Clinical Notes : Pharmacology

182. Understanding Pain

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An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Pain is subjective.

Each individual learns the meaning of the word "pain" through experiences related to injury in early life.


There is no physiological, imaging, or laboratory test that can identify or measure pain.


Pain is what the patient says it is.

Different levels of pain in response to the same stimulus may be experienced by individuals.

A uniform pain threshold does not exist.

Pain tolerance varies among and within individuals depending on factors including heredity, energy level, coping skills, and prior experiences with pain.

Individuals with chronic pain may be more sensitive to pain and other stimuli.

Pain vs Nociception


Pain is a conscious experience that results from brain activity in response to a noxious stimulus and engages the sensory, emotional and cognitive processes of the brain.


In general terms we can distinguish two dimensions or components of pain:

(a) sensory-discriminative and

(b) affective-emotional.

Nociception is the process by which information about a noxious stimulus is conveyed to the brain.

It is the total sum of neural activity that occurs prior to the cognitive processes that enable humans to identify a sensation as pain.


Nociception is necessary but not sufficient for the experience of pain.


The goal of pain therapies is to relieve pain whenever possible: from nociception to the conscious experience as well as to decrease the emotional response to the unpleasant experience.


Nociception should be treated even in unconscious patients who appear to be clinically unresponsive to pain to help prevent sensitization of pain pathways which can lead to chronic pain.




Classifying pain is helpful to guide assessment and treatment.

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Pathological processes never occur in isolation and consequently more than one mechanism may be present and more than one type of pain may be detected in a single patient; for example, inflammatory mechanisms are involved in neuropathic pain.


There are well-recognized pain disorders that are not easily classifiable.

Our understanding of their underlying mechanisms is still rudimentary though specific therapies for those disorders are well known; they include cancer pain, migraine and other primary headaches and wide-spread pain of the fibromyalgia type


Acute, chronic, acute-on- chronic pain


Acute pain is a common consequence of injury or illness, generally lessening shortly after onset and resolving once healing is complete.

Since healing occurs over a maximum of 3 months, pain persisting longer than 3 months is deemed chronic pain or persistent pain.

These are of two basic types of acute-on-chronic pain : pain flare and breakthrough pain

Pain flareis a transient increase in pain that can last for hours to days.

Flares are extremely common and generally benign although they may be perceived as harmful by the patient.

Pain intensity eventually returns to baseline.

Breakthrough pain is a term first used to describe a transitory exacerbation of pain (predictable or spontaneous) that occurs on a background of otherwise stable pain in a cancer patient receiving chronic opioid therapy.

The term is often over-used in clinical practice to describe any increase in pain.

Increases in pain may be categorized as incident related (i.e., caused by movement, cough, defecation, etc.), end-of-dose failure, or idiopathic.


Central, Peripheral pain


Central neuropathic pain is caused by a lesion or disease of the spinal cord and/or brain (eg, transverse myelitis).


Peripheral neuropathic pain includes post-herpetic neuralgia, trigeminal neuralgia, distal polyneuropathy, and neuropathic low back pain.


Referred pain occurs because both visceral and somatic afferents often converge on the same interneurons in the pain pathways. The location of the visceral receptor activation is thus “referred” to the somatic source.

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The convergence of nociceptor input from the viscera and the skin

Common sources of referred pain


Nociceptive, nociplastic and neuropathic pain


Nociceptive pain


Nociceptive pain is a medical term used to describe the pain from physical damage or potential damage to the body. ... It develops when the nociceptive nerve fibers are triggered by inflammation, chemicals, or physical events, such as stubbing a toe on a piece of furniture.


Nociplastic pain


Nociplastic pain is not associated with signs of neuropathy but is characterized by hypersensitivity in apparently normal tissues.


Nociplastic pain results from altered nociception despite no clear evidence of actual or threatened tissue damage or evidence of a lesion or disease.

Nociplastic pain is chronic, and types of nociplastic pain include fibromyalgia, irritable bowel syndrome, complex regional pain syndrome, and non-specific chronic low back pain.



Neuropathic pain


Neuropathic pain develops due to a lesion or disease of the somatosensory nervous system. Somatosensory nerves are located in the skin, muscles, joints, and fascia, with a variety of sensors that send signals to the spinal cord and eventually the brain for processing.

Damage to these nerves from a lesion or disease results in altered and disordered transmission of sensory signals into the spinal cord and brain.

Neuropathic pain is chronic, with some patients experiencing moderate pain, while others experience debilitating pain.

Neuropathic pain is characterised by allodynia and hyperalgesia.

Types of pain

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Allodynia, hyperalgesia

Allodynia is the perception of non-noxious stimuli as painful.         


In hyperalgesia, noxious stimuli produce exaggerated or prolonged pain.

Hyperalgesia arises from the sensitisation of nerves in and around the damaged area due to the release of molecules such as prostaglandin E2 and substance P.


Sensitisation can also occur centrally within the spinal cord.


Central sensitisation leads to hyperexcitability of second order neurons within the dorsal horn of the spinal cord.


The patient's experience of pain


How a patient experiences pain involves a variety of internal (intrinsic) processes that interact with external (extrinsic) environmental factors.


A patient's biological, psychosocial, social, and spiritual experiences provides the basis for how a patient copes with pain over time.

Biologic factors include previous pain experience, sleep/ fatigue, inflammatory status, and conditioning.


Psychosocial factors include depression, anxiety, catastrophizing, and resilience.


Social factors include work status, relationships, family, and finances.


Spiritual factors include values, religious faith, spiritual distress, and attitudes to suffering


Biopsychosocial Spiritual Context of Pain

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The Biopsychosocial Spiritual Context of Pain model captures all of these factors, recognizing that they may change over the course of a patient's pain experience.

This model can provide a comprehensive assessment to provide determination of the patient's goals for pain management, discussion of treatment options, confirmation of mutual expectations, revelation of the inherent risks of treatment, and establishment of realistic outcomes.


Empathy also can play a role in the patient's pain experience.


In patients with chronic pain, study results demonstrated that perceived increases in physicians’ empathy were directly and independently associated with pain relief and improvements in health-related quality of life (QoL).


Physicians who are rated as empathetic by their patients are more effective at relieving their patients’ pain

The Pain Pathway




Nociceptors are specialist receptors which are activated through various noxious stimuli.


Nociceptors can be found in the skin, muscle, joints, bone and organs (other than the brain) and can fire in response to a number of different stimuli.


Three types of nociceptors exist:

  • Mechanical nociceptors – detects sharp, pricking pain

  • Thermal and mechano-thermal nociceptors – detects sensations which elicit pain which is slow and burning, or cold and sharp in nature

  • Polymodal nociceptors – detects mechanical, thermal and chemical stimuli


Similar to other sensory modalities, each nociceptor has its own receptive field. This means one nociceptor will transduce the signal of pain when a particular region is skin is stimulated.

The size of receptive fields vary throughout the body and there is often overlap with neighbouring fields.

Areas such as the fingertips have smaller receptive fields than areas such as the forearm. In addition, they have a larger density of free nerve endings within this receptive field. This difference is important as it allows for greater acuity in detecting a sensory stimulus.

The size of cortical representation in the somatosensory cortex of a particular body part is also related to the size of the receptive fields in that body part. For example, because the fingertips have small receptive fields, and thus a greater degree of sensory acuity, they have a larger cortical representation.


First order neurons

Run from nociceptors into the spinal cord

First order neurons have one axon which splits into two branches, a peripheral branch (which extends towards the peripheries) and a central branch (which extends centrally into spinal cord/brainstem).


Aδ fibres.

Signals from mechanical, thermal and mechano-thermal nociceptors are transmitted to the dorsal horn of the spinal cord predominantly by Aδ fibres.

These myelinated fibres have a low threshold for firing and the fast conduction speed means they are responsible for transmitting the first pain felt.


In addition, Aδ fibres permit for the localisation of pain and form the afferent pathway for the reflexes elicited by pain. Aδ fibres predominantly terminate in Rexed laminae I where they mainly release the neurotransmitter glutamate.


C fibres

Polymodal nociceptors transmit their signals into the dorsal horn through C fibres.

C fibres are unmyelinated and a slow conduction speed.

For this reason, C fibres are responsible for the secondary pain we feel which is often dull, deep and throbbing in nature.

These fibres typically have large receptive fields and therefore lead to poor localisation of pain.

Compared to Aδ fibres, C fibres have a high threshold for firing. However, noxious stimuli can cause sensitisation of C fibres and reduce their threshold for firing.


First and second order neurons

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A variety of factors are released upon tissue damage which lead to the activation of nociceptors. These include:

  • Arachidonic acid

  • Potassium

  • 5-HT

  • Histamine

  • Bradykinin

  • Lactic acid

  • ATP

Many of these factors are also pro-inflammatory and lead to acute inflammation in the area of damage.

Neuromechanisms of pain

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Second order neurons

in the spinal cord to the thalamus.


Third order neurons

from the thalamus, project via the posterior limb of the internal capsule to terminate in the ipsilateral postcentral gyrus (primary somatosensory cortex).


The postcentral gyrus is somatotopically organised. Therefore, pain signals initiated in the hand will terminate in the area of the cortex dedicated to represent sensations of the hand.

Third order neurons

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Perceptive  modulation of pain


All pain has an affective-emotional component that influences the individual's behavioral responses.


Cognitive-behavioral therapies such as distraction, relaxation, and imagery operate at this level of the pain pathway.


Some patients have a dominant affective emotional component and present with increased pain behaviors, anxiety, and depression that must be treated in order to achieve effective pain control.


Ascending modulation of pain


Non-steroidal anti-inflammatory drugs inhibit the synthesis of prostaglandins, normally produced and released at the site of injury, and which in turn make neighboring nociceptors more responsive to noxious and innocuous stimuli.

Local anesthetics and some antiepileptic drugs block sodium channels and inhibit the production of action potentials along the nociceptive afferents.

Peripheral and spinal nerve blocks interfere with propagation of action potentials and pain transmission into the CNS (at the nociceptors, along the nerve, at the dorsal root ganglion and along the spinothalamic tracts)

Epidurally and intrathecally administered analgesics may provide presynaptic and postsynaptic inhibition of receptors at the level of dorsal horn neurons and affect the transmission of nociceptive impulses.


Descending modulation of pain


Certain antidepressants such as the tricylics and selective norepinephrine reuptake inhibitors (SNRIs) that inhibit the reuptake of serotonin and norepinephrine enhance descending inhibition.

This may explain their effectiveness in neuropathic and other types of pain.


Cognitive behavioral therapies are thought to modulate pain by reducing fear and anxiety.

Spinal cord stimulation, epidural and intrathecal delivery of drugs such as opioids also modify descending modulation.

Opioid analgesics have direct effects on descending modulation.

Opioid descending modulation of pain


Within the central nervous system there are three types of opioid receptors which regulate neurotransmission of pain signals. These receptors are called mu, delta and kappa opioid receptors.

They are all G protein coupled receptors and their activation leads to a reduction in neurotransmitter release and cell hyperpolarisation, reducing cell excitability. Exogenous opioids, such as morphine, provide excellent analgesia by acting on these receptors.


Likewise, the body contains endogenous opioids which can modulate pain physiologically. There are three types of endogenous opioids:

  • Β-endorphins – which predominately binds to mu opioid receptors

  • Dynorphins – which predominately bind to kappa opioid receptors

  • Enkephalins – which predominately bind to delta opioid receptors


Opioids can regulate pain on a number of levels, both within the spinal cord, brain stem and cortex.

Within the spinal cord both dynorphins and enkephalins can act to reduce the transmission of pain signals in the dorsal horn. This is because the pre-synaptic ends of second order neurons have opioid receptors within the membrane.

In addition, the post-synaptic end of first order neurons contain opioid receptors.

When endogenous opioids act on these receptors it reduces neurotransmitter release from the first order neuron, and causes hyperpolarisation of the second order neuron.

Together, this reduces the firing of action potentials in the second order neuron, blocking the transmission of pain signals.

Opioid receptor locations

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The gate control theory of pain

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1. Schug SA

The atypical opioids: buprenorphine, tramadol and tapentadol

MedicineToday : Conventional and Atypical Opioids Supplement September 2018


2. University of Wisconsin School of Medicine and Public Health

Pain management

Online resource



3. Chronic Pain Syndromes

BMJ Best Practice

Last reviewed:September 2019

Last updated:July  2018


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5. Buhrman M, Syk M, Burvall O, et al.

Individualized guided internet-delivered cognitive-behavior therapy for chronic pain patients with comorbid depression and anxiety: a randomized controlled trial.

Clin J Pain. 2015 Jun;31(6):504-16.


6. Pain Pathways

Teach me Physiology

Online resource


7. Dr Hassan

Physiology of pain Pathways and its modulation

Slide share

Online resource


8. Fong A,, Schug SA.

Pathophysiology of pain: a practical primer.

Plast Reconstr Surg. 2014 Oct;134(4 Suppl 2):8S-14S


9. Wuhrman E, Cooney MF

Acute Pain: Assessment and Treatment.

January 2011


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