Examining the Risks and Benefits from Benzodiazepines. Benzodiazepine Landscape in the United States

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1 Examining the Risks and Benefits from Benzodiazepines Benzodiazepine Landscape in the United States Rakesh Jain, MD, MPH Saundra Jain, MA, PsyD, LPC Clinical Professor Adjunct Clinical Affiliate Department of Psychiatry University of Texas at Austin Texas Tech Health Sciences Center School of Nursing School of Medicine Austin, Texas Midland, Texas Is Benzodiazepine (and Z Sedative Drug) Use Rare in America? Top 10 Prescriptions for Psychotropics Written in America (2013 Medical Expenditure Panel Survey) Answer These Agents are Utilized Very Frequently in the United States In 2013: There were 5,259,000 prescriptions for Alprazolam There were 4,865,000 prescriptions for Zolpidem There were 3,273,000 prescriptions for Clonazepam There were 3,165,000 prescriptions for Lorazepam SSRI = selective serotonin reuptake inhibitor; SARI = serotonin antagonist and reuptake inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor. Brand names are included in this table for participant clarification purposes only. No product promotion should be inferred. Moore TJ, et al. JAMA Intern Med. 2017;177(2): Moore TJ, et al. JAMA Intern Med. 2017;177(2): Who Exactly is Receiving the Anxiolytic/ Sedative/Hypnotic Class of Medications? US Adult Population Exposed to Psychiatric Drugs (%) All Numbers are high, but highest risk is associated with: 1. Female gender 2. Older age 3. White race Is There a Problem with the Use of Benzodiazepines? Moore TJ, et al. JAMA Intern Med. 2017;177(2):

2 BZD Link with Accidental Falls In a recent Finnish study of patients with or without AD, BZDR use was associated with an increased risk of hip fracture in persons: With AD HR increase is 1.4 Without AD HR increase is 1.6 In a questionnaire survey of 8000 people in 2 districts of Wales, BZD use was associated with injuries outside work and cognitive failures The risk of hip fractures in older adults can be increased by as much as 50% AD = Alzheimer s disease; BZD = benzodiazepine; BZDR = BZD and related drug; HR = hazard ratio. Wadsworth EJ, et al. Hum Psychopharmacol. 2005;20(6): Cumming RG, et al. CNS Drugs. 2003;17(11): Lader M. Addiction. 2011;106(12): Saarelainen L, et al. J Am Med Dir Assoc. 2017;18(1):87.e15-e87.e21. Duration of Use in Days BZD Use and Risk of Hip Fracture Register-based Medication Use and Alzheimer s disease (MEDALZ) study, including all community-dwelling persons diagnosed with AD in Finland during (n = 70,718) and their matched comparison persons without AD. BZDR use was associated with an increased risk of hip fracture in persons with and without AD (adjusted HR 1.4 [95% CI ] and 1.6 [95% CI ], respectively) CI = confidence interval. Saarelainen L, et al. J Am Med Dir Assoc. 2017;18(1):87.e15-e87.e21. A Publication from VA Clinicians BZDs have been linked to falls, fractures, cognitive decline, amnesia, impaired psychomotor speed (eg, motor vehicle accidents), and nursing home placement Such risks above are of greatest concern among older adults, who are more sensitive to medicines and most vulnerable to their consequences The pharmacokinetic and pharmacodynamic changes in the aging body and brain make older patients vulnerable As a result, all BZDs are on the list of Potentially Inappropriate Medications in the 2012 Beers Criteria VA = Veterans Affairs. Paquin AM, et al. Expert Opin Drug Saf. 2014;13(7): The Ugly Side of BZDs: It Plays an Important Part in Drug Overdose Deaths Individual drugs contributing most frequently Oklahoma State Drug Overdoses A total of 2112 fatal unintentional medication overdoses were identified Methadone Hydrocodone Alprazolam Oxycodone Diazepam 4.5% Crude overdose death rates increased 7-fold during the investigation period in 2006 Piercefield E, et al. Am J Prev Med. 2010;39(4): % 14.7% 19.3% 30.9% 0.0% 10.0% 20.0% 30.0% 40.0% BZD Use and Dementia Risk Case Control Studies Also Show Heightened Risk Independent German analysis: The World s Latest and Largest Meta-Analysis of Dementia Risk with BZDs Reveals... Meta-analysis pooled data from 8 studies. These 8 studies included 66,177 participants and 30,914 cases of dementia The regular use of BZDRs was associated with a significant increased risk of incident dementia for patients aged 60 years Adjusted OR 1.21, 95% CI The association was slightly stronger for long-acting substances than for short-acting ones A trend for increased risk for dementia with higher exposure was observed Conclusion: The restricted use of BZDRs may contribute to dementia prevention in the elderly BZDR = BZD and related z-substance; OR = odds ratio. Gomm W, et al. J Alzheimers Dis. 2016;54(2): Odds of dementia were 78% higher in those who used BZDs compared with those who did not use BZDs (OR 1.78; 95% CI ) Islam MM, et al. Neuroepidemiology. 2016;47(3-4):

3 BZD Use and Association with AD Emerging Data is Concerning Another Set of Very Large Databases FDA and Canadian Pharmacovigilance Data Set, Reveals Dose-effect relationship between BZD use and increased risk of AD in older people treated previously for > 3 months Higher risk for long-acting formulations Nature of the link cannot be definitively established BZD use may be an early marker of a condition associated with an increased risk of dementia Recommend shortest duration and short half-life formulations Billioti de Gage S, et al. BMJ. 2014;349:g5205. Takada M, et al. Int J Med Sci. 2016;13(11): US / FDA database revealed BZD use increased OR of dementia risk by 1.63 (n = 1,971,750) The Famous BMJ Gray Study from 2016 Are the Conclusions Corrrect? Does Cognition Improve after Withdrawal from Long-Term BZD Use? Over a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia, of whom 637 developed AD For dementia, the adjusted HRs associated with cumulative BZD use compared with nonuse were 1.25 (95% CI ) for 1 30 TSDDs; 1.31 ( ) for TSDDs; and 1.07 ( ) for 121 TSDDs Conclusion: The risk of dementia is slightly higher in people with minimal exposure to BZDs but not with the highest level of exposure. These results do not support a causal association between BZD use and dementia. Does cognitive function of long-term BZD users improve post-withdrawal? Are previous longterm BZD users still impaired at 6-month follow-up? given the mixed evidence regarding benzodiazepines and risk of dementia and that these drugs are associated with many adverse events, healthcare providers are still advised to avoid benzodiazepines TSSD = total standardized daily doses. Gray SL, et al. BMJ. 2016;352:i90. META-ANALYSIS OF 10 STUDIES Barker MJ, et al. Arch Clin Neuropsychol. 2004;19(3): Does Cognition Improve after Withdrawal from Long-Term BZD Use? (cont d) N = 297 N = 284 Improvement in cognitive function does occur following withdrawal from long-term BZD use Patients withdrawn from long-term BZD use continued to perform more poorly than controls across all cognitive categories, except sensory processing As age increased post-withdrawal cognitive recovery decreased on tasks of attention/concentration Overdose Situations with BZDs: Where Did These Medications Come From? Interviews were conducted with 31 patients who attended the ED following a medication overdose and typical stories regarding the acquisition of medications reported. Treatment Purposes, 77% Recreational Use, 16% Overdose, 7% Conclusion: We are the main suppliers of BZDs that are ultimately used in overdoses! Barker MJ, et al. Arch Clin Neuropsychol. 2004;19(3): ED = emergency department. Buykx P, et al. Aust N Z J Public Health. 2010;34(4):

4 Facts: Examining Recent Data ED Visits BZDs + Alcohol BZDs were involved in 123,572 of the 606,653 ED visits in 2011 that involved drugs and alcohol taken together (20.4%) Total ED Visits Non-medical use of BZDs Rose 149% from 2004 to Alprazolam indicated in ~ one-third of visits, and in ~ one-third of BZD-related suicide attempts Why are Benzodiazepines Addictive? Drug-Related Deaths Alprazolam 17% of drug-related deaths; at least 1 other drug (typically an opioid) identified in 97.5% of alprazolam cases (West Virginia forensic database). Deaths attributed to BZDs increased 5-fold from 1999 to 2009; Alprazolam second only to oxycodone with the highest increase in death rates Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits. Substance Abuse and Mental Health Services Administration. Accessed June 5, Shah NA, et al. Am J Addict. 2012;21 Suppl 1:S27-S34. Jann M, et al. J Pharm Pract. 2014;27(1):5-16. Understanding the GABA A Receptor and How BZDs Affect It The GABA A receptor consists of 5 transmembrane glycoprotein subunits arranged around the central chloride channel. Each subunit is composed of 4 domains (domains 1 through 4); domain 2 is the part of the monomeric subunit that lines the chloride channel. How BZDs Can Become Addicting in Some Patients BZDs increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABA A receptors in nearby interneurons Such disinhibition, which relies on α1-containing GABA A Rs expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement GABA = gamma-aminobutyric acid. BZDs increase the affinity of the GABA A receptor for GABA and the likelihood that the receptor will open for chloride ions. Data provide evidence that BZDs share defining pharmacologic features of addictive drugs through cell type-specific expression of α1-containing GABA A Rs in the ventral tegmental area benzodiazepines act through mechanisms similar to those of other drugs of abuse. - Tan KR, et al. Nature. 2010;463(7282): Who s at Risk to Develop BZD Addiction? A special characteristic of BZDs is that physical and mental dependence can develop in the absence of tolerance Clinical correlates of long-term BZD use are: Older age (> 65 years), Prescription by a Psychiatrist Regular use Use of a high dose, and Concomitant prescription of psychotropic drugs It can be assumed that the majority of consumed BZDs were not obtained on the black market but were prescribed by doctors. Furthermore, most patients are likely to have gone through a prolonged history of suffering before they were given BZD medication, so they desire rapid intervention and need it too. Cycle of BZD Use The good effectiveness in terms of the target symptoms creates great affinity in patients towards their medication even before manifest dependency develops. Without any doubt, doctors are crucially involved in the longterm prescribing of benzodiazepines. Patients therefore put pressure on their doctors who prescribe the drug to them. Those affected fear that their initial symptoms might return. In many cases, prescriptions are issued at patients explicitly expressed wishes. Okumura Y, et al. Drug Alcohol Depend. 2016;158: Janhsen K, et al. Dtsch Arztebl Int. 2015;112(1-2):1-7.

5 Are BZDs a Good or a Bad Idea? The Advantages and Disadvantages of Using BZDs Benzos are ALWAYS a good idea and we are way under prescribing it Benzos are ALWAYS a bad idea and we are way over prescribing it When it comes to prescribing BZDs, do you ever feel like this? It s Important to Establish a Few Things While a few patients develop problems associated with BZD use, most don t Most treatment guidelines do recommend the judicious use of BZDs The goal of this presentation is not to create fear mongering among us clinicians Many patients are on long-term BZD therapy and don t have problems associated with them. They should not be unnecessarily taken off these medications that can be harmful to their wellbeing. Let there be no doubt decades of experience has taught us that BZDs are often very helpful, many patients benefit preferentially from them, don t abuse them, and use them safely for prolonged periods of time Similarly, we cannot ignore the recent data emerging from addiction literature, ED settings, law enforcement, overdose databases, neurobiology literature, long-term epidemiological outcome data, etc. Therefore, framing any conversation along the lines of BZDs are good or BZDs are bad is fundamentally flawed The Pros and Cons Associated with BZD Use BZDs Have Several Positive Attributes Pharmacologic Benefits Therapeutic Uses Adverse Experiences Anticonvulsive Centrally muscle-relaxing Sedative/hypnotic Amnestic Anxiolytic, subduing excitement, and aggression Cerebral seizures Epilepsy Central spasticity Muscle tension Tetanus Sleep disturbances Premedication in anesthesiology Various applications in anesthesiology Tense, excited, and anxious states of various origins Stress shielding Muscle asthenia, ataxia Disturbance of gait Respiratory depression Diurnal sedation Reduced attentiveness Amnesia (anterograde) eg, when used as a hypnotic Indifference Retreat from reality Flattening of affect Low Cost Availability Rapid Relief of Symptoms Effective Therapy for Many Patients Möller HJ. J Clin Psychopharmacol. 1999;19(6 Suppl 2):S2-S11. Potts NL, et al. Can Fam Physician. 1992;38:

6 FDA Indications of Select BZDs Spectrum of Concerns Associated with Short- and Long-Term BZD Use Alprazolam Drug FDA Indication Panic disorder with or without agoraphobia. GAD Over-sedation Adverse Effects: Elderly Lorazepam Clonazepam Diazepam Temazepam Management of anxiety disorders, anxiety symptoms associated with depression Seizures, panic disorder Anxiety disorders, alcohol withdrawal, status epilepticus Muscle spams, surgical procedures Insomnia Drug Interactions Cognitive Difficulties Depression, Emotional Blunting Adverse Effects: Pregnancy Drug Abuse/Dependence Flurazepam Triazolam Insomnia Insomnia Neurodegeneration Socioeconomic Cost: Long-term BZD Use GAD = generalized anxiety disorder. US Food and Drug Administration. Drugs@FDA. Ashton CH. Benzodiazepines: How They Work And How To Withdraw. August Accessed June 5, Potts NL, et al. Can Fam Physician. 1992;38: Safety Measures When Using BZDs If You Do Decide to Taper: Some Advice Titrating Doses Close Observation & Follow-up Proper Screening Patient Education Potts NL, et al. Can Fam Physician. 1992;38: Getting to Better Know Our Common BZDs Kinetics BZD Taper and Withdrawal: Specific Suggestions Recommendations range from reducing the initial BZD dose by 50% every week or so, to reducing the daily dose by between 10% and 25% every 2 weeks A period of 4-to-6 or 4-to-8 weeks is suitable for withdrawal for most patients If possible, prolonged reductions over a period of many months should be avoided in order to prevent the withdrawal treatment from becoming the patient s morbid focus Today, approximately 35 benzodiazepine derivatives exist

7 When Not to Consider Taper or Withdrawal of BZDs Recognizing the Trifecta Cluster of Signs and Symptoms of BZD Withdrawal Those with a severe depressive episode or other major mental disorder who need BZDs for stabilization Some elderly patients as withdrawal can be difficult to achieve in some elderly persons with long-term, lowdose dependence on hypnotic agents For patients without any motivation for withdrawal If complete discontinuation of BZDs is unlikely, one can attempt to reduce the dose as a harm-reduction strategy Vegetative Symptoms Psychopathologic Symptoms Neurologic and Physical Complications What Does BZD Withdrawal Look Like? Differential Diagnosis of BZD Withdrawal Non-specific Symptoms Frequency (%) Insomnia 71 Anxiety 56 Mood swings 49 Myalgia/muscle twitching 49 Tremor 38 Headache 38 Nausea/vomiting/loss of appetite 36 Sweating 22 Blurred vision 20 Other Feelings of unreality 24 Complications Psychosis 7 Epileptic seizures 4 Sensory Disturbances Frequency (%) Hypersensitivity to Noise 38 Light 24 Smells 15 Touch 7 Hyposensitivity to Smells 15 Taste 4 Qualitative changes Movement > 24 Vision > 13 Taste 13 Hearing 2 Smells 2 Take-home message: Don t always assume that the patient is experiencing BZD withdrawal without engaging in a differential diagnosis process! Janhsen K, et al. Dtsch Arztebl Int. 2015;112(1-2):1-7. Create a Checklist A Framework before Beginning Taper Results of Analysis to See if Dose and Duration of BZD Use Would Impact Elderly Taper Success Safely stopping BZDs among older, chronic users is feasible and frequently successful Importantly, these authors did not find evidence suggestive of severe withdrawal symptoms or safety concerns, even with high BZD dose and long duration of use Paquin AM, et al. Expert Opin Drug Saf. 2014;13(7): Paquin AM, et al. Expert Opin Drug Saf. 2014;13(7):

8 Goals for Offering Psychotherapeutic Interventions in BZD Dependence Psychotherapeutic interventions for long-term BZD use have 3 goals: 1. Facilitate the withdrawal itself 2. Facilitate further abstinence 3. Treat the underlying disorder BZD Withdrawal Guidelines: UK Guidelines on Clinical Management Approximate dosages of common benzodiazepines and z-drugs equivalent to 5 mg of diazepam Drug Dose Chlordiazepoxide 15 mg Diazepam 5 mg Loprazolam 500 µg Lorazepam 500 µg Nitrazepam 5 mg Oxazepam 15 mg Temazepam Zaleplon Zopiclone 7.5 mg Zolpidem Lader M, et al. CNS Drugs. 2009;23(1): Loprazolam and nitrazepam are investigational drugs. Department of Health (England) and the Devolved Administrations. Drug Misuse and Dependence: UK Guidelines on Clinical Management Accessed June 5, BZD Withdrawal Guidelines: UK Guidelines on Clinical Management (cont d) How to Best Taper Off a BZD: Opposite to Country Western Dance Quick Quick Slow Slow! Drug Dose Chlordiazepoxide 15 mg Diazepam 5 mg Loprazolam 500 µg Lorazepam 500 µg Nitrazepam 5 mg Oxazepam 15 mg Temazepam Zaleplon Zopiclone 7.5 mg Zolpidem Convert current BZD into diazepam equivalent units Switch to once daily BZD, and then taper (discussed later) Diazepam recommend because of a specific benefit long-acting Alternative BZDs chlordiazepoxide and clonazepam Adjunct, alternate drugs to potentially utilize gabapentin, pregabalin, carbamazepine, etc. DOSE The early stages of withdrawal are easier to tolerate than the later and last stages. Lader M, et al. CNS Drugs. 2009;23(1): Department of Health (England) and the Devolved Administrations. Drug Misuse and Dependence: UK Guidelines on Clinical Management Accessed June 5, Lader M. Addiction. 2011;106(12): Lader M. Addiction. 2011;106(12): TIME Possible Medications to Help with BZD Taper and Withdrawal Carbamazepine Focus on CBT and Psychoeducation Pregabalin Gabapentin Note: Pregabalin and Gabapentin themselves have abuse / dependence risk. Keep this in mind if selecting these agents The use of carbamazepine, pregabalin, and gabapentin for this indication is off-label. Schweizer E, et al. Arch Gen Psychiatry. 1991;48(5): Oulis P, et al. Hum Psychopharmacol. 2008;23(4): Crockford D, et al. Can J Psychiatry. 2001;46(3):287.

9 Model of CBT What we think affects how we act and feel This Isn t Sound Advice! Nonsense! As long as you take it every day on schedule, you won t have to worry about addiction! CBT What we feel affects what we think and do What we do affects how we think and feel CBT = cognitive-behavioral therapy. Is Psychoeducation Worth the Time and Effort? McGill Experience: Using Psychoeducation Materials Produces Positive Results Accessed June 5, The McGill Experience: Study Results 261 participants 86% completed the 6-month follow-up 62% initiated conversation about BZD therapy cessation with physician and / or pharmacist At 6-month follow-up, 27% of intervention group discontinued BZDs At 6-month follow-up, 5% of control group discontinued BZDs Dose reduction occurred in an additional 11% ALL Patient Profiles Benefitted from Psychoeducation and Slow Taper These factors did NOT influence BZD therapy discontinuation: Age > 80 years Sex Duration of use Indication for use dose Previous attempts to taper Concomitant pharmacotherapy with 10 drugs/day Tannenbaum C, et al. JAMA Intern Med. 2014;174(6): Tannenbaum C, et al. JAMA Intern Med. 2014;174(6):

10 Withdrawing/Tapering Use CBT to Improve Outcomes: A Canadian Experiment CBT Add-On, Short- and Long-Term Results People with chronic insomnia who had been taking a BZD every night for > 3 months Randomly assigned to CBT plus gradual tapering or gradual tapering alone; CBT was provided by a psychologist in 8, weekly, small group CBT sessions Tapering was supervised by a physician, who met weekly with each participant over an 8-week period Main outcome measure was BZD discontinuation, confirmed by blood screening performed at each of 3 measurement points (immediately after completion of treatment and at 3- and 12-month follow-ups) 38% 77% 5.3 Discontinuation rate w/o CBT Discontinuation rate w/ CBT OR improvement At 3 months Baillargeon L, et al. CMAJ. 2003;169(10): Baillargeon L, et al. CMAJ. 2003;169(10): Results at 12-Month Follow-Up CBT and BZD Discontinuation 24% 70% 7.6 Discontinuation rate w/o CBT Discontinuation rate w/ CBT OR improvement RCT (N = 47) designed to compare the efficacy of 3 strategies for discontinuation of BZD treatment. Outpatients with panic disorder randomized to: 1) Conservative taper program alone, 2) Taper program plus individual relaxation treatment, or 3) Taper program plus individual exposure-based CBT. Intervention BZD-Free Status at 3-month follow-up BZD-Free Status at 6-month follow-up TAU TAU + IRT TAU + CBT Adjunctive CBT significantly increased the rates of successful BZD discontinuation relative to taper alone by the 6-month follow-up. Conclusion: CBT is a logical add-on to BZD taper/discontinuation plan Baillargeon L, et al. CMAJ. 2003;169(10): No evidence of a worsening of panic in the CBT group at the post-taper evaluations TAU = taper as usual; IRT = individual relaxation treatment. Otto MW, et al. Behav Res Ther. 2010;48(8): Combined Psychoeducation + CBT Great Resources for BZD Tapering In Conclusion

11 A Clinic s Experience with Initiating a Benzodiazepine Safety Initiative In Conclusion Part I: BZDs ARE Indeed Effective Medications Treatment Guidelines do indeed recommend the judicious use of these medications Mission Ensuring the provision of accessible, efficient and effective services supporting the health, dignity and independence of those we serve. Patients often use them without issue and long-term Creating a fear mongering environment regarding BZD use ultimately backfires and patients suffer as a result Lader M. Addiction. 2011;106(12): In Conclusion Part II: But on the Other Hand, Caution is Necessary The practical problems with benzodiazepines have persisted for 50 years, but have been ignored by many practitioners and almost all official bodies Between 1969 and 1982, diazepam was the most prescribed drug in America with more than 2.3 billion tablets sold in 1978 It is clear that official recommendations concerning the use of these medicines are widely ignored Top 3 Practical Take-Aways 1. Before using BZDs in any patient, a careful shortand long-term assessment of the risk-benefit is a necessity 2. Data is accumulating that risk of addiction and physical dependence of this class of medications is higher than originally anticipated 3. If a decision to slowly reduce or stop these medications is made in conjunction with the patient, there are now several well-studied pathways available to achieve this goal Lader M. Addiction. 2011;106(12): BZDs: How They Work and How to Withdraw (aka The Ashton Manual) Medical Research Information from a BZD Withdrawal Clinic Resources Ashton Manual Index Page Contents Page Introduction Chapter I: The benzodiazepines: what they do in the body Chapter II: How to withdraw from benzodiazepines after long-term use Chapter II: Slow withdrawal schedules Chapter III: Benzodiazepine withdrawal symptoms, acute and protracted Ashton CH. Benzodiazepines: How They Work And How To Withdraw. August Accessed June 5, 2017.