THE QUALITY OF PLACEBOS USED IN RANDOMIZED, CONTROLLED TRIALS OF LUMBAR AND PELVIC JOINT THRUST MANIPULATION - A SYSTEMATIC REVIEW
 
   

The Quality of Placebos used in Randomized,
Controlled Trials of Lumbar and Pelvic
Joint Thrust Manipulation - A Systematic Review

This section was compiled by Frank M. Painter, D.C.
Send all comments or additions to:
  Frankp@chiro.org
 
   

FROM:   Spine J. 2017 (Mar);   17 (3):   445–456

Aaron A. Puhl, MSc, DC, Christine J Reinhart, PhD, DC,
Jon B. Doan, PhD, Howard Vernon, PhD, DC

Able Body Health Clinic,
Lethbridge, Alberta, T1J 0J9.
puhlaa@gmail.com


BACKGROUND CONTEXT:   Spinal manipulative therapy (SMT) has been attributed with substantial non-specific effects. Accurate assessment of the non-specific effects of SMT relies on high-quality studies with low risk of bias that compare to appropriate placebos.

PURPOSE:   This review aims to characterize the types and qualities of placebo control procedures used in controlled trials of manually-applied, lumbar and pelvic (LP) SMT, and to evaluate the assessment of subject blinding and expectations.

STUDY DESIGN:   This is a systematic review of randomized, placebo-controlled trials.

METHODS:   We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Index to Chiropractic Literature and relevant bibliographies. We included randomized, placebo/sham-controlled trials where the index treatment was manually applied LP-SMT. There were no restrictions on the type of condition being investigated. Two independent reviewers selected the studies, assessed study quality and extracted the data. Relevant data were the type and quality of placebo control(s) used, the assessment of blinding and expectations and the results of those assessments.

RESULTS:   Twenty-five randomized, placebo-controlled trials were included in this review. There were 18 trials that used a sham manual SMT procedure for their placebo control intervention; the most common approach was with an SMT set-up, but without the application of any thrust. One small pilot study used an unequivocally indistinguishable placebo, 2 trials used placebos that had been validated as inert a priori, and 8 trials reported on success of subject blinding. Risk of bias was high or unclear, for all included studies.

CONCLUSIONS:   Imperfect placebos are ubiquitous in clinical trials of LP-SMT and few trials have assessed for successful subject blinding or balanced expectations of treatment success between active and control group subjects. There is thus a strong potential for unmasking of control subjects, unequal non-specific effects between active and control groups, and non-inert placebos in existing trials. Future trials should consider assessing the success of subject blinding and ensuring inertness of their placebo a priori, as a minimum standard for quality.

KEYWORDS:   Blinding; Control groups; Experimental design; Lumbar manipulation; Placebos; Spinal manipulation; Systematic review



From the FULL TEXT Article:

Introduction

The randomized controlled trial (RCT) is regarded as the gold standard for testing the efficacy of clinical interventions because this methodology minimizes the risk of bias, and as such, maximizes the internal validity of a trial. [1] The RCT design allows investigators to determine if a cause-effect relationship exists by assessing whether the subjects who receive a treatment under investigation (index treatment) are improved more rapidly, more completely, or more frequently than they would have been without it, or with an alternative treatment. [2, 3] The placebo-controlled RCT is used when investigators want to account for non-specific treatment effects, or those outcomes that do not depend on the intervention itself.

To provide reliable data, a placebo-controlled RCT relies on a control intervention that can account for all of the non-specific effects of the index treatment, but carry none (or very little) of the specific therapeutic benefits. [4–6] In addition to a high-quality placebo control, reliable study outcomes are also dependent on blinding subjects in the placebo group to the fact that their intervention is not expected to have any therapeutic effect. From a methodological point of view, when a trial fails to ensure that the placebo accounts for all the non-specific effects of the index treatment, or fails to ensure the placebo is inert, or fails to confirm that their control subjects were effectively blinded, it prevents accurate risk of bias assessment and makes it difficult to make confident interpretations from the trial results. It is thus important to assess the quality of placebos used in RCTs, in order to assist clinicians and researchers in determining the validity of the existing evidence and the utility of the placebo control procedures that have been described in the literature to date.

Spinal manipulative therapy (SMT) is an intervention commonly used by chiropractors, osteopaths and physical therapists as part of the overall care of musculoskeletal conditions, particularly low back pain. [7] It has been suggested that the clinical success of SMT relies significantly on non-specific effects. [8] Previous reviews have suggested that imperfect placebos are common in clinical trials for low back pain [6], as well as in trials employing cervical SMT. [5] The objectives of this review were to characterize the types and qualities of placebo control procedures used in RCTs of lumbar and pelvic SMT (LP-SMT), and to evaluate the assessment of subject blinding and expectations. The primary goal of these objectives was to identify areas for improvement in future controlled clinical trials of LP-SMT.



Discussion

The development of placebo manipulation procedures by SMT researchers has been challenging. [4, 5, 41] Reviews of clinical trials of SMT have reported on the deficiencies in this area. [5, 6] Similarly, this review found that imperfect placebos are ubiquitous in trials of LP-SMT, a finding that suggests that existing placebo-controlled trials of LP-SMT may be subject to bias. Key concerns about the placebos used in existing trials of LP-SMT are the lack of indistinguishability and the use of placebos that may not be inert. In addition, a common problem in trial design was failure to assess the balancing of subject expectations or the success of subject blinding.

      Placebo quality

In order to account for all non-specific effects, the ideal placebo should be indistinguishable from the active treatment in every way. Vernon et al. [5] provide four key features of active SMT that should be accounted for in an indistinguishable SMT placebo: 1) subject and therapist positioning and contact; 2) movement of the subject's body; 3) mechanical thrusting applied to the subject; and 4) the sound of cavitations. When indistinguishability is not possible, a placebo should at least be structurally equivalent so as to offer similar context and involve similar degrees of therapeutic contact. [6] However, because different placebo procedures are associated with different mechanisms and produce different therapeutic outcomes [42], it is unlikely that structural equivalence alone can successfully control for all of the variables that affect placebo effects in trials.

Only the small pilot validation RCT by Kawchuk et al. [20] met all of the indistinguishability criteria outlined in Vernon et al. [5] These investigators were able to conceal each of the indistinguishability criteria from subjects by using a general anaesthetic and performing the SMT/placebo procedures with subjects in a state of controlled unconsciousness. While the approach was deemed by the investigators as successful at blinding subjects, it is an expensive and relatively high-risk approach to blinding a control group for a relatively inexpensive and safe index treatment like SMT. The criterion least accounted for in the trials reviewed was the characteristic cavitation sounds associated with SMT. Other than anaesthesia, one trial used actual thrust manipulation to cause cavitations at alternate sites. However, this approach is limited by our current lack of understanding of the precise mechanisms of SMT [43, 44], and thus limits our ability to assume inertness. Two trials used a 'drop-piece release' on a treatment table to create a 'simulated' acoustic event. The drop-piece approach could offer the advantage of minimal forces needing to be applied to the subject’s spine in order to create the 'event', yet still offering a subject the context of 'something happening'. Moreover, this approach has been used successfully as part of the development of an indistinguishable placebo for cervical SMT. [45, 46]

With regard to inertness, it has been suggested that manual SMT can be characterized by 4 elements that contribute to the desired specific effect: 1) patient positioning; 2) location of applied load; 3) peak velocity of loading; and 4) peak load developed. [16] Only two studies using sham manipulation that were included in this review offered details on a priori validation of inertness. [16, 19] These each discussed earlier work that established a threshold of forces applied during SMT, above which there is an enhanced respiratory burst of isolated polymorphonuclear neutrophils. [47, 48] In the studies we reviewed, investigators intended to minimize any specific clinical effects of SMT by training participating clinicians to deliver loads that developed forces below this threshold when delivering a sham manipulation. The strength of this approach was the use of objective outcomes that could demonstrate no changes below a threshold of forces. However, as the mechanisms of SMT are not yet fully elucidated, we cannot confidently assume that the clinical outcomes of SMT are governed by the same threshold as the blood markers used. While no other trials reviewed discussed any previous validation work, most studies used sham SMT interventions involving a manual contact with no thrust. This approach would impart less force into the subject then the aforementioned ‘established force threshold for inertness’, and leads one to assume these shams are also inert.

      Blinding and expectations assessments

This review found that only a minority of trials of LP-SMT have assessed subject blinding (32%) and subject expectations (12%). There were 6 trials that reported successful blinding of subjects in their control groups [17, 20, 34, 37, 38, 40]; however, significant limitations to their placebos suggests that a risk of bias (ROB) may still exist. Kawchuk et al.’s use of a general anaesthetic procedure offers no clinical relevance. [20] Two clinical trials used sham SMT and reported successful blinding of their control groups; however, their 'placebo control' interventions were not structurally equivalent to the active treatment intervention.

Bialosky et al. [17] were successful at blinding their subjects and equalizing expectations when using an 'enhanced placebo' compared to SMT, where the ‘enhanced placebo’ group received a sham SMT plus positive verbal reinforcement regarding the efficacy of SMT. However, the same sham SMT without the positive verbal reinforcement (standard placebo) was not successful at blinding subjects and resulted in significantly lower expectations than the active SMT procedure. Similarly, Waagen et al. [34] were successful at blinding their subjects to the nature of their group allocation, but their control group received a sham SMT plus a paraspinal muscle massage. While the methodologies used by Bialosky et al. [17] and Waagen et al. [34] have successfully balanced expectations and improved subject blinding, their approaches sacrifice structural equivalence, risking imbalances in non-specific effects between groups and likely sacrificing the inertness of their placebo interventions. The remaining 3 clinical trials of LP-SMT that reported successful blinding [37, 38, 40] all used detuned diathermy modalities as their placebo intervention. This method sacrifices the indistinguishability of the placebo, which lessens the likelihood that investigators can successfully equalize expectations and account for other elements of SMT that modulate non-specific effects.

Two trials assessed blinding and reported they were unsuccessful. [18, 35] Both used structurally equivalent sham SMT procedures, but both only accounted for 50% of the indistinguishability criteria; each used a lumbar/pelvic SMT set-up, with gentle pressure applied to the spinal target, but without the application or simulation of any thrust, and without any audible component. It seems evident that subjects could become aware of their allocation to a sham intervention when there is nothing that occurs besides an SMT-like manual contact between the subject and investigator/clinician, but no ‘event’ fulfilling patient expectations that ‘something important has just happened’. It is possible that investigators could use this type of manual contact with no thrust placebo more successfully if they also used naïve subjects. A naïve sample (IE: subjects with no previous SMT experience) is less likely to be familiar with the positions, movements and sounds that are associated with SMT and thus less likely to have pre-conceived expectations or correctly guess group allocation.

      Risk of bias

In general, placebo-controlled trials of LP-SMT included in this review suffered from high or unclear risk of bias (ROB). Scores from both the PEDro and Cochrane ROB tools were most notably impacted by failure to ensure blinding of subjects and outcome assessors. As discussed previously, only 6 trials confirmed successful subject blinding and thus there were 19 trials that suffered from high (confirmed blinding failure) or unclear (no assessment of blinding) ROB in that regard. There were also 2 trials that did not blind outcome assessors, resulting in a high ROB. None of the trials attempted to blind the therapists involved and all trials lost one point on the PEDro score for this reason. The blinding of therapists providing manual therapy interventions could be considered an impossible task, but this limitation does introduce an unclear ROB. Allocation concealment was also a common issue, with 14 trials suffering from high or unclear ROB in this regard. Finally, placebo quality was considered for the 'other sources of bias' category in the Cochrane ROB tool and this review has illustrated how the quality of placebos used in all RCTs of LP-SMT to date have resulted in another unclear ROB.

Limitations

As with any investigation, this systematic review of placebo control procedures used in RCTs of LP-SMT has some limitations. While our systematic search used the strategy recommended by the Cochrane Back Review Group, it is possible that some relevant placebo-controlled RCTs were missed. The nature of the placebo effect is not yet fully understood and there are conceptual, theoretical, and methodological issues that generate controversy regarding development of ideal placebos and how to use them. [49] Moreover, the exact mechanisms of action of SMT are not yet known. [43, 44] For these reasons, the criteria used to evaluate successful blinding and balanced non-specific effects may not represent the best way to assess placebo SMT controls, and the general concept of SMT placebo inertness employed in this review may be incomplete or flawed. The procedures and criteria used are based on our current understanding of the placebo effect and SMT and further critical examination is encouraged.



Conclusions

The most commonly used placebo intervention in controlled trials of LP-SMT is manual contact with no thrust, which has never been shown to successfully blind subjects. To date, no clinical trial of LP-SMT has used an indistinguishable and structurally equivalent placebo. The majority of trials do not report on blinding success, or subject expectations regarding treatment success. While inertness might be assumed for control procedures where no forces are imparted to the subject, a great majority of trials used placebos that had not been formally validated as inert a priori. The potential for unmasking of control subjects, unbalanced non-specific effects, and non-inert placebos makes the interpretation of the reviewed clinical trials of LP-SMT difficult. Future placebo-controlled clinical trials of LP-SMT should consider assessing the success of subject blinding and ensuring inertness of their placebo a priori as a minimum standard for quality. The successful development of an indistinguishable and structurally equivalent cervical SMT placebo has been documented and future efforts should be spent developing a similarly appropriate placebo for LP-SMT. Future clinical trials should also consider the inclusion of 'no-treatment' control groups, in order to allow for the differentiation of placebo effects from natural history effects.



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