Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis
BMJ 2017; 356 doi: https://doi.org/10.1136/bmj.j760 (Published 14 March 2017) Cite this as: BMJ 2017;356:j760
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This very interesting paper is the epidemiological evidence of the respiratory depressant effect of opioids potentiated by associated benzodiazepines. But, it may be useful to look also for the pharmacodynamics of the drugs associated, to understand the rational (or its absence) of this drug association to treat pain, and also to understand the synergic mechanisms that lead to the respiratory depression, in order to avoid future predictable toxic associations.
Opioids are strong analgesics with the great risk of respiratory depression.
Benzodiazepines are GABAergic drugs that don’t have any analgesic activity, excluding the case of some muscular spasm (by its muscle relaxant activity), or the case of clonazepan on the trigeminal neuropathic pain. So it seems that there is no rational to justify the association of benzodiazepine with analgesics like opioids.
On the other side, this association increases the risk of respiratory depression of opioids, since benzodiazepines are also central nervous system depressors, and although their depressive effect is lower than that of barbiturates, they are may even depress the activity of the respiratory center when in overdose, and surely they potentiate the effect of other depressant agents such as opioids. Furthermore, by their relaxant effect on muscle tone may be dangerous on patients with obstructive sleep apnea.
All these reasons make very dangerous the association of these 2 kind of drugs, as it is emphasized by the recent guidelines (JAMA. 2016;315(15):1624-1645. doi:10.1001/jama.2016.1464 ).
Competing interests: No competing interests
This study is a nice addition to the literature of concurrent use of prescription opioids and benzodiazepines. In 2015, US Veterans Health Administration did a similar study and found that veterans receiving opioid analgesics and benzodiazepines were found to have an increased risk of death from drug overdose {1}. The patient population in this study is definitely more representative of United States. Employer based insurance comprises about half of US population {2}, but still only represents the working class. It leaves out the senior population with Medicare {3}. As the study did not include Medicaid patients, it leaves out children, pregnant women, seniors, individuals with disabilities and low-income families {4}.
In 1951, India pioneered National Family Welfare Program for the nation. The program now known as Reproductive Child Health-II program still uses “cafeteria choice” for the available range of contraceptive products {5}. One can very well understand the individualized treatment based philosophy behind it. It also works because it is a personal decision and most methods have minimal risks as compared to benefits. Victor Montori along with his colleagues have magnified and used this concept successfully as “Minimally Disruptive Medicine” for chronic medical illnesses {6, 7}. With the current evidence against concomitant use of opioids and benzodiazepines, one should aim for a discussion about benefit and harm in every case. Unfortunately, when the prescription trends ignore the black box warnings results could be disastrous. This is especially true for medications with drug-drug interactions, similar adverse effects and narrow therapeutic indices. The prescribing providers should not feel pressured by patient experience metrics. In a nationally representative sample, Fenton et al showed higher patient satisfaction was associated with higher prescription drug expenditures and increased mortality {8}.
Recent CDC guidelines for prescribing opioids for chronic pain also stress strongly on avoidance of concurrent use of prescription opioids and benzodiazepines {9}.
1. Park et al. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ 2015;350:h2698.
2. Kaiser Family Foundation. Health Insurance Coverage of the Total Population. http://kff.org/other/state-indicator/total-population/
3. Eligibility & Premium Calculator Home. U.S. Centers for Medicare & Medicaid Services. https://www.medicare.gov/eligibilitypremiumcalc/
4. Eligibility. U.S. Centers for Medicare & Medicaid Services. https://www.medicaid.gov/medicaid/eligibility/
5. Gupta et al. Determinants of Contraceptive Practices Among Eligible Couples of Urban Slum in Bankura District, West Bengal. J Family Med Prim Care. 2014 Oct-Dec; 3(4): 388–392.
6. Spencer-Bonilla et al. Minimally Disruptive Diabetes Care for the Elderly. Diabetes Technol Ther. 2016 Dec;18(12):759-761.
7. Gallacher et al. Understanding Patients’ Experiences of Treatment Burden in Chronic Heart Failure Using Normalization Process Theory. Ann Fam Med May 1, 2011 vol. 9 no. 3 235-243
8. Fenton et al. The Cost of Satisfaction A National Study of Patient Satisfaction, Health Care Utilization, Expenditures, and Mortality. Arch Intern Med. 2012;172(5):405-411.
9. Dowell et al. CDC Guideline for Prescribing Opioids for Chronic Pain— United States, 2016. JAMA. 2016;315(15):1624-1645.
Competing interests: No competing interests
Sun et al provide a helpful new finding on the increase in total and long term opioid prescribing in parts of the US, along with co-prescriptions of benzodiazepines and related increased risk of opiate overdose.
We suggest the assumptions about causation (which are not clear) underlying the calculations of how many overdoses could be reduced if practice were changed are too simple and are not justified.
Patient distress is likely to lead both to more benzodiazepine (and opioid) prescribing and directly to overdoses: A classic case of confounding. A clinical diagnosis of depression (among many other variables) was used to adjust the estimate, but because this was binary and the diagnosed prevalence of 17% is likely to be an underestimate for a population like this, much of the effect of mental distress is likely to remain unadjusted for.
So, if it is mental distress leading to both the benzodiazepine prescriptions and the overdoses, in at least some of the cases, eliminating benzodiazepine co-prescription with opioids is unlikely to reduce harm by the degree expected, or at all.
The clinical implications of this are that patients being prescribed opiates for whom distress is present or the co-prescription of psychotropic medications such as benzodiazepines is being considered, prescribers should think about underlying distress, definitive mental health problems, and risks. All problems identified should then be managed in accordance with the best evidence available.
Competing interests: No competing interests
It could be a life-threatening tragedy if the findings of a study involving many occasional, irregular and (in every sense) naïve US users of prescribed opiate analgesics were applied to patients in Methadone Maintenance Treatment (MMT) and other agonist maintenance programmes.
In the US and increasingly in other developed countries, opiates prescribed, wisely or not, for pain are being used increasingly as recreational drugs but in some important respects, these patients are very different from patients who have sought treatment for drug abuse and are established in MMT. The increased mortality of opiate users who abuse benzodiazepine (BDZ) drugs is well documented but the risk is largely determined by how they use their drugs rather than by straightforward drug interactions. When patients with little or no opiate tolerance take larger than normal amounts of their prescribed opiate, their risk of inadvertent death from opiate overdose is obviously increased and BDZs add to that risk. Their risk is also higher than for patients in MMT with relatively high tolerance, whose risk of inadvertent death from opiate overdose is thus greatly reduced.
Like poly-drug users in general, opiate users who seek licit or illicit BDZs are self-evidently a high-risk population because they tend to take more and bigger risks in many areas. They may take vast doses of BDZs and other drugs in a hedonistic and/or chaotic way and are more likely to inject drugs, share needles, have hepatitis C, abuse alcohol, and have unsafe sex [2]. They also have more frequent contact with the police [3] than opiate users who do not abuse BDZs.
When chaotic heroin users engage with MMT, they typically become less chaotic and use less heroin, or none. It is increasingly argued that similar improvements might (and do) follow BDZ maintenance and for similar reasons. We have recently published persuasive evidence that in this challenging group, BDZ maintenance with diazepam or clonazepam, incorporated into daily dispensed and supervised MMT, improves treatment retention and lowers rather than raises mortality [4]. More importantly, our findings strongly indicate that when patients appear to have responded favourably to BDZ maintenance, depriving them of it considerably increases mortality. It is likely to lead to more irresponsible use of BDZs that are now widely available via the internet without a prescription.
1. http://www.bmj.com/content/356/bmj.j760
2. Darke S, Swift W, Hall W, et al (1993) HIV risk-taking and psychosocial correlates of benzodiazepine use among methadone maintenance clients. Drug and Alcohol Dependence 34(1):67-70
3. Loxley W (2007) Benzodiazepine use and harms among police detainees in Australia. Trends Issues Crime Criminal Justice. Canberra, ACT Australian Institute of Criminology p336
4. http://journals.sagepub.com/doi/10.1177/0269881116675508
Competing interests: No competing interests
Rather than being entirely causal, there is likely an association with benzodiazepine use as a marker for those at higher risk of escalating dosage. Part of such a higher risk would likely be because of the anxiety-abating signal of the early peak opioid sensations. These likely operantly condition those suffering from anxiety, either constitutionally or as a result of difficult life circumstances and learned avoidance, to be the relief that they seek. Either an assurance that their physical pain will diminish allowing them to stop focussing or worrying about it or, simply because it is generally anxiety reducing and helps in escaping from the intolerable feelings associated with facing the realities of life.
As we know the actual sustained pain reducing effect when used regulalry is about 30%..... rather than getting high, most people who get into trouble are just trying to get by; and this whether it is more apparently about hopelessness or physical pain which also often becomes the substitute focus. We are in a "lost" time at the end of this indutsrialized age. The fabric which humans are adapted to is torn. This issue is but one more signal.
Competing interests: No competing interests
This is good to read a research article on "Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis" [1].
The harmful drug interaction of benzodiazepines and opioids is depressed respiration and increased sedation. This is related to additive actions of both the drugs, benzodiazepines slow down the central nervous system.
FDA is requiring boxed warnings on all opioid analgesic and benzodiazepine and also warn patients of the potential dangers of combined use of opioids and benzodiazepines [2,3].
Health care provider should not forget the "Pharmacology principles" in therapy, that play the role in patients care.
Regards,
Dr Rajiv Kumar
Faculty, Dept. of Pharmacology,
Government Medical College & Hospital Chandigarh-160030, India.
References:
1. BMJ 2017;356:j760
2. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm518697.htm
3. https://www.fda.gov/Drugs/DrugSafety/ucm518473.htm
Competing interests: No competing interests
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.
Authors:
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.
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Competing interests: No competing interests
Competing interests: No competing interests