outcome [4].

Conclusion

The course of back pain symptoms in observational studies follows a pattern that is similar to that in RCTs, notably in the size of the average improvement in pain intensity over time. This suggests that, in both types of studies, a general improvement in back pain symptoms and comparable responses to nonspecific effects related to seeking and receiving care occur regardless of the study design.

Declarations

Authors’ Affiliations

(1)
Arthritis Research UK Primary Care Centre, Primary Care Sciences, Keele University, Keele

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