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Invited Review Article

Twenty years of adverse drug reactions: a look back – part 1

Ferner, Robin E.a,b; Anton, Christopherb

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Adverse Drug Reaction Bulletin: April 2018 - Volume 309 - Issue 1 - p 1195-1198
doi: 10.1097/FAD.0000000000000033
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Abstract

Introduction

The Adverse Drug Reaction Bulletin was founded over 50 years ago by Dai Davies, a physician of the old school who edited it for more than 30 years with the help of his colleagues Professor John Thompson and later Dr Hugh de Glanville. We owe them a great debt. Sadly, Professor Davies died in 2002 and Professor Thompson in 2012. We took over the Bulletin 20 years ago and will shortly be handing over to Professor Kim Dalhoff and his colleague Dr Jon Andersen in Copenhagen. Professor Davies emphasized the clinical presentation as the starting point for studying ADRs. Here we set out briefly some of the more important and interesting clinical aspects that have emerged during our time at the Bulletin. The list only touches on a few of the relevant adverse reactions in the last 20 years, and omits some well known examples, such as myocardial infarction associated with rofecoxib use.1 We hope it nonetheless illustrates the range of ADRs, the way in which they sometimes resemble spontaneous conditions, and the factors that affect their occurrence in an individual, including the extent and duration of exposure to the agent and the individual's susceptibility.

Part 1 deals with musculoskeletal, gastrointestinal, central nervous system, psychiatric, and skin system organ classes and Part 2 will cover metabolic, immunological, respiratory, and cardiovascular system organ classes.

Musculoskeletal disorders

Bone fractures

The incidence of both vertebral and nonvertebral fractures is increased in patients taking oral glucocorticoids, as it is in patients with Cushing's disease.2 A recent meta-regression examined fracture rates in 1446 people enrolled in the control arms of studies of osteoporosis treatments in patients taking oral glucocorticoids.3 In the first 6 months of glucocorticoid therapy, vertebral and nonvertebral fracture rates were 5.1 [95% confidence interval (CI) 2.8–8.4] % per year, and 4.0 [95% CI 1.7–7.7] % per year, respectively. In chronic users, who had taken the drug for more than 6 months, they were 3.7 [95% CI 1.7–6.2] % per year and 4.5 [95% CI 1.0–9.5] % per year, respectively. The high rate of vertebral fracture in the first 6 months of therapy corresponds with the high rate of bone mineral loss during that time.

There is increasing evidence that antipsychotic drugs are also associated with increased fracture risk. There may be confounding by indication, since schizophrenia is potentially associated with factors that cause osteoporosis, but hyperprolactinaemia, induced by the antipsychotic drugs, may contribute.4

Increased fracture risk has also been seen in studies of treatment with opioids,5 proton-pump inhibitors,6 and possibly inhibitors of sodium-glucose transporter 2 (gliflozins),7 and low-molecular weight heparins used long-term.8

The 1990s saw widespread use of bisphosphonates to prevent fractures in patients with osteoporosis. In 2008, a group from Singapore reported 17 patients who had been taking alendronic acid for a mean of 4.8 years and who had sustained ‘low energy sub-trochanteric [femoral] fractures’, associated with prodromal pain and with characteristic radiographic appearances.9 A group from New York reported similar findings in 15 patients who had taken alendronic acid for a mean of 5.4 years.10 An industry-sponsored study of the records of 14 195 women in clinical trials subsequently concluded that ‘[t]here was no significant increase in risk associated with bisphosphonate use, but the study was underpowered for definitive conclusions’.11 A study funded by the Swedish Research Council clarified matters: the relative risk of atypical fractures, 47 [95% CI 26–87], was greatly elevated, but the absolute risk was low at 5 [95% CI 4–7] cases per 10 000 patient-years.12 The National Institute for Health and Clinical Excellence (NICE) recommends bisphosphonates for those whose risk of fragility (osteoporotic) fracture is greater than 1% over 10 years.13 The benefits and harms of bisphosphonates in an individual should be re-evaluated after 5 years of treatment.

Gastrointestinal system

Intussusception

Intussusception, in which one part of the bowel telescopes into the adjoining bowel, is rare in Europe and the United States. It occurs mainly in children, whose abdominal lymph nodes can enlarge with virus infections, and can be propelled onwards as a mass in the intestines. In adults, intussusception is usually seen in the context of bowel masses such as colon cancer. An old report of intestinal obstruction caused by intussusception attributed this to a gut wall haematoma in a patient who was taking the anticoagulant phenindione.14 A more recent report attributed intussusception in a 74-year-old man to the long-term use of indometacin, which caused strictures and fibrosis at the ileocaecal valve.15

In July 1999, the US Vaccine Adverse Event Reporting System identified 15 cases of intussusception in infants who had been immunized with RotaShield, a tetravalent vaccine against rotavirus, licensed in August 1998. Rotavirus causes diarrhoeal illness in young children and can lead to severe dehydration requiring hospital admission. Worldwide, several hundred thousand children die of the infection each year.16 RotaShield prevented half of all episodes of rotavirus diarrhoea and almost all hospital admissions when tested before licensing.17 There was more intussusception in 10 054 trial patients given active treatment than in placebo controls, but the rates (1 : 2000 vs. 1 : 5000) did not differ significantly.18 Postmarketing data from the USA estimated the risk of intussusception in the first week after immunization to increase four-fold.19 The manufacturer withdrew RotaShield, but two more vaccines, Rotarix and RotaTeq, became available after large premarketing studies. While there appears to be no overall increase in risk of intussusception in the year after immunization, there is an approximately five-fold risk in the first week after the first vaccine dose.20,21

Central nervous system disorders

Sleep attacks

Eight men who took the dopamine agonists pramipexole to treat Parkinson's disease suffered sudden irresistible sleep attacks causing them to fall asleep while driving; one patient afterwards suffered a similar attack when he took ropinirole.22 A review of 96 sleep attacks described patients who suddenly fell asleep while, for example, eating, talking or grooming a pet. The attacks last for 2–5 min before the individual wakes up abruptly.23

A meta-analysis of trials of the newer agents gave pooled risks of somnolence with ropinirole or pramipexole relative to placebo of 5.0 [95% CI 1.8–14].24 In normal volunteers, pramipexole reduces sleep latency.25

Narcolepsy

Sudden attacks of sleep are the hallmark of narcolepsy, a rare condition that usually arises spontaneously and is commonly hereditary. In 2009, a pandemic of H1N1 serotype influenza A led to widespread use of a vaccine (Pandemrix): about 30 million doses were administered.26 Suspicion of a link between immunization with Pandemrix and the development of narcolepsy led to detailed investigation. More than 900 cases were reported to the European Medicines Agency. In Finland, a task-force concluded that the rate of narcolepsy was 12.7 [95% CI 6.1–31] times higher in children aged 4–19 who had been immunized than in those who had not; a Swedish cohort study suggested a relative risk of 6.6 [95% CI 3.1–15]. However, as the condition is rare, the absolute risk was of the order of one in 15 000–25 000. No mechanism has been proposed, although there is a parallel between the vaccine-induced narcolepsy and the encephalitis lethargica of von Economo that followed the 1918 influenza pandemic.

Other topics

During the last 10 years, the Bulletin has had articles on drug-induced peripheral neuropathy,27 drugs that lower the seizure threshold,28 and drug-induced movement disorders.29

Psychiatric disorders

Impulse control disorders

Some drugs induce abnormal behaviour that includes impulsive or compulsive acts that fall into the category of ‘Disruptive, Impulse-Control, and Conduct Disorders’ as defined in the Diagnostic and Statistical Manual (DSM) of the American Psychiatric Association (the definitions differ between DSM-IV and DSM-V). These can take the form of ‘punding’ – complex repetitive behaviour without any obvious goal, such as making endless adjustments to mechanical devices, or sorting objects such as coins.30 Other compulsive behaviours include pathological gambling, hypersexuality, binge eating, and compulsive shopping.31 Sometimes the behaviour is criminal. In one case, 47-year-old woman developed ‘very severe kleptomaniac thoughts’ a fortnight after starting treatment with venlafaxine, and began stealing useless objects.32 A 33-year-old patient treated with pramipexole adopted almost 50 cats, and then was impelled to commit acts of ‘intentional severe cruelty’ towards them.33 An older man, treated with pramipexole, received a suspended sentence for a sexual offence because ‘his sexual inhibitions were markedly lessened by the medication, and his capacity to make proper judgments adversely affected’. Evidence was given that between January 2007 and October 2009 he engaged 162 different sex workers on 506 occasions, spending approximately £75 000.34

The drug-induced impulse control disorders, originally described in amphetamine addicts and subsequently in cocaine addicts, involve activation of central dopaminergic pathways, and are sometimes referred to as the dopamine dysregulation syndrome.35 They are now most commonly reported with dopamine agonists used to treat Parkinson's disease. The same behavioural adverse effects are seen when dopamine agonists are used to treat prolactin-secreting pituitary tumours.36 Indeed, the incidence of hypersexuality may be higher in this group, in whom dopamine agonists restore libido blunted by hyperprolactinaemia and also activate the dopaminergic reward pathways.

The probability of developing the syndrome may be as high as 18% in patients taking therapeutic doses of dopamine agonists for Parkinson's disease, according to a study of 267 patients with the condition, of whom 38 were taking therapeutic doses of dopamine agonists.37 Some patients developed more than one impulsive behaviour. The risk appears to be lower with infusion therapies.38

An analysis of the US Food and Drug Administration database demonstrated higher proportional reporting ratios for impulse control disorders with pramipexole and ropinirole than with bromocriptine or cabergoline, which were in turn higher than with rotigotine and apomorphine.39

Skin disorders

Acute generalized erythematous pustulosis

Serious cutaneous adverse reactions (SCARs) are important and sometimes fatal.40,41 In toxic epidermal necrolysis (TEN), in which there is extensive loss of skin and mucous membrane, mortality may be 30–40%42; survivors often suffer long-term sequelae.43 Drug reaction with eosinophilia and systemic symptoms (DRESS; formerly ‘drug rash with eosinophilia and systemic symptoms’) syndrome, in which a rash is accompanied by severe systemic upset and blood eosinophilia. DRESS was covered in the Bulletin in 2015.44 A study from the important multinational registry RegiSCAR identified 117 cases in 6½ years; two patients died.45

Acute generalized erythematous pustulosis (AGEP), a third important SCAR, is rarer than either TEN (or its less severe variant, Stevens–Johnson syndrome) or DRESS. An 18-year study at the Mayo Clinic found only 28 patients, none of whom died.46 There were no reported deaths in a Korean series of 36 patients recruited over 13 years in whom the diagnosis was confirmed by biopsy.47

AGEP usually occurs within hours to days of exposure to a precipitant. It is marked clinically by the rapid evolution of widespread oedematous erythema on which are multiple nonfollicular sterile pustules; the rash is accompanied by fever and systemic neutrophil leukocytosis. Many and various agents have been associated with AGEP. In the Mayo series, antibacterial agents including clindamycin, aminopenicillins and penicillins, and cephalosporins, were most often implicated, but so too were diltiazem, hydroxychloroquine, and allopurinol. Elsewhere, causes have included drugs such as carbamazepine, clopidogrel, itraconazole, herbal medicines, nonsteroidal anti-inflammatory drugs, oral prednisolone, radiocontrast media, and varenicline; but also lacquer chicken (Korean boiled chicken treated with poison ivy extracts),48 mercury,49 and spider bites.50,51 Most patients recover within two weeks after withdrawal of the offending agent.

It seems probable that T-lymphocytes sensitized to the implicated drug release neutrophil-activating cytokines, which lead to the systemic neutrophilia and for dermal infiltration by neutrophils.52 The prior sensitization would explain the short interval between exposure and onset, which would otherwise be uncharacteristic of a T-cell mediated delayed-type hypersensitivity reaction.

Acneiform rash

True acne, which generally affects the face, chest, and back and which afflicts nearly all teenagers, consists of a mixture of comedones (blackheads), papules, pustules, and sometimes cysts. Acneiform rashes may affect other areas, at other stages in life, and usually without comedones. Corticosteroids in supraphysiological doses as well as testosterone and related anabolic steroids commonly cause acne; other recognized causes are isoniazid, lithium treatment, and organic and inorganic halogen compounds, including polychlorinated biphenyls and dioxins.53 In the last few years, drugs that interact with epidermal growth factor pathways have emerged as important causes of acneiform rash. Other dermatological reactions to these agents include nail changes, hair loss, and increased thickness of the eyelashes.54

Epidermal growth factors (EGFs) stimulate receptors (EGFRs) that activate tyrosine kinases. The EGFR pathway is important in oncogenesis, and inhibition of the extracellular receptor or of the intracellular tyrosine kinase can cause tumours to regress. Monoclonal antibodies against EGFRs, such as cetuximab and panitumumab, and small-molecule inhibitors of tyrosine kinases, such as erlotinib and gefitinib, have found a place in the management of breast, lung, and gut cancer.

The agents that block EGF pathways do not inhibit haematological cell turn-over, and so avoid the leukopenia, thrombocytopenia, and anaemia that are common with other anticancer agents. They do, however, cause marked dermatological adverse reactions, notably a skin rash that resembles acne in its distribution and in having papules and pustules, but without comedones. As many as 90% of treated patients will develop the rash in the first few weeks of treatment. The cause of the rash is uncertain. It is likely that inhibition of the EGFR pathway causes cell death in normal keratinocytes as well as in tumour cells; the apoptotic keratinocytes release mediators that incite local inflammation, with histological evidence of inflammatory cell infiltrates.55 Ultraviolet light, which damages keratinocytes, may increase the severity of the rash in sun-exposed areas. The rash itself is sterile, but secondary infection with Staphylococcus aureus is common.

Conclusion

Many adverse reactions can mimic other diseases and a careful drug history is required to detect a drug as the causative agent. Individuals’ susceptibility to adverse reactions will vary and regulators have to balance benefit and harm to allow drugs which have serious adverse effects but benefit some patients to remain on the market, especially for diseases where there is limited therapeutic choice.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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