Table 1.
Challenges, hypotheses, and potential solutions to mitigate the intra-articular placebo effect.
| Evidence type | Outcome category | Outcome subcategory | Studies |
|---|---|---|---|
| Challenges | Impact on clinical trials (n = 10) |
Long-lasting | 334,41,51 |
| Varying placebo effect | 317,38,40 | ||
| Blinding may be unsuccessful | 1 33 | ||
| Difficult to estimate | 1 27 | ||
| Difficult to predict outcomes | 1 36 | ||
| Heterogeneity in placebo type | 1 57 | ||
| Publication bias; smaller placebo effect more likely to be published | 1 17 | ||
| Impact on active treatments (n = 8) |
Diminish/mask comparative efficacy of intra-articular therapies | 718,23,37,44,48,52,57 | |
| Difficult to market treatment options | 1 57 | ||
| Inflates strength of treatment arm | 1 29 | ||
| Other (n = 1) | Mechanism unknown | 1 27 | |
| Hypotheses | Biological (n = 8) |
Aspiration of synovial fluid | 622,39,40,46,50,56 |
| Dilution of inflammatory mediators | 218,27 | ||
| Psychological effect | 239,50 | ||
| Patient-related factors (n = 9) |
Patient education | 325,39,50 | |
| Patient expectation/beliefs a | 318,19,31 | ||
| Baseline pain a | 318,30,31 | ||
| Disease severity (high placebo effect in low Kellgren–Lawrence grade) | 1 45 | ||
| Patient knowledge of high-tech equipment | 1 9 | ||
| Patient perception of therapy as innovative | 1 9 | ||
| Treatment-related factors (n = 5) |
Route of administration a | 518,19,30,31,57 | |
| Frequency of treatment administration | 1 57 | ||
| Duration of treatment | 1 31 | ||
| Strength of active treatment | 1 30 | ||
| Confounders and trial design factors (n = 9) |
Comedications | 418,24,51,56 | |
| Clinical study setting and provider type | 418,31,47,51 | ||
| Large sample size a | 318,30,31 | ||
| Appropriate footwear | 1 25 | ||
| Assistive devices for ambulation | 1 25 | ||
| Lack of washout period | 1 53 | ||
| Occupational therapy or physiotherapy | 1 25 | ||
| Publicly funded trial | 1 31 | ||
| Rescue medication | 1 24 | ||
| Statistical methods cannot detect differences | 1 51 | ||
| Weight loss | 1 25 | ||
| Patient–physician interaction (n = 3) |
Physician confidence | 29,17 | |
| Culture | 1 17 | ||
| Personal attention factor | 1 48 | ||
| Physician optimism of treatment | 1 17 | ||
| Religion | 1 17 | ||
| Solutions | Clinical trial design and interpretation of results (n = 18) |
Awareness/weighing relevance of trials | 99,18,19,25,32,34,35,42,54 |
| Intra-articular saline not considered a placebo | 521,25,27,55,58 | ||
| Inclusion of a ‘no treatment’ arm or sham injection as control | 427,32,49,57 | ||
| Active treatment instead of placebo for control | 1 26 | ||
| Blinding needed | 1 28 | ||
| Inclusion of joint aspiration in placebo arm | 1 59 | ||
| Standardization across trials | 1 57 | ||
| Further research (n = 4) |
Use of individual patient data to provide insight into different predictors of placebo effect | 231,57 | |
| Research of mechanism of action | 1 25 | ||
| Research to identify key contextual elements that can be delivered by physicians to enhance treatment effects | 1 17 | ||
| Harnessing the placebo effect (n = 2) |
Make use of beneficial effects of placebo effect in chronic distressing conditions | 1 32 | |
| Placebo as an active comparator | 1 43 |
a
At least one of the cited studies reported the relationship between the placebo effect and the factor that was investigated to affect the placebo effect as nonsignificant.