Patients experiencing chronic pain are known to have encountered traumatic experiences and/or have developed post-traumatic stress disorder (PTSD). The treatment of such patients tends to be difficult because they usually exhibit severe pain, PTSD symptoms, anxiety, depression, functional impairment, and greater opioid use (1). Attention deficit hyperactivity disorder (ADHD), a neurodevelopmental disorder, is frequently associated with chronic pain, and the two are closely related (2–8). Furthermore, ADHD increases the chances of developing PTSD after experiencing a traumatic event because the individual exhibits inattentive and impulsive tendencies (9).

Of note, patients diagnosed with PTSD and ADHD are more likely to show cognitive dysfunctions in attention, working memory, executive function, and impulse control (10, 11), and present with functional somatic syndromes (9). The publication “The Body Keeps the Score,” reported that almost all of the 12 children who had suffered domestic abuse and visited the children’s clinic at the Massachusetts Mental Health Center had a previous diagnosis of ADHD (12). A meta-analysis between ADHD and PTSD showed that an ADHD diagnosis was associated with a four-fold increase in the risk of developing PTSD. Conversely, encountering traumatic experiences culminating in the development of PTSD was associated with a two-fold increase in risk of having comorbid ADHD (9). A recent genome-wide association study of 11 major psychiatric disorders, including ADHD, autism spectrum disorder, schizophrenia, mood disorders, and obsessive–compulsive disorder, showed that ADHD and PTSD were the most closely genetically correlated (13). Therefore, it has been suggested that ADHD and PTSD share a common neurobiological pathology (9). While patients with PTSD and ADHD are more difficult to treat, more likely to drop out of treatment, and tend to exhibit severe cognitive dysfunction, it was shown that the ADHD drug, atomoxetine (ATX), is effective in patients diagnosed with both disorders (10).

To our knowledge, there are no previous reports on comorbidity of chronic pain with PTSD and ADHD, therapeutic potential of ATX in improving cases of chronic pain with coexisting PTSD, and evaluation of cerebral blood flow in conjunction with the course of treatment for chronic pain with ATX. However, if chronic pain with PTSD is associated with ADHD, and if that pain and brain function can be improved with ADHD medications, it could provide an entirely novel solution against pain, thus, helping patients who are refractory to treatment. In this study, we present a case, in which ATX improved chronic pain with PTSD and improved cerebral blood flow.

The patient was a 56-year-old woman (height, 157 cm; weight, 45 kg); she had no childhood experiences of abuse or trauma and was an active girl with many friends. She graduated from high school and worked in an office until she married at the age of 22 years. No relevant medical history was reported in her family. She had a caring personality and took pleasure in helping others. She was in an adulterous relationship with her common-law husband, Mr. A, since 1995; she divorced her legal husband in 1998 because of being a victim of domestic violence (DV) and his relationships with other women.

The patient’s chief complaints were facial pain, headache between the eyebrows, and pain in the right upper extremity, which occurred at the site of another DV beating by Mr. A over a 6-year period from 1996 to 2002. Mr. A’s DV was severe, and approximately every 3 days he would repeatedly hit the patient all over her body with an iron pipe or strike her in the face with his fists. The patient could not leave him because of her responsibilities for debts of the company she ran with Mr. A. In January 2002, Mr. A was arrested and sentenced to 10 years in prison for repeated and prolonged sexual assaults on the patient’s daughter (who lived with them), and for confinement and attempting poisoning of the patient’s mother. On March 7, 2002, the patient’s mother was admitted to another hospital for treatment. The patient and her daughter were taken into custody and visited our hospital for physical and mental medical care.

To the best of our knowledge, this is the first reported case of ADHD coexisting with chronic pain accompanied by PTSD. It is reported that in psychiatric practices, the diagnosis of more than 80% of adult ADHD cases is missed (28). As cases of chronic pain with PTSD are often assigned to pain clinicians or orthopedic surgeons who are unfamiliar with ADHD treatment, ADHD comorbid with chronic pain is more likely to be overlooked. Hence, in cases of chronic pain with comorbid PTSD, aggressive screening for ADHD should be considered. In the present case, ADHD comorbidity was highly suspected by screening using CAARS, although there was no previous diagnosis of ADHD.

The patient’s tendency to be “caring and over-indulgent” corresponds to the hyperactivity and impulsivity component of ADHD, and her “inability to organize her thoughts quickly and cause an argument to defend herself against an attack” corresponds to the inattentiveness symptoms of ADHD. These symptoms of ADHD accompanied by low self-esteem (CAARS-S/O subscale D. Problems with Self-Concept) were presumed to have triggered DV both from her legal husband and Mr. A. It is known that at the site of a DV-related injury, excessive muscle tension can occur in anticipation to reduce the impact of the next violence, resulting in pain (29). In this case, the patient developed chronic pain in the face, head, and right upper limb, consistent with the DV injury sites.

In this case, ATX, an ADHD treatment, improved chronic pain with PTSD. The relationship between prefrontal cortex performance and noradrenaline (NA) and dopamine (DA) levels follows an “Inverted U-shaped” function. Maximal performance is achieved when both neurotransmitters are in moderation (30). ATX inhibits NA transporters in the prefrontal cortex and moderates NA and DA transmission, thereby enhancing the prefrontal cortex performance and improving ADHD symptoms (30). Furthermore, the prefrontal cortex is also functionally coupled with the descending pain inhibitory system, acting as a virtual filter to reduce unpleasant sensations like pain and itching (31, 32). Therefore, ATX has been reported to improve chronic pain associated with ADHD (7, 33).

Exposure to intense chronic stress, such as PTSD, causes phasic over-firing of NA and DA in the prefrontal cortex, exacerbating anxiety, and inattention due to hyperarousal. However, “long-term treatment” with ATX restores tonic neurotransmission of NA and DA in the prefrontal cortex, down-regulates phasic over-transmission of NA and DA, and desensitizes postsynaptic NA and DA receptors. As a result, the prefrontal cortex performance is increased, hyperarousal-generated anxiety is reduced, and ADHD-related symptoms are improved (30). In addition to improvements in CAARS, in our case, the ATX also improved scores on the IES-R sub-scales “Intrusion,” reflecting excessive attention to repetitive and intrusive trauma-related thoughts, and “Hyperarousal,” reflecting over-arousal. Our findings suggest that the improvement of chronic pain with PTSD with ATX is consistent with the theoretical pharmacological effects of ATX as described above.

The improvement in pain scores reported by the NRS and HADS was associated with higher ATX doses (90–120 mg/day). However, ATX administration was intermittent because of side effects and fluctuations recorded on each scale. When ATX was re-entered at a lower dose of 40 mg/day from Day 1,470 to Day 2,336, the degree of improvement was more modest than that at higher doses. Treatment was not interrupted and was maintained for longer periods, which resulted in improvements in pain-related measures, ADHD symptoms, and PTSD symptoms. The recommended ATX dose for adults is 80–120 mg/day (34), but when significant side effects emerge, a lower dose (e.g., 40 mg/day) with emphasis on “long-term maintenance” may lead to more stable improvements.

In the present case, along with the improvement in chronic pain with PTSD by ATX, there was also an improvement in cerebral blood flow, which, to our knowledge, is an insight that is firstly described. Functional brain imaging studies of patients with PTSD have reported hypo-reactivity of the medial prefrontal cortex, hyper-reactivity of the amygdala, and abnormal hippocampal responses (35). As impaired prefrontal cortex performance in patients with PTSD is regulated via NA and DA balance, it was thought that ATX may be successful in treating chronic pain associated with PTSD. Evidence for this was observed in the improvement of blood flow in the prefrontal cortex in three SPECT sessions conducted in our case, following ATX treatment. Previous studies using SPECT of ATX have reported that ATX reduced the bioavailability of DAT in the striatum in adolescents with ADHD (36) and increased cortical blood flow in the affected area in aphasia after stroke (37). In the present case, SPECT showed blood flow improvement in both striatum and cortex, which was consistent with previous studies. Changes in SPECT images observed in parallel with the course of treatment in the present case suggest that SPECT could be an objective measure of the effectiveness of chronic pain treatment (38).

There are three limitations to this study. First, the improvement in cerebral blood flow in this case may not only reflect the effect of ATX, but also be attributed to the patient’s resumption of work and reintegration into society. Second, as the course of treatment in this case was 6.5 years, the idea that the long passage of time since the onset of DV may have naturally reduced PTSD symptoms, which in turn may have improved pain, ADHD symptoms, and cerebral blood flow, should not be fully ruled out. Third, prolonged exposure, cognitive processing therapy, eye movement desensitization, and reprocessing therapy are usually recommended as treatments for PTSD (39). However, it has been noted that patients with PTSD tend to be less focused to receive these therapies in the first place, are less likely to benefit from them, and are more likely to drop out of treatment (9, 10). Moreover, because this tendency is more pronounced in cases of PTSD with ADHD, it has been suggested that ADHD medications should be used prior to receiving PTSD-specific treatment. In addition, as comorbid PTSD and ADHD can mutually exacerbate each other’s symptoms, it can be expected that medication for ADHD will also reduce PTSD symptoms (10, 40). Furthermore, it has been noted that there is a lack of psychologists in chronic pain healthcare settings, such as outpatient pain clinics, who are able to provide specialized treatment for PTSD (41). Therefore, medication for cases of PTSD with comorbid ADHD, as that presented in this report, could be an important treatment approach.

This study showed that chronic pain with PTSD may be comorbid with ADHD, and that ATX can improve cerebral blood flow and chronic pain associated with PTSD. Although the diagnosis of ADHD comorbid with chronic pain is easily missed, aggressive screening is important because once the diagnosis of comorbidity is confirmed, the option of an ADHD treatment, such as ATX, can be selected. Based on our results, ATX may be an ideal candidate for treatment for chronic pain after PTSD with ADHD. However, to our knowledge, this is the only case report reporting an association between chronic pain after PTSD and ADHD. Further research is needed to establish the inter-relationship between these disorders and their treatment.

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

This study was approved by the Research Ethics Committee of Tokyo University Hospital (approval no. 3678). Written informed consent was obtained from the patient for the publication of this case report.

SK, S-IN, and KM conceived the work and interpreted the data. SK, MT, and NS collected the data. SK, MT, and ToM managed the data. SK, MT, and TaM drafted the manuscript. SK, TaM, S-IN, and KU prepared the final manuscript. All authors approved the final manuscript.

This study was supported by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (grant number JP20K07755).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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