Challenging the Traditional Approach for the Conduct of Dentine Hypersensitivity Studies: Person-Centric Studies Connecting the Patient with Their Practitioner to Optimise the Clinical Outcome

 
Acute pain
Chronic pain
DH
Conducting pathways
Rapid
Slow
Rapid
Tissue injury
Clearly causal
Minor or absent
Clearly causal
Autonomic response
Present
Absent
Present
Biological value
High
Low
High
Mood
Anxiety
Depression, anxiety
Anxiety
Social effects
Slight
Marked
Slight
Effective treatment
Analgesics
Variable, sometimes none
Variable, sometimes none
Dysfunction
Possible
Present
Possible
Learned behaviour
No
Yes
Yes
Somatisation
No
Can be present
Can be present
Hypochondriasis
No
Can be present
Can be present
Acknowledgement from Curro (1990)
According to Holland et al. (1997), DH should therefore be evaluated either in terms of the stimulus intensity required to evoke pain (stimulus-based assessment) or as the subjective evaluation of the pain produced by a stimulus (response-based assessment); however, as has been discussed in Chap.​ 9, these measures do not necessarily take into account the impact of DH on everyday life. Traditionally, the presenting stimuli can be grouped into five main categories: mechanical, chemical, electrical, evaporative and thermal (Gillam et al. 2000). Stimulus-based methods usually involve the measurement of a pain threshold; response-based methods involve the estimation of pain severity. It is important to recognise that the stimulus being used must be both reliable and reproducible and that the procedures involved should be scientifically valid. The subjective evaluation of changes in the individual’s overall sensitivity to day-to-day experience may also be included in the assessment procedure at each visit; normally, this would be completed before the test stimuli are applied. This may be completed as a visual analogue scale (VAS) score, verbal score, labelled magnitude (LM) scales or part of a questionnaire at the end of a study although they may not necessarily take into account the impact of DH on the quality of life (QoL) of the participants (Gillam et al. 1997a, b, 2000; Heaton et al. 2013). Although subject diaries are often used in these studies, this may be primarily for compliance purposes rather than for QoL assessment per se. The number of time intervals where the participants’ pain is assessed may to some extent depend on the length of the study as well as the type of product being evaluated (professionally applied [in-office] or OTC). For example, one or two midpoint evaluations may be acceptable for a 12-week study (baseline 4, 8, 12 weeks), or for a study where an immediate desensitising effect is being evaluated, a post-application assessment after 5 min would be required.
The plethora of devices used in both clinical research and practice-based studies however would suggest that no one device was universally accepted as the ideal method for assessing DH (Gillam and Newman 1993; Gillam et al. 2000; Ide et al. 2001; Cuhna-Cruz et al. 2010). Furthermore, the stimuli used for testing the subjective response should represent real life and be hydrodynamic in nature. And if more than one stimulus is used in the assessment, the least severe stimulus should be used first, and the intervals between assessments should be sufficient to prevent any interaction. There is however limited published data on the recommended intervals between testing although a 10 min interval between tactile and thermal/evaporative stimuli has been accepted in clinical studies, the purpose of which to allow sufficient time for nerve recovery and for the patient to forget their last response (Gillam et al. 2000). Of the available devices used in the clinical studies, the cold air syringe (Gillam et al. 2000; Schiff et al. 2009, 2011) and a controlled tactile pressure probe (e.g. Yeaple probe, Xinix Research Inc, NH, Portsmouth, USA; Jay Sensitivity Sensor Probe, Global Health Research Group, New Delhi, India) (Gillam et al. 2000; Schiff et al. 2009, 2011; Hedge et al. 2013; Kakar and Kakar 2013; Kakar et al. 2013; Sowinski et al. 2013). Although these devices are often considered objective and reproducible when assessing DH, one cannot completely eliminate the occurrence of false positives that occur in particular with the Yeaple probe threshold measurements (Table 7.2). According to Curro et al. (2000), false positives are more likely to occur at the lower force levels (10–20 g. wt) and were almost twice as common at the qualifying visit than at subsequent visits. This may be the result of a possible learning effect on the part of both the subject and the assessor, and the number of these false positives may be reduced by having a pretreatment (allocation) training phase in the study design. The likely outcome of having a large number of false positives recorded for the tactile response is that proportionately this may increase the placebo response rather than the treatment response that in turn would reduce the size of the treatment effect (Curro et al. 2000). This observation may also be true for the thermal evaporative stimuli (e.g. cold air syringe). Other problems may also occur, for example, when assessing the subjective response using the various pain scales (see above), and one should not ignore the impact of the relationship between the assessor and subject or the learning curve experienced by the participant during the study that may in turn have an unintentional impact on the study results. Finally, one should consider the expectations of the individual participating in a clinical study and how they may interact over time. For example, participants with chronic conditions such as DH typically have episodic or fluctuating symptoms, and any potential change in these symptoms over time in clinical study may be one of improvement (the so-called expectancy effect) (Curro et al. 2000). Individuals participating in a clinical study may also anticipate that they will experience pain from a stimulus directed at a tooth, for example, when subjects are assessed (VAS) with the thermal/evaporative stimulus at the qualifying and subsequent visits. Initially, they may report a high pain score at the baseline, but when assessed again at a subsequent visit, they can reflect on the difference between their previous exposure to the stimulus and to the current discomfort and subsequently decide that the pain was not as bad and then indicate a lower pain score. The use of a pretreatment session overview may however help reduce these anomalies.

Table 7.2

Factors that may influence efficacy in DH studies
Factors that may influence efficacy in clinical studies
The episodic behaviour of the condition
Highly subjective nature of the pain response
Innervation
Physiology of the pulp and its changing response to stimuli
Clinical efficacy of desensitising agents may be at the lower end of the therapeutic range
Profound placebo effect reported in clinical studies
Hawthorne effect
Random variation in patient symptoms over time (regression to the mean/mode)
Small sample size
Tooth site and number
Investigator technique
Investigator/subject relationship
Choice and lack of standardisation of objective assessment
Occurrence of false positives from Yeaple probe evaluation (tactile)
Study duration
Variation of individual intake in food and drink
Seasonal weather variations
Acknowledgement modified from Addy et al. (2007)
As previously indicated, one of the problems, evaluating DH, is the highly subjective nature of the pain response despite the traditional approach to assess the pain response by the so-called objective methodology. The complete absence of pain from DH is probably the only true end-point measurement rather than attempting to quantify objective measures of tactile and thermal thresholds. However, this goal may be unrealistic for a number of reasons, and it is evident than when analysing the results from the various studies that while individuals within the test and control groups may report that they have a complete absence of pain, closer inspection of the means (and 95 % confidence intervals) clearly shows that there is still a level of unresolved pain. Therefore, a different approach in addressing the claims made on behalf of a Pharmaceutical or Consumer Health Care Company in relationship to the pain associated with DH, may therefore need to be investigated. Furthermore, both from the patient’s and clinician’s perspectives, it is important to manage the expectations of both parties as it may be unrealistic to expect the complete resolution of pain following OTC or in-office treatment. It may be more relevant and practical to consider the reduction of the impact of the treatment on the quality of life of the patient in that they are able to complete their day-to-day activities either by coping strategies or the associated pain is reduced.

Patient Selection, Study Design and Selection of Controls

Experienced investigators would probably agree that recruitment to DH clinical studies is fraught with difficulties, and this may be due in part to a number of reasons, for example, the limitation of sites that may exhibit DH is predominantly on the buccal or facial surfaces of the teeth which may be restricted due to attempts by clinicians to restore the non-carious cervical defects present in an individual’s mouth. The authors estimate that newer restorative procedures have made recruitment of potential participants into DH studies more difficult ranging from 1 in 3 some 25 years ago to approximately 1 in 8 today which may considerably increase the costs (to institutions and companies) of conducting these types of studies. A further problem may be due to the nature of the condition itself both in terms of its history (may have periods of spontaneous resolution) and the subsequent pain response on screening. The impact of this particular problem may be underestimated; generally speaking, individuals are included into DH studies on the basis of having a previous history of DH which may lead to difficulties in recruitment particularly when assessing pain scores in studies with the current exacting and inclusion/exclusion criteria. It is important however when recruiting individuals for a clinical study that the entry criteria are reasonable and realistic; otherwise, the investigator will struggle to recruit adequate numbers within the allocated time frame for completion of the study. This is particularly true when dealing with a highly subjective clinical condition such as DH. Care must therefore be taken when screening prospective participants not to recruit individuals who either report minimal or extreme discomfort since the statistical probability of measuring the pain response can only stay the same, worsen or improve, respectively. This phenomenon is called regression towards the mean or mode (Yates et al. 1998; Addy et al. 2007) and according to Jeffcoat (1993) can either magnify a product’s treatment effect if used on a severely affected population or minimise the effect when used in an under-affected population.
One of the inherent problems in conducting clinical studies is the interference of placebo and/or Hawthorne effects that may introduce bias into the study (Gillam 1997; Addy et al. 2007). This may be particularly true in pain studies such as relief of pain arising from DH, and one way to resolve this particular bias is the use of a double-blind placebo-controlled study (Jeffcoat 1993; Holland et al. 1997; ADA 1998, 2009, 2012). According to Schulz et al. (2010) the Randomized controlled trial (RCT), when appropriately designed, has been generally acknowledged as the gold standard for evaluating health care interventions. This viewpoint, however, has been recently challenged as a result of the number of ‘black box’ warnings placed on drugs by the FDA and the number of drugs subsequently removed from the market place by the Regulatory Authorities due to safety concerns (Kessler and Glasgow 2011; Silverman 2014). RCTs are now viewed as too restrictive and not representative as point-of-use by providers. RCTs conducted by highly trained specialists recruiting a ‘designer patient’ using the drug in a restrictive environment hardly yields results that would be robust and mimic use for the population at large. RCTs should therefore be reserved for early phase clinical studies when the safety profile has not been determined, when the delivery is complicated, and when the drug is directed at a compromised patient. In this type of study, all participants are allocated (random assignment) to either the test or control group, and the difference in outcome across groups will determine any significant efficacy of the test group. The design is simple and requires minimal prior knowledge of the cause of the disease in each group. This type of design, however, may result in an unequal distribution of high-risk individuals with multiple active sites, although this feature may be more of a problem in studies of less than 30 subjects. The use of stratification techniques, however, can be used to give balance across the groups. It is usual to stratify potentially confounding factors such as numbers of teeth, baseline sensitivity levels, age, gender, etc. From a practical point of view, it is generally easier to assign a treatment to each of the participants. This type of design has been recommended for clinical studies evaluating both OTC and in-office products although other types of study design have been used in DH studies such as cross-over and split-mouth (Gillam 1997). The use of a pretreatment period study design which enabled the participant(s) to be randomised into test and control groups and as such allows the participant to act at his/her own control as well as to compare that subject to the randomised control and other groups may also be utilised in DH studies (Page et al. 1995). For example, there may be advantages in having a 2–4-week pre-study evaluation period for sensitivity studies in which the participant is introduced to the pain scoring methods (visual analogue scales (VAS)) and is placed on a placebo or fluoride toothpaste. It would be anticipated at the end of such a period that (a) the participants understand what is expected of them with regard to the various assessments used when measuring the pain response, e.g., VAS, Schiff Air Sensitivity scores, LMS and (b) participants actually have ‘real sensitivity’ before being entered into the main study. One observation may be relevant here with respect to the Schiff air test as the patient’s reaction to the test is translated by the investigator thereby excluding the patient’s response. Those individuals fulfilling the entry criteria following this pretreatment period can then enter the study. One disadvantage of this type of study design, however, is that it adds to both cost and time. Other study designs that have also been reported in the literature involve the use of an adjunctive therapy (e.g. the application of a potassium-containing mouth rinse following routine toothbrushing with a fluoride toothpaste) (Gillam et al. 1996a; Yates et al.1998). This type of study, while widely utilised in antimicrobial therapy studies, has not been used routinely in DH studies, but there would be advantages in incorporating such a study design in evaluating the additional effect above what would normally be expected from using a commercially available fluoride toothpaste. DH studies may also lend themselves to an adaptive design where the knowledge of the patient population actually enrolled in the study, the variance of the study end point, event rates, and possibly the treatment effect itself available at interim may be used to change the study design or key parameters in order to improve the chances of success. Such adaptation, if appropriately implemented, has the potential to save resources; however, this implementation requires that the statistical validity of the study’s results be preserved (LaVange 2014). The US regulatory agency (FDA) has also recently issued draft guidance on adaptive designs, and the final version is in progress considering the public comments received (FDA guidance for Industry 2014).
According to Fleiss (1992), clinical studies may assess the efficacy, equivalence or superiority of a treatment and as such studies can be designed to test either products or ingredients of products. Products designed to reduce DH should therefore be tested in controlled clinical studies in which the test product is tested against (a) a negative control to establish efficacy and (b) a positive control to determine relative potency. In the absence of any negative controls with no demonstrable desensitising effects and any internationally accepted benchmark positive control, the test product may be tested against a minus-active control.
One of the problems, however, in this respect is that there is no agreed positive or negative control (the so-called gold standard) in DH studies (Holland et al. 1997). For example, several published studies have used minus-active controls that may not be representative of the final commercially available product sold over the counter (in the case of OTC products) (Gillam 1997). Furthermore, the characteristics, bio-equivalence, efficacy, etc., may be changed by addition/subtraction of different ingredients.
A further complication that continually appears to affect the interpretation of results from clinical studies of this nature is the reported placebo effect that can be as high as 40 % (Curro et al. 2000; West et al. 1997). Several investigators have also alluded to this obvious effect in their studies (Gillam 1997; Pearce et al. 1994; Chesters et al. 1992), but to what extent the placebo effect complicates the interpretation of the results of the study is difficult to predict. It should however be noted that according to Curro et al. (2000), the placebo effect observed in DH studies is not too dissimilar to those reported in other medical and dental therapeutic studies. For example, a review of 15 postoperative pain studies by Beecher (1955) quoted by Curro et al. (2000) concluded that on average symptoms were satisfactorily relieved by the placebo medication in 35 % of the patients (the placebo response range of 15–58 %). Compounding factors (Table 7.1) that may affect DH studies may also be complicated by the lack of acceptable positive and negative controls used in equivalence and superiority studies. Unlike gingivitis studies where the internationally accepted gold standard would be chlorhexidine, there does not appear to be an internationally accepted product which one could use as a positive control in such studies. Furthermore, the difficulty in using a negative control which may also exhibit a desensitising effect may also complicate the interpretation of the results and is also problematic (Gillam et al. 1996a, b; Gillam 1997; Pearce et al. 1994; Chesters et al. 1992). The use of a true placebo toothpaste, without any known desensitising ingredient, may however be problematic, and most studies would appear to use a fluoride-containing toothpaste as a negative control when evaluating a product. A final concern that may be expressed regarding these types of studies is whether the study population that are used for the studies are truly representative of those who suffer from the condition in real life, and perhaps more research should be initiated into the demographics of recruiting subjects for DH studies.
The study duration may also vary according to the purpose of the study, the nature of the agent tested, the hypothesis of the mechanism of action, the outcome measurements and their sensitivity and error. According to Gore and Altman (1982

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Nov 16, 2015 | Posted by in General Dentistry | Comments Off on Challenging the Traditional Approach for the Conduct of Dentine Hypersensitivity Studies: Person-Centric Studies Connecting the Patient with Their Practitioner to Optimise the Clinical Outcome
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