Sedative, Hypnotic, Anxiolytic Use Disorders

Psychiatry has been given the role of investigating, understanding, and treating the effects of stress, including anxiety, dysphoria, and feelings of discomfort. In addition to conventional psychotherapy models, psychiatrists worked on pharmacological therapies and consequently sedatives, anxiolytics, and hypnotics were created. By the 19th century, bromide salts, chloral hydrate, and paraldehyde were used in medicine. Subsequently, barbiturates were first synthesized for medical use in 1903, followed by meprobamate in 1950. ^[1] By 1959, the benzodiazepine chlordiazepoxide was created, giving rise to at least 3000 different benzodiazepines, of which 13 are currently marketed. ^[2]  New benzodiazepines are currently being developed as well. ^[3]

The therapeutic value of these agents as anxiolytics and hypnotics has been well established, and they continue to serve an important role in managing many debilitating anxiety symptoms in the context of both psychiatric disorders and medical illness. However, the toxic effects of these drugs have also been established, including various withdrawal syndromes, dependence, and tolerance.

Per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), the appropriate diagnosis for a prolonged and problematic pattern of use of these substances would be “Sedative, Hypnotic, or Anxiolytic Use Disorder.”  For acute intoxication and withdrawal, the DSM-5-TR diagnoses would be “Sedative, Hypnotic, or Anxiolytic Intoxication” and “Sedative, Hypnotic, or Anxiolytic Withdrawal,” respectively. ^[4] There are additional specifiers based on the severity of symptoms, remission status, and the presence of perceptual disturbances as well.

Case report

Mr. X is a 27-year-old white male with a past psychiatric history of anxiety, insomnia, and substance abuse and no past medical history who presents in the emergency department with a friend for confusion and diaphoresis.

He was recently seen at a community clinic 1 week ago for a sinus infection and was given a 10-day course of antibiotics, but did not receive his alprazolam refill. He states he has taken his antibiotics as prescribed for the past 10 days, but that his heart has been racing and his insomnia has worsened; his friend states that for the past 4 days he has been having difficulty following conversations and focusing on daily tasks. He has been off his alprazolam for 7 days because he ran out of his prescription. He denied any recent psychosocial stressors and did not endorse feelings of guilt, helplessness, or hopelessness. Furthermore, he denied any fever, nausea, vomiting, diarrhea, myalgia, abdominal cramps, and seizures. He denied any recent alcohol/illicit drug use.

Upon physical examination, he was found to be tachycardic (pulse, 110 beats/min) and hypertensive (blood pressure, 170/90 mm Hg). His medical workup, including CBC count, electrolyte panel, liver function tests, blood glucose level, and urine toxicology screen, and his lumbar puncture were within normal limits.

His mental status examination revealed a casually dressed male who appeared to be restless and irritable. His speech was normal in rate and content. His mood was subjectively anxious and objectively dysphoric, and his affect was congruent with mood. His thought form was linear and goal directed. There was no evidence of paranoid ideations/delusions. He denied any auditory or visual hallucinations. He was oriented to time, place, and person. He scored 30/30 on the Mini-Mental State Examination. He had good insight and judgment. He endorsed passive suicidal ideations. He denied any homicidal ideations.

Mr X was diagnosed with anxiolytic withdrawal due to recent abrupt discontinuation of benzodiazepines. He did not have symptoms suggestive of worsening infection, and there were no apparent stressors/neurovegetative symptoms to explain recurrence of depressive episode.

Gamma-aminobutyric acid (GABA) is the key inhibitory neurotransmitter involved in anxiety and in the anxiolytic action of psychotropic drugs used to treat anxiety disorders. GABA opens chloride (Cl) channels, causing an influx of Cl ions. The influx of Cl ions causes hyperpolarization of the neuron, subsequently inhibiting neuronal discharge. The action of hyperpolarization is reversed by the influx of calcium into the cell. ^[6]

The 3 major types of GABA receptors include GABA-A, GABA-B and GABA-C receptors. The GABA (A) receptor subunit, composed of multiple forms (eg, alpha, beta, gamma) has been proposed as the functional unit on which benzodiazepines and barbiturates operate. GABA-A receptors can be further classified as benzodiazepine-sensitive and benzodiazepine-insensitive based on structural differences between these receptor subtypes. The GABA-A receptor is a protein, which forms a chloride-selective ion channel and ligands. The metabolized benzodiazepine binds this site and stabilizes 3 different conformations. Classic benzodiazepines exert a positive effect by increasing the affinity of channel opening.  ^[7]

Benzodiazepine-sensitive GABA receptors with alpha-1 subunits may be most important for regulating sleep and are the presumed targets of sedative-hypnotic agents. On the other hand, benzodiazepine-sensitive GABA-A receptors with alpha-2 subunits may be most important for regulating anxiety and are presumed targets of anxiolytic agents. Flumazenil, a benzodiazepine antagonist, interacts with GABA-A receptors and can be used clinically to rapidly reverse the effects of benzodiazepine overdoses. ^[6]

The long-term pharmacodynamic interaction of benzodiazepines with the GABA receptor is thought to be extremely complex. After long-term benzodiazepine use, the receptor effects caused by the agonist are attenuated. This down-regulation of receptor response is not due to decrease in receptor number or to decreased affinity of the receptor for GABA. The basis for down-regulation seems to be in the coupling between GABA-binding site and the activation of the chloride ion channel. ^[8]

These changes are potential mechanisms of tolerance, withdrawal, and dependence. The abrupt cessation of benzodiazepines, as in the case of a patient discontinuing a benzodiazepine after long-term use, is thought to result in the classically described acute withdrawal symptoms as the inhibitory effect of benzodiazepines is removed, thus leading to a relative excitatory state.  ^[9]

Frequency

Sedative-hypnotics are among the most commonly prescribed psychoactive drugs by primary care physicians. Approximately 4.6% of all Americans have used legally prescribed anxiolytics, sedatives, or hypnotics in the past 30 days. ^[10] According to the 2014 National Survey on Drug Use and Health, 2.5% of the US population aged 12 or older (ie, 6.5 million people) used psychotherapeutic drugs for nonmedical purposes; of them, 1.9 million used tranquilizers and 330,000 used sedatives. ^[11]

A 2010 analysis of data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), found that of the 34,653 respondents aged 18-80 years who completed interviews during waves of the research from 2001-2002 and 2004-2005, 11.8% of respondents had received prescriptions for anxiety medication; 16% of this subgroup reported lifetime nonmedical use and 4.6% reported abuse of or dependence on these drugs. ^{[12, 13]}  The age group with highest lifetime prevalence of sedative (3%) and tranquilizer (6%) nonmedical use was 26-34 years, while those aged 18-25 years were most likely to have used them in the prior year. ^[14]   

The nonmedical use of anxiety prescriptions continues to garner clinical attention because abuse by patients has been increasing.

According to one study, the early onset of nonmedical use of prescription drugs was a significant predictor of prescription drug abuse and dependence. A higher percentage of individuals who began using prescription drugs nonmedically at or before age 13 years were found to have developed prescription drug abuse and dependence versus those individuals who began using at or after age 21 years. ^[15]  Furthermore, nearly 10% of those with nonmedical use met criteria for abuse/dependence.

These are important considerations for clinicians, given that they can screen for potential abuse/dependence in patients who present with anxiety or panic symptoms and offer alternative treatments or referrals.

Race-, sex-, and age-related demographics

Among adults, 12-month prevalence is greatest among Native Americans and Alaska Natives (0.8%), with rates of approximately 0.2% among African Americans, whites, and Hispanics and 0.1% among Asian Americans and Pacific Islanders. ^[4]

Rates of sedative, hypnotic, or anxiolytic use disorder are slightly greater among adult males (0.3%) than among adult females (0.2%). ^[4]

Sedatives, anxiolytics, and hypnotics are commonly prescribed for people in the sixth and seventh decades of life; however, nonmedical use is highest in people aged 26-35 years and higher in men compared with women and non-Hispanic whites compared with African Americans or Hispanics. ^[15]

Some individuals respond to treatment and stay in remission, while others experience periods of relapse, in which they begin sedative-hypnotic-anxiolytic use/abuse after a period of remission, and again meet the criteria for substance dependence. Some individuals are never able to abstain from use and do not experience any periods of remission.

Only a handful of studies have investigated the long-term success of benzodiazepine discontinuation programs. Most studies indicate a high relapse state; however, outcome is more favorable in those individuals who manage to complete a discontinuation program. ^[31] A 4- to 6-year post discharge follow-up study of patients primarily admitted for primary sedative-hypnotic dependence showed that 84% of the patients had resumed using sedative-hypnotics, 52% were abusing drugs at follow-up, and 42% had been readmitted for drug abuse. ^[32]

A 10-year follow-up study analyzed the importance of the physician-patient relationship and examined whether a discontinuation letter from the provider was enough motivation to stop using the medication. After 10 years, researchers found that 58% of patients had discontinued benzodiazepine use and overall those who had not discontinued their use had decreased their dose of benzodiazepines. Those who had discontinued by 21 months of the intervention had a higher rate of being abstinent at a 10-year follow-up. ^[33]

There is some data regarding the success of varying outpatient tapering schedules. In one study, at 36 months, 39% of patients in a written step dose reduction program, 41% in a structured intervention with stepped-dose reduction and follow-up visit, and 26% in a control group discontinued benzodiazepine use. The groups showed no significant differences in anxiety, depression, or sleep dissatisfaction. The results of this study imply that patients are likely to be as successful discontinuing benzodiazepine use by self-tapering with written instructions from their physician as they are from being followed up more closely during the taper by their provider. ^[49]  

Outcome is better in individuals with good social support, absence of psychiatric co-morbidity or remission of preexisting psychiatric symptoms, and absence of dependence on other drugs. ^[34]

Sedative-hypnotic abuse/dependence can affect the entire family, it is necessary to inform them of the pertinent issues. In certain cases, family members can be enablers. Research shows that family-based treatments may be superior to other individual and group treatment approaches. ^[50]  The NIH has published a guide surrounding the different types of family-based therapies and research supporting their use. ^[51]

It is important for the prescribing physician to know about the harmful effects and complications related to sedative-hypnotic use. Sedative-hypnotics were once believed to be helpful to patients suffering from a variety of psychological disorders, such as PTSD, but more recent studies have shown that they can actually be harmful. ^[52]  Often, the patient will seek supply of these drugs from many practitioners. Physicians may also benefit from feedback on their prescribing practices.

While no foolproof techniques exist to prevent malpractice, there are ways to reduce exposure to litigation procedures. An estimated 7% of all malpractice claims against psychiatrists result from medication errors and drug-related reactions. The most common pitfalls are as follows. ^[5]

• Failure to prescribe the appropriate dosages of medication for patient's requirements
• Failure to monitor and treat medication adverse effects
• Negligent prescription practices
• Prescription of addictive drugs to vulnerable patients
• Failure to refer a patient for consultation or treatment by a specialist
• Failure to communicate with other medical professionals who are involved with the care of the patient

All physicians are judged by certain standards of care and guidelines. Their actions are compared to the standards expected of an average physician in their community under the circumstances.

When treating a patient with any medication, meeting certain expectations can minimize unnecessary litigation. Note the following:

• Succinctly record the patient's history, in particular a history of alcohol use and any history of other substance-related disorders and results of physical examination. If possible, support this information with laboratory tests. 
• Clearly instruct the patient about the use and potential side effects of medication. Obtain an informed consent from the patient, especially if the drug has unpleasant effects.
• Maintain relevant documentation, especially for changes in medication or instructions. Record the precise number of pills given for potentially abused substances, such as sedative-hypnotics or anxiolytics.
• If the physician is uncomfortable prescribing a particular medication or treating a condition requiring that medication, it is advisable to consult a colleague or research the drug and situation through recently updated reference textbooks or other media.
• After starting the patient on any sedative, it is advisable to monitor his or her reaction to the medication. 
• Remain aware of current guidelines, drugs recently approved by the Food and Drug Administration, current or recent literature (e.g., alternative treatment approaches that do not require these medications), and relevant updates by pharmaceutical companies (e.g., reports of surveillance of side effects of these medications). Ignorance is not an acceptable excuse in legal action.
• Be cautious about approving drugs over the telephone without seeing the patient, and always review the pertinent records.