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Prescribed Dose of Opioids and Overdose: A Systematic Review and Meta-Analysis of Unintentional Prescription Opioid Overdose

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Abstract

Background

The rate of an unintentional drug overdose involving prescription opioids continues to rise. An understanding of the threshold dose and dose(s) associated with unintentional prescription opioid overdose will help to mitigate this epidemic.

Objective

The objective of this systematic review is to systematically synthesise and meta-analyse studies on doses of prescription opioids and ascertain the doses of opioids that are associated with increased risk of severe opioid poisoning or mortality.

Data Sources

A search of PubMed, EMBASE, CINAHL and Web of Science from inception to 16 January 2017 was conducted using search strategies and the MeSH (Medical Subject Headings) terms for studies of adult patients using prescription opioids who experienced an accidental overdose.

Study Selection

Of the 1332 studies identified, 117 were selected for full article review. Ten met the inclusion criteria for qualitative analysis, but only seven studies were meta-analysed. The included studies were in English, and participants met predetermined International Classification of Diseases (ICD) codes. Studies were excluded if they included only paediatric participants or the participants met the ICD code for intentional self-harm.

Data Extraction and Synthesis

Two researchers elaborated and validated a data extraction form. Data were then independently extracted by both reviewers as per this form. We assessed study quality using the Newcastle–Ottawa Scale (NOS) for non-randomised studies in meta-analyses. We performed a meta-regression using a random-effect model and summarised the results using relative risk (RR) and 95% confidence intervals (CIs). The threshold dose for an unintentional overdose is 20 morphine milligram equivalents (MME)/day. There were higher risks with larger doses: (1) ≤ 20 versus ≥ 21 MME/day: RR 2.81, 95% CI 1.09–7.22, p < 0.001; (2) ≤ 50 versus > 50 MME/day: RR 3.87, 95% CI 2.36–6.33, p < 0.001; (3) ≤ 100 versus > 100 MME/day: RR 4.28, 95% CI 2.61–7.1, p < 0.001; and (4) ≤ 50 versus > 50–100 MME/day: RR 3.09, 95% CI 1.84–5.18, p < 0.001). Heterogeneity was explained by the type of overdose event, inpatient or outpatient status, and length of observation. Type of pain (cancer or non-cancer pain) had no impact on heterogeneity.

Limitations

The definition of exposure in studies included in the meta-analysis was heterogeneous. Some studies defined exposure as the filling of a prescription while others defined exposure as the prescription of an opioid to the patient, and all studies assumed that patients took the prescribed opioid. Medications that may contribute to overdose, such as benzodiazepines and other drugs, were not considered.

Conclusions

A significantly increased risk of inadvertent prescription opioid overdose was found with 20–50 MME/day, with fatality more likely with opioid doses above 50 MME/day, although extensive heterogeneity was found with the dose comparisons. Clinicians should inform patients of this risk and monitor them closely.

Protocol Registration

This protocol was registered with PROSPERO 2017: CRD42017058426.

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References

  1. Kissin I. Long-term opioid treatment of chronic nonmalignant pain: unproven efficacy and neglected safety? J Pain Res. 2013;6:513–29.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Manchikanti L, Abdi S, Atluri S, Balog CC, Benyamin RM, Boswell MV, et al.; American Society of Interventional Pain Physicians. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part I—evidence assessment. Pain Physician. 2012;15(3 Suppl):S1–65.

  3. Volkow ND, Frieden TR, Hyde PS, Cha SS. Medication-assisted therapies—tackling the opioid-overdose epidemic. N Engl J Med. 2014;370(22):2063–6.

    Article  PubMed  Google Scholar 

  4. International Overdose Awareness Day. Overdose: worse than the road toll 2013. http://www.overdoseday.com/wp-content/uploads/Factsheet-Greater-than-the-Road-Toll-KE-FINAL-15-August-2013.pdf. Accessed 16 Feb 2017.

  5. Warner M, Chen LH, Makuc DM, Anderson RN, Minino AM. Drug poisoning deaths in the United States, 1980–2008. NCHS Data Brief. 2011;81:1–8.

    Google Scholar 

  6. Centers for Disease Control and Prevention. (CDC). Unintentional poisoning deaths—United States, 1999–2004. MMWR. 2007;56(5):93–6.

    Google Scholar 

  7. Hasegawa K, Brown DFM, Tsugawa Y, Camargo CA. Epidemiology of emergency department visits for opioid overdose: a population-based study. Mayo Clin Proc. 2014;89(4):462–71.

    Article  PubMed  Google Scholar 

  8. Fernandes K, Martins D, Juurlink D, Mamdani M, Paterson JM, Spooner L, et al. High-dose opioid prescribing and opioid-related hospitalization: a population-based study. PLoS One. 2016;11(12):e0167479.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Inocencio TJ, Carroll NV, Read EJ, Holdford DA. The economic burden of opioid-related poisoning in the United States. Pain Med. 2013;14(10):1534–47.

    Article  PubMed  Google Scholar 

  10. American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-5. Washington, DC: American Psychiatric Association; 2013.

    Book  Google Scholar 

  11. Dumas EO, Pollack GM. Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J. 2008;10(4):537–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Berecki-Gisolf J, Hassani-Mahmooei B, Clapperton A, McClure R. Prescription opioid dispensing and prescription opioid poisoning: population data from Victoria, Australia 2006 to 2013. Aust N Z J Public Health. 2017;41(1):85–91.

    Article  PubMed  Google Scholar 

  13. Dunn KM, Saunders KW, Rutter CM, Banta-Green CJ, Merrill JO, Sullivan MD, et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med. 2010;152(2):85–92.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zorzela L, Loke YK, Ioannidis JP, Golder S, Santaguida P, Altman DG, et al. PRISMA harms checklist: improving harms reporting in systematic reviews. BMJ. 2016;352:i157.

    Article  PubMed  Google Scholar 

  15. Herzig SJ, Rothberg MB, Cheung M, Ngo LH, Marcantonio ER. Opioid utilization and opioid-related adverse events in nonsurgical patients in US hospitals. J Hosp Med. 2014;9(2):73–81.

    Article  PubMed  Google Scholar 

  16. Paulozzi LJ, Kilbourne EM, Shah NG, Nolte KB, Desai HA, Landen MG, et al. A history of being prescribed controlled substances and risk of drug overdose death. Pain Med. 2012;13(1):87–95.

    Article  PubMed  Google Scholar 

  17. Ottawa Hospital Research Institute. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses 2014. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 14 Mar 2017.

  18. Bae J-M. A suggestion for quality assessment in systematic reviews of observational studies in nutritional epidemiology. Epidemiol Health. 2016;38:e2016014.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5.

    Article  PubMed  Google Scholar 

  20. Higgins JPT, Thompson SG. Controlling the risk of spurious findings from meta-regression. Stat Med. 2004;23(11):1663–82.

    Article  PubMed  Google Scholar 

  21. Gagnier JJ, Moher D, Boon H, Bombardier C, Beyene J. An empirical study using permutation-based resampling in meta-regression. Syst Rev. 2012;1(1):18.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Harbord RM, Higgins JPT. Meta-regression in Stata. Stata J. 2008;8(4):493–519.

    Google Scholar 

  23. Harbord RM, Harris RJ, Sterne JAC. Updated tests for small-study effects in meta-analyses. Stata J. 2009;9(2):197–210.

    Google Scholar 

  24. Dilokthornsakul P, Moore G, Campbell JD, Lodge R, Traugott C, Zerzan J, et al. Risk factors of prescription opioid overdose among Colorado Medicaid beneficiaries. J Pain. 2016;17(4):436–43.

    Article  PubMed  Google Scholar 

  25. Cochran G, Gordon AJ, Lo-Ciganic WH, Gellad WF, Frazier W, Lobo C, et al. An examination of claims-based predictors of overdose from a large Medicaid program. Med Care. 2017;55(3):291–8.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S. Cohort study of the impact of high-dose opioid analgesics on overdose mortality. Pain Med. 2016;17(1):85–98.

    PubMed  Google Scholar 

  27. Bohnert ASB, Valenstein M, Bair MJ, Ganoczy D, McCarthy JF, Ilgen MA, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305(13):1315–21.

    Article  CAS  PubMed  Google Scholar 

  28. Fulton-Kehoe D, Garg RK, Turner JA, Bauer AM, Sullivan MD, Wickizer TM, et al. Opioid poisonings and opioid adverse effects in workers in Washington State. Am J Ind Med. 2013;56(12):1452–62.

    Article  CAS  PubMed  Google Scholar 

  29. Fulton-Kehoe D, Sullivan MD, Turner JA, Garg RK, Bauer AM, Wickizer TM, et al. Opioid poisonings in Washington State Medicaid: trends, dosing, and guidelines. Med Care. 2015;53(8):679–85.

    Article  PubMed  Google Scholar 

  30. Larochelle MR, Liebschutz JM, Fang Z, Ross-Degnan D, Wharam JF, Zhang F. Opioid prescribing after nonfatal overdose and association with repeated overdose: a cohort study. Ann Intern Med. 2016;164(1):1–9.

    Article  PubMed  Google Scholar 

  31. Zedler B, Xie L, Wang L, Joyce A, Vick C, Kariburyo F, et al. Risk factors for serious prescription opioid-related toxicity or overdose among Veterans Health Administration patients. Pain Med. 2014;15(11):1911–29.

    Article  PubMed  Google Scholar 

  32. NCIS fact sheet. Opioids related deaths in Australia (2007–2011). Australia: National Coronial Information System; 2014. p. 1–20.

    Google Scholar 

  33. Australian Medicines Handbook. Morphine. In: Australian medicines handbook. Adelaide: Australian Medicines Handbook Pty Ltd; 2017. https://amhonline.amh.net.au/.

  34. MS Contin modified release tablets. In: MIMS Australia. St Leonards: MIMS Australia Pty Ltd; 2017. Available from: http://www.mims.com.au.

  35. Pattinson K. Opioids and the control of respiration. Br J Anaesth. 2008;100(6):747–58.

    Article  CAS  PubMed  Google Scholar 

  36. Iwabe T, Ozaki I, Hashizume A. The respiratory cycle modulates brain potentials, sympathetic activity, and subjective pain sensation induced by noxious stimulation. Neurosci Res. 2014;84:47–59.

    Article  PubMed  Google Scholar 

  37. Borgbjerg FM, Nielsen K, Franks J. Experimental pain stimulates respiration and attenuates morphine-induced respiratory depression: a controlled study in human volunteers. Pain. 1996;64(1):123.

    Article  CAS  PubMed  Google Scholar 

  38. Bourke DL. Respiratory effects of regional anesthesia during acute pain. Reg Anesth. 1993;18(6):361.

    CAS  PubMed  Google Scholar 

  39. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. JAMA. 2016;315(15):1624–45.

    Article  CAS  PubMed  Google Scholar 

  40. Cruccu G, Truini A. Tools for assessing neuropathic pain. PLoS Med. 2009;6(4):e1000045.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Sorg MH, Long DL, Abate MA, Kaplan JA, Kraner J, Greenwald MS, et al. Additive effects of cointoxicants in single-opioid induced deaths. Acad Forensic Pathol. 2016;6(3):532–42.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Garg KR, Fulton-Kehoe MD, Franklin MG. Patterns of opioid use and risk of opioid overdose death among medicaid patients. Med Care. 2017;55(7):661–8.

    Article  PubMed  Google Scholar 

  43. International classification of diseases. 10th rev. Geneva: WHO; 1992.

    Google Scholar 

  44. International classification of diseases. 9th rev. Geneva: WHO; 1977.

    Google Scholar 

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Acknowledgements

Special thanks to (a) Mr Glen Tapley, the Director of Pharmacy at the Maryborough Hospital for approving the time needed to complete this project and (b) Mr Olumuyiwa Omonaiye of Deakin University for assisting with part of the study selection.

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Authors and Affiliations

  1. Institute for Social Science Research, The University of Queensland, Indooroopilly, 4068, QLD, Australia

    Adeleke D. Adewumi, Joemer C. Maravilla & Rosa Alati

  2. Maryborough Hospital Pharmacy, Wide Bay Hospital and Health Service, 185 Walker Street, Maryborough, QLD, 4650, Australia

    Adeleke D. Adewumi

  3. School of Clinical Medicine, Rural Clinical School, The University of Queensland, Hervey Bay, 4655, QLD, Australia

    Adeleke D. Adewumi

  4. School of Pharmacy, The University of Queensland, 20 Cornwall St, Woolloongabba, QLD, 4102, Australia

    Samantha A. Hollingworth

  5. Centre for Youth Substance Abuse Research, The University of Queensland, St Lucia, 4067, QLD, Australia

    Jason P. Connor

  6. Discipline of Psychiatry, The University of Queensland, Herston, QLD, 4029, Australia

    Jason P. Connor

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  1. Adeleke D. Adewumi
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Correspondence to Adeleke D. Adewumi.

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Conflict of interest

Adeleke D. Adewumi was supported by the Australian Government’s Research Training Program (RTP) scholarship. The funder had no role in the design or conduct of this study, including the acquisition, analysis and interpretation of data, as well as in the preparation, review or approval of manuscript or in the decision to submit for publication. No other conflict of interest is declared by authors Samantha A. Hollingworth, Joemer C. Maravilla, Jason P. Connor and Rosa Alati.

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Adewumi, A.D., Hollingworth, S.A., Maravilla, J.C. et al. Prescribed Dose of Opioids and Overdose: A Systematic Review and Meta-Analysis of Unintentional Prescription Opioid Overdose. CNS Drugs 32, 101–116 (2018). https://doi.org/10.1007/s40263-018-0499-3

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