The relationship between insomnia and pain - Pathos

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The relationship between insomnia and pain

La relazione tra insonnia e dolore
Short review
Pathos 2022; 29, 2. Online 2022, Jun 15
Davide Cristina
Dipartimento Salute Mentale
ASP 7 Ragusa

Insomnia accounts for 90 percent of sleep disorders and in Italy it seems to affect more than half of the population aged over 50. Sleep disorders are present in 67-88 percent of chronic pain disorders and at least 50 percent  of patient with insomnia suffer from chronic pain conditions. Painful conditions are often associated with sleep disorders. Recent studies show that insomnia can be cause of chronic pain. Epidemiological studies also report that poor sleep quality is a risk factor for the development of chronic pain spread in a healthy population. Both pathological conditions are part of a reciprocity perspective (bidirectionality) and their treatment must have a multidisciplinary approach and can be pharmacological or not pharmacological.
L'insonnia rappresenta il 90 per cento dei disturbi del sonno e in Italia sembra interessare più della metà della popolazione di età sopra i 50 anni. I disturbi del sonno sono presenti in una percentuale che va dal 67 all’88 per cento dei disturbi del dolore cronico e almeno il 50 per cento degli individui con insonnia soffre di dolore cronico. Sebbene le condizioni dolorose croniche siano spesso associate a disturbi del sonno, recenti studi hanno individuato il ruolo dell’insonnia come causa predisponente e modulatore del dolore cronico. Studi epidemiologici indicano anche come la scarsa qualità del sonno sia un fattore di rischio per lo sviluppo di dolore cronico diffuso in una popolazione altrimenti sana. Entrambi i quadri patologici rientrano in un’ottica di reciprocità (bidirezionalità) e il loro trattamento deve avere un approccio multidisciplinare e può essere farmacologico o non farmacologico.
Key words
Insomnia, chronic, pain, central, treatment
Parole chiave
Insonnia, dolore, cronico, centrale, trattamento

Insomnia accounts for 90 percent of sleep disorders and in Italy it seems to affect more than half of the population aged over 50.1 It is more common in women, especially after menopause and late pregnancy, and in the elderly. Factors associated with the onset of insomnia include a personal or family history of insomnia, easy awakening, illness and the presence of pain. The three main categories according to the International Classification of Sleep Disorders 3rd edition are: short-term insomnia, chronic insomnia and other types of insomnia.2 DSM V (2014) diagnostic criteria for insomnia disorder are as follows:

Insomnia Disorder, DSMV
Quantitative and/or qualitative sleep dissatisfaction associated with one or more symptoms is reported
- Difficulty starting sleep
- Difficulty staying asleep with frequent awakenings
- Early awakening in the morning

The alteration of sleep causes clinically significant discomfort with social, academic and occupational impairment
- Difficulty sleeping occurs at least 3 times a week
- The sleep disorder persists for at least three months
- Sleep difficulties occur despite adequate conditions

Insomnia is not better explained by another sleep/wake disorder, it does not occur exclusively during another sleep disorder, it is not attributable to substance or drug abuse
- Mental disorders and coexisting medical conditions do not adequately explain insomnia
The disorder is specified on the basis of symptomatic persistence in:
- Episodic: persistence of symptoms for at least 1 month, but less than three months
- Chronic: symptoms last for at least 3 months
- Recurring: two or more episodes within 1 year

It is specified if there is comorbidity with non-sleep related mental disorder, if there is comorbidity with another medical condition or with other sleep disorders.The diagnosis of "insomnia disorder" is assigned if the disorder occurs as an independent or comorbid condition.3
Insomnia and sleep deprivation, whether prolonged or chronic, are associated with cognitive difficulties, anxiety and depression, substance and alcohol abuse, traffic accidents, poor work performance, decreased quality of life, and increased risk of cardiovascular disease. poor longevity and all cause mortality.2,4
It is very common to find general medical conditions comorbid with insomnia disorder: sleep disorders (circadian alteration, obstructive/central sleep apnea, narcolepsy, restless legs syndrome), systemic disorders (gastroesophageal reflux, nocturia, pain, disturbances movement disorders, fibromyalgia, chronic fatigue syndrome, asthma, diabetes, obesity, oncological diseases), psychiatric disorders (anxiety, post-traumatic stress disorder, various types of depression, substance abuse), neurological disorders (Parkinson's disease, migraine, dementia, cerebrovasculopathies, strokes, neuropathies, head trauma), and musculoskeletal (osteoarthritis, rheumatoid arthritis).5
.5 Insomnia and chronic pain conditions affect up to 50 percent and 31 percent of the elderly, respectively. In a study conducted in the United States, it was found that the chronic pain that afflicts half of the elderly appears to increase significantly with the worsening of the disease burden, leading to emotional distress with poor sleep quality and reduction of pain thresholds, the sensation of fatigue, aggravation of previous cognitive alterations.6,7
Chronic painful conditions are often associated with sleep disturbances, i.e. changes in the continuity and structure of sleep, as well as increased daytime sleepiness.8 Recent studies have shown that insomnia is a predisposing and modulator of painful states in chronic diseases (fibromyalgia, oncological diseases, osteoarthritis, migraines) in comorbidity with sleep disorders.9 Sleep disorders are present in 67 to 88 percent of chronic pain disorders and at least 50 percent of individuals with insomnia, suffer from chronic pain.10

The sleep
It is an active, rhythmic, and reversible physiological state, which is accompanied by a reduction in mobility and sensory response capacity. There are two types of sleep: non. Rapid Easy Movements (NREM) (slow or synchronized wave sleep) consists of 4 stages with progressively slower wave EEG up to stages 3 and 4 which characterizes complete synchronization (deep sleep) and sleep REM (paradoxical or desynchronized sleep) with desynchronized EEG with cortical electrical activity similar to wakefulness and rapid eye movements. The sleep cycle consists of the alternation of both REM and NREM phases, which alternate 4/5 times.11,12 This alternation, according to the theory of reciprocal inhibition, appears to be determined by cholinergic (excitatory) neurons in the integument mesophotic, called REM-on cells, and serotonergic (inhibitory) noradrenergic neurons in the REM-off locus cereuleus cell.13,14

Neural networks and neurochemistry of sleep
The sleep cycle is regulated by the suprachiasmatic nucleus of the hypothalamus; the reticular system at the level of the brainstem has the function of maintaining the waking state (activating ascending reticular system) and is divided into two branches: the first innervate the thalamus, the second projects to the lateral areas of the thalamus up to the medial region of the hemispheres and the cerebral cortex. When the action of the reticular formation is lowered, the action of the neuronal group of the raphe nucleus is established, which sends impulses to the cortex and to the thalamus, Thus deep sleep is established.15 During sleep by the two branches are blocked by the inhibition produced from ventrolateral preoptic gabaergic neurons (VTA) connected with the brain stem and hypothalamus. The two circuits inhibit each other (flip-flop switch model).12,15
Populations containing gamma-butyric acid (GABA) and glutamic acid (GLU) that promote wakefulness and sleep have recently been identified. GABAergic NREM neurons promote sleep, while glutamatergic neurons in the VTA promote wakefulness via projections to the lateral hypothalamus and nucleus accumbens (Nac). And finally, the GABAergic neurons located in the nucleus of the bed of the terminal stria promote wakefulness through an orexinergic mechanism.16 Orexin is an excitatory neurotransmitter produced by a hypothalamic neuronal cluster that presides over the regulation of sleep and appetite. The orexin system plays a neuromodulating role in the monoaminergic dopamine (DA), norepinephrine, serotonergic (5HT) and cholinergic systems which are, as we have seen, also at the basis of the activation of alertness. Orexin deficiency is strongly implicated in narcolepsy states.16

Assessment of insomnia
In clinical practice, when the patient complains of excessive daytime sleepiness, it is necessary to undergo a screening for sleep disorders: anamnestic collection, physical examination, and evaluation of disorders comorbid with insomnia and subsequently any more in-depth examinations. The most frequent daytime impairments caused by the insomnia disorder are asthenia, and  somnolence, especially in the elderly when there is comorbidity with a medical condition (chronic pain) or other sleep disorder (e.g. sleep apnea), attention and mood disturbances (DSM V 2014).3
There are different evaluation scales for sleep disorders: one of the most valid is the Epwort  Sleepiness Scale (Johns M.V. 1991) with high sensitivity and specificity. Evaluate daytime sleepiness using an 8-item questionnaire; high scores indicate the presence of behavioral symptoms of sleepiness: this category includes sleep disturbances, systemic disturbances, obstructive sleep apnea, chronic diseases, tumor states, etc. Low scores signal symptoms of fatigue, including anxiety, depression, and conditioning insomnia.17

Neurochemistry of sleep and pain
DA is a neurotransmitter that also plays an important role in regulating the sleep-wake cycle and the mechanisms of gratification. DA receptors are highly present in the ascending reticular activation system and raphe nucleus.18 Pain-induced alterations in DA signaling can affect sleep and wake modulation in the raphe nucleus, given the abundance of 5- neurons. HT and DA. The 5HT neurons of the raphe nucleus that are activated during the alert state can experience dysregulation during chronic pain contributing to periods of sleep loss even in the long term.19,20 Sleep deprivation can also downregulate the DA receptors. (D2 / D3) in the striatum and thalamus as demonstrated in a recent study using AD transporter blocking methylphenidate (DAT) .10 Sleep is considered to be a modulator of NAc function, pain, and sleep systems, positive valence (gratification).21
Drugs and opioid peptides perform regulation of algic signals of the descending pathways. Opioid receptors are found in multiple nuclei that actively regulate both sleep and pain, including the preoptic suprachiasmatic nuclei, which control sleep-wake cycles, and periaqueductal gray, which plays an important role in inhibiting pain of the descending pathway. These endogenously released peptides (endorphins) can modulate the mechanisms of signal translation and the intracellular processes that lead to the phosphorylation of proteins with alteration of gene expression which is the basis of analgesia, and neuroplastic changes such as hyperalgesia, sensitization, tolerance modulation memories of pain. Animal studies confirm that sleep deprivation alters the function of μ-receptors and opioids in mesolimbic circuits, decreases basal levels of endogenous opioids and regulates central opioid receptors.10,22,23

Types of pain and related insomnia
Chronic pain is associated with profound changes in personality and lifestyle and creates a vicious circle of suffering with a deterioration in the quality of life. Although acute pain is known to induce a deflection of mood, while chronic pain initially induces demoralization and subsequently depression, these are conditions that can, in any case, lead to and or interfere with sleep disorders. Chronic pain and depression are closely related and share the same neurophysiological areas and mechanisms of the CNS.24
Fibromyalgia causes widespread chronic pain characterized by decreased pressure pain threshold with hyperalgesia and allodynia, poor sleep quality, fatigue, and cognitive and mood disorders. Recent research indicates an abnormal perception of pain and central sensitization that characterizes fibromyalgia pathophysiology. Data from polysomnography show that these patients have short-wave sleep (abnormal α rhythms), indicative of wakefulness during non-REM sleep. Neuroimaging studies suggest that sleep dysfunction may not only be a consequence of pain, but also pathogenic. Sleep deprivation in healthy individuals can cause fibromyalgia-like symptoms, including myalgia, achiness, and fatigue.25
In acute pain conditions, fragmented sleep appears to increase the acute painful sensation. After a study on severe burn patients, it was shown that the quality of night sleep is a strong predictor of the intensity of pain perceived the following day. On the contrary, the intensity of pain during the day did not seem to influence the quality of sleep the following night.26
In migraines, pain, and sleep have a particular and partly controversial relationship; in fact, on the one hand, sleep is not very restorative before and during a migraine attack, and sleep deprivation is identified as a trigger, on the other, stable sleep has a therapeutic function on migraine and relapsing pain. Recent studies have tried to explain the relationship between migraine and sleep and a common substrate has been hypothesized at the level of hypothalamic structures and neurotransmitters dopamine, and serotonin.27
In a population study to determine the psychosocial factors that predict new-onset chronic pain, a random sample of subjects from different socio-demographic backgrounds was identified; More than 3000 subjects were identified who had no baseline pain and more than 300 who had new diffuse musculoskeletal pain on follow-up examination. The strongest predictors were premorbid somatic symptoms, disease course and sleep disturbances.28

Sleep disorders, as we have seen, have a high prevalence in diseases with chronic pain, and about half of the individuals with insomnia suffer from chronic pain. Chronic non-cancer pain is common throughout the world, with an estimated prevalence ranging from 8 to 60%. Both disorders have a strong impact on the quality of life, on the health of the affected subjects, and on society including the high costs. Chronic pain and insomnia disorder require a multidisciplinary approach that includes drug and non-drug treatment.29
The European lines for insomnia disorder have indicated non-pharmacological cognitive behavioral therapy (CTB-I) for chronic insomnia and adult insomnia as a first-line treatment; It is always important to observe the rules of sleep hygiene. Only in the presence of ineffectiveness or refusal of CBT-I by the patient is it switched to drug therapy (melatonin 2 mg prolonged-release for a period of 13 weeks, Z-drugs (zolpidem, zopiclone) in subjects under the age of 65 o Short / intermediate half-life benzodiazepines (triazolam, brotiazolam, lormetazepam) for 4 weeks o AD with sedative profile (trazodone up to 100 mg/day, amitriptyline).30

Extensive longitudinal studies support the reciprocal relationship between insomnia and pain disorders. The symptoms of insomnia significantly increase the risk of developing chronic pain in healthy subjects, while in subjects already suffering from pain, the latter is not a strong predictor of new incidence of pain. Many studies confirm that sleep deprivation produces hyperalgesia changes and can interfere with analgesic treatments involving opioidergic and serotonergic mechanisms of action, and predispose individuals to chronic pain or worsening of painful conditions.9,31
Chronic pain and insomnia disorder require a multidisciplinary approach that includes appropriate drug and non-drug treatment. On the basis of the principle of reciprocity, both pathological pictures tend to influence each other; therefore, by acting incisively on one disorder, there should be a good chance of improving the other as well.

Conflict of interest
The author declares that the article was prepared in the absence of a conflict of interest.
15th June 2022
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