Nociplastic Pain

Original Editor - Kapil Narale

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IASP Definition

Until 2017, pain mechanisms have been divided into “nociceptive pain” and “neuropathic pain”. Since these only include pain from two specific sources, there are a large group of patients without a valid pathophysiological identification for their experience of pain. This pain experienced is neither nociceptive nor neuropathic. Thus, this group comprises people who have neither obvious activation of nociceptors nor neuropathy, but clinical and psychophysical findings suggest altered nociceptive function.

Nociplastic pain is mechanistically different from nociceptive pain and neuropathic pain. Nociceptive pain consists of continuous damage and inflammation of bodily tissues. Neuropathic pain simply is categorised as pain from nerve damage. These terms are distinctly explained on their respective pages, following the links above.

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 CNS.

It consists of multifactorial processes from different inputs, which could be either a bottom-up response to a peripheral nociceptive or a neuropathic stimulus (known as central sensitisation), or a top-down CNS-driven response.

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, is 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 pain condition. It has been divided into 5 categories: chronic widespread pain (eg, fibromyalgia), complex regional pain syndrome, chronic primary headache and orofacial pain, chronic primary visceral pain, and chronic primary musculoskeletal pain.

As this is an umbrella term, nociplastic pain encompasses pain from stereotyping terms such as dysfunctionnal pain or medically unexplained somatic syndromes. Types of conditions that fall under the umbrella of Nociplastic Pain include: fibromyalgia, complex regional pain syndrome, other types of musculoskeletal pain such as chronic low back pain, visceral pain disorders such as irritable bowel syndrome and bladder pain syndrome.

It is seen that there isn't a single term that is fully suitable for describing someone's pain, and the pain experience can overlap between the 3 terms of nociceptive, neuropathic, and nociplastic pain. The terms describe one element or dimension o fthe pain experience.

Nociplastic Pain is not a diagnosis, but a descriptor of the pain that is being experienced.

Diseases associated with nociplastic pain

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

Chronic visceral pain syndrome is also associated with neuroplastic 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, which can be categorised as chronic primary headaches, orofacial pain, tension-type headaches, and migraines.

Stress, disability, depression, and anxiety may cause contributors to nociplastic pain.

Cancer patients may experience nociplastic pain as a result of the disease, and the treatment.

Other diseases that may relate 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.

Differentiating Nociplastic Pain and Central Sensitisation

The term central sensitisation describes pain hypersensitivity subsequent to a activation of a nociceptor from a noxious stimulus, which can be mediated centrally and/or peripherally. This term was denoted by Woolf, who coined the term 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 which closely associate 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 detected by Quantitative Sensory Testing, which can be detected beyond specific body regions.

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

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

Prevalence

Nociplastic conditions can have a varied prevalence. The prevalence is generally higher for female individuals. A review showed an estimatuion 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 n 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 contribution from all 3 categories. Feel free to see Table 1 in Buldy's et al (2023) for an outline of the 3 pathophysiological mechanisms of nociplastic pain.

The most likely cause of Nociceptive Pain may be attributed to a biopsychosocial model, which would attribute to a variety of facets and classifications leading to nociplastic pain. Such factors can include abuse (overdosing), environmental toxins, and genetic

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

Symptoms

The symptoms will include multifocal pain that is more widespread and/or severe than what is 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 on its own as in fibromyalgia or tension-type headache, or mixed with nociceptive or neuropathic pain as in chronic low back pain.

Testing and Diagnosis

In a study concerning nociplastic pain in mice, it was noted to be easier to induce nociplastic pain in female mice compared to male mice. There were also differences noted in pain mediation between male and female models, with male mice showing greater hypersensitivity than female mice. This activity is dictated by the microglia in the spinal cord. 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 be the sole contributor 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 patient indicated that varied mapping of the organization of the primary motor cortex, which may be the origin of nociplastic pain, when considering low back pain.

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

Diagnosis

In 2021, the IASP determined diagnostic criteria to identify nociplastic pain. Certain features including its characteristics, hypersensitivity, and the presence of comorbidities need to be accounted for. The identification and diagnosis is not a simple process, yet is complex.

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

Diagnosis can be attempted using diagnostic imaging. using 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, the method of simply excluding other conditions can be used, but can lead to misdiagnosis of the pain. There is not one simple diagnostic approach, thus the prevalence of nociplastic pain can be underestimated.

Outcome Measures

Quantitative Sensory Testing can be used, but is generally used in research, than clinical practice.

Sleeping Quality can be assessed using different tools, such as: 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) is a useful tool to diagnose fibromyalgia.

Diagnostic tools for neuropathic pain such as the painDETECT and Douleur Neuropathique 4 questionnaire can be used to 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.

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 very difficult to identify, and therefore devise with a suitable treatment.

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

Pharmacological treatment 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 seen to be ineffective with treating nociplastic pain, compared to nociceptive or neuropathic pain. A Cochrane review on NSAIDs therapy in fibromyalgia mentions that “NSAIDs cannot be regarded as useful for treating fibromyalgia”. Another Cochrane review mentions, in the case of LBP, that there are no significant differences between selective and non-selective NSAIDs. 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 nociplsstic pain. They are more effective in pain reduciton than SNRIs, but have adverse effects in older patients. SNRIs may have a positive effect on nociplastic pain compared to NASIDs. 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. Classic symptoms can include panic disorder and social phobia, and reduced quality of sleep compared to patients with other types of pain.

Children also have a stronger genetic component of rheumatoid disease

Comparison of Definitions

As can be seen, Nociplastic Pain is a 3rd dimension of Pain classification.

Nociception, Neuropathic, and Nociplastic Pain can be described by the IASP in the definitions on the following pages..

The definitions are explained in the following video:

Resources

• IASP Website
• WHO Website