Pain in Tourette Syndrome: A Comprehensive Review

Abstract

Objectives:

Recent survey data suggest that a high proportion of patients with Tourette syndrome (TS) experience pain, yet pain features in TS have not been previously investigated in a systematic manner. This article reviews the current understanding and impact of pain in TS as well as identifies possible areas for emphasis for future research on pain in TS.

Methods:

Using a comprehensive search strategy in two relevant research databases (PubMed and Scopus), we searched for relevant peer-reviewed, primary research articles, and review articles. Search terms used were Tourette syndrome, tic disorder, pain, pain management, sensory, and sensory gating.

Results:

A total of 116 pertinent articles were identified. Pain is reported by 47%–60% of individuals with TS and may relate to different aspects of tic phenomenology or other causes. Pain is more prevalent among TS patients than in the general population and negatively impacts quality of life. To standardize future research efforts, we propose the following classification: tic-related immediate pain, tic-related delayed injury/pain, suppression-related pain, premonitory urge-related pain, and associated primary pain syndromes. Altered sensory gating and interoceptive processing abnormalities are possible mechanisms contributing to pain in TS but warrant further study. Despite pain prevalence, most TS clinical rating scales and outcome measures used in therapeutic studies do not incorporate sufficient information regarding pain. Therapies known to improve pain in non-TS conditions that are also reported to improve tics have not been investigated for their effects on pain among TS patients.

Conclusion:

TS can be associated with a chronic pain syndrome that negatively affects quality of life. Future research using a systematic framework is needed to better understand pain cause(s) and prevalence, develop appropriate assessment methods, establish outcome measures, and understand mechanisms of pain in TS. Such investigations are likely to lead to therapeutic options for this troublesome symptom.

Introduction

Tourette syndrome (TS) is a neurodevelopmental condition characterized by motor and vocal tics (La Tourette, 1885). Tics vary widely between individuals in type, frequency, severity, and complexity (Johnson et al., 2023). They can be involuntary or semivoluntary, and can be preceded by a sensory phenomenon called a premonitory urge (Jankovic, 1997). Persons with TS may be able to partially or completely suppress a tic, although this varies across individuals and may be uncomfortable for a patient (Himle et al., 2008; Taylor et al., 2022). The premonitory urge may be relieved transiently after performing a tic (Kwak et al., 2003a). Tics may be classified as simple or complex (Jankovic, 2001). Simple motor tics are brief, repetitive, and involve one muscle group such as jerking of the head, shoulders, and torso, facial grimacing, and eye blinking (Jankovic, 2001). Complex motor tics involve more coordinated or sequenced movements involving multiple muscle groups such as throwing, running, jumping, or kicking (Jankovic, 2001). Simple vocal tics can include noises such as throat clearing, sniffing, humming, grunting, or squealing, while complex vocalizations include calling out a word or phrase that is linguistically meaningful (Jankovic, 2001). Tics in TS most commonly begin in individuals aged 3–8 years (Leckman et al., 1998). Tics may wax and wane over time, typically peaking in severity around age 10 (Leckman et al., 1998). The majority of patients with TS experience psychiatric comorbidities such as attention-deficit/hyperactivity disorder (ADHD) or obsessive compulsive disorder (OCD) (Kumar et al., 2016). In addition to these core features, recent survey data suggest a high prevalence of pain experienced by patients with TS (Anonymous 2022). In the 2022 Tourette Association of America Impact Survey, 72% of children and 97% of adults reported experiencing pain, with 61% of children and 62% of adults reporting feeling pain sometimes, often, or always (Anonymous 2022). In addition, 35% of adults reported needing a medical intervention, including surgery, for an “overuse injury” (Anonymous 2022).

The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” (Raja et al, 2020). The IASP makes the following notes on pain: (1) pain is a personal experience influenced by biological, psychological, and social factors; (2) pain is separate than nociception and cannot be inferred solely from activity in sensory neurons; (3) a person’s report of the experience of pain should be respected; (4) pain can serve an adaptive role but can have an adverse effect on functioning and well-being; and (5) inability to communicate does not negate the possibility that a person or nonhuman animal is experiencing pain (Raja et al, 2020). Chronic pain is defined as pain that persists or recurs for more than 3 months (Treede et al, 2019). In a chronic pain syndrome, pain can be the sole or leading complaint, requiring special treatment and care (Treede et al, 2019). In this scheme, proposed for the International Classification of Diseases developed by the World Health Organization, chronic primary pain is when the pain may be conceived of as a disease in its own right (examples include fibromyalgia and complex regional pain syndrome), while chronic secondary pain is that related to an underlying disease (e.g., chronic cancer-related pain, chronic neuropathic pain, chronic secondary visceral pain, chronic posttraumatic and postsurgical pain, chronic secondary headache and orofacial pain, and chronic secondary musculoskeletal pain) (Treede et al, 2019). Guidelines from the National Institute for Health and Care Excellence further delineate that in chronic primary pain, no underlying condition adequately accounts for the pain or its impact, and that in chronic secondary pain, there is an identifiable underlying condition that adequately accounts for the pain or its impact (Anonymous, 2021). In addition, both may coexist and flare- ups (a sudden, temporary worsening of symptoms, including more intense pain on a day-to-day basis, or changes in fatigue, stiffness function, or disease activity) are recognized (Anonymous, 2021).

Pain in TS could potentially be driven by multiple core features, including the physical nature of the tics themselves, their repetitive nature, the uncomfortable premonitory urges, or other as of yet unexplored associations. The following review is motivated by the frequent occurrence of pain in TS and its reported impact on quality of life (QoL) for persons with TS. The goal of the review is to survey our current understanding of the prevalence, causes, and mechanisms of pain in TS and how well the complexities of reporting and measuring pain phenomenon are currently integrated into clinical rating scales and outcome measures in treatment studies. We seek to identify areas where pain in TS can be further investigated or better integrated into future research efforts to help improve pain outcomes for patients.

Methods

The following parameters were used for a PubMed search yielding 560 articles: (“Tourette syndrome” OR “Tourette’s syndrome” OR “tic disorder*” OR “Tic Disorders”[Mesh]) AND (pain OR “pain management” OR headache OR “back pain” OR “neck pain” OR “Cervical myelopathy” OR “brain injury*” OR sensory OR “sensory gating” OR “sensorimotor gating” OR hyperalgesia OR “Sensory Thresholds”[Mesh] OR “Somatosensory Disorders”[Mesh] OR “Sensory Gating”[Mesh] OR “Pain”[Mesh] OR “Pain Management”[Mesh]). The following parameters were used for a Scopus search resulting in 1037 articles: (“Tourette syndrome” OR “Tourette’s syndrome” OR “tic disorder*” W/3 [pain OR “pain management” OR headache OR “back pain” OR “neck pain” OR “Cervical myelopathy” OR “brain injury*” OR sensory OR “sensory gating” OR “sensorimotor gating” OR hyperalgesia]). These searches were conducted in July 2023 and the resultant articles were screened and included in the review based on their relevance to prevalence of pain in TS, causes of pain in TS, mechanisms of altered pain perception in TS, or the measurement of pain in TS (e.g., clinical rating scales or outcome measures in studies of TS therapeutics). Supplemental searches for articles addressing the definitions of pain, TS clinical scales, studies of TS therapeutics, premonitory urge, and mechanisms of altered perception in different conditions associated with TS and pain (interoception and sensory gating) were also completed—in total 116 articles were included in the review. Information from these articles was organized according to their relevance to the following subjects: prevalence of pain in TS, causes of pain in TS, mechanisms of altered pain perception in TS, and measurement of pain in TS in either clinical rating scales or outcome measures in studies of TS therapeutics. Each of these topics is reviewed below and opportunities for areas of future research on pain in TS are explored.

Results

Among the articles reviewed, n = 10 provided background on TS or the definition of pain, of which eight were review articles, one was original research, and one was an observational study; N = 25 directly addressed the prevalence and different types of pain in TS, of which eight were survey studies, one was a review article, one was a guideline article, five were observational studies, one was original research, and nine were case studies; N = 39 directly addressed mechanisms of pain in TS, of which 12 were review articles, 24 were original research, 1 was an observational study, 1 was a survey study, and 1 was a case study; and N = 42 directly addressed measurement of pain in TS in either clinical rating scales or outcome measures in studies of TS therapeutics, of which 13 were review articles, 9 were original research articles, 9 were observational studies, and 11 were clinical trials.

Prevalence and impact of pain in TS

A study of health-related QoL assessed the EuroQol-5 Dimension (EQ-5D) in a German population of 200 adult patients with moderate severity of TS based on the Shapiro Tourette Syndrome Severity Scale (STSSS), and found that the domains most affected in this population were anxiety/depression (57.1%) followed by pain/discomfort (47.5%) (Müller-Vahl et al, 2010; Shapiro et al, 1988). The odds ratio for patients reporting some or extreme problems with pain/discomfort on the EQ-5D compared with the general population was 1.7 in this TS study population (Müller-Vahl et al, 2010).

In a dedicated investigation into pain in TS, children and their respective parents were interviewed and responses between the patients and their parents were compared (Małek, 2022). The survey used the Yale Global Tic Severity Scale (YGTSS), the PedsQL Pediatric Pain Questionnaire (PPQ), and the Pediatric Pain Coping Inventory (PPCI) to obtain information regarding tics and information regarding pain severity, location, and coping strategies (Małek, 2022). The children in the survey ranged from ages 6 to 18 with an average age of 12 years (Małek, 2022). A total of 60% of children reported pain in the past or present, while 72% of parents reported pain in their children with TS (Małek, 2022).

An online survey of multiple-choice and open-ended questions addressing tic-related pain and pain coping strategies was circulated via international TS patient associations, reaching patients from 18 countries (Taylor et al, 2022). A total of 181 participants aged 16–71 reported on causes of tic-related pain—97.8% experienced pain from the physical effort of motor tics (muscular/joint pain or cramping), 77.9% reported pain arising from repetitive tics (tendonitis, repetitive stress injury), 72.4% reported pain from injury due to tics, 66.3% reported pain from self-injurious tics (e.g., striking another object), 66.3% reported pain from the physical effort of vocal tics (e.g., sore throat, sore nose), 59.7% reported pain from physically suppressing tics, and 25.4% reported pain from premonitory urge (Taylor et al, 2022).

A total of 64.6% of these respondents answered “yes” when asked if they had sought professional help for their tic-related pains—most commonly they sought help from nonspecialist doctors (51.3%), physiotherapists (35.9%), neurologists (34.2%), psychologists (24.8%), or psychiatrists (20.5%) (Taylor et al, 2022). These patients were asked to rate the impact of tic-associated pain on different domains of their life; the most impacted domains included mood, sleep, and enjoyment of life (Taylor et al, 2022). TOURETTES ACTION, a U.K.-based support and research charity for people with TS, compiled survey responses from 345 patients with TS and found 87% of respondents stated that physical discomfort from tics affected their daily living from a “moderate amount” to a “great deal” (Anderson et al, 2019).

These reports indicate that the prevalence of pain in TS may relate to different aspects of tic phenomenology. In the next section, we review the types of pain experienced by patients with TS and propose a classification scheme of pain causes to help standardize the way pain is queried and quantified in studies of pain in TS patients.

Causes of pain

Previous work has attempted to characterize the different causes of pain reported by patients with TS. Riley and Lang used observations from a case series to organize pain into the following types: exertio nal pain caused by tics, traumatic pain caused by tics, pain caused by suppression of tics, and pain relieved by tics (Riley and Lang, 1989). However, studies investigating how TS patients describe pain do not always include information about the causes to which patients attribute their pain. For example, a retrospective analysis of pain descriptions found that it was most often described as musculoskeletal but that it could also be neuropathic (Lavenstein et al, 2016). The most common locations of pain included ocular, cervical, shoulder, back, abdominal, and joint pain and some also reported carpal tunnel pain (Lavenstein et al, 2016). Pain was most commonly associated with voluntary movement or in an attempt to suppress the tic (Lavenstein et al, 2016). A survey of children and their parents found common locations of pain to be cervical, throat, shoulder, ocular, and joint, although most children reported pain in more than one part of their body (Małek, 2022). The most common descriptors of pain from children included sharp (84%), stinging (75%), burning (63%), pressure (54%), exhausting (42%), stabbing (29%), and tingling (17%) (Małek, 2022). The authors found that tic severity correlated with intensity of pain and proposed that pain may be due to different characteristics of tics such as severity or frequency (Małek, 2022). However, for each of these specific locations and descriptors of pain, the authors did not ask patients to attribute the pain to a specific aspect of the tic.

Building from the schema described by Riley and Lang (Riley and Lang, 1989) and integrating responses from Taylor et al. (Taylor et al, 2022), we propose organizing different causes of pain in TS into the following categories: (1) tic-related immediate pain; (2) tic-related delayed injury/pain; (3) suppression-related pain; (4) premonitory urge-related pain; and (5) associated primary chronic pain syndromes (Table 1). An important aspect of history-taking to consider is that although some symptoms do qualify as “an unpleasant sensory and emotional experience,” patients may refer to them as “discomfort” or use other similar terms (see Müller-Vahl et al, 2010), rather than describing them as painful. Consistent use of an explicit categorization scheme may help to systematically elicit more precise and accurate information when investigating pain in TS. Examples of each category are explored below.

Table 1.

Proposed Classification of the Causes of Pain in Tourette Syndrome

Type of pain	Examples
Tic-related immediate	(A) Exertion of tic (i) Musculoskeletal/joint pain (ii) Neuropathic pain (due to compression of a nerve) (B) Trauma from tic (i) Pain in a body part struck by a moving limb (ii) Pain in a moving body part striking something nearby (iii) Pain from compulsive touching of hot or sharp objects (iv) Self-injurious tics (including biting) (v) Traumatic brain injury (vi) Neuropathic pain (due to immediate trauma to peripheral nerve/nerve root) (vii) Fracture (viii) Arterial dissection
Tic-related delayed injury/pain	Cervical myelopathy Neuropathic pain (due to spinal cord, radicular or peripheral nerve compression from repetitive tics) Repetitive stress injury (i.e., tendonitis) Retinal detachment
Suppression-related	Intentionally inducing pain to suppress tics Pain associated with attempting to suppress movement
Premonitory urge-related	Pain/discomfort associated with urges
Associated pain syndromes	Headache Migraine

Tic-related immediate pain

Pain may follow as an immediate consequence of a motor or vocal tic. In the case series by Riley and Lang, examples of pain caused by actual tic exertion include musculoskeletal or joint pain after excessive contraction or neuropathic pain due to radicular or peripheral nerve compression (Riley and Lang, 1989). Alternately, immediate pain could be associated with trauma following a tic, such as pain in a body part struck by a tic, pain in a body part striking a nearby object after a tic, self-injurious tics such as biting, and pain from compulsively touching hot or dangerous objects (Riley and Lang, 1989). For some patients, tics may even seem to require pain as a part of the tic to satisfy the urge and reduce tic frequency (Riley and Lang, 1989). For example, one patient would deliberately induce pain by biting the lips, inside of his cheeks, and tongue to reduce the frequency of his orolingual tics although this may be better categorized as tic-suppression-related pain (Riley and Lang, 1989). Another example of tic-related immediate pain is pain due to a traumatic injury following a tic. Although the connection between such injuries, tics, and comorbidities such as ADHD and OCD is not completely understood, two retrospective Taiwanese cohort studies using reimbursement claims found that children with TS had a higher risk of fractures (Lu et al, 2017) as well as traumatic brain injury (TBI) (Chen et al, 2019) compared with controls without TS. Neither of these studies specifically relates fractures or TBI to tic activity or severity, or assesses the degree of pain associated with them. However, they provide evidence that patients with TS are at increased risk of potentially painful injuries compared with those without TS.

Additional examples of painful injuries sustained immediately as a consequence of a tic exist. Margo et al. report on one patient with TS who made a jerking movement forward during an indirect ophthalmoscopic examination and sustained a conjunctival laceration, conjunctival hemorrhage, and corneal abrasion, while another jerked forward during a tonometry ophthalmic evaluation and sustained a corneal abrasion (Margo, 2002). Another TS patient experienced a stroke thought to be secondary to vertebral artery dissection, which the authors felt was most likely due to trauma from violent neck tics (Lehman et al, 2011). Additional vascular and cervical cord complications have been described associated with violent motor tics (Patterson et al, 2016). Based on the Taylor et al. survey, pain from the physical effort of motor tics (muscular/joint pain or cramping) and vocal tics (e.g., sore throat, sore nose) would fall into the category of tic-related immediate pain from execution of a tic(s), while pain from self-injurious tics (e.g., striking another object) would fall under the category of tic-related immediate pain from trauma (Taylor et al, 2022) (Table 1). The reported tics in the TOURETTES ACTION survey respo nses include another example of tic-related immediate pain in a patient with abdominal tics causing nausea and heartburn (Anderson et al, 2019). Other examples could include head banging tics, head/face punching, body punching/slapping, whiplash tics, and jaw-clenching tics (Baizabal-Carvallo et al, 2022).

Tic-related delayed injury/pain

Tics also can lead to increased risk of injury from accumulated exposure to tics and delayed tic-related pain/injury. Repetitive tics may produce painful conditions such as tendonitis or repetitive stress injuries (Taylor et al, 2022). Other examples may include repetitive tongue or mouth tics causing sores around the mouth, recurrent head and neck flicking tics resulting in whiplash, or eye rubbing tics leading to eye damage and loss of sight (Anderson et al, 2019). These types of injuries may be likely when tics have a compulsive quality, for example, needing to perform the tic a certain number of times, or until a “just right” feeling is achieved, despite other painful consequences of the tics.

There are also case reports of TS patients with severe motor tics eventually developing secondary injuries that can lead to chronic secondary pain due to accumulation of repeated movements or movement patterns. For example, Krauss et al. described two patients in whom repetitive motor tics involving the neck led to subsequent compressive myelopathy (Krauss and Jankovic, 1996). One of the patients developed local musculoskeletal neck pain in addition to neuropathic pain described as a pins and needles sensation throughout his entire body and numbness in his hands (Krauss and Jankovic, 1996). He was found to have herniated discs at C3-4, C4-5, C5-6, and C7 with secondary cervical stenosis and was treated with botulinum toxin injections with stabilization of his spinal cord symptoms (Krauss and Jankovic, 1996). The other had retrospondylosis from C3 to C5 and a Klippel-Feil malformation with fusion of the bodies of C2 and C3 and partial fusion of C5 and C6 (Krauss and Jankovic, 1996). He underwent two cervical decompressive surgeries, but still had eventual progression of his spinal cord symptoms (Krauss and Jankovic, 1996). Due to the patients developing their cervical myelopathy at the young ages of 21 and 23 and the temporal relation of their cervical disease in relation to their severe neck tics, their cervical disease was thought to be causally related to their TS (Krauss and Jankovic, 1996).

Similarly, Kim et al. reported a patient with TS who developed cervical myelopathy after hyperflexion–hyperextension motor neck tics (Kim et al, 2019). He was treated with botulinum toxin initially but eventually required cervical laminoplasty at C3-4-5-6 and posterior fusion at C2-3-4-5-6-7 which improved his symptoms (Kim et al, 2019). Lin et al. reported a case where a patient with head hyperextension tics developed a herniated intervertebral disk causing sensory symptoms (Lin et al, 2007). This patient was managed conservatively with no surgical intervention and medications to control tics due to family preference, and did not have progression of his symptoms (Lin et al, 2007). Huasen et al. report a case of a patient with TS with violent cervical tics leading to marked multilevel cervical degenerative changes at C4-5, C5-6, and C6-7, with canal narrowing and central high T2 cord signal abnormality between C4 and C7 (Huasen et al, 2014). The patient was not a candidate for cervical surgery due to her cervical tics, and botulinum toxin injections were only minimally helpful (Huasen et al, 2014). The patient underwent urgent deep brain stimulation (DBS) implantation to the bilateral anteromedial globus pallidus internus and motor tics rapidly and markedly improved as stimulator settings were increased and her cervical myelopathy symptoms stabilized (Huasen et al, 2014).

Lim et al. reported a case of a 25-year-old patient with a diagnosis of TS for 18 years with motor tics, including excessive blinking, blepharospasm, and jabbing or punching himself in the periorbital area, who developed visual symptoms and was discovered to have bilateral retinal detachment (Lim et al, 2004). As he had no risk factors for retinal detachment, this injury was thought to have been the result of repeated, self-induced trauma to the eyes (Lim et al, 2004). This type of tic can be referred to as a self-injurious behavior, a phenomenon that has been described as part of the phenomenology of TS and which Baizabal-Carvallo et al. define as a deliberate, repetitive, persistent infliction of self-harm not associated with suicidal ideation (Baizabal-Carvallo et al, 2022). Baizabal-Carvallo et al. further categorized self-injurious behavior into the following categories: tics or compulsions causing self-directed damage (such as self-punching or self-damaging with an object), tics or compulsions causing outward-directed damage (such as hitting an immobile object), or motor or phonic tics causing documented damage to a body part (such as phonic tics causing vocal cord damage) (Baizabal-Carvallo et al, 2022). It should be noted that the self-injurious behaviors in this report are directly related to physical tics or compulsive behaviors. To distinguish them from other forms of self-injurious behaviors that may be encountered in psychiatry, such as cutting behavior unrelated to tics, these manifestations in TS may be better referred to as “self-injurious tic behaviors.” In their cohort of 201 patients with TS, Baizabal-Carvallo et al. found that 16.9% of the patients demonstrated self-injurious tic or compulsive behaviors and these patients had a higher association of being treated with DBS than patients without such behaviors (Baizabal-Carvallo et al, 2022). Cheung et al. performed a retrospective chart review of 333 TS patients at an academic tertiary referral center and found that 5% of patients met the criteria for malignant TS, defined as TS-related symptoms severe enough to cause two or more emergency room visits or one or more hospitalizations (Cheung et al, 2007). Those with malignant TS were significantly more likely to demonstrate self-injurious behavior than patients not meeting this designation—underlining the clinical impact that these tic-related injuries can have for TS patients (Cheung et al, 2007).

Suppression-related pain

In terms of suppression-related pain, one patient from the Riley and Lang case series reported pain from the effort of trying to stay still while another reported pain associated with attempting to suppress an eye closure tic (Riley and Lang, 1989). It is possible that this type of experience may be referred to as “discomfort” by patients rather than as “pain”. As previously mentioned in the Tic-Related Immediate Pain section, another patient in the case series reported that experiencing pain in a certain body part would reduce the tendency of that body part to perform tics and so he would intentionally induce pain at times to suppress and gain a respite from his tics (e.g., biting his lips to reduce orolingual tics) (Riley and Lang, 1989). To our knowledge, no other examples of this cause of pain have been reported in the literature.

Premonitory urge-related pain

Premonitory urges preceding tics can also be uncomfortable or painful (Openneer et al, 2020). These urges are sensations that may be described with terms such as an “itch” or “pressure” in a body part or a “feeling” that something is “not right” (Openneer et al, 2020). Surveys indicate that 82% of individuals with tic disorders experience urges, with 57% considering premonitory urges more bothersome than the tics themselves (Cohen and Leckman, 1992). Ramsey et al. also defined a related entity known as urge intolerance—difficulty tolerating premonitory urges (Ramsey et al, 2022). Ramsey et al. studied 80 adult patients with an average age of 23 with TS and operationalized urge intolerance as a latent variable inferred via modeling from subject scores on the self-reported Premonitory Urge for Tics Scale (PUTS) and Distress Tolerance Scale (DTS) (Ramsey et al, 2022). The PUTS inquires about and rates aspects of urge frequency and severity, while the DTS inquires about and rates an individual’s ability to tolerate distress (Ramsey et al, 2022). Urge intolerance was constructed in a bifactor model where greater PUTS scores and higher DTS scores would lead to greater levels of urge intolerance—Ramsey et al. found in this patient sample that urge intolerance predicted tic severity and impairment (Ramsey et al, 2022). Although pain is not an explicit component of the urge, given the uncomfortable feelings or sensations that precede tics and the associated relief after tic performance, along with varying tolerance of these urges, the discomfort of the urge can be construed as unpleasant and likened to pain, especially by the IASP definition.

Associated primary pain syndromes

There are also comorbid primary pain conditions that can be associated with TS; migraine headache is one such studied comorbid pain condition. One study using a prospective questionnaire of 109 patients with a confirmed diagnosis of TS found that headaches were present in 55% of respondents, with the most common types being migraine and tension headaches (Ghosh et al, 2012). Respondents were younger than 22 years of age. (Ghosh et al, 2012). The rate of migraine in the TS respondents was four times greater than the reported rate in the general pediatric population, while the rate of tension headaches was five times greater than the reported rate in the general pediatric population (Ghosh et al, 2012). Another sample of TS patients from a tertiary referral center with an average age of 20.2 years were administered a migraine headache questionnaire based on the Headache Classification Committee of the International Headache Society (Kwak et al, 2003b). The authors found 25% reported symptoms satisfying the diagnostic criteria for migraine, significantly greater than the estimated 10%–13% prevalence of migraine in adult populations and the estimated 2%–10% prevalence in the general pediatric population (Kwak et al, 2003a). A systematic literature review of studies regarding the prevalence and characteristics of headache in patients with TS found that the proportion of headache among patients with TS was between 29% and 62%, while the proportion of migraine ranged between 13% and 43%, which was significantly higher compared with two control groups (Bearpark et al, 2020). To our knowledge, no other reports exist linking TS to other primary pain conditions.

Mechanisms of pain in TS

In addition to the high self-reported prevalence of premonitory urges in TS (Cohen and Leckman, 1992; Kurlan et al, 1989) and higher rates of comorbid pain, individuals with TS also report that they have heightened sensitivity to multimodal external stimuli, which can include sound, light, smell, and touch stimuli compared with healthy volunteers (Belluscio et al, 2011; Cox et al, 2018). Evidence of subjective hypersensitivity is also well-described in tic disorders, including co-occurring symptoms such as misophonia, or intolerance of specific sounds (Robinson et al, 2018). However, Belluscio et al. found no difference in objective testing of olfactory and tactile sensory thresholds between TS patients reporting heightened sensitivity and controls (Belluscio et al, 2011). Similarly, Schunke et al. used a standardized quantitative sensory battery to investigate pain thresholds for cold, heat, pinprick, and pressure, the experience of pain during nonpainful stimulation, and the pain rating for a series of painful stimuli compared with a single stimulus along with other thermal and mechanical sensory perceptual thresholds to external stimuli (Schunke et al, 2016). They did not find a significant difference between TS patients and healthy controls (Schunke et al, 2016).

Thus, it seems possible that the pain experience in TS may be related to hypersensitivity, but given the findings of Belluscio et al. and Schunke et al., this increased sensitivity does not seem to originate from altered sensory thresholds in the peripheral nervous system (Belluscio et al, 2011; Schunke et al, 2016). By contrast, two central perceptual mechanisms that could contribute to this heightened sensitivity and also possibly to pain experiences in persons with TS include sensory gating and sensory interoception.

Altered sensory gating hypothesis

Sensory gating refers to an individual’s ability to filter out redundant sensory stimuli via central processing to focus attention on novel environmental information (Isaacs and Riordan, 2020). Sensory gating has been studied in both the context of pain and TS separately. Sensory gating is commonly operationalized in studies by administering sensory stimuli to a test subject that will elicit either a motor response or an evoked cortical response and testing how repetitive sensory stimulation affects the response. The typical physiological response, referred to as habituation, is for the motor or sensory response to attenuate with repetitive stimulation—a form of sensory gating (Montoya et al, 2006).

Sensory gating or habituation has been found to be impaired in certain primary pain disorders such as migraine and fibromyalgia. In a study of patients with migraine, which measured sensory gating electrophysiologically via the P50 component of the auditory-evoked cortical potential in response to repeated auditory stimuli, Ambrosini et al. found that sensory gating was impaired in the migraine patients compared with healthy volunteers (Ambrosini et al, 2001). Siniatchkin et al. also found that migraine patients had impaired sensory gating using the P50 auditory-evoked potential to repeated auditory stimuli (Siniatchkin et al, 2003). In patients with fibromyalgia, a chronic musculoskeletal pain disorder, Montoya et al. tested sensory gating via evoked cortical responses to both auditory and somatosensory stimuli and found impaired sensory gating with somatosensory stimuli (Montoya et al, 2006). These results in chronic primary pain conditions suggest that impaired sensory gating may play some role in pain perception.

Sensory gating has also been found to be impaired in studies of patients with TS.

Kimura et al. performed a study in TS patients with simple or complex tics and healthy controls where premovement cortical sensory-evoked potentials (SEPs) were used to assess sensory gating (Kimura et al, 2023). Cortical SEPs were obtained from electrical stimulation at the median nerve in patients at rest and compared to a condition in which patients were instructed to extend their thumb after feeling the electrical stimulus (Kimura et al, 2023). This experimental setup has been established in healthy controls. Subjects who are instructed to move when receiving the electrical stimulus have attenuated SEPs compared with the patients who remain at rest and the ratio of attenuation reflects sensory gating (Shimazu et al, 1999). Kimura et al. found that TS patients older than 15 years with complex tics had impaired sensory gating by this measure compared with TS patients with simple tics and healthy controls, but there was no difference for patients younger than 15 (Kimura et al, 2023). This difference, however, may reflect an underpowered younger age group rather than a true age effect (Kimura et al, 2023).

Another set of studies in TS provides evidence of altered sensory gating when using the prepulse inhibition (PPI) paradigm. In this experimental setup, electromyography is used to measure a facial startle response to a stimulus. Sensory gating is observed when this response is decreased by a smaller warning or a prepulse stimulus (Castellanos et al, 1996). Multiple studies have found that in patients with TS, PPI is blunted compared with healthy controls with various forms of stimuli such as tactile and acoustic stimuli (Castellanos et al, 1996; Swerdlow et al, 2001; Buse et al, 2016). Buse et al. performed functional magnetic resonance imaging (fMRI) during PPI measurements and found that subjects with TS during reduced PPI had reduced recruitment of the middle frontal gyrus, superior parietal cortex, cingulate gyrus, and caudate body on blood oxygen-level-dependent activity on fMRI (Buse et al, 2016). Given the alteration of sensory gating in both patients with pain-associated conditions and patients with TS, further research could address whether or how altered sensory gating relates to pain reported by TS patients.

DBS is one treatment used in refractory cases of TS, and research in animal models of impaired PPI has shown that this treatment can influence or normalize PPI. For example, injection of the dopamine agonist apomorphine can impair PPI in rats and is used as an animal model of TS (Posch et al, 2012). Two studies of this animal model demonstrated that DBS in the rat’s entopeduncular nucleus (EPN), an equivalent to the human globus pallidus, and thalamic centromedian-parafasicular (CM-Pf) nucleus could improve apomorphine-induced PPI deficits in these rats (Posch et al, 2012; Elle et al, 2020). Another study with rats selectively bred for reduced PPI similarly showed that DBS to the CM-Pf complex improved PPI, while DBS implantation to the EPN improved PPI while subsequent stimulation had no additional effect (Angelov et al, 2014). Medication can have an effect on PPI in animal models as well. A rat model of absence epilepsy (WAG-Rij) was shown to have reduced PPI compared with control rats, and this PPI reduction was improved with lamotrigine (Celikyurt et al, 2012). If the relationship between TS, sensory gating, and PPI can be further elucidated, these animal models of impaired PPI could help inform the development of potential future therapeutics for TS that also improve pain.

Of additional interest, Schilke et al. hypothesize that PPI could be related to urge in TS and propose PPI as a possible marker for treatment response in tic-related disorders (Schilke et al, 2022). At this time, there is limited evidence connecting sensory gating and premonitory urge in TS. Sutherland Owens et al. did not find an association between sensory gating (operationalized by the Sensory Gating Inventory and Structured Interview for Assessing Perceptual Anomalies questionnaires) and premonitory urges (assessed by the PUTS and the University of Sao Paulo Sensory Phenomena Scale) (Sutherland Owens et al, 2011). However, they did not use an experimental measure such as PPI to measure sensory gating, so further studies with more formal measurements of PPI/sensory gating could be pursued to better establish this relationship, and further determine how it may relate to pain (Sutherland Owens et al, 2011). The exact relationship between objective correlates of sensory gating (e.g., PPI), premonitory urge, and pain in TS requires further elucidation to clarify the mechanisms of pain in TS.

Altered interoceptive processing

Interoception refers to the processing of bodily sensations, such as heartbeats and respiration (Critchley and Garfinkel, 2017; Hassanpour et al, 2018), and is a process by which an individual can capture an overall physiological representation of the state of the body via a variety of sensors (e.g., mechanosensors, chemoreceptors, or thermoreceptors) (Berntson and Khalsa, 2021). This information is transmitted centrally via ascending pathways and processed via the so-called central autonomic network, which includes the anterior cingulate cortex (ACC), insular cortex, thalamus, hypothalamus, amygdala, periaqueductal gray, parabrachial nucleus, nucleus tractus solitarius, locus coeruleus, and ventrolateral medulla. Anatomically, the insula is considered the primary interoceptive cortex and multiple interoceptive pathways (including pain, temperature, itch, visceral sensations, and others) converge on this location (Craig, 2002).

Phenomenologically, the urge to tic is interoceptive by nature and multiple studies indicate that this urge originates in the insula (Jackson et al, 2020; Tinaz et al, 2015) and may be a consequence of disordered interoceptive processes (Pile et al, 2018; Ganos et al, 2015). Visceral and somatic pain are also considered interoceptive and the neural networks activated during these types of pain are similar to those for other interoceptive processes (Ceunen et al, 2016; Berntson and Khalsa, 2021; Fenton et al, 2015; Tan et al, 2021). The fact that neural pathways related to urge to tic and pain processing overlap suggests a common mechanism that may not only help to explain their comorbidity but also offer pathophysiologic insights into the pain experiences reported by patients with TS.

Higher order interoceptive processing includes interpretation of interoceptive signals from both cognitive and emotional standpoints (Suksasilp and Garfinkel, 2022 ), and is encapsulated in the concept of interoceptive awareness (e.g., detection, attention, insight, magnitude, discrimination, accuracy, and sensibility) (Berntson and Khalsa, 2021). Subjective hypersensitivity to interoceptive stimuli, or heightened interoceptive sensibility, has been documented in patients with tic disorders (Eddy et al, 2014; Narapareddy et al, 2022) and pain disorders such as in irritable bowel syndrome, a visceral pain disorder (Kellow et al, 1991; Hubbard et al, 2015). However, the association between subjective and objective interoceptive experience is murky. For example, subjective urge severity in TS is not always shown to predict tic severity (Sutherland Owens et al, 2011) and it has been shown that subjective beliefs about interoceptive capacity do not necessarily correlate with the performance of interoceptive functions (Rae et al, 2019b; Suksasilp and Garfinkel, 2022).

Objective behavioral measurements of interoceptive performance, or interoceptive accuracy, are limited, due to the diffuse and internal nature of interoceptive experience (Schoeller et al, 2024). Methodological differences can also confound measurements of interoceptive performance. For example, in certain studies of heartbeat counting, a common measure of interoceptive accuracy, statistically significant results were not reproduced possibly due to differences in the number and duration of heartbeat counting trials (Ganos et al, 2015; Rae et al 2019b). With these limitations in mind, a systematic review of 11 studies examining chronic pain conditions such as fibromyalgia, chronic low back pain, somatization disorder, and migraine found that interoceptive accuracy may be lower in patients with chronic pain and may negatively correlate to symptom severity. While these studies were heterogeneous in the way that interoceptive accuracy was operationalized and in terms of patient populations (Di Lernia et al, 2016b), interoception has been suggested as a theoretical treatment target for chronic pain (Di Lernia et al, 2016a). Individuals with tics show performance deficits on heartbeat counting accuracy and discrimination tasks (Ganos et al, 2015; Rae et al, 2020, 2019a, 2019b), and these functional deficits predict characteristics relevant to impulsivity and urge to action (Rae et al, 2020). Interestingly, the mismatch between interoceptive beliefs and accuracy was greater among TS patients than controls, which may suggest that a higher order sensitivity to bodily sensations in TS exists, or that it is a disorder of interoceptive awareness (Rae et al, 2019b).

The relationship between interoception, urges, and pain remains to be completely understood. A reasonable hypothesis is that an interoceptive abnormality in TS affects urges and makes patients more vulnerable to pain. Given the aforementioned connections, these relationships represent an area of possible future study in better understanding the mechanistic underpinnings of pain in patients with TS.

Measurement of pain in TS

Various clinical rating scales and QoL metrics have been used to assess patients with TS. Martino et al. performed a systematic review of severity scales for tics and recommended the following: YGTSS, TS-Clinical Global Impressions (TS-CGI), Tourette’s Disorder Scale (TODS), STSSS, and PUTS (Martino et al, 2017). Their review found that the YGTSS was the most valid, comprehensive, reliable, and clinically useful instrument although it has a long administration time (Martino et al, 2017). The YGTSS is a commonly used clinical rating instrument that rates the severity of tic symptoms across number, frequency, intensity, complexity, interference, and global impairment (Leckman et al, 1989). Pain is included in the intensity component where a “severe” score includes the characterization that “[tics] may result in physical injury…because of their forceful expression” but pain is not directly present in any other intensity score or other components to the scale, including the global impairment component (Leckman et al, 1989). This more indirect inclusion of pain into the YGTSS does not provide details about type, severity, and consequences on pain in granular detail that could be helpful to obtain (Leckman et al, 1989).

Among the other common instruments in the review by Martino et al., the STSSS, TS-GCI and TODS do not include explicit measures of pain (A. K. Shapiro and Shapiro, 1984; Martino et al, 2017; Shytle et al, 2003). The PUTS, briefly discussed previously, contains nine items rated on a four-point ordinal scale (1 = not true at all, 4 = very much true) such as “right before I do a tic, I feel like my insides are itchy,” “right before I do a tic, I feel a pressure inside my brain or body,” and “right before I do a tic, I feel wound up or tense inside” (Woods et al, 2005). Although the PUTS contains items regarding sensation, none of the nine items is an explicitly painful sensation—also limiting the PUTS sensitivity to pain in TS patients (Woods et al, 2005). Thus, some of the major, commonly used screening instruments and scales for tics do not include an exact assessment of pain.

A number of studies have investigated QoL in TS patients using a variety of measures and rating scales. These along with previously mentioned measures and scales are summarized in Table 2. Notably, the Parent Tic Questionnaire (PTQ), EQ-5D, PedsQL PPQ, PPCI, and the Gilles de la Tourette Syndrome–Quality of Life Scale (GTS-QOL) do include some pain assessment or information relevant to pain, as summarized in Table 2, but without sufficient details to distinguish pain categories according to the scheme proposed in Table 1 (Chang et al, 2009; Müller-Vahl et al, 2010; Małek, 2022; Varni et al, 1996; Cavanna et al, 2008).

Table 2.

Measurement of Pain in Tourette Syndrome Clinical Rating Scales and Quality of Life Metrics

Clinical rating scales and QoL (quality of life) metrics	Measure of pain
Yale Global Tic Severity Scale (YGTSS)	Included in intensity component where a “severe” score includes the characterization that “[tics] may result in physical injury…because of their forceful expression” but more details or specificity regarding pain are not included (1)
Parent Tic Questionnaire (PTQ)	Involves rating a list of common types of tics on frequency and severity and does include in its instructions that if a tic is forceful or even painful that it should be rated more highly in severity, but more details or specificity regarding pain is not included (2)
Premonitory Urges for Tics Scale (PUTS)	Contains nine items rated on a four-point ordinal scale (1 = not true at all, 4 = very much true) including “right before I do a tic, I feel like my insides are itchy,” “right before I do a tic, I feel a pressure inside my brain or body,” and “right before I do a tic, I feel wound up or tense inside” that refer to sensations compatible with discomfort/pain, but more details or specificity regarding pain are not included (3)
EuroQol-5 Dimension (EQ-5D)	A global nondisease-specific quality of life inventory spanning five dimensions, one of which is pain/discomfort. Patients are asked for each dimension to select from the following options for each dimension: no problems, slight problems, moderate problems, severe problems, and extreme problems. More details or specificity regarding pain is not included (4)
PedsQL Pediatric Pain Questionnaire (PPQ)	Consists of three items: localization of pain, a visual analogue scale for present pain rating from 0 to 10, and a visual analogue scale for worst pain scored from 0 to10. More details or specificity regarding pain is not included (5)
Pediatric Pain Coping Inventory (PPCI)	41-item instrument listing different coping skills with respect to pain that the subjects will then mark whether they never (score 0), sometimes (score 1), or often (score 2). The 41 items each fall into one of five categories: Cognitive self-instruction, problem-solving, distraction, seeking social support, and helplessness. As this instrument focuses on coping skills, no specific questions are included about the etiology of pain (6)
The Gilles de la Tourette Syndrome–Quality of Life Scale (GTS-QOL)	27-item questionnaire with psychological, physical activities and activities of daily living, obsessive compulsive, and cognitive domains. Within questions assessing the physical activities domain, patients are asked about pain or injuries due to tics but no specific questions were asked about urge-related pain, suppression-related pain, or associated pain syndromes (7)
Shapiro Tourette syndrome Severity Scale (STSSS)	No direct measure (8)
Tourette Syndrome Clinical Global Impressions, (TS-CGI)	No direct measure (9)
Tourette’s Disorder Scale (TODS)	No direct measure (10)
Tourette syndrome symptom list	No direct measure (11)

(1) Leckman et al. (1989), (2) Chang et al. (2009), (3) Woods et al. (2005), (4) Müller-Vahl et al. (2010), (5) Małek (2022), (6) Varni et al. (1996), (7) Cavanna et al. (2008), (8) A. K. Shapiro and Shapiro (1984), (9) Martino et al. (2017), (10) Shytle et al. (2003), and (11) D. J. Cohen et al. (1980).

In conclusion, common clinical rating scales for TS do not assess the pain experience in this population beyond tic-related pain or injury. While QoL scales do capture some pain-related information, they are also not sufficiently detailed to identify the etiology of pain and categorize the pain into the causes previously identified (Table 1).

Treatments for pain in TS

Here, we review how pain is included as an outcome measure in studies of various treatments for patients with TS.

Medications

Systematic reviews of medication treatments for TS were reviewed to identify whether pain is included in outcome measures. Pringsheim et al. performed a comprehensive systematic review of randomized controlled trials (RCTs) for treatments for TS and chronic tic disorders, including medical therapies such as haloperidol (two studies), risperidone (two studies), aripiprazole (two studies), tiapride (one study), clonidine (three studies), Ningdong granule (one study), 5-Ling granule (one study), pimozide (three studies), ziprasidone (one study), metoclopramide (one study), guanfacine (three studies), and topiramate (one study) (Pringsheim et al, 2019). Among these studies, the primary outcome measures included the YGTSS, STSSS, TS-CGI, and Tic Symptom Self-Report, none of which explicitly examines pain. Two meta-analyses of treatment effects of aripiprazole and atypical antipsychotics for TS by Yang et al. and Budman et al., respectively, did not include outcomes that directly assessed for pain (Yang et al, 2015; Budman, 2014). Nor did any studies from a sample of more recent RCTs from 2014 to 2022 studying various medical treatments for TS (Murphy et al, 2017; Müller-Vahl et al, 2022; Abramovitch et al, 2015; Song et al, 2017). Only an older study of pergolide—by Gilbert et al.—used the Clinical Global Impressions of TS Severity, Clinical Global Impressions of TS-Improvement (CGI-TS-I), Caregiver Global Impression of Change (CaGI-C), and the GTS-QOL as secondary outcome measures (Gilbert et al, 2003). Of those outcomes, the GTS-QOL incorporates pain into the physical domain and the CaGI-C also incorporates pain into the assessment although details are limited and not separately reported (Staunton et al, 2021).

Overall, in trials investigating medications for TS, the YGTSS is the most commonly used primary outcome. It is rare for trials to include outcomes that account for pain using QoL measures, and these measures do not include much detail about causes of pain. Pain will need to be explicitly measured in future trials to gain insight into the effects of medication management on this TS feature.

Behavioral interventions

Behavioral interventions play an important role in the management of TS, including cognitive behavioral intervention for tics. In the comprehensive review by Pringsheim et. al, two RCTs studied the efficacy of behavior therapy and used YGTSS and a CGI-based scale, neither of which includes direct information about pain (Pringsheim et al, 2019).

From a sample of more recent studies, including behavioral therapy and sensorimotor strategies in children with neurodevelopmental disorders from 2018 and 2019, the YGTSS, CGI, PUTS, PTQ, and KIDSCREEN52 were used as outcome measures, but do not inquire directly into pain (Rizzo et al, 2018; Soler et al, 2019). KIDSCREEN-52 is a QoL metric that incorporates 10 domains but does not directly address pain (Rizzo et al, 2018). Rizzo et al. note that a number of studies investigating the treatment effect of behavioral therapy for TS use either YGTSS or tic frequency video ratings (Rizzo et al, 2018).

Despite the long-known importance of psychological and behavioral interventions in chronic pain management (Majeed et al, 2019), studies investigating behavioral interventions in TS lack outcomes that directly include pain. Behavioral interventions for TS can also focus on different methods breaking the cycle between premonitory urge to and the relief experienced after a tic, so an interesting area of future research could come from analyzing how urges and pain change in TS patients undergoing such interventions (Wilhelm et al, 2012).

Deep brain stimulation

DBS has been studied and utilized in the management of refractory TS where patients have severe symptoms that can include self-injurious behavior, emergency room visits for TS symptoms, and who have failed to respond to less invasive therapies. The comprehensive review by Pringsheim et al. included two RCTs of DBS, both of which used the YGTSS as the primary endpoint (Pringsheim et al, 2019).

We reviewed outcome measures from some recent publications about DBS in TS patients spanning 2016–2021, including three meta-analyses of case reports, case series, and clinical trials and a database registry study (Baldermann et al, 2016; Wehmeyer et al, 2021; Martinez-Ramirez et al, 2018; Xu et al, 2020). The targets in these studies included the globus pallidus internus (posteroventral or anteromedial), globus pallidus externus, thalamus (CM-Pf complex or centromedian nucleus–nucleus ventro-oralis internus), anterior limb of internal capsule/nucleus accumbens, and the subthalamic nucleus. Outcomes included YGTSS, Rush Video-Based Tic Rating Scale, CGI, modified Rush Videobased Tic Rating Scale (MRVS), Global Assessment of Functioning Scale (GAF), and GTS-QOL (Baldermann et al, 2016; Wehmeyer et al, 2021; Martinez-Ramirez et al, 2018; Xu et al, 2020). The only outcome that included some information about pain was the GTS-QOL.

In summary, pain was not well represented in the outcomes assessments included in studies of DBS for patients with TS. DBS also has been investigated for the treatment of chronic pain, although in different targets such as the ventral posterolateral and ventral posteromedial nucleus of the thalamus, the periventricular and periacqueductal gray matter, and the rostral ACC. Further work is required to understand whether DBS for TS improves pain reported by patients.

Botulinum toxin

Botulinum toxin injections can be used to control tics. In the comprehensive review by Pringsheim et al., only a single RCT was identified, performed by Marras et al. (Pringsheim et al, 2019). Marras et al. conducted a crossover RCT where the primary outcome was the number of treated tics per minute on a videotape segment, while secondary outcomes included the number of untreated tics per minute, STSSS, a numerical assessment of the urge to perform the treated tic (0–4), and the premonitory sensation associated with the treated tic (0–4), and the patient’s global impression of change (Marras et al, 2001). They did not include a metric including pain (Marras et al, 2001).

Rath et al. conducted an observational study of patients with TS undergoing botulinum injections and used a four-level scale (good-moderate-poor-no effect) as the outcome (Rath et al, 2010). Kwak et al. used a similar 0–4 clinical rating scale (0, no improvement, to 4, marked improvement in both severity and function) in an observational study of toxin injections in TS patients (Kwak et al, 2000). Data regarding pain were not explicitly collected in these studies. By contrast, the effects of botulinum toxin injections on pain in other conditions are well recognized, likely through both central signaling and peripheral mechanisms, including disorders such as chronic migraine, cervical dystonia, and neuropathic pain (Kumar, 2018). Further research investigating pain reduction following botulinum toxin injections in TS is warranted.

Cannabis and cannabinoids

Persons with TS reported use of cannabis- and cannabidiol (CBD)-based products as a self-management technique to deal with pain (Taylor et al, 2022). Cannabinoids such as delta-9-tetrahydrocannabinol (THC) and CBD have been studied with respect to their effects on pain in different conditions. McDonagh et al. performed a systematic review of cannabis-based products for chronic pain and found 18 RCTs and 7 observational studies, most of which included patients with neuropathic pain (56%) (McDonagh et al, 2022). They found that synthetic products with high THC-to-CBD ratios may be associated with moderate improvement in pain severity (≥30% improvement) with an increased risk for sedation (McDonagh et al, 2022). Mücke et al. reported a Cochrane review on cannabis-based products in patients with neuropathic pain, in which 16 studies showed that the use of such products may increase the number of people achieving 50% or greater pain relief compared with placebo with a number needed to benefit of 20, although with a low level of evidence (Mücke et al, 2018). They concluded that these medications may increase nervous system adverse events compared with placebo, also with low-quality evidence, but with a number needed to harm of 3, indicating that the potential harms of cannabis-based medicine in chronic neuropathic pain may outweigh the benefits (Mücke et al, 2018).

Pringsheim et al. identified two RCTs examining THC in TS (Pringsheim et al, 2019). These two studies investigated THC in patients with TS and used TS-CGI, the STSSS, YGTSS, TS symptom list, and a videotape-based rating scale but did not include metrics that measure pain (Müller-Vahl et al, 2003; Müller-Vahl et al, 2002). We reviewed a series of recent studies of cannabinoids studied in patients with TS published from 2017 to 2023, including a crossover RCT, prospective open-label study, and a retrospective study (Abi-Jaoude et al, 2017, 2023; Anis et al, 2022) where the outcomes used included YGTSS, PUTS, MRVS, CGI, and a general report rated 1–7 on various subjective reports, but not pain. Again, despite evidence of use and efficacy in chronic pain conditions, there is no direct evidence examining the effect of cannabinoids on pain phenomena in TS.

Acupuncture

Acupuncture is a complementary therapy for pain and has been studied as a treatment for tic disorders. A 2020 systematic review by He et al. examined studies of acupuncture for cancer pain and found seven high-quality sham-controlled RCTs showing acupuncture was associated with reduced pain intensity, although only with a moderate level of evidence (He et al, 2020).

Yu et al. performed a systematic review of RCTs of acupuncture for patients with TS and included as outcomes the YGTSS, STSSS, the Hopkins motor and vocal tic scale (which includes information about severity of a tic but nothing explicitly about pain), and GTS-QOL (Yu et al, 2016). The only measure that includes pain as mentioned prior is the GTS-QOL. In a recent study from 2021, You et al. performed a retrospective study evaluating acupuncture in TS patients using the YGTSS as the primary outcome (You et al, 2021). Thus, in both a systematic review and recent study, no outcomes providing detailed information about pain were utilized.

In summary, most of the research into TS therapeutics does not directly investigate pain and when it does, it is often in the form of QoL that does not decipher the cause of pain. Malek et al. surveyed common pain coping strategies in children and adolescents with TS—children commonly reported wishing for it to go away (60.9%), trying to be brave and not say anything (56.5%), telling my mother or father (56.5%), playing a game (52.2%), having my mother, father, or a friend sit with me (47.8%), knowing that I can ask for something that will make the pain or hurt feel better (47.8%), and asking for medicine (39.1%) (Małek, 2022). Adolescents commonly reported going to bed (76.5%), asking to be left alone (76.5%), lying down (70.6%), sleeping it off (70.6%), trying to be strong and not saying anything (70.6%), visiting with my friends (64.7%), playing a game (64.7%), try not to think about the pain or ignore the pain (64.7%), have my mother or father or a friend sit with me (47.1%), and know that I can ask for something that will make the pain feel better (29.4%) (Małek, 2022). Children tended to involve parents in their coping strategies more than adolescents who reported more isolation techniques, but both groups reported more commonly using strategies that were not based on professional support or using medication (Małek, 2022). It is possible that the lack of emphasis on pain as a problematic symptom, and the lack of understanding about how the different types and causes of pain respond to TS therapies both contribute to the low utilization of specific treatment interventions for pain in TS. Thus, more detailed data regarding pain and its response in TS treatment are needed.

Discussion

In this review, we have shown that pain is reported by 47%–60% of individuals with TS and may relate to different aspects of tic phenomenology or other causes. It negatively impacts QoL in patients with TS, such that TS should be recognized as a condition associated with a chronic secondary pain syndrome. Other primary pain conditions may also accompany TS, and patients with TS may experience different kinds of pain with different etiologies. We propose the following five categories of pain that can be experienced by patients with TS: immediate tic-related pain, delayed tic-related injury/pain, suppression-related pain, urge-related pain, and associated primary pain syndromes (Table 1). Altered sensory gating as measured by PPI in patients with TS indicates a possible role in urge or tic manifestations, which may drive painful experiences in this population. In addition, patients with TS may experience interoceptive hypersensitivity without evidence of peripheral sensory abnormalities, which may further modify the urge to tic. More research is necessary into how these aspects of sensory perception may influence the experience of pain in people with TS and whether this knowledge can direct a better understanding of appropriate treatment modalities.

Pain assessment is notably lacking in current TS clinical rating scales and without attention to the different causes of pain in TS. Our current understanding of pain prevalence and causes derives mainly from QoL and survey studies with dedicated but unstructured questions regarding pain. Based on a comprehensive literature review, a standardized approach to assessing pain severity and causality can now be structured based on the proposed five categories outlined in Table 1. The lack of a standardized approach has hampered our understanding about how available TS treatments can impact pain, despite the fact that many of them have well-established roles in the treatment of pain in other conditions. Most notably, behavioral therapies, botulinum toxin injections, cannabinoids, and acupuncture are all commonly used in treatment plans for chronic pain conditions. Future clinical trials should include a TS-specific pain assessment to more explicitly capture treatment effects on pain. It is possible that added evidence relating to pain improvement may facilitate medication adherence among TS patients. In addition, it is possible that such data could help guide clinicians in treating and counseling patients with TS about pain, given that most coping strategies reported by patients are not centered around professional help.

Clinical Significance and Conclusion

Due to the prevalence and negative impacts of pain on patients with TS, TS should be recognized as a condition associated with a chronic secondary pain syndrome. This warrants greater attention among TS stakeholders, including patients, clinicians, researchers, and regulatory authorities. There is a need for better assessment methods and more discriminating objective data about pain phenomena in TS. A standardized assessment approach can be structured based on the proposed classification scheme of pain causes in TS (Table 1). It is important to note that some patients may refer to relevant symptoms as discomfort rather than pain, so care must be exercised when developing or using assessment tools to accurately characterize the patient experience. Based on the present review, opportunities for future investigation into various aspects of chronic secondary pain in TS are presented in Table 3. These may be clinically relevant in that further understanding about the prevalence, etiology, and mechanisms of pain may have important therapeutic implications for patients.

Table 3.

Suggested Avenues of Further Research into the Chronic Pain Syndrome of Tourette Syndrome

Epidemiology of pain in TS (Tourette syndrome)	Larger scale epidemiological studies to better understand and characterize the increased prevalence of pain in TS, using the proposed classification scheme of pain causes (Table 1)
Pathophysiology of pain in TS	Determine whether various pain causes in TS relate to similar or different pathophysiologic mechanisms, including but not limited to altered interoceptive processing or sensory gating. For example, investigations could be designed to assess whether pain experienced due to tic-related immediate or delayed pain is similar or different to pain experienced due to suppression-related to premonitory urge-related pain
	Study how pain experiences or mechanisms in patients with TS are similar or different to other chronic pain conditions
Pain measurement tools	Develop TS-specific pain rating scales or tools, similar to the PUTS
Therapeutic investigations	Investigate whether existing treatments for tics that also have recognized benefits on pain in non-TS conditions, or other known pain therapies, can alleviate this troublesome symptom among TS patients

PUTS, Premonitory Urges for Tics Scale.

Authors’ Contributions

B.G.: Conceptualization, methodology, writing—original draft, and writing—review and editing. A.W.: Writing—original draft and writing—review and editing. J.J.-S.: Conceptualization, writing—review and editing, and supervision.

Disclosures

B.G.: None. A.W.: None. J.J.-S.: Consulting fees: Medtronic, BlueRock Therapeutics, Bracket/Signant, Teva, AbbVie, Alpha Omega, REGENXBIO, Praxis, and Kyowa Kirin. Data safety monitoring board member: BlueRock Therapeutics and Emalex. Research funding: Annovis, Sage, and Ono Pharmaceuticals.