Specialist Forum May 2021

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FORUM

Vol. 21 • No. 5 • May 2021

Egg timer testing

Pain in the brain

DULTA 30, 60 mg. Each tablet contains 30, 60 mg duloxetine respectively. S5 A46/1.2/0889, 890. NAM NS3 18/1.2/0126, 0127.

For full prescribing information, refer to the professional information approved by SAHPRA 29 September 2017. DAA641/03/2021.

CUSTOMER CARE LINE 0860 PHARMA (742 762) / +27 21 707 7000 www.pharmadynamics.co.za

SF | CONTENTS

May 2021 | Vol. 21 No. 5 www.medicalacademic.co.za

INSIDE this issue

4 EDITORIAL 6 EXPERT OPINION

A look at nuisance claims

30 PATIENT SAFETY

Pain-induced depression

Challenges and opportunities with respect to NCDs in SSA

34 PULMONOLOGY

The story of probiotics

12 ENDOCRINOLOGY

CPD: Pain in the brain

True 24-hour BP control

22 DERMATOLOGY

SAD, a complex and silent signature of asthma

37 PSYCHIATRY 40 GASTROENTEROLOGY

The global syndemic of obesity

15 NEUROLOGY 19 CARDIOLOGY

CPD: 5 steps to creating a nontoxic healthcare environment

CPD: Management in clinical practice of multiple face and scalp AK

In South Africa, 7 women 0% of , adult m 35% of e n an d 13 of child ren fall % in to the obe se overwe and igh catego t ry

26 WOMEN’S HEALTH

CPD: Egg timer testing

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All content in The Specialist Forum is sourced independently and under no circumstances should articles be considered promotional unless specified with a postscript.

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This article was independently sourced by Specialist Forum.

A look at nuisance claims Vanessa Rogers on behalf of Natmed Medical Defence

U

Where should the checks and balances lie in professional indemnity claims, and how do we stem the tide of claims, which would not have arisen had it not been for Covid-19?

njustified medical malpractice claims against healthcare practitioners could result in professional indemnity insurance premiums skyrocketing to the extent that medical malpractice insurance will become unaffordable.

If healthcare practitioners in the private sphere cannot afford the premiums, we will see more healthcare practitioners moving over to the public healthcare sector – where it is not compulsory for them to take up cover. This already is the case with obstetricians and gynaecologists.

Such an occurrence would be unfortunate when considering that these same healthcare practitioners have, since the start of the Covid-19 pandemic, risked their health and lives by working on the frontline under emergency circumstances.

Indeed, many healthcare practitioners and workers have turned their focus to saving the lives of Covid patients as a matter of priority.

Covid has resulted in a further crisis – a rise in medical malpractice claims against healthcare practitioners since the beginning of 2021. In many instances, claims that are unfounded and lack any merit are instituted due to litigants being advised that they have good prospects of succeeding with their claims. This then results in a waste of both the litigant’s and the court’s time, and in the litigants’ hopes being dashed in the process.

There are numerous reasons for the rise in medical malpractice claims following a pandemic such as Covid. Other than litigants being incorrectly advised, and in certain instances being misled into believing that there is a likelihood of their claims succeeding, claims of this nature are likely to result in some monetary gain where a settlement offer is made on a purely commercial basis – that is, where the healthcare practitioner makes an offer in settlement with a view to disposing of the claim in order to avoid unnecessary legal costs being incurred.

It is also likely that the courts will be sympathetic towards litigants who are allegedly victims of medical malpractice during the COVID-19 pandemic.

Healthcare practitioners have taken strain of late due to a constrained earning

capacity. This has resulted in our healthcare practitioners being placed at increased risk of being exposed to claims being instituted against them for medical malpractice, which is further exacerbated by the fact that claims have increased in light of the pandemic.

Each legal case should be assessed according to the circumstances that gave rise to the claim. Various factors should be considered. These include: » Whether there was a valid cause of action and any breach of duty on the part of the healthcare practitioner because of a substandard level of treatment and care being provided » Whether the standard of care and treatment provided resulted in any harm, injury, death and/or financial loss to the patient.

A proper assessment must be performed, and a litigant should be informed of the prospects of succeeding with a claim. Unfortunately, this is not always the case and it is a rather unfortunate state of affairs given the great sacrifices our healthcare fraternity has made on a personal and professional level since the start of the pandemic.

Healthcare professionals pay their premiums and, in return, they are covered in circumstances where a claim is instituted against them and an adverse finding is made, provided that they have met the terms and conditions of their professional indemnity policies. The insurer is there to fit the bill in accordance with the limits of the policy schedule.

The position in the public sector differs in that the Department of Health is allocated a fixed amount in terms of the Minister of Finance’s national budget. These funds are used for the upkeep of hospitals, the payment of hospital staff salaries, as well as for purposes of settling medico-legal claims and attorney costs.

The legal acts which govern this industry would not see it eroded by a plethora of nuisance claims demanding inappropriate compensation – especially as the courts’ approach in general is to afford a plaintiff his/her day in court. What tends, then, to transpire is that a ‘nuisance offer’ is made as soon as possible to dispose of a claim to avoid unnecessary legal costs being incurred. SF

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TREVICTA

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paliperidone palmitate prolonged release suspension for injection

THE INTRODUCING TREVICTA® PLAN* Help your patients to take ownership of their schizophrenia with the enduring efficacy and convenience of the unique four-per-year (4PY) TREVICTA®. 1,2,3,4,5,6

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THE TREVICTA® PLAN * The TREVICTA® Plan is the initiation of XEPLION® then moving to TREVICTA® when stabilised - in line with the approved indications for both treatments.7 XEPLION® is indicated for maintenance treatment of schizophrenia and for the prevention of recurrence of symptoms of schizophrenia. 8 TREVICTA®, a 3-monthly injection is indicated for the maintenance treatment of schizophrenia in adult patients who are clinically stable on 1-monthly paliperidone palmitate injectable product. 7 For full prescribing information refer to the professional information leaflet.

References: 1. Schreiner A, Bergmans P, Cherubin P, et al. A Prospective Flexible-Dose Study of Paliperidone Palmitate In Nonacute But Symptomatic Patients With Schizophrenia Previously Unsuccessfully Treated With Oral Antipsychotic Agents. Clinical Therapeutics 2014;36(10):1372-1388e1. 2. Berwaerts J, Liu Y, Gopal S, et al. Efficacy and Safety of the 3-Month Formulation of Paliperidone Palmitate vs Placebo for Relapse Prevention of Schizophrenia. A Randomized Clinical Trial. JAMA Psychiatry 2015;72(8):830-839. 3. Savitz A, Xu H, Gopal S, et al. Efficacy and Safety of Paliperidone Palmitate 3-Monthly Formulation for Patients with Schizophrenia: A Randomized, Multicenter, Double-Blind, Noninferiority Study. International Journal of Neuropharmacology 2016;19(7):1-14. 4. Hargarter L, Bergmans P, Cherubin P, et al. Once-monthly paliperidone palmitate in recently diagnosed and chronic non-acute patients with schizophrenia. Expert Opinion on Pharmacology 2016;17(8):1043-1053. 5. Caroli F, Raymondet P, Izard I, et al. Opinions of French patients with schizophrenia regarding injectable medication. Patient Preference and Adherence 2011;5:165-171. 6. Gopal S, Vermeulen A, Nandy P, et al. Practical Guidance for Dosing and Switching from Paliperidone Palmitate 1-Monthly to 3-Monthly Formulation in Schizophrenia. Current Medical Research and Opinion 2015;31(1):2043-2054. 7. TREVICTA® Professional Information. December 2020. 8. Xeplion Professional Information Leaflet. (May 2019).

S5 TREVICTA® 175 mg, 263 mg, 350 mg, 525 mg prolonged release suspension for injection. 175 mg prolonged release suspension for injection: Each pre-filled syringe contains 273 mg paliperidone palmitate equivalent to 175 mg paliperidone. 263 mg prolonged suspension for injection: Each pre-filled syringe contains 410 mg paliperidone palmitate equivalent to 263 mg paliperidone. 350 mg prolonged release suspension for injection: Each pre-filled syringe contains 546 mg paliperidone palmitate equivalent to 350 mg paliperidone. 525 mg prolonged release suspension for injection: Each pre-filled syringe contains 819 mg paliperidone palmitate equivalent to 525 mg paliperidone. Marketing Authorisation Number/s: EU/1/14/971/007; EU/1/14/971/008; EU/1/14/971/009; EU/1/14/971/010. For full prescribing information, refer to the latest professional information leaflet. December 2020.

JANSSEN PHARMACEUTICA (PTY) LTD, (Reg. No. 1980/011122/07), No 2, Medical Street, Halfway House, Midrand, 1685. www.janssen.com. Medical Info Line: 0860 11 11 17.

S5 XEPLION® 50, 75, 100 or 150mg Prolonged release suspension for intramuscular injection. Each pre-filled syringe contains sterile paliperidone palmitate equivalent to 50, 75, 100 or 150mg of paliperidone respectively.

Reg. Nos.:44/2.6.5/0866; 44/2.6.5/0867; 44/2.6.5/0868;44/2.6.5/0870. For full prescribing information, refer to the latest professional information insert. May 2019 JANSSEN PHARMACEUTICA (PTY) LTD, (Reg. No. 1980/011122/07), No 2, Medical Street, Halfway House, Midrand, 1685. www.janssen.com. Medical Info Line: 0860 11 11 17.

CP-213128

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This article was independently sourced by Specialist Forum.

Challenges and opportunities with respect to NCDs in SSA

Most countries in sub-Saharan Africa (SSA) are presently going through an epidemiological transition with the rising burden of non-communicable diseases (NCDs), in addition to the huge disease burden from poorly controlled communicable diseases and childhood illnesses.1 Abstract The rise in the prevalence of noncommunicable diseases (NCDs) in subSaharan Africa (SSA) is at a stage where the burden of disease has tremendous financial and health implications. By evaluating the issues contributing to this phenomenon, this article will assess the commonest NCDs, factors influencing their development and what could be done to address this relentless attack on the populations of SSA, especially with the waves of pandemics occurring in the 21st century.

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lobally, death and disability from NCDs are rising fastest in SSA and it was projected in 2011 that the rise in NCDs will outpace reduction in communicable diseases leading to a double burden of disease, which we see today. 2 NCDs lead to 41 million deaths annually, accounting for 76% of the global mortality.

About 15 million of the deaths will occur prematurely (between the ages of 35-69 years) and 85% of these deaths will occur in low- and middle-income countries (LMICs). 3 A clear relationship is evident between premature NCD mortality and country income

By Prof Amam Mbakwem (Nigeria), Dr Adri Kok (South Africa), Prof Elijah Ogola (Kenya), Prof Jean-Baptiste Anzouan-Kacou (Côte d'Ivoire), Dr Niraksha Jithoo (South Africa) levels. In 2016, 78% of all NCD deaths and 85% of premature adult NCD deaths, occurred in LMICs. Adults in LMICs face the highest risk of dying from an NCD. In 2016, the World Health Organization (WHO) estimates of NCDs accounting for all deaths by country, were 27% in Kenya, 29% in Nigeria, 37% in Cote d’Ivoire, 35% in Cameroon, 42% in Senegal and 51% in South Africa. 3 The rise in NCDs has been attributed to the increase in risk factors such as an ageing population, adoption of unhealthy western diets, increasing prevalence of hypertension, smoking, obesity, physical inactivity, and

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alcohol consumption. Increasing urbanisation with rural to urban migration and the attendant stress of slum dwelling also plays a part.

Studies have shown an increasing burden of cardiovascular disease (CVD), diabetes, chronic respiratory diseases, cancers, and an increase in mental health disorders.4,5 The majority of the NCD deaths in 2018 are related to CVDs accounting for 17.9 million deaths annually, followed by cancers (9 million), respiratory diseases (3.9million) and diabetes (1.6 million) and these account for 80% of the premature deaths. 3 At the beginning of the last century, CVDs were responsible for fewer than 10% of all deaths worldwide. Today, there is a striking difference with the figure approximately 30%.6 Some 80% of the burden now occurs in developing countries and more than 50% occurs in those under 70 years of age.7 This has placed an added strain on the fragile health care systems and infrastructure in most countries on the African continent.

Cardiovascular disease burden in SSA Africa is home to more than one billion people and is one of the major contributors to the global burden of CVD. 8 In 2013, nearly one million deaths were attributable to CVD in SSA, constituting 38.3% of non-communicable disease deaths and 11.3% of deaths from all causes in the region. 9 SSA contributed 5.5% of global CVD deaths.

This accounts for an almost two-fold increase (81%) in the number of CVD related deaths since 1990, from 529 880 deaths in 1990 to 958 713 deaths in 2003 (95% uncertainty intervals [UI]).9 There were more deaths due to CVDs in women (512 269) than in men (445 445) and more deaths from stroke (409 840) than ischaemic heart disease (258 939). Deaths for all components of CVDs also increased. 9 Given the overwhelming burden of noncardiac-related infectious diseases (including malaria and the broader epidemic of HIV/ AIDS), CVDs are often overlooked as a matter of health importance. Some urban communities in SSA are characterised by the increase of chronic diseases and an emergence of diseases closely related to hypertension.10 The prevalence pattern of the CVDs is distinctly different in SSA compared with the rest of the world: infectious and inflammatory causes are relatively more common and atherosclerosis relatively less common. 8 As parts of SSA urbanise and life expectancy increases, a larger share of the population may develop higher CVD rates, along with persistence of the lower CVD rates in poorer rural areas. 8 In SSA, the epidemiology of CVD may differ across certain groups of the population.

Different exposure to known and unknown risk factors, unhealthy lifestyles (prevalence of smoking, obesity and alcohol consumption) and access to healthcare and environmental conditions, including traditional customs could be the main reasons.10, 11 From a regional perspective some contrast among regions in Africa may exist and epidemiology of CVD could therefore differ. Historically the lipid profiles of African individuals were considered largely favourable, reflecting traditional lifestyles that include high levels of physical activity and diets low in fat, which resulted in low rates of atherosclerotic disease.10

more o t e om le a is h c peop i r n f o A i l l ne bi ajor o m n e a h t th ne of o s i o the t s and r o D ibut of CV contr n e d l bur globa Diabetes Diabetes is one of the most common NCDs globally. It is the fourth or fifth leading cause of death in most high-income countries and there is substantial evidence that it is epidemic in many economically developing and newly industrialised countries. About 77% of people with diabetes live in LMICs.12 This in itself is very likely underestimated, as the majority of cases may go undiagnosed, since many patients are unaware that they may have diabetes. Genetics, some environmental factors and viral infections have been shown to increase the risk of type 1 diabetes. Type 2 diabetes risk factors due to an increased western lifestyle in SSA include, but are not limited to: family history of diabetes, being overweight, unhealthy diet, physical inactivity, ageing, and poor nutrition during pregnancy.12 Despite national guidelines, protocols and treatment algorithms being available in many countries, they are still not effectively implemented in all countries across SSA. Without effective prevention and management programmes, the number of people with diabetes globally is expected to rise from 387 million people in 2014 to 592 million people by 2035.12 Inadequate primary healthcare and availability of oral anti-diabetic medication and insulin result in poor control and inevitable complications, both microvascular and macrovascular.

Respiratory diseases Chronic respiratory diseases pose a major public health problem, with an estimated 3.91 million deaths in 2017, accounting for 7% of all deaths worldwide. Between 1990 and 2017, the total number of deaths due to chronic respiratory diseases increased by 18.0%, from 3.32 million in 1990 to 3.91 million in 2017.13 The contribution of risk factors including smoking, environmental pollution and a high body mass index to mortality and disability adjusted life years supports the need for urgent efforts to reduce exposure to risk factors. Regions with a low socio-demographic index were found to have the greatest burden of disease.13 In 2017, 21 600 deaths were due to pneumoconiosis. The age standardised mortality rate of pneumoconiosis varied with the highest being from 1.76 per 100 000 people in Papua New Guinea to the lowest in Moldova of 0.0041 per 100 000 people. African countries such as Swaziland, Lesotho, Madagascar, Central African Republic, Somalia and South Africa had the age standardised mortality rate of pneumoconiosis above 0.5 per 100 000 people.13

Cancer Cancer is the second leading cause of death globally, accounting for an estimated 9.6 million deaths or one in six deaths in 2018, with approximately 70% of deaths occurring in LIMCs.14 Lung, prostate, colorectal, stomach and liver cancer are the most common types of cancer in men, while breast, colorectal, lung, cervical and thyroid cancer are the most common types of cancer in women.14 The cancer burden continues to grow globally, exerting tremendous physical, emotional and financial strain on individuals, families, communities and health systems.14 Large numbers of cancer patients globally do not have access to timely quality diagnosis and treatment. Many health systems in LMICs are least prepared to manage this burden.14 Late-stage presentation and inaccessible diagnosis and treatment are common. In 2017, only 26% of low-income countries reported having pathology services generally available in the public sector. Less than 30% of low-income countries reported availability of treatment services compared to 90% in high-income countries.14 In countries where health systems are strong, survival rates of many types of cancers are improving due to accessible early detection, quality treatment and survivorship care. That being said, only one in five LMICs have the necessary data to drive cancer policy.14 In 2018, the cancer incidence and mortality statistics across Africa as per the Globocan data showed that the incidence of cancer in both

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sexes had the highest new cases in Eastern Africa (332 177), followed by Northern Africa (283 219), Western Africa (229 459), Southern Africa (114 582) and Middle Africa (95 735).15 The number of deaths across Africa in 2018 was highest in Eastern Africa (230 968), followed by Northern Africa (178 754), Western Africa (153 332), Middle Africa (68 763) and Southern Africa (61 670).15

Mental health and wellbeing are central to reducing the global burden of NCDs, as emphasised by the WHO’s mental health action plan for 2013-2020. Diabetes, CVD, cancer and respiratory diseases commonly co-occur with both common mental disorders such as depression and anxiety disorders and severe mental illnesses such as schizophrenia and bipolar disorder.16 Epidemiological studies have found significant associations within and across countries

While there has been profound progress made in the health of populations over the last three decades, (including in SSA with improved life expectancy), the rise of NCDs threatens to reverse these gains and stall social and economic developments.17 While evidence is consistent on the growing health and economic consequences of NCDs in SSA, specific efforts aimed at addressing NCD prevention and control remain less than optimum and country level progress of implementing evidence backed cost-effective NCD prevention approaches such as tobacco taxation and restrictions on marketing of

(above US$10 000 per capita PPP) do not systemically give higher priority to health in their public spending.18 In contrast, a few lower income countries including Ethiopia, Gambia, Malawi and Swaziland allocate more than 15% of their public spending to the health sector, as can be seen in the Figure 1.18 When states become richer, public spending on health as a proportion of total public expenditure does not systematically increase, and in most cases public expenditure on health is not responsive to increased state revenues, as should be the case.18 Donor funding for health is still important in many LMICs, with 20 LMICs in SSA relying on donor funding for more than one-fifth of their health spending.19 Most of these funds, however, are targeted at mitigating communicable disease, maternal and infant mortality thereby deepening the neglect of NCDs in these countries. 20

between CVD and common mental disorders.

In the World Mental Health Surveys, odds ratios for the association of heart disease with mental disorders were 2.1 for mood disorders, 2.2 for anxiety disorders and 1.4 for alcohol misuse or dependence across countries.16 A dose-response association was seen between the increasing number of mental disorders and heart disease and there were strong associations between early onset common mental disorders and adult onset heart disease, as well as between early childhood adversities and adult onset heart disease.16 Although mental disorders are associated with greater disability than physical conditions, they are less likely to receive treatment across the globe. This may partly reflect higher levels of stigmatisation experienced by those with

unhealthy food and drinks is slow.17 Similarly, increasing interest to employ multi-sectoral approaches (MSA) in NCD prevention and policy is impeded by policy maker inertia, as well as limited knowledge on the mechanisms of MSA application in NCD prevention, their co-ordination, and potential successes in SSA.17 In 2001, African Union (AU) heads of state pledged to allocate at least 15% of annual expenditure to health under the Abuja Declaration. As at 2014, most countries are below the Abuja AU Declaration. Government health prioritisation does not seem to be associated with national income or level of government revenues in the African region.18 Higher per capita income countries such as Algeria, Botswana, Equatorial Guinea, Gabon, Mauritius, Seychelles and South Africa

Poor health insurance coverage has led to catastrophic spending for healthcare in many SSA countries and the rubrics of assessing health care delivery using under-five and maternal mortality has also contributed to the neglect of NCDs. The poor health insurance coverage and out-of-pocket payment for health services have resulted in late presentations and poor outcomes associated with NCDs. 20 The menace of poor quality and counterfeit drugs constitutes another major issue for public health in SSA. 21 As a consequence of this, treatment failures may adversely affect patient treatment outcome. 22 More research is needed in this area to institute measures to fight against those counterfeiting drugs. 23 The Covid-19 pandemic, which started in December 2019, is associated with more severe disease, higher morbidity and mortality

Mental health

mental disorders compared with people with physical conditions. Risk factors for NCDs such as tobacco use, unhealthy diet, physical inactivity, and harmful alcohol use commonly cluster in people with mental disorders, where they may have multiplicative effects.16

Challenges

Figure 1: Government health prioritisation and GDP per capita, 201418

Source: Global Health Expenditure Database, WHO, 2016

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in patients with underlying CVD and CVD risk factors. 24-27 Mortality, though low (2%-3%) in the general population, rises to 10% in patients with underlying CVDs. 27 Hypertension and diabetes are the most common CV risk factors seen in patients with severe disease. 28,29 Outcomes in Covid-19 have been shown to be worse in patients with underlying CVD or CV risk factors and people living with NCDs are at higher risk of severe Covid-19-related illness and death. 30 The outcomes will probably be worse in SSA because of the rising burden of NCDs and low levels of optimal management due to both personal and systemic problems in the healthcare delivery system. This was especially evident in South Africa, which had the highest number of Covid-19 infections in Africa. 31 Patients with co-morbidities suffered worse outcomes and higher mortality rates. The influence of high burden of communicable

burden of routine follow-up for NCDs. The nonavailability and often high cost of medicines and investigations for NCD, is also a challenge in SSA.

Research on NCDs in Africa has been limited to predominantly small case series in addition to population studies, mainly on risk factors.

The Covid-19 pandemic is a wake-up call for governments in SSA to re-strategise and retool healthcare policies and delivery systems using a more holistic (including NCD prevention and care) people centric approach that is indigenous in collaboration with the other sectors that impact the health of the population.37,38 There is also an opportunity for health systems analysis evaluating the best ways of integrating NCD care into primary health care that already has established pathways for communicable diseases. This would require some basic equipment like functioning

diseases like TB and HIV on CVD in LMICs, requires further research. An awareness of the problems due to the associations seen between chronic and infectious disease in SSA should be top of mind in order to manage patients more efficiently, in light of Covid-19 and CVD on the continent. 31 Most countries in SSA have very fragile health systems struggling to cope with the double burden of disease, both communicable and rising NCDs. According to the WHO, prevention and treatment services for NCDs have been severely disrupted since the Covid-19 pandemic began. 30 The additional burden of the Covid-19 could lead to total collapse of the systems.

The Covid-19 pandemic has also caused health services in many countries to be either partially or completely disrupted with regards to hypertension treatment, treatment for diabetes and diabetes-related complications, cancer treatment and CV emergencies. 30 The postponement of public screening programmes such as breast and cervical cancer is also widespread. Unsurprisingly, there appears to be a correlation between levels of disruption to services for treating NCDs and the evolution of the Covid-19 outbreak in a country.30 Poor infrastructure, as well as under trained and poorly motivated personnel together with a shortage of staff exist at many of the primary health centres across SSA. These primary health centres lack the basic infrastructure to deal with NCDs. The lack of properly functioning sphygmomanometers, glucometers, weighing scales and strips for urinalysis is a reality here. These, together with a lack of models for chronic care, has led to secondary and tertiary centres, which in many countries may be centres of excellence, being inundated with the

A number of epidemiologic studies have been done in the recent past, mainly from hospitalised patients. 32 Higher level research including cohort studies, randomised controlled trials and implementation science lags behind. Despite the rising prevalence of CVD in SSA, the lack of research constitutes a significant challenge for the countries in the region. Worldwide scientific publishing activity over the past decade indicates that most countries in SSA have very low levels of publication. 32 In 2004, 31 of the world’s 193 countries produced 97.5% of the world’s most cited papers. South Africa, at number 29, was the only SSA country on this list. 33 There has, however, been a significant improvement in health research in the WHO African Region since 2000. The per cent share of first authors from Africa contributing to worldwide research publications per year increased from 0.7% in 2000, to 1.3% in 2014, with South Africa, Nigeria and Kenya contributing to 52% of the publications. 34 In a recent paper, Ettarth showed that the number of publications involving multiple SSA countries account for less than 10% of the total number of multi-country publications that included at least one SSA country, with a low level of collaboration between French speaking and English speaking countries in the region. 35 Primordial prevention, early detection and appropriate treatment are key components of the response to NCDs. To alter the trajectory of NCD epidemiology, research must be one of the main goals in order to fill the important knowledge gap. This will provide thorough and reliable data on the magnitude of the disability burden of NCDs in SSA. 36 Important efforts are needed to curb the burden of NCDs in the region, starting with the

sphygmomanometers, weighing scales, glucometers and urinalysis strips. These basic tools will ensure adequate follow-up at the primary care level without the patients traveling long distances to the tertiary or secondary centres. 38,39 Another advantage will be the reduction in the cost of transportation, which is a major part of the cost of care in SSA. Policy proposal that has been advocated to improve the primary care response will include improving data on communicable diseases and NCDs, implementing a structured approach to improved primary care delivery and ensuring quality of clinical care, aligning the response to health transition with health system strengthening. 38,39 Proper integration of services at the primary care level leveraging on lessons learnt from management of HIV would reduce cost and redundancy in delivering care for patients with NCDs.40, 41 This is also an opportunity for up-skilling personnel at the primary care level and community health workers. Continuous professional development using online training and leveraging on the available technologies will reduce the cost of up-skilling the health workers in rural areas.42 Development of standard operating procedures (SOPs), charts, algorithms for screening, simple treatment guidelines, follow-up, referral and teleconsulting facilities so that specialists can assist the rural healthcare workers with evaluation of difficult cases, will enable safe task shifting and sharing.42 The high cost of medicines and medical equipment could be better managed through waivers on import duties for medication and medical equipment. There should be a concerted effort towards local and/or regional

r ance c , D es, CV diseases t e b a y Di rator i p s e ccur and r only co-o n comm h commo bot s with order s i d l a ment Research priorities

provision of reliable epidemiological estimates of NCDs and their drivers in order to appropriately inform prevention and control strategies.36 Such efforts will aid in informing national health systems on how to design and implement effective interventions for specific NCDs and prioritise the resources required by countries.36

Opportunities

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production of essential medicines for NCDs, making use of harmonisation of drug approvals available in the region, as well as improved supply chain management.

This has become more crucial with the experience of disruption in drug shipment and supplies during the Covid-19 pandemic and border closures. In addition, local production of some of the basic medications for NDCs will reduce the cost of prescriptions and improve uptake and adherence.

There is also the added advantage of economic growth and employment opportunities in these countries. This will reduce the cost of these essential elements in the management of CVDs in the SSA region. Where this is not feasible, there should be some subsidy for medications used to treat NCDs. Some governments in SSA have begun taking action to reduce the rise in risk factors by implementing policies such as the taxation of tobacco, alcohol and unhealthy food items.

people by providing universal healthcare and mental health services, screening services, brief interventions targeting NCD risk factors in primary care and access to affordable drugs for the prevention and control of NCDs. This will ultimately be beneficial to the general population, more so during the Covid-19 pandemic where many people are facing unemployment, career/financial stressors, low social engagement, divorce or poor emotional resilience.43 The challenges and opportunities in the management of NCDs in SSA are summarised in Table 1.

This could be more broadly implemented across the region. Health systems can support

these campaigns must be assessed.

Governments should assume a holistic

Recommendations There are multiple factors accounting for the rapid rise in NCDs across SSA. The answer to the increase in NCDs is multi-facetted and must include education and awareness as well as effective interventions and research. Money must be spent wisely and the best impact of

view of health and strengthen inter-sectoral collaboration between ministries of health, agriculture, housing, education and urban development. These different aspect impact on health and healthcare delivery both directly and indirectly.

It is time for our governments to honour their commitments to achieve universal health coverage by increasing insurance coverage for the general population, whilst ensuring that coherent NCD policies are available at a national level. Health systems can support patients by providing universal healthcare and mental health services, screening services, brief interventions targeting NCD risk factors in primary care and access to affordable drugs for the prevention and control of NCDs.43 There needs to be increased budgetary allocation to health with goal oriented and integrated spending to improve the health care delivery system addressing both the communicable and NCDs.44 The departments of health in SSA countries need to understand the challenge of the NCDs on the fiscus and how this will continue to escalate if appropriate primary care interventions and management are not instituted timeously. This will cost much more if preventative care is not effective.

The major NCDs (CVD, diabetes, chronic respiratory diseases, cancer and mental disorders) are often associated with older age groups, but the evidence suggests that they affect people of all ages.43 Goverment’s NCD preventive policies should also address the youth and adolescents so that the risk factors are tackled early, timely and in an appropriate manner. This is importatnt because 15 million deaths attributable to NCDs occur between ages of 30- and 69 years.

Taking early, appropriate, timely and collective action is important if we are to reduce premature mortality related to NCDs by a third by 2030.43 NCDs are set to overtake communicable, maternal, neonatal and nutritional diseases as the leading cause of disability and mortality in the region over the next decade. Policy makers must recognise that the inability to control NCDs is a major barrier to the attainment of Sustainable Development Goals 1, 2 and 3. 36

Conclusion NCDs are a major contributor to disability and mortality in the SSA region. Precise, swift action is needed from a public health perspective on prevention and treatment modalities. This is possible through multisectoral approaches, collaboration of governments, departments of health, medical societies, academia, private sector and civil societies in order to address the burden of disease.

SF | EXPERT OPINION

May 2021 | Vol. 21 No. 5 www.medicalacademic.co.za

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The scientific writer is Kiasha Naicker of Karadon (Pty) Ltd. The scientific writer was sponsored by Pfizer Laboratories (Pty) Ltd.

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This article was independently sourced by Specialist Forum.

The global syndemic of OBESITY OBESITY Obesity is a complex, chronic disease, which can cause a multitude of other diseases with severe morbidities and mortality. Obesity is rising worldwide and has a disturbing economic burden, both direct and indirect, which continues to rise.1

O

besity figures from 1975 to 2014 confirm that we are getting fatter, and it is predicted that by 2025, global obesity prevalence will reach 18% in men and 21% in women. Severe obesity will affect about 6% of men and 9% of women.

Swinburn et al call this the ‘global syndemic of obesity’. 2 A syndemic is not merely a comorbidity. Syndemics are characterised by biological and social interactions between conditions and states, interactions that increase a person’s susceptibility to harm or worsen their health outcomes. 3 Swinburn et al compared the data (1975 to 2014) of more than 19.2 million participants (9.9 million men and 9.3 million women) aged 18 years or older whose height and weight had been measured. Data in 186 countries, which cover 99% of the world’s population, were included. 2 They found: » Global age-standardised mean body mass index (BMI) increased from 21.7kg/m2 in 1975 to 24.2kg/m2 in 2014 in men, and from 22.1kg/m2

in 1975 to 24.4kg/m2 in 2014 in women » Regional mean BMIs in 2014 for men ranged from 21.4kg/m2 in central Africa and south Asia to 29.2kg/m2 in Polynesia and Micronesia » Age-standardised prevalence of obesity increased from 3.2% in 1975 to 10·8% in 2014 in men, and from 6.4% to 14.9% in women.

About 2% of the world’s men and 5% of women were severely obese (BMI ≥35kg/m2) » Globally, prevalence of morbid obesity was 0.64% in men and 1.6% in women.

In South Africa, 70% of women, 35% of adult men and 13% of children fall into the obese and overweight category. Only 30% engage in regular formal physical activity and 82% consumer high calorie low nutritional and processed fast foods. Do not wait – more than ever, it is important to lose weight, according to Dr Gary Hudson, a specialist physician with an interest in weight management.4 Although it is not the most accurate, Dr Hudson said that BMI is still a very important clinical measurement, and that even those with a BMI of just >25kg/m2, which is literally just above the normal weight range,

seem to correlate with a higher incidence of serious disease, particularly when combined with a comorbidity such as hypertension.4 Swinburn et al too caution that high BMI is an important risk factor for cardiovascular (CV) and kidney diseases, diabetes, some cancers, and musculoskeletal disorders. 2

What drives obesity?

Obesity, explain Lean et al, is not just a state of excess of body fat or BMI above an arbitrary cut-off. It should be viewed as a disease process of excess body fat accumulation that has interacting (epi-) genetic and environmental causes as well as multiple pathological consequences. Obesity tends to run in families, they add, and is augmented by environmental drivers. These include poor education and socioeconomic situations. 5

Multidisciplinary approach to weight management The basic weapons against many diseases, including obesity is diet and exercise, weapons available to most of our patients but not nearly enough take advantage of them, stressed Dr Hudson.4 Speaking at the South African launch of liraglutide on 6 February 2021, Dr Sean Wharton: Co-chair of the 2020 Canadian Obesity Guidelines, said obesity should be managed using evidence-based chronic disease management principles.6 People who are living with obesity should have access to evidence-informed interventions, which should include:6 » Medical nutrition therapy

Liraglutide injection 3 mg is the only GLP-1 approved in South Africa for weight management1-6

NOW AVAILABLE IN SOUTH AFRICA NEW

I have the will to work out every day.

But I still need help to lose weight and keep it off.

liraglutide injection 3mg

ROBERTO, Civil Servant; Age: 48 BMI: 39

Your patients with obesity have the will. You can offer them the way.

Saxenda® key benefits:

Patients achieved significant and sustained weight loss throughout 1-year and 3-year trials7,8

Patients also experienced significant improvements in cardiometabolic risk factors and complications7

Similar to natural GLP-1, Saxenda® works to decrease appetite and thereby reduce food intake1

The long-term safety profile of Saxenda® has been well established1,8

Obesity is a chronic disease.9 References: 1. Saxenda® Professional Information. 2. Victoza® Professional Information. 3. Xultophy® Professional Information. 4. TRULICITY Professional Information. 5. BYETTA Professional Information. 6. South African Health Products Regulatory Authority (SAHPRA). Registered Health Products [online 2020][cited 2020 October 09]; Available from URL: https://www.sahpra.org.za/registered-health-products/. 7. Wadden, T.A., Hollander, P., Klein, S., Niswender, K., Woo, V., Hale, P.M. and Aronne, L., 2013. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. International journal of obesity, 37(11), pp. 8 . le Roux CW, Astrup A, Fujioka K, et al.; for the SCALE Obesity and Prediabetes NN8022-1839 Study Group. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet. 2017;389(10077):1399-1409. 9. Bray GA, Kim KK, Wilding JPH; on behalf of the World Obesity Federation. Obesity: a chronic relapsing progressive disease process. A position statement of the World Obesity Federation. Obes Rev. 2017;18(7):715-723.

Abbreviated Professional Information Proprietary Name: Saxenda® Scheduling Status: S4 Composition: One ml of solution contains 6 mg of liraglutide and phenol 0,55 % m/v as the preservative. Indications: Saxenda® is indicated as an adjunct to a reduced-calorie diet and increased physical activity for medically supervised chronic weight management programme in adult patients with an initial Body Mass Index (BMI) of: • ≥ 30 kg/m2 (obese), or • ≥ 27 kg/m2 to < 30 kg/m2 (overweight) in the presence of at least one weight related comorbidity such as dysglycaemia (pre-diabetes and type 2 diabetes mellitus), hypertension, dyslipidaemia, or obstructive sleep apnoea. Contra-Indications: • Hypersensitivity to liraglutide or to any of the excipients listed under Composition. • Pregnancy and lactation. Warnings & Special Precautions: Saxenda® must not be used as a substitute for insulin. There is limited experience in patients with congestive heart failure New York Heart Association (NYHA) class I - II and Saxenda® should therefore be used with caution. There is no experience in patients with congestive heart failure NYHA class III - IV and Saxenda® is therefore not recommended in these patients. The safety and efficacy of Saxenda® have not been established in the following patients, viz: • Treated with other products for weight management, • With obesity secondary to endocrinological or eating disorders or to treatment with medicinal products that may cause weight gain, • With severe renal impairment, • With severe hepatic impairment, • With inflammatory bowel disease and diabetic gastroparesis. Use in these patients is not recommended. Use of Saxenda® has been associated with the risk of developing acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Saxenda® should be discontinued; if acute pancreatitis is confirmed, Saxenda® should not be restarted. In clinical trials, a higher rate of cholelithiasis and cholecystitis was observed in patients treated with Saxenda® than in patients on placebo. Patients should be informed of the characteristic symptoms of cholelithiasis and cholecystitis. In clinical trials in type 2 diabetes, thyroid adverse events, including increased blood calcitonin, goitre and thyroid neoplasm have been reported in patients with pre-existing thyroid disease. Saxenda® should therefore be used with caution in patients with thyroid disease. An increase in heart rate was observed in clinical trials. Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients should be informed of the symptoms of increased heart rate (palpitations or feelings of a racing heartbeat while at rest). For patients who experience a clinically relevant sustained increase in resting heart rate, treatment with Saxenda® should be discontinued. Patients treated with Saxenda® should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion. Patients with type 2 diabetes receiving Saxenda® in combination with a sulphonylurea have an increased risk of hypoglycaemia. Pregnancy and lactation: Saxenda® should not be used during pregnancy and lactation. Dosage and Directions for Use: The starting dose is 0,6 mg once daily. The dose should be increased to 3.0 mg once daily in increments of 0,6 mg with at least one week intervals to improve gastro-intestinal tolerability. If escalation to the next dose step is not tolerated for two consecutive weeks, consider discontinuing treatment. Daily doses higher than 3,0 mg are not recommended. Saxenda® is for subcutaneous use only. It must not be administered intravenously or intramuscularly. Saxenda® is administered once daily at any time, independent of meals. However, it is preferable that Saxenda® is injected around the same time of the day. It should be injected in the abdomen, thigh or upper arm. Saxenda® should not be used in combination with another GLP-1 receptor agonist. When initiating Saxenda®, consider reducing the dose of concomitantly administered insulin or insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycaemia Saxenda® is not recommended for use in children below 18 years of age due to lack of data. Side Effects: Gastrointestinal reactions were the most frequently reported adverse reactions during treatment with Saxenda®. Very common side effects are nausea, vomiting diarrhoea, constipation. Common side effects include: Hypoglycaemia, insomnia, dizziness, dysgeusia, dry mouth, dyspepsia, gastritis, gastro-oesophageal reflux disease, abdominal pain upper, flatulence, eructation, abdominal distension, cholelithiasis, injection site reactions, asthenia & fatigue. Uncommon side effects include: dehydration, tachycardia, pancreatitis, cholecystitis, urticaria & malaise. Rare side effects include: anaphylactic reaction, acute renal failure & renal impairment. Overdosage: With overdose, the patients reported severe nausea, vomiting and diarrhoea, but recovered without complications. None of the patients reported severe hypoglycaemia. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. Reg. No.: 50/21.13/1091. For full prescribing information, refer to the Professional Information approved by the Regulatory Authority.

Novo Nordisk (Pty) Ltd. Reg. No.: 1959/000833/07. 150 Rivonia Road, 10 Marion Street Office Park, Building C1, Sandton, Johannesburg, 2196, South Africa.

Tel: (011) 202 0500. Fax: (011) 807 7989. www.novonordisk.com. 16518T. ZA21SX00008. March 2021.

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Box 1: Dietary recommendations The new Canadian guidelines specifically mention the fact that healthcare practitioners should dispense with the word ‘diet’, which has a lot of negative aspects to it and is associated with a decrease in calories only. The term ‘medical nutrition therapy’ is used in the guidelines. Healthy eating habits appropriate for their medical condition is encouraged. If they have diabetes or prediabetes for instance, this will mean a low-carbohydrate dietary intervention, the Dietary Approaches to Stop Hypertension diet for high blood pressure, the Mediterranean diet for coronary artery disease.6 » Physical activity » Psychological interventions » Pharmacotherapy » Surgery.

The authors of the guideline developed a five step approach to obesity management:6

Step 1: Ask Be aware of bias. Do not assume that all patients living with obesity are prepared to initiate obesity management. Ask patients’ permission to discuss obesity before proceeding.6

Step 2: Assess Measure BMI and waist circumference.

Remember that measuring the BMI is not the most important, said Dr Wharton, but should rather be used to measure health parameters for epidemiological purposes. Measure the waist circumference in individuals with a BMI 25kg/ m2-35kg/m2. It is not necessary to measure waist circumference in BMI <25kg/m2, and in a BMI > 35kg/m2 because it is well-known that there will be an increased waist circumference.6 If you have a patient with a BMI of 28kg/m2 and the waist circumference is elevated, that is where the risk is. He added that overweight white males (BMI 25kg/m2-35kg/m2) often have significantly elevated waist circumferences and have a risk of metabolic conditions such as coronary artery disease.6 He recommended taking a comprehensive history of the patient and identify some of the root causes why they may have gained weight in the past, what were the complications and what are some of the barriers to treatment. Other measurements to do are blood pressure, fasting plasma glucose (FPG), HbA1c and lipid profile.6 Dr Wharton said they use the Edmonton Obesity Staging System (EOSS) staging tool (see figure 1) to determine the severity of the person’s elevated weight. If there are a lot of medical conditions associated with their elevated weight, they are at a higher stage, and that determines how aggressive we will be with our treatment, he explained.6

Step 3: Advise No one loses weight unless there are less calories. Medical nutrition therapy or having an appropriate diet (see box 1 for recommendations is a cornerstone, as is physical activity (see box 2 for recommendations), said Dr Wharton.6 The important part is the ability to maintain the dietary options and physical activity is rooted in three major interventions:6 » Psychological: Weight loss is not just about willpower, it is about how to maintain behavioural aspects based on emotional eating, coping and strategies; and managing sleep, time and stress. Cognitive behavioural therapy is the most important treatment option but cannot be done easily by the individual on their own. It often requires the assistance of a healthcare provider who is trained in psychological intervention. » Pharmacotherapy: In Canada, there are three interventions approved for weight management: Liraglutide, naltrexone/ bupropion in a combination tablet), and orlistat. Please note that nalteroxone/ bupropion is not registered for use in weight management in South Africa. Criteria are: BMI ≥30kg/m2 or BMI ≥27kg/m2 with obesity (adiposity) or a related complication. » Surgery: Bariatric surgery procedure should be decided by a surgeon in discussion with the patient. options include sleeve gastrectomy, Roux-en-Y gastric bypass or biliopancreatic diversion with/without duodenal switch. Criteria are: BMI ≥40kg/m2 or BMI ≥35-40kg/m2 with an obesity (adiposity) related complication, or BMI ≥30kg/m2 with poorly controlled type 2 diabetes (T2DM).

It is very difficult to maintain dietary interventions and physical activity in the long run without these three major pillars, said Dr Wharton.

Steps 4 and 5: Agree and Assist Agree on realistic expectations, sustainable behavioural goals, and health outcomes. Agree on a personalised action plan that is practical and sustainable and addresses the drivers of weight gain. Long-term goals have more value than short-term goals, said Dr Wharton.6 Assist in identifying and addressing drivers and barriers. Provide education and resources. Refer to appropriate providers or interdisciplinary teams (if available). Arrange for regular, timely follow up.6

Considerations in the use of pharmacotherapy for obesity According to Dr Wharton if a patient meets the criteria (BMI ≥30kg/m2 or BMI ≥27kg/m2 with obesity-related comorbidities such as T2DM), pharmacotherapy can be initiated.6 Consider stopping or changing medications

Box 2: Physical activity recommendations Physical activity should include 30-60 minutes of moderate to vigorous intensity aerobic physical activity on most days of the week. There is not a significant amount of weight loss, but it leads to better health.6 Aerobic physical activity (30–60 minutes of moderate to vigorous intensity most days of the week) can be considered for adults who want to: 6 » Achieve small amounts of body weight and fat loss » Achieve reduction in abdominal visceral fat and ectopic fat, such as liver and heart fat even in the absence of weight loss » Favour weight maintenance after weight loss » Favour the maintenance of fat-free mass during weight loss » Increase cardiorespiratory fitness and mobility. associated with elevated weight if possible, comorbidities and specific features. For example, explained Dr Wharton, in diabetes, prediabetes, hypertension, obstructive sleep apnoea, and polycystic ovarian syndrome, glucagon-like peptide-1 receptor agonists are recommended as first-line therapy.6 For cravings, depression and smoking, there is evidence for the naltrexone/ bupropion combination as a first-line agent, liraglutide is the second choice and orlistat the third choice.

As mentioned above, combination naltrexone/ bupropion is not registered in South Africa for weight management. In Canada, liraglutide is considered the first choice for diabetes and prediabetes patients, naltrexone/ bupropion is the second choice and orlistat the third choice.6 Assess the patient after three months on the therapeutic dose, based on whether they have been successful in preventing any of the aspects that are concerning, such as diabetes, prediabetes, and cravings. If these things have improved, continue treatment. If there are no or limited improvements, look at adding a second medication or stopping the first medication.6

Conclusions Obesity is a growing healthcare concern and is associated with numerous complications that negatively affect the individual, healthcare utilisation and society. A paradigm shift is needed to effectively manage the condition.

It should be viewed as a chronic disease that requires changes to the physiology of the affected individual. Calorie restriction should not be the main focus of management but should incorporate a holistic approach that includes lifestyle modification, psychotherapy, pharmacotherapy and surgery.

References available on request. SF

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This article was independently sourced by Specialist Forum.

Pain in the brain

The International Association of Pain updated their definition of neuropathic pain (NP) in 2018. According to the new definition, NP is caused by a lesion or disease of the somatosensory nervous system. The old definition described it as ‘pain initiated or caused by a primary lesion, dysfunction or transitory perturbation of the peripheral or central nervous system (CNS)’.1

L

imited data are available on the prevalence of NP in South Africa.

International studies estimate that the prevalence of NP is between 7%-8% in the general population. However, if conditions such as diabetes (26%), herpes zoster/ shingles (19%), and postsurgical pain (10%) are included in estimates, the incidence is much higher. Furthermore, 35% of patients with HIV experience NP.1,2,3,7

What causes neuropathic pain?

Patients often use words such as burning, pins and needles (paresthesia), tingling, numbness, electric shocks/shooting, crawling (formication), itching, and intolerance to temperature, to describe their experiences. 3 In more advanced cases, patients may describe pain arising from stimuli that are not usually painful (eg allodynia) or pain from

normally painful stimuli that is out of proportion to what would be expected (eg hyperalgesia). 3 Numerous causes of NP have been identified and can be broadly categorised into peripheral and central pain. The most common cause of peripheral is traumatic nerve injury (either from an accident or surgery). 3,4 Other causes of peripheral NP include for example diabetic peripheral polyneuropathy, chemotherapy-induced peripheral neuropathy,

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radicular pain, and postsurgical chronic neuropathic pain.1,2,3 Causes of central NP include multiple sclerosis, poststroke pain, spinal cord injury–related pain, postherpetic neuralgia, complex regional pain syndrome, and trigeminal neuralgia.3

nts patie f o t 35% erience Abou exp HI V h t i pain c w i h t opa neur

Stepwise algorithm Bates and colleagues describe the diagnosis and treatment of NP as challenging. To aid clinicians, they developed a multidisciplinary, stepwise algorithm.4

Step 1: History and assessment Identifying so-called red flags, which may indicate conditions that require urgent interventions (eg spinal cord compression) is the priority in assessing any pain symptoms.

Secondly, the clinician should identify patients where it may be possible to treat the pain by treating the underlying cause and also to identify particular types of pain, which may require specialised treatment.4 Taking a thorough history can aid the clinician in identifying the site of pain, radiation, precipitating factors, duration, character, pattern, intensity, aggravating and relieving factors and associated symptoms.4 Apart from the symptoms mentioned above, other symptoms that may support a diagnosis of neuropathic pain include descriptions of areas of numbness or symptoms of concurrent motor or autonomic nerve involvement.4

Step 2: Quantify the consequences of pain Poorly controlled pain impacts the quality of life (QoL) of both the patient and his/her caregiver. NP may influence the patient’s ability to take part in for example social activities and exercise. It also has an effect on his/her independence, mood and sleep. Combined, these negative consequences may impact the efficacy of pain control. Quantifying the impact on the patient’s QoL can therefore aid in decision-making regarding the management and treatment of NP. 3,4 Tools that can be used in quantifying NP’s impact on the patient’s QoL include validated questionnaires. The objective of these tools is to identify the presence of NP and measure

or quantifying the impact it has on the patient’s quality of life. Bates et al recommend PainDetect, Douleur Neuropathique en 4 Questions (DN4), and the Leeds Assessment of Neuropathic Symptoms (LANSS).4 The PainDetect questionnaire is completed by the patient and has a sensitivity and specificity of 85% and 80%, respectively.

The DN4 questionnaire includes seven pain discriminators and three examination findings.

A score of 4+ indicates that NP is likely. The DN4 has a sensitivity and specificity of 83% and 90%. The LANSS questionnaire includes five symptom descriptors and two examination findings. Its sensitivity and specificity are 82%–91% and 80%–94%. Pain intensity can be measured using the numeric rating scale and/ or the visual analogue scale.4 It is also important to keep in mind that the patient’s beliefs, attitudes, and behaviours will also influence the efficacy of pain control and ultimately outcomes. During consultations ask

Bates et al emphasise the importance of multidisciplinary care. The team responsible for the management and treatment of patients with NP should include for example a psychologist, physiotherapist, exercise coach, and a masseuse. Therapy to address issues such as depression, anxiety, pain catastrophising, sleep disturbance or deconditioning, to name but a few should be initiated early in the management plan to improve outcomes.4 The above-mentioned modalities can be trailed alone without pharmacological or interventional strategies but should be limited to a duration of six to eight weeks. If adequate pain relief is not achieved within this time, first-line medications should be initiated, stress Bates et al.4 Realistic therapy goals for neuropathic pain are:5 » Pain reduction by ≥30% » Improvement of sleep quality

the patient about his/her understanding of his/ her pain, the meaning of his/her pain, his/her expectations, and goals as well as previous pain control treatment that might not have been successful.4

» Improvement of quality of life » Preservation of social activity and relationships » Maintaining the ability to work » Improved functionality.

Bates et al caution that before initiating

Step 3: Examination According to Bates et al, about 50% of patients who experience musculoskeletal pain use words that are commonly used to describe NP (eg shooting and tingling), and 30% of patients with non-NP will describe burning. As a result, it is often difficult to make a definitive diagnosis.

In such instances, a thorough examination is crucial. The main aim of an examination is to rule in, or out, the relevant neural pathways related to the patient’s history.4 They recommend an evaluation of tone, strength, reflexes, sensation, and vasomotor/ sudomotor activity using a paperclip or pin to test pinprick sensation, a cotton ball, or fingers to test light touch, a reflex hammer cooled with tap water to test response to cold, a tuning fork at 128Hz for vibration sensation and a thermometer to assess vasomotor responses.4 Sensory changes should be rated as increased, decreased or normal. A patient with NP generally demonstrates decreased sensation to some sensory modalities and report pain in response to others.4 If a neural lesion is suspected, the authors recommend an electroneuromyography and a nerve stimulation study. These can be used to improve the definition of the affected region/area.4

Step 4: Refer for specialised care or initiate treatment Should the examination fail to reveal a clear diagnosis, but NP is still suspected, the patient should be referred to a neurologist or a clinician specialising in pain management.4

Don’t let neuropathic pain rob them of living

Reduces neuropathic pain in adults.

Improves functioning.1,2

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.

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.

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. 13993J. M3377 Exp: 10/2022.

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treatment, potential side effects and possible drug-drug interactions should be considered – especially in patients with comorbidities. For instance, in patients with diabetic neuropathy, poor glycaemic control worsens symptoms and by improving glycaemic control may reduce progression of neuropathy.4 HIV-associated neuropathy presents an even more complex picture. Starting antiretrovirals may initially improve symptoms although nerve damage may progress. Some antiretrovirals can cause neuropathy, and neurotoxicity may also be a feature of concomitant medicines such as isoniazid in patients co-infected with tuberculosis.4 According to the authors of the 2020 German guideline on the management of NP, ‘gabapentin and pregabalin shall be used as preferred first choice for the management of chronic NP of any aetiology’. 5 The 2020 National Institute for Health and Care Excellence guidance recommend that

The 2018 South African guideline recommends four classes of agents for use in the treatment of NP: Gabapentinoids (pregabalin and gabapentin), tricyclic antidepressants (TCA), serotonin and noradrenaline reuptake inhibitors (SNRI) and opioids.7 For the treatment of peripheral NP, firstline therapy consists of oral monotherapy using a pregabalin or gabapentin, a low-dose TCA (amitriptyline) or a SNRI (duloxetine or venlafaxine). Pregabalin is usually the agent of choice. Central NP is often difficult to treat but responds to similar treatment. 7 Bates et al recommend a three- to eightweek trial. The efficacy of the prescribed treatment should be reviewed midway and at the end of the trial.4 If the patient does not receive significant relief or has adverse effects from medication, then dosing should be adjusted, an alternative medication or combination therapy should be tried, or the patient should be considered for a

all NP (except trigeminal neuralgia) should be treated with either amitriptyline, duloxetine, gabapentin or pregabalin as initial treatment. Carbamazepine is recommended as initial treatment for trigeminal neuralgia.6

trial of neurostimulation.4

How effective are gabapentanoids?

Gabapentin and pregabalin are anticonvulsant medications that act by blocking presynaptic alpha-2-delta calcium channels in the dorsal horn, inhibiting neurotransmitter release.4,5 Gabapentin and pregabalin both have been shown to be effective in post-herpetic neuralgia and diabetic peripheral neuropathy. Pregabalin also has been shown to be superior to placebo in the treatment of spinal cord injury.4 A Cochrane review of gabapentin for chronic neuropathic pain in adults confirmed that gabapentin is associated with greater rates of pain relief compared with placebo in post-herpetic neuralgia and diabetic peripheral neuropathy.4,5 Finnerup et al also assessed the efficacy of pregabalin. The combined number-neededto-treat of 25 randomised controlled trials was 7.7, and the number-needed-to-harm was 13.9. Unlike gabapentin, they also reported a dose response, with a greater response being seen in those taking 600mg daily than in those taking 300mg. Pregabalin has also been shown to decrease health care and non–health care costs compared with gabapentin in the treatment of peripheral NP.4,5 Bates et al recommend that gabapentanoids should be trialled for a four- to six-week period with two weeks at the maximum tolerated dose.

Poorly tolerated side effects or inadequate pain relief should prompt dosage adjustment, cessation of the medication, progression to other firstline agents, or a trial of combination therapy. The most common adverse effects include somnolence, fatigue, dizziness, and lower extremity oedema.4

Conclusion NP negatively impacts patient’s and caregivers’

QoL. It is a debilitating condition, difficult to diagnose, and can only partially responsive to treatment. A multidisciplinary, structured stepwise approach is needed to decrease pain and attain an acceptable QoL for patients.

First-line pharmacotherapy includes gabapentin and pregabalin.

l entra c f o es n Caus ic pai h t a op troke s neur t s o p de eg onal i u l g c e r n i x mple o c , e, and m pain o r synd ralgia u e pain n l mina trige

References 1. Murnion BP. Neuropathic pain: current definition and review of drug treatment. Aust Prescr, 2018.

2. Machado-Duque ME, Gaviria-Mendoza A, Machado-Alba JE and Castano N. Evaluation of Treatment Patterns and Direct Costs Associated with the Management of Neuropathic Pain. Pain Research and Management, 2020.

3. Finnerup NB, Kuner R ad Jensen TS. Neuropathic Pain: From Mechanisms to Treatment. Physiological Reviews, 2020.

4. Bates D, Schulteis BC, Hanes MC et al. A Comprehensive Algorithm for Management of Neuropathic Pain. Pain Medicine, 2019.

5. Schlereth T et al. Guideline diagnosis and noninterventional therapy of neuropathic pain of the German Society of Neurology (deutsche Gesellschaft für Neurologie). Neurological Research and Practice, 2020.

6. NICE. Neuropathic pain – pharmacological management The pharmacological management of neuropathic pain in adults in non-specialist settings. https://www.nice.org.uk/guidance/cg173/ evidence/full-guideline-pdf-4840898221 7. Patel S. Guidelines for the treatment of neuropathic pain in South Africa. SAMJ, 2018. SF

To com plete this mo nth’s C PD questio nnaire, please go t o www.m edicalac ademic.c o.za and na v igate t o t he C PD sec tion of the we bsite.

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True 24-hour BP control

This article was independently sourced by Specialist Forum.

An increase in blood pressure (BP) – defined as systemic hypertension – is considered a clinical disorder when this change threatens biologic functions. Hypertension has been shown to affect the circulatory, pulmonary and urinary systems amongst others.1

C

ardiovascular disease (CVD) is the leading cause of death worldwide.

Hypertension is a major risk factor for CVD and is present in 69% of patients with a first myocardial infarction, in 77% of patients with a first stroke, in 74% of patients with chronic heart failure, and in 60% of patients with peripheral arterial disease.1,2 The International Society of Hypertension (ISH) defines hypertension as: Systolic blood pressure (SBP) in the office or clinic of ≥140mmHg and/or diastolic blood pressure (DBP) of ≥90mmHg following repeated examination. 3 The 2020 ISH Practice Guidelines, recommends lifestyle modifications as the first step in the treatment of hypertension. However, the majority of patients with hypertension will eventually require pharmacotherapy. Studies show that mortality risk doubles with increases in SBP from 120mmHg to 140mmHg and from 140mmHg to 160mmHg in all age groups.1,3 The guideline recommends the use of angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs), as well and dihydropyridine calcium channel blockers as initial pharmacotherapy. 3

Milestone in the history of hypertension treatment Dézsi describes the development of ARBs in the 1990s as a ‘milestone in the history of hypertension treatment’, adding to the range of possibilities for personalised therapy, especially for patients who cannot tolerate ACE-Is.4 ARBs have shown excellent efficacy, they have no negative metabolic effects and they cause no accumulation of bradykinin. They also

have an ability to activate the angiotensin II type 2 receptors, which causes vasodilatation in the small vessels and may leads to additional cardiac and renal protection.4 Additive BP lowering effects have been demonstrated when ARBs are combined with thiazide diuretics or dihydropyridine calcium channel blockers, augmenting hypertension control. Furthermore, ARBs have proven mortality and morbidity effects in heart failure and chronic renal disease, particularly when associated with type 2 diabetes (T2DM). 5 Apart from heart failure and renal disease, compelling indications for the use of ARBs include post-myocardial infarction, diabetic nephropathy, proteinuria/microalbuminuria, left ventricular hypertrophy, atrial fibrillation, metabolic syndrome and obesity, renal dysfunction, chronic stable angina, and ACE-I induced cough.4,6

BP variability Numerous studies have demonstrated that 24hour ambulatory BP monitoring (ABPM) should be an integral part of hypertension care. ABPM plays a crucial role in quantifying the degree of BP variability over 24 hours. BP variability over this period has been shown to be a significant and independent risk factor for CV morbidity and mortality.1,7 The most commonly utilised data for clinical purposes is 24-hour average BP, daytime BP, night-time BP, and nocturnal dipping patterns. The thresholds for normality depend on the measurement used and on the current definition of normal BP.1 In most people, BP rises rapidly after waking up in the morning and at the start of

daily activity. BP has two main peaks – in the morning and afternoon. Generally, a 24-hour mean BP of 125/75mmHg or less, a daytime BP of 130/80mmHg or less, or a night-time BP of 110/65mmHg or less with a nocturnal dipping of 10% to 20%, are considered normal values for ABPM.1,8 Monitoring of morning BP rise is an important aspect in the treatment of hypertension, and prevention of CV complications. morning BP rise is associated with an increased risk (by 40%) of CV and cerebrovascular problems, and sudden death. 8 Studies indicate adverse effects of morning hypertension such as subclinical target organ damage, namely left ventricular myocardial mass increase, left atrial dilatation, and thickening of the intima-media carotid artery complex.8 Uncontrolled morning BP is a sign of inadequate antihypertensive therapy, insufficient dosage of drugs, or use of shortacting drugs, and is detected in the majority of patients (from 17% to 60%) treated for hypertension, according to various studies. 8 There are currently eight ARBs on the market.

Telmisartan has the longest half-life (24-hours), followed by olmesartan (12-14 hours), irbesartan (11–15 hours), eprosartan (5-9 hours), valsartan (6 hours) and losartan (2 hours).5 Three of the eight ARBs (candesartan cilexetil, olmesartan medoxomil, azilsartan medoxomil) are prodrugs and require activation in the gastrointestinal tract and liver to their active forms (candesartan, olmesartan, and azilsartan, respectively). The ARBs eprosartan, irbesartan, telmisartan, and valsartan are not prodrugs and therefore do not require metabolic activation. 5

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The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60% to 80% (the highest among the ARBs with telmisartan in second place with 43%). Irbesartan has a faster onset of action (1.3–3 hours) compared to candesartan (2-5 hours), and valsartan (2-4 hours).5

ARB efficacy and safety Irbesartan has demonstrated a high efficacy in lowering BP – comparable with ACE-I and superior to other ARBs. Irbesartan 300mg/day has been found to have superior antihypertensive effects compared to losartan 100mg/day, while irbesartan 150mg/day demonstrated greater BP reductions than valsartan 80mg/day.5,9,10 The tolerability profiles of ARBs are similar to placebo and superior to ACE-Is. ACE-Is have been shown to increase the risk of cough twoto three-fold over placebo and may cause up to 0.1%-0.2% rates of angioedema, which can be life threatening in some cases. 5 Cough and angioedema most likely result from the accumulation of bradykinin and substance P, which are both degraded by ACE, and they recur with the reintroduction of ACE-Is inhibitor or use of another ACE-I. 5 A number of studies evaluating the comparative efficacy and safety ARBs, reported low discontinuation rates in irbesartan. One study reported a 1.2% discontinuation rate in the irbesartan group due to adverse events including fatigue, malaise and cough, while others reported a 1.4%, 2.1% and 0.5% rate, which is comparable to placebo (3.4%), and the lower dose of irbesartan (150mg) (2.1%). 9,10,11

t nce to e r tmen e a h e d r a t n ive No rtens e p y f antih 80% o – % 0 1 s and t s t n c e i e t a aff sive p n e ers of t v r i e r p d hy ey 3 the k f o rol t e n n o o c is al BP m i t p subo

and T2DM. In the Irbesartan Diabetic Nephropathy Trial involving hypertensive patients with diabetic nephropathy, the irbesartan arm had a 37% lower risk of doubling the serum creatinine versus the amlodipine arm and 33% lower than the placebo group.

Development of end stage renal disease was nominally lower with irbesartan use compared with amlodipine use and placebo.8 The Irbesartan in Patients with T2D and Microalbuminuria trial showed that over a period of 12 months, patients with hypertension, T2DM and microalbuminuria, fewer participants progressed to macroalbuminuria when treated with irbesartan compared to placebo with hazard ratios of 0.30 in the irbesartan 300mg/ day and 0.61 in the irbesartan 150mg/day.12 In the case of chronic kidney disease, renal excretion of serum uric acid (SUA) is decreased, resulting in hyperuricemia. Several observations indicate that hyperuricemia is an independent risk factor for CVD. About 25% of patients with hypertension have raised SUA levels, which increase if loop or thiazide diuretics are added to therapy.7 Irbesartan reduced BP significantly after one, six and 12 months’ treatment. No participants showed significant change in estimated glomerular filtration rate from baseline level throughout the period. The multiple logistic regression analysis revealed that SUA baseline significantly influenced SUA decline after six to 12 months. In patients whose SUA baseline was ≥5.9mg/dL, the SUA was significantly decreased from 6.6±0.16 mg/dL to 6.2±0.16mg/dL, after 12 months’ irbesartan treatment. In the SUA baseline <5.9mg/dL group, the SUA did not show significant change over the monitoring period.7 It has also been shown to be more costeffective than standard therapy including betablockers, diuretics and non-dihydropyridine calcium channel blockers at all stages of kidney disease. Based on efficacy data from the Irbesartan Diabetic Nephropathy Trial and Reduction of Endpoints in noninsulin dependant DM) with the Angiotensin II Antagonist Losartan Study, it has also demonstrated cost savings over losartan in late stage renal disease.6

Conclusion Irbesartan in diabetes and kidney disease The prevalence of chronic kidney disease (CKD) is estimated to be around 22%. Patients with uncontrolled BP, overweight/obesity, dyslipidaemia, and diabetes have the highest risk (43.3%, 33.7%, 27.3% and 28.2% respectively).

Age was an independent risk factor.13 Irbesartan is indicated for the treatment of renal disease in adult patients with hypertension

ACE-1 and ARBs are recommended by guidelines as first-line pharmacotherapy for the treatment of hypertension. Apart from superior BP lowering and few side-effects, irbesartan also offers renal protection to hypertensive patients at risk of renal disease.

References 1. Pena-Hernandex C, Nugent K and Tuncel M. Twenty-

2. Aronow WS. Treatment of systemic hypertension.

Am J Cardiovasc Dis, 2012.

3. Unger T, Borghi C, Charchar F et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension, 2020.

4. Dezsi CA. The Different Therapeutic Choices with ARBs. Which One to Give? When? Why? Am J Cardiovasc Drugs, 2016.

s ount c c a on tensi r e p Hy n 9.3 a h r, t ore r yea e m p r o s f death n o i l l acco b mi o t g assin illion m 8 surp ound 1 r a h t r wi r yea e p s death

5. Abraham HMA, White CM and White WB. the Angiotensin Receptor Blockers in the Management of Hypertension and Other Cardiovascular Diseases.

Drug Saf, 2015.

6. Bramlage P, Durand-Zaleski, Desai N et al. The value of irbesartan in the management of hypertension.

Expert Opin Pharmacother, 2009.

7. Parati G and Schumacher H. Blood pressure variability over 24 h: prognostic implications and treatment perspectives. An assessment using the smoothness index with telmisartan–amlodipine monotherapy and combination. Hypertension Research, 2014.

8. Rasputina L and Didenko D. Clinical and functional predictors that cause a decrease of indicators of morning blood pressure profile in antihypertensive telmisartan-based therapy. Biomedical Research and Therapy, 2020.

9. Kassler-Taub K, Littlejohn T, Elliott W et al.

Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-tomoderate hypertension. Irbesartan/Losartan Study Investigators. Am J Hypertens, 1998.

10. Mancia G, Korlipara K, van Rossum P et al. A107: Irbesartan results in superior blood pressure reduction vs valsartan. American Journal of Hypertension, 2000.

11. Oparil S, Williams D, Chrysant SG et al.

Comparative efficacy of olmesartan, losartan, valsartan, and irbesartan in the control of essential hypertension. J Clin Hypertens (Greenwich), 2001.

12. Parving HH et al. Irbesartan in Patients with T2D and Microalbuminuria. N Eng J Med, 2001.

13. Bahrey D, Gebremedhn G, Mariye T et al. Prevalence and associated factors of chronic kidney disease among adult hypertensive patients in Tigray

Four-Hour Ambulatory Blood Pressure Monitoring. J

teaching hospitals: a cross-sectional study. BMC

Prim Care Community Health, 2020.

Research Notes, 2019. SF

135/87

122/78

Numbers that Matter 117/74

125/82 128/86

142/97

9/10 SA hypertension patients have inadequately controlled hypertension 1

Renoprotective effects of irbesartan go beyond its effect on BP 2

References: 1. Berry KM, Parker W, Mchiza ZJ, et al. Quantifying unmet need for hypertension care in South Africa through a care cascade: evidence from the SANHANES, 20112012. BMJ Glob Health 2017;2:e000348. 2. Ravera M, et al. Prevention and treatment of diabetic nephropathy: the program for irbesartan mortality and morbidity evaluation. J Am Soc Nephrol 2005;16:S48–S52.

S3 IRBEWIN® 150; 300 (tablets) respectively. Each tablet contains 150 mg; 300 mg of irbesartan respectively. Reg. No’s.: IRBEWIN® 150; 300: A40/7.1.3/0288; 0289 respectively.

For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority.

Zentiva South Africa (Pty) Ltd, a sanofi company. Reg. no.: 1931/002901/07. Sanofi House, 2 Bond Street, Grand Central Ext. 1, Midrand, 1685. Tel: (011) 256 3700. Fax: (011) 256 3707. www.zentiva.com. MAT-ZA-2000439 - 1.0 - 08/2020

log on to www.sanofihealthconnect.co.za to join the Sanofi Hypertension Academy http://surl.sanofi.com/hypertension

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This article was independently sourced by Specialist Forum.

www.medicalacademic.co.za

Management in clinical practice of MULTIPLE MULTIPLE face and scalp AK

Actinic keratoses (AKs) are one of the top three most common skin disorders seen in clinical practice. AKs, also known as solar keratoses, are caused by long-term sun exposure, and about 75% of all reported lesions present on the head, neck, and forearms.1,2,3,5

P

revalence rates range from 24%60%. Population‐based data from the Rotterdam Study and the Australian Skin Cancer Cohort estimate that 24% (the Netherlands) to 60% (Australia) of people older than 50 years have at least one AK.1,3,5,7 Prevalence rises with age and peeks between the ages of 70 and 80. Apart from excessive exposure to ultraviolet radiation (UV) and age, other risk factors include phototypes I and II (see box 1), previous history of cutaneous neoplasms and male gender.1,3,5,7 The prevalence of AKs is increasing worldwide, partly due to environmental factors, such as thinning of the ozone layer and more UV radiation. Other factors include lifestyle choices such as increased tanning (outside and sunbed). 2 Despite the high prevalence of AKs, there seems to be a lack of awareness among the general public and primary care physicians about the potential consequences of the condition. AKs are often a pre-cursor to squamous cell carcinoma (SCC) and basal cell carcinoma (BCC).1,7 Patients do not necessarily seek care for asymptomatic AKs and often only seek medical care when they have more than one lesion.

Primary care physicians are often not aware of

the different treatment modalities for AKs due to a lack of dermatological training.7 In resource limited countries with only a few trained dermatologists, primary care physicians then become the gatekeepers to specialist care. Several international bodies, including the United States Preventative Services Task Force, stress that appropriate awareness campaigns about AKs and its treatment should be undertaken among the general public as well as primary care physicians, and primary care AKs guidelines are essential.7 The Netherlands (2015) took the lead in publishing AKs guidelines directed at primary care physicians, followed by the British Primary Care Dermatology Society (2020).7,9

What do AKs look like?

AKs present as macules, papules, or plaques with superficial scales on a red base, which are classified based on histological features.

They may also be pigmented and show variable degrees of infiltration.

A single AK lesion may have one of three possible outcomes:8

It can enter spontaneous remission

1

2

Remain stable without further progression

Transform over time into in situ or invasive carcinoma.

When lesions multiply, they lead to field cancerisation, a process in which a singular cell accumulates genetic mutations following carcinogen exposure and then divides to create a field of monoclonal premalignant cells.1,2,5,6 The field starts from a single stem cell. The stem cell then undergoes one or more genetic changes, which allows it to grow. The stem cell then divides, forming a patch of clonal daughter cells, which displace the surrounding normal epithelium.6 This growth eventually leads to a dysplastic field of monoclonal cells. No invasive growth or metastases are visible yet but over time, continued carcinogenic exposure (eg ultraviolet radiation [UV]) causes additional genetic alterations among different cells in the field.

If left untreated, this leads to new subclonal proliferations, eventually forming a carcinoma.

Patients with more than five AKs are at high risk of SCC. The likelihood of AKs progressing to SCC ranges between 0.025% and 16% per year, and it is an accumulative risk over years, eg 0.6% at year one, and 2.6% at year four. 4,5,8

3

How are AK diagnosed?

Although the diagnosis of AKs is based on

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clinical examination, in some cases a skin biopsy or histopathological examination are necessary. Major criteria for biopsies: 5 » Large lesions (>1cm in diameter) » Bleeding » Ulceration or induration » Rapid lesional growth and erythema.

Minor criteria are: » Intense lesional pruritus » Pain » Pigmentation » Hyperkeratosis » Palpable lesion.

In the absence of response to usual treatments and presence of some unusual characteristics may also be associated with the progression of AKs to SCC and indicate the need for histopathological examination. 5 AKs are graded as follows based on their thickness:10 » Grade 1 (mild): Pink or grey marks with slight scale or gritty to touch

Based on histopathological examination, AKs can further be categorised into seven subtypes:5 1. Hypertrophic 2. Atrophic 3. Bowenoid 4. Acantholytic 5. Epidermolytic 6. Lichenoid 7. Pigmented.

The 2020 British Primary Care Dermatology Society guideline recommends the following:9

» Grade 2 (moderate): Thicker hyperkeratosis and easily detected » Grade 3 (severe): Hypertrophic, thick keratin » Field change: Confluent areas of several centimetres or more with a range of features matching any or all of the grades of AK.

appearance and seldom exceed more than 1cm in diameter. Surface scales are rough, usually white, although in patients with skin type I AKs are often easier felt than seen. Lesions are flat, but some lesions can have significant amounts of scale (eg hypertrophic or Bowenoid AK).

Figure 1: Grading of AK

Source: Goldenburg11

Clinical examination There is often a background of significant sun-damaged skin with pigment irregularity, telangiectasia, erythema and collagenosis (a yellow papularity of the skin). The following factors should be taken into consideration: Distribution: Reflects the intensity of sunexposure with the greatest number of lesions occurring on the head, neck, forearms and hands.

Morphology: Lesions usually take on a similar

Dermoscopic features » A red pseudonetwork » Strawberry-like appearance » Structures may not be visible if there is a lot of scale.

When should a patient be referred to a dermatologist?

The British Association of Dermatologists recommends referral for specialist care when:10 Í AKs fail to respond to standard treatments Í Multiple or relapsing AKs represent a management challenge Í AKs occur in long‐term immunosuppressed patients Í Lesions are likely to be AKs, but there is concern that they might be SCC (use the two‐week‐wait route for possible skin cancer), for example when they are: » Bleeding » Painful » Thickened with substance when held between finger and thumb.

How are AK treated?

Treatment of AKs depends on the clinical presentation of the lesions: It may be targeted at specific lesions (lesion directed)

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or at multiple lesions over a large area (field directed). Sometimes both treatment approaches are combined. 2,10 A number of treatment options are available for AKs, although no universal standard has yet been established. Therapy options include cryosurgery, curettage, excision surgery, photodynamic therapy (PDT), and topical treatments (5-fluorouracil [5-FU] cream, diclofenac gel, imiquimod [IMQ] cream and ingenol mebutate [IM] gel). 2 A recent study found that cryotherapy is the most used AK treatment by both primary care physicians (78%) and dermatologists (41%– 56%). Topical agents were the second most used treatment by dermatologists (13%–21%) but were rarely applied in primary care (2%).

As mentioned, the low utilisation of topical agents is due to a lack of awareness of different treatment modalities.7 When choosing a therapy, treatment should be individualised and consider lesion‐, patient‐

Compared to 5-FU, the hazard ratio for treatment failure was 2.03 with IMQ, 2.73 with MAL-PDT, and 3.33 with IM. No unexpected toxic effects were documented. 3 The authors concluded that at 12 months after the end of treatment in patients with multiple actinic keratosis lesions on the head, 5-FU was the most effective of four fielddirected treatments. 3

and treatment‐related factors. Some topical therapies have long treatment durations (up to 16 weeks). This, in addition to photosensitivity, can reduce the ability of patients to tolerate commonly occurring local skin reactions, such as erythema, ulcerations and crusting.11 This can negatively impact quality of life, lead to poor adherence and ultimately result in suboptimal effectiveness of some treatments. In contrast, treatment adherence and quality of life are both improved with short‐duration topical field treatments that have short resolution times for local skin responses. Thus, when adherence to treatment is an issue for patients, short‐duration topical field treatments are a good option. Treatment regimens that are simple may also increase patient adherence.11

The authors concluded that 5-FU cream should be considered as the first-choice treatment option for multiple AKs in the head and neck region. The authors concluded that 5-FU cream should be considered as the first-choice treatment option for multiple AKs in the head and neck area.4

What is the best treatment option for AK? Efficacy and safety Jansen et al (2019) investigated the effectiveness of four frequently used fielddirected treatments (for multiple lesions in a continuous area). Patients (624) were randomly assigned to treatment with 5-FU, IMQ, methyl aminolevulinate PDT (MAL-PDT), or 0.015% IM gel. 3 The primary outcome was the proportion of patients with a reduction of 75% or more in the number of AK lesions from baseline to 12 months after the end of treatment. Both a modified intention-to-treat analysis and a perprotocol analysis were performed. 3 At 12 months after the end of treatment, the cumulative probability of remaining free from treatment failure was significantly higher among patients who received 5-FU (74.7%) than among those who received IMQ (53.9%), MAL-PDT (37.7%), or IM (28.9%). 3

Cost-effectiveness Jansen et al (2020) conducted the first analysis examining the cost-effectiveness of topical 5-FU, IMQ , IM and MAL-PDT for AK in the head and neck region. The outcome measure was expressed as the incremental costeffectiveness ratio, which is the incremental costs per additional patient with ≥75% lesion reduction compared with baseline.4 The trial showed that 5‐FU was a more effective and less expensive field treatment option when compared with other treatments.

Conclusion Due to various factors like environmental changes and lifestyle choices, the prevalence of AK is predicted to increase over the next few years. Public awareness about the serious consequences of AK (eg progression to SCC and BCC) seem to be lacking and needs addressing. Primary healthcare physicians are often the first port of call for patients but seem to lack awareness about the different treatment options available. The development of primary care AK guidelines and physicians education are required. Various treatment options are available for AK. Studies have shown that compared to other modalities, 5-FU cream is more efficacious, safe, and cost-effective.

References

head and neck area performed in the Netherlands.

Br J Dermatol, 2020.

5. Prieto C, Reinehr H, Marchiori R and Bakos M. Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects. Anais Brasileiros de Dermatologia, 2020.

6. Lanoue J, Chen C and Goldenberg G. Actinic Keratosis as a Marker of Field Cancerization in Excision Specimens of Cutaneous Malignancies.

Cutis, 2016.

7. Noels EC, Hollenstein LM, van Egmond S et al. Healthcare utilization and management of actinic keratosis in primary and secondary care: a complementary database analysis. Br J Dermatol, 2019.

8. Guorgis G, Anderson CD, Lyth J and Falk M. Actinic Keratosis Diagnosis and Increased Risk of Developing Skin Cancer: A 10-year Cohort Study of 17,651 Patients in Sweden. ActaDV, 2020.

9. PCDS. Actinic keratosis (syn. solar keratosis).

Primary Care Dermatology Society (2020). https:// www.guidelines.co.uk/skin-and-wound-care/pcdsactinic-keratosis-guideline/250776.article.

10. De Berker D, McGregor JM, Mustapa MFM et al.

British Association of Dermatologists’ guidelines for the care of patients with actinic keratosis 2017. Br J Dermatol, 2017.

11. Goldenberg G. Treatment considerations in actinic keratosis. Journal of the European Academy of Dermatology and Venereology, 2017.

12. Oakley A. Fitzpatrick skin phototype. DermnetNZ. https://dermnetnz.org/topics/skin-phototype/. SF

1. Savarya J, Tineb MC, Weberc A and Dorey J. Management and clinical practice of multiple face and scalp actinic keratosis in France. Journal of Market Access & Health Policy, 2019.

2. Chetty Praven, Choi F and Mitchell T. Primary Care Review of Actinic Keratosis and Its Therapeutic Options: A Global Perspective. Dermatol Ther, 2015.

3. Jansen MHE, Kessels J, Nelemans PJ et al.

Randomized Trial of Four Treatment Approaches for Actinic Keratosis. N Engl J Med, 2019.

4. Jansen MHE, Kessels J, Merks I et al. A trial-based cost-effectiveness analysis of topical 5-fluorouracil vs. imiquimod vs. ingenol mebutate vs. methyl aminolaevulinate conventional photodynamic therapy for the treatment of actinic keratosis in the

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Egg timer testing

Ovaries undergo much more serious effects of ageing than any other tissue of the female body. When a woman is younger than 30, she has an 85% chance to conceive within one year. At the age of 30, there is a 75% chance to conceive within the first year. This chance declines to 66% at the age of 35 and 44% at the age of 40.1,2

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elayed motherhood – voluntary or involuntary – is a common patient factor in reproductive medicine.

According to the American Centres for Disease Control and Prevention, about 33% of women >35 years will need help to conceive, with many turning to assisted reproductive technology (ART) such as in vitro fertilisation (IVF) for help. By 2018, an estimated eight million babies were born as a result of IVF and other advanced fertility treatments 5,13,16,19

.

Although most women are mindful of their socalled ‘ticking biological or reproductive clock’, they (and men) significantly overestimate female fertility potential >35 years. In addition, they are not always aware that age-related egg decline has a similar effect on the success of IVF-assisted conception as on natural conception. 2,4,5,18 As shown above, the probability of achieving a pregnancy within one year is significantly higher in women <30 years than those in women <35 years. IVF treatment cannot

reverse age-related infertility. 5 Studies show that the chance of a live birth from one complete IVF cycle (which includes all fresh and frozen-thawed embryo transfers following one ovarian stimulation) is about:15 » 43% for women aged 30 to 34 » 31% for women aged 35 to 39 » 11% for women aged 40 to 44.

Surveys suggest that 75% of women of reproductive age are interested in knowing their fertility status, with 80% of participants

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in one survey stating that they would bring forward their plans for children if faced with an adverse fertility screening result.

They also indicated that if they had a better understanding of their declining reproductive status, they would reconsider their decisions to delay motherhood.4,19 The American College of Obstetricians and Gynecologists (ACOG) recommends that women should be made aware that their window to conceive may be shorter than anticipated, thus providing them with the opportunity to attempt to conceive sooner rather than later.6 The Royal College of Obstetricians and Gynaecologists (United Kingdom) adds that women also have the right to be made aware that pregnancy at an advanced age is associated with risks. 5 These include obstetric haemorrhage, preeclampsia, pregnancy induced hypertension, gestational diabetes, higher rate

The rest of the follicles are lost due to apoptosis, a form of programmed cell death, or ‘cellular suicide’. This process continues for about seven months during periods when there is no ovulation, such as pregnancy, breastfeeding or use of oral contraceptives. 5 Between the ages of 35-45, the decline of female fertility is associated with the reduced likelihood of conception and the increased probability that a pregnancy will terminate (eg the loss of embryo, pregnancy, foetal, and spontaneous abortion) sooner or later after conception or implantation. 5 When a female reaches the age of 45, the follicle pool usually decreases below a critical value of about 1000 or less. Follicles and irregular cyclic changes are often the first clinical signs of ovarian ageing and the start of menopause.2,5,8

of caesarean section deliveries, unfavourable perinatal outcomes for the neonate – preterm delivery, low birth weight and admission to neonatal intensive care unit. Pre-existing comorbidities are also more common in women with more advanced age, thus further complicating pregnancy. 5 The American Society for Reproductive Medicine encourages all healthcare providers to speak to their patients about their reproductive plans at all stages of their reproductive life.

Opening this dialogue and educating patients facilitates their decision making.9

releasing hormone (GnRH) pulse generator in the hypothalamus. This dysregulation is due to a progressive lack of neuroendocrine control from other brain parts, resulting in changes in the regular GnRH pulse pattern. 5 The first sign of this change is the early elevation of follicle stimulating hormone (FSH), which leads to acceleration of follicle depletion.

Elevated FSH is associated with shorter follicular phase and cycle lengths in ageing women (late 30s to mid- 40s). 5,17 There are two major theories that might explain the origin of reproductive or ovarian ageing:5 It is driven by the ovary itself: The rise of FSH is only secondary to loss of ovarian follicles and reduction of inhibin level Dysregulation of hypothalamic GnRH production, leading to a rise in FSH levels and an increased loss of follicles. 5 Numerous gynaecologic disorders/diseases and treatments, environmental and genetic factors have been postulated as contributing to ovarian ageing and OR. 5 These factors include:5 » Ovarian toxicants » Cigarette smoking » Alcohol abuse or chronic alcoholism » Nutritional deficiencies » Oxidative stress » Some metabolic disorders » Autoimmunity » Long term stress-depression » Iatrogenic treatments (pelvic surgeries, chemo- and radiotherapy) » Ovary inflammation » Pelvic infection or tubal disease » Severe endometriosis » Meiotic division errors » Chromosomal abnormalities » Gene and mitochondrial DNA mutations in oocytes

Why do women’s infertility decline with age?

Unlike sperm generation in the male, the follicular pool in women is unidirectional and the rate of decrease accelerates as a woman grows older. During the ageing process, both the quantity and quality of the oocytes in the ovaries decrease. 5,6 The main function of the ovary is to produce a mature and viable oocyte, capable of fertilisation that subsequently leads to embryo development and implantation.13 At birth, each ovary has a fixed number of oocytes available for folliculogenesis (the growth and development of ovarian follicles from primordial to preovulatory stages) during later life. The quality and quantity of primordial follicles make up the ovarian reserve (OR) of a woman. The more follicles present (known as the antral follicle count [AFC]), the greater a woman’s OR.10,13,15 Healthy females generally have around 400 000-500 000 primordial follicles at the start of puberty. Each of these contain an immature ovum. Between 300-400 follicles reach maturity during a woman’s reproductive life span. 5,6

Reproductive ageing Reproductive or ovarian ageing is associated with a dysregulation of the gonadotrophin

» Family history of early menopause in connection with the ovary ageing » Depletion of ovarian follicles and reduced ability to produce oocytes competent for fertilisation and further development as well as infertility.

Egg timer test The decline rate of OR varies among women, making it a challenge to estimate an individual’s remaining reproductive function.

Therefore, it is recommended that a woman’s reproductive potential is tested prior to providing family planning advice to those who opt to delay motherhood.1 According to the ACOG, when should OR testing be conducted in woman? The ACOG recommends OR testing in women >35 years who have not conceived after six months of attempting pregnancy and women at high risk of diminished OR (see risk factors above). 5,6 Apart from age, OR is based on baseline FSH level, baseline AFC, and baseline serum anti-Mullerian hormone (AMH) level (see table 1 for age appropriate AMH serum levels).1

1

2

What is AMH and what is its value?

AMH is a dimeric glycoprotein expressed by granulosa cells of pre-antral and early antral follicles during the female reproductive life span. Then, it is released into the follicular fluid and blood vessels. In clinical practice its levels are measured in peripheral blood.11,13,14,18 AMH plays a significant role in the development of reproductive organs in both sexes during the embryonic period. In an adult woman its role probably comprises the regulation of folliculogenesis, predominantly in the mechanism of inhibiting primordial follicle recruitment, and decreasing the sensitivity of small antral follicles to FSH activity.18 AMH expression is highest in secondary, preantral, and small antral follicles up until about 4mm in size. It stops being expressed by granulosa cells when the follicle measures in the 4mm-8mm range.11,13,14 Serum AMH levels are low before puberty, but after puberty, it reaches a maximum level and then its concentration progressively declines as a sign of exhaustion of total follicular reserve throughout reproductive life, reaching undetectable values by menopause.11

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What are the best markers of OR? Serum AMH concentrations and ultrasounddetermined AFC are the best tests of OR as they have been reported to be excellent markers of quantitative OR when analysed against both histologically assessed primordial follicle number, or quantitative response to gonadotrophin stimulation in IVF treatment.10 AMH testing – often referred to as the egg timer test or the golden marker – is the preferred biomarker for OR and is used to predict the OR state and the growing follicle pool.10 Studies dating back 20 years, showed that serum AMH levels strongly correlate with the number of growing follicles and that both decline with increasing age. Based on these initial studies, serum AMH proposed as an indirect marker for OR.12 According to Tal and Seifer, AMH testing is the most sensitive. It correlates strongly with the primordial follicle pool, has an inverse correlation with chronologic age and reliably predicts ovarian response in ART.18 In a systematic review of studies in women undergoing controlled ovarian stimulation with gonadotropins, low AMH cut-off points (0.1ng/ mL-1.66 ng/mL) have been found to have sensitivities ranging between 44%-97% and specificities ranging between 41%-100% for prediction of poor ovarian response.18 In a meta-analysis that included 28 studies, AMH was found to have good predictive ability for poor ovarian response, with an area under the curve of 0.78.42 Moreover, AMH has remarkable utility in predicting ovarian hyperstimulation to gonadotropin stimulation, with sensitivities ranging from 53%-90.5% and specificities ranging from 70%-94.9% when using cut-off values of 3.36ng/mL-5.0 ng/mL.18 However, despite its strong correlation with ovarian response to stimulation in ART, AMH is a poor predictor of nonpregnancy with sensitivities between 19%-66%, and specificities between 55%-89% when using cut-offs ranging between 1.0ng/mL-3.22ng/mL.18 Moreover, AMH values were not associated with fecundability in unassisted conceptions in a cohort of fecund women with a history of one or two losses. These data are consistent with AMH being a predictive marker of oocyte quantity but not quality.18 While some argue that egg quality trumps quantity, Moolhuijsen and Visser argue that qualitative and quantitative OR are inter-related since unilateral oophorectomy has been reported to result in an immediate increase in the rate of oocyte aneuploidy.12 Similarly, several studies have reported an increased chance of conceiving a genetically abnormal pregnancy or having a miscarriage for women with diminished OR. Furthermore, one prospective study has reported a significant reduction in the chances of

immediate conception (in the next six months) in those women with diminished OR (AMH ≤ 0.7ng/mL), even after controlling for the confounder of maternal age.12 Moolhuisjen and Visser propose the following protocol for OR screening:12

reserve screening. Australian Journal of Primary Health, 2020.

5. Polulniewicz M, Issat T and Jakimiuk A. In vitro fertilization and age. When old is too old? Menopause Review, 2015.

6. American College of Obstetrics and Gynecology.

Ovarian Reserve Testing. Obstetrics & Gynecology, 2015.

7. Tremellen K and Savulescu J. Ovarian reserve screening: a scientific and ethical analysis. Human Reproduction, 2014.

8. Ulrich ND and Marsh ME. Ovarian reserve testing: A review of the options, their applications, and their limitations. Clin Obstet Gynecol, 2019.

9. ASRM. Testing and interpreting measures of ovarian reserve: a committee opinion Practice Committee of the American Society for Reproductive Medicine. ASRM Pages, 2020.

10. Iwase A, Nakamura T, Osuka S et al. Anti-Müllerian hormone as a marker of ovarian reserve: What have we learned, and what should we know? Reprod Med Biol, 2016.

11. Dewailly D and Laven J. AMH, the primary marker for fertility European Journal of Endocrinology, 2019.

12. Moolhuijsen LME and Visser JA. Anti-Müllerian Hormone and Ovarian Reserve: Update on Assessing Ovarian Function. The Journal of Clinical Endocrinology & Metabolism, 2020.

13. Sharma N and Chakrabarti C. Ovarian Reserve.

Innovations in Assisted Reproduction, 2019.

14. Parry JP and Koch CA. Ovarian Reserve Testing.

EndoText, 2019.

15. Better Health Channel. Age and fertility. https://www.betterhealth.vic.gov.au/health/ ConditionsAndTreatments/age-and-fertility 16. CDC. What is Infertility? https://www.cdc.gov/ reproductivehealth/features/what-is-infertility/ index.html 17. McTavish KJ, Jimenez M, Walters KA et al.

Rising Follicle-Stimulating Hormone Levels with Age Accelerate Female Reproductive Failure.

Endocrinology, 2007.

18. Tal R and Seifer DB. Ovarian reserve testing: a user’s guide. American Journal of Obstetrics & Gynecology, 2017.

19. European Society of Human Reproduction and Embryology. More than 8 million babies born from IVF since the world’s first in 1978. https://www. sciencedaily.com/releases/2018/07/180703084127. htm SF

References 1. Amanvermez R and Touson M. An Update on Ovarian Aging and Ovarian Reserve Tests. Int J Fertil Steril, 2016.

2. Delbaere I, Verbiest S and Tyden T. Knowledge about the impact of age on fertility: a brief review.

Upsala Journal of Medical Sciences, 2020.

3. Moreno-Ortiz H, Acosta ID, Lucena-Quevedo E et al.

Ovarian Reserve Markers: An Update. InterTechOpen, 2020.

4. Evans A, de Lacey S and Tremellen K. Australians’ understanding of the decline in fertility with increasing age and attitudes towards ovarian

To com plete this mo nth’s C PD questio nnaire, please go t o www.m edicalac ademic.c o.za and na v ig ate t o t he C PD sec tion of the we bsite.

100 μ

NEW

triptorelin acetate 100 µg/1ml • GONAPEPTYL® DAILY is indicated for down-regulation and prevention of premature luteinising hormone (LH) surges in women undergoing controlled ovarian hyperstimulation for assisted reproductive technologies (ART)1 • The GnRH agonist GONAPEPTYL® DAILY is an analogue of natural hypothalamic GnRH2,3 • GONAPEPTYL® DAILY is provided in a convenient pre-filled syringe avoiding the need for patients to daily reconstitute a powder with solvent1

References: 1. GONAPEPTYL DAILY Registered Package Insert, dated 11 August 2020. 2. Ortmann O, et al. Gonadotrophin-releasing hormone (GnRH) and GnRH agonists: mechanisms of action. Reprod Biomed Online 2002;5 Suppl 1(3):1–7. 3. Millar RP, et al. Gonadotropin-releasing hormone receptors.

Endocr Rev 2004;25:235–275 S4 GONAPEPTYL DAILY. Each syringe with 1 ml solution contains 100 µg triptorelin acetate equivalent to 95,6 micrograms triptorelin free base. Reg. No. 46/21.10/0169.

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION: Ferring (Pty.) Ltd. Route 21 Corporate Park, 6 Regency Drive, Irene Ext 30, Pretoria, South Africa. Tel: +27 12 345 6358. Fax: +27 12 345 1156. www.ferring.co.za. GONAPEPTYL, FERRING, and the FERRING logo are registered trademarks of Ferring B.V. For full prescribing information please refer to the package insert approved by the medicines regulatory authority. https://bit.ly/3hUP4km. 2021/019 Date of preparation: April 2021.

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steps to creating a non-toxic healthcare environment

A new study found that microplastic pollution is spiralling around the globe, leading to the ‘plastification’ of the planet. The World Economic Forum estimates that by 2050 the world’s oceans will contain more plastic than fish, and National Geographic found that 73% of all worldwide beach litter is plastic.1,2,3

I

n 2010 South Africa ranked 11th on the list of the worst offenders regarding plastic pollution in the ocean. Only 16% of the country’s plastic is recycled and the rest is discarded in landfills where they end up in rivers and eventually the ocean (an estimated eight million metric tons per annum).9 Single-use plastics and plastic packaging present a substantial part of the problem.

Single-use plastic products and devices have without doubt ‘revolutionised’ healthcare and are expected to continue to do so.

However, the medical fraternity – one of the biggest consumers of plastic – has an ethical

*HCWH Europe is a non-profit network of European hospitals and healthcare providers, healthcare systems, local authorities, research/academic institutions, and environmental and health organisations. Their mission is to transform the European healthcare sector so that it reduces its environmental footprint, becomes a community anchor for sustainability, and a leader in the global movement for environmental health and justice.6

responsibility to use products that are less hazardous for patients, according to Health Care Without Harm (HCWH) Europe*.4,5 One way to go about this is to ‘adopt a precautionary approach’ and replace medical products that do not contain hazardous substances

such as phthalates and bisphenol A (BPA) in their composition, recommends the HCWH.4

Impact of plastic on human health It has been shown that these substances can leach into patients during their use and

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compromise patient safety. Foetuses, children and pregnant women are the most vulnerable groups.4 Phthalates and BPA contain endocrine disrupting chemicals (EDCs), which may interfere with the normal functioning of the human endocrine system. European biomonitoring studies have detected phthalates and BPA in almost every individual analysed, and in a variety of human tissues and fluids such as placental tissue, breast milk, amniotic fluid, urine, blood, cord blood, sperm and saliva.4 Although it is difficult to prove a causal link, write the authors of the HCWH report, evidence is emerging that EDCs may be the cause of the steady increase over the past few decades in endocrine-related diseases such as breast and testicular cancers, thyroid disorders, infertility and diabetes. Plastic has been used commercially since the 1930s.4,7

Plastic in the healthcare environment Exposure to hazardous chemicals through medical products can be enteral (via the digestive tract), parenteral (IV), transcutaneous (via the skin) or through inhalation.4 Dietary indigestion of phthalates and BPA accounts for the majority of human exposure.

Several studies have described phthalates, (particularly di-2-ethylhexyl phthalate [DEHP]), leaching from medical devices and recorded levels in urine and blood.4 Phthalates are primarily used as softeners (plasticiser) in plastics to make them more flexible and are abundant in polyvinyl chloride (PVC) medical devices such as blood bags, intravenous bags, tubing, catheters, respiratory masks or disposable gloves. About 40% of all plastic-based medical devices are made from PVC.4 DEHP is the most commonly used phthalate plasticiser used in medical products. Up to 95% of all medical products contain DEHP. It is used in intravenous (IV) bags and medical tubing.

Leaching of DEHP from PVC medical products has been a concern since the late 1960s.4 DEHP is a known toxin that has been shown to affect the liver, kidneys, lungs, and the reproductive system (eg sperm abnormalities and lower testosterone levels), and neurodevelopmental disorders (eg neurodevelopment, including lower IQ, and problems with attention and hyperactivity, and poorer social communication). In animal studies it has also been shown to cause birth defects.10,11 Recent human studies confirmed some of the adverse impacts of DEHP on male reproductive tract development. The major male reproductive anomaly associated with phthalates is testicular dysgenesis syndrome, characterised by hypospadias, cryptorchidism, undescended testes, reduced anogenital distance, reduction in sperm count and quality, sterility, and the occurrence of testicular cancer.10,12

Anogenital distance is the most sensitive marker for estimating the impact of phthalates in human males. This anomaly is associated with prenatal exposure of the male foetus to phthalates while in the womb.12 DEHP has also have been associated with allergies, asthma, wheezing, hay fever, itchy rashes, and eczema in adults. These phthalates are hypothesised to affect disease of the airways through increased levels of oxidative stress and secretion of several inflammatory cytokines like interleukin 4 and 5 as well as inferno gama-γ gene.12 DEHP can cross the placenta, resulting in foetal exposures. In a study of cord blood of 84 human babies, the researchers found that 88% of newborns had detectable levels of either DEHP or mono-(2-ethylhexyl) phthalate (MEHP), with a mean concentration of DEHP of 1.19µg/ml. Babies with MEHP in their cord blood showed a significantly lower gestational age (27-42 weeks) in comparison to the MEHP

medical devices, and urinary catheters have demonstrated releases of BPA.4 Length of contact time (duration of exposure), temperature and pH, among other parameters, has been shown to increase the release of BPA from polycarbonate.4 The SCENIHR opinion on the safety of the use of BPA in medical products concluded that there is a risk when BPA is directly available for systemic exposure after non-oral exposure routes, especially for neonates in intensive care units, infants undergoing prolonged medical procedures, and for dialysis patients.4 The risk of adverse effects due to BPA may exist in patients undergoing dialysis treatment since BPA accumulates in systemic circulation due to reduced renal clearance.4

negative infants (37-42 weeks).11 A cross-sectional study was carried out to assess whether biomarkers of phenols and phthalates in urine of women undergoing IVF treatment are correlated with expression of extracellular vesicles (EV)-miRNAs in their follicular fluid. The urine samples were collected from participants during ovarian stimulation and the day oocyte was retrieved.

Results indicated that hsa-miR-125b and hsamiR-15b were positively related with DEHP, while levels of hsa-miR-106b, and hsa-miR374a were inversely related with DEHP.13 BPA is used as a monomer in the production of polymers such as polycarbonate, epoxy resins, polysulfone and polyacrylate. BPA has applications in medical products that have both direct and indirect contact with patients including those made of polycarbonate, polysulfone, and PVC such as medical tubing, catheters, haemodialysers, newborn incubators, syringes, and blood oxygenators.4

BPA-free devices, which can fulfil the same function. Several manufacturers offer products where phthalates/PVC or BPA have been replaced by alternative materials or substances.4 Although the benefit of medical devices has also to be considered, the SCENIHR recommends that, where practical, medical devices that do not leach should be used.4

At risk groups According to the Scientific Committee on Emerging and Newly Identified Health (SCENIHR) premature neonates in neonatal intensive care units, infants subjected to repeated medical treatment using medical devices, and patients undergoing haemodialysis are at risk of DEHP-induced effects.4 Patients in a neonatal intensive care unit (NICU) are exposed to phthalate mixtures through the complex materials used concurrently in NICU care: Respiratory circuits, intravenous equipment, enteral feeding supplies, and incubators are likely vehicles of phthalate exposure.4 Whilst evidence of BPA leaching into patients is more limited, dialysers, dental materials, circulation equipment, neonatal care

Alternatives that do not leach Exposure to phthalates or BPA can be minimised by adopting a precautionary approach and replacing medical devices with phthalate- and

Phthalate alternatives Alternative substances for replacing phthalates exist for a number of products, including the majority of applications in medical devices.

Phthalate-free or PVC-free medical devices are available for nearly all product categories except blood bags.4 In the Plastics Scorecard: Evaluating the Chemical Footprint of Plastics report, the plastic footprint of polyolefin and PVC in IV bags was compared. The results of the comparison showed that the substitution of PVC bags by polyolefin-based polymers greatly reduced the chemical footprint of the products.4

BPA alternatives The substitution of BPA can be done by replacing BPA with chemical alternatives or by substituting the plastic polymer with another plastic polymer or material. Known alternatives to BPA or to the plastic polymer containing BPA that are used in medical devices include many of the alternatives for phthalates such as polyethylene, polypropylene, polyurethane, silicone and acetylo-nitrile-butadiene-styrene.

Other common replacements include ceramic, stainless steel, glass and acrylic.4

Procuring safer medical devices In Europe, many hospitals are moving away from products and devices that contain hazardous chemicals. The first step of many

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hospitals has been to identify which products contain substances of concern and develop an internal substitution strategy or policy.

Many have launched substitution projects, particularly targeting DEHP and PVC in medical devices. These strategies and policies help hospitals in their purchasing decisions. 4 In 2019 HCWH Europe published guidelines for the procurement of safer medical devices.

Their recommendations include:8

Step 1: Conduct a baseline assessment Having an accurate picture of the full procurement process (including the purchasing and use of medical devices) is a crucial step in identifying how environmental and health considerations can best be integrated.

Collecting data will support prioritisation and provide compelling arguments to inform the decision-making process. Such data can include lists of procured devices and their manufacturers, overviews of purchasing and maintenance costs, information on the usage of procured devices, and staff satisfaction. This data can be used to raise awareness amongst staff and other stakeholders about the risk of hazardous chemicals in medical devices and the industry’s manufacturing practices. A baseline assessment is an important first step, reviewing your organisation’s current procurement practices will help to develop a clear and coherent procurement and substitution strategy and carefully design an action plan.

Step 2: Prioritise products to be phased-out Spending and usage data gathered in the baseline assessment can be cross-referenced with information available on the safety data sheet of individual products as well as socially responsible manufacturing requirements, allowing for a product matrix to be developed.

With this information, particularly problematic products can be identified for potential substitution based on environmental and social criteria. Since it will not be possible phase out all hazardous chemicals immediately, one useful approach is to identify potentially vulnerable patient groups (eg neonates), or specific procedures where substitution will have the greatest impact. Another useful approach is to begin with products that are more easily substituted and scale up substitution product by product.

Step 3: Identify alternatives Once a specific set of products has been identified for potential substitution, the next step it to identify safer and more sustainable alternatives. Although this can be challenging, there are some existing tools/platforms that can assist in this process for example HCWH Europe’s Safer Medical Device Database

(www.safermedicaldevices.org). The database contains over 150 products that are PVCfree or where phthalates have not been intentionally added. The database is also useful for regulatory bodies when dealing with the pre-market authorisation process of medical devices and for manufacturers to promote their safer products.

Step 4: Raising awareness internally and getting buy-in Implementing any sustainable procurement strategy/policy or substitution plan requires leadership support, as well as the engagement and commitment of management, colleagues from different departments, and external stakeholders. A key group of people to engage in driving a shift towards more sustainable medical devices are the clinicians that ultimately use the product. However, they are often not actually aware of the wider implications beyond functionality and cost.

Clinicians need to be engaged as early as possible in the procurement process, along with other stakeholders who can introduce sustainability principles into the decisionmaking process. For detailed information on how to structure an effective awareness campaign, go to https://bit.ly/2P3QDD0.

Step 5: Tender preparation and contract monitoring An effective and participatory substitution plan, paired with a meaningful stakeholder engagement process, should also underpin each step of your procurement process, and contribute to its success. For details about the information that should be contained in the tender document and how to monitor contracts, go to https://bit.ly/2P3QDD0.

Conclusion Plastic was first used commercially in the 1930s. The healthcare industry is one of the biggest consumers of plastic products and devices. Evidence is emerging that hazardous chemicals – known as endocrine disruptors – such as phthalates and BPA leach into patients.

Over the past few decades, there has been a steady increase in endocrine-related diseases such as breast and testicular cancers, thyroid disorders, infertility and diabetes. Foetuses, children, and pregnant women are the most vulnerable groups. HCWH Europe recommends ‘adopting a precautionary approach’ and replacing medical devices that do not contain hazardous substances such as phthalates and BPA in their composition. A number of companies now manufacture products that do not contain these chemicals. HCWH recommends a stepwise process to facilitate the phasing-out of harmful medical products and devices.

References 1. Brahney J, Mahowald N, Prank M et al. Constraining the atmospheric limb of the plastic cycle. PNAS, 2021.

2. Kaplan S. By 2050, There Will Be More Plastic than Fish in the World’s Oceans, Study Says. The Washington Post. 2016. www.washingtonpost. com/news/morningmix/wp/2016/01/20/by-2050there-will-be-more-plastic-than-fish-in-the-worldsoceans-studysays/?utm_term=.bd739415f414 3. Parker L. A Whopping 91% of Plastic Isn’t Recycled. National Geographic, 2018. https://www. nationalgeographic.com/science/article/plasticproduced-recycling-waste-ocean-trash-debrisenvironment 4. Health Care Without Harm (HCWH). Nontoxic Health Care: Alternatives to Hazardous Chemicals in Medical Devices: Phthalates and Bisphenol A. Second Edition, 2019.

5. Johnsen T. When plastics revolutionised healthcare – medical devices in a historical perspective. https://pvcmed.org/healthcare/ when-plastics-revolutionised-healthcare/ 6. HCWH Europe. Who we are. https://noharmeurope.org/content/europe/who-we-are 7. Czuba L. Application of Plastics in Medical Devices and Equipment. Handbook of Polymer Applications in Medicine and Medical Devices, 2014.

8. HCWH Europe (2019). Guidelines for the procurement of safer medical devices. https:// noharm-europe.org/sites/default/files/documentsfiles/5720/Guidelines_for_Procurement_of_Safer_ and_Sustainable_Medical_Devices_Final_WEB.pdf.

9. Hankel L and Burgess M. Plastic Marine Pollution in South Africa. National OCIMS, 2018.

10. Ruzickova K, Cobbing M, Rossi M and Belazzi T. Preventing Harm from Phthalates, Avoiding PVC in Hospitals. HCWH, 2004.

11. HCWH. Phthalates and DEHP. https:// noharm-uscanada.org/issues/us-canada/ phthalates-and-dehp 12. Dutta S, Haggert DK, Rappolee DA and Ruden DM. Phthalate Exposure and Long-Term Epigenomic Consequences: A Review. Front Genet, 2020.

13. Martinez RM, Hauser R, Liang L et al. Urinary concentrations of phenols and phthalate metabolites reflect extracellular vesicle microRNA expression in follicular fluid. Environmental International, 2019. SF

To com plete this mo nth’s C PD questio nnaire, please go t o www.m edicalac ademic.c o.za and na v ig ate t o t he C PD sec tion of the we bsite.

Freeflex® • DEHP/PVC Free1 • Latex Free1 • Free of Plasticisers1

Developed with the future in mind Reference: 1) Fresenius Kabi data on file.

Fresenius Kabi South Africa (Pty) Ltd, Reg. No.: 1998/006230/07 Stand 7, Growthpoint Business Park 162 Tonetti Street, Halfway House Extension 7, Midrand, Gauteng, 1685 PO Box 4156, Halfway House 1685 Tel: + 27 11 545 0000 Fax: + 27 11 545 0060 www.fresenius-kabi.co.za SSA_9_4_2021_V1

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SAD SAD, a complex and silent signature of asthma

This article was independently sourced by Specialist Forum.

Research shows that small airways dysfunction (SAD) is present in 91% of patients with asthma and are involved across almost all disease severities. Patients with severe asthma are especially affected.

Untreated SAD has been proposed as a contributing factor to inadequate disease control in 50%–60% of patients.1,2

S

mall airways (internal diameter ≤2mm or internal perimeter of ≤6mm) are located beyond the 7th and 8th generation of the tracheobronchial tree and account for >98% of the cross sectional area of the lung, ending in the alveolar sacs.

They have no cartilage to support their structure and collapse easily on constriction.4,5 Asthma is characterised by chronic inflammation and airway hyper‐reactivity leading to cough, wheeze, difficulty in breathing and chest tightness. Recent studies show that inflammation is associated with bronchial hyper-responsiveness, worsening of asthma symptoms and increased exacerbations. Small airways are narrowed in patients with asthma as a result of inflammation. 2,5 Postma et al describe SAD as ‘a complex and silent signature of asthma’. Small airways are considered ‘silent’ because of their relatively low impact on the whole resistance of the respiratory tree compared to larger airways. 2,5

Assessing SAD According to Postma et al although SAD is well recognised in asthma, its role in the severity and control of asthma is unclear. In the AssessmenT of smalL Airways involvemeNT In aSthma (ATLANTIS) study, the team investigated which combination of biomarkers, physiological tests and imaging markers best measure the presence and extent of SAD in asthma patients. 2

The study is the most comprehensive evaluation of SAD to date and included 773 patients with a confirmed diagnosis of asthma, and 99 controls without airway obstruction, normal spirometry as well as airways responsiveness, and smoked for a maximum of 10 pack-years. 2 Asthma patients’ disease had to be under control using any previous regular asthma treatment (including so-called rescue β2-agonists

alone) at a stable dose for more than eight weeks before baseline, and they smoked for a maximum of 10 pack-years in their lifetime.2 Diagnosis had to be supported by objective evidence at baseline or during the past five years. Objective evidence included positive airway hyperresponsiveness to methacholine, positive reversibility (a change in FEV1 ≥12% and ≥200mL within 30 min) after treatment with 400μg of salbutamol in a metered-dose

Beclomethasone + Formoterol

REACH1, TREAT2,3, BENEFIT4,5

e n fi a r t x e The

experience

The only extra-fine ICS/LABA combination1,4,5,6,7 Efficient deposition in the entire lung, including the small airways1 Uniform treatment of inflammation and bronchoconstriction through the entire bronchial tree4 Now reimbursed on all With the exception of KeyCare

options

Greater asthma control at a lower ICS dose vs. larger particle ICS/LABA combinations*4,5

*vs. budesonide/formoterol (Dry Powder Inhaler) and vs. fluticasone propionate/salmeterol (pressurised metered dose inhaler and Dry Powder Inhaler)5 ICS – inhaled corticosteroid; LABA – long-acting beta2-agonist, GINA - Global Initiative for Asthma References: 1. De Backer W, Devolder A, Poli G, et al. Lung deposition of BDP/formoterol HFA pMDI in healthy volunteers, asthmatic, and COPD patients. J Aerosol Med & Pulm Drug Delivery 2010;23:1-12. DOI 10.1089/jamp.2009.0772.

2. Paggiaro P, Nicolini G, Papi A. Extrafine beclomethasone dipropionate/formoterol hydrofluoroalkane-propelled inhaler in asthma. Expert Rev Resp Med 2008;2(2):161-165. 3. Papi A, Paggiaro P, Nicolini G, et al. Beclomethasone/formoterol vs fluticasone/salmeterol inhaled combination in moderate to severe asthma. Allergy 2007;62:1182-1188. 4. Müller V, G.lffy G, Eszes N, et al. Asthma control in patients receiving inhaled corticosteroid and long-acting beta2-agonist fixed combinations. A real-life study comparing dry powder inhalers and a pressurized metered dose inhaler extrafine formulation. Pulmonary Medicine 2011;11:40. 5. Terzano C, Cremonesi G, Girbino G, et al. 1-year prospective real life monitoring of asthma control and quality of life in Italy. Resp Research 2012;13:112. 6. Innuvair® approved package insert. July 2017. 7. Vos W, De Backer J, Poli G, et al. Novel functional imaging of changes in small airways of patients treated with extrafine beclomethasone/formoterol. Respiration 2013. DOI: 10.1159/000347120. 8. Global Initiative for Asthma (GINA). Pocket guide for asthma management and prevention (for adults and children older than 5 years).

Updated 2020. Available from https://ginasthma.org/wp-content/uploads/2020/04/Main-pocket-guide_2020_04_03-final-wms.pdf

S4 INNUVAIR® Inhaler. Each metered dose contains beclomethasone dipropionate 100 μg; formoterol fumarate dihydrate 6 μg. Reg. No. 42/21.5.1/0895. For full prescribing information refer to the package insert approved by the medicines regulatory authority. 2021041410118144.

Under license from CHIESI FARMACEUTICI S.p.A. Companies Register Office - Parma N.15739, Registered with the Administrative Economic Register: 159271, Via Palermo, 26 A (ingresso Via G. Chiesi 1) 43122 Parma, Tel: +39 0521 2791, http://www.chiesigroup.com. Adcock Ingram Limited. Reg. No. 1949/034385/06. Private Bag X69, Bryanston, 2021, South Africa. Tel. +27 11 635 0000 www.adcock.com.

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Box 1: Most common asthma clinical phenotypes11

inhaler with or without a spacer, variability in peak expiratory flow of more than 20% (measured over seven days), or documented reversibility after a cycle (eg four weeks) of maintenance anti-asthma treatment. 2 All participants were assessed using spirometry, body plethysmography, impulse oscillometry and multiple breath nitrogen washout. Patients with asthma were also assessed using questionnaires about disease control, asthma-related quality of life, as well as health status. Selected participants also underwent computed tomography (CT) scans. 2 The team used structural equation modelling to assess the contribution of all physiological and CT variables to SAD in asthma patients. The results were used to define clinical SAD and CT SAD scores and to classify asthma patients into SAD groups. They compared asthma severity, control, and healthcare use during the past year

by SAD score and by SAD group. 2

Box 2: Spirometry

Box 3: Impulse oscillometry

Spirometry is the most commonly performed lung function test in clinical practice. Spirometry should be used as the first line investigation for asthma in adults and in children over five, according to the 2021 National Institute of Health and Care Excellence guidance. A forced expiratory volume in one second to forced vital capacity (FEV1/FVC) ratio of less than 70% should be considered a positive test for obstructive airway disease. These patients should then be offered a bronchodilator reversibility test, which measures the ability to reverse obstruction in the airways by using bronchodilators. An improvement in FEV1 of 12% or more, together with an increase in volume of 200ml or more, should be considered a positive test. Postma et al identified spirometry tests of Forced Expiratory Flow (FEF25-72 and FEF50) or a decrease in Forced Vital Capacity (FVC) as best suited for SAD measurement. 2,9

Recent studies have shown that impulse oscillometry is useful in diagnosing asthma and assessing control – especially in children. Impulse oscillometry measures airway resistance and reactance during tidal breathing. While conventional spirometry requires a forced expiratory manoeuvre, impulse oscillometry is an effort-independent and patient-friendly modality for evaluating lung function and peripheral airway dysfunction. Sound waves are superimposed on normal tidal breathing, and the disturbances in flow and pressure caused by the external waves are used to calculate parameters describing the resistance to airflow and reactive parameters that mostly relate to efficient storage and return of energy by the lung. Importantly, impulse oscillometry can differentiate small airway obstruction from large airway obstruction and is more sensitive than spirometry for peripheral airway disease. 8,10

SAD findings

References

Postma and team found that SAD was present in asthma of all severities and showed proportionally more structural and functional abnormalities with increasing clinical severity (Global Initiative for Asthma severity stages [GINA 5], see table 1).

Model-based clustering identified two clinical SAD groups. Patients in group 1 (n=452) had milder SAD compared to group 2. Patients in group 2 (n=312) had abnormal physiological SAD results compared to group 1. In addition group 2 patients had more severe asthma (with regard to asthma control, treatments, exacerbations, and quality of life) than group 1.

The authors found that the difference between the two clinical SAD groups was particularly clear with SAD measurements related to spirometry (see box 2) and impulse oscillometry (see box 3). They concluded that these two tests were the most effective in identifying SAD in clinical practice because they are easy to use.

Postma et al concluded that the clinical classification of SAD into two groups using impulse oscillometry and spirometry is meaningful given its association with GINA severity stages, asthma control, quality of life and exacerbations.

According to Zinellu et al, evaluating the functional and inflammatory impairment of small airways should be part of the routine evaluation of all asthma patients, and not just to measure disease severity. Assessment could help in identifying the clinical phenotype (see box 1) and guide treatment decisions.4

1. Van den Bosch, James AL, and Tiddens HAWM. Structure and function of small airways in asthma patients revisited.

European Respiratory Review, 2021.

2. Postma DS, Brightling C, Baldi S et al. Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study.

Lancet Respir Med, 2019.

3. Carpaij OA, Muiser S, Bell AJ et al. Assessing small airways dysfunction in asthma, asthma remission and healthy controls using particles in exhaled air. ERJ Open Research, 2019.

4. Carr TF, Altisheh R, and Ziet M. Small airways disease and severe asthma. WAOJ, 2018.

5. Zinellu E, Piras B, Ruzitte GG et al. Recent Advances in Inflammation and Treatment of Small Airways in Asthma. Int J Mol Sci, 2019.

6. Enilari O and Sinha S. The global impact of asthma in adult populations. Ann Glob Health, 2019.

7. Parsons J and Mastronarde J. Asthma: Clinical Manifestations and Management. Pulmonary Advisor. https://www.pulmonologyadvisor.com/home/ decision-support-in-medicine/pulmonary-medicine/ asthma-clinical-manifestations-and-management/.

8. Desiraju K and Agrawal A. Impulse oscillometry: The state-ofart for lung function testing. Lung India, 2016.

9. NICE (2021). Asthma: diagnosis, monitoring and chronic asthma management. https://www.nice.org.uk/guidance/ ng80/chapter/Recommendations#objective-tests-fordiagnosing-asthma-in-adults-young-people-and-childrenaged-5-and-over 10. Park J-H, Lee JH, Kim H-J et al. Usefulness of impulse oscillometry for the assessment of bronchodilator response in elderly patients with chronic obstructive airway disease. J Thorac Dis, 2019.

11. GINA. Global Strategy for Asthma Prevention. https:// ginasthma.org/wp-content/uploads/2018/04/wms-GINA2018-report-V1.3-002.pdf SF

SF | PSYCHIATRY

May 2021 | Vol. 21 No. 5 www.medicalacademic.co.za

This article was independently sourced by Specialist Forum.

Pain-induced DEPRESSION DEPRESSION

P

atients suffering from chronic paininduced depression exhibit a poorer prognosis than those with chronic pain only. Chronic pain and depression are closely correlated in terms of occurrence and development and are able to mutually promote their own severity progress.

Neuroplasticity changes In recent years, studies have revealed considerable overlaps between pain- and depression-induced neuroplasticity and neurobiological mechanism changes.

Such overlaps are vital to facilitating the occurrence and development of chronic pain-induced depression.

Neuroplasticity crucially affects the occurrence and development of chronic pain and depression and may involve the same brain structures, neurotransmitters, and signalling pathways.

Through exploring the common neuroplasticity changes of these two disorders,

About 20% of people are affected by pain and depression. Depression is one of the leading contributors to the global disease burden. Studies show that chronic pain, as a stress state, often induce depression, and that up to 85% of patients with chronic pain are affected by severe depression. new targeted therapeutic drugs should be able to be developed or these disorders’ common

targets should be able to be identified for precise treatment of chronic pain-induced

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depression, which will surely contribute to the improvement of life quality and prognosis in patients suffering from these disorders.

Analgesic drugs to treat chronic pain-induced depression Opioids The potential of opioids in treating chronic pain-induced depression is well established, however, the use of opioids has been controversial because of patients’ severe dependence and addiction to them. The longterm use of opioids has been shown to increase the risk of depression and to even cause hyperalgesia, which can lead to depression.

Scherrer et al found that patients taking opioids for 31 to 90 days had an 18% higher risk for depression than those taking opioids for one to 30 days. Additionally, depression may prolong the duration of opioid use.

The duration of opioid use in patients with a history of depression was found to be three times longer than that in patients without depression, according to Braden et al.

Therefore, the extensive application of opioids for treating chronic pain-induced depression remains to be further studied and explored.

5-HT and NE reuptake at the synapse site and then enhance endogenous pain inhibition of the central nervous system (CNS).

They are helpful for easing many chronic pains, especially neuropathic pain.

Rowbotham and colleagues compared three antidepressants and confirmed that all three drugs can reduce pain experienced by postherpetic neuralgia patients. The tricyclics desipramine and amitriptyline were well tolerated and provided more meaningful pain relief in 53%–80% of participants (n=47).

ticity s a l p o ts Neur affec y l l a cruci e and c n e r ic ccur hron c the o f o ment on p o l e ressi p dev e d and pain

Benzodiazepines Benzodiazepines have been demonstrated to have a certain therapeutic effect in treating chronic pains, including neuropathic pain or inflammatory pain.

The analgesic mechanism of the benzodiazepines may be associated with the antihyperalgesic effect of the GABA A receptor, which is a molecular target of the benzodiazepines in the spinal cord. Because the GABA A receptors, including the α1, α2, α3, or α5 subunit, have also been found to be involved in mood regulation, benzodiazepines have a potential in treating chronic paininduced depression.

Antidepressants for treating chronic pain-induced depression Monoamine oxidase inhibitor The mechanism of classical monoamine oxidase inhibitor (MAO-I) is irreversible inhibition of MAO by covalent binding to the active site of the enzyme, but it is nonspecific and can inhibit the liver microsomal enzyme system, which affects the metabolism of many drugs. In addition, some classic MAO-I themselves have hepatotoxicity, so they are clinically no longer used for treating depression.

Tricyclic antidepressant drugs Tricyclic antidepressants (TCAs) are traditional antidepressant drugs, commonly including amitriptyline, imipramine, nortriptyline, and desipramine. The action mechanism of tricyclic antidepressant drugs may be to first inhibit

Monoamine reuptake inhibitors For monoamine neurotransmitters, neurotransmitter reuptake is one of the most important determinants of signal kinetics and regulation of neurotransmitter reuptake also helps regulate the activity of the nervous network across the CNS, thus achieving an antidepressant effect.

With more in-depth studies on the treatment mechanism of monoamine neurotransmitters in antidepression and pain relief, inhibitors including selective 5-HT reuptake inhibitors (SSRIs) and 5-HT, and norepinephrine reuptake inhibitors (NE) reuptake inhibitors (SNRIs) have emerged unceasingly and have gradually become first-line drugs for clinical antidepressant therapy.

Antidepressant pharmacological mechanisms of SSRIs and SNRIs are to selectively act on some 5-HT and/or NE receptor subtypes and block their reuptake to increase 5-HT and/or NE that are available for biological uses in the synaptic cleft of nerve cells, thus further enhancing monoamine neurotransmission and having an antidepressant effect.

The 5-HT and NE reuptake inhibitor antidepressants have been confirmed by numerous studies to be efficacious in chronic neuropathic pain patients. Furthermore, average pain relief (recorded via a diary) and maximum pain intensity (retrospective assessment via a computer program) in patients with chronic neuropathic pain

were found to be significantly lower with antidepressant venlafaxine, a 5-HT and SNRI, compared with a placebo in Tasmuth et al’s randomised, double-blind study.

Glutamatergic antidepressant drugs As a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, has been used for anaesthetisation since the 1960s and was reported in 2000 to rapidly improve depressive symptoms, including refractory depression within several hours.

However, it has been associated with side effects such as dizziness, blurred vision, headache, nausea or vomiting, dry mouth, poor coordination and restlessness. Therefore, the safety and efficacy of ketamine and other NMDA receptor antagonists for treating chronic paininduced depression remain to be further explored.

Adjuvant psychotherapy In addition to the neural plasticity mechanism described above, psychosocial factors also have a significant effect on the occurrence and development of chronic pain-induced depression.

Therefore, appropriate adjuvant psychotherapy also has a crucial role in treating chronic pain-induced depression, which has been confirmed in many clinical investigations.

For example, by means of randomised clinical trials of 342 patients with chronic back pain between 20 and 70 years of age, the group that received cognitive behavioural therapy versus usual care showed greater improvement in function (adjusted mean difference in range). Furthermore, Eccleston et al, through a retrospective analysis of 37 clinical randomised trials, found that, for children and adolescents with headache, psychological therapy decreased treatment pain and follow-up pain.

Thus, psychotherapy contributes to the relief from clinical symptoms, shortens the duration of the recovery cycle, improves patients’ prognosis, and is recommended as a necessary adjuvant therapy for chronic pain-induced depression.

Conclusion Pain and depression are closely correlated from the perspectives of both brain regions and the neurological function system, whereby chronic pain may lead to depression. One of the important causes for chronic pain leading to depression appears to be the crucial effect of common neuroplasticity changes on the occurrence and development of the two disorders in question (see Figure 1).

Reference Sheng J, Liu S, Wang Y et al. The Link between Depression and Chronic Pain: Neural Mechanisms in the Brain. Neural Plast, 2017. doi: 10.1155/2017/9724371 SF

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This article was independently sourced by Specialist Forum.

The story of probiotics 1860 Nobel laureate Louis Pasteur identifies the microorganisms responsible for the process of fermentation.

1882 Nobel laureate, Elie Metchnikoff studies the effect of microorganisms responsible for the process of fermentation on human health. He links the longevity of Bulgarian rural people to the regular consumption of fermented dairy products such as yogurt.

The World Health Organization (WHO) and the Food and Agricultural Organization (FAO) of the United Nations formulate the current definition of probiotics as ‘live microorganisms which, when administered in an adequate amount, confer a health benefit to the host’.

The American Food and Drug Administration (FDA) declare that the majority of the probiotic organisms are generally regarded as safe.

1899 1901

Henry Tissier isolates Bifidobacteria from the stools of breast-fed infants.

He finds that they were a predominant component of the intestinal flora in healthy humans and later recommends the administration of Bifidobacteria to infants with diarrhoea.

Several studies show that L. reuteri are safe in adults, children, infants, and even in an HIV-infected population.

Microbiologist Martinus Willem Beijerinck describes the genus Lactobacilli of which Lactobacillus reuteri is one of the most studied. L. reuteri is named after Gerhard Reuter, a German microbiologist who spent most of his career attempting to understand the human intestinal microbiota with a focus on Lactobacilli and bifidobacteria.

Roy Fuller further expands the definition of probiotics as ‘a live microbial feed supplement, which beneficially affects the host animal by improving its intestinal microbial balance’.

1905 Stamen Grigorov discovers the first probiotic strain of bacillus in Bulgarian yogurt, called Lactobacillus bulgaricus.

Whipps et al introduce the term ‘microbiome’, setting the stage for the launch of the Human Microbiome Project (HMP).

1988

1992

1998‑2016

2000 2001 2002 WHO/FAO draft guidelines regarding the evaluation of probiotics in various food products.

The International Scientific Association for Probiotics and Prebiotics (ISAPP) is established.

2008 The FDA publishes its working definition of probiotics, classifying them as live biotherapeutics: Live microorganisms with an intended therapeutic effect in humans, including bacteria and yeast used in disease prevention or treatment, intended local or regional action.

It includes probiotics for clinical use.

2014 The ISAPP publishes an expert consensus document on the scope and appropriate use of the term probiotic: Live microorganisms, which when administered in adequate amounts confer a health benefit on the host.

2015 The global retail market value for probiotics reaches almost R6b (including sales of probiotic supplements, fermented milk products, and yogurt).

2016 Sawh et al show that probiotics are beneficial in the prevention of severe necrotising enterocolitis (NEC) and death in preterm infants.

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The story of probiotics is as old as human history, as it is closely related to the use of fermented food. About 10 000 years ago farming started to replace hunting and gathering, and people began to produce fermented food and beverages such as bread, kumis, kefir, cheese, beer and wine. Subsequently the beneficial health properties and therapeutic use of fermented products – especially on gut microbiota – have been shown in numerous studies.

The modern history of probiotics starts in the late 1800s. Here are some selected highlights: Alfred Nissle notices that during a severe outbreak of shigellosis among German soldiers, one soldier was not affected. He isolates a non-pathogenic strain of Escherichia coli from the faeces of this soldier and postulates that the strain prevented the soldier from acquiring shigellosis. This is subsequently interpreted to be a so-called probiotic.

1917 1929 Biochemists Arthur Harden and Hans Euler-Chelpin are awarded the Noble Prize for elucidating how yeast cells cause fermentation.

Microbiologist Minoru Shirota discovers bacterial flora that survives passage through the gut after ingestion. He isolates and cultivates a Lactobacillus casei strain, which leads to the commercial production of the first fermented bacteria-containing drink, Yakult, still manufactured and sold worldwide.

Nobel laureate Werner Kollath introduces the term ‘probiotic’ (latin pro and the greek βιοσ meaning for life) to describe various organic and inorganic supplements that were believed to have the ability to restore the health of malnourished patients.

1930

1953 1962

1965 1973 1974 Roy Parker proposes that the term probiotic should include not only microbial organisms but also other substances that contributed to intestinal microbial balance.

Urologist Andrew Bruce sets the wheels in motion for considering Lactobacilli for the treatment of urinary tract infections in women. He postulates that replenishment of lactobacilli into the vagina where Escherichia coli were dominant after repeated urinary tract infections and antibiotic treatments, might restore homeostasis, and protect the host.

Daniel Lilly and Rosalie Stillwell expand the definition of probiotics to represent ‘substances secreted by one organism which stimulate the growth of another’.

The Working Group on Probiotics of the European Society of Pediatric, Gastroenterology, Hepatology and Nutrition, recommends the use of S. boulardii in the prevention of Clostridium difficile-associated diarrhoea.

In addition, they recommend LGG and S. boulardii, L. reuteri for the management of infantile colic, and as a conjoint treatment for the management of H. pylori.

The World Gastroenterology Organisation (WGO)publishes its guidelines. Based on evidence, they found that probiotics are effective in:

Panigrahi et al publish a large study showing probiotics can prevent sepsis in newborns and NEC in low birth weight, premature babies.

• Eradicating Helicobacter pylori

Gregor Reid publishes a study showing the efficacy of probiotics in improving vaginal microbiota and reducing infection recurrence.

• Improving immune response

2017

Ferdinand Vergin proposes the term ‘probiotika’ to describe active substances that are essential for a healthy development of life.

• Preventing of colorectal cancer • Preventing and treating diarrhoea

• Preventing and treating hepatic encephalopathy • Preventing further relapse of pouchitis after the induction of remission with antibiotics.

Achieving higher response and remission rates in mild to moderately active UC in both adult and paediatric populations

1954

L. reuteri is isolated

• Reducing abdominal bloating and flatulence in patients with irritable bowel syndrome (IBS)

The American Gastroenterological Association published its updated guideline, which recommends the use of probiotics for:

• Ameliorating pain and providing global relief in patients with IBS • Alleviating symptoms and improving the quality of life in patients with functional abdominal pain • Reducing crying time in breastfed infants with colic • Improving lactose digestion and reducing symptoms related to lactose intolerance • Reducing the risk of NEC in preterm neonates • Mitigating steatohepatitis in adults and children with nonalcoholic fatty liver disease.

2011/2017 2018

The label ‘probiotic’ is often misused by being applied to products that do not meet the criteria (see box 3). The FDA publishes a draft policy on quantitative labelling of dietary supplements containing live microbials as a guidance for Industry.

• For preterm (born before 37 weeks), low birthweight (< 2500 g) infants, specific probiotics can prevent death and NEC, lessen the number of days required to reach full feeds, and shorten the length of the hospital stay • Prevention of C. difficile infection in adults and children who take antibiotics • Management of pouchitis, a complication of UC that has been treated surgically.

2020

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Box 1: Modern probiotics Modern probiotics were designed for two basic reasons: To replenish organisms that are naturally in a given niche but whose numbers have been depleted and illness has occurred. This could be the use of Lactobacillus crispatus in the vagina to counter bacterial vaginosis or ascension of E. coli into the bladder Strains are selected because they have properties that counter pathogens/conditions causing illness, with an aim of restoring health and ideally allowing the indigenous beneficial microbes to return. The example would be to orally administer Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14, which are not species highly prevalent in the vagina, but whose administration results in recovery from infection and the return of indigenous L. crispatus and L. iners

1

2

Box 2: Choosing an appropriate probiotic product for your patient Recommendations of probiotics, especially in a clinical setting, should tie specific strains to the claimed benefits based on human studies. Some strains will have unique properties that may account for certain neurological, immunological, and antimicrobial activities.

The WGO notes that the optimal dose of probiotics depends on the strain and product. The organisation therefore recommends that clinicians who advise their patients to use probiotics specify the probiotic strains, doses, and duration of use that studies in humans have shown to be beneficial.

Finally, the WGO recommends that probiotic supplement users check the labels of probiotic supplements for recommended storage conditions, for example, some require refrigeration, whereas others can be stored at room temperature.

Let food be your me dicine and me dic be your ine fo – Hippo od. crates Box 3: Probiotic criteria Probiotics are confirmed to be safe and should adhere to certain conditions. For example, probiotics should: » Not lose their properties during storage » Normally be present in the human intestines » Be able to survive in the gastrointestinal tract and colonise the intestinal cells » Have beneficial effects on human health » Display antagonism against pathogenic microorganisms » Not demonstrate any noticeable sideeffects. The potential health benefits of probiotics tend to be strain specific and generalisations of probiotic benefits do not attribute to different strains within one species.

References AGA. Probiotics. https://gastro.org/practice-guidance/ gi-patient-center/topic/probiotics/ Awaisheh SS. Probiotic Food Products Classes, Types, and Processing. Probiotics (book), 2012.

FDA. Policy Regarding Quantitative Labeling of Dietary Supplements Containing Live Microbials: Guidance for Industry. https://www.fda.gov/media/115730/ download Gasbarrini G, Fiorenza B and Gramenzi A. Probiotics History. Journal of Clinical Gastroenterology, 2016.

Gogineni VK, Morrow LE, Greogry PJ and Malesker MA.

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Granisetron Fresenius 1 mg/ml (1 ml) Granisetron Fresenius 1 mg/ml (3 ml)

IN STOCK

Concentrate for solution for injection/infusion INDICATIONS: For the prevention or treatment of nausea and vomiting induced by cytostatic therapy (chemotherapy and radiotherapy) and for the prevention and treatment of post-operative nausea and vomiting.1

Identifies Granisetron Fresenius1

For full prescribing information refer to professional information approved by the South African Health Products Regulatory Authority.

S4 GRANISETRON FRESENIUS 1 mg/ml (1 ml): 44/5.7.2/0671 S4 GRANISETRON FRESENIUs 1 mg/ml (3 ml): 44/5.7.2/0672

Reference: 1. Fresenius Kabi data on file.

Fresenius Kabi South Africa (Pty) Ltd, Reg. No.: 1998/006230/07 Stand 7, Growthpoint Business Park 162 Tonetti Street, Halfway House Extension 7, Midrand, Gauteng, 1685 PO Box 4156, Halfway House 1685 Tel: + 27 11 545 0000 Fax: + 27 11 545 0060 www.fresenius-kabi.co.za IMA_13_3_2021_V1

Identifies the location of a small cut to help breaking/ opening the ampoule1