Chronic Pain and Muscle Tension in ADHD—Neurophysiological Correlates

For information on chronic pain and increased muscle tone as symptoms of ADHD, see Chronic Pain / Muscle Tension in ADHD in the Symptoms chapter
For information on fibromyalgia as a comorbidity of ADHD, see Fibromyalgia as a Comorbidity of ADHD in the article “Diagnosis / Comorbidity in ADHD / Somatic Comorbidities in ADHD”

1. Chronic Pain—Development and Causes¶

1.1. Chronic Pain and Dopamine¶

The dopamine system may be involved in ADHD, chronic pain, and the modulation of muscle tone.¹² Chronic pain, depression, and anxiety disorders show a high rate of comorbidity.³ Up to 80% of people with severe depression or Parkinson’s disease report comorbid pain, 2 to 3 times more frequently than persons without these conditions.³⁴ In Parkinson’s disease, musculoskeletal pain is the most commonly reported type of pain, occurring in 40% to 90% of cases.⁵⁴

The dopamine agonist apomorphine has analgesic effects.⁶ Lesions of dopaminergic terminals or dopaminergic neurons in the midbrain (striatum, substantia nigra, VTA) cause pronounced pain responses.⁷ Levodopa, used to treat Parkinson’s disease, alleviates chronic pain.⁸
The dopaminergic mesolimbic reward circuit and the endocannabinoid system are involved in the pathophysiology of chronic pain, specifically in both pain perception and pain relief.³⁹¹⁰
In anesthetized rats, painful pinching of the tail during the stimulus triggers a release of dopamine in the dorsal striatum and the NAc core, and after the stimulus ends, a release of dopamine in the NAc shell.¹¹
Fibromyalgia, a chronic pain syndrome, is associated with reduced dopamine release¹²¹³ and reduced availability of D2/D3 receptors in the cortex¹⁴.
The mesolimbic reward circuit plays a role in pain perception and in the anticipation of pain relief.¹⁵

Painful stimuli are encoded by the mesolimbic dopamine circuit. Chronic pain reduces tonic dopamine levels. A pain-induced reduction in tonic dopamine correlates with an increased evoked phasic dopamine release.¹⁶ This is consistent with the model developed by Grace of reduced tonic and increased phasic dopamine firing in ADHD. See Tonic and Phasic Dopamine in Explanatory Models for ADHD in the section Dopamine In the chapter Neurological Aspects.
People with chronic pain show reduced responsiveness within the mesolimbic dopamine system to significant stimuli, lower D2 receptor binding, and lower presynaptic dopamine activity in the striatum at rest and following an acute pain stimulus.¹⁷ In animals, chronic pain leads to reduced c-Fos activation in the VTA, decreased total dopamine levels, and a reduction in D2 receptors in the striatum.¹⁷
Conversely, a reduction in dopamine in the brain caused by acute depletion of the dopamine precursors phenylalanine and tyrosine resulted in increased subjective pain sensitivity (the degree to which pain was perceived as unpleasant) without altering sensory pain perception.¹⁸
In 6-OHDA mice, in which dopamine synthesis is chemically impaired and which thus serve as an animal model for ADHD, increased pain sensitivity was observed. This pain sensitivity was likely mediated by α- and β-adrenergic as well as D2/D3 receptors. Atomoxetine¹⁹, like MPH²⁰, was able to reduce the increased pain sensitivity associated with ADHD.
Stimulation of the substantia nigra, one of the brain’s two main sources of dopamine, alleviates pain by activating spinal cord neurons via dopaminergic signaling pathways.^{2122 23} Painful stimuli trigger a release of dopamine in the dorsolateral striatum, which correlates with the subjective perception of pain intensity. Similarly, the ventral striatum is clearly linked to the emotional dimension of the human pain process and to pain anticipation.²⁴

In Parkinson’s disease, which is also characterized by a dopamine deficiency, 30 to 50 percent of people with ADHD suffer from increased pain sensitivity.²⁵ This can be alleviated with dopaminergic medication²⁶, such as levodopa or deep brain stimulation.²⁷

Conversely, in schizophrenia—which is associated with elevated dopamine levels—pain perception is reduced.²⁸²⁹

According to Stray, motor disinhibition and increased muscle tone in ADHD are directly associated with dysregulation of the dopamine and norepinephrine systems.³⁰
This is consistent with the fact that, in ADHD, increased muscle tone is reduced by methylphenidate³¹ and that a norepinephrine reuptake inhibitor (orphenadrine, Norflex®) acts as a skeletal muscle relaxant. Norepinephrine reuptake inhibitors are also used as ADHD medications (atomoxetine, viloxazine).

A study reports an elevated sphingomyelin-to-ceramide ratio in patients with lower back pain³² (who also fall within the typical ADHD spectrum). Acid sphingomyelinase (ASM, sphingomyelin phosphodiesterase 1, encoded by the ADHD candidate gene SMPD1) Breaks down sphingomyelin into ceramide. When sphingomyelin levels are high and ceramide levels are low, this suggests low S-ASM activity. Given this, FIASMA (ASM inhibitors) such as amitriptyline could be detrimental and increase the risk of muscle tension. It remains to be seen whether this theory holds true for ADHD.

To date, research on pain sensitivity has been conducted using only two animal models of ADHD:³³

SHR, an animal model for ADHD, showed

• reduced pain relief (analgesia) in response to harmful stimuli³⁴
• a decrease in norepinephrine in the dorsal horn of the spinal cord in response to nociceptive stimuli. Normally, there would be an increase.³⁵ This decrease suggests reduced endogenous pain suppression (analgesia) in ADHD.³³
• More active norepinephrine synthesis under conditions of pain³⁵ n SHR showed:
  • more enzymes that synthesize norepinephrine in the dorsal horn of the spinal cord
  • elevated extracellular norepinephrine levels in the dorsal horn of the spinal cord
• Excessive norepinephrine synthesis in a pain-free state could lead to overexpression of NET and downregulation of the α2A receptor. This could lead to reduced norepinephrine activity during NSIA and weakened descending pain inhibition.³³ SHR showed:
  • more norepinephrine transporters in the posterior horn of the spinal cord
  • fewer α2A receptors in the dorsal horn of the spinal cord
• Atomoxetine reduced pain sensitivity³⁵

Mice treated with 6-hydroxydopamine (6-OHDA), another animal model of ADHD, showed³⁶

• as a sign of increased baseline nociceptive sensitivity

  • increased licking of the hind legs in response to thermal or mechanical stimuli
  • increased sensitivity to pathological inflammatory stimuli

• in lamina II of the posterior horn of the spinal cord were

  • the inhibitory synaptic connections remain unchanged
  • the excitatory connections were significantly increased
    • This could promote pain sensitization

• Pain sensitivity in 6-OHDA mice is thought to be mediated by¹⁹

  • α-adrenergic receptors
  • β-adrenergic receptors
  • D2 receptors
  • D3 receptors

• Increased spontaneous activity of the ACC-PI signaling pathway.³⁶ The ACC-PI signaling pathway (from the ACC to the posterior insula, PI) controls central sensitization mechanisms. ADHD-related ACC-PI activity can increase or decrease pain sensitivity and may trigger hyperactivity (ergomania).³³

  • caused by a sex-specific neuroinflammatory response to dopamine (DA) neuron loss induced by 6-OHDA³⁷
    • Males: Dopamine loss triggered inflammation only in the ACC
      • Consequences:
        • Hyperactivity
        • no increased sensitivity to pain (no hyperalgesia)
    • Females: Dopamine depletion triggered inflammation in the ACC-PI signaling pathway
      • Consequences:
        • no hyperactivity
        • increased sensitivity to pain (hyperalgesia)
      • may explain why
        • The prevalence of fibromyalgia^{3839 40 41} and other pain disorders⁴²⁴³ is higher among women
        • Hyperactivity is less common in women
  • Increased ACC activity in response to mechanical stimulation of the contralateral hind limb³⁶
    • resulting in an increased firing rate in second-order nociceptive neurons in the dorsal horn of the spinal cord
      • further lowering the pain threshold
  • Inhibition of the ACC-PI pathway suppressed action potentials in the dorsal horn and increased the pain threshold³⁶

• Atomoxetine was able to reduce pain sensitivity in 6-OHDA-treated mice¹⁹

The endocannabinoid system modulates the dopaminergic system in a variety of ways, including in relation to reward processing, and also plays a crucial role in pain perception.³
More on the interaction between endocannabinoids and dopamine in the article “Cannabinoids” in the “Neurotransmitters” section of the “Neurological Aspects” chapter.

1.2. Additional Mechanisms Underlying Chronic Pain in ADHD¶

The following are discussed as additional common mechanisms underlying ADHD and chronic pain:¹

• Genetic factors⁴⁴

• Trauma⁴⁴⁴⁵

• Pain receptors (opioid receptors, cannabinoid receptors, alpha-2 adrenoreceptors)⁴⁴

• GABAergic neurosteroids (allopregnanolone, pregnanolone), progesterone⁴⁴

• HPA axis dysfunction⁴⁴

• Neuroinflammation⁴⁴⁴⁶

• BDNF⁴⁴

• altered sensitivity to pain⁴⁶

• prolonged muscle contraction, high muscle tone⁴⁷

  • Nearly 90% of children and adults with ADHD exhibit motor dysregulation, which leads to persistently high muscle tone
  • This could contribute to the development of chronic muscle pain in ADHD⁴⁸
  • A highly significant correlation was found between muscular regulation problems and pain intensity⁴⁸
    • The ADHD group showed increased muscle tone in the neck, back, chest, shoulders, hips (i.e., the axial and proximal stabilizing muscles), and legs⁴⁸ Increased muscle tone in these muscles was also observed in children with ADHD.

• Histamine pathway⁴⁹

1.3. Causes of Fibromyalgia¶

For fibromyalgia, an interplay of several pathogenic mechanisms has been proposed as a neurophysiological pathway:⁵⁰⁴⁵

• Increased activity in the excitatory pain pathways from the bottom up
  • Increase in neurotransmitters such as
    • Substance P
    • Nitrogen oxide
    • Nerve growth factor (NGF)
    • Glutamate.
• Reduced activity in inhibitory top-down pathways
  • reduced levels of
    • Dopamine
    • Norepinephrine
    • Serotonin
    • endogenous opioids
• As a consequence of the imbalance caused by overactive pain pathways and underactive prefrontal inhibition:
  • functional central sensitization
  • which has evolved into a structured, centralized awareness-raising effort
    • a widespread decrease in the pain threshold
    • Increase in the accumulation over time
    • prolonged aftereffects of harmful stimuli
    • reduced overall pain tolerance
• In addition, concurrent chronic sympathetic hyperactivity, combined with increased sensitivity to acute stress, exacerbates symptoms of pain and fatigue
• The HPA axis is impaired in the sense of chronic hypoactivity
  • Flattening of daily cortisol fluctuations
    also contributes to pain symptoms, fatigue, and depression
• Peripheral pathogenic processes
  • Alterations in nociceptor sensitivity
  • immunological changes
  • local metabolic mechanisms in the muscles
    • ATP depletion
    • Lactic acid accumulation
    • Hypocarbia

Dopamine is also involved in fibromyalgia.²
Pain perception and attention influence each other.⁵¹
For somatoform disorders such as fibromyalgia, irritable bowel syndrome, functional dyspeptic syndrome, and temporomandibular joint dysfunction, melatonin is thought to be a potential treatment option for pain symptoms.⁵²

2. Muscle Tone - Causes¶

2.1. Muscle Tone and Dopamine¶

Dopamine affects skeletal muscle tone and can therefore directly control movement:⁵³
The dopamine agonist apomorphine activated motor neurons of the trigeminal nerve and significantly increased the tone of the masseter (a chewing muscle) and the tensor palatini (a muscle of the soft palate that aids in swallowing). This excitatory effect is mediated by D1-like receptors, as specific activation of D1-like receptors increased muscle tone, and blockade of these receptors prevented dopamine-induced activation of the motor neurons. Blockade of D1-like receptors alone had no detectable effect on the basal tone of the masseter and tensor palatini, suggesting that, at least during isoflurane anesthesia, there is no functional dopamine drive to trigeminal motor neurons. D2-like receptors, on the other hand, did not affect either the function of trigeminal motor neurons or the tone of the masseter or tensor palatini muscles.

In tests measuring muscle tension, 64 to 84 percent of people with ADHD showed significant impairments, compared with 0 percent of persons without ADHD.⁵⁴

Prolonged muscle tension can cause chronic pain.⁴⁷

A person with ADHD told us that his severe neck and shoulder tension—which he had experienced for decades—decreased significantly when he drastically reduced his chronic alcohol consumption.

2.2. Additional Mechanisms Underlying High Muscle Tension in ADHD¶

• The reticular system
  • is involved in⁴⁸
    • Regulation of arousal
    • Maintaining muscle tone.
  • The reticular formation can, in this context, ⁴⁸
    • engage several muscles at the same time
    • Modulate body position adjustments for balance
    • This affects the stabilizing muscles (the proximal limb muscles and the muscles that stabilize the spine).
  • The reticulospinal system (the totality of descending fibers from the reticular formation) is important for⁴⁸
    • Regulation of Postural Control
    • Regulation of Movement
    • Decreased muscle activity during REM sleep