Prescription prevalence and patterns of painkillers among women in gynecological practices

Painkillers are one of the most commonly prescribed drug classes [1] and are used for a variety of diseases (e.g. headaches [2], arthritis [3], traumatic injuries [4], postoperative pain [5] and cancer) [6 ]. In 2016, between 22% and 57% of patients in general practices in Europe received painkiller prescriptions [7]. Paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs; e.g. ibuprofen or ketoprofen) and opioids (e.g. morphine or fentanyl) are the most commonly used painkillers today. These medicines are available with a prescription or without a prescription, depending on the medication and country. Pain is a very common symptom in women, making its effective treatment extremely important in this population [8–10]. One of the most common types of pain in women is chronic pelvic pain, which can be related to endometriosis [11], premenstrual syndrome [12] or urinary tract infections [13]. In recent years, there has been increasing interest in pain medication prescribing patterns among women [7,14–23]. For example, a 2017 study showed that between 25% and 60% of women in France, Germany and the UK were prescribed such drugs [7]. Other researchers estimated in an Australian study of over 20,400 participants that 13% of women complaining of chronic pain had recently taken opioids and 19% had received non-opioids [20]. Although these studies are of great interest, they were not conducted in gynecological practices in Germany and it is difficult to generalize their results to this setting. The aim of the present study was therefore to analyze the prescription prevalence and patterns of painkillers in gynecological practices in Germany.

>> The present retrospective study used data from the nationwide Disease Analyzer database (IQVIA). This database includes demographic, clinical and pharmaceutical data obtained in anonymized form from a nationwide sample of general medical and specialist practices [24]. The selection process for the Disease Analyzer database is based on summary statistics for all doctors in Germany, which are published annually by the German Medical Association. IQVIA's Statistics Department uses these statistics to determine panel design using the following categories: physician specialty, state, size class, and physician age. Each specialty (e.g. gynecology) has a similar distribution regarding these variables. IQVIA regularly analyzes the quality of the data, and the Disease Analyzer database was found to be representative of primary care and specialist practices [24]. In addition, the database has already been used in several studies focusing on pain and pain treatment [7,25,26].
Study population, outcomes and covariates
This study is based on 142 gynecological practices that continuously provided data from January 1, 2008 to December 31, 2017. All women aged ≥18 years who visited one of the 142 practices at least once between 2008 and the end of 2017 were included. All practices were analyzed for the entire study period (2008-2017). The primary outcome was the prevalence of painkiller prescriptions in gynecological practices per study year, defined as the proportion of women who received painkillers in this setting in the year under review. The denominator was the number of women who visited one of the gynecological practices at least once that year. The following drug classes were included in the analysis: anti-inflammatory and anti-rheumatic products, non-steroids (Anatomical-therapeutic-chemical [ATC] classification system: M01A) and analgesics (N02) including opioids (N02A), migraine drugs (N02C) and other analgesics and antipyretics (N02B) . All prescription types available in Germany were taken into account: prescriptions reimbursed by a statutory health insurance company, private prescriptions (partially reimbursed by a private health insurance company) and green prescriptions (paid by the patient). The secondary endpoint was the most common diagnoses (unspecified and specified diagnoses) associated with the prescription of these drugs. Unspecified diagnoses included abdominal and pelvic pain (International Classification of Diseases, 10th edition [ICD-10]: R10), back pain (M54), pain and other conditions related to the female genital organs and menstrual cycle (N94) , pain, not classified elsewhere (R52) and headache (R51). Specified pain diagnoses included migraine (G43), cystitis (N30), urinary tract infection, site unspecified (N39.0), mastitis (N61), mastodynia (N64.4), salpingitis and oophoritis (N70), unspecified Parametritis (N73.2), Acute vaginitis (N76.0), Acute vulvitis (N76.2), Vulvar abscess (N76.4), Endometriosis (N80), Other and unspecified ovarian cysts (N83.2), Malignant Neoplasms of the mammary gland (C50), Malignant neoplasm of the cervix uteri (C53), Malignant neoplasm of the ovary (C56) and Leiomyoma of the uterus (D25). These analyzes were performed based only on prescriptions that were associated with diagnoses (approximately 60% of all prescriptions). Last but not least, age was considered as a demographic variable.
Statistical analyses
Only descriptive statistics were used for this cross-sectional study. All analyzes were performed using SAS 9.4 (SAS Institute, Cary, NC, USA).
Results
The present study examined 1,191,589 women who visited a gynecological practice at least once during the study period (2008-2017). The prevalence of painkiller prescriptions in women decreased from 2.0% in 2008 to 1.4% in 2017 (Table 1), while the average age of women increased from 37.6 to 39.6 years and the average number of painkiller prescriptions per patient remained stable (1.2). In 2017, 5,331 people were prescribed painkillers (median prevalence of 1%), and the prevalence in the different gynecological practices ranged between 0% and 9% (Fig. 1). The prevalence by age group is shown in Figure 2. This prevalence ranged from 0.8% in people over 60 to 1.6% in people between 18 and 50. The most commonly prescribed painkillers can be found in Figure 3. The most frequently prescribed drug was ibuprofen, which accounted for 36% and 41% of all analgesics prescribed to women in 2008 and 2016, respectively. Finally, the diagnoses associated with the prescription of these medications are listed in Table 2. Diclofenac, ibuprofen, and metamizole were most commonly prescribed for abdominal and pelvic pain (27.6% to 44.6% of prescriptions), whereas naproxen, acetaminophen, and opioids were prescribed primarily for pain and other conditions related to the female genital organs and menstrual cycle (62, 3% of the prescriptions), headache (22.3% of the prescriptions), and malignant neoplasms of the mammary gland (25.5% of the prescriptions) were prescribed. In addition, triptans were prescribed for either migraine (96.1%) or unspecified headache (3.9%).
discussion

The present study, which included more than 1.19 million women in gynecological practices in Germany from 2008 to the end of 2017, found that the proportion of women who had received painkiller prescriptions was approximately 1% - 2% and declined during the study period the average age of treatment recipients increased. In addition, ibuprofen was the most commonly prescribed drug and was primarily used for abdominal and pelvic pain. Diclofenac and metamizole were also prescribed for the treatment of abdominal and pelvic pain, while naproxen was mainly prescribed for pain and other conditions related to the female genital organs and the menstrual cycle, paracetamol for headache, triptans for migraines, and opioids for breast cancer.
The main finding of this study is that the prevalence of drug prescriptions given to women to treat pain in gynecological practices in Germany was below 2% and has decreased in recent years. There are several hypotheses that could explain this relatively low prevalence. First, it is conceivable that women affected by painful disorders may have used over-the-counter medications to relieve their pain. In 2015, Sarganas and colleagues showed in two representative population-based surveys in Germany (7,099 and 7,091 participants, respectively) that the use of over-the-counter medications accounted for over 50% of total analgesic consumption [17]. In the same year, researchers from Norway observed that among approximately 40,000 study participants, 47% of the sample had used over-the-counter medicines at least once a week in the month before the study, and that the prevalence was particularly high in women [16].
Taken together, these two studies show that the majority of women are likely using over-the-counter medications to treat their pain. Second, it is possible that patients treated in gynecological practices received prescriptions for analgesics not from their gynecologists but from their primary care physicians. Consistent with this hypothesis, in a recent study of more than 4.2 million patients from three European countries (France, Germany and the United Kingdom), we found that 25% to 60% of women treated in general practices received painkiller prescriptions [7]. In another study, in which the study population for 59% consisted of women, it was reported that approximately 19% of the sample suffered from chronic pain and that over 86% of the subpopulation were prescribed painkillers [27].
The three most commonly prescribed analgesics were paracetamol (43%), opioids (34%), and NSAIDs (22%). These studies clearly show that primary care physicians play a key role in the treatment and management of pain in women. Another interesting finding from this study is that the prevalence of women receiving pain medication in gynecology practices decreased between 2008 and 2017. This decline may be due to the fact that other practices specializing in pain have opened their doors in Germany in the last decade [28].
In this study, ibuprofen accounted for 36% to 41% of all analgesic prescriptions in gynecology practices. Ibuprofen has an interesting efficacy and safety profile, with an analgesic effect achieved through moderate inhibition of the prostaglandins cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) [29]. The time that ibuprofen stays in the body is short, which explains the low side effects (gastrointestinal, cardiovascular and kidney). We also found that 8% to 15% of women treated in gynecology practices were prescribed metamizole. This finding is particularly concerning because the use of this drug is associated with an increased risk of agranulocytosis [30] and it has been withdrawn from the market in many countries [31]. Another important finding of the study is that the most commonly prescribed medications were used for various diseases. In accordance with international guidelines [32], two NSAIDs (i.e. diclofenac and ibuprofen) were typically prescribed for abdominal and pelvic pain.
A review of 140 studies found that the prevalence of chronic pelvic pain in the general female population ranges from 6% to 27% [9], highlighting the major impact of this type of pain on women's health. In addition, naproxen, another NSAID, was administered for pain and other conditions related to the female genital organs and menstrual cycle. Since naproxen appears to have no effect on the reproductive cycle [33] and has a longer half-life and duration of action, it is an important drug for the treatment of pain in gynecological practices. Paracetamol has been prescribed for headaches, and several studies and guidelines indicate that this drug is effective in treating this common condition [34,35]. Furthermore, our study confirmed that triptans, ie drugs that act as serotonin receptor agonists, are mainly prescribed to people with migraines and other types of headaches [36]. This result is in line with current European treatment guidelines for migraine [37]. Finally, the fact that opioids were often prescribed to women with breast cancer may indicate that cancer patients often suffer from severe pain that is not relieved by first-line therapies (e.g. NSAIDs or acetaminophen) and the use of Require morphine and its derivatives. Based on the latest guidelines from the European Society for Medical Oncology, opioids are recommended for the treatment of moderate and severe pain in adult cancer patients [38].
This study has several limitations that should be mentioned here. First, only about 60% of the prescriptions were linked to clinical diagnoses, which may have introduced bias in our analyses. Second, because women may have also been treated in other practices (e.g., family practice or neurology practice), it is conceivable that we underestimated the frequency of analgesic prescriptions in this population. Since the prescriptions of painkillers by general practitioners can have a significant influence on the painkiller prescriptions by gynecologists, it is very difficult to evaluate the changes in the prescribing behavior of gynecologists without taking these into account. Third, analysis of treatment dose and duration could have allowed a better understanding of analgesic prescribing patterns in gynecological practices. Fourth, we did not have information on the demographic and clinical factors that may have contraindicated the prescription of certain analgesics. Finally, there was no data on the number and type of painkillers taken before the drug in question was prescribed, although these previous prescriptions may have influenced the choice of therapy by the gynecologist in question. The main strengths of the study are the number of women included in the analysis, the length of the study period and the type of data, which allowed an unbiased estimate of painkiller prescriptions issued in gynecological practices in Germany.
The prevalence of painkiller prescriptions among women treated in gynecological practices was low and decreased between 2008 and 2017. Further studies are needed to gain a better understanding of the factors that influence the likelihood of receiving an analgesic prescription in this setting. <<