Uncovering the Hidden Burden of Pharmaceutical Poisoning in High-Income and Low-Middle-Income Countries: A Scoping Review

Pharmaceutical poisoning is a significant global public health concern, causing approximately 190,000 deaths annually. This scoping review aims to comprehensively map the available literature on pharmaceutical poisoning and compare patterns between high-income countries (HICs) and low-middle-income countries (LMICs). A systematic search was performed across the following databases: Embase, PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and CINAHL. Studies included were from 1 January 2011 to 31 December 2020, in English, with full text available. Seventy-nine articles were included in the study; 21 were from LMICs and 58 were from HICs. Toxic exposure was largely intentional (77%) in LMICs and accidental (68%) in HICs. Drugs acting on the nervous system were responsible for 95% of toxicities worldwide with analgesics accounting for the largest subtherapeutic group in both LMICs (40%) and HICs (58%). Notable statistics were that HICs accounted for 99% of opioid overdoses, and LMICs accounted for 19% of anti-epileptic-induced toxicities. Overall, the medical outcomes due to poisonings were generally worse in LMICs. The review provides possible interventions to target specific geographic locations, based on the trends identified, to reduce the burden worldwide. Many gaps within the literature were recognised, calling for more robust analytical research.


Introduction
Toxic exposure to medicines remains a significant, under-recognised global public health concern.The World Drug Report estimates that pharmaceutical poisoning causes 190,000 fatalities annually [1]; with non-fatal poisoning 20-30 times more prevalent and often causing long-term morbidities [2].The most prevalent long-term conditions are respiratory, renal or hepatic failure, cognitive impairment, and hypoxic brain injury, depending on the drug(s) involved [3].This severely reduces patients' quality of life and puts a strain on healthcare services and society worldwide.
Drug-induced toxicities require immediate action by emergency medicine and national toxicology centres.This creates immense pressure on healthcare systems, apparent from observing hospital admissions alone.In the United Kingdom (UK), approximately 100,000 patients present to emergency departments annually due to drug poisoning, which in turn is responsible for 10% of general ward admissions [4].Likewise, almost 75% of drug overdose cases in Japan require ambulance services, which account for 15% of intensive care unit (ICU) admissions [5].Similar trends have been observed worldwide highlighting the burden on emergency services, consuming valuable resources and delaying care for other life-threatening emergencies [5].
Pharmacy 2023, 11, 184 2 of 47 Pharmaceutical poisoning can be categorised as intentional (deliberate) or unintentional (accidental).The latter ranks fifth in European injury-related mortality, with the highest rates in Lithuania, Ireland, Estonia, Romania and Latvia [6].Most unintentional drug poisoning cases occur in children under five, from having a natural curiosity to explore unfamiliar objects and failing to recognise the associated dangers due to their developing cognitive function [7].Such incidents are most common within a household setting where 10-20% of child exposures are due to their grandparent's medicines being easily accessible [8].Many co-morbidities in the elderly require multiple medications, which accumulate in homes [9].Patients often self-manage their medicines using blister packs, removing the drugs from their original, child-resistant, packaging-consequently increasing the risk of accidental consumption and overdose [10].Therapeutic errors can also cause unintentional toxicity as well accidental consumption.Such errors are often caused by dosing errors, especially for high-risk medications with a narrow therapeutic index [6].
Alarmingly, most drug toxicity cases are due to intentional self-harm.These intentional exposures occur in countries worldwide regardless of income status, often due to distressing life events, poverty, and psychiatric illnesses, with the highest rates among adults aged 33-44 [11,12].In 2016, over one billion people worldwide were diagnosed with a mental health condition, 20% of whom were children or adolescents [13,14].Many of these patients are prescribed drugs to help manage their conditions, highlighting the magnitude of the population's vulnerability and exposure to medicines with potential toxicities.Over 60% of drug poisoning suicides in Asia are from people with psychiatric conditions, highlighting the correlation between mental illness and pharmaceutical poisoning [1,15,16].Furthermore, overdosing with prescribed and over-the-counter medicines accounts for 79% of UK emergency department presentations due to self-harm [3,16,17].
Opioids are the major cause of drug-induced toxicity globally [18].In the Global Burden of Disease Study 2017, 109,500 people died from opioid usage, including prescription, synthetic, and illegal opioids [17,19].Due to relaxed drug classification and illicit marketplaces availability, the USA has an opioid pandemic.Indeed, over the past 20 years, the USA opioid pandemic has quadrupled in mortality [20].Similarly, opioids are the main driver of fatal overdoses in Europe, responsible for approximately eight out of 10 drug-induced deaths [21].The UK and Germany, in particular, account for almost half (47%) of all opioid overdose mortalities in Europe [22].
Socioeconomic marginalisation and cultural differences affect pharmaceutical poisoning regionally.In high-income countries (HICs), medicines are responsible for over 50% of all poisonings [23].In contrast, in low-middle-income countries (LMICs) such as Ethiopia, India, and Sri Lanka, household products, organophosphates, and pesticides are the major contributors to poisonings, with pharmaceuticals accounting for as little as 10% of toxicities [24].Because a substantial portion of the population in these places rely on agriculture for money or work, such products are readily available and commonly misused [25,26].However, drug-overdose mortality is still estimated to be four times higher in LMICs compared to HICs [27].These inconsistencies are caused by differences in global medicine regulation authority.The lack of regulatory bodies in many LMICs leads to poor access to quality medicines, a higher risk of exposure to falsified drugs, poor prescribing policies, and lenient laws surrounding over-the-counter medicines, where 60% of drugs in developing countries are prescribed or sold inappropriately [28][29][30], contributing to global drug-poisoning disparities.
While extensive literature has been published on pharmaceutical poisoning in specific countries, no efforts have been made to collate this data and analyse trends globally.This would provide an overall evaluation of the key themes of pharmaceutical poisoning and highlight the impact of a country's income level on such patterns.
This scoping review aims to identify the available literature and compare the patterns of pharmaceutical poisoning between LMICs and HICs, specifically focusing on the reason(s) for exposure, the drug(s) responsible, and the medical outcome(s).All drug poi- Search results were imported into Endnote 20 (Thomson Reuters, New York, NY, USA) where they were grouped according to the database they were sourced from.Each group was then uploaded to Covidence for screening where duplicates of articles were removed.Two reviewers (CC and AL) independently screened all titles and abstracts of the remaining articles.Bibliographies of relevant studies were also checked for additional publications.Full-texts of potentially relevant studies were then reviewed independently by both reviewers to confirm eligibility according to the inclusion and exclusion criteria.Any discrepancies were discussed between both reviewers, and if a consensus could not be reached, the lead researcher (SAJ) was consulted.

Study Selection
Studies were included if they fulfilled the following criteria: (1) the study reported on poisoning due to pharmaceuticals; (2) the published date was between 1 January 2011-31 December 2020; (3) full texts and abstracts were available in English; (4) the country where the study was conducted was stated; and (5) the article stated both the reason(s) (e.g., accidental or intentional) and outcome(s) (e.g., length of hospital stay, morbidity or mortality) of the poisoning.Studies were excluded from this review if: (1) they reported on poisoning due to toxins other than medicines (e.g., household products, pesticides etc.) or there was no separation of results between different toxins; and (2) they reported on illicit drug poisoning or did not separate results between medicinal drugs and illicit substances.Reviews, systemic reviews, scoping reviews, meta-analyses, in vitro and in vivo studies, animal studies, conference abstracts or proceedings, reports, letters to the editor, and comments were also excluded.

Data Extraction and Synthesis
A data-charting form was developed to capsulate the variables required to be extracted from the included studies.This was trialed on five articles to ensure the relevant data was easily charted and the form was altered accordingly.The following data were extracted and tabulated from included studies: (1) author and year of publication; (2) study design and objectives; (3) location of the study; (4) sample size; (5) demographic characteristics including age and gender; (6) reason for exposure; (7) drug(s) responsible for toxicity; and (8) patient-related outcome(s) of poisoning.Extracted information from studies were grouped according to the income status of the country where the study was conducted.Income status was categorised into 'LMIC' and 'HIC' with reference to the World Bank Country Classifications by Income Level 2021-2022, defined by gross national income per capita [34].In order to aid identification of the common drug classifications responsible for the poisoning, the Anatomic Therapeutic Chemical (ATC) and Defined Daily Dose (DDD) (ATC/DDD) Toolkit was used to classify drugs into the organ or biological system they target [35].Some publications present the outcome of the drug poisoning according to the Poisoning Severity Score (PSS), which ranks the severity of the toxicity.The system scores poison outcomes as (0) no effect (patient is asymptomatic); (1) minor effect (mild symptoms); (2) moderate effect (prolonged symptoms); (3) severe (life-threatening symptoms with significant residual disability or disfigurement), or (4) fatal [36].Finally, age categories were defined and categorised using the WHO definition, which states that a child is under the age of 18 and an adult is 18 years or over.These categories were used when analysing patient demographic trends and the effect of age on pharmaceutical poisoning [37].Key patterns identified from the extracted data were summarised narratively with the aid of tables and charts into key categories.

Characteristics of Included Studies
The initial search identified 135,936 publications, with four additional studies identified during a manual search on Google Scholar.After screening titles and abstracts, 1359 studies met the inclusion criteria.Full texts of the 1359 studies were assessed for eligibility, where a further 1280 were excluded for the following reasons: wrong study design (n = 796), no separation of results between pharmaceutical drugs and illicit substances (n = 239), no separation of results between pharmaceutical poison and other types of poisoning (n = 111), no full-text available (n = 62), and the study failed to state the reason(s) for poisoning (n = 50) or outcome(s) (n = 22).This resulted in 79 studies being included in the data synthesis of this scoping review, as summarised in the PRISMA-ScR diagram (Figure 1).Of the included studies, eight were prospective studies: one survey, five cross-sectional studies, one cohort study, and one observational follow-up.The remaining 71 were retrospective studies: 63 cohort and eight cross-sectional studies.Tables presenting a summary of the study characteristics included in this review can be found in Tables A1 and A2 in Appendix B.

Overview
The collective sample size of participants was 1,660,165 (HICs: 1,653,519; LMICs: 6646), with ages ranging from one month old to 100 years old.Of the total study group where gender was stated, 51.1% were female (n = 694,234).Twenty-one of the studies (27%) were conducted in LMICs: one each in Algeria, Argentina, Jordan, Morocco, Romania, South Africa, and Sri Lanka; two in India, three in Turkey, and nine in Iran.Fifty-eight studies (73%) were conducted in HICs: 27 in the USA, four in Switzerland, three each in Canada, France, and Denmark; two each in Australia, Israel, Japan, Poland, Finland, and Saudi Arabia, and one study each in the Czech Republic, Republic of Ireland, New Zealand, Singapore, Taiwan, and the UK (Table 2).
Table 2. List of all countries and their economic status where studies were conducted.

Trends
The results of the scoping review are presented in three broad categories: (i) the reason behind the exposure to drug poisoning, (ii) the pharmaceutical agent responsible for toxicity, and (iii) the medical outcomes of poisonings.

Reason behind Toxic Exposure
The reason for poisoning was classified into two broad categories: intentional or unintentional (accidental).Of the overall sample size, 95% (n = 1,577,159) stated the known reason for being exposed to the drugs at toxic levels with the remaining 5% unknown.For studies that were set in LMICs, 76.2% of exposures were intentional (n = 4809).Further reasons for intentional poisoning were stated for 67% (n = 3216), with attempted suicide accounting for 91.8% (n = 2952), self-harm for 5.3% (n = 172), relationship conflicts noted for 2.2% (n = 72) and homicide for 0.6% (n = 20).For the 23.8% (n = 1503) of patients that were exposed to drug poisoning accidently, detailed reasons were given for 15% (n = 232) and included 31.5% due to careless storage (n = 72), 18.1% due to parental mistakes (n = 42), 18.5% due to therapeutic errors (n = 43), and 31.9%due to ingestion by children while playing (n = 74).

Types of Pharmaceuticals Responsible for Poisoning
Using the Anatomical Therapeutic Chemical (ATC) Classification toolkit via the WHO, causative drugs responsible for poisoning were divided into the 1st level classification, which has 14 main anatomical or pharmacological groups (Table 3).Of the studies that specifically mentioned the drug(s) responsible for the poisoning, 94.7% (n = 1,368,876) were pharmaceuticals categorised under 'Nervous System': 54% (n = 3069) and 95% (n = 1,365,780) in LMICs and HICs respectively.Looking more closely at the 'Nervous System' identified the therapeutic subgroups most commonly responsible (Table 4).In LMICs, 40% (n = 1236) of the central nervous system (CNS)-acting medicines exposed were analgesics, of which 39% were paracetamol, and 31% were from exposure to prescription opioids.In HICs, analgesics accounted for close to 60% of drugs acting on the nervous system, of which 73% (n = 567,925) were prescription opioids and 25% (n = 198,282) paracetamol.Psychoanaleptics (antidepressants, psychostim-ulants, and anti-dementia drugs) accounted for more than 30% (n = 461,019) of CNS agents.When looking at the global exposures to nervous system agents, LMICs were responsible for less than 1% of toxicities from analgesics, psycholeptics, and psychoanaleptics; 4% of drugs used in opioid dependence, and 19% of toxicities due to antiepileptics.).Across all studies, the average time hospitalised varied from 17.1 h to 13.9 days ranging from 5 h to 91 days [38,54,73].Less than 1% (n = 11,237) were admitted to the ICU due to poison exposure, where admissions accounted for 10% of the LMIC population outcomes (n = 666) and less than 1% of HIC outcomes (n = 10,571).The most common medical outcomes were all observed in less than 1% of the total study size and included acute kidney injury (n = 9126), organ failure (n = 2765), coma (n = 6776), respiratory depression (n = 6839) and seizures (n = 418).

Discussion
After synthesising the data from the 79 papers that met the inclusion criteria, specific trends between economically developed and developing countries were identified, and research gaps were recognised.

Reason behind Toxic Exposure
The disparity in reasons for pharmaceutical poisoning between LMICs and HICs was remarkable.Over 75% of LMICs' exposures were deliberate self-poisonings, with 92% further stating overdose with the intent of suicide.Previous literature has recognised the gravity of the issue in the developing world, with eight of the top ten countries with the highest suicide rates being LMICs [104].In contrast, accidental exposure to pharmaceuticals accounted for 68% of toxicities in HICs, with over 94% of these due to therapeutic errors, including administration errors, consuming multiple medicines with the same active ingredient, adverse drug reactions, and poor storage leading to child exposure.This finding may be due to more efficient error reporting and surveillance systems in developed countries [105].
With regard to the effect of age on poisoning, the results reaffirmed that child toxicities are predominantly unintentional, with adults mostly intentional in both LMICs and HICs [7].The disparity in the causes of pharmaceutical poisoning between LMIC and HIC is likely attributable to a number of socioeconomic factors, including the availability of healthcare resources, poverty, access to treatment and support services, cultural attitudes towards mental health, and other socioeconomic factors.Higher rates of intentional self-poisoning with suicidal intent in LMICs reflect a lack of access to mental health resources and support, poverty and bad living conditions, or a cultural stigma associated with seeking assistance for mental health difficulties.In contrast, accidental poisonings may be more widespread in HICs due to higher access and availability of pharmaceutical medications, and a lack of knowledge or education regarding their proper use and potential risks [106][107][108].

Types of Pharmaceuticals Responsible for Poisoning
The overwhelming majority (94.7%) of pharmaceutical toxicities worldwide were from drugs acting on the nervous system, with analgesics accounting for the largest sub-group responsible.Opioids were responsible for most analgesic exposures, with the problem largely residing in HICs, likely due to their accessibility in these areas being far greater than for LMICs, where a considerable lack of pain relief medications is available [109].Indeed, in a Lancet Commission Report, it was reported that only 0.1 metric tonne of morphine-equivalent opioids are delivered to LMICs, from almost 300 metric tonnes [110].Furthermore, overprescribing and long-term use of opioids are considered the root cause of toxicities in HICs due to risks of dependence, often leading to misuse and overconsumption [111].Medicines used in opioid substitution treatment were also commonly responsible for the poisoning, perhaps due to the vulnerability of patients receiving such treatment and the risk of co-ingesting opiates along with substitution therapy.
Findings from this review also revealed that poisoning due to psychoanaleptics accounted for the second largest subtherapeutic group in HICs, while psycholeptics were the second largest in LMICs.Similar results have previously been reported where analgesics, psycholeptics (mostly benzodiazepines), and pschoanaleptics (particularly antidepressants) were the groups largely responsible for intoxication [112].The results also matched previous findings where toxicity due to a combination of drugs was common in LMICs and HICs due to the risks of drug-drug interactions.Despite these three subgroups accounting for most pharmaceutical toxicities worldwide, LMICs were responsible for less than 1% of these poisonings meaning the problem significantly exists within HICs.However, a subgroup where LMICs were particularly accountable for the global burden was exposure to antiepileptics, where almost 20% of toxicities occurred in these developing countries.Part of the explanation may be that 85% of epileptic patients reside in LMICs [113].Furthermore, antiepileptics are approved for a number of indications besides the treatment of epilepsy, including neuropathic pain and mood stabilisation, common conditions prevalent in these areas and two major groups vulnerable to intentional overdose and suicide ideation [113,114].Additionally, access to anticonvulsants is far more attainable than analgesics in these deprived countries, particularly first-generation anticonvulsants, which are notorious for their poor safety profile with a high risk of toxicity in comparison to second-generation agents [113].

The Outcome of Pharmaceutical Poisoning
Analysing the outcome of drug-related poisoning, findings revealed that 85% and 20% of those exposed were in LMICs and HICs respectively, with the duration of hospital stay ranging from five hours to 91 days.Admissions to the ICU were over 10 times more common in the developing world, and fatality rates from overdose were almost twice as high compared to HICs.This can be explained by the intent affecting the outcome where there is a direct correlation between the dose consumed and a worse prognosis.Thus, mortalities are higher in LMICs as far larger quantities are likely to be consumed when the exposure was intentional.Furthermore, the disparities in healthcare resources are also responsible for poorer outcomes.Access to healthcare resources and poison information centres that advise on the management of poisoning is far scarcer in LMICs, leading to delayed treatment and interventions, increasing the exposure length and ultimately worsening the outcome [115].For studies in this scoping review that reported according to the PSS, most outcomes were asymptomatic and mild in severity, and very little of the study population suffered from severe (life-threatening) or fatal effects.Therefore, findings reveal that pharmaceutical poisoning is associated with more short-term illnesses and morbidities than mortality.

Future Research and Recommendations
When considering the geographical location of included studies, an uneven distribution between those conducted in LMICs and HICs was apparent.Despite over 85% of the world's population residing in LMICs, there was a poor representation of the developing world, with 73% of the studies reporting on HICs [114].Thus, obtaining an in-depth comparison of poisoning patterns between the economically developed and developing world was difficult.The low number of papers could be due to the exclusion of a large number of papers which did not separate between poisoning due to pharmaceuticals and other types of poisons.However, the lack of poison information centres partly justifies this, a major resource for collecting such data.According to the WHO, only 47% of countries have an established poison centre, with African, Eastern Mediterranean, and Western Pacific regions particularly lacking [116].Therefore, it should be a public health priority for governments to invest funding into establishing and strengthening these centres.This would not only improve surveillance for future research but also guide managing drug-induced poisons, thus improving outcomes.
Globally, the expenditure on mental health services is inadequate and is disproportionately worse in LMICs compared to HICs, with regard to the magnitude of the problem and the poisonings that arise from it [114].It is estimated that globally, there is an average of 3.96 psychiatrists per 100,000 people.However, in developing countries such as Ethiopia, India, Nigeria, and Pakistan, those rates are 0.04, 0.301, 0.06, and 0.185, respectively [114].Furthermore, within countries, there are large variations in access to mental health workers, with the majority often concentrated in urban areas meaning those living rurally have poor access and minimal support available [114].There is an urgent need to train and employ more individuals in the mental health workforce to increase accessibility to nonpharmacological treatment.This would also limit the prescribing of psycholeptics and psychoanaleptics; two major drug classes highlighted in this scoping review to be responsible for toxicities.Furthermore, setting up referral schemes after patients are discharged from an intentional overdose to provide appropriate support would reduce the likelihood of reoccurrence.
Due to the overwhelming impact of opioids on the burden of pharmaceutical poisoning, it is essential that improvements in national policies are made in the areas where opioid overdose is particularly problematic.There is an urgent need for improved legislation and policies with regard to the prescribing and duration of treatment with opioids as well as improved education on chronic pain management.Furthermore, better recognition of those requiring support from addiction services and increased access to the opioid-reversal agent naloxone would reduce the burden of opioid toxicities [117].
Those most vulnerable to opioid toxicity are often regular patients to pharmacies [118]; thus, having a supply of naloxone in every pharmacy and training staff on recognising the signs of an overdose and the protocol to follow would be immense in the prevention of life-threatening toxicities.That being said, it is important to consider the difficulties of implementing such strategies in both HICs and LMICs.In HICs such as the USA, there are relaxed policies and opioids are easily accessible [119].While in LMICs, pharmacy services are reported to be lacking, with the drive being profit over patient care [120].Furthermore, access to medicines is also limited [121], so having naloxone available in every community pharmacy may be logistically difficult.Perhaps having a national initiative scheme available to pharmacies to widen access to services within the community would help improve patient-centred care and reduce toxicities from occurring or refer those who present at risk in a reasonable time.
Many countries have yet to prioritise poisoning prevention strategies despite the severity of the issue.Public health campaigns focusing on increasing parental awareness of storing medicines in their original packaging and keeping them out of sight and reach of children are required to prevent the risk of confusing them for 'sweets' [6].Many intentional poisonings are often impulsive; thus, limiting the accumulation of medicines stored in households by promoting safe disposal via pharmacies would be an effective strategy.Such campaigns could be promoted within healthcare settings and social media should be utilised to target large audiences [122].
Several research gaps were identified whilst conducting this scoping review.As discussed above, data available from LMICs were minimal, underlining the need for more robust analytical studies to reduce the disparity and underrepresentation of the developing world.In addition, research understanding the barriers to establishing poison information centres in LMICs and how these could be addressed would be valuable for enhancing the response to drug-induced toxicity in these regions despite the availability of multiple guidelines for establishing poison centres and other aspects of dealing with poisonings [33,123].
To address the disparity in patterns of pharmaceutical poisoning between LMICs and HICs, a less costly strategy of increasing awareness would be beneficial.This could be achieved by collecting and analysing the attitudes and competencies of healthcare professionals practising outside of hospitals towards managing drug-induced poisonings.This research could identify areas where further education and awareness of resources available, such as tox-based apps, would improve the triaging of patients and reduce unnecessary referrals from community settings to emergency departments.
As well as this, the findings revealed that hospitalisation and utilisation of emergency departments is a common outcome of drug-related poisoning despite many toxicities being asymptomatic or mild in severity.Thus, attempts to collect and analyse the attitudes and competencies of healthcare professionals practising in sectors beyond hospitals in advising and managing drug-induced poisons would be valuable.Additional personnel or qualified emergency physicians and the development of multidisciplinary teams in major hospitals in LMICs are also required to address the issue of pharmaceutical poisoning better.This will ensure that patients in emergency settings receive prompt and effective care and lessen the burden on the healthcare system.
Generative AI technology has the ability to revolutionise how individuals obtain information about poisonings and seek medical care.By providing free and immediate access to information about various types of poisonings, their symptoms, and risk reduction strategies, this technology can assist individuals in determining if they or someone they know has been exposed to a harmful substance, thereby facilitating more targeted and effective treatment.There are limitations to chatbot AI technology despite its potential benefits.Challenges such as the quality and diversity of training data, the limitations of preprogrammed responses, and platform constraints can impact the accuracy and relevancy of the delivered information.It is crucial to use chatbot AI technology to complement professional medical advice, not as a replacement.

Strengths and Limitations
This scoping review is the first attempt to collate the broad field of literature and identify patterns of pharmaceutical poisoning at a global level.A few limitations were noted.Firstly, only articles that were available in English were included, which likely limited the data available in non-native English-speaking countries.Secondly, a large number of initial studies were found during the search.Despite this ensuring all relevant papers were captured, it perhaps reflects that the search strategy was not specific enough to the study's aims.We also excluded from the scoping review all categories of reports, ranging from individual institution annual reports to health organization reports, that would have provided a deeper understanding of the trend.However, this will necessitate translation in addition to other difficulties, as not all nations have such reports.
Thirdly, the USA was overrepresented in this review accounting for 47% of HIC studies.Although this highlights the ongoing issues in the USA with the opioid epidemic, it reduces the attempt to analyse trends of pharmaceutical poisoning in HICs in general.In addition, the reported trend may be understated due to the availability of panels of substance analysis in various nations.Despite this, the majority of poisoning cases are treated based on clinical judgment of the information acquired, and drug concentration monitoring is not always used to determine causality.Finally, where articles collected the data from poison databases, this often required voluntary reporting.Self-reported data has the potential risk of bias, thus, the accuracy of poison reports is unknown.Furthermore, data is also compiled from the volume of calls poison centres receive from physicians.However, many physicians are familiar with the diagnosis and management plan for oftenoccurring toxicities and so do not need to refer to the centres for advice.Thus, the available data is unlikely to comprehensively reflect the magnitude of the problem.

Conclusions
This review is the first attempt to analyse the data available on pharmaceutical poisoning worldwide.Findings reveal that most drug toxicities are intentional in LMICs and accidental in HICs.Globally, the problem mostly lies with drugs acting on the nervous system, particularly analgesics, and medical outcomes from poisoning are generally worse in LMICs.Implementation of the suggested recommendations including the establishment of poison information centres worldwide, strengthening mental health resources, tightening medicine regulations, improving healthcare professional awareness surrounding drug toxicity and public health prevention campaigns would make a positive contribution towards alleviating the burden of these preventable injuries.Despite recognising the epidemiological patterns of poisoning, gaps in the literature were recognised calling for more robust analytical research.

Figure 2 .
Figure 2. Comparing the reason behind pharmaceutical poisoning between LMIC and HIC's.

Table 4 .
Drugs responsible for poisoning in LMIC and HIC studies categorised into the ATC 2nd level classification for drugs acting on the nervous system.

Table A1 .
Characteristics and data extracted from included studies set in low-middle income countries.

Table A2 .
General characteristics of included studies set in high-income countries.

Table A2 .
Cont.Where available, age ranges are displayed in brackets below the noted age categories and mean age of the sample size.