https://orcid.org/0000-0001-5478-0514
ABSTRACT
Background
Opioid dependence has become a public health problem in several countries.
Methods
A cohort study was used to assess first-time dispensed opioids, in 2012–2015, by drug type, doses, oral morphine equivalents, and diagnoses, in Sweden. First-time opioid users aged 18–64 years, previously cancer-free and opioid-naïve for at least 6.5 years, were studied. Time trends in opioid use in Sweden 2006–2021 were also studied.
Results
During the study, 617,568 patients were dispensed opioids for the first time. The crude proportion of first-time opioid users in the population was 2.7% in 2012 and 2.6% in 2015.
The combination product of codeine and paracetamol was the most frequent dispensed opioid with 322,818 patients (52.3%), followed by tramadol (120,271, 19.6%) and oxycodone (104,418, 16.9%). From 2012 to 2015, tramadol as first dispensed opioid dropped from 26.5% to 13.7% and oxycodone increased from 10.0% to 24.4%. For the four most commonly dispensed opioids, the median initial dispensal ranged from 250 to 400 oral morphine equivalents.
The most common indication was fracture of the lower leg during inpatient care and back pain for specialized outpatient care.
Conclusion
Trends in dispensed opioids in Sweden show a shift from tramadol to oxycodone, but do not show an increase in total opioid use.
Introduction
Opioids play an important role in healthcare as analgesics, during and after surgical procedures, in severe acute pain and cancer pain. However, there is little evidence for the effectiveness of opioids in the treatment of chronic noncancer pain (Genova et al., Citation2020). Further, treatment with opioids always involves a risk of the patient developing addiction (Mercadante, Citation2019).
In the United States, opioid dependence has become a considerable public health problem. Legal sales of prescription opioids have quadrupled in the United States in the last decades, which has been accompanied by an increase in opioid-related deaths (Centers for Disease Control and prevention CDC, Citation2011; Guy et al., Citation2017). In European countries, there have also been increases in the sales of prescription opioids (Engi et al., Citation2022; Kalkman et al., Citation2019; Moriarty et al., Citation2022; Roussin et al., Citation2022; Ruscitto et al., Citation2015; Schubert et al., Citation2013; Xie et al., Citation2022; Zin et al., Citation2014). However, the situation in Europe, and between countries in Europe, may be different from the one in the United States due to different healthcare systems, opioid-prescribing habits, guidelines on opioid prescribing, and attitudes toward pharmacological pain treatment. Nevertheless, also in Europe there are reports of previously opioid-naïve patients that develop persistent opioid use after short-term opioid treatment (Howard et al., Citation2020; Karhade et al., Citation2020).
Comprehensive studies of the use of opioids are needed from a public health and a regulatory perspective to better understand prescribing patterns. A better understanding of prescribing patterns can help to initiate actions to encourage appropriate prescribing in accordance with product information, treatment recommendations, and guidelines.
This study uses individual data of users of opioids linked from several national health data registers to assess first-time dispensed opioids by drug type, doses, and diagnoses in Sweden. Trends in opioid use in the working-age population in Sweden 2006–2021 were also studied.
Methods
Study design
This is a retrospective register linkage study on routinely collected data, covering the entire adult population of Sweden. The study cohort comprises all adults aged 18–64 years, permanently residing in Sweden and with a first dispensed opioid in 2012–2015. The date of the first dispensation was defined as their index date. To select only opioid-naïve patients, those with any dispensed opioid within 6.5 years prior to index date were excluded. Also, patients with a record of a cancer diagnosis, except non-melanoma skin cancer, prior to or 3 months after index date, were excluded. The total Swedish population in 2015 was 9,851,017, of whom 5,878,713 were aged between 18 and 64 years (Ludvigsson et al., Citation2016; Statistics Sweden, Citation2022).
National health data registers
The nationwide Prescribed Drug Register, which started in July 2005, was used to identify dispensed opioids and concomitant psychotropic medication (Wettermark et al., Citation2007). The National Patient Register, which has had an almost complete coverage of all hospitalized patients in Sweden since 1987, was used to identify diagnoses in both inpatient and specialized outpatient care related to the opioid prescription, as well as records of psychiatric specialized care and care for addiction disorders. All hospital admissions and visits to a physician in specialized outpatient care must be reported to the register. Primary care is not recorded in the register (Ludvigsson et al., Citation2011). The Cancer Register was used to identify date and diagnoses of cancer (Barlow et al., Citation2009).
The open access statistical database on pharmaceuticals was used to assess trends in opioid use in the general population (National Board of Health and Welfare, Statistical database, Citation2022a).
Opioid types
The following opioid types identified by their Anatomical Therapeutic Chemical (ATC) classification were included in the analyses (WHO Collaborating Centre for Drug Statistics Methodology, Citation2022); hydromorphone (N02AA03), morphine (N02AA01), oxycodone (N02AA05), fixed combination of oxycodone and naloxone (N02AA55), codeine combinations (N02AA59), ketobemidone (N02AB0), pethidine (N02AB02), fentanyl (N02AB03), dextropropoxyphene (N02AC04) (marketing authorization expired in Sweden 2011), buprenorphine (N02AE01), fixed combination of morphine and spasmolytic (N02AG01), fixed combination of ketobemidone and spasmolytic (N0AG02), fixed combination of codeine and paracetamol (N02AJ06), fixed combination of codeine and ibuprofen (N02AJ08), codeine and other non-opioid analgesics (N02AJ09), tramadol (N02A×01), tapentadol (N02A×06), and codeine (R05DA04).
Prescriber characteristics
The workplace of the prescriber of the first-dispensed opioid of each patient was defined, based on the type of workplace and the prescriber’s occupation in conjunction with a record of an inpatient stay, discharge or a specialized outpatient care visit. The workplace was grouped in a mutually exclusive hierarchy; (i) dental care (the prescriber works in dental care or workplace is “unknown” but prescriber’s occupation is dentist), (ii) primary care (prescriber workplace is in primary care), (iii) inpatient care (patient is discharged from in-patient care on the same day or day before the date of the prescription), (iv) specialized outpatient care (patient has a visit to specialized outpatient care on the same day or day before the date of the prescription), (v) unknown (patient is discharged from inpatient care or has a visit in specialized outcare within 2–90 days before the date of the prescription), (vi) no visit recorded (prescriber is neither dentist nor from primary care and the patient has no record of any discharge or visit in inpatient or outpatient care within 90 days prior to the prescription).
Oral morphine equivalents
Total dispensed amount in milligrams, of the first-dispensed opioid and the respective oral morphine equivalent (OME), is presented. The opioids’ relative analgetic effect is compared to the OME of 1 for morphine. For calculation of OME, both national and international guidelines were used. For oxycodone, an OME of 2 was used as recommended in several guidelines in the Nordic countries as opposed to an OME of 1.5 used in many other countries (Dowell et al., Citation2016; Nielsen et al., Citation2016; Norsk Legemiddelhåndbok, Citation2022; Region Skåne, Citation2018).
Indication for opioid prescription
Information on the indication for treatment is not recorded in a structured way on the prescription in Sweden. For patients receiving their prescription from inpatient or specialized outpatient care, the main diagnosis for the admission or visit on the same day or the day before date of prescription was therefore instead assessed. Diagnoses were coded and grouped to the first three digits according to the Swedish clinical modification of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10-SE) (i.e., S821 and S826 were both coded as S82-fracture of the lower leg, including ankle) (National Board of Health and Welfare, Citation2022b).
Comorbid psychiatric and addiction disorders
Comorbid psychiatric and addiction disorders were defined as having any visit in psychiatric specialized outpatient care or hospitalization with a main diagnosis of mental or behavioral diagnosis (ICD-10-SE: F05-F99) within 5 years before index date, or a filled prescription for any psychotropic drug or drug for addiction disorders, within 5 years before the index date; antipsychotics (ATC: N05A), antidepressants (N06A), psychostimulants (N06BA, except N06BA07) or drugs used in addictive disorders (N07BB or N07BC).
Patients were classified as (i) no psychiatric disorder, (ii) psychiatric disorder but not addiction disorder, and (iii) addiction disorder with or without concomitant psychiatric disorder.
Statistical calculations
Standard descriptive statistics were used to describe the study cohort and the utilization patterns. Statistical analysis was performed in the SAS software, version 9.4 and R version 3.5.1 (R Core Team, Citation2018).
Results
Trend in opioid use in the general population
From 2006 to 2021, there has been a shift in dispensed opioids from tramadol to oxycodone. The combination of codeine and paracetamol has for long been the most dispensed opioid, but from 2019 oxycodone in the most dispensed opioid ().
Figure 1. Number of patients, aged 20–64 years, per 1000 inhabitants dispensed at least one opioid. Sweden, 2006–2021.
First-dispensed opioid in opioid-naïve and cancer-free patients
During 2012–2015, a total of 617,680 opioid-naïve, cancer-free patients aged 18–64 years (50.1% men) were dispensed opioids. The crude proportion of first-time opioid users in the population was 2.7% in 2012 and 2.6% in 2015. Those aged 18–24 years accounted for around 13% of all dispensations and those aged 25–34, 35–44, 45–54, and 55–64 years for 20%, 21%, 24%, and 21%, respectively.
The fixed combination of codeine and paracetamol was the most frequent dispensed opioid in 2012 to 2015 with 322,818 patients (52.3%), followed by tramadol (120,271, 19.5%) and oxycodone (104,418, 16.9%). From 2012 to 2015, tramadol as first-dispensed opioid dropped from 26.5% to 13.7% and oxycodone increased from 10.0% to 24.4% ().
Table 1. First-dispensed opioid by substance, per year, number of dispensations (N), and the proportion of all dispensed opioid that year (%). Persons 18–64 years old in Sweden with a first opioid prescription in 2012–2015, free of any opioid prescription the preceding 6.5 years.
Prescriber characteristics
Around one-third of the dispensations were from specialized outpatient care (32.8%) and primary care (28.3%). Dental care accounted for 9.3% of all first dispensations ().
Table 2. Prescriber’s workplace for first-dispensed opioid. In total, 617,568 women and men aged 18–64 years in Sweden with a first -dispensed prescription of opioids, 2012–2015, free of any opioid prescription the preceding 6.5 years.
Oral morphine equivalents
In , the dispensed amount and corresponding oral morphine equivalents for each opioid is presented. The dispensed relative analgesic effect of tramadol was higher (median 400 OME) than morphine (median 250 OME) and that of codeine (median 225 OME) in fixed combination with paracetamol was lower. The dispensed relative analgesic effect of oxycodone was similar to morphine and that of oxycodone in combination with naloxone was higher.
Table 3. Prescribed amount of (mg) opioids at first-dispensed prescription recalculated as oral morphine equivalents (OME)*. Persons aged 18–64 years in Sweden with a first dispensed opioid 2012 to 2015, with no prior dispensed opioid prescription the previous 6.5 years. Mean, median, and 25th and 90th percentile. Oral formulations only.
Indication for opioid prescription
Fracture of the lower leg was the most common indication in inpatient care, and dorsalgia (back pain) was the most common indication in specialized outpatient care, including day surgery, for first-dispensed opioid. These indications were followed by hip and knee replacement surgery and fracture of the lower arm and internal derangement of knee for in- and outpatient care respectively ().
Table 4. The 20 most common main diagnoses in inpatient care, accounting for 48,843 (48.9%) of the total 99,903 admissions linked to first-dispensed medication. And the 20 most common main diagnoses in specialized outpatient care, including day surgery, accounting for 110,839 (54.7%) of the total 202,804 visits linked to first-dispensed medication. Persons aged 18–64 years in Sweden with a first-dispensed medication 2012–2015, with no prior opioid dispensal the previous 6.5 years.
Comorbid psychiatric and addiction disorders
In total, 485,659 (78.6%) patients had no concomitant comorbid psychiatric or addiction disorder, 112,909 (18.3%) patients had a concomitant comorbid psychiatric disorder but not addiction disorder and 19,000 (3.1%) patients had a concomitant comorbid addiction disorder. First-dispensed opioid was very similar between the groups, with only morphine being slightly more common (5.2% compared to 3.6%) and opioids with spasmolytics slightly less common (1.9% compared to 4.0%) in those with a history of addiction disorder compared to those with no history of psychiatric or addiction disorder (data not shown).
Discussion
Exploring trends in dispensed opioids to opioid naïve cancer-free patients in Sweden from 2012 to 2015 do not show an increase in opioid use. There has been a shift from tramadol to oxycodone, but codeine in combination with paracetamol is still by far the most frequently dispensed opioid. The dispensed amount of opioid, with respect to the analgesic effect (when comparing oral morphine equivalents), was equivalent regardless of the dispensed opioid.
Orthopedic surgical procedures in inpatient care and day surgery, and dorsalgia in specialized outpatient care were the most common indications for getting an opioid prescribed. This is in line with recommendations to prescribe opioids for short-term postoperative pain. It is also similar to findings in Finland, a neighboring country with similar universal tax-financed healthcare system where postsurgical pain was the most common indication for initiating opioids followed by musculoskeletal pain (Keto et al., Citation2022). Despite the shift in type of opioid prescribed, the prescribed amount in oral morphine equivalents is similar between substances. The dispensed amount of opioid was between 250 and 400 OME, similar to in Finland, where the mean initial dispensed OME was 256 (Keto et al., Citation2022). In Spain, there has been an increase in OME despite a modest increase in opioid users (Xie et al., Citation2022). However, the calculations of oral morphine equivalents are dependent on the assumptions made on their relative effect. In Sweden, an OME of 2 for oxycodone is used as opposed to 1.5 used in other countries (Dowell et al., Citation2016; Nielsen et al., Citation2016; Norsk Legemiddelhåndbok, Citation2022; Region Skåne, Citation2018).
Several countries in Europe report an increased use of prescribed opioids (Engi et al., Citation2022; Häuser et al., Citation2021; Kalkman et al., Citation2019; Moriarty et al., Citation2022; Roussin et al., Citation2022; Ruscitto et al., Citation2015; Schubert et al., Citation2013; Zin et al., Citation2014). However, there are not yet clear signs of a substantial increased use of prescription opioids in the Nordic countries (Jarlbaek, Citation2019; Keto et al., Citation2022). Some explanations might be different healthcare systems, opioid prescribing habits, guidelines on opioid prescribing, and regulatory and legislative demands from the authorities.
Opioid prescribing habits differ between the Nordic countries (Jarlbaek, Citation2019). The International Narcotics Control Board has reported an increase in opioid use in Scandinavian countries (Berterame et al., Citation2016; International Narcotics Control Board, Citation2016). However, the report has been criticized to have methodological problems and to not reflect the actual medical use of opioids (Bäckryd et al., Citation2021). In Denmark, there was a markedly decreased use of tramadol from early 2017, coinciding in time with media attention on risk of addiction, and with regulatory actions taken by the Danish Medicines Agency (Sørensen et al., Citation2021). In Sweden, a decline in tramadol use started already in 2011 (Ljung, Grünewald, et al., Citation2021). In Finland, the proportion of the population prescribed opioids has been stable, but the average prescribed quantity has increased (Keto et al., Citation2022). In Norway, an increased prescription of opioids has been linked to an increase in accidental pharmaceutical opioid overdose deaths (Gjersing & Amundsen, Citation2022).
Given that morphine is generally recommended as a first-line treatment for acute severe pain in Sweden, it is somewhat unexpected that the prescription of oxycodone is higher than that of morphine. The reasons for this could be multiple, e.g., oxycodone being recommended in patients with renal impairment and oxycodone having a longer half-life and better enteral bioavailability than morphine. Further reasons could be increased awareness of the availability and pharmacological properties of oxycodone, expedited by a marketing campaign, and the fact that morphine has been in short supply for extended periods of time, leaving oxycodone the only available strong orally administered opioid.
In Sweden, dentists are not authorized to prescribe oxycodone, but are restricted to combinations with codeine and to tramadol, morphine, and ketobemidone. Most opioids prescribed by dentists are combinations of codeine and paracetamol. This is in accordance with national recommendations where tramadol is not recommended for the treatment of dental pain. However, in the same recommendations a restriction in the use of codeine is suggested, based on the risk of side effects and dependence. Instead, a short-duration treatment with a low dose of morphine could be considered in cases when the pain cannot be controlled by a combination with paracetamol and an NSAID.
Patients with previous psychiatric care or addiction care were prescribed opioids in a similar pattern as those without such ccmorbidity. The risk of subsequent substance-related morbidity among young adults prescribed opioids seems to be not as high as previously anticipated (Quinn et al., Citation2020). However, it is not possible to draw any conclusions about whether patients with previous psychiatric care or addiction care are prescribed opioids to a greater or lesser extent compared to those without such comorbidity as this study only covers patients who have been prescribed opioids; we have no information on those with pain but who were denied an opioid prescription. However, the proportion of history of psychiatric care is similar to a cancer-free general population (unpublished data from dataset introduced in Ljung, Sundström, et al., Citation2021). Also, history of psychiatric care among first opioid users is similar to what has been reported from Finland (Keto et al., Citation2022). The major strength of our study is the population-based cohort design, including unique individual data on all first-time users of prescription opioids, complete follow-up, and large sample size. Other advantages include the availability of excellent data on comorbid conditions, concomitant medicine use, and prescriber characteristics from complete and valid nationwide Swedish registers.
However, there are some limitations to consider. Opioids that are requisitioned to hospital wards and hospital-connected outpatients are not included as these data are not possible to link to a specific patient. The analyses are based on filled prescriptions of the patients, not the actual intake of medicine. The patient register contains information on hospitalizations and doctor’s visits to specialized outpatient care, but there is some under-reporting foremost from private care providers (Ludvigsson et al., Citation2016). The loss of diagnosis in the inpatient care is very small, while in the specialized outpatient care during the years studied it was around 5–10%. Data on visits and diagnoses in primary care is not available. This study only covers legal prescribing of opioids. To note, tramadol is still the largest prescription drug that is illegally imported and distributed in Sweden according to the Swedish Customs statistics on customs seizures (Swedish Customs, Citation2022).
Conclusion
Although this study does not show any increased new prescribing of opioids, a clear shift from tramadol to oxycodone is noted. Considering recent attention to reports of increased dependence on opioids in the United States and guidelines on opioid prescribing in Sweden, it can be assumed that the prescription pattern has continued to change from the period studied. The combination of codeine and paracetamol still accounts for about half of all opioid prescriptions. New prescriptions of opioids are largely made for short-term postoperative pain and pain relief in fractures. Hence, in general opioid prescriptions in Sweden seem to be in line with national recommendations.
Authors’ contributions
All authors developed the hypothesis and study design. CB obtained ethical approval. MG managed data and did the statistical analysis, with contributions from RL. CB, PT, and RL did the literature search. CB and RL wrote the first and successive drafts of the manuscript. All authors contributed to study concept and design, analysis and interpretation of data, and drafting or critical revision of the manuscript for important intellectual content. CB and RL had full access to the data in the study and had final responsibility for the decision to submit for publication.
Ethical approval
The study was approved by the Regional Ethical Review Board in Uppsala, Sweden (ethical approval number 2018/426).
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
According to Swedish Law the data cannot be placed in a publicly available repository. Researchers can after ethical approval from the Swedish Ethical Review Authority (www.etikprovningsmyndigheten.se) apply for data from the National Board of Health and Welfare, Stockholm, Sweden (www.socialstyrelsen.se).
Additional information
Funding
References
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