CoChat
Sign Up
Cited by 307Opioid Use Disorder TreatmentSubstance Abuse Treatment and OutcomesHIV, Drug Use, Sexual Risk

Risk of death during and after opiate substitution treatment in primary care: prospective observational study in UK General Practice Research Database

Open access
Cornish, R., Macleod, J., Strang, J., Vickerman, P., Hickman, M.·2010·BMJ
DOI 10.1136/bmj.c5475PMC PMC2965139
Open this paper in CoChat — free accountOpen PDF

Abstract

OBJECTIVE: To investigate the effect of opiate substitution treatment at the beginning and end of treatment and according to duration of treatment. DESIGN: Prospective cohort study. Setting UK General Practice Research Database. PARTICIPANTS: Primary care patients with a diagnosis of substance misuse prescribed methadone or buprenorphine during 1990-2005. 5577 patients with 267 003 prescriptions for opiate substitution treatment followed-up (17 732 years) until one year after the expiry of their last prescription, the date of death before this time had elapsed, or the date of transfer away from the practice. MAIN OUTCOME MEASURES: Mortality rates and rate ratios comparing periods in and out of treatment adjusted for sex, age, calendar year, and comorbidity; standardised mortality ratios comparing opiate users' mortality with general population mortality rates. RESULTS: Crude mortality rates were 0.7 per 100 person years on opiate substitution treatment and 1.3 per 100 person years off treatment; standardised mortality ratios were 5.3 (95% confidence interval 4.0 to 6.8) on treatment and 10.9 (9.0 to 13.1) off treatment. Men using opiates had approximately twice the risk of death of women (morality rate ratio 2.0, 1.4 to 2.9). In the first two weeks of opiate substitution treatment the crude mortality rate was 1.7 per 100 person years: 3.1 (1.5 to 6.6) times higher (after adjustment for sex, age group, calendar period, and comorbidity) than the rate during the rest of time on treatment. The crude mortality rate was 4.8 per 100 person years in weeks 1-2 after treatment stopped, 4.3 in weeks 3-4, and 0.95 during the rest of time off treatment: 9 (5.4 to 14.9), 8 (4.7 to 13.7), and 1.9 (1.3 to 2.8) times higher than the baseline risk of mortality during treatment. Opiate substitution treatment has a greater than 85% chance of reducing overall mortality among opiate users if the average duration approaches or exceeds 12 months. CONCLUSIONS: Clinicians and patients should be aware of the increased mortality risk at the start of opiate substitution treatment and immediately after stopping treatment. Further research is needed to investigate the effect of average duration of opiate substitution treatment on drug related mortality.

AI snapshot

Written from the paper’s full text.

TL;DR

In a UK primary care cohort of opiate users prescribed methadone or buprenorphine, mortality was lower during opiate substitution treatment than off treatment, but risk was elevated in the first weeks of treatment and immediately after stopping. The authors estimate that treatment is likely to reduce overall mortality only when average duration approaches or exceeds 12 months.

Key findings

  • Crude mortality was 0.7 per 100 person years on treatment versus 1.3 per 100 person years off treatment; adjusted mortality rate ratio off versus on treatment was 2.29 (95% CI 1.67 to 3.14), and standardised mortality ratios were 5.3 (4.0 to 6.8) on treatment and 10.9 (9.0 to 13.1) off treatment.
  • In the first two weeks of treatment, crude mortality was 1.7 per 100 person years, with an adjusted rate ratio of 3.11 (1.47 to 6.59) compared with the remainder of time on treatment; weeks 3-4 had a crude rate of 1.32 per 100 person years and adjusted rate ratio 2.38 (0.95 to 5.99).
  • After treatment stopped, crude mortality was 4.80 per 100 person years in weeks 1-2 and 4.25 in weeks 3-4, with adjusted rate ratios of 9.01 (5.43 to 14.90) and 8.01 (4.70 to 13.66) versus the stable on-treatment period; during the remainder of time off treatment, the crude rate was 0.95 per 100 person years and adjusted rate ratio 1.91 (1.32 to 2.76).
  • The modelled probability that opiate substitution treatment reduces overall mortality was less than 25% at 20-30 weeks’ average duration, 65% at 40 weeks, and greater than 85% if average duration approaches or exceeds 12 months.

Methods

  • Prospective cohort study using the UK General Practice Research Database, including primary care patients with a diagnosis of substance misuse prescribed methadone or buprenorphine during 1990-2005: 5,577 patients, 267,003 prescriptions, and 17,732 person years of follow-up until one year after the last prescription, death, or transfer away from the practice.
  • Time on treatment was defined from prescription expiry, with gaps of less than 28 days counted as on treatment; oral dihydrocodeine prescriptions were included as opiate substitution treatment.
  • Poisson regression estimated mortality rate ratios adjusted for sex, age group, calendar period, comorbidity score, treatment episode, and episodes with at least one dose at or above recommended maintenance thresholds; indirect standardised mortality ratios used 1998 sex-specific death rates for England and Wales, with sensitivity analyses restricted to final treatment episodes and excluding dihydrocodeine.

Limitations

  • The paper states that classification of time on and off treatment was complicated by gaps in dose, duration, or quantity data, which may have diluted or exaggerated mortality differences; findings were similar in a sensitivity analysis restricted to the last treatment episode.
  • The paper states that patients transferring out of the database had no active follow-up, that their characteristics differed from those completing follow-up, and that unrecorded confounders could bias results; follow-up was restricted to 12 months after treatment to limit misclassification.
  • The paper states that covariates were limited, the comorbidity index was not ideal or opiate-specific, there was no measure of intervention quality or intensity, outcome was all-cause mortality without cause-specific data, and the duration analyses were modelled rather than directly observed; evident from the text, the observational design cannot establish causality.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1136/bmj.c5475

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 38 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The adjusted death rate in the first month after opiate substitution treatment stopped was more than four times higher (mortality rate ratio 4.20, 95% CI 2.53 to 6.96) than in the subsequent period off treatment.

    “The adjusted death rate in the first month after treatment stopped was more than four times higher (mortality rate ratio 4.20, 2.53 to 6.96) than in the subsequent period off treatment.”
    Quote in the paperSubstantial claim
  • Findingown data

    The crude mortality rate in weeks 1-2 after opiate substitution treatment stopped was 4.8 per 100 person years.

    “The crude mortality rate was 4.8 per 100 person years in weeks 1-2 after treatment stopped, 4.3 in weeks 3-4, and 0.95 during the rest of time off treatment: 9 (5.4 to 14.9), 8 (4.7 to 13.7), and 1.9 (1.3 to 2.8) times higher than the baseline risk of mortality during treatment.”
    • Also stated in: § Effect of opiate substitution treatment on mortality · plain
      “Mortality was also raised substantially in the period immediately after treatment, at 4.8 per 100 person years in the first two weeks and 4.3 per 100 person years in weeks three to four”
    Quote in the paperSubstantial claim
  • Findingown data

    In the first two weeks of opiate substitution treatment, the crude mortality rate was 1.7 per 100 person years.

    “In the first two weeks of opiate substitution treatment the crude mortality rate was 1.7 per 100 person years: 3.1 (1.5 to 6.6) times higher (after adjustment for sex, age group, calendar period, and comorbidity) than the rate during the rest of time on treatment.”
    • Also stated in: § Effect of opiate substitution treatment on mortality · plain
      “The mortality rate was raised in the first four weeks: 1.7 per 100 person years in the first two weeks and 1.3 per 100 person years in weeks three to four”
    Quote in the paperSubstantial claim
  • Findingown data

    Among opiate users, men had approximately twice the mortality rate of women (adjusted mortality rate ratio 1.97, 95% CI 1.36 to 2.85).

    “Men using opiates had approximately twice the risk of death of women (morality rate ratio 2.0, 1.4 to 2.9).”
    • Also stated in: § Effect of opiate substitution treatment on mortality · plain
      “Male | 142 | 12 461.2 | 1.14 | 1.67 (1.16 to 2.40) | 0.004 | | 1.97 (1.36 to 2.85) | <0.001 | <0.001”
    Quote in the paperNot a substantial claim
  • Findingown data

    The crude mortality rate among patients on opiate substitution treatment was 0.7 per 100 person years.

    “Crude mortality rates were 0.7 per 100 person years on opiate substitution treatment and 1.3 per 100 person years off treatment; standardised mortality ratios were 5.3 (95% confidence interval 4.0 to 6.8) on treatment and 10.9 (9.0 to 13.1) off treatment.”
    • Also stated in: § Effect of opiate substitution treatment on mortality · plain
      “The crude mortality rate off treatment was almost double that on treatment (1.3 v 0.7 per 100 person years)”
    Quote in the paperSubstantial claim
  • May combine two claims. 19
  • Classified as probably not a substantial claim. 23

  • May combine two claims.

    Findingown data

    The adjusted mortality rate ratio for the first 28 days on methadone was 2.8 (95% CI 1.1 to 7.0) and for the first 28 days on buprenorphine was 2.5 (95% CI 0.3 to 18.5), compared with the risk of death on methadone after the first 28 days of treatment.

    “For example, the adjusted mortality rate ratio was 2.8 (1.1 to 7.0) and 2.5 (0.3 to 18.5) for the first 28 days on methadone or buprenorphine and 9.5 (5.1 to 17.5) and 15.7 (6.7 to 36.9) for the first 28 days off methadone or buprenorphine, compared with the risk of death on methadone after the first 28 days of treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The adjusted mortality rate ratio for the first 28 days off methadone was 9.5 (95% CI 5.1 to 17.5) and for the first 28 days off buprenorphine was 15.7 (95% CI 6.7 to 36.9), compared with the risk of death on methadone after the first 28 days of treatment.

    “For example, the adjusted mortality rate ratio was 2.8 (1.1 to 7.0) and 2.5 (0.3 to 18.5) for the first 28 days on methadone or buprenorphine and 9.5 (5.1 to 17.5) and 15.7 (6.7 to 36.9) for the first 28 days off methadone or buprenorphine, compared with the risk of death on methadone after the first 28 days of treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The mortality rate ratio in the first 28 days off treatment was 8.75 (95% CI 2.34 to 32.75) with evidence of tapered prescribing and 8.27 (95% CI 4.78 to 14.30) without such evidence.

    “The mortality rate ratios in first 28 days off treatment were 8.75 (2.34 to 32.75) with evidence of tapered prescribing and 8.27 (4.78 to 14.30) without such evidence (interaction test: χ2=0.32, df=2, P=0.9).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The start of opiate substitution treatment (the first 28 days) may be associated with an increased risk of death.

    “Treatment guidelines and recent studies have suggested that the start of treatment (the first 28 days) may be associated with an increased risk of death.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 23 24 25 26

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    A sensitivity analysis was done by restricting the analysis to patients with no prescriptions for oral dihydrocodeine to test whether the findings were the same for patients receiving only methadone or buprenorphine.

    “We also restricted the analysis to patients with no prescriptions for oral dihydrocodeine to test whether the findings were the same for patients receiving only methadone or buprenorphine.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study fitted an interaction to test whether a difference existed in the risk of death in the first 28 days off treatment for patients with evidence of tapered prescribing before treatment ceased.

    “In addition, we fitted an interaction to test whether a difference existed in the risk of death in the first 28 days “off treatment” for patients with evidence of tapered prescribing before treatment ceased.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The mortality rate ratios comparing periods in and out of treatment were adjusted for potential confounders (sex, age group, calendar period, comorbidity score, treatment episode, and episodes with one opiate substitution treatment at or above recommended levels for maintenance).

    “We used Poisson regression to estimate mortality rate ratios comparing periods in and out of treatment, adjusted for potential confounders (sex, age group, calendar period, comorbidity score, treatment episode, and episodes with one opiate substitution treatment at or above recommended levels for maintenance).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    We restricted follow-up to 12 months after treatment, as any misclassification of patients (and person years) at risk is likely to be small because the rate of cessation/long term abstinence is low.

    “For this reason, we restricted follow-up to 12 months after treatment, as any misclassification of patients (and person years) at risk is likely to be small because the rate of cessation/long term abstinence is low33 34”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] Sweeting MJ, De AD, Ades AE, Hickman M. Estimating the prevalence of ex-injecting drug use in the population. Stat Methods Med Res 2009; 18: 381-95. 19036912 10.1177/0962280208094704

      Not checked in the free run.

    • cites [34] Kimber J, Copeland L, Hickman M, Macleod J, McKenzie J, De Angelis D, et al. Survival and cessation in injecting opiate users, a prospective observational study of outcomes and the effect of opiate substitute treatment. BMJ 2010; 340: c3172. 10.1136/bmj.c3172 PMC2895695 20595255

      Not checked in the free run.

    • Rests on an assumption: Some patients who left treatment will have stopped their opiate use and therefore have been at substantially less risk of death than patients who relapsed.

  • May combine two claims.

    Interpretationcitation

    The overall risk of death, standardised mortality ratios, and overall difference in mortality between time on and off treatment for opiate users in UK primary care in this study are consistent with international literature.

    “The overall risk of death, standardised mortality ratios, and overall difference in mortality between time on and off treatment for opiate users in UK primary care in this study are consistent with international literature.4 36”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Degenhardt L, Bucello C, Mathers B, Briegleb C, Ali H, Hickman M, et al. Mortality among regular or dependent users of heroin and other opioids: a systematic review and meta-analysis of cohort studies. Addiction [forthcoming]. 10.1111/j.1360-0443.2010.03140.x 21054613

      Not checked in the free run.

    • cites [36] Hulse GK, English DR, Milne E, Holman CD. The quantification of mortality resulting from the regular use of illicit opiates. Addiction 1999; 94: 221-9. 10396790 10.1046/j.1360-0443.1999.9422216.x

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Between 1990 and 2005, 1647 (30%) patients transferred out of their practices: 743 during opiate substitution treatment and 904 in the 12 months after treatment.

    “Between 1990 and 2005, 1647 (30%) patients transferred out of their practices: 743 during opiate substitution treatment and 904 in the 12 months after treatment (8% and 10% of the person years of follow-up).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Long term follow-up of injecting drug users from a single primary care centre suggests that survival is substantially improved with each year of exposure to opiate substitution treatment.

    “Long term follow-up of injecting drug users from a single primary care centre suggests that survival is substantially improved with each year of exposure to opiate substitution treatment,34 as we estimate in figure 2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Kimber J, Copeland L, Hickman M, Macleod J, McKenzie J, De Angelis D, et al. Survival and cessation in injecting opiate users, a prospective observational study of outcomes and the effect of opiate substitute treatment. BMJ 2010; 340: c3172. 10.1136/bmj.c3172 PMC2895695 20595255

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Excluding patients who had ever had a prescription for dihydrocodeine did not alter the overall findings.

    “Excluding patients who had ever had a prescription for dihydrocodeine (n=1480 patients) did not alter the overall findings”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The outcome of our study was all cause mortality, as we had no information on specific causes of death.

    “Fourthly, the outcome of our study was all cause mortality, as we had no information on specific causes of death.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    The net benefit of opiate substitution treatment on overall mortality may relate to the average duration of treatment.

    “We hypothesise that the net benefit of opiate substitution treatment on overall mortality may relate to the average duration of treatment.”
    • Also stated in: § Implications for policy and practice · hedged
      “The effect of opiate substitution treatment on overall drug related mortality may relate to the average duration of treatment in the population”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Our comparisons of the risk of death in exposed and unexposed populations by duration of opiate substitution treatment are calculated effects and not directly observed effects.

    “Finally, our comparisons of the risk of death in exposed and unexposed populations by duration of opiate substitution treatment are calculated effects and not directly observed effects.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    No trial is likely to have sufficient power to measure the effect of duration of opiate substitution treatment on overall risk of death.

    “Nevertheless, no trial is likely to have sufficient power to measure the effect of duration of opiate substitution treatment on overall risk of death, so future analyses must inevitably be derived from observational cohorts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Classification of time on and off treatment was complicated by occasional gaps in the information on doses, duration, or quantity prescribed, which may have led to an underestimate or overestimate of the mortality on or off treatment and therefore have diluted or exaggerated the difference between them.

    “Firstly, classification of time on and off treatment was complicated by occasional gaps in the information on doses, duration, or quantity prescribed, which may have led to an underestimate or overestimate of the mortality on or off treatment and therefore have diluted or exaggerated the difference between them.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Other factors or unrecorded confounders may be associated with both mortality and transferring from the study practice (loss to follow-up) that could be a source of bias.

    “However, other factors or unrecorded confounders may be associated with both mortality and transferring from the study practice (loss to follow-up) that could be a source of bias.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    At longer treatment durations approaching or exceeding a year, opiate substitution treatment is highly likely (more than 85% chance) to reduce the overall mortality in opiate users and lead to a decline in the number of drug related deaths.

    “at longer treatment durations approaching or exceeding a year, opiate substitution treatment is highly likely (more than 85% chance) to reduce the overall mortality in opiate users and lead to a decline in the number of drug related deaths.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Patients who transferred out of the database (about 10% per year) had no active follow-up, and patients' opiate use after leaving opiate substitution treatment was not followed up.

    “Secondly, patients who transferred out of the database (which in our study was about 10% per year) had no active follow-up, and patients’ opiate use after leaving opiate substitution treatment was not followed up.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    A sensitivity analysis was done by restricting the analysis to each patient's final treatment episode.

    “Therefore, we did a sensitivity analysis by restricting the analysis to each patient’s final treatment episode.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    The study may have misclassified time on and off treatment and introduced bias, for example if patients were genuinely off treatment during a gap of less than 28 days between prescriptions.

    “We may have misclassified time on and off treatment (in our attempt to allow for missing information on prescriptions) and introduced bias—for example, if occasions existed when patients were genuinely off treatment during a gap of less than 28 days between prescriptions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Previous studies in the UK have shown that most deaths among active opiate users will be due to overdose.

    “Although previous studies in the UK have shown that most deaths among active opiate users will be due to overdose”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Bargagli AM, Hickman M, Davoli M, Perucci CA, Schifano P, Buster M, et al. Drug-related mortality and its impact on adult mortality in eight European countries. Eur J Public Health 2006; 16: 198-202. 16157612 10.1093/eurpub/cki168

      Not checked in the free run.

    • cites [27] Davoli M, Bargagli AM, Perucci CA, Schifano P, Belleudi V, Hickman M, et al. Risk of fatal overdose during and after specialist drug treatment: the VEdeTTE study, a national multi-site prospective cohort study. Addiction 2007; 102: 1954-9. 18031430 10.1111/j.1360-0443.2007.02025.x

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study fitted an interaction to test for differences in the risk of death at different treatment periods between methadone and buprenorphine.

    “We fitted an interaction to test for differences in the risk of death at different treatment periods between methadone and buprenorphine.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Patients who transferred out during the study were more likely to be women, to be younger, and to have less comorbidity.

    “Patients who transferred out during the study were more likely to be women (34% v 29%), to be younger (65% v 55% aged under 30), and to have less comorbidity (58% v 63% with lowest comorbid score).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The study in Australia showed that these deaths were primarily due to overdose and other injury.

    “the study in Australia showed that these deaths were primarily due to overdose and other injury.24”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Degenhardt L, Randall D, Hall W, Law M, Butler T, Burns L. Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: risk factors and lives saved. Drug Alcohol Depend 2009; 105: 9-15. 19608355 10.1016/j.drugalcdep.2009.05.021

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    We found a substantially larger difference in mortality in the first month after treatment stopped than did either the study in Australia (mortality rate ratio approximately 3) or the one in Holland (mortality rate ratio approximately 1).

    “In contrast, we found a substantially larger difference in mortality in the first month after treatment stopped than did either the study in Australia (mortality rate ratio approximately 3) or the one in Holland (mortality rate ratio approximately 1).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Buster MC, van Brussel GH, van den Brink W. An increase in overdose mortality during the first 2 weeks after entering or re-entering methadone treatment in Amsterdam. Addiction 2002; 97: 993-1001. 12144602 10.1046/j.1360-0443.2002.00179.x

      Not checked in the free run.

    • cites [24] Degenhardt L, Randall D, Hall W, Law M, Butler T, Burns L. Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: risk factors and lives saved. Drug Alcohol Depend 2009; 105: 9-15. 19608355 10.1016/j.drugalcdep.2009.05.021

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    An excess risk of death exists in the period immediately after opiate substitution treatment ends.

    “Furthermore, findings in two large cohorts in Italy and Australia have suggested that an excess risk of death exists in the period immediately after treatment ends.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 24 27

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    We had no factors that could measure the quality or intensity of the intervention, which may have a bearing on both the risk of death at starting opiate substitution treatment and the likelihood of relapse and death in the period immediately after treatment.

    “More importantly, we had no factors that could measure the quality or intensity of the intervention, which may have a bearing on both the risk of death at starting opiate substitution treatment and the likelihood of relapse and death in the period immediately after treatment.26 35”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Department of Health and the devolved administrations. Drug misuse and dependence: UK guidelines on clinical management. Department of Health, 2007.

      Not checked in the free run.

    • cites [35] Zador D. Methadone maintenance: making it better. Addiction 2007; 102: 350-1. 17298640 10.1111/j.1360-0443.2007.01783.x

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The data are consistent with other studies.

    “the data are consistent with other studies.19 24 27”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Fugelstad A, Stenbacka M, Leifman A, Nylander M, Thiblin I. Methadone maintenance treatment: the balance between life-saving treatment and fatal poisonings. Addiction 2007; 102: 406-12. 17298648 10.1111/j.1360-0443.2006.01714.x

      Not checked in the free run.

    • cites [24] Degenhardt L, Randall D, Hall W, Law M, Butler T, Burns L. Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: risk factors and lives saved. Drug Alcohol Depend 2009; 105: 9-15. 19608355 10.1016/j.drugalcdep.2009.05.021

      Not checked in the free run.

    • cites [27] Davoli M, Bargagli AM, Perucci CA, Schifano P, Belleudi V, Hickman M, et al. Risk of fatal overdose during and after specialist drug treatment: the VEdeTTE study, a national multi-site prospective cohort study. Addiction 2007; 102: 1954-9. 18031430 10.1111/j.1360-0443.2007.02025.x

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Large scale observational studies are needed because the risk of death in the first four weeks of starting or stopping treatment is comparatively high, transient, and unlikely to be detected in any general practice or even specialist drug clinic or by any randomised controlled trial.

    “Large scale observational studies are needed because although the risk of death in the first four weeks of starting or stopping treatment is comparatively high, it is transient and unlikely to be detected in any general practice or even specialist drug clinic or by any randomised controlled trial.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    We adjusted for an index of comorbidity, but it was not an ideal measure and it was not specific to opiate users.

    “For example, we adjusted for an index of comorbidity, but it was not an ideal measure and it was not specific to opiate users.29”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Perkins AJ, Kroenke K, Unutzer J, Katon W, Williams JW, Hope C, et al. Common comorbidity scales were similar in their ability to predict health care costs and mortality. J Clin Epidemiol 2004; 57: 1040-8. 15528055 10.1016/j.jclinepi.2004.03.002

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The difference in mortality between opiate users in and out of treatment is stark and well known.

    “The difference in mortality between opiate users in and out of treatment is stark and well known, but fewer studies have investigated the risk of death at the start of or immediately after treatment.13 19 25 35”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev 2009; 3: CD002209. 19588333 10.1002/14651858.CD002209.pub2 PMC7097731

      Not checked in the free run.

    • cites [19] Fugelstad A, Stenbacka M, Leifman A, Nylander M, Thiblin I. Methadone maintenance treatment: the balance between life-saving treatment and fatal poisonings. Addiction 2007; 102: 406-12. 17298648 10.1111/j.1360-0443.2006.01714.x

      Not checked in the free run.

    • cites [25] Caplehorn JR, Drummer OH. Mortality associated with New South Wales methadone programs in 1994: lives lost and saved. Med J Aust 1999; 170: 104-9. 10065120 10.5694/j.1326-5377.1999.tb127675.x

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    McCowan and colleagues showed that overall survival was unrelated to recommended levels of methadone prescription.

    “In addition, McCowan and colleagues showed that overall survival was unrelated to recommended levels of methadone prescription.39”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] McCowan C, Kidd B, Fahey T. Factors associated with mortality in Scottish patients receiving methadone in primary care: retrospective cohort study. BMJ 2009; 338: b2225. 19535400 10.1136/bmj.b2225 PMC3273784

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some studies have shown a greater difference in the risk of overdose during and after treatment than for all cause mortality.

    “some studies have shown a greater difference in the risk of overdose during and after treatment than for all cause mortality, which we would not have detected.2 27”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Bargagli AM, Hickman M, Davoli M, Perucci CA, Schifano P, Buster M, et al. Drug-related mortality and its impact on adult mortality in eight European countries. Eur J Public Health 2006; 16: 198-202. 16157612 10.1093/eurpub/cki168

      Not checked in the free run.

    • cites [27] Davoli M, Bargagli AM, Perucci CA, Schifano P, Belleudi V, Hickman M, et al. Risk of fatal overdose during and after specialist drug treatment: the VEdeTTE study, a national multi-site prospective cohort study. Addiction 2007; 102: 1954-9. 18031430 10.1111/j.1360-0443.2007.02025.x

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Our study could not test mechanisms, so any inference in this regard must be cautious.

    “Our study could not test mechanisms, so any inference in this regard must be cautious.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Provision of opiate substitution treatment has substantially increased in the UK, but the total number of deaths due to overdose of opiates has remained stable and national targets to reduce their number have not been met.

    “Finally, provision of opiate substitution treatment has substantially increased in the UK,7 but the total number of deaths due to overdose of opiates has remained stable and national targets to reduce their number have not been met.6”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Morgan O, Griffiths C, Hickman M. Association between availability of heroin and methadone and fatal poisoning in England and Wales 1993-2004. Int J Epidemiol 2006; 35: 1579-85. 17077102 10.1093/ije/dyl207

      Not checked in the free run.

    • cites [6] Morgan O, Vicente J, Griffiths P, Hickman M. Trends in overdose deaths from drug misuse in Europe: what do the data tell us? Addiction 2008; 103: 699-700. 18412741 10.1111/j.1360-0443.2007.02102.x

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Induction on to opiate substitution treatment, especially with methadone, also poses risks in terms of overdose if the initial dose is too high or if patients continue to use non-prescribed opiates, and the change may be a cause of mental distress.

    “Induction on to opiate substitution treatment, especially with methadone, also poses risks in terms of overdose if the initial dose is too high or if patients continue to use non-prescribed opiates, and the change may be a cause of mental distress.24 26”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Degenhardt L, Randall D, Hall W, Law M, Butler T, Burns L. Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: risk factors and lives saved. Drug Alcohol Depend 2009; 105: 9-15. 19608355 10.1016/j.drugalcdep.2009.05.021

      Not checked in the free run.

    • cites [26] Department of Health and the devolved administrations. Drug misuse and dependence: UK guidelines on clinical management. Department of Health, 2007.

      Not checked in the free run.

38 of 38

  • The paper relies on this without support.

    The General Practice Research Database accurately and completely records prescriptions, diagnoses, and deaths for the study population.

    “The data for this study come from the General Practice Research Database (www.gprd.com), a large database of anonymised patients’ records from more than 460 general practices in the UK. It collects data from 3.5 million patients, equivalent to around 5.5% of the UK’s population.”

  • The paper relies on this without support.

    Patients in the General Practice Research Database with a diagnosis of substance misuse prescribed methadone or buprenorphine are representative of opiate users receiving opiate substitution treatment in UK primary care.

    “The study cohort consisted of patients who received at least one prescription for methadone or buprenorphine between 1 January 1990 and 31 December 2005 and who had a recorded diagnosis of substance misuse.”

  • The paper relies on this without support.

    Patients do not genuinely stop and restart opiate substitution treatment within a four-week period in general practice.

    “We chose this period because the prescription data within long term treatment episodes could be incomplete and we considered it unlikely that a patient would genuinely stop and restart treatment in general practice within a four week period.”

  • The paper relies on this without support.

    The model used to project the effect of average duration of opiate substitution treatment on mortality is correctly specified.

    “Opiate substitution treatment has a greater than 85% chance of reducing overall mortality among opiate users if the average duration approaches or exceeds 12 months.”

  • The paper relies on this without support.

    The adjusted mortality rate ratios are not substantially confounded by unmeasured factors.

    “We used Poisson regression to estimate mortality rate ratios comparing periods in and out of treatment, adjusted for potential confounders (sex, age group, calendar period, comorbidity score, treatment episode, and episodes with one opiate substitution treatment at or above recommended levels for maintenance).”

  • The authors state this as an assumption.

    The mortality of patients who transferred out of the database was the same as for those who remained in their practice, given adjustment for the characteristics that were recorded.

    “We assumed, therefore, that the mortality of patients who transferred was the same as for those who remained in their practice, given adjustment for the characteristics that were recorded.”

  • The paper relies on this without support.

    The General Practice Research Database provides a large, reasonably representative sample of patients taking opiate substitution treatment.

    “The General Practice Research Database covers approximately 5% of the population in general practice and provides a large, reasonably representative sample of patients taking opiate substitution treatment.”

  • The paper relies on this without support.

    Some patients who left treatment will have stopped their opiate use and therefore have been at substantially less risk of death than patients who relapsed.

    “In addition, some patients who left treatment will have stopped their opiate use (and therefore have been at substantially less risk of death than were patients who relapsed).”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Successful strategies to reduce opioid overdoses include wider implementation of rescue medications such as naloxone to reverse opioid overdose and enhanced access to drug treatment with medications such as buprenorphine.

    “Successful strategies to reduce opioid overdoses include wider implementation of rescue medications such as naloxone to reverse opioid overdose and enhanced access to drug treatment with medications such as buprenorphine (Albert et al., 2011; Centers for Disease Control and Prevention, 2012; Cornish et al., 2010).”

    From National trends in pharmaceutical opioid related overdose deaths compared to other substance related overdose deaths: 1999-2009. (2013) · cites this paper as Cornish et al., 2010

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • 2005-6 crude mortality rate ratio does not match the rates

    Minor

    The reported crude mortality rates give a ratio of 0.88/1.73 = 0.51 relative to 1990-4, not 0.56.

    Reported 0.56 · recomputed 0.508671

  • 1995-9 crude mortality rate ratio does not match the rates

    Minor

    The reported crude mortality rates give a ratio of 1.08/1.73 = 0.62 relative to 1990-4, not 0.70.

    Reported 0.7 · recomputed 0.624277

  • Maintenance-threshold percentage should be 25%

    Minor

    Of the 13,118 episodes with daily-dose data, 3,261 is 24.86%, which rounds to 25%, not 24%. Table 1 also reports 25%.

    Reported 24 · recomputed 24.858972

3 of 3

Cites

Flagged first, then by citations

1 of the 46 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Cornish, R., Macleod, J., Strang, J., Vickerman, P., & Hickman, M.
Affiliations
  • University of Bristol (GB)
  • King's College London (GB)
Corresponding author
Hickman, M.
ORCID
Venue
BMJ
Publisher
BMJ
Published
2010-10-26
Volume
341
Issue
oct26 2
Pages
c5475-c5475
ISSN
  • 0007-1447 (ISSN-L)
  • 0959-8138
  • 1468-5833
DOI
10.1136/bmj.c5475
PMC
PMC2965139
OpenAlex
W1965862609
Semantic Scholar
da7344e54fb53247f2067d1ebb4f412774ca22dc
Cited by
307
References
46
Citations by year
2026: 2 · 2025: 13 · 2024: 11 · 2023: 11 · 2022: 11 · 2021: 30 · 2020: 27 · 2019: 21 · 2018: 24 · 2017: 23 · 2016: 19 · 2015: 28 · 2014: 23 · 2013: 20 · 2012: 21
FWCI
19.97
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • BMJ (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • Explore Bristol Research (submittedVersion)
Funders
Economic and Social Research Council (ES/G007543/1)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
  • Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
  • Health Sciences › Medicine › Epidemiology › HIV, Drug Use, Sexual Risk
Keywords
opioid substitution therapy, mortality, methadone, buprenorphine, opioid use disorder, substance abuse, treatment duration, early mortality risk, sex differences in mortality, primary care, general practice
MeSH terms
Adolescent, Adult, Buprenorphine, Female, United Kingdom, Humans, Male, Methadone, Middle Aged, Opioid-Related Disorders, Narcotics, Prospective Studies, Risk Factors, Time Factors, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review