The effect of methylphenidate on pain perception thresholds in children with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) in pediatric cases is characterized by hyperactivity, impulsivity, and/or inattention and affects 5% of children worldwide. The symptoms impact on cognitive, educational, behavioral, and emotional functioning [1]. Children with ADHD also exhibit problems with motor coordination, balance, and somatosensory functions outside the primary clinical area [2‐4].

Despite being one of the most extensively researched psychiatric disorders, the mechanism underlying the symptoms of ADHD is not completely understood [5]. Numerous studies have shown that ADHD has substantial biological origins, including problems in neurotransmitter systems in the brain. Genetic, imaging, and pharmacological studies support the idea that ADHD is primarily caused by dopamine dysfunction [6]. Moreover, a functional dopaminergic neurotransmitter system is of crucial importance, not solely for higher cognitive functions, but also for components of human perception such as olfaction, audition, vision, and sensory sensitivity [7‐10]. Given the complex character of ADHD, the majority of current research has focused on cognitive and behavioral abilities linked to attentive and executive functions, while the sensory dimension has received little attention. Increasing evidence indicates that dopamine also plays a role in other perceptive deficiencies, such as color perception, tactile perception, and pain perception, in addition to the fundamental symptoms of ADHD [11‐13].

Stimulants used to treat ADHD, such as methylphenidate (MPH) and amphetamine, help improve attention, concentration, and impulse control by increasing levels of neurotransmitters such as dopamine and norepinephrine in the brain [14]. Methylphenidate has been shown to exhibit positive effects on emotional processing, cognitive motivation, working memory, and social behavior, in addition to core symptoms in ADHD [15‐18]. The therapeutic effects of MPH are attributed to its ability to produce slow, steady increases in dopamine that mimic tonic firing in the brain [19]. However, the side-effects of MPH, such as appetite suppression, insomnia and negative emotional symptoms, should also be remembered [20].

Accumulating data suggest that dopamine is also implicated in pain processing [21, 22]. Many regions of the central nervous system involved in pain processing contain a high density of dopamine receptors, whose activation can be analgesic in both humans and animals [23, 24]. Moreover, a small number of clinical researchers have asserted that dopaminergic medications help alleviate chronic pain [25, 26].

The dopaminergic anomalies exhibited by individuals with ADHD are likely to result in altered pain perception. Pain sensitivity in children with ADHD is one of the least frequently studied aspects of the condition. However, this may be particularly important to these children, as they are more likely to experience painful events due to their higher accident rates [27].

A limited number of studies have examined pain perception in children with ADHD. Scherder et al. evaluated the pain perception of children and adolescents with ADHD, their unaffected siblings, and healthy controls using the children’s pain inventory [28]. Those authors found no differences in pain perception between the groups. In the following part of that study, children and adolescents with ADHD and their unaffected siblings were asked to donate blood and to evaluate the intensity and emotionality of pain experienced following venipuncture. Children and adolescents with ADHD reported lower pain perception compared to unaffected siblings [28]. Northover et al. compared sensory pain between adolescents with pure ADHD and those with ADHD plus conduct disorder (CD) through the application of thermal heat to the skin of the palm of the hand. Although adolescents with ADHD plus CD exhibited considerably longer pain threshold times and were more tolerant to pain than those with pure ADHD, the physiological responses and skin conductance levels were identical in the two groups [29].

Research has also investigated pain in adults with ADHD and revealed a decrease in pain thresholds. In one study, in which pain sensitivity was evaluated psychophysically, the ADHD participants without methylphenidate (MPH) had a considerably lower cold pain threshold and cold tolerance compared to controls. Both the cold threshold and tolerance of ADHD patients treated with MPH increased significantly in comparison to those who did not receive medication. That study suggests that individuals with ADHD are more sensitive to pain and that MPH may have antinociceptive qualities [12]. Recent research indicates that ADHD increases pain perception and that generalized pain is more common in patients with ADHD than in control individuals [30, 31].

The purpose of this study is to contribute to the literature concerning the relationship between ADHD diagnosis, MPH therapy, and pain thresholds, since findings regarding the change in pain perception in children with ADHD are both scarce and inconsistent. In terms of deficits in dopaminergic pathways in ADHD and the mechanism of action of MPH in these pathways, we hypothesized that the pain threshold would be lower in patients with ADHD and would differ between the MPH, non-MPH, and healthy control groups.

One hundred twenty-three individuals were included in the study, with 41 age- and gender-matched participants in each group. The average age was 10 (8.0-12.25) years. Each group consisted of 11 (26.8%) girls and 30 (73.2%) boys. Mean CPRS-R:S scores were 42.11 ± 18.72 for all ADHD patients, 47.34 ± 18.38 in the ADHD without MPH group, and 36.87 ± 17.77 in the ADHD with MPH group.

Chronic pain was present in 34 (41.46%) of all ADHD patients, in 19 (46.34%) members of the ADHD without MPH group, 15 (36.58%) of the ADHD with MPH group, and 19 (46.34%) of the healthy control group. No statistically significant difference was observed between the three groups in terms of the presence of chronic pain (p = 0.743).

Pain severity was 50 (30.0–50.0) mm in both the ADHD without MPH and ADHD with MPH groups, compared to 40.0 (40.0–50.0) mm in the healthy control group. No statistically significant difference in pain severity was observed between the two ADHD groups (p = 0.907).

The analysis results of between all ADHD patients and the healthy controls in terms of PPT values are given in Table 1.

Measurements and comparisons between the three groups’ PPT values are given in Table 2.

No relationships were determined between CPRS:S scores and PPT values in the frontal, trapezius, supraspinatus, deltoid, trochanter, tibia, lateral epicondyle, or thoracal 2 regions in the ADHD patients (p = 0.739, 0.992, 0.969, 0.981, 0.075, 0.311, 0.921, and 0.812, respectively). No relationships were observed between CPRS:S scores and PPT values in the thoracal 2, deltoid, frontal, trapezius, supraspinatus, lateral epicondyle, trochanter, or tibia areas in the ADHD with MPH group (p = 0.700, 0.831, 0.745, 0.823, 0.827, 0.867, 0.250, and 0.532, respectively). Finally, no relationships were found between CPRS:S scores and PPT values in the frontal, trapezius, supraspinatus, thoracal 2, deltoid, lateral epicondyle, trochanter, or tibia areas in the ADHD without MPH group (p = 0.079, 0.365, 0.332, 0.808, 0.922, 0.395, 0.121, and 0.520, respectively).

This study compared the presence and perception of chronic pain, and pain thresholds using the pressure pain test in children with ADHD and healthy controls and examined the relation of MPH treatment on these parameters. The presence of chronic pain and pain perception were similar between the groups. Children with ADHD had lower pain thresholds than the healthy controls. However, lower regional pain thresholds were observed in the ADHD group without MPH compared to both the healthy control and ADHD with MPH groups. Although the pain thresholds of the ADHD with MPH group were regionally lower than those of the healthy controls, low pain thresholds were observed in fewer regions compared to the ADHD without MPH group.

To the best of our knowledge, this study is the first to evaluate both chronic pain perception and pain thresholds in children with ADHD using the pressure pain test applied to eight parts of the body. This study contributes to the literature by showing that pain thresholds are low in children with ADHD and supports previous research focusing on adults [12, 30]. Similarly to these studies, children with ADHD were more sensitive to pain sensation, and MPH may help normalize the pain experienced by these individuals by raising their pain thresholds. However, our findings were inconsistent with some previous studies assessing pain thresholds. Scherder et al. reported that children with ADHD exhibited lower pain perception than their healthy siblings. In that study, siblings were enrolled instead of healthy controls, and psychiatric disorders other than ADHD were not excluded in the siblings [28]. Northover et al. found that ADHD may be associated with high pain thresholds. However, that study compared pain sensitivity in children with ADHD with and without diagnoses of comorbid conduct disorder, and no healthy control group was enrolled. It was not therefore possible to determine whether individuals with ADHD have lower or higher pain sensitivity. However, the association between ADHD severity and higher pain sensitivity in that study is compatible with our own findings concerning the disorder [29]. However, the present study found no relation between symptom severity and pain thresholds. Studies with larger sample sizes are now needed to clarify this relationship.

Scarce and inconsistent findings have been reported regarding changes in pain perception in children with ADHD. Among the previous studies evaluating pain perception in ADHD, Scherder et al. found no difference in pain perception compared to controls, a finding consistent with the present study [28]. A different study evaluating the effect of MPH treatment on pain perception found that children and adolescents with ADHD without MPH treatment exhibited lower pain perception compared to both healthy controls and ADHD patients treated with MPH [39]. The difference may be attributable to methodological differences in the assessment of pain perception. Wolff et al. did not exclude additional psychiatric disorders in their study, and used parental ratings to assess pain perception. However, external ratings may not be accurate since pain is a subjective perception and cannot be accurately evaluated by someone other than the individual concerned (31). At the same time, in that study, children with ADHD were asked to estimate the perceived severity of pain deriving from painful events experienced in the previous three months. The present study evaluated the perceived severity of chronic pain (persisting for more than three months) experienced by children with ADHD without additional psychiatric disorders. As children with ADHD were still experiencing this pain, it may be assumed that less memory bias was involved in determining the perceived severity of pain. However, the suggestion in that study that MPH increases the perception of pain cannot be completely excluded in the present research, because we did not consider the duration of medication use in the children in the treatment group. The use of medication may have normalized pain perception in children with ADHD. A higher prevalence of chronic pain was observed in women diagnosed with autism spectrum disorder (ASD) and/or ADHD in one study [31]. The fact that only women were selected in that study and that diseases that may affect pain perception, such as ASD, were included may explain the discrepancy in the present study.

Deficits in time perception [40], emotional perception skills [41], and self-awareness of cognitive functions have been reported in children with ADHD [42, 43]. Boys with ADHD tend to exaggerate their performances in order to maintain a positive self-image [44]. Our study found a lower pain threshold in the ADHD group, which may have led children with the disorder to report more chronic pain perception. However, pain perception was similar between the groups in the present study. This may be attributable to the low awareness of sensory perception in children with ADHD. Another explanation may involve an effort to underestimate their pain, similar to the positive bias in children with ADHD concerning their competence.

The low pain threshold in ADHD may be co-present with the etiological consequences of the disorder. First, dysfunction of the locus coeruleus (LC) has been described in ADHD through a defect in the number of noradrenergic receptors [45]. A deficiency in the LC/noradrenergic system [46], part of the pain system [47] and which exhibits pain-suppressive properties, may play a role in the reduced pain threshold in ADHD [28]. Second, dopamine has been shown to affect the stages of pain processing [21]. It has been suggested that dysfunction of dopamine pathways in ADHD [48] may lead to changes in pain thresholds. Third, corticotropin-releasing hormone (CRH), secreted by the hypothalamic-pituitary-adrenal (HPA) system, exhibits an analgesic effect [49]. The decreased CRH activity due to the hypoactive HPA axis observed in ADHD [50] may lead to a lower pain threshold. Dysfunction in these three pain-related systems may cause children with ADHD to be more sensitive to painful stimuli by lowering the pain threshold. Studies have reported that individuals who have experienced significant pain in their lives have a lower tolerance to cold pain [51]. Individuals with ADHD are more likely to experience painful situations due to suffering more accidents and greater exposure to medical procedures [52]. The greater pain experiences in children with ADHD may increase pain sensitivity by lowering the pain threshold.

The model of the vigilance regulation in ADHD (hypoarousal hypothesis) interprets patients’ hyperactivity and sensory input seeking as an autoregulatory attempt to balance wakefulness by creating a stimulating environment. Hypoarousal in ADHD has mainly been demonstrated by means of skin conductance and electroencephalography [53]. The low pain threshold in ADHD may make these patients more sensitive to painful stimuli due to autoregulatory sensory seeking. Stimulants effectively reduce attention deficits and sensation-seeking behavior in individuals with ADHD [54, 55]. This may explain the change in pain threshold in our ADHD group treated with MPH.

In the present study, the pain thresholds of the ADHD with MPH group were higher than those of the group not receiving MPH. The analgesic effect of MPH treatment has been reported in several chronic pain conditions [56, 57]. In a recent randomized placebo-controlled trial, MPH was found to cause an increase in the cold pain threshold in healthy men [58]. Studies have shown that dopamine agonists such as amphetamine cause opioid secretion in healthy individuals [59, 60]. The release of opioids after stimulants in children with ADHD may explain the antinociceptive effect and the change in pain threshold in the treatment group. MPH can also inhibit norepinephrine reuptake in addition to the dopaminergic system [61]. The analgesic effects of drugs with norepinephrine reuptake inhibitor properties [62] may explain the difference in the pain threshold in the ADHD with MPH group. However, the higher pain threshold value in the ADHD group receiving MPH may also be due to the drug’s general therapeutic effect [12]. The increase in the ability to maintain performance of an activity and task with treatment in individuals with ADHD may explain the change in pain threshold.

The particular strengths of this study are that pain thresholds were measured using induced pain, and that the clinician who measured this was blinded to the study groups. Research has emphasized that MPH affects pain perception and thresholds in ADHD, and this effect should be evaluated [12, 29]. The fact that the treatment-naïve ADHD group in the present study had never used MPH before because they had not been previously diagnosed showed that the change in pain threshold in ADHD was independent of the drug’s therapeutic effect. Other strengths of this study are that it considered the patients’ medication use status and excluded those with additional psychiatric disorders, in contrast to other studies of pain in ADHD.

However, this study also has a number of limitations. Pain threshold and pain perception are distinct concepts. This study evaluated pain perception in chronic pain and pain thresholds with induced pain. Investigating pain perception during induced pain may lead to a better understanding of these pain-related variables. Using physiological measures (e.g., electrodermal activity) to assess sensitization to induced pain may yield a better understanding of pain perception changes in children with ADHD. Pain thresholds may vary due to exposure to external events, such as harsh parental discipline and peer bullying [29]. Experiencing the pain of social rejection, exclusion, or loss involves the same neural areas that process physical pain [63]. The relationship between pain perception and ADHD should be evaluated by considering gender and the type of ADHD, and also comorbid psychiatric conditions. Future research should be designed to take these factors into account.

The findings of this study show that children with ADHD have a low pain threshold, and that MPH may raise this. Experimental investigation of the dopaminergic and opioid systems in the brain will provide a better understanding of pain changes in ADHD. Families and clinicians must be aware of situations that may cause pain in children with ADHD. These patients’ low threshold for pain may lead them to experience more pain. Finally, the fact that children with ADHD do not report pain to painful stimuli does not necessarily mean that they do not experience it.