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Research Paper

Guideline-recommended vs high-dose long-term opioid therapy for chronic noncancer pain is associated with better health outcomes: data from a representative sample of the German population

Häuser, Winfrieda,b,*; Schubert, Tinoc; Scherbaum, Norbertd; Tölle, Thomase

Author Information
doi: 10.1097/j.pain.0000000000001067
  • Free
  • Global Year 2018

1. Introduction

Long-term opioid therapy (LTOT) is a treatment option for some patients with defined chronic noncancer pain (CNCP) conditions such as neuropathic and osteoarthritis pain according to recent interdisciplinary and evidence-based guidelines.19 The US American National Institute of Health guideline has defined the daily morphine equivalent dose (MEQ/d) requiring particular caution as 50 mg/d for general practitioners and 90 mg/d for specialists.3 In Germany, the MEQ/d requiring attention is 120 mg/d16 and that for Canada is 90 mg/d.3 The recommendations for threshold doses of MEQ/d were based for all 3 guidelines on (1) lack of evidence for a dose-dependent efficacy of opioids, (2) evidence for negative health outcomes associated with LTOT including overdoses and opioid-associated hospital admissions7 and opioid-related mortality13 for those exceeding doses of 50 mg MEQ/d, traffic accidents for doses exceeding 100 MEQ/d,14 higher rates of substance use disorders, and worse patient-reported pain outcomes and more health care utilization when exceeding doses of 50 mg MEQ/d,25 and (3) expert consensus. In addition, the German guideline referred to the MEQ/d for long-term open-label extension studies for CNCP which did not exceed 120 mg/d in most trials.16

Health care expenditures for opioid users are largely high because of higher prescription costs and greater contact with the health care system (outpatient visits, emergency room visits, and inpatient lengths of stay).22 Studies conducted in North America have been in selected patient populations (eg, veterans; socioeconomically disadvantaged persons; members of a single Health Maintenance Organization), and those addressing health costs have compared patients with LTOT with nonopioid users.22 There have been no European studies evaluating health care outcomes for CNCP in patients receiving guideline-recommended dose opioid treatment compared with high-dose LTOT. Therefore, this study aimed to assess whether guideline-recommended LTOT compared with high-dose LTOT for CNCP is associated with better health outcomes (risky opioid therapy, abuse and addiction of prescribed opioids, and health care costs) in a large patient sample representative of the general German population in terms of sex and age.

2. Methods

2.1. Study design and data source

This retrospective cross-sectional observational study was based on an anonymized German health claims database and included 4,028,618 persons insured by 69 German statutory health insurances. This data set included 5.0% of the population covered by statutory health insurances from January 1, 2014, to December 31, 2014. Furthermore, data were adjusted for age and sex distribution in the German population in accordance with the Federal Statistical Office based on the year 20139 to ensure adequate data representation. Privately insured patients in Germany were not included in this study. The study design followed the recommendations of the German society for epidemiology.12

2.2. Medical variables

The data set was identified by the ICD-10-GM (German Modification of International Classification of Diseases) codes for the classification of diseases.10 Diagnoses assigned to a patient by a primary care physician in the year 2014, with the additional code “secured” was used for the analysis. Patients with any cancer diagnosis (ICD-10 C00-D48) or maintenance treatment of opiate addiction (ICD-Code B20, B21, B22, B23.0, B23.8, B24, U60.3, U60.1, U60.2, U60.9, U61.1, U61.2, U61.3, U61.9, U85, and Z21) were excluded from the analysis. Patients with incomplete insurance periods in 2014 were excluded as complete data were not available for analysis. Both incident and prevalent cases were included for the analysis.

ICD-10 diagnoses for each quarter of the study period were selected. The ICD-10 diagnoses of chronic pain R52 and somatoform pain disorder F45.4x were selected as tracer diagnoses of a “chronic pain disease.”24 Orthopedic surgery-related diagnoses (osteoarthritis diagnoses M16-17, low back pain diagnoses M40-54, and osteoporosis diagnoses M80-85) were selected for tracer diagnoses of “chronic pain location” because these diagnoses were the most frequent pain locations in the global burden of disease study 2010.31 As tracer diagnoses for medical diseases, we selected the most frequent diagnoses for internal diseases in adult Germans, namely type 2 diabetes E11, obesity E66, hypertension I10, hyperlipidemia E78, and coronary heart disease I25.28 In addition, we selected diagnoses of depression F32 to 34 and sleep disorders F51 as tracer diagnoses for psychiatric disorders. Depressive disorders were frequently associated with chronic pain in the World Health Organization study in primary care settings.15

Abuse and dependence of prescribed opioids were defined by a diagnosis of abuse and/or dependence in inpatient settings with the following ICD-10 codes F10.* (mental and behavioural disorders due to use of alcohol); F11.* (mental and behavioural disorders due to use of opioids); F13.* (mental and behavioural disorders due to use of sedatives or hypnotics); F19.* (mental and behavioural disorders due to multiple drug use and use of other psychoactive substances); and T40.* (poisoning by narcotics and psychodysleptics [hallucinogens]).24 Outpatient diagnoses of abuse and/or dependence were not considered.

2.3. Medication variables

The data set included the Anatomical Therapeutic Chemical (ATC) Classification for outpatient drugs prescribed and delivered.11 Prescriptions for the following opioids were included in the analysis: tramadol, tilidine/naloxone, fentanyl, oxycodone, morphine, codeine, hydromorphone, buprenorphine, tapentadol, dihydrocodeine, pethidine, oxycodone, and levomethadone. It is not possible to obtain prescriptions for opioids from private physicians and prescriptions not qualifying for reimbursement from insurance in Germany, except for tramadol and tilidine in fixed combination with naloxone which require out-of-pocket expenses. All other opioids can only be prescribed by special formulae. We excluded methadone (N07BC02) and combinations of buprenorphine (N07BC51) from the analysis because these drugs are used to treat heroin addiction in Germany.

The ATC Classification with defined daily doses was adapted and multiplied with the equivalent factor to calculate the oral MEQ. The average MEQ/d of opioid dispensed was calculated for 365 days exposure by summing the MEQs for the prescriptions dispensed for the 365-day period and dividing by 365.24 Data related to opioids prescribed during hospital admissions during the study period were not available and, therefore, were not included in the calculation of MEQ/d.

Long-term opioid therapy was defined as consecutive prescriptions for opioid medications over a minimum of 3 quarters (one-quarter = 3 months), over a 12-month period between January 1, 2014, and December 31, 2014.24,30 Patients were categorized into 2 groups, those above and those below the threshold of 120 mgMEQ/d, according to the German interdisciplinary guideline for LTOT for CNCP.16 Patients prescribed ≥120 mg MEQd were consequently defined as patients with high-dose LTOT.

Comedication with other centrally acting drugs was identified by the ATC as follows: anticonvulsants (ATC N03A), antidepressants (ATC N06A), neuroleptics (ATC N05A), anxiolytics (N05B), and hypnotics and sedatives (N05C) (WHO, 2009). We defined risky opioid therapy as the combination of opioids with anxiolytics, hypnotics and sedatives, N05BA*, or N05CD*1 which is discouraged by recent evidence-based guidelines.18

2.4. Health costs

Average costs were calculated for 5 different resource use categories: inpatient care (hospital), outpatient care (office), prescribed pharmaceuticals (outpatient setting only), sick pay, medical aids, and remedies. Total costs were calculated as the sum of the 5 resource use categories.

2.5. Statistical analysis

Variables were analysed descriptively using frequencies and percentages for categorical variables and mean values with SDs for continuous variables. Group comparisons of insured persons with and without high-dose opioid therapy were conducted with regard to demographic variables, the frequency of diagnoses of chronic pain, internal diseases, orthopedic surgery-related diagnoses and mental disorder, diagnoses of abuse and/or dependence, and comedication with psychotropic drugs and health care costs. Chi-squared tests for categorical variables and t-tests for continuous variables were used. To address multiple testing, a P-value of P < 0.001 was used in all statistical tests for determining statistical significance. We used the software SAS 9.4, SAS Institute, Cary (North Carolina), USA, for statistical analyses.

2.6. Ethical approval

This study used anonymized existing health claim data and, therefore, was exempt from the need for ethical approval and patient informed consent.

3. Results

3.1. Prevalence of long-term opioid therapy and of high-dose opioid prescriptions

A total of 169,911 of 4,028,618 million (4.2%) insured persons received at least 1 outpatient opioid prescription during the study period. A total of 31,737 persons (0.8% of the total population and 18.7% of those with at least 1 opioid prescription) met the criteria of LTOT. A total of 3,145 of 31,737 (9.9%) persons with a LTOT met the criteria of high-dose LTOT (MEQ/d ≥ 120). The average prescribed MEQ/d per quarter for all those with LTOT was 48.0 mg (SD = 46.2). The average mean prescribed MEQ/day for those with high-dose opioid prescriptions was 211 mg (SD 124; minimum = 120 mg; maximum = 2.19 g) and for the guideline-recommended opioid dose group was 30 mg (SD 26.3; minimum = 1 mg, maximum = 119 mg).

3.2. Demographic characteristics

Persons with German guideline-recommended opioid dose therapy were older and more frequently woman than persons with high-dose LTOT (both P-values <0.001). The average difference in age can be explained by a greater number of persons between 40 and 59 years in the high-dose LTOT group vs persons aged 60 years or older in the German guideline-recommended dose group (Table 1).

Table 1:
Comparison of demographic variables of insureds with German guideline-recommended dose long-term opioid therapy (LTOT) (<120 mg morphine equivalent/day) and in insureds with high-dose LTOT (≥120 mg morphine equivalent/day).

3.3. Clinical characteristics

Persons with German guideline-recommended dosage of LTOT were less frequently diagnosed with chronic pain disease (48.2% vs 70.6%), somatoform pain disorder (15.3% vs 27.3%), disk lesions (27.9% vs 32.7%), osteoporosis (25.6% vs 30.0%), and depression (39.1% vs 48.6%) and more frequently with hyperlipidemia (40.9% vs 37.7%) and hypertension (73.5% vs 69.1%) than persons with high-dose LTOT (all P-values < 0.001) (Table 2).

Table 2:
Comparison of clinical variables of insureds with German guideline-recommended dose long-term opioid therapy (LTOT) (<120 mg morphine equivalent/day) and of insureds with high-dose LTOT (≥120 mg morphine equivalent/day).

3.4. Negative health outcomes

3.4.1. Risky opioid therapy

Persons with German guideline-recommended dosage of LTOT were less frequently prescribed tranquilizers (11.1% vs 14.3%), antidepressants (38.2% vs 53.1%), anticonvulsants (21.0% vs 32.5%), and antipsychotics (12.8% vs 14.0%) and less frequently received opioid prescriptions by more than 3 physicians (6.3% vs 8.5%) than persons with high-dose LTOT (all P-values <0.001).

3.4.2. Abuse and/or dependence of prescribed opioids

A total of 464/28.128 (1.6%) of persons with German guideline-recommended dosage of LTOT and 91/3054 (2.9%) of those with high-dose LTOT had hospital admissions because of mental and/or behavioral disorders or intoxication related to opioids and multiple substances (χ2 = 26.6; P < 0.001) (Table 3).

Table 3:
Comparison of risky opioid therapy in insureds with German guideline-recommended dose long-term opioid therapy (LTOT) (<120 mg morphine equivalent/day) and in insureds with high-dose LTOT (≥120 mg morphine equivalent/day).

3.4.3. Health costs

Total health costs were lower in the German guideline-recommended opioid dose group (7259 €/year) than in the high-dose group (10,732 €/year). The difference was due to higher costs for pharmaceuticals in outpatient care (2282 vs 5402 €/year) (both P-values <0.001) (Table 4).

Table 4:
Comparison of annual total costs, hospital costs, pharmaceutical costs, and other costs of insureds with German guideline-recommended dose long-term opioid therapy (LTOT) (<120 mg morphine equivalent/day) and in insureds with high-dose LTOT (≥120 mg morphine equivalent/day).

4. Discussion

4.1. Summary of main results

German guideline-recommended opioid dosing compared with high dose LTOT for CNCP was associated with better health outcomes (lower rates of risky opioid therapy, hospital stays indicative of abuse and/or dependence of prescribed opioids, and lower health care costs) in a large sample representative of the German population in terms of sex and age.

4.2. Comparison with other studies

4.2.1. Prevalence of (high dose) long-term opioid therapy for chronic noncancer pain

The different definitions of LTOT and high-dose LTOT complicate the comparison of study results across different countries. In a representative population survey in Denmark, the prevalence of CNCP increased from 2000 to 2013, with a subsequent annual increase in prevalence of opioid use from 4.1% to 5.7% among CNCP individuals.2 In a US study of managed care claims database conducted between 2005 and 2008, the prevalence of LTOT (defined by >120 days of supply more than 6 months) was 1.3%.22 The prevalence rate of LTOT for insured persons identified in a large German statutory health insurance company in 2013 was 1.3%.24

A total of 1.8% of individuals of Group Health Cooperative (GHC), which provides comprehensive care on a prepaid basis to about 500,000 persons in Washington State, were prescribed ≥100 mg MEQ/d within a 3-month study period between 1997 and 2005.7 In 2004, high-dose opioid therapy (≥100 mg MEQ/d) was prescribed for chronic low back pain in US primary care settings for 8.6% of patients who received opioids for 90+ consecutive days.21 Twenty-three percent of patients with CNCP in a UK primary care study were prescribed opioid doses ≥100 mg MEQ/d in the study period between 2000 and 2010.33 In a previous study of a large single German health statutory company, the percentage of persons prescribed high-dose opioid therapy (defined by ≥ 100 mg MEQ/d) among LTOT users was 15.5%.24 In our study, 9.9% of patients received opioid prescriptions in at least three-quarters for an opioid dose of ≥ 120 MEQ/d.

4.2.2. Negative outcomes associated with high-dose long-term opioid therapy Risky opioid therapy

Our results confirm North American data on higher rates of risky opioid therapy (combination of opioid/benzodiazepine therapy and high-dose opioid therapy), which was observed in selected populations (veterans), with access to multiple prescribers1,32 and in presence of comorbid mental disorders.27,29 A recent US study found evidence of greater opioid receipt among commercially insured patients with a breadth of psychiatric conditions.27 Opioid prescribing in the first world countries seems to follow a pattern in which patients who are at the highest risk of adverse outcomes from opioids, namely the ones with mental disorders, are more likely to receive high-dose LTOT.27 Substance abuse and dependence

The different definitions and types of assessment of substance abuse and dependence associated with LTOT hamper comparisons of various study results and have, therefore, restricted our comparisons to the claims-based diagnoses. A total of 1.3% of insured persons with LTOT (defined by >180 days of supply per year) for CNCP were diagnosed with opioid abuse and dependence in a US private insurance database in 2004.6 Three percent of both the HealthCore and Arkansas Medicaid samples had a claims-based opioid abuse and or dependence diagnosis when there was at least 90 days of continuous opioid use for CNCP within a 6-month period during the study period 2001 to 2004.8 The prevalence rate of diagnoses indicative of abuse and/or dependence in our sample was 3-fold higher (1.75% vs 0.59%) than that for a German study conducted in 2012 with insured persons in 1 statutory health insurance company, named BEK/GEK24 but lower than observed in the abovementioned US studies.6,8

Our results confirm North American data on higher rates of opioid use disorder in the setting of high-dose LTOT which was defined as ≥ 120 mg MEQ/d in the TROUP study8 and as ≥ 50 mg MEQ/d by Morasco et al.25 Health care costs

The annual costs of German guideline-recommended and high-dose LTOT in our study were lower than costs reported for US studies. A US study used a managed care claims database, including geographically diverse commercial, Medicare Advantage, and Medicaid health plan members between 2005 and 2008. The chronic opioid use was defined as at least 120 days of a qualifying opioid over any consecutive 6 months during the identification period. Costs of ambulatory and emergency room visits, inpatient admissions, pharmacy costs, and investigations were $23,049 per enrollee.22 In a study of insured persons in 14 geographically dispersed commercial health plans conducted between 2007 and 2011, all-cause medical costs per patient-year in the first 6 months of the initiation of a LTOT (>182 days of opioid supply) were $27,365 and declined after the first 6 months of treatment to $15,815.20

4.3. Open questions requiring research

Whereas the association between increasing opioid dose and increasing risks is well-documented, much less is known about the prescriber clinical determinants that lead to, or might have justified higher dose therapy. Similarly, little is known about the risks and outcomes associated with limiting opioid dose in certain patients with debilitating pain conditions who do not obtain adequate pain control with other therapeutic modalities or with guideline-recommended doses. We have not analysed our data set using the MEQ/d thresholds of the CDC and the Canadian guideline.

4.4. Strengths and limitations

4.4.1. Strength

This study is based on a large sample of the German statutory health insurances and is representative for the German population in terms of age and sex.

4.4.2. Limitations

  1. The statutory health insurances database used billing data, which are designed for invoices and not for research activities. All claims-based analyses are subject to possible coding errors and undercoding.22
  2. Ten percent of the German population are members of private health insurance companies. Because access to private health insurance in Germany requires a threshold of monthly income, there are differences between persons insured by statutory vs private health insurance companies with regard to socioeconomic status and health (care) behavior.19 Therefore, the study sample is not completely representative of the general German population in terms of socioeconomic status.
  3. Our primary data did not provide demographic information such as ethnicity, education level, and income. Analyses in this study were unadjusted for these potential covariates.
  4. The data set did not allow for adjustment of our analyses for a comorbidity index. Our univariate comparisons did not find large differences between the 2 groups in the frequency of orthopedic surgery-related and internal diseases-related diagnoses, but differences were observed for psychiatric diagnoses.
  5. The opioid MEQ/d dose was not included in the data set and had to be calculated. The defined daily dose used for these analyses probably do not reflect opioid doses used in contemporary chronic pain treatment.26
  6. There is no clinical patient information, and we do not know whether the dispensed drugs were used immediately, saved for later use, diverted, or not used at all. The assumption that all drugs were used at a time close to dispensing likely causes an overestimation of drug use.
  7. Because doses of opioids during hospital stays were not included in the data, we have underestimated the MEQ/d for patients with hospital admissions. However, the total amount due to these prescriptions is likely a small fraction of all opioid use and is unlikely to have an important effect on overall trends.
  8. Most probably, the study criteria applied have high specificity but poor sensitivity for identifying abuse and/or dependence of prescribed opioids in the population, as there were no interviews exploring behavioural patterns of opioid prescription abuse. We relied only on inpatient data to identify a diagnosis of substance-related disorder. It was not possible to evaluate illicit drug use. Therefore, we may have underestimated the prevalence of abuse and/or dependence of prescribed opioids.
  9. There are fundamental differences between the national health care systems.17 Data from Germany might not be valid for other countries.
  10. As this study was cross-sectional, associations cannot distinguish between cause and effect, and results should be interpreted with care.

5. Conclusions

Our study confirms the recommendations that attention should be given to MEQ/d opioid dose according to recent evidence-based guidelines for LTOT for CNCP.18 The average dose that provides the best benefit/risk ratio still needs to be determined.5

A recent study of US veterans demonstrated that initiatives to reduce risky prescribing (>100 MEQ/d and concurrent benzodiazepines) can be successful.23 The tools of this latter initiative should be adapted to other health care systems and tested for feasibility and effectiveness.

The high prevalence of mental disorders in the group with high-dose LTOT highlights recommendations of recent guidelines on opioid therapy for CNCP to pay special attention to patients with concomitant chronic pain and psychiatric disorders, and to include mental health care specialists into the team providing multicomponent treatment.3,4,16

Conflict of interest statement

The acquisition of data and the data analysis by LinkCare was financially supported by Indivior. The sponsor had no role in the design of the study, in the collection, analyses and interpretation of the data, in the writing of the manuscript, and in the decision to submit the paper for publication. The manuscript with the data analyses was made available to the sponsor after acceptance of the manuscript. W. Häuser received 1 honorarium for an educational lecture by Grünenthal in the past 3 years. T. Schubert received 1 honorarium for data analysis in the past 3 years from Indivior. N. Scherbaum received honoraria for several activities (advisory boards, lectures, manuscripts, and educational material) by Abbvie, Janssen-Cilag, Lundbeck, Medice, Mundipharma, Reckitt-Benckiser/Indivior, and Sanofi-Aventis. T. Tölle has received speaking fees and travel expenses from Pfizer, Lilly, Grünenthal, Mundipharma, Indivior, Janssen, and Astellas.


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Opioids; Chronic noncancer pain; Guidelines; Health outcomes

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