Impact of Withdrawal of Extended‐Release Morphine 5 mg on Hospital Analgesic Utilization

1. Introduction and Background

In April 2024, extended‐release (ER) morphine 5 mg (Contalgin) was withdrawn from the Danish market [1]. This formulation has been widely used in Denmark to facilitate gradual dose reductions during opioid tapering.

Market withdrawals or shortages of commonly used medicines can lead to changes in drug utilization and therapeutic substitution [2]. Such changes may have important implications for patient safety. Following withdrawal of morphine ER 5 mg, the lowest marketed ER strength increased to 10 mg, removing a low‐dose option and limiting small dose adjustments. The available substitution strategies have different clinical implications: switching to a higher‐strength morphine formulation may increase opioid exposure, whereas substitution with immediate‐release (IR) morphine alters release characteristics and dosing schedule. Switching to another opioid requires careful dose conversion because opioids differ in potency and responses to equianalgesic doses vary between individuals. Consequently, opioid switching may result in excessive opioid exposure and adverse effects or, conversely, inadequate analgesia [3]. These considerations may be particularly relevant in older patients, who are more susceptible to opioid‐related adverse effects [4, 5].

How withdrawal of morphine ER 5 mg affected analgesic utilization in hospital practice in Denmark remains largely unknown. We therefore examined changes in hospital analgesic utilization in the North Denmark Region following withdrawal of morphine ER 5 mg.

2. Materials and Methods

2.1. Study Design and Setting

This observational drug utilization study was conducted at the Hospital Pharmacy in the North Denmark Region and the Department of Clinical Pharmacology, Aalborg University Hospital. Denmark has a predominantly tax‐funded healthcare system organized into five regions responsible for hospital services and primary care. The North Denmark Region, the smallest of the five regions, has approximately 0.6 million inhabitants, corresponding to about 10% of the Danish population [6]. Somatic hospital care in the region is provided through Aalborg University Hospital and North Denmark Regional Hospital, which together comprise several hospital sites across the region. The departments included in the present study were located within both hospital organizations, and medicines were supplied through the regional Hospital Pharmacy.

The study was registered with the data protection office at Aalborg University Hospital (K2025‐048) and was conducted in accordance with the Basic & Clinical Pharmacology & Toxicology policy for experimental and clinical studies [7] and with the principles for transparency and reproducibility described in ‘Making Transparency and Reproducibility a Hallmark of Nordic Real‐World Evidence’ [8].

2.2. Data Sources

Data were obtained from ApoVision, a Microsoft Dynamics NAV‐based financial management and logistics system used by Danish hospital pharmacies. The dataset comprised pharmacy‐to‐department supply data on orally administered analgesics for orthopaedic surgery, geriatric, emergency and post‐anaesthesia care units in the North Denmark Region. Extracted variables included hospital department, route of administration, medicinal product, ATC classification and month and year of supply. Medicine supply was expressed as defined daily doses (DDDs), which were extracted directly from ApoVision; each medication package in the system has a predefined DDD value, and no study‐specific conversion to DDDs was performed.

Following market withdrawal in April 2024, morphine ER 5 mg remained available through special import as an unregistered medicinal product. The hospital departments were informed about the possibility of special import; however, use of the unregistered morphine ER 5 mg product required a dispensing permit from the Danish Medicines Agency for each department. Supply of the unregistered medicinal product was included in the analysis.

As the months immediately following market withdrawal were considered a transition period, August 2024 was selected as the start of the post‐withdrawal observation period. December 2024 represented the data cut‐off for the analysis, resulting in a 5‐month post‐withdrawal period. The corresponding months, August–December 2023, were used as the pre‐withdrawal comparator to minimize potential seasonal variation.

2.3. Drug Classification and Outcome Measures

Analgesics were identified and grouped using ATC codes and included morphine (N02AA01), oxycodone (N02AA05), tramadol (N02AX02), other opioids (codeine [R05DA04], buprenorphine [N02AE01], ketobemidone [N02AG02] and tapentadol [N02AX06]), paracetamol (N02BE01), non‐steroidal anti‐inflammatory and antirheumatic drugs (M01A), gabapentinoids (gabapentin (N02BF01) and pregabalin [N02BF02]) and antidepressants (amitriptyline [N06AA09], nortriptyline [N06AA10], venlafaxine [N06AX16] and duloxetine [N06AX21]). Total opioid consumption was defined as the sum of DDDs for all included opioid formulations.

2.4. Statistical Analysis

Analyses and figures were generated using R (Version 4.3.0). Drug utilization was summarized descriptively as DDDs in the pre‐ and post‐withdrawal periods. No formal statistical comparisons were performed.

2.5. Use of Artificial Intelligence

OpenAI ChatGPT was used for language editing and refinement of the manuscript. All content was critically reviewed and approved by the authors, who take full responsibility for the final manuscript.

3. Results

Overall opioid utilization was similar before and after withdrawal of morphine ER 5 mg (9887 vs. 10 270 DDD). The proportion of morphine ER 5 mg decreased from 5.5% to 2.6% of total opioid utilization. In contrast, utilization of morphine ER 10 mg increased from 16.0% to 21.1%, and that of morphine IR 10 mg increased from 30.5% to 37.5%, whereas utilization of higher‐strength morphine formulations (> 10 mg) remained low and changed little during the study period. Morphine accounted for 56.5% of total opioid utilization before withdrawal and 65.5% thereafter. Oxycodone utilization remained largely unchanged overall, whereas tramadol utilization declined, most notably for the IR formulation (10.6% to 3.8%). Among non‐opioid analgesics, utilization of paracetamol increased by 12.1% and antidepressants by 27.5%, whereas NSAID and gabapentinoid utilization changed little.

Orthopaedic surgery departments accounted for 62% of opioid utilization. Following withdrawal of morphine ER 5 mg, utilization shifted towards morphine IR 10 mg and morphine ER 10 mg (Figure 1). Tramadol utilization decreased, whereas oxycodone remained largely unchanged. Utilization of paracetamol, gabapentinoids and antidepressants increased.

FIGURE 1.

Utilization of orally administered analgesics before and after withdrawal of extended‐release (ER) morphine 5 mg across selected hospital departments in the North Denmark Region. Dispensed defined daily doses (DDD) are shown for the pre‐withdrawal period (August–December 2023; dark grey bars) and the post‐withdrawal period (August–December 2024; light blue bars) in departments of orthopaedic surgery, emergency departments, geriatric departments and post‐anaesthesia care units. Analgesics are grouped by opioid formulation and non‐opioid analgesic class. Note the different y‐axis scales between panels.

Emergency departments accounted for 20% of opioid utilization and showed a similar pattern, with increased utilization of morphine IR 10 mg and morphine ER 10 mg. Smaller increases were observed for oxycodone ER 10 mg and oxycodone IR 5 mg. Utilization of NSAIDs, gabapentinoids and antidepressants increased, whereas paracetamol utilization remained stable.

Geriatric departments accounted for 3% of opioid utilization. Utilization of morphine IR 10 mg decreased, whereas morphine ER 10 mg and oxycodone ER increased. Utilization of paracetamol, gabapentinoids and antidepressants increased, whereas NSAID utilization declined.

Post‐anaesthesia care units accounted for 15% of opioid utilization and did not use morphine ER 5 mg either before or after withdrawal. Nevertheless, utilization of morphine IR 10 mg and morphine ER 10 mg increased, whereas oxycodone and tramadol IR utilization decreased. Paracetamol utilization increased, whereas NSAID and gabapentinoid utilization remained largely unchanged.

4. Discussion

Overall opioid utilization remained stable following withdrawal of morphine ER 5 mg. The decline in use of morphine ER 5 mg was accompanied by increased utilization of morphine ER 10 mg and morphine IR 10 mg, whereas oxycodone utilization remained largely unchanged and tramadol utilization declined. These findings suggest substitution within morphine formulations rather than a shift towards alternative opioids. This pattern is consistent with Danish recommendations, which consider morphine the preferred first‐line opioid when opioid treatment is necessary [9], and with guidance advising against substitution with oxycodone following withdrawal of morphine ER 5 mg [10], given its higher potency and lack of demonstrated safety advantages over morphine [11].

The observed increase in morphine ER 10 mg and morphine IR 10 mg is consistent with a shift towards higher‐strength tablets and alternative morphine formulations following withdrawal of morphine ER 5 mg. Whether this resulted in higher prescribed or administered opioid doses cannot be determined from the available data. Although the increased use of morphine ER 10 mg may reflect substitution with a higher tablet strength in some patients, morphine IR 10 mg tablets include a score line allowing administration of 5 mg doses, which may have facilitated continued use of lower morphine doses. Notably, utilization of higher‐strength morphine formulations (> 10 mg) remained low throughout the study period. The increased use of morphine IR in orthopaedic surgery, emergency and post‐anaesthesia care units may also reflect a broader preference for IR formulations in acute and perioperative pain management [12].

Tramadol utilization declined between the study periods, consistent with national trends that may reflect regulatory actions and increased awareness of tramadol‐related adverse effects [13]. Together with existing recommendations regarding opioid choice [9] and the preference for IR formulations in acute and perioperative pain management [12], these concurrent trends in opioid prescribing practice may have contributed to some of the observed differences between 2023 and 2024, limiting the extent to which they can be attributed specifically to the withdrawal of morphine ER 5 mg.

Changes in utilization of non‐opioid analgesics were also evident. The observed increase in paracetamol use may be consistent with recommendations favouring paracetamol as first‐line treatment [9]. Likewise, utilization of antidepressants increased, possibly reflecting greater use of adjuvant analgesics for selected chronic pain conditions, for which duloxetine, venlafaxine and amitriptyline have demonstrated analgesic efficacy [14].

An important limitation of this study is the lack of patient‐level data. The extent to which the observed changes translated into differences in prescribed or administered opioid doses, opioid exposure, analgesic effectiveness or adverse events could therefore not be determined. The results should therefore be considered descriptive indicators of medication supply rather than patient‐level prescribing or medication use. Ward‐level dispensing data may also be influenced by stock management or bulk purchasing. Analyses were, however, based on aggregated dispensing over 5‐month periods before and after withdrawal in order to reduce the influence of short‐term fluctuations in purchasing patterns. Another limitation is that the study was conducted in a single Danish region, and patterns may differ in other regions and settings. Furthermore, the descriptive design precludes causal inference, and unmeasured factors, including potential differences in healthcare activity between the study periods, may have influenced the findings. As data on admissions, hospital contacts or bed‐days were not available, absolute analgesic utilization could not be expressed relative to healthcare activity. This limitation may be particularly relevant to the interpretation of absolute DDDs. Several of the observed substitution patterns, however, were based on the relative contribution of individual opioid formulations to total opioid utilization and may therefore be less sensitive to differences in overall healthcare activity. Despite these limitations, the study provides real‐world insight into hospital‐level changes in analgesic utilization following withdrawal of a commonly used opioid formulation.

In conclusion, withdrawal of morphine ER 5 mg was followed by increased utilization of morphine ER 10 mg and morphine IR 10 mg, whereas oxycodone utilization remained stable and tramadol utilization declined. Increased use of paracetamol and antidepressants was also observed. As the study was based on ward‐level drug supply, the findings do not allow conclusions regarding patient‐level dosing, analgesic effectiveness or safety outcomes. Overall, the findings suggest substitution within morphine formulations rather than a shift towards alternative opioids following withdrawal of a commonly used opioid formulation.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data are available from the corresponding author upon reasonable request.