Confronting Addiction

From the 11th Annual Fundamentals of Addiction Medicine, sponsored by the Providence Regional Medical Center, Everett, WA

Educational Objectives

The goal of this program is to improve management of patients undergoing substance withdrawal and to review char­acteristics and effects of benzodiazepines. After hearing and assimilating this program, the clinician will be better able to:

1.   Recommend appropriate levels of care for detoxification.

2.   Recognize substances and conditions that warrant inpatient detoxification.

3.   Manage symptoms, such as insomnia and hypertension, during alcohol and opioid withdrawal.

4.   Discuss pharmacokinetic differences of commonly used benzodiazepines.

5.   Describe symptoms of benzodiazepine withdrawal, and effects of benzodiazepines on cognition and psycho­motor performance.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning com­mittee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Patz is on the Speakers’ Bureau for Reck­itt Benckiser. Dr. Juergens is on the Speakers’ Bureau for Forest Pharamaceuticals, Lilly, sanofi-aventis, and Wyeth Pharmaceuti­cals. Dr. Juergens presents information in his lecture that is related to off-label or investigative use of a therapy, product, or device. The planning committee reported nothing to disclose.

Acknowledgements

Drs. Patz and Juergens spoke in Seattle, WA, at the 11th Annual Fundamentals of Addiction Medicine Conference, pre­sented March 5-9, 2009, by the Providence Regional Medical Center in Everett, WA. The Audio-Digest Foundation thanks the speakers and the Providence Regional Medical Center for their cooperation in the production of this program.

Medically Supervised Withdrawal

John D. Patz, DO, Family Physician, Providence Behavioral Health Services, Providence Regional Medical Center, Everett, WA

Success rates of detoxification: study of 100 alcoholics followed for 8 yr  —  after detoxification alone, 3% remained sober for 1 yr; after detoxification and 2 to 3 Alcoholics Anonymous (AA) meetings per week, nearly 75% re­mained sober for 1 yr; study of 100 heroin addicts followed for 20 yr  —  after detoxification in hospital bed or jail cell, only 3% achieve 1 yr of abstinence; highest success rate (71%) at 1 yr in those who went to jail, followed by 1 yr of parole; alcohol remission rates  —  success rate at 1 yr with formal treatment after detoxification, »20% (at 3 yr, »25%); when coupled with AA, success rate at 1 yr nearly 40% (at 3 yr, nearly 50%)

Benzodiazepines: speaker limits prescription of benzodiazepines to recovering patients in clinical practice because they mimic effects of alcohol

Opioid dependence: <20% of opioid addicts achieve long-term abstinence; opioid addiction reduces life expectancy by one-third

Changes in brain: drugs of addiction (eg, alcohol, benzodiazepines, cocaine, amphetamines, marijuana, nicotine) cause mesolimbic dopamine system to release higher amounts of dopamine, resulting in brain changes; changes in dopamine receptors and diminished dopamine function reversible; opioids and μ receptors  —  endorphin system ex­tremely complex; development of tolerance to opioids demonstrates neuroadaptability of this system; reversibility of neuroadaptive change unknown

American Society of Addiction Medicine (ASAM) dimension criteria: risk for acute intoxication and/or with­drawal potential (determine appropriate level of care); coexisting biomedical and psychiatric conditions; readiness for change; risk for relapse, continued use, or ongoing problems; supportive environment

ASAM levels of care: ambulatory detoxification without extended onsite monitoring  —  eg, physician’s office or home health care agency; monitored service at predetermined level; ambulatory detoxification with extended onsite monitoring  —  eg, day hospital; clinically managed residential detoxification  —  eg, social detoxification; nonmedi­cal; provides peer support; medically monitored inpatient detoxification  —  eg, freestanding detoxification; 24-hr medical supervision; medically managed intensive inpatient detoxification  —  can occur in high-attention detoxifi­cation unit or in hospital bed

Substances and conditions warranting inpatient detoxification: alcohol  —  history of withdrawal seizures or delir­ium tremens (DTs); pregnancy; coexisting medical or psychiatric diagnosis; opioids  —  consider “grade inflation”; patients now consume higher quantities of pharmaceutical agents (eg, oxycodone [eg, OxyContin]); benzodiazepines  —  patients at risk for seizure and profound anxiety

Laboratory screening: urinalysis for drugs; pregnancy, HIV, hepatitis C, and tuberculosis; check breath or blood al­cohol level on admission

Risk for harm: assess suicidal tendencies or feelings of despair; assess intent to harm others (with duty to inform)

Nutritional support: balanced diet; alcoholism  —  give thiamine before calorie supplementation to reduce risk for worsening mentation due to Wernicke-Korsakoff syndrome; give oral folate replacement; opioid addiction  —  protein calorie malnutrition more common

Nicotine: maintenance drug; triggers mesolimbic dopamine system; some patients substitute nicotine addiction for alcohol or drugs after detoxification; nicotine transdermal patch commonly prescribed for nicotine replacement; varenicline (Chantix)  —  in Food and Drug Administration (FDA) trials, 40% stopped smoking; FDA trials did not look at patients with mental health conditions; patients report vivid dreams and active hallucinations; reasonable to offer smoking cessation during drug or alcohol detoxification; speaker recommends against starting bupropion (eg, Wellbutrin)

Insomnia: associated with opioid withdrawal; trazodone (Desyrel)  —  relatively inexpensive; 50 to 100 mg effective in 30% to 40% of patients (higher doses may increase efficacy); approved by FDA for depression rather than sleep; quetiapine (Seroquel)  —  atypical antipsychotic; most commonly used to treat manic phase of bipolar disorder; 25 to 75 mg at bedtime helpful for sleep; expensive; other agents  —  chloral hydrate effective for sleep; speaker does not prescribe g-aminobutyric acid (GABA) receptor agonists (eg, zolpidem [eg, Ambien], zaleplon [Sonata], and  [Lunesta]; too similar to benzodiazepines; can produce rebound insomnia when discontinued); sleep hygiene  —  advise patients to arise at same time every day

Management of GI symptoms: reflux  —  antacids; H₂-blockers; proton pump inhibitors; vomiting  —  speaker avoids phenothiazines (eg, promethazine [eg, Phenergan], prochlorperazine [eg, Compazine]) in alcoholics due to poten­tial to lower seizure threshold; no advantage with ondansetron (Zofran); treat diarrhea and constipation

Neurologic symptoms: primary feature of alcohol withdrawal; sweats; tremor; headache; irritability; seizure; DTs; do Clinical Institute Withdrawal Assessment of symptoms to determine need for medication

Medications for alcohol detoxification: benzodiazepines  —  in 57 studies, effective against seizures, compared to placebo; no prominent difference between benzodiazepines and other drugs; safety data sparse and fragmented; anticonvulsants  —  data comparing anticonvulsants to placebo limited; no clear difference between anticonvul­sants and other drugs; larger, well-defined studies needed on benzodiazepines and anticonvulsants; carbamaze­pine (eg, Tegretol) studied most; divalproex (eg, Depakote) commonly used; using benzodiazepines  —  start with short-acting agent (eg, lorazepam [eg, Ativan]); move to long-acting agent (eg, chlordiazepoxide [eg, Librium]) and taper slowly; lorazepam has slightly euphoric effect; early sobriety  —  feeling of restlessness, irritability, and discontent associated with elevated levels of glutamate; acamprosate (Campral) may be useful in normalizing glutamate levels

DTs: continue benzodiazepines, and add antipsychotic to control symptoms; give haloperidol (eg, Haldol; 2-5 mg q4h) with 1 mg of benztropine (eg, Cogentin) to prevent extrapyramidal side effects; one-on-one “sitter” helpful (alternative to use of restraints); consider lorazepam (not metabolized in liver) for patients in hepatic failure; in patients with cognitive issues, consider head injury and obtain imaging studies

Hypertension: due to sympathetic hyperactivity (“fight or flight”); start b-blockers low (25-50 mg) and titrate up as needed; be cautious in patients with asthma (atenolol safer than older b-blockers); be cautious in patients on other “blockers” (eg, calcium channel blockers, a₂-blockers); give oral or IV volume support

Opioid detoxification: withdrawal peaks on day 3 or 4; taper sedating medications; before returning patients to com­munity, hold for additional day with no sedation to ensure withdrawal symptoms do not worsen; before transfer­ring patients to inpatient facility,  dose of chlordiazepoxide should be <100 mg, and phenobarbital <120 mg; since opioids interact with other biologic systems (eg, endocrine), recovery times vary; methadone taper primar­ily done in outpatient federally approved methadone clinics; buprenorphine taper  —  done as outpatient; deter­mine whether taper should be long or short; withdrawal symptoms expected at end of taper

Management of symptoms: hypertension  —  clonidine; b-blockers (be cautious when using multiple blockers); anxiety  —  best treatment is to talk with patient; hydroxyzine (eg, Vistaril); restless leg syndrome  —  cyclobenzaprine (eg, Flexeril) of unclear benefit; low doses of pramipexole (eg, Mirapex) or ropinirole (eg, Requip); treat insomnia

Buprenorphine vs methadone: no difference in short-term outcome for detoxification; withdrawal symptoms may resolve more quickly with buprenorphine

Benzodiazepine detoxification: give longer-acting agent as sedative (eg, phenobarbital, 30-90 mg q4h); anticonvul­sants (eg, divalproex or gabapentin [eg, Neurontin]) reduce risk for withdrawal seizures and help relieve profound anxiety (continue for ³1 mo after patient leaves detoxification facility); discharge to home or inpatient treatment fa­cility with treatment plan; patients with comorbidities may need higher level of care; some patients leave against medical advice; evaluation by county-designated mental health professional required when patient at risk for harm to self or others

Co-occurring psychiatric disorders: patient history during substance-free intervals useful; period of sobriety before starting psychotropic medications recommended; during detoxification, use of antidepressants without mood stabi­lizer not advisable, as large proportion of patients with bipolar disorder also have substance use disorder; antide­pressant alone has 80% chance of causing treatment-induced affective switch, or mixed state (ie, agitated depression, possibly leading to suicide) in bipolar patients

Use, Abuse, and Untoward Effects of Benzodiazepines

Steven M. Juergens, MD, Assistant Clinical Professor of Psychiatry, University of Washington Medical School, Seattle; Private Practice, Bellevue, WA

Introduction: in United States, 1% to 2% use benzodiazepines daily; more commonly used by women than men (3:1), and more commonly by whites than blacks (2:1); elderly patients constitute largest group of long-term users

Treatment of anxiety and panic disorders: study found modest increase in use of selective serotonin reuptake in­hibitors (SSRIs) over 10 yr; benzodiazepines most commonly used medication for panic disorder; patients using SSRIs did not have more favorable outcomes or better rate of remission than those using benzodiazepines

Benzodiazepine receptor: benzodiazepines enhance synaptic actions of GABA (inhibitory neurotransmitter) and in­crease frequency of GABA receptor opening (barbiturates and high-dose alcohol prolong opening of receptor); a1 subunit  —  60% of benzodiazepine receptors; associated with sedation, amnesia, ataxia, and some anticonvulsant ef­fects; activity site for zolpidem (eg, Ambien) and zaleplon (Sonata); a₂ subunit  —15% of benzodiazepine receptors; associated with anxiolytic effects; activity site for diazepam (eg, Valium), clonazepam (Klonopin), and alprazolam (eg, Xanax; works at a₂ and a1 subunits); benzodiazepines increase affinity of GABA for its receptor and augment effects; antagonists used for benzodiazepine overdose include flumazenil (used to treat cocaine, alcohol, and am­phetamine dependence)

Pharmacokinetics: potency  —  0.25 mg of clonazepam equal to 5.00 mg of diazepam (1 mg tid of clonazepam equal to 20 mg tid of diazepam); 0.5 mg of alprazolam equal to 5.0 mg of diazepam; onset of action  —  most rapid with diazepam and chlorazepate; half-life and accumulation  —  alprazolam and lorazepam fairly short acting (in long-term users, onset of withdrawal symptoms within 1-2 days; 2-3 days in long-term users of diazepam or clonaze­pam)

Metabolism: glucuronide conjugation  —  half-lives of drugs (eg, lorazepam, temazepam [eg, Restoril], oxazepam) remain consistent across ages of patients; metabolism rapid and products inactive; microsomal oxidization  —  half-lives of drugs (eg, diazepam, triazolam [Halcion], midazolam, alprazolam) increase with age of patient; half-life of diazepam increases from 20 hr at 20 yr to 90 hr at 90 yr, and metabolite active, with even longer half-life; uptake  —  benzodiazepines highly lipophilic and rapidly enter brain tissue; rapidity of gastrointestinal (GI) absorption rate-limiting step; tablets more rapidly absorbed than capsules; most benzodiazepines cross blood-brain barrier; lorazepam can be given intramuscularly (IM); uptake of IM diazepam unpredictable

Withdrawal symptoms: similar to symptoms of anxiety disorder; irritability; anxiety; sweating; headache; muscle ache; insomnia; memory difficulties; nausea; depersonalization; delirium; grand mal seizures; difficult to distin­guish withdrawal symptoms from symptoms or relapse of original anxiety state; rebound common; causes of in­creased symptoms  —  higher doses of benzodiazepines; agents with short half-lives (eg, alprazolam, lorazepam; controversial); longer duration of treatment (controversial); rapid taper; agents with higher potency; panic disorder; refractory symptoms of anxiety and depression; substance use; personality disorder; symptoms tend to develop within 24 hr of stopping short-acting agents, and 3 to 10 days after stopping longer-acting benzodiazepines; may need to reinstitute benzodiazepine (followed by more gradual taper), or try pregabalin (Lyrica) or gabapentin; usual withdrawal lasts 5 to 28 days with protracted withdrawal (ie, increased anxiety; gradually improves after 1-6 mo)

Tapering benzodiazepines: 3 yr after successful tapering, »75% remain off benzodiazepines (vs 14% who refuse to taper); patients who remained off benzodiazepines for 3 yr had lower levels of anxiety and depression, compared to patients who continued benzodiazepines; most severe withdrawal associated with quickly eliminated high-potency drugs (eg, alprazolam, lorazepam, triazolam); method  —  usually takes 2 to 3 mo (can take years); gradually taper first 50% of dose, and more slowly over each successive 25%; consider replacement with clonazepam or barbitu­rates if patient on short-acting, high potency agent (10 mg of Valium equal to 30 mg of phenobarbital; reduce by 30 mg/day); add anticonvulsants (eg, carbamazepine [eg, Tegretol], valproic acid); cognitive behavioral therapy and group therapy helpful; adding pregabalin (»300 mg) effective for generalized anxiety disorder

Adverse effects of benzodiazepines: memory  —  impaired consolidation of memory (ie, transfer from short-term to long-term memory); blackouts and antegrade amnesia; elderly most sensitive to effects; memory improves with dis­continuation of drug; worse with alcohol; psychomotor performance  —  decreased psychomotor speed; long-term users may do better than recent starters; increased likelihood of ataxia and poor balance; decreased attention (may impair driving); worse with age, peak levels, increased dose, alcohol use; cognition  —  meta-analysis of 13 studies over 20 yr found long-term users of benzodiazepines (equivalent of 17 mg diazepam daily average) consistently more impaired than controls across all cognitive categories, including, memory, speed of processing information, verbal memory, motor control, and general intelligence; after discontinuation of benzodiazepines, cognition im­proved, but never to level of nonbenzodiazepine-using controls (ie, potential for permanent cognitive defects); falls    —   increased risk for falls and femur fractures; worse with older age, increased dose, recent start of benzodiaz­epine, or use with other agents (eg, other benzodiazepines or antidepressants); anxiety and depression   — benzodiazepines may exacerbate depression; some studies show lower levels of anxiety after discontinuation of benzodiazepine; studies show benzodiazepine users may not be aware of problems with interaction, anxiety, or mood, but family members or friends see problematic behavior; be concerned about suicide (often associated with polydrug use; benzodiazepines on board in »35% suicide deaths)

Suggested Reading

Amato L et al: Effectiveness of interventions on opiate withdrawal treatment: an overview of systematic reviews. Drug Alcohol De­pend 73:219, 2004; Barker MJ et al: Cognitive effects of long-term benzodiazepine use: a meta-analysis. CNS Drugs 18:37, 2004; Bruce SE et al: Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia? Am J Psychiatry 160:1432, 2003; Gowing L et al: Buprenorphine for the management of opioid withdrawal. Cochrane Database Syst Rev 19:CD002025, 2006; Lader M et al: Withdrawing benzodiazepines in primary care. CNS Drugs 23:19, 2009; Ntais C et al: Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev 20:CD005063, 2005; O'Connor K et al: Cognitive-behav­ioural, pharmacological and psychosocial predictors of outcome during tapered discontinuation of benzodiazepine. Clin Psychol Psy­chother 15:1, 2008; O'Connor KP et al: Psychological distress and adaptational problems associated with benzodiazepine withdrawal and outcome: a replication. Addict Behav 229:583, 2004; Piper ME et al: Assessing dimensions of nicotine dependence: an evaluation of the Nicotine Dependence Syndrome Scale (NDSS) and the Wisconsin Inventory of Smoking Dependence Motives (WISDM). Nicotine Tob Res 10:1009, 2008; Polycarpou A et al: Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev 20:CD005064, 2005; Rickels K et al: Pharmacologic strategies for discontinuing benzodiazepine treatment. J Clin Psychophar­macol 19:12S, 1999; Rickels K et al: Psychomotor performance of long-term benzodiazepine users before, during, and after benzo­diazepine discontinuation. J Clin Psychopharmacol 19:107, 1999; Smyth B et al: Life expectancy and productivity loss among narcotics addicts thirty-three years after index treatment. J Addict Dis 25:37, 2006; Timko C et al: Long-term outcomes of alcohol use disorders: comparing untreated individuals with those in alcoholics anonymous and formal treatment. J Stud Alcohol 61:529, 2000; Vaillant GE: What can long-term follow-up teach us about relapse and prevention of relapse in addiction? Br J Addict 83:1147, 1988; Voshaar RC et al: Predictors of long-term benzodiazepine abstinence in participants of a randomized controlled ben­zodiazepine withdrawal program. Can J Psychiatry 51:445, 2006.