Abstract
Objective
This study was aimed to explore the pharmacoepidemiology of chronic noncancer pain (CNCP) patients who required chronic opioid therapy (COT) in the Taiwanese population.
Methods
Using the Taiwan National Health Insurance Research Database during 2008–2009, COT-requiring CNCP patients were identified by the inclusion criteria of both chronic analgesic requirement for > 3 months per year and long-term use of controlled opioids for > 28 therapeutic days during any 3-month period in ambulatory visits with malignancy-related pain excluded. Their demographic data and pharmacoepidemiological characteristics of opioid consumption and opioid prescriptions issued in ambulatory visits were analyzed.
Results
In total, 159 patients were enrolled as COT-requiring CNCP patients, and the prevalence was calculated at 0.016% in a 2-year period. Females were outnumbered by males (45.3% vs. 54.7%). Almost 60% of them were of working age and 93.7% belonged to low-income households, as in the health insurance claims, probably implying socioeconomic disadvantages associated with CNCP. The leading three diagnoses were unspecified myalgia and myositis, lumbago, and abdominal pain of unspecified site. The most common department from where these 159 CNCP patients obtained their opioid prescriptions was the emergency department (27.6%), ensued by a pain clinic (25.3%), but they could acquire only a few opioid therapeutic days through emergency department visits. Moreover, pain clinic satisfied the majority of opioid therapeutic days. Among all opioids, morphine was the most frequently prescribed in opioid-obtaining ambulatory visits, accounting for most of the opioid therapeutic days as well as opioid consumption.
Conclusion
COT-requiring CNCP patients were easily associated with adverse socioeconomic liabilities and often visited emergency department as well as pain clinics. Morphine was the main opioid used for their chronic pain. Transfer of COT-requiring CNCP patients to appropriate departments is strongly recommended for efficient long-term pharmacotherapy for their chronic pain.
Keywords
chronic noncancer pain; chronic opioid therapy; opioid therapeutic days;
1. Introduction
Chronic noncancer pain (CNCP) is a widespread health problem with pervasive negative effects on physical function and quality of life of the affected individuals.1 In general, all chronic pain conditions other than pain at the end of life or malignancy-related pain are collectively labeled as CNCP.2CNCP patients have a higher incidence of pre-existing psychological disorders, and the considerable impact of psychological distress on the pain extent of CNCP have also been well highlighted.1, 3
The treatment for CNCP remains a challenge to the primary care physicians, and some of chronic pain patients were poorly satisfied with the treatment they received in primary care clinics.4 Pharmacological treatment is still the mainstay for the treatment of CNCP, and nonpharmacologic strategies, such as nerve blocks and interventional treatments, are also helpful in alleviating chronic pain for some CNCP patients.5, 6 As the intractable CNCP cases stand, physicians could consider obligatorily chronic use of opioids for selective patients whose severe CNCP failed to be relieved by nonsteroidal anti-inflammatory drugs, cyclooxygenase-II inhibitors, or weak opioid agonists other than controlled opioid drugs.7, 8, 9 However, the safety, effectiveness and abuse potential of chronic opioid therapy (COT) in patients with chronic noncancer pain still open to debate and under controversies, given the rising prevalence of opioid abuse.10
The prevalence of CNCP varied widely in different countries. The 1-month prevalence of moderate-to-severe CNCP, estimated using systematic review principles, was 19% in pan-Europe.11 Using a literature review, this prevalence was estimated to be 16% in Denmark and 18% in Sweden.12 The prevalence of CNCP, defined as continuous or intermittent pain for at least 6 months, was reported to be 29% among Canadian adults, as surveyed by telephone in 2001.13 In an article, the prevalence of mild chronic pain among the Taiwanese people living in Taipei City was estimated to be 40%, based on the interview of only 219 elderly people with a structured questionnaire.14Considerable heterogeneity existed in the prevalence in different countries due to a great variety in the population chosen, research methods, pain severity, and chronicity definitions of CNCP in different studies. Nevertheless, the prevalence of CNCP seemingly continues to increase.15, 16
A particular subgroup of CNCP patients who required COT regularly requests for more endeavors and medical expertise to get their pain abated, and usually demands more medical services, and often are troubled with more comorbidities.2, 17 The 1-year prevalence of COT-requiring CNCP was estimated to be 0.65% in a United States state population survey using insurance claims database, and 3% in Denmark from an interview and questionnaire survey.18, 19 However, the prevalence of CNCP in Taiwan was rarely investigated, especially among the severe CNCP patients who demanded COT regularly. Lin et al2 reported that the number of COT-requiring CNCP patients, who were officially superintended and registered on record in the database of the National Bureau of Controlled Drugs (NBCD), Taiwan, in August 2001, was only 114.2 However, it only stood for a confined subgroup of COT-requiring CNCP patients who had severe pain, consumed opioids for a longer time, and were overseen strictly under governmental NBCD surveillance, hardly portraying the actual conditions of CNCP patients treated with opioids habitually in the Taiwanese population. Since clear understanding of CNCP circumstances is important to manage these patients and improve the quality of pain control, we aimed to explore pharmacoepidemiology of CNCP patients who required COT in the Taiwanese population.
2. Materials and methods
2.1. Materials
In this retrospective cohort study, we aimed to investigate the epidemiology and medical care utilization of COT-requiring CNCP patients in Taiwan, based on the analyses of secondary data of both 2008 and 2009 from the National Health Insurance Research Database. Created by Taiwan National Health Research Institutes, National Health Insurance Research Database was a representative database of a population of 1 million, which was derived systematically from the entire insurance claim database for reimbursement for beneficiaries of the Taiwan National Health Insurance program. Taiwan launched a single-payer health insurance program in 1996, which provided medical care to over 96% of Taiwanese population enrolled in the program. Since then, a tremendous amount of computerized data, including enrollment data, hospitalization data, drug exposure data, disease diagnosis data, and original claim data for reimbursement, has been accumulated. This database is available to the researchers in Taiwan and suitable for cohort studies on a population-based basis.
2.2. Methods
First, noncancer patients, who had no malignancy diagnosis during follow-up in 2008 and 2009, were recruited by means of elimination with the Classification of international code of Diseases—9th edition (ICP-9) of malignant neoplasms (ICD-9 codes: 140-209 and 230-239) in both inpatient and outpatient claim records from a National Health Insurance Research Database representative database of 1 million population.20
Second, among all noncancer patients, those who both have persistently taken analgesic agents, exclusive of oral or parental nonsteroidal anti-inflammatory drugs and other nonopioid drugs, for over 3 months in 1 year and have managed with controlled opioids confined to outpatient visits for > 28 therapeutic days during any period of 3 months would be enrolled as targeted COT-requiring CNCP patients. Drug prescriptions during hospitalization or at discharge would not be included. This CNCP criterion was comparable with the regulatory ordinance in “Precautions of Long-term Narcotic Prescription for Physicians to Patients with Intractable Chronic Non-cancer Pain” announced in 2004 by the Taiwan Food and Drug Administration (TFDA), Department of Health, Executive Yuan. The controlled opioids commonly used in ambulatory clinics for pain control and regulated by TFDA in 2008 and 2009 included morphine injection (drug codes: A005886209, A005891209, B021452299, A005862209, and B021452243), regular morphine tablet (drug code: A005860100), slow-release morphine tablet (drug codes: B019000100, A042534100, B019001100, and B023779100), meperidine injection (drug code: A005874209), meperidine tablet (drug code: A005858100), transdermal fentanyl patch (drug codes: A050018311, A0517173CS, B021523314, B021525321, B022898314, B022899321, B0248423CS, B0248703B9, and B024889311), codeine injection (drug code: A005889209), codeine tablet (drug codes: A005857100 and A005865100), and sublingual buprenorphine tablet (drug code: B021625100). All these were targeted in this study. Outpatient prescriptions of these five drugs were strictly controlled and overseen under TFDA surveillance. The medical claim records of codeine prescription were excluded if prescribed for diseases of the respiratory system diagnosed (ICD-9 codes: 460-519).
The 2-year CNCP prevalence was computed because our own insurance claim databank of 2 years hardly showed a long-term annual trend through the years and the 1-year prevalence of COT-requiring CNCP in the Taiwanese population was very low. Demographic attributes of COT-requiring CNCP patients, including gender, age, district of group insurance units, community urbanization, and household income, were analyzed. The degree of community urbanization of the local district where the patients lived was determined using standards proposed in a previous survey of Taiwan township development.21 The household economic status of CNCP enrollees was determined from their policy identities while joining into Taiwan National Health Insurance program. The demographic low-income household was Category 5 in the insured object classification of the National Health Insurance claim, which was qualified equally to the low-income household members stipulated in Social Assistance Act of Taiwan. The insured of category 5 means someone whose average household member income, divided by all family members, is below the essential minimum of subsistence allowance per person per month. In Taiwan, the minimum income was NTD 9210 in 2008, with limited chattel per person and limited real estate per household.
Furthermore, opioid pharmacotherapies in these COT-requiring CNCP patients were also investigated, including all outpatient visits for their pain issue, opioid consumption, and clinical pain disorders, which indicated their opioid medication. To understand utilization of medical services in these patients, we calculated the frequencies of outpatient visits in different departments from their outpatient reimbursement claims, including analgesic- and opioid-obtaining outpatient visits. The outpatient visits in which several nonopioid analgesics and opioids were prescribed would be counted once only.
To view opioid consumption of CNCP patients, the authors used both opioid therapeutic day (OTD) and oral morphine equivalent dose (OMEQ), instead of medical expenditure, for compatibility with the inclusion criterion of therapeutic day of COT-requiring CNCP in the TFDA regulations. OTD in our study was defined as the duration of days that physicians intended to stifle chronic pain while prescribing opioids to CNCP patients in a single outpatient visit. OMEQ means equivalent dosages of strong opioids (administered through oral, parenteral, or transdermal routes) relative to analgesic strength of oral morphine.22, 23 OMEQ conversion factors used were as follows: 1.0 for morphine oral intake, 3 for morphine intravenous or intramuscular injection, 0.25 for codeine intra- muscular injection, 0.15 for codeine oral intake, 3.0 for fentanyl transdermal route (from mcg/hr to mg/day), 0.4 for meperidine intravenous or intramuscular injection, 0.1 for meperidine oral intake, and 40 for buprenorphine sublingual use.22 Average OMEQ per ambulatory visit was presented as medians with the 25th and 75thquartiles (Q1 and Q3). Average OTD per opioid-obtaining ambulatory visit, OMEQ, and OTD per opioid prescription were presented as mean ± standard deviation.
It is common that more than one diagnostic code, up to a maximum of three, is given for a single outpatient visit. Diagnosed pain disorders of these patients were classified according to chapter codes in ICD-9, including infectious and parasitic diseases (ICD-9 codes: 001–139); neoplasms (ICD-9 codes: 140–239); endocrine, nutritional and metabolic diseases, and immunity disorders (ICD-9 codes: 240–279); disorders of blood (ICD-9 codes: 280–289); mental disorders (ICD-9 codes: 290–319); diseases of the nervous system and sense organs (ICD-9 codes: 320–389); diseases of circulatory system (ICD-9 codes: 390–459); diseases of the respiratory system (ICD-9 codes: 460–519); diseases of the digestive system (ICD-9 codes: 520–579); diseases of the genitourinary system (ICD-9 codes: 580–629); complications of pregnancy, childbirth and the puerperium (ICD-9 codes: 630–677); diseases of the skin and subcutaneous system (ICD-9 codes: 680–709); diseases of the musculoskeletal system and connective tissue (ICD-9 codes: 710–739); symptoms, signs, and ill-defined conditions (ICD-9 codes: 780–799); and injury and poisoning (ICD-9 codes: 800–999).
Throughout this study, we followed the guidelines and rules for investigation with human individuals set by the institutional review board of E-DA Hospital (IRB number: EMRP-101-055).
3. Results
Data of only 159 CNCP patients, who had been suffering from CNCP and required long-term opioid therapy in 2008 and 2009, were collected from the National Health Insurance Database of 1 million population, and the 2-year prevalence was calculated to be 0.016%. Among 159 COT-requiring CNCP patients, the number of males was more than that of females; 59.7% of them were of working age (25–65 years), and patients aged over 65 years accounted for over 40%. Most of these patients lived in urbanized communities (59.1%), especially in Taipei Capital district. Particularly worthy of note, 93.7% of these patients belonged to low-income households, as per the health insurance policy (Table 1).
Nearly half of CNCP patents (46.5%) had visited the emergency department (ED), and over one-fifth (20.8%) had visited pain clinics to obtain opioids for pain control. These CNCP patients seemingly obtained opioid prescriptions more easily in outpatient visits than pain clinic visits (86.5%, 527 opioid-obtaining visits vs. 609 analgesic-asking visits). Moreover, pain clinics accounted for 44.9% of the total OTD and 74.2% of the total OMEQ of all COT-requiring CNCP patients. Although pain clinics and emergency medicine departments accounted for over half of opioid-obtaining outpatient visits (53.0%), CNCP patients could get only a few OTDs (1.1 ± 0.4 days) in a single visit to the ED (Table 2).
More than half of CNCP patents took codeine (57.9%) or morphine (50.9%) for their CNCP. Morphine, codeine, and fentanyl, listed in a decreasing order accounted for most of OTDs of five opioid drugs (88.0%). Surprisingly, in outpatient visits, injection prescriptions of morphine, codeine, and meperidine were prescribed to 36.5%, 11.9%, and 35.2% of 159 CNCP patients, respectively, even on a chronic basis. Among all opioids and drug formulas, morphine SR and regular tablets per oral accounted for the majority of OMEQ (74.1%, summed up) and 43.5% of OTD. The most frequently prescribed opioid was morphine, followed by meperidine, in opioid-obtaining outpatient visits (Table 3).
The leading causes of 159 COT-requiring CNCP patients asking for opioids were unspecified myalgia and myositis (ICD-9 729.1), followed by lumbago (ICD-9 724.2) and abdominal pain of unspecified site (ICD-9 789.00). Unspecified neuralgia; neuritis and radiculitis (ICD-9 729.2), synonymous with neuropathic pain; and headache (ICD-9 784.0) were the next commonest causes among these patients (Table 4).
4. Discussion
Our study disclosed that only 159 COT-requiring CNCP patients were enrolled in a representative 1 million Taiwanese population during the 2-year period of 2008 and 2009, and its 2-year prevalence was estimated to be 0.016%, far less than in the United States (1-year prevalence 0.65%) or in Denmark (1-year prevalence 3%).18, 19 The differences in the COT-requiring CNCP prevalence among various populations resulted partly from the distinct definitions of chronic opioid use, for example, long-term opioid use (OTDs) for over 4 weeks in any 3-month period in Taiwan and chronic opioid use for at least 6 months in the United States, and regular or continuous opioid use in Denmark.18, 19 The coding of ICD9 conditions in the Taiwan medical system might not be adequately accurate; hence, the use of ICD9 codes might introduce selection bias into the study. However, malignancies are of great clinical significance to clinicians, and it is hard to skip malignancy diagnosis completely in all claim records of ambulatory visits and inpatient admissions within the period of 2 years if cancer pain exists; thus, it is appropriate to use ICD9 codes as exclusion criteria to define the noncancer group from all patients. The definition of COT in our study conformed to the official regulations of TFDA, and COT-requiring CNCP patients should be registered in Taiwan with the NBCD, TFDA. Known allegedly, COT-requiring CNCP patients registered in the NBCD list in the whole Taiwan population of 23 million in 2008 and 2009 were counted at several hundred. (The authors failed to get the exact number of registered CNCP patients in NBCD.) The possible causes of the great variation in the COT-requiring CNCP prevalence between the previously published Lin et al's2 report in 2001, NBCD registry, and ours in the same Taiwanese population were the failure of submission to NBCD surveillance in some cases, obtaining opioids from different departments and different physicians, disparity of study years with annual trend of CNCP prevalence, and obviously diverse study methods. Furthermore, several barriers to long-term opioid therapy might also result in a low prevalence of COT-requiring CNCP in the Taiwanese population, including popular negative beliefs about opioid use, nonacceptance by the local society, and strict legal regulation from the government in Taiwan.24, 25 Thus, the real prevalence of severe CNCP might probably be underestimated in Taiwan because of some barriers to COT.
Most of epidemiological CNCP surveys agreed that females are more likely to experience CNCP than males, and the overall prevalence of CNCP increases with age.12, 26, 27 Nevertheless, male COT-requiring CNCP patients outnumbered female patients in our research, and the underlying reason remains unclear. In our research, 60% of these 159 patients (average age 59.2 years) were of working age (25–65 years). Meanwhile, a low-income household prevalence of a remarkably-high 93.7% was disclosed in this group, suggesting that severe CNCP usually have a significant adverse impact on the economic advantages of the victims.17, 27, 28 Although low-income households, determined by the health insurance claim, did not necessarily reflect the patient's real occupational incapacity, this identity implied that CNCP brought about economic burdens, probably making it difficult for patient families to maintain their basic standard of living. Accordingly, severe CNCP that necessitates COT regularly could cause significant impairment in occupational performance and worse economic households, justifying the need of physical/occupational therapy when appropriate in combination with drug therapy.29
As evident from their analgesic-seeking behaviors, 46.5% of CNCP patients have visited EDs for their pain issues and ED interpreted 27.8% of opioid-obtaining outpatient visits. Although ED was a major place for them to get their pain managed, ED could provide only a few therapeutic days, implying that ED was a less-than-optimal choice to treat CNCP patients on a chronic basis.30 This phenomenon of ED overutilization popularized among COT-requiring CNCP patients was comparable with the context disclosed in other researches.30, 31 Nevertheless, in our study, we found that these patients obtained opioid prescriptions only in 13% of their analgesic-obtaining ambulatory visits and usually gained prescribed opioids from 1.8 ± 1.2 different departments (mean ± standard deviation, data not shown). Particularly contrary to the common speculation that these patients came to ED because they lacked a primary care physician, COT-requiring CNCP patients were also treated under other subspecialist's care in the meantime, suggesting inadequate pain relief.32 Pain clinic was the major department to satisfy their pharmacological need to alleviate chronic pain, which made for about one-quarter of opioid-obtaining ambulatory visits and accounted for a significant portion of opioid consumption (74.2% of OMEQ) and therapeutic duration (44.9% of OTD) of all opioids. Yet only 20.8% of CNCP patents visited pain clinics to obtain opioids for pain control, although pain subspecialists were supposed to be more efficient experts in pain management or have more positive attitudes toward CNCP patients.4 Thus, more efforts are needed to place COT-requiring CNCP patients in the appropriate place to manage their pain problems on a chronic basis.
For COT-requiring CNCP patients, morphine was most frequently prescribed, followed by meperidine, in opioid-obtaining outpatient visits. Morphine also accounted for the majority of opioids consumed in OMEQ and also for the most OTDs among all opioids, followed by codeine and transdermal fentanyl patch. Thus, morphine was the most important opioid used for chronic pain management in these patients. Furthermore, we found that injection formulas of morphine, codeine, and meperidine were given to some CNCP patients even on a chronic basis. Although meperidine is not recommended for chronic pain management, meperidine still accounted for 29.5% of opioid prescriptions among these 159 patients and meperidine injections were ordered in 95.0% of all meperidine prescriptions. Moreover, COT-requiring CNCP patients could get only a small number of meperidine therapeutic days (1.6 ± 2.7 days) in a single prescription. This accorded with the belief that meperidine is prescribed continuously to CNCP patients by some physicians in spite of the long list of potential side effects of chronic meperidine use and the availability of other effective opioids.33 The common use of meperidine in CNCP patients conformed with the previous findings that meperidine was prescribed improperly and increasingly to nonoperation patients without cancer diagnoses in the ambulatory/emergency settings in Taiwan.20Conclusively, further investigation of the appropriateness of opioid use in COT-requiring CNCP patients is warranted.
The leading diseases that made COT-requiring CNCP patients ask for opioids in ambulatory visits were unspecified myalgia and myositis (ICD-9 729.1), followed by lumbago (ICD-9 724.2); abdominal pain of unspecified site (ICD-9 789.00); neuralgia, neuritis, and radiculitis, unspecified (ICD-9 729.2); and headache (ICD-9 784.0). Our major concerns about the true etiology of CNCP were the fact that multiple diagnostic codes were usually given for single outpatient visit, and overlapping entity or ambiguities between unspecified myalgia, myositis, lumbago, unspecified neuralgia, neuritis, and radiculitis probably existed. Because unspecified myalgia and myositis (ICD-9 729.1), lumbago (ICD-9 724.2), unspecified backache (ICD-9 734.5), and lumbosacral spondylosis without myelopathy (ICD-9 721.3) took a great part in the visit causes, we could conclude that the diseases of the musculoskeletal system and connective tissue remained the main causes of COT-requiring CNCP. Nevertheless, this conclusion coincided with previous CNCP studies that lower back pain was the major syndrome of CNCP.27, 34, 35 Abdominal pain of an unspecified site (ICD-9 789.00) was the third common diagnosis for CNCP patients, yet chronic pancreatitis (ICD-9 577.1) coexisted in 36.6% cases (data not shown) of abdominal pain of unspecified site. The aforementioned findings that COT-requiring CNCP patients had diverse diagnoses in ambulatory services probably implied the heterogeneity of the underlying conditions of CNCP, or multiple pain sites involved in pain syndrome.36
5. Conclusion
Most of COT-requiring CNCP patients were low-income thresholds associated with unfavorable socioeconomic status, and some of them frequented EDs for short-term pain relief, making it necessary to allocate these patients to appropriate departments that could provide efficient analgesic management on a chronic basis, to enhance their well-being as well as medical utilization. Our findings also suggest that further investigation of the appropriateness and effectiveness of opioid use in CNCP patients is necessary to improve their pain control.
Acknowledgments
This study was sponsored by E-DA Hospital, under its Institutional Research Project Program (institution project number: EDAHP-101032). This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health, and managed by National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, Department of Health, or National Health Research Institutes.
