In total, 8 studies, representing a sample size of 1861 patients with HD, age range 36 to 57 years, reported the prevalence of pain (Table 4). A random-effect meta-analysis demonstrated a sample-weighted prevalence of pain of 41.3% (95% confidence interval: 36%-46%, Fig. 2) with substantial heterogeneity (I2 = 75.3%). The prevalence ranged from 10% to 75% (Table 4). Four studies measured the prevalence of pain with the EQ-5D-3L,20,28,88,91 and the other studies used the SF-36,87 VAS,86 BPI,85 or a specific software system.47 In only 4 studies was pain severity a consideration in the reporting of pain prevalence.20,28,88,91 Furthermore, 6 studies evaluated the presence of pain in the last 24 hours,20,28,85,86,88,91 one study in the last 4 weeks,87 and in one study, it was not clear which question(s) was asked regarding the presence of pain.47
To our knowledge, this is the first systematic review and meta-analysis to provide a comprehensive overview of the prevalence of pain and the pain burden in patients with HD. The sample-weighted prevalence of pain in patients with HD was 41.3%, which is comparable with the prevalence in another neurodegenerative disease (Parkinson disease: 40%-60%).15 Besides the prevalence, this meta-analysis demonstrates that the pain burden is significantly lower than that in the general population.
The findings could, however, be influenced by a variety of confounding variables such as age, sex, drug treatment, motor functions, cognitive, emotional and behavioral disturbances, comorbidity, severity and duration of the disease, and site and types of pain (eg, nociceptive vs neuropathic and acute vs chronic pain). Of the studies included in this review, only one demonstrated a significant association between pain and age, sex, analgesic medication, motor functions, comorbid conditions, and severity of disease in HD.87 Moreover, a higher score of depression and anxiety, taking analgesic medication, and having comorbid conditions were associated with an increase in the odds of greater pain severity in HD. However, behavioral disturbances (such as irritability) in HD were not associated with an increased chance of greater pain severity.87 Other studies have demonstrated that pain could be a significant predictor for anxiety in HD,5,26 but the association between pain and depression in HD seems to be less clear.42 It is worthwhile mentioning that the prevalence of depression in HD is around 40% and twice as high compared with the general population.32,69 In Parkinson disease, however, pain and depression have repeatedly been demonstrated as being inversely correlated.29,58,73 It is likely that the same inverse correlation could be found in patients with HD. Besides the use of analgesics, the use of psychoactive drug could be an important variable influencing the pain prevalence and its burden. More specifically, neuroleptics (dopamine receptor blocking)31,79 and antidepressants30,63,65 frequently do have an analgesic effect. None of the studies in this review demonstrates the prevalence and the burden of pain in relation to the use of neuroleptics or antidepressants. It is worthwhile mentioning that only one study demonstrated no difference in laser-evoked pain between the HD group using neuroleptics and the group using no medication.86 The findings concerning the prevalence of pain and its burden in this study could also be influenced by the fact that none of the included studies controlled for the different pain types (nociceptive vs neuropathic and acute vs chronic pain). Finally, cognitive disturbances in patients with HD could be a variable influencing the findings. For instance, one-third of the patients with HD are unaware of deficits (anosognosia).27,41,82,90 Lack of awareness of impairments in memory, behavioral, executive, and motor functions has been described in HD.81 It is plausible that patients with HD may be unaware of pain. Furthermore, other cognitive disturbances, such as general slowing of thought processes, memory problems, and executive dysfunctions (problems in planning, initiating actions, and mental flexibility), have been demonstrated in HD.25 These cognitive disturbances could (negatively) interfere with the capacity to understand the questions posed in pain tools and to communicate about the history of the experienced pain. It is important to note that the cognitive disturbance can occur 15 years before diagnosable motor onset, and so, early attention to choosing the right pain tool is advisable.33,62,66,67,76,83
Despite the potential confounding variables, it is striking that the meta-analysis demonstrates a significantly lower pain burden in HD compared with that in the general population. First, this could be explained by an affected sensory-discriminative, emotional-affective, and cognitive-evaluative dimension of pain, causing an inadequate reaction to pain stimuli. As already mentioned, the striatum is involved in avoidance of pain or aversive stimuli,46,53,54 in minimizing physical harm,22 the subjective experience/salience of pain,78 motor response to pain,12 and the evaluation of painful stimuli.10 In line with these results, one animal study demonstrated that preonset HD mice exhibited less pain behavior compared with a control group.54 In addition, an impairment of painful stimuli transmission has been demonstrated in patients with HD, which may cause an impaired pain expression.71,85,86 Furthermore, atrophy of other brain areas belonging to the pain matrix such as the anterior cingulate cortex, insula, thalamus, amygdala, prefrontal cortex, and the primary and secondary somatosensory cortices, has been demonstrated in (pre) manifest patients with HD.13,24,36,43 Based on these findings, one might presume that all the dimensions of pain in patients with HD could be affected, resulting in a diminished pain burden.
The symptom burden and concerns of patients with HD vary during the different stages of the disease. In premanifest HD, most patients report problems in the social domain (eg, complicated family relationship and lack of support from environment), whereas in the manifest stage, physical themes are more frequently reported (swallowing food, driving performance, and walking).40 It is understandable that due to the severity and extensiveness of HD in the different health domains, pain could be a minor problem affecting the QoL and is, therefore, less frequently reported.21
The strengths of this systematic review are the inclusion of 5 electronic databases, applying a standard study design according to the PRISMA guidelines, and having a standardized research protocol published in Prospero. In addition, the included studies are evaluated on the basis of different risks of bias with a validated tool.
This review does, however, have some limitations. The inclusion and exclusion criteria were broad, resulting in the inclusion of a wide variety of studies. The heterogeneity is, therefore, considerable. Furthermore, the included studies have several methodological shortcomings that could influence the reliability of the findings. Regarding the prevalence of pain, any type of pain was included in the analysis, without any consideration of the severity or type of pain. Furthermore, no specific inclusion criteria were set in the review about predefining the definition of pain (eg, a cut-off score on a pain tool) or about the pain tool. Investigating the prevalence of pain was the main objective in only one study.87 Confounding variables affecting the prevalence of pain and its burden are insufficiently controlled for and the findings are, therefore, mainly based on low-quality studies. Furthermore, none of the included studies investigated the prevalence of pain, pain burden, and QoL in the same cohort. Nor did any of the studies include a control group to compare the findings. Most of the included studies were cross-sectional, and so, causality of the affected pain dimensions could not be determined. In this review, the pain burden has been compared with that in the general population; the norms could, however, be outdated.
As well as taking into account the different confounding variables that could potentially affect the prevalence and the burden of pain, future research should investigate the prevalence of pain, pain burden, and QoL in the same cohort and compare the findings with a control group or updated norms. Furthermore, it is recommended that future studies predefine the definition of pain, according the International Association for the Study of Pain (IASP).55 Reliable and validated pain tools should also be adopted. The gold standard for investigating pain is to use unidimensional patient's self-reported scales (such as the Numeric Rating Scale, VAS, and Verbal Rating/Descriptor Scale) in cognitively intact adults.38 Multidimensional pain tools (for instance, short-form McGill Pain Questionnaire and the BPI) are recommended for assessing factors such as the quality and temporal sequence of pain, the affective contribution, and the patient's belief system.44 As already mentioned, both unidimensional and multidimensional self-reported pain measurements require the capacity to understand the questions and to communicate about the pain experienced, which could be challenging in patients with HD because of cognitive disturbances.
R.A.C. Roos reports that the institution received payment from TEVA Pharmaceuticals. K.F. van der Zwaan reports that the LUMC receives grants from the European Huntington's Disease Network and Cure Hunting Initiative. The remaining authors have no conflicts of interest to declare.
The authors thank the librarian, Mrs L. Schoonmade, who assisted in the development of the search strategy. Furthermore, the authors acknowledge the statistician, Dr E. Zwet, of the Leiden University Medical Center for the contribution to the meta-analysis. In addition, the authors are grateful to neuropsychologist, Prof Dr E. Scherder, of the Free University (VU) of Amsterdam, for his valuable advice regarding this topic.
Author contributions: G.P. Sprenger conceived the review. G.P. Sprenger and K.F. van der Zwaan did the systematic search, selected papers, and extracted the data. G.P. Sprenger conducted the statistical analyses. G.P. Sprenger drafted the manuscript with critical revision from all authors. All authors reviewed the article before submission.
G.P. Sprenger received financial support from his employer, Amstelring. This is a nursing home located in Amsterdam, the Netherlands.
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