{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T13:24:49Z","timestamp":1773926689096,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.16431.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T00:00:00Z","timestamp":1620172800000}}],"reference-count":49,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T00:00:00Z","timestamp":1620172800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N00616X\/1"],"award-info":[{"award-number":["MR\/N00616X\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC_PC_19002"],"award-info":[{"award-number":["MC_PC_19002"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["CFC0111"],"award-info":[{"award-number":["CFC0111"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012338","name":"Alan Turing Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012338","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["209706"],"award-info":[{"award-number":["209706"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["086091"],"award-info":[{"award-number":["086091"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["2018-11-ST2-016"],"award-info":[{"award-number":["2018-11-ST2-016"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns3:p>\n                    <ns3:bold>Background:<\/ns3:bold>\n                    People who use illicit opioids such as heroin have substantial health needs, but there are few longitudinal studies of general health and healthcare in this population. Most research to date has focused on a narrow set of outcomes, including overdoses and HIV or hepatitis infections. We developed and validated a cohort using UK primary care electronic health records (Clinical Practice Research Datalink GOLD and AURUM databases) to facilitate research into healthcare use by people who use illicit opioid use (HUPIO).\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Methods:<\/ns3:bold>\n                    Participants are patients in England with primary care records indicating a history of illicit opioid use. We identified codes including prescriptions of opioid agonist therapies (methadone and buprenorphine) and clinical observations such as \u2018heroin dependence\u2019. We constructed a cohort of patients with at least one of these codes and aged 18-64 at cohort entry, with follow-up between January 1997 and March 2020. We validated the cohort by comparing patient characteristics and mortality rates to other cohorts of people who use illicit opioids, with different recruitment methods.\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Results:<\/ns3:bold>\n                    Up to March 2020, the HUPIO cohort included 138,761 patients with a history of illicit opioid use. Demographic characteristics and all-cause mortality were similar to existing cohorts: 69% were male; the median age at index for patients in CPRD AURUM (the database with more included participants) was 35.3 (interquartile range 29.1-42.6); the average age of new cohort entrants increased over time; 76% had records indicating current tobacco smoking; patients disproportionately lived in deprived neighbourhoods; and all-cause mortality risk was 6.6 (95% CI 6.5-6.7) times the general population of England.\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Conclusions:<\/ns3:bold>\n                    Primary care data offer new opportunities to study holistic health outcomes and healthcare of this population. The large sample enables investigation of rare outcomes, whilst the availability of linkage to external datasets allows investigation of hospital use, cancer treatment, and mortality.\n                  <\/ns3:p>","DOI":"10.12688\/wellcomeopenres.16431.2","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T05:36:43Z","timestamp":1620193003000},"page":"282","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Healthcare use by people who use illicit opioids (HUPIO): development of a cohort based on electronic primary care records in England"],"prefix":"10.12688","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3698-7196","authenticated-orcid":false,"given":"Dan","family":"Lewer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prianka","family":"Padmanathan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Qummer ul Arfeen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9612-7791","authenticated-orcid":false,"given":"Spiros","family":"Denaxas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6888-2212","authenticated-orcid":false,"given":"Harriet","family":"Forbes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arturo","family":"Gonzalez-Izquierdo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matt","family":"Hickman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2021,5,5]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41572-019-0137-5","article-title":"Opioid use disorder.","volume":"6","author":"J Strang","year":"2020","journal-title":"Nat Rev Dis Primer."},{"key":"ref-2","doi-asserted-by":"publisher","article-title":"Diagnostic And Statistical Manual Of Mental Disorders, 5th edn.","year":"2013","DOI":"10.1176\/appi.books.9780890425596"},{"key":"ref-3","article-title":"ICD-11 for Mortality and Morbidity Statistics.","year":"2020"},{"key":"ref-4","doi-asserted-by":"publisher","first-page":"2393-2404","DOI":"10.1111\/add.15111","article-title":"Estimating the prevalence of problem drug use from drug-related mortality data.","volume":"115","author":"H Jones","year":"2020","journal-title":"Addiction."},{"key":"ref-5","doi-asserted-by":"publisher","first-page":"426-7","DOI":"10.3399\/bjgp18X698597","article-title":"Managing addiction to prescribed opioids: the job of general practice?","volume":"68","author":"J Leach","year":"2018","journal-title":"Br J Gen Pract."},{"key":"ref-6","doi-asserted-by":"publisher","first-page":"7-8","DOI":"10.1177\/2049463712439131","article-title":"Opioid prescribing in the UK: can we avert a public health disaster?","volume":"6","author":"C Stannard","year":"2012","journal-title":"Br J Pain."},{"key":"ref-7","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1001\/jamapsychiatry.2019.4170","article-title":"All-Cause and Cause-Specific Mortality Among People Using Extramedical Opioids: A Systematic Review and Meta-analysis.","volume":"77","author":"S Larney","year":"2020","journal-title":"JAMA Psychiatry."},{"key":"ref-8","doi-asserted-by":"publisher","first-page":"17-23","DOI":"10.1016\/j.drugalcdep.2014.09.782","article-title":"National record linkage study of mortality for a large cohort of opioid users ascertained by drug treatment or criminal justice sources in England, 2005 \u2013 2009.","volume":"146","author":"M Pierce","year":"2015","journal-title":"Drug Alcohol Depend."},{"key":"ref-9","doi-asserted-by":"publisher","first-page":"321-9","DOI":"10.1016\/j.jsat.2005.02.007","article-title":"An overview of systematic reviews of the effectiveness of opiate maintenance therapies: available evidence to inform clinical practice and research.","volume":"28","author":"L Amato","year":"2005","journal-title":"J Subst Abuse Treat."},{"key":"ref-10","doi-asserted-by":"publisher","first-page":"697-707","DOI":"10.1111\/j.1360-0443.2004.00752.x","article-title":"Economic analysis of costs and consequences of the treatment of drug misuse: 2-year outcome data from the National Treatment Outcome Research Study (NTORS).","volume":"99","author":"C Godfrey","year":"2004","journal-title":"Addiction."},{"key":"ref-11","doi-asserted-by":"publisher","first-page":"1094-104","DOI":"10.1093\/cid\/ciw416","article-title":"Impact of Opioid Substitution Therapy on Antiretroviral Therapy Outcomes: A Systematic Review and Meta-Analysis.","volume":"63","author":"A Low","year":"2016","journal-title":"Clin Infect Dis."},{"key":"ref-12","doi-asserted-by":"publisher","first-page":"e5945-e5945","DOI":"10.1136\/bmj.e5945","article-title":"Opiate substitution treatment and HIV transmission in people who inject drugs: systematic review and meta-analysis.","volume":"345","author":"G MacArthur","year":"2012","journal-title":"BMJ."},{"key":"ref-13","doi-asserted-by":"publisher","first-page":"1157-65","DOI":"10.1093\/cid\/civ476","article-title":"The Effects of Opioid Substitution Treatment and Highly Active Antiretroviral Therapy on the Cause-Specific Risk of Mortality Among HIV-Positive People Who Inject Drugs.","volume":"61","author":"B Nosyk","year":"2015","journal-title":"Clin Infect Dis."},{"key":"ref-14","doi-asserted-by":"publisher","first-page":"1011-1023","DOI":"10.1111\/add.14892","article-title":"Frequency of healthcare utilisation by adults who use illicit drugs: a systematic review and meta-analysis.","volume":"115","author":"D Lewer","year":"2020","journal-title":"Addiction."},{"key":"ref-15","article-title":"ACMD report: ageing cohort of drug users.","year":"2019"},{"key":"ref-16","doi-asserted-by":"publisher","first-page":"107525","DOI":"10.1016\/j.drugalcdep.2019.06.027","article-title":"Causes of hospital admission and mortality among 6683 people who use heroin: A cohort study comparing relative and absolute risks.","volume":"204","author":"D Lewer","year":"2019","journal-title":"Drug Alcohol Depend."},{"key":"ref-17","doi-asserted-by":"publisher","first-page":"1625-38","DOI":"10.1093\/ije\/dys188","article-title":"Data Resource Profile: Cardiovascular disease research using linked bespoke studies and electronic health records (CALIBER).","volume":"41","author":"S Denaxas","year":"2012","journal-title":"Int J Epidemiol."},{"key":"ref-18","doi-asserted-by":"publisher","first-page":"827-36","DOI":"10.1093\/ije\/dyv098","article-title":"Data Resource Profile: Clinical Practice Research Datalink (CPRD).","volume":"44","author":"E Herrett","year":"2015","journal-title":"Int J Epidemiol."},{"key":"ref-19","doi-asserted-by":"publisher","first-page":"1740-1740g","DOI":"10.1093\/ije\/dyz034","article-title":"Data resource profile: Clinical Practice Research Datalink (CPRD) Aurum.","volume":"48","author":"A Wolf","year":"2019","journal-title":"Int J Epidemiol."},{"key":"ref-20","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1001\/archpsyc.58.5.503","article-title":"A 33-Year Follow-up of Narcotics Addicts.","volume":"58","author":"Y Hser","year":"2001","journal-title":"Arch Gen Psychiatry."},{"key":"ref-21","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/1471-244X-11-122","article-title":"Substance abuse and psychiatric co-morbidity as predictors of premature mortality in Swedish drug abusers a prospective longitudinal study 1970 - 2006.","volume":"11","author":"A Nyhl\u00e9n","year":"2011","journal-title":"BMC Psychiatry."},{"key":"ref-22","doi-asserted-by":"publisher","first-page":"1299-308","DOI":"10.1111\/j.1360-0443.1994.tb03309.x","article-title":"Death and survival in a cohort of heroin addicts from London clinics: a 22-year follow-up study.","volume":"89","author":"E Oppenheimer","year":"1994","journal-title":"Addiction."},{"key":"ref-23","article-title":"Healthcare use by people who use illicit opioids (HUPIO): development of a cohort based on electronic primary care records in England (extended data)","author":"D Lewer","year":"2020"},{"key":"ref-24","article-title":"Clinical Knowledge Summary: Opioid Dependence.","year":"2019"},{"key":"ref-25","article-title":"Methadone Hydrochloride.","year":"2020"},{"key":"ref-26","article-title":"Buprenorphine.","year":"2020"},{"key":"ref-27","doi-asserted-by":"publisher","first-page":"1461-76","DOI":"10.1111\/add.14188","article-title":"The impact of buprenorphine and methadone on mortality: a primary care cohort study in the United Kingdom.","volume":"113","author":"M Hickman","year":"2018","journal-title":"Addiction."},{"key":"ref-28","article-title":"Adult substance misuse statistics from the National Drug Treatment Monitoring System (NDTMS): 1 April 2017 to 31 March 2018"},{"key":"ref-29","doi-asserted-by":"publisher","DOI":"10.1101\/2020.04.07.20049015","article-title":"Time trends and prescribing patterns of opioid drugs in UK primary care patients with non-cancer pain: a retrospective cohort study.","author":"M Jani","year":"2020","journal-title":"medRxiv."},{"key":"ref-30","article-title":"Shooting Up: Infections among people who inject drugs in the UK, 2018 - an update, December 2019","author":"E Heinsbroek","year":"2019"},{"key":"ref-31","doi-asserted-by":"publisher","first-page":"220-30","DOI":"10.1111\/add.13099","article-title":"An international systematic review of smoking prevalence in addiction treatment.","volume":"111","author":"J Guydish","year":"2016","journal-title":"Addiction."},{"key":"ref-32","article-title":"CALIBER Smoking status phenotype","author":"M Pujades-Rodriguez","year":"2012"},{"key":"ref-33","article-title":"Estimates of the Prevalence of Opiate Use and\/or Crack Cocaine Use, 2016\/17: Sweep 13 report","author":"G Hay","year":"2019"},{"key":"ref-34","article-title":"Deaths related to drug poisoning in England and Wales: 2018 registrations","year":"2019"},{"key":"ref-35","doi-asserted-by":"publisher","first-page":"e0174818","DOI":"10.1371\/journal.pone.0174818","article-title":"Epidemiology of alcohol dependence in UK primary care: Results from a large observational study using the Clinical Practice Research Datalink.","volume":"12","author":"A Thompson","year":"2017","journal-title":"PLoS One."},{"key":"ref-36","article-title":"Hard edges: mapping severe and multiple disadvantage","author":"G Bramley","year":"2015"},{"key":"ref-37","article-title":"Population estimates and deaths by single year of age for England and Wales and the UK, 1961 to 2017","year":"2018"},{"key":"ref-38","article-title":"R: A Language and Environment for Statistical Computing","year":"2020"},{"key":"ref-39","article-title":"People who inject drugs: HIV and viral hepatitis unlinked anonymous monitoring survey tables (psychoactive): 2019 update","year":"2019"},{"key":"ref-40","doi-asserted-by":"publisher","first-page":"908-22","DOI":"10.1002\/ejp.1357","article-title":"Risk of adverse events in patients prescribed long-term opioids: A cohort study in the UK Clinical Practice Research Datalink.","volume":"23","author":"J Bedson","year":"2019","journal-title":"Eur J Pain."},{"key":"ref-41","doi-asserted-by":"publisher","first-page":"1701-8","DOI":"10.1002\/ejp.1256","article-title":"Increased risk of reproductive dysfunction in women prescribed long-term opioids for musculoskeletal pain: A matched cohort study in the Clinical Practice Research Datalink.","volume":"22","author":"E Richardson","year":"2018","journal-title":"Eur J Pain."},{"key":"ref-42","doi-asserted-by":"publisher","first-page":"847-50","DOI":"10.1136\/jech.2004.030833","article-title":"Substance misuse and psychiatric illness: prospective observational study using the general practice research database.","volume":"59","author":"M Frisher","year":"2005","journal-title":"J Epidemiol Community Health."},{"key":"ref-43","doi-asserted-by":"publisher","first-page":"240-7","DOI":"10.4321\/S0213-61632013000400002","article-title":"Incidence of psychoses among drug dependent patients in primary care with no psychiatric history: A retrospective observational matched-cohort study.","volume":"27","author":"M Frisher","year":"2013","journal-title":"Eur J Psychiatry."},{"key":"ref-44","doi-asserted-by":"publisher","first-page":"c5475","DOI":"10.1136\/bmj.c5475","article-title":"Risk of death during and after opiate substitution treatment in primary care: prospective observational study in UK General Practice Research Database.","volume":"341","author":"R Cornish","year":"2010","journal-title":"BMJ."},{"key":"ref-45","doi-asserted-by":"publisher","first-page":"1-92","DOI":"10.3310\/hsdr07030","article-title":"The impact of opiate substitution treatment on mortality risk in drug addicts: a natural experiment study.","volume":"7","author":"C Steer","year":"2019","journal-title":"Health Serv Deliv Res."},{"key":"ref-46","doi-asserted-by":"publisher","first-page":"923-33","DOI":"10.1002\/pds.4811","article-title":"Methods to generate and validate a Pregnancy Register in the UK Clinical Practice Research Datalink primary care database.","volume":"28","author":"C Minassian","year":"2019","journal-title":"Pharmacoepidemiol Drug Saf."},{"key":"ref-47","doi-asserted-by":"publisher","first-page":"1899-911","DOI":"10.1016\/S0140-6736(14)60685-1","article-title":"Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1\u00b725 million people.","volume":"383","author":"E Rapsomaniki","year":"2014","journal-title":"Lancet."},{"key":"ref-48","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s12954-018-0233-y","article-title":"'Care and Prevent': rationale for investigating skin and soft tissue infections and AA amyloidosis among people who inject drugs in London.","volume":"15","author":"M Harris","year":"2018","journal-title":"Harm Reduct J."},{"key":"ref-49","doi-asserted-by":"publisher","first-page":"e234-e244","DOI":"10.3399\/bjgp18X695309","article-title":"Factors influencing recording of drug misuse in primary care: a qualitative study of GPs in England.","volume":"68","author":"H Davies-Kershaw","year":"2018","journal-title":"Br J Gen Pract."}],"container-title":["Wellcome Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/5-282\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/5-282\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/5-282\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T09:54:10Z","timestamp":1773914050000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/5-282\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,5]]},"references-count":49,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.16431.2","relation":{"has-version":[{"id-type":"doi","id":"10.12688\/wellcomeopenres.16431.1","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.18411.r43677","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.18411.r43677","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,5]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/5-282\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.18081.r41740, Dhanya Nambiar, Monash University, Melbourne, 21 Dec 2020, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/5-282\/v1#referee-response-41740","order":0,"name":"referee-response-41740","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Dan Lewer<\/b>; \n<i>Posted: 20 Apr 2021<\/i>; Many thanks for reviewing our article. We have updated the article following your feedback. In addition, we have some specific responses to your comments and questions:  Comment: Over such a long recruitment period, are participants comparable in terms of case ascertainment ie. do you expect that identifying opioid use has become better or worse over the period? And have there been any changes in the healthcare system such as access to OAT or uptake of primary care over the recruitment period?  Response: Yes, there have been changes in both the population and healthcare system that mean case ascertainment is likely to change over time. Two important examples are (1) decreasing investment in OAT since 2010, which may reduce case ascertainment because patients have less overall contact with health services (though OAT is generally delivered in specialist community settings rather than by GPs); (2) the increasing age of the population greater health needs - which may improve case ascertainment as people have a greater need to see their GP. Restricting analyses to limited time periods (or stratifying by time period) may help - which we have now recommended in the paragraph above 'implications for future research'.  Comment: Are all deaths reliably linked to both GOLD and AURUM records?  Response: The first version of this article used death data in primary care records. Since then, we have received linked mortality data from the Office for National Statistics for the HUPIO cohort. The mortality rates and ratios in the revised paper use this data. While there are undoubtedly errors in the linkage process, it is generally considered to be high quality and miss few deaths. The linkage uses NHS numbers, a unique identifier that is assigned to everyone registered at a GP practice, in combination with other identifiers. Further information about the linkage methodology is available here: Padmanabhan S, Carty L, Cameron E, Ghosh RE, Williams R, Strongman H. Approach to record linkage of primary care data from Clinical Practice Research Datalink to other health-related patient data: overview and implications. Eur J Epidemiol. 2019;34(1):91-99. doi:10.1007\/s10654-018-0442-4  Comment: In Table 1, considering the length of the study period, do you know why the median follow up period was relatively short at under 4 years? Do patients frequently transfer out of GP practices, or is this specific to this cohort?  Response: There are two reasons for this. First, GP practices are continually joining and exiting CPRD. The pool of practices participating in CPRD GOLD is shrinking, and when a practice leaves the database then follow-up for the patient ends. Likewise, the pool of practices for CPRD AURUM is growing and many practices joined later than 1997. Second, this is a mobile population and patients do frequently transfer out of GP practices. We have added a note to the table to clarify that these values are the follow-up duration for primary care data only, and longer follow-up is available where linked data are used (such as Hospital Episode Statistics or Office for National Statistics mortality records). In later analyses we will used matched cohorts of patients who do not have a history of illicit opioid use, for comparison. In these cohorts, follow-up is typically a bit longer because the general population is less mobile than people who use illicit opioids.  Comment: Are participants uniquely identifiable across different participating GP practices over the study period? In future, it would be interesting to compare the frequency at which they present to primary and other healthcare services. This may speak to some of the current limitations such as I) how representative the cohort is to other international opioid using populations in terms of health service use, and ii) determine if there are subgroups within the cohort with distinct patterns of primary care use (that may have other distinct characteristics such as drug use patterns, homelessness, deprivation, etc).  Response: No, unfortunately participants are not uniquely identifiable across different participanting GP practices. It is possible that some patients move from one participating practice to another, and therefore appear in the data twice. This is thought to be sufficiently rare in CPRD that each &quot;patient&quot; (in fact a patient-registration episode) can reasonably be considered unique. We agree that it will be interesting to analyse healthcare frequency. CPRD provides linkage to hospital data, and this will allow comparison with existing studies of hospital admissions in patients recruited via specialist OAT clinics.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/5-282\/v2#referee-comment-4587","order":1,"name":"referee-comment-4587","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.18411.r43677, Sally McManus, School of Health Sciences, City, University of London, London, 05 May 2021, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/5-282\/v2#referee-response-43677","order":2,"name":"referee-response-43677","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by the Wellcome Trust through an Institutional Strategic Support Grant to Health Data Research UK [209706] and a Project Grant that supports SD [086091].\r\n\r\nDL is funded by a National Institute of Health Research Doctoral Research Fellowship [DRF-2018-11-ST2-016]. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. PP\u2019s PhD Clinical Fellowship is funded by the MRC Addiction Research Clinical Training programme [MR\/N00616X\/1]. SD is supported by Health Data Research UK [NIWA1], and the Alan Turing Institute. The Institute of Health Informatics at UCL and Health Data Research UK are funded by a coalition led by MRC [CFC0111]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}