Why the Interest?

• 33 years in chronic pain rehabilitation Benzodiazepines • Many patients are dysfunctional, depressed, in Chronic Pain regressed, and cognitively impaired while taking opioids plus benzodiazepines. • Engendered a negative attitude Edward Covington, MD • Stimulated curiosity about what we Cleveland Clinic Foundation do and do not know about these drugs in pain patients, especially in combination with opioids

Disclaimer History

Much of the data that I could find is quite old • For centuries, humans have sought anxiolysis, euphoria • Alcohol was followed by sedatives and anxiolytics • 19th century – Bromides (“take a powder”), choral hydrate (Mickey Finn), paraldehyde • Barbiturates synthesized in 1903 • Meprobamate in 1950

Benzodiazepine Introduction Benzodiazepine Use in America

• Chlordiazepoxide introduced in 1960 • BZs are the most prescribed CNS depressants • Addictiveness and lethality of barbiturates (and similar drugs) led to their replacement by BZs • Estimated past year prevalence of BZ use in • Use of BZs increased dramatically the USA = 12.9% – US sales peaked in 1975 – Anxiolytics / hypnotics accounted for 10% of all • 14.2% of these have taken the drug ≥ 12 mo prescriptions Barker MJ et al. Arch Clin Neuropsychology 2004;19:437-454 • WHO recommended scheduling BZs in the early • About 100 million prescriptions in 1999 1980s DEA

Lader, M: J Subs Abuse Treatment 1991;8:53-59

1 Mechanism of Tranquilization How Reinforcing are BZs?

- • GABA binding permits Cl influx Humans • Hyperpolarizes cell, •Normal (light drinkers without anxiety or insomnia) rendering it less excitable – BZ (diazepam, lorazepam, flurazepam) not preferred to placebo •Moderate social drinkers, no hx alcohol problems • BZ binds to GABA A receptor • Potentiates GABA effect – Benzodiazepines (po) are reinforcers – Three studies confirm – Increases opening frequency Animals • Cell becomes more refractory •Oral BZs • Subtypes of BZ receptors 8/18 studies in primates and rats did not show evidence of reinforcement – α1 – sedative •IV – α2 – anxiolytic Reinforcement demonstrated with alprazolam, chlordiazepoxide, clorazepate, clonazepam, diazepam, flurazepam, lorazepam, – α1, α2, and α5 – anticonvulsant bromazepam, medazepam, midazolam, and triazolam – All BZs bind, to variable extents, with all subtypes Griffiths & Weerts Psychopharmacology (Berl). 1997;134(1):1-37.

Conventional Wisdom

• Most chronic benzodiazepine users do not escalate their original dose, even after many years. BZ Abuse in the Community

• The reinforcing effects are considerably weaker than other sedative hypnotics, Conflicting information stimulants, and opiates, but stronger than drugs with little abuse potential, e.g., chlorpromazine.

Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Washington, DC, APA, 1990

“Pharmacies Besieged by Addicted Thieves” Street Prices 2006

The New York Times • Diazepam and clonazepam ≈ $2.00-$4.00/pill February 6, 2011 • Many who seek these drugs for a "high" quickly move on to other agents • More than 1,800 US pharmacy robberies in • High risk for continued misuse of BZs: the last three years – Heroin dependent / methadone maintenance • 75%+ admitted taking BZs to enhance • The most common targets are oxycodone, intoxication or treat withdrawal hydrocodone, and Xanax . – Alcoholic • Perhaps for anxiety, insomnia, withdrawal sxs Drug and alcohol abuse: a clinical guide to diagnosis and treatment. Marck A Schuckit. Springer, New York, 2006

2 Preferred Drugs on the Street BZ Use Patterns

• Short-acting • Recreational abuse of BZs alone is uncommon – rapid onset – Commonly taken as part of polysubstance -abuse • Highly lipophilic • Motivations – e.g., diazepam – Euphoria • Short half-life and high potency – Augment euphoriant effect of other drugs, especially opiates – lorazepam, alprazolam • Up to 80% of opiate abusers take BZs • Clonazepam – high potency, long half-life – To ease the "crash" from cocaine – To ease EtOH sxs – Perceived as "safe" • 29%-33% of alcohol abusers take BZs – Frequently abused as a street drug

Roache & Meisch. Psychiatric Annals 1995;25(3):153-7. Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Washington, DC, APA, 1990

The TEDS Report Nonmedical Use (Treatment Episode Data Set) 6/2/11

• Most nonmedical use is occasional use of therapeutic doses for sx relief – Not associated with escalation or high-dose abuse

Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Washington, DC, APA, 1990

That is ... Most nonmedical use is not “recreational use”

http://oas.samhsa.gov/2k11/028/TEDS028BenzoAdmissions.cfm

The TEDS Report Prevalence of Abuse / Dependence (Treatment Episode Data Set) 6/2/11

• BZ admissions ~tripled from 1998-2008 • Difficult to determine – Overall CD admissions increased 11% • 2002 survey: ≈ 200,000 Americans treated for sedative / hypnotic use • Admissions for rx of BZ abuse – often in the context of other SUD – 1.3% of all CD admissions in 1998 • During the same period – 3.2% in 2008 – 2.2 million received rx for EtOH-related disorders – 84.8% white, 56% ♂ – 100 times more – Rate of treatment for alcoholism was ≈1% of the population, • 96% also abused other substances treatment for CNS depressants was 0.07% – In > 75% of these, BZ was the 2°drug of Wesson. D. R.. Smith. D. E.. Ling. W.. & Seymour. R. B. Sedative-hypnotics. In J. H. abuse Lowinson. P. Ruiz, R. B. Millman, & J. G. Langrod (Eds.). Substance Abuse: A Comprehensive Textbook (4th cd.). Baltimore. MD: Lippincott. Williams & Wilkins. SAMHSA 2004. pp. 302-312. http://oas.samhsa.gov/2k11/028/TEDS028BenzoAdmissions.cfm

3 Prevalence of Substance Use Disorder National Comorbidity Survey

• N = 8098 • Substance use disorder develops in 5-10% – representative sample of adults • Up to 10% of general medical/surgical patients and 30% • 17.0% had been prescribed sedatives, denied of patients with serious psychiatric histories have felt misuse psychologically dependent on antianxiety or hypnotic • 7.1% reported non-prescribed use drugs • Lifetime prevalence of self-perceived sedative dependence was 0.5% • Sedative use and misuse associated with Wesson DR et al. in JH Lowinson, P Ruiz, RB Millman, JG Langrod (Eds.). Substance Abuse: A Comprehensive Textbook (4th ed.). – psychopathology Baltimore. MD: Lippincott. Williams & Wilkins. 2004. pp. 302-312. – suicide risk – parental abuse of Rx medications Goodwin RD et al. Addiction. 2002;97(5):555-62.

Anxiolytic SUD Is Uncommon

• N= 34,653 face-to-face surveys – National Epidemiologic Survey on Alcohol and Related Conditions

• 11.8% of respondents had received rx for anxiolytic, of whom: – 16.0% reported lifetime nonmedical use – 4.6% reported abuse / dependence

Fenton MC et al. Am J Psychiatry 2010;167(10):1247-53 Annual Numbers of New Nonmedical Users of Prescription Type Drugs, by Drug Category: 1965–2000

Diazepam Antihyperalgesic in Mice

• Loss of DH inhibition is a major factor in chronic pain • Spinal BZs are profoundly antihyperalgesic in Benzodiazepine Use in Pain animals and humans • Knockout mice with BZ-insensitive GABA A receptor a1 subunit are resistant to motor/sedative action of diazepam How widespread? • Formalin test: How useful? – Systemic diazepam was antinociceptive without sedation • Suggests that systemic BZs reduce pain at cord level

Knabl J et al. Pain 141 (2009) 233–238.

4 Benzodiazepines Do Help Pain Benzodiazepines Do Not Help Pain

• Hydroxyzine, prochlorperazine, chlordiazepoxide vs PBO • 100 chronic pain patients – Adjunctive to analgesics in cancer and arthritic pain – Alprazolam 1.5 mg/d • 9 pts, each exposed to 3 phases with drugs and 1 with PBO – No other interventions – Double-blind, counter-balanced design – Each phase lasted 2 weeks • 83 evaluated at 12 weeks • Assessed – Pre- and post-phase anxiety, depression, hostility – 61 (73.5%) showed improvement – Daily pain, mood, and medication intake – 5 discontinued because of side effects • No antianxiety drug was better than PBO – Mean pain score (0-5 scale) decreased from – For pain, analgesic use or hostility • Chlordiazepoxide 3.6 to 2.2. – Reduced anxiety and depression Westbrook L et al., Clin J Pain. 1990; 6(1):32-6. – Produced most side effects (e.g., drowsiness) Yosselson-Superstine S et al. Isr J Med Sci. 1985; 21(2): 113-7.

Midazolam Reduces Morphine Analgesia BZs May Worsen Pain in Mice

• ICV midazolam • Mouse model – Produced hyperalgesia on tail flick response – Tail flick, hot plate tests – Attenuated morphine analgesia – Morphine (10 mg/kg) pre-medication – Midazolam or diazepam given i.p. • Both effects antagonized by ICV flumazenil – Both BZs • decreased morphine analgesia • decreased indomethacin analgesia

Ito K et al. Eur J Pharmacol. 2008;586(1-3):139-44. Pakulska W, Czarnecka E.Pharmazie. 2001;56(1):89-91.

BZs Worsen Sciatica? BZs in Low Back Pain

• Acute lumbar disc prolapse with sciatica • Acute LBP • RCT, n = 60 – Diazepam ≡ placebo • Given PT, NSAIDs x 7 days Hingorani K. Ann Phys Med 1996;8:303–6. • Plus placebo vs diazepam • Pain reduction at day 7 • Review of RCTs – 60% vs. 50% reduction of distance of referred pain (p < 0.05) – Little efficacy of diazepam in acute LBP • Hospital LOS – Either no or only minor benefit from BZs in – PBO 8d, BZ 10 days (p = 0.008) chronic LBP • Probability of ≥ 50% pain reduction van Tulder MW et al. Eur Spine J. 2006;15 Suppl 1:S64-81 – Twice as high in placebo patients (p < 0.0015) Brötz D et al. Pain 2010;149:470–475

5 BZs in Back Pain – Cochrane Review BZ Antagonism Reduces Postop Pain

• After pre-op diazepam, flumazenil (BZ • 8 trials of BZs antagonist) reduced postop morphine, NSAID – Duration 5-14 days • Acute LBP requirement Gear RW et al, Pain 1997 – 1 high quality trial found diazepam ≡ placebo – Another (lower quality) found diazepam > PBO (pain, • 32 herniorraphy patients overall improvement) – DB, RCT • Chronic low back pain – PRN analgesia: – 2 high quality trials – Tetrazepam increased odds of not experiencing pain • MS 2 mg vs MS 2 mg + flumazenil 0.2 mg relief or global improvement – Flumazenil patients – Lower quality, placebo controlled trial of diazepam • Less morphine (14.1 vs 9.5) found no benefit Chou & Huffman, Ann Intern Med. 2007;147:505-514. • More comfortable Weinbroum AA et al. Clin J Pain. 2000;16(3):193-199.

Efficacy in Chronic Use Challenged – Most Use Is Long Term UK – Committee on Review of Medicines - 1980

• Noted lack of firm evidence of efficacy of … long-term Based on several US drug surveys: BZs in insomnia and anxiety. • US IOM, White House Office of Drug Policy, and NIDA •Griffiths & Weeks calculated: concurred: •Almost 90% of anxiolytics and > 80% of – “There is little evidence that sedative hypnotics, including hypnotics sold in the US were consumed by BZs, continue to be effective when used nightly over long people reporting daily use x ≥ 4 months periods.” •Continuous users account for ~70% of • Most hypnotics lose sleep-promoting properties within 3- anxiolytic and 60% of hypnotic drug sales. 14 days’ continuous use. • Little evidence that BZs help anxiety after 4 months. Griffiths RR, Weerts EM: Psychopharmacology (1997) 134:137

Committee on Review of Medicines, BMJ 1980;2:719-720

Does Prolonged Use Worsen Anxiety? BZ Starters – Rate of Attrition

• Long-term BZ users may have less anxiety after discontinuation Ashton 1987; Cantopher et al. 1990; Rickels et al. 1990; Schweizer et al. 1990

• And less anxiety than continued users Rickels et al. 1991

• Conclusion: some chronic BZ use may be maintained by preventing rebound anxiety or withdrawal rather than reducing anxiety

Griffiths & Weerts. Psychopharmacology (Berl) 1997;134(1):1-37 .

D Isacson et al. J Clin Epidemiol 1992;45(4):429-436,

6 BZ Use in Chronic Pain Conclusions So Far

• N = 114 chronic pain patients • BZs are heavily used in chronic pain – Academic pain management service • 38% taking ≥ 1 BZ at assessment, of whom: • Addiction (as usually understood) is – 46% ≥ 2 years uncommon – 58% concomitant opioids • Evidence of acute benefit is small – 86% using (all / in part) for sleep • As many sleep problems as non-BZ group • Evidence of chronic benefit is absent • No signs of excessive intake • Use tends to be chronic – But only 1 patient stopped benzodiazepines King SA, Strain JJ. Clin J Pain 1990;6(2):143-147.

Accidents

• Synergistic toxicity with other depressants – Fatal overdoses in combination with EtOH, opiates Adverse Effects • Falls, hip / femur fractures • Increased MVAs Longo LP, Johnson B. Am Fam Physician. 2000;61(7):2121-8 The Down Side • N = 1213 forensic autopsies – Active participant in MVA (driver, pedestrian) – Ethanol – 34.7% – BZs – 3.6% – THC – 2.2% Mravcík V et al. Cent Eur J Public Health 2007;15(4):158-62

Rebound Physical Dependence

• Likely after 4 mo of regular, daily dosing • N = 48 patients with panic disorder – Withdrawal and rebound symptoms • Alprazolam 4-10 mg/d x 8 mo – Sufficiently severe to hamper weaning – χ = 5.2 mg/d – 0-40% dependent after 6 mo of treatment • Double-blind, controlled, prospective studies • 4 week taper – 4-8 months is critical time for development of therapeutic dose dependence • 90+% had marked withdrawal symptoms • Duration > dose as predictor of dependence • Prevented discontinuation in 33% Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Washington, DC, Rickels K et al. Arch Gen Psychiatry. 1993;50(1):61-8 APA, 1990

7 Benzodiazepines – A Cause of Depression from BZs Depression?

• Numerous case series describe onset / • Cleveland Clinic Data exacerbation of depression after BZ initiation Chronic Pain Rehabilitation Program • Affect tended to normalize with dose reduction or elimination –Patients on opioids or BZs had higher depression scores than those receiving neither. • Clinical trials of anxiety disorders report depression as a side effect –Direction of causality cannot be determined.

• Overall, risk seems small in therapeutic use Dan Fishman, 2010 unpublished

Smith & Salzman. Hosp Community Psychiatry. 1991;42(11):1101-2.

“Downhill Spiral” Opioids + Sedatives and Status

Does chronic opioid use lead to a downhill spiral? • N = 150 chronic pain patients – Referred for psych evaluation •Retrospective study: n = 243 consecutive patients •Answer – yes, but … •Association between poor status and opioid use • Opioids and opioid + sedative groups disappeared when controlled for BZs – More pain-related surgeries, drug expense, •Benzodiazepine use was associated with: hospitalizations, functional impairment, daytime – Functional impairment reclining

– Healthcare utilization Turner JA et al. Pain 1982; 12:357-363 – Depression – Pain •Effects were small Ciccone DS, et al. J Pain Symptom Manage. 2000;20:180–192.

Effects on Cognition Cognitive Effects of BZs

• Acute • Literature is contradictory – Traveler’s amnesia • Heterogeneity of psychiatric diagnoses – Perform normally • Concomitant use of alcohol, other drugs – Recall acutely – Later no recall • Variable doses Stewart SA, J Clin Psychiatry 2005;661Suppl 21:9-13 • Variable definitions of long-term use • Impair consolidation phase, without impairing • Variable time since last dose sensory intake or retention • Effect of anxiety on test performance – A person who has taken a BZ will remember what he has just been told, but may be unable to recall it later. Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Washington, DC, APA, 1990

8 Anterograde Amnesia Early Findings of Cognitive Impairment

• High-dose IV for presurgical anesthesia • 196 admissions to Hopkins Pain Treatment Center • Therapeutic po doses of short T ½, high-potency BZs – Compared users of BZs, opioids, both, neither – Especially if with alcohol – EEG, WAIS, Memory Quotient, and Bender Gestalt • Impairment of memory after po dose – Most common deficit is impaired acquisition of • Patients taking BZs alone new material after a delay in time – Reduced cognition in 10/13 – Not associated with degree of psychomotor – EEG slowing or fast waves in 8/13 impairment and sedation – No effect on the recall of information learned prior • 40/106 were taking both BZs + opioid at admission to dosing • The elderly are more vulnerable Hendler N et al. Am J Psychiatry 1980;137(7):828-831 Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Washington, DC, APA, 1990

Cognition Following Withdrawal of Cognitive Effects of Long-Term BZs Long-Term Benzodiazepines

• Meta-analysis – 13 studies – neuropsychological tests • 13 studies – Mean age – 47.6 (21–75) years – Use – 10 (1-29) years – Mean dose ≈ 17.2 mg/d diazepam – Mean BZ use – 9.9 (1-34) yrs – Age – 47.1 (21-75) • Tests categorized into 12 domains – Mean time between initial and • Long-term BZ users more impaired post-withdrawal assessment = than controls in all categories 3 mo • Effect sizes: –1.30 to to –0.42 – 80% excluded hx heavy (χ = –0.74) alcohol/drug use – Moderate-to-large, suggesting significantly impaired vs controls in all Barker MJ et al. Arch Clin areas Neuropsychology 2004;19:437-454 Barker MJ et al. CNS Drugs. 2004;18(1):37-48

BZ + Opioid Lethality

• Medullary ventral respiratory group – Excitation mediated by EAAs, e.g. glutamate • In 2006 • About half of all U.S. opioid-related deaths – Inhibition mediated via GABA, especially GABA A – Activated by BZs, alcohol, barbiturates involved more than one drug • µ and δ agonists depress respiration mostly via ↓ in • Benzodiazepines were mentioned most glutamate-induced excitation frequently • Many (most?) ODs are due to combined effects of • Involved in 17% of the deaths opioids + other drugs – Mostly alcohol and BZs Warner M et al. NCHS Data Brief 2009;22:1–8. – Weak respiratory depressants but augment morphine White & Irvine. Addiction 1999;94(7):961-72.

9 Prescription Drug Fatalities: Utah Overdose Deaths – Women in Rural Virginia “Significant Other” Interviews

• n= 432 OD deaths • n=330 medical examiner cases – 10/08-10/09. • Most common drug classes detected – 278 involved at least one opioid – 240 no illicit drugs – opioids (72.4%) – 38 ≥ one illicit – interviews on 385 – antidepressants (60.9%) • Commonly mentioned drugs: – sedative/anxiolytic/muscle relaxant (48.8%) – Oxycodone > methadone, hydrocodone and alprazolam. – all three classes in 27% • 83% of decedents had chronic pain.

Wunsch MJ et al. J Opioid Manag. 2009; 5(4):228-36.

Johnson E. http://health.utah.gov/prescription/advisory%20committee/UtahDrugOverdoseDecedentInterviewsReport2009. pdf

Increased Mortality in BZ Users

• Two Norwegian counties • Cohort of 14,951 – Aged 40–42 years Use in Pain – Actual Practice – Excluded hx of CV disease, DM – Health surveys in 1985–1989 – Mean follow-up 18 years Which Pain Patients Receive BZs • Risk of death increased with frequency of BZ use – OR for daily anxiolytics/hypnotics were 3.1 ♂ and 2.7 ♀ – After adjusting for painkiller use and smoking: hazard ratios 2.4 ♂ and 2.1 ♀ Hausken AM et al. Pharmacoepidemiol Drug Saf 2007;16(8):91318.

“Operant Pain Patients” Predictors of Prolonged / High Dose Use Use / Misuse More Drugs

• N=106 1) Current or prior sedative / hypnotic – Psychiatric pts with pain dependence – Hospital pts with psych consult – Including alcohol and BZs – Computerized interview • Scored pain for operant vs respondent 2) Chronic medical or psychiatric illnesses characteristics 3) Chronic dysphoria and/or personality • Operant pain patients disorders (borderline or dependent) – More likely to use minor tranquilizers, sedatives, antidepressants and opioids 4) Chronic sleep difficulties – More likely to misuse them Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force Report of the American Psychiatric Association. Ziesat HA et al. Addict Behav. 1979;4(3):263-6. Washington, DC, APA, 1990

10 In Practice – BZ Use Predicts Opioid Use Patients at Highest Risk Receive the Most Drugs More than Does Pain

• N = 4 million Kaiser Northern California (solid) • Prevalence of long-term opioid • N = 17,074 who were opioid free in 2000–2001 use for CNMP by drug or alcohol Group Health (dashed) diagnosis and opioid diagnosis in • Linked to Norwegian Prescription Database the prior 2 years. during 2004–2007 • Individuals with SUDs: – higher dose regimens • OR for moderate-high prescription frequency of – more days supply opioids for previous BZ users was 7.7 – more likely to receive Schedule II opioids • BZ use was stronger predictor of opioid use than – Twice the rates of concurrent sedative-hypnotics pain – More likely to receive 180+

days of sedative-hypnotics Prevalencelong-term(%) use opioid • Benzodiazepine users had more disability, CV • Similar patterns (p<0.0001) disease and musculoskeletal pain when comparing persons with opioid use disorder to those Skurtveit S. Pain Medicine 2010; 11: 805–814 without an opioid use disorder. Constance M et al. Pain 145 (2009) 287–293

High Opioids Predict BZ Prescription Cleveland Clinic Chronic Pain Rehabilitation Program % using BZs • N = 478 veterans with CNMP – Taking ≥ 180 mg/d MS equivalent • Of 100 consecutive opioid-addicted patients χ = 324.9 mg/d • 66 also used bzs – 90+ consecutive days • 23 abused bzs • VS High dose – Traditional-dose (5-179 mg/day; n=500) Low dose • 26 used non bz hypnotics – No opioid (n=500) None • 4 abused non bz hypnotics • High-dose patients • 7 used Soma – more likely to have ≥ 4 pain diagnoses • 2 abused Soma – highest rates of medical, psychiatric, and substance use disorders • 22/100 used none of these – 32.0% of high dose received concurrent BZ rx Morasco BJ et al. Pain 2010;151(3):625-32.ix

Cleveland Clinic Summary – Chronic Pain Rehabilitation Program Benzodiazepines in Chronic Pain

• BZ use disorders comprise a very small portion of addictive • 27 consecutive pts diagnosed with disorders in the US and world wide sedative/hypnotic abuse / dependence – Despite the fact that 12% of adults and 40% of pain patients use or – 2000-2009 have used them • Many (most?) addicts, with or without chronic pain, use BZs • 23 also had opioid abuse/dependence – Alcoholics, opioid addicts, cocaine addicts • BZs probably do not help pain, and they impair function • Patients usually don’t escalate doses, no handsfulls of pills • Of the remaining 4 • But they can’t stop – 2 also abused alcohol • Are they addicted? – 1 abused alcohol and barbiturates – Tolerance, dependence, inability to stop, no misuse – Consequences? They attribute to pain, others attribute to opioids, – 1 abused non-benzodiazepine hypnotics but some portion of impairment is likely bz-related. Unpublished data

11 Summary – Non-BZ Hypnotic Abuse Benzodiazepines in Chronic Pain

• There is a group of people with chronic pain who use • Abuse and dependence with zolpidem and zopiclone (non US drug, both opioids and bzs similar to eszopiclone) • Mostly in patients with prior SUD, other psychiatric conditions. – Often in high doses • French experience: • They have high levels of: – In 1993 <1% of abuse / dependence reports included zolpidem – Functional impairment – By 2002 almost 5.5% – Pain – 6th most common rx forgery in 1998 and #1 by 2004. – Addiction – Surveys of drug abusers: Patients using zolpidem increased from <1% in 1998 to 4% in – Psychiatric comorbidity 2001. • The direction of the arrow of causality is unclear – Nearly all patients abusing zolpidem were abusing more than • They improve with weaning one drug, 1/2 also using a benzodiazepine and 4/10 using cannabis. Carson S et al. , McDonagh MS, Thakurta S, et al. Drug Class Review: Newer Drugs for Insomnia: Final Report Update 2 [Internet]. Portland (OR): Oregon Health & Science University; 2008

What are we doing? Weaning / Detoxification What should we do?

• Not the focus of this presentation • The worst candidates are prescribed the most • However: sedatives – Many AEDs permit patients to comfortably and rapidly reduce / eliminate BZs, Soma, and non-BZ • This probably worsens functional impairment hypnotics and quality of life • Examples • Therefore – – Pregabalin Management should include weaning – Valproic acid Replacement with alternate therapies for – Gabapentin anxiety, sleep – Carbamazepine • Extended use may be required for subtle protracted withdrawal

Gabapentenoids Ease BZ Reduction Pregabalin for Alcohol Withdrawal

• Compared pregabalin to gabapentin • Lorazepam vs pregabalin and tiapride in alcohol withdrawal • Norwegian Prescription Database • N=111 • All prescriptions for the two drugs 2004-2007 – 3 groups • Patients – Treatment duration =14 d – Psychiatric – Maximum daily doses: – Epilepsy pregabalin 450 mg, tiapride 800 mg, lorazepam 10 mg – Neuropathic pain • All showed reduction in CIWA-Ar score over time – Non-specified • Pregabalin group • Measured use of BZs 182 days before and after – Higher reduction on headache and orientation (P < 0.01) initiation of pregabalin and gabapentin – Larger number remaining alcohol free (P < 0.05). • 15%-29% of patients were able to stop using BZs • Efficacy of pregabalin was superior to tiapride, used largely in research trials and, for some measures, to that of the 'gold after starting pregabalin or gabapentin. standard', lorazepam. Bramness JG, et al. Basic Clin Pharmacol Toxicol. 2010 Martinotti G et al. Addiction. 2010;105(2):288-99

12 Parsimonious Polypharmacy

Anxiolytic Analgesic

β-blockers NSAIDs AEDs Local anesthetics Benzodiazepines Neuroleptics? Topicals Alternatives Antiarrhythmics Opioids TCAs SNRIs If not benzodiazepines, SSRIs carisoprodol, hypnotics Bupropion Then what?

Antidepressant

TCAs for Anxiety Antidepressants for GAD

• Strongly anxiolytic • Review of RCTs – Doxepin is as anxiolytic as diazepam – Imipramine d'Elia G, et al. Acta Psychiatr Scand Suppl. 1974;255:35–46. – Venlafaxine Bianchi GN, Phillips J. Psychopharmacologia 1972;25:86–95 – Paroxetine • Additional benefits – All superior to placebo – Promote sleep – Reduce neuropathic pain, fibromyalgia and migraine – Improve mood Kapczinski F, et al. Cochrane Database Syst Rev. 2003;(2):CD003592.

Generalized Anxiety Disorder Pregabalin & Venlafaxine in GAD

Moderate to Marked Improvement 28 PGB-400 mg/day (n=94)* 26 HAM-A Total PGB-600 mg/day (n=104)* 80 † 24 Score VENLA-75 mg/day (n=110) 70 Placebo (n=100) 22 60 20 50 18

Percent 40 16 30 14 Mean HAM-A Mean Score 20 12 10 10 0 Base Wk 1 Wk 2 Wk 3 Wk 4 Wk 6 LOCF- Week End Diazepam Trazodone Imipramine Placebo *PGB (400 mg and 600 mg) significant vs placebo Weeks 1 through 6. †VENLA significant vs placebo Weeks 2 through 6. PGB = pregabalin; VENLA = venlafaxine Rickels K et al. Arch Gen Psychiatry. 1993;50:884-895. Montgomery SA, et al. J Clin Psychiatry 2006;67:771–82.

13 Duloxetine in GAD Antiepileptics in Anxiety Disorders (Major depression excluded)

Mean Change in Total HAM-A Score Mean Change in Sheehan Disability Scale (self-rated impairment from 0–10) • Strongest placebo-controlled evidence Treatment week – Pregabalin 0 1 2 4 7 10 LOCF Global Work Social Family/Home 0 0 • Social phobia • GAD -4 -2 *** *** *** *** *** *** • Smaller/less-robust controlled trials *** -4 -8 // – Gabapentin *** *** -6 • Social phobia -12 *** *** *** *** // – Lamotrigine *** -8 *** *** -16 *** *** • Post-traumatic stress disorder -10 *** P <.001 vs placebo – Valproic acid * P <.05 vs placebo • Panic disorder Placebo (n=175) Duloxetine 60 mg/day (n=168) Duloxetine 120 mg/day (n=170) Van Ameringen M, et al. Drugs. 2004;64:2199–2220. Koponen H, et al. Anxiety Disorders Association of America 2006.

AEDs vs Benzodiazepines for Anxiety Conclusions

• Evidence is present, but not conclusive: • Despite being among the most used of all drugs, • Function rates of addiction and abuse are low. – Benzodiazepines impair function • Issue appears to be impairment > addiction – AEDs improve function • Toxicity with opioids – especially high dose – is a serious concern • Addiction • Sedative abuse / dependence in CNMP is relatively – Benzodiazepines pose addiction risk uncommon – AEDs lack addiction risk • Functional impact is likely to be major • Pain – Especially in combination with multiple other psychoactive substances – Benzodiazepines lack analgesic effects – In people who are already impaired – AEDs diminish neuropathic pain, migraine, • Evidence of benefit in chronic pain is minimal visceral hyperalgesia

Final Conclusions

• Benzodiazepines / sedatives are probably mildly harmful for many CNMP patients • They are seriously harmful for a few • Alternatives exist that Facilitate weaning Improve pain / function • Suggestions – Very short term use only – Wean those taking them long term – Use antidepressants, AEDs for anxiety, sleep

14