Benzodiazepine (BZD) abuse has become a significant public health concern, leading to serious health consequences, especially when combined with other central nervous system depressants like opioids and alcohol. Emergency room visits and fatalities related to benzos have increased dramatically in recent years. While prescription drug abuse is gaining more attention, the specifics of benzodiazepine addiction remain under-recognized. For most people, benzodiazepines carry a low risk of addiction. However, certain individuals, particularly those with a history of substance use disorders, are at a higher risk. Education, prevention, and early identification are crucial steps in addressing and reducing benzodiazepine addiction.
What are Benzodiazepines?
Benzodiazepines were first introduced to the US market in 1960, with chlordiazepoxide being the first approved medication in this class for clinical use.1 They quickly became popular due to their perceived safer profile, especially regarding respiratory depression, compared to older drugs like barbiturates.1,2
About two decades later, scientists began to understand how benzodiazepines work.1 They enhance the effects of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, at the GABAA receptor. This action increases chloride ion flow in neurons, leading to a calming effect.3 While the mechanism was being discovered, clinicians started noticing cases of benzodiazepine abuse and dependence.1 The diagnostic criteria for sedative, hypnotic, or anxiolytic use disorder are detailed in Table 1.4
TABLE 1: Diagnostic criteria for sedative, hypnotic, or anxiolytic use disorder according to DSM-5.
Diagnostic and Statistical Manual of Mental Disorders, 5th edition, diagnostic criteria for sedative, hypnotic, or anxiolytic use disorderaTable showing DSM-5 diagnostic criteria for sedative, hypnotic, or anxiolytic use disorder.
Despite the long-standing awareness of addiction risks, understanding how to identify at-risk individuals and effectively treat benzodiazepine addiction remains a challenge. While prescription opioid abuse has been a major focus, benzodiazepines, despite safer alternatives, remain among the most commonly prescribed medications.5
How Common is Benzo Addiction?
In 2008, approximately 75 million benzodiazepine prescriptions were written in the United States.5 Between 4% and 5% of the general population uses benzodiazepines.5,6 Usage increases with age, and women are prescribed benzodiazepines twice as often as men.5,7 Individuals already taking opioids are significantly more likely to also receive a benzodiazepine prescription.7,8
Most people use benzodiazepines as prescribed. However, less than 2% escalate to high doses, and even fewer meet the stricter criteria for benzodiazepine abuse or dependence.9,10 For the general population, benzodiazepines have a relatively low potential for addiction.11 Certain groups are at a higher risk of benzodiazepine addiction, particularly those with a personal or family history of substance use disorders.12 Benzodiazepine abuse can manifest in two ways: deliberate recreational abuse to get high, and unintentional abuse that starts with legitimate use but evolves into misuse.13
Benzodiazepine misuse and addiction are growing concerns. An estimated 2.3% to 18% of Americans have misused sedatives or tranquilizers for nonmedical purposes at some point in their lives.14–16 Nearly 10% of these individuals met the criteria for abuse or dependence.14 In 2010, approximately 186,000 new benzodiazepine abusers emerged.17 Emergency departments have seen a significant 139% increase in benzodiazepine-related visits.18 Older age and the presence of other drugs are linked to more severe outcomes, including death.19 Admissions to treatment programs for benzodiazepine abuse nearly tripled from 1998 to 2008, while overall substance abuse treatment admissions increased by only 11% during the same period.20
Who is at Risk of Benzo Addiction? Risk Factors
Risk factors for benzodiazepine addiction and the demographics of this population differ in some notable ways from other substance abuse populations. Firstly, non-Hispanic white individuals are predominantly affected. The role of gender is less clear, as studies vary on the predominant gender in benzodiazepine abuse populations.15,16,20–22 Young adults between 18 and 35 years old constitute the largest group of benzodiazepine abusers.20,21 Benzodiazepine use, misuse, and addiction are strongly associated with co-occurring psychiatric disorders and a personal or family history of substance use disorders.12,15,23,24 Comorbid psychiatric disorders are more prevalent in benzodiazepine abusers compared to other substance abuse populations.20,21 Approximately 40% of benzodiazepine abusers report a co-existing psychiatric disorder, highlighting the importance for clinicians to address both the mental health condition and the benzodiazepine addiction.20 Individuals with a history of alcohol abuse or dependence and antisocial personality disorder appear to be at particularly high risk of benzodiazepine addiction compared to those without these conditions or those with alcohol abuse without antisocial personality disorder.22
The Danger of Polysubstance Abuse with Benzos
Benzodiazepine abuse most often occurs alongside the abuse of other substances. For most individuals, benzodiazepines are secondary drugs of abuse, with fewer reporting them as their primary drug of abuse.20 The most common primary drugs of abuse are opioids (54.2%) and alcohol (24.7%).21 Around 1 in 5 individuals abusing alcohol also abuse benzodiazepines.22,25 Benzodiazepines are used to amplify the euphoric effects of other drugs, reduce unwanted side effects like insomnia from stimulants, and ease withdrawal symptoms.2,26,27 People who abuse benzodiazepines in combination with other drugs typically consume much higher doses of benzodiazepines than those who abuse only benzodiazepines.28
In 2010, benzodiazepines were involved in 408,021 emergency department visits, accounting for one-third of all visits related to pharmaceutical misuse and abuse.18 Emergency department visits specifically due to nonmedical use of benzodiazepines combined with opioids increased significantly, from 11 per 100,000 in 2004 to 34.2 per 100,000 in 2011. Benzodiazepine involvement in opioid-related deaths also rose dramatically, from 18% in 2004 to 31% in 2011. Opioids and benzodiazepines are the two most frequent classes of prescription drugs involved in overdose deaths.29 Death rates from all prescription drugs have surged in recent years.30 Individuals prescribed both a benzodiazepine and an opioid had an almost 15 times greater risk of drug-related death compared to those not prescribed either drug.31 Treatment program admissions for combined opioid and benzodiazepine abuse have skyrocketed, increasing by 570% from 2000 to 2010.21
Opioids can cause significant respiratory depression, and this effect is amplified when combined with benzodiazepines or alcohol. The interaction between opioids and benzodiazepines is complex. Breathing requires activation of excitatory amino acid receptors, while inhibition is mediated through GABA receptors. Respiration is controlled in the brain’s medulla and is influenced by peripheral chemoreceptors that respond to changes in oxygen and carbon dioxide levels.32 Benzodiazepines, by increasing GABA activity, reduce respiratory motor amplitude and frequency. Benzodiazepines alone rarely cause death.2,12,33,34 They are relatively weak respiratory depressants on their own, but become potent when combined with opioids.32 Opioids act on μ opioid receptors, reducing sensitivity to oxygen and carbon dioxide changes and decreasing tidal volume and respiratory rate.3,32 Tolerance to opioid-induced respiratory depression develops slowly and incompletely compared to analgesic tolerance.32
Individuals undergoing opioid replacement therapy with methadone or buprenorphine are particularly vulnerable to benzodiazepine misuse and addiction.35–37 Reasons for this high rate of abuse in this population include high levels of psychological distress, recreational use, sleep problems, minimizing withdrawal symptoms, reducing negative effects of other substances like stimulant-induced insomnia, and a perception that benzodiazepines are not dangerous.35,36 The lifetime prevalence of benzodiazepine abuse was 66.3%, and current abuse was 50.8% among methadone maintenance patients.36 More than half of benzodiazepine users in methadone programs started using benzodiazepines after beginning methadone treatment.38 Benzodiazepine use with methadone is linked to a 60% increase in opioid-related deaths.39 A major advantage of buprenorphine over methadone is its ceiling effect, especially concerning respiratory depression. However, this ceiling effect is lost when buprenorphine is combined with benzodiazepines.40 Among buprenorphine-experienced individuals, 67% reported concurrent benzodiazepine use, with about a third obtaining benzodiazepines from multiple or illicit sources.37
Alcohol is involved in 1 in 4 emergency department visits related to benzodiazepine abuse and 1 in 5 benzodiazepine-related deaths.18 Both alcohol and benzodiazepines bind to distinct sites on the GABAA receptor, resulting in synergistic drug actions. Pharmacodynamic interactions, while not fully understood, lead to additive central nervous system depression, requiring lower concentrations to cause fatal outcomes.41 Benzodiazepine-related emergency department visits involving alcohol are highest in the 45 to 54 age group, but deaths are most frequent in those 60 and older.42 Despite alcohol’s significant role in various health problems, recent data indicate that only 1 in 6 adults in the United States has ever discussed alcohol use with a healthcare professional.43 Prescribers and pharmacists must educate patients about the risks of combining alcohol and benzodiazepines. Healthcare professionals should also intervene and offer referrals when problematic alcohol use is suspected or identified.
Understanding Benzo Abuse Liability
Systematic studies on the differences in abuse potential within the benzodiazepine class are lacking. Pharmacokinetic differences are thought to contribute to abuse liability. Lipophilicity, or fat solubility, affects the onset of action.44 Agents with higher lipophilicity and shorter half-lives appear to have greater abuse potential.11,13 The chemical properties of common benzodiazepines are compared in Table 2.44 Laboratory studies on subjective and reinforcing effects, medical professional experience, testimonies from drug abusers, and epidemiological studies suggest diazepam has the highest abuse liability.45 Diazepam, alprazolam, and lorazepam received the highest subjective ratings for the “high” they produce among known drug abusers, compared to oxazepam, clorazepate, and chlordiazepoxide, which seem to have lower abuse potential.2,11,45,46 Recreational drug users, when blinded, perceived diazepam as more desirable than equipotent doses of alprazolam and lorazepam.47 However, alprazolam and clonazepam are the benzodiazepines most frequently linked to abuse-related emergency department visits, with alprazolam involvement being more than double that of clonazepam.48 Alprazolam is the most prescribed benzodiazepine in the United States, with over 44 million prescriptions dispensed in 2009, nearly twice the number of clonazepam prescriptions, the second most prescribed benzodiazepine in the US. Ease of access may contribute to alprazolam’s abuse.49 While pharmacokinetics and drug user preferences play a significant role in abuse potential, prescribing patterns and drug availability are likely equally important factors.50
TABLE 2: Pharmacokinetic properties of common benzodiazepines.
What Can Healthcare Professionals Do About Benzo Addiction?
Prescription drug diversion sources are numerous, including both healthcare-related and non-healthcare-related avenues. The most commonly reported healthcare source of benzodiazepine diversion is a regular prescriber, followed by “script doctors” (providers who sell prescriptions), doctor shopping (patients obtaining multiple prescriptions from different providers), and pharmacy diversion (e.g., undercounting pills, employee theft).51 Recommendations for identifying high-risk individuals and reducing benzodiazepine addiction include: taking a thorough personal and family substance use history, conducting urine drug screens, frequent monitoring for abuse signs, reassessing the risks and benefits of ongoing therapy, prescribing limited quantities of as-needed doses to reduce physical dependence, and carefully differentiating between physical dependence and addiction.12
“Pharmacy shoppers,” defined as individuals receiving the same benzodiazepine prescription at two pharmacies within 7 days, have a 5.2 times greater risk of escalating to high benzodiazepine doses compared to other long-term benzodiazepine users.9 “Doctor shoppers,” or individuals visiting 4 or more clinicians in a 6-month period, are more likely to be female and have twice the risk of drug-related death compared to non-shoppers. Pharmacy shoppers, defined as filling controlled substance prescriptions at 4 or more pharmacies within 6 months, had a 3 times higher risk compared to non-shoppers.31,32 Prescription drug monitoring programs are valuable tools for identifying prescription drug abuse patterns.
Over 90% of unintentional pharmaceutical overdose fatalities show at least one indicator of substance abuse, such as a known history of substance abuse, drug diversion, nonmedical routes of administration, more than 5 prescribers of controlled substances, contributing alcohol or illicit drug use, previous overdose, and current opioid replacement therapy.33 Both prescribers and pharmacists must be aware of these risks, utilize prescription drug monitoring programs, accurately identify drug abusers, and take appropriate steps to mitigate risks. Further strategies to reduce abuse include limiting the dose, quantity, and refills on each prescription.52 Diversion is most common among young adults, who typically obtain drugs from peers or family members.8,33,52
Past efforts to restrict benzodiazepines, such as triplicate prescriptions implemented in New York in 1989, aimed to reduce prescribing. While these measures did reduce overall benzodiazepine prescribing, they also had unintended negative consequences. They disproportionately reduced prescribing for low-income and minority populations and inappropriately restricted access for legitimate medical use.53–56 Healthcare providers and lawmakers must be cautious when implementing laws and strategies to address prescription drug abuse to avoid hindering appropriate patient care.
Some clinicians argue that the medical community has overreacted to benzodiazepine addiction risks, potentially leading to underprescribing a safe and effective class of medications. They advocate for responsible, continued benzodiazepine prescribing.57 While benzodiazepines have abuse potential, especially in substance abuse populations, it is crucial to balance risks with benefits. Prescribers must also consider the risks of untreated conditions. Poorly managed or untreated anxiety or insomnia can increase the risk of alcohol relapse.58 Evidence-based pharmacotherapy and agents with lower abuse potential should be first-line treatments when appropriate. However, benzodiazepines may be indicated for some patients at higher risk of abuse. In such cases, thorough patient education on the risks of combining these drugs with alcohol or other substances, discussion of diversion risks, prescribing benzodiazepines with lower abuse potential, monitoring for adverse effects, and vigilance for inappropriate use are essential.
Conclusion: Addressing Benzo Addiction Effectively
Prescription drug abuse has reached epidemic proportions, and current efforts to reduce associated harm are not succeeding, with rates continuing to rise. Further research is needed to better understand the risk factors for benzodiazepine addiction. Despite the risks of abuse and diversion, benzodiazepines remain a safe and effective class of medications with a role in therapy. Lawmakers and healthcare professionals face the challenge of reducing abuse while ensuring access for patients who genuinely need them. Emphasis should be placed on reducing inappropriate prescribing rather than limiting all prescribing. Education is vital. Healthcare professionals must be knowledgeable about abuse patterns and diversion trends. It is crucial for prescribers and pharmacists to educate patients not only about personal risks but also the risks of medication sharing. Identifying benzodiazepine addiction risk factors before prescribing, utilizing safer alternatives when possible, and implementing appropriate interventions to address ongoing abuse are critical steps in battling this growing problem. Expanding substance abuse treatment programs and increasing funding for these programs will be essential in tackling this challenge in the future.
Footnotes
Disclosures: This material is based on work supported by resources and facilities at the Fargo Veterans Affairs Health Care System. The views expressed do not represent the Department of Veterans Affairs or the US government.
