Journal of Psychosocial Nursing and Mental Health Services

Psychopharmacology 

A Question About the Safety of Buprenorphine/Naloxone and Benzodiazepine Drugs

Robert H. Howland, MD

Abstract

Drug overdose is the leading cause of injury death in the United States, and most deaths are related to prescription drugs. A substantial proportion of these deaths involve opioid or benzodiazepine drugs, and many overdoses include a combination of both drug classes. Buprenorphine/naloxone has an unusual pharmacology that distinguishes it from other opioid drugs. Animal and human studies have found that buprenorphine is associated with a ceiling to its cardio-respiratory depressant effect at higher doses, such that it may have a wider safety margin compared to other opioid drugs. Compared to buprenorphine alone, buprenorphine/naloxone is associated with less cardiorespiratory depression. Drug safety data from the National Poison Data System, Drug Abuse Warning Network, and other sources suggest that the safety of buprenorphine/naloxone is favorable compared to the morbidity and mortality associated with other opioid drugs and other classes of psychotropic drugs. [Journal of Psychosocial Nursing and Mental Health Services, 53(12), 11–14.]

Abstract

Drug overdose is the leading cause of injury death in the United States, and most deaths are related to prescription drugs. A substantial proportion of these deaths involve opioid or benzodiazepine drugs, and many overdoses include a combination of both drug classes. Buprenorphine/naloxone has an unusual pharmacology that distinguishes it from other opioid drugs. Animal and human studies have found that buprenorphine is associated with a ceiling to its cardio-respiratory depressant effect at higher doses, such that it may have a wider safety margin compared to other opioid drugs. Compared to buprenorphine alone, buprenorphine/naloxone is associated with less cardiorespiratory depression. Drug safety data from the National Poison Data System, Drug Abuse Warning Network, and other sources suggest that the safety of buprenorphine/naloxone is favorable compared to the morbidity and mortality associated with other opioid drugs and other classes of psychotropic drugs. [Journal of Psychosocial Nursing and Mental Health Services, 53(12), 11–14.]

Exploring psychotherapeutic issues and agents in clinical practice

According to data from the Centers for Disease Control and Prevention (CDC; 2015), drug overdose was the leading cause of injury death in the United States in 2013. Among the 43,982 drug overdose deaths that year, 52% (22,767 deaths) were related to prescription drugs. Of these 22,767 deaths, 71% involved opioid drugs and 31% involved benzodiazepine drugs. Many of these overdoses included a combination of both drug classes. Apropos to this topic, I received the following e-mail message several months ago from a clinician I work with:

In reviewing charts today, I noticed that client S.E. is being prescribed Xanax by you and also received Suboxone from another provider. What made me curious about this is that in our D&A [drug and alcohol] program, our policy is to not prescribe any Benzo [benzodiazepine] medication with Suboxone due to the possibility of negative interactions and possible respiratory suppression. We often advise our clients that are being prescribed both of these to ask their doctor to look at other medication options. I know that you see her in MH [mental health] but I wanted to see what your thoughts or experience has been with this combination.

In this month's column, I describe my thoughts on this important clinical question by reviewing the safety of buprenorphine/naloxone (Suboxone®) alone and together with the benzodiazepine drug alprazolam (Xanax®).

How Does the Pharmacology of Buprenorphine/Naloxone Relate to its Safety?

Opioid drug effects are mediated by three major opioid receptor subtypes, referred to as Mu-opioid (MOP), Kappa-opioid (KOP), and Delta-opioid (DOP), although other receptor subtypes have been characterized.

Buprenorphine (Buprenex®; Subutex®), a synthetic opioid drug, is a partial agonist at MOP and KOP receptors and an antagonist at DOP receptors (Cowan, 2007). A partial agonist drug typically is only partly as effective as a full agonist, even at higher doses. The mixed agonist/antagonist receptor properties of buprenorphine may result in more of a blunting effect on euphoria compared to other opioid drugs, although abuse still occurs with buprenorphine and it is regulated as a Schedule III drug (Drug Enforcement Agency [DEA], 2013). Curiously, however, there does not appear to be a ceiling to buprenorphine's analgesic effect with higher doses, as might be expected for a partial agonist drug (Cowan, 2007).

Drugs that are MOP agonists are known to have cardiorespiratory depressant effects, which are particular safety concerns with overdoses of many opioid drugs. In contrast to the lack of an analgesic ceiling effect, the partial agonist receptor effects of buprenorphine have been associated with a ceiling to its cardiorespiratory depressant effect at higher doses (Cowan, 2007). As a result, buprenorphine may have a wider safety margin compared to other opioid drugs.

Naloxone (Narcan®) is an opioid receptor antagonist drug, with greatest binding to the MOP receptor, but also binding to KOP and DOP receptors. Naloxone is used to treat opioid drug intoxication or overdoses, as it rapidly reverses cardiorespiratory depression. Naloxone itself does not have analgesic or euphorigenic effects. Because naloxone is poorly absorbed orally, it is typically administered by injection, but is now available in an intranasal formulation.

Buprenorphine/naloxone is an oral combination product that contains a 4:1 ratio of buprenorphine to naloxone. Naloxone was incorporated into a combination product to diminish the abuse potential of buprenorphine, especially if the combination is injected. This ratio was chosen to optimize the safety of the combination without significantly affecting the intended therapeutic benefit of buprenorphine (Mendelson & Jones, 2003). Compared to buprenorphine alone, the combination buprenorphine/naloxone is associated with less euphoria or cardiorespiratory depression (Cowan, 2007). The 8 mg tablet of Suboxone contains 2 mg of naloxone, a dose that fully reverses the respiratory depressive effect of buprenorphine (van Dorp et al., 2006). Case reports have described the oral and intravenous use of buprenorphine/naloxone to reverse the effects of acute heroin overdose (Welsh, Sherman, & Tobin, 2008; Yokell, Zaller, Green, McKenzie, & Rich, 2012).

Drug Safety Data from the National Poison Data System (NPDS)

The NPDS is the data warehouse for the 57 regional poison control centers in the United States and American territories. According to U.S. data in 2013 from the NPDS, the top five substance categories most frequently involved in fatal and non-fatal human exposures were (a) analgesic drugs (including prescription and non-prescription opioid and non-opioid drugs), (b) cosmetics/personal care products, (c) household cleaning substances, (d) sedative/hypnotic/antipsychotic drugs, and (e) antidepressant drugs (Mowry, Spyker, Cantilena, McMillan, & Ford, 2014).

The 2013 NPDS database includes information on nonpharmaceutical and pharmaceutical exposures in approximately 2.2 million human cases. Many cases involved exposure to multiple substances. Buprenorphine or buprenorphine/naloxone was mentioned in 3,321 cases, of which 2,067 were single exposures to the product alone. Serious outcomes (defined as moderate or major adverse effects or death) occurred in 20% of single exposures to the buprenorphine product (415 cases). The only death was reported in a 5-year-old child who inadvertently ingested buprenorphine/naloxone. Methadone was mentioned in 3,777 cases, with serious outcomes in 35% of 1,504 single methadone exposure cases (including 22 deaths). For comparison, tramadol (Ultram®) was mentioned in 13,086 cases, with 6,534 single exposures and serious outcomes in 19% of single exposures (including four deaths). Benzodiazepine drugs as a group were mentioned in 74,935 cases, with serious outcomes reported in 13% of the 27,684 single drug exposures (including 19 deaths) (Mowry et al., 2014).

In the NPDS database, 2,113 human pharmaceutical and nonpharmaceutical exposures resulting in death were documented. For perspective in comparison to buprenorphine, I will highlight data on tramadol, methadone, and alprazolam, although the majority of fatal cases involved multiple substances. Among these 2,113 cases, alprazolam was mentioned in 190 cases, methadone in 162 cases, tramadol in 68 cases, buprenorphine/naloxone in seven cases, and buprenorphine in five cases. The first-ranked substance (judged to be most likely responsible for the death) was a pharmaceutical in 1,710 fatalities. These 1,710 first-ranked pharmaceuticals included 690 analgesic drugs, 414 stimulants/street drugs, 174 cardiovascular drugs, 133 antidepressant drugs, and 100 sedative/hypnotic/antipsychotic drugs. Of note, the first-ranked pharmaceuticals include methadone (109 cases), tramadol (23 cases), alprazolam (23 cases), buprenorphine (two cases), and buprenorphine/naloxone (two cases).

All but one of the 12 fatalities associated with buprenorphine or buprenorphine/naloxone involved multiple drugs: other drugs in six cases; alprazolam and other drugs in three cases; clonazepam (Klonopin®) and other drugs in one case; and alprazolam, clonazepam, and other drugs in one case.

Drug Abuse Warning Network (DAWN)

The DAWN program, part of the Substance Abuse and Mental Health Services Administration (2014), is a public health surveillance system reporting on drug-related visits to hospital emergency departments (EDs). It is used to monitor trends in drug misuse and abuse; identify the emergence of new substances and drug combinations; assess health hazards associated with drug use and abuse; and estimate the impact of drug use, misuse, and abuse on the health care system.

Data from the National Estimates of Drug-Related Emergency Department Visits for the years 2004–2011 are available to review on the DAWN website (access http://www.samhsa.gov/data/emergency-department-data-dawn). These data are reported for all ED visits, non-medical use of pharmaceuticals ED visits, and drug misuse and abuse ED visits. Data are calculated as ED visit rates per 100,000 population.

For 2011, the following ED visits rates were reported: buprenorphine/combinations (11.2); methadone (28.8); tramadol/combinations (17.5); opiate/opioid drugs (274.5); alprazolam (63.4); benzodiazepine drugs (173.6); antidepressant drugs (78.6); and anti-psychotic drugs (56.6).

The following drug misuse and abuse ED visits rates were reported: buprenorphine/combinations (8.2); methadone (24.3); tramadol/combinations (7.0); opiate/opioid drugs (178.6); alprazolam (49.4); benzodiazepine drugs (136.6); antidepressant drugs (34.8); and antipsychotic drugs (24.5).

The following non-medical use of pharmaceuticals ED visits rates were reported: buprenorphine/combinations (6.9); methadone (21.5); tramadol/combinations (6.4); opiate/opioid drugs (156.6); alprazolam (39.7); benzodiazepine drugs (114.8); antidepressant drugs (28.6); and antipsychotic drugs (19.9).

U.S. Food and Drug Administration (FDA) Data on the Safety of Buprenorphine

According to an analysis of data from the FDA conducted by the New York Times (Sontag, 2013), buprenorphine or buprenorphine/naloxone was suspected in 690 deaths (420 in the United States) reported to the FDA from Spring 2003 to September 2013. More than one half of these deaths involved other substances. Only two of 224 cases where route of administration was specified in these deaths involved injection of the drug. During this same period, 2,826 deaths from methadone were reported to the FDA.

Although the number of deaths attributable to buprenorphine is likely underreported, this may be true for methadone and other drugs as well. Methadone is associated with a disproportionately high death rate compared to other opioid drugs (CDC, 2012). Moreover, compared to methadone and five other opioid drugs, buprenorphine had the lowest death rate (CDC, 2012). Also, indirect comparison of data from population cross-sectional studies suggests that mortality with buprenorphine may be lower than that with methadone (Connock et al., 2007).

Conclusion

According to the DEA (2013), 9.3 million buprenorphine prescriptions were dispensed in the United States in 2012 and 2.5 million were dispensed in the first 3 months of 2013. Based on these prescription numbers and the 690 deaths reported to the FDA, the death rate for buprenorphine is not overly alarming, especially when one considers the morbidity and mortality associated with the use, misuse, and abuse of other opioid drugs as well as other classes of psychotropic drugs, as documented by the NPDS and DAWN data.

In an e-mail response to my colleague who questioned the use of Xanax and Suboxone, I provided a much abbreviated version of the information reviewed in this column. I ended my e-mail with the following comment: “As you know, I don't automatically or generally reach for my alprazolam script pad when seeing these types of patients, but every clinical situation is unique. There are general principles, but no hard and fast rules.” This patient was already taking alprazolam when she transferred care to our clinic. I chose to continue it based on my interpretation of her appropriate prescription use as well as my overall risk–benefit assessment of its safety together with buprenorphine/naloxone. The unusual pharmacology of buprenorphine/naloxone compared to other opioid drugs has important clinical implications for its safety that nurses should understand. Nurses should also be aware of publicly available information on drug safety in the real world, such as the NPDS and DAWN, as this can provide context for understanding the relative safety of many different drugs or drug classes.

References

  • Centers for Disease Control and Prevention. (2012). Vital signs: Risk for overdose from methadone used for pain relief—United States, 1999–2010. MMWR Morbidity and Mortality Weekly Report, 61, 493–497.
  • Centers for Disease Control and Prevention. (2015). Prescription drug overdose data. Retrieved from http://www.cdc.gov/drugoverdose/data/overdose.html
  • Connock, M., Juarez-Garcia, A., Jowett, S., Frew, E., Liu, Z., Taylor, R.J. & Taylor, R.S. (2007). Methadone and buprenorphine for the management of opioid dependence: A systematic review and economic evaluation. Health Technology Assessment, 11, 1–171. doi:10.3310/hta11090 [CrossRef]
  • Cowan, A. (2007). Buprenorphine: The basic pharmacology revisited. Journal of Addiction Medicine, 1, 68–72. doi:10.1097/ADM.0b013e31806c9202 [CrossRef]
  • Drug Enforcement Agency. (2013). Buprenorphine (Trade names: Buprenex®, Suboxone®, Subutex®). Retrieved from http://www.deadiversion.usdoj.gov/drug_chem_info/buprenorphine.pdf
  • Mendelson, J. & Jones, R.T. (2003). Clinical and pharmacological evaluation of buprenorphine and naloxone combinations: Why the 4:1 ratio for treatment?Drug and Alcohol Dependence, 70(2 Suppl.), S29–S37. doi:10.1016/S0376-8716(03)00057-7 [CrossRef]
  • Mowry, J.B., Spyker, D.A., Cantilena, L.R. Jr.. , McMillan, N. & Ford, M. (2014). 2013 annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 31st annual report. Clinical Toxicology (Philadelphia, PA), 52, 1032–1283. doi:10.3109/15563650.2014.987397 [CrossRef]
  • Sontag, D. (2013, November16). Addiction treatment with a dark side. Retrieved from http://www.nytimes.com/2013/11/17/health/in-demand-in-clinics-and-on-the-street-bupe-can-be-savior-or-menace.html
  • Substance Abuse and Mental Health Services Administration. (2014). Emergency department data/DAWN. Retrieved from http://www.samhsa.gov/data/emergency-department-data-dawn
  • van Dorp, E., Yassen, A., Sarton, E., Romberg, R., Olofsen, E., Teppema, L. & Dahan, A. (2006). Naloxone reversal of buprenorphine-induced respiratory depression. Anesthesiology, 105, 51–57. doi:10.1097/00000542-200607000-00012 [CrossRef]
  • Welsh, C., Sherman, S.G. & Tobin, K.E. (2008). A case of heroin overdose reversed by sublingually administered buprenorphine/nalox-one (Suboxone). Addiction, 103, 1226–1228. doi:10.1111/j.1360-0443.2008.02244.x [CrossRef]
  • Yokell, M.A., Zaller, N.D., Green, T.C., McKenzie, M. & Rich, J.D. (2012). Intravenous use of illicit buprenorphine/naloxone to reverse an acute heroin overdose. Journal of Opioid Management, 8, 63–66. doi:10.5055/jom.2012.0098 [CrossRef]
Authors

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

The author has disclosed no potential conflicts of interest, financial or otherwise.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O'Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.

10.3928/02793695-20151117-01

Sign up to receive

Journal E-contents