Neurodegenerative diseases are critical problems that seriously affect the social economy and patients’ quality of life. Huntington’s disease (HD) is a genetic neurodegenerative disease represented by progressive dysfunction, including motor damage and psychiatric impairments (Dale and van Duijn, 2015; Maiuri et al., 2019), and has a 50% risk of being inherited by children (McColgan and Tabrizi, 2018). The average lifespan of HD is approximately 20 years from initial symptoms to death. To date, the main studies and treatments of HD focus on motor and cognitive problems, thereby ignoring pain issues, even though some patients complain about painful indications.

Pain is an unpleasant feeling or emotional injury, often identified through oral description, questionnaires or pain evaluation (de Tommaso et al., 2016a; Buhmann et al., 2020). Pain is a troublesome problem and has been extensively studied in Alzheimer’s disease (AD), Parkinson’s disease (PD) and motor neuron diseases (MND), with prevalence of 38–75%, 68–95% and 19–85%, respectively (de Tommaso et al., 2016a). Surprisingly, few articles about pain in HD have been reported, as pain is not considered a major theme because HD patients prefer to consult about motor issues rather than sensory problems. It is well-known that pain occurs in patients with normal sensory systems once they receive direct or indirect damage (Yam et al., 2018; Tsuda, 2021). Because of neurodegeneration, HD patients show sensory dysfunctions and abnormal pain behaviors that are rarely mentioned (de Tommaso et al., 2016a). In addition, chorea and cognitive symptoms deteriorate significantly as HD progresses, and patients with mental problems, such as issues with memory, emotion, and social cognition, find it difficult to describe their painful suffering, resulting in pain issues being greatly ignored and overlooked (Snowden, 2017; Achterberg et al., 2021).

This review intends to discuss research on pain in HD, including neuropathology, prevalence, symptoms, impacting factors and possible mechanisms. Overall, more studies and explorations of pain in HD are urgently required in the future.

It is difficult to obtain an exact prevalence estimation because HD is a rare disease with a great diversity of influencing factors. Because of geographical differences, epidemiological investigations often show under- or over-assessment of the total population (Snowden, 2017). Present data indicate that the average HD prevalence is approximately 5–10/100,000 in the UK but much higher in Scotland and England (Evans et al., 2013). The highest reported in North America is 13.7/100,000 (Fisher and Hayden, 2014; McColgan and Tabrizi, 2018). HD prevalence is higher in Europe than in Asia, at approximately 0.1–0.7/100,000 (Pringsheim et al., 2012; Sipila et al., 2015; Xu and Wu, 2015). In addition, lower prevalence is observed in black species rather than white and mixed species (McColgan and Tabrizi, 2018). The prevalence difference between ethnic groups might be closely associated with different HTT genotypes (Xu and Wu, 2015; Baig et al., 2016).

Huntingtin protein (Htt, 350kD) is abundantly expressed in the central nervous system, and its mutation can trigger HD. In general, there are approximately 17–20 CAG repeats in the Htt gene on chromosome 4 (Wyant et al., 2017). Abnormal CAG length is considered to be responsible for genic mutation and HD occurrence. Due to CAG expansion, the causative gene is considered to have neuronal toxicity and cause HD disease (McColgan and Tabrizi, 2018). There is a great correlation between CGA length, morbidity and progression: longer CGA repeats are usually linked with earlier onset and a higher rate. HD cases were reported to have more than 35 repeats, and people with a CAG size of 30–35 are deemed to gain little HD (Rubinsztein et al., 1996). Nevertheless, mutant gene carriers with more than 39 CAG repeats are predicted to develop disease and exhibit symptoms within several years (Rubinsztein et al., 1996; McColgan and Tabrizi, 2018; Figure 1).

HD is a brain-derived degenerative disease with widespread and progressive brain shrinkage, structural decline and functional impairment, especially in the striatum (Reiner et al., 1988; Fjodorova et al., 2015; Reiner and Deng, 2018). Although the striatum is the initial pathological site, there is still progressive damage in different cortical layers of the HD brain, from posterior to anterior, that generates symptoms during the whole lifespan (Rosas et al., 2002; Nana et al., 2014; Jimenez-Sanchez et al., 2017). Other areas, including the hippocampus, thalamus, and cerebellum, also undergo various levels of neuronal loss on the basis of HD stages. In addition, HD patients also display other symptoms, such as weight loss, muscle defects, and cardiac damage (Arenas et al., 1998; Gilbert, 2009). In general, males and females are impacted equally, and the average age of HD onset with symptoms is approximately 20–65 years, lasting about 20 years and then developing severe intellectual disability and eventually leading to death (Snowden, 2017; Wyant et al., 2017).

CAG length can expand when passed down from parents to children, especially when delivered through males, therefore leading to a high probability of HD symptoms appearing in childhood and adolescence prior to age 21, which is identified as Juvenile Huntington’s disease (JHD)(Reyes Molon et al., 2010; Quigley, 2017). JHD develops and progresses more rapidly than adult HD because of the extensive CAG repeats with a high mutation rate and longer length compared with their parents (Quarrell et al., 2012). Motor impairments remain the main symptoms in JHD, including chorea, gait changes, speech deficits and so on (Robertson et al., 2012; Snowden, 2017). Cognitive decline and psychiatric factors are also manifested in JHD, such as learning and memory problems, anxiety, aggression and depression, speech and language impairments (Fusilli et al., 2018; Cronin et al., 2019; Lesinskiene et al., 2020). Due to a series of functional deficiencies, suicide frequently occurs in JHD.

Mutant huntingtin (mHtt) can cause severe neuronal dysfunction, especially in medium spiny neurons (MSNs) in the striatum area, which is selectively susceptible to mHtt (Bohanna et al., 2008; Sprenger et al., 2019). Both autopsy reports and magnetic resonance imaging (MRI) have revealed tremendous atrophy in the striatum and cortical white matter (Bohanna et al., 2008; Tabrizi et al., 2011; McColgan and Tabrizi, 2018). Striatal degeneration can appear in the early HD phase, sometimes 10–15 years earlier than clinical detection (Paulsen et al., 2008; Wolf et al., 2013). It is well known that the striatum is a crucial part of the “pain matrix” and deals with various pain-related processes, such as sensorial discrimination, emotional processing, and cognitive evaluation (Fenton et al., 2015; Frediani and Bussone, 2019; Faraj et al., 2021). The striatum is principally responsible for affective- or cognitive- pain dimensions (Thompson and Neugebauer, 2019; Zhou et al., 2019; Tan and Kuner, 2021), which are crucial to determining the level of suffering from uncomfortable pain and then remembering, integrating and responding appropriately (Price, 2000; Nees and Becker, 2018). In addition, unusual sensory activation of the cortex has been discovered in HD (Boecker et al., 1999). Other brain areas associated with the “pain matrix” that are responsible for multiple pain dimensions include cortex, insula, thalamus, and somatosensory cortices (Apkarian et al., 2005; Perrotta et al., 2012; Cardenas Fernandez, 2015). Relevant to previous studies, different levels of atrophy have been discovered in the “pain matrix” regions of HD patient brains. Disease progression is greatly linked with the atrophy level in the HD brain (Bohanna et al., 2008; Coppen et al., 2016, 2018; Wilson et al., 2018; Johnson and Gregory, 2019). The basal ganglia are closely related to acute and chronic pain and show some changes in pain processing. In the mid stage of HD, an obvious delay in pain progression was found at the spinal cord level compared with the general population (De Tommaso et al., 2011; Perrotta et al., 2012; de Tommaso et al., 2016b). Overall, dysfunction at any degree and in any area has the possibility of causing unmodulated, transient or sustained pain.

Pain has been studied and reported in AD, PD and other neurological disorders. However, pain in HD has rarely received attention, with only a few studies concerning pain issues. Several clinical studies have shown that pain in HD patients is greatly ignored and treated insufficiently, hence it is becoming a seriously undervalued issue (Andrich et al., 2009; de Tommaso et al., 2016a).

Pain development is closely influenced by psychological features, including depression, anxiety, apathy and irritability. Psychiatric symptoms occur frequently during all HD periods, especially the late stage, with an onset of approximately 33–76% (van Duijn et al., 2007, 2014). Some early studies reported that HD patients with depression had obviously painful symptoms; the greater the levels of anxiety and depression, the greater the severity of pain (Albin and Young, 1988; Arran et al., 2014). One study with 1474 HD gene carriers found that the pain prevalence ranged from 32% in the early period to 50% in the late period (Underwood et al., 2017), which was similar to another small sample study with a pain prevalence ranging from 11–62% (De Tommaso et al., 2011; Calvert et al., 2013). Another meta-analysis reported that the average pain prevalence in HD was about 41%, ranging from 36 to 46% (Sprenger et al., 2019). Recently, a worldwide pain-HD investigation showed that in HD mutation carriers, 34% had pain intervention, 17% underwent painful conditions, and 13% were treated with analgesics. For HD carriers without mutation, 42% had pain intervention and pain frequency was 12% in the middle period and 15% in the late period (Sprenger et al., 2021). The average prevalence of JHD in total HD cases is approximately 5–10% (Reyes Molon et al., 2010; Quigley, 2017; Lesinskiene et al., 2020).

As an essential non-motor feature, pain has been undervalued and not linked with HD for a long time until a brief report in 1988 said that two HD cases had strong sensory symptoms. One patient described an unusual sensory feeling as intermittent “bee-sting pain”, which occasionally occurred on any body part, lasting several seconds or minutes. The pain frequency and intensity became worse in the following months, and rare therapeutic approaches could reduce his pain (Albin and Young, 1988). Another HD victim also suffered an uncomfortable sensation and intermittent, sharp-tingling pain in her arms and legs. She continued to complain of severe “lancinating pain” and auditory abnormality. Both eventually committed suicide (Albin and Young, 1988). These two cases only represent a small part of the HD population, indicating the essential role of sensory problems in HD, which cannot be overlooked. Some other studies have also shown abnormal sensory-induced potentials in HD patients (Oepen et al., 1981; Ehle et al., 1984). A marathon runner experienced serious muscle pain after running, which continued for several weeks and worsened his performance (Kosinski et al., 2007). In addition, a study with 90 sample, aimed to study pain in premanifest period HD and found that approximately 49% of them used narcotics, but only 14% used narcotics in the general population (Sprenger et al., 2019). The high use of narcotics indicates that pain is indeed a severe but unrecognized symptom in HD.

Studies concentrating on pain in HD display controversial results. In a study of HD with 19 cases, 11 patients estimated a high pain score, but only 3 of them obtained analgesia treatment (McColgan and Tabrizi, 2018). Another study with 28 HD samples reported that HD patients display a slowing pain development, and only 3 mild-stage patients expressed pain responses after laser stimuli (De Tommaso et al., 2011). Cognitive deficiency includes damage to language, memory, attention and decision-making, which could result in abnormal behavior in HD patients (Singh and Agrawal, 2021). Slow pain progression might disturb sensory information integration and then lead to insufficient or inaccurate behavior in response to painful issues. An increasing number of studies have shown that HD patients experience pain but show a deficit in pain recognition. Because of motor and cognitive deficits, later-stage HD patients rarely complain of pain even with serious pain symptoms, suggesting the possibility of pain signal transfer delay or dysfunction (Albin and Young, 1988; Andrich et al., 2009; Baez et al., 2015). In addition to cognitive deficits, there are other behavioral abnormalities in HD, including emotional damage (psychosis, depression, anxiety) and empathy deficits, which cause negative pain recognition (Baez et al., 2015). The painful stimuli may interrupt sensorimotor information integration (Fil-Balkan et al., 2018; Millian-Morell et al., 2018) and lead to global deterioration of HD (De Tommaso et al., 2011; de Tommaso et al., 2016a).

There are still some other interesting findings concerning specific pain in HD. It has been reported that a series of abnormal pain events occur and change as the disease develops, including back pain, headache, limb pain, abdominal pain (Sprenger et al., 2021). In an elderly study, the relationship between gastroesophageal inflammation and HD was explored. Many HD patients have gastritis or esophagitis symptoms but without complaints, which has an obvious relationship with the duration and severity of HD (Andrich et al., 2009). The increase in abdominal pain might be highly related to the gastroesophageal disturbances in the end HD stage. Additionally, fractures seem to increase as HD progresses, which might be linked with bone density alteration (Carroll et al., 2015).

The correlation between pain and HD is interesting, involving a series of affecting factors. First, HD itself may cause pain and is rarely treated, partly due to the insufficient awareness of pain from physicians, which is supported by the incoherence between painful conditions and analgesic use (Sprenger et al., 2021). Second, neuronal loss or dysfunction could also cause a lack of self-awareness in HD, making it difficult to gather pain-related data through self-evaluation (Madariaga et al., 2021). Third, the incoherence between pain and HD might be clarified by basal ganglia disturbance, which could increase pain severity but with less or no pain behavior, probably owing to disorders in sensation, motor function and/or cognition (Borsook et al., 2010). Fourth, emotional factors are critical and closely linked with pain behavior in the HD population. A high frequency of emotional issues, such as depression and anxiety, are popular in the HD manifest periods (Sprenger et al., 2021). Finally, different pain criteria could cause different pain assessment data, which might underestimate the pain prevalence in the HD population. For example, specific dystonia is not considered a painful symptom, but it frequently appears and triggers pain in HD progression (Buhmann et al., 2020).

As HD progresses, an increasing number of affecting factors appear and are present, such as sex, illness stage, daily exercise, medicine and so on, and these factors interact with one another. Therefore, systematic studies are required to explore the detailed relationship between pain and HD in the future.

As a typical genetic disease, HD is primarily characterized by motor and psychiatric dysfunction, and rarely focuses on pain abnormalities. Here, we outline some potential mechanisms associated with pain in HD, summarized in Figure 2.

HD, as a classic neurodegenerative disorder, provides scientists with ideas for many interesting studies on social, financial and medical issues. Pain is one of the major features, a subjective and direct way to express discomfort and suffering. As HD progresses, pain can be produced directly by many elements, such as neuron loss, atrophy, muscle decline, and bone density reduction; however, subjective pain behavior might be limited or concealed owing to motor and sensory dysfunction and cognitive deficiency. Because of cognitive problems, HD patients suffer from pain but rarely complain, resulting in pain that is limited and neglected, therefore leading to underestimation and no treatments. As a result of insufficient attention, special evaluations and therapeutic guidelines are unavailable, and clinical treatments for pain are limited to analgesics and anti-inflammatory agents without a full speculation of potential mechanisms. However, in many other diseases, particularly AD and PD, specific scales and treatments are used and applied to pain issues, which are considered fully as a major symptom instead of a secondary problem.

This review notes that the major issues related to pain are medical neglect and carelessness, as attention and treatment are mostly focused on motor-related symptoms. Hence, health doctors and caregivers should pay more attention to pain problems during HD progression, especially in the later stage. The correlation between HD and pain should be further investigated. Current studies and evidence associated with pain in HD suggest a huge challenge and opportunity for scientists in the neuronal-pain field. Future studies should focus on pain-related factors and intrinsic mechanisms, pay more attention to specific scales, equipment, treatments and identify effective therapeutic methods for HD patients undergoing pain conditions.

GC and JP designed and drafted the manuscript. All authors contributed to the manuscript revision and approved the final version.