PainNCT03778450
Long-term Opioid Therapy, Misuse and Mortality in Patients With Chronic Non-cancer Pain in Germany
An observational study of Pain, run by LinkCare GmbH at 1 site in Germany.
Trial summary
Among patients receiving opioids for noncancer pain, recent research in North America showed a strong association between doses and opioid-related mortality, especially at dosages exceeding thresholds recommended in recent guidelines. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Pain
- What is being tested?
- Analgesics, Opioid and Non-Opioid Analgesic
- How many people
- 3,232 participants
- Where
- 1 siteGermany
- Study dates
- 5 Dec 2018to 31 Aug 2019
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: The database contains data on around 4 million insured people from 69 German statutory health insurances (SHI). German SHI system comprises of approximately 120 independent health insurance companies. Funds paid by these SHI to any provider of health care (e.g. hospitals, physicians, pharmacies, psychotherapists and physiotherapists) represent almost the complete picture of the total health care costs of individual patients. All health insurance data can be linked to patients' demographics including age and gender. T
Who may be able to join
- Patients are only included if they have been diagnosed in at least three quarters in the study period with one of the following diagnoses: R51, R52*, M00*-M99*, G43*-G44*, G50.0 or G50.1, F45.4*, G62*, or E10.4*-E14.4 plus G63.3. At least one diagnoses must be between 1 January 2012 and index treatment and main and secondary hospital diagnoses (i.e. Haupt- und Nebendiagnosen) will be used to include the patients.
Who cannot join
- Patients with present opioid and non-opioid pain medication prescriptions in 2012 are excluded from analysis (therapy-naïve patients only).
- Cancer patients will be excluded if the cancer diagnosis is accompanied by at least one of the following treatments in the same quarter: radiation therapy or chemotherapy all defined by the OPS codes in. Diagnoses will be assessed via ICD-10 diagnoses during the inclusion period from 1 January 2012 until index treatment and main and secondary hospital diagnoses (i.e. Haupt- und Nebendiagnosen) will be taken into account.
- Palliative care, coded by ICD-10 code Z51.5 or OPS code 8-982*, 8-98e*, 8-98h* before index date is excluded
- Opioid substitution treatment with ICD-10 code Z51.83 in the study period is excluded.
Trial locations and contacts
1 site in 1 country.
About this study
Among patients receiving opioids for noncancer pain, recent research in North America showed a strong association between doses and opioid-related mortality, especially at dosages exceeding thresholds recommended in recent guidelines. However, the focus on over-dosage may underestimate overall opioid-related mortality and data on death associated with opioid use in a population-based cohort of chronic noncancer pain patients in Europe is scarce. Especially comparative studies studying the safety of long-term opioid therapy in a real-world setting relative to non-opioid medication for chronic noncancer pain are needed in a European context.
Read the detailed description
This is a cross-sectional observational cohort study between 2012 and 2017 of patients with chronic noncancer pain. The primary objective is to investigate the association between mortality among patients with chronic noncancer pain with long-term opioid-therapy compared to non-opioid pain medication. The data will be retrieved from an anonymized German health claims database including 4,00,000 persons insured by 69 German statutory health insurances. The data set includes 5.0% of the population covered by statutory health insurances from January 1, 2012, to December 31, 2017. Only anonymized and aggregated data (no directly or indirectly identifying data) will be extracted.
Patients with headache, diseases of the musculoskeletal system and connective tissue, migraine, trigeminal neuralgia, atypical facial pain, persistent somatoform pain disorder, polyneuropathies, or diabetes mellitus with neurological complications in at least 3 quarters between 01.01.2012 and their first pain medication claim are analyzed. Patients will be stratified in an opioid and a non-opioid group and will be compared with a propensity score matching approach.
Patients' follow-up period include 5 years after start treatment and chronic pain diagnosis between 01.01.2013 and 31.12.2017. Each patient will be censored at death (death date), switching of study group, 12 months without treatment or followed-up 5 years until last known record for the, whichever happens first. The main analyses will be analyzed with a multivariate Cox proportional hazards regression.
- Conditions
- Pain
- Being tested
- Analgesics, Opioid, Non-Opioid Analgesic
- Medical subject headings
- Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Analgesics, OpioidDrug
Also called Opioid Group
Patients are included in the long-term opioid group if they started an opioid-therapy between 2013 and 2017 and received consecutive prescriptions for opioid medications over a minimum of 3 quarters, over a 60-month period between January 1, 2013, and December 31, 2017. The treatment will be assessed using the ATC codes of opioid
treatment N02AA01, N02AA05, N02AB03, N02AE01, N02AX02, N02AX01, N02AX06) reported in reimbursed medicines to patients.
Non-Opioid AnalgesicDrug
Also called Non-Opioid Group
Patients with non-opioid pain medication are included, if they received a medication therapy with anticonvulsants (gabapentin, pregabalin, carbamazepine), antidepressants or non-opioid analgesics (NSAIDs, Metamizole) over a minimum of 3 quarters, over a 60-month period between January 1, 2013, and December 31, 2017. The non-opioid treatment will be assessed using the ATC codes (N03AX12, N03AX16, N03AF01) of treatment reported in reimbursed medicines to patients.
| Study group | Role | What they receive |
|---|---|---|
| Analgesics, Opioid | Patients are only included if they have been diagnosed in at least three quarters in the study period with one of the following diagnoses: R51, R52*, M00*-M99*, G43*-G44*, G50.0 or G50.1, F45.4*, G62*, or E10.4*-E14.4 plus G63.3. At least one diagnoses must be between 1 January 2012 and index treatment and main and secondary hospital diagnoses (i.e. Haupt- und Nebendiagnosen) will be used to include the patients. Receives: Drug: Analgesics, Opioid | |
| Non-Opioid Analgesic | Patients are only included if they have been diagnosed in at least three quarters in 2012 with one of the following diagnoses: R51, R52*, M00*-M99*, G43*-G44*, G50.0 or G50.1, F45.4*, G62*, or E10.4*-E14.4 plus G63.3.At least one diagnoses must be between 1 January 2012 and index treatment and main and secondary hospital diagnoses (i.e. Haupt- und Nebendiagnosen) will be used to include the patients. Receives: Drug: Non-Opioid Analgesic |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mortality
Primary endpoint is death by any course in the study follow-up. Death will be assessed during the follow-up period by number of patients who deceased during follow-up period (2013 - 2017) via the date of death in German claims data base.
Measured: 2013 - 2017
Secondary outcomes (8)
Hospitalization due to any course
Hospitalization will be assessed via the number of hospitalisations (calculated by counting the number of discharge dates (KH_Fall. Entlassungsdatum) in the year of interest, hospitalization rate. The rate of hospitalization will be estimated as the number of patients with at least one hospitalization during the follow-up period divided by person-time of follow-up, censoring at time of death, last known record for the patient in the database, or 31st December 2017 (end of latest data cut), whichever is earlier.
Measured: 2013 - 2017
Number of ICU-stays
Intensive care unit (ICU-stay) stay is defined as patient's stay based on specialty of departement in hospital (KH_OPS.Fachabteilung = 3600).
Measured: 2013 - 2017
Hospitalization with to misuse or addiction
The hospitalization with misuse or addiction will be analysed, if principal (main) diagnosis at discharge date between January 1st 2013 and December 31st 2017 contains at least one ICD-10 diagnosis of misuse/addiction: F10* or F11* or F13* or F19* or T40*
Measured: 2013 - 2017
Number of coding of procedures in hospitals
Coding of procedures in hospitals that indicate number of patients that were hospitalized with severe diseases such as cardiovascular diseases will be assessed via OPS-Codes provided in the protocol
Measured: 2013 - 2017
Number of patients with a ca misuse or addiction diagnosis in the outpatient sector
The number of patients with a least one coding of ICD 10 codes of a misuse or addiction diagnosis in the outpatient sector will be assessed via number of codings of misuse/addiction (ICD Codes = F10* or F11* or F13* or F19* or T40*) in outpatient sector by general practitioner or a specialist (e.g. psychiatrist), as ensured diagnosis (Diagnosesicherheit='G').
Measured: 2013 - 2017
Number of sick leave days
Sick leave will be assessed as an absolute number number of days being off work of patients in 2013-2017 .
Measured: 2013 - 2017
Number of hospital deaths
Hospital deaths will be assessed via reason of discharge = death (Entlassgrund = Tod)
Measured: 2013 - 2017
Number of main- and secondary discharge diagnoses
Main- and secondary discharge diagnoses from hospital deaths will be assessed as the TOP 20 diagnoses of patients who deceased during a hospital stay
Measured: 2013 - 2017
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Dec 2018
- Study start5 Dec 2018
- Primary completion31 Aug 2019
- Study completion31 Aug 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for PainStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 3,232 participants (actual)
Sponsor and investigators
- Lead sponsor
- LinkCare GmbH
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Grünenthal GmbH, Klinikum Saarbrücken, Ruhr University of Bochum, Technical University of Munich
- Responsible party
- Principal investigator, Tino Schubert, LinkCare GmbH
- Investigators
- Tino Schubert, Study director, LinkCare GmbH
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03778450
- Sponsor's protocol ID
- VF_1014_1040_Study Protocol
- Status last verified
- Sep 2019
- First submitted
- 7 Dec 2018
- Last updated
- 4 Sep 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Hauser W, Schubert T, Vogelmann T, Maier C, Fitzcharles MA, Tolle T. All-cause mortality in patients with long-term opioid therapy compared with non-opioid analgesics for chronic non-cancer pain: a database study. BMC Med. 2020 Jul 15;18(1):162. doi: 10.1186/s12916-020-01644-4.
PubMed 32664901
Study at a glance
From the registry record, last updated by the sponsor on 4 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Long-term Opioid Therapy, Misuse and Mortality in Patients With Chronic Non-cancer Pain in Germany
- ClinicalTrials.gov ID
- NCT03778450
- Acronym / sponsor ID
- VF_1014_1040_Study Protocol
- Conditions
- Pain
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 3,232 participants (actual)
- Lead sponsor
- LinkCare GmbHIndustry (pharma, biotech, devices)
- Collaborators
- Grünenthal GmbH, Klinikum Saarbrücken, Ruhr University of Bochum, Technical University of Munich
- Study start
- 5 Dec 2018 (actual)
- Primary completion
- 31 Aug 2019 (actual)
- Study completion
- 31 Aug 2019 (actual)
- First posted
- 19 Dec 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Among patients receiving opioids for noncancer pain, recent research in North America showed a strong association between doses and opioid-related mortality, especially at dosages exceeding thresholds recommended in recent guidelines. However, the focus on over-dosage may underestimate overall opioid-related mortality and data on death associated with opioid use in a population-based cohort of chronic noncancer pain patients in Europe is scarce. Especially comparative studies studying the safety of long-term opioid therapy in a real-world setting relative to non-opioid medication for chronic noncancer pain are needed in a European context.
Detailed description
This is a cross-sectional observational cohort study between 2012 and 2017 of patients with chronic noncancer pain. The primary objective is to investigate the association between mortality among patients with chronic noncancer pain with long-term opioid-therapy compared to non-opioid pain medication. The data will be retrieved from an anonymized German health claims database including 4,00,000 persons insured by 69 German statutory health insurances. The data set includes 5.0% of the population covered by statutory health insurances from January 1, 2012, to December 31, 2017. Only anonymized and aggregated data (no directly or indirectly identifying data) will be extracted.
Patients with headache, diseases of the musculoskeletal system and connective tissue, migraine, trigeminal neuralgia, atypical facial pain, persistent somatoform pain disorder, polyneuropathies, or diabetes mellitus with neurological complications in at least 3 quarters between 01.01.2012 and their first pain medication claim are analyzed. Patients will be stratified in an opioid and a non-opioid group and will be compared with a propensity score matching approach.
Patients' follow-up period include 5 years after start treatment and chronic pain diagnosis between 01.01.2013 and 31.12.2017. Each patient will be censored at death (death date), switching of study group, 12 months without treatment or followed-up 5 years until last known record for the, whichever happens first. The main analyses will be analyzed with a multivariate Cox proportional hazards regression.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Analgesics, Opioid | – | Drug: Analgesics, OpioidPatients are only included if they have been diagnosed in at least three quarters in the study period with one of the following diagnoses: R51, R52*, M00*-M99*, G43*-G44*, G50.0 or G50.1, F45.4*, G62*, or E10.4*-E14.4 plus G63.3. At least one diagnoses must be between 1 January 2012 and index treatment and main and secondary hospital diagnoses (i.e. Haupt- und Nebendiagnosen) will be used to include the patients. |
| Non-Opioid Analgesic | – | Drug: Non-Opioid AnalgesicPatients are only included if they have been diagnosed in at least three quarters in 2012 with one of the following diagnoses: R51, R52*, M00*-M99*, G43*-G44*, G50.0 or G50.1, F45.4*, G62*, or E10.4*-E14.4 plus G63.3.At least one diagnoses must be between 1 January 2012 and index treatment and main and secondary hospital diagnoses (i.e. Haupt- und Nebendiagnosen) will be used to include the patients. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- The database contains data on around 4 million insured people from 69 German statutory health insurances (SHI). German SHI system comprises of approximately 120 independent health insurance companies. Funds paid by these SHI to any provider of health care (e.g. hospitals, physicians, pharmacies, psychotherapists and physiotherapists) represent almost the complete picture of the total health care costs of individual patients. All health insurance data can be linked to patients' demographics including age and gender. T
Key inclusion criteria (1 listed)
- Patients are only included if they have been diagnosed in at least three quarters in the study period with one of the following diagnoses: R51, R52*, M00*-M99*, G43*-G44*, G50.0 or G50.1, F45.4*, G62*, or E10.4*-E14.4 plus G63.3. At least one diagnoses must be between 1 January 2012 and index treatment and main and secondary hospital diagnoses (i.e. Haupt- und Nebendiagnosen) will be used to include the patients.
Key exclusion criteria (4 listed)
- Patients with present opioid and non-opioid pain medication prescriptions in 2012 are excluded from analysis (therapy-naïve patients only).
- Cancer patients will be excluded if the cancer diagnosis is accompanied by at least one of the following treatments in the same quarter: radiation therapy or chemotherapy all defined by the OPS codes in. Diagnoses will be assessed via ICD-10 diagnoses during the inclusion period from 1 January 2012 until index treatment and main and secondary hospital diagnoses (i.e. Haupt- und Nebendiagnosen) will be taken into account.
- Palliative care, coded by ICD-10 code Z51.5 or OPS code 8-982*, 8-98e*, 8-98h* before index date is excluded
- Opioid substitution treatment with ICD-10 code Z51.83 in the study period is excluded.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Analgesics, OpioidAlso: Opioid GroupPatients are included in the long-term opioid group if they started an opioid-therapy between 2013 and 2017 and received consecutive prescriptions for opioid medications over a minimum of 3 quarters, over a 60-month period between January 1, 2013, and December 31, 2017. The treatment will be assessed using the ATC codes of opioid treatment N02AA01, N02AA05, N02AB03, N02AE01, N02AX02, N02AX01, N02AX06) reported in reimbursed medicines to patients. | Drug | Analgesics, Opioid |
| Non-Opioid AnalgesicAlso: Non-Opioid GroupPatients with non-opioid pain medication are included, if they received a medication therapy with anticonvulsants (gabapentin, pregabalin, carbamazepine), antidepressants or non-opioid analgesics (NSAIDs, Metamizole) over a minimum of 3 quarters, over a 60-month period between January 1, 2013, and December 31, 2017. The non-opioid treatment will be assessed using the ATC codes (N03AX12, N03AX16, N03AF01) of treatment reported in reimbursed medicines to patients. | Drug | Non-Opioid Analgesic |
Primary outcome
Mortality
Time frame: 2013 - 2017
Primary endpoint is death by any course in the study follow-up. Death will be assessed during the follow-up period by number of patients who deceased during follow-up period (2013 - 2017) via the date of death in German claims data base.
8 secondary outcomes
Hospitalization due to any course
Time frame: 2013 - 2017
Number of ICU-stays
Time frame: 2013 - 2017
Hospitalization with to misuse or addiction
Time frame: 2013 - 2017
Number of coding of procedures in hospitals
Time frame: 2013 - 2017
Number of patients with a ca misuse or addiction diagnosis in the outpatient sector
Time frame: 2013 - 2017
Number of sick leave days
Time frame: 2013 - 2017
Number of hospital deaths
Time frame: 2013 - 2017
Number of main- and secondary discharge diagnoses
Time frame: 2013 - 2017
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Sep 2019.
- Derived from this study: PubMed 32664901Hauser W, Schubert T, Vogelmann T, Maier C, Fitzcharles MA, Tolle T. All-cause mortality in patients with long-term opioid therapy compared with non-opioid analgesics for chronic non-cancer pain: a database study. BMC Med. 2020 Jul 15;18(1):162. doi: 10.1186/s12916-020-01644-4.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Tino Schubert study director
LinkCare GmbH
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Pain, run by LinkCare GmbH at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mortality (time frame: 2013 - 2017). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03778450, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Sep 2019.