K. Ing Lorenzini1, L. Wainstein1, F. Curtin1, V. Trombert2, D. Zekry2, G. Gold3, V. Piguet1, J. Desmeules1
1. Division of Clinical Pharmacology and Toxicology, Multidisciplinary Pain Center, Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, University Hospitals of Geneva, Switzerland; 2. Division of Internal Medicine for the aged, Department of Rehabilitation and Geriatrics, University Hospitals of Geneva, Switzerland; 3. Division of Geriatrics, Department of Rehabilitation and Geriatrics, University Hospitals of Geneva, Switzerland
Corresponding Author: Kuntheavy Ing Lorenzini, PhD, University Hospitals of Geneva, Division of Clinical Pharmacology and Toxicology, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva, Switzerland, Telephone: +41795535074, Fax: +41223729945, Email: Kuntheavyemail@example.com
J Frailty Aging 2022;in press
Published online April 28, 2022, http://dx.doi.org/10.14283/jfa.2022.35
Opioid use has much increased in several countries during the last two decades, accompanied by a rise in associated morbidity and mortality, especially in the United States. Data on a possible opioid crisis are scarcer in Europe. We performed a study aiming to assess the frequency of adverse drug reactions (ADR) related to opioids in patients presenting to the emergency unit (EU) of a geriatric tertiary Swiss University Hospital. This particular setting is intended for patients aged 75 and older. Our retrospective, monocentric survey of opioid use and related ADR was conducted over two months in 2018. The main and secondary outcomes were the frequency of EU visits considered due to an opioid ADR and insufficient pain relief, respectively. Current opioid use was identified in 20.3% (n=99) of the 487 included EU visits (mean age 86). An ADR was the suspected cause of the EU visit in 22 opioid users, mainly fall-related injury and gastrointestinal disorders. All these patients had at least one comorbid condition. In 19/22 cases (86%) of ADR, a drug-drug interaction might have been involved. In 12 opioid users (12%), insufficient pain relief was suspected as the cause of the EU visit. In conclusion, one-third of opioid users visiting a geriatric EU consulted for a problem related to its use mainly adverse drug-related reaction (22%) followed by insufficient pain relief (12%).
Key words: Opioids, oldest-old patients, adverse drug reaction, pain, emergency.
Pain is a highly prevalent condition. In Europe, approximately 20% of the adult population suffers from chronic non-cancer pain (CNCP) (1). Prevalence rates for pain are expected to increase as populations continue to age (2). The National Health and Aging Trends Study, conducted in 7610 participants from the United States (US) aged 65 years and older, estimated the prevalence of bothersome pain in the previous month to be 52.9% (3).
Analgesics are among the most frequently used drugs. In the US, surveys estimated that around 20% of patients consulting a doctor for acute or CNCP received a prescription for opioids (4). As older adults often suffer from more chronic pain than their younger counterparts they may be more likely to use opioids. In a population of community-dwelling older adults with multimorbidity, pain was the most frequently reported symptom, occurring during the preceding weeks in 43% of the participants (5). Schear et al recently reported that two-thirds of older adults admitted with moderate-to-severe pain received an opioid prescription at discharge (6). On the other hand, opioid prescription in elderly people may have potentially more serious consequences than in young patients. From a general point of view, several studies have suggested that increasing age might be a risk factor for the occurrence of adverse drug reaction (ADR) and this is due to various factors, such as changes in drug metabolism, frailty, multimorbidity, geriatric syndromes or cognitive impairments which could lead to medication errors (7). In a Korean study, the frequency of opioid-induced adverse reactions in a cohort of male patients aged 65 years and older was reported to reach almost 30% (8). Opioid-related ADR can include fall for example. In a retrospective cohort study that involved 67,929 patients aged 65 and older, filling an opioid prescription during the two past weeks was associated with a more than doubled risk of fall-related injury (9).
To the best of our knowledge, opioid-related morbidity data in Switzerland is currently lacking. Therefore, the objective of our retrospective study was to assess the frequency of emergency unit (EU) visits that were due to an ADR caused by opioid use in a Swiss University Hospital. As we aimed to focus on a very elderly population, this study was conducted at the Geneva geriatric University Hospital.
We performed a retrospective, monocentric, observational study which primarily aimed to assess the frequency of EU visits due to an opioid suspected adverse drug reaction (ADR) in the geriatric EU of University Hospitals of Geneva.
According to the definition of the Council for International Organizations of Medical Sciences (CIOMS), ADR is defined as a response to a medicinal product which is noxious and unintended. Response in this context means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility. Adverse reactions may arise from the use of the product within or outside the terms of the marketing authorization or from occupational exposure. Conditions of use outside the marketing authorization include off-label use, overdose, misuse, abuse, and medication errors (10).
We also assessed the frequency of patients with insufficient pain relief as a cause of EU visits. ADRs were described according to MedDRA (Medical Dictionary for Regulatory Activities) terminology (available through our institutional subscription).
The causal link between the current use of opioids and the ADR was systematically evaluated by two clinical pharmacologists of the Division of Clinical Pharmacology and Toxicology, using the WHO-Uppsala Monitoring Centre system for standardized case causality assessment (11).
Setting and population
We conducted a survey of opioid use and related ADR over nine weeks in 2018 that included two non-consecutive months (May and September) and one week in August during the heatwave. The periods were chosen to represent three different seasons. We voluntarily did not include a month during the winter to exclude potential bias due to the influenza epidemics.
In November 2016 a new geriatric emergency unit (EU) opened within the 300-bed Geriatric Hospital of the Geneva University Hospitals. It receives patients over the age of 75, with medical, non-surgical, and non-vital urgency. This service is open 7 days a week from 8 a.m. to 7 p.m. Study population was defined by all patients who visited the geriatric EU during the study period. Their electronic health records (EHR) were reviewed by a clinical pharmacologist to identify patients with current use of prescription opioids at home, which allowed to determine the prevalence of opioid users. The EHRs of opioid users were finally reviewed by two clinical pharmacologists (one of them also working in the pain center) to assess whether the EU visit was due to an ADR related to opioid use. Patients aged under 75 were excluded from the analysis. When considering patients taking opioids, we excluded cases in which the only implicated was an illicit or an unspecified opioid (e.g. diagnosis of opioid overdose but no indication of opioid in the EHR).
Our primary outcome was the frequency of EU visits in the geriatric EU from University Hospitals of Geneva during the study period that were deemed to be caused by an opioid ADR.
Secondary outcomes included the frequency of EU visits due to insufficient pain relief. Finally, we evaluated the frequency of hospitalization, and 30-days mortality.
Data source and variables
All data were obtained from the EHR of the University Hospitals of Geneva. For all patients who visited the geriatric EU, we collected the patient institutional number (allowing reversible anonymization), gender, and age at the time of the EU visit. For the opioid users, we also collected: opioid name and dose, concomitant drugs, indication for opioid use, the reason for EU visit, hospital admission after EU visit, and 30-days mortality. For the patients displaying an ADR due to opioids, we also collected the Functional Independence Measure (FIM) score which is routinely used in our hospital in geriatric patients to assess their functional status during hospitalization. Based on 18 items of physical, psychological, and social function, it allows assessing the patient’s level of disability. Total scores range from 18 (lowest) to 126 (highest level of function) (12).
We also analyzed the contribution of drug-drug interaction (DDI). We used the computerized interaction database system Lexi-Interact® in Lexicomp (13). For pharmacodynamic DDI, we concluded the presence of a DDI when the observed ADR was mentioned in the summary of product characteristics (SmPC) of both the opioid and the concomitant drug. For example, constipation is mentioned in the SmPC of morphine and loperamide, although no DDI between these drugs is detected by Lexi-Interact®.
Descriptive statistics using frequencies and means (+/- standard deviation) were used to describe our primary and secondary endpoints. Comparison tests (Chi-square for categorical variables and Student t-test for continuous variables) were used when comparing data between groups. P<0.05 was considered significant. All analyses were performed using the SPSS® software package, version 25 (IBM corporation, Armonk, NY, USA).
This study was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. It obtained approval from the local ethics committee (local study number: GE-CCER 2017-02217).
A total of 573 patients’ visits in the geriatric EU occurred during the study period, 86 were excluded (figure 1). The main reasons for exclusion were young age (under 75) and patients with duplicated administrative admissions. Among the 487 remaining patients’ visits, current opioid use was identified in 99 (20.3%) of them. Demographic characteristics were not different between opioid non-users and opioid users. The patients’ mean age was 86 years (Table 1).
EU: emergency unit; ADR: adverse drug reaction
a. Person Chi-square, asymptomatic significance 2-sided; b. Student t test
A weak opioid use was identified in approximately one-third of the cases (36.5%), and strong opioids represented two-thirds of the cases (63.5%). The most frequently used weak opioid was tramadol, alone or as a fixed-dose combination with acetaminophen (29% of all opioids). The most frequently used strong opioids were buprenorphine (26%) followed by morphine (14%). Chronic non-cancer pain was the main indication for both weak and strong opioids (40% and 70% respectively), followed by acute pain (18% and 14% respectively). No patient used opioids for substitution therapy.
An ADR was suspected as the cause of the EU visit in 22 opioid users. Chronic non-cancer pain was the most frequent indication (17/22 patients). All these patients had at least one comorbid condition (mean number of active comorbidities per patient: 6.3, maximum: 11). The most frequent comorbid conditions were cardiovascular diseases, musculoskeletal disorders (17 patients each), and neuropsychiatric disorders (16 patients). The mean FIM score was 76 (min: 33; max: 117). In these cases of ADR, no case overdose, misuse, abuse, and withdrawal syndrome was identified. Therefore, the frequency of EU visits considered as an ADR due to opioid use was 4.5% when considering the whole population visiting the EU as the denominator. Specifically, among opioid users, this frequency was 22.2%. Among these 22 patients, a total of 28 ADR were observed, mainly represented by injury (n=11) (fall) and gastrointestinal disorders (n=9) (constipation, fecaloma, nausea, and vomiting). Urinary retention was observed in five patients and nervous system disorders in three patients (delirium, dizziness). All these 22 patients received other drugs in addition to their opioid. The mean number of comedications was 10.2 (min: 3, max: 20). In 19 of the 22 patients presenting ADR (86%), a DDI was present, with a total of 39 drugs involved. In 50% of the cases, the co-involved treatment was a drug affecting the nervous system (antiepileptics, psycholeptics, and psychoanaleptics) and the DDI was considered mainly pharmacodynamic. The other involved therapeutic groups were drugs acting on the alimentary tract and metabolism (15.4%) and the cardiovascular system (15.4%).
In 12 opioid users, insufficient pain relief (pain not responding to the current pharmacological treatment) was suspected as the cause of EU visit. Six of them were taking tramadol, oxycodone, or codeine. None of them were taking a CYP2D6 inhibitor.
Almost all opioid users were hospitalized (>90%). When comparing opioid users whose EU visit was related or not to their opioid treatment, the rate of hospitalization (94.1% versus 93.8%) and the 30-days mortality (5.9% versus 12.3%) were not significantly different. Two patients of the 34 patients whose EU visit was opioid-related died, but in none of the cases, the death cause was considered as associated with opioids. In one case, the 93-year-old patient died from cardiac decompensation and sepsis. In the other case, the 96-year-old patient died from severe sepsis.
Our results provide the first epidemiological data regarding opioid-related morbidity in elderly patients (75 years and older) in Geneva, Switzerland. We observed that the frequency of ADR due to opioid use in elderly patients presenting to a geriatric emergency unit was 4.5%. In these ADRs, no case of overdose, misuse, abuse, and withdrawal syndrome was identified.
Wertli et al. recently performed two studies based on Swiss insurance claims. The included data were based on adults (age 18 years and older) covered by the Helsana health insurance group. Their first study showed a 100% increase in the use of strong opioids between 2006 and 2013 (14). Their second study, performed on 2006-2014 insurance claims, showed that in 83% of recurrent episodes with strong opioids (2 or more reimbursed claims), the indication was non-cancer pain (15). A third Swiss study estimated the frequency of opioid use at the time of presentation in the EU at 4.95% over five years (2013-2017) (16). In a Swiss retrospective study, an opioid prescription was associated with potentially avoidable hospital readmission (adjusted odds ratio: 1.3; 95% confidence interval (95%IC) 1.1-1.6) (17). However, none of these studies analyzed the relationship between ADR and/or EU visits and opioid prescription.
Our study also provides data about opioid use in oldest-old patients. Although we are aware that our study population is not representative of the general elderly population, we found in our sample of very elderly patients presenting to a geriatric emergency unit a high rate of opioid use, approximately 20%, and mainly strong opioids as compared to the 5% found in the aforementioned Swiss study (16). Our focus on an elderly group of patients is likely one of the main reasons for such a high rate.
A large US study based on 12-year data (148,509 visits) from the National Medical Care Surveys documented an opioid use before the visit in 6.0% of visits by older adults in 2009-2010 (18), but other studies have shown rates similar to ours. In a study in Australian elderly patients, 31.8% had documented opioid use, and 22.1% took regularly dosed opioids, mainly buprenorphine, oxycodone, and codeine. Patients were more likely to be on regular opioids if they had a history of musculoskeletal pain or no other specified pain (19). Another recent Dutch study in older patients showed a progressive increase in the percentage of patients receiving at least one opioid from 2005, reaching 11.4% in 2017. More than 30% of the patients with an opioid used strong opioids chronically (longer than 3 months), and the majority of the diagnoses recorded with opioid were for musculoskeletal problems (20).
When pooling adverse drug reactions and insufficient pain relief, we notably observed that in more than one-third of patients on opioids, the EU visit was possibly related to opioids. Several studies have suggested that individuals with chronic pain and those on opioids frequently use healthcare services. Choi et al. showed in their study based on US data from the National Survey on Drug Use and Health (2 years: 2015-2016, 17,608 respondents aged 50 and older) that 37% of patients who used opioids had any past-year EU visit, representing a more than two times likelihood of EU visit as compared to non-users (21). In a retrospective cohort analysis on 105,910,042 US adult commercially insured individuals, the expected rates of EU visits were approximately eight times higher in patients on chronic opioids as compared to the overall cohort (22). In a US study assessing emergency department visits for drug-related adverse events, opioids were among the most commonly implicated drug classes. In patients aged 65 and older, anticoagulants, antidiabetic drugs, and opioids even accounted for 60% of the implicated drugs (23). In a prospective observational study on 18,820 adult patients admitted over six months (from November 2001 to April 2002) assessing for the cause of admission to hospital in England, 1225 admissions were related to an ADR, giving a prevalence of 6.5%. If drugs most commonly implicated included low dose aspirin, non-steroidal anti-inflammatory drugs (n=363, 29.6%) and diuretics (n=334, 27.3%), opioids still accounted for 6 % (n=73) of all admissions (24).
Polypharmacy increases the risk of ADR and is frequent in older people. More than half of them take five or more drugs concomitantly (7). In a case-control study, the odds ratio of ADR associated with the intake of 3-7 drugs was 4.1 (95%IC 2.4-6.9). For 8 drugs and more, the OR was 6.4 (95%IC 3.7-11.0) (25). Polypharmacy puts the patient at risk of drug-drug interactions (DDI), at a pharmacokinetic and/or pharmacodynamic level. In 20 of our 23 patients presenting ADR, a pharmacodynamic DDI was present, which involved a drug affecting the nervous system in half of the cases. The association of an opioid with sedatives, antihistamines, antipsychotics, or muscle relaxants can lead to an increased risk of respiratory depression, hypotension, or sedation (26). In a retrospective cohort analysis on 2,533,878 US adult patients prescribed opioids chronically, nearly two-thirds of individuals who had an opioid-related EU visit also had an overlapping benzodiazepine prescription (22). Therefore, the risks and benefits of concomitantly using several therapeutic classes acting on the central nervous system should carefully be assessed regularly, especially in elderly patients. Some opioids are metabolized by cytochrome P450 (CYP), such as codeine, tramadol, and oxycodone (CYP2D6), or buprenorphine and fentanyl (CYP3A4) (26). Drugs inhibiting bioactivation can reduce the effects of certain opioids. In our study, 6 of the 14 patients displaying insufficient pain relief were taking tramadol, oxycodone, or codeine, which all require a metabolic activation mediated by CYP2D6 to exert analgesia. None of these patients were concomitantly receiving a known CYP2D6 inhibitor. This apparent inefficacy might have been due to CYP2D6 genetic polymorphism, which was not assessed in our study. Indeed, CYP2D6 poor metabolizers showed decreased analgesia and lower levels of codeine and tramadol active metabolites when compared with CYP2D6 extensive metabolizers (27). One author suggested that when prescribing opioids in older adults, low-dose of strong opioids should be preferred to weak opioids because of better effectiveness and safety (28). Other hypotheses to explain inadequate relief may simply be insufficient dose or the development of tolerance after chronic use.
Fall-related injuries were one of the most frequent events in our study, occurring in 11 of our patients. This is not surprising since opioid use has been associated with an increased risk of falls in several studies (9, 29, 30). For example, a US study in 2595 participants aged 65 years and older found that relative to no current use, new initiation of opioids was associated with an increased risk for fall-related injury (hazard ratio (HR) = 3.25; 95% confidence interval (CI) = 2.44–4.31), as was prevalent current use (HR = 1.79; 95%CI = 1.32–2.42) (31). Moreover, the presence of comorbid conditions might have put our patients at risk of ADR. Multimorbidity is defined as the concomitant presence of two or more coexisting chronic diseases in the same patient. The risk of ADR seems to increase with an increasing number of comorbidities (7). Multimorbidity is very prevalent in elderly patients. For example, a recent cohort Spanish study showed that 98% of their patients had at least two chronic conditions, with a median number of 8 chronic conditions per patient (32). In a study assessing multimorbidity and opioid prescribing in older adults admitted with pain, almost every patient had moderate-to-extremely severe morbidity affecting two or three organ systems (6). In our study population, 10 out of the 11 patients who were admitted because of a fall injury suffered from at least one cardiovascular (e.g. hypertension, atrial fibrillation) and musculoskeletal condition (e.g. chronic pain, osteoporosis). Comorbid conditions such as osteoporosis can also be the cause of pain (33). Moreover, chronic pain has been reported to be negatively correlated with severe frailty (34). A frailty index score above 0.16 has been shown to double the risk of ADR (35). Although we did not specifically assess the frailty in our patients, we measured a mean FIM score of 76 in our patients presenting with ADRs, which is suggestive of a moderate to low functional status. A FIM score of 73 has been measured in a population of 100 patients with pre-frail status (36).
The occurrence of an ADR can lead to medical consultations and EU visits, and so can pain insufficiently relieved. Indeed in one-third of our patients for which the EU was related to current opioid use, the reason for the visit was insufficient pain relief. For example, a Canadian pilot study in 58 chronic pain patients, found the following main reasons for consulting the EU: inability to manage pain (60%), concern about the cause of the pain (16%), and waiting for medical advice (10%) (37). This is not surprising since there is little good-quality evidence that strong opioids are effective in chronic non-cancer pain (38).
The particular setting of the geriatric emergency unit, the small number of cases included in our study, the retrospective design, and the particularity of the Swiss health care system were the main limitations of our study. We are aware that the setting of our geriatric EU is very specific to our hospital, being limited to patients aged 75 and over, and restricted to non-vital urgency. This setting is not representative of general emergency departments nor the general population and this limits the external validity of our results. On the other hand, from a medical point of view, this specific geriatric setting allows a more targeted management of this very elderly population.
We were unable to interview patients while in the EU and also to clarify compliance issues. Moreover, inaccuracies in the health records could not be verified and some data such as indication for use, dose (e.g. recent dose changes), or co-medications could be missing. Issues such as misuse or abuse that have not been found in our study, might also have been missed because of the retrospective design. Our opiate-related EU visits rate is high and could have been overestimated. Other co-medications or co-morbidities may have participated in the ADR. However, we have tried to reduce this bias by a double pharmacological evaluation with the validated causality assessment scale of WHO. Moreover, even in these possible cases, the risk in the elderly subject seemed to us sufficiently major to be taken into account.
Finally, the Swiss health care system is quite different from other health care systems, which may limit comparison with other studies. It is decentralized with 26 administrative regions and in contrast with France for example, we have several health insurance payers. Strong opioids need a special prescription with 3 copies (physician, pharmacy, and insurance) which aims to limit the risk of abuse. However, as there is no national database, patients with multiple prescribers cannot easily be identified (15).
Our study was the first survey assessing the frequency of opioid-related problems focusing on a very old population in Switzerland. We observed a high rate of prescription opioids use specifically in elderly people visiting an emergency unit, with approximately one-third of these opioid users consulting for a problem related to this use, mainly adverse drug reaction (22%) followed by pain insufficiently relieved (12%). The emergency unit visits can be an opportunity to systematically evaluate the appropriateness, effectiveness, and safety of medication regimens and to screen drug-related problems. In the broader context of increasing opioid use, our results should be confirmed in a larger population with a prospective design allowing a patient follow-up.
Acknowledgements: Not applicable
Declaration of Conflicting Interests: The authors declare that they have no competing interests.
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