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Abstract
Objective Fibromyalgia syndrome (FMS) is characterised by widespread pain and is associated with mood disorders such as depression as well as poor sleep quality. These in turn have been linked to increased risk of suicidal ideation. Clinical guidelines generally do not recommended opioids in FMS, but they are routinely prescribed to a considerable proportion of FMS patients. We assessed the association of long-term opioid prescription for FMS with risk of depression, sleep disorders and suicidal ideation, when compared with short-term opioid use.
Methods Retrospective cohort study combing several population-wide databases covering a population of five million inhabitants, including all adults who received an initial opioid prescription from 2014 to 2018 specifically prescribed for FMS. We examined the occurrence of depression, sleep disorders or suicidal ideation outcomes in patients with an initial long-term opioid prescription (>90 days) versus those who received a short-term treatment (<29 days). We employed multivariable Cox regression modelling and inverse probability of treatment weighting based on propensity scores and we performed several sensitivity analyses.
Results 10 334 patients initiated short-term (8309, 80.40%) or long-term (2025, 19.60%) opioids for FMS. In main adjusted analyses, long-term opioid use was associated with an increased risk for depression (HR: 1.58, 95% CI 1.29 to 1.95) and sleep disorder (HR: 1.30, 95% CI 1.09 to 1.55) but not with suicidal ideation (HR: 1.59, 95% CI 0.96 to 2.62). In models assessing outcomes since day 90, an increased risk for suicidal ideation was observed (HR: 1.76, 95% CI 1.05 to 2.98).
Conclusion These findings suggest that continued opioid use for 90 days or more may aggravate depression and sleep problems in patients with FMS when compared with patterns of short-term treatment.
- epidemiology
- fibromyalgia
- health services research
- analgesics
- outcome assessment, health care
Data availability statement
Data are available upon reasonable request. The datasets presented in this article are not readily available due to legal restrictions on sharing the data set as regulated by the Valencia regional government by means of legal resolution by the Valencia Health Agency [2009/13312] which forbids the dissemination of data to third parties (accessible at: http://www.san.gva.es/documents/152919/157920/resolucionsolicituddatos.pdf). Upon request, authors can allow access to the databases to verify the accuracy of the analysis or the reproducibility of the study. Requests to access the datasets should be directed to Management Office of the Data Commission in the Valencia Health Agency (email: solicitud_datos@gva.es; telephone numbers: +34 961-928207; +34 961-928198).
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
A few studies with important limitations have reported a potential effect of opioids on sleep quality and depression in patients with fibromyalgia syndrome (FMS). We found no evidence on suicidal ideation, opioids and FMS. The differential effect of short versus long-term opioid therapy on these outcomes has not been established.
WHAT THIS STUDY ADDS
This population-based, propensity-weighted cohort study showed that initiating long-term opioids for FMS was associated with an increased risk for depression and sleep disorders, but not for suicidal ideation, when compared with patterns of short-term initiation.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
In a context of prevalent opioid use to treat FMS in clinical practice despite their apparent lack of effectiveness, long-term opioid therapy was associated with a higher risk of adverse outcomes when compared with short-term use.
Introduction
Fibromyalgia syndrome (FMS), the third most frequent musculoskeletal condition,1 is a chronic disease characterised by widespread pain and is associated with mood disorders, including depression, also accompanied by symptoms such as poor sleep quality and functional disability.2 These factors have, in turn, been linked to increased risk of suicidal ideation. Prevalence rates in people with FMS are remarkably higher than in the general population.3–5
Many observational studies have reported that opioids are routinely prescribed to a considerable proportion of patients with FMS, including long-term treatments and strong opioids,6–12 despite these patterns have been associated to poorer health outcomes.1 13 Most clinical guidelines generally recommend against the use of opioids for FMS,14–17 but some authors recognise a potential, empirical role in lack of effect of preferred therapeutic approaches, when used as a rescue therapy, for short periods of time and for selected patients.18 19
Opioid use increases the risk of adverse events, including some common FMS-related symptoms such as sleep disorders, depression and suicidal ideation.20–24 Sustained opioid use over time especially is associated to a myriad of potential, serious adverse outcomes13 and there is evidence that FMS is a predictor for long-term opioid use in older adults.25 However, little is known about the effect of long-term use of opioids on relevant FMS comorbidities in patients with FMS.
Our aim was to assess the association of long-term opioids prescribed for FMS with the occurrence of depression, sleep disorders and suicidal ideation events, when compared short-term opioid use.
Methods
Design, setting and data sources
In this retrospective cohort study, we combined several population-wide databases from the Valencia Health System Integrated Database (VID), covering a population of five million inhabitants.26 The Valencia Health System is a universal, single-provider, free at the point of use, public health system organised into Health Departments that make up the healthcare provision network in the region.26 VID is a set of publicly owned, population-based healthcare, clinical and administrative electronic databases in the region of Valencia in Spain that can be linked by means of a single personal identification number and provides comprehensive information for the region’s population since 2008.26 VID includes sociodemographic and administrative data (sex assigned at birth, age, nationality) as well as healthcare information such as diagnoses, procedures, laboratory data, outpatient pharmaceutical prescriptions and dispensing (including brand and generic name, formulation, strength and dosing schedule/regime), hospitalisations, mortality, healthcare utilisation and public health data.26 Both specialists and primary care physicians can prescribe opioids in Spain, and dispensing is subjected to a tight, formal control and registry. Treatments for one specific medication in VID may be established for as long as 12 months and may be extended for longer periods, but prescriptions are commonly refilled monthly or shorter (eg, one treatment for 6 months may include, eg, 6 monthly prescriptions).27 Finally, clinical guidance in Spain is aligned with general, internationally shared recommendations on the use of prescription opioids for pain management, such as the adherence to the WHO analgesic ladder that remains the general reference guide for pain management, although being developed for cancer pain, the endorsement of the use of opioids only after employing non-opioid alternatives, or the recommendation of using the lowest effective potency and for the shortest possible time.28–31
Participants
We included all patients aged 18 years old and over at the moment of initiating therapy who received an initial opioid prescription from 1 January 2014 to 30 September 2018, with an indication for FMS (figure 1). In VID, prescribing doctors must specify the single indication for which every prescription is issued, allowing for the identification of opioid prescriptions issued specifically for FMS. Patients prescribed opioids at any point during the study period for cancer conditions were excluded (see online supplemental table S1 for codes employed in the study using the International Classification of Diseases Clinical Modification, Ninth and Tenth Editions -ICD9CM and ICD10CM). People without general healthcare coverage (mainly certain Spanish government employees whose prescriptions are reimbursed by mutual societies for civil servants and are thus not included in the pharmacy databases of the Valencia Health System) and patients not registered in the municipal census (non-residents or temporary residents) were excluded because of limitations on follow-up (figure 1).
Supplemental material
Flowchart. *A total of 15 patients that initiated opioid treatment for fibromyalgia with fentanyl ultrafast, morphine short-acting, buprenorphine short-acting, hydromorphone short-acting, morphine long-acting. ** Patients with a previous outcome of interest before the index date were excluded from each outcome-based analysis; patients included in every outcome-based analysis are shown.
Initial opioid prescription
The index date (date of the initial prescription) was defined as the date when an opioid treatment for FMS was prescribed, without having an opioid prescription in the previous 6 months for non-cancer pain,27 irrespective of the indication. This time spam sits in the middle of the range of possible definitions found in the literature to define naïve opioid user, and it appears reasonable for medications that may be taken chronic, but intermittently, leading to separate episodes of treatment. In this way, patients could have more than one initiation in the period (which would constitute different, subsequent episodes of care); only the first was considered for analysis32 (see figure 1). Only patients with at least 90 days of follow-up since the index date were included (figure 1). Opioids initially included were classified as tramadol, codeine, long-acting (morphine-extended and controlled release, transdermal fentanyl, oxycodone-extended release, transdermal buprenorphine, hydromorphone-extended release, tapentadol-extended release), short-acting (standard release formulations of morphine, oxycodone or buprenorphine), and ultrafast opioids (transmucosal fentanyl formulations; see Anatomical Therapeutic Chemical classification-ATC-codes of drugs included in the study in online supplemental material S2). Some were finally excluded from analysis after restricting our cohort to patients prescribed opioids for FMS, due to low numbers (figure 1). Low-dose codeine formulations containing less than 30 mg per dose unit were excluded as these are mainly indicated for the treatment of influenza and cold symptoms in our setting.32 Methadone (whose use is restricted to drug addiction programmes in Spain), pethidine and pentazocine were not considered due to marginal volume.
Variables
We included patient sociodemographic and lifestyle variables: age (mean and age strata: 18–44 years old; 45–65; 65–74; 75 and over), sex assigned at birth, nationality (Spanish, European, non-European), income level (retrieved from the pharmaceutical copayment system that classifies the population in different income strata: less than 18.000 euros year, 18.000 to 100.000 euros/year, more than 100.000 euros year), registered alcohol and tobacco use and registered comorbidities in the electronic medical record at baseline (hypertension, ischaemic cardiomyopathy, heart failure, congestive obstructive pulmonary disease, diabetes, renal and liver disease, dementia, depression, drug use, personality disorders, psychotic disorders, anxiety and other psychiatric disorders); see online supplemental material S1 for codes employed. Treatment initiation was characterised using the following variables: choice of opioid (finally included drugs were tramadol, long-acting formulations of fentanyl, oxycodone, tapentadol or buprenorphine and codeine), daily morphine milligram equivalents (MME) of the first prescription (mean and MME strata: less than 50; 50–90; 90–120; more than 120), and percentage of patients with concomitant use (or overlap) of benzodiazepines, gabapentinoids or antipsychotics. Overlap was ascertained when patients received at least one prescription for at least one of these drugs with days’ supply overlapping with the index date (date of initial opioid therapy).32 To estimate daily MME, we used prescription information to identify milligrams prescribed and days’ supply and an MME conversion table27 (see online supplemental material S3).
Exposure
Long-term use was defined as an initial episode of prescription of opioids for FMS for 90 days or more after the index date, based on the days covered with medication prescribed since initiation.33 This time span is used in many studies and clinical guidelines to define chronic or long-term opioid use.14 34–37 Duration of the initial episode was calculated as the sum of the duration of the initial prescription and the duration of all subsequent opioid prescriptions after initiation with a gap less than 30 days without prescription.33 In the main analysis, short-term opioid use (comparator group) was defined as an initial prescription of opioids for FMS for 29 days or less using the same operational rules.
Outcomes
We examined the occurrence of depression, sleep disorders or suicidal ideation outcomes in patients with an initial long-term opioid prescription versus those who received a short-term treatment. Outcomes were captured from hospitalisation, emergency department and ambulatory healthcare databases in VID via ICD9CM and ICD10CM codes (online supplemental material S1). For hospital and emergency department records where multiple ICD codes may be registered in a single contact, only the principal code was considered. ICD codes in primary care records are activated in the primary care electronic medical record during visits as main reason for visitation; all were employed. For every outcome-based analysis, patients were followed from the index date until the first outcome, death or end of study (31 December 2018); also for every outcome-based analysis, patients with a prior outcome of interest before the index date were excluded. Prior outcomes were identified using active ICD codes in the VID electronic medical record in the 365 days before the index date. Diagnostic codes in VID are activated at the onset of a disease and may remain activated unless it is deactivated after disease resolution; typically, diagnostic codes for chronic conditions remain active for life. Therefore, ICD codes remaining active during the 365 days before the index date may have been activated at any time during the life of the patient (see figure 1 for patients included in each analysis).
Analysis
First, we described baseline patient characteristics and the characteristics of treatment initiation, overall and for short-term and long-term initiators. P values were estimated using χ2 for categorical variables and ANOVA for continuous variables. For continuous covariates with skewed distribution, the Kruskal-Wallis test was used. Second, as main analysis, we used an intention to treat approach to estimate the increased risk of sleep disturbance, depression and suicidal ideation in long versus short-term users. We estimated the incidence rates by 1000 person-years of the first event for each outcome, overall and for each group and, plotted Kaplan-Meier survival curves over the observation window of 5 years for long and short-term users. Then, we carried out multivariable Cox regression modelling using the following covariates: age (as a categorical variable, ref. 18 to 44 years old), sex assigned at birth (ref: men), all comorbidities and lifestyle variables, choice of opioid (ref. tramadol) and daily MME (as continuous variable). To adjust for potential confounding, we used inverse probability of treatment weighting (IPTW) based on propensity scores, a method that allows balancing without losing generalisability. Propensity scores for each outcome were calculated based on the probability of initiating long-term opioids and using the same covariates employed for regression modelling, to generate patient-specific stabilised weights. Covariate balance between the weighted exposure cohorts was assessed using standardised mean differences, with standardised differences <0.10 suggesting adequate balance. Third, we performed several sensitivity analyses. We rerun the analysis censoring patients in the short-term group if they initiated a prescription for more than 29 days during follow-up. We also ran a competing risk regression analysis (using the Fine and Gray method) considering mortality as the competing event for each outcome. Additionally, we rerun the analyses considering outcomes occurring from day 90, instead of the index date; in this model, we included outcomes experienced from the index date to day 90 as an additional covariate. Finally, we used an on treatment/per protocol approach with dispensation data instead of prescription data to define exposure and censoring patients in the short-term group if they initiated long-term opioids. Two-sided p values of less than 0.05 were considered significant in all analyses. Analyses were performed using STATA V.14 and R V.3.6.0. The investigators were granted access to the databases used to create the study population and performed several quality checks (consistency assessments, range and logic checks) before the linkage of the databases using a pseudonymised single identification number. The study was reported using the RECORD checklist for observational studies using routinely collected health data.
Patient and public involvement
No patients or the public were directly involved in this study.
Results
We ended up with 10 334 patients initiating either short-term (8309 patients, 80.40%) or long-term (2025 patients, 19.60%) opioid therapy for FMS (figure 1). Long-term opioid users were more prone to be women (89.4% vs 69.59% in the short-term group, p<0.001) had more anxiety (68.9% vs 51.9%, p>0.001), depression (45.1% vs 25.9%, p>0.001), psychotic disorders (11.3% vs 6.9%, p>0.001), sleep disorders (36.4% vs 25.9%, p>0.001), dementia (4.2% vs 3.1%, p=0.012) and other psychiatric disorders (14.5% vs 19.2%, p>0.001), and had more registered tobacco use (14.8% vs 16.8%, p=0.027; table 1). Daily MME in the long-term group was 17.5 vs 12.9 (p>0.001) in the short-term group and overlap with benzodiazepines (50% vs 32.8%, p>0.001), gabapentinoids (14.7% vs 5.4%, p>0.001) and antipsychotics (4.5% vs 2.9%, p>0.001) at baseline was higher in long-term initiators (table 2). Mean follow-up was 981 days for short-term versus 921 days for long-term users. Standardised differences after IPTW showed adequate covariate balance at baseline for all analyses (online supplemental material S4).
Patient characteristics at baseline, overall and for short-term and long-term users
Characteristics of treatment initiation, overall and for short-term and long-term users
Weighted incidence rates were elevated for the three outcomes in long-term users when compared with short-term users (see figure 2 and online supplemental figures S1–S7 for Kaplan-Meier curves). In main adjusted analyses, long-term opioid use was associated with an increased risk for depression (HR: 1.58, 95% CI 1.29 to 1.95) and sleep disorders (HR: 1.3, 95% CI 1.09 to 1.55) but not for suicidal ideation (HR: 1.59, 95% CI 0.96 to 2.62). Analyses considering death as a competing risk, censoring short-term users if they initiate a non-short-term opioid treatment and per protocol analyses using dispensation data and ensuring that short-term initiators remain short-term users during all follow-up yielded comparable results. In models assessing outcomes since day 90, long-term use was associated with an increased risk of suicidal ideation (HR: 1.76, 95% CI 1.05 to 2.98, see figure 2 and online supplemental tables S8–S22).
Risk of depression, sleep disorders and suicidal ideation among long-term versus short-term opioid users.
Discussion
We showed that patients initiating long-term opioids prescribed to treat FMS were exposed to a higher risk of depression and sleep disorders when compared with those initiating short-term opioids for FMS. There was a trend towards an increased risk of suicidal ideation in the long-term use group, but the association was non-significant in all models but one sensitivity analysis. These findings suggest that continued opioid use for 90 days or more may aggravate common comorbidities of FMS when compared with patterns of short-term treatment, and that shorter treatments may be preferable.
Use of opioids in FMS is controversial. Evidence does not support their use and clinical practice guidelines generally recommend avoiding opioids to treat FMS-related pain,14–19 but still opioid use in FMS is prevalent in clinical practice.6–12 In our study, tramadol was prescribed as initial therapy to more than four over five patients. Evidence supporting its use is based in four small-sized (459 patients overall, followed for 2 months in three studies and 6 months in one study), low-quality clinical trials where tramadol showed modest pain relief, but only when combined with acetaminophen,38 a drug that paradoxically is generally not recommended to treat FMS.1 39 With regard to patients prescribed long-acting opioids as initial treatment, these patterns contradict pain management clinical guidelines,14 28–31 which generally adopt the stepped approach of the WHO Analgesic Ladder40 that recommends starting opioid treatment with second step alternatives (tramadol or codeine). Owing to the complex polysymptomatology of FMS as well as the lack of a full understanding of the physio and psychopathological drivers of the condition, diagnosis and therapeutic management are essentially clinical and empirical. For instance, even if substantial evidence suggests that traditional analgesia with non-steroidal anti-inflammatory drugs or opioids is not effective in treating FMS, these drugs are fundamental to deactivate concomitant peripheral forms of pain, such as osteoarthritic pain, that may otherwise induce central sensitisation in a feedback loop for pain maintenance in FMS.41 42 Additionally, evidence from a recent systematic review suggests that most of the currently available pharmacotherapies for the management of FMS are not supported by high-quality evidence, and that the effect size of the observed associations in available studies might not be clinically important to patients.43 In this way, clinical management of FMS is highly individualised and symptom-based, and it is argued that opioids may play a role when other strategies alone fail to provide sufficient pain control and when used for the shortest time possible.15–18
However, opioid use, especially when sustained over time, is associated with a higher risk of severe events, including addiction, misuse, severe respiratory and cardiovascular events and death.13 14 25 Opioid use has also been linked to poor sleep outcomes, increase mood disorders and increased risk of suicidal ideation,20–24 which are common symptoms of FMS and may be aggravated by opioid use. Moreover, FMS has been identified as a risk factor for long-term opioid use in patients initiating opioid therapy.8 25 In light of our findings, clinicians deciding to start opioids for FMS should carefully consider and monitor the duration of the treatment as well as the potential effects of the therapy on the mood and sleep quality of their patients.
To our knowledge, this is the first study to address the effect of long-term opioid use when compared with short-term opioid use on these outcomes in patients with FMS. Evidence on the association between the risk of sleep disorders and depression and the use of opioids in patients with FMS is thin, and available studies are subjected to many important limitations: they include a small number of patients, followed for short periods of time, are limited to a single centre, or employ suboptimal designs to compare between patterns of prescription.44–49 Regarding suicidality, there is evidence of increased risk in patients with FMS,4 5 50 but we found no studies on the effect of opioids on the incidence of suicidal thoughts in these patients. In our work, we used a large, population-based cohort of patients, with a mean follow-up of two and a half years. We employed an active comparator, new-user design, with a clear definition of eligibility criteria and treatment strategies, and we used propensity scores to account for potential confounding; we provided multiple sensitivity analyses including death as a competing risk or using dispensation instead of prescription data.
Our study is subjected to several limitations. First, the VID databases gather several real-world clinical practice data and contain information as registered by health professionals during routine clinical practice, but data are not specifically prepared for research. In this sense, studies based on real-world clinical information like the VID are at risk of well-known biases such a differential recording, misclassification bias or missing data.27 However, prescription data and data from hospital records, which are pivotal to our study, are of high quality as they are used either for billing purposes or are reviewed by coding specialists. Second, despite accounting for many relevant covariates in the adjustment, we may have missed some potentially relevant information and thus we cannot rule out residual confounding. For instance, we failed to include pain-related comorbidities or antidepressant medication in our study, which is widely employed in FMS and may be used differently by short and long-term opioid users. In this sense, our results must be interpreted with caution. Third, by design, we excluded some groups of patients, such as patients who initiated with treatments lasting more than 30 and less than 90 days, or patients not treated with opioids. In this sense, our results suggest that short-term prescription patterns may be less risky than long-term prescription behaviour. Importantly, short-term opioid use may also be associated with an increased risk of adverse outcomes, and a careful consideration of the risks and benefits of initiating opioids in patients with FMS and strict monitoring is warranted, even when prescribed for short periods of time. Comparison between patients treated for FMS with opioids versus non-opioid medication is also warranted: 40%–90% of patients with FMS are not prescribed opioids,51 evidence shows that the odds of suicidality in patients with chronic non-cancer pain are two to three times greater than in controls without chronic pain,52 53 and suicidality risk in patients with FMS is an up to a thirty-fold increase with respect to the general population.54 Fourth, information on inpatient medication is not available in VID, which may result in some misestimation.27 Fifth, we used prescription information to define the initial prescription, in an intention-to-treat analysis, therefore we may be overestimating the exposure of primary non-adherent patients (those who do not fill the first prescription).55 We provided sensitivity analyses using dispensation data to define short and long-term use instead of prescription information that yielded similar results that of our main analysis. Finally, the generalisation of our results to other settings outside Spain, or even to other Spanish regions, should be approached with caution.
Opioids are not recommended to treat pain in patients with FMS and may worsen common FMS comorbidities, such as sleep and depression disorders. However, they are routinely employed in clinical practice, and when used for prolonged periods they may lead to worse outcomes. Our results are in line with recommendations to avoid long-term opioid therapy in patients with FMS.
Data availability statement
Data are available upon reasonable request. The datasets presented in this article are not readily available due to legal restrictions on sharing the data set as regulated by the Valencia regional government by means of legal resolution by the Valencia Health Agency [2009/13312] which forbids the dissemination of data to third parties (accessible at: http://www.san.gva.es/documents/152919/157920/resolucionsolicituddatos.pdf). Upon request, authors can allow access to the databases to verify the accuracy of the analysis or the reproducibility of the study. Requests to access the datasets should be directed to Management Office of the Data Commission in the Valencia Health Agency (email: solicitud_datos@gva.es; telephone numbers: +34 961-928207; +34 961-928198).
Ethics statements
Patient consent for publication
Ethics approval
This study was approved by the Ethics Committee for Drug Research of the 'Hospital Clínico-Universitario de Valencia' (Reference: F-CE-GeVA 14 V.1.2; 21 March 2019), who waived the informed consent requirement given the retrospective design with pseudonymised data and minimal risk to participants.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors GS is the guarantor of the study, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: IH, SP, GS, AG-S. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: AG-S. Critical review of the manuscript for important intellectual content: all authors. Statistical analysis: CR, IH. Supervision: GS, IH, SP, AG-S.
Funding This study was funded with grant PI21/01413 (Use and Misuse of Prescription Opioids 2011-2021. A Population-Based Cohort in Four Autonomous Communities. The OPI-SNS Study) from the Health Institute Carlos III, Ministry of Science, Innovation and Universities, co-funded by the European Union; and grant RD21/0016/0006, funded by the Carlos III Health Institute (ISCIII), Ministry of Science, Innovation and Universities, and the Recovery, Transformation and Resilience Plan through NextGenerationEU European funds. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer-reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.