Diagnosis And Treatment Of Intractable Idiopathic Orofacial Pain With Attention‑defcit/ Hyperactivity Disorder Part 1

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【Contact】Email: george.deng@wecistanche.com / WhatsApp:008613632399501/Wechat:13632399501

Attention-deficit/hyperactivity disorder (ADHD) has been reported to be associated with primary chronic pain syndromes, such as fibromyalgia, migraine, and chronic low back pain. Although idiopathic orofacial pain (IOP) is classified as burning mouth syndrome or persistent idiopathic facial or dentoalveolar pain and as a primary chronic pain, the association between IOP and ADHD has not been investigated. This retrospective cohort study investigated the severity of ADHD symptoms measured using the ADHD scale and the effects of treatment using ADHD drugs and the dopamine system stabilizer aripiprazole. The participants were 25 consecutive patients with refractory IOP referred to a psychiatrist and diagnosed with coexisting ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-5. The ADHD scale scores were higher in patients with intractable IOP than those in the general population. Pharmacotherapy used in this study led to clinically significant improvements in pain, anxiety/depression, and pain catastrophizing. Intractable IOP and ADHD were shown to be associated. In the future, screening and pharmacotherapy for ADHD should be considered in the treatment of intractable IOP.

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Abbreviations

5-HT 5-Hydroxytryptamine 

ADHD Attention-deficit/hyperactivity disorder 

APZ Aripiprazole 

ATX Atomoxetine 

BMS Burning mouth syndrome 

CAARS-O Connors' Adult ADHD Rating Scale Observer-version 

CAARS-S Connors' Adult ADHD Rating Scale Self-Report 

CI Confidence interval 

DIVA Diagnostic Interview for ADHD in Adults 

DSM-5 Diagnostic and Statistical Manual of Mental Disorders-5 

HADS Hospital Anxiety and Depression Scale 

HADS-A Hospital Anxiety and Depression Scale, subscale for assessing anxiety

According to the International Classification of Orofacial Pain (ICOP), 1st edition, idiopathic orofacial pain (IOP) is defined as unilateral or bilateral intraoral or facial pain of unknown etiology in the distributions of one or more branches of the trigeminal nerve(s)1. Pain is usually persistent, moderately intense, non-localized, and described as dull, oppressive, or burning. IOP is further classified as burning mouth syndrome (BMS), persistent idiopathic facial pain (PIFP), or persistent idiopathic dentoalveolar pain (PIDAP). BMS is characterized by bilateral, superficial, persistent pain in the oral mucosa, with a predilection for the lingual apex, lingual border, and palate; it occurs more commonly in women than in men, especially after menopause2. PIFP is persistent facial and/or oral pain of unclear localization with various symptoms and female predilection3. PIDAP is a deep pain in the teeth and alveolar region with well-defended localization, relatively low age of onset, and little gender difference; 70–83% of incidences are triggered by dental treatment4.

The incidences of BMS and PIFP, including PIDAP, in the general population, are 0.1–3.9%5 and 0.03%6, respectively. However, in clinical settings, such as oral-facial pain clinics, the incidence is reportedly 7.72% for  BMS7, 10–21% for PIFP at orofacial pain clinics3, and 2.1% for PIDAP at tertiary medical centers4.

The pathophysiology of all three disorders is unclear; however, psychosomatic factors and central nervous system dysfunction are reportedly involved8, and tricyclic antidepressants (TCAs)9 and cognitive behavioral therapy10 are likely to be effective. IOP is a difficult disease to treat as its response to various therapies is inconsistent, with limited efficacy. IOP has a spontaneous remission rate of 3–4% even 5–6 years after the diagnosis is confirmed11, and patients with IOP may visit several dentists and doctors to understand the cause of their pain and for effective treatment. Although dental procedures may provide temporary improvement in the symptoms, they may subsequently reoccur in other teeth and the original locations, triggering a vicious cycle of further invasive procedures at the patient’s request and despite the dentist’s good intentions. Throughout this process, the patient may lose multiple healthy teeth and experience pain in the entire orofacial region. Therefore, clinicians have great difficulty in managing patients with IOP12.

It was reported that 41.3% of patients with IOP had a history of a mental disorder before the onset of pain, approximately half of the patients had long-term psychiatric disorders, and one-third had a psychiatric comorbidity at the time the survey was conducted, indicating that mental disorders show a chronic, long-term course. The most common psychiatric comorbidities were major depression, anxiety disorder, and Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) anxious and fearful Cluster C personality disorders (avoidant, dependent, and obsessive–compulsive personality disorders)8. In addition, the majority of the patients also had one or more other chronic pain symptoms, and almost all patients had other pain symptoms when they developed orofacial pain, suggesting that the three IOP disorders have common vulnerabilities to chronic pain and psychiatric disorders. IOP disorders are reportedly caused by dysfunction of the dopaminergic system, and it has been proposed that they are on the same neuroplastic pain spectrum, only with different degrees of disability8,13.

Attention-deficit/hyperactivity disorder (ADHD), a developmental disorder, is also reportedly associated with chronic pain. ADHD is characterized by attention deficit, hyperactivity, and/or impulsivity, which persists for a relatively long period from childhood to adulthood and causes dysfunction in daily living14. The pathophysiology of ADHD is dysfunction of the dopaminergic and noradrenergic nervous systems. Psychostimulants that enhance dopamine neurotransmission, selective noradrenaline reuptake inhibitors, noradrenergic alpha-2 receptor agonists15, and dopamine system stabilizers16 can improve ADHD symptoms. Previous studies suggested that ADHD is associated with fbromyalgia17–22, migraine23, and chronic lower back pain. These pain disorders are classified as primary pain syndromes in the International Classification of Disease, Eleventh Revision26, suggesting that ADHD is likely to coexist with chronic primary pain. IOP is also classified as a type of primary chronic pain; however, although no previous reports on a connection between IOP and ADHD are available, similar to IOP, patients with ADHD are more likely to experience depression, anxiety disorders, and DSM-5 anxious and fearful Cluster C personality disorders than the general population27. As the neuropathology of ADHD is also thought to be caused by dopaminergic system dysfunction28, IOP and ADHD may coexist as they share common origins.

Herein, we conducted a retrospective cohort study of patients with intractable IOP referred to a psychiatrist by specialists in psychosomatic dental care due to difficulty in managing their symptoms to delineate the characteristics of refractory patients. This study focused on the severity of ADHD symptoms measured using the ADHD scale, and the effectiveness of treatment using ADHD drugs and the dopamine system stabilizer aripiprazole (APZ) in intractable IOP.

Methods

Study design, settings, and patients. This cohort study retrospectively investigated the ADHD scale scores and ADHD diagnoses in patients with refractory IOP during the initial visit to examine whether there is an association between intractable IOP and ADHD. The severity of ADHD symptoms was assessed using Conners' Adult ADHD Rating Scale (CAARS), and ADHD was diagnosed according to the DSM-5. The attending psychiatrist (S.K.) routinely performs the CAARS evaluation on the patient’s first visit.

We reviewed the clinical assessments of pain, mood, and catastrophic thinking conducted by the psychiatrist in every routine session, along with the medication algorithms followed by the psychiatrist in his usual practice, and evaluated the results of the practice through longitudinal analysis. Pain intensity was assessed using the Numerical Rating Scale (NRS), mood using the Hospital Anxiety and Depression Scale (HADS), and catastrophic thinking using the Pain Catastrophizing Scale (PCS), and compared before and after treatment. Dr. SK routinely evaluated patients using the "Pain NRS," the "HADS", and the "PCS”, and provided feedback on the scale scores to the patients at each visit.

Thirty consecutive patients with refractory IOP were referred to a psychiatrist (S.K.) at the Pain Center of our university hospital between May 2016 and March 2020 with suspected somatic symptom disorder after it was determined that treatment would be difficult by a specialist in psychosomatic dentistry at a tertiary medical center. The diagnosis of IOP was made by a specialist in psychosomatic dentistry who referred the patient. The definition of intractable IOP is undefined; therefore, we defined this condition as a strong and lasting IOP that did not respond to psychoeducation, psychotherapy, and the use of three or more medications (e.g., antidepressants, analgesics, or anticonvulsants). These patients were treated by their dentist and referred to our university hospital because further treatment was difficult. This retrospective cohort study was conducted by the Declaration of Helsinki of the World Medical Association.

Inclusion and exclusion criteria. Of the 30 patients with intractable IOP mentioned above, patients diagnosed with ADHD were included as the subjects in this study. Patients under 18 years of age or with impaired judgment due to severe psychosis, manic status, or depression were excluded from this study.

Assessment and diagnosis of ADHD. All participants and their families were instructed to answer the long version of the Connors' Adult ADHD Rating Scale Self-Report (CAARS-S) or the observer-version (CAARS-O) at the time of their first medical examination in this study29,30. The CAARS-S and CAARS-O have eight subscales and calculate the T-scores for each. Patients with a T-score greater than 65 on the CAARS-S or CAARS-O were classified as CAARS positive, indicating a clinically significant level of ADHD symptoms. The CAARS is widely used as a measure of ADHD symptoms in adults aged≥18 years.

Diagnosis of ADHD was made by a psychiatrist (S.K.) at the time of the first visit according to the criteria of the DSM-514. The diagnosis was verified using the semi-structured Diagnostic Interview for ADHD in Adults 2.0 (DIVA 2.0)31 conducted on the first visit as well. DIVA 2.0 provides typical examples of dysfunction in the 18 diagnostic criteria for ADHD and five domains (work/education, romantic/family relationships, social interactions, leisure/hobbies, and confidence/self-image) caused by the ADHD symptoms in daily life from childhood through adulthood, and is an aid to ADHD diagnosis. According to the DSM-5 diagnostic criteria, ADHD in a person aged>17 years is diagnosed if at least five of the nine inattention symptoms or at least five of the nine hyperactive/impulsive symptoms are present. ADHD is classified into three types: predominantly inattentive, predominantly hyperactive-impulsive, and combined.

Assessment of pain. Pain duration (months) was defined as the period from the onset of IOP to the patient's first visit to our pain center. Pain intensity was evaluated using the NRS32, an 11-point pain rating scale, with 0 indicating no pain and 10 indicating the highest pain. The NRS assesses the maximum, minimum, and average pain intensities of patients. The minimum clinically important difference (MCID) was a −1 point (or −15.0%) decrease on the NRS. A reduction of −2 points (or −33.0%) or more on the NRS is considered an optimal improvement.

Assessment of mood state. Anxiety and depression were evaluated using the HADS34. The HADS is a validated assessment scale for screening psychological distress in non-psychiatric patients in clinical practice consisting of 14 questions, seven of which form a subscale for assessing anxiety (HADS-A), and the remaining seven form a subscale for assessing depression (HADS-D). All items were scored on a 4-point scale ranging from 0 to 3, with 21 points each for HADS-A and HADS-D as the highest score. HADS-A/D results of 8 points or higher on each subscale were considered clinical manifestations of anxiety and depression35. Based on previous studies, the MCID of the HADS was set to 1.5 36.

Assessment of pain catastrophizing. Catastrophic thinking associated with pain was evaluated using the PCS37. More intense catastrophic thinking increases the intensity of pain and daily life disability and increases the likelihood of the pain becoming chronic38. PCS is a self-administered questionnaire comprising 13 items; the scores for each question range from 0 to 4, with a possible total score of 0 to 52 points. A total of 30 points on the PCS corresponded to the 75th percentile of PCS score distribution in patients with chronic pain. Patients with a score above the 75th percentile were at high risk of developing chronic pain. MCID for PCS was between 38 and 44%40.

Statistical analyses. Statistical analyses were performed using the JMP Pro version 16 (SAS Institute Japan, Tokyo, Japan). Since CAARS separates Japanese standardized groups for men and women, the CAARS subscale scores for IOP patients with ADHD were analyzed separately for men and women with the Japanese standardized group. The results of the two-tailed independent samples t-test were expressed as mean differences and 95% confidence intervals (CIs). The changes in outcome variables from an individual baseline to the endpoint were analyzed using paired-sample tests. The points and percent improvement in pain NRS per dental diagnosis were evaluated using a one-way analysis of variance and Tukey's test for post-hoc analysis. The statistical significance level was set at P<0.05 for convenience; however, considering the risk of type 1 error, its interpretation should be limited to that of a reference to observe the overall trend only. In addition, P values adjusted by the Bonferroni method are provided as corrected P values.

Medication. The medication algorithm used by Dr. SK in his usual practice is shown in Fig. 1. In cases where the patient had no contraindications for the medication, the first drug of choice was the psychostimulant methylphenidate (MP)15. In cases where MP did not result in sufficient improvement or with intolerable adverse effects, the patient underwent combination therapy with MP and the selective norepinephrine reuptake inhibitor atomoxetine (ATX)15 or switched to ATX. In cases where ATX administration did not result in sufficient improvement or with intolerable adverse effects, the patient underwent combination therapy with APZ or switched to APZ. APZ is a partial agonist of dopamine D2 receptors; it is also called a dopamine system stabilizer as it suppresses excessive dopamine activity or activates it when dopamine is underactive15. APZ is thought to improve ADHD16, chronic pain41, and IOP42,43. In cases where APZ administration did not result in sufficient improvement or with intolerable adverse effects, the patient underwent combination therapy with clonidine, a noradrenergic alpha 2 receptor agonist that is effective for ADHD15, or switched to clonidine. The therapeutic effects on pain NRS, HADS, and PCS were judged 2 months after the prescription was revised with sufficient improvement, in the absence of any side effects that prevented the patients from continuing the drug.

Ethics approval and consent to participate. This study was approved by the Research Ethics Committee of Tokyo University Hospital (approval no. 3678). Informed consent was obtained orally from all subjects on the occasion of clinic visits, and all subjects provided written informed consent for participation in and publication of this study. Furthermore, the participants were guaranteed the opportunity to withdraw or refuse participation and informed that they could opt out of this study through the University of Tokyo Hospital website homepage.

Results

Clinical characteristics. To elucidate the clinical characteristics and treatment methods of intractable IOP with ADHD, of the 30 consecutive IOP patients referred, 25 patients with both IOP and ADHD (83.3%) were included in our analyses.

In the IOP subcategory, 14 patients had BMS, six had PIDAP, and five had PIFP. Table 1 shows the patients' demographic and clinical characteristics. The average pain duration was 107.2 months, signifying that the patients were refractory patients who had suffered long-term pain. Among the 25 patients with a history of receiving prescription medicine, 15 (60.0%) had a history of tricyclic antidepressant use, 10 (40.0%) of clonazepam use, nine (36.0%) of pregabalin use, 19 (76.0%) of other anticonvulsant use, 10 (40.0%) of duloxetine use, two (8.0%) of potent opioid use, six (24.0%) of tramadol hydrochloride use, six (24.0%) of nonsteroidal anti-inflammatory drug use, 25 (100%) of selective serotonin reuptake inhibitor and other antidepressant use, 19 (76.0%) of atypical antipsychotic use, and 12 (48.0%) of sleeping medication use.

Among the 25 patients, 19 (76.0%) had a history of psychiatric treatment, with somatic symptom disorder in nine (36.0%), depression in 10 (40.0%), anxiety disorders in five (20.0%), bipolar disorder in one (4.0%), posttraumatic stress disorder in one (4.0%), dissociation disorder in one (4.0%), and suicide attempt in one patient (4.0%). All 19 patients with a history of psychiatric treatment underwent psychiatric pharmacotherapy; however, there was no improvement in the symptoms of chronic orofacial pain.

The number of items of the diagnostic criteria for ADHD in the DSM-5 (inattention/hyperactivity-impulsivity) that each patient met is shown in Table S1 of Supplementary Information. Investigation on the ADHD subtypes indicated that three patients (12.0%) suffered from the inattentive type, two (8.0%) from the hyperactive type, and 20 (80.0%) from the combined type.

The mean scores of the eight subscales (A-H) of the CAARS-S and CAARS-O in patients with IOP are summarized in Table 2 for all patients and by sex. The comparison of CAARS scores between patients with intractable IOP with ADHD (men: 5, women: 20) and the general population in Japan (men: 245, women: 270)30 is also shown in Table 2, and the results are shown separately for men and women on the eight CAARS-S/O subscales because CAARS standardization is set by gender. Since one of the criteria for the diagnosis of ADHD is that the degree of its symptoms is disproportionate to the standard developmental level, and to increase the validity of the  ADHD diagnosis, we compared the CAARS scores of patients with intractable IOP with those of a standardized sample of Japanese subjects. The CAARS subscale T-scores were categorized at 5-point intervals, with T-scores of 45–55 considered “average”, 56–60 considered “slightly atypical”, 61–65 considered “mildly atypical”, 66–70 considered “moderately atypical”, and 71 or greater considered “markedly atypical”. A higher T-score for each subscale indicated more severe ADHD symptoms.

Among the eight subscales of the CAARS, subscales E, F, and G assess the extent to which a patient’s ADHD symptoms meet the criteria of DSM-IV; subscale H, called the ADHD index, indicates the extent to which a patient’s ADHD symptoms require treatment. Except for the CAARS-S subscale E for men, which was not significantly different from the standardized sample, both male and female patients with intractable IOP in this study had significantly higher scores on subscales E, F, and G on both CAARS-S/O compared with standardized samples. On subscale H of the CAARS-S/O, both male and female patients with intractable IOP scored significantly higher than the standardized sample on the CAARS-S/O.

Furthermore, although not shown in Table 2, among the eight subscales of the CAARS-S/O for patients, male patients had significantly higher scores than female patients on CAARS-O subscale A (mean difference: 14.8; CI, 3.3–26.3; P=0.01), CAARS-O subscale E (mean difference: 20.6; CI, 6.0–35.1; P=0.008), CAARS-O subscale F (mean difference: 19.8; CI, 4.0–35.6; P = 0.02), CAARS-O subscale G (mean difference: 21.2; CI, 7.2–35.1; P=0.004), and CAARS-O subscale H (mean difference: 12.6; CI, 1.1–24.1; P=0.03).

Medication regimen and outcomes. Five of the 25 patients with IOP diagnosed with ADHD did not undergo pharmacotherapy (patients who did not wish to receive pharmacotherapy received outpatient cognitive behavioral therapy with Dr. SK as an alternative protocol). The changes in the pain scale scores before and after treatment for the 20 patients (BMS: 12, PIFP: 5, PIDAP: 3) who underwent pharmacotherapy according to the treatment regimen used in this study are shown in Table 3. In the treatment group, the maximum, minimum, and average pain NRS improved by 2.8±2.5, 1.6±2.6, and 2.7±2.6 points, respectively. PCS showed an improvement of 13.1±14.8 points, indicating statistically significant differences.

The administered dose of each medication and the percentage improvement in the average NRS for pain are shown in Table S1 of Supplementary Information. The average dose of MP monotherapy was 39.6±19.7 mg/day, with a 41.7±45.0% improvement. The average doses of the combination of MP and ATX were 57.0±26.0 mg/day and 76.7±45.1 mg/day, respectively, with a 46.7±61.1% improvement. The average doses of the combination of ATX and APZ were 72 mg/day and 6 mg/day, respectively, with a 100±0.0% improvement. The average dose of ATX monotherapy was 110.0±20.0 mg/day, with a 53.1±22.6% improvement. The doses of the combination of  ATX and APZ were 80.0 mg/day and 6.0 mg/day, respectively, with a 100±0.0% improvement. The APZ monotherapy dose was 7.5±3.9 mg/day, with 68.3±16.9% improvement. The CL monotherapy dose was 300.0 mg/day, with a 20.0±0.0% improvement. There were no significant differences in the NRS improvement scores or percentages according to sex, age, or medication. When investigated using the dental diagnosis (BMS, PIDAP, and PIFP), one-way analysis of variance showed no significant difference in the number of improved NRS points  (BMS: 2.7 ± 2.8, PIDAP: 0.0 ± 1.0, PIFP: 4.4 ± 0.9) (F(2,19) = 3.36 P = 0.059); however, there was a significant difference in the percentage of improved NRS (BMS: 50.7 ±38.9%, PIDAP: −1.9 ±17.2%, PIFP: 79.8 ±23.2%) (F(2,19)=5.50 P<0.05), and post-hoc analysis (Tukey's test) showed a significant difference in PIDAP vs. PIFP  (P<0.05).

【Contact】Email: george.deng@wecistanche.com / WhatsApp:008613632399501/Wechat:13632399501