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Medical Education For B

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Issue 6 - 2021

• Pain:Recognisingthedifferenttypesofpain

• Paintypesandclassification

• Complicationsofgoutyarthritis

• UsingNSAIDssafely

Sponsoredby:

M3946

CPD Accredited

Reduces neuropathic pain in adults. Improves functioning.1,2

Don’t let neuropathic pain rob them of living

Mylan (Pty) Ltd. Reg. No.: 1949/035112/07. 4 Brewery Street, Isando, Kempton Park, 1600. Tel: (011) 451 1300. Fax: (011) 451 1400. www.mylansa.co.za. M3377 Exp: 10/2022.

PREGABALIN MYLAN 25 mg (Capsule). Reg. No.: 46/2.5/0219. Each hard capsule contains 25 mg of pregabalin. PREGABALIN MYLAN 75 mg (Capsule). Reg. No.: 46/2.5/0220. Each hard capsule contains 75 mg of pregabalin. PREGABALIN MYLAN 150 mg (Capsule). Reg. No.: 46/2.5/0221. Each hard capsule contains 150 mg of pregabalin.For full prescribing information refer to the Professional Information approved by the Regulatory Authority.

References: 1. Rosenstock J, Tuchman M, LaMoreaux L, et al. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 2004;110:628-638. 2. Sabatowski R, Gálvez R, Cherry DA, et al. The 1008-045 Study Group. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain 2004;109:26-35.

17860L Pregabalin Advert Pharmacy Focus R.indd 1 2021/08/27 14:16

DisclaimerThe content contained in this publication contains medical or health sciences information and is intended for professional use within the medical field. Discussions views and recommendations as to medical procedures, products, choice of drugs and drug dosages are the views of the authors. The views expressed by the editor or authors in this newsletter do not necessarily reflect those of the sponsors or publishers. The sponsors, publishers and editor will not be liable for any damages or injuries of any kind arising from the use or misuse of information provided in this publication and do not support the use of products for off label indications. Production Editors: Ann Lake, Helen Gonçalves Design: Jane Gouveia

Enquiries: Ann Lake Publications - 011 802 8847 Email: lakeann@mweb.co.za

EditorialMrs Lee Baker

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Pain: Recognising the differenttypesofpainProf Romy Parker

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PaintypesandclassificationDr Tarin Penberthy

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ComplicationsofgoutyarthritisDr Cathy Spargo

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UsingNSAIDssafelyDr Roland van Rensburg

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Editorial

Mrs Lee BakerManaging Director, Amayeza Info Services, Weltevreden Park, Johannesburg

e are still living in a crazy world. Currently, most of us are between the COVID-19 waves and frantically assisting with administering the vaccines. Our only hope of getting ahead of this pandemic is to ensure that as many people as possible get the vaccine. Meanwhile, as I said before, life goes on and unfortunately people still suffer

from other conditions which require advice and assistance from pharmacists.

The topic of pain continues from the last issue and the first two articles, Recognising different types of pain by Professor Parker, and pain types and classification by Dr Penberthy, highlight the importance of differentiating between the types of pain, in order to treat it appropriately. I found the definition of pain and the fact that pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors very interesting. The difference between nociceptive, nociplastic and neuropathic pain is not always easy to understand, but these articles explain them very well.

The analgesic ladder on page 7 lays out the plan for management of the progression of pain and is a useful guide for pharmacists to understand how the doctors are treating a patient. Dr Penberthy gives very good advice regarding the different options for treatment. She also has a useful table describing the peripheral and central causes of neuropathic pain. It is also important to note that there are other therapies besides medicines to treat some types of pain, such as psychological therapies and non-pharmacological treatments such as patient education, promotion of quality of life and continued participation in work, physical and social activities, especially for nociplastic pain.

The third article discusses the very common condition, gouty arthritis. This is probably one of the most common reasons why a man asks for help from a pharmacist. According to Dr Spargo, inadequate treatment of gout can result in a number of recurrent attacks, chronic inflammation, joint damage, subclinical crystal deposition, and tophi formation, which can result in limited activity. Frequent acute gout episodes can increase the risk of cardiovascular mortality, which can be exacerbated by frequent use of NSAIDs. Pharmacists should be alert to any clients who repeatedly come into the pharmacy for “gout cocktails” and should council them regarding the importance of controlling their gout and not overusing colchicine and NSAIDs. Many patients whose gout is not controlled are taking allopurinol, but their dose may not be adequate. Dr Spargo explains that the goal of treatment with allopurinol should be 0.35mmol/L uric acid and in order to achieve this, treatment should start low (100mg daily) and go slow (increase by 50-100 mg monthly). Rather than focusing on what to cut out of a diet, (there are so many different sources of advice regarding this) people suffering from gout should focus on getting their uric acid levels correct, and pharmacists can play an important advisory role here.

The last article in this issue on page 13, by Dr van Rensburg, is in my mind, one of the most important articles as it discusses the use and safety of NSAIDs. With many of the NSAIDs being available over the counter, there is the potential for over use, and it is important to explain the risks to customers. In some instances it is also important to choose a product that has less gastrointestinal effects or less cardiovascular effects, depending on the patient. Before recommending a particular NSAID, remember to check for drug interactions. I wonder how many people taking an SSRI, go into a pharmacy and just ask for a diclofenac for their pain? Remember the adage “if you have to use an NSAID, use the lowest effective dose for the shortest period of time.”

Reduces neuropathic pain in adults. Improves functioning.1,2

Don’t let neuropathic pain rob them of living

Mylan (Pty) Ltd. Reg. No.: 1949/035112/07. 4 Brewery Street, Isando, Kempton Park, 1600. Tel: (011) 451 1300. Fax: (011) 451 1400. www.mylansa.co.za. M3377 Exp: 10/2022.

PREGABALIN MYLAN 25 mg (Capsule). Reg. No.: 46/2.5/0219. Each hard capsule contains 25 mg of pregabalin. PREGABALIN MYLAN 75 mg (Capsule). Reg. No.: 46/2.5/0220. Each hard capsule contains 75 mg of pregabalin. PREGABALIN MYLAN 150 mg (Capsule). Reg. No.: 46/2.5/0221. Each hard capsule contains 150 mg of pregabalin.For full prescribing information refer to the Professional Information approved by the Regulatory Authority.

References: 1. Rosenstock J, Tuchman M, LaMoreaux L, et al. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 2004;110:628-638. 2. Sabatowski R, Gálvez R, Cherry DA, et al. The 1008-045 Study Group. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain 2004;109:26-35.

17860L Pregabalin Advert Pharmacy Focus R.indd 1 2021/08/27 14:16

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Pain: Recognising the different types of pain

ProfRomyParkerBSc(Phys);BSc(Med)(Hons)Ex.Sci(Phys);MSc(Pain);PhDProfessor and Director of the Pain Management Unit; Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, UCT and Groote Schuur Hospital, Cape Town

ain, a simple word with com-plex meaning, is the reason for 80% of consultations at the pri-mary healthcare level.1 The definition of pain was updated

in 2020 with an additional six notes to ex-pand our understanding (see text box).2 A key point in this definition is that pain and nociception are not the same thing. Pain can be understood as a high order somatosensory construct of the con-scious brain in response to a perception of threat.3 Nociception is the nervous system process of encoding potentially noxious stimuli. Nociception does not al-ways result in pain, it is not unusual to have a cut or a bruise and not have ex-perienced pain at the time of the tissue damage, i.e. the nociceptors would have fired but the brain did not construct an experience of pain. Similarly, pain is not dependent on nociception. It is possible to feel pain even when there is no actual or potential tissue damage.

Time-based classifications ofpainTo simplify the treatment of pain, it is helpful to classify it. Initially, pain was classified by time as either acute or chronic. Acute pain is pain present for 6 weeks to three months,4 while chronic pain is defined as pain present on most days for more than three months.4 It is useful to consider why these time-points have been used. These time-points relate to tissue healing time. Acute pain is pain associated with normal tissue healing processes and is common in the first two stages of healing – the inflammatory phase (7-10 days) and the regenerative phase (6 weeks). Acute pain may continue during the third phase of healing, the remodelling phase which lasts up to three months. Most tissues have healed by three months, therefore, pain which is occurring for more than three months is regarded as a problem, in and of itself – this is chronic pain.5 Chronic pain is pain which occurs despite evidence of tissue healing. Therefore, the first critical step when assessing a person with pain, is to establish how long the pain has been present for to be able to categorise it as acute or chronic.

Mechanism-basedclassificationsofpainThe second critical step when assessing a person with pain, is to establish the mechanism of pain. Mechanism-based classifications of pain assist the health care professional to evaluate the underlying physiological mechanisms which are contributing to the perception of threat i.e. pain. This means that activity in the peripheral nervous system, the central nervous system (spinal cord and cortical) and in the immune and endocrine systems needs to be considered. After all, it is these systems that are the targets of treatment to reduce pain. The three mechanism-based classifications of pain are nociceptive pain, neuropathic pain and nociplastic pain.4

NociceptivePainNociceptive pain is pain that is occurring due to activity in the nociceptors due to damage or potential damage of tissues.4 Nociceptive pain is often acute, and is associated with evidence of inflammation (heat, redness, swelling) and can be regarded as adaptive or helpful as it alters behaviour to protect injured tissue while it heals. Nociceptive pain also behaves in a typical manner with sufferers being able to clearly identify aggravating and

easing factors and timeline since the initial insult. Nociceptive pain indicates that there is a high level of activity in the peripheral nervous system, which is then transmitted via the second order neuron in the spinal cord to the brain where the experience of pain is created. The primary targets of treatment for nociceptive pain are the peripheral nervous system and the brain.

NeuropathicpainNeuropathic pain is pain that is occurring due to lesion or disease of the somatosensory nervous system.4 Neuropathic pain can be acute or chronic. Perhaps the most common neuropathic pain is painful diabetic neuropathy. This type of pain is regarded as maladaptive or unhelpful as the tissues are not damaged and changing behaviour to prevent pain and protect the tissues does not assist with healing as it does with nociceptive pain. Neuropathic pain can be recognised by its typical presentation of burning, electrical, pins and needles and numbness with allodynia (pain from normally non-painful stimuli). Lesion or disease of the sensory nervous system results in spontaneous ectopic firing of the neurons which rapidly leads to sensitisation of second order neurons in the spinal cord with increased

Textbox:Definitionofpain

PAIN: An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.

Six key notes:1. Pain is always a personal experience that is influenced to varying degrees

by biological, psychological, and social factors.2. Pain and nociception are different phenomena. Pain cannot be inferred

solely from activity in sensory neurons.3. Through their life experiences, individuals learn the concept of pain.4. A person’s report of an experience as pain should be respected.5. Although pain usually serves an adaptive role, it may have adverse

effects on function and social and psychological well-being.6. Verbal description is only one of several behaviours to express pain;

inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain.

(Raja et al, 2020)

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expression of ion-channels. Hence, the primary target of treatment is the synapse between the first and second order neuron in the spinal cord, and the brain.

NociplasticpainNociplastic pain is pain that is occurring due to altered plasticity of the nociceptive system.6 Nociplastic pain is typically chronic, present for more than three months. Nociplastic pain occurs when the nervous system becomes sensitised i.e. the firing thresholds of nociceptors (peripheral and central) lowers, and the responsiveness of the nociceptive system increases. With a lowered firing threshold and increased responsiveness to stimulation, people with nociplastic pain experience pain from stimuli that are not dangerous. These stimuli can range from touch, deep palpation, and movement to stress.6 In addition to increased sensitivity, people with nociplastic pain also have impairment of the descending inhibitory mechanisms i.e. their endogenous opioidergic, serotonergic, dopaminergic and cannabinoid systems which modulate nociception (and therefore pain), do not work. This means that people with nociplastic pain may find that exercise makes their pain worse, not better, because these systems are not activated. Nociplastic pain can be recognised by its chronicity (more than 3 months); its lack of association with inflammatory nociceptive processes; the way it is described without clearly identifiable mechanical aggravating and easing factors; its distribution which does not fit peripheral nerve nor nerve root distribution and finally by its responsiveness to exercise, mood and stress. People suffering from nociplastic pain are not psychosomatic, they are living with a nervous system which is sensitised. Common nociplastic pains include fibromyalgia and chronic low back pain. The primary targets of treatment in nociplastic pain are in the central nervous system, both at the spinal cord and cortical levels.

These different types of pain can overlap (Figure 1).7 The patient with a painful knee from osteoarthritis may have chronic nociceptive and nociplastic pain because the stimulus has been present for so long that the nervous system becomes sensitised.8 Similarly, the patient with painful joints from rheumatoid arthritis may experience acute nociceptive on chronic nociplastic pain when they are experiencing a flare up of their

disease, while the pain that they experience during disease remission in those same joints would be chronic nociplastic. Recognising the different mechanisms of pain helps the health care professional to design treatments that target the underlying physiology.

TargetingtreatmenttothepainmechanismThe first target for treatment in all of these types of pain is the brain. Remember, pain is a sensation and emotion the brain creates in response to a perception of threat. Therefore, to effectively treat pain we must understand what the threat is, and perhaps the most helpful question to ask is: “What do you think is wrong?” or “What are you afraid might be wrong?”. The answer to this question will help the health care professional reassure the sufferer about what is, or is not causing their pain.9,10 For example, someone suffering from chronic low back pain might be worried that the ongoing pain means their spine is crumbling, however, if they are suffering from nociplastic pain we can reassure them that their spine is fine but the nerves around the spine have become very sensitive and are sending danger (nociceptive) messages and causing pain despite the fact that there is no danger.

The peripheral nervous system is the next target of treatment in nociceptive pain.11 Reducing inflammatory media-tors at the site of tissue damage with non-steroidal anti-inflammatories is

appropriate, coupled with analgesics to target the activity in the central nervous system (from paracetamol to opioids depending on severity). However, this approach is not effective for neuropath-ic and nociplastic pain.

The spinal cord is the second target of treatment for neuropathic pain after targeting the brain.12 Treatments used focus on reducing the increased activity at the synapse between the first and second order neurons. The first line medications recommended for neuropathic pain are the tricyclic antidepressants, SNRI’s, pregabalin and gabapentin.

For nociplastic pain, the targets of treatment are the central nervous system – spinal cord and brain. The primary treatment is pain neuroscience education – teaching the sufferer that their pain is not an indication that something is wrong, their pain is about a sensitised system (a burglar alarm which keeps going off when no one is breaking into the house).13 The second target is to restore activity in the descending inhibitory mechanisms with tricyclic antidepressants and serotonin and norepinephrine reuptake inhibitors (SNRIs) the first line choices coupled with exercise and mindfulness-based activities and sleep hygiene.14

ConclusionUltimately, to be effective in managing pain the health care professional must recognise that the sensory and emotional experience of pain is being

NociceptivePain

NeuropathicPain

NociplasticPain

Figure1.Typesofpainoftenoverlap

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produced because of a perception of threat. Find out what the threat factors in this person’s life might be. Then, identify the mechanism of pain (nociceptive, neuropathic or nociplastic) to design treatment which targets the nervous system activity contributing to pain. Finally manage all co-morbidities as activity in the immune and endocrine systems all upregulate the nervous system and will increase pain.

References1. Breivik, H., et al., Survey of chronic

pain in Europe: prevalence, impact on daily life, and treatment. 2006. 10(4): p. 287-333.

2. Raja, S.N., et al., The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. PAIN, 2020. 161(9): p. 1976-1982.

3. Moseley, G.L. and A. Arntz, The context of a noxious stimulus affects the pain it evokes. Pain, 2007. 133(1-3): p. 64-71.

4. IASP, T.F.o.T., Pain Terms, A Current List with Definitions and Notes on Usage, in Classification of Chronic Pain, H. Merskey and N. Bogduk, Editors. 1994, IASP: Seattle. p. 209-214.

5. Loeser, J.D., Pain and suffering. Clin J Pain, 2000. 16(2 Suppl): p. S2-6.

6. Kosek, E., et al., Chronic nociplastic pain affecting the musculoskeletal system: clinical criteria and grading system. Pain, 2021.

7. Stanos, S., et al., Rethinking chronic pain in a primary care setting. Postgrad Med, 2016. 128(5): p. 502-15.

8. Bailly, F., et al., Part of pain labelled neuropathic in rheumatic disease might be rather nociplastic. RMD Open, 2020. 6(2).

9. Moseley, G.L., Whole of community pain education for back pain. Why does first-line care get almost no attention and what exactly are we waiting for? Br J Sports Med, 2019. 53(10): p. 588-589.

10. Moseley, L., Combined physiotherapy and education is efficacious for chronic low back pain. Aust J Physiother, 2002. 48(4): p. 297-302.

11. Schug, S., et al., Acute Pain Management: Scientific Evidence. 2020, ANZCA & FPM: Melbourne.

12. Chetty, S., et al., Clinical practice

guidelines for management of neuropathic pain: expert panel recommendations for South Africa. S Afr Med J, 2012. 102(5): p. 312-25.

13. Watson, J.A., et al., Pain Neuroscience Education for Adults With Chronic Musculoskeletal Pain: A Mixed-Methods Systematic Review and Meta-Analysis. J Pain, 2019. 20(10): p. 1140 e1-1140 e22.

14. Ferro Moura Franco, K., et al., Prescription of exercises for the treatment of chronic pain along the continuum of nociplastic pain: A systematic review with meta-analysis. Eur J Pain, 2021. 25(1): p. 51-70.

TAk

E H

OM

E P

OIn

TS • Pain is a sensory and emotional experience the brain

creates in response to a perception of threat• Nociception is activity in the nervous system in response

to actually or potentially noxious stimuli• It is possible to have pain without nociception• It is possible to have nociception and no pain• Acute pain is associated with normal tissue healing

processes• Chronic pain is pain that continues despite tissue healing

being complete• Nociceptive pain is pain associated with tissue damage• Neuropathic pain is pain due to lesion or disease of the

sensory nervous system• Nociplastic pain is pain due to a sensitised nervous

system and is not an indication of tissue damage.• Identifying the type of pain means treatment will

target the appropriate physiological mechanism, in the peripheral nervous system, in the spinal cord, and in the brain

As a healthcare professional (HCP), you can effortlessly complete all your CPD* compliance requirements on the SAMA* accredited, Medical Practice Consulting (MPC) Online Education System, without having to leave the comfort of your own home or practice.

The MPC System is built around the MPC CPD Manager, a tool that provides HCPs with the unique functionality to electronically submit your CPD activity records directly to the HPCSA* at the click of the button when audited.

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Register today on www.mpconsulting.co.za.

* CME=Continued Medical Education, SAMA= South African Medical Association, HPCSA= Health Professions Council of South Africa

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Pain types and classification

DrTarinPenberthyGeneral & Interventional Pain Practitioner, Netcare Milpark Hospital & Helen Joseph HospitalJohannesburg

he International Association for the Study of Pain (IASP) re-cently updated their defini-tion of pain. The revised defi-nition is “An unpleasant

sensory and emotional experience as-sociated with, or resembling that associ-ated with, actual or potential tissue dam-age.” It is expanded upon by the addition of six key notes and the etymology of the word pain for further valuable con-text:• ● Pain is always a personal experience

that is influenced to varying degrees by biological, psychological, and so-cial factors.

• ● Pain and nociception are different phenomena. Pain cannot be inferred solely from activity in sensory neu-rons.

• ● Through their life experiences, indi-viduals learn the concept of pain.

• ● A person’s report of an experience as pain should be respected.

• ● Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being.

• ● Verbal description is only one of several behaviours to express pain; inability to communicate does not negate the possibility that a human or a non-human experiences pain.

According to the Task Force Chair, Dr Srinivasa N Raja, in an interview cov-ering these new changes, the earlier definition of pain emphasised verbal self-reporting, therefore excluding non-verbal behaviours suggestive of pain in populations such as the elder-ly and neonates. He also noted that in more recent years, research has indi-cated that some types of pain (namely, nociplastic pain), may not be associated with injury but rather a dysfunction of the nervous system.1

Physiologyofpain

NociceptionvspainThe definition of nociception by the IASP2 is “the neural process of encoding noxious stimuli”.

The physiology of pain is best summarised in an article by Ryan Moffat et al - “the process of nociception starts with the activation of nociceptors (specialised sensory receptors in the peripheral nervous system (PNS) known as Aδ- and C-nociceptors) by a noxious stimulus (thermal/chemical/ mechanical). This leads to an electric impulse being produced (transduction). Once transduced and generated, action potentials (which result from activation of specific sodium channels) are conducted to the central nervous system (CNS) primarily via two types of primary afferent fibres (Aδ●- and C-fibres).

Nociceptive impulses travel along pe-ripheral nerve fibres (peripheral trans-mission) to the dorsal horn of the spinal cord where they synapse with the second order neurons (synaptic transmission). Here, the impulse is further transmitted via neurons which cross the spinal cord and ascend to the thalamus and brain-stem nuclei (central transmission). The nociceptive impulses are then relayed to multiple areas of the brain including the somatosensory cortex, the insula, frontal lobes and limbic system. These signals can be amplified or dampened at vari-ous points in the pathway to facilitate or inhibit transmission, thereby enhancing or reducing the sensation of pain (mod-ulation).

This process is then interpreted as pain, together with the input of psychological, social and environmental factors, by a conscious person (perception). Multiple areas of the brain are involved. Conscious perception of pain occurs when these signals are conveyed to the brain, in particular the somatosensory region of the cerebral cortex”.3

Milton Cohen et al4 wrote an article, in 2018, explaining that pain is a subjective experience that arguably exists only in the person that feels it (first-person perspective). Nociception is defined as observable activity in the nervous system in response to an adequate stimulus (third-person perspective). An example to illustrate this is a person who is under general anaesthesia does not experience pain as they are not conscious and therefore do not have the ability to evaluate a stimulus and situation. In other words, only the biological process of nociception occurs.

Paintypes

AcutepainThis is pain that occurs suddenly and has a well-defined course. It could be related to a medical diagnosis or condition, a medical or surgical procedure or a disease flare of a chronic condition (acute-on-chronic). It is of a limited

Figure1.NewadaptationoftheanalgesicladderNSAID-non-steroidalanti-inflammatorydrug,PCApatient-controlledanalgesia

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duration (less than three, sometimes six months) and goes away when the underlying cause is treated. It may be accompanied by other symptoms such as anxiety, emotional distress etc.

Treatment is relatively straightforward - the appropriate analgesics are used for the correct pain type using the new adaptation of the WHO analgesic ladder (Figure1). Note that this ladder works in a bidirectional manner and the prescriber does not have to start at Step 1, if the pain is significant enough for use of Step 3 agents. As the pain experience adapts, so too does the management thereof.

ChronicpainChronic Pain lasts more than three to six months despite the original injury healing. It may be associated with a long-term illness, but in some syndromes there is no apparent cause. This type of pain may be associated with pain symptoms and signs, but also comprises problems in the patients sensory, emotional, social, cognitive and psychological realms.

Chronic pain is a lot harder to treat and it is essential that it is managed with a multidisciplinary team covering the full biopsychosocial model of treatment. The bidirectional adapted analgesic ladder (Figure 1) can still be used for the pharmacological management of chronic pain, with additional multidisciplinary management.

NociceptivepainThis pain arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors (note: the term is used to describe pain occurring with a normally functioning somatosensory nervous system to contrast with the abnormal function seen in neuropathic pain).2

Nociceptors are found in various organs of the body and are often referred to as somatic nociceptive pain (e.g. skin, muscles, tendons, joints, periosteum, connective tissue and blood vessels). Nociceptors are also found in viscera but they are only activated in response to pathological change (e.g. traction on the mesentery, inflammation or distension of hollow muscular walled organs).

As the somatosensory system is intact, the full physiological process of nociception occurs, beginning with the activation of nociceptors by a noxious stimulus. This process may then be perceived as pain, if the person is conscious.

NeuropathicpainNeuropathic pain is caused by a lesion or disease of the somatosensory ner-vous system. Note: Neuropathic pain is a clinical description (and not a diagnosis) which requires a demonstrable lesion or a disease that satisfies neurological di-agnostic criteria. The presence of symp-toms or signs (e.g. allodynia, hyperal-gesia, dysaesthesia) alone does not justify the use of the term neuropathic. To assist in the diagnosis of neuropathic pain, the DN4 (Douleur Neuropathique4) Questionnaire could be used.

Neuropathic pain can be divided into peripheral or central in origin. The former being distal to, and the latter proximal to, the dorsal root ganglion of the first order neuron (Table1).

NociplasticpainNociplastic pain can be mechanistically defined as pain arising from altered function of pain-related sensory pathways in the PNS and CNS, causing increased sensitivity.5 It arises from altered nociception despite no clear evidence of actual or threatened tissue damage or evidence of a disease or lesion of the somatosensory system causing the pain.2 It can occur in isolation, as often occurs in conditions such as fibromyalgia or tension-type headache, or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain, as might occur in chronic low back or neck pain.5

The pathophysiology that underlies this type of pain is not entirely understood, but it is thought that augmented CNS pain and sensory processing, as well as altered pain modulation, play prominent roles. It does not require the exclusion of pathophysiological factors such as low-grade inflammation that may be concurrent or function as a perpetuating trigger.

These patients present with multifocal or generalised pain that is more widespread and/or intense, than would be expected given the amount of identifiable tissue or nerve damage, or lack thereof. Pain assessment should include location, intensity and interference with daily activities.5

Other CNS-derived symptoms, such as fatigue, sleep, memory, and mood disturbances almost always accompany this type of pain. Some of these symptoms may be assessed with the use of questionnaires.

It is important to recognise this type of pain, since it will respond to different therapies than nociceptive or neuropathic pain, with a decreased responsiveness to peripherally directed therapies such as anti-inflammatory drugs and opioids, surgery, or injections.5

In general, these conditions are treated with minimal drugs, rather focusing on the other modalities of treating pain. Treatment generally requires both physical and psychological therapies, along with pain neuroscience education.

Pharmacological management ofchronicpainIn order to choose the most appropriate analgesic medication(s), a full assessment of the pain problem is required. Once a diagnosis is made, then a treatment plan can be made.

The choice of pharmacotherapy is dictated by a combination of:• ● Severity (WHO ladder)• ● Source (nociceptive (somatic or vis-

ceral) vs neuropathic vs nociplastic)• ● Time course (acute vs chronic vs

acute-on-chronic)• ● Patient’s age• ● Comorbidities• ● Side effect profile and patient toler-

ance

To avoid side effects from high doses, and due to the synergistic mechanisms of different classes of drugs, pain is best treated with multimodal analgesics. The analgesic(s) need to be given at the correct intervals (i.e. 8 hourly rather than tds), in the correct mode of administration (PO vs IV vs IMI), for the correct type of pain (nociceptive vs neuropathic vs nociplastic).

A practical way to look at the management of treating pain is by using Figure 2.

The primary analgesics are divided into non-opioids (e.g. paracetamol, NSAID’s, coxib’s) and opioids (e.g. weak opioids - tramadol, codeine or stronger opioids - morphine, pethidine, buprenorphine, fentanyl, methadone and oxycodone etc). These primary analgesics are the cornerstone of treatment of nociceptive pain.

The adjuvants are divided into two categories and are used for the treatment of neuropathic pain.

1.Secondaryanalgesics• ● Anticonvulsants

– ●Gabapentanoids (●●α2δ● calcium

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channel blockers) – gabapentin and pregabalin

– ● Others – carbamazepine (only for trigeminal neuralgia), lamotrigine

• ● ●α2 central agonists - clonidine, dex-medetomidine

• ● N-methyl D-aspartate (NMDA re-ceptor antagonist) - ketamine

• ● TRPV1 receptor agonist - capsaicin• ● Local anaesthetics - lignocaine

patches• ● Muscle relaxants – baclofen, cyclo-

benzaprine, orphenadrine, metho-carbamol

• ● Cannabinoids

2.Moodstabilisers• ● Tricyclic analgesics - amitriptyline,

imipramine• ● Serotonin and norepinephrine re-

uptake inhibitors (SNRI’s) - duloxe-tine and venlafaxine

• ● (Selective serotonin reuptake inhib-itors (SSRIs) - these are not as ef-fective in treating pain, but will help mood symptoms)

The principles of treating nociplastic pain5 are based much more on therapies other than pharmacotherapy. Examples include psychological therapies and non-pharmacological treatments such as patient education, promotion of qual-ity of life and continued participation in work, physical and social activities, and interdisciplinary care. When pharma-cotherapy is needed, centrally acting drugs such as tricyclics, SNRIs and ga-bapentinoids are recommended. It is best to avoid opioid type drugs due to the poor response of this type of pain to opioids as well as the side effects such as addiction and opioid hyperalgesia. It is also important to treat any psychiatric comorbidities.

Guideline resourcesThere are multiple South African and International guidelines for the management of pain, which I strongly encourage all health care practitioners who deal with pain patients, to peruse. Here are links to some of the available guidelines:• Clinical practice guidelines for man-

agement of neuropathic pain: Expert panel recommendations for South Africahttp://www.samj.org.za/index.php/samj/article/view/5472

• Acute Pain Guidelines - South Afri-can Pharmaceutical Journalhttp://www.sapj.co.za/index.php/SAPJ/article/view/2346

• South African Acute Pain Guidelineshttp://www.sajaa.co.za/index.php/sajaa/issue/view/121

• Guide to the Treatment of Cancer Pain in South Africa; 2015https://painsa.org.za/wp-content/uploads/2016/02/A5-Guide-to-treatment-of-Cancer-Pain-2015.pdf

• The 2021 UK National Institute for Health and Care Excellence (NICE) guidance on chronic painhttps://www.nice.org.uk/guidance/ng193

SummaryThe revised (2020) definition of pain is “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”

Pain is not purely a physical experience. It is a multidimensional dynamic interaction by physiological, psychological and social factors that reciprocally influence each other.

Pain is not only a product of injury/ illness/potential tissue damage. It is an experience in what is going on in your body, mind and in your environmental or social context based on past experiences and memories.

Pain can be described in a variety of ways. These all affect the work-up and management decisions at every level. The most common are:• ● Acute vs chronic vs acute-on-

chronic• ● Nociceptive vs neuropathic vs noci-

plastic vs mixed• ● Malignant vs nonmalignant

Pain is treated in a biopsychsocial manner with multimodal analgesics only being a part of the biological management.

Pain has been included in the new ICD11 classification system. For the first time it includes diagnostic codes for chronic pain along with codes for the most common and clinically relevant groups of chronic pain conditions. This should improve patient care by facilitating multidisciplinary pain management.

Referencesavailableonrequest.

Table1

Centralcausesofneuropathicpain Peripheralcausesofneuropathicpain

Spinal stenosis causing compression on neural tissue

Polyneuropathy (e.g. chemotherapy, HIV, diabetes, alcohol)

Myelopathy (HIV, post ischaemia or radiation)

Entrapment neuropathies

Post stroke pain Tumour infiltration of nerves

Syringomyelia Peripheral nerve injury

Parkinson’s disease Postherpetic neuralgia

Spinal cord injury Neuropathy due to toxic exposure

Multiple sclerosis Radiation induced plexopathy

Figure 2

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References: 1. Escudero-Contreras A, Vazquez-Mellado Cervantes J, Collantes-Estevez E. Update on the clinical pharmacology of etoricoxib, a potent cyclooxygenase-2 inhibitor. Future Rheumatol 2007;2(6):545-565. 2. Brooks P, Kubler P. Etoricoxib for arthritis and pain management. Therapeutics and Clinical Risk Management 2006;2(1):45– 57.

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References: 1. Escudero-Contreras A, Vazquez-Mellado Cervantes J, Collantes-Estevez E. Update on the clinical pharmacology of etoricoxib, a potent cyclooxygenase-2 inhibitor. Future Rheumatol 2007;2(6):545-565. 2. Brooks P, Kubler P. Etoricoxib for arthritis and pain management. Therapeutics and Clinical Risk Management 2006;2(1):45– 57.

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had a history of myocardialinfarction, and 10% had a history of stroke.

Chronic gouty disease can be associat-ed with poor kidney and cardiovascular outcomes. Gouty patients die mainly from cardiovascular events and sev-eral studies have shown that gout is an independent cardiovascular risk fac-tor, even more so when gout is severe. Screening for other cardiovascular risk factors is recommended at the time of gout diagnosis and throughout follow up. In large databases, obesity is linked both to incident gout and to risk of re-current flares. Hyperuricemia may play a role in the occurrence of hyperten-sion, heart disease, type II diabetes and renal impairment.

This independent effect of gout on cardiovascular mortality adds onto frequently associated comorbidities but may also be affected by frequent

non-steroidal anti-inflammatory drugstaken during acute flares.

Acuteflares are characterised by sud-den severe attacks of pain, swelling and erythema in one or more joints. Charac-teristically the great toe is the joint most usually associated with gout in up to 73 % of patients and pain experienced during acute 1st Metatarsalphalangeal (MTP) arthritis is considerable and remains present following the resolution of acute symptoms. First MTP pain is a chronic foot problem in people with gout. Al-though it is unclear whether these clin-ical symptoms are a consequence of pain-avoidance, joint damage, synovial inflammation, mechanical obstruction by tophi, or a combination of these factors, the clinical implications of symptomat-ic 1st MTP gout on the ability to under-take everyday weight-bearing activities, such as walking, are recognised as im-portant features of the disease. People

Complications of gouty arthritis

DrCathySpargoMBChB(UCT),FCP(SA),CertRheumatology(SA)SpecialistPhysicianandrheumatologistPinelands,CapeTown

out is a common, complex inflammatory arthritis caused by monosodium urate crys-tal deposition in and around a joint. This affects 1-4% of

the general population and the preva-lence increases with age. The preva-lence of both hyperuricemia and gout has risen in the last decades in devel-oped countries and therefore the bur-den of gout has increased. This is linked to higher protein and calorie intake, bev-erages sweetened with high fructose corn syrup, purine intake in beer, and lower physical activity. The role of ge-netic predisposition is becoming more evident. Acute gout occurs following hy-peruricemia in the blood (where mono-sodium urate is soluble) followed by crystal deposition in the peripheries. This in turn results in recurrent flares of acute goutyarthritiswhich may progress to a chronic arthropathy if hyperuricemia persists. Most patients are initially entire-ly asymptomatic during intercritical peri-ods, however imaging studies have shown that crystal deposition can prog-ress even in the absence of clinical fea-tures of joint inflammation and crystal deposition and subclinical inflammation may precede the clinical onset of gout.

In the chronic phase, crystal deposits further induce chronic inflammatory responses that may lead to damage of the joint structures, known as chronic gouty arthritis or chronic gout, which is usually associated with the presence of subcutaneous deposits of crystals or tophi. As deposits grow and co-mor-bidities increase, gout becomes even more severe and difficult to treat, and may then be known asrefractorygout. As such, gout should be viewed as a chronic progressive disease if serum uric acid levels are not appropriately lowered. By lowering serum uric acid levels, disappearance of clinical fea-tures of gout can be obtained. Accord-ing to the 2007–2008 National Health and Nutrition Examination Survey data (NHANES), 74% of participants with gout had hypertension, 71% had stage 2 or greater chronic kidney disease, 53% were obese, 26% had diabetes, 14%

Theprevalenceofbothhyperuricemiaandgouthasriseninthelastdecadesindevelopedcountriesandthereforetheburdenofgouthas

increased.

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12

with gout walk significantly slower and demonstrate gait patterns consistent with 1st MTP pain-avoidance strategies

Frequent acute gouty episodes have deleterious consequences on joint function, health resources utilisation, quality of life and may increase cardio-vascular mortality.

CourseofuntreatedgoutIn chronic tophaceous gout, joint space narrowing, bone erosions and proliferat-ing bone can be observed on x-ray and ultrasound may show joint effusions, sy-novitis and bone erosions. Gout should be one of the most manageable rheu-matic diseases, however poor manage-ment often results in frequent use of non-steroidal anti-inflammatories, oral or intramuscular steroids, analgesics and colchicine. In turn there is increased risk of renal disease, gastric ulceration, and weight gain and, in the setting of colchi-cine, diarrhoea. Unless uric acid lowering therapy is effectively started relatively early in the disease course, patients often continue to self-medicate and to use in-creasingly high disease of all three drug types (steroids, colchicine and NSAIDs) without achieving the goal of reducing their serum uric acid. If underlying renal function is impaired to start off with, this often creates a negative cycle of fur-ther aggravating impaired renal function (NSAIDs) or further increasing weight gain (steroids) and at the same time, not reducing the frequency of acute flares as the serum uric remains high. In addition there is an increased likelihood of patients requiring joint replacement surgery, for joints damaged by chronic tophaceous gout. Some patients request excision of tophi. This is in turn often complicated by wounds which are slow to heal. Chron-ic pain in and of itself results in reduced mobility with further increase in weight and increased use of analgesics and in-creased risk of sick leave days. Health-care utilisation costs for those with poorly treated chronic gout are often very high and patients have frequent emergency room visits.

GoutandtheriskofchronickidneydiseaseandnephrolithiasisChronic kidney disease (CKD) is an inde-pendent risk factor for the development of gout but gout may also predispose to renal disease due to hyperuricemia, chronic inflammation, comorbid hyper-tension and diabetes mellitus as well as use of NSAIDs. Patients with gout were more than twice as likely to have CKD stage >=3 and more than 1.5 times more

likely to have ever had nephrolithiasis as people who did not have gout. Renal damage can result from co-morbid hy-pertension and diabetes, hyperuricemia mediated endothelial dysfunction and renovascular disease as well as use of NSAIDs. Although allopurinol was previ-ously thought to have a deleterious ef-fect on renal function, more recently it has been suggested that it may protect against the progression of CKD. Inflam-mation in gout is increasingly recognised to persist in the inter critical period be-tween acute attacks, raising the possibil-ity that inflammatory mechanisms con-tribute to vascular risk.

The clinical implications are that pa-tients with gout should be screened for CKD and treated if present, along with its associated risk factors such as hypertension and diabetes mellitus (which are also risk factors for gout)

Qualityoflife(QOL)deficitsingoutpatientsHealth related QOL is impaired in those with gout compared to age and sex-matched controls. This may be due to disease-specific features such as ex-cruciatingly painful attacks, frequency of attacks, number of joints involved in an attack, pain between attacks and joint damage due to accumulation of tophi. Surveys in patients with chronic gout have revealed limitation of daily and rec-reational activities, reduced work pro-ductivity, anxiety regarding the unpre-dictability of a flare and concern about drug interactions when treating their gout. Many patients expressed concern and confusion regarding dietary restric-tions. Many dietary restrictions in lay lit-erature appear conflicting and many pa-tients with gout do not understand the genetic and renal contributions to their underlying gout. Whilst good intake of water reduces the risk of flares, and low fat dairy products may also reduce the risk of flares, spirits and beer (including low alcohol beer) are associated with in-creased risk of flares. Even one can of fizzy soda per day will increase risk of acute flares. However, in chronic gout, dietary restrictions alone, will never be adequate to control the disease without the addition of uric acid lowering agents.

Recent data suggest a higher rate of as-sociated depressive disorders amongst gout patients, particularly those with active and untreated disease.

GastrointestinalsideeffectsoftherapyBoth colchicine and NSAIDs are as-

sociated with gastrointestinal adverse events. The risk of GI complications and heart failure are higher with NSAIDs than with colchicine.

Treat to Target The main management issues relating to gout are related to poor patient ad-herence to allopurinol, but also due to poor management by treating physi-cians to reduce the serum uric acid to the goal of 0.35mmol/L. The previous rule that allopurinol should be stopped during an acute flare, meant that many patients were more often not taking their allopurinol than taking it and hence their gout remained poorly controlled. To avoid the clinical inertia in treating chronic gout, and hence to reduce the risks of long term complications, the fol-lowing should be applied to the initiation and ongoing therapy with allopurinol:• Treat to target uric acid of

0.35mmol/L• Start low and go slow: Start allopu-

rinol at 100mg daily and increase by 50 or 100mg monthly

• Tight control: regular monitoring of serum uric acid and increasing of al-lopurinol dose until uric acid target is met

• Continue to keep serum uric acid low in order to facilitate resolution of tophi

• In one study, median dose of allo-purinol required to reach target was 400mg.

SummaryGout is a significant cause of morbidi-ty, disability, lost work days, and high healthcare utilisation due to intermit-tent attacks, chronic inflammation, and joint damage. Inadequately treated gout leads to recurrent attacks, chronic inflammation, joint damage, subclinical crystal deposition, and tophi formation, which can result in limited activity, de-pendence on others, recurrent work absences, decreased work productiv-ity, and high rates of healthcare utili-zation. Gout should be regarded as a systemic disease. If gout is inadequate-ly treated then there are myriad associ-ated problems including cardiovascular and renal disease. Patients need to be carefully advised as to the inadequacy of diet alone as a control mechanism for chronic gout and also educated as to the need to reach the target serum uric with the help of allopurinol in the long term. This will reduce the burden of crystals and damage.

Referencesavailableonrequest.

13

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Using NSAIDs safely

DrRolandvanRensburgMBChB,DipHIVMan(SA),FCClinPharm(SA)Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch UniversityPain Clinic, Tygerberg Academic Hospital

on-steroidal anti-inflamma-tory drugs (NSAIDs) have become an integral part of the management of inflam-matory pain since its phar-

maceutical discovery in the 1960s.1 The NSAIDs cover a variety of chemical en-tities, including acetylated salicylates (aspirin), propionic acids (ibuprofen, naproxen), acetic acids (diclofenac, in-domethacin, ketorolac), enolic acids, also known as the oxicams (lornoxicam, meloxicam, piroxicam), and the selec-tive cyclooxygenase (COX)-2 inhibitors (celecoxib, etoricoxib, parecoxib).2 Both the pharmacological action and ad-verse effects of NSAIDs can be attribut-ed to their ability to inhibit COX, the en-zyme system responsible for prostaglandin synthesis.3 Several forms of prostaglandins with differential func-tions exist, and these isoforms are pri-marily generated by the two main COX enzymes: COX-1 and COX-2. The COX-1 enzyme is variably expressed in nearly all tissues, most notably in the gut, kid-ney vasculature, and platelets, and is responsible for regulating normal cel-lular processes.4 COX-2 is generally un-detectable in most tissues – except for its constitutive expression in the brain, kidney, and bone – but is highly induc-ible in states of inflammation, leading to the production of proinflammatory prostaglandins.4

NSAIDs act as anti-inflammatories by inhibiting pro-inflammatory prostaglan-din synthesis, but the selection and de-gree of COX inhibition varies depending on the specific NSAID used.5 NSAIDs that inhibit both COX-1 and COX-2 are termed non-selective, and include the oxicams. Therefore, while inflamma-tion is suppressed by COX-2 inhibition, adverse effects related to COX-1 inhi-bition in the gut, kidneys, and platelets are more pertinent.3 For this reason the more selective COX2 inhibitors (termed coxibs) were developed. While they do have a reduced propensity to cause adverse effects of the gut, kidneys, and platelets, cardiovascular adverse effects are more prominent with their use.6

NotableNSAIDadverseeffectsNSAIDs are generally considered to be safe, but have been associated with nu-merous adverse effects. Selected no-table adverse effects will be discussed here.

Gastrointestinal tractNSAIDs may induce dyspepsia, peptic ulcer disease, and bleeding in the gas-trointestinal tract. The risk is attenuated with selective COX-2 inhibitors, but is never fully eliminated. The pathogen-esis of these gastrointestinal toxicities is complex and multifactorial, but ap-pears to be mainly driven by gastric prostaglandin inhibition, leading to re-duced secretion of protective gastric juices.7 The stomach and duodenum mucosa are then exposed to gastric acid, and ulceration and bleeding may follow. NSAIDs that cause COX-1 inhi-bition in platelets – leading to inhibition of platelet aggregation – may further compound the bleeding risk. Current guidelines recommend the administra-tion of gastroprotective drugs, mainly a proton-pump inhibitor (PPI), to patients at high risk of gastrointestinal bleed-ing.8,9 These include patients older than 65 years of age, a history of peptic ul-cer disease, or on concomitant warfarin, aspirin, or corticosteroids. To note, a me-ta-analysis of 112 randomised controlled trials found no evidence supporting the effectiveness of H2-receptor antago-nists for gastroprotection at standard doses.10

To reduce the incidence of gastrointes-tinal bleeding, enteric-coated (or buff-ered) aspirin has been proposed. Enter-ic-coated aspirin is designed to resist disintegration in the stomach, dissolving in the more neutral-to-alkaline environ-ment of the duodenum. Although en-teric-coated aspirin may reduce signs of ulceration on endoscopy, it does not protect against the clinically relevant endpoint of gastrointestinal bleeding.11 This is in keeping with the current under-standing of NSAIDs’ mechanism of gas-trointestinal toxicity, since injury severe enough to induce bleeding is thought to reflect the systemic rather than the

local effects of aspirin.12 Several large meta-analyses have been conducted to assess the risk of gastrointestinal tox-icity related to specific NSAIDs. While the data had significant confounders, NSAIDs associated with the highest gastrointestinal complications were in-domethacin, followed by naproxen, di-clofenac, and piroxicam. Ibuprofen had the lowest risk, but it was still increased compared to non-NSAID users.13

The use of selective serotonin reuptake inhibitors (SSRIs) has also been associ-ated with an increased risk of gastro-intestinal bleeding. A meta-analysis of observational studies showed a signifi-cantly increased odds of developing gastrointestinal bleeding when used as monotherapy, and even more so when used concomitantly with NSAIDs.14

RenalNSAID use can lead to several renal complications, including acute tubular necrosis (ATN) leading to acute kidney injury, increased blood pressure, and acute interstitial nephritis (AIN). ATN is thought to develop primarily due to al-terations in renal blood flow dynamics.15 Prostaglandins in the renal vasculature cause vasodilation when blood flow to the kidneys is low. NSAIDs inhibiting re-nal prostaglandins subsequently attenu-ate the protective vasodilatory response, and acute kidney injury may ensue. In healthy individuals the effects of NSAIDs on renal haemodynamics are probably minimal,15 but may become significant in older age, patients with chronic kid-ney disease, or in states of volume de-pletion (e.g. diarrhoea, vomiting, heart failure).16 NSAIDs administered in the context of volume depletion may also cause electrolyte disturbances, such as hyponatraemia, hypokalaemia, and oedema.15,17 The mechanism by which NSAIDs cause increased blood pres-sure is not fully understood, but appears to be secondary to COX-2 inhibition.18 The absolute increase in blood pressure is likely minimal, but may contribute to the increase in cardiovascular risk that is seen particularly with the selective COX-2 inhibitors.19 AIN may also develop with

F O C U S

14

both non-selective NSAID and selective COX-2 inhibitor use, but is a rare, idio-syncratic adverse drug reaction associ-ated with hypersensitivity.20 AIN usually presents as a decline in kidney function not related to another cause, and may be associated with the classical signs of a rash, fever, and a raised eosinophil count on blood testing, although these findings are often absent.21 The devel-opment of AIN is not dose-dependent, and the onset after NSAID exposure is highly variable, ranging from a few days to many months on treatment.22

CVSCOX-2 inhibition appears to be the main reason for the adverse cardiovascular effects of NSAIDs. The selective COX-2 inhibitors have a much greater affinity for the COX-2 enzyme, reducing the ad-verse effects on the gut and kidney, and minimising platelet inhibition.23 However, as these drugs primarily inhibit COX-2, there is a shift to the more unopposed COX-1 prostaglandin effects, which are vasoconstrictive and pro-thrombotic in nature.24 As such, increased adverse car-diovascular events such as myocardial infarctions and strokes have been noted to occur with selective COX-2 inhibitors, although it can occur with any NSAID.6 Interestingly, the addition of low-dose aspirin to counteract the pro-thrombotic effects of selective COX-2 inhibitors has not been found to result in significantly decreased cardiovascular events.24 In a large meta-analysis25 all NSAIDs were found to increase the risk of adverse cardiovascular events, especially the selective COX-2 inhibitors, but naprox-en was found to have a much lower risk. The benefits of selective COX-2 inhibitors should therefore be weighed up against the potential cardiovascular risks. It has also been shown that NSAIDs can reduce the effectiveness of aspirin.26 Patients on aspirin for cardiovascular risk reduction should therefore take aspirin at least 30 minutes before the dose of NSAID.9

OtherRare, but potentially life-threatening, hypersensitivity reactions like Ste-vens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) have been described with NSAID use.27 These present as blistering skin lesions usu-ally involving the mucous membranes. Any NSAID can cause SJS or TEN, but a large observational study identified the oxicams as having the highest risk.27

NSAIDs are associated with several complications in pregnancy and lacta-tion. NSAIDs have been linked to spon-

taneous abortion in the first trimester,28 and foetal kidney injury leading to low amniotic fluid if used from 20 weeks’ gestation onwards.29 NSAIDs have also been shown to cause premature closure of the ductus arteriosus, the foetal blood vessel shunting blood away from the lungs in utero, if used in the third trimes-ter.28 There is limited data on the safety of most NSAIDs during breastfeeding. However, the World Health Organiza-tion (WHO) considers ibuprofen at usual recommended doses to be compatible with breasfeeding,30 as it is secreted into breastmilk in very small amounts, and has the most safety information avail-able.28,31

ConsiderationsforsafeuseNSAIDs are associated with numerous adverse effects, but the risk can be re-duced by considering a few core prin-ciples: Patient factors, drug interactions, and the selection of NSAID.• Patient factors: NSAIDs are best

avoided in patients with risk factors for gastrointestinal, renal, or cardio-vascular adverse effects, as well as in the elderly. If NSAID administration is unavoidable, the most appropri-ate NSAID at the lowest effective dose for the shortest time should be used, with further measures to reduce adverse effects (such as the co-administration of a PPI for gastro-protection in patients at risk of gas-trointestinal bleeding). Cautions and contraindications to NSAIDs should be checked at every prescription and dispensing opportunity, as co-morbidities may develop and evolve over time.

• Drug interactions: NSAIDs may aug-ment bleeding risk when co-admin-istered with drugs such as antiplate-lets, anticoagulants, corticosteroids, or SSRIs.32,33 The drug interaction with antiplatelets is purportedly related to the further inhibition of platelet ag-gregation.34 The drug interaction with anticoagulants seems to be related to the additive bleeding risk of the antiplatelet effects of NSAIDs to the clotting factor inhibition of the anti-coagulants,35 and is more prominent with non-selective NSAIDs.32 Addi-tionally, increases in the international normalised ratio (INR) in patients on warfarin have been observed when NSAIDs are administered concomi-tantly.36 The mechanism is currently not fully understood, and while the selective COX-2 inhibitors may the-oretically have a reduced effect on platelet function, increases in the INR of patients on selective COX-2 inhibitors have been observed.37 NSAIDs in combination with both an angiotensin-converting enzyme (ACE) inhibitor (or angiotensin re-ceptor blocker) and a diuretic was shown to increase the risk of acute kidney injury in a large cohort study.38 NSAIDs have also been shown to significantly increase the risk of gas-trointestinal bleeding when used in combination with SSRIs.39 A possible mechanism for this interaction is the depletion of platelet serotonin by SSRIs, a substance involved in plate-let aggregation.39

• NSAID selection: While different NSAIDs have similar efficacy at equi-potent doses in the general popu-

TAk

E H

OM

E P

OIn

TS • NSAIDs are generally considered to be safe, but are

associated with several adverse effects.• The main adverse effects are related to the

gastrointestinal, renal, and cardiovascular systems.• Bleeding and thrombosis are the most common adverse

effects, but rare cutaneous hypersensitivity reactions have been reported.

• The bleeding risk may be augmented when NSAIDs are administered concomitantly with antiplatelets, anticoagulants, and SSRIs.

• NSAIDs should be avoided in patients with risk factors for the adverse gastrointestinal, renal, and cardiovascular system effects.

• NSAIDs are not recommended in pregnancy and lactation.

• Adverse effects of NSAIDs may be reduced by careful consideration of patient factors, drug interactions, the need for an NSAID, the choice of NSAID, and employing protective measures in patients at risk.

15

F O C U S

el-adults-standard-treatment-guidelines-and-es-sential-medicines-list-2nd. Accessed July 15, 2021.

10. Hooper L, Brown TJ, Elliott R, Payne K, Roberts C, Symmons D. The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: System-atic review. BMJ. 2004;329(7472):948. doi:10.1136/BMJ.38232.680567.EB

11. Kelly JP, Kaufman DW, Jurgelon JM, Sheehan J, Koff RS, Shapiro S. Risk of aspirin-associated major up-per-gastrointestinal bleeding with enteric-coated or buffered product. Lancet. 1996;348(9039):1413-1416. doi:10.1016/S0140-6736(96)01254-8

12. van Oijen MGH, Dieleman JP, Laheij RJF, Sturken-boom MCJM, Jansen JBMJ, Verheugt FWA. Pep-tic ulcerations are related to systemic rather than local effects of low-dose aspirin. Clin Gastroen-terol Hepatol. 2008;6(3):309-313. doi:10.1016/J.CGH.2007.12.018

13. Richy F, Bruyere O, Ethgen O, et al. Time dependent risk of gastrointestinal complications induced by non-steroidal anti-inflammatory drug use: A con-sensus statement using a meta-analytic approach. Ann Rheum Dis. 2004;63(7):759-766. doi:10.1136/ARD.2003.015925

14. Loke YK, Trivedi AN, Singh S. Meta-analysis: gas-trointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non-ste-roidal anti-inflammatory drugs. Aliment Phar-macol Ther. 2008;27(1):31-40. doi:10.1111/J.1365-2036.2007.03541.X

15. Oates JA, FitzGerald GA, Branch RA, Jackson EK, Knapp HR, Roberts LJI. Clinical implications of prostaglandin and thromboxane A2 formation. N Engl J Med. 2010;319(11):689-698. doi:10.1056/NEJM198809153191106

16. Patrono C, Dunn MJ. The clinical significance of in-hibition of renal prostaglandin synthesis. Kidney Int. 1987;32(1):1-12. doi:10.1038/KI.1987.164

17. Schlondorff D. Renal complications of nonsteroidal anti-inflammatory drugs. Kidney Int. 1993;44(3):643-653. doi:10.1038/KI.1993.293

18. White WB. Cardiovascular effects of the cycloox-ygenase inhibitors. Hypertension. 2007;49(3):408-418. doi:10.1161/01.HYP.0000258106.74139.25

19. Messerli FH, Sichrovsky T. Does the pro-hyperten-sive effect of cyclooxygenase-2 inhibitors account for the increased risk in cardiovascular disease? Am J Cardiol. 2005;96(6):872-873. doi:10.1016/J.AMJCARD.2005.05.038

20. Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis. 2014;64(4):558-566. doi:10.1053/J.AJKD.2014.04.027

21. Baker RJ, Pusey CD. The changing profile of acute tubulointerstitial nephritis. Nephrol Dial Transplant. 2004;19(1):8-11. doi:10.1093/NDT/GFG464

22. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. http://dx.doi.org/101056/NEJM198403013100905. 2 0 1 0 ; 3 1 0 ( 9 ) : 5 6 3 - 5 7 2 . d o i : 1 0 . 1 0 5 6 /NEJM198403013100905

23. FitzGerald GA, Patrono C. The coxibs, selec-tive inhibitors of cyclooxygenase-2. N Engl J Med. 2001;345(6):433-442. doi:10.1056/NEJM200108093450607

24. Ong CKS, Lirk P, Tan CH, Seymour RA. An evi-dence-based update on nonsteroidal anti-in-flammatory drugs. Clin Med Res. 2007;5(1):19-34. doi:10.3121/cmr.2007.698

25. Baigent C, Bhala N, Emberson J, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individ-ual participant data from randomised trials. Lan-cet. 2013;382(9894):769-779. doi:10.1016/S0140-6736(13)60900-9

26. Meek IL, Vonkeman HE, Kasemier J, Movig KLL, van de Laar MAFJ. Interference of NSAIDs with the thrombocyte inhibitory effect of aspirin: A placebo-controlled, ex vivo, serial placebo-con-trolled serial crossover study. Eur J Clin Pharma-col. 2012;69(3):365-371. doi:10.1007/S00228-012-1370-Y

27. Mockenhaupt M, Kelly JP, Kaufman D, Stern RS, SCAR Study Group. The risk of Stevens-John-son syndrome and toxic epidermal necrolysis associated with nonsteroidal antiinflammatory drugs: A multinational perspective. J Rheumatol. 2003;30(10):2234-2240. https://europepmc.org/article/med/14528522.

28. Bloor M, Paech M. Nonsteroidal anti-inflamma-tory drugs during pregnancy and the initiation of lactation. Anesth Analg. 2013;116(5):1063-1075.

doi:10.1213/ANE.0B013E31828A4B5429. US Food and Drug Administration. FDA recom-

mends avoiding use of NSAIDs in pregnancy at 20 weeks or later because they can result in low am-niotic fluid. https://www.fda.gov/media/142967/download. Published October 15, 2020. Accessed July 17, 2021.

30. World Health Organization. Breastfeeding and maternal medication. Recommendations for Drugs in the Eleventh WHO Model List of Essen-tial Drugs. https://apps.who.int/iris/bitstream/handle/10665/62435/55732.pdf?sequence=1&is-Allowed=y. Published 2002. Accessed July 17, 2021.

31. Rigourd V, De Villepin B, Amirouche A, et al. Ibu-profen concentrations in human mature milk - First data about pharmacokinetics study in breast milk with AOR-10127 “Antalait” study. Ther Drug Monit. 2014;36(5):590-596. doi:10.1097/FTD.0000000000000058

32. Olsen A-MS, Gislason GH, McGettigan P, et al. Asso-ciation of NSAID use with risk of bleeding and car-diovascular events in patients receiving antithrom-botic therapy after myocardial infarction. JAMA. 2015;313(8):805-814. doi:10.1001/JAMA.2015.0809

33. Battistella M, Mamdami MM, Juurlink DN, Rabe-neck L, Laupacis A. Risk of upper gastrointesti-nal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med. 2005;165(2):189-192. doi:10.1001/ARCHINTE.165.2.189

34. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med. 2010;330(18):1287-1294. doi:10.1056/NEJM199405053301808

35. Lamberts M, Lip GYH, Hansen ML, et al. Relation of nonsteroidal anti-inflammatory drugs to serious bleeding and thromboembolism risk in patients with atrial fibrillation receiving antithrombotic ther-apy: A nationwide cohort study. Ann Intern Med. 2014;161(10):690-698. doi:10.7326/M13-1581

36. van Dijk KN, Plat AW, C van Dijk AA, et al. Poten-tial interaction between acenocoumarol and di-clofenac, naproxen and ibuprofen and role of CY-P2C9 genotype. Thromb Haemost. 2004;91:95-101. doi:10.1160/TH03-05-0325

37. Knijff-Dutmer EA, Van der Palen J, Schut G, Van de Laar MA. The influence of cyclo-oxygenase spec-ificity of non-steroidal anti-inflammatory drugs on bleeding complications in concomitant couma-rine users. QJM. 2003;96(7):513-520. doi:10.1093/QJMED/HCG090

38. Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S. Con-current use of diuretics, angiotensin converting en-zyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: Nested case-control study. BMJ. 2013;346(7890). doi:10.1136/BMJ.E8525

39. Anglin R, Yuan Y, Moayyedi P, Tse F, Armstrong D, Leontiadis GI. Risk of upper gastrointestinal bleed-ing with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflam-matory use: A systematic review and meta-anal-ysis. Am J Gastroenterol. 2014;109(6):811-819. doi:10.1038/AJG.2014.82

40. Chou R, McDonagh MS, Nakamoto E, Griffin J. An-algesics for osteoarthritis: An update of the 2006 comparative effectiveness review. Agency Healthc Res Qual. 2011;(38). https://www.ncbi.nlm.nih.gov/books/NBK65646/. Accessed July 17, 2021.

41. Meade EA, Smith WL, Dewitts DL. Differential in-hibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and oth-er non-steroidal anti-inflammatory drugs. J Biol Chem. 1993;268(9):6610-6614. doi:10.1016/S0021-9258(18)53294-4

42. Buttgereit F, Burmester GR, Simon LS. Gastroin-testinal toxic side effects of nonsteroidal anti-in-flammatory drugs and cyclooxygenase-2–specific inhibitors. Am J Med. 2001;110(3):13-19. doi:10.1016/S0002-9343(00)00728-2

43. Rollason V, Samer C, Daali Y, Desmeules J. Predic-tion by pharmacogenetics of safety and efficacy of non-steroidal anti- inflammatory drugs: A review. Curr Drug Metab. 2014;15(3):326-343. doi:10.2174/1389200215666140202214454

44. Derry S, Moore RA, Rabbie R. Topical NSAIDs for chronic musculoskeletal pain in adults. Co-chrane database Syst Rev. 2012;9(4):CD007400. doi:10.1002/14651858.CD007400.PUB2

lation, significant variation between individuals exists for both adverse effects and efficacy.40 These varia-tions may be related to differences in the relative inhibition of COX-1 and COX-2 for different NSAIDs,41,42 or to pharmacogenetic factors affecting NSAID disposition and response.43 Patients may therefore prefer one NSAID to another, based on previ-ous experiences and comorbidities. Where the topical route of adminis-tration is available (such as for limit-ed knee osteoarthritis), it may be the more appropriate route to reduce systemic exposure of NSAIDs and limit adverse effects.44

ConclusionNSAIDs are a broad class of drugs that are ubiquitous in the current manage-ment of pain and inflammation. NSAIDs are generally considered to be safe, but have been associated with several ad-verse effects. Rational prescribing and the consideration of the risks and bene-fits associated with NSAIDs may attenu-ate some of these adverse effects. Pre-scribers and dispensers should regularly re-evaluate the need for NSAIDs in pa-tients. Where NSAIDs are unavoidable and reasonable for a prolonged period of time, they should be administered at the lowest effective dose for the short-est period of time possible, with further measures to reduce adverse effects.

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ti-inflammatory drugs (NSAIDs): Cyclooxygenase (COX) inhibition and beyond. J Pharm Pharm Sci. 2008;11(2):81s-110s. doi:10.18433/J3T886

2. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) - StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK547742/. Accessed July 14, 2021.

3. Van Rensburg R, Reuter H. An overview of analge-sics: NSAIDs, paracetamol, and topical analgesics (Part 1). South African Fam Pract. 2019;61(S1):S4-S10. doi:10.1080/20786190.2019.1610228

4. Dubois RN, Abramson SB, Crofford L, et al. Cy-clooxygenase in biology and disease. FASEB J. 1998;12(12):1063-1073. http://www.ncbi.nlm.nih.gov/pubmed/9737710. Accessed December 18, 2018.

5. Oates JA, Wood AJJ, Brooks PM, Day RO. Nonste-roidal antiinflammatory drugs — Differences and similarities. N Engl J Med. 1991;324(24):1716-1725. doi:10.1056/NEJM199106133242407

6. Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-infl ammatory drugs: Meta-analyses of in-dividual participant data from randomised trials. Lancet. 2013;382(9894):769-779. doi:10.1016/S0140-6736(13)60900-9

7. Langman MJS, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individu-al non-steroidal anti-inflammatory drugs. Lancet. 1994;343(8905):1075-1078. doi:10.1016/S0140-6736(94)90185-6

8. Lanza FL, Chan FKL, Quigley EMM. Guidelines for prevention of NSAID-related ulcer complica-tions. Am J Gastroenterol. 2009;104(3):728-738. doi:10.1038/AJG.2009.115

9. National Department of Health. Hospital Level (Adults) Standard Treatment Guidelines and Es-sential Medicines List, 2nd Edition. 2019. https://www.knowledgehub.org.za/elibrary/hospital-lev-

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