The US FDA Adverse Event Reporting System (FAERS): A Complementary Source of Intoxication Data

The stable growth in the reporting of DSPs to the FAERS in the last two decades, primarily from the US and Europe, is plausibly related to both the evolution of spontaneous reporting systems and to the increase in suicides observed in the US [3]. Reassuringly, we observed no increase in fatal DSPs, supporting the efficacy of current preventative approaches focused on reducing the fatality of available means rather than the frequency of attempts. With more than 40,000 DSP reports at the end of 2021, the FAERS is emerging as an alternative source of fatal and non-fatal intoxication data, complementing already in-use forensic and non-forensic sources.

Monitoring Trends and Seasonality

FAERS data provide a source to timely and cheaply monitor variations in DSP reporting. We found a seasonality with higher peaks of reporting in the winter and lower peaks in June, and major peaks in DSP reporting in 2007–2008 and 2019–2020. Studies supporting winter [40] and spring peaks [41, 42] exist, and major events, such as the global financial crisis in 2007–2008 and the coronavirus disease 2019 (COVID-19) pandemic in 2019–2020, may indeed have precipitated cases of suicidal ideation [43]. Nonetheless, whether trends in the reporting represent trends in events is highly debatable. When investigating the available event dates, most of these results were lost. Therefore, speculations about DSP trends should carefully consider the kind of date chosen, and also the potential bias resulting from regulatory actions and mass media communications [44]. For example, we observed a peak in varenicline DSP in 2007, in correspondence with an FDA investigation on varenicline-induced suicidal ideation and self-harm. The FDA added a black-box warning to the varenicline package insert in 2009, but subsequent studies failed to establish causality and the warning was removed in 2016 [45].

Identifying Targets for Preventative Approaches

FAERS intoxication data provide a promising source to identify drugs reported in DSP and drive preventative actions. Coherently with recent studies [46], the most common means for DSP were psychotropic (i.e., antidepressants, antipsychotics, anxiolytics, and sedatives) and analgesic drugs (i.e., paracetamol, opioids, and NSAIDs), together with antiepileptics, antihistamines, amlodipine, metformin, and varenicline. Paracetamol was by far the most widely recorded drug, at least partly because of its availability. Anxiolytics and opioids played a less important role in DSP compared with previous findings [10]. This inconsistency can have both temporal and geographical explanations since FAERS data allow information to be obtained for quite an extended period (2004–2021) from many different countries.

More than 50% of DSP reports recorded multiple substance intake (elsewhere estimated at 56.3% [47]), which was associated with a higher CFR. The network analysis highlighted a trend to use drugs of the same therapeutic area together (i.e., psychotropic, analgesic, and cardiovascular/metabolic). This peculiar pattern of use is plausibly explained by availability, with paracetamol being present in every house. The other available drugs depend on the pathologies diagnosed to the house inhabitants [48].

Drugs from the pain cluster showed an important role in fatal DSPs (oxycodone, 60.8% of fatalities), because of both their lethality and their potential for abuse, but plausibly also for resistant pain as a risk factor for committing suicide [49]. Another drug with a high reported fatality was bupropion (CFR 34.6%), plausibly because it is more available to people with a higher determination towards suicide since it is approved to palliate suicidal ideation. Patients taking bupropion to commit suicide may therefore take higher doses, combine multiple drugs, or attempt suicide when and where it is more difficult for healthcare professionals to intervene. These results were in line with previous findings [10] that opioid and antidepressant overdoses are more lethal than overdoses with other pharmaceuticals, and point to the need for further preventative interventions targeting these drug classes.

Identifying Potential Risk Factors

A large body of research has focused on the demographics of suicide victims, the methods people use to take their own lives, and the means of prevention. It is well known that traumatic deaths are common in male victims, whereas females prefer less violent deaths and less fatal means, although this depends on age, nationality, and mental health status [1, 6, 50].

FAERS rich data allow to further characterize DSP demographics. We found a higher reporting of DSP in young adults (37 [23–51]), with fatalities being reported more often in older men. Both alcohol use and psychiatric comorbidities were more common in DSPs.

Alcohol represents the psychoactive substance most commonly identified in blood samples in suicidal poisonings [48, 51]. The recording of alcohol use, plausibly describing acute consumption of moderate-to-high doses, was more frequent in fatal DSPs. Alcohol may therefore not only be associated with an increased risk of suicide attempts [52] but also with a greater intent to die, although existing evidence suggests that at very high alcohol doses less lethal means are chosen [53].

The finding that psychiatric comorbidity was less recorded in fatal than in non-fatal DSPs may be related to not only the prophylactic value of the psychiatric care [54] but also to the fact that relapsing suicide attempters are usually diagnosed with a psychiatric condition and may contribute with multiple reports of attempted suicide.

Characterizing Drug-Specific Deliberate Self-Poisonings

FAERS data may also be used to characterize drug-specific DSPs, including their toxidrome.

Paracetamol overdose represents the most common DSP in the industrialized world [55] and a growing problem in developing countries [56]. Coherently, paracetamol was the main drug reported as a primary suspect in both fatal and non-fatal DSP cases. In 54% of cases, paracetamol recorded at least one concomitant (primarily analgesics and alcohol). It is the drug involved in DSP with the highest concomitance with alcohol use, with potential dose-dependent interactions [57, 58]. Being the most available drug, its temporal trend and demographic distribution shape and reflect the temporal trend and the demographic distribution of DSPs. It showed peaks of reporting in 2007, 2015 and 2020, and a higher contribution by women and younger people. The association of paracetamol overdose with hepatic disorders (e.g., acute hepatic failure) and nausea, coherently with the literature [59], supports the utility of our method to identify toxicity events. Its reported CFR was 24.3%, and higher in multiple drug intake (32%). This reported CFR, much higher than in clinical trials [59], may be related to a differential reporting rate of serious and non-serious DSP cases.

Promethazine DSP reports were mostly submitted in Sweden in 2018–2019. Indeed, in Sweden, both promethazine sales and DSP cases have recently peaked [60]. Promethazine overdoses are much more commonly reported in women (75.3%) and affect the youngest population among the five drugs investigated (24 [18–33]). In 37% of cases, it was reported with at least one concomitant, the most frequent being zopiclone, propiomazine, and paracetamol. Its reported CFR was the lowest (0.5%; only seven fatal cases). Although we found that almost all DSP reports with promethazine specified suicide as a reason for use, this active ingredient is used in many different formulations as a recreational (euphoric and hallucinogenic) drug (e.g., ‘purple drank’ [61]). A study on promethazine abuse/misuse in EudraVigilance (the European spontaneous reporting system) found 557 cases and a reported CFR of 55% [62]. This difference in the reported outcome should be further investigated and may be related to potential differences in the relevant catchment areas and peculiar pattern of drug use. We found the main feature of promethazine overdoses was delirium, associated with akathisia, anxiety, confusion, somnolence, and mydriasis, which were also the main events reported in observational studies [62]. We could not calculate the dose-lethality relationship since we only found seven fatal cases.

Amlodipine (a concomitant in at least 61% of cases) and metformin (a concomitant in at least 39% of cases) instead had a higher contribution by men and older people. Metformin recorded a higher reported CFR (20.3% death and 32.5% life-threatening overdoses), while amlodipine recorded fewer deaths (13.9%) but more life-threatening events (40.1%). Metformin overdose was associated primarily with acidosis, and also with shock, frequently concomitant with severe renal impairment. This toxidrome is commonly known as MALA (metformin-associated lactic acidosis), an event that rarely occurs at therapeutic doses [63] in the lack of independent risk factors [64]. Amlodipine was associated primarily with shock and also with acidosis. This toxidrome includes severe hypotension and reflex tachycardia, and may culminate in pulmonary edema and cardiovascular shock with fatal outcome [65]. Furthermore, we found that both drugs were reported with respiratory failure and acute kidney injury, and were reported to affect glycemia (mainly increased in amlodipine, decreased in metformin) and hypokalemia in amlodipine and hyperkalemia in metformin). Finally, metformin was associated with vomiting, while amlodipine was associated with cardiac arrhythmias and heart failure. In 119 cases they were reported together.

Quetiapine is frequently used for conditions at high suicide risk, such as psychotic and mood disorders [66]. The 2-week delay in therapeutic effect requires careful monitoring of these patients, especially in the early stages of treatment and following dosage changes. Quetiapine recorded a higher contribution by women (65.4%) and was often reported together with paracetamol, venlafaxine and diazepam, primarily with sedation and coma, and with aspiration pneumonia. In general, the reported signs and symptoms of quetiapine DSP can be attributed to enhancement of the known pharmacological effects of the drug [67].

Estimating LDs

FAERS data also include information about the therapy regimen and dosages. It may therefore allow a dose–lethality relationship in humans to be estimated.

For paracetamol, the high number of reports with a specified dose, and the heterogeneity in exposure levels, allowed us to investigate the relationship between doses and lethality. Our model estimated LD25 ≈ 150g, LD50 ≈ 250g, and LD75 ≈ 325g. Although it allowed the general trend of fatality in DSPs to be predicted, the paracetamol exposure level was only able to explain very little of the variability in individual outcomes, which plausibly depends also on weight, comorbidities, concomitants, dilution in time, medical intervention, and route of administration (e.g., a few cases specified that the drug was smashed and snorted). With FAERS data, which are often incomplete and unverified, it is difficult to have an homogenous compilation of all the fields, and therefore it is difficult to design more accurate models. Although the Rumack–Matthew nomogram already predicts the risk of hepatotoxicity associated with paracetamol concentration [68], it does not accurately work in case of repeated overdose, when the formulation is slow-release, when the time of ingestion is unknown, or when patients present after more than 24 h. Therefore, new tools have been developed to predict the risk of hepatotoxicity based on reported doses [56]. Our model may lead to the development of a complementary tool able to predict lethality.

The low number of reports specifying the accurate dose of intoxication for the other drugs did not allow us to obtain a satisfying logistic regression model. It is possible that, in the future, the collection of more data will allow a better logistic regression to be performed.

Limitations and Strengths

Our study has limitations inherent to spontaneous reporting systems analysis (e.g., underreporting, unverified and incomplete reports, notoriety bias). Therefore, the use of the FAERS is appropriate only to generate hypotheses to be verified by further studies.

A first, more specific, limitation lies within the definition of the query for case retrieval. Our study focused on DSP, identified using the MedDRA terms ‘self-poisoning deliberate’ and ‘intentional overdose’. In this way, we deliberately excluded unintentional pharmaceutical overdose deaths (estimated to be 83% of the total overdose deaths [69]) and accidental overdoses due to intentional exposure (e.g., a patient taking the dose twice because forgetting the first administration should be reported using more appropriate combinations of terms: ‘product dose confusion’, ‘extra dose administered’, ‘accidental overdose’). Instead, we could not exclude a priori that our query might retrieve some non-suicidal intentional overdose reports as DSP (e.g., opioid abuse [70], and promethazine to experience hallucinations [61]), but the fact that, a posteriori, most DSP reports retrieved also recorded suicide-related terms reassured us that this was a minor problem.

A second more specific limitation lies with the possibility that some specific systematic biases linked to suicide may confound our analyses. For example, it is possible that fatal attempts were reported more often than non-fatal attempts, leading to the reported CFR being an overestimation of the real fatality rate. On the other side, it is plausibly easier to obtain information on the dosage for non-fatal cases, resulting in underestimated (lower) dose-lethality curves. Furthermore, many factors, apart from the ingested dose, may influence the outcome, including the concomitants, the lack or delay of medical intervention, and the route of administration. Spontaneous reports do not allow us to confidently take them into account.

Because of its general scope, this study may have overlooked specific drugs that, while not being the most reported, are particularly lethal, on the rise [71, 72], or commonly abused in parties [73]. Furthermore, even if the FAERS gathers reports from the entire world, 94% of the cases are from North America and Europe, and its representativity for other continents, and in particular for the global South, is limited.

Apart from these limitations, spontaneous reporting systems allow the inexpensive collection of timely and large amounts of information from the entire world and from complex and heterogeneous conditions. Compared with other sources of forensic data, they allow the collection of information on both fatal and non-fatal events, and on any kind of drug. The high number of rich-in-information reports gathered by the FAERS may be used for a drug-by-drug assessment useful to design more informed and specific regulatory interventions. Its real-time representativity, in particular, may detect emerging problems in a timely manner and drive appropriate interventions to limit intentional overdose deaths. The dosage information, when enough data are gathered and accurately cleaned, may also be useful in estimating real-world LDs. Our methodology may therefore be applied to the FAERS to investigate more specific emerging problems. It could also be applied to other, more representative databases to gain a better insight on specific countries or regions.