Reconsidering Benzodiazepines and Z-Drug Prescriptions: Responsible Prescribing and Deprescribing

Published:September 03, 2020DOI:https://doi.org/10.1016/j.nurpra.2020.08.004

      Highlights

      • Long-term benzodiazepines and Z-drugs use is common but is not best practice.
      • Long-term use of hypnotics is not effective for the treatment of anxiety or insomnia.
      • Primary care providers prescribe most of the hypnotic drugs in the United States.
      • Primary care nurse practitioners can be leaders in education and initiation of deprescribing protocols.
      • Nurse practitioners can affect practice policies and interventions targeting responsible prescribing.

      Abstract

      Benzodiazepines and sedative-hypnotic (Z-drugs), collectively termed hypnotic drugs, bind to γ-aminobutyric acid receptors, the primary inhibitory neurotransmitters in the brain. Hypnotic drugs are among the most prescribed medications worldwide, with primary care providers leading this prescribing trend, primarily for the management of insomnia and anxiety. There is no evidence to support the use of long-term hypnotics, and evidence regarding the risks associated with long-term use of hypnotics is growing. However, it is not too late to reverse this hazardous prescribing trend and incorporate responsible hypnotic prescribing and describing practices

      Keywords

      American Association of Nurse Practitioners (AANP) members may receive 1.0 continuing education contact hours, including 1.0 hour of pharmacology credit, approved by AANP, by reading this article and completing the online posttest and evaluation at aanp.inreachce.com.
      In the shadows of our national opioid crisis lurks another troubling prescription drug epidemic. In the last 2 decades, concerns have escalated regarding short- and long-term risks associated with benzodiazepine (BZD) and sedative-hypnotic (Z-drug) use (collectively termed hypnotic drugs). Research indicates that primary care clinicians prescribe most of the hypnotic drugs; thus, it is critical that primary care nurse practitioners (NPs) understand the risks associated with these medications.
      • Agarwal S.D.
      • Landon B.E.
      Patterns in outpatient benzodiazepine prescribing in the United States.
      • Olfson M.
      • King M.
      • Schoenbaum M.
      Benzodiazepine use in the United States.
      • Kaufmann C.N.
      • Spira A.P.
      • Depp C.A.
      • Mojtabai R.
      Continuing versus new prescriptions for sedative-hypnotic medications: United States, 2005-2012.
      This review aims to increase the understanding of NPs working in primary care settings on the hazards of hypnotic drugs and therefore empowering them to affect policy surrounding safe prescribing of hypnotics and implement deprescribing guidelines in clinical practice. This review provides an overview of the history of hypnotics, their mechanisms of action, and the growing body of evidence demonstrating the potential harm these medications may cause. Finally, this review briefly discusses responsible prescribing and how to safely deprescribe these medications in a primary care setting.

      Mechanism of Action and History

      The BZD mechanism of action is on γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system.
      • Vargas R.A.
      The GABAergic system: an overview of physiology, physiopathology and therapeutics.
      GABA works alongside the excitatory neurotransmitter glutamate to achieve homeostasis of neuronal excitation within the brain. In embryos, GABAergic neurons develop within the white matter of the brain and play an excitatory role in the development of neuronal circuitry and synaptogenesis. In the mature brain, these GABAergic neurons migrate into the brain’s cortex and become heavily concentrated within the limbic system, cerebral cortex, hippocampus, basal ganglia, thalamus, hypothalamus, pituitary gland, and brain stem.
      GABA then shifts to an inhibitory role, balancing presynaptic and postsynaptic excitation throughout the many GABAergic circuits.
      • Vargas R.A.
      The GABAergic system: an overview of physiology, physiopathology and therapeutics.
      As an inhibitory neurotransmitter, GABA has a key role in regulating multiple systems, including neurogenesis, sleep-wake cycles, endocrine changes, and cognition. GABA is also implicated in multiple pathologies, including anxiety, depression, schizophrenia, addiction, sleep disorders, autoimmune diseases, and pain syndromes.
      • Vargas R.A.
      The GABAergic system: an overview of physiology, physiopathology and therapeutics.
      The 3 known GABA receptors in brain are GABAA, GABAB, and GABAC; however, in adults, GABA works primarily on the fast-acting postsynaptic ionotropic GABAA receptors.
      • Vargas R.A.
      The GABAergic system: an overview of physiology, physiopathology and therapeutics.
      Although there are numerous subunits of the GABAA receptor, BZDs act by binding nonselectively to the α-1, α-2, and α-3 GABAA receptors units.
      • Vargas R.A.
      The GABAergic system: an overview of physiology, physiopathology and therapeutics.
      ,
      • Sigel E.
      • Steinmann M.E.
      Structure, function, and modulation of GABAA receptors.
      BZDs are allosteric modulators; therefore, they increase the effect of GABA on the GABAA receptor, leading to antianxiety and sedative effects.
      • Vargas R.A.
      The GABAergic system: an overview of physiology, physiopathology and therapeutics.
      ,
      • Sigel E.
      • Steinmann M.E.
      Structure, function, and modulation of GABAA receptors.
      Z-drugs work on the same GABAA receptors as BZDs, resulting in their hypnotic effect; however, the Z-drugs are only selective for the α-1 GABAA subunit. This selectivity allows for the sedative-hypnotic effects but yields less anxiolytic or anticonvulsant action.
      • Vargas R.A.
      The GABAergic system: an overview of physiology, physiopathology and therapeutics.
      ,
      • Agravat A.
      ‘Z’-hypnotics versus benzodiazepines for the treatment of insomnia.
      BZDs were a welcome addition to the medication options in the 1950s.
      • Wick J.Y.
      The history of benzodiazepines.
      Chlordiazepoxide was marketed as a novel drug to replace barbiturates, which had become well known for problematic respiratory depression leading to accidental and suicidal overdose deaths. BZD prescriptions quickly grew in popularity, and throughout the 1970s, BZDs were consistently among the most frequently prescribed medications in the United States. It was not until the 1980s that prescribers began to recognize concerning trends of prescription abuse and dependence among patients. International concern over the potential harm of BZDs ignited the largest class action lawsuit in the United Kingdom, with claims that drug manufacturers intentionally misled prescribers by downplaying known adverse outcomes and risk of dependence among BZD users.
      • Wick J.Y.
      The history of benzodiazepines.
      Zolpidem, zaleplon, and eszopiclone, classified as sedative-hypnotics, were introduced in the 1990s and became known collectively as the Z-drugs. The relatively short half-lives of these medications were thought to make sedative-hypnotics ideal replacements for BZDs in the treatment of insomnia due to the assumed reduced potential for tolerance and dependence.
      • Kaufmann C.N.
      • Spira A.P.
      • Depp C.A.
      • Mojtabai R.
      Continuing versus new prescriptions for sedative-hypnotic medications: United States, 2005-2012.
      Unfortunately, recent research has revealed that Z-drugs are not a better alternative, because they have similar risk of respiratory depression, abuse potential, and significant withdrawal syndromes.
      • Agravat A.
      ‘Z’-hypnotics versus benzodiazepines for the treatment of insomnia.
      In addition, the Z-drugs became well known for their potential to cause parasomnias and dangerous sleep-related behaviors.
      • Agravat A.
      ‘Z’-hypnotics versus benzodiazepines for the treatment of insomnia.
      Table 1 provides for a list of US Food and Drug Administration-approved BZDs and Z-drugs and a comparison of the clinical pharmacokinetics and risk profiles.
      Table 1Pharmacokinetics, Adverse Effects, Contraindications, and Black Box Warnings for Benzodiazepines and Z-Drugs
      NameShort Acting
      Benzodiazepines. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed June 14, 2020. https://fco.factsandcomparisons.com
      Intermediate Acting
      Benzodiazepines. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed June 14, 2020. https://fco.factsandcomparisons.com
      Long Acting
      Benzodiazepines. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed June 14, 2020. https://fco.factsandcomparisons.com
      Daily Dose (mg)
      Benzodiazepines: Frequency will depend on indication of use. Z-drugs: Frequency is typically before bedtime.
      ,
      Benzodiazepines. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed June 14, 2020. https://fco.factsandcomparisons.com
      Half-life (in hours for parent drug)
      Benzodiazepines. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed June 14, 2020. https://fco.factsandcomparisons.com
      Sedatives and hypnotics, nonbarbiturate. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed: June 14, 2020. https://fco.factsandcomparisons.com. Accessed: June 14, 2020.
      Adverse Effects
      Only common adverse effects (>5% of users report).
      ContraindicationsBlack Box

      Warnings
      • Agarwal S.D.
      • Landon B.E.
      Patterns in outpatient benzodiazepine prescribing in the United States.
      Benzodiazepines
       AlprazolamX0.5-6IR: 6-27CNS

      Ataxia

      Confusion (IR)

      Depression

      Dizziness

      Drowsiness

      Dysarthria

      Fatigue

      Irritability (IR)

      Memory impairment

      Sedation

      Dermatologic

      Skin rash (IR)

      Endocrine

      Libido change

      Menstrual disease (IR)

      Weight gain/loss

      Gastrointestinal

      Constipation

      Decreased/increased appetite

      Nausea

      Sialorrhea

      Xerostomia
      Acute narrow-angle glaucoma

      Breast-feeding

      Coadministration with CYP3A4 inhibitors

      Hypersensitivity
      Concomitant use with opioids

      Results in sedation, respiratory depression, coma, and death
       Alprazolam extended release (ER)X0.5-6ER: 11-16
       ChlordiazepoxideX5-10024-48None reported

      >5%
      Hypersensitivity
       ClonazepamX0.5-417-60CNS

      Ataxia

      Depression

      Dizziness

      Drowsiness

      Fatigue

      Memory impairment

      Gastrointestinal

      Constipation

      Genitourinary

      Dysmenorrhea

      Respiratory

      Sinusitis

      Upper respiratory tract infection
      Acute narrow-angle glaucoma

      Breast-feeding

      Hypersensitivity

      Significant liver disease

      Use during pregnancy should be reported to North American Antiepileptic Drug (NAAED) Pregnancy Registry
       ClorazepateX15-60Not significantNone reportedAcute narrow-angle glaucoma

      Breast-feeding

      Hypersensitivity

      Use during pregnancy should be reported to North American Antiepileptic Drug (NAAED) Pregnancy Registry
       DiazepamX4-40IM: ~60-72

      IV: 33-45

      Oral: 44-48

      Rectal: 45-46
      None reported

      >5%
      Acute and untreated narrow-angle glaucoma

      Breast-feeding

      Hypersensitivity

      Infants < 6 months old

      Myasthenia gravis

      Severe respiratory impairment

      Significant liver disease

      Sleep apnea

      Severe respiratory impairment
       LorazepamX0.5-6

      0.5-4 (hypnotic)
      IM: ~13 to 18

      IV: ~14

      Oral: ~12
      CNS

      Dizziness

      Sedation
      Acute narrow-angle glaucoma

      Hypersensitivity

      Intraarterial use

      Sleep apnea (injection)

      Severe respiratory impairment (injection)
       OxazepamX30-120

      15-20 (hypnotic)
      ~8None reported

      >5%
      Hypersensitivity

      Treatment for psychoses
      NameShort Acting
      Sedatives and hypnotics, nonbarbiturate. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed: June 14, 2020. https://fco.factsandcomparisons.com. Accessed: June 14, 2020.
      Intermediate Acting
      Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165(2):125-139. https://doi.org/10.7326/M15-2175
      Long Acting
      Sedatives and hypnotics, nonbarbiturate. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed: June 14, 2020. https://fco.factsandcomparisons.com. Accessed: June 14, 2020.
      Daily Dose (mg)
      Benzodiazepines: Frequency will depend on indication of use. Z-drugs: Frequency is typically before bedtime.
      Half-life (hours)
      Sedatives and hypnotics, nonbarbiturate. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed: June 14, 2020. https://fco.factsandcomparisons.com. Accessed: June 14, 2020.
      Side Effects
      Only common adverse effects (>5% of users report).
      ContraindicationsBlack Box Warnings
      Z-drugs
       ZolpidemXIR and sublingual: Initial: 5

      Max: 10

      ER:

      Initial: 6.25

      Max: 12.5

      Sublingual (awakening with 4 hours sleep):

      Male: 3.5

      Female: 1.753
      IR, ER:

      ~ 2.5

      Spray: ~ 3

      Sublingual tablet: ~ 3
      Anxiety

      Dizziness

      Drowsiness

      Headache

      Nausea
      Zolpidem tartrate oral. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed June 23, 2020. https://fco.factsandcomparisons.com
      Complex sleeping disorders after taking medication

      Hypersensitivity
      Zolpidem tartrate oral. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed June 23, 2020. https://fco.factsandcomparisons.com
      Complex sleep disorders (sleep-walking, sleep-driving)
      • Kaufmann C.N.
      • Spira A.P.
      • Depp C.A.
      • Mojtabai R.
      Continuing versus new prescriptions for sedative-hypnotic medications: United States, 2005-2012.
       EszopicloneXInitial: 1

      Max: 34
      ~ 6Dysgeusia

      Dyspepsia

      Headache

      Infection

      Nausea

      Xerostomia
      Eszopiclone oral. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed June 23, 2020. https://fco.factsandcomparisons.com
      Complex sleeping disorders after taking medication

      Hypersensitivity
      Eszopiclone oral. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed June 23, 2020. https://fco.factsandcomparisons.com
      Complex sleep disorders (sleep-walking, sleep-driving)
      • Vargas R.A.
      The GABAergic system: an overview of physiology, physiopathology and therapeutics.
       ZaleplonXInitial: 5 and 10

      Max: 20
      Zaleplon oral. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed: June 23, 2020. https://fco.factsandcomparisons.com
      1Asthenia

      Headache

      Dizziness

      Drowsiness

      Nausea

      Abdominal pain
      Zaleplon oral. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed: June 23, 2020. https://fco.factsandcomparisons.com
      Complex sleeping disorders after taking medication

      Hypersensitivity
      Zaleplon oral. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed: June 23, 2020. https://fco.factsandcomparisons.com
      Complex sleep disorders (sleep-walking, sleep-driving)
      • Sigel E.
      • Steinmann M.E.
      Structure, function, and modulation of GABAA receptors.
      CNS = central nervous system; CYP3A4 = cytochrome P; IVIM = intramuscular; IR = immediate release; IV = intravenous.
      Table 1 References
      a Benzodiazepines: Frequency will depend on indication of use. Z-drugs: Frequency is typically before bedtime.
      b Only common adverse effects (>5% of users report).
      1. Benzodiazepines. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed June 14, 2020. https://fco.factsandcomparisons.com
      2. Sedatives and hypnotics, nonbarbiturate. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed: June 14, 2020. https://fco.factsandcomparisons.com. Accessed: June 14, 2020.
      3. Zolpidem tartrate oral. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed June 23, 2020. https://fco.factsandcomparisons.com
      4. Eszopiclone oral. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed June 23, 2020. https://fco.factsandcomparisons.com
      5. Zaleplon oral. In: Facts and Comparisons [database online]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2020. Accessed: June 23, 2020. https://fco.factsandcomparisons.com

      Prescribing Trends

      Despite evidence of harm from long-term use of both BZDs and Z-drugs and numerous guidelines recommending against this practice, prescription rates for all hypnotics continue to climb.
      • Agarwal S.D.
      • Landon B.E.
      Patterns in outpatient benzodiazepine prescribing in the United States.
      • Olfson M.
      • King M.
      • Schoenbaum M.
      Benzodiazepine use in the United States.
      • Kaufmann C.N.
      • Spira A.P.
      • Depp C.A.
      • Mojtabai R.
      Continuing versus new prescriptions for sedative-hypnotic medications: United States, 2005-2012.
      ,
      • Bachhuber M.A.
      • Hennessy S.
      • Cunningham C.O.
      • Starrels J.L.
      Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996-2013.
      • Maust D.T.
      • Lin L.A.
      • Blow F.C.
      Benzodiazepine use and misuse among adults in the United States.
      • Moore T.J.
      • Mattison D.R.
      Adult utilization of psychiatric drugs and differences by sex, age, and race.
      BZDs are among the most prescribed drugs internationally.
      • Olfson M.
      • King M.
      • Schoenbaum M.
      Benzodiazepine use in the United States.
      In 2019, BZDs were the second most frequently prescribed psychotropic drug next to antidepressants.
      • Olfson M.
      • King M.
      • Schoenbaum M.
      Benzodiazepine use in the United States.
      ,
      • Moore T.J.
      • Mattison D.R.
      Adult utilization of psychiatric drugs and differences by sex, age, and race.
      Between 2003 and 2015, BZDs were most commonly prescribed for anxiety and depression, with more than 30% of provider visits with these complaints resulting in BZD prescriptions.
      • Agarwal S.D.
      • Landon B.E.
      Patterns in outpatient benzodiazepine prescribing in the United States.
      BZDs were also commonly prescribed for chronic pain and insomnia, with 8.5% of visits for pain and 25.6% of visits for insomnia resulting in a BZD prescription in 2015.
      • Agarwal S.D.
      • Landon B.E.
      Patterns in outpatient benzodiazepine prescribing in the United States.
      Similar prescribing trends are seen with the Z-drugs, with the odds of a Z-drug prescription for insomnia increasing by 45% from 2005 to 2012.
      • Kaufmann C.N.
      • Spira A.P.
      • Depp C.A.
      • Mojtabai R.
      Continuing versus new prescriptions for sedative-hypnotic medications: United States, 2005-2012.
      From 1996 to 2013, the number of US adults filling a BZD prescription increased by 67%, translating into 13.5 million prescriptions in 2013. During this time, the average cumulative quantities prescribed per prescription rose by 140% and doses increased by 327%.
      • Bachhuber M.A.
      • Hennessy S.
      • Cunningham C.O.
      • Starrels J.L.
      Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996-2013.
      Predictive factors for BZD use include higher education levels, older age, and female sex, with women across all age groups being more than twice as likely to be prescribed a BZD compared with men.
      • Olfson M.
      • King M.
      • Schoenbaum M.
      Benzodiazepine use in the United States.
      ,
      • Maust D.T.
      • Lin L.A.
      • Blow F.C.
      Benzodiazepine use and misuse among adults in the United States.
      Continuation of long-term prescriptions accounts for much of the growth in prescription rates. Long-term prescriptions for BZDs and Z-drugs have increased in elderly populations, including those 81 years old and older. This is concerning, considering that BZDs and Z-drugs are included in the Beers Criteria, with strong recommendations to avoid all hypnotic drugs in the elderly.
      • Kaufmann C.N.
      • Spira A.P.
      • Depp C.A.
      • Mojtabai R.
      Continuing versus new prescriptions for sedative-hypnotic medications: United States, 2005-2012.
      ,
      American Geriatrics Society Beers Criteria Update Expert Panel
      American Geriatrics Society 2019 Updated AGS Beers Criteria for potentially inappropriate medication use in older adults.
      The rate of BZD-related overdose deaths increased by more than 700% from 1999 to 2016,
      • Agarwal S.D.
      • Landon B.E.
      Patterns in outpatient benzodiazepine prescribing in the United States.
      with older adults, African Americans, and Hispanics most at risk for fatal outcomes.
      • Agarwal S.D.
      • Landon B.E.
      Patterns in outpatient benzodiazepine prescribing in the United States.
      ,
      • Bachhuber M.A.
      • Hennessy S.
      • Cunningham C.O.
      • Starrels J.L.
      Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996-2013.
      Primary care providers (PCPs) write most of the BZD prescriptions.
      • Agarwal S.D.
      • Landon B.E.
      Patterns in outpatient benzodiazepine prescribing in the United States.
      ,
      • Olfson M.
      • King M.
      • Schoenbaum M.
      Benzodiazepine use in the United States.
      ,
      • Kaufmann C.N.
      • Spira A.P.
      • Depp C.A.
      • Mojtabai R.
      Continuing versus new prescriptions for sedative-hypnotic medications: United States, 2005-2012.
      The number of visits to any health care provider resulting in a BZD prescription nearly doubled from 2003 to 2015. BZD prescription rates by psychiatric prescribers did not increase, however, but rates among PCPs increased by 208% (3.6% to 7.5%).
      • Agarwal S.D.
      • Landon B.E.
      Patterns in outpatient benzodiazepine prescribing in the United States.
      Among adults who are prescribed long-term BZDs, more than 90% receive them exclusively from a PCP or a nonpsychiatric prescriber.
      • Olfson M.
      • King M.
      • Schoenbaum M.
      Benzodiazepine use in the United States.
      Z-drug prescribing trends from 1993 to 2010 are similar, with most prescriptions originating from PCPs and increases in Z-drug prescriptions rates only seen among nonpsychiatric presribers.
      • Kaufmann C.N.
      • Spira A.P.
      • Depp C.A.
      • Mojtabai R.
      Continuing versus new prescriptions for sedative-hypnotic medications: United States, 2005-2012.

      Risks

       Falls and Fracture

      The association of hypnotic drugs with overall fall risk (and subsequent risk for fractures) is clear, with likely mechanisms including sedation, increased reaction time, disrupted gait and balance, and impaired vision and cognition.
      • Bakken M.S.
      • Engeland A.
      • Engesӕter L.B.
      • Ranhoff A.H.
      • Hunskaar S.
      • Ruths S.
      Risk of hip fracture among older people using anxiolytic and hypnotic drugs: a nationwide prospective cohort study.
      ,
      • Xing D.
      • Ma X.L.
      • Ma J.X.
      • Wang J.
      • Yang Y.
      • Chen Y.
      Association between use of benzodiazepines and risk of fractures: a meta-analysis.
      A meta-analysis investigating BZDs use and hip fractures found that BZD use was associated with a 50% increased risk of falling.
      • Xing D.
      • Ma X.L.
      • Ma J.X.
      • Wang J.
      • Yang Y.
      • Chen Y.
      Association between use of benzodiazepines and risk of fractures: a meta-analysis.
      The highest fall risk was associated with higher doses of BZDs and use of short-acting BZD formulations.
      • Bakken M.S.
      • Engeland A.
      • Engesӕter L.B.
      • Ranhoff A.H.
      • Hunskaar S.
      • Ruths S.
      Risk of hip fracture among older people using anxiolytic and hypnotic drugs: a nationwide prospective cohort study.
      ,
      • Xing D.
      • Ma X.L.
      • Ma J.X.
      • Wang J.
      • Yang Y.
      • Chen Y.
      Association between use of benzodiazepines and risk of fractures: a meta-analysis.
      Use of Z-drugs demonstrates a similar fall risk; however, associated falls seem to be isolated to nighttime falls only.
      • Bakken M.S.
      • Engeland A.
      • Engesӕter L.B.
      • Ranhoff A.H.
      • Hunskaar S.
      • Ruths S.
      Risk of hip fracture among older people using anxiolytic and hypnotic drugs: a nationwide prospective cohort study.

       Dementia

      Hypnotic drugs may be associated with development of dementia; however, research investigating hypnotics and dementia involve nonrandomized cohort studies, which are inherently more vulnerable to bias.
      • He Q.
      • Chen X.
      • Wu T.
      • Li L.
      • Fei X.
      Risk of dementia in long-term benzodiazepine users: evidence from a meta-analysis of observational studies.
      • Lucchetta R.C.
      • da Mata B.P.M.
      • Mastroianni P.D.
      Association between development of dementia and use of benzodiazepines: a systematic review and meta-analysis.
      • Penninkilampi R.
      • Eslick G.D.
      A systematic review and meta-analysis of the risk of dementia associated with benzodiazepine use, after controlling for protopathic bias.
      Additionally, insomnia is a known precursor of dementia; therefore, it is difficult to determine whether the increased rates of dementia in users of hypnotic drugs results from use of these drugs or simply that individuals in the prodrome of dementia are more likely to be prescribed a hypnotic.
      • Chen P.-L.
      • Lee W.-J.
      • Sun W.-Z.
      • Oyang Y.-J.
      • Fuh J.-L.
      Risk of dementia in patients with insomnia and long-term use of hypnotics: a population-based retrospective cohort study.
      ,
      • Richardson K.
      • Mattishent K.
      • Loke Y.K.
      • et al.
      History of benzodiazepine prescriptions and risk of dementia.
      Recent rigorous meta-analyses offer compelling evidence that hypnotics may cause dementia, while controlling for confounding variables. Use of hypnotic drugs is associated with a higher risk of dementia, with similar risk of harm for both BZDs and Z-drugs.
      • Chen P.-L.
      • Lee W.-J.
      • Sun W.-Z.
      • Oyang Y.-J.
      • Fuh J.-L.
      Risk of dementia in patients with insomnia and long-term use of hypnotics: a population-based retrospective cohort study.
      BZD use was correlated with a 21% to 28% increased dementia risk, with the highest risk for patients taking long-acting BZDs and those using BZDs for longer periods of time.
      • He Q.
      • Chen X.
      • Wu T.
      • Li L.
      • Fei X.
      Risk of dementia in long-term benzodiazepine users: evidence from a meta-analysis of observational studies.
      ,
      • Lucchetta R.C.
      • da Mata B.P.M.
      • Mastroianni P.D.
      Association between development of dementia and use of benzodiazepines: a systematic review and meta-analysis.
      Although all classifications and doses of hypnotic drugs were associated with an increased risk for dementia, higher doses were associated with a 53% risk of developing dementia.
      • Chen P.-L.
      • Lee W.-J.
      • Sun W.-Z.
      • Oyang Y.-J.
      • Fuh J.-L.
      Risk of dementia in patients with insomnia and long-term use of hypnotics: a population-based retrospective cohort study.
      ,
      • Lee J.
      • Jung S.J.
      • Choi J-w
      • Shin A.
      • Lee Y.J.
      Use of sedative-hypnotics and the risk of Alzheimer’s dementia: a retrospective cohort study.

       Overall Mortality

      Hypnotic drug use has also been associated with an increased risk of death; however, the causal relationship between these medications and death remains controversial, with inconsistent results across a few studies.
      • Choi J.-W.
      • Lee J.
      • Jung S.J.
      • Shin A.
      • Lee Y.J.
      Use of sedative-hypnotics and mortality: a population-based retrospective cohort study.
      • Kripke D.F.
      • Langer R.D.
      • Kline L.E.
      Hypnotics’ association with mortality or cancer: a matched cohort study.
      • Weich S.
      • Pearce H.L.
      • Croft P.
      • et al.
      Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study.
      In a large US cohort study, Z-drug users had 4.6 times the hazard of all-cause mortality compared with controls.
      • Kripke D.F.
      • Langer R.D.
      • Kline L.E.
      Hypnotics’ association with mortality or cancer: a matched cohort study.
      This study demonstrated a dose-response gradient, but even patients who used the lowest number of Z-drugs (< 18 pills in a year) had more than 3 times the risk of dying compared with nonusers.
      • Kripke D.F.
      • Langer R.D.
      • Kline L.E.
      Hypnotics’ association with mortality or cancer: a matched cohort study.
      In a retrospective cohort study of primary care patients in the UK, the hazard of dying doubled among BZD or Z-drug users compared with matched controls.
      • Weich S.
      • Pearce H.L.
      • Croft P.
      • et al.
      Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study.
      Multiple mechanisms link increased mortality with hypnotic drugs. First, mortality risk is likely due to falls leading to hip fractures, which increase mortality in the elderly.
      • Choi J.-W.
      • Lee J.
      • Jung S.J.
      • Shin A.
      • Lee Y.J.
      Use of sedative-hypnotics and mortality: a population-based retrospective cohort study.
      In addition, high doses of hypnotic medications are associated with potentially lethal central nervous system (CNS) depression. This risk is heightened when combined with alcohol or other depressants such as opioids.
      • Kripke D.F.
      • Langer R.D.
      • Kline L.E.
      Hypnotics’ association with mortality or cancer: a matched cohort study.
      In 2013, BZDs were involved in 31% of prescription drug overdose deaths, and 75% of all opioid-related deaths involved a BZD.
      • Bachhuber M.A.
      • Hennessy S.
      • Cunningham C.O.
      • Starrels J.L.
      Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996-2013.
      Concurrent use of alcohol or other central CNS depressants should be considered an absolute contraindications for prescription of hypnotics due to increased respiratory suppression.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      All hypnotics display additive CNS depression with alcohol, but the Z-drug zolpidem has demonstrated synergistic effects with alcohol, antipsychotic drugs, and even small doses of antidepressants; therefore, the risks of death with zolpidem are even higher.
      • Choi J.-W.
      • Lee J.
      • Jung S.J.
      • Shin A.
      • Lee Y.J.
      Use of sedative-hypnotics and mortality: a population-based retrospective cohort study.
      Another mechanism of death is motor vehicle accidents, up to twice the risk for hypnotic users vs nonhypnotic users due to daytime somnolence from use the previous night.
      • Choi J.-W.
      • Lee J.
      • Jung S.J.
      • Shin A.
      • Lee Y.J.
      Use of sedative-hypnotics and mortality: a population-based retrospective cohort study.
      ,
      • Kripke D.F.
      • Langer R.D.
      • Kline L.E.
      Hypnotics’ association with mortality or cancer: a matched cohort study.
      Users of hypnotics are also at increased risk of suicide. Hypnotics are commonly used as a lethal agent in suicide deaths.
      • Kripke D.F.
      • Langer R.D.
      • Kline L.E.
      Hypnotics’ association with mortality or cancer: a matched cohort study.
      ,
      • McCall W.V.
      • Benca R.M.
      • Rosenquist P.B.
      • et al.
      Hypnotic medications and suicide: risk, mechanisms, mitigation, and the FDA.
      Even more alarming is evidence that hypnotic drugs can cause parasomnias, which can lead to suicide ideation and behaviors in individuals with no known previous suicide ideation.
      • McCall W.V.
      • Benca R.M.
      • Rosenquist P.B.
      • et al.
      Hypnotic medications and suicide: risk, mechanisms, mitigation, and the FDA.

      Responsible Prescribing of Hypnotic Drugs

      Unfortunately, there are no clinical guidelines targeted specifically to prescribing hypnotics. Instead, condition-specific guidelines must be reviewed individually for clinical decision support regarding BZD prescribing (Table 2). Although some variation exists in the literature, a prescription for a hypnotic drug is usually defined as long-term when use exceeds 2 to 4 weeks, although some research has extended this window up to 120 days of use.
      • Olfson M.
      • King M.
      • Schoenbaum M.
      Benzodiazepine use in the United States.
      ,
      • Dell’Osso B.
      • Albert U.
      • Atti A.R.
      • et al.
      Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.
      With few exceptions, responsible prescribing of hypnotics should be limited to 2 weeks of treatment or less.
      • Dell’Osso B.
      • Albert U.
      • Atti A.R.
      • et al.
      Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.
      Table 2Evidence-Based Algorithms for Deprescribing Hypnotics and Treatment Guidelines for Disorders for which Hypnotics are Commonly Prescribed
      DeprescribingInsomnia
      • America College of Physicians
        Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165(2):125-139. https://doi.org/10.7326/M15-2175
        : https://www.acpjournals.org/doi/pdf/10.7326/M15-2175
      • Veterans Affairs/Department of Defense
        Department of Veterans Affairs & Department of Defense. VA/DoD Clinical practice guideline for the management of chronic insomnia disorder and obstructive sleep apnea. Version 1.0, October 2019. Accessed May 18, 2020. https://www.healthquality.va.gov/guidelines/CD/ insomnia/VADoDSleepCPGFinal508.pdf
        : https://www.healthquality.va.gov/guidelines/ CD/ insomnia/VADoDSleepCPGFinal508.pdf
      Posttraumatic Stress Disorder (PTSD)
      • American Psychological Association
        American Psychological Association. Clinical Practice Guideline for the Treatment of Posttraumatic Stress Disorder (PTSD) in Adults. February 24, 2017. Accessed May 18, 2020. https://www.apa.org/ptsd-guideline/ptsd.pdf
        : https://www.apa.org/ptsd-guideline/ptsd.pdf
      • Generalized Anxiety Disorder (GAD)
      • GAD + Panic
        National Institute for Health and Care Excellence (Clinical Guideline CG113). Generalised anxiety disorder and panic disorder in adults: management. Updated July 26, 2019. Accessed May 18, 2020. https://www.nice.org.uk/guidance/CG113
        : https://www.nice.org.uk/guidance/cg113
      • Anxiety + PTSD + Obsessive Compulsive Disorder (OCD):
        Katzman MA, Bleau P, Blier P, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14(Suppl 1):S1. https://doi.org/10.1186/1471-244X-14-S1-S1
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120194/pdf/1471-244X-14-S1-S1.pdf
      Table 2.References
      1. Pottie K, Thompson W, Davies S, et al. Deprescribing benzodiazepine receptor agonists: evidence-based clinical practice guideline. Can Fam Physician. 2018;64(5):339-351.
      2. Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165(2):125-139. https://doi.org/10.7326/M15-2175
      3. Department of Veterans Affairs & Department of Defense. VA/DoD Clinical practice guideline for the management of chronic insomnia disorder and obstructive sleep apnea. Version 1.0, October 2019. Accessed May 18, 2020. https://www.healthquality.va.gov/guidelines/CD/ insomnia/VADoDSleepCPGFinal508.pdf
      4. American Psychological Association. Clinical Practice Guideline for the Treatment of Posttraumatic Stress Disorder (PTSD) in Adults. February 24, 2017. Accessed May 18, 2020. https://www.apa.org/ptsd-guideline/ptsd.pdf
      5. National Institute for Health and Care Excellence (Clinical Guideline CG113). Generalised anxiety disorder and panic disorder in adults: management. Updated July 26, 2019. Accessed May 18, 2020. https://www.nice.org.uk/guidance/CG113
      6. Katzman MA, Bleau P, Blier P, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14(Suppl 1):S1. https://doi.org/10.1186/1471-244X-14-S1-S1
      Short-term use of BZDs (< 2 weeks) is appropriate for several conditions, including catatonia, alcohol withdrawal, bipolar mania, status epilepticus, stabilization of acute behavioral agitation, and sedation before office or surgical procedures.
      • Dell’Osso B.
      • Albert U.
      • Atti A.R.
      • et al.
      Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.
      Unfortunately, in the primary care setting, hypnotic drugs are most frequently prescribed for the treatment of anxiety and insomnia, with more than half of these prescriptions for long-term BZD use. Yet, no research or clinical guidelines support long-term BZD use. When guidelines for the treatment of these conditions are reviewed, there is little support for the benefit of BZD or Z-drugs for these conditions and increasing concern that hypnotics may cause harm.
      • Dell’Osso B.
      • Albert U.
      • Atti A.R.
      • et al.
      Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.

       Sleep Disorders

      Sleep disorders are a common presentation in primary care settings, with an estimated 10% of the US population and 20% of older adults suffering from chronic insomnia. Treatment of insomnia and sleep-related disorders is the most common reason that PCPs prescribe BZDs.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      Quantifying just how many prescriptions for BZDs are designated for the treatment of insomnia is difficult, because BZDs are used nonselectively for many conditions. Best estimates are that approximately 25% of visits to a PCP with a complaint of insomnia end in a BZD prescription, with many of the prescriptions becoming long-term (> 120 days).
      • Agarwal S.D.
      • Landon B.E.
      Patterns in outpatient benzodiazepine prescribing in the United States.
      Treatment guidelines offer very specific recommendations for the responsible use of BZD and Z-drugs for insomnia. There is no clinical evidence to support the use of long-term BZD or Z-drugs for the treatment of insomnia and sleep-related disorders. Consequently, use of hypnotics should be limited to short-term use only.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      ,
      • Dell’Osso B.
      • Albert U.
      • Atti A.R.
      • et al.
      Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.
      Even more caution should be used when prescribing hypnotics for elderly patients who are more sensitive to the adverse effects of these medications.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      ,
      • Dell’Osso B.
      • Albert U.
      • Atti A.R.
      • et al.
      Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.
      Elderly patients who use hypnotic drugs are at an increased risk for fracture (odds ratio, 1.6), injury (odds ratio, 2.05), and cognitive impairments.
      • Treves N.
      • Perlman A.
      • Geron L.K.
      • Asaly A.
      • Matok I.
      Z-drugs and risk for falls and fractures in older adults—a systematic review and meta-analysis.
      If hypnotics are used in this vulnerable population, care should be taken to select a short-acting BZD, and dose reductions are recommended for patients older than 60 years.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      Short-term use of hypnotic drugs for insomnia typically yields positive results. Patients report faster sleep onset and fewer night awakenings.
      • Dell’Osso B.
      • Albert U.
      • Atti A.R.
      • et al.
      Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.
      However, once BZD or Z-drug use exceeds 2 to 4 weeks, benefits diminish. In fact, long-term use of BZDs or Z-drugs is associated with overall worsening of sleep quality, disruption of sleep patterns, and an increase in arousal throughout the night.
      • Dell’Osso B.
      • Albert U.
      • Atti A.R.
      • et al.
      Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.
      Tolerance to the sedative effects of all hypnotic drugs can develop within 1 to 2 weeks of use.
      • Dell’Osso B.
      • Albert U.
      • Atti A.R.
      • et al.
      Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.
      As noted earlier, Z-drugs were once seen as a better alternative to BZDs due to their receptor selectivity. However, Z-drugs are no more effective than BZDs in the long-term treatment of insomnia and have similar risk profiles and significant risk of withdrawal.
      • Agravat A.
      ‘Z’-hypnotics versus benzodiazepines for the treatment of insomnia.
      Clinicians are urged to use alternative interventions for the first-line treatment of insomnia. Underlying health conditions that may be causing insomnia, such as obstructive sleep apnea, anxiety disorders, substance abuse, and menopause, among others, should be considered, and care should be taken to address these first. First-line treatments should include reinforcing good sleep hygiene strategies, daily exercise, and cognitive behavioral strategies such as Cognitive Behavioral Therapy for Insomnia.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

       Anxiety Disorders

      Next to insomnia and sleep-related disorders, treatment of anxiety is the second most common reason that BZDs are prescribed in primary care settings.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      BZD prescriptions for the treatment of anxiety are often written for scheduled daily doses but can also be prescribed on an as-needed basis to target acute symptoms. In either instance, when these BZDs prescriptions are provided to patients for extended periods, patients are at risk of developing BZD dependence, withdrawal symptoms, and BZD misue.
      • Olfson M.
      • King M.
      • Schoenbaum M.
      Benzodiazepine use in the United States.
      ,
      • Maust D.T.
      • Lin L.A.
      • Blow F.C.
      Benzodiazepine use and misuse among adults in the United States.
      More than 75% of prescriptions for BZDs are for short-acting formulations
      • Olfson M.
      • King M.
      • Schoenbaum M.
      Benzodiazepine use in the United States.
      (Table 1), which are more likely to be misused or abused.
      • Maust D.T.
      • Lin L.A.
      • Blow F.C.
      Benzodiazepine use and misuse among adults in the United States.
      The most common reason individuals report BZD misuse is to self-manage anxiety symptoms. This occurs in the form of use without a prescription and using more often than prescribed.
      • Maust D.T.
      • Lin L.A.
      • Blow F.C.
      Benzodiazepine use and misuse among adults in the United States.
      Despite widespread long-term use of BZDs for the treatment of anxiety, there is no evidence to support this clinical practice.
      • Dell’Osso B.
      • Albert U.
      • Atti A.R.
      • et al.
      Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.
      As many as 75% of patients diagnosed with posttraumatic stress disorder (PTSD) will be prescribed long-term BZDs to treat associated symptoms.
      • Guina J.
      • Rossetter S.R.
      • DeRhodes B.J.
      • Nahhas R.W.
      • Welton R.S.
      Benzodiazepines for PTSD: a systematic review and meta-analysis.
      However, a 2015 meta-analysis examined the practice of BZDs in the treatment of PTSD and found that long-term use of BZD use was not only ineffective but was also associated with overall worsening of PTSD symptoms.
      • Guina J.
      • Rossetter S.R.
      • DeRhodes B.J.
      • Nahhas R.W.
      • Welton R.S.
      Benzodiazepines for PTSD: a systematic review and meta-analysis.
      Furthermore, these studies found that when BZDs were used after acute traumatic events, individuals were more likely to later develop PTSD than individuals who were not prescribed BZD.
      • Guina J.
      • Rossetter S.R.
      • DeRhodes B.J.
      • Nahhas R.W.
      • Welton R.S.
      Benzodiazepines for PTSD: a systematic review and meta-analysis.
      One-quarter of patients treated for obsessive compulsive disorder (OCD) are prescribed BZDs; however, research has failed to demonstrate any benefit of adjunctive BZD compared with placebo in the treatment of OCD.
      • Dell’Osso B.
      • Albert U.
      • Atti A.R.
      • et al.
      Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.
      Additionally, BZDs were not superior to selective serotonin reuptake inhibitors in onset of action or effectiveness in patients with OCD. For these reasons, use of BZDs in the treatment of OCD and PTSD should be considered contraindicated.
      • Dell’Osso B.
      • Albert U.
      • Atti A.R.
      • et al.
      Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.
      Clinical guidelines for the treatment of panic disorder, generalized anxiety disorder, and social anxiety disorder include BZDs as second- or third-line treatment options but recommend more appropriate alternatives, such as selective serotonin reuptake inhibitors and cognitive behavioral therapy for the long-term management of these chronic health conditions.
      • Dell’Osso B.
      • Albert U.
      • Atti A.R.
      • et al.
      Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.
      If a BZD is prescribed in the treatment of these conditions, use should be limited to 2 to 4 weeks or less.
      Despite guideline recommendations, BZDs are commonly prescribed off-label for the long-term management anxiety symptoms, particularly in the primary care setting. Anxiety disorders are often lifelong conditions requiring long-term psychopharmacologic management; therefore, prescribers must carefully consider the significant potential of drug dependence and overall BZD risks when considering these medications.
      • Dell’Osso B.
      • Albert U.
      • Atti A.R.
      • et al.
      Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.

      Deprescribing

      Clients who have been prescribed long-term hypnotics should be advised against continued use. The first step in deprescribing is to partner with the client, educate on the risks of continued use, and develop a careful timeline for tapering.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      Several studies have demonstrated that engaging clients in motivational interviewing before beginning the deprescribing process increases the rate of successful cessation.
      • Dou C.
      • Rebane J.
      • Bardal S.
      Interventions to improve benzodiazepine tapering success in the elderly: a systematic review.
      Referral for cognitive behavioral therapy to support clients during deprescribing is also recommended for improved outcomes.
      • Dou C.
      • Rebane J.
      • Bardal S.
      Interventions to improve benzodiazepine tapering success in the elderly: a systematic review.
      Finally, addressing the underlying reasons that the hypnotic drugs are being prescribed and taking steps to manage symptoms using safer alternatives is critical. It is beyond the scope of this review to comment on the best treatment options for every condition for which hypnotic drugs are used; thus, the use of current, valid clinical guidelines is recommended to guide these treatment decisions.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      ,
      • Pottie K.
      • Thompson W.
      • Davies S.
      • et al.
      Deprescribing benzodiazepine receptor agonists: evidence-based clinical practice guideline.
      The process of deprescribing hypnotic drugs in long-term users can be quite challenging but can be appropriately managed in the primary care setting for most individuals.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      ,
      National Institute of Health Care Excellence (NICE)
      Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia. Technology appraisal guidance [TA77].
      Patients who are appropriate for deprescribing in a primary care setting include those who are committed to the process, have strong support systems, and do not have a history of substance abuse or complicated withdrawal.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      For individuals who do not meet these criteria, or if difficulty arises during the deprescribing process, NPs in a primary care setting should consider expert psychiatric consultation.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      ,
      • Pottie K.
      • Thompson W.
      • Davies S.
      • et al.
      Deprescribing benzodiazepine receptor agonists: evidence-based clinical practice guideline.
      It is important for primary care NPs to recognize that hypnotic dependence can occur quickly and without any misuse by the patient. An estimated 30% to 50% of patients who have used BZDs long-term will be physically dependent on the medications, and providers can expect that 50% of all patients will experience withdrawal during the deprescribing period,
      • Dou C.
      • Rebane J.
      • Bardal S.
      Interventions to improve benzodiazepine tapering success in the elderly: a systematic review.
      ,
      National Institute of Health Care Excellence (NICE)
      Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia. Technology appraisal guidance [TA77].
      including hypersensitivity to environmental stimuli, extreme anxiety, rebound insomnia, psychosis, delirium, and seizures.
      • Hood S.D.
      • Norman A.
      • Hince D.A.
      • Melichar J.K.
      • Hulse G.K.
      Benzodiazepine dependence and its treatment with low dose flumazenil.
      Overall, clients tend to report fewer withdrawal symptoms from Z-drugs, with the most common complaint being rebound insomnia.
      • Dou C.
      • Rebane J.
      • Bardal S.
      Interventions to improve benzodiazepine tapering success in the elderly: a systematic review.
      Unfortunately, many clients who have used hypnotics to manage insomnia will mistake rebound insomnia for evidence that the hypnotic was having a therapeutic benefit. This may cause primary care NPs to resume the hypnotic and sabotage deprescribing progress; but, if the client and NP continue with the schedule as planned, this withdrawal symptom will resolve in time (generally < 1 week).
      • Dou C.
      • Rebane J.
      • Bardal S.
      Interventions to improve benzodiazepine tapering success in the elderly: a systematic review.
      Deaths caused by hypnotic withdrawal are rare; nevertheless, abrupt discontinuation of hypnotics in long-term users is not recommended, especially if used at high doses.
      • Dou C.
      • Rebane J.
      • Bardal S.
      Interventions to improve benzodiazepine tapering success in the elderly: a systematic review.
      ,
      • Hood S.D.
      • Norman A.
      • Hince D.A.
      • Melichar J.K.
      • Hulse G.K.
      Benzodiazepine dependence and its treatment with low dose flumazenil.
      ,
      • Lann M.A.
      • Molina D.K.
      A fatal case of benzodiazepine withdrawal.
      Withdrawal symptoms have been documented during the acute deprescribing window lasting 5 to 28 days.
      • Hood S.D.
      • Norman A.
      • Hince D.A.
      • Melichar J.K.
      • Hulse G.K.
      Benzodiazepine dependence and its treatment with low dose flumazenil.
      Protracted withdrawal is experienced by 10% to 25% of long-term users of hypnotic drugs and can last 12 months or more.
      • Hood S.D.
      • Norman A.
      • Hince D.A.
      • Melichar J.K.
      • Hulse G.K.
      Benzodiazepine dependence and its treatment with low dose flumazenil.
      The goal of deprescribing should be a gradual reduction in dose over a period of 3 months; however, some long-term users of hypnotic drugs will require extended tapers of 12 months or more.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      Several methods have been proposed to minimize withdrawal symptoms.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      ,
      • Pottie K.
      • Thompson W.
      • Davies S.
      • et al.
      Deprescribing benzodiazepine receptor agonists: evidence-based clinical practice guideline.
      NPs can consider switching a BZD with a short half life to a longer-acting BZD of equivalent dose (ie, diazepam or lorazepam), because this may improve tolerability of the deprescribing process. Switching to a long-acting BZD is not required, because this method has not demonstrated higher rates of successful taper.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      ,
      • Dou C.
      • Rebane J.
      • Bardal S.
      Interventions to improve benzodiazepine tapering success in the elderly: a systematic review.
      ,
      • Pottie K.
      • Thompson W.
      • Davies S.
      • et al.
      Deprescribing benzodiazepine receptor agonists: evidence-based clinical practice guideline.
      ,
      • Hood S.D.
      • Norman A.
      • Hince D.A.
      • Melichar J.K.
      • Hulse G.K.
      Benzodiazepine dependence and its treatment with low dose flumazenil.
      There is no universal taper schedule recommended, but clinical experts recommend doses be reduced gradually. Although some clients may tolerate faster deprescribing, it is best to reduce hypnotic doses by approximately 10% to 25% every 2 weeks.

      National Institute of Health Care Excellence (NICE) clinical knowledge summary. Benzodizepine and z-drug withdrawal. Last revised April 2020. http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal. Accessed August 26, 2020.

      ,
      • Dou C.
      • Rebane J.
      • Bardal S.
      Interventions to improve benzodiazepine tapering success in the elderly: a systematic review.
      Some clients may require even slower tapers.
      • Dou C.
      • Rebane J.
      • Bardal S.
      Interventions to improve benzodiazepine tapering success in the elderly: a systematic review.
      Unfortunately, not enough evidence exists to recommend any specific adjunctive pharmacotherapy to support hypnotic deprescribing, but experts agree that gradual and systematic deprescribing can lead to successful discontinuation of hypnotic drugs in up to 80% of patients.
      • Dou C.
      • Rebane J.
      • Bardal S.
      Interventions to improve benzodiazepine tapering success in the elderly: a systematic review.
      Table 2 includes a deprescribing guideline and algorithm for primary care NPs.

      Conclusion

      Hypnotic drugs remain among the most frequently prescribed medications internationally, despite meaningful and clinically significant risks for patients. The most common reasons these medications are prescribed are for the management of insomnia and anxiety, yet there is no evidence that hypnotic drugs are effective as long-term treatment options. In fact, a growing body of evidence in the last decade suggests that chronic use of BZDs worsens clinical outcomes and leads to adverse events. PCPs are responsible for most long-term prescriptions for BZDs, especially in elderly populations who are most vulnerable to risks. Therefore, NPs working in primary care settings are ideal candidates to lead efforts to reduce the prescribing patterns of hypnotic drugs and initiate practice policies for safely deprescribing these medications. Successful discontinuation of hypnotic drugs is possible through close collaboration with clients.

      Acknowledgment

      The authors would like to acknowledge Megan Meier and Dr. Melissa Hunter from the Drug Information Center with the University of Wyoming’s School of Pharmacy for developing and creating Table 1.

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      Biography

      All of the authors are affiliated with the Fay W. Whitney School of Nursing, University of Wyoming, Laramie, Wyoming. Nancy McGee, DNP, PMHNP-BC, is a clinical associate professor, and can be contacted at [email protected] . J'Laine Proctor, DNP, FNP-C, PMHNP-BC is a clinical associate professor, Ann Marie Hart, PhD, FNP-BC, is a professor, DNP Program Director, and Mary Burman, PhD, is professor emeritus.