Intended for healthcare professionals

Rapid response to:


Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis

BMJ 2017; 356 doi: (Published 14 March 2017) Cite this as: BMJ 2017;356:j760

Rapid Response:

Co-prescription of Opioids and Benzodiazepines

Prescription opioid over dose is one of the major preventable causes of emergency department (ED) visits in the United States (US). Over 250000 ED visits related to prescription opioid over doses were reported from 2006 to 2011 (1). The average annual expenses to take care of these patients is over $14000 (2). It costed approximately over $14 billion during the above 5-year period. Recent studies showed approximately 12 .5% of patients on opioids are also on prescribed BZD in the US (1, 3, 4). There appears to be a wide geographical variation in co-prescription of these medications. A study done in Norwegian population showed 60% opioid users also use BZD or related hypnotics (5).

Sun et al. impressively addressed one of the most concerning and top national public health issues by increasing awareness of combination of opioids and benzodiazepines (BZD). Notably, similar results were seen in a study done on the US veterans who are on opioids, where risk of over dose and death associated with benzodiazepines (BZD) was in dose response fashion (6).

In this study, the prevalence and incidence of overdose is possibly higher in chronic users compared to intermittent users. During the period of 2001 to 2010, more number (15.5%) of patients in chronic pain clinic are co-prescribed with BZD than in acute pain clinics (8.1%). Similarly, other sedative hypnotics co-prescription ranged from 32 to 36% (7). In an ED, 3% patients receiving opioid prescription are co-prescribed with BZD from 2006-2012, and the odds of co-prescription were increased significantly with subsequent ER visits (8). Thus, longer the exposure to these medications, the higher the risk of overdose. This warrants close monitoring of all patients on controlled substances.

There could be a variety of reasons why this combination can be at risk of over dose. Providers may co-prescribe BZD with opioids for its anxiolytic and skeletal muscle relaxant effects. It is also known to be used for insomnia, mania, depression etc. However, BZD may increase the euphoric effect of opioids leading to potential misuse and co-abuse with other medications. Also, cytochrome P450 plays a role in the metabolism of opioids and certain BZD, inhibitors of which can lead to decreased clearance of these drugs, predisposing patients to overdose (9, 10). Primary care patients receiving opioids who are on concurrent BZD are more likely to refill opioids earlier than those using cocaine (11). Further, BZD are associated with increased risk of suicidal attempt (12).

In addition to BZD, certain non-benzodiazepines are significantly associated with death when used with opioids. Alcoholism, non-BZD sedatives & hypnotics, and other central nervous system depressants may increase the risk of over dose in patients on opioids (9, 13). Depression, female sex and pain severity are the factors which are more associated with opioids and BZD co-prescription (14) which indicates the need for further studies to focus on such areas.

Half-life of opioids can range from few hours to 7 days, whereas half-life of BZD can range from <24 hours to 30 days, depending up on whether they are short or long acting, chronicity of their use and other comorbidities (9). The study was unable to single out a culprit medication, what more likely caused the overdose? Is the overdose more related to opioids or BZD or both? Selection of patients with the criteria of at least one day of overlap may be too short, may exaggerate or underestimate risk of over dose (real culprit) of one drug (opioid) over another (BZD) or vice versa. Similarly, study did not discuss other variables like onset and duration of overlap and time after which patients had an ER visit which may help to increase the specificity of the study.

The study was done in privately insured patients. The magnitude of the problem appears to be much more in Medicare and Medicaid population than privately insured patients. Since the introduction of Medicare Part D, Medicare appears to be the largest payer for opioid related drugs compared to other insurances including private payers. This is more prevalent for ages younger than 65 years (15). However, intentional opioid overdoses are found to be more common in privately insured patients, whereas unintentional overdoses in Medicare patients (1).

In the appropriate clinical context, using non-opioids as initial management strategy is one of the first steps in preventing opioid related adverse events. Center for Disease Control guidelines in 2016 on the use of opioids in chronic pain recommended against the use of concurrent BZD and opioids. Establishing treatment goals, starting with lowest effective dose, constantly reassessing benefits and risks are other important steps described to fight opioid epidemic (16).

Co-prescription of naloxone with opioids had 63% fewer ER visits in 1 year compared to those do were not prescribed (17). Collaboration of physicians with patients, family members and pharmacists may improve the adherence to naloxone and improve survival. In a study done in veteran population showed that the pharmacy consults helped to reduce co-prescription of opioids and BZD significantly (18, 19). Increased number of primary care providers appears to be favoring naloxone co-prescription with opioids and their opioid prescribing strategy has not changed with naloxone co-prescription (20). In addition to using non-opioid methods as one of the first steps in treating pain, using naloxone is a major step in preventing opioid over dose at the primary care level. In addition to patient’s acceptance, logistics, attitude of providers towards prescription and evidence gap are found to be major barriers for naloxone prescription (21, 22).

Recognizing high-risk patients and acting accordingly is another important strategy in preventing overdose. Improving physician-patient communication and patient education help to improve adherence to treatment strategies and appropriate use of medication by patients. Urine drug testing helps to determine treatment adherence and concurrent polysubstance abuse to determine high risk behaviors. Provider’s participation in prescription monitoring programs is critical to determine doctor shopping and concurrent use of other substances especially those under schedule II-IV (9, 23, 24). In addition to meticulous consideration of opioids-BZD co-prescription and increasing usability of naloxone, further research is needed for possible co-prescription of flumazenil for patients at risk of BZD over dose, like naloxone.

Gandam Venkata, Himabindu1
Chauhan, Gaurav1
Sandeep Ram, Bhuvaneswari1
Talari, Goutham2

1. Henry Ford Health System
2799 West Grand Blvd Detroit, MI 48202
Anesthesiology resident
Department of Anesthesiology
Henry Ford Health System
Detroit, Michigan, USA.

2. Assistant Professor of Medicine
Department of Internal Medicine
University of Kentucky College of Medicine,
Lexington, Kentucky, USA.

1. Tadros A, Layman SM, Davis SM, Davidov DM, Cimino S. Emergency Visits for Prescription Opioid Poisonings. The Journal of emergency medicine. 2015;49(6):871-7.
2. Kirson NY, Scarpati LM, Enloe CJ, Dincer AP, Birnbaum HG, Mayne TJ. The Economic Burden of Opioid Abuse: Updated Findings. Journal of managed care & specialty pharmacy. 2017;23(4):427-45.
3. 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 (Clinical research ed). 2017;356:j760.
4. Zin CS, Ismail F. Co-prescription of opioids with benzodiazepine and other co-medications among opioid users: differential in opioid doses. Journal of pain research. 2017;10:249-57.
5. Mellbye A, Svendsen K, Borchgrevink PC, Skurtveit S, Fredheim OM. Concomitant medication among persistent opioid users with chronic non-malignant pain. Acta Anaesthesiol Scand. 2012;56(10):1267-76.
6. Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ (Clinical research ed). 2015;350:h2698.
7. Larochelle MR, Zhang F, Ross-Degnan D, Wharam JF. Trends in opioid prescribing and co-prescribing of sedative hypnotics for acute and chronic musculoskeletal pain: 2001-2010. Pharmacoepidemiology and drug safety. 2015;24(8):885-92.
8. Kim HS, McCarthy DM, Mark Courtney D, Lank PM, Lambert BL. Benzodiazepine-opioid co-prescribing in a national probability sample of ED encounters. The American journal of emergency medicine. 2017;35(3):458-64.
9. Gudin JA, Mogali S, Jones JD, Comer SD. Risks, management, and monitoring of combination opioid, benzodiazepines, and/or alcohol use. Postgraduate medicine. 2013;125(4):115-30.
10. Jones JD, Mogali S, Comer SD. Polydrug abuse: a review of opioid and benzodiazepine combination use. Drug Alcohol Depend. 2012;125(1-2):8-18.
11. Park TW, Saitz R, Nelson KP, Xuan Z, Liebschutz JM, Lasser KE. The association between benzodiazepine prescription and aberrant drug-related behaviors in primary care patients receiving opioids for chronic pain. Substance abuse. 2016;37(4):516-20.
12. Dodds TJ. Prescribed Benzodiazepines and Suicide Risk: A Review of the Literature. The Primary Care Companion for CNS Disorders. 2017;19(2).
13. Abrahamsson T, Berge J, Ojehagen A, Hakansson A. Benzodiazepine, z-drug and pregabalin prescriptions and mortality among patients in opioid maintenance treatment-A nation-wide register-based open cohort study. Drug Alcohol Depend. 2017;174:58-64.
14. Cunningham JL, Craner JR, Evans MM, Hooten WM. Benzodiazepine use in patients with chronic pain in an interdisciplinary pain rehabilitation program. Journal of pain research. 2017;10:311-7.
15. Zhou C, Florence CS, Dowell D. Payments For Opioids Shifted Substantially To Public And Private Insurers While Consumer Spending Declined, 1999-2012. Health affairs (Project Hope). 2016;35(5):824-31.
16. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain--United States, 2016. Jama. 2016;315(15):1624-45.
17. Coffin PO, Behar E, Rowe C, Santos GM, Coffa D, Bald M, et al. Nonrandomized Intervention Study of Naloxone Coprescription for Primary Care Patients Receiving Long-Term Opioid Therapy for Pain. Annals of internal medicine. 2016;165(4):245-52.
18. Pardo D, Miller L, Chiulli D. Implementation of a pharmacy consult to reduce co-prescribing of opioids and benzodiazepines in a Veteran population. Substance abuse. 2017:1-4.
19. Wermeling DP. Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access. Therapeutic Advances in Drug Safety. 2015;6(1):20-31.
20. Behar E, Rowe C, Santos GM, Coffa D, Turner C, Santos NC, et al. Acceptability of Naloxone Co-Prescription Among Primary Care Providers Treating Patients on Long-Term Opioid Therapy for Pain. Journal of general internal medicine. 2017;32(3):291-5.
21. Binswanger IA, Koester S, Mueller SR, Gardner EM, Goddard K, Glanz JM. Overdose Education and Naloxone for Patients Prescribed Opioids in Primary Care: A Qualitative Study of Primary Care Staff. Journal of general internal medicine. 2015;30(12):1837-44.
22. Mueller SR, Koester S, Glanz JM, Gardner EM, Binswanger IA. Attitudes Toward Naloxone Prescribing in Clinical Settings: A Qualitative Study of Patients Prescribed High Dose Opioids for Chronic Non-Cancer Pain. Journal of general internal medicine. 2017;32(3):277-83.
23. Manchikanti L, Abdi S, Atluri S, Balog CC, Benyamin RM, Boswell MV, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2--guidance. Pain physician. 2012;15(3 Suppl):S67-116.
24. Sowa EM, Fellers JC, Raisinghani RS, Santa Cruz MR, Hidalgo PC, Lee MS, et al. Prevalence of Substance Misuse in New Patients in an Outpatient Psychiatry Clinic Using a Prescription Monitoring Program. The Primary Care Companion for CNS Disorders. 2014;16(1).

Competing interests: No competing interests

Competing interests: No competing interests

06 April 2017
Himabindu Gandam Venkata
Anesthesiology resident
Chauhan Gaurav (Henry Ford Health System), Bhuvaneswari Sandeep Ram (Henry Ford Health System), Goutham Talari (University of Kentucky)
Deparment of Anesthesiology, Henry Ford Health System.
2799 West Grand Blvd Detroit, MI 48202