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A Review with a focus on mechanism and management of inflammation

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A Review with a focus on mechanism and management of inflammation

Clinical practice remains an empirical and often unsatisfactory journey for patients, whose individual responses to treatment cannot be predicted.3 A mechanistic approach to address chronic pain has been actively promoted over the past few decades in an attempt to exploit the growing understanding of underlying pathological processes as a means to improve patient management.3 This article provides a brief review on the classification of pain and some treatment guidelines. In addition, the mechanism and role of inflammation in pain and some guidelines on the use of anti-inflammatories for pain management are provided.

Classification of pain

The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage": emphasizing both the physical and emotional nature of pain.4

Pain is a multimodal phenomenon with sensory, physiological, cognitive, affective, behavioural and spiritual components. Thus, the way in which pain is experienced, is altered by emotions (affective component), behavioural responses to pain, beliefs, attitudes, spiritual and cultural attitudes about pain and pain control, by modifying the transmission of unpleasant (noxious) stimuli to the brain.4 There are no pain pathways, only nociceptive pathways. 2

The most commonly used systems to classify pain include:4
• The pathophysiological mechanism of pain (nociceptive or neuropathic pain)
• The duration of pain (chronic or acute, breakthrough pain)
• The aetiology (malignant or non-malignant)
• The anatomic location of pain

Nociceptive pain

Specific pain receptors (called nociceptors)4 are widely distributed throughout the body5 and somatic nociceptive pain is caused by activation of nociceptors located in surface tissues such as skin, mucosa of the mouth, nose, urethra, anus, etc. or deep tissues such as bone, joint, muscle or connective tissue.4 These nociceptors are sensitive to noxious stimuli such as heat, cold, vibration, tissue disruption,4 ischaemia, degranulation of mast cells, infection and inflammation, secretions from inflammatory cells or induction of enzymes such as cyclooxygenase 2 (COX-2).5

Visceral nociceptive pain is caused by the activation of nociceptors located in the internal organs enclosed within a cavity, such as thoracic and abdominal organs and can occur due to infection, distension from liquid or gas, or stretching or compression, usually due to solid tumours.4 Sensitisation of nociceptors results in transduction of noxious stimuli into electrical activity by ion channels.3-5 These electrical signals are transported via the C and A-6 fibres to nociceptor cells in the dorsal root ganglia (or trigeminal ganglion for the head and oral cavity) in the superficial dorsal horn.3 Information is conveyed to laminae where neurotransmitters (such as glutamate and neuropeptides such as substance P) are released to trigger post-synaptic receptors.5

Signals follow five major ascending spinal cord projection pathways.5 Signals following the spinothalamic tract get processed in the thalamus and somatosensory cortex to provide information on the type and site of the pain.2 The spinoreticular and spinomesencephalic tracts mediate the affective and emotional components of the nociceptive stimulus.5 The cingulate cortex, insula, periaqueductal grey (PAG), reticular formation and prefrontal cortex receive multiple inputs to coordinate autonomic and emotional responses. 2

Tracts originate in the cortex, PAG and brain stem nuclei and terminate in the dorsal horn, modulating the nociceptive input.2 A feature of sensory processing is that not all of the signals received from receptors are perceived. The limited processing capacity of the brain is optimised by prioritising behaviourally relevant signals while suppressing less important signals.5

Neuropathic pain

Neuropathic pain was redefined as "pain caused by a lesion or disease in the somatosensory nervous system"5 and is caused by structural damage and nerve cell dysfunction in the peripheral or central nervous system (CNS). Any process that can cause damage to the nerves, such as traumatic, metabolic, infectious, toxic, ischaemic or immune-mediated pathological conditions, can result in neuropathic pain. Neuropathic pain can be either peripheral due to a lesion or disease affecting the peripheral nerve, dorsal root ganglion or dorsal root; or it can be central due to a lesion affecting the CNS. However, a clear distinction is not always possible.4 Table 1 provides some differentiating features of nociceptive and neuropathic pain.

Mixed pain

The different pathophysiological mechanisms described can operate together to cause mixed pain. Neuropathic pain may co-exist with nociceptive pain and patients may, at times, experience mixed pain consisting of somatic, visceral and neuropathic pain all at the same time, or separately at different times. Examples of such conditions include trauma that damages tissues and nerves, burns that affect skin and nerve endings and cancer that causes external nerve compression, as well as nerve infiltration.4

Acute pain, as a result of tissue injury, is felt immediately following injury. Although it is severe in intensity, it is usually short-lasting, generally disappearing when the injury heals.4 Acute pain is more difficult to manage if permitted to become severe and it is imperative to treat acute pain promptly and effectively.6

Chronic pain is continuous or recurrent pain that persists beyond the expected normal time of healing, usually longer than three months.4 Excessive concern about addiction contributes to the under-treatment of pain. Analgesics, especially opioids, are under-prescribed and under-dosed for both acute and chronic pain.6 Acute pain can progress into chronic pain and the following are risk factors for the development of chronic pain:2

• Intense and prolonged preoperative and/or postoperative pain
• Repeated surgery
• Chemotherapy and/or radiotherapy perioperatively
• Postoperative complications such as infection

Some surgical procedures are also associated with an increased incidence of chronic pain and the risk seems to be highest with amputations, thoracotomy, inguinal hernia repair, mastectomy and cholecystectomy, although it can occur following other procedures as well.2 Interventions that can prevent chronic postsurgical pain are divided into four broad groups and include regional and neuraxial analgesia, pharmacotherapy, surgery and multidisciplinary nonpharmacological interventions.5

The basic principles of pain management

Pain evaluation and treatment adjustments based on pain intensity

Regular pain evaluation is as important and basic as monitoring blood pressure, pulse rate, temperature and respiratory rate in the patient with acute pain and pain is therefore considered to be the fifth vital sign.2 It is important to use scales that are simple to administer and easy for the patient to understand.2 A large number of validated scales are listed in the literature and the assessment tool selected should be appropriate to the patient's developmental age, cognitive status and emotional status.2

Some assessment tools work on a 10-point scale.2 Acute pain (e.g. postoperatively) should be assessed every 15 minutes and if the patient rates their pain higher than a 5 on the scale, the patient should have their analgesic treatment reviewed.2 Assessments should continue every 15 minutes until the patient is pain-free at rest and during movement, after which assessments can be done hourly for 6 hours, followed by 4 hourly monitoring.2 Pain assessed as more than 5 at any time requires adjustment of pain treatment.2 In the meantime, investigation of any complications that can be the cause of pain (such as infection or deep vein thrombosis) should continue.2 Patients should also be monitored for side effects from the medication such as respiratory depression, excessive sedation, nausea and vomiting.2Table 2 provides a guideline on the recommended treatment options based on the intensity of pain.2

When pain is constantly present, analgesics should be administered at regular intervals while monitoring sideeffects ("by the clock" and not on an "as needed" basis), with the addition of "rescue doses" for intermittent and breakthrough pain4.

Multimodal management

Since pain is a multimodal, complex experience involving multiple neural sites (including peripheral nerves, the spinal cord and higher brain centres)3, with sensory, physiological, cognitive, affective, behavioural and spiritual components, 4 it would make sense to follow a multimodal treatment approach. This would include psychological interventions like cognitive behavioural therapy and treatment of negative affect for patients suffering from depression and pain catastrophizing.3 Multimodal analgesia describes the use of different types of drugs, not exceeding the recommended dose of any one, used in combination to increase efficacy, but also to decrease the incidence of side-effects. Agents used in multimodal analgesia include local anaesthetics, simple analgesics, opioids and tramadol, inhalational agents and anxiolytics, among others.2

Nonselective NSAIDs are integral components of multimodal analgesia.5 When given in combination with patientcontrolled intravenous morphine after surgery, they result in better analgesia, lower incidence of postoperative nausea and vomiting and a reduction in the use of opioids.5 Combining NSAIDs and paracetamol is also more effective than the use of either of these analgesics on their own.5 The benefits of multimodal analgesia include earlier oral intake, ambulation and hospital discharge for postoperative patients as well as higher levels of participation in activities necessary for recovery. It may also reduce postoperative morbidity, mortality and costs.6

Inflammation and pain

The role of inflammation in pain

Tissue damage induces COX-2 production, leading to synthesis of prostaglandins,3 growth factors (e.g. nerve growth factor (NGF)), cytokines (interleukins IL-6,IL-1 􀀄) and tumour necrosis factor-a,4 that result in inflammation, peripheral sensitisation of nociceptors and consequently, increased pain perception.5 In addition to the changes induced in nociceptors by peripheral inflammation, changes also occur in the CNS.3 Systemically acting cytokines lead to a marked increase in COX-2 in the spinal cord neurons. This seems to be key in the development of mechanical hyperalgesia in the inflamed area. The local expression of COX-2 at the inflamed sites also drives heat hypersensitivity.3 Therefore, drugs which reduce peripheral prostaglandin concentration, thereby leading to reduced peripheral sensitisation, play an important role in analgesia.7

The use of NSAIDs in the treatment of inflammatory pain

Mechanism of action and classification of NSA/Ds

NSAIDs act by blocking the two main isoforms of cyclooxygenase (COX-1 and COX-2) enzymes responsible for the synthesis of prostaglandins.8 In general, mild somatic pain (originating in surface tissue or deep tissue such as bone, joints, muscle or connective tissue) responds well to oral non-opioids such as paracetamol, NSAIDs, topical agents (local anaesthetics) and physical treatments such as rest, ice, compression and elevation.6 Both traditional NSAIDs and cyclooxygenase 2 inhibitors (COXIBs) are commonly prescribed to relieve pain and inflammation.1 Table 3 provides a summary of NSAIDs available in South Africa.9

Efficacy

A recent network meta-analysis compared diclofenac to other traditional NSAIDs and COX-2 inhibitors in terms of safety and efficacy in the treatment of osteoarthritis and rheumatoid arthritis.1 Etoricoxib (60 mg/day) and diclofenac (150 mg/day) showed similar efficacy rates and both were more likely to be effective in alleviating pain than celecoxib (200 mg/day), naproxen (1000 mg/day) and ibuprofen (2400 mg/day).1 Lower doses of diclofenac were comparable to all other treatments both in alleviating pain and improving physical function.1

A Cochrane review reported that there was no significant difference in pain scores between meloxicam and naproxen, celecoxib and naproxen or rofecoxib and naproxen for non-chronic pain in children and adolescents.11 Similarly, another review reported that COX-2 selective, partially selective, or non-selective oral NSAIDs are similarly effective in controlling pain.12 Thus, drug choice is dictated by the safety profile, according to different risk factors, and patients' concomitant medical conditions.12

Safety

Prostaglandins regulate many physiological functions, including gastric mucosal protection, bronchodilation, renal tubular function and intrarenal vasodilatation.5 Endothelial prostacycline leads to vasodilatation and prevents platelet adhesion.5 Thromboxane is produced from platelets by COX and results in platelet aggregation and vasoconstriction.5 These functions are regulated by COX-1, with the exception of prostacycline synthesis which is regulated by COX-2.5 Unfortunately, the mechanism of action of NSAIDs resulting in these effects is also responsible for their adverse effects8 with the major concerns relating to gastrointestinal (GI), renal and cardiovascular (CV) systems.5 In the perioperative and acute postoperative period, the main concerns are renal impairment, interference with platelet function, wound and bone healing and peptic ulceration or bronchospasm in individuals at risk.5

Upper GI complications

GI side-effects from NSAIDs arise from both topical injury and COX-1 inhibition. NSAIDs are associated with a 3-fold to 5-fold increase in the risk of upper GI complications, including peptic ulcer perforation, obstruction and bleeding. These side-effects occur even with the use of parenteral formulations. Although COX-2 selective agents are associated with fewer GI complications, there is still an increased risk of upper GI complications.12 Piroxicam and ketorolac were associated with the highest relative risk of upper GI complications in a systematic review and meta-analysis whilst celecoxib and ibuprofen were associated with the lowest relative risk.10•12

Risk factors for NSAID-associated GI events includes age ≥ 60 years, male gender, dyspepsia, history of peptic ulcer (especially bleeding ulcer) and CV disease. Risk also increases with the use of antiplatelet agents (e.g. aspirin), corticosteroids, anticoagulants (e.g. warfarin) and higher doses of NSAIDs.10

CV complications

It has been postulated that the increased CV risk associated with the use of NSAIDs may be related to the degree of COX-1 and COX-2 potency8 and based on previous assumptions, it seems that the higher the level of COX-2 inhibition and the lower the level of COX-1 inhibition, the greater the thrombotic risk related to NSAIDs.8 However, the association of NSAIDs with increased CV risk is a complex issue and today there is little doubt that all oral NSAIDs, selective, and non-selective, have the potential to increase the risk of serious CV events.12 Patients with a considerable CV risk should avoid high doses of diclofenac and ibuprofen as well as COX-2 selective inhibitors. Naproxen, used for short periods of time, is preferred for patients already taking low dose aspirin.8 High dosages of naproxen exert a near complete COX-1 inhibition, which suggests a possible protective effect for myocardial infarction compared with rofecoxib.8 Naproxen should be administered 2 hours after the aspirin to avoid a potential drug interaction.8

For patients with high CV risk factors who should avoid NSAIDs, treatment options may include the use of paracetamol, aspirin, tramadol or the short-term use of opioids.10 If NSAIDs are necessary, the lowest dose should be used for the shortest possible period.10

Renal function

COX-2 is constitutively expressed in the kidney and has been implicated in the maintenance of renal blood flow, mediation of renin release and regulation of sodium excretion.5 Non-selective NSAIDs (ibuprofen and naproxen) as well as etoricoxib displayed similar low risks with regard to effects on renal function with chronic use.5 The risk of acute kidney injury has been shown to increase with a decrease in COX-2 selectivity and appears to be lowest for celecoxib.5 A single dose of parecoxib 80 mg had no effect on any parameter of renal function in patients undergoing laparoscopic hysterectomy, and only transient changes were seen after 3 days' treatment with parecoxib 40 mg in elderly patients undergoing major orthopaedic surgery.5 However, both non-selective NSAIDs as well as COXIBs showed a significantly increased risk of renal failure following administration in cardiac surgery patients.5 The risk-benefit ratio for COXIBs as a discharge medication after orthopaedic surgery is superior to that for non-selective NSAIDs.5 This may be due to the lack of platelet inhibition resulting in less postoperative blood loss when compared to non-selective NSAIDS.7 The risk for gastric ulceration is also lower than that seen with non-selective NSAIDs. Furthermore, COXIBs do not cause bronchospasm in patients with NSAID-exacerbated respiratory disease and the concerns about CV complications have not eventuated with short-term use of parecoxib or even long-term use of celecoxib.7

Conclusion

Substantial improvements in chronic pain management could be possible if a more strategic and coordinated approach to identify and target the specific mechanism driving the presenting pain phenotype can be developed.3 Identification of the pain state (nociceptive, neuropathic, inflammatory and centralised/ dysfunctional), pain mechanism (e.g., peripheral sensitisation) and molecular target could serve as the foundation for a new era of individualised and precision pain medicine.3 Until sensitive and precise diagnostic tools of mechanisms and molecular targeted treatments become available, pain diagnosis must continue to rely on clinical diagnostic criteria.3 For decades, anti-inflammatory drugs such as NSAIDs and COXIBs have been the cornerstone in management of pain due to peripheral sensitisation.1 NSAIDs are useful in the treatment of several different types of pain and although no NSAID is free of risk, this can be minimised by selecting an NSAID based on individual patient risk factors.70

References:

1. van Walsem A, Pandhi S, Nixon RM, et al. Relative benefit-risk comparing diclofenac to other traditional non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors in patients with osteoarthritis or rheumatoid arthritis: a network meta-analysis.Arthritis research & therapy 2015;17(1):66.
2. South African Society of Anaesthesiologists (SASA). South African acute pain guidelines. 2015.
3. Vardeh D, Mannion RJ, Woolf CJ. Toward a mechanism-based approach to pain diagnosis. The Journal of Pain 2016;17(9}:TS0-69.
4. World Health Organization. Guidelines on the pharmacological treatment of persisting pain in children with medical illnesses. 2012.
5. Schug SA, Palmer GM, Scott DA, et a/. Acute Pain Management: Scientific Evidence. 2015:lxiv.
6. National Pharmaceutical Council. Pain: Current understanding of assessment, management and treatments. Section IV: Management of acute pain and chronic non-cancer pain.
7. Pogatzki-Zahn EM, Segelcke D, Schug SA. Postoperative pain-from mechanisms to treatment. Pain Reports 2017;2(2):e588.
8. Fanelli A, Ghisi D, Aprile PL, eta/. Cardiovascular and cerebrovascular risk with nonsteroidal anti-inflammatory drugs and cyclooxygenase 2 inhibitors: latest evidence and clinical implications. Therapeutic advances in drug safety 2017;8(6):173-82.
9. Division of Clinical Pharmacology, Faculty of Health Sciences, University of Cape Town. South African Medicines Formulary. 10th ed. Rossiter 0, ed. Cape Town: Health and Medical Publishing Group, 2012:395-402
10. Clinical Resource, Safety Comparison of NSAIDs. Pharmacist's Letter/Prescriber's Letter. January 2017.
11. Eccleston C, Cooper TE, Fisher E, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) for chronic non-cancer pain in children and adolescents. Cochrane Database of Systematic Reviews. 2017, Issue 8. Art no.:CD 012537.
12. Pelletier J-P, Martel-Pelletier J, Rannou F, et al. Efficacy and safety of oral NSAIDs and analgesics in the management of osteoarthritis: Evidence from real-life setting trials and surveys. Seminars in arthritis and rheumatism 2016;45(4}: S22-S27.

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