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Background:
Systematic Review

A Systematic Review of Potential Opioid Prescribing Safety Indicators

by
Wael Y. Khawagi
1,†,
Neetu Bansal
2,3,*,†,
Nan Shang
2,3 and
Li-Chia Chen
2,3
1
Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia
2
Centre for Pharmacoepidemiology and Drug Safety, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK
3
Manchester Academic Health Science Centre, Oxford Road, Manchester, M13 9PT, UK
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Pharmacoepidemiology 2025, 4(1), 4; https://doi.org/10.3390/pharma4010004
Submission received: 12 December 2024 / Revised: 30 December 2024 / Accepted: 6 January 2025 / Published: 8 January 2025
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Abstract

:
Background/Objectives: This systematic review aimed to identify a comprehensive list of potential opioid-related indicators from the published literature to assess prescribing safety in any setting. Methods: Studies that reported prescribing indicators from 1990 to 2019 were retrieved from a previously published systematic review. A subsequent search was conducted from seven electronic databases to identify additional studies from 2019 to June 2024. Potential opioid safety prescribing indicators were extracted from studies that reported prescribing indicators of non-injectable opioids prescribed to adults with concerns about the potential risk of harm. The retrieved indicators were split by each opioid, and duplicates were removed. The identified indicators were categorized by the type of problem, medication, patient condition/disease, and the risk of the indicators. Results: A total of 99 unique opioid-specific prescribing indicators were identified from 53 included articles. Overall, 42 (42%) opioid prescribing indicators focused on a specific class of opioids. Pethidine, tramadol, and fentanyl were the most frequently reported drugs (n = 22, 22%). The indicators account for six types of problems: medication inappropriate for the population (n = 20), omission (n = 8), inappropriate duration (n = 10), inadequate monitoring (n = 2), drug–disease interaction (n = 26), and drug–drug interaction (n = 33). Of all the indicators, older age (over 65) is the most common risk factor (n = 38, 39%). Central nervous system-related adverse effects are the risk of concern for the 28 (29%) indicators associated with drug–drug interactions. Furthermore, five of the six ’omission’ indicators are related to ’without using laxatives’. Conclusions: This review identified a comprehensive set of indicators for flagging patients at high risk of opioid-related harm, thereby supporting informed decision-making in optimizing opioid utilization. However, further research is essential to validate these indicators and evaluate their feasibility across diverse healthcare settings.

1. Introduction

Opioids, one type of potent analgesic, remain the mainstay approach for treating acute moderate to severe pain after surgery and for cancer-related pain [1,2]. However, in recent decades, opioid analgesics have been increasingly used in patients with chronic non-cancer pain in Western countries [3]. Chronic pain, commonly lasting for three or more months, affects one-third and one-half of the United Kingdom (UK) population [4,5]. Due to the complex mechanisms of pain physiology and pathology, multimodal biopsychosocial treatments, including non-pharmacological options, are recommended for managing chronic primary pain rather than analgesics alone [6]. Yet the marked increase in opioids used for chronic pain has become a public health concern [7].
There is a lack of evidence to support the long-term effectiveness of opioids for managing chronic pain [8]; instead, much of the literature has revealed dose-dependent adverse effects and the risk of severe harm, including drug abuse, addiction, nausea, constipation, respiratory depression, dependence, and overdose associated with prolonged opioid use [8,9]. Furthermore, studies have shown that opioids are commonly associated with preventable adverse drug reactions, emphasizing the need for strong preventive strategies, such as safety indicators, to reduce opioid-related harm [10].
Opioid safety is of particular concern in some vulnerable patient groups [11], such as older people, as age-related pharmacokinetic and pharmacodynamic changes may increase the sensitivity to adverse drug effects [12]. Furthermore, older patients with chronic pain may also have multiple co-morbidities and become potential polypharmacy candidates, consequently having a higher risk of adverse drug–drug interactions [12,13]. Sex differences also play a role in opioid safety, with men and women experiencing different patterns of adverse events [14]. Therefore, it is important to systematically identify and review patients on long-term opioids, considering factors such as age, sex, and polypharmacy.
Prescribing quality indicators are widely used in identifying the effectiveness of prescribing problematic or inappropriate polypharmacy as part of the quality indicators of healthcare services by allowing relevant stakeholders, e.g., health boards, primary care clusters, general practices, and prescribers, to compare their current prescribing practice against an agreed quality standard [15,16]. Furthermore, prescribing safety indicators focusing on potentially hazardous prescribing and inadequate medication monitoring practices that place patients at risk of harm can be used to monitor prescribing safety and prevent prescribing-related harm [16]. The development of prescribing indicators should be evidence-based, transparent, easily understood, and, ideally, validated by a group of experts using a consensus-based methodology [17].
Although numerous sets of prescribing quality and safety indicators and inappropriate prescribing criteria have been developed for different populations and settings, there is no consensus on opioid safety prescribing indicators to prevent potentially hazardous consequences. Therefore, as a foundation for developing evidence-based opioid prescribing safety indicators, we hypothesized that the indicators included in the published literature would provide a stronger rationale that can be further developed and applied to local settings, considering different practice environments and patients’ unmet needs. The aim of this systematic review was to comprehensively identify the existing literature on prescribing indicators and criteria across various settings and to extract individual potential prescribing safety indicators or tools specifically related to opioid prescribing that could be utilized to assess prescribing safety in adults.

2. Results

2.1. Selection of Studies

Of the 13,410 records identified, 4774 duplicates and 921 ineligible records published before 2019 were removed (Figure 1). After screening the titles and abstracts of the remaining 7715 records, 7623 were excluded for lacking prescribing indicators, leaving 92 for full-text review. From these, 44 articles published from 2019 to 2024 that reported prescribing indicators were selected, with 48 excluded for reasons including lack of indicator development (n = 29), application of existing indicators (n = 7), adaptation or translation for other countries (n = 2), duplicate data (n = 1), or conference abstracts (n = 9). Combining these 44 articles with 79 studies from Khawagi et al.’s review [15] yielded 123 articles for full-text review. Ultimately, 53 articles were included in this systematic review. The remaining 70 were excluded for lacking opioid-specific indicators (n = 52), reporting outdated indicators (n = 10), omitting safety indicators (n = 2), or exclusively focusing on pediatric (n = 4), palliative care (n = 1), or duplicating data (n = 1). The full list of the studies can be found in Table S1.

2.2. Characteristics of the Included Articles

The 53 included studies that reported at least one opioid-related prescribing indicator [2,9,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68] were mainly published during the periods of 2020–2024 (n = 18) [2,19,20,29,33,43,44,45,52,60,61,62,63,64,65,66,67,68], 2010–2019 (n = 21) [21,23,24,25,26,28,30,31,32,34,36,38,39,42,46,48,51,54,55,56,57], and 2000–2009 (n = 13) [9,18,22,27,35,37,41,47,49,50,53,58,59], and only one study was published in 1990–1999 [40]. Furthermore, except for two studies that developed indicators for international use [24,67], most of the studies (n = 23) aimed to develop indicators to be used in Europe [2,9,19,20,23,26,28,29,30,31,32,33,36,39,41,45,48,49,50,53,56,61,66], followed by North America (n = 12) [18,25,35,37,40,44,46,47,55,57,59,62], Asia (n = 9) [22,34,43,51,52,58,60,63,64], Australia and New Zealand (n = 5) [21,27,54,65,68], and South America (n = 2) [38,42].

2.2.1. Target Population and Setting

Although 9 (17%) of the 53 studies did not specify the target population [2,9,21,22,26,37,41,46,53], older people were the most common target population (n = 38; 72%). The older adult population was primarily defined as age ≥ 65 years old (n = 35) [18,19,20,27,28,29,30,31,32,34,35,36,38,39,40,42,43,44,45,47,48,50,54,56,57,58,59,60,61,62,63,64,65,66,68], except for in two studies, which defined older adults as age ≥ 70 [49,51], and another study, which defined older adults as ≥75 years old [52]. In addition, although adults (n = 3) [24,55,67], middle-aged patients (n = 2) [23,33], and patients with chronic kidney disease (n = 1) [25] were also investigated, these studies did not specify the age in defining the study population, except for two studies defining middle age as 45–64 years old [23,33].
Of the 53 studies, 20 (38%) did not specify the setting to apply the indicators [19,20,23,28,31,32,33,38,40,42,43,44,45,48,56,58,60,63,66,68] and 4 (8%) implemented the indicators in multiple settings [22,34,61,62]. The remaining 29 studies focused on applying the indicators in various settings, including hospitals (n = 6, 11%) [21,24,27,30,51,54], primary care (general practices) (n = 3, 6%) [29,52,67], community pharmacy (n = 4, 8%) [25,37,46,57], long-term care settings (care home or nursing home) (n = 3, 6%) [18,50,64], prison (n = 1, 2%) [2], and the community (n = 12, 23%) [9,26,35,36,39,41,47,49,53,55,59,65].

2.2.2. Method to Identify and Validate Prescribing Indicators

Most of the studies (n = 33, 62%) retrieved the indicators from multiple sources or strategies [2,19,20,23,24,25,27,29,31,32,33,34,37,38,39,40,42,45,46,49,50,53,55,56,57,58,60,61,62,63,64,65,67], and 20 (38%) studies only adapted one information source or strategy [9,18,21,22,26,28,30,35,36,41,43,44,47,48,51,52,54,59,66,68]. Literature review (n = 31, 58%) [2,18,19,21,24,25,26,28,29,31,32,35,37,38,39,43,44,45,49,50,53,55,58,60,61,62,63,64,65,66,67] and referring to an old version of the indicators (n = 12, 23%) [20,29,34,36,40,42,45,51,56,59,62,68] were the most frequently used strategies to retrieve opioid-related indicators.
Except for one study [22], all the studies reported the validation method of prescribing indicators, and the most frequently used was the Delphi method (n = 39, 74%) [9,18,19,20,23,24,28,29,30,31,32,34,35,37,38,39,40,41,42,43,44,45,48,49,51,52,54,55,58,59,60,61,62,63,64,65,66,67,68]. The remaining studies used the RAND/UCLA appropriateness method (RAM) (n = 5, 9%) [21,25,26,53,56], expert panel method (n = 4, 8%) [2,27,47,50], non-specific consensus method (n = 2, 4%) [46,57], combination of Delphi and cross-sectional study (n = 1, 2%) [33], and nominal group technique (n = 1, 2%) [36].
In addition, various types of consensus methodologies were applied. For example, of the 38 studies that adopted a Delphi consensus approach, 22 studies reported a Delphi method [9,19,20,23,24,30,31,35,38,39,41,43,44,45,48,51,58,61,63,64,66,68], and 16 applied a modified Delphi method [18,28,29,32,34,40,42,49,52,54,55,59,60,62,65,67]; similarly, of the five studies that reported using the RAM method, two applied a modified RAM [21,26].

2.3. Categories of Opioid-Related Prescribing Indicators

Overall, 171 original opioid prescribing indicators were identified from the 53 studies. After merging indicators for the same drugs or items of the same drug class, 99 opioid-related prescribing indicators were identified (Table S2). Of the indicators, 57 (58%) focused on the classification of opioids using the terms ‘opioids’ (n = 51) and ‘strong opioids’ (n = 6). For the remaining 42 indicators, tramadol, fentanyl, and pethidine were the most frequently reported drugs (Table 1).
When classifying the 99 indicators into six types of prescribing problems, drug–drug interaction was the most common type (n = 33, 33%), followed by drug–disease interaction (n = 26, 26%), prescribing to an inappropriate population (n = 20, 20%), inappropriate duration (n = 10, 10%), omission (n = 8, 8%), and inadequate monitoring (n = 2, 2%). Within each group, similar indicators were further grouped to provide a simplified summary of the pivotal characteristics of the indicators (Table 2).

2.3.1. Drug–Drug Interaction

The 33 drug–drug interaction indicators identified in this review can be summarized into 15 groups (Table 3). These indicators describe opioids as a class or specific drug interacting with another therapeutic class (e.g., prescribing opioids with a tricyclic antidepressant to patients over 65 years), with medications that pose the same risk (e.g., prescribing opioids with another fall-risk-increasing drug to patients aged > 65 years), with specific medications (e.g., prescribing an opioid with gabapentin or pregabalin), or with another opioid (e.g., combined prescribing of pure agonist and partial agonist opioids). Most of the concern over drug–drug interactions is due to the drugs’ pharmacological effects on the central nervous system.

2.3.2. Drug–Disease Interaction

The 26 indicators focused on drug–disease interactions were summarized in 10 groups (Table S2). These referred to opioids prescribed to patients with varying conditions, such as constipation, chronic obstructive pulmonary disease, benign prostatic hyperplasia, renal and hepatic impairment, epilepsy, delirium, and dementia (Figure 2).

2.3.3. Potentially Inappropriate Medication for the Population

In total, 19 of 20 indicators of ‘potentially inappropriate medication for the population’ were related to prescribing opioids to patients older than 65 years. Of these, only two indicators referred to opioids being prescribed as a class for patients over 65 years. The remaining 17 indicators referred to a specific opioid prescribed to the same older adult population (Table S2). The remaining indicator referred to prescribing opioids during pregnancy.

2.3.4. Omission

Seven of the eight omission indicators described patients being prescribed opioids as a class without being prescribed a laxative. The remaining indicator described prescribing long-acting opioids to patients older than 65 years without short-acting opioids for breakthrough pain (Table 3). Of the seven indicators related to omitting a laxative, four specified that the prescribing was for patients over the age of 65 years, and three specified prescribing the opioid over two weeks, more than four weeks or over the long term (Table S2).

2.3.5. Inappropriate Duration

Of the ten indicators focused on inappropriate duration, six indicators described patients being prescribed strong opioids as a class, concerning the long-term prescribing of strong opioids to patients over 65 years with mild to moderate pain, regular prescribing of strong opioid analgesics, prescribing opioids to patients with a history of alcohol addiction, medical history of falling, and prescribing at a dose of more than 120 mg morphine equivalent dose per day and for more than three months after surgery. The remaining three indicators referred to prescribing a specific opioid, including prescribing codeine for more than two weeks to patients over 65 years or long-term prescribing of pentazocine to patients older than 65 years, and prescribing tramadol, buprenorphine or oxycodone to patients with a medical history of ventricular tachycardia. (Table S2).

2.3.6. Inadequate Monitoring

Two indicators described inadequate monitoring. This indicator described prescribing opioids to patients over 65 years without monitoring their renal function and persistent prescription of opioid analgesics to a patient with constipation and without a concurrently prescribed laxative.

3. Discussion

This study identified published opioid prescribing indicators that could potentially improve prescribing safety for adults by flagging hazardous risks across clinical settings. Most of the indicators are based on expert consensus and clinical guidelines, reflecting the implicit knowledge and best practices that healthcare professionals have developed. The development and use of prescribing quality and safety indicators are crucial in improving healthcare quality and preventing prescribing-related harm [69]. However, the lack of consensus on opioid safety prescribing indicators highlights the need for evidence-based indicators to guide prescribing practices and enhance patient safety. This review offers a valuable foundation for developing opioid safety indicators that can be validated and implemented in clinical practice.
The risks associated with opioids are not remarkably different from those of other medications; however, the potential severity of the consequences may vary [11]. It is prudent to note that advanced age alone is not necessarily a cause for concern; nonetheless, older adults are particularly susceptible due to age-related pharmacokinetic and pharmacodynamic changes, pre-existing comorbidities, and polypharmacy, which are prevalent in this age group [11,70]. Specific populations, such as those with chronic pain, warrant particular attention, as chronic pain is more prevalent among older adults, who often manage multiple coexisting conditions, further contributing to polypharmacy [70,71].
Drug–drug interactions were identified as the most common prescribing problems, emphasizing the need for vigilance in identifying and managing potential interactions when prescribing opioids [72,73]. Within this category, various opioids (either as a class or specific drugs) should be highlighted. This finding aligns with previous studies highlighting the risks associated with polypharmacy, particularly in the older population [70]. Prescribing indicators targeting drug–drug interactions can serve as valuable tools to guide healthcare professionals in optimizing medication regimes and minimizing harm [64].
Most of the concerns related to polypharmacy primarily revolve around central nervous system (CNS) implications, emphasizing the need to prioritize vigilance regarding severe consequences, such as CNS depression [71]. This aligns with the recognized potential for opioids to cause CNS-related adverse effects, such as sedation, respiratory depression, and cognitive impairment [74]. However, given the complex nature of pain management, individualized risk assessment and a patient-centered approach are essential, rather than relying solely on predefined indicators [75]. Similarly, drug–disease interactions raise concerns regarding the potential risks for patients with a history of certain diseases, highlighting the need for a consensus-based approach to apply these indicators effectively [76].
Many indicators, beyond those specific to opioid classes, also address the patient’s conditions, diseases, or medical history. The most frequent condition-related indicator is ‘opioids prescribed without laxatives’, highlighting the significance of considering potential adverse effects with detrimental impacts on patients’ quality of life and medication safety when prescribing opioids to patients with specific conditions. Compared to drug interactions and inappropriate use in specific populations, indicators for omission, duration, and monitoring are more specific and easier to implement. Nevertheless, decisions on whether to prescribe laxatives should still be patient-centered, incorporating shared decision-making based on the best available evidence. This also suggests the importance of a patient-centered prescribing approach, accounting for individual patient characteristics and medical histories to optimize opioid safety.
A strength of this study is its comprehensive approach, which includes the most recently updated list of opioid-related indicators across all opioid types. Our rigorous review process, involving experts in methodology (WK and LCC) and a specialist practitioner (NB) reviewing identified indicators, adds confidence to the validity and reliability of our results. However, we acknowledge some limitations. Restricting the search to the published literature in English may have introduced publication bias and excluded relevant unpublished studies or gray literature. Additionally, by focusing on indicators related to potential harm, some broader indicators, which are still relevant to improving overall treatment outcomes, have been overlooked. For instance, indicators related to patient adherence to prescribed opioid regimens or the integration of non-pharmacological treatments (such as physical therapy, cognitive-behavioral therapy, or alternative pain management strategies) were not prioritized in this review. Furthermore, while the indicators offer a robust approach to identifying risk, some lack strong supporting evidence on specific adverse outcomes, which may make implementation challenging. This can affect practitioners’ and patients’ willingness to adopt these indicators, and it also complicates measuring the effectiveness of these safety strategies [77].
Nevertheless, this review provides an extensive overview of opioid prescribing indicators, tracing the evolution of safety practices. While these indicators are not yet fully validated, they serve as a foundation for further research. International research and clinical groups may use these findings to adapt indicators for validation and feasibility studies in specific countries and specific healthcare settings. The identified indicators could also be used to update and enhance existing prescribing safety assessment tools, such as PIM tools, to address opioid safety better. These tools are widely used in clinical practice for deprescribing and medication management, and incorporating the latest opioid-related safety indicators would help to ensure that they more accurately reflect current evidence on the risks associated with opioid prescribing, particularly for vulnerable populations.

4. Materials and Methods

This review followed the principles of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance [78]. The protocol for this systematic review was registered with PROSPERO (CRD42022343776).

4.1. Eligibility Criteria

This review included studies that specifically focus on developing, validating, or updating explicit indicators or criteria designed to assess prescribing safety. The studies had to report at least one opioid-specific indicator, with particular emphasis on those that address potential harm in the target population (adults 18+ years). Opioid definitions were sourced from reputable references such as the American Society of Health-System Pharmacists Drug Information, British National Formulary, and Martindale [79,80,81].
Studies were excluded if they focused exclusively on children and adolescents, patients with cancer-related pain or palliative care, or injectable opioids. Additionally, studies were excluded if they only reported the incidence of existing prescribing indicators in clinical settings or if they reported older versions of updated tools or criteria (i.e., only the most recent versions were included). Furthermore, studies that reported implicit indicators (i.e., non-drug-specific) or quality indicators not explicitly focused on the risk of harm (e.g., patients older than 65 years on long-acting opioids with breakthrough pain but not on short-acting opioids) were also excluded.

4.2. Information Sources and Literature Search Strategy

The literature search was designed to capture explicit prescribing indicators from 1990 to 2024 comprehensively. To this end, we first utilized a systematic review by Khawagi et al. (2019) [15], which identified prescribing indicators from 1990 to 2019. Next, we conducted an updated review covering studies published between 2019 and June 2024.
The original search strategy used by Khawagi et al. aimed to retrieve explicit prescribing indicators across a broad range of contexts [15]. This approach utilized three sets of search terms encompassing medication safety, quality measures, and indicator development/validation. The broad search approach was deliberately chosen to ensure the inclusion of opioid-related prescribing indicators, which are often embedded within general sets of prescribing indicators, like the STOPP/START and Beers Criteria [61,62]. By using this comprehensive approach rather than narrowing the search to opioid-specific terms, we minimized the risk of omitting valuable indicators that are part of these established safety criteria. This strategy enabled the identification of opioid-related safety indicators within broader prescribing sets while also including studies that focused explicitly on opioids. Through this approach, Khawagi et al. retrieved 79 articles reporting on various prescribing indicators published from 1990 to 2019, with no restrictions on publication language, study design, country, setting, or population [15]. This timeframe spans back to the earliest criteria, beginning with the Beers Criteria in 1991, which first addressed inappropriate prescribing [82].
An updated search was then conducted using the same strategy and terms from Khawagi et al. [15] to identify relevant studies published from 2019 to 30 June 2024. The databases searched included Medline, Embase, PsycINFO, Web of Science, Health Management Information Consortium (HMIC), International Pharmaceutical Abstracts (IPA), and Cumulative Index to Nursing and Allied Health Literature (CINAHL) (see Supplementary File S1 for detailed search strategies).

4.3. Study Selection

Titles and abstracts were independently screened by two reviewers (WK, NS) to identify eligible studies. Discrepancies were resolved through full-text screening, and eligible articles were further reviewed according to inclusion and exclusion criteria and clinical expertise. Any disagreements were discussed with a third reviewer (LCC or NB) to reach a consensus, with exclusion reasons documented. Finally, full texts from Khawagi et al.’s review (n = 79) and the updated review were examined to identify studies reporting opioid-specific prescribing safety indicators.

4.4. Data Extraction and Synthesis

Two reviewers (NS, WK) extracted data and verified them with two others (NB, LCC). Extracted data covered study details, methodology, and opioid-related indicators. Indicators were standardized into the following format: Prescribing opioids [class or medicine] +/− with other drugs [class or medicine] +/− to a patient +/− aged [age] +/− with disease [+/− conditions indicating potential opioid-related harm]. Duplicates were removed, and indicators involving multiple opioids were split by specific medication. Indicators were grouped into six categories: inappropriate population, drug–disease interaction, drug–drug interaction, inappropriate duration, inadequate monitoring, and omission (Table 3). These categories were adapted from previous studies [15,18,83,84]. A summarized compact version of the included indicators was also provided, combining similar overlapped indicators. A descriptive analysis of the above items was selected, and numbers and percentages were calculated when appropriate.

4.5. Quality Assessment

Given the diverse objectives and methodologies of the included studies and the reliance of most studies on consensus methods for indicator development, we refrained from conducting a formal assessment of their methodological quality, as, to our knowledge, there are no established tools to evaluate the quality of such consensus-based studies. Nonetheless, we did discuss specific aspects of study quality, such as indicator selection methods and validation procedures, in subsequent sections of this paper.

5. Conclusions

This systematic review identified a range of potential opioid safety prescribing indicators from the published literature. These indicators can contribute to developing evidence-based prescribing practices and preventing potential harm associated with opioid use. Further validation using relevant healthcare data and the implementation of these indicators in different clinical settings are necessary to enhance patient safety and optimize opioid prescribing practices. Future research should also explore the feasibility and effectiveness of these indicators and consider their integration into clinical guidelines and decision-support systems to support healthcare professionals in delivering safe and effective opioid therapy.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/pharma4010004/s1. Table S1: Summary of included studies; Table S2: List of opioid safety prescribing indicators; Supplementary File S1: Search strategies.

Author Contributions

Conceptualization, L.-C.C.; methodology, W.Y.K., N.B. and L.-C.C.; validation, L.-C.C., W.Y.K., N.B. and N.S.; formal analysis, W.Y.K., N.B. and N.S.; investigation, W.Y.K., N.B. and N.S.; data curation, W.Y.K., N.B. and N.S.; writing—original draft preparation, W.Y.K., N.B. and N.S.; writing—review and editing, all authors; visualization, W.Y.K. and N.B.; supervision, L.-C.C.; project administration, L.-C.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

The data supporting the findings of this study are available within the article and its Supplementary Materials. Additional details are available upon reasonable request from the corresponding author.

Acknowledgments

We thank Wan-Chuen Liao for her assistance in checking and proofreading this manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

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Pharmacoepidemiology 04 00004 g001
Figure 1. Process of selecting the literature and retrieving opioid prescribing indicators.
Figure 1. Process of selecting the literature and retrieving opioid prescribing indicators.
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Pharmacoepidemiology 04 00004 g002
Figure 2. Indicators concerning the prescription problems related to drug–disease or drug–drug interactions.
Figure 2. Indicators concerning the prescription problems related to drug–disease or drug–drug interactions.
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Table 1. Opioid analgesics and categories reported across six types of prescribing problems.
Table 1. Opioid analgesics and categories reported across six types of prescribing problems.
Opioid DrugPIMOmissionInappropriate DurationInadequate MonitoringDDSIDDISubtotal
Opioids2652162051
Strong opioids123 6
Buprenorphine1 1
Codeine1 1 2
Dextromethorphan/quinidine1 1
Dextropropoxyphene1 12
Fentanyl1 236
Meperidine1 1
Hydromorphone1 1
Methadone1 1
Morphine1 1 2
Narcotic antitussives1 1
Oxycodone/naloxone1 1
Oxycodone 11
Pentazocine1 1 2
Pethidine1 326
Propoxyphene1 12
Tapentadol1 1
Tilidine/naloxone1 1
Tramadol1 4510
Subtotal20892263399
(Note) PIM: potentially inappropriate medication for the population, DDSI: drug–disease interaction, DDI: drug–drug interaction.
Table 2. Summary of opioid safety prescribing indicators.
Table 2. Summary of opioid safety prescribing indicators.
Type of IndicatorsSummary of Opioid Safety Prescribing Indicators
Potentially inappropriate medication for the population
(n = 2 from 20 indicators)
1.
Prescribing an opioid to a patient older than 65 years
2.
Acute or persistent prescription of opioid analgesics to a woman during pregnancy
Omission
(n = 2 from 8 indicators)
1.
Prescribing an opioid analgesic without concurrent use of a laxative
2.
Prescribing long-acting opioids to a patient older than 65 years without short-acting opioids for breakthrough pain
Inappropriate duration
(n = 8 from 10 indicators)
1.
Long-term prescribing of strong opioids to a patient older than 65 years with mild to moderate pain
2.
Long-term prescribing of opioids to elderly patients with osteoarthritis
3.
Regular prescribing of a strong opioid analgesic
4.
Persistent prescription of opioid analgesics to a patient with a medical history of alcohol addiction, abuse or dependence
5.
Persistent prescription of a strong opioid analgesic to a patient with a medical history of ventricular tachycardia
6.
Persistent prescription of opioid analgesics to a patient aged over 65 years with a recent medical history of falling
7.
Persistent prescription of one or more opioid analgesics at a dose above the equivalent of 120 mg of oral morphine per day
8.
Acute or persistent prescription of opioid analgesics to a patient for more than three months following the patient’s discharge from the hospital after surgery
Inadequate monitoring
(n = 2 from 2 indicators)
1.
Prescribing opioids to a patient over 65 years without monitoring renal function
2.
Persistent prescription of opioid analgesics to a patient with constipation and without a concurrently prescribed laxative
Drug–disease interaction
(n = 10 from 26 indicators)
1.
Prescribing opioids to a patient with constipation, cirrhosis, renal failure, history of benign prostatic hyperplasia, or bladder atony
2.
Prescribing opioids to a patient older than 65 with a history of constipation, chronic obstructive pulmonary disease, fractures, syncope, or postural hypotension
3.
Prescribing tramadol to a patient older than 65 with a history of epilepsy
4.
Prescribing pethidine to a patient older than 65 years with a history of delirium
5.
Prescribing pethidine to a patient with chronic kidney disease (creatinine clearance < 60 mL/min)
6.
Prescribing opioids to a patient older than 65 years with a history of dementia or cognitive impairment
7.
Persistent prescribing of opioids to a patient with paralytic ileus
8.
Persistent prescription of opioid analgesics to a patient with myasthenia gravis
9.
Prescription of codeine or morphine to a patient with severe renal impairment, i.e., with the most recent eGFR < 30 mL/min per 1.73 m2
10.
Persistent prescription of opioid analgesics to a patient with at least moderate hepatic impairment
Drug–drug interaction
(n = 15 from 33 indicators)
1.
Prescribing opioids with methadone, buprenorphine, gabapentin or pregabalin
2.
Prescribing opioids with benzodiazepines or barbiturates to a patient older than 65 years
3.
Prescribing opioids with anticholinergics to a patient older than 65 years
4.
Prescribing opioids with another fall-risk-increasing drug to a patient older than 65 years
5.
Prescribing opioids with another drug that acts on the central nervous system to a patient older than 65 years
6.
Combined prescribing of two immediate-released/modified-released opioids.
7.
Combined prescribing of pure agonist and partial agonist opioids.
8.
Prescribing two opioid analgesics to a middle-aged ‘45–64 years old’ patient
9.
Prescribing tramadol or fentanyl with other serotonergic agents
10.
Prescribing opioids with antiepileptics (carbamazepine, phenytoin or phenobarbital)
11.
Prescribing fentanyl or oxycodone with CYP3A4 inhibitors to a patient over 65 years
12.
Prescribing dextropropoxyphene concurrently with paracetamol to a patient older than 65 years
13.
Prescribing propoxyphene with carbamazepine
14.
Prescribing opioids with any combination of ≥ 2 medications such as antidepressants, benzodiazepines, antipsychotics, antiepileptics, non-benzodiazepine drugs (Z drugs)
15.
Prescribing opioids with angiotensin-converting enzyme inhibitors or diuretics
(Note) Ninety-nine indicators were identified. The complete list can be found in Table S2.
Table 3. Definitions of the six types of prescribing problems.
Table 3. Definitions of the six types of prescribing problems.
Type of IndicatorPrescribing Problem
Potentially inappropriate medication for the populationMedication that is potentially prescribed inappropriately to a specific population.
OmissionMedication should be prescribed with a specific diagnosis, condition, or prescription.
Inappropriate durationMedication that was prescribed for an inappropriate duration.
Inadequate monitoringMedications that were not monitored adequately.
Drug–disease interactionMedication that is potentially prescribed inappropriately for a specific diagnosis or condition.
Drug–drug interactionMedication that potentially interacts with another medication.
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Khawagi, W.Y.; Bansal, N.; Shang, N.; Chen, L.-C. A Systematic Review of Potential Opioid Prescribing Safety Indicators. Pharmacoepidemiology 2025, 4, 4. https://doi.org/10.3390/pharma4010004

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Khawagi WY, Bansal N, Shang N, Chen L-C. A Systematic Review of Potential Opioid Prescribing Safety Indicators. Pharmacoepidemiology. 2025; 4(1):4. https://doi.org/10.3390/pharma4010004

Chicago/Turabian Style

Khawagi, Wael Y., Neetu Bansal, Nan Shang, and Li-Chia Chen. 2025. "A Systematic Review of Potential Opioid Prescribing Safety Indicators" Pharmacoepidemiology 4, no. 1: 4. https://doi.org/10.3390/pharma4010004

APA Style

Khawagi, W. Y., Bansal, N., Shang, N., & Chen, L.-C. (2025). A Systematic Review of Potential Opioid Prescribing Safety Indicators. Pharmacoepidemiology, 4(1), 4. https://doi.org/10.3390/pharma4010004

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