In 2018 The International Association for the Study of Pain (IASP) set up a task force to review the then current definition of pain, with the intent of having a more specific, simple and practical definition of pain, aligned with modern conceptualisations, and a better understanding of the personal experience of pain.⁵ Two years later, in 2020, the task force accepted the definition of pain as follows: "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage."⁵

Classifying pain

As such, there are no pain pathways, only nociceptor pathways.⁴ Pain is referred to as being “nociceptive”, which translates to being “sensitive to noxious stimuli”.² The processing of the noxious and potentially tissue-damaging stimuli involves the interaction of the peripheral nervous system (PNS) and central nervous system (CNS) and is known as nociception.^1,6

The PNS encompasses nerves and ganglia outside of the brain and spinal cord and serves to connect the body’s organs and extremities to the CNS.⁷ The CNS, consisting of the brain and spinal cord, integrates, interprets and coordinates information received from the PNS and then sends a response to effector organs.⁷

Peripheral, central, intracellular and synaptic modifications are allowed for by the CNS.⁸ As a result of the adaptability of the CNS, acute pain can lead to long-term changes resulting in a modified response to sensory input, known as neuroplasticity.⁸

Classification or identifying the type of pain helps in determining treatment.⁹ Pain classification as “acute” or “chronic” is based on tissue healing time. The normal tissue healing process is usually around 6 weeks but may continue until approximately 3 months during the tissue regenerative phase.⁹ Acute pain is therefore defined as pain that is present for 6 weeks to 3 months.⁹ Chronic pain is pain that lasts beyond the regenerative phase and occurs despite evidence of tissue healing.⁹

Basic pain mechanisms

Identifying acute or chronic pain does not necessarily identify the underlying pathology.⁶ A mechanism-based classification helps evaluate the diverse nature of pain in order to better target pain relief.^6,9

According to Australia and New Zealand Guidelines, the heterogeneity of pain may be addressed by identifying the underlying physiological mechanisms of pain within a framework, namely:^6,9

• Nociceptive and inflammatory classes of physiological or adaptive pain, together with
• Neuropathic and Nociplastic (CNS dysfunctional) classes of pathological or maladaptive pain

 

Nociceptive and inflammatory pain

Peripheral nociceptors are the bare nerve endings of primary afferent fibres.^1,2,6 Nociceptors are distributed throughout the body, including the skin, muscle, joints and viscera.^1,2

Transduction involves the stimulation of nociceptors at the tissue sites by noxious stimuli, such as temperature extremes, high pressures and tissue damaging inflammation.^6,10 Nociceptors are also sensitised by substances (referred to as inflammatory soup chemicals) released as a result of tissue damage.^1,2,4 These chemicals include, amongst others, hydrogen and potassium ions, bradykinin, histamine, noradrenaline, 5-hydroxytryptamine (5-HT), prostaglandin, substance P, leukotrienes, and nerve growth factor.^1,2,4

Transmission of the induced action potential then occurs along afferent pain nerve fibres (nociceptive primary afferents) that converge onto neuronal cell bodies located in either the dorsal root ganglion or the trigeminal ganglia (first-order neurons) depending on where the stimulus is initiated.^1,2,6

Glutamate and neuropeptides (such as substance P) are released by the primary afferent fibres, which interact with other afferents and second-order neurons within the laminae of the dorsal horn.^1,6 Second order neurons in the dorsal horn may be nociceptive specific high threshold neurons and wide dynamic range (WDR) neurons. WDR neurons, when sensitised, respond and discharge in response to tactile non-noxious stimuli (allodynia).⁸

The action potential is transmitted via the spinal cord to the CNS.^2,6 There are two routes for signals to be conducted, namely via the ascending pathway and the descending pathway.⁷

• Ascending pathways: nerves carry signals upwards from the body via the spinal cord towards the brain⁷
• Descending inhibitory pathways: nerves go downward from the brain to the reflex organs via the spinal cord⁷

 

Nociception is modulated by action on the primary afferents and neurons at the level of the dorsal horn.⁸ Transmission is inhibited towards the cortex and other higher centres.⁸ Descending inhibitory fibres originate in the cortex, periaqueductal grey (PAG) and brainstem nuclei, and their fibres terminate in the dorsal horn.⁸

Modulation of nociceptive signals occurs when the descending inhibitory pathways from the brain and brainstem are stimulated. This results in an alteration of the afferent signals received and interpreted by the brain.¹⁰ Interestingly, the brain has limited processing capacity, and not all the signals received from nociceptors are perceived.⁶ The brain can prioritise behaviourally relevant signals and suppress those less important.⁶

Nociceptors differ in their sensitivities (thresholds) and may be categorised according to their response to mechanical, thermal and/or chemical stimulation.² Two main categories of primary afferent nociceptors, namely A-delta fibres and C fibres respond to noxious stimuli.^6,7 Polymodal (respond to mechanical, thermal and chemical stimuli) C-fibres are the most prevalent of the peripheral nociceptors.⁶

Silent nociceptors are dormant nociceptors that only become responsive to mechanical stimulation in the presence of inflammation and tissue injury.² It is postulated that continuous stimulation from tissue damage reduces the threshold of these receptors, thereby activating them.² Pain resulting from a stimulus that does not usually produce pain, is referred to as allodynia.² Allodynia may also be explained when structural changes occur as a result of damaged peripheral neurons rerouting and connecting to sensory receptors.²

Inflammation occurs as a natural response to tissue injury and helps to initiate tissue repair.⁷ Hyperalgesia (a lowered threshold to thermal or mechanical stimulation resulting in an enhanced pain perception), as well as allodynia and sympathetic maintained pain, can occur as a result of inflammation.⁷ The localised inflammatory response results in the release of free arachidonic acid (AA), which is then converted via the cyclooxygenase pathway (COX) into prostaglandins (PG).⁷ Prostaglandin is the key component in the sensitisation of the nociceptors.⁷ Inflammatory pain may be classified as acute or chronic. Acute inflammatory pain is usually mediated by A-delta fibres as a response to harmful stimuli, whereas chronic inflammatory pain is mediated by C-fibres and lasts beyond the typical healing time.⁷

The repetitive stimulation of nociceptors causes an intensification of nociceptive information.⁷ Central sensitisation occurs in the dorsal horn as a result of repetitive stimulation of N-methyl-D aspartic acid (NMDA) receptors, leading to secondary hyperalgesia.⁸ Secondary hyperalgesia or allodynia occurs as a result of sensitisation of the surrounding uninjured tissue.⁷

Neuropathic pain is defined as pain that originates in the nervous system and may be further subdivided into "central" or "peripheral".^8,6 The IASP defines neuropathic pain as "pain caused by a lesion or disease of the somatosensory system."⁶ This type of pain, which may be acute (following trauma or surgery) or chronic, is often referred to as nerve injury or impairment, and is associated with allodynia.^7,9

Injury or disease of the sensory nervous system leads to spontaneous ectopic firing of the neurons, resulting in enhanced sensitisation of second order neurons in the spinal cord and an increased expression of ion channels.⁹ Neuropathic pain is typically described as a burning, electrical, pins and needles or a numbness.⁹

Nociplastic pain

Symptoms of neuropathic pain occurring without nerve injury is referred to as nociplastic pain.⁶ The mechanism of nociplastic pain is not fully understood, but is thought to occur as a result of a sensitised nervous system (peripheral and central), which increases the responsiveness of the nociceptive system.⁹ In addition to having a sensitised nervous system, there is altered pain modulation due to an impaired descending inhibitory mechanism.^9,11

The pain experienced comes from stimuli that is non-noxious, such as touch, movement or deep palpation.⁹ Other symptoms, such as fatigue, sleep, memory and mood problems are also associated with a sensitised CNS in patients with nociplastic pain.¹¹

Conditions such as fibromyalgia and tension-type headache are examples of where nociplastic pain can occur in isolation.¹¹

Modulating pain

The transmission of pain is dependent on the balance between excitatory and inhibitory influences acting on the neuronal circuits of the somatosensory system.⁷

Excitatory neurotransmitters include substance P, neurokinin 1, glutamate.

At the dorsal horn level, these excitatory neurotransmitters activate low threshold receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and neurokinin 1 (NK-1)). In turn, these activate the high threshold NMDA receptor.⁸

Inhibitory neurotransmitters at the dorsal horn include noradrenaline, dopamine, serotonin, histamine, oxytocin, acetylcholine, γ-aminobutyric acid (GABA), glycine and opioids.⁸

Pain modulation may be accomplished by decreasing excitation and/or increasing inhibition at the spinal cord level.⁸

Managing pain

Nociceptive, neuropathic and nociplastic types of pain can often overlap.⁹ Effective pain management is dependent on the health care professional’s understanding of the impact that the patient’s perception of pain (i.e. the emotional or sensory experience of pain) has on the pain, as well as identifying the type or mechanism of the pain.⁹ Other factors that contribute to pain, such as the immune system and the endocrine system also need to be taken into account to effectively manage pain.⁹

The modified WHO analgesic ladder has been used as a guide in managing cancer pain, as well as a guide in the management of acute and chronic non-cancer pain and painful chronic conditions, such as musculoskeletal disorders, neuropathic pain disorders, and degenerative disorders.¹² While large-scale studies are needed to evaluate this pain management strategy, up to 80% of patients have benefited from this approach to pain management.¹²

The ladder is based on the premise that the physician has adequate knowledge about pain, is able to properly evaluate the degree of pain and prescribe the appropriate medications accordingly.¹²

The modified WHO ladder adopts a bidirectional approach to pain management, as well as an added 4th step which incorporates non-pharmacologic procedures in the therapy path which may be added in conjunction to strong opioids or other medications in the treatment of persistent pain.¹² The bidirectional approach allows for the strongest analgesic to be used for intense pain as the initial therapy, stepping down as pain is alleviated, and for the using of a step-up approach for chronic pain.¹² As chronic pain is alleviated or resolved, a step-down approach may be adopted.¹²

The ladder approach to pain focuses predominantly on the physical aspects of pain and has limitations in the management of pure neuropathic pain conditions and other clinical conditions, such as fibromyalgia.¹²

The IASP suggests, focusing on the mechanism of pain and the mechanism of action of the drugs in order to treat the pain.¹²

The first objective in managing any type of pain, is to address the psychological aspect.^4,9 Regardless of the type of pain, nociceptive, neuropathic, nociplastic, or a combination of these, the primary target is the brain.^4,9

Psychological factors known to affect the experience of pain include:^4,14

• Catastrophising and focusing on the pain
• Secondary gain (defined as “a benefit (as sympathetic attention or time off work) associated with a physical or psychological disorder”)
• Environmental factors, fear avoidance and anxiety

Secondary to the brain, the peripheral nervous system is the target for nociceptive pain.⁹ This would therefore involve, for example, the use of NSAIDs and corticosteroids to treat chronic nociceptive inflammatory pain, while opioids and non-opioid analgesics would be preferred in the management of low-inflammatory nociceptive pain.¹²

Neuropathic and nociplastic pain require a different secondary approach.⁹ Treatment focusing on the synapse between first and second order neurons in the spinal cord is a secondary target for managing neuropathic pain.⁹ Antidepressants and anticonvulsants would therefore be more suited in the management of neuropathic pain.¹² Paracetamol and NSAIDs have no documented effect in the treatment of neuropathic pain.¹⁵

Nociplastic pain management targets both the brain and spinal cord.⁹ A multimodal approach to this pain is required and involves primarily non-pharmacological pain methods, such as educating the patient about their pain, promoting self-management and teaching good life habits (such as sleep, hygiene, exercise, cognitive behavioural therapies and mindfulness).¹¹ These non-pharmacological methods may be coupled with pharmacological therapies that target the descending inhibitory mechanisms.⁹ Medications which may be used in the management of nociplastic pain include centrally-acting pain modulators, such as tricyclic antidepressants (TCAs), serotonin, noradrenaline reuptake inhibitors (SNRIs) and gabapentinoids.¹¹ NSAIDs and non-opioid analgesics are not particularly effective for the management of nociplastic pain. Opioids should be avoided altogether, as they are less effective (possibly due to the higher concentrations of endogenous opiates) and are likely to be associated with increased risks.¹¹

Progression of acute to chronic pain

Certain factors may increase the risk of acute pain progressing to chronic pain.⁴ These factors include repeated surgeries, postoperative complications, perioperative chemotherapy and/or radiotherapy, as well as prolonged and intense preoperative and/or postoperative pain.⁴ The mechanism of this progression from acute to chronic pain is thought to be due to central sensitisation (repetitive constant stimulation of the nociceptive system through C-fibre activity leading to progressive increase in pain experience) and wind-up phenomena (sensitised dorsal horn cell causing an exaggerated response to a gentle stimulus).^4,16

Pain management medications

Paracetamol

Paracetamol is an analgesic indicated for mild to moderate pain. It also has antipyretic properties. Paracetamol may be used as adjunctive therapy for moderate to severe pain in patients already taking opioids.¹⁵

Paracetamol has no documented effect in the management of neuropathic pain.¹⁵

Mechanism of Action (MOA)

The MOA of paracetamol is not fully understood. It has limited peripheral action and is more likely to have a central effect involving multiple pathways. There are no known endogenous binding sites for paracetamol (as is the case with opioids). Although paracetamol has shown weak inhibition of peripheral cyclooxygenase activity (only when low levels of inflammation are present) and also prevents prostaglandin production at cellular level (independent of COX activity), it does not have anti-inflammatory properties.^6,10,15 Analgesia and antipyresis occurs as a result of the decrease in central nervous system prostaglandin synthesis.¹⁵

Nonsteroidal anti-inflammatories (NSAIDs)

NSAIDs are used in the management of mild to moderate pain, including pain associated with inflammation.¹⁵ As in the case of paracetamol, they provide temporary relief from pyresis.¹⁵

NSAIDs may be classified as:⁸

• Nonselective NSAIDs (nsNSAIDs)
• Coxibs (selective and specific COX-2 inhibitors)

 

The COX-1 enzyme is expressed in nearly all tissues and is responsible for regulating normal cellular (physiological) processes, such as maintaining gastrointestinal mucosa lining, kidney function and platelet aggregation.¹⁰ The COX-2 enzyme is undetectable in most tissues, except for the brain, kidney and bone. In inflammatory states, the COX-2 enzyme is highly inducible leading to the production of pro-inflammatory prostaglandins.¹⁰ The effects of prostaglandin synthesis are dependent on the expression of COX-1 and COX-2 in different tissues at the inflammation sites.¹⁰ Many of the physiological adverse effects associated with nsNSAID use are attributed to COX-1 inhibition.⁶

The induction of COX-2 within the spinal cord has been shown to play a role in central sensitisation.⁶

Opioids

The analgesic effect of opioids is achieved mainly in the CNS, where stimulation of the descending inhibitory pathways in the midbrain attenuates ascending nociceptive signals in the dorsal horn.¹⁸ The dorsal horn nerve fibres and other peripheral nociceptors may also be directly stimulated by opioids, which attenuates ascending signals.¹⁸

Opioids are diverse and have varying degrees of potency.¹⁸ The analgesic effect of opioid agonists, as well as their side-effect profile, is predominantly due to the activation of the mu opioid receptor.¹⁸ As opiate receptors are mainly located presynaptically, stimulation of these receptors results in a reduction of neurotransmitter release from the primary afferent neuron.⁴ Loss of opioid receptors presynaptically, and the formation of a metabolite, morphine 3 glucuronide (M3G) that antagonises opioid analgesia, may occur as a result of nerve injury and inflammation.⁴

Conventional opioids achieve analgesia by acting on opioid receptors. However, some opioids are able to achieve their analgesic effect by additional, or alternate interactions with opioid receptors (referred to as "atypical opioids").⁶

Opioids may act as:^4,8,18

• Agonists: for example, morphine, codeine, hydromorphone, oxycodone
• Partial agonist (dualists): for example, buprenorphine
• Atypical opioids: for example, tapentadol, tramadol
• Antagonists: for example, naloxone

 

N-methyl-D-aspartate receptor (NMDA) antagonists

NMDA receptors are found in the dorsal horn of the spinal cord and are activated indirectly by substance P, neurokinin 1 and glutamate.⁸

Ketamine, an NMDA receptor antagonist:⁸

• Provides analgesia and potentially modulates the development of chronic pain
• Works synergistically with opioids, and may decrease tolerance to opioids
• May be used in opioid-tolerant patients to reduce opioid requirements

Other NMDA antagonists include magnesium, nitrous oxide and dextromethorphan (may decrease the use of other analgesics post tonsillectomy in adults).⁸

α₂ agonists

α₂ agonists modulate nociception via descending pathways.^4,6,8 Clonidine

• A selective alpha-2 agonist which has been shown to have an opioid-sparing effect
• As premedication, used as a sedative and for pre-emptive analgesia
• More effective than placebo in the management of opioid-withdrawal symptoms.

 

Dexmedetomidine

• Highly selective alpha-2 agonist
• Used for moderate to severe pain
• When administered systemically intraoperatively, has been shown to reduce pain intensity as well as opioid consumption versus placebo
• Use reduces the need for rescue analgesia and extends time to first rescue analgesia

Local Anaesthetics

Local anaesthetics inhibit sodium ion channels on the surface of nerve cell membranes.¹⁵ This action disrupts neuronal excitation and/or conduction of nerve impulses locally, without having a systemic effect.^8,15

Local anaesthetics differ in their duration of action, potency and systemic toxicity.⁶

Short-acting local anaesthetics, e.g., lignocaine are used in acute pain management.⁸ Lignocaine is commonly used topically in the management of postherpetic neuralgia and peripheral neuropathic pain.¹⁵

Duration of effect is dependent on:

• Site of administration
• Dose administered
• Presence or absence of vasoconstrictors

A short-to intermediate acting local anaesthetic, mepivacaine, is used mainly in intraoperative anaesthesia.⁶

Long-acting local anaesthetics, include for example, bupivacaine, levobupivacaine, ropivacaine.⁸

Adjuvants

The term adjuvant, or co-analgesic, refers to medications used in the management of pain that do not have analgesic effects per se and are usually used for other indications.¹² Adjuvants may be indicated as first-line therapy for specific pain conditions, e.g., diabetic neuropathy.¹²

Adjuvants include:¹²

• Antidepressants, e.g., tricyclic antidepressants (TCAs), serotonin-noradrenaline reuptake inhibitors (SNRIs)
• Anticonvulsants, e.g., Gabapentin and Pregabalin
• Topical therapies, e.g., topical anaesthetics, capsaicin, corticosteroids, bisphosphonates and cannabinoids

 

Combination analgesics⁴

Combination analgesia is used frequently in South Africa, the intentions of which are to improve analgesia and reduce the dose of each analgesic to reduce the risk of adverse events.⁴

Multimodal (or “balanced”) analgesia refers to the use of different medications with different modes of action, such as local anaesthetics, simple analgesics, anxiolytics, opioids, tramadol and inhalational agents (amongst others) in combination in order to decrease the incidence of side-effects and enhance efficacy.^6,8

Paracetamol in combination with a NSAID is more effective than either of these analgesics used alone.⁶ An increased analgesic efficacy is also shown when paracetamol is combined with opioids, such as tramadol or codeine.⁶

The paracetamol dose is usually decreased when used in combination with other analgesics, such as NSAID and/or codeine.⁴ Overdose of paracetamol may occur if a patient is receiving paracetamol via another route, such as IV or via suppository, and a combination analgesic preparation containing paracetamol is added.⁴

Conclusion

The importance of identifying different types of pain and their underlying mechanism is vital, as different types of pain respond to different therapies.¹¹ The most suitable treatment modality will depend on the type of pain, patient factors, disease factors and the characteristics, as well as the efficacy and tolerability of the drug.¹⁰ Failing to properly manage acute pain postoperatively increases the risk of neuropathic pain development and also increases the risk of acute pain progressing to a chronic pain syndrome.⁸

References:

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3. Cosio D. The Perseverence Loop: The Psychology of pain and factors in pain perception. Pract Pain Manag. [cited 15 dec 2021; updated 4 Feb 2020]. Pg 19-22. Available from: https://www.practicalpainmanagement.com/treatments/psychological/perseverance-loop-psychology-pain-factors-pain-perception.

4. Chetty S, Frolich E, Penfold P, et al. Acute pain guidelines. S Afr Pharm J. Vol 83 No 9 (2016). Available from: http://www.sapj.co.za/index.php/SAPJ/article/view/2346.

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6. Schug SA, Palmer GM, Scott DA, et al. Acute Pain Management: Scientific Evidence (5th edition), ANZCA & FPM, Melbourne.

7. Yam MF, Loh YC, Tan CS, et al. General pathways of pain sensation and the major neurotransmitters involved in pain regulation. Int J Mol Sci. 2018;19(8):2164. Published 2018 Jul 24. doi:10.3390/ijms19082164.

8. South African Society of Anaesthesiologists (SASA). South African acute pain guidelines. 2015.

9. Parker R. Pain: Recognising the different types of pain. Pharmacy Focus. Issue 6-2021.

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11. Fitzcharles M, Cohen S, Clauw D, et al. Nociplastic pain: towards an understanding of prevalent pain conditions. Lancet. 2021;397:2098-2110. doi:10.1016/S0140-6736(21)00392-5.

12. Anekar AA, Cascella M. WHO analgesic ladder. [Updated 2021 May 18]. Available from: https://www.ncbi.nlm. http://nih.gov/books/NBK554435/.

13. Vargas-Schaffer G. Is the WHO analgesic ladder still valid? Twenty-four years of experience. Can Fam Physician. 2010;56(6):514-517. Adapted from: Fig2 New adaptation of the analgesic ladder.

14. Merriam-Webster. Secondary gain. In http://Merriam-Webster.com medical dictionary. Retrieved February 13, 2022, from https://www.merriam-webster.com/medical/secondary%20gain.

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16. IAHPC Pallipedia. Central sensitization (wind-up). https://pallipedia.org/central-sensitization-wind-up/. Accessed February 13, 2022.

17. Ghlichloo I, Gerriets V. Nonsteroidal anti-inflammatory drugs (NSAIDs) [Updated 2021 May 12]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547742/.

18. van Rensburg, Reuter H. An onverview of analgesics: opioids, tramadol, and tapentadol (Part 2). S Afr Fam Pract. 2019;61(2):16-23. DOI:https://doi.org/10.4102/safp.v61i2.5001.

19. Rossiter D. South African Medicines Formulary (SAMF). 13th Edition. Buprenorphine.