Furthermore, no additional significant differences in these characteristics between the 2 study groups were found.
3.2. Baseline characteristics
There were no adverse or side effects (eg, on blood pressure, vigilance, or respiratory function) seen among the participants over the observational period of 8 hours. In addition, no substantial variations of the observed values were seen.
Regarding the 4 observational scales provided, only the CNPI total score during movement shows a marginal significant difference between the 2 study groups (P = 0.05). No significant differences in other assessments could be seen before intervention, regardless of treatment group (Table 2).
All participants were recorded to have various illnesses that are most likely associated with pain, particularly degenerative joint diseases (75.6%), osteoarthritis (66.7%), fractures with surgery (51.1%), falls with bruising (40%), and osteoporosis with fractures (37.8%). There were no significant differences between the 2 study groups regarding possible pain causes. Although the total number of possible causes differed in the 2 study groups (66 vs 93), there was a small although not significant difference seen between the study groups concerning “causes of pain per participant” in favour of the placebo group (Table 3). Almost 70% of the participants were estimated by the study team to have acute pain. Acute pain was determined by considering medical records and identifying diagnoses, typically associated with acute pain, such as hip fractures.
Regarding the primary objective of this study PAINAD-G total scores (t1-t2) did not differ significantly in both study groups, neither if the observation took place at rest or during movement (P = 0.85 and 0.65, respectively) (Table 4).
To exploit the power of the “quasi cross-over design,” whereby each patient serves as his own control, a secondary analysis was conducted by both verum phases (t1-t2 and t2-t3, n = 45 patients) comparing with the placebo group at t1 to t2 (n = 24 patients). The second placebo group at t2 to t3 could not be used for analysis because of residual analgesic effects in this study group (Fig. 1). Similarly, PAINAD-G total scores did not differ significantly in both study groups (P = 0.88 [rest] and 0.41 [movement], respectively).
To exclude possible influences of moderate cognitive decline, an additional analysis was conducted after excluding participants with MMSE scores >10. Likewise, there was no significant difference seen between the study groups (rest or during movement) regarding the primary outcome (P = 0.92 and 0.77, respectively).
Similarly, no differences were seen when considering single items of the PAINAD-G (t1-t2) (such as breathing and vocalization), regardless of observation at rest or during movement (Table 5).
There were no significant difference seen between the 3 study centres regarding PAINAD-G scores in the 2 study groups (verum and placebo) at rest and during movement (P = 0.76 and 0.24 [rest] or 0.84 and 0.43 [movement], respectively) (not shown).
Figure 3 depicts the course of the PAINAD-G scores and the associated box plots (observation during movement) during the 6-hour observational period.
Similar results were seen in the other observational tools (BISAD and ALGOPLUS) except CNPI. The latter was the only tool to show a marginal significant difference in the 2 study groups at rest (Table 6).
Correlations between the observational tools differed at the 3 measurement points (t1, t2, and t3) (Table 7). For example, correlation between PAINAD-G and BISAD ranged from P = 0.609 at t1 to 0.805 at t3. Mostly, correlations increased over time, but not exclusively. Moderate to high correlations between the 4 pain assessment tools ranged from P = 0.414 to 0.805 (P = 0.01). The highest correlation was seen between PAINAD-G and BISAD, followed by PAINAD-G and CNPI.
3.5. Verification of the equivalent hypothesis
Examination of the equivalent hypothesis revealed ≤0.3 mean differences between the verum group (t1-t2) and placebo group (t2-t3), at rest and during movement (Table 8). Regardless of whether a placebo was given before the verum or not, no difference was seen in the 2 study groups. This can be interpreted as independence of the placebo effect before treatment (equivalence not statistical significance, P > 0.05).
The purpose of the current study was to confirm the construct validity of the PAINAD-G scale, and to examine whether it actually measures pain effectively within the population for which this instrument was originally designed, namely noncommunicative patients with advanced dementia.
In contrast to a preliminary study,1 which demonstrated a marked effect after pain treatment, the current study could not detect any significant differences between the 2 study groups regarding pain behaviour in people with advanced dementia, expected to be in pain. Pain treatment with an analgesic WHO level III medication compared with placebo did not lead to significantly lower behaviour scores as measured by the PAINAD-G scale.
Equally, our findings suggest that none of the other 3 observational tools used in the study were able to demonstrate a significant difference between the study groups. The marginal significant difference in the 2 study groups at rest using the CNPI is attributable to the slightly differing data distribution, as indicated by equal medians, and, thus, is negligible.
However, correlations among the 4 observational tools were mostly moderate to high, which can be interpreted as additional proof of the underlying validation concept according to the concurrent validity (comparing the score of one tool to another). Higher correlations between assessments that seem to measure similar constructs should support their validity and can be seen as additional evidence. Correlations increased from t1 to t3. Nevertheless, there was no obvious reason for that arising from the study design or data recording. A possible association between rising correlations at a later time points due to increased validity of the measurement instruments or a more sensitive assessment of pain by the staff can neither be sufficiently excluded nor be confirmed.
Several reasons can be discussed, which may explain our results:
Without exception, none of the applied observational tools showed, compared with the placebo group, sufficient sensitivity to change/responsiveness after analgesic intervention. Responsiveness represents an important prerequisite for proper treatment. Up to now, only a few studies have investigated the responsiveness of pain assessment tools used in people suffering from dementia. Husebo et al.15 found 4 studies that reported responsiveness, whereby the Mobilization-Observation-Behaviour-Intensity-Dementia (MOBID)-2 Pain Scale was the only tool that has been tested in advanced dementia and according to the latest COSMIN recommendations. In only 2 of the 4 studies, the investigator was subject to a blind procedure (MOBID and Algoplus), both with promising effects regarding responsiveness after analgesic treatment. However, Husebo et al. ended with the conclusion that the evidence regarding responsiveness of pain assessment tools is still limited.15
Regarding sensitivity to change/responsiveness, our study could demonstrate significant reduction of pain behaviour after intervention too; however, we would only have expected significant changes in the verum group.
A possible effect that may explain our observation is called the Hawthorne effect.24 This effect is a type of reaction in which study participants modify or improve their behaviour in response to their awareness of being observed.26 In general, pain management is more than giving an analgesic. Every contact to the patient during the study can be interpreted as social intervention and might influence the results such as the Hawthorne effect. In addition, nonpharmacological pain treatment should be considered. Despite reducing these influences as much as possible while establishing strict guidelines during the study, we cannot absolutely exclude certain external influences. Hence, intervention in this study does also not consist only of administering medication, but in accurate monitoring and help during movement over at least 5 minutes.
Other placebo effects that may influence our results are the natural course of the disease and the Rosenthal effect.26 All diseases have a natural course that includes fluctuations in symptomatology that may explain, at least in some parts, our results. The Rosenthal effect describe the phenomenon that positive expectations and beliefs of the study lead have an influence on the person observed.
People with advanced dementia would not be expected to remember previous care, and therefore, this effect would be expected to be very low in people with advanced dementia. Similar, it is largely unclear if positive expectations can influence patients with advanced dementia. However, we did see a strong reduction in behaviour in the placebo group too. Basler et al.,1 as well as Jordan et al.,16 were able to show effectiveness of intervention to treat pain measured using the PAINAD. They demonstrated a significant reduction in pain behaviour after analgesic treatment. But although these first PAINAD studies were neither controlled nor blind, the study presented here was double-blind, randomised, and placebo-controlled. Blinding excludes bias such as expectation by the carers.3
Sedation, as another potential influence factor for the effectiveness of observational tools, seems not to have a substantial impact on our current results. The RASS assessment demonstrated no significant deviations regarding alertness.
One important issue that has to be discussed is whether the fundamental construct regarding validity was consistent. Validation requires a well-established gold standard against which a new assessment method needs to be tested. Self-report is mainly considered as the gold standard for identifying the presence and intensity of pain.12 However, this gold standard is no longer applicable in people with advanced dementia. This is why we used a different method to prove validity in a double-blind, randomised, placebo-controlled design, assuming that sufficient analgesic treatment should lead to substantial reduction in pain behaviour and could be interpreted as strong proof for the validity of the assessment tool being used.
Because of the need for a verbal response, previous studies have been conducted with people suffering from not more than moderate cognitive impairment.21 This study focused on patients suffering from very advanced dementia (average MMSE: 5.5) and probable pain unable to verbally communicate. Thus, observational assessment tools may reach their limits in advanced dementia, although they are designed for this group.
The fact that almost 70% of the participants were estimated as suffering from acute pain-associated conditions could be interpreted as strong indication that the patients likely were in pain—an important precondition of the fundamental construct. However, our results could not demonstrate any difference between the 2 study groups.
Another aspect that might support the fundamental construct is the correlation between the different assessments tools used in the study. Pain assessment instruments that are supposed to measure pain in people with advanced dementia should demonstrate a higher correlation (=concurrent validity). Hence, moderate to high correlations, as seen in the study, may to a certain extent support the fundamental construct.
Pain is a subjective experience; thus, the gold standard in pain assessment is self-report. However, where self-report is not any longer applicable due to cognitive impairment, alternative ways to assess patient's pain must be found. One aspect in this context—also regarding the fundamental construct—is to measure pain at rest and during movement.12,15 Pain avoidance may mask pain behaviour, whereas moving detects pain signs. Indeed, our results showed consistently lower levels of behaviour at rest. This so-called floor effect is a general problem of observational tools. Therefore, results at rest are often insufficient and can only provide limited information as is the case in the current study. By contrast, movement provokes observable pain signs usually to a considerable degree. The typical differences between rest and during movement regarding pain signs can be used as further proof of the fundamental construct.
Similar effects can be seen regarding correlations between the observational tools used in the study. They were considerably lower at rest than during movement. This also underlines the effect of “movement” in detecting pain and can be used as additional proof for the fundamental construct.
PAINAD-G seems to detect particularly emotional aspects in the context of pain. Might it be possible that these emotional aspects increasingly disappear in advanced dementia? In line with other authors,6 observable behaviour seems to be demonstrated differently in more advanced dementia. Various expressions of pain in different patients, disease stages, and aetiologies of the dementia can all play a part regarding observable pain behaviour. Therefore, findings in people with earlier stages of dementia cannot easily be transferred to advanced stages.
Another question that may arise is whether the onset of the study was introduced too soon after admission. In general, behaviour can be affected by multiple internal and external factors. Pain is one important influence factor—but not the only one. Jordan et al.16 also mentioned a high proportion of false-positive results using the PAINAD, indicating the importance of seeking other potential causes of particular behaviour than pain. Perhaps, in our study, we assessed agitation or anxiety because of environmental changes rather than real pain behaviour. Because of ethical considerations, we began treatment within the first 24 hours after admission, assuming that all our participants were suffering from substantial pain that had not yet been adequately treated. Our results might have been influenced so heavily by other factors besides pain that no differences between the study groups could be demonstrated at this early stage of hospital stay.
According to Snow et al.,33 pain assessment in people with dementia must probably go beyond a unidimensional model of pain assessment. It is a complex communication process and can be affected by several influence factors. Pain recognition in people with dementia starts with a nociceptive stimulus, leading to pain sensation, followed by pain perception, followed by the exhibition of external signs of pain, followed by an external rater's observation, and finally interpretation of those external signs. Every step can be influenced by patient's factors (eg, sex, physical status, behaviour, cognitive impairment, and delirium), method factors (eg, assessment instrument), and rater factors (eg, pain knowledge/beliefs and relationship with patient).33 In the end, using a standardized tool is only one step in a complex diagnostic process.
The analgesic oxycodone might not be as effective in people with advanced dementia as in people without (or with mild to moderate) dementia. Oxycodone is generally known as effective analgesia.11 However, our knowledge regarding pharmacokinetics of analgesics in general, but also for oxycodone, in older patients is limited. This is even truer in the context of dementia and additional multimorbidity. A recent review from Husebo et al.15 about pain treatment in people with dementia concludes that there is still a weak evidence base for all analgesics in dementia, and well-powered randomized controlled trials are lacking. Nevertheless, we have to deal with the issue. Although findings are gathered from healthier and younger participants, thinking in analogy is an appropriate and agreed procedure in Geriatric Medicine—despite the weaknesses. Taking into account the pharmacokinetics of oxycodone, with first analgesic effects after 1 hour in younger people and maximum concentration 3 hours after administration, effects should also be seen after 3 hours in older people.
To date, there is no evidence if oxycodone is similarly effective in people with advanced dementia. Generally, the effectiveness of analgesics is explained by 2 different effects: the analgesic and the placebo effect, which complement each other.2 Placebo effects refer to improvements in patient's symptoms that are attributable to their participation in a therapeutic encounter, with its rituals, symbols, and interactions, generating expectancy and conditioning by the patient.26 Placebo effects can arise, eg, in the context of verbal and nonverbal communication, empathy, touch, diagnostic and therapeutic tools, and hospital environment. The effect is based on activation of specific areas of the brain, related to anticipation and reward, especially the prefrontal cortex and its connections to the rest of the brain.3 In the course of some types of dementia, the placebo effect diminishes and is finally no longer detectable in an advanced stage of the disease, especially when the frontal lobe of the brain is affected. Beside the global cognitive function, impairment of the connectivity between the prefrontal lobes and the rest of the brain seems to play a crucial role in triggering placebo mechanism.3 It can be argued that the fundamental precondition that the analgesic works as effectively in people with advanced dementia as in people without (or with mild to moderate) dementia was not present. According to the recommendations of Benedetti et al.3 who concluded that pain treatment should be adjusted to compensate for the loss of placebo effect, higher doses of oxycodone might be necessary to reach the same effect.
Because of ethical reasons, pre-existing analgesic treatment WHO level I as well as existing long-term medications were continued unchanged. However, effects of pre-existing treatments were estimated as minimal and consequently negligible, because of the strict inclusion criteria. Thus, patients with PAINAD-G scales ≥4 at the enrolment stage of the study indicate insufficient analgesic treatment and therefore were seen as eligible for the study, regardless of an existing analgesic level I. Conversely, those with lower scores, perhaps because of an analgesic level I treatment, were interpreted as sufficiently treated and consequently excluded from the study.
As we know from cognitive unimpaired patients, combinations of peripheral and central-acting analgesics are very common in pain treatment and reflect a usual therapeutic strategy. By contrast, WHO level I analgesics alone are frequently insufficient for providing pain reduction, underlying the frequent need of combination therapy.
From our point of view, we do not believe that the continuation of analgesic I level drugs has had a substantial influence on our results. Finally, study patients seemed to suffer from substantial pain, indicated by PANAD-G scores ≥4. We are convinced that the missing success of the observational tools can not only be explained by screwed distribution of WHO I analgesics for the benefit of the placebo group. However, despite this assumption, we cannot exclude with absolute certainty that the real effect of these pre-existing analgesics was underestimated and may explain at least parts of our findings.
Besides the limitations that were mentioned earlier and despite the particular attention being paid to delirium, we may have overlooked an intercurrent delirium in some of our patients and may not have reliably excluded them from the study using the CAM assessment. If so, some of our results might be explained by dementia and additional delirium, despite all accurateness.
Regardless of the high study standard, intensive training at the beginning of the study and close monitoring during the study by the principal investigator with repeated visits and additional phone contact to each study centre to control the progress of the study, to answer upcoming questions, and to clarify misunderstandings, we cannot absolutely exclude irregularities in the assessments conducted by the different study nurses, which may partially explain our results as well. However, every initially trained study nurse remained loyal to the project, so that there was no loss of qualified assessors.
Participants, eligible for the study, were unlikely to be able to communicate their pain because of cognitive reasons. Not the cognitive impairment level but the inability to explain pain was used as key criteria. This approach contained a considerable risk of including patients with less severe dementia and, as a consequence, might have had an influence on the results. But indeed, the study showed that eligible patients suffered mostly from severe dementia, indicating an MMSE score lower or equal to 10 (>80%). In addition, although the FAST score measures slightly different aspects of dementia compared with the MMSE, namely the additional attention paid to the physical dependency, the FAST demonstrates that only participants with severe or very severe cognitive impairment were selected. However, as secondary analyses suggest, after excluding those with moderate cognitive impairment (classified by the MMSE), results were similar (not significant!) regarding the primary objective.
Many patients had to be screened in the 3 study centres to find eligible noncommunicative participants with advanced dementia—showing that we examined a very special study group. Our results are gathered in special health care settings, namely acute geriatric hospitals. Simple transferability to other settings, such as nursing homes, has to be seen critically.
Finally, our findings refer exclusively to assessment instruments used in the study. A comparable study with other pain observational tools may lead to different results.
In view of these results, does it make sense to continue pain assessment with (these) observational tools in patients with advanced/severe dementia? Doubts are not something new. However, despite certain concerns over the past few years, most authors recommend using these instruments, probably due to a lack of alternatives.12 Nevertheless, our results may show that it is already highly doubtful whether (at least) these instruments are sensitive enough to detect changes after sufficient pain treatment in advanced dementia. Clinicians have to be aware that a score in these instruments does not necessarily mean that a patient is suffering from pain. There is a variety of reasons for observable behaviour. Further investigations are needed to examine whether similar findings can be seen in people living in nursing homes. Nursing home settings have the advantage that a possible confounder, such as a new environment for the participants, could be excluded in the results. Participants, who have already been living longer in this environment, should not be substantially influenced. On the other hand, these instruments increase carers' awareness of pain and improve the discussion within the therapeutic team.18 This might be the most important benefit of these standardised assessments—despite their imperfections. Observational tools can be helpful, but again, a critical appraisal of the overall situation is needed to integrate the results into the entire care process.
Conflict of interest statement
In addition to the grant (see above), A. Lukas and M. Schuler received remuneration in the course of giving individual lectures at Mundipharma GmbH and Grünenthal GmbH over the last 5 years. Neither the Robert Bosch Foundation nor Mundipharma and Grünenthal had any influence on the content of this article. The remaining authors have no conflicts of interest to disclose.
Registration number: DRKS00000525. Universal Trial Number (UTN): U1111-1116-6820.
The authors thank Paul East and Julie Humble for intensively reviewing the manuscript. They also thank Frank Naumann, Nadine Martin, Manuela Meißner, and Stephanie Thiel from the Geriatric Hospital Woltersdorf/Berlin, Michael Grass and Denise Goike from Diakoniekrankenhaus Mannheim, Geriatric department, as well as Christiane Küenzlen-Honold, Karin Rupp, and Antje Wieland from Geriatric Centre Ulm for participating in the study, screening eligible participants and conducting the assessment. The authors would especially acknowledge the invaluable advice and support of Professor Nikolaus, who unfortunately passed away too early without seeing the completion of this study.
The PAINAD-G II study was kindly supported by Mundipharma GmbH, Limburg, Germany. A. Lukas was funded by a Forschungskolleg Geriatrie grant from the Robert Bosch Foundation, Stuttgart, Germany (Project number: 32.5.1141.0039.0). The sponsors had no role in the design, methods, subject recruitment, data collection, analysis, or preparation of the manuscript.
Author contributions: A. Lukas initiated and conceptualized the study, formulated the hypothesis, designed the study, conducted the training, supervised the data collection, analysed the data, and drafted and revised the manuscript. U. Hagg-Grün had the daily responsibility for running the study and collecting data. He was also involved in planning the study, has analysed and interpreted the data, and drafted and revised the manuscript. B. Mayer designed the study, performed the randomization procedure, and was extensively involved in the statistical planning and analyses. He also drafted and revised the manuscript. T. Fischer designed the study, conducted the training, analysed the data, and drafted and revised the manuscript. M. Schuler conceptualized the study, formulated the hypothesis, designed the study, supervised the data collection, analysed the data, and drafted and revised the manuscript. All authors participated in critical revision of the article for intellectual content. All authors have read and approved the final manuscript.
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Keywords:© 2019 International Association for the Study of Pain
Pain; Dementia; Validation; PAINAD; Observational tool; Pain assessment