Abstract
Spontaneous reporting is based on the experience of all healthcare professionals (HCPs) but also consumers/non‐HCPs and therefore reveals a broad picture of a drug's adverse reactions. Recent studies found substantial differences between reports from these varying sources including the reports' completeness. Using the example of opioid‐associated abuse, dependence, or withdrawal, this study analyzed the completeness and characteristics of spontaneous reports from Germany focusing on the reporter. Based on EudraVigilance data, we included all cases of abuse, dependence, or withdrawal associated with opioids indicated for pain therapy and filed from Germany until 2018. Completeness and characteristics were analyzed by a reporter (physician, pharmacist, other HCPs, consumers/non‐HCPs) and also by time period to account for other influencing factors. In total, 1721 cases were included, mainly filed by physicians (38.5%) and pharmacists (30.7%). Completeness of demographics varied from 74.5% (other HCPs) to 42.7% (consumers/non‐HCPs). Consumers/non‐HCPs most often provided any indication/comorbidity (75.2%), whereas this was the case for only 20.2% of pharmacists. Large differences between the reporters were found for almost all characteristics. Other HCPs far more often coded a history of drug abuse, dependence, or withdrawal than other reporters (46.9% vs. 11.6%–24.2%, respectively), and fatal outcomes were also mainly filed by other HCPs (68.1% vs. 14.8%–20.4% by all other reporters). Differences in completeness and characteristics were also observed over time. Studies analyzing spontaneous data should consider potential differences between the various reporting groups in terms of completeness and characteristics. Further, the impact of other influencing factors has to be assessed.
Keywords: abuse, completeness of reports, dependence, EudraVigilance, opioids, spontaneous reporting, withdrawal
1. PURPOSE
Spontaneous reporting is a mainstay of pharmacovigilance since it allows monitoring a drug's safety throughout its complete (post‐marketing) life cycle. 1 , 2 Reports cover all potential users and are based on the experience of all healthcare professionals (HCPs) 1 but also consumers/non‐HCPs therefore revealing a broad picture of adverse drug reactions (ADRs). An ADR is a response to a medicinal product that is noxious and unintended and which may arise from use within the terms of the marketing authorization or (following changes in July 2012) also outside these terms (including off‐label use, overdose, misuse, abuse, and medication errors). 3
The usefulness of spontaneous reports depends on their completeness and accuracy. 4 In the WHO's VigiBase the completeness varied substantially between reporters with physicians filing the highest proportion of well‐documented reports (24%). 4 A recent study based on the United States (US) Food and Drug Administration adverse event reporting system (FAERS) found that the completeness of indication(s) was far higher in reports filed by consumers than in those by physicians and other HCPs. 5 Further, consumers tended to report concomitant drugs more completely than pharmacists, physicians, and other HCPs. 5 Another analysis based on FAERS data observed that consumers were more likely to report other opioid‐related ADRs than HCPs. 6
In Germany, ADR reporting is determined by physicians' and pharmacists' professional regulations, and although consumer reporting was possible before, since 2012, after legal changes in the European Union (EU), 7 direct online forms for consumers are available. The number of spontaneous reports has been rising steadily and reporting has noticeably increased from pharmacists/other HCPs and from patients. 8 However, studies based on spontaneous reports do often not analyze potential differences between these varying sources in terms of the reports' completeness and characteristics. We used the example of opioids and the ADRs abuse, dependence, and withdrawal to analyze the characteristics and completeness of reports from Germany focusing on the reporter's occupation/role.
2. METHODS
2.1. Study design, data source, and case identification
We performed a retrospective analysis based on data from EudraVigilance, a system collecting information on suspected ADRs for authorized medicines in the European Economic Area (see Supplement for further information). 2 Cases were identified according to the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) “drug abuse, dependence, and withdrawal” (narrow search, see Table S1).
We included all cases from Germany filed until 2018 and referring to opioids indicated for pain therapy as suspected or interacting drugs: tilidine (incl. combinations with naloxone), tramadol, morphine, fentanyl, oxycodone, oxycodone/naloxone, hydromorphone, and tapentadol. We excluded, for example, levomethadone or the fixed combination buprenorphine/naloxone since several brands containing these agents are indicated for opioid substitution therapy (see Supplement for further information).
2.2. Characteristics and completeness of information
Examining the respective data elements, we included the following items: The reporter's occupation was ranked (physician, pharmacist, other HCP, and consumer/non‐HCP). For each case, age and sex were assessed. Using different levels and groupings of MedDRA (i.e., preferred terms, system organ classes, SMQ), information on (potential) indication and comorbidity/medical history was extracted from the respective fields. Fields containing additional free texts were not included. The duration of opioid use was converted into days. Examined medication encompassed also recreational drugs and whether at least one other medication besides the opioid(s) was coded. Last, the ADR's seriousness (i.e., the reaction results in death, is life threatening, requires hospitalization or prolongation of hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or other medically important information) and outcome (i.e., fatal vs. nonfatal) were examined. For all variables, comprehensive plausibility checks were performed.
Completeness was analyzed separately for each item. If a given item (e.g., age) was coded as unknown or no information was provided, information for this item was considered missing.
2.3. Statistical analyses
First, we calculated the proportion of completeness for each item (i.e., the number of reports with nonmissing information for the item divided by the number of all reports) by reporter. Second, we analyzed case characteristics using descriptive statistics (median, interquartile range [IQR], and percentages). Only reports with nonmissing information for the respective item were included in these analyses. Third, time trends were displayed by reporter and opioid(s). Fourth, subgroup analyses were conducted for the most commonly reported drug (tilidine). Last, analyses were rerun stratified by reporting period (before 2013 vs. 2013–2018) to account for legal changes at the end of the former period. These changes relate to (i) consumer reporting, (ii) the ADR definition, and (iii) the scheduling status of tilidine (immediate‐release preparations becoming subject to the regulations of the Narcotic Drugs Prescription Ordinance, see Supplement for further information).
All analyses were performed using SAS, Version 9.4 (SAS Institute Inc).
Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 9 and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20. 10
3. RESULTS
In total, 1721 cases of opioid‐associated abuse, dependence, or withdrawal from Germany were included (1980–2018, Figure 1) with the sharpest increase from 2002 to 2003 (+213%). Reports were mainly filed by physicians (38.5%) and pharmacists (30.7%) and to a lesser extent by other HCPs (14.1%) and consumers/non‐HCPs (12.0%). The most commonly reported drugs were tilidine (27.8%) and tramadol (26.1%), followed by morphine (12.3%) and fentanyl (11.9%), displaying substantial variations by year (Figure S1).
FIGURE 1.
Number of reports of cases of opioid‐associated abuse, dependence, or withdrawal from Germany by reporter and year. HCP, health care professional.
Overall, a case's sex was more often reported than their age, and complete demographic information ranged from 74.5% (other HCPs) and 69.4% (physicians) to 42.7% (consumers/non‐HCPs, Table 1). Consumers/non‐HCPs most often provided any indication/comorbidity (75.2%) and the ADR's outcome (59.2%) whereas these items were least complete in pharmacy‐filed reports (20.2% and 17.6%, respectively).
TABLE 1.
Characteristics of cases of suspected opioid‐associated abuse, dependence, or withdrawal from Germany by reporter.
| Physician (N = 663) | Pharmacist (N = 529) | Other HCP (N = 243) | Consumer/non‐HCP (N = 206) | Overall (N = 1721) | |
|---|---|---|---|---|---|
| Opioid(s) | (N = 663; 100%) | (N = 529; 100%) | (N = 243; 100%) | (N = 206; 100%) | (N = 1721; 100%) |
| Tilidine (incl. combinations with naloxone) | 18.6% | 52.4% | 12.3% | 16.0% | 27.8% |
| Tramadol | 26.8% | 26.5% | 21.8% | 33.0% | 26.1% |
| Morphine | 9.5% | 4.0% | 39.1% | 5.3% | 12.3% |
| Fentanyl | 14.9% | 8.5% | 9.9% | 16.5% | 11.9% |
| Oxycodone | 11.2% | 3.2% | 7.0% | 13.1% | 9.2% |
| Oxycodone/naloxone | 5.3% | 1.5% | 0.8% | 5.8% | 3.3% |
| Hydromorphone | 3.5% | 0.9% | 1.2% | 0.5% | 2.0% |
| Tapentadol | 3.0% | 0.2% | 0.8% | 2.4% | 1.6% |
| Multiple opioids | 7.2% | 2.8% | 7.0% | 7.3% | 5.8% |
| Age (years) | (N = 455; 68.6%) | (N = 291; 55.0%) | (N = 176; 72.4%) | (N = 89; 43.2%) | (N = 1073; 62.3%) |
| Median (IQR) | 45 (30–58) | 37 (26–49) | 39 (31–50) | 47 (32–66) | 41 (29–54) |
| Age group | (N = 465; 70.1%) | (N = 292; 55.2%) | (N = 183; 75.3%) | (N = 89; 43.2%) | (N = 1091; 63.4%) |
| <18 years d | 10.1% | 9.2% | 7.1% | 3.4% | 8.4% |
| 18–39 years | 29.7% | 45.5% | 45.4% | 32.6% | 38.0% |
| 40–59 years | 38.1% | 33.9% | 34.4% | 27.0% | 35.3% |
| 60–79 years | 16.1% | 8.9% | 10.4% | 28.1% | 13.8% |
| ≥80 years | 6.0% | 2.4% | 2.7% | 9.0% | 4.4% |
| Sex | (N = 637; 96.1%) | (N = 458; 86.6%) | (N = 209; 86.0%) | (N = 191; 92.7%) | (N = 1539; 89.4%) |
| Female | 49.5% | 42.1% | 40.5% | 41.4% | 45.0% |
| Male | 50.5% | 57.9% | 59.5% | 58.6% | 55.0% |
| Information on age group and sex | (N = 460; 69.4%) | (N = 289; 54.6%) | (N = 181; 74.5%) | (N = 88; 42.7%) | (N = 1054; 61.2%) |
| Indication/comorbidity (history of…) e | (N = 364; 54.9%) | (N = 107; 20.2%) | (N = 98; 40.3%) | (N = 155; 75.2%) | (N = 751; 43.6%) |
| Pain a | 37.1% | 43.0% | 19.4% | 41.9% | 35.4% |
| Musculoskeletal and connective tissue disorders b | 35.2% | 24.3% | 17.3% | 37.4% | 31.7% |
| Neoplasms benign, malignant and unspecified incl. cysts and polyps b | 7.7% | 4.7% | 4.1% | 3.2% | 5.6% |
| Depression (excl. suicide/self‐injury) c | 15.7% | 0.9% | 14.3% | 6.5% | 11.5% |
| Suicide/self‐injury c | 8.8% | 0.9% | 14.3% | 0.0% | 6.3% |
| Drug abuse, dependence or withdrawal c | 24.2% | 15.9% | 46.9% | 11.6% | 23.2% |
| Duration of opioid use (days) | (N = 242; 36.5%) | (N = 24; 4.5%) | (N = 46; 18.9%) | (N = 61; 29.6%) | (N = 379; 22.0%) |
| Median (IQR) | 1 (1–29) | 52 (17.5–161.5) | 1 (1–1) | 366 (5–1827) | 1 (1–184) |
| Medication/drugs e | (N = 663; 100%) | (N = 529; 100%) | (N = 243; 100%) | (N = 206; 100%) | (N = 1721; 100%) |
| At least one other medication/drug | 70.1% | 23.8% | 76.1% | 43.2% | 53.1% |
| Antidepressants | 21.7% | 4.3% | 22.6% | 7.3% | 14.2% |
| Antipsychotics | 9.0% | 0.9% | 7.8% | 3.9% | 5.5% |
| Benzodiazepines | 21.0% | 7.0% | 28.8% | 11.7% | 16.9% |
| Drugs for opioid dependence | 4.2% | 0.6% | 27.2% | 2.4% | 6.0% |
| Alcohol | 8.6% | 0.0% | 10.7% | 2.4% | 5.4% |
| Cannabis | 1.5% | 0.2% | 9.1% | 1.0% | 2.0% |
| Cocaine | 0.6% | 0.4% | 13.6% | 0.5% | 2.6% |
| Seriousness criteria f | (N = 603; 91.0%) | (N = 359; 67.9%) | (N = 239; 98.4%) | (N = 192; 93.2%) | (N = 1447; 84.1%) |
| Any criterion fulfilled | 98.7% | 96.9% | 99.6% | 97.9% | 98.3% |
| Outcome | (N = 345; 52.0%) | (N = 93; 17.6%) | (N = 135; 55.6%) | (N = 122; 59.2%) | (N = 750; 43.6%) |
| Fatal | 14.8% | 20.4% | 68.1% | 14.8% | 29.9% |
Notes: For 77 cases, no reporter qualification was given. The qualification “lawyer” (three cases) was not reported separately.Ns in brackets represent the denominators excluding missing and “unknown” information, the percentages refer to the resulting completeness for the respecting item. For instance, 637 of 663 reports submitted by physicians included valid information on sex, which is displayed as “(N = 637; 96.1%).” The proportions of females (49.5%) and males (50.5%) refer to these 637 reports.
Abbreviations: HCP, health care professional; IQR, interquartile range.
Preferred term.
System organ class (SOC).
Standardized MedDRA Query (SMQ).
Includes cases with a coded age group referring to persons <18 (e.g. adolescents).
Multiple indications/comorbidities, medication/drugs possible.
Includes “results in death,” “life threatening,” “requires hospitalization/prolongation of hospitalization,” “results in disability/incapacity,” “congenital anomaly/birth defect,” and “other medically important information.”
Large differences were found between the reporters' mainly coded opioids (tramadol (physicians, consumers/non‐HCPs), tilidine (pharmacists), and morphine (other HCPs)) and all other characteristics except whether any seriousness criterion was fulfilled. Other HCPs far more often recorded a history of drug abuse, dependence, or withdrawal than other reporters (46.9% vs. 11.6%–24.2%, respectively). The median duration of opioid use varied between 1 day (physicians, other HCPs) and 366 days (consumers/non‐HCPs). Cases with a reported duration of use and a history of suicide/self‐injury (n = 23) used opioids for a median of 1 day (IQR: 1–1) whereas it was 184 days (IQR: 4–1095) in those with only other indications/comorbidities (n = 171, data not shown).
Use of any other medication/drugs was often reported by other HCPs (76.1%) and physicians (70.1%) but by only 23.8% of pharmacists. Fatal outcomes were mainly filed by other HCPs (68.1% vs. 14.8%–20.4% by all other reporters).
The proportion of consumer/non‐HCP reports increased from 8.7% before 2013 to 18.5% in 2013–2018 (Table S2). Reactions referring to drug abuse and dependence slightly decreased (91.6% vs. 87.1%). The proportion of completeness for demographics was slightly lower in the later time period whereas reporting of indication/comorbidity improved during the study, especially in pharmacist‐filed reports. While overall fatality increased from 25.7% (before 2013) to 34.5% (2013–2018), the increase was most pronounced for pharmacists (5.7% to 29.3%) and other HCPs (38.6% to 82.4%).
Completeness of demographics in tilidine‐associated cases was slightly higher compared with all cases, whereas all other items were less complete (Table S3). Tilidine cases were more often male and reports were less often fatal but overall patterns were comparable to all cases.
4. DISCUSSION
Using the example of suspected opioid‐associated abuse, dependence, or withdrawal as defined by MedDRA terminology, we found that cases from Germany differed substantially by reporters in terms of completeness and case characteristics but also when comparing two different time periods.
4.1. Completeness of information
Overall, reporting for several items was less complete compared to studies based on FAERS or French pharmacovigilance data. 5 , 11 While about 70% of reports by physicians and other HCPs in our study were complete for demographics with more missing information for the other items, pharmacies' reports were least complete with respect to almost all items. This tendency was also observed in VigiBase where (overall and in Germany) pharmacists' reports were less often well‐documented than those by physicians. 4 This is in contrast to other studies where pharmacists provided the most complete information for concomitant drugs/the ADR's outcome 11 and the drug's indication, respectively. 5 German pharmacists lack knowledge of indication/medical history since these are not (generally) mandatory on the prescription forms. The often missing information for demographics, however, may indicate that German pharmacists consider their role in ADR reporting as less important. 12 However, given this study's focus, pharmacies might be the only place where nonmedical use of opioids reveals itself via prescription form tampering (although coded rarely in our analysis). Further, if patients fill their prescriptions in one pharmacy, parallel prescribing by several physicians (“doctor shopping”) might be detected here. Therefore, complete case characteristics seem crucial. Consumers' reports were surprisingly complete, especially with respect to indication. Good reporting was also found by a US study which concluded that consumers may be more meticulous and eager to report all information compared with HCPs since the latter are often under time pressure. 5
4.2. Different opioids and clienteles
Reports filed by physicians and consumers were dominated by tramadol, the most frequently misused opioid according to a German internet drug forum. 13 In contrast, pharmacies most often reported tilidine, which, before legal changes, had been commonly issued on private prescriptions. 14 Therefore, and specific to this setting, the reason for this drug's dominance might be attributed to the different clienteles. Interestingly, when considering the most recent years, the high number of reports referring to tramadol (2017) and morphine (2018) do not reflect German trends in opioid prescription volumes which especially in the last years are largely dominated by tilidine. Although opioid prescription volumes in Germany increased during the study period, the sharpest increases observed in our study (e.g. 2002/2003 or 2004/2005) seem not to be mirrored by general trends (see Supplement).
In reports by physicians, most likely reflecting usual medical care, musculoskeletal disorders dominated as a potential indication, and a history of abuse was common as was depression. While pharmacies, in terms of general characteristics, seemed to describe less serious cases, other HCPs recorded high proportions of recreational drugs and/or abuse history, and the highest fatality. This seems in line with the high proportion of a history of suicide/self‐injury and the short time of opioid use being mostly coded by physicians and other HCP pointing to a context outside usual medical care such as emergency services or emergency rooms. Finally, consumers' reports most often referred to long‐term use; opioid dependence and withdrawal were common and are likely to be detected in a private setting. Further, and in accordance with other studies, ADRs that are perceived subjectively or affect quality of life such as fatigue was most commonly reported by consumers. 6 , 7 , 8
4.3. Legal changes during the study period
The increase in consumer reporting, as also observed in a EudraVigilance‐based study analyzing patient reporting in the EU, 7 affected the composition of reporting groups. These changes may dilute or mask other effects such as the increase of fatal reports by pharmacists and other HCPs observed in our study which was less pronounced in the overall group. The slight changes we found with respect to the reported reactions may be influenced by the general changes (broadening) of the ADR definition. However, since the number of unreported cases is not known, this cannot be verified. Last, changes in the scheduling of tilidine led to a substantial decrease in reports referring to this opioid and (by extension) the reporting by pharmacists which, again, probably influenced the results for the two time periods.
4.4. Strengths and limitations
The study's strengths are the large series of reports covering nearly 40 years and the consideration of the different groups of HCPs and consumers/non‐HCPs. Limitations are attributed to the nature of the data such as probable underreporting 1 which is disproportionally often observed for older drugs and known ADRs. 15 Therefore and since the number of users of the respective opioids is unknown, conclusions in terms of risks cannot be drawn. Although focusing on opioids indicated for pain therapy, products might have been used in the context of opioid replacement therapy.
It also seems conceivable that other reporting obstacles including unfamiliarity with the spontaneous reporting system 15 might differ between reporters. It was further not possible to determine whether data were unknown/unavailable or the reporter chose not to include them. Additionally, the setting (in‐ vs. outpatient) is not provided by EudraVigilance. The same applies to the specialties of the reporting physicians and the other HCPs which hampers the interpretation. Reporters are confronted with different opioids and clienteles/settings, it is therefore not possible to disentangle these effects, however, reporting differences were still pronounced when considering only one drug and smaller time periods.
Last, our study was based on only one country which hampers generalization but supports that the observed differences relate to the reporters and not the (different) healthcare systems.
5. CONCLUSIONS
Using the example of opioid‐associated abuse, dependence, or withdrawal, we found that reporting characteristics and the completeness of reported items differed substantially depending on the reporter. Further, several regulatory and legal changes during the study period probably influenced our findings. It seems plausible that these aspects also affect studies examining other drugs and/or ADRs. Therefore, when analyzing spontaneous data, potential differences between the various reporting groups in terms of completeness and characteristics as well as the impact of other influencing factors have to be considered.
AUTHOR CONTRIBUTIONS
Falk Hoffmann and Kathrin Jobski designed the study, wrote the protocol, undertook the statistical analysis, and wrote the first draft of the manuscript. Carsten Bantel provided clinical expertise and wrote the manuscript.
FUNDING INFORMATION
No funding was received for this study.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
ETHICS STATEMENT
For this study, a waiver was obtained from the Medical Ethics Committee of the Carl von Ossietzky University Oldenburg (2019‐043).
Supporting information
Data S1
ACKNOWLEDGMENTS
The authors would like to thank the European Medicines Agency (EMA) for providing the data. Open Access funding enabled and organized by Projekt DEAL.
Jobski K, Bantel C, Hoffmann F. Characteristics and completeness of spontaneous reports by reporter's role in Germany: An analysis of the EudraVigilance database using the example of opioid‐associated abuse, dependence, or withdrawal. Pharmacol Res Perspect. 2023;00:e1077. doi: 10.1002/prp2.1077
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from EMA. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the authors with the permission of EMA.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1
Data Availability Statement
The data that support the findings of this study are available from EMA. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the authors with the permission of EMA.