Nociplastic Pain

Original Editor - Kapil Narale

Top Contributors - Kapil Narale, Kim Jackson, Ewa Jaraczewska, Candace Goh, Melissa Coetsee and Sehriban Ozmen  

Introduction

Until 2017, pain mechanisms have been divided into “nociceptive pain” and “neuropathic pain”. Since this classification only includes pain from two specific sources, a large group of patients remained without a valid pathophysiological identification for their experience of pain, which is neither nociceptive nor neuropathic. Thus, this group comprises people with no obvious activation of nociceptors nor neuropathy but whose clinical and psychophysical findings suggest altered nociceptive function.

Pain Categories

There is no single term that is fully suitable for describing someone's pain, and the pain experience can overlap between the terms of nociceptive, neuropathic, and nociplastic pain. These terms describe one element or dimension of the pain experience.

Nociceptive Pain

Nociceptive pain consists of continuous damage and inflammation of bodily tissues.

Neuropathic Pain

Neuropathic pain is simply categorised as pain from nerve damage.

These terms are distinctly explained on their respective pages, following the links above.

Nociplastic Pain

Nociplastic pain is mechanistically different from nociceptive pain and neuropathic pain.

• It is an umbrella term
• It can be defined as chronic pain leading towards an altered nociceptive function.
• It results in increased sensitivity from the altered function of pain-related sensory pathways in the periphery and central nervous system (CNS).
• It consists of multifactorial processes from different inputs, which could be either a bottom-up response to a peripheral nociceptive, a neuropathic stimulus (known as central sensitisation), or a top-down CNS-driven response.
• It is not a diagnosis but a descriptor of the pain experienced.
• It encompasses pain from stereotypical terms such as dysfunctional pain or medically unexplained somatic syndromes.
• Conditions that fall under the umbrella of Nociplastic Pain include fibromyalgia, complex regional pain syndrome, other musculoskeletal pain such as chronic low back pain, and visceral pain disorders such as irritable bowel syndrome and bladder pain syndrome.

The video below compares and introduces:

• Nociceptive, neuropathic, and nociplastic pain, detailing causes, diagnosis, and treatment.

• The spinal cord as a "pain control box," emphasising its role in modulating pain signals to the brain.

International Association for the Study of Pain (IASP) Definition

The following is the definition recommended by the IASP:

"Nociplastic Pain is a term used to describe persistent pain that arises from altered nociception, despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors, or evidence for disease or lesion of the somatosensory system causing the pain."

Chronic primary pain conditions, subdivided by the IASP, are defined as chronic pain in one or more anatomic regions accompanied by marked emotional distress or disability. This term is distinct in explaining the pain condition and cannot be explained by another chronic condition. It has been divided into 5 categories:

• chronic widespread pain (e.g., fibromyalgia)
• complex regional pain syndrome
• chronic primary headache and oro-facial pain
• chronic primary visceral pain
• chronic primary musculoskeletal pain

Chronic pain can also be described as:

1. Pain persisting >3 months
2. Regional pain distribution as opposed to a specific or discrete location
3. Pain that cannot be outlined with a nociceptive or neuropathic mechanism
4. Experiencing pain hypersensitivity in the area of pain (with the presence of peripheral or central sensitisation),

Diseases Associated with Nociplastic Pain

Fibromyalgia is the most common health condition associated with nociplastic pain.

Chronic visceral pain syndrome is also associated with nociplastic pain, with chronic primary visceral pain being the main symptom. Chronic pelvic pain may include nociceptive and/or nociplastic pain. Chronic headaches can have nociplastic pain, categorised as chronic primary headaches, orofacial pain, tension-type headaches, and migraines.

Stress, disability, depression, and anxiety may cause fators contributing to nociplastic pain. Cancer patients may experience nociplastic pain due to the disease and/or the treatment. Other diseases related to nociplastic pain include rheumatoid arthritis, osteoarthritis, gluteal syndrome, electrical injury, multiple sclerosis, cerebral palsy, and spina bifida, Parkinson’s disease, and post-COVID pain.

Nociplastic Pain vs Central Sensitisation

Nociplastic pain was previously known as central pain or central sensitisation. Nociplastic pain occurs from variations of nociceptive processing in the central nervous system (CNS), which leads to central sensitisation, which can be displayed as increased central excitability or decreased central inhibition.

Nociplastic pain does not have to have peripheral nociceptive activity but can have nociceptive and nociplastic mechanisms, including peripheral and central sensitisation.

Central sensitisation describes pain hypersensitivity subsequent to activating a nociceptor from a noxious stimulus, which can be mediated centrally and/or peripherally. This term was denoted by Woolf, who coined central sensitisation to represent spinal mechanisms responding to continuous peripheral input. Central sensitisation was introduced to help explain the central and specific hypersensitivity correlated with chronic pain conditions such as peripheral neuropathic pain, fibromyalgia, headache, temporomandibular disorder, irritable bowel syndrome (IBS), and interstitial cystitis. These are the classic disorders closely associated with the labelling and classification of nociplastic pain and, thus, are said to be caused by central sensitisation. The intensity of pain detected can be assessed with Quantitative Sensory Testing (QST), and often involves multiple body regions.

The expanding pain characterised by hyperalgesia (enhanced response of pain to painful stimuli) and allodynia (pain elicited by normally non-noxious stimuli) hints at a supraspinal dysfunction rather than one that is purely spinal-related. In addition to the widespread pain and tenderness related to the symptoms of nociplastic disorders, patients in a study examining nociplastic pain, had other symptoms suggestive of CNS involvement, such as fatigue, sleep, mood and memory difficulties, and cognitive dysfunctions. Furthermore, sensitivity to non-nociceptive sensory stimuli such as light (photosensitivity) and sound (hyperacusis) was apparent.

Pain amplification can be brought on by abnormalities in pain processing in the CNS and peripheral nervous system (PNS), such as increased facilitative activity and reduced descending inhibition, which can also be detected by QST tests.

The facilitative activity can include temporal summation or heightening pain perception subsequent to continuous noxious stimuli, which can be secondary to a gradual build-up (i.e., a heightened spinal neuron response after C-fibre or, A-δ activation), and the growth of receptive fields, and hyperalgesia and/or allodynia, coupled with central sensitisation. Therefore, the decreased descending modulation can present as allodynia or hyperalgesia.

Please refer below at the end of the 'Treatment' section, for the video from Dr. Andrea Furlan, for an explanation on Central Sensitisation and its treatment.

Characteristics of Nociplastic Pain

Prevalence

Nociplastic conditions can have a varied prevalence. The prevalence is generally higher for female individuals. A review showed an estimation between 5% and 15% of the general population suffering from nociplastic pain. The pain conditions can occur in any geographic, demographic, and socio-economic class. Genetics, epigenetics, environmental, and psychosocial factors can contribute to the manifestation of such syndromes.

Pathophysiology

Nociplastic pain does not involve tissue damage that can activate nociceptors. It also does not involve nerve damage which would lead to neuropathic pain. However, it is present in chronic conditions.

Nociplastic Pain can be divided into 3 categories:

• Supraspinal mechanism - hyperresponsiveness to pain stimuli, hyperactivity, connectivity between regions of the brain in charge of pain perception
  • Nociplastic pain is believed to be equipped with decreased connectivity and activity of brain areas for pain inhibition.
  • There is an increased concentration of Substance P and glutamine levels in cerebrospinal fluid, with inhibition of GABAergic transmission
  • Variance also exists in the shape and size of grey and white matter in areas relating to pain

• Spinal mechanisms - this involves regional clustering and narrowing of signals from different pain loci spinal cord reorganisation, amplified spinal reflex transmission, and decreased spinal inhibition
• Peripheral Mechanisms - this is related to the proliferation of sodium channels and sympatho-afferent coupling

Generally, the experience of pain involves contributions from all three categories. See Table 1 in Buldy et al. (2023) for an outline of the three pathophysiological mechanisms of nociplastic pain.

The most likely cause of nociplastic pain may relate to the biopsychosocial model, which would attribute to various facets and classifications leading to nociplastic pain. Such factors include abuse (overdosing), environmental toxins, and genetic abnormalities.

Nociplastic pain can be identified as a syndrome. This helps encompass a vast array of symptoms without any clear pathophysiological mechanism. This differs from a disease with a clearly defined pathophysiological mechanism with defined objective diagnostic measures.

Here is a video explaining the possible causes, behaviour and diagnosis of nociplastic pain:

• Chronic pain can persist even after treating the cause acute pain
• Nociplastic pain indicates a malfunctioning pain system that needs retraining
• Identifying patterns, signs/symptoms
• Pain caused from surgery and broken bones

Symptoms

The symptoms will include multifocal pain more widespread and/or severe than expected from the identified or observed tissue or nerve damage. Other CNS-derived symptoms can include fatigue, sleep, memory, and mood problems.

Nociplastic pain can occur independently, as in fibromyalgia or tension-type headache, or mixed with nociceptive or neuropathic pain, as in chronic low back pain.

Here is a video explaining some of the common symptoms of nociplastic pain, which include:

• the difficulty of identifying the cause of the pain
• the location and localisation of the pain
• The sudden onset, and constant/unremitting type of pain
• The unresponsiveness to traditional treatment methods
• The association with disrupted sleep, being accompanied by fatigue, depression, anxiety, and other disturbing sensations

Diagnosis and Outcome Measures

A study concerning nociplastic pain in mice found it easier to induce nociplastic pain in female mice than in male mice. There were also differences in pain medication between male and female models, with male mice showing more significant hypersensitivity than female mice. The microglia in the spinal cord dictate this activity. With the female model, there was minimal sensory activity outside the injured location, making the microglia less hypersensitive outside the injured location.

Other studies indicate that brain plasticity may contribute to nociplastic changes.

The onset and severity of nociplastic pain can be correlated with heightened primary emotions, such as anger, and secondary emotions, which are emotional reactions to primary emotions. A study on low back patients indicated that varied mapping of the organization of the primary motor cortex might be the origin of nociplastic pain when considering low back pain.

As seen with fibromyalgia, there was a correlation between c-reactive protein and the magnitude and intensity of pain experienced.

Diagnosis

In 2021, the IASP determined diagnostic criteria to identify nociplastic pain. Certain features, characteristics, hypersensitivities, and co-morbidities must be accounted for. The identification and diagnosis is not a simple process, thus is complex.

The mnemonic RATE (recognise, assess, treat, evaluate) can be used to identify suspected cases of nociplastic pain. A physical examination and previous medical history should help indicate a person's likeliness of exhibiting nociplastic symptoms such as repeated medical system use as may be with developing biopsychosocial factors and can be seen with dull, fluctuating, widespread pain.

Diagnosis can be attempted using diagnostic imaging. It includes methods such as functional neuroimaging, activation pattern and brain mapping with positron emission tomography (PET), magnetic resonance imaging (MRI), and electromyography (EMG).

When diagnosing nociplastic pain, excluding other conditions can be used but can lead to misdiagnosis. There is not one simple diagnostic approach. Thus, the prevalence of nociplastic pain can be underestimated.

Outcome Measures

Quantitative Sensory Testing can be used. The original protocol is mostly used in research and is very time-consuming, but reliable bedside tests have been validated and be very useful to gain understanding regarding underlying pain mechanisms.

Sleeping Quality can be assessed using different tools, such as the Pittsburgh Sleep Quality Index, the Leeds Sleep Evaluation Questionnaire, the Insomnia Severity Index, the Medical Outcomes Study Sleep Scale, and wrist actigraphy.

The Central Sensitisation Inventory (CSI) helps indicate central sensitisation, but also helps indicate comorbidities, which can relate to nociplastic pain, as noted by the IASP.

The Skorupska Protocol, a measurement of bodily stress, can be used as an outcome measure. The Nociplastic-based Fibromyalgia Features (NFF) are helpful for diagnosing fibromyalgia.

Diagnostic tools for neuropathic pain, such as the painDETECT and Douleur Neuropathique 4 questionnaire, can detect nociplastic pain.

Please see Table 2 in Buldys et al, 2023, for a chart of different outcome measures used to measure aspects of nociplastic pain as it relates to pain and psychosocial measures.

Here is a video on diagnosing nociplastic pain, which highlights:

• Since it is difficult to diagnose, nociplastic pain can be seen as psychosomatic pain, and is often missed.
• Brain scans can be used to detect widespread increase in brain activity, mainly used in research.
• Ways to test for Nocipalstic pain
  • Test tactile acuity - test using 2-point sensitivity or sharp/dull discrimination
  • Test pain-pressure threshold with a pressure algometer
  • Using a validated questionnaire like the Central Sensitisation Inventory - pain can be identified with unique signs and symptoms

Treatment

When it comes to nociplastic pain, the main focus of treatment is to reduce symptoms and help improve quality of life. Nociplastic conditions are difficult to identify and to decide on a suitable treatment. Possible conventional treatments include education, exercise, massage, manipulation, and/or TENS. A non-pharmacological physiotherapeutic approach to treatment is known to be the best approach. Patients are seen to respond better to central than peripheral targeted therapies.

Non-Pharmacological Approach

Education can help vary (decrease) how pain is processed in the brain. This can help increase their pain threshold and increase their central inhibition. Education on the underlying central mechanisms would be helpful for these patients. With education, patients can be introduced to graded exposure to gradually help build their tolerance and minimise pain.

Exercise Therapy helps with analgesia through distraction and elimination of nociceptive and nociplastic pain mechanisms due to the activation of the descending inhibitory mechanisms, with increases in endogenous opioids and varied serotonin function. It is shown that regular exercise can help prevent chronic pain. It decreases central excitability and the neurotransmitters being facilitated in the spinal cord, brain stem, and cortical nociceptive sites. Animal models help demonstrate that regular aerobic exercise helps increase the release of endogenous opioids in the midbrain and brain stem through the periaqueductal grey and rostral ventromedial medulla, thus helping with descending modulation and promoting analgesic effects.

Regular exercise decreases glial cell activation, increases anti-inflammatory cytokines, and decreases inflammatory cytokines in the spinal cord. QST results in healthy adults show that greater levels of exercise correlate with decreased central excitability, increased pain thresholds, and increased inhibition. Therefore, regular exercise can help reduce pain perception by changing central nociceptive processing and increasing central inhibition. This makes exercise very suitable for individuals with nociplastic pain.

Whereas patients with nociceptive or neuropathic pain may benefit from specific exercises, patients with nociplastic pain would benefit from generalised strengthening or an aerobic conditioning program helping to vary central inhibition and excitation.

Manual Therapy consisting of massage and/or joint mobilisations can help modulate central pain mechanisms. Massage and mobilisations help activate descending inhibitory pathways, which provide an analgesic effect via different neurotransmitters and receptors in the body. Joint mobilisations can reduce glial cell activity in the spinal cord. They reduce central excitability, which can be indicated by a reduction in measured temporal summation in the area of primary hyperalgesia, and reduced secondary hyperalgesia in individuals with chronic pain.

TENS helps reduce central inhibition and increase central excitability. High and low-frequency TENS analgesia has been shown to activate multiple central pathways, including the spinal cord, rostral ventromedial medulla, periaqueductal grey, and many cortical sites. M-opioid and serotonin receptors (low frequency) and delta-opioid receptors (high frequency) are some of the central inhibitory neurotransmitters involved, commonly seen in people with chronic pain. TENS reduces pain by activating the spinal cord's GABA receptors and muscarinic receptors (M1, M3). In addition, TENS reduces central sensitisation from the activity of nociceptive dorsal horn neurons. It also helps decrease the release and activation of excitatory neurotransmitters (glutamate and substance P), glial cell activation, and inflammatory cytokines and mediators in the dorsal horn. For individuals with fibromyalgia, high-frequency TENS restores central inhibition and helps amplify the pressure-pain thresholds at and around the stimulated site. With these mechanisms of TENS, central inhibitory pathways are activated, and central sensitisation is reduced to reduce pain and hyperalgesia.

Cognitive Behavioural Therapy (CBT) is also an effective method. Emotional Awareness and Expression Therapy (EAET) also effectively reduces pain intensity and coexisting symptoms. It is seen that CBT and EAET have similar efficacy. Exercise, education, and weight management are effective therapies, as well as massage and acupuncture.

Here is a video describing methods of treatment for nociplastic pain, which include :

1. Pain neuroscience education - helping to identify the sources of pain
2. Graded pacing - a strategic way to improve activity tolerance without eliciting flareups
3. Brain based Drills
4. Re-sensitising Drills
5. Nervous System Calming Strategies

In addition, this video provides more specific examples of non-drug pain management strategies like pacing, drills, and nervous system reset strategies

Pharmacological Approach

Pharmacological treatments are widely used to treat pain, depending on the type of pain. However, non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol, opioids, and muscle relaxants are ineffective in treating nociplastic pain, compared to nociceptive or neuropathic pain. A Cochrane review on NSAID therapy on patients with fibromyalgia mentions that “NSAIDs cannot be regarded as useful for treating fibromyalgia”. Another Cochrane review mentions that there are no significant differences between selective and non-selective NSAIDs in the case of LBP. In the case of opioid therapy, however, a minor analgesic effect is seen only in fibromyalgia. It is also seen that opioid therapy can aggravate pain in patients with fibromyalgia.

Tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and gabapentinoids are another group of treatment agents. TCAs can be noted to be effective in the treatment of nociplastic pain. They are more effective in pain reduction than SNRIs but have adverse effects in older patients. SNRIs may have a positive effect on nociplastic pain compared to NSAIDs. Pre-gabalin is recommended for the treatment of fibromyalgia. Antieplieptic drugs can also be used for nociplastic pain.

Children and Nociplastic Pain

Nociplastic pain can also occur in children. One in five children and adolescents experience chronic pain that is constant or recurring. Classic symptoms can include panic disorder, social phobia, and reduced quality of sleep compared to patients with other types of pain.

In a study by Ocay et al (2023), children that experienced nociplastic pain had the symptoms of pain hypersensitivity in the area of pain, heightened symptoms of panic and social phobia, and reduced sleep quality. In this study, children between the ages of 4-18 were assessed. Children with nociplastic pain experienced thermal hyperalgesia and mechanical hyperalgesia somatosensory profile, had an increased loss of function related to mechanical and vibrational sensation, had pain hypersensitivity to mechanical or thermal stimuli, and also had a higher pain intensity when being assessed compared to the previous month. Altered brain function is also possible, which can lead to poor pain-related outcomes such as pain interference, pain catastrophising, fatigue, anxiety, and depression.

Similar to adult patients, paediatric patients can be diagnosed through screening, via pain questionnaires and qualitative sensory testing. Paediatric patients with nociplastic pain resulted with a poorer outcome after receiving medical intervention or treatment, compared to patients without nociplastic pain.

Possible medication that can be administered include non-steroidal anti-inflammatory drugs (NSAIDs) (eg ibuprofen, celecoxib), muscle relaxants (eg baclofen), opiates (eg morphine), anti-depressants (eg amitriptyline), anti-epileptics (eg gabapentin), anti-migraine agents, oral corticosteroids, sedatives (eg benzodiazepines), or other analgesics and antipyretics agents (eg acetaminophen, clonidine, magnesium, etc). Possible treatments can encompass peripheral nerve and interfacial plane single blocks, pulsed radiofrequency, or local infiltrations.

There was a lower proportion of patients that had a meaningful clinical outcome who had nociplastic pain, compared to those with non-nociplastic pain, after treatment.

Outcome Measures with Paediatrics

There are various possible outcome measures as applicable to paediatrics and adolescents, their parents, and families. The Functional Disability Inventory (FDI) questionnaire, Revised Child Anxiety and Depression Scale (RCADS) questionnaire, and Pittsburgh Sleep Quality Index (PSQI) questionnaire helps indicate children's self-reported level of disability, their subjective interpretation of depression and anxiety, and sleep quality. The RCADS constitutes subscales representing separation anxiety disorder, generalised anxiety disorder, panic disorder, social phobia, obsessive compulsive disorder, and low mood (major depressive disorder). The Douleur Neuropathique 4 (DN4) questionnaire helps indicate if there is a presence of a neuropathic component. This questionnaire is completed by the patients with their physicians. The Pain Catastrophizing Scale for Children (PCS-C) was completed by patients to assess their negative thoughts or feelings while experiencing pain.

Family burden in relation to the paediatric care is assessed with the the Impact on Family Scale (IOFS), which is completed by the parents of the patients. On this scale, a higher score indicates a worse impact on the family and their social wellbeing as a result of the chronic paediatric illness. The Pain Catastrophising Scale for Parents (PCS-P) can also be used. This help indicate the negative thoughts or feelings of the parents while their child is experiencing pain, and thus is completed by the parents of the paediatric patient.

The Patients’ Global Impression of Change scale (PGIC) is a post-treatment clinical outcome measure that can be used. It is a 7-point scale, which encompasses a patient’s beliefs toward their treatment confidence and efficacy, and their cumulative feeling of improvement in their respective health condition. The treatment can be diminished and ceased once the patient has gained a significant improvement with their experience of pain and related factors. This would be achieved when the patient can return to a regular school attendance, has normal physical function, is without pain, is not using any pain medication, and has a PGIC score of 6 or 7.

Resources

This is a link to a video with 8 tips about how to explain your nociplastic pain to your GP, Doctor, or Medical Professional:

Some of the main points from this video include:

Being anxious about explaining your pain to your doctor, and making sure you include all the details, make sure you get your questions answered, explain how the pain is affecting you, get a proper diagnosis, and a patient-centered individualised treatment plan.

The SOCRATES method helps the Doctor get information they need about the pain:

S: Site - Where does it hurt? The Doctor needs to know the localisation of the chronic pain. They will ask the patient to indicate the sites of pain on a body diagram. They would want to know where the pain occurs first, and which site of pain is the most bothersome. If there are any other sites, they would also want to know about these.

O: Onset - What were you doing when the pain started? Is it associated with an injury, accident, another disease, or treatment or another condition? Did it start abruptly or slowly?

C: Characteristics - What does the pain feel like? Ask the patient to describe how the pain feels to them. It would provide hints as to if the pain is inflammatory, neuropathic, myofascial - words such as: hot, burning, electrical shocks, ice-cold, tiring, heavy, diffuse, throbbing, numbing, can be used to describe the characteristics of the pain.

R: Radiation - Does the pain radiate to other areas of the body? Pain can radiate from the neck down the arm, or from the buttock down the thigh. Headaches can also be a result of neck pain, and the Doctor would be able to determine the source coming from the neck.

A: Associated Symptoms - Are there any symptoms associated with the pain? Other symptoms such as nausea, fever, dizziness, muscle paralysis, joint stiffness, muscle cramps, incontinence of bladder or bowel can be present - these can suggest specific causes or more urgent problems

T: Time - When did the pain start? How long has it been there? The Doctor wants to know the pattern of the pain as well - is it constant or intermittent? Is there a time of the day that the pain is worse? If the pain is worse when you wake up, it can suggest an inflammatory arthritis. If the pain is worse after activity, that would suggest muscle strain or myofascial trigger points. Pain that is worse at night and better during the day could suggest bone diseases or bone metastases.

E: Exacerbating - What are the aggravating or easing factors? What makes it worse? What makes it better? Does movement make it better? Anxiety? Frustration? Sadness? Does the patient take pain killers? Do they help? How much does the pain improve? Does the pain get better with heat or ice? If it gets better with ice, it is likely inflammation. If it gets worse with ice, it is likely neuropathic. If it gets better with NSAIDs, it suggests inflammation, but if it gets better with antidepressants, it suggests neuropathic pain. All pain goes away when the person is distracted, but if it completely goes away when distracted, it suggests nociplastic pain

S: Severity - What is the intensity of the pain? What is the rating of intensity from 0-10? What is the rating right now? The highest in the past 7 days? The lowest in the past 7 days? The average in the past 7 days? It may be hard to assign a number since the pain is more complex than just a number, but a rating is still needed. The Doctor would want to know if the pain level is ever 0. If it is 0, then it can be easier to determine a treatment plan. The Doctor would want the patient to assign pain scores before and after treatment, to understand if there was a difference, and if the treatment was effective.

The order of the questions is not what is important, but ensuring you include them all when taking a pain history. The pain history may take about 1-1.5 hours to gather, and you want to obtain other information such as medicaitons, other medical conditions, family history, psychological status, habits, work, and relationships. A thorough physical examination also needs to be completed. Time also needs to be saved for the Doctor to explain further steps and treatment progression/prognosis to the patient.

Other Resources

Information as presented at the beginning of this page can be found on the IASP Website:

• IASP Website