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All-Cause and Drug-Related Medical Events Associated with Overuse of Gabapentin and/or Opioid Medications: A Retrospective Cohort Analysis of a Commercially Insured US Population

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A Letter to the Editor to this article was published on 03 May 2018

Abstract

Introduction

Overuse of gabapentin and/or opioids occurs in a small percentage of patients at > 3-fold labeled dosages. Gabapentin may potentiate opioid effects.

Objective

The aim was to assess patient harm, defined as use of inpatient hospital (IPH) or emergency department (ED) services, associated with overuse of gabapentin with or without concomitant overuse of opioids.

Data source

Data were sourced from the Truven Health MarketScan® Commercial Claims and Encounters database, for the years 2013–2015.

Eligibility criteria

The eligibility criteria were two or more claims (billed encounters) and ≥120 days of treatment with gabapentin and/or opioids.

Methods

Cohort identification was based on daily-dosage thresholds of 50 morphine-milligram equivalents and 3600 mg of gabapentin in a 12-month follow-up: (1) no overuse; (2) mild overuse (two or more claims or two or fewer calendar quarters over threshold); and (3) sustained overuse (three or more over-threshold calendar quarters). IPH and ED use were measured for 6 months after the first overuse date (cohorts 2 and 3) or a randomly assigned date (cohort 1). Logistic regression analyses controlled for pre-treatment IPH/ED utilization, indication, addiction diagnosis, concomitant sedative/hypnotic use, and demographics.

Results

All-cause and drug-related IPH/ED utilization increased monotonically with degree of overuse, particularly of more than one medication. Sustained overuse of gabapentin multiplied odds of all-cause IPH by 1.366 [95% confidence interval (CI) 1.055–1.769], drug-related IPH by 1.440 (95% CI 1.010–2.053), and IPH/ED for altered mental status (e.g., euphoria, anxiety) by 1.864 (95% CI 1.324–2.624). Sustained overuse of both medications quadrupled odds of all-cause IPH, drug-related IPH, and IPH/ED for altered mental status or respiratory depression.

Conclusion

Despite modest effects of gabapentin overuse alone, overuse of gabapentin with opioids may increase risk of harm and health-service utilization, supporting calls to make gabapentin a controlled substance in the USA.

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References

  1. Rudd RA, Aleshire N, Zibbell JE, Gladden RM. Increases in drug and opioid overdose deaths—United States, 2000–2014. MMWR Morb Mortal Wkly Rep. 2016;64(50):1378–82.

    Article  PubMed  Google Scholar 

  2. Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA. 2013;309(7):657–9. doi:10.1001/jama.2013.272.

    Article  CAS  PubMed  Google Scholar 

  3. Cai R, Crane E, Poneleit K. Emergency department visits involving nonmedical use of selected prescription drugs—United States, 2004–2008. MMWR Morb Mortal Wkly Rep. 2010;59(23):705–9.

    Google Scholar 

  4. Choo EK, Douriez C, Green T. Gender and prescription opioid misuse in the emergency department. Acad Emerg Med. 2014;21(12):1493–8. doi:10.1111/acem.12547.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sun EC, Dixit A, Humphreys K, Darnall BD, Baker LC, Mackey S. Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. BMJ. 2017;356:j760. doi:10.1136/bmj.j760.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Jones CM, McAninch JK. Emergency department visits and overdose deaths from combined use of opioids and benzodiazepines. Am J Prev Med. 2015;49(4):493–501. doi:10.1016/j.amepre.2015.03.040.

    Article  PubMed  Google Scholar 

  7. Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert ASB. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ. 2015;350:h2698. doi:10.1136/bmj.h2698.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Abrahamsson T, Berge J, Ojehagen A, Hakansson A. Benzodiazpine, z-drug and pregabalin prescriptions and mortality among patients in opioid maintenance treatment—a nation-wide register-based open cohort study. Drug Alcohol Depen. 2017;174:58–64. doi:10.1016/j.drugalcdep.2017.01.013.

    Article  CAS  Google Scholar 

  9. Peckham AM, Fairman KA, Sclar DA. Prevalence of gabapentin abuse: comparison with agents with known abuse potential in a commercially insured U.S. population. Clin Drug Investig. 2017;37(8):763–73. doi:10.1007/s40261-017-0530-3.

    Article  CAS  PubMed  Google Scholar 

  10. Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Addiction. 2016;111(7):1160–74. doi:10.1111/add.13324.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bastiaens L, Galus J, Mazur C. Abuse of gabapentin is associated with opioid addiction. Psychiatr Q. 2016;87(4):763–7. doi:10.1007/s11126-016-9421-7.

    Article  PubMed  Google Scholar 

  12. Hallas J. Drug utilization statistics for individual-level pharmacy dispensing data. Pharmacoepidemiol Drug Saf. 2005;14(7):455–63. doi:10.1002/pds.1063.

    Article  PubMed  Google Scholar 

  13. Gjerden P, Bramness JG, Slordal L. The use and potential abuse of anticholinergic antiparkinson drugs in Norway: a pharmacoepidemiological study. Br J Clin Pharmacol. 2008;67(2):228–33. doi:10.1111/j.1365-2125.2008.03342.x.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Birt J, Johnston J, Nelson D. Exploration of claims-based utilization measures for detecting potential nonmedical use of prescription drugs. J Manag Care Pharm. 2014;20(6):639–46. doi:10.18553/jmcp.2014.20.6.639.

    Google Scholar 

  15. Reeves RR, Ladner ME. Potentiation of the effect of buprenorphine/naloxone with gabapentin or quetiapine. Am J Psychiatry. 2014;171(6):691. doi:10.1176/appi.ajp.2014.13111526.

    Article  PubMed  Google Scholar 

  16. Shimoyama M, Shimoyama N, Inturrisi CE, Elliott KJ. Gabapentin enhances the antinociceptive effects of spinal morphine in the rat tail-flick test. Pain. 1997;72(3):375–82. doi:10.1016/S0304-3959(97)00065-1.

    Article  CAS  PubMed  Google Scholar 

  17. Eckhardt K, Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Gabapentin enhances the analgesic effect of morphine in health volunteers. Anesth Analg. 2000;91(1):185–91. doi:10.1213/00000539-200007000-00035.

    CAS  PubMed  Google Scholar 

  18. Matthews EA, Dickenson AH. A combination of gabapentin and morphine mediates enhanced inhibitory effects on dorsal horn neuronal responses in a rat model of neuropathy. Anesthesiology. 2002;96:633–40. doi:10.1097/00000542-200203000-00020.

    Article  CAS  PubMed  Google Scholar 

  19. Vallejo R, Barkin RL, Wang VC. Pharmacology of opioids in the treatment of chronic pain syndromes. Pain Physician. 2011;14:E343–60.

    PubMed  Google Scholar 

  20. Rose MA, Kam PCA. Gabapentin: pharmacology and its use in pain management. Anaesthesia. 2002;57(5):451–62. doi:10.1046/j.0003-2409.2001.02399.x.

    Article  CAS  PubMed  Google Scholar 

  21. Starner CI, Qiu Y, Karaca-Mandic P, Gleason PP. Association of a controlled substance scoring algorithm with health care costs and hospitalizations: a cohort study. J Manag Care Pharm. 2016;22(12):1403–10.

    Google Scholar 

  22. Finley EP, Garcia A, Rosen K, McGeary D, Pugh MJ, Potter JS. Evaluating the impact of prescription drug monitoring program implementation: a scoping review. BMC Health Serv Res. 2017;17:420.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Neurontin® [package insert]. New York: Pfizer, Inc.; 2015. http://labeling.pfizer.com/ShowLabeling.aspx?id=630. Accessed 5 May 2017.

  24. Volkow ND, McLellan AT. Opioid abuse in chronic pain—misconceptions and mitigation strategies. N Engl J Med. 2016;374:1253–63.

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Grattan A, Sullivan MD, Saunders KW, Campbell CI, Von Korff MR. Depression and prescription opioid misuse among chronic opioid therapy recipients with no history of substance abuse. Ann Fam Med. 2012;10(4):304–11.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Deyo RA, Smith DH, Johnson ES, et al. Prescription opioids for back pain and use of medications for erectile dysfunction. Spine. 2013;38(11):909–15.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Sun EC, Darnall BD, Baker LC, Mackey S. Incidence of a risk factors for chronic opioid use among opioid-naïve patients in the postoperative period. JAMA Intern Med. 2016;176(9):1286–93.

    Article  PubMed  Google Scholar 

  29. U.S. Centers for Disease Control and Prevention. Calculating total daily dose of opioids for safer dosage [Internet]. 15 Mar 2017 [cited 5 May 2017]. https://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-a.pdf. Accessed 5 May 2017.

  30. Modi A, Gold DT, Yang X, Fan CP, Sajjan SG. Association between gastrointestinal events and health care resource utilization among patients with osteoporosis: analysis of a US managed care population. J Manag Care Spec Pharm. 2015;21(9):811–21.

    Article  PubMed  Google Scholar 

  31. Dalal MR, Robinson SB, Sullivan SD. Real-world evaluation of the effects of counseling and education in diabetes management. Diabetes Spectr. 2014;27(4):235–43. doi:10.2337/diaspect.27.4.235.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ivanova JI, Hayes-Larson E, Sorg RA, Birnbaum HG, Berner T. Healthcare resource use and costs of privately insured patients who switch, discontinue, or persist on anti-muscarinic therapy for overactive bladder. J Med Econ. 2014;17(10):741–50. doi:10.3111/13696998.2014.941066.

    Article  PubMed  Google Scholar 

  33. Rice JB, Kirson NY, Shei A, Cummings AKG, Bodnar K, Birnbaum HG, et al. Estimating the costs of opioid abuse and dependence from an employer perspective: a retrospective analysis using administrative claims data. Appl Health Econ Health Policy. 2014;12:435–46. doi:10.1007/s40258-014-0102-0.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Norton JW. Gabapentin withdrawal syndrome. Clin Neuropharmacol. 2001;24(4):245–6. doi:10.1097/00002826-200107000-00011.

    Article  CAS  PubMed  Google Scholar 

  35. Pittenger C, Desan PH. Gabapentin abuse, and delirium tremens upon gabapentin withdrawal. J Clin Psychiatry. 2007;68:483–4. doi:10.4088/JCP.v68n0320a.

    Article  PubMed  Google Scholar 

  36. Victorri-Vigneau C, Guerlais M, Jolliet P. Abuse, dependency and withdrawal with gabapentin: a first case report. Pharmacopsychiatry. 2007;40(1):43–4. doi:10.1055/s-2006-958522.

    Article  CAS  PubMed  Google Scholar 

  37. Kruszewski SP, Paczynski RP, Kahn DA. Gabapentin-induced delirium and dependence. J Psychiatr Pract. 2009;15(4):314–9. doi:10.1097/01.pra.0000358318.73684.df.

    Article  PubMed  Google Scholar 

  38. Hellwig TR, Hammerquist R, Termaat J. Withdrawal symptoms after gabapentin discontinuation. Am J Health Syst Pharm. 2010;67(11):910–2. doi:10.2146/ajhp090313.

    Article  PubMed  Google Scholar 

  39. Rohman L, Hebron A. Acute dystonic reaction caused by gabapentin. J Emerg Med. 2013;46:e89. doi:10.1016/j.jemermed.2013.08.024.

    Article  PubMed  Google Scholar 

  40. See S, Hendricks E, Hsiung L. Akathisia induced by gabapentin withdrawal. Ann Pharmacother. 2011;45(6):e31. doi:10.1345/aph.1Q057.

    Article  PubMed  Google Scholar 

  41. Dahan A, Overdyk F, Smith T, Aarts L, Niesters M. Pharmacovigilance: a review of opioid-induced respiratory depression in chronic pain patients. Pain Physician. 2013;16(2):E85–94.

    PubMed  Google Scholar 

  42. Miller JE. The Chicago Guide to Writing about Numbers. Chicago: University of Chicago; 2004.

    Book  Google Scholar 

  43. Motheral BR, Fairman KA. The use of claims databases for outcomes research: rationale, challenges, and strategies. Clin Ther. 1997;19(2):347–66.

    Article  Google Scholar 

  44. IBM SPSS. Mantel-Haenszel test for trend available in crosstabs [Internet]. 2016 [cited 21 Jul 2017]. http://www-01.ibm.com/support/docview.wss?uid=swg21477269. Accessed July 21, 2017.

  45. Marshall BDL, Krieger MS, Yedinak JL, Banerjee P, Alexander-Scott NE, Rich JD, et al. Epidemiology of fentanyl-involved drug overdose deaths: a geospatial retrospective study in Rhode Island, USA. Int J Drug Policy. 2017. doi:10.1016/j.drugpo.2017.05.029 (Epub ahead of print).

    Google Scholar 

  46. Yoo YC, Na S, Jeong JJ, Choi EM, Moon BE, Lee JR. Dose-dependent attenuation by fentanyl on cough during emergence from general anesthesia. Acta Anaesthesiol Scand. 2011;55(10):1215–20.

    Article  CAS  PubMed  Google Scholar 

  47. Steenland K, Deddens JA. A practical guide to dose-response analyses and risk assessment in occupational epidemiology. Epidemiology. 2004;15(1):63–70.

    Article  PubMed  Google Scholar 

  48. Back SE, Payne R, Waldrop AE, Smith A, Reeves S, Brady KT. Prescription opioid aberrant behaviors: a pilot study of gender differences. Clin J Pain. 2009;25(6):477–84. doi:10.1097/AJP.0b013e31819c2c2f.

    Article  PubMed  PubMed Central  Google Scholar 

  49. World Health Organization. Information sheet on opioid overdose [Internet]. 2014 [cited 5 May 2017]. http://www.who.int/substance_abuse/information-sheet/en/. Accessed 5 May 2017.

  50. Leong C, Mamdani MM, Gomes T, Juurlink DN, Macdonald EM, Yogendran M. Antiepileptic use for epilepsy and nonepilepsy disorders. Neurology. 2016;86(10):939–46. doi:10.1212/WNL.0000000000002446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Plinke EJ, Persinger SC, Zinsmaster DS. Effective Dec 1, pharmacies, prescribers, and wholesalers must report gabapentin to Ohio Automated Rx Reporting System [Internet]. 2016 [cited 5 May 2017]. http://www.natlawreview.com/article/effective-dec-1-pharmacies-prescribers-and-wholesalers-must-report-gabapentin-to. Accessed 5 May 2017.

  52. Important Notice: Gabapentin becomes a Schedule 5 controlled substance in Kentucky [Internet]. 2017 [cited 5 May 2017]. http://www.chfs.ky.gov/NR/rdonlyres/92D10F1A-8842-4E6D-B9D2-935741E2926E/0/KentuckyGabapentinFactSheet.pdf. Accessed 5 May 2017.

  53. Fairman KA. Health Care Research Done Right. Denver: Outskirts Press; 2012.

    Google Scholar 

  54. Schifano F, D’Offizi S, Piccione M, Corazza O, Deluca P, Davey Z, et al. Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data. Psychother Psychosom. 2011;80(2):118–22. doi:10.1159/000321079.

    Article  PubMed  Google Scholar 

  55. Motheral B, Brooks J, Clark MA, et al. A checklist for retrospective database studies—report of the ISPOR task force on retrospective databases. Value Health. 2003;6:90–7.

    Article  PubMed  Google Scholar 

  56. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965 58:295–300. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1898525/pdf/procrsmed00196-0010.pdf.

  57. Cavalieri TA. Managing pain in geriatric patients. J Am Osteopath Assoc. 2007;107(4):ES10–6.

    Google Scholar 

  58. Vestal C. States gear up to help Medicaid enrollees beat addictions [Internet]. 2015 [cited 5 May 2017]. http://www.pewtrusts.org/en/research-and-analysis/blogs/stateline/2015/1/13/states-gear-up-to-help-medicaid-enrollees-beat-addictions. Accessed 5 May 2017.

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Acknowledgements

The authors gratefully acknowledge the analytic assistance provided by Jonah H. Rucker.

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Authors and Affiliations

  1. Department of Pharmacy Practice, Midwestern University College of Pharmacy-Glendale, 19555 N. 59th Avenue, Glendale, AZ, 85308, USA

    Alyssa M. Peckham, Kathleen A. Fairman & David A. Sclar

Authors
  1. Alyssa M. Peckham
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  2. Kathleen A. Fairman
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  3. David A. Sclar
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Contributions

All three authors contributed to study concept and design. KAF analyzed the data, and results were interpreted by all three authors. AMP and KAF drafted the manuscript, and all three authors reviewed and revised it critically for intellectual content, and approved the version to be published.

Corresponding author

Correspondence to Alyssa M. Peckham.

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Ethics approval

The Institutional Review Board (IRB) Committee of Midwestern University (Glendale, Arizona) found that this study fulfilled criteria for IRB Exemption per Code of Federal Regulations, Title 45, Part 46, Sect. 101 (45 CFR 46.101).

Funding

No sources of funding were used to assist in the preparation of this study.

Conflict of interest

The authors have no relationships (financial, employment, or other) relevant to the topic of this article. Alyssa M. Peckham, Kathleen A. Fairman, and David A. Sclar declare that they have no conflicts of interest.

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Peckham, A.M., Fairman, K.A. & Sclar, D.A. All-Cause and Drug-Related Medical Events Associated with Overuse of Gabapentin and/or Opioid Medications: A Retrospective Cohort Analysis of a Commercially Insured US Population. Drug Saf 41, 213–228 (2018). https://doi.org/10.1007/s40264-017-0595-1

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