Risks, management, and monitoring of combination opioid, benzodiazepines, and/or alcohol use

Abstract

The concurrent use of opioids, benzodiazepines (BZDs), and/or alcohol poses a formidable challenge for clinicians who manage chronic pain. While the escalating use of opioid analgesics for the treatment of chronic pain and the concomitant rise in opioid-related abuse and misuse are widely recognized trends, the contribution of combination use of BZDs, alcohol, and/or other sedative agents to opioid-related morbidity and mortality is underappreciated, even when these agents are used appropriately. Patients with chronic pain who use opioid analgesics along with BZDs and/or alcohol are at higher risk for fatal/nonfatal overdose and have more aberrant behaviors. Few practice guidelines for BZD treatment are readily available, especially when they are combined clinically with opioid analgesics and other central nervous system-depressant agents. However, coadministration of these agents produces a defined increase in rates of adverse events, overdose, and death, warranting close monitoring and consideration when treating patients with pain. To improve patient outcomes, ongoing screening for aberrant behavior, monitoring of treatment compliance, documentation of medical necessity, and the adjustment of treatment to clinical changes are essential. In this article, we review the prevalence and pharmacologic consequences of BZDs and/or alcohol use among patients with pain on chronic opioid therapy, as well as the importance of urine drug testing, an indispensable tool for therapeutic drug monitoring, which helps to ensure the continued safety of patients. Regardless of risk or known aberrant drug-related behaviors, patients on chronic opioid therapy should periodically undergo urine drug testing to confirm adherence to the treatment plan.

Figure 1

Primary substance of abuse among treatment admissions reporting secondary benzodiazepine abuse: 2008. Benzodiazepines were reported as a drug of abuse by approximately 60 200 treatment admissions. The majority of patients indicated that they initiated benzodiazepine use after the abuse of another substance. The primary substance of abuse was opioids in the group aged 18 to 44 years, opioids as well as alcohol in the group aged ≥ 45 years, and marijuana in the group aged 12 to 17 years. Percentages may sum to < 100% because a small number of admissions did not report a primary substance of abuse.

Figure 2

Number of ED visits involving misused or abused drugs according to major substance of abuse: 2004–2011. The Drug Abuse Warning Network collects demographic and visit-level information on ED visits resulting from substance misuse or abuse, adverse reactions to drugs taken as prescribed, accidental ingestion of drugs, drug-related suicide attempt, and other drug-related medical emergencies. Only those data for visits involving misused or abused drugs are shown. Curves represent data obtained for the major substance of abuse; however, multiple drugs may be involved in each visit. Data from illicit drugs have been omitted. Alcohol combined with other drugs is recorded for all ages and alcohol only for patients aged ≤ 20 years. Abbreviation: ED, emergency department.

Figure 3

Diazepam coadministered with buprenorphine increases subjective drug effects and impairs cognitive performance. Diazepam (0 or 40 mg) was administered to patients maintained on buprenorphine therapy (n = 7) being treated with 100% of their normal buprenorphine dose (mean 11.1 ± 2.8 mg). A) Subjective drug effects were determined using visual analog scales of “strength of drug effect,” “sedation,” and “liking of drug effect” at 0, 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours after dosing. B) Functional impairment was determined by increases in visual reaction time, a measure of sensory-motor performance, and cancellation time, a measure of focused attention, as well as a decrease in coding skills using the DSST. Data are expressed as mean plus standard error of the mean. P values denote significant paired differences versus the diazepam 0 mg condition. Reprinted from Drug and Alcohol Dependence, Volume 91, Edition 2–3, Lintzeris N, Mitchell TB, Bond AJ, Nestor L, Strang J. Pharmacodynamics of diazepam co-administered with methadone or buprenorphine under high dose conditions in opioid dependent patients. Pages 187–194, Copyright 2007, with permission from Elsevier. Abbreviation: DSST, Digit Symbol Substitution Test.

Figure 4

In vitro dissolution of Avinza^® (Pfizer Inc; morphine sulfate extended-release capsules) increases in an alcohol concentration–dependent manner. Avinza^® (30 mg) was dissolved in 900 mL of buffer solutions containing ethanol (0%, 4%, 20%, and 40%). The dissolution without ethanol shows a controlled rate of release over a 24-hour period, which is similar to that of 4% ethanol. Dissolution of Avinza^® in 20% and 40% ethanol is accelerated, with 80% of drug released in < 1 hour.

Figure 5

Oxycodone combined with ethanol increases several abuse liability–related subjective effects. During separate sessions, 14 healthy volunteers received placebo capsule with placebo beverage, placebo capsule with ethanol 0.3 g/kg beverage, oxycodone 10 mg with placebo beverage, and oxycodone 10 mg with ethanol 0.3 g/kg beverage. The ethanol 0.3 g/kg dose is roughly equivalent to 1.5 standard-sized drinks. Oxycodone (or placebo) was administered 45 minutes before the ethanol (or placebo) drinking period so that both would peak at approximately the same time. Participants were asked to complete assessment forms 24 hours following each session. Data are expressed as mean plus standard error of the mean. P values represent significant differences from placebo. *P < 0.05.

Figure 6

Alcohol abuse/dependence correlates with long-term opioid analgesic use. Outpatient pharmacy and clinical databases from the New England Veterans Integrated Service Network between January 1, 1998 and June 30, 2001 were analyzed for duration, dose, and dose changes of oxycodone/acetaminophen prescriptions. Diagnosis of alcohol abuse/dependence was defined by the International Classification of Diseases, Ninth Revision, Clinical Modification and determined from the medical records.

Figure 7

Concurrent use of alcohol and/or sedatives among patients with chronic noncancer pain on long-term opioid therapy. Telephone surveys and electronic health care data of 1848 patients prescribed long-term opioid therapy for chronic noncancer pain were assessed. Concurrent alcohol use was based on self-report of ≥ 2 drinks within 2 hours before or after taking opiates within the past 2 weeks. Concurrent sedative use was defined as receiving sedatives for ≥ 45 days of the 90 days preceding interview according to pharmacy data.

Figure 8

Rates of concurrent alcohol and/or sedative use among patients with pain on chronic opioid therapy with and without an SUD. Telephone surveys and electronic health care data of 1848 patients prescribed long-term opioid therapy for chronic noncancer pain were assessed. Concurrent alcohol use was based on self-report of ≥ 2 drinks within 2 hours before or after taking opiates within the past 2 weeks. Concurrent sedative use was defined as receiving sedatives for ≥ 45 days of the 90 days preceding interview according to pharmacy data. Substance use disorders were classified by either a diagnosis of drug or alcohol abuse or dependence according to electronic data in the 3 years before the survey, patient self-report, or a score of ≥ 7 on the Alcohol Use Disorders Identification Test–Consumption. Abbreviation: SUD, substance abuse disorder.

Figure 9

Alcohol Use Disorders Identification Test–Consumption questions. A score of ≥ 4 for men or ≥ 3 for women is considered positive and optimal for identifying hazardous drinking or active alcohol use disorders.

Figure 10

UDT results among patients with chronic pain (N = 470). Urine drug testing was performed using gas chromatography/mass spectrometry technology. Abnormal UDT results were defined as the absence of a prescribed opioid, the presence of an additional nonprescribed controlled substance, the detection of an illicit substance, or an adulterated urine sample. Abbreviation: UDT, urine drug testing.

Figure 11

Benzodiazepine classes according to metabolism. A) The majority of BZDs are metabolized to oxazepam. B) Nitrobenzodiazepines and C) triazolobenzodiazepines are metabolized to their corresponding amino or hydroxyl compounds without being converted to oxazepam. D) Other BZDs have unique metabolic pathways. Abbreviation: BZD, benzodiazepines. Source: Data on file. Alere Toxicology, Waltham, MA.

Figure 12

Alcohol metabolism.

Figure 13

Flow chart for the Screening, Brief Intervention, and Referral to Treatment process.