A research synthesis of therapeutic interventions for whiplash-associated disorder ( WAD ) : Part 3 – interventions for subacute WAD

1Lawson Health Research Institute; 2Department of Physical Medicine and Rehabilitation, Parkwood Hospital, St Joseph’s Health Care; 3Schulich School of Medicine and Dentistry; 4School of Physical Therapy, Faculty of Health Sciences, University of Western Ontario, London, Ontario Correspondence: Dr Robert W Teasell, Department of Physical Medicine and Rehabilitation, Parkwood Hospital, St Joseph’s Health Care, 801 Commissioners Road East, London, Ontario N6C 5J1. Telephone 519-685-4000 ext 44559, fax 519-685-4023, e-mail robert.teasell@sjhc.london.on.ca The term ‘whiplash-associated disorder’ (WAD) describes the consequences of a whiplash injury, defined as bony and soft tissue injuries of the neck caused by rapid acceleration immediately followed by rapid deceleration of the neck and head (1), almost invariably occurring as a consequence of a motor vehicle collision (MVC). With annual North American incidence rates estimated to be between 70 and 329 per 100,000 people (1,2), whiplash injuries are the most common injury following an MVC (2,3). Although it is widely held that the majority of whiplash patients recover naturally within revieW

a few months of their injury, recent research (4) suggests that recovery is often prolonged, with an estimated 50% of patients still complaining of neck pain one year after injury.Moreover, WAD is associated with significant economic costs as a result of lost work productivity, medical care, legal services and other disability-related expenses (5,6).Given the scope and cost of WAD, developing effective therapies that help to reduce pain and disability chronicity is of obvious importance.
In 1995, the Quebec Task Force (QTF) published its benchmark review (1) of the scientific literature and expert opinion on WAD.One of the primary conclusions of the report was that the majority of therapeutic interventions used in the treatment of WAD had undergone little to no scientific investigation.Accordingly, the QTF emphasized the need for more and higher quality research.More recently, Conlin et al (7,8) conducted a systematic review of the whiplash treatment literature (including studies published from 1993 to 2003) and noted that despite the QTF's recommendations, "remarkably little quality research" (8) had been published in the area of WAD management.
The objective of the present review is to update and expand previous work by evaluating the strength of evidence for therapies initiated during the acute (less than two weeks), subacute (two to 12 weeks) and chronic (longer than 12 weeks) stages of WAD.Treatments were grouped according to time from injury to assist clinicians in deciding on an appropriate treatment course.Previous reviews of the whiplash literature have focused on acute and chronic WAD, incorporating patients in the subacute phase of their injury into either one or both categories.However, there is no indication that therapies effective during the acute or chronic stages of WAD will also be effective when delivered during the subacute phase, and vice-versa.As well, most treatment takes place in the subacute phase for whiplash patients.The present article, the third in a five-part series, evaluates the evidence for interventions initiated during the subacute (two to 12 weeks) phase of WAD.

MeThoD
The following is a brief summary of the methods used for the current review.A more detailed explanation of the methodology is provided in the first article of the present series (9).A multistage screening process was conducted to identify all literature that evaluated therapeutic interventions for WAD published from January 1980 to March 2009, regardless of study design.Multiple databases were searched (including PubMed, CINAHL, EMBASE, PsycINFO, Web of Science and the Cochrane Central Register of Controlled Trials [CENTRAL]) using the following search terms: whiplash AND (therapy OR treatment OR intervention OR rehabilitation OR surgery OR neurotomy).The literature search was limited to clinical studies written in English that examined adult (18 years of age and older) human populations.A study was deemed eligible for review if it met the following criteria established a priori: • The purpose of the study was to evaluate the effects of one or more clearly defined treatment protocols for WAD (eg, 'physiotherapy' without further elaboration was not considered to be a clearly defined protocol).• At least 60% of the participants in the study sample must have experienced a whiplash injury resulting from an MVC; alternatively, the sample must have included a distinct and separately analyzed subgroup of MVC-related whiplash patients.• Evaluation of the treatment effect must have involved measurable outcomes.• Sample included at least three participants with a whiplash injury.
In total, the search procedure yielded 969 citations, 387 of which were duplicates.On screening titles and abstracts for relevance, 121 articles were considered for full review and, after applying inclusion criteria, 83 articles were selected for full review.Information abstracted from studies that met inclusion criteria was organized into tables, and studies were grouped according to the type of intervention.For the present review, only studies in which the interventions were initiated during the subacute stage (ie, between two and 12 weeks after injury) were included.However, in some cases, it was difficult to determine exactly when patients began an intervention; for example, in some studies, the only indication of time from injury was the study's exclusion criteria regarding the maximum duration of symptoms.In such cases, these maximum values were used to categorize the study, assuming that the value defined the intended treatment stage.Therefore, some of the studies categorized as investigating subacute interventions may also include a percentage of patients treated during the acute phase.
All of the included randomized controlled trials (RCTs) were evaluated for methodological quality using a standardized rating scale -the Physiotherapy Evidence Database (PEDro) scale.This evaluation tool was specifically designed for assessing physical therapy research and has been validated for the quality assessment of RCTs (10).The PEDro scale consists of 10 equally weighted yes/no questions relating to issues of methodological quality, and can be accessed at www.pedro.org.au/english/downloads/pedro-scale/.Two independent raters reviewed each article and discrepancies were resolved through consensus or, when that was not possible, by a third rater.Studies with PEDro scores of 9 to 10 were considered to be of 'excellent' methodological quality, while scores of 6 to 8 were considered to be of 'good' quality and scores of 4 to 5 were considered to be of 'fair' quality.Studies scoring below 4 were judged to be of 'poor' quality and were considered to be methodologically equivalent to non-RCTs for the purpose of formulating conclusions.These descriptive terms of quality assessment were used to simplify the interpretation of results; however, it is important to note that these terms are only intended to provide an indication of a study's rating on the PEDro scale.Non-RCTs were not assigned a PEDro score and were instead given a 'no score' designation.
Due to the limited number of studies investigating each of the specific WAD interventions, it was decided that both meta-analytical and levels-of-evidence approaches would be inappropriate.Therefore, a narrative approach was used to summarize the findings and formulate conclusions.
Because studies using a nonexperimental or uncontrolled design are generally considered to be of inferior quality, these types of studies were only used to formulate conclusions in the absence of RCTs or when the results of RCTs were conflicting.In addition, when the results of RCTs were conflicting, studies with higher PEDro scores were weighted more heavily.

ResULTs
Six RCTs and seven non-RCTs were identified that evaluated therapeutic interventions initiated during the subacute stage of WAD (ie, between two and 12 weeks after injury) and met the inclusion criteria.The median PEDro score of the RCTs was 6, with scores ranging from 4 to 8 (Table 1).The most common methodological limitation of these RCTs was a failure to blind patients and therapists, with only one study actually achieving this.Furthermore, only two of the studies conducted their analyses on an intention-to-treat basis, and only three of the six used concealed allocation.In all, the studies included in the analysis involved interventions that were in one of four different treatment categories: exercise programs, interdisciplinary interventions, manual joint manipulation and injection-based interventions.

exercise programs
Two RCTs of good quality and three non-RCTs evaluated the use of exercise programs in the treatment of subacute WAD (Table 2).The two RCTs produced somewhat conflicting results.While Bunketorp et al (11) demonstrated that a supervised exercise program was more effective over the short term than an equivalent unsupervised program, Scholten-Peeters et al (12) found that the addition of an exercise component to a program of education and advice actually impeded recovery compared with education and advice alone.However, because Bunketorp et al (11) did not include a 'no' exercise control group, it is not clear whether patients improved in response to the exercise program or simply did better when they were supervised.Furthermore, in the study by Scholten-Peeters et al (12), because the experimental group was treated by a physiotherapist and the control group was treated by a general practitioner, it was difficult to determine whether the difference could be accounted for by the added exercises or the nature of the therapeutic involvement.
The results from the three non-RCTs do not help to clarify these findings.Cassidy et al (13) reported that patients who were referred to a fitness program recovered 32% slower than patients who were not referred for any treatment.This program was an aggressive work-hardening type of exercise program and seemed to suggest that these types of formal exercise programs in the subacute phase may be detrimental; however, these results may simply indicate that patients who do not require therapy recover faster than those who do, presumably because they have less severe injuries.Similarly, both Amirfeyz et al ( 14) and Goodman and Frew (15) reported that physiotherapy programs are significantly more likely to lead to improvement when they are initiated early (within the first three months or six weeks, respectively) rather than later.Although these studies found that early therapy is better than later therapy, the results may be explained by the fact that patients with chronic WAD are less likely to improve than patients at an earlier stage.

Conclusions regarding exercise programs in subacute WAD:
While a supervised exercise program may be more effective than an unsupervised program over the short term, and earlier therapy appears to be more effective than later therapy, the use of fitness and exercise programs during the subacute stage of WAD may actually be counterproductive.In particular, an aggressive work-hardening type of approach may be detrimental at this stage.

Interdisciplinary interventions
Three studies (one RCT and two non-RCTs) were identified that investigated an interdisciplinary approach in which psychological counselling was combined with another type of therapy (Table 3).In an RCT of fair quality, Provinciali et al (16) reported that an exercise program complemented by psychological counselling was more effective in reducing pain and sick leave than an intervention consisting of passive physiotherapy modalities.While these results suggest that a more complex interdisciplinary approach is more effective than physiotherapy alone, it is not clear which component of this intervention was responsible for the observed treatment effect (ie, the psychological component, the combination of several therapies or the active rather than the passive nature of the treatment) -a problem compounded by the fact that neither the patients nor the therapists were blinded to what were very disparate interventions.
The other two studies do not help to clarify this issue.In a case series that included 75 patients, Adams et al (17) found that patients who began interdisciplinary therapy within three months of injury were significantly more likely to return to work than those who began therapy after six months; however, without a control group, this study may only demonstrate that individuals with chronic WAD are less likely to improve than individuals with subacute WAD.Suissa et al (18) conducted a population-based cohort study and found that patients who participated in an interdisciplinary program after four weeks of standard therapy experienced a significantly higher rate of insurance file closure and compensation ending one year after injury.However, the validity of time to Scholten-Peeters et al (12), 2006 Fernández-des-las-Peñas et al (22), 2004 Provinciali et al (16), 1996 Fernández-des-las-Peñas et al (23)

Conclusions regarding interdisciplinary interventions in subacute WAD:
There is some evidence that interdisciplinary interventions may be more effective in reducing pain and sick leave than passive physiotherapy modalities, although more research is needed to determine which components of such interventions are beneficial.There is also some evidence that patients who receive interdisciplinary treatment earlier are more likely to return to work, but it is uncertain whether this simply reflects natural history or is a consequence of the intervention.

Manual joint manipulation
Four studies (two RCTs of fair quality and two case series) were identified that assessed the efficacy of joint manipulation for subacute WAD patients (Table 4).Results from both of the RCTs (22,23) suggest that thoracic and cervical spinal manipulations are effective in reducing pain and improving cervical ROM.However, because both of these studies used relatively short follow-up periods (one week and one month post-treatment, respectively), it is not clear whether this intervention resulted in any long-term benefit.Furthermore, neither of these two studies were blinded in any way, which introduced a number of important biases into the evaluation of the efficacy of the intervention.Similarly, although the results of the two case series (24,25) supported chiropractic manipulation, it is difficult to interpret the significance of their findings.Specifically, Suter et al (24) failed to include several pertinent details of their study (including the length of treatment, follow-up duration and the significance of their findings), while Osterbauer et al (25) evaluated 10 patients with a wide range of time since injury (from same day to 13 months).
Conclusions regarding manual joint manipulation in subacute WAD: Although there is some evidence that joint manipulation may be of short-term benefit to patients in the subacute stage of WAD, further research using more rigorous methodology is needed before definitive conclusions can be drawn.

Injection-based interventions
One study was identified that investigated the use of botulinum toxin injections during the subacute stage of WAD (Table 5).In this RCT of good quality, Carroll (26) reported that while patients in both the active and placebo groups showed improvement in pain, disability and cervical ROM, those who received the active treatment tended to make slightly larger, albeit nonsignificant, gains at both four weeks and three months post-treatment.The authors concluded that botulinum toxin injections may have a small treatment effect but that a much larger sample size would be needed to detect a significant difference.

Conclusions regarding injection-based interventions in subacute WAD:
Based on the results of one RCT, it does not appear that botulinum toxin injections are any more effective than placebo in the treatment of subacute WAD, although further study is needed involving RCTs with larger sample sizes.

DIsCUssIon
Compared with the acute and chronic phases of WAD, there is substantially less research investigating the treatment of WAD initiated during the subacute phase, despite the fact that this is a period of time in which many treatments are initiated.Thirteen studies were identified that met inclusion criteria and evaluated interventions initiated during the subacute phase.Several conclusions were reached, although these conclusions should be viewed cautiously because they are based on the results of one or two RCTs, and methodological quality is a concern.While exercise programs appear to be effective in the treatment of acute and chronic WAD (27,28), the effectiveness of exercise programs for the treatment of subacute WAD has not been demonstrated.Moreover, there is some evidence that aggressive work-hardening programs may be detrimental during this stage of recovery.Only one RCT (12) compared exercise with another intervention, and this study did not blind patients or therapists.Further research is needed to determine the role of exercise during subacute WAD and to evaluate the relative effectiveness of various exercise regimens, particularly those that are less aggressive.There was positive, albeit weak, evidence that both interdisciplinary interventions and manual joint manipulation may provide some benefit during the subacute phase of WAD; however, given that the evidence for both of these interventions is derived from studies that were not blinded and only followed patients for a short period of time, further research is clearly needed before definitive conclusions can be drawn regarding the effectiveness of these two treatments.Based on one study, the use of botulinum toxin injections in subacute WAD is not supported, but more research is needed.
The present review was limited by several methodological concerns.First, because of the small number of studies in the whiplash literature, particularly for the treatment of subacute WAD, the inclusion criteria were quite broad.All studies were included regardless of study design as long as 60% of the sample experienced a WAD and the study included a sample of at least three participants with a whiplash injury.This may have resulted in the inclusion of some studies of lower scientific merit; however, such studies were only used to formulate conclusions in the absence of superior RCTs and these limitations were noted in the conclusions themselves as well as in the discussion.Second, there are limitations with the quality assessment process used in the current review to assess the methodological quality of RCTs.For example, it is possible that an RCT with significant between-group differences at baseline that does not blind patients, therapists or assessors could still have a PEDro score of 6 and be considered a study of good methodological quality despite these significant limitations.Again, these issues were noted in relevant conclusions and study descriptions.Nevertheless, these measures do not negate the need for readers to be 'critical consumers' of the material presented.According to Dufton et al (29), each additional month of time lag between sustaining a whiplash injury and seeking treatment is associated with a 20% increase in the odds of experiencing prolonged injury-related disability.Moreover,  although the estimates of recovery rates vary widely, a substantial proportion of WAD patients are still symptomatic during the subacute phase of the disorder (30).While several conclusions were reached in the present review (Table 6), the evidence was not strong for any of the treatments that were evaluated.Although some of the evidence regarding interventions initiated during the acute phase of WAD can be extrapolated to patients in the subacute phase, it should not be assumed that treatments that are effective during one stage will also be effective or appropriate during another.Further investigation and the identification of effective therapies for patients suffering from subacute WAD are important, not only to relieve these patients' symptoms, but also to attempt to reduce the progression to chronic pain and disability.

TAble 6
Summary of evidence for subacute whiplash-associated disorder (WAD) therapies

Intervention Conclusions
Exercise programs While a supervised exercise program may be more effective than an unsupervised program over the short term, and earlier therapy appears to be more effective than later therapy, the use of fitness and exercise programs during the subacute stage of WAD may actually be counterproductive.In particular, an aggressive work-hardening type of approach may be detrimental at this stage Interdisciplinary There is some evidence that interdisciplinary interventions may be more effective in reducing pain and sick leave than passive physiotherapy modalities, although more research is needed to determine which components of such interventions are beneficial.There is also some evidence that patients who receive interdisciplinary treatment earlier are more likely to return to work but it is uncertain whether this simply reflects natural history or is a consequence of the intervention Manual joint manipulation Although there is some evidence that joint manipulation may be of short-term benefit to patients in the subacute stage of WAD, further research using more rigorous methodology is needed before definitive conclusions can be drawn

Injection based
Based on the results of one randomized controlled trial, it does not appear that botulinum toxin injections are any more effective than placebo in the treatment of subacute WAD, although further study is needed involving randomized controlled trials with larger sample sizes

TAble 4 Summary of studies evaluating manual joint manipulation for subacute whiplash-associated disorder (WAD) Reference, year, country, score Population and methods Outcome measures Results
At 6 weeks, mean pain scores decreased from 44.1 to 10.5 (P<0.001) and total ROM increased from 234° to 297° (P<0.001).Of the 7 patients who responded by the 1-year follow-up, all but one had reported at least minimal categorical improvement from 6 weeks ns No score; PEDro Physiotherapy Evidence Database; ROM Range of motion; VAS Visual analogue scale